DK175069B1 - Pyrocatechol derivatives - Google Patents

Pyrocatechol derivatives Download PDF

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DK175069B1
DK175069B1 DK198700820A DK82087A DK175069B1 DK 175069 B1 DK175069 B1 DK 175069B1 DK 198700820 A DK198700820 A DK 198700820A DK 82087 A DK82087 A DK 82087A DK 175069 B1 DK175069 B1 DK 175069B1
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hydroxy
mono
amino
carbamoyl
group
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DK198700820A
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DK82087D0 (en
DK82087A (en
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Karl Bernauer
Janos Borgulya
Hans Bruderer
Gerhard Zuercher
Da Prada Mose
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Hoffmann La Roche
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Description

DK 175069 B1 iDK 175069 B1 i

Catecholderivaterne med den almene formel la 5 ?a ηο\Λ.The catechol derivatives of the general formula la 5? A ηο \ Λ.

Rc Ia HORc Ia HO

Rb 10 hvor Ra er nitro eller cyano, Rb er hydrogen eller halogen, Rc er halogen, nitro, cyano eller gruppen -(AVfQJm-R1 eller *(A)n-Q-R2, A er eventuelt med lavere alkyl substitueret 15 vinylen, n er 0 eller 1, m er 0 eller 1, R‘ er gruppen -COR3, en carbocyclisk, aromatisk gruppe eller en via et carbonatom bundet aromatisk eller delvist umættet heterocyclisk gruppe, R2 er hydrogen eller en eventuelt substitueret mættet eller delvist umættet lavere carbonhydridgruppe, R3 er hydroxy, amino, en via et oxygenatom eller en imino- eller lavere alkyliminogruppe bundet, eventuelt substitueret mættet eller delvist umættet, lavere 20 carbonhydridgruppe eller en via et ringnitrogenatom bundet, mættet N-holdig heterocyclisk gruppe, Q er gruppen -CO- eller >C=N-(Z)P-R4, Z er oxygen eller en iminogruppe, p er 0 eller 1, og R* er hydrogen eller en eventuelt substitueret og eventuelt via en carbonylgruppe bundet, mættet eller delvist umættet lavere carbonhydridgruppe, de under fysiologiske betingelser hydrolyserbare ester- og etherderivater og de 25 farmaceutiske acceptable salte deraf har værdifulde farmakologiske egenskaber. Disse forbindelser hæmmer især enzymet catechol-O-methyl-transferase (COMT), som er et opløseligt, magnesiumafhængigt enzym, som katalyserer overførelsen af methylgruppen fra S-adenosylmethionin pi et catecholsubstrat, hvorved de tilsvarende methylethere dannes. Egnede substrater, som O-methyleres og dermed deaktiveres af COMT, er f.eks.Rb 10 wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is halogen, nitro, cyano or the group - (AVfQJm-R1 or * (A) nQ-R2, A is optionally lower alkyl substituted with vinylene, n is 0 or 1, m is 0 or 1, R 'is the group -COR 3, a carbocyclic, aromatic group or an aromatic or partially unsaturated heterocyclic group bonded via a carbon atom, R 2 is hydrogen or an optionally substituted saturated or partially unsaturated lower hydrocarbon group, R 3 is hydroxy, amino, a bonded via an oxygen atom or an imino or lower alkylimino group, optionally substituted saturated or partially unsaturated, lower hydrocarbon group or a saturated N-containing heterocyclic group bonded via a ring nitrogen atom, Q is the group -CO- or> C = N- (Z) P-R4, Z is oxygen or an imino group, p is 0 or 1, and R * is hydrogen or an optionally substituted and optionally substituted via a carbonyl group, saturated or partially unsaturated lower hydrocarbon group, those under physiological condition hydrolyzable ester and ether derivatives and the pharmaceutically acceptable salts thereof have valuable pharmacological properties. In particular, these compounds inhibit the enzyme catechol-O-methyl-transferase (COMT), which is a soluble, magnesium-dependent enzyme which catalyzes the transfer of the methyl group from S-adenosylmethionine to a catechol substrate to form the corresponding methyl ethers. Suitable substrates which are O-methylated and thus deactivated by COMT are e.g.

30 ekstraneuronale catecholaminer og exogent administrerede terapeutiske aktive forbindelser med catechol-struktur.30 extraneuronal catecholamines and exogenously administered therapeutically active compounds with catechol structure.

De ovennævnte forbindelser med formlen la kan følgelig anvendes ved forebyggelse eller bekæmpelse af sygdomme, ved hvilke deaktivering af ekstraneuronale catecholaminer 35 v.h.a. COMT spiller en rolle, f.eks. ved forebyggelse eller bekæmpelse af depressioner. I disse tilfælde kan forbindelserne med den ovenstående formel la anvendes som enkeltforbindelser eller i kombination med andre terapeutisk aktive forbindelser, som påvirker sygdomsforløbet på gunstig måde. Forbindelserne med formlen Ia kan imidlertid også anvendes som co-lægemiddel til andre terapeutisk virksomme stoffer.Accordingly, the above compounds of formula Ia can be used in the prevention or control of diseases in which deactivation of extraneuronal catecholamines 35 v.h.a. COMT plays a role, e.g. in the prevention or control of depression. In these cases, the compounds of the above formula Ia can be used as single compounds or in combination with other therapeutically active compounds which have a beneficial effect on the course of the disease. However, the compounds of formula Ia can also be used as co-drugs for other therapeutically active substances.

^ \ I f vwv fc* I^ \ I f vwv fc * I

22

Forbindelserne med formlen la kan imidlertid også anvendes til at forbedre forebyggelsen eller bekæmpelsen af sygdomme med terapeutiske aktive forbindelser, som udviser en catecholstruktur. Som eksempel kan nævnes behandling af Parkinsons sygdom og af 5 Parkinsonisme med L-Dopa, som er en terapeutisk aktiv forbindelse med catecholstruktur.However, the compounds of formula Ia may also be used to enhance the prevention or control of diseases with therapeutically active compounds which exhibit a catechol structure. Examples include treatment of Parkinson's disease and of Parkinsonism with L-Dopa, which is a therapeutically active compound with catechol structure.

I sådanne tilfælde kan forbindelserne med formlen la anvendes i form af et co-lægemiddel eller som kombinationspræparater.In such cases, the compounds of formula Ia may be used in the form of a co-drug or as combination preparations.

En yderligere mulighed for anvendelse af de ovennævnte.forbindelser med formlen la 10 ligger indenfor diagnostikområdet. Efter administration af [J8F]-6-fluor-L-Dopa kan (,eF]-Dopamin gøres synlig i hjernen v.h.a. positronemissionstomografi. Ved tilsætning af en forbindelse med den ovennævnte formel la hæmmes COMT, hvorved dannelsen af £I8F]-3-O-methyldopa forhindres. I fraværelse af en COMT-hæmmer ville det dannede [,8F]-3-0-methyldopa trænge ind i hjernen og føre til en stærk forhøjet baggrund, hvilket i væsentlig 15 grad ville vanskeliggøre diagnosticeringen.A further possibility of using the above compounds of formula Ia 10 is within the scope of diagnostics. After administration of [J8F] -6-fluoro-L-Dopa, (, eF] -Dopamine can be made visible in the brain by positron emission tomography. By adding a compound of the above formula Ia, COMT is inhibited, whereby the formation of £ I8F] -3- O-methyldopa is prevented.In the absence of a COMT inhibitor, the formed [, 8F] -3-0-methyldopa would penetrate the brain and lead to a strongly elevated background, which would significantly 15 degrees complicate the diagnosis.

Den ovennævnte formel la omfatter såvel kendte som hidtil ukendte forbindelser. De i og for sig kendte forbindelser med formlen la falder ind under den almene formel la1The above formula Ia comprises both known and novel compounds. The compounds of formula Ia known per se fall within the general formula Ia1

20 HO20 HO

\ ^ \ A 5-rc- Ial\ ^ \ A 5-rc- Ial

H(/ RCH (/ RC

Rb 25 hvor Ra er nitro eller cyano, Rb er hydrogen eller halogen, Rc” er nitro, cyano eller gruppen -(A)n-COOH eller -(A)n-Q-H, A er eventuelt med lavere alkyl substitueret vinylen, n er 0 eller 1, Q er gruppen -CO- eller >C=N-(Z)P-R4, Z er oxygen eller en iminogruppe, p er 0 eller 1, og R* er hydrogen eller en eventuelt substitueret og eventuelt via en carbonylgruppe bundet, mættet eller delvist umættet lavere carbonhydridgruppe, idet Ra 30 er nitro, hvis Rc” er cyano eller nitro, under fysiologiske betingelser hydrolyserbare ester- og etherderivater deraf, og farmaceutisk acceptable salte deraf.Rb where Ra is nitro or cyano, Rb is hydrogen or halogen, Rc 'is nitro, cyano or the group - (A) n-COOH or - (A) nQH, A is optionally lower alkyl substituted vinylene, n is 0 or 1, Q is the group -CO- or> C = N- (Z) P-R 4, Z is oxygen or an imino group, p is 0 or 1, and R * is hydrogen or an optionally substituted and optionally bonded via a carbonyl group, saturated or partially unsaturated lower hydrocarbon group, Ra 30 being nitro, if R c 'is cyano or nitro, under physiological conditions hydrolysable ester and ether derivatives thereof, and pharmaceutically acceptable salts thereof.

Lignende forbindelser er kendt fra EP-A-142 283.1 GB-A-2 038 819 beskrives 3,5-35 dinitrophenyl i forbindelse med fremstillingen af eksplosive forbindelser. I Chem. Abstr. 92, 146 461x beskrives blandt andre 5-chlor-2,3-dihydrobenzonitril og 4,5-dichlor-2,3* dihydrobenzonitril. 1 J. Antibiot. 35, 1361-1366 (1982) beskrives fremstillingen og reduktionen af 3,4-dihydroxy-5-nittrobenzosyre. Chem. Abstr. 29, 54421 (1935) angår fremstillingen af 3,4-dihydroxy-5-nitro-kanelsyre.Similar compounds are known from EP-A-142 283.1 GB-A-2 038 819 3.5-35 dinitrophenyl are described in connection with the preparation of explosive compounds. In Chem. Abstr. 92,146,461x describes, among others, 5-chloro-2,3-dihydrobenzonitrile and 4,5-dichloro-2,3 * dihydrobenzonitrile. 1 J. Antibiot. 35, 1361-1366 (1982) describes the preparation and reduction of 3,4-dihydroxy-5-nitrobenzoic acid. Chem. Abstr. 29, 54421 (1935) relates to the preparation of 3,4-dihydroxy-5-nitro-cinnamic acid.

3 DK 175069 B13 DK 175069 B1

Ved de hidtil ukendte forbindelser med formlen la drejer det sig om forbindelser med den almene formel Ib 5 H0\ Å 0/W- lb 10 HO -\b 15 hvor Ra er nitro eller cyano, Rb er hydrogen eller halogen,The novel compounds of the formula Ia are compounds of the general formula Ib 5 H0 \ Å 0 / W- lb 10 HO - \ b 15 wherein Ra is nitro or cyano, Rb is hydrogen or halogen,

Rc' er nitro, cyano eller gruppen -(A)n-(Q)m-Rn eller -{A)n-Q-R21, A er eventuelt med lavere alkyl substitueret vinylen, n er 0 eller 1, m er 0 eller 1, R11 er gruppen -COR31, en carbocyclisk, aromatisk gruppe eller en via et carbonatom bundet aromatisk eller delvist umættet heterocyclisk gruppe, R21 er en eventuelt substitueret mættet eller delvist 20 umættet lavere carbonhydridgruppe, R31 er hydroxy, amino, en via et oxygenatom eller en imino- eller lavere alkyliminogruppe bundet eventuelt substitueret mættet eller delvist umættet lavere carbonhydridgruppe eller en via et ringnitrogenatom bundet mættet N-holdig heterocyclisk gruppe, Q er gruppen -CO eller >C=N-(Z)P-R4, Z er oxygen eller en iminogruppe, p er 0 eller 1, og R4 hydrogen eller en eventuelt substitueret og eventuelt via 25 en carbonylgruppe bundet, mættet eller delvist umættet lavere carbonhydridgruppe, idet Ra er cyano, hvis Rc’ er cyano eller nitro, og R31 har en betydning forskellig fra hydroxy, når m er 0, og de under fysiologiske betingelser hydrolyserbare ester- og etherdérivater deraf og farmaceutisk acceptable salte deraf.Rc 'is nitro, cyano or the group - (A) n- (Q) m-Rn or - {A) nQ-R21, A is optionally lower alkyl substituted vinylene, n is 0 or 1, m is 0 or 1, R11 is the group -COR31, a carbocyclic, aromatic group or an aromatic or partially unsaturated heterocyclic group bonded via a carbon atom, R21 is an optionally substituted saturated or partially unsaturated lower hydrocarbon group, R31 is hydroxy, amino, an oxygen atom or an imino or lower alkylimino group bonded optionally substituted saturated or partially unsaturated lower hydrocarbon group or a saturated N-containing heterocyclic group bonded via a ring nitrogen atom, Q is the group -CO or> C = N- (Z) P-R 4, Z is oxygen or an imino group , p is 0 or 1, and R 4 is hydrogen or an optionally substituted and optionally via a carbonyl group bonded, saturated or partially unsaturated lower hydrocarbon group, wherein R a is cyano, if R c 'is cyano or nitro, and R 31 has a meaning other than hydroxy , when m is 0, and those below physiological conditions hydrolysable ester and ether derivatives thereof and pharmaceutically acceptable salts thereof.

30 • Den foreliggende opfindelses genstand er: de ovennævnte forbindelser med den almene formel la og de nævnte derivater deraf til anvendelse som terapeutisk aktive forbindelser; lægemidler baseret pi disse forbindelser og derivater; fremstilling af sådanne lægemidler; anvendelse af disse forbindelser og derivater ved forebyggelse eller bekæmpelse af 35 sygdomme; anvendelse af disse forbindelser og derivater til fremstilling af lægemidler, som eventuelt som en ønsket bivirkning hæmmer enzymet COMT; forbindelserne med den ovennævnte formel Ib og de nævnte derivater deraf som sådanne; fremstilling af sådanne forbindelser og derivater; samt mellemprodukter til fremstilling deraf.The object of the present invention is: the above-mentioned compounds of the general formula Ia and the said derivatives thereof for use as therapeutically active compounds; drugs based on these compounds and derivatives; manufacture of such drugs; use of these compounds and derivatives in the prevention or control of 35 diseases; use of these compounds and derivatives for the manufacture of medicaments which, as a desired side effect, inhibit the enzyme COMT; the compounds of the above formula Ib and the said derivatives thereof as such; preparation of such compounds and derivatives; as well as intermediates for their manufacture.

L/l\ I I VVUø U IL / l \ I I VVUø U I

44

Udtrykket “lavere" betegner grupper og forbindelser med højst 7, fortrinsvis højst 4 carbonatomer. Udtrykket "alkyl" taget for sig selv eller i sammensætninger såsom "alkylgruppe", "alkoxy", "alkylthio" og "alkylimino" betegner ligekædede eller forgrenede mættede carbonhydridgrupper såsom methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, i-5 butyl og t-butyl. Udtrykket "mættet eller delvist umættet lavere carbonhydridgruppe" betegner åbenkædede eller cycliske grupper og kombinationer deraf. Eksempler på mættede og delvist umættede lavere carbonhydridgrupper er: lavere alkylgrupper som defineret ovenfor; lavere alkenylgrupper såsom 2-propenyl, 2-butenyl, 3-butenyl og 2-methyl-2-propenyl; eventuelt med lavere alkylgruppper substituerede C3-7-cycloalkyl- og 10 Ce-jo-bicycloalkylgrupper, såsom cyclopropyl, cyclopentyl, 2-methylcyclopentyl, cyclohexyl og 3-methylcyclohexyl, eventuelt med lavere alkylgrupper substituerede lavere cycloalkenylgrupper, såsom 3-eyclopentenyl, l-methyl-3-cyclopentenyl og 3-cydohexenyl; med lavere cycloalkyl- eller cycloalkenylgrupper substituerede lavere alkyl- eller alkenylgrupper, såsom cydopropylmethyl, cyclopropylethyl, cydopentylmethyl, 15 cyclohexylmethyl, 2-cydohexenylmethyl og 3-cydopropyl-2-propenyl. De lavere alkenylgrupper indeholder fortrinsvis 2-4 carbonatomer; cycloalkyl- og cycloalkenylgrupperne indeholder fortrinsvis 3-6 carbonatomer.The term "lower" denotes groups and compounds having at most 7, preferably at most 4 carbon atoms, the term "alkyl" taken alone or in compositions such as "alkyl group", "alkoxy", "alkylthio" and "alkylimino" denotes straight or branched chain saturated hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, i-5-butyl and t-butyl The term "saturated or partially unsaturated lower hydrocarbon group" denotes open-chain or cyclic groups and combinations thereof Examples of saturated and partially unsaturated lower hydrocarbon groups are: lower alkyl groups as defined above, lower alkenyl groups such as 2-propenyl, 2-butenyl, 3-butenyl and 2-methyl-2-propenyl, optionally substituted with lower alkyl groups C 3-7 cycloalkyl and C 10 bicycloalkyl groups such as cyclopropyl, cyclopentyl, 2-methylcyclopentyl, cyclohexyl and 3-methylcyclohexyl, optionally lower cycloalkenyl groups substituted by lower alkyl groups such as 3-cyclopentenyl, 1-methyl-3-cyclop either ethyl and 3-cydohexenyl; lower alkyl or alkenyl groups substituted with lower cycloalkyl or cycloalkenyl groups, such as cydopropylmethyl, cyclopropylethyl, cydopentylmethyl, cyclohexylmethyl, 2-cydohexenylmethyl and 3-cydopropyl-2-propenyl. The lower alkenyl groups preferably contain 2-4 carbon atoms; the cycloalkyl and cycloalkenyl groups preferably contain 3-6 carbon atoms.

Som substituenter for de ovennævnte lavere carbonhydridgrupper kommer følgende på 20 tale: hydroxy, cyano, nitro, halogen, amino, lavere alkylamino, di(lavere alkyljamino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyljcarbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino og lavere alkylthio. De mættede eller delvist umættede lavere 25 carbonhydridgrupper er fortrinsvis usubstituerede eller mono- eller disubstituerede.As substituents for the above lower hydrocarbon groups, the following are possible: hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyljamino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl , carbamoyl, mono- or di (lower alkylcarbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino and lower alkylthio. The saturated or partially unsaturated lower hydrocarbon groups are preferably unsubstituted or mono- or disubstituted.

Udtrykket "aryl" betegner carbocydiske aromatiske grupper, og nærmere betegnet fortrinsvis mono- eller bicydiske grupper. Særlig foretrukne carbocydiske aromatiske grupper er phenyl- og napthylgrupper, især phenylgrupper. Disse grupper er eventuelt 30 substitueret med: halogen, trifluormethyl, nitro, amino, mono- eller di(lavere alkyljamino, lavere alkyl, lavere alkoxy, lavere alkylthio, lavere alkanoyl, lavere alkoxycarbonyl, carboxy, hydroxy, cyano, lavere alkanoyloxy, carbamoyl, mono- eller diflavere alkyljcarbamoyl, lavere alkylendioxy, lavere alkanoylamino eller lavere alkoxycarbonylamino. De carbocydiske aromatiske grupper er fortrinsvis usubstituerede 35 eller mono- eller disubstituerede.The term "aryl" denotes carbocydic aromatic groups, and more particularly, preferably mono- or bicydic groups. Particularly preferred carbocydic aromatic groups are phenyl and naphthyl groups, especially phenyl groups. These groups are optionally substituted with: halogen, trifluoromethyl, nitro, amino, mono- or di (lower alkylamino, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, carboxy, hydroxy, cyano, lower alkanoyloxy, carbamoyl, mono- or diflaver alkylcarbamoyl, lower alkylenedioxy, lower alkanoylamino or lower alkoxycarbonylamino The carbocydic aromatic groups are preferably unsubstituted or mono- or disubstituted.

Udtrykket "aromatiske eller delvist umættede heterocycliske grupper" betegner fortrinsvis en mono-, di- eller tricyclisk aromatisk eller delvist umættet heterocydisk gruppe med op til 5 heteroatomer fra klassen bestående af nitrogen, svovl og oxygen. Disse heterocycliske 5 DK 175069 B1 grupper indeholder fortrinsvis 1-4 nitrogenatomer og/eller et oxygen- eller svovlatom. De er fortrinsvis mono- eller bicydiske. Heteroatomerne er fortrinsvis fordelt pi 1 eller 2 ringe, idet nitrogenatomer samtidig også kan være bestanddele af 2 ringe. De heterocycliske grupper er fortrinsvis aromatiske. De kan være substituerede, idet de i si 5 tilfælde fortrinsvis er mono-, di- eller trisubstituerede. Som substituenter kommer følgende på tale: halogen, trifluormethyl, nitro, carboxy, amino, arylamino, lavere alkyl, lavere alkoxy, hydroxy, lavere alkoxycarbonyl, lavere alkanoyl, lavere alkanoyloxy, oxo, lavere alkylendioxy, mercapto, lavere alkylthio, lavere alkylamino, di(lavere alkyl)amino, C3.7-cycloalkylamino, Ce.jo'bicycloalkylamino, lavere alkanoylamino, lavere 10 alkoxycarbonylamino, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, cyano, aryl, aryl-lavere alkyl, aryl-lavere alkylamino, heteroaryl, heteroaryl-lavere alkyl, heteroarylamino og C3.7-cycloalkyl. De monocycliske heterocycliske grupper er fortrinsvis 5- eller 6-leddede og indeholder højst fire heteroatomer. De bicydiske heterocycliske grupper er fortrinsvis fra 8- til 10-leddede, idet de enkelte ringe fortrinsvis er 5- eller 6-leddede.The term "aromatic or partially unsaturated heterocyclic groups" preferably denotes a mono-, di- or tricyclic aromatic or partially unsaturated heterocydic group having up to 5 heteroatoms from the class consisting of nitrogen, sulfur and oxygen. These heterocyclic groups preferably contain 1-4 nitrogen atoms and / or an oxygen or sulfur atom. They are preferably mono- or bicydic. The heteroatoms are preferably distributed in 1 or 2 rings, nitrogen atoms can at the same time also be constituents of 2 rings. The heterocyclic groups are preferably aromatic. They may be substituted, in which case they are preferably mono-, di- or trisubstituted. Suitable substituents are the following: halogen, trifluoromethyl, nitro, carboxy, amino, arylamino, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto, lower alkylthio, lower alkylamino, di (lower alkyl) amino, C 3-7 cycloalkylamino, C 1-10 bicycloalkylamino, lower alkanoylamino, lower alkoxycarbonylamino, carbamoyl, mono- or di (lower alkyl) carbamoyl, cyano, aryl, aryl-lower alkyl, aryl-lower alkylamino , heteroaryl, heteroaryl-lower alkyl, heteroarylamino and C 3-7 cycloalkyl. The monocyclic heterocyclic groups are preferably 5- or 6-membered and contain at most four heteroatoms. The bicydic heterocyclic groups are preferably from 8- to 10-membered, the individual rings being preferably 5- or 6-membered.

1515

Som eksempler på sådanne heterocycliske grupper kan nævnes følgende: pyridyt, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, benzoxazinyl, chinoxalinyl, benzopyranyl, benzimidazolyl, indolyl, imidazothiazolyl, imidazothiadiazolyl, 20 imidazopyridyl, benzothiazinyl, benzochinoxaiinyl og imidazobenzothiazolyl.Examples of such heterocyclic groups are the following: pyridyte, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, benzoxinyl, benzoxinyl, benzoxinyl imidazothiadiazolyl, imidazopyridyl, benzothiazinyl, benzoquinoxaminyl and imidazobenzothiazolyl.

Udtrykket "heteroaryl" betegner aromatiske, heterocycliske grupper som defineret ovenfor.The term "heteroaryl" denotes aromatic heterocyclic groups as defined above.

Udtrykket "en via et ringnitrogenatom bundet, mættet N-holdig heterocydisk gruppe" 25 betegner fortrinsvis en 3-7-leddet, især en 4-6-leddet, mættet N-heterocycel, som ud over det nævnte nitrogenatom endvidere kan indholde et oxygen-, svovl- eller nitrogenatom som et andet heteroatom. Disse mættede N-heterocycler kan endvidere være mono- eller disubstituerede med: lavere alkyl, hydroxy, lavere alkoxy, lavere alkanoyloxy, lavere hydroxyalkyl, lavere alkoxyalkyl, lavere alkanoyloxyalkyl, lavere alkoxycarbonyl, lavere 30 alkanoyl, carbamoyl, mono- eller di(lavere alkyljcarbamoyl, oxo og/eller lavere alkylendioxy.The term "a saturated N-containing heterocydic group bonded via a ring nitrogen atom" preferably denotes a 3-7-membered, in particular a 4-6-membered, saturated N-heterocycle, which in addition to said nitrogen atom may further contain an oxygen-containing , sulfur or nitrogen atom as another heteroatom. These saturated N-heterocycles may further be mono- or disubstituted with: lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di (lower alkylcarbamoyl). , oxo and / or lower alkylenedioxy.

Som eksempel på sådanne N-holdige heterocycliske grupper kan nævnes følgende: 4-morpholinyl, 1-pyrrolidinyl og 1-azetidinyl.Examples of such N-containing heterocyclic groups are the following: 4-morpholinyl, 1-pyrrolidinyl and 1-azetidinyl.

3535

For de under fysiologiske betingelser hydrolyserbare ester- eller etherdenvater drejer det sig fortrinsvis om forbindelser med formlen la, hvor mindst 1 af de 2 phenoliske hydroxygrupper er acyleret med en lavere fedtsyre eller er forethret med en lavere 1-alkoxycarbonyloxy-l-alkyl-, lavere 1-alkanoyloxy-l-alkyl- eller med en lavere 2-oxo-l- k#ix i f ww w i 6 alkylgruppe.The ester or ether denvates which can be hydrolysable under physiological conditions are preferably compounds of the formula Ia, in which at least 1 of the 2 phenolic hydroxy groups is acylated with a lower fatty acid or is etherified with a lower 1-alkoxycarbonyloxy-1-alkyl-, lower 1-alkanoyloxy-1-alkyl- or with a lower 2-oxo-1-k # ix if ww wi 6 alkyl group.

Substituenten Ra er fortrinsvis nitro. Substituenten Rb befinder sig fortrinsvis i p-stilling i forhold til substituenten Ra og er fortrinsvis hydrogen, chlor eller fluor, idet betydningen 5 hydrogen især foretrækkes. Substituenten Rc' er fortrinsvis gruppen -CO-R11, idet Rner en aromatisk enkærnet carbocyclisk gruppe eller en via et carbonatom bundet aromatisk enkærnet heterocydisk gruppe med 1-3 nitrogenatomer som heteroringled. I en særlig foretrukket udførselsform er Ru en eventuelt med halogen, trifluormethyl, cyano, hydroxy eller lavere alkyl mono- eller disubstitueret phenylgruppe eller en pyridylgruppe.The substituent Ra is preferably nitro. The substituent Rb is preferably in the p-position relative to the substituent Ra and is preferably hydrogen, chlorine or fluorine, with the meaning hydrogen being particularly preferred. The substituent Rc 'is preferably the group -CO-R11, Rner being an aromatic mononuclear carbocyclic group or an aromatic mononuclear heterocydic group bonded via a carbon atom having 1-3 nitrogen atoms as heterocycles. In a particularly preferred embodiment, Ru is an optionally halo, trifluoromethyl, cyano, hydroxy or lower alkyl mono- or disubstituted phenyl group or a pyridyl group.

1010

Inden for rammerne af den foreliggende opfindelse er specielt foretrukne forbindelser følgende: 3.4- dihydroxy-5-nitrobenzophenon, 15 2'-fluor-3,4-dihydroxy-5-nitrobenzophenon og 3.4- dihydroxy-5-nitrophenyl-4-pyridylketon.Within the scope of the present invention, particularly preferred compounds are the following: 3,4-dihydroxy-5-nitrobenzophenone, 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone and 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone.

Forbindelserne med formlen Ib, de under fysiologiske betingelser hydrolyserbare ester- og etherderivater og de farmaceutisk acceptable salte deraf kan ifølge opfindelsen fremstilles 20 ved, at a) den/de lavere alkylethergruppe/grupper i en forbindelse med den almene formel II 25The compounds of formula Ib, the ester and ether derivatives which can be hydrolysed under physiological conditions and the pharmaceutically acceptable salts thereof can be prepared according to the invention by: a) the lower alkyl ether group (s) in a compound of general formula II

\ ii _ , II\ ii _, II

/%v""Rc R' θ' ·\./% v "" Rc R 'θ' · \.

30 Rb hvor et af symbolerne R og R' er lavere alkyl, og det andet er hydrogen eller lavere alkyl, 35 og Ra, Rb og Rc‘ har de ovenfor anførte betydninger fraspaltes, eller b) en forbindelse med den almene formel Ib1 DK 175069 B1 7 η\Λ. αRb wherein one of the symbols R and R 'is lower alkyl and the other is hydrogen or lower alkyl, 35 and Ra, Rb and Rc' have the meanings given above, or b) a compound of the general formula Ib1 DK 175069 B1 7 η \ Λ. α

Rb 10 hvor X betegner en forspaltelig enhed, og Ra, Rb, A og n har de ovenfor anførte betydninger, omsættes med et thioamid, thiourinstof, thiocarbonsyrehydrazid, thiosemicarbazid, amidin, guamdin, amidrazon, aminoguanidin, cydisk amidin, 1,2-diamin, 1,2-aminothiol eller en 1,2-aminoalkohol, og det vundne cydokondensationsprodukt om ønsket dehydrogeneres, 15 eller c) en forbindelse med den almene formel Ib2 20 H(VX 2 Λ V,J-<A>n-C°-C00RM 15 HO ^ "Rb 10 where X represents a leaving group and Ra, Rb, A and n have the meanings given above are reacted with a thioamide, thiourea, thiocarboxylic acid hydrazide, thiosemicarbazide, amidine, guamdine, amidrazone, aminoguanidine, cydic amidine, 1,2-diamine , 1,2-aminothiol or a 1,2-amino alcohol, and the cydocondensation product obtained, if desired, dehydrogenated, or c) a compound of the general formula Ib2 20 H (VX 2 Λ V, J- <A> nC ° -C00RM 15 HO

Rb 25 hvor R" er lavere alkyl, og Ra, Rb, A og n har de ovenfor anførte betydninger, omsættes med en 1,2-diamin, 1,2-aminothiol, 1,2-aminoalkohol, semicarbazid, 30 thiosemicarbazid, amidrazon eller en aminoguanidin, og det vundne cydokondensationsprodukt om ønsket dehydrogeneres, eller d) en forbindelse med den ovennævnte formel Ib1 omsættes med en pbp-aminocarbonylforbindelse, eller 35Rb 25 where R "is lower alkyl and Ra, Rb, A and n have the meanings given above are reacted with a 1,2-diamine, 1,2-aminothiol, 1,2-amino alcohol, semicarbazide, thiosemicarbazide, amidrazone or an aminoguanidine, and the cydocondensation product obtained is dehydrogenated if desired, or d) a compound of the above formula Ib1 is reacted with a pbp-aminocarbonyl compound, or

e) i en forbindelse med den almene formel III, la2 eller IVe) in a compound of the general formula III, la2 or IV

L/rV I I JUU3 U IL / rV I I JUU3 U I

88

9H0 9N CHO9H0 9N CHO

H0W\ ”V\ 2 H0N/\.H0W \ ”V \ 2 H0N / \.

111 ' HO/i^y'CH° 13 eller AV"CH0 1V111 'HO / i ^ y'CH ° 13 or AV "CH0 1V

H0 Rb H0 ' Rb «θ' N-\b 5 hvor Rc"' er nitro, cyano eller gruppen -(A)n-R12, og R12 er gruppen -COR31, en carbocyclisk aromatisk gruppe eller en via et carbonatom bundet, aromatisk eller 10 delvist umættet heterocyclisk gruppe, og Ra, Rb, A, n og R31 har de ovenfor anførte betydninger, eller i et di-Olavere alkanoylderivat deraf, carboxaldehydgruppen/grupperne omdannes til cyanogruppen/gruppeme, eller 15 f) et di-O-lavere alkanoylderivat af en carboxylsyre med den almene formel la3 eller Ib3 HO Λ 3 20 \. IaJ eller HOv Λ.H0 Rb H0 'Rb «eller' N- \ b 5 where Rc" 'is nitro, cyano or the group - (A) n-R12, and R12 is the group -COR31, a carbocyclic aromatic group or an aromatic bonded via a carbon atom or 10 partially unsaturated heterocyclic group, and Ra, Rb, A, n and R31 have the meanings given above, or in a di-Olavere alkanoyl derivative thereof, the carboxaldehyde group (s) are converted to the cyano group (s), or f) a di-O- lower alkanoyl derivative of a carboxylic acid of the general formula Ia3 or Ib3 HO Λ 3 20 \. IaJ or HOv Λ.

\ II \ «\ II \ «

✓ % V” (Λ)n~COOH Ϊ « IbJ✓% V ”(Λ) n ~ COOH Ϊ« IbJ

HO7 /% V‘(A)n‘C°-C00HHO7 /% V ‘(A) n‘ C ° -C00H

Rb HO Ν·\.Rb HO Ν · \.

KDKD

2525

hvor Ra, Rb, A og n har de ovenfor anførte betydninger, i nærværelse af et kondensationsmiddel eller et reaktivt derivat af et di-O-lavere alkanoylderivat af en carboxylsyre med formlen la3 eller Ib3 omsættes med en forbindelse 30 med den almene formel VIwherein Ra, Rb, A and n have the meanings given above, in the presence of a condensing agent or a reactive derivative of a di-O-lower alkanoyl derivative of a carboxylic acid of the formula Ia3 or Ib3 is reacted with a compound 30 of the general formula VI

HO-R5 V oder HNRtR7 VI 35 hvor R5 er en eventuelt substitueret mættet eller delvist umættet lavere 9 DK 175069 B1 carbonhydridgruppe, R6 er hydrogen eller lavere alkyl, og R7 er hydrogen eller en eventuelt substitueret mættet eller delvist umættet lavere carbonhydridgruppe, eller R6 og R7 tilsammen med nitrogenatomet betegner en mættet N-holdig heterocydisk gruppe, 5 eller g) en forbindelse med den ovennævnte formel Ib2 eller med den almene formel Ib4 10 8 ?a »V Λ > '· » . Ib 8 /'%Ve‘Rc R80HO-R5 V or HNRtR7 VI 35 wherein R5 is an optionally substituted saturated or partially unsaturated lower hydrocarbon group, R6 is hydrogen or lower alkyl and R7 is hydrogen or an optionally substituted saturated or partially unsaturated lower hydrocarbon group, or R6 and R7 together with the nitrogen atom represents a saturated N-containing heterocydic group, 5 or g) a compound of the above formula Ib2 or of the general formula Ib4 10 8? A «V Λ> '·». Ib 8 / '% Ve‘Rc R80

Rb 15 hvor R8 er lavere alkanoyl, og Ra, Rb og Rc' har de ovenfor anførte betydninger, hydrolyseres, eller h) en forbindelse med den almene formel Ib5 20 HVX 5 V,j-COR·*· Ib 2S H0 N*\b hvor Ra og Rb har de ovenfor anførte betydninger, og R,M er hydrogen eller lavere alkyl,Rb 15 wherein R8 is lower alkanoyl and Ra, Rb and Rc 'have the meanings given above are hydrolyzed, or h) a compound of the general formula Ib5 20 HVX 5 V, j-COR · * · Ib 2S H0 N * \ b wherein Ra and Rb have the meanings given above and R, M is hydrogen or lower alkyl,

30 eller et di-O-lavere alkanoylderivat deraf i nærværelse af en sekundær amin omsættes ' med en forbindelse med den almene formel VIIOr a di-O-lower alkanoyl derivative thereof in the presence of a secondary amine is reacted with a compound of general formula VII

CH3CO-R23 VIICH3CO-R23 VII

35 hvor R23 er en eventuelt substitueret, mættet eller delvist umættet lavere carbonhydridgruppe, eller 1 en forbindelse med den almene formel Ib6 DK 175069 Bl ίοWherein R23 is an optionally substituted, saturated or partially unsaturated lower hydrocarbon group, or a compound of the general formula Ib6 DK 175069 Bl ίο

"\A"\ A

• « O• «O

5 110/%.V"(A)'1'co'cl|2'coo,i'' Ib5 110 /%. V "(A) '1'co'cl | 2'coo, i' 'Ib

Kb hvor Ra, Rb, A, n og R" har de ovenfor anførte betydninger, 10 omsættes med en hydrazin eller en amidin, ellerKb wherein Ra, Rb, A, n and R "have the meanings given above are reacted with a hydrazine or an amidine, or

j) en forbindelse med den ovennævnte formel Ib, hvor m er 1, og Q er gruppen -CO-, omsættes med en forbindelse med den almene formel VIIIj) a compound of the above formula Ib, wherein m is 1 and Q is the group -CO-, is reacted with a compound of general formula VIII

15 H2N-(Z)P-R4 VIIIH2N- (Z) P-R4 VIII

hvor Z, p og R4 har de ovenfor anførte betydninger, og om ønsket k) en forbindelse med den ovennævnte formel Ib omdannes til et under fysiologiske 20 betingelser hydrolyserbart ester- eller etherderivat eller et farmaceutisk acceptabelt salt deraf.wherein Z, p and R4 have the meanings given above and, if desired, k) a compound of the above formula Ib is converted into a physiologically hydrolyzable ester or ether derivative or a pharmaceutically acceptable salt thereof.

Ifølge fremgangsmidevariant a) kan forbindelserne med formlen Ib fremstilles ved, at ethergruppen/grupperne i en forbindelse med formlen II fraspaltes. Denne etherspaltning 25 kan udføres ved i og for sig kendte og for enhver fagmand sædvanlige metoder.According to process variant a), the compounds of formula Ib can be prepared by leaving the ether group (s) in a compound of formula II. This ether cleavage can be carried out by methods known per se and customary to any person skilled in the art.

Etherspaltningen kan eksempelvis foretages ved behandling med brombrinte i et egnet opløsningsmiddel. Egnede opløsningsmidler er f.eks. vand, eddikesyre og blandinger deraf.The ether cleavage can be carried out, for example, by treatment with hydrogen bromide in a suitable solvent. Suitable solvents are e.g. water, acetic acid and mixtures thereof.

Der arbejdes fortrinsvis ved forhøjet temperatur, f.eks. i temperaturområdet fra ca. 100°C til reaktionsblandingens kogepunkt. Der anvendes fortrinsvis 48% brombrintesyre eller 30 blandinger deraf med eddikesyre.Work is preferably carried out at elevated temperature, e.g. in the temperature range from approx. 100 ° C to the boiling point of the reaction mixture. Preferably 48% hydrobromic acid or mixtures thereof with acetic acid are used.

Etherspaltningen kan også udføres ved behandling med bortribromid i et egnet opløsningsmiddel ved temperaturer fra ca. -60°C til ca. stuetemperatur. Egnede opløsningsmidler er især halogenerede lavere carbonhydrider, såsom methylenchlorid, 35 chloroform og lignende. Yderligere egnede metoder er: behandling med pyridiniumhydrochlorid ved temperaturer fra ca. 150°C til ca. 250°C og behandling med natriumjodid/siliciumtetrachlorid i et inert organisk opløsningsmiddel ved forhøjet temperatur, f.eks. ved reaktionsblandingens tilbagesvalingstemperatur. Egnede opløsningsmidler til den sidste fremgangsmåde er f.eks. acetonitril, aromatiske carbonhydrider, såsom benzen eller toluen, blandinger deraf og lignende.The ether cleavage can also be carried out by treatment with boron tribromide in a suitable solvent at temperatures from approx. -60 ° C to approx. room temperature. Suitable solvents are in particular halogenated lower hydrocarbons such as methylene chloride, chloroform and the like. Further suitable methods are: treatment with pyridinium hydrochloride at temperatures from approx. 150 ° C to approx. 250 ° C and treatment with sodium iodide / silicon tetrachloride in an inert organic solvent at elevated temperature, e.g. at the reflux temperature of the reaction mixture. Suitable solvents for the latter process are e.g. acetonitrile, aromatic hydrocarbons such as benzene or toluene, mixtures thereof and the like.

11 DK 175069 B111 DK 175069 B1

Ifølge fremgangsmådevariant b) kan der fremstilles forbindelser med den almene formel Ib7 5 ?a ,KV-.According to process variant b), compounds of the general formula Ib7 5? A, KV- can be prepared.

Λν-w,-«1 Ib ho ·ν 10 hvor Ra, Rb, A og n har de ovenfor anførte betydninger, og Q1 er en gruppe med formlen /Ke /NHRf ,N-Nv .N-N.Λν-w, - «1 Ib ho · ν 10 where Ra, Rb, A and n have the meanings given above and Q1 is a group of the formula / Ke / NHRf, N-Nv .N-N.

/N=j /N=j -·( )*-Re -·( 15 "Xj <a), 'X.j. (b), -S (c), *-S (d), .Rp .NlIRf N=·' ,N=T /N=NV κΝ=Ν „ -< (Π —C >-Re ‘9)' ^«-NlliU (h), (β)' *-Ah (f)' ^»-Π· '-ν' 20 n-./R9 /Rg U)' ",N.-N/’"Rh {R) b2W’ ~*\ )*-Rh (k')r/ N = j / N = j - · () * - Re - · (15 "Xj <a), 'Xj (b), -S (c), * -S (d), .Rp .NlIRf N = · ', N = T / N = NV κΝ = Ν „- <(Π —C> -Re' 9) '^« - NlliU (h), (β)' * -Ah (f) '^ »- Π · '-Ν' 20 n-./R9 / Rg U) '", N.-N /'" Rh {R) b2W '~ * \) * - Rh (k') r

25 XRf *=NXRf * = N

/N-<R9 N-/Rg ”"\_s/“"Rh (1> °der —^ 0)*-Rh ("O, 30 Re er hydrogen, lavere alkyl, C3.7-cydoalkyl, aryl, heteroaryl, aryl-lavere alkyl eller heteroaryl-lavere alkyl, Rf er hydrogen, aryl, aryl-lavere alkyl, lavere alkyl, lavere alkoxycarbonyl, heteroaryl, heteroaryl-lavere alkyl, Ce.i0-bicyctoalkyl eller C3.7-cydoalkyl,Rh (1> ° der - ^ 0) * - Rh ("0, Re is hydrogen, lower alkyl, C3,7-cydoalkyl, aryl, heteroaryl , aryl-lower alkyl or heteroaryl-lower alkyl, Rf is hydrogen, aryl, aryl-lower alkyl, lower alkyl, lower alkoxycarbonyl, heteroaryl, heteroaryl-lower alkyl, C 1-10 bicyctoalkyl or C 3-7 cydoalkyl,

Rg og Rh hver er hydrogen, cyano, lavere alkyl, C3.7-cydoalkyl, aryl, aryl-lavere alkyl, heteroaryl eller heteroaryl-lavere alkyl, eller Rg og Rh tilsammen med de to carbonatomer 35 til hvilke de er bundet, er en carbocydisk aromatisk gruppe eller en aromatisk eller delvist umættet heterocydisk gruppe, den punkterede linie er en fakultativ binding, og Q4 sammen med carbon- og nitrogenatomet er en aromatisk eller delvist umættet heterocydisk gruppe, som indeholder mindst éet nitrogenatom som heteroringled.R 9 and R 6 are each hydrogen, cyano, lower alkyl, C 3-7 cycloalkyl, aryl, aryl-lower alkyl, heteroaryl or heteroaryl-lower alkyl, or R 9 and R 5 together with the two carbon atoms to which they are attached are a carbocydic aromatic group or an aromatic or partially unsaturated heterocydic group, the dotted line is an optional bond, and Q4 together with the carbon and nitrogen atom is an aromatic or partially unsaturated heterocydic group containing at least one nitrogen atom as heterocycle.

12 υκ bi12 υκ bi

Egnede opløsningsmidler til dette fremgangsmådeaspekt er lavere alkoholer, såsom ethanol, n-butanol, n-hexanol og ethylenglykol, åbenkædede og cydiske ethere, som eventuelt endvidere kan indeholde frie hydroxygrupper såsom tetrahydrofuran, dioxan, t-butylmethylether, ethylenglykoldimethylether, diethylenglykoldimethylether, 5 ethylenglykolmonomethylether og diethylenglykolmonomethylether, acetonitril, dimethylformamid, dimethylacetamid og dimethylsulfoxid. Den ønskede reaktion kan også udføres uden opløsningsmiddel ved tør opvarmning af reaktanterne. Reaktionen udføres fortrinsvis ved forhøjet temperatur, f.eks. i området fra ca. 50°C til 150°C, idet der fortrinsvis arbejdes ved opløsningsmidlets kogepunkt, forsåvidt der arbejdes i nærværelse 10 af et opløsningsmiddel og kogepunktet ligger i det nævnte område.Suitable solvents for this process aspect are lower alcohols such as ethanol, n-butanol, n-hexanol and ethylene glycol, open chain and cydic ethers which may optionally additionally contain free hydroxy groups such as tetrahydrofuran, dioxane, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl monomethyl ether, 5 diethylene glycol monomethyl ether, acetonitrile, dimethylformamide, dimethylacetamide and dimethylsulfoxide. The desired reaction can also be carried out without solvent by dry heating the reactants. The reaction is preferably carried out at elevated temperature, e.g. in the area from approx. 50 ° C to 150 ° C, preferably working at the boiling point of the solvent, insofar as working in the presence of a solvent and the boiling point is in the said range.

Ifølge fremgangsmådevariant c) kan der fremstilles forbindelser med den almene formel Ib8 ?aAccording to process variant c), compounds of the general formula Ib8? A can be prepared

hu. /-Ahu. / -A

15 Χχί-Μ.-Ο*· 1,0 hvor Ra, Rb, A og n har de ovenfor anførte betydninger, og Q2 er en gruppe med formlen 20 j .. /hg /R9 /R9 i ”·\ (n)' *·< (o, ').-Rh (p), /."$ y*-0 O Kf v </ 25 1<J)' K)"SH ID. (S) oder ./" \l </'~\ «/"% 30 /N-Nn )*-NUR£ (t)15 Χχί-Μ.-Ο * · 1.0 where Ra, Rb, A and n have the meanings given above and Q2 is a group of the formula 20 j .. / hg / R9 / R9 i ”· \ (n) '* · <(O,') .- Rh (p), /."$ y * -0 O Kf v </ 25 1 <J) 'K) "SH ID. (S) oder ./ "\ l </ '~ \« / "% 30 / N-Nn) * - NUR £ (t)

0 H0 H

35 hvor Re, Rf, Rg, Rh og den punkterede linie har de ovenfor anførte betydninger.Where Re, Rf, Rg, Rh and the dotted line have the meanings given above.

Omsætningen ifølge fremgangsmådevariant c) kan udføres under de samme reaktionsbetingelser som fremgangsmådevariant b).The reaction according to process variant c) can be carried out under the same reaction conditions as process variant b).

13 DK 175069 B113 DK 175069 B1

Ifølge fremgangsmådevariant d) kan der fremstilles forbindelser med den almene formel Ib9 5 H0W'n „ I II ,~3 IbAccording to process variant d), compounds of the general formula Ib9 5 H0W'n „I II, ~ 3 Ib can be prepared

HDHD

10 hvor Q3 er en gruppe med formlen (u) /Rg 5_*3 (u) 15 / - \Where Q3 is a group of the formula (u) / Rg 5_ * 3 (u) 15 / - \

Re Rh og Ra, Rb, Re, Rf, Rg, Rh, A, n og den punkterede linie har de ovenfor anførte betydninger.Re Rh and Ra, Rb, Re, Rf, Rg, Rh, A, n and the dotted line have the meanings given above.

2020

Også fremgangsmådevariant d) kan udføres under de samme reaktionsbetingelser som fremgangsmådevariant b).Process variant d) can also be carried out under the same reaction conditions as process variant b).

Ifølge fremgangsmådevariant e) kan der fremstilles forbindelser med formlen Ib, hvor Ra 25 er cyano, Rc‘ er nitro, cyano eller gruppen -(A)„-R12, og R12 er gruppen -COR31, en carbocydisk, aromatisk gruppe eller en via et carbonatom bundet aromatisk eller delvist umættet heterocyclisk gruppe, og Rb, A, n og R31 har de ovenfor anførte betydninger. Omdannelsen af carboxaldehydgruppen/grupperne til cyanogruppen/grupperne kan foretages ved i og for sig kendte og for enhver fagmand sædvanlige metoder. Eksempelvis 30 kan en forbindelse med formlen la2, III eller IV behandles med hydroxylamin-O-sulfonsyre ved forhøjet temperatur, idet der fortrinsvis anvendes vand som opløsningsmiddel.According to process variant e), compounds of formula Ib can be prepared, wherein Ra 25 is cyano, R c 'is nitro, cyano or the group - (A) n - R 12, and R 12 is the group -COR 31, a carbocydic, aromatic group or a carbon atom bonded aromatic or partially unsaturated heterocyclic group and Rb, A, n and R31 have the meanings given above. The conversion of the carboxaldehyde group (s) to the cyano group (s) can be carried out by methods known per se and customary to any person skilled in the art. For example, a compound of formula Ia2, III or IV may be treated with hydroxylamine-O-sulfonic acid at elevated temperature, preferably using water as the solvent.

Reaktionen kan udføres i et temperaturområde fra ca. 50°C til ca. 100°C.The reaction can be carried out in a temperature range from approx. 50 ° C to approx. 100 ° C.

Ifølge fremgangsmådevariant f) kan der fremstilles di-O-lavere alkanoylderivater af 35 forbindelser med formlen Ib, hvor Rc' er gruppen -(A)n-(CO)m-COR32, R32 er amino, en via et oxygenatom eller en imino- eller lavere alkyliminogruppe bundet, eventuelt substitueret, mættet eller delvist umættet lavere carbonhydridgruppe, eller en via et ringnitrogenatom bundet mættet N-holdig heterocyclisk gruppe, og A, n, m har de ovenfor anførte betydninger. Også denne reaktion kan udføres ved i og for sig kendte og for enhver DK 175069 Bl 14 fagmand sædvanlige metoder. Lavere alkylestere kan eksempelvis fremstilles ved, at carboxylsyre behandles med den tilsvarende lavere alkohol i nærværelse af en syre, idet der som opløsningsmiddel fortrinsvis anvendes den tilsvarende lavere alkohol. Egnede syrer er f.eks. mineralsyre, såsom chlorbrinte og organiske sulfonsyrer, såsom p-toluensul-5 fonsyre. Reaktionstemperaturen ligger fortrinsvis i et område fra stuetemperatur til det valgte opløsningsmiddels kogepunkt.According to process variant f) di-O-lower alkanoyl derivatives of compounds of formula Ib can be prepared, wherein Rc 'is the group - (A) n- (CO) m-COR32, R32 is amino, one via an oxygen atom or an amino or lower alkylimino group bonded, optionally substituted, saturated or partially unsaturated lower hydrocarbon group, or a saturated N-containing heterocyclic group bonded via a ring nitrogen atom, and A, n, m have the meanings given above. This reaction can also be carried out by methods known per se and customary to any person skilled in the art. Lower alkyl esters can be prepared, for example, by treating carboxylic acid with the corresponding lower alcohol in the presence of an acid, the corresponding lower alcohol preferably being used as solvent. Suitable acids are e.g. mineral acid such as hydrochloric acid and organic sulfonic acids such as p-toluenesulfonic acid. The reaction temperature is preferably in a range from room temperature to the boiling point of the selected solvent.

De øvrige estere og amiderne fremstilles fortrinsvis ved at gå ud fra reaktive carboxylsyrederivater. Egnede reaktive carboxylsyrederivater er f.eks. de tilsvarende 10 carboxylsyrehalogenider, især carboxylsyrechloriderne, tilsvarende carboxylsyreanhydrider og blandede anhydrider (f.eks. med trifluoreddikesyre og organiske sulfonsyrer, såsom mesitylensulfonsyre og p-toluensulfonsyre), tilsvarende carboxylsyreimidazolider og lignende. Der arbejdes hensigtsmæssigt i nærværelse af et syrebindende middel og i et inert organisk opløsningsmiddel. Egnede syrebindende midler er f.eks. tertiære aminer, 15 såsom triethylaminer og pyridin. Ved fremstillingen af amider kan der som syrebindende middel også anvendes overskud af amin med formlen VI. Egnede opløsningsmidler er f.eks. åbenkædede og cydiske ethere såsom tetrahydrofuran, diethylether, t-butylmethylether, dioxan, ethylenglykol, dimethylether og lignende, halogenerede carbonhydrider, såsom methylenchlorid, chloroform og 1,2-dichlorethan, acetonitril og 20 dimethylformamid.The other esters and amides are preferably prepared starting from reactive carboxylic acid derivatives. Suitable reactive carboxylic acid derivatives are e.g. the corresponding carboxylic acid halides, especially the carboxylic acid chlorides, corresponding carboxylic acid anhydrides and mixed anhydrides (e.g. with trifluoroacetic acid and organic sulfonic acids such as mesitylenesulfonic acid and p-toluenesulfonic acid), corresponding carboxylic acid imidazolides and the like. Work is expedient in the presence of an acid-binding agent and in an inert organic solvent. Suitable acid scavengers are e.g. tertiary amines, such as triethylamines and pyridine. Excess amine of the formula VI can also be used as the acid-binding agent in the preparation of amides. Suitable solvents are e.g. open-chain and cydic ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethylene glycol, dimethyl ether and the like, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, acetonitrile and dimethylformamide.

Også hydrolysen af forbindelser med formlen Ib4 til de tilsvarende catecholderivater ifølge fremgangsvariant g) kan udføres ved i og for sig kendte og for enhver fagmand sædvanlige metoder. Hydrolysen kan eksempelvis udføres ved behandling med et 25 alkalimetalhydroxid, såsom natrium- eller kaliumhydroxid, i et egnet opløsningsmiddel.The hydrolysis of compounds of the formula Ib4 to the corresponding catechol derivatives according to process variant g) can also be carried out by methods known per se and customary to a person skilled in the art. The hydrolysis can be carried out, for example, by treatment with an alkali metal hydroxide, such as sodium or potassium hydroxide, in a suitable solvent.

Egnede opløsningsmidler er f.eks. lavere alkoholer såsom methanol, og vand eller blandinger deraf. Hydrolysen kan f.eks. udføres i et temperaturområde fra ca. 0“C til opløsningsmidlets kogepunkt, idet der dog fortrinsvis arbejdes ved stuetemperatur.Suitable solvents are e.g. lower alcohols such as methanol, and water or mixtures thereof. The hydrolysis can e.g. performed in a temperature range from approx. 0 “C to the boiling point of the solvent, although preferably working at room temperature.

30 Ifølge fremgangsmådevariant h) kan der fremstilles forbindelser med den almene formel Ib10 ?aAccording to process variant h), compounds of the general formula Ib10? A can be prepared

HCV'. IblOHCV '. IblO

35 v‘i-C(R,M)=CH-CO-R23 »O7 hvor Ra, Rb, R"’ og R23 har de ovenfor anførte betydninger, samt tilsvarende di-O-lavere 15 DK 175069 B1 alkanoylderivater deraf. Som sekundær amin anvendes der fortrinsvis cycliske aminer såsom pyrrolidin, piperidin, morpholin og thiomorpholin. Egnede opløsningsmidler til denne fremgangsmåde er f.eks. åbenkaedede og cycliske ethere, såsom tetrahydrofuran, diethylether, t-butylmethylether, dioxan, ethylenglykol og dimethylether, halogenerede 5 carbonhydrider såsom methylenchlorid, chloroform og 1,2-dichlorethan, acetonitril og dimethylformamid. Reaktionstemperaturen ligger hensigtsmæssigt i et område fra ca. 0°C til det valgte opløsningsmiddels kogepunkt, idet der fortrinsvis arbejdes ved stuetemperatur. 1 en særlig foretrukken udførelsesform udføres reaktionen i nærværelse af en syre, fortrinsvis en carboxylsyre, såsom eddikesyre.35 v'iC (R, M) = CH-CO-R23 »O7 where Ra, Rb, R" 'and R23 have the meanings given above, as well as corresponding di-O-lower alkanoyl derivatives thereof. As secondary amine cyclic amines such as pyrrolidine, piperidine, morpholine and thiomorpholine are preferably used Suitable solvents for this process are, for example, open-chain and cyclic ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethylene glycol and dimethyl ether, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, acetonitrile and dimethylformamide The reaction temperature is suitably in a range from about 0 ° C to the boiling point of the selected solvent, preferably operating at room temperature. In a particularly preferred embodiment, the reaction is carried out in the presence of an acid, preferably a carboxylic acid such as acetic acid.

1010

Ifølge fremgangsmådevariant i) kan der fremstilles forbindelser med den almene formel H>" BaAccording to process variant i) compounds of the general formula H> "Ba can be prepared

Ht\ 11-1 ti ... n5 Ib 15 HO 'Λ* hvor Q5 er gruppen yRi Re ^Ν"ΐ ,N-< 20 ~\_J (V» -( > I»)Ht \ 11-1 ti ... n5 Ib 15 HO 'Λ * where Q5 is the group yRi Re ^ Ν "ΐ, N- <20 ~ \ _J (V» - (> I »)

" NOH eller ‘"•-OH"NOH or '" • -OH

og Ra, Rb, Re, Rf, A og n har de ovenfor anførte betydninger.and Ra, Rb, Re, Rf, A and n have the meanings given above.

2525

Egnede opløsningsmidler til denne fremgangsmåde er f.eks. lavere alkoholer, såsom methanol og ethanol, åbenkaedede og cycliske ethere såsom tetrahydrofuran, diethylether, t-butylmethylether, dioxan, ethylenglykol og dimethylether, acetonitril og dimethylformamid. Der arbejdes fortrinsvis ved forhøjet temperatur, f.eks. i et område fra 30 ca. 50°C til det valgte opløsningsmiddels kogepunkt, idet der fortrinsvis arbejdes ved det valgte opløsningsmiddels kogepunkt.Suitable solvents for this process are e.g. lower alcohols such as methanol and ethanol, open-chain and cyclic ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethylene glycol and dimethyl ether, acetonitrile and dimethylformamide. Work is preferably carried out at elevated temperature, e.g. in an area from 30 approx. 50 ° C to the boiling point of the selected solvent, preferably working at the boiling point of the selected solvent.

Ifølge fremgangsmådevariant j) kan der fremstilles forbindelser med den almene formel Ib,? 35 ?a "°N Ri 12 i s « i(S Ib H°'X\b " V«Z,P-B4 16 DK 175009 bl hvor Ri er gruppen -COR3', en carbocydisk, aromatisk gruppe eller en via et carbonatom bundet aromatisk eller delvist umættet heterocydisk gruppe, eller en eventuelt substitueret mættet eller delvist umættet lavere carbonhydridgruppe, og Ra, Rb, R1 2 3 4 5 6, R\ A, 2, n og p har de ovenfor anførte betydninger. Også denne fremgangsmåde kan udføres i 5 og for sig kendte og for enhver fagmand sædvanlige metoder. Egnede opløsningsmidler er f.eks. lavere alkoholer, såsom methanol og ethanol, dimethylformamid og vand.According to process variant j) compounds of the general formula Ib 35? A "° N R 12 12 is« i (S Ib H ° 'X \ b "V« Z, P-B4 16 DK 175009 bl where R 1 is the group -COR 3', a carbocydic, aromatic group or one via a carbon atom bonded aromatic or partially unsaturated heterocydic group, or an optionally substituted saturated or partially unsaturated lower hydrocarbon group, and Ra, Rb, R1 2 3 4 5 6, R \ A, 2, n and p have the meanings given above. carried out in 5 methods known per se and customary to any person skilled in the art Suitable solvents are, for example, lower alcohols such as methanol and ethanol, dimethylformamide and water.

Reaktionen udføres hensigtsmæssigt ved stuetemperatur.The reaction is conveniently carried out at room temperature.

Ifølge fremgangsmådevariant k) kan forbindelserne med formlen Ib omdannes til under 10 fysiologiske betingelser hydrolyserbare ester- eller etherderivater. Egnede og under fysiologiske betingelser hydrolyserbare esterderivater er især forbindelserne med formlen Ib, hvor mindst en af de to phenoliske hydroxygrupper er acyleret med en lavere fedtsyre.According to process variant k), the compounds of the formula Ib can be converted into ester or ether derivatives which can be hydrolysable under physiological conditions. Suitable ester derivatives which can be hydrolysable under physiological conditions are in particular the compounds of the formula Ib in which at least one of the two phenolic hydroxy groups is acylated with a lower fatty acid.

Disse forbindelser kan fremstilles ved i og for sig kendte og for enhver fagmand sædvanlige metoder. I en foretrukken udførelsesform udføres acyleringen med det 15 tilsvarende lavere fedtsyreanhydrid i nærværelse af en katalytisk mængde af en stærk syre, idet der som opløsningsmiddel fortrinsvis anvendes overskud af fedtsyreanhydrid.These compounds can be prepared by methods known per se and customary to any person skilled in the art. In a preferred embodiment, the acylation is carried out with the correspondingly lower fatty acid anhydride in the presence of a catalytic amount of a strong acid, the excess fatty acid anhydride preferably being used as solvent.

Egnede syrer er f.eks. svovlsyre og organiske sulfonsyrer, såsom p-toluensulfonsyre.Suitable acids are e.g. sulfuric acid and organic sulfonic acids, such as p-toluenesulfonic acid.

Egnede og under fysiologiske betingelser hydrolyserbare etherderivater er f.eks.Suitable and under physiological conditions hydrolysable ether derivatives are e.g.

20 forbindelser med formlen Ib, hvor mindst en af de to phenoliske hydroxygrupper er forethret med en lavere 1-alkoxycarbonyloxy-l-alkyl, lavere 1-alkanoyloxy-l-alkyl- eller med en lavere 2-oxo-l-alkylgruppe. Foretheringen kan udføres ved i og for sig kendte og for enhver fagmand sædvanlige metoder. Eksempelvis kan en forbindelse med formlen Ib omsættes med et lavere 1-alkoxycarbonyloxy-l-alkyl-, et lavere 1-alkanoyloxy-l-alkyl-25 eller et lavere 2-oxo-l-alkylhalogenid, idet denne forethring hensigtsmæssigt udføres i nærværelse af en base. Som halogenider kommer især iodider på tale. Egnede baser er f.eks. alkalimetalhydroxid og alkalimetalcarbonater, såsom natriumhydroxid og natriumcarbonat.Compounds of formula Ib, wherein at least one of the two phenolic hydroxy groups is etherified with a lower 1-alkoxycarbonyloxy-1-alkyl, lower 1-alkanoyloxy-1-alkyl- or with a lower 2-oxo-1-alkyl group. The etherification can be carried out by methods known per se and customary to any person skilled in the art. For example, a compound of formula Ib may be reacted with a lower 1-alkoxycarbonyloxy-1-alkyl-, a lower 1-alkanoyloxy-1-alkyl-25 or a lower 2-oxo-1-alkyl halide, this etherification being conveniently carried out in the presence of a base. As halides, iodides in particular come into play. Suitable bases are e.g. alkali metal hydroxide and alkali metal carbonates such as sodium hydroxide and sodium carbonate.

Ifølge fremgangsmådevariant k) kan forbindelser med den ovennævnte formel Ib også 2 omdannes til farmaceutisk acceptable salte. Som salte kommer især salte med 3 farmaceutisk acceptable baser i betragtning. Som eksempler på sådanne salte kan nævnes 4 alkalimetalsaltene, såsom natrium- og kaliumsaltene. Disse salte kan fremstilles ved i og 5 for sig kendte og for enhver fagmand sædvanlige metoder.According to process variant k), compounds of the above formula Ib can also be converted into pharmaceutically acceptable salts. Suitable salts are especially salts with 3 pharmaceutically acceptable bases. Examples of such salts are the alkali metal salts, such as the sodium and potassium salts. These salts can be prepared by methods known per se and customary to any person skilled in the art.

66

De forskellige som udgangsforbindelser anvendte forbindelser er kendte eller kan fremstilles ved i og for sig kendte metoder. De nedenstående eksempler indeholder detaljerede angivelser vedrørende fremstilling af disse udgangsforbindelser.The various compounds used as starting compounds are known or can be prepared by methods known per se. The following examples provide detailed information regarding the preparation of these starting compounds.

17 DK 175069 B117 DK 175069 B1

Som allerede nævnt indledningsvis hæmmer forbindelserne med formlen la enzymet COMT. Denne virkning kan fastslås kvantitativt på følgende måde: rottelever-homogenat inkuberes i nærværelse af et egnet substrat som beskrevet i J. Neurochem. 38. 191-195 (1982) og COMT-aktiviteten måles. 1 en anden forsøgsrække udføres inkubationen i 5 nærværelse af en forbindelse med formlen la. Ud fra forskellen i den målte COMT-aktivitet lader IC50 sig derefter beregne. IC50 angives i nmol/l og er den koncentration i inkubationsblandingen, som er nødvendig for at nedsætte COMT-aktiviteten med 50%. I nedenstående tabel er IC50-værdierne for nogle forbindelser med formlen la angivet.As already mentioned initially, the compounds of formula Ia inhibit the enzyme COMT. This effect can be determined quantitatively as follows: rat liver homogenate is incubated in the presence of a suitable substrate as described in J. Neurochem. 38. 191-195 (1982) and COMT activity is measured. In a second series of experiments, the incubation is carried out in the presence of a compound of formula Ia. Based on the difference in the measured COMT activity, the IC50 can then be calculated. IC50 is expressed in nmol / l and is the concentration in the incubation mixture required to reduce COMT activity by 50%. In the table below, the IC 50 values for some compounds of formula Ia are given.

Denne tabel indeholder endvidere angivelser af den akutte toxicitet af disse forbindelser 10 (LDS0 i rng/kg ved enkelt oral administration til mus).This table also contains indications of the acute toxicity of these compounds 10 (LDS0 in rng / kg when administered single to mice).

Forbindelse med formlen la 1C50 i nmol/l LD50 i mg/kg p.o.Compound of formula Ia 1C50 in nmol / l LD50 in mg / kg p.o.

3.4- dihydroxy-5-nitrophenyl- 15 2-pyridylketon 53,4 1250-2500 3.4- dihydroxy-5-nitrophenyl- 3- pyridylketon 47,0 1000-2000 3.4- dihydroxy-5-nitrophenyl- 4- pyridylketon 67,0 1000-2000 20 3,4-dihydroxy-5-nitrobenzoe- syre-n-butylester 20,0 312- 625 3.4- dihydroxy-5-nitro-kanel- syre-n-butylester 25,9 2500-5000 3.4- dihydroxy-5-nitrophenyl- 25 glyoxylsyreethylester 48,1 1250-2500 3.4- dihydroxy-5-nitrobenzophe- non 48,0 500-1000 3.5- dinitropyrocatechol 36,9 500-1000 2'-fluor-3,4-dihydroxy-5-nitro- 30 benzophenon 42,0 312- 6253,4-dihydroxy-5-nitrophenyl-2-pyridyl ketone 53.4 1250-2500 3,4-dihydroxy-5-nitrophenyl-3-pyridyl ketone 47.0 1000-2000 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone 67.0 1000 -2000 20 3,4-dihydroxy-5-nitrobenzoic acid n-butyl ester 20.0 312- 625 3,4-dihydroxy-5-nitro-cinnamic acid n-butyl ester 25.9 2500-5000 3.4-dihydroxy-5 -nitrophenyl-glyoxylic acid ethyl ester 48.1 1250-2500 3.4- dihydroxy-5-nitrobenzophenone 48.0 500-1000 3,5-dinitropyrocatechol 36.9 500-1000 2'-fluoro-3,4-dihydroxy-5-nitro- Benzophenone 42.0 312- 625

De beskrevne stoffer kan finde anvendelse som lægemidler, f.eks. i form af farmaceutiske præparater til enteral eller parenteral anvendelse. Forbindelserne med formel la kan eksempelvis indgives peroralt, f.eks. i form af tabletter, laktabletter, drageer, hårde og 35 bløde gelatinekapsler, opløsninger, emulsioner eller suspensioner, rektalt, f.eks. i form af suppositorier, eller parenteralt, f.eks. i form af injektionsopløsninger.The substances described can be used as drugs, e.g. in the form of pharmaceutical preparations for enteral or parenteral use. The compounds of formula Ia may, for example, be administered orally, e.g. in the form of tablets, lactate tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

18 UK Ί f5Ut>9 Dl18 UK Ί f5Ut> 9 Dl

Fremstillingen af de farmaceutiske præparater kan udføres på for en hver fagmand sædvanlig mide, idet forbindelserne med formel la, eventuelt i kombination med andre terapeutisk værdifulde stoffer, sammen med egnede ikke*toxiske inerte terapeutisk acceptable faste eller flydende bærematerialer, og de sædvanlige farmaceutiske hjælpe-5 stoffer eventuelt bringes i en galenisk administrationsform.The preparation of the pharmaceutical compositions can be carried out in a manner customary for any person skilled in the art, the compounds of formula Ia, optionally in combination with other therapeutically valuable substances, together with suitable non-toxic inert therapeutically acceptable solid or liquid carriers, and the usual pharmaceutical excipients. 5 substances may be brought into a galenic administration form.

Som bærematerialer egner såvel uorganiske som organiske bærematerialer sig. Således kan der til tabletter, laktabletter, drageer og hårde gelatinekapsler anvendes f.eks. lactose, majsstivelse eller derivater deraf, talkum, stearinsyre eller salte deraf som bærematerialer.Both inorganic and organic carriers are suitable as carrier materials. Thus, for tablets, lactate tablets, dragees and hard gelatin capsules, e.g. lactose, maize starch or derivatives thereof, talc, stearic acid or its salts as carriers.

10 Til bløde gelatinekapsler egner sig som bærere, f.eks. planteolier, voksarter, fedtstoffer og halvfaste og flydende polyoler (alt efter den aktive bestanddels beskaffenhed er en bærer imidlertid ikke nødvendig for bløde gelatinekapsler). Til fremstilling af opløsninger og sirupper egner sig som bæremateriale f.eks. vand, polyoler, saccharose, invertsukker og glucose. Til injektionsopløsninger egner sig som bærematerialer f.eks. vand, alkoholer, 15 polyoler, glyceroler og planteolier. Til suppositorier egner sig som bærematerialer f.eks. naturlige eller hærdede olier, voksarter, fedtstoffer og halvflydende eller flydende polyoler.For soft gelatin capsules suitable as carriers, e.g. vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient, a carrier is not necessary for soft gelatine capsules). For the preparation of solutions and syrups suitable as carrier material e.g. water, polyols, sucrose, invert sugar and glucose. Suitable for injection solutions as carrier materials e.g. water, alcohols, 15 polyols, glycerols and vegetable oils. Suitable for suppositories as carrier materials e.g. natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.

Som farmaceutiske hjælpestoffer kommer de sædvanlige konserveringsmidler, opløsningsformidlende stoffer, stabiliseringsmidler, befugtningsmidler, emulgeringsmidler, 20 midler til smagsforbedring såsom sødemidler og aromatiseringsmidler, farvestoffer, salte til forandring af det osmotiske tryk, puffere, overtræksmiddel og antioxidanter på tale.As pharmaceutical excipients are the usual preservatives, solubilizers, stabilizers, wetting agents, emulsifying agents, flavoring agents such as sweetening and flavoring agents, coloring agents, salts for altering the osmotic pressure, buffers, coatings and antioxidants.

Doseringen af de beskrevne stoffer kan, afhængig af den sygdom, der skal behandles, patientens alder og individuelle tilstand og af applikationsmåden, variere indenfor vide 25 grænser og skal naturligvis i hvert enkelt tilfælde tilpasses de individuelle omstændigheder. Ved forbedring af behandlingen af Parkinsons sygdom og af Parkinsonisme med L-dopa kommer der for voksne patienter en daglig dosis fra ca. 25 mg til ca. 1.000 mg, især fra ca. 100 mg til ca. 300 mg i betragtning. Alt efter dosering er det endvidere hensigtsmæssigt at administrere dagsdosen i flere doseringsenheder.The dosage of the substances described can, depending on the disease to be treated, the patient's age and individual condition and the mode of application, vary within wide limits and must, of course, be adapted to the individual circumstances in each individual case. By improving the treatment of Parkinson's disease and of Parkinsonism with L-dopa, for adults patients a daily dose of approx. 25 mg to approx. 1,000 mg, especially from approx. 100 mg to approx. 300 mg in consideration. Depending on the dosage, it is also advisable to administer the daily dose in several dosage units.

3030

De farmaceutiske præparater ifølge opfindelsen indeholder hensigtsmæssigt fra ca. 25 mg til ca. 300 mg, fortrinsvis fra ca. 50 mg til ca. 150 mg af en forbindelse med formlen la eller et under fysiologiske betingelser hydrolyserbart ester- eller etherderivat eller et farmaceutisk acceptabelt salt deraf.The pharmaceutical compositions according to the invention suitably contain from approx. 25 mg to approx. 300 mg, preferably from approx. 50 mg to approx. 150 mg of a compound of formula Ia or a ester or ether derivative hydrolysable under physiological conditions or a pharmaceutically acceptable salt thereof.

Nedenstående eksempler skal nærmere illustrere opfindelsen uden dog at begrænse dens omfang.The following examples are intended to further illustrate the invention without, however, limiting its scope.

35 EKSEMPEL 1 19 DK 175069 B1 a) Til 17,1 g (86,7 mmol) 4-hydroxy-3-methoxy-5-nitrobenzaldehyd sættes 170 ml konstant kogende brombrintesyre, og der opvarmes i 3,5 timer under tilbagesvaling. Efter 5 afkøling suges det udfældede bundfald fra, vaskes to gange med isvand og tages op i ethylacetat. Den organiske fase vaskes med 2 x 50 ml kogsaltopløsning, tørres over magnesiumsulfat og inddampes under vandstrålevacuum. De vundne krystaller tages op i methylenchlorid, hvorpå der filtreres på den 10-dobbelte mængde silicagel. Det vundne materiale krystalliseres af ethylacetat/isopropylether. Der fås 3,4-dihydroxy-5-10 nitrobenzaldehyd i form af gule krystaller med smeltepunkt 142-143°C.EXAMPLE 1 19 GB 175069 B1 a) To 17.1 g (86.7 mmol) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde is added 170 ml of constantly boiling hydrobromic acid and heated for 3.5 hours under reflux. After cooling, the precipitate is filtered off with suction, washed twice with ice water and taken up in ethyl acetate. The organic phase is washed with brine (2 x 50 ml), dried over magnesium sulphate and evaporated in vacuo. The crystals obtained are taken up in methylene chloride, after which the 10-fold amount of silica gel is filtered. The material obtained is crystallized from ethyl acetate / isopropyl ether. 3,4-Dihydroxy-5-10 nitrobenzaldehyde is obtained in the form of yellow crystals, m.p. 142-143 ° C.

b) Til en opløsning af 1,83 g (10 mmol) 3,4-dihydroxy-5-nitrobenzaldehyd i 25 ml vand sættes der en opløsning af 1,7 g (15 mmol) hydroxylamin-O-sulfonsyre i 6 ml vand, der omrøres derefter i 3,5 timer ved 65°C og afkøles, og det udfældede bundfald suges fra og 15 tages op i ethylacetat. Den organiske fase tørres over natriumsulfat og inddampes under vandstrålevakuum. De vundne krystaller krystalliseres af ethylacetat/n-hexan. Der fas 3,4-dihydroxy-5-nitrobenzonitril i form af gule krystaller med smeltepunkt 194-195°C.b) To a solution of 1.83 g (10 mmol) of 3,4-dihydroxy-5-nitrobenzaldehyde in 25 ml of water is added a solution of 1.7 g (15 mmol) of hydroxylamine-O-sulfonic acid in 6 ml of water, it is then stirred for 3.5 hours at 65 ° C and cooled and the precipitated precipitate is filtered off with suction and taken up in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated under a jet stream of water. The crystals obtained are crystallized from ethyl acetate / n-hexane. 3,4-Dihydroxy-5-nitrobenzonitrile is formed in the form of yellow crystals, m.p. 194-195 ° C.

20 EKSEMPEL 2 aa) Til 4,1 g 4-(-benzyloxy)-3-methoxy-brombenzen opløst i 40 ml tetrahydrofuran dryppes der ved -70^ i løbet af 10 minutter 10 ml 1,4 M tert. butyllithiumopløsning i hexan. Efter 2 timers omrøring ved -70eC tilsættes der i løbet af 5 min. 1 ml pyridin-3- 25 carbaldehyd. Reaktionsblandingen omrøres i 1 time ved -70°C og i 2 timer ved 0°C og hældes ud i 100 ml IN saltsyre. Der ekstraheres med 3 x 50 ml ether. De forenede etherfaser vaskes md 100 ml IN saltsyre og 20 ml vand. De forenede vandfaser gøres alkaliske med vandig ammoniakopløsning og ekstraheres med 3 x 100 ml methylenchlorid.EXAMPLE 2 aa) To 4.1 g of 4 - (- benzyloxy) -3-methoxy-bromobenzene dissolved in 40 ml of tetrahydrofuran, 10 ml of 1.4 M tert are added dropwise at -70 ° over 10 minutes. butyllithium solution in hexane. After stirring for 2 hours at -70 ° C, add over 5 minutes. 1 ml pyridine-3-carbaldehyde. The reaction mixture is stirred for 1 hour at -70 ° C and for 2 hours at 0 ° C and poured into 100 ml of 1N hydrochloric acid. Extract with 3 x 50 ml of ether. The combined ether phases are washed with 100 ml of 1N hydrochloric acid and 20 ml of water. The combined aqueous phases are made alkaline with aqueous ammonia solution and extracted with methylene chloride (3 x 100 ml).

De forenede methylenchloridfaser tørres over natriumsulfat og inddampes. Der fis a-[4-30 (benzyloxy)-3-methoxyphenyl]-3-pyridinmethanol som en olie.The combined methylene chloride phases are dried over sodium sulfate and evaporated. There is α- [4-30 (benzyloxy) -3-methoxyphenyl] -3-pyridinemethanol as an oil.

ab) På analog måde fås der ved anvendelse af pyridin-4-carbaldehyd a-[4-(benzyloxy)-3-methoxyphenyl]-4-pyridinmethanol som olie.ab) In an analogous manner, using pyridine-4-carbaldehyde α- [4- (benzyloxy) -3-methoxyphenyl] -4-pyridinemethanol as oil.

35 ba) Til 3,2 g a-[4-(benzyloxy)-5-methoxyphenyl]-3-pyridinmethanol, suspenderet i 50 ml vand, sættes der 2,5 g kaliumpermanganat, hvorpå der omrøres i 30 min ved 90°C. Efter tilsætning af yderligere 1,0 g kaliumpermanganat og omrøring i yderligere 30 min. ved 90°C afkøles der til stuetemperatur og ekstraheres med 2 x 150 ml ethylacetat. De forenede ethylacetatfaser vaskes med kogsaltopløsning, tørres over natriumsulfat og35 ba) To 3.2 g of α- [4- (benzyloxy) -5-methoxyphenyl] -3-pyridinemethanol, suspended in 50 ml of water, add 2.5 g of potassium permanganate, then stir for 30 minutes at 90 ° C . After adding an additional 1.0 g of potassium permanganate and stirring for an additional 30 min. at 90 ° C, cool to room temperature and extract with 2 x 150 ml of ethyl acetate. The combined ethyl acetate phases are washed with brine, dried over sodium sulfate and

L/l\ I f VUV« U IL / l \ I f VUV «U I

20 inddampes. Den således vundne remanens chromatograferes på 50 g silicagel med ethyiacetat. Efter omkrystallisering af methylenchlorid/hexan fås 4-(benzyloxy)-3-methoxyphenyl 3-pyridylketon med smeltepunkt 76°C.20 is evaporated. The residue thus obtained is chromatographed on 50 g of silica gel with ethyl acetate. After recrystallization from methylene chloride / hexane, 4- (benzyloxy) -3-methoxyphenyl 3-pyridyl ketone with a melting point of 76 ° C is obtained.

5 bb) Ud fra a-[4-(benzyloxy)-3-methoxyphenyl]-4-pyridinmethanol fås der på en analog måde 4-(benzyloxy-3-methoxyphenyl 4-pyridylketon med smeltepunkt 85-87eC (methylenchlorid/hexan).5 bb) From α- [4- (benzyloxy) -3-methoxyphenyl] -4-pyridinemethanol, 4- (benzyloxy-3-methoxyphenyl 4-pyridyl ketone with a melting point of 85-87 ° C (methylene chloride / hexane) is obtained in an analogous manner.

ca) Til 20 g 4-(benzyloxy-3-methoxyphenyl 3-pyridylketon opløst i 200 ml 10 methylenchlorid dryppes der i løbet af 15 min. ved 10°C 50 ml 33% brombrintesyre i eddikesyre. Efter 3 timers omrøring ved 20°C hældes reaktionsblandingen ud i en blanding af 100 ml koncentreret vandig ammoniak og is. Ved tilsætning af eddikesyre justeres pH til 6. Methylenchloridfasen skilles fra; den vandige fase ekstraheres med endnu 2 x 100 ml methylenchlorid. De forenede methylenchloridfaser tørres over natriumsulfat og 15 inddampes. Remanensen omkrystalliseres af methylenchlorid/hexan. Der fås 4-hydroxy-3-methoxyphenyl-3-pyridylketon med smeltepunkt 150-15l°C.ca) To 20 g of 4- (benzyloxy-3-methoxyphenyl 3-pyridyl ketone dissolved in 200 ml of methylene chloride are added dropwise over 15 minutes at 10 ° C 50 ml of 33% hydrobromic acid in acetic acid, after stirring for 3 hours at 20 ° C The reaction mixture is poured into a mixture of 100 ml of concentrated aqueous ammonia and ice.Adjusting with acetic acid, the pH is adjusted to 6. The methylene chloride phase is separated off, the aqueous phase is extracted with a further 2 x 100 ml of methylene chloride, the combined methylene chloride phases are dried over sodium sulphate. The residue is recrystallized from methylene chloride / hexane to give 4-hydroxy-3-methoxyphenyl-3-pyridyl ketone, m.p. 150 DEG-151 DEG.

cb) Ud fra 4-(benzyloxy)-3-methoxyphenyl-4-pyridylketon fås på analog måde 4-hydroxy- 3-methoxyphenyl 4-pyridylketon med smeltepunkt 215-218°C (acetonitril).cb) From 4- (benzyloxy) -3-methoxyphenyl-4-pyridyl ketone 4-hydroxy-3-methoxyphenyl 4-pyridyl ketone with melting point 215-218 ° C (acetonitrile) is obtained in an analogous manner.

20 da) Til 1,15 g 4-hydroxy-3-methoxyphenyl-3-pyridylketon opløst i 15 ml eddikesyre dryppes der ved stuetemperatur 0,38 ml 65% salpetersyre. Efter 2 timers omrøring hældes reaktionsblandingen ud i 120 ml isvand, hvorpå der justeres til pH 5 ved hjælp af koncentreret ammoniak, og det dannede bundfald filtreres fra. Den således vundne 25 remanens opvarmes under tilbagesvaling i 20 ml acetonitril, hvorpå der igen filtreres. Der fås 4-hydroxy-3-methoxy-5-nitrophenyl-3-pyridylketon som brune krystaller med smeltepunkt 193eC.20 da) To 1.15 g of 4-hydroxy-3-methoxyphenyl-3-pyridyl ketone dissolved in 15 ml of acetic acid, 0.38 ml of 65% nitric acid are added dropwise at room temperature. After stirring for 2 hours, the reaction mixture is poured into 120 ml of ice water, then adjusted to pH 5 with concentrated ammonia and the precipitate formed is filtered off. The residue thus obtained is heated under reflux in 20 ml of acetonitrile, after which it is filtered again. 4-Hydroxy-3-methoxy-5-nitrophenyl-3-pyridyl ketone is obtained as brown crystals, m.p. 193 ° C.

db) Ud fra 4-hydroxy-3-methoxy-phenyl-4-pyridylketon fås der på analog måde 4-30 hydroxy-3-methoxy*5-nitrophenyl-4-pyridylketon med smeltepunkt 240°C.db) From 4-hydroxy-3-methoxy-phenyl-4-pyridyl ketone, 4-30 hydroxy-3-methoxy * 5-nitrophenyl-4-pyridyl ketone with a melting point of 240 ° C is obtained.

e) 3,5 g 4-hydroxy-3-methoxy-5-nitrophenyl-3-pyridylketon opløst i 70 ml 48% vandig brombrintesyre omrøres i 18 timer ved 100°C. Derefter inddampes reaktionsblandingen under formindsket tryk. Remanensen omkrystalliseres ved vand. Der fås 3,4-dihydroxy-5- 35 nitro-phenyl-3-pyridylketon-hydrobromid med smeltepunkt 265°C.e) 3.5 g of 4-hydroxy-3-methoxy-5-nitrophenyl-3-pyridyl ketone dissolved in 70 ml of 48% aqueous hydrobromic acid are stirred for 18 hours at 100 ° C. The reaction mixture is then evaporated under reduced pressure. The residue is recrystallized from water. 3,4-Dihydroxy-5-nitro-phenyl-3-pyridyl ketone hydrobromide with a melting point of 265 ° C is obtained.

f) Ud fra 4*hydroxy-3-methoxy-5-nitrophenyl-4-pyridylketon fås på analog måde 3,4-dihydroxy-5-nitrophenyl-4-pyridylketon med smeltepunkt 246°C (af vand).f) From 4 * hydroxy-3-methoxy-5-nitrophenyl-4-pyridyl ketone, 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone with a melting point of 246 ° C (of water) is obtained in an analogous manner.

21 DK 175069 B1 g) 13,2 g 3,4-dihydroxy-5-nitrophenyl-4-pyridylketon suspenderes i 500 ml methanol, og under omrøring tilsættes der 4,88 g methansulfonsyre. Suspensionen opvarmes i 60 min. under tilbagesvaling. Derefter afkøles der til 10°C, og krystallerne suges fra og vaskes med 2 x 30 ml methanol. Der fis 3,4-dihydroxy-5-nitrophenyl-4-pyridylketon-methansulfonat 5 med smeltepunkt 260-26ΓΌ (sønderdeling).21 DK 175069 B1 g) 13.2 g of 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone are suspended in 500 ml of methanol and 4.88 g of methanesulfonic acid are added with stirring. The suspension is heated for 60 min. during reflux. It is then cooled to 10 ° C and the crystals are filtered off with suction and washed with 2 x 30 ml of methanol. There is 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone methanesulfonate 5, m.p. 260-26ΓΌ (dec.).

EKSEMPEL 3 10 a) En opløsning af 2,6 g (12,2 mmol) 4-hydroxy-3-methoxy-5-nitro-benzoesyre i 26 ml konstant kogende brombrintesyre opvarmes i 2 timer under tilbagesvaling. Efter afkøling destilleres opløsningsmidlet af under vandstrålevakuum. Den krystallinske remanens omkrystalliseres af 50 ml kogende vand. Der fis 3,4-dihydroxy-5-nitrobenzoesyre i form af gule krystaller med smeltepunkt 224-226°C.EXAMPLE 3 a) A solution of 2.6 g (12.2 mmol) of 4-hydroxy-3-methoxy-5-nitro-benzoic acid in 26 ml of constantly boiling hydrobromic acid is heated for 2 hours under reflux. After cooling, the solvent is distilled off under water jet vacuum. The crystalline residue is recrystallized from 50 ml of boiling water. There is 3,4-dihydroxy-5-nitrobenzoic acid as yellow crystals, m.p. 224-226 ° C.

15 b) Til 1,0 g (5 mmol) 3,4 dihydroxy-5-nitrobenzoesyre sættes der 20 ml methanolisk saltsyreopløsning, og der omrøres i 3 timer ved 45°C, og efter fjernelse af opløsningsmidlet tages remanensen op i methylenchlorid. Den organiske fase vaskes med kogsaltopløsning, tørres over natriumsulfat og inddampes. Det vundne krystallinske produkt tages op i 20 methylenchlorid og filtreres på den 1 O-dobbelte mængde silicagel. Det vundne materiale omkrystalliseres af ethylacetat/n-hexan. Der fis 3,4-dihydroxy-5-nitrobenzoesyremethylester i form af gule kryller med smeltepunkt 144-145°C.15 b) To 1.0 g (5 mmol) of 3,4 dihydroxy-5-nitrobenzoic acid is added 20 ml of methanolic hydrochloric acid solution and stirred for 3 hours at 45 ° C and after removal of the solvent the residue is taken up in methylene chloride. The organic phase is washed with brine, dried over sodium sulfate and evaporated. The crystalline product obtained is taken up in methylene chloride and filtered on the 1 O-double amount of silica gel. The recovered material is recrystallized from ethyl acetate / n-hexane. 3,4-Dihydroxy-5-nitrobenzoic acid methyl ester is formed in the form of yellow crystals, m.p. 144-145 ° C.

Ud fra 3,4-dihydroxy-5-nitrobenzoesyre fås på analog måde følgende estere: 25 c) 3,4 dihydroxy-5-nitrobenzoesyre-ethylester med smeltepunkt 106-107°C (af ethylacetat/n-hexan), d) 3,4-dihydroxy-5-nitrobenzoesyre-n-butylester med smeltepunkt 73-74°C (af 30 methylenchlorid) og e) 3,4-dihydroxy-5-nitrobenzoesyre-n-hexylester med smeltepunkt 44-45aC. (af isopropylether).From 3,4-dihydroxy-5-nitrobenzoic acid, the following esters are obtained in an analogous manner: c) 3,4-dihydroxy-5-nitrobenzoic acid ethyl ester, m.p. 106-107 ° C (of ethyl acetate / n-hexane), d) 3 , 4-dihydroxy-5-nitrobenzoic acid n-butyl ester with melting point 73-74 ° C (of methylene chloride) and e) 3,4-dihydroxy-5-nitrobenzoic acid n-hexyl ester with melting point 44-45aC. (of isopropyl ether).

35 EKSEMPEL 4 a) Til 10,0 g 3,4-dimethoxy-5-nitrobenzaidehyd opløst i 150 ml tetrahydrofuran dryppes der ved -20°C og i løbet af 15 min. 25 ml 2 M-phenyllithiumopløsning (i benzen/ether (7:3)), og reaktionsblandingen omrøres i 1 time ved 0°C og 2 timer ved 20°C. Derefter tilEXAMPLE 4 a) To 10.0 g of 3,4-dimethoxy-5-nitrobenzaide hydrate dissolved in 150 ml of tetrahydrofuran is added dropwise at -20 ° C and over 15 minutes. 25 ml of 2 M-phenyllithium solution (in benzene / ether (7: 3)) and the reaction mixture is stirred for 1 hour at 0 ° C and 2 hours at 20 ° C. Then to

ΜIX I ff WVWW fc* IΜIX I ff WVWW fc * I

22 sættes der 150 ml 2 N-svovlsyre og ekstraheres med 3 x 150 ml ether. De forenede etherfaser vaskes med kogsaltopløsning og tørres over natriumsulfat og inddampes. Den således vundne remanens chromatograferes på 180 g silicagel med methylenchlorid.22 Add 150 ml of 2 N-sulfuric acid and extract with 3 x 150 ml of ether. The combined ether phases are washed with brine and dried over sodium sulfate and evaporated. The residue thus obtained is chromatographed on 180 g of silica gel with methylene chloride.

Herved fås 3,4-dimethoxy-5-nitrobenzohydrol som et amorft fast stof.This gives 3,4-dimethoxy-5-nitrobenzohydrol as an amorphous solid.

5 b) Til 2,5 g 3,4-dimethoxy-5-nitrobenzohydrol opløst i 50 ml methylenchlorid sættes der 2,2 g pyridiniumchlorchromat, hvorpå der omrøres i 2 timer ved stuetemperatur. Derefter filtreres de uopløste bestandele fra. Filtratet inddampes, og remanensen chromatograferes på 60 g silicagel med methylenchlorid. Derved fås der efter krystallisering af 10 methylenchlorid/hexan 3,4-dimethoxy-5-nitrobenzophenon med smeltepunkt 78-80°C.B) To 2.5 g of 3,4-dimethoxy-5-nitrobenzohydrol dissolved in 50 ml of methylene chloride is added 2.2 g of pyridinium chlorochromate, then stirred for 2 hours at room temperature. The undissolved constituents are then filtered off. The filtrate is evaporated and the residue is chromatographed on 60 g of silica gel with methylene chloride. After crystallization of methylene chloride / hexane, 3,4-dimethoxy-5-nitrobenzophenone with a melting point of 78-80 ° C is obtained.

c) 0,5 g 3,4 dimethoxy-5-nitrobenzophenon omrøres i 30 timer ved 110°C i en blanding af 4 ml eddikesyre og 4 ml 48% vandig brombrintesyre. Derefter inddampes reaktionsblandingen til tørhed. Remanensen tages op i methylenchlorid. Der vaskes med 15 vand, tørres over natriumsulfat og inddampes. Efter omkrystallisering af methylenchlorid/hexan fås 3,4-dihydroxy-5-nitrobenzophenon med smeltepunkt 132°C.c) 0.5 g of 3,4-dimethoxy-5-nitrobenzophenone are stirred for 30 hours at 110 ° C in a mixture of 4 ml of acetic acid and 4 ml of 48% aqueous hydrobromic acid. The reaction mixture is then evaporated to dryness. The residue is taken up in methylene chloride. Wash with water, dry over sodium sulfate and evaporate. After recrystallization from methylene chloride / hexane, 3,4-dihydroxy-5-nitrobenzophenone with a melting point of 132 ° C is obtained.

EKSEMPEL 5 20 a) 4,9 g (0,2 mol) magnesium suspenderes i 15 ml absolut ethanol og opvarmes efter tilsætning af 1 ml tetrachlorkulstof til reaktionen starter. Derefter tildryppes der under omrøring en opløsning af 31,8 g (0,2 mol) malonsyrerediethylester i 19,9 ml absolut ethanol og 80 ml absolut toluen på en sådan måde, at temperaturen ligger mellem 50® og 25 60°C. Derefter røres der videre i 1 time ved denne temperatur, hvorpå reaktionsblandingen afkøles til -5°C, og der tildryppes en opløsning af 49,3 g (0,2 mol), 3,4-dimethoxy-5-nitrobenzoylchlorid (smeltepunkt 82-85°C) i 300 ml absolut toluen og 50 ml absolut tetra-hydrofuran på en sådan måde, at temperaturen ikke overstiger -5°C. Derefter omrøres der videre natten over ved stuetemperatur. Efter afdestillering af opløsningsmidlet opløses 30 remanensen i 500 ml ethylacetat. Under omrøring og isafkøling tilsættes der en iskold opløsning af 12 ml koncentreret svovlsyre i 80 ml vand. Den organiske fase vaskes med kogsaltopløsning, tørres over magnesiumsulfat og inddampes. Den vundne olie chromatograferes på den 10-dobbelte mængde silicagel med methylenchlorid. Det vundne krystallinske materiale omkrystalhseres af isopropylether. Herved fås 3,4-dimethoxy-5-35 nitrobenzoylmalonsyrediethylester i form af lyst beigefarvet krystaller med smeltepunkt 70°C.EXAMPLE 5 a) 4.9 g (0.2 mol) of magnesium are suspended in 15 ml of absolute ethanol and heated after adding 1 ml of carbon tetrachloride until the reaction starts. Then a solution of 31.8 g (0.2 mol) of malonic acid diethyl ester in 19.9 ml of absolute ethanol and 80 ml of absolute toluene is added dropwise with stirring in such a way that the temperature is between 50® and 60 ° C. The mixture is then stirred for a further 1 hour at this temperature, after which the reaction mixture is cooled to -5 [deg.] C. and a solution of 49.3 g (0.2 mol) of 3,4-dimethoxy-5-nitrobenzoyl chloride (melting point 82-) is added dropwise. 85 ° C) in 300 ml of absolute toluene and 50 ml of absolute tetrahydrofuran in such a way that the temperature does not exceed -5 ° C. Then stir further overnight at room temperature. After distilling off the solvent, the residue is dissolved in 500 ml of ethyl acetate. While stirring and ice-cooling, add an ice-cold solution of 12 ml of concentrated sulfuric acid in 80 ml of water. The organic phase is washed with brine, dried over magnesium sulphate and evaporated. The oil obtained is chromatographed on the 10-fold amount of silica gel with methylene chloride. The crystalline material obtained is recrystallized from isopropyl ether. This gives 3,4-dimethoxy-5-35 nitrobenzoylmalonic acid diethyl ester in the form of light beige crystals with a melting point of 70 ° C.

b) 19,0 g (51,4 mmol) 3,4-dimethoxy-5-nitrobenzoylmalonsyrediethylester opløses i 100 ml isseddike, og der tilsættes 5 dråber koncentreret svovlsyre, og opvarmes i 16 timer 23 DK 175069 B1 under tiibagesvaling. Eddikesyren destilleres af i vandstrilevakuum ved 60°C, og til remanensen tilsættes der 3 x 250 ml toluen, idet der hver gang inddampes. Den krystallinske remanens ekstraheres med ethylacetat. Den organiske fase vaskes med vand, tørres over magnesiumsulfat og inddampes. De vundne krystaller chromatograferes 5 pi dén 30-dobbélte mængde silicagel med toluen. Det vundne krystallinske materiale omkrystallisteres af isopropylether. Herved fis 3’,4’ dimethoxy-5'-nitroacetophenon i form af gule krystaller med smeltepunkt 86-87°C.b) 19.0 g (51.4 mmol) of 3,4-dimethoxy-5-nitrobenzoylmalonic acid diethyl ester are dissolved in 100 ml of glacial acetic acid and 5 drops of concentrated sulfuric acid are added and heated for 16 hours under reflux. The acetic acid is distilled off in a water spray vacuum at 60 ° C and 3 x 250 ml of toluene are added to the residue, evaporating each time. The crystalline residue is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The crystals obtained are chromatographed on 5 [mu] l of the 30-fold amount of silica gel with toluene. The crystalline material obtained is recrystallized from isopropyl ether. Hereby 3 ', 4' dimethoxy-5'-nitroacetophenone in the form of yellow crystals with melting point 86-87 ° C.

c) Til 2 g (8,9 mmol) 3‘,4’-dimethoxy-5’-nitroacetophenon sættes der 10 30 ml konstant kogende brombrintesyre og omrøres i 2,5 timer ved 140°C. Efter afkøling hældes det ud i 200 ml isvand og ekstraheres med 3 x 100 ml ethylacetat. Den organiske fase vaskes med 2 x 25 ml kogsaltopløsning og tørres over natriumsulfat og inddampes.c) To 2 g (8.9 mmol) of 3 ', 4'-dimethoxy-5'-nitroacetophenone is added 10 30 ml of constantly boiling hydrobromic acid and stirred for 2.5 hours at 140 ° C. After cooling, it is poured into 200 ml of ice water and extracted with 3 x 100 ml of ethyl acetate. The organic phase is washed with brine (2 x 25 ml) and dried over sodium sulphate and evaporated.

Det vundne produkt filtreres med ethylacetat over den 20-dobbelte mængde silicagel. Ved omkrystallisering af det vundne materiale med vand fås 3’,4’-dihydroxy-5·-15 nitroacetophenon i form af gule krystaller med smeltepunkt 159-160°C.The product obtained is filtered with ethyl acetate over 20 times the amount of silica gel. Recrystallization of the recovered material with water gives 3 ', 4'-dihydroxy-5 · -15 nitroacetophenone as yellow crystals, m.p. 159-160 ° C.

Ved at gi ud fra 4,-hydroxy-3’-methoxy-5’-nitroacetophenon fås den samme forbindelse ved behandling med brombrintesyre ved kogning.By giving 4,-hydroxy-3'-methoxy-5'-nitroacetophenone, the same compound is obtained by treatment with hydrobromic acid by boiling.

20 EKSEMPEL 6 a) 100 g (0,8 mol) guajacol opløses i 136,4 g (0,86 mol) isosmørsyreanhydrid, og der tilsættes 120 g (0,88 mol) vandfrit zinkchlorid, (hvorved alt går | opløsning), og 25 reaktionsblandingen opvarmes ved 155° C og afkøles efter 3 min. Remanensen underkastes først vanddampdestillation for at fjerne de let flygtige dele og ekstraheres derefter 3 x 500 ml ether. Den organiske fase vaskes med 2 x 250 ml vand, 150 ml mættet hydrogencarbonatopløsning og igen med 250 ml vand, tørres over natriumsulfat og inddampes i vandstrilevakuum. Den vundne brune harpiks destilleres i højvakuum.EXAMPLE 6 a) Dissolve 100 g (0.8 mol) of guajacol in 136.4 g (0.86 mol) of isobutyric anhydride and add 120 g (0.88 mol) of anhydrous zinc chloride (whereby everything goes | solution), and the reaction mixture is heated at 155 ° C and cooled after 3 minutes. The residue is first subjected to steam distillation to remove the volatiles and then extracted with 3 x 500 ml of ether. The organic phase is washed with 2 x 250 ml of water, 150 ml of saturated bicarbonate solution and again with 250 ml of water, dried over sodium sulphate and evaporated in a water-spray vacuum. The obtained brown resin is distilled in a high vacuum.

30 Destillatet med kogepunkt 105*120°C (6,67 Pa) opløses i ether, hvorpå der tilsættes n-hexan til begyndende krystallisation. De vundne krystaller omkrystalliseres af ether/hexan.The distillate with boiling point 105 * 120 ° C (6.67 Pa) is dissolved in ether and then n-hexane is added to begin crystallization. The crystals obtained are recrystallized from ether / hexane.

Herved fås 4,-hydroxy-3'-methoxy-2-methyl-propiophenon i form af farveløse krystaller med smeltepunkt 86-87°C.This gives 4, -hydroxy-3'-methoxy-2-methyl-propiophenone in the form of colorless crystals, m.p. 86-87 ° C.

35 b) 15,0 g (77,2 mmol) 4,-hydroxy-3'-methoxy-2-methyl-propiophenon opløses i 300 ml iseddike, og der tildryppes under omrøring og i løbet af 15 min 7,65 ml 50,5% saltpetersyre (11,2 N) i 40 ml iseddike. Efter 15 min. hældes reaktionsblandingen ud i isvand, og de udfældede krystaller suges fra, vaskes med vand og opløses i methylenchlorid.35 b) 15.0 g (77.2 mmol) of 4, -hydroxy-3'-methoxy-2-methyl-propiophenone are dissolved in 300 ml of glacial acetic acid and added dropwise with stirring and over 15 minutes 7.65 ml of 50 .5% nitric acid (11.2 N) in 40 ml of glacial acetic acid. After 15 min. the reaction mixture is poured into ice water and the precipitated crystals are filtered off with suction, washed with water and dissolved in methylene chloride.

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Opløsningen tørres over natriumsulfat og inddampes. Det vundne råprodukt tages op i methylenchlorid, og filtreres over 100 g silicagel. De således vundne krystaller omkrystalliseres af methylenchlorid/n-hexan. Herved fås 4’-hydroxy-3’-methoxy-2-methyl-5 5'-nitropropiophenon i form af gule krystaller med smeltepunkt 85-87°C.The solution is dried over sodium sulfate and evaporated. The crude product obtained is taken up in methylene chloride and filtered through 100 g of silica gel. The crystals thus obtained are recrystallized from methylene chloride / n-hexane. This gives 4'-hydroxy-3'-methoxy-2-methyl-5 5'-nitropropiophenone as yellow crystals, m.p. 85-87 ° C.

c) Til 8,0 g (33,4 mmol) 4'-hydroxy-3'-methoxy*2-methyl-5’-nitropropiophenon sættes der 64 g pyridinhydrochlorid og omrøres i 45 min. ved 180®C. Efter afkøling hældes reaktionsblandingen ud i 500 ml isvand, hvorpå blandingen gøres sur med 20 ml 3N-10 saltsyre og ekstraheres med methylenchlorid. Den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes i vandstrålevakuum. Efter krystallisering af methylenchlorid/n-hexan fås 3',4,-dihydroxy-2-methyl-5'-nitropropiophenon i form af gule krystaller med smeltepunkt 98-99°C.c) To 8.0 g (33.4 mmol) of 4'-hydroxy-3'-methoxy * 2-methyl-5'-nitropropiophenone is added 64 g of pyridine hydrochloride and stirred for 45 minutes. at 180 ° C. After cooling, the reaction mixture is poured into 500 ml of ice water, then the mixture is acidified with 20 ml of 3N-10 hydrochloric acid and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. After crystallization of methylene chloride / n-hexane, 3 ', 4, -dihydroxy-2-methyl-5'-nitropropiophenone is obtained in the form of yellow crystals, m.p. 98-99 ° C.

15 EKSEMPEL 7 a) 100 g (805,5 mmol) guajacol opløses i 136,4 g (86,2 mmol) smørsyreanhydrid, og der tilsættes 120 g (880 mmol) zinkchlorid, opvarmes som angivet i eksempel 6.a t 3 min.EXAMPLE 7 a) Dissolve 100 g (805.5 mmol) of guajacol in 136.4 g (86.2 mmol) of butyric anhydride and add 120 g (880 mmol) of zinc chloride, heat as indicated in Example 6.a for 3 min.

20 og oparbejdes som beskrevet. Det efter højvakuumdestillation vundne råprodukt chromatograferes med toluen på 600 g silicagel. Efter omkrystallisering af ether/n-hexan fås 4’-hydroxy-3'-methoxy-butyrophenon i form af farveløse krystaller med smeltepunkt 40-41°C.20 and worked up as described. The crude product obtained after high vacuum distillation is chromatographed with toluene on 600 g of silica gel. After recrystallization from ether / n-hexane, 4'-hydroxy-3'-methoxy-butyrophenone is obtained in the form of colorless crystals, m.p. 40-41 ° C.

25 b) Til en opløsning af 12,7 g (65,4 mmol) 4'-hydroxy-3’-methoxybutyrophenon i 250 ml iseddike dryppes der under omrøring i løbet af 10 min. 6,5 ml 11,2 N saltpetersyre. Der omrøres derefter i 15 min. reaktionsblandingen hældes ud i isvand, og det udfældede bundfald filtreres fra, vaskes med isvand og tages op i methylenchlorid. Me-thylenchloridopløsningen filtreres over 50 g silicagel. Det vundne materiale 30 omkrystalliseres af methylenchlorid/n-hexan. Herved fås 4’-hydroxy-3'-methoxy-5'-nitrobutyrophenon i form af gule krystaller med smeltepunkt 92-93eC.B) To a solution of 12.7 g (65.4 mmol) of 4'-hydroxy-3'-methoxybutyrophenone in 250 ml of glacial acetic acid is added dropwise with stirring over 10 minutes. 6.5 ml of 11.2 N nitric acid. Stir then for 15 minutes. the reaction mixture is poured into ice water and the precipitate is filtered off, washed with ice water and taken up in methylene chloride. The methylene chloride solution is filtered over 50 g of silica gel. The recovered material 30 is recrystallized from methylene chloride / n-hexane. This gives 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone as yellow crystals, m.p. 92-93 ° C.

c) Til 10,2 g (42,6 mmol) 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenon sættes der 80 g pyridinhydrochlorid og omrøres derefter i 40 min. ved 200°C. Efter afkølingen hældes 35 reaktionsblandingen ud i 500 ml isvand. Der tilsættes 30 ml 3 N saltssyre og ekstraheres med methylenchlorid. Den organiske fase tørres over natriumsulfat og inddampes. Det vundne råprodukt chromatograferes med methylenchlorid på 150 g silicagel. Det vundne materiale omkrystalliseres med methylenchlorid/n-hexan. Herved fås S'^’-dihydroxy-S’-nitrobutyrophenon i form af gule krystaller med smeltepunkt 88-90°C.c) To 10.2 g (42.6 mmol) of 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone is added 80 g of pyridine hydrochloride and then stirred for 40 minutes. at 200 ° C. After cooling, the reaction mixture is poured into 500 ml of ice water. Add 30 ml of 3 N hydrochloric acid and extract with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is chromatographed with methylene chloride on 150 g of silica gel. The recovered material is recrystallized from methylene chloride / n-hexane. This gives S '^' - dihydroxy-S'-nitrobutyrophenone in the form of yellow crystals with a melting point of 88-90 ° C.

25 DK 175069 B1 EKSEMPEL 8 5 a) 2,25 g (10 mmol) 3,4-dihydroxy-5-nitrokanelsyre opløses i 50 ml methanol og saltsyregas ledes gennem denne opløsning i 10 min. Efter 1 time tilsættes der 50 ml isopropylether, og det udfældede bundfald suges fra og vaskes med isopropylether. Efter omkrystallisering af methanol/ether fås 3,4-dihydroxy-5-nitrokanelsyremethy!ester i form af gule krystaller med smeltepunkt 186-187°C.25 GB 175069 B1 EXAMPLE 8 5 a) 2.25 g (10 mmol) of 3,4-dihydroxy-5-nitrocinnamic acid are dissolved in 50 ml of methanol and hydrochloric acid gas is passed through this solution for 10 min. After 1 hour, 50 ml of isopropyl ether are added and the precipitate is filtered off with suction and washed with isopropyl ether. After recrystallization from methanol / ether, 3,4-dihydroxy-5-nitrocinnamic acid methyl ester is obtained in the form of yellow crystals, m.p. 186-187 ° C.

10 b) Ud fra 3,4-dihydroxy-5-nitrokanelsyre og butanolisk saltsyreopløsning fås på analog måde 3,4-dihydroxy-5-nitrokanelsyre-n-butylester i form af gullige krystaller med smeltepunkt 129-130°C.B) From 3,4-dihydroxy-5-nitrocinnamic acid and butanolic hydrochloric acid solution, 3,4-dihydroxy-5-nitrocinnamic acid n-butyl ester is obtained in an analogous manner in the form of yellowish crystals, m.p. 129-130 ° C.

15 EKSEMPEL 9 5,0 g (13,5 mmol) 3,4-dimethoxy-5-nitrobenzoylmalonsyreediethylester opløses i 50 ml absolut methylenchlorid. Efter afkøling til -20VC tildryppes der under omrøring en opløsning 20 af 16,9 g (67,5 mmol) bortribomid i 30 ml methylenchlorid på en sådan måde, at temperaturen ikke overstiger -20°C. Derefter omrøres der natten over ved stuetemperatur. Efter tilsætning af 80 ml ethanol omrøres der i 30 min. ved stuetemperatur, hvorefter opløsningsmidlet destilleres af i vandstrålevakuum. Remanensen tilsættes vand og ekstraheres med methylenchlorid. Den organiske fase vaskes med vand, tørres over 25 natriumsulfat og inddampes. Det vundne råprodukt filtreres med ethylacetat over 50 g silicagel. Den vundne krystallinske remanens omkrystalliseres af methylenchlorid/n-hexan.EXAMPLE 9 5.0 g (13.5 mmol) of 3,4-dimethoxy-5-nitrobenzoylmalonic acid diethyl ester are dissolved in 50 ml of absolute methylene chloride. After cooling to -20 ° C, a solution of 16.9 g (67.5 mmol) of boron tribomide in 30 ml of methylene chloride is added dropwise with stirring in such a way that the temperature does not exceed -20 ° C. Then stir overnight at room temperature. After adding 80 ml of ethanol, stir for 30 minutes. at room temperature, after which the solvent is distilled off in a water jet vacuum. The residue is added to water and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is filtered with ethyl acetate over 50 g of silica gel. The crystalline residue obtained is recrystallized from methylene chloride / n-hexane.

Herved fås 3,4-dihydroxy-5-nitro-benzoyleddikesyreethylester i form af gule krystaller med smeltepunkt 141-142DC.This gives 3,4-dihydroxy-5-nitro-benzoylacetic acid ethyl ester in the form of yellow crystals, m.p. 141-142 ° C.

30 EKSEMPEL 10 a) Til en opløsning af 1,49 g (12,3 mmol) 2-phenylethylamin i 100 ml methylenchlorid sættes der 1,26 g triethylamin. Under omrøring til dryppes der en opløsning af 3,0 g 3,4-35 dimethoxy-5-nitrobenzoylchlorid i 100 ml methylenchlorid, hvorpå der omrøres videre i 15 min. Den organiske fase ekstraheres derefter med 2 x 50 ml isvand, tørres over natriumsulfat og inddampes i vandstrålevakuum. Efter omkrystallisering af methylenchlorid/n-hexan fås 3,4-dimethoxy-5-nitro-N-phenethylbenzamid i form af lyst beigefarvede nåle med smeltepunkt 121-122°C.EXAMPLE 10 a) To a solution of 1.49 g (12.3 mmol) of 2-phenylethylamine in 100 ml of methylene chloride is added 1.26 g of triethylamine. While stirring, a solution of 3.0 g of 3,4-35 dimethoxy-5-nitrobenzoyl chloride in 100 ml of methylene chloride is added dropwise, followed by further stirring for 15 minutes. The organic phase is then extracted with 2 x 50 ml of ice water, dried over sodium sulphate and evaporated in a water jet vacuum. After recrystallization from methylene chloride / n-hexane, 3,4-dimethoxy-5-nitro-N-phenethylbenzamide is obtained in the form of light beige needles, m.p. 121-122 ° C.

26 DK 175069 bl26 DK 175069 bl

b) 3,6 (10,9 mmol) 3,4-dimethoxy-5-mtro-n-phenethylbenzamid opvarmes med 36 ml phosphoroxychlorid under en kvælstofatmosfaere i 96 timer under tilbagesvaling. Efter afdestillering af det overskydende phosphoroxychlorid i vandstrålevakuum ved 60°Cb) 3.6 (10.9 mmol) 3,4-dimethoxy-5-nitro-n-phenethylbenzamide is heated with 36 ml of phosphorus oxychloride under a nitrogen atmosphere for 96 hours under reflux. After distilling off the excess phosphorus oxychloride in a water jet vacuum at 60 ° C

5 tilsættes der 3 x 100 ml toluen, idet opløsningsmidlet hver gang destilleres af. Remanensen tages op i methylenchlorid. Den organiske fase vaskes med vand, tørres over natriumsulfat, og inddampes i vandstrålevakuum. Den vundne røde harpiks chromatograferes med methylenchlorid/ ethylacetat (1:1) på 120 g silicagel. Herved fås 1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisochinolin i form af en gul harpiks.5, add 3 x 100 ml of toluene, distilling off the solvent each time. The residue is taken up in methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. The red resin obtained is chromatographed with methylene chloride / ethyl acetate (1: 1) on 120 g of silica gel. There is obtained 1- (3,4-dimethoxy-5-nitrophenyl) -3,4-dihydroisoquinoline in the form of a yellow resin.

10 c) Til 1,4 g (4,5 mmol) l-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisochinolin sættes der 15 ml konstant kogende brombrintesyre og opvarmes til kogning under en kvælstofatmosfære i 1,5 time under tilbagesvaling. Efter afdestillering af brombrintesyren i vandstrålevakuum omkrystalliseres den krystallinske remanens af acetone. Herved fås 5- 15 (3,4-dihydro-l-isochinolinyl)-3-nitropyrocatechol hydrobromid i form af gule krystaller med smeltepunkt > 250° (sønderdeling).C) To 1.4 g (4.5 mmol) of 1- (3,4-dimethoxy-5-nitrophenyl) -3,4-dihydroisoquinoline, add 15 ml of constantly boiling hydrobromic acid and heat to boiling under a nitrogen atmosphere for 1, 5 hours under reflux. After distilling off the hydrobromic acid in a water jet vacuum, the crystalline residue is recrystallized from acetone. This gives 5- (3,4-dihydro-1-isoquinolinyl) -3-nitropyrocatechol hydrobromide in the form of yellow crystals with a melting point> 250 ° (decomposition).

EKSEMPEL 11 20 a) Til 5,0 g (27,7 mmol) 4-hydroxy-5-methoxy-isophtalaldehyd sættes der 50 ml konstant kogende brombrintesyre og opvarmes til kogning under en argonatmosfære i 3 timer under tilbagesvaling og under omrøring. Efter afkøling tilsættes der 50 ml isvand, og det udfældede bundfald suges fra og vaskes med vand. Råproduktet tages op i ethylacetat 25 og filtreres over 50 g aluminiumoxid (aktivitetstrin II). Det vundne krystallinske materiale omkrystalliseres til ethylacetat/nhexan. Herved fås 4,5-dihydroxyisophthalaldehyd i form af svagt orangefarvede krystaller med smeltepunkt 201-202°C.EXAMPLE 11 20 a) To 5.0 g (27.7 mmol) of 4-hydroxy-5-methoxy-isophthalaldehyde is added 50 ml of constantly boiling hydrobromic acid and heated to boiling under an argon atmosphere for 3 hours under reflux and with stirring. After cooling, 50 ml of ice water are added and the precipitate is filtered off with suction and washed with water. The crude product is taken up in ethyl acetate 25 and filtered over 50 g of alumina (activity stage II). The crystalline material recovered is recrystallized from ethyl acetate / nhexane. This gives 4,5-dihydroxyisophthalaldehyde in the form of pale orange crystals, m.p. 201-202 ° C.

b) Til en opløsning af 2,0 g (12,0 mmol) 4,5-dihydroxyisophthalaldehyd i 20 ml vand 30 dryppes der under omrøring ved 30°C en opløsning af 3,27 g (28,9 mmol) hydroxylamin- O-sulfonsyre i 12 ml vand, hvorpå temperaturen holdes ved 65°C i 10 timer. Efter afkøling suges det udfældede bundfald fra, vaskes med vand og tages op i ethylacetat. Den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes i vandstrålevakuum. Efter omkrystallisering af ethylacetat fås 4,5-dihydroxyisophthalonitril i 35 form af gule krystaller, som sønderdeles ved over 300°C.b) To a solution of 2.0 g (12.0 mmol) of 4,5-dihydroxyisophthalaldehyde in 20 ml of water 30 is added dropwise with stirring at 30 ° C a solution of 3.27 g (28.9 mmol) of hydroxylamine. -sulfonic acid in 12 ml of water, whereupon the temperature is maintained at 65 ° C for 10 hours. After cooling, the precipitated precipitate is filtered off with suction, washed with water and taken up in ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. After recrystallization from ethyl acetate, 4,5-dihydroxyisophthalonitrile is obtained in the form of yellow crystals which decompose at above 300 ° C.

EKSEMPEL 12 27 DK 175069 B1 a) Til en opløsning af 112,5 g 2-brom-4,-hydroxy-3,-methoxyacetophenon i 560 ml iseddike dryppes der under omrøring og i løbet af 30 min. ved 20-25°C en opløsning af 38 g rygende salpetersyre (96%) i 50 ml iseddike. Derved fælder gulbrune krystaller sig ud.EXAMPLE 12 27 GB 175069 B1 a) To a solution of 112.5 g of 2-bromo-4, -hydroxy-3, -methoxyacetophenone in 560 ml of glacial acetic acid is added dropwise with stirring and over 30 minutes. at 20-25 ° C a solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid. This causes yellow-brown crystals to precipitate.

Efter 90 min. hældes reaktionsblandingen ud i 300 g is. Krystallerne suges fra, vaskes med 5 1000 ml vand, og opløses i 1000 ml methylenchlorid. Den organiske fase vaskes med mættet kogsaltopløsning, tørres over natriumsulfat, filtreres, og filtratet inddampes ved 50°C i vandstrålevakuum, indtil begyndende krystallisation. Det til stuetemperatur afkølede krystallisat suges fra, og vaskes med en smule methylenchlorid. Herved fås 2-brom-4'-hydroxy-3‘-methoxy-5'-nitroacetophenon med smeltepunkt 147-149eC.After 90 min. pour the reaction mixture into 300 g of ice. The crystals are filtered off with suction, washed with 1000 ml of water and dissolved in 1000 ml of methylene chloride. The organic phase is washed with saturated brine, dried over sodium sulfate, filtered and the filtrate is evaporated at 50 ° C in a water jet vacuum until crystallization begins. The crystallizate cooled to room temperature is filtered off with suction and washed with a little methylene chloride. This gives 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone, m.p. 147-149 ° C.

10 b) Metode A: ba) Til en suspension af 580,1 mg 2-brom-4’-hydroxy-3’-methoxy-5’-nitroacetophenon i 10 ml ethanol sættes der 443,8 mg selendioxid, og der opvarmes i 71 timer under 15 tilbagesvaling. Derefter filtreres reaktionsblandingen for selen og inddampes. Remanensen opløses i methylenchlorid og vaskes med mættet natriumkloridopløsning, tørres over natriumsulfat, filtreres og inddampes. Herved fås 4-hydroxy-3-methoxy-S-nitrophenylglyoxylsyreethylester med smeltepunkt 165-167eC (af ethanol).10 b) Method A: ba) To a suspension of 580.1 mg of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 10 ml of ethanol, add 443.8 mg of selenium dioxide and heat in 71 hours under 15 reflux. The reaction mixture is then filtered for selenium and evaporated. The residue is dissolved in methylene chloride and washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. This gives 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid ethyl ester, m.p. 165 DEG-167 DEG C. (of ethanol).

20 På analog mide fås følgende: bb) Ud fra 2-brom-4,-hydroxy-3,-methoxy-5,-nitroacetophenon og n-butanol fås 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyre-n-butylester med smeltepunkt 105-107°C.In analogous manner the following are obtained: bb) From 2-bromo-4, -hydroxy-3, -methoxy-5, -nitroacetophenone and n-butanol, 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid n-butyl ester is obtained with melting point 105-107 ° C.

(af ethanol) og 25 bc) Ud fra 2-brom-4'-hydroxy-3‘-methoxy-5,-nitroacetophenon og n-hexanol fås 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyre med smeltepunkt 103-105eC. (af n-hexanol/petroleumsether).(of ethanol) and 25 bc) From 2-bromo-4'-hydroxy-3'-methoxy-5, -nitroacetophenone and n-hexanol, 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid is obtained, m.p. 103-105 ° C. (of n-hexanol / petroleum ether).

30 c) Metode B: ca) Til en suspension af 29,01 g 2-brom-4'-hydroxy-3'-methoxy-5’-nitroacetophenon i 300 ml tert. butanol sættes der 27,74 g selendioxid, og der opvarmes til kogning i 18 timer under tilbagesvaling. Den varme reaktionsblanding suges under eftervaskning med 35 methylenchlorid gennem et filterhjælpemiddel af diatoméejord. Filtratet inddampes, og remanensen opstemmes i 150 ml varm methylenchlorid. Det krystallinske bundfald suges fra og vaskes med en smule methylenchlorid. Herved fås 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyre med smeltepunkt 169-171°C.C) Method B: ca) To a suspension of 29.01 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 300 ml of tert. butanol is added 27.74 g of selenium dioxide and heated to boiling for 18 hours under reflux. The hot reaction mixture is aspirated during post-washing with methylene chloride through a diatomaceous earth filter aid. The filtrate is evaporated and the residue is taken up in 150 ml of hot methylene chloride. The crystalline precipitate is filtered off with suction and washed with a little methylene chloride. This gives 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid, m.p. 169-171 ° C.

28 UK 17dUt>9 ΒΊ 2,42 g 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyre opløses i 25 ml tørt N,N-dimethylformamid, og der tilsættes ved stuetemperatur 50 mg 4-dimethylaminopyridin og 920 mg tørt methanol, og blandingen afkøles derefter med isbad til 0°C, og der tilsættes 2,27 g Ν,Ν-dicyclohexylcarbodiimid. Efter 10 min. fjernes isbadet, og reaktionsblandingen 5 omrøres i endnu 1 time ved stuetemperatur. Derefter inddampes der. Remanensen opløses i ethylacetat, hvorpå uopløst urinstof filtreres fra, og filtratet vaskes 4 gange med vand, tørres over natriumsulfat, filtreres og inddampes. Herved fås 4 - hydroxy-3-methoxy- 5-nitrophenylglyoxylsyremethylester med smeltepunkt 155-157°C (af methy-lenchlorid/ether.28 UK 17dUt> 9 ΒΊ 2.42 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid are dissolved in 25 ml of dry N, N-dimethylformamide and 50 mg of 4-dimethylaminopyridine and 920 mg of dry methanol are added at room temperature, and the mixture then cooled with ice bath to 0 ° C and 2.27 g of Ν, Ν-dicyclohexylcarbodiimide are added. After 10 min. the ice bath is removed and the reaction mixture is stirred for another 1 hour at room temperature. Then evaporate. The residue is dissolved in ethyl acetate, then undissolved urea is filtered off and the filtrate is washed 4 times with water, dried over sodium sulphate, filtered and evaporated. This gives 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid methyl ester, m.p. 155-157 ° C (of methylene chloride / ether).

10 På analog måde fås følgende: cb) Ud fra 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyre og ethanol fås 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyreethylester med smeltepunkt 165-167°C (af ethanol) og 15 cc) Ud fra 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyre og isopropanol fås 4-hydroxy- 3-methoxy-5-nitrophenylglyoxylsyre-i-propylether med smeltepunkt 99-101°C (af isopropanol).In an analogous manner the following is obtained: cb) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid and ethanol 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid ethyl ester with melting point 165-167 ° C (of ethanol) and 15 cc From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid and isopropanol, 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid i-propyl ether is obtained, m.p. 99-101 ° C (of isopropanol).

20 d) Til en suspension af 17,2 g 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyreethylester i 100 ml tørt acetonitril og 100 ml tørt toluen sættes der 10,53 g natriumiodid og 11,9 g siliciumtetrachlorid og opvarmes i 47 timer under tilbagesvaling. Derefter inddampes reaktionsblandingen, og remanensen destilleres af med 6 x 200 ml toluen. Den vundne remanens deles mellem vand og ether og filtreres gennem et filterhjælpemiddel af 25 diatoméejord. Den etheriske fase vaskes 4 gange med mættet kogsaltopløsning, tørres over natriumsulfat, filtreres og inddampes. Den olieagtige remanens behandles 3 gange med ether, og aktivt kul. Herved fås 3,4-dihydroxy-5-nitrophenylglyoxylsyrethylester med smeltepunkt 77-79°C (af ether/n-hexan).D) To a suspension of 17.2 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid ethyl ester in 100 ml of dry acetonitrile and 100 ml of dry toluene are added 10.53 g of sodium iodide and 11.9 g of silicon tetrachloride and heated for 47 hours. during reflux. The reaction mixture is then evaporated off and the residue is distilled off with 6 x 200 ml of toluene. The residue obtained is partitioned between water and ether and filtered through a 25 diatomaceous earth filter aid. The ether phase is washed 4 times with saturated brine, dried over sodium sulfate, filtered and evaporated. The oily residue is treated 3 times with ether and activated carbon. This gives 3,4-dihydroxy-5-nitrophenylglyoxylic acid ethyl ester, m.p. 77-79 ° C (of ether / n-hexane).

30 På analog måde fås: e) Ud fra 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyremethylester fås 3,4-dihydroxy- 5-nitrophenylglyoxylsyremethyiester som et gult destillat ved 145-150°C og 10,67 Pa.In an analogous manner are obtained: e) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid methyl ester, 3,4-dihydroxy-5-nitrophenylglyoxylic acid methyl ester is obtained as a yellow distillate at 145-150 ° C and 10.67 Pa.

35 f) Ud fra 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyreisopropylester fås 3,4- dihydroxy-5-nitrophenylglyoxylsyreisoprophylester som et gult destillat ved 155-160°C og 12,0 Pa.F) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid isopropyl ester, 3,4-dihydroxy-5-nitrophenylglyoxylic acid isopropyl ester is obtained as a yellow distillate at 155-160 ° C and 12.0 Pa.

29 DK 175069 B1 g) Ud fra 4-hydroxy-3-methoxy-5-mtrophenylglyoxylsyre-n-butylester fås 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-butylester som et gult destillat ved 160-165°C og 10,67 Pa og 5 h) Ud fra 4-hydroxy-3-methoxy-5-nitrophenylglyoxylsyre-n-hexylester fås fås 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester som et gult destillat ved 165-170°C og 12,0 Pa.29 DK 175069 B1 g) From 4-hydroxy-3-methoxy-5-macrophenylglyoxylic acid n-butyl ester 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-butyl ester is obtained as a yellow distillate at 160-165 ° C and 10, 67 Pa and 5 h) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid n-hexyl ester, 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester is obtained as a yellow distillate at 165-170 ° C and 12 , 0 Pa.

10 EKSEMPEL 13 236,1 mg 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester opløses i 15 ml ethanol, og der tilsættes 7,59 ml 0,1 N-natriumhydroxydopløsning. Efter 1 time inddampes den rødgule opløsning. Det vundne natriumsalt af 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-15 hexylester krystalliseres af vand og har et smeltepunkt på p/p 300°.EXAMPLE 13 236.1 mg of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester are dissolved in 15 ml of ethanol and 7.59 ml of 0.1 N sodium hydroxide solution are added. After 1 hour, the red-yellow solution is evaporated. The sodium salt of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-15 hexyl ester obtained is crystallized from water and has a melting point of p / p 300 °.

EKSEMPEL 14 20 Til en opløsning af 3,18 g 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester i 47,5 ml ethanol sættes der 1,11 g O-methylhydroxylamin-hydrochlorid 1,95 g natriumacetat og 2,5 ml vand og opvarmes i 5 timer til kogning under tilbagesvaling. Derefter inddampes reaktionsblandingen, og der sættes ether og vand til remanensen. Den organiske fase vaskes med mættet natriumchloridopløsning, tørres over natriumsulfat, filtreres og 25 inddampes. Remanensen chromatograferes på silicagel med methylenchlorid. Herved fis en 7:3 blanding af E- og Z-3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester-0-methyloxim, som en rødlig olie; 80 MHz NMR-Spektrum (CDCI3): signal for O-methyl ved 3,96 og 4,05 ppm.EXAMPLE 14 To a solution of 3.18 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester in 47.5 ml of ethanol is added 1.11 g of O-methylhydroxylamine hydrochloride, 1.95 g of sodium acetate and 2.5 ml of water and heat for 5 hours to reflux. Then the reaction mixture is evaporated and ether and water are added to the residue. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with methylene chloride. Here, a 7: 3 mixture of E- and Z-3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester-O-methyloxime is formed as a reddish oil; 80 MHz NMR Spectrum (CDCl 3): δ signal for O-methyl at 3.96 and 4.05 ppm.

30 EKSEMPEL 15EXAMPLE 15

Til en opløsning af 5,1 g 3,4-dihydroxy-5-nitrophenylglyoxylsyreethylester i tørt methylenchlorid ved -10°C sættes der dråbevis i løbet af 15 min. 25 g bortribromid. Der omrøres i 1 time ved - 10°C og derefter i 17 timer ved stuetemperatur. Derefter 35 inddampes reaktionsblandingen, og remanensen tilsættes forsigtigt vand og omrøres i endnu 30 min. ved 50°C. Efter afkøling til stuetemperatur suges det fnugagtige bundfald fra. Den vandige fase syrnes med 10 ml 1 N-saltsyre, ekstraheres 4 gange med ether, og de forenede organiske ekstrakter vaskes 4 gange med mættet natriumchloridopløsning, tørres over natriumsulfat, filtreres og inddampes. Råproduktet filtreres 3 gange efterTo a solution of 5.1 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid ethyl ester in dry methylene chloride at -10 ° C is added dropwise over 15 minutes. 25 g boron tribromide. Stir for 1 hour at -10 ° C and then for 17 hours at room temperature. Then the reaction mixture is evaporated and the residue is carefully added to water and stirred for another 30 minutes. at 50 ° C. After cooling to room temperature, the fluffy precipitate is sucked off. The aqueous phase is acidified with 10 ml of 1 N hydrochloric acid, extracted 4 times with ether and the combined organic extracts are washed 4 times with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The crude product is filtered 3 times after

h/l\ I I s/VVW U Ih / l \ I I s / VVW U I

30 hinanden gennem et filterhjælpemiddel af diatoméejord. Herved fås 3,4-dihydroxy-5* nitrophenylglyoxylsyre med smeltepunkt 172-l74eC (af isopropylether).30 each other through a filter aid of diatomaceous earth. This gives 3,4-dihydroxy-5 * nitrophenylglyoxylic acid, m.p. 172 DEG-174 DEG C. (of isopropyl ether).

5 EKSEMPEL 16 a) En blanding af 3,93 g 3,4-dihydroxy-5-nitrophenylglyoxylsyren-hexylester og 1,38 g 2-aminophenol bringes til smeltning ved 120°C under omrøring. Smelten krystalliserer efter 5 min. Efter 2 timer afkøles der og omkrystalliseres med methanol. Herved fås 3- 10 (3,4-dihydroxy-5-nitrophenyl)-2H-l,4-benzoxazin-2-on med smeltepunkt 202-204°C.EXAMPLE 16 a) A mixture of 3.93 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid hexyl ester and 1.38 g of 2-aminophenol is melted at 120 ° C with stirring. The melt crystallizes after 5 min. After 2 hours, cool and recrystallize from methanol. There is obtained 3- (3,4-dihydroxy-5-nitrophenyl) -2H-1,4-benzoxazin-2-one, m.p. 202-204 ° C.

På analog måde fås følgende: b) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 2amino-p-kresol fås 3-15 (3,4-dihydroxy-5-nitrophenyl)-6-methyl-2h-l,4 -benzoxazin-2-on med smeltepunkt 233- 235“C (af methanol/methylenchlorid), c) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 2amino-4-propylphenol fås 3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-l,4-benzoxazin-2-on med 20 smeltepunkt 200-202°C (af methanol), d) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 3amino-4-hydroxybenzoesyre fås 3 (3,4-dihydroxy-5-nitrophenyl)-2-oxo-2H-l,4-benzoxazin-6-carbonsyre med smeltepunkt 286-287°C (af acetone/petroleumsether), 25 e) Ud fra 3,4-dihydroxy-5-nitrophenylg!yoxy!syre-n-hexylester og 2amino-4-chlorphenol fås 6-chlor-3-(3,4-dihydroxy-5-mtrophenyl)-2H-l,4-benzoxazin-2-on med smeltepunkt 241-243°C (af methanol), 30 f) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 2-am«no-4,6-dichlorphenol fås 6,8-dichlor-3-(3,4-dihydroxy-5-nitrophenyl)-2H-l,4-benzoxazin-2-on med smeltepunkt 237-239eC (af ethanol/ether) og g) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 2amino-5-nitrophenol 35 fås 3-(3,4 dihydroxy-5*nitrophenyl)-7-nitro-2H-l,4-benzoxazin-2-on med smeltepunkt 253-255°C (af acetonitril/ ethanol).In an analogous manner the following are obtained: b) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 2 amino-p-cresol are obtained 3-15 (3,4-dihydroxy-5-nitrophenyl) -6-methyl-2h 1,4-benzoxazin-2-one, m.p. 233-235 ° C (of methanol / methylene chloride), c) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 2 amino-4-propylphenol (3,4-dihydroxy-5-nitrophenyl) -6-propyl-2H-1,4-benzoxazin-2-one, m.p. 200-202 ° C (of methanol), d) From 3,4-dihydroxy- 5-Nitrophenylglyoxylic acid n-hexyl ester and 3 amino-4-hydroxybenzoic acid give 3 (3,4-dihydroxy-5-nitrophenyl) -2-oxo-2H-1,4-benzoxazine-6-carboxylic acid, m.p. 286-287 ° C ( of acetone / petroleum ether), 25 e) From 3,4-dihydroxy-5-nitrophenylglyoxy acid n-hexyl ester and 2 amino-4-chlorophenol 6-chloro-3- (3,4-dihydroxy-5- macrophenyl) -2H-1,4-benzoxazin-2-one, m.p. 241-243 ° C (of methanol), 30 f) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 2-amino -4,6-dichlorophenol gives 6,8-dichloro-3- (3,4-dihydroxy-5-nitrophenyl) -2H 1,4-Benzoxazin-2-one, m.p. 237 DEG-239 DEG C. (of ethanol / ether) and g) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 2 amino-5-nitrophenol 35, 3- ( 3,4 dihydroxy-5 (nitrophenyl) -7-nitro-2H-1,4-benzoxazin-2-one, m.p. 253-255 ° C (of acetonitrile / ethanol).

__ 31 DK 175069 B1 EKSEMPEL 17 a) En blanding af 396,0 mg 3,4-dihydroxy-5-nitrophenylglyoxylsyre -n-hexylester og 137,6 mg 1,2-phenylendiamin opvarmes i 60 min ved 120°C. Derefter slaemmes 5 blandingen op i methanol, sugefiltreres og omkrystalliseres af N,N- dimethylformamid/vand. Herved fås 3-(3,4-dihydroxy-5-nitrophenyl)-2(lH)-chinoxalinon med smeltepunkt >300°C.__ 31 GB 175069 B1 EXAMPLE 17 a) A mixture of 396.0 mg of 3,4-dihydroxy-5-nitrophenylglyoxylic acid -n-hexyl ester and 137.6 mg of 1,2-phenylenediamine is heated for 60 minutes at 120 ° C. The mixture is then slurried in methanol, filtered off with suction and recrystallized from N, N-dimethylformamide / water. This gives 3- (3,4-dihydroxy-5-nitrophenyl) -2 (1H) -quinoxalinone, m.p.> 300 ° C.

På analog måde fås følgende: 10 b) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og N-methyl-1,2-phenylendiamin fås l-methyl-3-(3,4-dihydroxy-5-nitrophenyl-2(lH)-chinoxalinon med smeltepunkt 271-273eC (af methanol), 15 c) Udfra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og N-propyl-1,2-phenylendiamin fås l-propyl-3-(3,4-dihydroxy-5-nitrophenyl-2(lH)-chinoxalinon med smeltepunkt 183-185°C (af methanol), d) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 4,5-dimethyl-l,2- 20 phenylendiamin fås 3-{3,4-dihydroxy-5-nitrophenyl)-6,7-dimethyl-2(lH)-chinoxalinon med smeltepunkt >300°C (af N,N-dimethylformamid/vand), e) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 4,5-dichlor-l,2-phenylendiamin fås 6,7-dichlor-3-(3,4-dihydroxy-5-mtrophenyl)-2(lH)-chinoxalinon med 25 smeltepunkt >300eC (af N,N-dimethylformamid/vand), f) Ud fra 3,4-dihydroxy-5-nitrophenyiglyoxylsyre-n-hexylester og 3-chlor-5-trifluormethyl-l,2-phenylendiamin fås en 1:1 blanding af 8(og 5)-chlor-3-(3,4-dihydroxy- 5-nitrophenyl)-6-(og 7)-trifluormethyl-2(lH)-chinoxalinon med smeltepunkt >300°C (af 30 N,N-dimethylformamid/vand), g) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 4-methoxy- 1,2-phenylendiamin fås en 1:1 blanding af 3-(3,4-dihydroxy-5-nitrophenyl)-6(og 7)-methoxy-2(lH)-chinoxalinon med smeltepunkt >300°C (af ethanol/ether) 35 h) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 4-nitro-1,2-phenylendiamin fås en 1:1 blanding af 3-{3,4-dihydroxy-5-nitrophenyl)-6(og 7)-nitro-2(lH)-chinoxalinon med smeltepunkt >300°C (af Ν,Ν-dimethylformamid/vand) og, 32 DK 175069 Bl i) Ud fra 3,4-dihydroxy-5-nitrophenylglyoxylsyre*n-hexylester og N-hexyl-1,2-phenylendiamin fås l-hexyl-3-(3,4-dihydroxy-5-nitrophenyl)-2H-chinoxalinon med smeltepunkt 152-154°C (af methanol).In an analogous manner the following is obtained: 10 b) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and N-methyl-1,2-phenylenediamine there is obtained 1-methyl-3- (3,4-dihydroxy-5- nitrophenyl-2 (1H) -quinoxalinone, m.p. 271-273 ° C (of methanol), 15 c) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and N-propyl-1,2-phenylenediamine, 1-propyl- 3- (3,4-Dihydroxy-5-nitrophenyl-2 (1H) -quinoxalinone, m.p. 183-185 ° C (of methanol), d) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 4 .5-dimethyl-1,2-phenylenediamine gives 3- {3,4-dihydroxy-5-nitrophenyl) -6,7-dimethyl-2 (1H) -quinoxalinone, m.p. dimethylformamide / water), e) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 4,5-dichloro-1,2-phenylenediamine 6,7-dichloro-3- (3,4-dihydroxy- 5-Metrophenyl) -2 (1H) -quinoxalinone with melting point> 300 ° C (of N, N-dimethylformamide / water), f) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 3-chloro -trifluoromethyl-1,2-phenylenediamine gives a 1: 1 mixture of 8 (and 5) -chloro-3- (3,4-dihydroxy-5-nitrophenyl) -6- (and 7) -trifluoromethyl-2 (1H) -quinoxalinone with melting point> 300 ° C (of 30 N, N -dimethylformamide / water), g) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 4-methoxy-1,2-phenylenediamine a 1: 1 mixture of 3- (3,4-dihydroxy-5 is obtained -nitrophenyl) -6 (and 7) -methoxy-2 (1H) -quinoxalinone with melting point> 300 ° C (of ethanol / ether) 35 h) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 4 -nitro-1,2-phenylenediamine gives a 1: 1 mixture of 3- {3,4-dihydroxy-5-nitrophenyl) -6 (and 7) -nitro-2 (1H) -quinoxalinone with melting point> 300 ° C ( of Ν, Ν-dimethylformamide / water) and, 32 DK 175069 Bl i) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid * n-hexyl ester and N-hexyl-1,2-phenylenediamine there is obtained 1-hexyl-3- ( 3,4-dihydroxy-5-nitrophenyl) -2H-quinoxalinone, m.p. 152-154 ° C (of methanol).

5 EKSEMPEL 18EXAMPLE 18

En opløsning af 1,07 g 3,4-dihydroxy-5-nitrophenylglyoxylsyre-n-hexylester og 696,3 mg 2,3-diaminonaphthalen i 3 ml 1-hexanol bringes under tilbagesvaling i 3 timer til kogning.A solution of 1.07 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 696.3 mg of 2,3-diaminonaphthalene in 3 ml of 1-hexanol is brought to reflux for 3 hours to boil.

10 Reaktionsblandingen afkøles derefter og fortyndes med methanol. Det rå produkt suges fra og omkrystalliseres af Ν,Ν-dimethylformamid/vand. Herved fås 3-(3,4-dihydroxy-5-nitrophenyl)benzolg]chinoxalin-2(lH)-on med smeltepunkt >300°C.The reaction mixture is then cooled and diluted with methanol. The crude product is filtered off with suction and recrystallized from Ν, Ν-dimethylformamide / water. This gives 3- (3,4-dihydroxy-5-nitrophenyl) benzolg] quinoxalin-2 (1H) -one, m.p.> 300 ° C.

15 EKSEMPEL 19EXAMPLE 19

En suspension af 2,05 g og 3,4-dihydroxy-5-nitrophenyl-glyoxylsyre-hexylester og 600,8 mg thiosemicarbazid omrøres intensivt i 30 min. ved 90eC. Derefter afkøles blandingen til 40eC, og der tilsættes en opløsning af 870,1 mg natriumhydroxid i 15 ml vand. Derefter 20 opvarmes opløsningen i 30 min. ved 90°C. Reaktionsblandingen afkøles til stuetemperatur og tilsættes dråbevis 2 ml koncentreret saltsyre. Det udkrystalliserede produkt suges fra og opløses derefter i ethylacetat. Der vaskes med mættet kogesaltopløsning, tørres over natriumsulfat, filtreres og inddampes. Herved fås 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-l,2,4-triazin-5(4H)-on med smeltepunkt 282-284eC (af ethanol).A suspension of 2.05 g and 3,4-dihydroxy-5-nitrophenyl-glyoxylic acid hexyl ester and 600.8 mg of thiosemicarbazide is stirred vigorously for 30 minutes. at 90 ° C. The mixture is then cooled to 40 DEG C. and a solution of 870.1 mg of sodium hydroxide in 15 ml of water is added. Then the solution is heated for 30 minutes. at 90 ° C. The reaction mixture is cooled to room temperature and 2 ml of concentrated hydrochloric acid are added dropwise. The crystallized product is filtered off with suction and then dissolved in ethyl acetate. Wash with saturated brine, dry over sodium sulfate, filter and evaporate. There is obtained 6- (3,4-dihydroxy-5-nitrophenyl) -3-mercapto-1,2,4-triazin-5 (4H) -one, m.p. 282-284 ° C (of ethanol).

25 EKSEMPEL 20 aaa) Til en suspension af 2,9 g 2-brom-4'-hydroxy-3'-methoxy-5,*nitroacetophenon og 30 761,2 mg thiourinstof i 170 ml ethanol sættes der ved 60°C 820,3 mg natriumacetat og omrøres i 6 timer. Derefter inddampes reaktionsblandingen, og remanensen tilsættes 170 ml vand og opvarmes i 30 min. til 60°C. Efter afkøling suges produktet fra og vaskes med vand. Herved fås 4-(2-amino-4-thiazolyl)-2-methoxy-nitrophenol med smeltepunkt 248-250°C (af ethanol).EXAMPLE 20 aaa) To a suspension of 2.9 g of 2-bromo-4'-hydroxy-3'-methoxy-5, * nitroacetophenone and 30,761.2 mg of thiourea in 170 ml of ethanol is added at 60 ° C 820, 3 mg of sodium acetate and stir for 6 hours. Then the reaction mixture is evaporated and the residue is added with 170 ml of water and heated for 30 minutes. to 60 ° C. After cooling, the product is sucked off and washed with water. This gives 4- (2-amino-4-thiazolyl) -2-methoxy-nitrophenol, m.p. 248-250 ° C (of ethanol).

På analog måde fås følgende: 35 33 DK 175069 B1 aab) Ud fra 2-brom-4'-hydroxy-3’-methoxy-5'-nitroacetophenon og N-phenylthiourinstof fås 4-(2-ani!ino-4-thiazolyl)-2-methoxy-6-nitrophenol med smeltepunkt 185-187°C (af ether).In an analogous manner the following is obtained: 35 33 DK 175069 B1 aab) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and N-phenylthiourea are obtained 4- (2-anilino-4-thiazolyl -2-methoxy-6-nitrophenol, m.p. 185-187 ° C (of ether).

5 aba) Til en opløsning af 4,88 g 6-amino-4'-{trifluormethyl)-hexananilid-hydrochlorid i 70 ml vand sættes 50 ml 1,2-dichlorethan og 3,56 g calciumcarbonat. Til suspensionen sættes der i løbet af 60 min. og under omrøring ved stuetemperatur en opløsning af 2,6 g thiophosgen i 1,7 ml toluen. Efter 16 timer suges bundfaldet fra og den organiske fase vaskes med 1 N-saltsyre og vand. Efter tørring over natriumsulfat og filtrering inddampes 10 der. Herved fås råt 4'-(trifluormethyl)hexananilid-6-isothiocyanat abb) Til en opløsning af 5,2 g råt 4'-(trifluormethyl)hexananilid-6-isothiocyanat i 60 ml ethanol sættes der 100 ml koncentreret ammoniakopløsning. Efter 30 minutter inddampes reaktionsblandingen. Remanensen opløses i ethylacetat, vaskes med vand, tørres over 15 natriumsulfat, filtreres og inddampes. Herved fis T[5-[(a,a,a-trifluor-p- tolyl)carbamoyl]pentyl]-2-thiourinstof med smeltepunkt 140-142°Ο (af ethanol).5 aba) To a solution of 4.88 g of 6-amino-4 '- (trifluoromethyl) -hexananilide hydrochloride in 70 ml of water is added 50 ml of 1,2-dichloroethane and 3.56 g of calcium carbonate. To the suspension is added in 60 minutes. and with stirring at room temperature a solution of 2.6 g of thiophosgene in 1.7 ml of toluene. After 16 hours, the precipitate is filtered off with suction and the organic phase is washed with 1 N hydrochloric acid and water. After drying over sodium sulfate and filtration, evaporate 10. This gives crude 4 '- (trifluoromethyl) hexananilide-6-isothiocyanate abb) To a solution of 5.2 g of crude 4' - (trifluoromethyl) hexananilide-6-isothiocyanate in 60 ml of ethanol is added 100 ml of concentrated ammonia solution. After 30 minutes, the reaction mixture is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered and evaporated. Hereby fis T [5 - [(α, α, α-trifluoro-p-tolyl) carbamoyl] pentyl] -2-thiourea with melting point 140-142 ° Ο (of ethanol).

abc) Til en suspension af 666,7 mg l-[5-[a,a,a-trifluor-p-tolyl) carbamoy]pentyl]-2-thiourinstof og 580,2 mg 2-brom-4'-hydroxy-3’-methoxy-5'-nitroacetophenon i 50 ml 20 ethanol sættes der ved 60eC 164,2 mg natriumacetat. Herved opstår en rødliggul opløsning. Efter 90 minutter inddampes reaktionsblandingen, der sættes vand til remanensen, og bundfaldet suges fra og vaskes med 4 x 10 ml vand. Herved fås 6-[[4-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-thiazolyl]amino]-4'-(trif!uormethyl)hexananilid med smeltepunkt 160-162°C (af ethanol).abc) For a suspension of 666.7 mg of 1- [5- [α, α, α-trifluoro-p-tolyl) carbamoyl] pentyl] -2-thiourea and 580.2 mg of 2-bromo-4'-hydroxy 3'-Methoxy-5'-nitroacetophenone in 50 ml of ethanol is added at 60 ° C 164.2 mg of sodium acetate. This gives a reddish-yellow solution. After 90 minutes, the reaction mixture is evaporated, water is added to the residue and the precipitate is filtered off with suction and washed with 4 x 10 ml of water. This gives 6 - [[4- (4-hydroxy-3-methoxy-5-nitrophenyl) -2-thiazolyl] amino] -4 '- (trifluoromethyl) hexananilide, m.p. 160-162 ° C (of ethanol).

25 ac) En opløsning af 29,0 g 2-brom-4’-hydroxy-3,-methoxy-5‘-nitroacetophenon og 13,5 g 2- aminoacetophenon i 250 ml tørt Ν,Ν-dimethylformamid omrøres ved 90°C i 16 timer. Reaktionsblandingen inddampes derefter til ca. 2/3 og hældes ud i isvand. De udskilte krystaller suges fra og opløses i methylenchlorid. Der vaskes med mættet kog- 30 saltopløsning, tørres over natriumsulfat, filtreres og inddampes. Herved fås 2-(4-hydroxy- 3- methoxy-5-nitrobenzoyl)-3-methylindol med smeltepunkt 195-197eC (af methylenchlorid/methanol).Ac) A solution of 29.0 g of 2-bromo-4'-hydroxy-3, -methoxy-5'-nitroacetophenone and 13.5 g of 2-aminoacetophenone in 250 ml of dry Ν, Ν-dimethylformamide is stirred at 90 ° C for 16 hours. The reaction mixture is then evaporated to approx. 2/3 and pour into ice water. The precipitated crystals are sucked off and dissolved in methylene chloride. Wash with saturated brine, dry over sodium sulfate, filter and evaporate. This gives 2- (4-hydroxy-3-methoxy-5-nitrobenzoyl) -3-methylindole, m.p. 195 DEG-97 DEG C. (of methylene chloride / methanol).

ada)TiJ en suspension af 14,5 g 2-brom-4'-hydroxy-3'-methoxy-5’-nitroacetophenon og 35 5,41 g l,2*phenylendiamin i 350 ml methanol sættes der 4,92 g natriumacetat, og blandingen opvarmes til kogning under tilbagesvaling i 22 timer. Derefter inddampes reaktionsblandingen, remanensen opløses i methylenchlorid, og denne opløsning vaskes 4 gange med vand, tørres over natriumsulfat, filtreres og inddampes. Herved fås 2-(4-ada) To a suspension of 14.5 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 35.41 g, 2 * of phenylenediamine in 350 ml of methanol is added 4.92 g of sodium acetate, and the mixture is heated to reflux for 22 hours. The reaction mixture is then evaporated, the residue is dissolved in methylene chloride and this solution is washed 4 times with water, dried over sodium sulphate, filtered and evaporated. This gives 2- (4-

Ulv 1 f 0U03 D IWolf 1 f 0U03 D I

34 hydroxy-3-methoxy-5-nitrophenyl)chinoxalin med smeltepunkt 195-197°C (af methylenchlorid/ methanol).34 hydroxy-3-methoxy-5-nitrophenyl) quinoxaline, m.p. 195-197 ° C (of methylene chloride / methanol).

På analog måde fås følgende: 5 adb) Ud fra 2-brom-4’-hydroxy-3‘-methoxy-5’-nitroacetophenon og 4,5-dimethyl-l,2-phenylendiamin fås 6,7-dimethyl-2-(4-hydroxy-3-methoxy-5-nitrophenyl)chinoxalin med smeltepunkt 207-209°C (af methylenchlorid/methanol).In an analogous manner the following is obtained: 5 adb) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 4,5-dimethyl-1,2-phenylenediamine 6,7-dimethyl-2- (4-hydroxy-3-methoxy-5-nitrophenyl) quinoxaline, m.p. 207-209 ° C (of methylene chloride / methanol).

10 b) Til en suspension af 267,3 mg 4-{2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol i 10 ml tørt methylenchlorid sættes der ved -20°C 1,25 g bortribromid. Efter tilsætning omrøres der i endnu en time ved -20°C og uden afkøling ved stuetemperatur i 18 timer. Derefter inddampes reaktionsblandingen, og remanensen tilsættes forsigtigt vand og omrøres i 30 minutter ved 50eC. Efter afkøling til stuetemperatur suges det rå produkt fra og vaskes 15 med en smule vand. Herved fås 5-(2-amino-4-thiazolyl)-3-mtropyrocatechol-hydrobromid med smeltepunkt 244-246°C (af methanol).B) To a suspension of 267.3 mg of 4- (2-amino-4-thiazolyl) -2-methoxy-6-nitrophenol in 10 ml of dry methylene chloride is added at -20 ° C 1.25 g of boron tribromide. After addition, stir for another hour at -20 ° C and without cooling at room temperature for 18 hours. Then the reaction mixture is evaporated and the residue is carefully added to water and stirred for 30 minutes at 50 ° C. After cooling to room temperature, the crude product is filtered off with suction and washed with a little water. This gives 5- (2-amino-4-thiazolyl) -3-metropyrocatechol hydrobromide, m.p. 244-246 ° C (of methanol).

Pi analog måde fås følgende: 20 c) Ud fra 4-(2*anilino-4-thiazolyl)-2-methoxy-6-nitrophenol fås 5-(2-anilino-4-thiazolyl)- 3-nitropyrocatechol med smeltepunkt 202-204eC (af methanol), d) Ud fra 6-[[4-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-thiazolyl]amino]-4’-(trifluormethyl)hexananilid fås 6-[[4-(3,4-dihydroxy-5-nitrophenyl)-2-thiazolyl]amino>4’- 25 (trifluormethyl)hexananilid med smeltepunkt 214-216°C (af methanol), e) Ud fra 2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-3-methylindol fås 5-brom-2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindol med smeltepunkt 265-267°C (af methanol), 30 f) Ud fra 2-(4-hydroxy-3-methoxy-5-nitrophenyl)chinoxalin fås 2-(3,4-dihydroxy-5-nitrophenyl)chinoxalin med smeltepunkt 241-243eC (af methanol) og g) Ud fra 6,7-dimethyl-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-chinoxalin fås 6,7-dimethyl-2-(3,4-dihydroxy-5-nitrophenyl)chinoxalin med smeltepunkt 274-276°C (af 35 methanol).In an analogous manner the following is obtained: 20 c) From 4- (2 * anilino-4-thiazolyl) -2-methoxy-6-nitrophenol there is obtained 5- (2-anilino-4-thiazolyl) -3-nitropyrocatechol with melting point 202- 204 ° C (of methanol), d) From 6 - [[4- (4-hydroxy-3-methoxy-5-nitrophenyl) -2-thiazolyl] amino] -4 '- (trifluoromethyl) hexananilide there is obtained 6 - [[4 - (3,4-dihydroxy-5-nitrophenyl) -2-thiazolyl] amino> 4'-25 (trifluoromethyl) hexananilide, m.p. 214-216 ° C (of methanol), e) From 2- (4-hydroxy- 3-Methoxy-5-nitrobenzoyl) -3-methylindole gives 5-bromo-2- (3,4-dihydroxy-5-nitrobenzoyl) -3-methylindole, m.p. 265-267 ° C (of methanol), 30 f) from 2- (4-hydroxy-3-methoxy-5-nitrophenyl) quinoxaline is obtained 2- (3,4-dihydroxy-5-nitrophenyl) quinoxaline with melting point 241-243 ° C (of methanol) and g) From 6,7- dimethyl-2- (4-hydroxy-3-methoxy-5-nitrophenyl) -quinoxaline 6,7-dimethyl-2- (3,4-dihydroxy-5-nitrophenyl) quinoxaline, m.p. 274-276 ° C (of 35 methanol).

EKSEMPEL 21 35 DK 175069 B1EXAMPLE 21 35 DK 175069 B1

En blanding af 3,12 g 2-brom-3\4’-dihydroxy>i5faatøtiaphenon og 849,3 mg thioacetamid opvarmes til kogning i 40 ml ethanol i 18 timer under tilbagesvaling. Efter afkøling suges krystallerne fra og omkrystalliseres af methanol/isopropanol. Herved fis 5-(2-methyl-4-thiazolyl)-3'-nitropyrocatechol-hydrobromid med smeltepunkt 280-282°C.A mixture of 3.12 g of 2-bromo-3,4'-dihydroxy-5-phthalothaphenone and 849.3 mg of thioacetamide is heated to boiling in 40 ml of ethanol for 18 hours under reflux. After cooling, the crystals are filtered off with suction and recrystallized from methanol / isopropanol. This gives 5- (2-methyl-4-thiazolyl) -3'-nitropyrocatechol hydrobromide, m.p. 280-282 ° C.

5 EKSEMPEL 22EXAMPLE 22

En opløsning af 1,38 g 2-brom-3,,4,-dihydroxy-5,-nitroacetophenon og 461 mg 10 thiosemicarbazid i 20 ml n*butanol opvarmes til kogning i 60 minutter under tilbagesvaling. Efter afkøling til stuetemperatur suges krystallerne fra og omkrystalliseres af n-butanol. Herved fis 5-(2-amino-6H-l,3,4-thiadiazin-5-yl)-3-nitropyrocatechol-hydrobromid med smeltepunkt 265-267°C.A solution of 1.38 g of 2-bromo-3,4,4-dihydroxy-5,4-nitroacetophenone and 461 mg of thiosemicarbazide in 20 ml of n * butanol is heated to boiling for 60 minutes under reflux. After cooling to room temperature, the crystals are filtered off with suction and recrystallized from n-butanol. This gives 5- (2-amino-6H-1,3,4-thiadiazin-5-yl) -3-nitropyrocatechol hydrobromide, m.p. 265-267 ° C.

15 EKSEMPEL 23EXAMPLE 23

En opløsning af 1,38 g 2-brom-3‘,4'-dihydroxy-5'-nitroacetophenon og 505,7 mg 2-amino* 1,3,4-thiadiazol i 25 ml n-butanol opvarmes til kogning i 7 timer under tilbagesvaling.A solution of 1.38 g of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone and 505.7 mg of 2-amino * 1,3,4-thiadiazole in 25 ml of n-butanol is heated to boiling in 7 hours under reflux.

20 Derefter afkøles reaktionsblandingen til stuetemperatur, og de udskilte krystaller suges fra. Herved fis 5-(imidazo[2,l-bJ-l,3,4-thiadiazol-6-yl)-3-nitropyrocatechol med smeltepunkt 278-280°C (af methanol).The reaction mixture is then cooled to room temperature and the precipitated crystals are filtered off with suction. Hereby, 5- (imidazo [2,1-bJ-1,3,4-thiadiazol-6-yl) -3-nitropyrocatechol, m.p. 278-280 ° C (of methanol).

25 EKSEMPEL 24EXAMPLE 24

En blanding af 2,78 g 2-brom-3',4'-dihydroxy-5’-nitroacetophenon, 1,01 g 2-aminothiazol og 40 ml ethanol opvarmes til kogning i 23 timer under tilbagesvaling. Derefter afkøles reaktionsblandingen til stuetemperatur, og krystallerne suges fra. Herved fis 5-30 (imidazo[2,l-b)-thiadiazol-6-yl)-3-nitropyrocatechol-hydrobromid med smeltepunkt 286-288°C (af methanol).A mixture of 2.78 g of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone, 1.01 g of 2-aminothiazole and 40 ml of ethanol is heated to boiling for 23 hours under reflux. The reaction mixture is then cooled to room temperature and the crystals are filtered off with suction. Hereby, 5-30 (imidazo [2,1-b) -thiadiazol-6-yl) -3-nitropyrocatechol hydrobromide, m.p. 286-288 ° C (of methanol).

EKSEMPEL 25 35EXAMPLE 25 35

En blanding af 1,95 g 2-brom-3’,4'-dihydroxy-5'-nitroacetophenon, 1,06 g 2-aminobenzothiazol og 50 ml ethanol opvarmes til kogning i 17 timer under tilbagesvaling. Reaktionsblandingen afkøles derefter til stuetemperatur, hvorpå krystallerne suges fra.A mixture of 1.95 g of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone, 1.06 g of 2-aminobenzothiazole and 50 ml of ethanol is heated to boiling for 17 hours under reflux. The reaction mixture is then cooled to room temperature and the crystals are filtered off with suction.

UK. 1 09 D IUK. 1 09 D I

3636

Herved fås 5-(imidazo[2,l-b]benzothiazol-2-yl)-3-nitropyrocatechol med smeltepunkt 303-305°C (af Ν,Ν-dimethylformamid/methanol).This gives 5- (imidazo [2,1-b] benzothiazol-2-yl) -3-nitropyrocatechol, m.p. 303-305 ° C (of Ν, Ν-dimethylformamide / methanol).

5 EKSEMPEL 26EXAMPLE 26

En blanding af 2,78 g 2-brom-3',4,-dihydroxy-5’-nitroacetophenon, 1,51 g 2-aminothiophenol og 50 ml ethanol opvarmes til kogning i 1 time under tilbagesvaling. Reaktionsblandingen afkøles derefter til stuetemperatur, hvorpå krystallerne suges fra.A mixture of 2.78 g of 2-bromo-3 ', 4, -dihydroxy-5'-nitroacetophenone, 1.51 g of 2-aminothiophenol and 50 ml of ethanol is heated to boiling for 1 hour under reflux. The reaction mixture is then cooled to room temperature and the crystals are filtered off with suction.

10 Herved fås 5-(2H-l,4-benzothiazin-3-yl)-3-nitropyrocatechol med smeltepunkt 302-304°C (af N, N-dimethylfarmamid/methanol).This gives 5- (2H-1,4-benzothiazin-3-yl) -3-nitropyrocatechol, m.p. 302-304 ° C (of N, N-dimethylpharmamide / methanol).

EKSEMPEL 27 15EXAMPLE 27 15

En blanding af 987,5 mg 2-brom-3',4,-dihydroxy-5'-nitroacetophenon og 1,01 g 2-aminopyridin bringes til smeltning ved 110°C. Efter 30 minutter tilsættes der 15 ml ethanol og opvarmes til kogning i 3 timer under tilbagesvaling. Derefter afkøles reaktionsblandingen til stuetemperatur, og krystallerne suges fra. Herved fås 5-20 (imidazo[l,2-a]pyridin-3-yl)-3-nitropyrocatechol med smeltepunkt 250-252*0 (af Ν,Ν-dimethylformamid/methanol).A mixture of 987.5 mg of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone and 1.01 g of 2-aminopyridine is melted at 110 ° C. After 30 minutes, add 15 ml of ethanol and heat to boiling for 3 hours under reflux. The reaction mixture is then cooled to room temperature and the crystals are filtered off with suction. This gives 5-20 (imidazo [1,2-a] pyridin-3-yl) -3-nitropyrocatechol, m.p. 250-252 * 0 (of Ν, Ν-dimethylformamide / methanol).

EKSEMPEL 28 25 a) Til en opløsning af 10,7 g 4-hydroxy-3-methoxy-5-nitrobenzoesyre i 500 ml tørt tetrahydrofuran sættes der 8,9 g Ι,Γ-carbonyldiimidazol, hvorefter reaktionsblandingen opvarmes i 5 timer til 65-70*C. Derefter afkøles der til stuetemperatur og tildryppes i løbet af 15 minutter en opløsning af 21,6 g 6-aminohexyl-t-butylcarbamat i 50 ml tørt tetra- 30 hydrofuran. Derefter opvarmes reaktionsblandingen i 18 timer til 65-70°C og inddampes, og remanensen opslæmmes i acetylacetat og sugefiltreres, og det frafiltrerede materiale chromatograferes med acetone/methylenchlorid (3:1) på kieselgel. Herved fås (6-(4-hydroxy-5-nitro-m-anisamido)hexyl)-t-butylcarbamat med smeltepunkt 145-147°C (af isopropanol).EXAMPLE 28 a) To a solution of 10.7 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 500 ml of dry tetrahydrofuran is added 8.9 g of Ι, Γ-carbonyldiimidazole, after which the reaction mixture is heated for 5 hours to 65- 70 ° C. The mixture is then cooled to room temperature and a solution of 21.6 g of 6-aminohexyl t-butyl carbamate in 50 ml of dry tetrahydrofuran is added dropwise over 15 minutes. Then the reaction mixture is heated for 18 hours to 65-70 ° C and evaporated, and the residue is slurried in acetyl acetate and suction filtered and the filtered material is chromatographed with acetone / methylene chloride (3: 1) on silica gel. This gives (6- (4-hydroxy-5-nitro-m-anisamido) hexyl) -t-butylcarbamate, m.p. 145-147 ° C (of isopropanol).

35 b) Til en opløsning af 4,1 g [7-(4-hydroxy-5-nitro-m-anisamido)hexyl]-t-butylcarbamat i 80 ml iseddike sættes der ved stuetemperatur 5,8 ml brombrintesyre i iseddike (p/p33%).B) To a solution of 4.1 g of [7- (4-hydroxy-5-nitro-m-anisamido) hexyl] -t-butyl carbamate in 80 ml of glacial acetic acid is added at room temperature 5.8 ml of hydrobromic acid in glacial acetic acid (p / p33%).

Der omrøres i 2 timer, og de udfældede krystaller suges fra og vaskes med ether. Herved 37 DK 175069 B1 fis N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamid-hydrobromid med smeltepunkt 207-209°C (af isopropanol).Stir for 2 hours and the precipitated crystals are filtered off with suction and washed with ether. Hereby 37 DK 175069 B1 fis N- (6-aminohexyl) -4-hydroxy-5-nitro-m-anisamide hydrobromide, m.p. 207-209 ° C (of isopropanol).

c) Til en suspension af 392,3 mg N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamid-5 hydrobromid i 25 ml tørt methylenchlorid sættes der ved -20°C 1,25 g bortribromid. Efter tilsætningen omrøres der i 1 time ved -20°C og derefter i 17 timer ved stuetemperatur.c) To a suspension of 392.3 mg of N- (6-aminohexyl) -4-hydroxy-5-nitro-m-anisamide-5 hydrobromide in 25 ml of dry methylene chloride is added at -20 ° C 1.25 g of boron tribromide. After the addition, stir for 1 hour at -20 ° C and then for 17 hours at room temperature.

Derefter inddampes reaktionsblandingen, og remanensen tilsættes 10 mt vand og omrøres i 1 time ved stuetemperatur. Efter afdampning af vandet chromatograferes remanensen med toluen/ethanol (1:1) på Sephadex LH 20. Herved fås N-6-aminohexyl-3,4-dihydroxy-10 5-nitrobenzamid-hydrobromid med smeltepunkt 205-207°C (af ethanol).The reaction mixture is then evaporated and the residue is added with 10 ml of water and stirred for 1 hour at room temperature. After evaporation of the water, the residue is chromatographed with toluene / ethanol (1: 1) on Sephadex LH 20. This gives N-6-aminohexyl-3,4-dihydroxy-5 5-nitrobenzamide hydrobromide, m.p. 205-207 ° C (of ethanol). ).

EKSEMPEL 29 15 aa) En opløsning af 4,93 g 5-nitrovanillin og 2,7 g 1,2-phenylendiamin i 45 ml methanol og 15 nitrobenzen opvarmes til kogning under tilbagesvaling. Efter 15 minutter begynder der at fælde krystaller ud fra den røde opløsning. Efter 18 timer afkøles reaktionsblandingen til stuetemperatur og fortyndes med 60 ml methanol. Krystallerne suges fra og vaskes med methanol. Herved fås 4-(2-benzimidazolyl)-2-methoxy-6-20 nitrophenol med smeltepunkt 198-200°C (af N,N-dimethylformamid/methanol).EXAMPLE 29 15 aa) A solution of 4.93 g of 5-nitrovanillin and 2.7 g of 1,2-phenylenediamine in 45 ml of methanol and 15 nitrobenzene is heated to reflux. After 15 minutes, crystals begin to precipitate from the red solution. After 18 hours, the reaction mixture is cooled to room temperature and diluted with 60 ml of methanol. The crystals are sucked off and washed with methanol. This gives 4- (2-benzimidazolyl) -2-methoxy-6-20 nitrophenol, m.p. 198-200 ° C (of N, N-dimethylformamide / methanol).

Pa analog måde fås følgende: ab) Ud fra 5-nitrovanilin og 4,5-dichlor-l,2-phenylendiamin fås 4-(5,6-dichlor-2-25 benzimidazolyl)-2-methoxy-6-nitrophenol med smeltepunkt 258-260°C (af N,N-dimethylformamid/ether).In an analogous manner the following are obtained: ab) From 5-nitrovaniline and 4,5-dichloro-1,2-phenylenediamine 4- (5,6-dichloro-2-benzimidazolyl) -2-methoxy-6-nitrophenol with melting point is obtained 258-260 ° C (of N, N-dimethylformamide / ether).

b) En suspension af 860,1 mg 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol og 10 ml iseddike og 10 ml 48% brombrintesyre opvarmes til kogning under tilbagesvaling i 72 30 timer. Derefter inddampes der, og til remanensen sættes der 4 x 50 ml toluen, som hver gang destilleres af. Herved fås 5-(2-benzimidazolyl)-3-nitropyrocatechol med smeltepunkt >300°C (af acetone/vand).b) A suspension of 860.1 mg of 4- (2-benzimidazolyl) -2-methoxy-6-nitrophenol and 10 ml of glacial acetic acid and 10 ml of 48% hydrobromic acid is heated to reflux for 72 hours. Then evaporate and add to the residue 4 x 50 ml of toluene, which are distilled off each time. This gives 5- (2-benzimidazolyl) -3-nitropyrocatechol with a melting point> 300 ° C (of acetone / water).

På analog måde fås følgende: 35 c) Af 4-(5,6-dichlor-2-benzimidazolyi)-2-methoxy-6-nitrophenol fås 5-(5,6-dichlor-2-benzimidazolyl)-3-nitropyrocatechol med smeltepunkt 282-284°C (af acetone/vand).In an analogous manner the following is obtained: c) Of 4- (5,6-dichloro-2-benzimidazolyl) -2-methoxy-6-nitrophenol, 5- (5,6-dichloro-2-benzimidazolyl) -3-nitropyrocatechol is obtained with mp 282-284 ° C (of acetone / water).

EKSEMPEL 30 UK 175069 Bl 38EXAMPLE 30 UK 175069 Bl 38

Til en suspension af 29,0 g 2-brom-4'-hydroxy-3’-methoxy-5‘-nitroacetophenon i 700 ml tørt methylenchlorid sættes der ved -20eC og i løbet af 30 minutter en opløsning af 5 125,3 mg bortribromid i 300 ml tørt methylenchlorid. Efter tilsætningen omrøres der i endnu en time ved -20°C og 16 timer ved stuetemperatur, hvorefter der inddampes, og der til remanensen under isafkøling forsigtigt tilsættes vand og omrøres i 30 minutter ved 50°C. Efter afkøling ekstraheres der med ether, og den etheriske fase vaskes med vand, tørres over natriumsulfat, filtreres og inddampes. Herved fås 2-brom-3',4'-dihydroxy-5'-10 nitroacetophenon med smeltepunkt 138-140°C (af methylenchlorid).To a suspension of 29.0 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 700 ml of dry methylene chloride is added at -20 ° C and over 30 minutes a solution of 5 125.3 mg boron tribromide in 300 ml of dry methylene chloride. After the addition, stir for a further hour at -20 ° C and 16 hours at room temperature, then evaporate and carefully add water to the residue under ice-cooling and stir for 30 minutes at 50 ° C. After cooling, it is extracted with ether and the ether phase is washed with water, dried over sodium sulphate, filtered and evaporated. This gives 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone, m.p. 138-140 ° C (of methylene chloride).

i EKSEMPEL 31 15 a) En opløsning af 3,6 g 3,4-dihydroxy-5-nitrophenylglyoxylsyreethylester i 30 ml eddikesyreanhydrid opvarmes i 30 minutter ved 110eC i nærværelse af en katalytisk mængde koncentreret svovlsyre og afkøles derefter til stuetemperatur, og reaktionsblandingen hældes ud i 150 ml vand og omrøres i 60 minutter. Der ekstraheres med ether og vaskes med natriumchloridopløsning, og de forenede organiske ekstrakter 20 tørres over natriumsulfat, filtreres og inddampes. Herved fås 3,4-diacetoxy-5-nitrophenylglyoxylsyre med smeltepunkt 87-89°C (af ether/petroleumsether).in EXAMPLE 31 a) A solution of 3.6 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid ethyl ester in 30 ml of acetic anhydride is heated for 30 minutes at 110 ° C in the presence of a catalytic amount of concentrated sulfuric acid and then cooled to room temperature and the reaction mixture is poured. in 150 ml of water and stir for 60 minutes. It is extracted with ether and washed with sodium chloride solution, and the combined organic extracts are dried over sodium sulfate, filtered and evaporated. This gives 3,4-diacetoxy-5-nitrophenylglyoxylic acid, m.p. 87-89 ° C (of ether / petroleum ether).

På analog måde fås følgende: 25 b) ud fra 3-(3,4-dihydroxy-5*nitrophenyt)-2H-l,4~benzoxazin-2-on fås 3-(3,4-diacetoxy- 5-nitrophenyl)-2H-l,4-benzoxazin-2-on med smeltepunkt 186-188°C (af methylench lorid/methanol), c) Ud fra 3-(3,4-dihydroxy-5-nitrophenyl)*2(lH)-chinoxalinon fås 3-(3,4-diacetoxy-5-30 nitrophenyl)-2(lH)-chinoxalinon med smeltepunkt 241-243°C (af methylenchlorid/methanol), d) ud fra 3,4-dihydroxy-5-nitrobenzophenon fås 3,4-diacetoxy-5-nitrobenzophenon med smeltepunkt 141-143°C (af methylenchlorid/ether).In an analogous manner the following is obtained: b) from 3- (3,4-dihydroxy-5 * nitrophenyl) -2H-1,4-benzoxazin-2-one gives 3- (3,4-diacetoxy-5-nitrophenyl) -2H-1,4-benzoxazin-2-one, m.p. 186-188 ° C (of methylene chloride / methanol), c) From 3- (3,4-dihydroxy-5-nitrophenyl) * 2 (1H) - quinoxalinone is obtained from 3- (3,4-diacetoxy-5-30 nitrophenyl) -2 (1H) -quinoxalinone, m.p. 241-243 ° C (of methylene chloride / methanol), d) from 3,4-dihydroxy-5-nitrobenzophenone 3,4-diacetoxy-5-nitrobenzophenone with melting point 141-143 ° C (of methylene chloride / ether) is obtained.

35 e) ud fra 2’-fluor*3,4-dihydroxy-5-nitrobenzophenon fås 3,4-diacetoxy-2'-fluor-5-nitrobenzophenon med smeltepunkt 122-124QC (af ether) og 39 DK 175069 B1 f) af 3,4-dihydroxy-5-nitrophenyi-4-pyridylketon fås 3,4-diacetoxy-5-nitrophenyl-4-pyridyfketon med smeltepunkt 148-150°C (af methylenchlorid/ether).35 e) from 2'-fluoro * 3,4-dihydroxy-5-nitrobenzophenone there is obtained 3,4-diacetoxy-2'-fluoro-5-nitrobenzophenone, m.p. 122 DEG-124 DEG C. (of ether) and 39 DK 175069 B1 f) of 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone, 3,4-diacetoxy-5-nitrophenyl-4-pyridyl ketone with a melting point of 148-150 ° C (of methylene chloride / ether) is obtained.

5 EKSEMPEL 32 a) En opløsning af 2,0 g 3,5-dinitropyrocatechol i 25 ml propionsyreanhydrid opvarmes i 18 timer ved 110°C i nærværelse af en katalytisk mængde koncentreret svovlsyre, det overskydende anhydrid destilleres af ved 70eC i højvacuum (1,33 Pa), og remanensen 10 opløses i methylenchlorid, vaskes med vand, tørres over natriumsulfat, filtreres og inddampes. Herved fås l,2-dipropionyloxy-3,5-dinitrobenzen med smeltepunkt 74-76“C (af methylenchlorid/petroleumsether).EXAMPLE 32 a) A solution of 2.0 g of 3,5-dinitropyrocatechol in 25 ml of propionic anhydride is heated for 18 hours at 110 ° C in the presence of a catalytic amount of concentrated sulfuric acid, the excess anhydride is distilled off at 70 ° C in high vacuum (1, 33 Pa) and the residue 10 is dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. This gives 1,2-dipropionyloxy-3,5-dinitrobenzene, m.p. 74-76 ° C (of methylene chloride / petroleum ether).

På analog måde fås følgende: 15 b) Ud fra 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-on fås 3-(3,4- dipropionyloxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-on med smeltepunkt 158-160°C (af methylenchlorid), 20 c) udfra 6-chlor-3-(3,4-dihydroxy-5-nitrophenyl)-2H-l,4-benzoxazin-2-on fås 5-(6-chlor-2-oxo-2H-l,4-benzoxazin-3-yl)-3-nitro-o-phenylen-dipropionat med smeltepunkt 148-l50eC (af methylenchlorid/ether), d) ud fra 3-(3,4-dihydroxy-5-nitrophenyl)-7-nitro-2H-l,4-benzoxazin-2-on fås 3-nitro-5-25 (7-nitro-2-oxo-2H-l,4-benzbxazin-3-yl)-0-phenylen-dipropionat med smeltepunkt 177- 179°C (af methanol), e) af 3-(3,4-dihydroxy-5-nitrophenyl)-2-oxo-2H-l,4-benzoxazin-6-carbonsyre fås 3-[3,4-bis(propionyloxy)-5-nitrophenyl]-2-oxo-2H-l,4-benzoxazin-6-carbonsyre med 30 smeltepunkt 192-194°C (af methylenchlorid), f) ud fra 3-nitro-5-(2-chinoxalinyl)pyrocatechol fås 3-nitro-5-(2-chinoxalinyl-0-phenylen-dipropionat med smeltepunkt 152-154°C (af methylenchlorid/ether), 35 g) ud fra 5-(2-benzimidazolyl-3-nitropyrocatechol fås 5-(2-benzimidazolyl)-3-nitro-o-phenylen-dipropionat med smeltepunkt 179-181°C (af ether), UK 1 /bUby bl 40 h) ud fra 6,7-dichlor-3-(3,4-dihydroxy-5-nitrophenyl)-2(lH)-chlnoxalinon fås 5-(6,7-dichlor-3,4-dihydro-3-oxo-2-Chinoxalinyl)-3-nitro-o-phenylen-dipropionat med smeltepunkt 260-262eC (af methylenchlorid), 5 i) ud fra 5-brom-2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methyMndol fas 5-brom-2-{3,4-dipropionyloxy-5-nitrobenzoyl)-3-methylindol med smeltepunkt 196-198°C (af ether) og j) ud fra 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-l,2,4-triazin-5(4H)-on fås 3-nitro'5-(2,3,4,5-tetrahydro-5-oxo-3-thioxo-as-triazin-6-yl)-o-phenylen-dipropionat med 10 smeltepunkt 237-239°C (af ether).In an analogous manner the following is obtained: b) From 3- (3,4-dihydroxy-5-nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one there is obtained 3- (3,4-dipropionyloxy- 5-nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one, m.p. 158-160 ° C (of methylene chloride), 20 c) from 6-chloro-3- (3,4-dihydroxy-5 -nitrophenyl) -2H-1,4-benzoxazin-2-one gives 5- (6-chloro-2-oxo-2H-1,4-benzoxazin-3-yl) -3-nitro-o-phenylene dipropionate with mp 148-150 ° C (of methylene chloride / ether), d) from 3- (3,4-dihydroxy-5-nitrophenyl) -7-nitro-2H-1,4-benzoxazin-2-one 3-nitro-5 -25 (7-nitro-2-oxo-2H-1,4-benzoxazin-3-yl) -O-phenylene dipropionate, m.p. 177-179 ° C (of methanol), e) of 3- (3.4 -dihydroxy-5-nitrophenyl) -2-oxo-2H-1,4-benzoxazine-6-carboxylic acid obtain 3- [3,4-bis (propionyloxy) -5-nitrophenyl] -2-oxo-2H-1,4 -benzoxazine-6-carbonic acid with melting point 192-194 ° C (of methylene chloride), f) from 3-nitro-5- (2-quinoxalinyl) pyrocatechol 3-nitro-5- (2-quinoxalinyl-O-phenylene -dipropionate with melting point 152-154 ° C (of methylene chloride / ether), 35 g) from 5- (2-Benzimidazolyl-3-nitropyrocatechol 5- (2-benzimidazolyl) -3-nitro-o-phenylene dipropionate with melting point 179-181 ° C (of ether), UK 1 / buby bl 40 h) from 6,7-dichloro-3- (3,4-dihydroxy-5-nitrophenyl) -2 (1H) -quinoxalinone there is obtained 5- (6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl ) -3-nitro-o-phenylene dipropionate with melting point 260-262 ° C (of methylene chloride), 5 i) from 5-bromo-2- (3,4-dihydroxy-5-nitrobenzoyl) -3-methylindole phase 5- bromo-2- (3,4-dipropionyloxy-5-nitrobenzoyl) -3-methylindole, m.p. 196-198 ° C (of ether) and j) from 6- (3,4-dihydroxy-5-nitrophenyl) -3 -mercapto-1,2,4-triazin-5 (4H) -one is obtained 3-nitro-5- (2,3,4,5-tetrahydro-5-oxo-3-thioxo-as-triazin-6-yl ) -o-phenylene dipropionate with melting point 237-239 ° C (of ether).

EKSEMPEL 33 15 a) En opløsning af 1,09 g 3,4-dihydroxy-5-nitrophenylglyoxylsyreethylester i 6 ml isosmørsyreanhydrid opvarmes i 17 timer ved 110eC i nærværelse af en katalytisk mængde koncentreret svovlsyre. Derefter sættes der til reaktionsblandingen 10 x 10 ml toluen, idet der hver gang inddampes ved 80°C og 18,7 mbar. Der olieagtige remanens destilleres i kuglerør ved 175-180“C og 8,0 Pa. Herved fås 3,4-diisobutyryloxy-5-20 mtrophenylglyoxylsyreethylester.EXAMPLE 33 a) A solution of 1.09 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid ethyl ester in 6 ml of isobutyric anhydride is heated for 17 hours at 110 ° C in the presence of a catalytic amount of concentrated sulfuric acid. Then 10 x 10 ml of toluene are added to the reaction mixture, each time evaporating at 80 ° C and 18.7 mbar. The oily residue is distilled in ball tubes at 175-180 ° C and 8.0 Pa. This gives 3,4-diisobutyryloxy-5-20 methrophenylglyoxylic acid ethyl ester.

På analog måde fås følgende: b) Ud fra 3,5-dinitropyrocatechol fås l,2-diisobutyryloxy-3,5-dinitrobenzen med 25 smeltepunkt 78-80°C (af ether), c) ud fra 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-on fås 3-(3,4-diisobutyryloxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-on med smeltepunkt 142-144°C (af ether), 30 d) ud fra 2-(3,4-dihydroxy-5-nitrophenyl)chinoxalin fås 2-(3,4-diisobutyryloxy-5-nitropheny!)chinoxalin med smeltepunkt 155-I57°c (af ether), e) ud fra l-methyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(lH)-chinoxalinon fås l-methyl-3-35 (3,4-diisobutyryloxy-5-nitrophenyl)-2(lH-chinoxafinon med smeltepunkt 138-148CC (af ether), 41 DK 175069 B1 f) ud fra 5-(imidazo[2,l-b]-l,3,4-thiadiazol-6-yl)-3*nitropyrocatechol fås 5* (imidazo[2,l-b]-l,3,4-thiadiazol-6-yl)-3-nitro-o*phenylen-diisobutyrat med smeltepunkt 169-171°C (af methylenchlorid), 5 g) af 2-brom-3’,4'-dihydroxy-5'-nitroacetophenon fås 5-(bromacetyl)-3-nitro-o-phenylen-diisobutyrat med smeltepunkt 56-58°C (af methylenchlorid/hexan), h) Ud fra 5-(2-amino-4-thiazolyl)-3-nitropyrocatechol*hydrobromid fås 3-nitro-5-(2-isobutyramido-4-thiazolyl)-o-phenylen-diisobutyrat med smeltepunkt 157-159°C (af 10 methylenchlorid/ether), i) Ud fra 5-(2-3ηηίηο-6Η-1,3,4-υΊΪ3άΐ3Ζϊη-5-γΙ)-3-ηίΐΓορνΓοε3ί€θΗοΙ-Ι^Γθ^οηΓ^ fås 3-nitro-5-(2-isobutyramido-4-isobutyryl-l,3,4-thiadiazin-5-yl)-o-phenylen-diisobutyrat med smeltepunkt 177-179°C (af ether), 15 j) Ud fra 3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-l,4-benzoxazin-2-on fås 3-nitro- 5-(2-oxo-6-propyl-2H-l,4-benzoxazin-3-yl)*o-phenylen-diisobutyrat med smeltepunkt 13T133°C (af methanol), 20 k) ud fra 5-(imidazo[l,2-a]pyridin-3-yl)-3-nitropyrocatechol fås 5-(imidazo[l,2- a] pyridin-3-yl)-3-mtro-o-phenylen-diisobutyrat med smeltepunkt 137-139°C (af ether), l) ud fra 5-(imidazo[2,l-b]benzothiazol-2-yl)-3-nitropyrocatechol fås 5-(imidazo[2,l- b] benzothiazol-2-yl)-3-nitro-o-phenylen-diisobutyrat med smeltepunkt 197-199°C (af 25 methylenchlorid/ether) og m) ud fra 3,4-dihydroxy-5-nitrophenyl-2-pyridylketon-hydrobromid fås 3-nitro-5-(2-pyridylcarbonyl)-o-phenylen-diisobutyrat med smeltepunkt 83-85°C (af ether/hexan).In an analogous manner the following are obtained: b) From 3,5-dinitropyrocatechol there is obtained 1,2-diisobutyryloxy-3,5-dinitrobenzene with melting point 78-80 ° C (of ether), c) from 3- (3,4 -dihydroxy-5-nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one obtain 3- (3,4-diisobutyryloxy-5-nitrophenyl) -6-methyl-2H-1,4-benzoxazine- 2-one with melting point 142-144 ° C (of ether), 30 d) from 2- (3,4-dihydroxy-5-nitrophenyl) quinoxaline is obtained 2- (3,4-diisobutyryloxy-5-nitrophenyl) quinoxaline with melting point 155 DEG-157 DEG C. (of ether), e) from 1-methyl-3- (3,4-dihydroxy-5-nitrophenyl) -2 (1H) -quinoxalinone there is obtained 1-methyl-3-35 (3 , 4-diisobutyryloxy-5-nitrophenyl) -2 (1H-quinoxafinone, m.p. 138 DEG-148 DEG C. (of ether), 41 DK 175069 B1 f) from 5- (imidazo [2,1b] -1,3,4-thiadiazole -6-yl) -3 * nitropyrocatechol gives 5 * (imidazo [2,1b] -1,3,4-thiadiazol-6-yl) -3-nitro-o * phenylene diisobutyrate, m.p. 169-171 ° C ( of methylene chloride), 5 g) of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone obtain 5- (bromoacetyl) -3-nitro-o-phenylene diisobutyrate with melting point 56-58 ° C (of me thylene chloride / hexane), h) From 5- (2-amino-4-thiazolyl) -3-nitropyrocatechol * hydrobromide 3-nitro-5- (2-isobutyramido-4-thiazolyl) -o-phenylene diisobutyrate with melting point is obtained 157-159 ° C (of 10 methylene chloride / ether), i) From 5- (2-3ηηίηο-6Η-1,3,4-υΊΪ3άΐ3Ζϊη-5-γΙ) -3-ηίΐΓορνΓοε3ί € θΗοΙ-Ι ^ Γθ ^ οηΓ 3-Nitro-5- (2-isobutyramido-4-isobutyryl-1,3,4-thiadiazin-5-yl) -o-phenylene diisobutyrate, m.p. 177-179 ° C (of ether), 15 g) From 3- (3,4-dihydroxy-5-nitrophenyl) -6-propyl-2H-1,4-benzoxazin-2-one, 3-nitro-5- (2-oxo-6-propyl-2H-1) is obtained , 4-benzoxazin-3-yl) * o-phenylene diisobutyrate, m.p. 13 DEG-133 DEG C. (of methanol), 20 k) from 5- (imidazo [1,2-a] pyridin-3-yl) -3- nitropyrocatechol is obtained 5- (imidazo [1,2-a] pyridin-3-yl) -3-nitro-o-phenylene diisobutyrate, m.p. 137-139 ° C (of ether), 1) from 5- (imidazo [ 2,1b] benzothiazol-2-yl) -3-nitropyrocatechol gives 5- (imidazo [2,1-b] benzothiazol-2-yl) -3-nitro-o-phenylene diisobutyrate, m.p. 197-199 ° C ( of methylene chloride / ether) and m) from 3,4-d Hydroxy-5-nitrophenyl-2-pyridyl ketone hydrobromide gives 3-nitro-5- (2-pyridylcarbonyl) -o-phenylene diisobutyrate, m.p. 83-85 ° C (of ether / hexane).

30 EKSEMPEL 34 a) En opløsning af 613,0 mg 3,4-dihydroxy-5-nitrophenylglyoxylsyreethylester i 4 ml pivaloylsyreanhydrid opvarmes i 17 timer ved 100°C i nærværelse af en katalytisk 35 mængde koncentreret svovlsyre, og den afkølede opløsning tilsættes ether, vaskes med mættet natriumchloridopløsning, tørres over natriumsulfat, filtreres og inddampes. Til remanensen sættes 10 x 10 ml toluen, idet der hver gang inddampes. Efter kuglerørsdestillation (luftbad) ved 175-180°C og 4,0 Pa fås 3,4-dipivaloyloxy-5-nitrophenylglyoxylsyreethylester.EXAMPLE 34 a) A solution of 613.0 mg of 3,4-dihydroxy-5-nitrophenylglyoxylic acid ethyl ester in 4 ml of pivaloylic acid anhydride is heated for 17 hours at 100 ° C in the presence of a catalytic amount of concentrated sulfuric acid, and the cooled solution is added ether, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. To the residue is added 10 x 10 ml of toluene, evaporating each time. After ball tube distillation (air bath) at 175-180 ° C and 4.0 Pa, 3,4-dipivaloyloxy-5-nitrophenylglyoxylic acid ethyl ester is obtained.

UK Ί /ouoy Dl 42 p! analog mide fis følgende: b) Ud fra 3-(3,4-Dihydroxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-on fås 3-(3,4-5 dipivaloyloxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-on med smeltepunkt 180- 182°C (af ether), c) ud fra 3,4-dihydroxy-5-nitrobenzophenon fis 3,4-dipivaloyloxy-5-nitrobenzophenon med smeltepunkt 101-103°C (af t-butylmethylether) og 10 d) ud fra 2'-fluor-3,4-dihydroxy-5-nitrobenzophenon fås 3,4-dipivaloyloxy-2‘-fluorbenzophenon med smeltepunkt 74-76° (af petroleumsether ts.)· 15 EKSEMPEL 35UK Ί / ouoy Dl 42 p! analogous to the following: b) From 3- (3,4-Dihydroxy-5-nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one obtain 3- (3,4-5 dipivaloyloxy-5 -nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one, m.p. 180-182 ° C (of ether), c) from 3,4-dihydroxy-5-nitrobenzophenone fis 3,4-dipivaloyloxy -5-nitrobenzophenone with melting point 101-103 ° C (of t-butyl methyl ether) and 10 d) from 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone there is obtained 3,4-dipivaloyloxy-2'-fluorobenzophenone with melting point 74-76 ° (of petroleum ether ts.) · EXAMPLE 35

En opløsning af 1,7 g 3-(3,4-dihydroxy-5-nitropheny))-2(lH)-chmoxalinon i 17 ml n-heptansyreanhydrid opvarmes i 17 timer ved 110°C i nærværelse af en katalyseret mængde koncentreret svovlsyre, hvorefter det overskydende anhydrid destilleres af i 20 højvacuum, remanensen opløses i methylenchlorid, og den organiske opløsning vaskes med vand, tørres over natriumsulfat, filtreres og inddampes. Herved fås 5-(l,2-dihydro-2-oxo-3-chinoxaliny!)-3-nitro-o-phenylen-diheptanoat med smeltepunkt 186-188°C (af methy lenchlorid/ether).A solution of 1.7 g of 3- (3,4-dihydroxy-5-nitrophenyl)) - 2 (1H) -moxalinone in 17 ml of n-heptanoic anhydride is heated for 17 hours at 110 ° C in the presence of a catalyzed amount of concentrated sulfuric acid. , the excess anhydride is distilled off in a high vacuum, the residue is dissolved in methylene chloride and the organic solution is washed with water, dried over sodium sulphate, filtered and evaporated. This gives 5- (1,2-dihydro-2-oxo-3-quinoxaline) -3-nitro-o-phenylene diheptanoate, m.p. 186-188 ° C (of methylene chloride / ether).

25 EKSEMPEL 36 a) Til en opløsning af 1,35 g 2-bromo-3’,4'-dihydroxy-5,-nitroacetophenon i 25 ml alkohol sættes der 1,26 g natriumacetat og opvarmes til kogning under tilbagesvaling.EXAMPLE 36 a) To a solution of 1.35 g of 2-bromo-3 ', 4'-dihydroxy-5, -nitroacetophenone in 25 ml of alcohol is added 1.26 g of sodium acetate and heated to reflux.

30 Efter 6 timer filtreres reaktionsblandingen for udfældet natriumbromid og inddampes.After 6 hours, the reaction mixture is filtered for precipitated sodium bromide and evaporated.

Remanensen opløses i ethylacetat. Der vaskes med mættet kogsaltopløsning, tørres over natriumsulfat, filtreres og inddampes ved 50°C. Herved fis (3,4-dihydroxy-5-nitrobenzoyl)methylacetat med smeltepunkt 166-168°C (af ethylacetat/ether).The residue is dissolved in ethyl acetate. Wash with saturated brine, dry over sodium sulfate, filter and evaporate at 50 ° C. Hereby fis (3,4-dihydroxy-5-nitrobenzoyl) methyl acetate, m.p. 166-168 ° C (of ethyl acetate / ether).

35 Pa analog måde fås følgende: b) Ud fra 2-brom-3’,4'-dihydroxy-5,-nitroacetophenon og natriumisobutyrat fås (3,4-dihydroxy-5-nitrobenzoyl)methylisobutyrat med smeltepunkt 120-122°C (ethylacetat/ether), og 43 DK 175069 B1 c) ud fra 2-brom-3’/4'-dihydroxy-5,-nitroacetophenon og 3,4-dihydroxy-5-nitrophenylglyoxylsyre-natriumsalt fis 3,4-dihydroxy-5-nitrophenacyl (3,4-dihydroxy-5-nitrobenzoyl)-formiat med smeltepunkt 224-226°C (af methanol/ethylacetat).In an analogous manner the following are obtained: b) From 2-bromo-3 ', 4'-dihydroxy-5, -nitroacetophenone and sodium isobutyrate are obtained (3,4-dihydroxy-5-nitrobenzoyl) methyl isobutyrate with melting point 120-122 ° C ( ethyl acetate / ether), and 43) from 2-bromo-3 '/ 4'-dihydroxy-5, -nitroacetophenone and 3,4-dihydroxy-5-nitrophenylglyoxylic acid sodium salt fis 3,4-dihydroxy-5 -nitrophenacyl (3,4-dihydroxy-5-nitrobenzoyl) -formate, m.p. 224-226 ° C (of methanol / ethyl acetate).

5 EKSEMPEL 37EXAMPLE 37

Til en suspension af 2,91 g 2-brom-3',4,-dihydroxy-5'-nitroacetophenon sættes der 1,31 g 10 thionicotinamid i 50 ml alkohol og opvarmes til kogning i 2 timer under tilbagesvaling.To a suspension of 2.91 g of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone is added 1.31 g of 10 thionicotinamide in 50 ml of alcohol and heated to reflux for 2 hours.

Efter afkøling til stuetemperatur suges krystallerne fra og omkrystalliseres af N,N-dime-thylformamid/alkohol. Herved fås 3-nitro-5-[2-(3-pyridyl)-4-thiazolyl]pyrocatechol med smeltepunkt 279-281°C.After cooling to room temperature, the crystals are filtered off with suction and recrystallized from N, N-dimethylformamide / alcohol. This gives 3-nitro-5- [2- (3-pyridyl) -4-thiazolyl] pyrocatechol, m.p. 279-281 ° C.

15 EKSEMPEL 38EXAMPLE 38

En opløsning af 5,52 g 2-brom-3',4'-dihydroxy-5’-nitroacetophenon og 2,7 g 2-aminoacetophenon i 100 ml tørt Ν,Ν-dimethylformamid omrøres i 24 timer ved 90°C. Reaktionsblandingen inddampes, og remanensen opløses i ethylacetat, vaskes med vand, 20 tørres over natriumsulfat, filtreres og inddampes. Herved fås 2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindol med smeltepunkt 212-214°C (af n-butanol).A solution of 5.52 g of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone and 2.7 g of 2-aminoacetophenone in 100 ml of dry Ν, Ν-dimethylformamide is stirred for 24 hours at 90 ° C. The reaction mixture is evaporated and the residue is dissolved in ethyl acetate, washed with water, dried over sodium sulphate, filtered and evaporated. This gives 2- (3,4-dihydroxy-5-nitrobenzoyl) -3-methylindole, m.p. 212-214 ° C (of n-butanol).

EKSEMPEL 39 25EXAMPLE 39 25

Til en suspension af 7,32 g 2-brom-3',4,-dihydroxy-5,-nitroacetophenon sættes der 4,06 g l-(3-pyridinyl)-2-thiourinstof i 100 ml n-butanol og opvarmes til kogning i 3 timer under tilbagesvaling. Efter afkøling til stuetemperatur suges krystallerne fra og omkrystalliseres af n-butanol. Herved fås 3-nitro-5-[2-(3-pyridylamino)-4-thiazdlyl]pyrocatechol-30 hydrobromid med smeltepunkt >300°C.To a suspension of 7.32 g of 2-bromo-3 ', 4, -dihydroxy-5, -nitroacetophenone is added 4.06 g of 1- (3-pyridinyl) -2-thiourea in 100 ml of n-butanol and heated to cook for 3 hours under reflux. After cooling to room temperature, the crystals are filtered off with suction and recrystallized from n-butanol. There is obtained 3-nitro-5- [2- (3-pyridylamino) -4-thiazidyl] pyrocatechol hydrobromide, m.p.> 300 ° C.

EKSEMPEL 40 35 Til en suspension af 6,35 g 2-brom-3,,4'-dihydroxy-5'-nitroacetophenon sættes der 4,68 g l-(3-chinolinyl)-2-thiourinstof i 150 ml n-butanol og opvarmes til kogning i 3 timer under tilbagesvaling. Efter afkøling til stuetemperatur suges krystallerne fra og omkrystalliseres sig af n-butanol. Herved fås 3-nitro-5-[2-(3-chinolinylamino)-4-thiazolyl]pyrocatechol-hydrobromid med smeltepunkt >300°C.EXAMPLE 40 35 To a suspension of 6.35 g of 2-bromo-3,4'-dihydroxy-5'-nitroacetophenone is added 4.68 g of 1- (3-quinolinyl) -2-thiourea in 150 ml of n-butanol and heated to boiling for 3 hours under reflux. After cooling to room temperature, the crystals are filtered off with suction and recrystallized from n-butanol. This gives 3-nitro-5- [2- (3-quinolinylamino) -4-thiazolyl] pyrocatechol hydrobromide, m.p.> 300 ° C.

EKSEMPEL 41 UIV I /3UD9 D I 44 5 Til en suspension af 8,28 g 2-brom-3',4’-dihydroxy-5'-nitroacetophenon sættes der 6,37 g rac-l-(2-exo-bornyl)-2-thiourinstof i 100 ml n-butanol og opvarmes til kogning i 3 timer under tilbagesvaling. Efter afkøling til stuetemperatur suges krystallerne fra og omkrystalliseres sig af n-butanol. Herved fås rac-3-nitro-5-[2-(2-exo-bornylamino)-4-thiazolyl]pyrocatechol-hydrobromid med smeltepunkt >262-264°C.EXAMPLE 41 UIV I / 3UD9 DI 44 5 To a suspension of 8.28 g of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone is added 6.37 g of rac-1- (2-exo-bornyl) -2-thiourea in 100 ml of n-butanol and heat to boiling for 3 hours under reflux. After cooling to room temperature, the crystals are filtered off with suction and recrystallized from n-butanol. This gives rac-3-nitro-5- [2- (2-exo-bornylamino) -4-thiazolyl] pyrocatechol hydrobromide, m.p.> 262-264 ° C.

10 EKSEMPEL 42EXAMPLE 42

Til 0,875 ml pyrrolidin i 35 ml tetrahydrofuran ved 5°C sættes der 0,605 ml eddikesyre og derefter 1,73 g 3,4-dihydroxy-5-nitrobenzaldehyd og 2,87 g 6-oxo-4‘-15 (trifluormethyl)heptananilid og omrøres i 56 timer under argon ved 23°C. Den efter inddampning af reaktionsblandingen vundne remanens deles mellem ethylacetat og IN natriumhydroxidopløsning. De forenede natriumhydroxidekstrakter gøres sure ved hjælp af koncentreret saltsyre og ekstraheres med ethylacetat, og de forenede ethylacetatekstrakter vaskes med mættet kogsaltopløsning, tørres over natriumsulfat og 20 inddampes, og remanensen chromatograferes på 120 g silicagel med methylenchlorid/methanol (91:9). Efter omkrystallisering af ethylacetat/petroleumsether fås (E)-8-(3,4-dihydroxy-5-nitrophenyl)-6-oxo-4’-(trifluormethyl)-7-octenanilid med smeltepunkt 194-197°C.To 0.875 ml of pyrrolidine in 35 ml of tetrahydrofuran at 5 ° C is added 0.605 ml of acetic acid and then 1.73 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.87 g of 6-oxo-4'-15 (trifluoromethyl) heptananilide and Stir for 56 hours under argon at 23 ° C. The residue obtained after evaporation of the reaction mixture is partitioned between ethyl acetate and 1N sodium hydroxide solution. The combined sodium hydroxide extracts are acidified with concentrated hydrochloric acid and extracted with ethyl acetate, and the combined ethyl acetate extracts are washed with saturated brine, dried over sodium sulphate and evaporated and the residue is chromatographed on 120 g of silica gel with methylene chloride (91: 9 methylene chloride). After recrystallization from ethyl acetate / petroleum ether, (E) -8- (3,4-dihydroxy-5-nitrophenyl) -6-oxo-4 '- (trifluoromethyl) -7-octenanilide, m.p. 194-197 ° C is obtained.

25 EKSEMPEL 43 a) 26,0 g 2-chlor-3-hydroxy-p-anisaldehyd opløses i 400 ml eddikesyreanhydrid og 5 ml pyridin. Der omrøres i 8 timer ved 80eC, hvorefter reaktionsblandingen inddampes, 30 remanensen deles mellem isvand og methylenchlorid, den organiske fase tørres over natriumsulfat og inddampes, og remanensen omkrystalliseres af methylenchlorid/petrole-umsether. Herved fås 2-chlor-3-formyl-6-methoxyphenyl-acetat med smeltepunkt 48-50°C.EXAMPLE 43 a) 26.0 g of 2-chloro-3-hydroxy-p-anisaldehyde are dissolved in 400 ml of acetic anhydride and 5 ml of pyridine. The mixture is stirred for 8 hours at 80 DEG C., after which the reaction mixture is evaporated, the residue is partitioned between ice water and methylene chloride, the organic phase is dried over sodium sulphate and evaporated and the residue is recrystallized from methylene chloride / petroleum ether. This gives 2-chloro-3-formyl-6-methoxyphenyl acetate, m.p. 48-50 ° C.

35 b) 38 g 2-chlor-3-formyl-6-methoxyphenyl-acetat sættes portionsvis i løbet af 15 minutter til 150 ml 98% saltpetersyre ved mellem -5eC og -10“C. Efter 30 minutters omrøring ved -5°C hældes reaktionsblandingen ud i 1,5 I isvand og ekstraheres med 3 x 500 ml methylenchlorid. De forenede organiske faser vaskes med isvand, tørres over natriumsulfat og inddampes. Remanensen krystalliseres af ether, herved fås 2-chlor-3- 45 DK 175069 B1 formyl-6-methoxy-5-nitrophenyl-acetat med smeltepunkt 84-85eC.35 b) 38 g of 2-chloro-3-formyl-6-methoxyphenyl acetate are added portionwise over 15 minutes to 150 ml of 98% nitric acid at between -5 ° C and -10 ° C. After stirring for 30 minutes at -5 ° C, the reaction mixture is poured into 1.5 l of ice water and extracted with methylene chloride (3 x 500 ml). The combined organic phases are washed with ice water, dried over sodium sulfate and evaporated. The residue is crystallized from ether to give 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate, m.p. 84-85 ° C.

c) 35,8 g 2-chlor-3-formyl-6-methoxy-5-nitrophenyl-acetat opløses i 300 ml methanol.c) 35.8 g of 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate are dissolved in 300 ml of methanol.

Efter tilsætning af 145 ml IN natriumhydroxidopløsning omrøres der i en time ved 23°C.After adding 145 ml of 1N sodium hydroxide solution, stir for one hour at 23 ° C.

5 Efter afdampning af methanolen fortyndes remanensen med isvand, gøres sur ved hjælp af 2N-saltsyre og ekstraheres med 2 x 400 ml ethylacetat. De organiske faser vaskes med mættet kogsaltopløsning, tørres over natriumsulfat og inddampes. Remanensen omkrystafliseres af methylenchlorid/petroleumsether. Herved fås 2-chlor-3-hydroxy-5-nitro-p-anisaldehyd med smeltepunkt 130°C.After evaporation of the methanol, the residue is diluted with ice water, acidified with 2N hydrochloric acid and extracted with 2 x 400 ml of ethyl acetate. The organic phases are washed with saturated brine, dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride / petroleum ether. This gives 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde, m.p. 130 ° C.

10 d) 1,3 g 2-chlor-3-hydroxy-5-nitro-p-anisaldehyd opløses i 80 fnl methylenchlorid, der tilsættes 0,82 ml bortribromid, omrøres i 18 timer ved 23°C, reaktionsblandingen tilsættes under isafkøling 5 ml methanol og inddampes, og remanensen tørres i højvacuum, udludes i vand, filtreres og omkrystalliseres af acetonitril. Herved fås 2-chlor-3,4-dihydroxy-5- 15 nitrobenzaldehyd med smeltepunkt 193-195°C.D) 1.3 g of 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde are dissolved in 80 μl of methylene chloride, 0.82 ml of boron tribromide are added, stirred for 18 hours at 23 ° C, the reaction mixture is added under ice-cooling. ml of methanol and evaporate and the residue is dried in a high vacuum, eluted in water, filtered and recrystallized from acetonitrile. This gives 2-chloro-3,4-dihydroxy-5-nitrobenzaldehyde, m.p. 193-195 ° C.

EKSEMPEL 44 20 a) En blanding af 30 g 2-chlor-3-hydroxy-p-anisaldehyd og 230 ml ethanol omrøres i 4 timer ved 70°C i nærværelse af 12,3 g hydroxylaminhydrochlorid, hvorefter reaktionsblandingen inddampes, og remanensen tørres i højvakuum og omkrystalliseres af methanol/vand. Herved fås 2-chlor-3-hydroxy-p-anisaldehyd-oxim med smeltepunkt 174-176eC.EXAMPLE 44 20 a) A mixture of 30 g of 2-chloro-3-hydroxy-p-anisaldehyde and 230 ml of ethanol is stirred for 4 hours at 70 ° C in the presence of 12.3 g of hydroxylamine hydrochloride, after which the reaction mixture is evaporated and the residue is dried in high vacuum and recrystallized from methanol / water. This gives 2-chloro-3-hydroxy-p-anisaldehyde oxime, m.p. 174-176 ° C.

25 b) 21 g 2-chlor-3-hydroxy-p-anisaldehyd-oxim opvarmes i 20 timer under tilbagesvaling sammen med 400 ml eddikesyreanhydrid. Herefter inddampes reaktionsblandingen, og der sættes 300 ml isvand til remanensen, omrøres i 1 time og dekanteres, den således vundne remanens deles mellem methylenchlorid og vand, den organiske fase tørres over 30 natriumsuifat og inddampes, remanensen tørres i højvacuum og chromatograferes på 200 g silicagel med methylenchlorid og omkrystalliseres af methylenchlorid/petroleumsether. Herved fås 2-chlor-3-cyano-6-methoxyphenyl-acetat med smeltepunkt 97-99°C.B) 21 g of 2-chloro-3-hydroxy-p-anisaldehyde oxime are heated at reflux for 20 hours together with 400 ml of acetic anhydride. The reaction mixture is then evaporated and 300 ml of ice water are added to the residue, stirred for 1 hour and decanted, the residue thus obtained partitioned between methylene chloride and water, the organic phase dried over sodium sulfate and evaporated, the residue dried in high vacuum and chromatographed on 200 g of silica gel. with methylene chloride and recrystallized from methylene chloride / petroleum ether. This gives 2-chloro-3-cyano-6-methoxyphenyl acetate, m.p. 97-99 ° C.

35 c) Ud fra 2-chlor-3-cyano-6-methoxyphenyl-acetat fås analogt med eksemplerne 43b og 43c 2-chlor-3-hydroxy-5-nitro-p-anisonitril med smeltepunkt l57-159eC (methylenchlorid/hexan).C) From 2-chloro-3-cyano-6-methoxyphenyl acetate analogous to examples 43b and 43c are obtained 2-chloro-3-hydroxy-5-nitro-p-anisonitrile, m.p. 175 DEG-159 DEG C. (methylene chloride / hexane) .

d) Ud fra 2-chlor-3-hydroxy-5-nitro-p-anisonitril fås analogt med eksempel 43d 2-chlor- DK 175069 B1 46 3,4-drhydroxy-5-nitrO'benzonitril med smeltepunkt 180°C (acetonitril).d) From 2-chloro-3-hydroxy-5-nitro-p-anisonitrile is obtained analogously to Example 43d 2-chloro-3,4-hydroxy-5-nitrO'benzonitrile with melting point 180 ° C (acetonitrile ).

EKSEMPEL 45 5 a) 5,5 g a-chlor-2*fluor-3,4'dimethoxytoluen og 4,05 g kaliumacetat i 50 ml dimethylformamid omrøres i 25 timer ved 80°C. Derefter hældes reaktionsblandingen ud i 150 ml isvand og ekstraheres med ether. Etherfaserne vaskes med kogsaltopløsning, tørres over natriumsulfat og inddampes. Herved fis 2-fluor-3,4-dimethoxybenzyl-acetat 10 som en olie.EXAMPLE 45 5 a) 5.5 g of α-chloro-2 * fluoro-3,4'-dimethoxytoluene and 4.05 g of potassium acetate in 50 ml of dimethylformamide are stirred for 25 hours at 80 ° C. Then the reaction mixture is poured into 150 ml of ice water and extracted with ether. The ether phases are washed with brine, dried over sodium sulfate and evaporated. This gives 2-fluoro-3,4-dimethoxybenzyl acetate 10 as an oil.

b) 5,4 g 2-fluor-3,4-dimethoxybenzyl-acetat opvarmes sammen med 50 ml methanol og 50 ml lN-natriumhydroxid i 1,5 time til 80°C. Efter afdampning af methanolen ekstraheres remanensen med methylenchlorid. De forenede ekstrakter vaskes med vand, tørres over 15 natriumsulfat og inddampes. Remanensen chromatograferes på 80 g silicagel med methylenchlorid/methanol (95:5). Herved fis 2-fluor-3,4-dimethoxybenzylalkohol som olie.b) 5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate are heated together with 50 ml of methanol and 50 ml of 1N sodium hydroxide for 1.5 hours at 80 ° C. After evaporation of the methanol, the residue is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 80 g of silica gel with methylene chloride / methanol (95: 5). Hereby fis 2-fluoro-3,4-dimethoxybenzyl alcohol as oil.

c) 3,0 g 2-fluor-3,4-dimethoxybenzylalkohol og 5,0 g mangandioxid opvarmes sammen 20 med 50 ml benzen i 1 time under tilbagesvaling. Derefter frafiltreres de uopløselige dele under vaskning med methylenchlorid. Filtratet inddampes, og remansen omkrystalliseres af methylenchlorid/hexan. Herved fås 2-fluor-3,4-dimethoxybenzaldehyd med smeltepunkt 52-54°C.c) 3.0 g of 2-fluoro-3,4-dimethoxybenzyl alcohol and 5.0 g of manganese dioxide are heated together with 50 ml of benzene for 1 hour under reflux. The insoluble parts are then filtered off while washing with methylene chloride. The filtrate is evaporated and the residue is recrystallized from methylene chloride / hexane. This gives 2-fluoro-3,4-dimethoxybenzaldehyde, m.p. 52-54 ° C.

25 d) 4,4 g 2-fluor-3,4-dimethoxybenzaldehyd og 1,83 g hydroxylaminhydrochlorid opvarmes sammen med 30 ml ethanol i 5 timer under titbagesvaiing. Derefter inddampes reaktionsblandingen, og den i højvacuum ved 236C tørrede remanens hældes i 40 ml phosphoroxychlorid. Efter 2,5 timers omrøring ved 23°C inddampes reaktionsblandingen, remanensen behandles med isvand, og det således dannede bundfald filtreres fra, vaskes 30 med vand og tages op i methylenchlorid, og methylenchloridopløsningen tørres over natriumsulfat og inddampes. Ved omkrystallisering af remanensen af methylenchlorid/-hexan fås 2-fluor'3,4-dimethoxybenzonitril med smeltepunkt 64-65°C.D) 4.4 g of 2-fluoro-3,4-dimethoxybenzaldehyde and 1.83 g of hydroxylamine hydrochloride are heated together with 30 ml of ethanol for 5 hours with titration. The reaction mixture is then evaporated and the residue, dried in a high vacuum at 236 DEG C., is poured into 40 ml of phosphorus oxychloride. After stirring for 2.5 hours at 23 ° C, the reaction mixture is evaporated, the residue is treated with ice water and the precipitate thus formed is filtered off, washed with water and taken up in methylene chloride, and the methylene chloride solution is dried over sodium sulphate and evaporated. Recrystallization of the residue of methylene chloride / hexane gives 2-fluoro-3,4-dimethoxybenzonitrile, m.p. 64-65 ° C.

e) 2,0 g 2-fluor-3,4-dimethoxybenzonitril opløses i 60 ml methylenchlorid, og der 35 tilsættes 1,1 ml bortribromid, omrøres i 1 time ved 23°C, tilsættes derefter yderligere 1,0 ml bortribromid og omrøres i yderligere 80 minutter ved 23°C. Herefter hældes reaktionsblandingen ud i 100 ml iskold mættet natriumhydrogencarbonatopløsning, hvorpå der ekstraheres 2 x 300 ml ether, og de forenede etherfaser vaskes 2 gange med kogsaltsopløsning, tørres over natriumsulfat og inddampes, og remanensen 47 DK 175069 B1 chromatograferes på 50 g silicagel med methylenchlorid og methylenchlorid/methanol (97:3). Herved fås 2-fluor-3-hydroxy-p-anisonitril med smeltepunkt 198*200°C.e) 2.0 g of 2-fluoro-3,4-dimethoxybenzonitrile are dissolved in 60 ml of methylene chloride and 1.1 ml of boron tribromide are added, stirred for 1 hour at 23 ° C, then another 1.0 ml of boron tribromide are added and stirred for a further 80 minutes at 23 ° C. Then the reaction mixture is poured into 100 ml of ice-cold saturated sodium hydrogen carbonate solution, then 2 x 300 ml of ether are extracted and the combined ether phases are washed twice with brine, dried over sodium sulphate and evaporated and the residue is chromatographed on methylene chloride and 50 g of silica gel. methylene chloride / methanol (97: 3). This gives 2-fluoro-3-hydroxy-p-anisonitrile, m.p. 198 DEG-200 DEG.

f) 0,9 g 2-fiuor-3-hydroxy-p-anisonitril opløses i 10 ml eddikesyreanhydrid og 0,5 ml 5 pyridin, hvorpå der omrøres i 2 timer ved 120°C. Derefter inddampes reaktionsblandingen, og remanensen deles mellem isvand og methylenchlorid. Den organiske fase tørres over natriumsulfat og inddampes, og remanensen omkrystalliseres af methylenchlorid/hexan.f) 0.9 g of 2-fluoro-3-hydroxy-p-anisonitrile are dissolved in 10 ml of acetic anhydride and 0.5 ml of pyridine, then stirred for 2 hours at 120 ° C. The reaction mixture is then evaporated and the residue is partitioned between ice water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated and the residue is recrystallized from methylene chloride / hexane.

Herved fis 3-cyano-2-fluor-6-methoxyphenyl-acetat med smeltepunkt 90-91°C.This gives 3-cyano-2-fluoro-6-methoxyphenyl acetate, m.p. 90-91 ° C.

10 g) 0,8 g 3-cyano-2-fluor-6-methoxyphenyl-acetat hældes i 3 portioner i 5 ml 96% saltpetersyre ved -15°C, hvorpå der omrøres i 1 time ved -10°C. Herefter hældes reaktionsblandingen ud i 50 g is. Der ekstraheres med 2 x 70 ml acetylacetat. De forenede organiske faser vaskes med mættet natriumchloridopløsning, tørres over natriumsulfat og inddampes. Den således vundne remanens opløses i 50 ml lN-natriumcarbonatopløsning 15 og 50 ml methanol, hvorpå der omrøres i 1 time ved 23*C, og methanolen destilleres af.10 g) 0.8 g of 3-cyano-2-fluoro-6-methoxyphenyl acetate are poured into 3 portions in 5 ml of 96% nitric acid at -15 ° C, then stirred for 1 hour at -10 ° C. Then the reaction mixture is poured into 50 g of ice. Extract with 2 x 70 ml of acetyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue thus obtained is dissolved in 50 ml of 1N sodium carbonate solution 15 and 50 ml of methanol, then stirred for 1 hour at 23 DEG C. and the methanol is distilled off.

Den tilbageblevne vandige fase gøres ved 0°C sur til pH 2 med koncentreret saltsyre og ekstraheres med 2 x 100 ml ethylacetat. De forenede organiske faser vaskes med mættet natriumchloridopløsning, tørres over natriumsulfat og inddampes, og remanensen chromatograferes på 45 g kieselgel med methylenchlorid/methanol (97:3). Efter 20 omkrystallisering af ether/hexan fås 2-fluor-3-hydroxy-5-nitro-p-anisonitril med smeltepunkt 112-113°C.The remaining aqueous phase is acidified at 0 ° C to pH 2 with concentrated hydrochloric acid and extracted with 2 x 100 ml of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated, and the residue was chromatographed on 45 g of silica gel with methylene chloride / methanol (97: 3). After recrystallization from ether / hexane, 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile with a melting point of 112-113 ° C is obtained.

h) 550 mg 2-fluor-3-hydroxy-5-nitro-p-anisonitril opløses i 30 ml methylenchlorid, hvorpå der tilsættes 0,44 ml bortribromid. Efter 6 timers omrøring ved 23°C tilsættes der 25 yderligere 0,1 bortribromid, hvorpå der omrøres i endnu 1,5 time ved 23®C. Herefter tilsættes der ved -15°C 3 ml ethanol. Reaktionsblandingen inddampes, og remanensen tørres ved 23°C højvacuum. Ved omkrystallisering af ether/hexan fås 2-fluor-3,4-dihydroxy-5-nitrobenzonitril med smeltepunkt 154*0.h) 550 mg of 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile are dissolved in 30 ml of methylene chloride and then 0.44 ml of boron tribromide are added. After stirring for 6 hours at 23 DEG C., a further 0.1 boron tribromide is added and the mixture is stirred for a further 1.5 hours at 23 DEG C. Then 3 ml of ethanol are added at -15 ° C. The reaction mixture is evaporated and the residue is dried at 23 ° C high vacuum. Recrystallization from ether / hexane gave 2-fluoro-3,4-dihydroxy-5-nitrobenzonitrile, m.p. 154 DEG.

30 EKSEMPEL 46 a) 9,5 g 3,4-dimethoxy-5-nitrobenzoesyre suspenderes i 95 ml thionylcholrid. Der omrøres i 1 time ved 80°C. Ved inddampning 2 gange under tilsætning af absolut toluen 35 fås 10 g 3,4-dimethoxy-5-nitrobenzoesyrechlorid, som opløses i 100 ml tetrahydrofuran.EXAMPLE 46 a) 9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid are suspended in 95 ml of thionyl chloride. Stir for 1 hour at 80 ° C. Evaporation twice with the addition of absolute toluene 35 gives 10 g of 3,4-dimethoxy-5-nitrobenzoic acid chloride, which is dissolved in 100 ml of tetrahydrofuran.

Denne opløsning dryppes til 300 ml 28% vandig ammoniak. Derefter omrøres i 2 timer ved 40°C og afkøles til 5°C. Det krystallinske bundfald filtreres fra. Herved fås 3,4-dimethoxy- 5-nitrobenzamid med smeltepunkt 182-185°C.This solution is added dropwise to 300 ml of 28% aqueous ammonia. Then stir for 2 hours at 40 ° C and cool to 5 ° C. The crystalline precipitate is filtered off. This gives 3,4-dimethoxy-5-nitrobenzamide, m.p. 182-185 ° C.

48 UK 175UWJ bl b) Under isafkøling ledes 2,46 g chlor ind i en blanding af 8,0 g natriumhydroxid, 50 ml vand og 30 g is. Herefter tilsættes der langsomt 6,5 g 3,4-dimethoxy-5-nitrobenzamid, suspenderet i 5 ml tetrahydrofuran. Reaktionsblandingen opvarmes i løbet af 30 minutter til 70eC, omrøres i 1 time ved 70°C og afkøles til 5eC, og de udfældede krystaller filtreres 5 fra. Herved fås 3,4-dimethoxy-5-nitroanilin med smeltepunkt 129-131°C. Ved ekstraktion af filtratet med ethylacetat, tørring af ekstrakten over natriumsulfat, inddampning og krystallisering af remanensen under tilsætning af ether kan der fås en yderligere portion 3.4- dimethoxy-5-nitroanilin.48 UK 175UWJ bl b) Under ice-cooling, 2.46 g of chlorine are introduced into a mixture of 8.0 g of sodium hydroxide, 50 ml of water and 30 g of ice. Then 6.5 g of 3,4-dimethoxy-5-nitrobenzamide, suspended in 5 ml of tetrahydrofuran, are slowly added. The reaction mixture is heated to 70 ° C over 30 minutes, stirred for 1 hour at 70 ° C and cooled to 5 ° C and the precipitated crystals are filtered off. This gives 3,4-dimethoxy-5-nitroaniline, m.p. 129-131 ° C. By extracting the filtrate with ethyl acetate, drying the extract over sodium sulfate, evaporating and crystallizing the residue while adding ether, an additional portion of 3,4-dimethoxy-5-nitroaniline can be obtained.

10 c) 10 g fint pulveriseret 3,4-dimethoxy-5-nitroanilin suspenderes i 15 ml 12 N-saltsyre og 40 ml vand, hvorpå der omrøres ved 30°C i 1 time. Herefter tildryppes der ved -5°C og i løbet af 15 minutter 3,8 g natriumnitrit opløst i 20 ml vand. Der omrøres i 30 minutter ved -5°C, og den kolde diazoniumsaltopløsning dryppes i løbet af 45 minutter til 100 ml pyridin ved 40eC. Derefter omrøres der i 1 time ved 70eC. Reaktionsblandingen inddampes, og 15 remanensen tages op i 300 ml ethylacetat. Der ekstraheres med 3 x 200 ml 2N-saltsyre.C) 10 g of finely powdered 3,4-dimethoxy-5-nitroaniline are suspended in 15 ml of 12 N hydrochloric acid and 40 ml of water, then stirred at 30 ° C for 1 hour. Then, at -5 ° C and 3.8 g of sodium nitrite dissolved in 20 ml of water are added dropwise over 15 minutes. Stir for 30 minutes at -5 ° C and the cold diazonium salt solution is added dropwise over 45 minutes to 100 ml of pyridine at 40 ° C. Then stir for 1 hour at 70 ° C. The reaction mixture is evaporated and the residue is taken up in 300 ml of ethyl acetate. Extract with 3 x 200 ml of 2N hydrochloric acid.

Den sure vandfase justeres til pH 9 ved hjælp af koncentreret ammoniak og ekstraheres med methylenchlorid. De forenede methylenchloridekstrakter tørres over natriumsulfat og inddampes, og remanensen chromatograferes på 250 g silicagel med ethylacetat. Efter krystallisering af methylenchlorid/hexan fås 2-(3,4-dimethoxy-5-nitrophenyl)pyridin med 20 smeltepunkt 89-90°C.The acidic aqueous phase is adjusted to pH 9 using concentrated ammonia and extracted with methylene chloride. The combined methylene chloride extracts were dried over sodium sulfate and evaporated, and the residue was chromatographed on 250 g of silica gel with ethyl acetate. After crystallization of methylene chloride / hexane, 2- (3,4-dimethoxy-5-nitrophenyl) pyridine with a melting point of 89-90 ° C is obtained.

d) 1,5 g 2*(3,4-dimethoxy-5-nitrophenyl)pyridin opløses i 30 ml 48% vandig brombrintesyre. Reaktionsblandingen omrøres i 16 timer ved 100°C og i 18 timer ved 230C. Det derved dannede bundfald filtreres fra og omkrystalliseres af methanol/ether.d) 1.5 g of 2 * (3,4-dimethoxy-5-nitrophenyl) pyridine are dissolved in 30 ml of 48% aqueous hydrobromic acid. The reaction mixture is stirred for 16 hours at 100 ° C and for 18 hours at 23 ° C. The precipitate thus formed is filtered off and recrystallized from methanol / ether.

25 Herved fås 3-nitro-5-(2-pyridyl)pyrocatechol-hydrobromid med smeltepunkt 239-240°C.This gives 3-nitro-5- (2-pyridyl) pyrocatechol hydrobromide, m.p. 239-240 ° C.

EKSEMPEL 47 30 a) Til 2,76 ml 2-brompyridin opløst i 30 ml absolut tetrahydrofuran sættes der ved -60°C i løbet af 30 minutter 19,2 ml 1,6 M n-butyllithiumopløsning i hexan, hvorpå der omrøres i 30 minutter ved -60°C. Derefter tildryppes der ved -40°C og i løbet af 30 minutter 6,0 g 3.4- dimethoxy-5-nitrobenzaldehyd opløst i 50 ml tetrahydrofuran. Reaktionsblandingen opvarmes i løbet af 2 timer til 0°C, hældes ud i isvand og ekstraheres med ethylacetat. De 35 forenede ekstrakter tørres over natriumsulfat og inddampes, og remanensen chromatograferes på 200 g silicagel med ethylacetat. Hermed fås a-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinmethanol som en brun olie.EXAMPLE 47 30 a) To 2.76 ml of 2-bromopyridine dissolved in 30 ml of absolute tetrahydrofuran is added at -60 ° C over 30 minutes 19.2 ml of 1.6 M n-butyllithium solution in hexane, then stirred for 30 minutes. minutes at -60 ° C. Then 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 50 ml of tetrahydrofuran are added dropwise at -40 [deg.] C. and over 30 minutes. The reaction mixture is heated to 0 ° C over 2 hours, poured into ice water and extracted with ethyl acetate. The 35 combined extracts are dried over sodium sulfate and evaporated and the residue is chromatographed on 200 g of silica gel with ethyl acetate. There is obtained α- (3,4-dimethoxy-5-nitrophenyl) -2-pyridinemethanol as a brown oil.

b) Til 4,0 g a-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinmethanol opløst i 100 ml acetone — 49 DK 175069 B1 sættes der under stadig opvarmning og tilbagesvaling og i løbet af et tidsrum på 2,5 timer 7 g mangandioxid portionsvis. Herefter opvarmes der i yderligere 2 timer under tilbagesvaling. Derefter filtreres mangansaltene fra, og den efter inddampning vundne remanens omkrystalliseres af ether/hexan. Herved fås 3,4-dimethoxy-5-nitrophenyl-2-5 pyridylketon med smeltepunkt 113°C.b) To 4.0 g of α- (3,4-dimethoxy-5-nitrophenyl) -2-pyridinemethanol dissolved in 100 ml of acetone - 49 DK 175069 B1 are added under constant heating and reflux and over a period of 2, 5 hours 7 g manganese dioxide portionwise. Then heat for a further 2 hours under reflux. The manganese salts are then filtered off and the residue obtained after evaporation is recrystallized from ether / hexane. This gives 3,4-dimethoxy-5-nitrophenyl-2-5 pyridyl ketone, m.p. 113 ° C.

c) 1,5 g 3,4-dimethoxy-5-nitrophenyl-2-pyridylketon opløst i 30 ml 48% brombrintesyre omrøres i 18 timer ved 100°C. Herefter inddampes reaktionsblandingen, og remanensen omkrystalliseres af acetonitril/methanol. Herved fis 3,4-dihydroxy-5-nitrophenyl-2-10 pyridylketon-hydrobromid med smeltepunkt 213°C.c) 1.5 g of 3,4-dimethoxy-5-nitrophenyl-2-pyridyl ketone dissolved in 30 ml of 48% hydrobromic acid are stirred for 18 hours at 100 ° C. The reaction mixture is then evaporated and the residue is recrystallized from acetonitrile / methanol. This gives 3,4-dihydroxy-5-nitrophenyl-2-10 pyridyl ketone hydrobromide, m.p. 213 ° C.

EKSEMPEL 48 15 a) Til 2,25 g 3',4'-dimethoxy-5’-nitroacetophenon opløst i 50 ml ethanol sættes der 11,3 g tindichlorid-dihydrat, hvorefter der omrøres i 30 minutter ved 75°C. Herefter hældes reaktionsblandingen ud i 100 g is, neutraliseres med ca. 300 ml mættet natriumhydrogencarbonatopløsning og tilsættes 150 ml methylenchlorid. Der filtreres, og methylenchloridfasen skilles fra. Denne tørres over natriumsulfat og inddampes, og 20 remanensen omkrystalliseres af ether/petroleumsether. Herved fås S'-amino-S’^’-dimethoxyacetophenon med smeltepunkt 63-65°C.EXAMPLE 48 a) To 2.25 g of 3 ', 4'-dimethoxy-5'-nitroacetophenone dissolved in 50 ml of ethanol is added 11.3 g of tin dichloride dihydrate, then stirred for 30 minutes at 75 ° C. Then the reaction mixture is poured into 100 g of ice, neutralized with approx. 300 ml of saturated sodium bicarbonate solution and add 150 ml of methylene chloride. Filter and separate the methylene chloride phase. This is dried over sodium sulphate and evaporated and the residue is recrystallized from ether / petroleum ether. This gives S'-amino-S '' '' dimethoxyacetophenone, m.p. 63-65 ° C.

b) Til 14,0 g S'-amino-S’^'-dimethoxyacetophenon opløst i 155 ml 1 N-saltsyre dryppes der ved 0°C og i løbet af 20 minutter en opløsning af 5,2 g natriumnitrit i 20 ml vand. Efter 25 30 minutters omrøring ved -2°C dryppes den kolde diazoniumsaltopløsning i løbet af 30 minutter ved 5-10°C til en opløsning af 8,7 g kobber(I)cyanid og 5,45 g kaliumcyanid i 60 ml vand. Efter endt tilsætning tilsættes der 200 ml methylenchlorid, og reaktionsblandingen omrøres i 3 timer ved 23°C og filtreres derefter. Den organiske fase skilles fra, vaskes med vand, tørres over natriumsulfat og inddampes. Remanensen 30 omkrystalliseres af methylenchlorid/petroleumsether. Herved fås 5'-cyano-3',4'-dimethoxyacetophenon med smeltepunkt 125-126°C.b) To 14.0 g of S'-amino-S '' '' - dimethoxyacetophenone dissolved in 155 ml of 1 N hydrochloric acid, drip a solution of 5.2 g of sodium nitrite into 20 ml of water over 20 minutes. . After stirring for 30 minutes at -2 ° C, the cold diazonium salt solution is added dropwise over 30 minutes at 5-10 ° C to a solution of 8.7 g of copper (I) cyanide and 5.45 g of potassium cyanide in 60 ml of water. After the addition is complete, 200 ml of methylene chloride are added and the reaction mixture is stirred for 3 hours at 23 ° C and then filtered. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride / petroleum ether. This gives 5'-cyano-3 ', 4'-dimethoxyacetophenone, m.p. 125-126 ° C.

c) 3,75 g aluminiumspulver og 28,5 g iod opvarmes i 160 ml absolut benzen i 2 timer under tilbagesvaling. Ved 20°C tilsættes der derefter 3,0 g 5'-cyano-3,,4’- 35 dimethoxyacetophenon og 0,5 g tetra-n-butylammoniumiodid, hvorpå der opvarmes i en time under tilbagesvaling. Herefter tilsættes der ved 20°C 50 g is og filtreres. Remanensen vaskes med ethylacetat. Faserne adskilles, og den vandige fase ekstraheres endnu 2 gange med ethylacetat. De forenede organiske faser vaskes med 20% natriumthiosulfatopløsning, tørres over natriumsulfat og inddampes. Den derved vundne 50 DK 175069 Bl remanens opløses i 20 ml eddikesyreanhydrid og 0,5 ml pyridin og omrøres i 6 timer ved 120°C. Derefter inddampes blandingen, og remanensen deles mellem methylenchlorid og isvand. Methylenchloridfasen tørres over natriumsulfat og inddampes, og remanensen chromatograferes på 100 g silicagel med methylenchlorid. Efter omkrystallisering af ether 5 fås S’-cyano-S'^'-diacetoxyacetophenon med smeltepunkt 76-79°C.c) Heat 3.75 g of aluminum powder and 28.5 g of iodine in 160 ml of absolute benzene for 2 hours under reflux. At 20 [deg.] C., 3.0 g of 5'-cyano-3,4'-dimethoxyacetophenone and 0.5 g of tetra-n-butylammonium iodide are then added and the mixture is heated under reflux for one hour. Then 50 g of ice are added at 20 ° C and filtered. The residue is washed with ethyl acetate. The phases are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are washed with 20% sodium thiosulphate solution, dried over sodium sulphate and evaporated. The 50 DK 175069 B1 residue thus obtained is dissolved in 20 ml of acetic anhydride and 0.5 ml of pyridine and stirred for 6 hours at 120 ° C. The mixture is then evaporated and the residue is partitioned between methylene chloride and ice water. The methylene chloride phase is dried over sodium sulfate and evaporated and the residue is chromatographed on 100 g of silica gel with methylene chloride. After recrystallization from ether 5, S'-cyano-S '' '- diacetoxyacetophenone with melting point 76-79 ° C is obtained.

EKSEMPEL 49 10 Til 0,33 g 5’'Cyano-3',4'-diacetoxyacetophenon opløst i 3,3 ml methanol sættes der 2,7 ml 1,0 N natriumhydroxidopløsning, og reaktionsblandingen omrøres i 45 minutter ved 23°C.EXAMPLE 49 10 To 0.33 g of 5 '' cyano-3 ', 4'-diacetoxyacetophenone dissolved in 3.3 ml of methanol is added 2.7 ml of 1.0 N sodium hydroxide solution and the reaction mixture is stirred for 45 minutes at 23 ° C.

Derefter gøres den sur med 2N-saltsyre, fortyndes med 5 ml mættet kogsaltopløsning og ekstraheres med 2 x 30 ml ethylacetat. De forenede ethylacetatfaser tørres over natriumsulfat og inddampes. Remanensen omkrystalliseres af toluen/acetonitril. Herved 15 fås 5’-cyano-3’,4'-dihydroxyacetophenon som brunlige krystaller, som sønderdeles over 215°C.It is then acidified with 2N hydrochloric acid, diluted with 5 ml of saturated brine and extracted with 2 x 30 ml of ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The residue is recrystallized from toluene / acetonitrile. This gives 5'-cyano-3 ', 4'-dihydroxyacetophenone as brownish crystals which decompose above 215 ° C.

EKSEMPEL 50 20 a) Til 1,9 g S'-cyano-S’^’-dimethoxyacetophenon opløst i 30 ml tetrahydrofuran dryppes der ved stuetemperatur og i løbet af 45 minutter 3,48 g phenyltrimethylammoniumbromid-dibromid opløst i 30 ml tetrahydrofuran, hvorpå der omrøres i 30 minutter. Herefter hældes reaktionsblandingen ud i 120 ml isvand og ekstraheres med 3 x 70 ml 25 methylenchlorid. De forenede methylenchloridfaser vaskes med 2N-svovlsyre, tørres over natriumsulfat og inddampes. Remanensen chromatograferes på 20 g silicagel med methylenchlorid. Efter omkrystallisering af methylenchlorid/hexan fis 5-(brom-acetyl)-2,3-dimethoxybenzonitril med smeltepunkt 138-141°C.EXAMPLE 50 a) To 1.9 g of S'-cyano-S stir for 30 minutes. Then the reaction mixture is poured into 120 ml of ice water and extracted with methylene chloride (3 x 70 ml). The combined methylene chloride phases are washed with 2N sulfuric acid, dried over sodium sulfate and evaporated. The residue is chromatographed on 20 g of silica gel with methylene chloride. After recrystallization from methylene chloride / hexane fis 5- (bromo-acetyl) -2,3-dimethoxybenzonitrile, m.p. 138-141 ° C.

30 b) 1,45 g 5-(bromacetyl)-2,3-dimethoxybenzonitril og 1,12 g selendioxid i 10 ml n- hexanol omrøres i 18 timer ved 120°C. Efter afkøling til stuetemperatur fortyndes der med 20 ml methylenchlorid og filtreres. Filtratet vaskes med vand, tørres over natriumsulfat og inddampes. Remanensen chromatograferes på 70 g silicagel med hexan/ether (2:1).B) 1.45 g of 5- (bromoacetyl) -2,3-dimethoxybenzonitrile and 1.12 g of selenium dioxide in 10 ml of n-hexanol are stirred for 18 hours at 120 ° C. After cooling to room temperature, dilute with 20 ml of methylene chloride and filter. The filtrate is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 70 g of silica gel with hexane / ether (2: 1).

Herved fås hexyl-(3-cyano-4,5-dimethoxyphenyl)glyoxylat som en olie.This gives hexyl (3-cyano-4,5-dimethoxyphenyl) glyoxylate as an oil.

35 c) Til 4,0 g hexyl-(3-cyano-4,5-dimethoxyphenyl)glyoxylat opløst i 100 ml methylenchlorid dryppes der under isafkøling og i løbet af 20 minutter 4,8 ml bortri bromid opløst i 20 ml methylenchlorid, og reaktionsblandingen omrøres i 18 timer ved stuetemperatur. Derefter tildryppes der ved -60°C 40 ml methanol, omrøres i 1 time ved 51 DK 175069 B1 stuetemperatur og inddampes. Remanensen tages op i methanol. Der opvarmes i 10 minutter under tilbagesvaling, inddampes til tørhed og tørres i højvacuum. Det således vundne råprodukt omkrystalliseres af acetonitril. Herved fis methyl-(3-cyano-4,5-dihydroxyphenyl)-glyoxylat med smeltepunkt 252°C.C) To 4.0 g of hexyl (3-cyano-4,5-dimethoxyphenyl) glyoxylate dissolved in 100 ml of methylene chloride is added dropwise under ice-cooling and in 20 minutes 4.8 ml of boron bromide dissolved in 20 ml of methylene chloride, and the reaction mixture is stirred for 18 hours at room temperature. Then 40 ml of methanol are added dropwise at -60 [deg.] C., stirred for 1 hour at room temperature and evaporated. The residue is taken up in methanol. Heat at reflux for 10 minutes, evaporate to dryness and dry in high vacuum. The crude product thus obtained is recrystallized from acetonitrile. This gives methyl (3-cyano-4,5-dihydroxyphenyl) glyoxylate, m.p. 252 ° C.

5 EKSEMPEL 51 1,075 g methyl-(3-cyano-4,5-dihydroxyphenyl)glyoxylat og 0,60 g 2-amino-p-kresol 10 omrøres i 2 ml dimethylformamid i 70 minutter ved 120°C. Derefter afkøles reaktionsblandingen til stuetemperatur og fortyndes med 15 ml vand. Bundfaldet filtreres fra og tørres i 6 timer ved 80°C i vandstrålevacuum. Efter omkrystallisering af acetonitril fis 2,3-dihydroxy-5-(6-methyl-2-oxo-2H-l,4-benzoxazin-3-yl)benzonitril med smeltepunkt 278-280°C.EXAMPLE 51 1.075 g of methyl (3-cyano-4,5-dihydroxyphenyl) glyoxylate and 0.60 g of 2-amino-p-cresol are stirred in 2 ml of dimethylformamide for 70 minutes at 120 ° C. The reaction mixture is then cooled to room temperature and diluted with 15 ml of water. The precipitate is filtered off and dried for 6 hours at 80 ° C in a water jet vacuum. After recrystallization from acetonitrile, 2,3-dihydroxy-5- (6-methyl-2-oxo-2H-1,4-benzoxazin-3-yl) benzonitrile, m.p. 278-280 ° C.

15 EKSEMPEL 52 a) Til en opløsning af 2,5 g (10,2 mmol) 3,4-dimethoxy-5-nitro-benzoylchlorid i 10 ml 20 absolut tetrahydrofuran sættes der 1,1 ml isocyaneddikesyreethylester og derefter en opløsning af 3,0 ml triethylamin i 10 ml tetrahydrofuran, og der omrøres i 48 timer ved stuetemperatur. Efter afdestiilering af opløsningsmidlet ekstraheres der med ethyl-acetat/vand. Det efter inddampning vundne råprodukt chromatograferes på den 20-dobbelte mængde silicagel med ethylacetat. Efter omkrystallisering af ethylacetat/hexan 25 fås ethyl-5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolcarboxylat i form af gule krystaller med smeltepunkt 109-110°C.EXAMPLE 52 a) To a solution of 2.5 g (10.2 mmol) of 3,4-dimethoxy-5-nitro-benzoyl chloride in 10 ml of absolute tetrahydrofuran is added 1.1 ml of isocyanacetic acid ethyl ester and then a solution of 3 0 ml of triethylamine in 10 ml of tetrahydrofuran and stir for 48 hours at room temperature. After distilling off the solvent, extract with ethyl acetate / water. The crude product obtained after evaporation is chromatographed on the 20-fold amount of silica gel with ethyl acetate. After recrystallization from ethyl acetate / hexane 25, ethyl 5- (3,4-dimethoxy-5-nitrophenyl) -4-oxazole carboxylate is obtained in the form of yellow crystals, m.p. 109-110 ° C.

b) Til 1,0 g (3,1 mmol) ethyl-5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolcarboxylat sættes der 10 ml konstant kogende brombrintesyre og der omrøres i 2 timer ved 140°C.b) To 1.0 g (3.1 mmol) of ethyl 5- (3,4-dimethoxy-5-nitrophenyl) -4-oxazole carboxylate is added 10 ml of constantly boiling hydrobromic acid and stirred for 2 hours at 140 ° C.

30 Efter afdestiilering af den overskydende brombrintesyre omfældes den gule remanens af ethanol/acetone. Herved fås 2-amino-3’,4'-dihydroxy-5’-nitroacetophenon-hydrobromid i form af gule krystaller med smeltepunkt >250°C (sønderdeling).After distilling off the excess hydrobromic acid, the yellow residue is precipitated with ethanol / acetone. This gives 2-amino-3 ', 4'-dihydroxy-5'-nitroacetophenone hydrobromide in the form of yellow crystals with a melting point> 250 ° C (decomposition).

35 EKSEMPEL 53 a) Til 10 g (34 mmol) ethyl-(3,4-dimethoxy-5-nitrobenzoyl)-acetat suspenderet i 100 ml ethanol sættes der 1,7 g (37 mmol) methylhydrazin og der opvarmes i 16 timer under tilbagesvaling. Efter afdestiilering af ca. 50 ml ethanol afkøles der til 0°C, og det udfældede ui\ i i «;uua u i 52 bundfald suges fra. Efter omkrystallisering af ethanol fås 3-(3,4-dimethoxy-5-nitrophenyl)- l-methylpyrazol-5-ol i form af gule krystaller med smeltepunkt 200-202°C.EXAMPLE 53 a) To 10 g (34 mmol) of ethyl (3,4-dimethoxy-5-nitrobenzoyl) -acetate suspended in 100 ml of ethanol is added 1.7 g (37 mmol) of methylhydrazine and heated for 16 hours under reflux. After distilling off approx. 50 ml of ethanol are cooled to 0 [deg.] C. and the precipitated ui \ i i «; uua u i 52 precipitate is filtered off with suction. After recrystallization from ethanol, 3- (3,4-dimethoxy-5-nitrophenyl) -1-methylpyrazol-5-ol is obtained in the form of yellow crystals, m.p. 200-202 ° C.

b) 2,0 g (7,2 mmol) 3-(3,4-dimethoxy-5-nitrophenyl)-l-methylpyrazol-5-ol suspenderes 5 i 100 ml methylenchlorid. Efter afkøling til -40°C tildryppes der i løbet af 1 time en opløsning af 4,9 ml bortribromid i 60 ml methylenchlorid. Derefter omrøres der i 16 timer ved stuetemperatur, afkøles til -20°C og tilsættes 100 ml ethanol i løbet af 30 minutter.b) 2.0 g (7.2 mmol) of 3- (3,4-dimethoxy-5-nitrophenyl) -1-methylpyrazol-5-ol are suspended in 100 ml of methylene chloride. After cooling to -40 [deg.] C., a solution of 4.9 ml of boron tribromide in 60 ml of methylene chloride is added dropwise over 1 hour. The mixture is then stirred for 16 hours at room temperature, cooled to -20 [deg.] C. and 100 ml of ethanol are added over 30 minutes.

Efter omrøring ved stuetemperatur i 1 time afdestilleres opløsningsmidlet i vandstrålevacuum ved 40°C. Til remanensen sættes der 3 x 100 ml af en blanding af 10 ethanol og toluen, idet opløsningsmidlet hver gang destilleres af. Remanensen om krystalliseres af ethanol. Herved fås 5-(5-hydroxy-l-methylpyrazol-3-yl)-3-nitropyrocatechol-hydrobromid i form af gule krystaller med smeltepunkt >250eC.After stirring at room temperature for 1 hour, the solvent is distilled off in a water jet vacuum at 40 ° C. To the residue is added 3 x 100 ml of a mixture of 10 ethanol and toluene, the solvent being distilled off each time. The residue is crystallized from ethanol. This gives 5- (5-hydroxy-1-methylpyrazol-3-yl) -3-nitropyrocatechol hydrobromide in the form of yellow crystals with a melting point> 250 ° C.

15 EKSEMPEL 54 a) Til 16,8 g (0,7 g-atom) magnesium sættes der 15 ml ethanol, og efter tilsætning af 2 ml carbontetrachlorid startes reaktionen ved opvarmning. Under omrøring dryppes der i løbet af ca. 30 minutter en opløsning af 130,3 g tert.butylethylmalonat i 70 ml ethanol og 20 600 ml absolut ether til på en sådan måde, at reaktionen forløber ved til-bagesvalingstemperaturen. Derefter omrøres der videre i 3 timer ved 50°C, og opløsningsmidlet destilleres af ved 40°C i vandstrålevacuum. Remanensen opløses i 900 ml tetrahydrofuran. Til denne opløsning dryppes der under omrøring ved 50°C en opløsning af 170 g (0,7 mol) 3,4-dimethoxy-5-nitrobenzoylchlorid i 700 ml absolut tetrahydrofuran og 25 omrøres i 1 time ved tilbagesvalingstemperaturen. Opløsningsmidlet destilleres af ved 40“C i vandstrålevacuum. Til remanensen sættes 11 ether. Under afkøling og omrøring tilsættes der 260 ml 3N-svovlsyre og omrøres i 30 minutter. Den vandige fase ekstraheres med 2 x 600 ml ether. Den organiske fase vaskes med vand til neutral reaktion, tørres over natriumsulfat og inddampes. Den vundne brune olie filtreres med toluen over 1 kg 30 silicagel. Den vundne blanding, der består af ethyl-tert.butyl-(3,4-dimethoxy*5- nitrobenzoyl)ma!onat og ethyl-(3,4-dimethoxy-5-nitrobenzoyl)acetat, opløses i 600 ml methylenchlorid, og under omrøring i løbet af ca. 30 minutter tilsættes 193 ml trifluoreddikesyre. Derefter omrøres der i 2 timer ved 40°C og inddampes derefter ved 40eC i vandstrålevacuum. Den vundne olie ekstraheres med ether/vand. Den organiske 35 fase tørres over natriumsulfat og inddampes. Efter opløsning i diisopropylether/hexan og afkøling suges de udfældede krystaller fra og omkrystalliseres af diisopropylether. Herved fås ethyl-(3,4-dimethoxy-5-nitrobenzoyl)acetat i form svagt gullige krystaller med smeltepunkt 67-68“C.EXAMPLE 54 a) To 16.8 g (0.7 g atom) of magnesium is added 15 ml of ethanol, and after adding 2 ml of carbon tetrachloride, the reaction is started by heating. While stirring, drip in approx. 30 minutes a solution of 130.3 g of tert-butyl ethyl malonate in 70 ml of ethanol and 20 600 ml of absolute ether is added in such a way that the reaction proceeds at reflux temperature. The mixture is then further stirred for 3 hours at 50 [deg.] C. and the solvent is distilled off at 40 [deg.] C. in a water jet vacuum. The residue is dissolved in 900 ml of tetrahydrofuran. To this solution is added dropwise with stirring at 50 ° C a solution of 170 g (0.7 mol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 700 ml of absolute tetrahydrofuran and stirred for 1 hour at reflux temperature. The solvent is distilled off at 40 ° C in a water jet vacuum. To the residue is added 11 ethers. While cooling and stirring, 260 ml of 3N-sulfuric acid are added and stirred for 30 minutes. The aqueous phase is extracted with ether (2 x 600 ml). The organic phase is washed with water until neutral, dried over sodium sulfate and evaporated. The brown oil obtained is filtered with toluene over 1 kg of silica gel. The resulting mixture consisting of ethyl tert-butyl (3,4-dimethoxy-5-nitrobenzoyl) malonate and ethyl (3,4-dimethoxy-5-nitrobenzoyl) acetate is dissolved in 600 ml of methylene chloride, and while stirring during approx. 303 ml of trifluoroacetic acid are added over 30 minutes. The mixture is then stirred for 2 hours at 40 [deg.] C. and then evaporated at 40 [deg.] C. in a water jet vacuum. The oil obtained is extracted with ether / water. The organic phase is dried over sodium sulfate and evaporated. After dissolving in diisopropyl ether / hexane and cooling, the precipitated crystals are filtered off with suction and recrystallized from diisopropyl ether. This gives ethyl (3,4-dimethoxy-5-nitrobenzoyl) acetate in the form of pale yellow crystals, m.p. 67-68 ° C.

53 DK 175069 B1 b) 10,0 g (33,6 mmol) ethyl-(3,4-dimethoxy-5-nitrobenzoyl)acetat omsættes med 4,0 g (37 mmol) phenylhydrazin analogt med eksempel 53a. Efter omkrystallisering af methylenchlorid/ethanol fås 3-(3,4-dimethoxy-5-nitrophenyl)-l-phenyl-2-pyrazolin-5-on i form af gule krystaller med smeltepunkt 190-192°C.53 DK 175069 B1 b) 10.0 g (33.6 mmol) of ethyl (3,4-dimethoxy-5-nitrobenzoyl) acetate are reacted with 4.0 g (37 mmol) of phenylhydrazine analogously to Example 53a. After recrystallization from methylene chloride / ethanol, 3- (3,4-dimethoxy-5-nitrophenyl) -1-phenyl-2-pyrazolin-5-one is obtained as yellow crystals, m.p. 190-192 ° C.

5 c) Med bortribromid fås analogt med eksempel 53b 5-(5*hydroxy-l-phenylpyrazol-3-yl)- 3-nitropyrocatechol-hydrobromid i form at gule krystaller med smeltepunkt >220°C (sønderdeling).C) With boron tribromide, analogous to Example 53b, 5- (5 * hydroxy-1-phenylpyrazol-3-yl) -3-nitropyrocatechol hydrobromide is obtained in the form of yellow crystals with a melting point> 220 ° C (decomposition).

10 EKSEMPEL 55 20,1 g diethyl-(3,4-dimethoxy-5-nitrobenzoyl)malonat opløses i 200 ml methylenchlorid, hvorefter der afkøles til -20°C og ved denne temperatur under omrøring og i løbet af 15 15 minutter tildryppes en opløsning af 68,1 g bortribromid i 120 ml methylenchlorid. Derefter omrøres der natten over ved stuetemperatur. Efter afkøling til -20°C tilsættes der 300 ml ethanol og omrøres i 30 minutter ved stuetemperatur. Opløsningsmidlet destilleres af i vandstrålevacuum ved 40°C. Til remanensen sættes der 300 ml isvand og methylenchlorid.EXAMPLE 55 20.1 g of diethyl (3,4-dimethoxy-5-nitrobenzoyl) malonate are dissolved in 200 ml of methylene chloride, then cooled to -20 ° C and at this temperature with stirring and over 15 minutes a drop is added. solution of 68.1 g of boron tribromide in 120 ml of methylene chloride. Then stir overnight at room temperature. After cooling to -20 ° C, 300 ml of ethanol are added and stirred for 30 minutes at room temperature. The solvent is distilled off in a water jet vacuum at 40 ° C. To the residue is added 300 ml of ice water and methylene chloride.

Den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes. Det 20 vundne råprodukt chromatograferes på den tidobbelte mængde silicagel med toluen. Efter krystallisering af methylenchlorid/hexan fås ethyl-3,4-dihydroxy*5-nitrobenzoyl)acetat i form af gule krystaller med smeltepunkt 136-137°C.The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is chromatographed on ten times the amount of silica gel with toluene. After crystallization of methylene chloride / hexane, ethyl 3,4-dihydroxy (5-nitrobenzoyl) acetate is obtained in the form of yellow crystals, m.p. 136-137 ° C.

25 EKSEMPEL 56 2,0 g (7,4 mmol) ethyl-(3,4-dihydroxy-5-nitrobenzoyl)acetat suspenderes i 50 ml ethanol.EXAMPLE 56 2.0 g (7.4 mmol) of ethyl (3,4-dihydroxy-5-nitrobenzoyl) acetate are suspended in 50 ml of ethanol.

Efter tilsætning af 0,4 g hydrazinhydrat holdes blandingen i 16 timer ved tilbagesvalingstemperatur. Efter afdestillering af opløsningsmidlet holdes remanensen ved 30 kogning i 5 minutter sammen med 50 ml ethylacetat. Det udfældede bundfald suges fra, og filtratet inddampes til 10 ml. De i kuide udfældede krystaller suges fra. Herved fås 5-(5-hydroxypyrazol-3-yl)-3-nitropyrocatechol i form af orangefarvede krystaller med smeltepunkt 228°C (sønderdeling).After the addition of 0.4 g of hydrazine hydrate, the mixture is kept at reflux temperature for 16 hours. After distilling off the solvent, the residue is kept at boiling for 5 minutes together with 50 ml of ethyl acetate. The precipitated precipitate is filtered off with suction and the filtrate is evaporated to 10 ml. The crystals precipitated in kuide are sucked off. This gives 5- (5-hydroxypyrazol-3-yl) -3-nitropyrocatechol in the form of orange crystals with a melting point of 228 ° C (decomposition).

35 EKSEMPEL 57EXAMPLE 57

Til 7,3 g (36,66 mmol) 3,4-dihydroxy-5-nitrobenzoesyre sættes der 30 ml eddikesyreanhydrid, hvorpå blandingen holdes ved tilbagesvalingstemperatur i 8 timer. Reaktionsblandingen hældes ud i is. Det udfældede bundfald suges fra, vaskes med vand 54 uh i /^uoy bi og tages op i methylenchlorid. Den organiske fase tøaes under natriumsulfat og inddampes. Den vundne remanens omkrystalliseres koldt af methylenchlorid/n-hexan. Herved fås 3,4-diacetoxy-5-nitrobenzoesyre i form af farveløse krystaller med smeltepunkt 126-127eC.To 7.3 g (36.66 mmol) of 3,4-dihydroxy-5-nitrobenzoic acid is added 30 ml of acetic anhydride, whereupon the mixture is kept at reflux temperature for 8 hours. The reaction mixture is poured into ice. The precipitated precipitate is filtered off with suction, washed with water 54 [mu] l in .mu.l bi and taken up in methylene chloride. The organic phase is thawed under sodium sulfate and evaporated. The residue obtained is cold recrystallized from methylene chloride / n-hexane. This gives 3,4-diacetoxy-5-nitrobenzoic acid in the form of colorless crystals, m.p. 126-127 ° C.

5 EKSEMPEL 58 a) Til 9,7 g (32,2 mmol) 3,4-diacetoxy-5-nitrobenzoesyre sættes der 12,5 ml 10 thionylchlorid, hvorpå der omrøres i 1,5 time ved 100°C. Efter afdestillering af det overskydende thionylchlorid destilleres 5-(chlorcarbonyl)-2-nitro-o-phenylendiacetaten, kogepunkt 160°C (26,7 Pa).EXAMPLE 58 a) To 9.7 g (32.2 mmol) of 3,4-diacetoxy-5-nitrobenzoic acid is added 12.5 ml of thionyl chloride, then stirred for 1.5 hours at 100 ° C. After distilling off the excess thionyl chloride, the 5- (chlorocarbonyl) -2-nitro-o-phenylene diacetate, boiling point 160 ° C (26.7 Pa), is distilled off.

b) 3,2 g (10,6 mmol) 5-(chlorcarbonyl)-2-nitro-o-phenylendiacetat opløses i 50 ml 15 dimethylformamid. Til den iskolde opløsning sættes der under omrøring en opløsning af 2.2 ml diethylamin i 20 ml dimethylformamid. Derefter omrøres der i 1 time ved stuetemperatur, hvorpå opløsningsmidlet destilleres af i vandstrålevacuum ved 50°C. Til den vundne remanens sættes der vand og methylenchlorid. Den organiske fase tørres over natriumsulfat og inddampes. Den vundne gule harpiks krystalliseres af 20 methylenchlorid/ether. Herved fås N,N-diethyl-3,4-dihydroxy-5-nitrobenzamid i form af gule krystaller med smeltepunkt 145-146°C.b) 3.2 g (10.6 mmol) of 5- (chlorocarbonyl) -2-nitro-o-phenylene diacetate are dissolved in 50 ml of dimethylformamide. To the ice-cold solution is added with stirring a solution of 2.2 ml of diethylamine in 20 ml of dimethylformamide. The mixture is then stirred for 1 hour at room temperature, after which the solvent is distilled off in a water jet vacuum at 50 ° C. To the obtained residue are added water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The yellow resin obtained is crystallized from methylene chloride / ether. This gives N, N-diethyl-3,4-dihydroxy-5-nitrobenzamide as yellow crystals, m.p. 145-146 ° C.

EKSEMPEL 59 3.2 g (10,6 mmol) 5-(chlorcarbonyl)-2-nitro-o-phenylen-diacetat opløses i 50 ml 25 dimethylformamid, hvorpå der under omrøring ved 0-5°C og i løbet af 40 minutter tilsættes en opløsning af 3,02 ml 2,2-diethylaminoethylamin i 20 ml dimethylformamid.EXAMPLE 59 3.2 g (10.6 mmol) of 5- (chlorocarbonyl) -2-nitro-o-phenylene diacetate are dissolved in 50 ml of dimethylformamide, then a mixture is added with stirring at 0-5 ° C and over 40 minutes a solution of 3.02 ml of 2,2-diethylaminoethylamine in 20 ml of dimethylformamide.

Derefter omrøres der i 30 minutter ved stuetemperatur. Opløsningsmidlet destilleres af i vandstrålevacuum ved 60°C. Remanensen ekstraheres med 2 x 20 ml ethanol, opløses i varm ethanol og tilsættes et overskud af ethanolisk saltsyre, hvorefter der inddampes.Then stir for 30 minutes at room temperature. The solvent is distilled off in a water jet vacuum at 60 ° C. The residue is extracted with 2 x 20 ml of ethanol, dissolved in hot ethanol and an excess of ethanolic hydrochloric acid is added, after which it is evaporated.

30 Efter omkrystallisering af ethanol/ethylacetat fås N-[2-(diethylamino)ethyl)-3,4-dihydroxy-5-nitrobenzamid-hydrochlorid i form af gule krystaller med smeltepunkt 139eC (sønderdeling).After recrystallization from ethanol / ethyl acetate, N- [2- (diethylamino) ethyl) -3,4-dihydroxy-5-nitrobenzamide hydrochloride is obtained in the form of yellow crystals, m.p. 139 ° C (dec.).

35 EKSEMPEL 60 a) Til 10,0 g (47,4 mmol) 2,3-dimethoxy-5-nitrobenzaldehyd sættes der 50 ml iseddike og 50 ml konstant kogende brombrintesyre, hvorefter blandingen holdes ved tilbagesvalingstemperatur i 7 timer. Efter tilsætning af is suges det udfældede bundfald 55 DK 175069 B1 fra, vaskes med vand og tages op i ethylacetat. Den organiske fase tørres over natriumsul· fat og inddampes. Det vundne råprodukt filtreres med ethylacetat over silicagel. Efter krystallisering af ethylacetat/hexan fås 2,3-dihydroxy*5-nitrobenzaldehyd i form af brunlige krystaller nied smeltepunkt 225-228°C.EXAMPLE 60 a) To 10.0 g (47.4 mmol) of 2,3-dimethoxy-5-nitrobenzaldehyde are added 50 ml of glacial acetic acid and 50 ml of constantly boiling hydrobromic acid, after which the mixture is kept at reflux temperature for 7 hours. After adding ice, the precipitated precipitate is sucked off, washed with water and taken up in ethyl acetate. The organic phase is dried over sodium sulphate and evaporated. The crude product obtained is filtered with ethyl acetate over silica gel. After crystallization of ethyl acetate / hexane, 2,3-dihydroxy * 5-nitrobenzaldehyde is obtained as brownish crystals, m.p. 225-228 ° C.

5 b) 4,5 g 2,3-dihydroxy-5-nitrobenzaldehyd suspenderes i 75 ml vand. Efter tilsætning af 4,2 g hydroxylamin-o-sulfonsyre omrøres der i 16 timer ved 65°C. Efter afkøling suges de udfældede krystaller fra og vaskes med vand. Filtratet ekstraheres med ethylacetat. Krystallerne og den tørrede organiske fase forenes, hvorefter der inddampes, og remanensen 10 omkrystalliseres af diisopropylether. Herved fås 2,3-dihydroxy-5-nitrobenzonitril i form af gule krystaller med smeltepunkt 186-188°C.B) 4.5 g of 2,3-dihydroxy-5-nitrobenzaldehyde are suspended in 75 ml of water. After adding 4.2 g of hydroxylamine-o-sulfonic acid, the mixture is stirred for 16 hours at 65 ° C. After cooling, the precipitated crystals are sucked off and washed with water. The filtrate is extracted with ethyl acetate. The crystals and the dried organic phase are combined, then evaporated and the residue 10 is recrystallized from diisopropyl ether. This gives 2,3-dihydroxy-5-nitrobenzonitrile as yellow crystals, m.p. 186-188 ° C.

EKSEMPEL 61 15 a) 4,0 g (19,2 mmol) 3,4-dimethoxy-5-nitro-behzomtril opløses i 50 ml dimethylformamid, hvorefter der tilsættes 1,66 g ammoniumchlorid og 2,02 g natriumazid og der omrøres i 31 timer ved 125®C. Efter henholdsvis 8 og 15 timer tilsættes der endnu en gang den samme mængde ammoniumchlorid og natriumazid. Efter afkøling hældes blandingen ud i is. Det udfældede bundfald suges fra, vaskes med vand og tørres. Herved 20 fås 2-methoxy-6-nitro-4-(lH-tetrazol-5-yl)phenol i form af orangefarvede krystaller med smeltepunkt >240eC (sønderdeling).EXAMPLE 61 a) 4.0 g (19.2 mmol) of 3,4-dimethoxy-5-nitro-behomotril are dissolved in 50 ml of dimethylformamide, then 1.66 g of ammonium chloride and 2.02 g of sodium azide are added and stirred in 31 hours at 125 ° C. After 8 and 15 hours, respectively, the same amount of ammonium chloride and sodium azide are added again. After cooling, pour the mixture into ice. The precipitated precipitate is filtered off with suction, washed with water and dried. This gives 2-methoxy-6-nitro-4- (1H-tetrazol-5-yl) phenol in the form of orange crystals with a melting point> 240 ° C (decomposition).

b) Trl 4,0 g (16,9 mmol) 2-methoxy-6-nitro-4-(lH-tetrazol-5-yl)phenol sættes der 40 ml konstant kogende brombrintesyre, hvorpå der omrøres under nitrogenatmosfære i 8 timer 25 ved 140°C. Efter afkøling hældes blandingen ud i is. Det udfældede bundfald suges fra og omkrystalliseres af ether. Herved fås 3-nitro-5-(lH-tetrazol-5-yl)pyrocatechol i form af orangefarvede krystaller med smeltepunkt >240eC (sønderdeling). 1 EKSEMPEL 62b) Trl 4.0 g (16.9 mmol) of 2-methoxy-6-nitro-4- (1H-tetrazol-5-yl) phenol are added 40 ml of constantly boiling hydrobromic acid, then stirred under a nitrogen atmosphere for 8 hours 25 at 140 ° C. After cooling, pour the mixture into ice. The precipitated precipitate is filtered off with suction and recrystallized from ether. This gives 3-nitro-5- (1H-tetrazol-5-yl) pyrocatechol in the form of orange crystals with a melting point> 240 ° C (decomposition). 1 EXAMPLE 62

Til 130 ml koncentreret svovlsyre sættes der under omrøring og i løbet af 10 minutter portionsvis i alt 7,2 g (40 mmol) 3,4-dihydroxy-5-nitrobenzonitril, hvorpå der omrøres i 4 timer ved 50°C. Reaktionsblandingen hældes ud i 800 ml isvand. Det udfældede bundfald 35 suges fra, vaskes med vand og tages op i ethylacetat. Den organiske fase tørres over natriumsulfat og inddampes. Efter omkrystallisering af acetone/ethylacetat fås 3,4-dihydroxy-5-nitrobenzamid i form af orangefarvede krystaller med smeltepunkt 235-236°C.To 130 ml of concentrated sulfuric acid is added, with stirring and over 10 minutes, a total of 7.2 g (40 mmol) of 3,4-dihydroxy-5-nitrobenzonitrile, then stirring for 4 hours at 50 ° C. The reaction mixture is poured into 800 ml of ice water. The precipitated precipitate 35 is filtered off with suction, washed with water and taken up in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. After recrystallization from acetone / ethyl acetate, 3,4-dihydroxy-5-nitrobenzamide is obtained in the form of orange crystals, m.p. 235-236 ° C.

EKSEMPEL 63EXAMPLE 63

UI\ I i OUOS D IUI \ I i OUOS D I

56 a) Til en suspension af 3,6 g (82,5 mimol) af en 55% natriumhydriddispersion i 50 ml 5 absolut dimethylformamid dryppes under argonatmosfære og i løbet af 15 minutter en opløsning af 11,25 g (82,6 mmol) 2-hydroxyacetophenon i 100 ml absolut dimethylformamid og der omrøres i 1 time ved stuetemperatur. Efter afkøling til 0*C tildryppes der i løbet af 20 minutter en opløsning af 20,3 g (82,6 mmol) 3,4-dimethoxy-5-nitrobenzoylchlorid i 100 ml absolut dimethylformamid og der omrøres ved stuetemperatur 10 natten over. Reaktionsblandingen hældes ud i isvand, hvorefter der ekstraheres med 2 x 250 ml ethylacetat. Den organiske fase ekstraheres med 2 x 100 ml kogsaltopløsning, tørres over natriumsulfat og inddampes. Den vundne brune olie opvarmes i 100 ml toluen.56 a) To a suspension of 3.6 g (82.5 mmol) of a 55% sodium hydride dispersion in 50 ml of 5 absolute dimethylformamide is added dropwise under an argon atmosphere and in 15 minutes a solution of 11.25 g (82.6 mmol) 2-Hydroxyacetophenone in 100 ml of absolute dimethylformamide and stir for 1 hour at room temperature. After cooling to 0 DEG C., a solution of 20.3 g (82.6 mmol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of absolute dimethylformamide is added dropwise over 20 minutes and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water, after which it is extracted with ethyl acetate (2 x 250 ml). The organic phase is extracted with brine (2 x 100 ml), dried over sodium sulphate and evaporated. The brown oil obtained is heated in 100 ml of toluene.

Den udfældede bundfald suges fra, og filtratet chromatograferes på den 30-dobbelte mængde sillcagel med toluen/ethylacetat (4:1). Efter omkrystallisering af 15 ethylacetat/hexan fås o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoat i form af gule krystaller med smeltepunkt 108-109°C.The precipitated precipitate is filtered off with suction and the filtrate is chromatographed on the 30-fold amount of silica gel with toluene / ethyl acetate (4: 1). After recrystallization from ethyl acetate / hexane, o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoate is obtained as yellow crystals, m.p. 108-109 ° C.

b) 10,0 g (29 mmol) o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoat opløses i 50 ml pyridin. Efter tilsætning af 8,12 g (144 mmol) pulveriseret og tørret kaliumhydroxid 20 omrøres der i 5 minutter ved 80°C. Efter afkøling hældes blandingen ud i is. Den vandige opløsning gøres sur ved tilsætning af 3N-saltsyre. Det udfældede bundfald suges fra. Efter omkrystallisering af ethylacetat/hexan fås l-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-l,3-propandion i form af gullige krystaller med smeltepunkt 188-189°C.b) Dissolve 10.0 g (29 mmol) of o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoate in 50 ml of pyridine. After adding 8.12 g (144 mmol) of powdered and dried potassium hydroxide, stir for 5 minutes at 80 ° C. After cooling, pour the mixture into ice. The aqueous solution is acidified by the addition of 3N hydrochloric acid. The precipitated precipitate is sucked off. After recrystallization from ethyl acetate / hexane, 1- (o-hydroxyphenyl) -3- (3,4-dimethoxy-5-nitrophenyl) -1,3-propanedione is obtained in the form of yellowish crystals, m.p. 188-189 ° C.

25 c) Til en opløsning af 500 mg (1,45 mmol) l-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5' nitrophenyl)-l,3-propandion i 50 ml methylenchlorid dryppes der under omrøring og argonatmosfære ved -20°C og i løbet af 20 minutter en opløsning af 1,82 g (0,7 ml) bortribromid i 20 ml methylenchlorid, hvorefter der omrøres natten over ved stuetemperatur. Efter afkøling til -20°C tilsættes der dråbevis 25 ml ethanol og inddampes ved 40°C i 30 vandstrålevacuum. Efter omfældning af ethanol fås l-(3,4-dihydroxy-5-nitrophenyl)-3-(o-hydroxyphenyl)-l,3-propandion i form af gule krystaller med smeltepunkt 251-252°C.C) To a solution of 500 mg (1.45 mmol) of 1- (o-hydroxyphenyl) -3- (3,4-dimethoxy-5 'nitrophenyl) -1,3-propanedione in 50 ml of methylene chloride is added dropwise with stirring and argon atmosphere at -20 ° C and a solution of 1.82 g (0.7 ml) of boron tribromide in 20 ml of methylene chloride over 20 minutes, after which it is stirred overnight at room temperature. After cooling to -20 ° C, 25 ml of ethanol are added dropwise and evaporated at 40 ° C in a water jet vacuum. After precipitation of ethanol, 1- (3,4-dihydroxy-5-nitrophenyl) -3- (o-hydroxyphenyl) -1,3-propanedione is obtained in the form of yellow crystals, m.p. 251-252 ° C.

EKSEMPEL 64 35 a) Til en opløsning af 2,0 g (5,79 mmol) o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoat i 12,5 ml iseddike sættes der 0,94 g natriumacetat, og blandingen holdes i 4 timer ved tilbagesvalingstemperatur. Efter afkøling hældes blandingen ud i isvand. De udfældede krystaller suges fra. Efter omkrystallisering af ethylacetat/hexan fås 2-(3,4-dimethoxy-5- 57 DK 175069 B1 nitrophenyl)-4H-l-benzopyran-4-on i form af farveløse krystaller med smeltepunkt 216-217°C.EXAMPLE 64 35 a) To a solution of 2.0 g (5.79 mmol) of o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoate in 12.5 ml of glacial acetic acid is added 0.94 g of sodium acetate and the mixture is kept in 4 hours at reflux temperature. After cooling, the mixture is poured into ice water. The precipitated crystals are sucked off. After recrystallization from ethyl acetate / hexane, 2- (3,4-dimethoxy-5-nitrophenyl) -4H-1-benzopyran-4-one is obtained as colorless crystals, m.p. 216-217 ° C.

b) Til en opløsning af 1,0 g (2,9 mmol) 2-(3,4-dimethoxy-5-nitrophenyl)-4H-l-5 benzopyran-4-on i 100 ml methylenchlorid dryppes der ved -10°C under en argonatmosfære og i løbet af 30 minutter en opløsning af 10 ml bortribromid i 50 ml methylenchlorid, hvorefter der omrøres natten over ved stuetemperatur. Efter afkøling til -20°C tildryppes der 20 ml ethanol. Derefter inddampes blandingen ved 40°C i vandstrålevacuum. Den vundne gule remanens ekstraheres med vand/ethylacetat. Den 10 organiske fase vaskes med vand, tørres over natriumsulfat og inddampes. Efter omkrystallisering af ethanol/ethylacetat fås 2-(3,4-dihydroxy-5-nitrophenyl)-4H-l-benzopyran-4-on i form af gule krystaller med smeltepunkt >240°C (sønderdeling).b) To a solution of 1.0 g (2.9 mmol) of 2- (3,4-dimethoxy-5-nitrophenyl) -4H-1-5 benzopyran-4-one in 100 ml of methylene chloride is added dropwise at -10 ° C under an argon atmosphere and a solution of 10 ml of boron tribromide in 50 ml of methylene chloride over 30 minutes, then stirring overnight at room temperature. After cooling to -20 ° C, 20 ml of ethanol are added dropwise. The mixture is then evaporated at 40 ° C in a water jet vacuum. The yellow residue obtained is extracted with water / ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. After recrystallization from ethanol / ethyl acetate, 2- (3,4-dihydroxy-5-nitrophenyl) -4H-1-benzopyran-4-one is obtained in the form of yellow crystals, m.p.> 240 ° C (dec.).

15 EKSEMPEL 65 a) Til 33,0 g 4-brombenzotrifluorid (opløst i 150 ml tetrahydrofuran) dryppes der ved -70aC og i løbet af 20 minutter 92 ml 1,6 M n-butyllithiumopløsning i hexan. Efter 45 minutter omrøring ved -70°C tildryppes der ved mellem -70°C og -60°C 36 g 3-methoxy-4- 20 benzyloxybenzaldehyd (opløst i 100 ml tetrahydrofuran). Reaktionsblandingen omrøres i 2 timer ved -70°C og 1 time ved 0°C, hældes ud i en blanding af is og 100 ml 2N-svovlsyre og ekstraheres med 2 x 500 ml ether. De forenede etherfaser vaskes med mættet kogsaltopløsning, tørres over natriumsulfat og inddampes. Herved fås 4-(benzyloxy)-3-methoxy-4'-(trifluormethyl)benzhydrol, som kan anvendes direkte i det efterfølgende 25 reaktionstrin.EXAMPLE 65 a) To 33.0 g of 4-bromobenzotrifluoride (dissolved in 150 ml of tetrahydrofuran) is added dropwise at -70 DEG C. and in 20 minutes 92 ml of 1.6 M n-butyllithium solution in hexane. After stirring for 45 minutes at -70 [deg.] C., 36 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 100 ml of tetrahydrofuran) are added dropwise at -70 DEG-60 DEG C. The reaction mixture is stirred for 2 hours at -70 ° C and 1 hour at 0 ° C, poured into a mixture of ice and 100 ml of 2N sulfuric acid and extracted with 2 x 500 ml of ether. The combined ether phases are washed with saturated brine, dried over sodium sulfate and evaporated. This gives 4- (benzyloxy) -3-methoxy-4 '- (trifluoromethyl) benzhydrol, which can be used directly in the subsequent reaction step.

b) Til 52,6 g 4-(benzyloxy)-3-methoxy-4'-(trifluormethyl)benzhydrol (opløst i 500 ml methylenchlorid) sættes der ved 20°C og i løbet af 10 minutter 30,6 g pyridiniumchlorchromat og omrøres i 2 timer ved 20°C. Derefter filtreres det dannede 30 bundfald fra og vaskes med methylenchlorid. Filtratet inddampes, og remanensen chromatograferes på 150 g silicagel med methylenchlorid. Efter omkrystallisering af methylenchlorid/hexan fås 4-(benzyloxy)-3-methoxy-4'-(trifluormethyl)benzophenon med smeltepunkt 101°C.b) To 52.6 g of 4- (benzyloxy) -3-methoxy-4 '- (trifluoromethyl) benzhydrol (dissolved in 500 ml of methylene chloride) is added at 20 ° C and in 10 minutes 30.6 g of pyridinium chlorochromate and stirred for 2 hours at 20 ° C. The precipitate formed is then filtered off and washed with methylene chloride. The filtrate is evaporated and the residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization from methylene chloride / hexane, 4- (benzyloxy) -3-methoxy-4 '- (trifluoromethyl) benzophenone with a melting point of 101 ° C is obtained.

35 c) Til 20 g 4-(benzyloxy)-3-methoxy-4'-(trifluormethyl)-benzophenon (opløst i 150 ml methylenchlorid) sættes der ved 10°C og i løbet af 15 minutter 70 ml 33% brombrintesyre i eddikesyre. Efter 1,5 times omrøring ved 20°C hældes reaktionsblandingen i 600 ml isvand; methylenchioridfasen skilles fra, og den vandige fase ekstraheres med endnu 2 x 100 ml methylenchlorid. De forenede methylenchloridfaser vaskes med 600 ml vand, ui\. i /ouoy m 58 I tørres over natriumsulfat og inddampes. Remanensen chromatograferes pi 150 g silicagel I med methylenchlorid. Efter omkrystallisering af methylenchlorid/hexan fås 4-hydroxy-3- I methoxy-4'-(trifluormethyl)benzophenon med smeltepunkt 97eC.35 c) To 20 g of 4- (benzyloxy) -3-methoxy-4 '- (trifluoromethyl) -benzophenone (dissolved in 150 ml of methylene chloride) is added at 10 ° C and in 15 minutes 70 ml of 33% hydrobromic acid in acetic acid . After stirring for 1.5 hours at 20 ° C, the reaction mixture is poured into 600 ml of ice water; the methylene chloride phase is separated off and the aqueous phase is extracted with a further 2 x 100 ml of methylene chloride. The combined methylene chloride phases are washed with 600 ml of water, ui \. i / ouoy m 58 I dry over sodium sulphate and evaporate. The residue is chromatographed on 150 g of silica gel I with methylene chloride. After recrystallization from methylene chloride / hexane, 4-hydroxy-3-methoxy-4 '- (trifluoromethyl) benzophenone with melting point 97 ° C is obtained.

I 5 d) Til 12,8 g 4-hydroxy-3-methoxy-4'-(trifluormethyl)benzophenon (opløst i 160 ml I eddikesyre) dryppes der ved 20°C og i løbet af 10 minutter 3,2 ml 65% saltpetersyre. Efter I 1,5 times omrøring hældes reaktionsblandingen ud i 600 ml isvand, og det dannede I bundfald filtreres fra, vaskes med vand og opløses i methylenchlorid. Methylen- I chloridopløsningen tørres over natriumsulfat og inddampes, og remanensen I 10 omkrystalliseres af methylenchlorid/hexan. Herved fås 4-hydroxy-3-methoxy-5-nitro-4‘- I (trifluormethyl)benzophenon med smeltepunkt 172°C.I 5 d) To 12.8 g of 4-hydroxy-3-methoxy-4 '- (trifluoromethyl) benzophenone (dissolved in 160 ml of acetic acid) is added dropwise at 20 [deg.] C. and in 10 minutes 3.2 ml of 65% hydrochloric acid. After stirring for 1.5 hours, the reaction mixture is poured into 600 ml of ice water and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene-I chloride solution is dried over sodium sulfate and evaporated and the residue I10 is recrystallized from methylene chloride / hexane. This gives 4-hydroxy-3-methoxy-5-nitro-4'-I (trifluoromethyl) benzophenone, m.p. 172 ° C.

I e) 2,0 g 4-hydroxy-3-methoxy-5-nitro-4,-(trifluormethyl)benzophenon (opløst i 20 ml I 33% brombrintesyre i eddikesyre) omrøres i 18 timer ved 90°C. Herefter tilsættes der I 15 20 ml 48% vandig brombrintesyre, hvorefter der omrøres i yderligere 18 timer ved 110°C.I e) 2.0 g of 4-hydroxy-3-methoxy-5-nitro-4 - (trifluoromethyl) benzophenone (dissolved in 20 ml in 33% hydrobromic acid in acetic acid) are stirred for 18 hours at 90 ° C. Then add 20 ml of 48% aqueous hydrobromic acid, stirring for a further 18 hours at 110 ° C.

I Derefter inddampes reaktionsblandingen under formindsket tryk, og remanensen I krystalliseres af vand. Herved fås 3,4-dihydroxy-5-nitro-4'-(trifluormethyl)benzophenon I med smeltepunkt 116-118°C.Then the reaction mixture is evaporated under reduced pressure and the residue I is crystallized from water. This gives 3,4-dihydroxy-5-nitro-4 '- (trifluoromethyl) benzophenone I, m.p. 116-118 ° C.

I 20 I EKSEMPEL 66 I a) Til 18,7 g 4-hydroxy-3-methoxy-5'nitro-4'-(trifluormethyl)benzophenon (opløst i I 250 ml tetrahydrofuran) sættes der ved stuetemperatur 27,5 ml 2N- I 25 kaliumhydroxidopløsning, hvorefter der inddampes. Til remanensen sættes der 200 ml I toluen, hvorpå der igen inddampes. Herefter opvarmes blandingen med 400 ml toluen i 4 I timer under vandudskillelse og tilbagesvaling. Der destilleres 100 ml toluen af, og der I tilsættes 10 ml dimethylformamid og 20 ml dimethylsulfat (frisk destilleret), hvorefter derI 20 I EXAMPLE 66 I a) To 18.7 g of 4-hydroxy-3-methoxy-5'-nitro-4 '- (trifluoromethyl) benzophenone (dissolved in 250 ml of tetrahydrofuran) is added at room temperature 27.5 ml of 2N- In 25 potassium hydroxide solution, after which evaporate. To the residue is added 200 ml of toluene, then evaporated again. The mixture is then heated with 400 ml of toluene for 4 l for hours under water separation and reflux. 100 ml of toluene are distilled off and 10 ml of dimethylformamide and 20 ml of dimethyl sulphate (freshly distilled) are added, after which

I opvarmes i 5 timer under tilbagesvaling. Derefter tilsættes der ved 20°C 300 ml INI heat for 5 hours under reflux. Then 300 ml of IN are added at 20 ° C

I 30 natronhydroxidopløsning. Reaktionsblandingen omrøres i 30 minutter, og der tilsættes I 200 ml ether. Den organiske fase skilles fra; den vandige fase ekstraheres med 2 x 100 ml I ether; de forenede etherfaser tørres over natriumsulfat og inddampes, og remanensen I chromatograferes på 70 g silicagel med methylenchlorid. Efter omkrystallisering af I methylenchlorid/hexan fås 3,4-dimethoxy-5-nitro-4*-(trifluormethyl)benzophenon med I 35 smeltepunkt 115°C.In sodium hydroxide solution. The reaction mixture is stirred for 30 minutes and 200 ml of ether are added. The organic phase is separated; the aqueous phase is extracted with ether (2 x 100 ml); the combined ether phases are dried over sodium sulphate and evaporated and the residue I is chromatographed on 70 g of silica gel with methylene chloride. After recrystallization from methylene chloride / hexane, 3,4-dimethoxy-5-nitro-4 * - (trifluoromethyl) benzophenone with a melting point of 115 DEG C. is obtained.

I b) Til 16,0 g 3,4-dimethoxy-5-nitro-4'-(trifluormethyl)benzophenon (opløst i 300 ml I ethanol) sættes der 49,5 g tindichlorid-dihydrat, hvorefter der omrøres i 30 minutter ved I 75°C. Herefter hældes reaktionsblandingen ud i 800 ml isvand. Blandingen neutraliseres I med 28% natriumhydroxidopløsning og ekstraheres med 3 x 600 ml methylenchlorid. De 59 DK 175069 B1 forenede methylenchloridfaser vaskes med vand, tørres over natriumsulfat og inddampes.I b) To 16.0 g of 3,4-dimethoxy-5-nitro-4 '- (trifluoromethyl) benzophenone (dissolved in 300 ml of ethanol) is added 49.5 g of tin dichloride dihydrate, then stirred for 30 minutes at At 75 ° C. Then the reaction mixture is poured into 800 ml of ice water. The mixture is neutralized with 28% sodium hydroxide solution and extracted with methylene chloride (3 x 600 ml). The combined methylene chloride phases are washed with water, dried over sodium sulfate and evaporated.

Efter omkrystallisering af methylenchlorid/hexan fis 5-amino-3,4-dimethoxy-4'-(trifluormethyl)benzophenon med smeltepunkt 95-96°C.After recrystallization from methylene chloride / hexane, 5-amino-3,4-dimethoxy-4 '- (trifluoromethyl) benzophenone, m.p. 95-96 ° C.

5 c) 3,25 g S-amino-S^-dimethoxy-d'-itrifluormethyObenzophenon (opløst i 50 ml acetone) bitver efter tilsætning af 15 ml 2N svovlsyre inddampet under reduceret tryk. Den således vundne remanens suspenderes i 20 ml eddikesyre, fortyndes med 100 ml vand, hvorefter der ved 5°C tilsættes en opløsning af 700 mg natriumnitrit i 10 ml vand. Der omrøres i 1 time ved 5°C. Herefter filtreres diazoniumsaltopløsningen, sættes til en 10 opløsning af 2,0 g natriumcyanid og 1,0 g kopper(I)cyanid i 20 ml vand ved 5°C og omrøres i 1 time ved 5°C. Derefter tilsættes der 200 ml methylenchlorid. Uopløselige andele filtreres fra. Faserne adskilles; den vandige fase ekstraheres med endnu 2 x 100 ml methylenchlorid. De forenede methylenchloridfaser vaskes med vand, tørres over natriumsulfat og inddampes. Remanensen chromatograferes på 30 g silicagel med 15 methylenchlorid. Efter omkrystallisering af methylenchlorid/hexan fås 5-cyano-3,4-dimethoxy-4’-{trifluormethyl)benzophenon med smeltepunkt 130°C.C) 3.25 g of S-amino-S 4 -dimethoxy-d'-itrifluoromethylbenzophenone (dissolved in 50 ml of acetone) bitver after addition of 15 ml of 2N sulfuric acid evaporated under reduced pressure. The residue thus obtained is suspended in 20 ml of acetic acid, diluted with 100 ml of water, after which a solution of 700 mg of sodium nitrite in 10 ml of water is added at 5 ° C. Stir for 1 hour at 5 ° C. Then the diazonium salt solution is filtered, added to a solution of 2.0 g of sodium cyanide and 1.0 g of cups (I) cyanide in 20 ml of water at 5 ° C and stirred for 1 hour at 5 ° C. Then 200 ml of methylene chloride are added. Insoluble proportions are filtered off. The phases are separated; the aqueous phase is extracted with a further 2 x 100 ml of methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 30 g of silica gel with methylene chloride. After recrystallization from methylene chloride / hexane, 5-cyano-3,4-dimethoxy-4 '- (trifluoromethyl) benzophenone with a melting point of 130 ° C is obtained.

d) Til 1,5 g 5-cyano-3,4-dimethoxy-4'-{trifluormethyl)benzophenon (opløst i 75 ml methylenchlorid) sættes der ved 5°C 2,18 ml bortribromid, hvorefter der omrøres ved 20 stuetemperatur i 18 timer. Derefter fortyndes reaktionsblandingen med 50 ml methylenchlorid. Blandingen opvarmes i yderligere 4 timer under tilbagesvaling, og ved -70°C tilsættes der 15 ml methanol, omrøres i 2 timer ved stuetemperatur og inddampes, og remansen tørres i vacuum og deles mellem ethylacetat og isvand. Den vandige fase ekstraheres endnu 2 gange med ethylacetat. De forenede ethylacetatfaser tørres over 25 natriumsulfat og inddampes. Det således vundne materiale omrøres i 6 timer ved 130°C sammen med 10 ml eddikesyreanhydrid og 1 ml pyridin. Blandingen inddampes, og remanensen deles mellem isvand og methylenchlorid. Methylenchloridfasen tørres over natriumsulfat og inddampes, og remanensen chromatograferes på 30 g silicagel med methylenchlorid. Det således vundne diacetat opløses i 10 ml methanol. Der tilsættes 30 4,2 ml lN-natriumhydroxidopløsning, omrøres i 1 time ved 0°C, neutraliseres med eddikesyre, inddampes og deles mellem ethylacetat og mættet kogesaltopløsning.d) To 1.5 g of 5-cyano-3,4-dimethoxy-4 '- (trifluoromethyl) benzophenone (dissolved in 75 ml of methylene chloride) is added at 5 ° C 2.18 ml of boron tribromide, after which it is stirred at room temperature in 18 hours. The reaction mixture is then diluted with 50 ml of methylene chloride. The mixture is heated for a further 4 hours under reflux and at -70 ° C 15 ml of methanol are added, stirred for 2 hours at room temperature and evaporated and the residue is dried in vacuo and partitioned between ethyl acetate and ice water. The aqueous phase is extracted twice more with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The material thus obtained is stirred for 6 hours at 130 ° C together with 10 ml of acetic anhydride and 1 ml of pyridine. The mixture is evaporated and the residue is partitioned between ice water and methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated and the residue is chromatographed on 30 g of silica gel with methylene chloride. The diacetate thus obtained is dissolved in 10 ml of methanol. Add 4.2 ml of 1N sodium hydroxide solution, stir for 1 hour at 0 ° C, neutralize with acetic acid, evaporate and partition between ethyl acetate and saturated brine.

Ethyiacetatfaseme tørres over natriumsulfat og inddampes, og remanensen omkrystalliseres af methylenchlorid. Herved fås 5-cyano-3,4-dihydroxy-4'-(trifluormethyl)benzophenon med smeltepunkt 204-206°C.The ethyl acetate phases are dried over sodium sulfate and evaporated and the residue is recrystallized from methylene chloride. This gives 5-cyano-3,4-dihydroxy-4 '- (trifluoromethyl) benzophenone, m.p. 204-206 ° C.

35 På analog måde fås følgende: al) Ud fra 2,-fluor-4-hydroxy-3-methoxy-5-nitrobenzophenon fås 3,4-dimethoxy-2’*fluor* 5-nttrobenzophenon med smeltepunkt 86-88°C (af ether/petroleumsether, ts.).In an analogous manner the following are obtained: a1) From 2, -fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone, 3,4-dimethoxy-2 '* fluoro * 5-nitrobenzophenone with melting point 86-88 ° C is obtained ( of ether / petroleum ether, ts.).

_ bl) Ud fra 3,4-dimethoxy-2'-fluor-5-nitrobenzophenon fås 5-amino-3,4-dimethoxy-2’- fluorbenzophenon med smeltepunkt 93-95°C (af ether/petroleumsether, ts.).Bl) From 3,4-dimethoxy-2'-fluoro-5-nitrobenzophenone, 5-amino-3,4-dimethoxy-2'-fluorobenzophenone is obtained, m.p. 93-95 ° C (of ether / petroleum ether, ts.) .

DK 175069 B1 60 5 cl) Ud fra 5-amino-3,4-dimethoxy-2‘-fluorbenzophenon fås 5-benzoyl-2,3-dimethoxy-2·-fluorbenzonitril med smeltepunkt 132-34°C (af methylenchlorid/petroleumsether, ts.) og dl) ud fra 5-benzoyl-2,3-dimethoxy-2‘-fluorbenzonitril fås 5-benzoyl-2,3-dihydroxy-2'-fluorbenzonitril med smeltepunkt 228-230°C (af methylenchlorid/petroleumsether, ts.).DK 175069 B1 60 5 cl) From 5-amino-3,4-dimethoxy-2'-fluorobenzophenone 5-benzoyl-2,3-dimethoxy-2 · -fluorobenzonitrile with melting point 132-34 ° C (of methylene chloride / petroleum ether is obtained , ts.) and dl) from 5-benzoyl-2,3-dimethoxy-2'-fluorobenzonitrile 5-benzoyl-2,3-dihydroxy-2'-fluorobenzonitrile with a melting point of 228-230 ° C (of methylene chloride / petroleum ether , ts.).

10 På analog måde fås følgende: b2) Ud fra 3,4-dimethoxy*5-nitrobenzophenon fås 5-amino-3,4-dimethoxybenzophenon som amorft fast stof, 15 c2) ud fra 5-amino-3,4-dimethoxybenzophenon fås 5-benzoyl-2,3-dimethoxybenzonitril med smeltepunkt 98-100°C (af ether/hexan) og d2) ud fra 5-benzoyl-2,3-dimethoxybenzonitril fås 5-benzoyl-2,3-dihydroxybenzonitril 20 med smeltepunkt 212-214°C (af ethylacetat/ether).In an analogous manner the following are obtained: b2) From 3,4-dimethoxy * 5-nitrobenzophenone is obtained 5-amino-3,4-dimethoxybenzophenone as amorphous solid, 15 c2) from 5-amino-3,4-dimethoxybenzophenone is obtained 5-Benzoyl-2,3-dimethoxybenzonitrile, m.p. 98-100 ° C (of ether / hexane) and d2) from 5-benzoyl-2,3-dimethoxybenzonitrile, 5-benzoyl-2,3-dihydroxybenzonitrile 20, m.p. -214 ° C (of ethyl acetate / ether).

EKSEMPEL 67 25 a) Til en opløsning af 2,68 g (32,64 mmol) 1-methylimidazol og 6,6 g (65,14 mmol) triethylamin i 80 ml pyridin dryppes der en opløsning af 16,0 g (65,14 mmol) 3,4-dimethoxy-5-nitrobenzoytchlorid i 80 ml pyridin, hvorpå der omrøres i 3 timer ved 60°C.EXAMPLE 67 25 a) To a solution of 2.68 g (32.64 mmol) of 1-methylimidazole and 6.6 g (65.14 mmol) of triethylamine in 80 ml of pyridine is added dropwise a solution of 16.0 g (65, 14 mmol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 80 ml of pyridine, then stirring for 3 hours at 60 ° C.

Efter tilsætning af 1,70 ml 3N-natriumhydroxidopløsning omrøres der videre i 1 time, hvorefter blandingen hældes ud i isvand. De udfældede grå krystaller suges fra og tages 30 op i ethylacetat, hvorefter den organiske fase tørres over magnesiumsulfat, og opløsningsmidlet destilleres af. Efter omkrystallisering af ethylacetat/hexan fås 3,4-dimethoxy-5-nitrophenyl-(l-methylimidazol-2-yl)keton i form af farveløse krystaller med smeltepunkt 144-145°C.After adding 1.70 ml of 3N sodium hydroxide solution, stirring is continued for 1 hour, after which the mixture is poured into ice water. The precipitated gray crystals are filtered off with suction and taken up in ethyl acetate, after which the organic phase is dried over magnesium sulphate and the solvent is distilled off. After recrystallization from ethyl acetate / hexane, 3,4-dimethoxy-5-nitrophenyl- (1-methylimidazol-2-yl) ketone is obtained in the form of colorless crystals, m.p. 144-145 ° C.

35 b) Til 5,0 g (17,17 mmol) 3,4-dimethoxy-5-nitrophenyl-(l-methylimidazol-2-yl)keton sættes der 50 ml 48% brombrintesyre, hvorefter der omrøres i 2 timer ved tilbagesvalingstemperatur. Efter afkøling suges det udfældede bundfald fra, vaskes med isvand og omkrystalliseres af ethanol. Herved fås 3,4-dihydroxy-5-nitrophenyl-(l-methylimidazol-2-yl)keton-hydrobromid i form af gule krystaller med sønderdelingspunkt 61 DK 175069 B1 >240eC.B) To 5.0 g (17.17 mmol) of 3,4-dimethoxy-5-nitrophenyl- (1-methylimidazol-2-yl) ketone is added 50 ml of 48% hydrobromic acid, then stirred for 2 hours at reflux temperature . After cooling, the precipitated precipitate is filtered off with suction, washed with ice water and recrystallized from ethanol. This gives 3,4-dihydroxy-5-nitrophenyl- (1-methylimidazol-2-yl) ketone hydrobromide in the form of yellow crystals with decomposition point 61 DK 175069 B1> 240eC.

EKSEMPEL 68 5EXAMPLE 68 5

Ud fra 3,4-dimethoxy-5-nitrobenzoylchlorid og 1-benzylimidazo! fås analogt med eksempel 67 l*benzyl-imidazol-2-yl-(3,4-dimethoxy-5-nitrophenyl)keton i form af farveløse krystaller med smeltepunkt 134*135°C (af methylenchlorid/hexan) og derudfra ved hjælp af brombrintesyre l-benzyl-imidazol-2-yl (3,4-dihydroxy-5-nitrophenyl)keton-hydrobromid 10 som gule krystaller med smeltepunkt 218-219°C (sønderdeling).From 3,4-dimethoxy-5-nitrobenzoyl chloride and 1-benzylimidazole! obtained analogously to Example 67 1 * benzyl-imidazol-2-yl- (3,4-dimethoxy-5-nitrophenyl) ketone in the form of colorless crystals, m.p. 134 DEG-135 DEG C. (of methylene chloride / hexane) and from there by means of hydrobromic acid 1-benzyl-imidazol-2-yl (3,4-dihydroxy-5-nitrophenyl) ketone hydrobromide 10 as yellow crystals, m.p. 218-219 ° C (dec.).

EKSEMPEL 69 a) Til en opløsning af 13,0 g (53,13 mmol) 3,4-dimethoxy-5-nitrobenzoylchlorid og 5,4 g 15 (53,13 mmol) triethylamin i 80 ml acetonitril dryppes der under iskøling og i løbet af 10 minutter en opløsning af 10,0 g (53,13 mmol) l-[(benzyloxy)methyl]imidazol i 50 ml acetonitril på en sådan måde, at temperaturen ikke overstiger 25°C. Derefter omrøres der videre i 3 timer, hvorefter opløsningsmidlet destilleres af. Efter tilsætning af vand ekstraheres der med acetylacetat. Efter 2 ganges vaskning med vand tørres den organiske 20 fase over natriumsulfat og inddampes. Den vundne olie chromatograferes på 600 g silicagel med toluen/ethylacetat (95:5). Herved fås l-[(benzyloxy)methyl]imidazol-2-yl-(3,4-dimethoxy-5-nitrophenyl)keton som en gullig olie.EXAMPLE 69 a) To a solution of 13.0 g (53.13 mmol) of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4 g of 15 (53.13 mmol) of triethylamine in 80 ml of acetonitrile is added dropwise under ice-cooling and in in 10 minutes a solution of 10.0 g (53.13 mmol) of 1 - [(benzyloxy) methyl] imidazole in 50 ml of acetonitrile in such a way that the temperature does not exceed 25 ° C. The mixture is then stirred for a further 3 hours, after which the solvent is distilled off. After adding water, extract with acetyl acetate. After washing twice with water, the organic phase is dried over sodium sulphate and evaporated. The recovered oil is chromatographed on 600 g of silica gel with toluene / ethyl acetate (95: 5). There is obtained 1 - [(benzyloxy) methyl] imidazol-2-yl- (3,4-dimethoxy-5-nitrophenyl) ketone as a yellowish oil.

b) Efter behandling med brombrintesyre fås analogt med eksempel 67b) 3,4-dihydroxy-25 5-nitrophenyl-(imidazol-2-yl)keton-hydrobromid som gule krystaller med smeltepunkt 247-248°C.b) After treatment with hydrobromic acid, analogous to Example 67b), 3,4-dihydroxy-5-nitrophenyl- (imidazol-2-yl) ketone hydrobromide is obtained as yellow crystals, m.p. 247-248 ° C.

EKSEMPEL 70 30 a) En opløsning af 25,0 g (120,16 mmol) 3-bromchinolin opløses i 200 ml tør ether og afkøles til -60cC. Ved denne temperatur tildryppes der i løbet af 15 minutter 75,1 ml (120,16 mmol) af en 1,6-molær opløsning af n-butyllithium, hvorpå der omrøres i 10 minutter. Derefter tildryppes der ved -60°C en opløsning af 26,5 g (109,2 mmol) 35 vamllinbenzylether i 250 ml tør ether, omrøres derefter i endnu 3 timer ved stuetemperatur, hældes ud i ca. 1,5 I isvand og ekstraheres med 3 x 600 ml ethylacetat.EXAMPLE 70 30 a) A solution of 25.0 g (120.16 mmol) of 3-bromoquinoline is dissolved in 200 ml of dry ether and cooled to -60 ° C. At this temperature, 75.1 ml (120.16 mmol) of a 1.6 molar solution of n-butyllithium are added dropwise over 15 minutes, followed by stirring for 10 minutes. Then a solution of 26.5 g (109.2 mmol) of 35 ml of benzyl ether in 250 ml of dry ether is added dropwise at -60 [deg.] C., then stirred for a further 3 hours at room temperature, poured out into approx. 1.5 L of ice water and extracted with 3 x 600 mL of ethyl acetate.

De organiske faser vaskes med vand, tørres over natriumsulfat og inddampes. Den vundne olie chromatograferes på 1 kg silicagel med med methylenchlorid/ethylacetat (1:1). Det vundne krystallinske råprodukt omfældes af ethylacetat. Herved fås a-[4-benzyloxy)-3-The organic phases are washed with water, dried over sodium sulfate and evaporated. The recovered oil is chromatographed on 1 kg of silica gel with methylene chloride / ethyl acetate (1: 1). The crude crystalline crude product obtained is precipitated from ethyl acetate. This gives α- [4-benzyloxy) -3-

L/l\ I t/W? U IL / l \ I t / W? U I

62 methoxyphenyl]-3-chinolinmethanol i form af farveløse krystaller med smeltepunkt 124-125°C.62 methoxyphenyl] -3-quinolinemethanol in the form of colorless crystals, m.p. 124-125 ° C.

b) En opløsning af 6,2 g (16,7 mmol) a-[4-(benzyloxy)-3-methoxyphenyl]-3-5 chinolinmethanol i 200 ml methylenchlorid omrøres i 2 timer ved tilbagesvalingstemperatur efter tilsætning af 62 g mangandioxid. Efter afkøling suges bundfaldet fra og vaskes med methylenchlorid. Filtratet inddampes, og den vundne olie opløses i varm ether, hvorefter der tilsættes en smule pentan. De udfældede krystaller suges fra. Herved fås 4-(benzyloxy)-3-methoxyphenyl-(3*chinolin)keton i form af farveløse 10 krystaller med smeltepunkt 110-111°C.b) A solution of 6.2 g (16.7 mmol) of α- [4- (benzyloxy) -3-methoxyphenyl] -3-5 quinoline methanol in 200 ml of methylene chloride is stirred for 2 hours at reflux temperature after the addition of 62 g of manganese dioxide. After cooling, the precipitate is filtered off with suction and washed with methylene chloride. The filtrate is evaporated and the oil obtained is dissolved in hot ether, after which a little pentane is added. The precipitated crystals are sucked off. This gives 4- (benzyloxy) -3-methoxyphenyl- (3 * quinoline) ketone in the form of colorless crystals, m.p. 110-111 ° C.

c) Til 11,0 g (29,78 mmol) 4-(benzyloxy)-3-methoxyphenyl-(3-chinolin)keton sættes der 50 ml trifluoreddikesyre, hvorefter der omrøres ved stuetemperatur i 2 timer. Efter afdestillering af trifluoreddikesyren tilsættes der 2 x 50 ml ethanol, idet opløsningsmidlet 15 hver gang destilleres af. Den vundne olie krystalliseres ved tilsætning af ethanol. Efter omkrystallisering af ethanol fås 4-hydroxy-3-methoxyphenyl-(3-chinolinyl)keton i form af gullige krystaller med smeltepunkt 196-197°C.c) To 11.0 g (29.78 mmol) of 4- (benzyloxy) -3-methoxyphenyl- (3-quinoline) ketone is added 50 ml of trifluoroacetic acid, then stirred at room temperature for 2 hours. After distilling off the trifluoroacetic acid, 2 x 50 ml of ethanol are added, the solvent being distilled off each time. The oil obtained is crystallized by adding ethanol. After recrystallization from ethanol, 4-hydroxy-3-methoxyphenyl- (3-quinolinyl) ketone is obtained in the form of yellowish crystals, m.p. 196-197 ° C.

d) Til en opløsning af 5,5 g (19,69 mmol) 4-hydroxy-3-methoxyphenyl-(3- 20 chinolinyl)keton i 300 ml iseddike dryppes der ved 15°C en opløsning af 1,91 ml 65% saltpetersyre i 20 ml iseddike, hvorefter der omrøres videre i 2 timer ved denne temperatur. Det hele hældes derefter ud i isvand og ekstraheres med 3 x 300 ml ethylacetat. Den organiske fase vaskes med 5 x 100 ml vand, tørres over natriumsulfat og inddampes. Efter tilsætning af ethylacetat til remanensen fås 4-hydroxy-3-methoxy-5-25 nitrophenyl-(3-chino!inyl)keton i form af gule krystaller med smeltepunkt 220-221eC (sønderdeling).d) To a solution of 5.5 g (19.69 mmol) of 4-hydroxy-3-methoxyphenyl- (3-quinolinyl) ketone in 300 ml of glacial acetic acid is added dropwise at 15 ° C a solution of 1.91 ml of 65% nitric acid in 20 ml of glacial acetic acid, after which it is further stirred for 2 hours at this temperature. The whole is then poured into ice water and extracted with 3 x 300 ml of ethyl acetate. The organic phase is washed with 5 x 100 ml of water, dried over sodium sulphate and evaporated. After adding ethyl acetate to the residue, 4-hydroxy-3-methoxy-5-25 nitrophenyl- (3-quinolinyl) ketone is obtained in the form of yellow crystals, m.p. 220-221 ° C (dec.).

e) Til 820 mg (2,53 mmol) 4-hydroxy-3-methoxy-5-nitrophenyl-(3-chinolinyl)keton sættes der 50 ml 48% brombrintesyre, og blandingen holdes i 3 timer ved 30 tilbagesvalingstemperatur. Efter afdestillering af brombrintesyre ved 50°C sættes der 70 ml varmt vand til remanensen, og de uopløselige dele suges fra. Herved fås 3,4-dihydroxy-5-nitrophenyl-(3-chinolinyl)keton-hydrobromid i form af gule krystaller med smeltepunkt 270eC (sønderdeling).e) To 820 mg (2.53 mmol) of 4-hydroxy-3-methoxy-5-nitrophenyl- (3-quinolinyl) ketone is added 50 ml of 48% hydrobromic acid and the mixture is kept for 3 hours at reflux temperature. After distilling off hydrobromic acid at 50 ° C, 70 ml of hot water are added to the residue and the insoluble parts are sucked off. This gives 3,4-dihydroxy-5-nitrophenyl- (3-quinolinyl) ketone hydrobromide in the form of yellow crystals, m.p. 270 DEG C. (dec.).

35 EKSEMPEL 71EXAMPLE 71

Analogt med eksempel 70 fås a-[4-(benzyloxy)-3-methoxyphenyl]-4-chinolinmethanol som farveløse krystaller med smeltepunkt 117-118°C (ethylacetat), ud fra hvilket der med 63 DK 175069 B1 mangandioxyd fås 4-(benzyloxy)-3-methoxyphenyl-(4-isochinolinyl)keton som farveløse krystaller med smeltepunkt 126,5-127,5°C, ud fra hvilket der med trifluoreddikesyre fås 4-hydroxy-3-methoxyphenyl-(4-isochinolinyl)keton som gule krystaller med smeltepunkt 197,5-198,5eC, ud fra hvilket der ved nitrering med saltpetersyre i iseddike og 5 efterfølgende behandling med brombrintesyre fås 3,4-dihydroxy-5-nitrophenyl-(4-isochinolinyl)keton-hydrobromid som gule krystaller med smeltepunkt 256°C (sønderdeling).Analogously to Example 70, α- [4- (benzyloxy) -3-methoxyphenyl] -4-quinolinemethanol is obtained as colorless crystals, m.p. 117-118 ° C (ethyl acetate), from which manganese dioxide is obtained with 63 (17). benzyloxy) -3-methoxyphenyl- (4-isoquinolinyl) ketone as colorless crystals, m.p. 126.5-127.5 ° C, from which trifluoroacetic acid gives 4-hydroxy-3-methoxyphenyl- (4-isoquinolinyl) ketone as yellow crystals, m.p. 197.5-198.5 ° C, from which 3,4-dihydroxy-5-nitrophenyl- (4-isoquinolinyl) ketone hydrobromide is obtained as yellow crystals by nitration with hydrochloric acid in glacial acetic acid and subsequent treatment with hydrobromic acid. with melting point 256 ° C (decomposition).

10 EKSEMPEL 72EXAMPLE 72

Analogt med eksempel 70 fås a-[4-(benzyloxy)-3-methoxyphenyl]-2-naphthalenmethanol som farveløse krystaller (ethylacetat/hexan) med smeltepunkt 113-114°C, ud fra hvilket der med mangandioxyd fås 4-(benzyloxy)-3-methoxyphenyl-(2-naphthyl)keton som 15 farveløse krystaller (ethylacetat/hexan) med smeltepunkt 104-105eC, ud fra hvilket der ved behandling med trifluoreddikesyre og nitrering med saltpetersyre i iseddike fås 4-hydroxy-3-methoxy-5-nitrophenyl-(2-naphthyl)keton som gule krystaller med smeltepunkt 187-188°C, og ud fra hvilket der ved behandling med brombrintesyre fås 3,4-dihydroxy-5-nitrophenyl (2-naphthyl)ketonhydrobromid som gule krystaller med smeltepunkt 184-20 185°C.In analogy to Example 70, α- [4- (benzyloxy) -3-methoxyphenyl] -2-naphthalenemethanol is obtained as colorless crystals (ethyl acetate / hexane), m.p. 113-114 ° C, from which 4- (benzyloxy) is obtained with manganese dioxide. -3-methoxyphenyl- (2-naphthyl) ketone as 15 colorless crystals (ethyl acetate / hexane) with melting point 104-105 ° C, from which 4-hydroxy-3-methoxy-5 is obtained by treatment with trifluoroacetic acid and nitration with hydrochloric acid in glacial acetic acid. -nitrophenyl- (2-naphthyl) ketone as yellow crystals with melting point 187-188 ° C, from which 3,4-dihydroxy-5-nitrophenyl (2-naphthyl) ketone hydrobromide is obtained as yellow crystals with melting point by treatment with hydrobromic acid 184-20 185 ° C.

EKSEMPEL 73 25 a) Til en opløsning af 20,0 g (100,5 mmo!) 3-phenylpropylbromid i 300 ml ether sættes der under omrøring ved -60°C og i løbet af 15 minutter 71,8 ml af en 1,4 molær opløsning (100,5 mmol) tert.butyllithium i pentan. Efter 10 minutter ved denne temperatur tildryppes der i løbet af 15 minutter en opløsning af 22,14 g (91,36 mmol) vanil-linbenzylether i 200 ml ether, hvorpå der omrøres videre i 2 timer. Blandingen hældes ud i 30 1 liter isvand og ekstraheres med 3 x 500 ml ethylacetat. Den organiske fase vaskes med 2 x 200 ml vand, tørres under natriumsulfat og inddampes. Den vundne olie chromatograferes på 1 kg silicagel med methylenchlorid. De vundne krystaller omfældes af ether/pentan. Herved fås 4-{benzyloxy)-3-methoxy-a-(3-phenylpropyl)benzyialkohol i form af farveløse krystaller med smeltepunkt 71-73°C.EXAMPLE 73 a) To a solution of 20.0 g (100.5 mmol) of 3-phenylpropyl bromide in 300 ml of ether is added with stirring at -60 ° C and in 15 minutes 71.8 ml of a 1, 4 molar solution (100.5 mmol) of tert-butyllithium in pentane. After 10 minutes at this temperature, a solution of 22.14 g (91.36 mmol) of vanillin-benzyl ether in 200 ml of ether is added dropwise over 15 minutes, followed by further stirring for 2 hours. The mixture is poured into 30 l of ice water and extracted with 3 x 500 ml of ethyl acetate. The organic phase is washed with water (2 x 200 ml), dried over sodium sulphate and evaporated. The oil obtained is chromatographed on 1 kg of silica gel with methylene chloride. The crystals obtained are precipitated by ether / pentane. This gives 4- {benzyloxy) -3-methoxy-α- (3-phenylpropyl) benzyl alcohol in the form of colorless crystals, m.p. 71-73 ° C.

35 b) Til en opløsning af 9,0 g (24,83 mmol) 4-(benzyloxy)-3-methoxy-a-(3-phenylpropy!)benzylalkohol i 250 ml methylenchlorid sættes der 90 g mangandioxyd, og blandingen holdes i 2 timer ved tilbagesvalingstemperatur. Efter afkøling suges bundfaldet fra og vaskes med methylenchlorid. Filtratet inddampes, og remanensen omkrystalliseres urv 11o i 64B) To a solution of 9.0 g (24.83 mmol) of 4- (benzyloxy) -3-methoxy-α- (3-phenylpropyl) benzyl alcohol in 250 ml of methylene chloride is added 90 g of manganese dioxide and the mixture is kept in 2 hours at reflux temperature. After cooling, the precipitate is filtered off with suction and washed with methylene chloride. The filtrate is evaporated and the residue is recrystallized from crude 110 in 64

af ethylacetat/ether. Herved fås 4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenon i form af farveløse krystaller med smeltepunkt 81-82°Cof ethyl acetate / ether. This gives 4 '- (benzyloxy) -3'-methoxy-4-phenylbutyrophenone in the form of colorless crystals, m.p. 81-82 ° C.

c) En opløsning af 7,0 g (19,42 mmol) 4'-(benzyloxy)'3‘-methoxy-4- 5 phenylbutyrophenon i 40 ml 33% brombrintesyre i iseddike omrøres i 5 timer ved stuetemperatur og hældes derefter ud i 500 ml isvand. Efter tilsætning af koncentreret ammoniak justeres opløsningen til pH 6,0 og ekstraheres med 3 x 250 ml ethylacetat. Den organiske fase vaskes med 3 x 50 ml vand, tørres over natriumsulfat og inddampes. Den vundne olie opløses i 20 ml ether, hvorefter der tilsættes hexan indtil blandingen bliver 10 uklar og den lades udkrystallisere. Herved fås farveløs 4’-hydroxy*3’*methoxy-4-phenylbutyrophenon med smeltepunkt 91-92eC.c) A solution of 7.0 g (19.42 mmol) of 4 '- (benzyloxy)' 3'-methoxy-4-phenylbutyrophenone in 40 ml of 33% hydrobromic acid in glacial acetic acid is stirred for 5 hours at room temperature and then poured into 500 ml of ice water. After adding concentrated ammonia, the solution is adjusted to pH 6.0 and extracted with 3 x 250 ml of ethyl acetate. The organic phase is washed with 3 x 50 ml of water, dried over sodium sulphate and evaporated. The recovered oil is dissolved in 20 ml of ether, then hexane is added until the mixture becomes cloudy and it is allowed to crystallize out. This gives a colorless 4'-hydroxy * 3 '* methoxy-4-phenylbutyrophenone, m.p. 91-92 ° C.

d) Til en opløsning af 2,2 g (8,14 mmol) 4'-hydroxy-3'-methoxy-4-phenylbutyrophenon i 25 ml iseddike dryppes der en opløsning af 0,79 ml 65% saltpetersyre i 25 ml iseddike og 15 omrøres videre i 2 timer ved stuetemperatur. Det hele hældes ud i 150 ml isvand, og efter tilsætning af 20 ml 3N saltsyre ekstraheres der med 3 x 75 ml ethylacetat. Den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes. Det vundne råprodukt tages op i ethylacetat og filtreres over 75 g silicagel. Efter omkrystallisering af acetonitril fås 4,-hydroxy-3’-methoxy-5’-nitro-4-phenylbutyrophenon i form af gule krystaller med 20 smeltepunkt 120-121°C.d) To a solution of 2.2 g (8.14 mmol) of 4'-hydroxy-3'-methoxy-4-phenylbutyrophenone in 25 ml of glacial acetic acid is added dropwise to a solution of 0.79 ml of 65% hydrochloric acid in 25 ml of glacial acetic acid and 15 is further stirred for 2 hours at room temperature. The whole is poured into 150 ml of ice water and, after adding 20 ml of 3N hydrochloric acid, it is extracted with 3 x 75 ml of ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is taken up in ethyl acetate and filtered over 75 g of silica gel. After recrystallization from acetonitrile, 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone is obtained as yellow crystals, m.p. 120-121 ° C.

e) 1,0 g (3,2 mmol) 4,-hydroxy-3‘-methoxy-5’-nitro-4-phenylbutyrophenon holdes sammen med 8 g pyridinhydrochlorid i 1 time ved 200°C. Reaktionsblandingen hældes i endnu varm tilstand ud i isvand og ekstraheres med ethylacetat. Den organiske fase 25 vaskes med lN*saltsyre og derefter med vand, tørres over natriumsulfat og inddampes.e) 1.0 g (3.2 mmol) of 4, -hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone are kept together with 8 g of pyridine hydrochloride for 1 hour at 200 ° C. The reaction mixture is poured into ice water while still hot and extracted with ethyl acetate. The organic phase 25 is washed with 1N * hydrochloric acid and then with water, dried over sodium sulphate and evaporated.

Den vundne mørke remanens chromatograferes på den 30-dobbelte mængde silicagel med ethylacetat. Ud fra methylenchlorid/hexan fås 3’,4’-dihydroxy-5'-nitro-4-phenylbutyrophenon i form af gule krystaller med smeltepunkt 118-119°C.The obtained dark residue is chromatographed on the 30-fold amount of silica gel with ethyl acetate. From methylene chloride / hexane, 3 ', 4'-dihydroxy-5'-nitro-4-phenylbutyrophenone is obtained in the form of yellow crystals, m.p. 118-119 ° C.

30 EKSEMPEL 74 a) Til en opløsning af 10,0 g (47,4 mmol) 3,4-dimethoxy-5-nitrobenzaldehyd i 100 ml dioxan sættes der en opløsning af 14,68 g (225,4 mmol) kaliumcyanid i 20 ml vand. Der 35 tildryppes nu i løbet af 30 minutter 18,81 ml (190,76 mmol) 37% saltsyre under omrøring.EXAMPLE 74 a) To a solution of 10.0 g (47.4 mmol) of 3,4-dimethoxy-5-nitrobenzaldehyde in 100 ml of dioxane is added a solution of 14.68 g (225.4 mmol) of potassium cyanide in 20 ml. ml of water. 18.81 ml (190.76 mmol) of 37% hydrochloric acid are now added dropwise over 30 minutes with stirring.

Efter tilsætning af 120 ml ether drives den overskydende blåsyregas ud ved tilledning af argon. Reaktionsblandingen filtreres overen filterhjælper af kieselgur, og den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes. Det dannede a-hydroxy* 3,4-dimethoxyphenylacetonitril (gullig olie) opløses i 200 ml ether, hvorefter der tilsættes 65 DK 175069 B1 20 ml ethano!, afkøles til 0°C og i 30 minutter tilledes saltsyregas. Efter 3 timer suges det udfældede farveløse bundfald fra og omfældes af ethanol/ether. Herved fås ethyl-(3,4-dimethoxy-5-nitrophenyl)hydroxyacetimidat-hydrochlorid.After adding 120 ml of ether, the excess hydrocyanic gas is expelled by the addition of argon. The reaction mixture is filtered through a kieselguhr filter aid and the organic phase is washed with water, dried over sodium sulphate and evaporated. The α-hydroxy * 3,4-dimethoxyphenylacetonitrile (yellowish oil) formed is dissolved in 200 ml of ether, then 20 ml of ethanol are added, cooled to 0 [deg.] C. and hydrochloric acid gas is added for 30 minutes. After 3 hours, the precipitated colorless precipitate is filtered off with suction and precipitated from ethanol / ether. This gives ethyl (3,4-dimethoxy-5-nitrophenyl) hydroxyacetimidate hydrochloride.

5 b) 19,7 g (61,46 mmol) ethyl-(3,4-dimethoxy-5-nitro-phenyl)hydroxyacetimidat-hydrochlorid opløses i 500 ml ethanol, hvorpå der efter tilsætning af 6,73 g (61,46 mmol) o-phenylendiamin omrøres i 2 timer ved stuetemperatur og derefter holdes natten over ved tilbagesvalingstemperatur. Efter afdestillering af opløsningsmidlet tilsættes der 50 ml vand, gøres alkalisk med sodaopløsning og ekstraheres med 2 x 250 ml methylenchlorid.B) 19.7 g (61.46 mmol) of ethyl (3,4-dimethoxy-5-nitro-phenyl) hydroxyacetimidate hydrochloride are dissolved in 500 ml of ethanol, whereupon after the addition of 6.73 g (61.46 mmol) o-phenylenediamine is stirred for 2 hours at room temperature and then kept overnight at reflux temperature. After distilling off the solvent, 50 ml of water are added, made alkaline with soda solution and extracted with methylene chloride (2 x 250 ml).

10 Den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes. Den vundne orangefarvede remanens chromatograferes pi 400 g silicagel med methylenchlorid/ethylacetat (1:1). Ud fra ether/hexan fås a-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolmethanol i form af gullige krystaller med smeltepunkt 50°C (sønderdeling).The organic phase is washed with water, dried over sodium sulfate and evaporated. The orange residue obtained is chromatographed on 400 g of silica gel with methylene chloride / ethyl acetate (1: 1). From ether / hexane, α- (3,4-dimethoxy-5-nitrophenyl) -2-benzimidazolemethanol is obtained in the form of yellowish crystals, m.p. 50 ° C (dec.).

15 c) 13,2 g (40,1 mmol) a-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolmethanol opløses i 200 ml methylenchlorid, hvorpå der efter tilsætning af 130 g mangandioxid omrøres i 2 timer ved tilbagesvalingstemperatur. Efter filtrering destilleres opløsningsmidlet af. Herved fås 2-benzimidazolyl-(3,4-dimethoxy-5-nitrophenyl)keton i 20 form af gullige krystaller med smeltepunkt 212-213°C.C) 13.2 g (40.1 mmol) of α- (3,4-dimethoxy-5-nitrophenyl) -2-benzimidazole methanol are dissolved in 200 ml of methylene chloride and the mixture is stirred for 2 hours at reflux temperature after adding 130 g of manganese dioxide. . After filtration, the solvent is distilled off. This gives 2-benzimidazolyl- (3,4-dimethoxy-5-nitrophenyl) ketone in the form of yellowish crystals, m.p. 212-213 ° C.

d) 1,0 g (3,05 mmol) 2-benzimidazolyl-(3,4-dimethoxy-5-nitrophenyl)keton og 8,0 g pyridin-hydrochlorid holdes i 60 minutter ved 200°C. Den mørke opløsning hældes i endnu varm tilstand ud i isvand og ekstraheres med 3 x 100 ml ethylacetat. Den organiske fase 25 vaskes med vand, tørres over natriumsulfat og inddampes. Efter omkrystallisering af ethylacetat/hexan fås 2-benzimidazolyl-(3,4-dihydroxy-5-nitrophenyl)keton i form af gule krystaller med smeltepunkt 249-250°C. 1 EKSEMPEL 75 a) 30,0 g (132 mmol) 3,4-dimethoxy-5-nitrobenzoesyre opløses i 250 ml tetrahydrofuran, hvorpå der efter tilsætning af 21,85 g (135 mmol) Ι,Γ-carbonyldiimidazol omrøres i 2 timer ved tilbagesvalingstemperatur. Det hele hældes ud i 300 ml isvand, og 35 de udfældede krystaller suges fra efter omrøring i 30 minutter. Krystallerne tages op i methylenchlorid, hvorefter den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes. Efter krystallisering af methylenchlorid/hexan fås l-(3,4-dimethoxy-5-nitrobenzoyl)imidazol i form af farveløse krystaller med smeltepunkt 136-137°C.d) 1.0 g (3.05 mmol) of 2-benzimidazolyl- (3,4-dimethoxy-5-nitrophenyl) ketone and 8.0 g of pyridine hydrochloride are kept for 60 minutes at 200 ° C. In a still hot state, the dark solution is poured into ice water and extracted with 3 x 100 ml of ethyl acetate. The organic phase 25 is washed with water, dried over sodium sulfate and evaporated. After recrystallization from ethyl acetate / hexane, 2-benzimidazolyl- (3,4-dihydroxy-5-nitrophenyl) ketone is obtained as yellow crystals, m.p. 249-250 ° C. EXAMPLE 75 a) Dissolve 30.0 g (132 mmol) of 3,4-dimethoxy-5-nitrobenzoic acid in 250 ml of tetrahydrofuran and then, after adding 21.85 g (135 mmol) of Ι, Γ-carbonyldiimidazole, stir for 2 hours. at reflux temperature. The whole is poured into 300 ml of ice water and the precipitated crystals are sucked off after stirring for 30 minutes. The crystals are taken up in methylene chloride, after which the organic phase is washed with water, dried over sodium sulphate and evaporated. After crystallization of methylene chloride / hexane, 1- (3,4-dimethoxy-5-nitrobenzoyl) imidazole is obtained in the form of colorless crystals, m.p. 136-137 ° C.

66 UK 175U&9 bl b) Til 10,0 g (36,1 mmol) l-(3,4-dimethoxy-5-nitrobenzoyl)-imidazol i 50 ml dimethylformamid sættes der 6,95 g (93,8 mmol) acetamidoxim, hvorpå der omrøres i 1 time ved 70°C. Efter afkøling hældes det hele ud i 500 ml isvand og omrøres i 30 minutter.66 UK 175U & 9 bl b) To 10.0 g (36.1 mmol) of 1- (3,4-dimethoxy-5-nitrobenzoyl) -imidazole in 50 ml of dimethylformamide is added 6.95 g (93.8 mmol) of acetamidoxime, then stirring for 1 hour at 70 ° C. After cooling, pour the whole into 500 ml of ice water and stir for 30 minutes.

De udfældede krystaller suges fra og vaskes med vand. Efter krystallisering af ethylacetat 5 fås N’-[(3,4-dimethoxy-5-nitrobenzoyl)oxy)acetamidin i form af farveløse krystaller med smeltepunkt 165-166°C.The precipitated crystals are sucked off and washed with water. After crystallization of ethyl acetate 5, N '- [(3,4-dimethoxy-5-nitrobenzoyl) oxy) acetamidine is obtained in the form of colorless crystals, m.p. 165-166 ° C.

c) 2,0 g (7,2 mmol) N'~[(3,4-dimethoxy-5-nitrobenzoyl)-oxy)acetamidin i 20 ml iseddike holdes i 1 time ved tilbagesvalingstemperatur. Efter afdestillering af iseddiken omfældes I 10 den krystallinske remanens af ether/hexan. Herved fås 5-(3,4-dimethoxy-5*nitrophenyl)- I 3-methyl-l,2,4-oxadiazol i form af farveløse krystaller med smeltepunkt 111°C.c) 2.0 g (7.2 mmol) of N '- [(3,4-dimethoxy-5-nitrobenzoyl) -oxy) acetamidine in 20 ml of glacial acetic acid are kept for 1 hour at reflux temperature. After distilling off the glacial acetic acid, the crystalline residue is precipitated from ether / hexane. This gives 5- (3,4-dimethoxy-5 * nitrophenyl) -1-3-methyl-1,2,4-oxadiazole as colorless crystals, m.p. 111 ° C.

I d) 2,5 g (9,43 mmol) 5-(3,4*dimethoxy-5-nitrophenyl)-5-methyl-l,2,4-oxadiazol opløses I i 70 ml methylenchlorid. Efter afkøling til -60eC tildryppes der i løbet af 20 minutter og I 15 under omrøring en opløsning af 23,62 g (94,3 mmol) bortribromid i 50 ml methylenchlorid, I hvorefter blandingen holdes ved tilbagesvalingstemperatur i 48 timer. Efter afkøling til - I 60eC tilsættes der 60 ml ethanol og omrøres derefter i 30 minutter ved stuetemperatur, I Den gule opløsning inddampes til tørhed, hvorpå der til remanensen sættes 3 x 100 ml I toluen/ethanol (1:1), og opløsningsmidlet hver gang destilleres af. Efter krystalliseringen I 20 af ethanol fås 5-(3-methyl-l,2,4-oxadiazol-5-yl)-3-nitropyrocatechol i form af gule I krystaller med smeltepunkt 201-202"C.I d) 2.5 g (9.43 mmol) of 5- (3,4 * dimethoxy-5-nitrophenyl) -5-methyl-1,2,4-oxadiazole are dissolved in 70 ml of methylene chloride. After cooling to -60 DEG C., a solution of 23.62 g (94.3 mmol) of boron tribromide in 50 ml of methylene chloride is added dropwise over 20 minutes with stirring, after which the mixture is kept at reflux temperature for 48 hours. After cooling to 60 DEG C., 60 ml of ethanol are added and the mixture is then stirred for 30 minutes at room temperature. The yellow solution is evaporated to dryness, then 3 x 100 ml of toluene / ethanol (1: 1) are added to the residue and the solvent each time is distilled off. After the crystallization of ethanol, 5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-nitropyrocatechol is obtained as yellow I crystals, m.p. 201 DEG-202 DEG.

I EKSEMPEL 76 I 25 I a) Til 35,0 g l-brom-2-fluorbenzen (opløst i 600 ml tetrahydrofuran) dryppes der ved - I 70°C og i løbet af 30 minutter 143,8 ml af en 1,53M opløsning af N-butyllithium i hexan.I EXAMPLE 76 I 25 I a) To 35.0 g of 1-bromo-2-fluorobenzene (dissolved in 600 ml of tetrahydrofuran) drip at - I 70 ° C and in 30 minutes 143.8 ml of a 1.53M solution of N-butyllithium in hexane.

I Efter 60 minutters omrøring ved -70°C tildryppes der i løbet af 30 minutter 48,5 g 3- I methoxy-4-benzyloxybenzaldehyd opløst i 450 ml tetrahydrofuran. Reaktionsblandingen I 30 omrøres i 2 timer ved -70°C og i 30 minutter ved 0“C, hældes ud i en blanding af is og I 150 ml 2N svovlsyre og ekstraheres med 3 x 500 ml ether. De forenede etherfaser vaskes I med mættet kogsaltopløsning, tørres over natriumsulfat og inddampes. Herved fås 4-(ben- I zyloxy)-2'-fluor-3-methoxybenzhydrol som en gullig olie, som kan anvendes direkte i det I efterfølgende reaktionstrin.After stirring for 60 minutes at -70 DEG C., 48.5 g of 3 l of methoxy-4-benzyloxybenzaldehyde dissolved in 450 ml of tetrahydrofuran are added dropwise over 30 minutes. The reaction mixture is stirred for 30 hours at -70 DEG C. and for 30 minutes at 0 DEG C., poured into a mixture of ice and 150 ml of 2N sulfuric acid and extracted with ether (3 x 500 ml). The combined ether phases are washed with saturated brine, dried over sodium sulfate and evaporated. This gives 4- (benzyloxy) -2'-fluoro-3-methoxybenzhydrol as a yellowish oil which can be used directly in the subsequent reaction step.

I 35 I På analog måde fås: I al) Ud fra 3-methoxy-4-benzyloxybenzaldehyd og l-brom-3-fluor-benzen fås 4- I (benzyloxy)-3‘-fluor-3-methoxybenzhydrol som en olie; 67 DK 175069 B1 a2) ud fra 3-methoxy-4-benzyloxybenzaldehyd og l-brom-4-fluor-benzol fås 4* (benzyloxy)-4'-fluor-3-methoxybenzhydrol som en olie: 5 a3) ud fra 3-methoxy-4-benzyloxybenzaldehyd og l-brom-2,6-difluorbenzen fås 4-(benzyloxy)-2,,6’-difluor-3-methoxy-benzhydrol som en olie; a4) ud fra 3-methoxy-4-benzyloxybenzaldehyd og l-brom-2-chlorbenzen fås 4-(benzyloxy)-2’-chlor-3-methoxybenzhydrol som en olie; 10 a5) ud fra 3-methoxy-4-benzyloxybenzaldehyd og l-brom-3-chlorbenzen fas 4-(benzyloxy)-3’-chlor-3-methoxybenzhydrol som en olie; a6) ud fra 3-methoxy-4-benzyloxybenzaldehyd og l-brom-4-chlorbenzen fås 4-15 (benzyloxy)-4'-chlor-3-methoxybenzhydrol som en olie; a7) ud fra 4-benzyloxy-3-methoxybenza!dehyd og 2-bromtoluen fås 4-(benzyloxy)-3-methoxy-2‘-methylbenzhydrol som en olie: 20 a8) ud fra 3-methoxy-4-benzyloxybenzaldehyd og 4-bromtoluen fås 4-(benzyloxy)-3-methoxy-4‘-methylbenzhydrol som en olie; a9) ud fra 3-methoxy-4-benzyloxybenzaldehyd og 1-brombenzonitril fås 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol som en olie og 25 alO) ud fra 3-methoxy-4-benzyloxybenzaldehyd og l-brom-2-trifluormethylbenzen fås 4* (benzyloxy)-3-methoxy-2'-(trifluormethyl)benzhydrol som en olie.I 35 I In an analogous manner are obtained: I al) From 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-3-fluoro-benzene there is obtained 4- I (benzyloxy) -3'-fluoro-3-methoxybenzhydrol as an oil; 67 DK 175069 B1 a2) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-4-fluoro-benzene 4 * (benzyloxy) -4'-fluoro-3-methoxybenzhydrol is obtained as an oil: 5 a3) from 3 -methoxy-4-benzyloxybenzaldehyde and 1-bromo-2,6-difluorobenzene give 4- (benzyloxy) -2,6,6'-difluoro-3-methoxy-benzhydrol as an oil; a4) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-2-chlorobenzene 4- (benzyloxy) -2'-chloro-3-methoxybenzhydrol is obtained as an oil; A5) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-3-chlorobenzene phase 4- (benzyloxy) -3'-chloro-3-methoxybenzhydrol as an oil; a6) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-4-chlorobenzene there are obtained 4-15 (benzyloxy) -4'-chloro-3-methoxybenzhydrol as an oil; a7) from 4-benzyloxy-3-methoxybenzaldehyde and 2-bromotoluene 4- (benzyloxy) -3-methoxy-2'-methylbenzhydrol is obtained as an oil: 20 a8) from 3-methoxy-4-benzyloxybenzaldehyde and 4 -bromotoluene gives 4- (benzyloxy) -3-methoxy-4'-methylbenzhydrol as an oil; a9) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromobenzonitrile obtain 4- (benzyloxy) -2'-cyano-3-methoxybenzhydrol as an oil and 25 alO) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo -2-Trifluoromethylbenzene gives 4 * (benzyloxy) -3-methoxy-2 '- (trifluoromethyl) benzhydrol as an oil.

b) Til 69,8 g 4-(benzyloxy)-2'-fluor-3-methoxybenzhydrol opløst i 600 ml methylenchlorid sættes der ved 20°C og i løbet af 30 minutter 45,3 g 30 pyridiniumchlorchromat og omrøres i 3 timer ved 20°C. Derefter filtreres det dannede bundfald fra og vaskes med methylenchlorid. Filtratet inddampes, og remanensen filtreres på 100 g silicagel med ether. Efter omkrystalliseringen af ether fås 4-(benzyloxy)-2’-fluor- 3-methoxybenzophenon med smeltepunkt 118-120eC.b) To 69.8 g of 4- (benzyloxy) -2'-fluoro-3-methoxybenzhydrol dissolved in 600 ml of methylene chloride is added at 20 ° C and in 30 minutes 45.3 g of pyridinium chlorochromate and stirred for 3 hours at 20 ° C. The precipitate formed is then filtered off and washed with methylene chloride. The filtrate is evaporated and the residue is filtered on 100 g of silica gel with ether. After the recrystallization from ether, 4- (benzyloxy) -2'-fluoro-3-methoxybenzophenone with a melting point of 118-120 ° C is obtained.

35 På analog måde fås følgende: bl) Ud fra 4-(benzyloxy)-3'-fluor-3-methoxybenzhydrol fås 4-(benzyloxy)-3‘-fIuor-3-methoxybenzophenon som amorft fast stof; 68 υκ. i /ijuoy di b2) ud fra 4-(benzyloxy)-4‘-fluor-3-methoxybenzhydrol fås 4-(benzyloxy)-4’-fluor-3-methoxybenzophenon med smeltepunkt 99-l01eC {af ether/hexan); b3) ud fra 4-(benzyloxy)*2’,6’-difluor-3-methoxybenzhydrol fås 4-(benzyloxy)-2',6'-5 difluor-3-methoxybenzophenon med smeltepunkt 139-141°C (af methylenchlorid/ether); b4) ud fra 4*(benzyloxy)-2’*chlor-3-methoxybenzhydrol fås 4-(benzyloxy)-2'-chlor-3-methoxybenzophenon med smeltepunkt 128-130°C (af ether); 10 b5) ud fra 4-(benzyloxy)*3’-chlor-3-methoxybenzhydrol fås 4-(benzyloxy)-3’-chlor-3-methoxybenzophenon som amorft fast stof; b6) ud fra 4-(benzyloxy)-4'-chlor-3-methoxybenzhydrol fås 4*(benzyloxy)-4‘-chlor-3-methoxybenzophenon med smeltepunkt 106-108°C (af methylenchlorid/hexan); 15 b7) ud fra 4-(benzyloxy)-3-methoxy-2'-methylbenzhydrol fås 4-(benzyloxy)-3-methoxy-2’-methylbenzophenon med smeltepunkt 86-88°C (af isopropylether); b8) ud fra 4-{benzyloxy)-3'methoxy-4'-methylbenzhydrol fås 4-(benzyloxy)-3-methoxy-20 4'-methylbenzophenon med smeltepunkt 79-81*0 (af ether/hexan); b9) ud fra 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol fås 4-(benzyloxy)-2’-cyano-3-methoxybenzophenon som amorft fast stof, og 25 blO) ud fra 4-(benzyloxy)-3-methoxy-2’-(trif!uormethyl)benzhydrol fås 4-(benzyloxy)-3-methoxy-2‘-(trifluormethyl)-benzophenon med smeltepunkt 103-105°C (af ether).In an analogous manner the following are obtained: b1) From 4- (benzyloxy) -3'-fluoro-3-methoxybenzhydrol 4- (benzyloxy) -3'-fluoro-3-methoxybenzophenone is obtained as an amorphous solid; 68 υκ. (b2) from 4- (benzyloxy) -4'-fluoro-3-methoxybenzhydrol there is obtained 4- (benzyloxy) -4'-fluoro-3-methoxybenzophenone, m.p. 99 DEG-10 DEG C. (ether / hexane); b3) from 4- (benzyloxy) * 2 ', 6'-difluoro-3-methoxybenzhydrol 4- (benzyloxy) -2', 6'-5 difluoro-3-methoxybenzophenone with melting point 139-141 ° C (of methylene chloride / ether); b4) from 4 * (benzyloxy) -2 '* chloro-3-methoxybenzhydrol 4- (benzyloxy) -2'-chloro-3-methoxybenzophenone with melting point 128-130 ° C (of ether) is obtained; B5) from 4- (benzyloxy) * 3'-chloro-3-methoxybenzhydrol 4- (benzyloxy) -3'-chloro-3-methoxybenzophenone is obtained as an amorphous solid; b6) from 4- (benzyloxy) -4'-chloro-3-methoxybenzhydrol 4 * (benzyloxy) -4'-chloro-3-methoxybenzophenone with melting point 106-108 ° C (of methylene chloride / hexane) is obtained; B7) from 4- (benzyloxy) -3-methoxy-2'-methylbenzhydrol 4- (benzyloxy) -3-methoxy-2'-methylbenzophenone with melting point 86-88 ° C (of isopropyl ether) is obtained; b8) from 4- {benzyloxy) -3'-methoxy-4'-methylbenzhydrol 4- (benzyloxy) -3-methoxy-4'-methylbenzophenone with melting point 79-81 * 0 (of ether / hexane) is obtained; b9) from 4- (benzyloxy) -2'-cyano-3-methoxybenzhydrol 4- (benzyloxy) -2'-cyano-3-methoxybenzophenone is obtained as an amorphous solid, and 25 b10) from 4- (benzyloxy) - 3-Methoxy-2 '- (trifluoromethyl) benzhydrol gives 4- (benzyloxy) -3-methoxy-2' - (trifluoromethyl) -benzophenone, m.p. 103-105 ° C (of ether).

c) Til 42,4 g 4-(benzyloxy)-2'-fluor-3-methoxybenzophenon opløst i 450 ml methylenchlorid sættes der ved 20-25°C og i løbet af 20 minutter 170 ml 33% 30 brombrintesyre i iseddike. Efter 1,5 times omrøring ved 20°C hældes reaktionsblandingen ud i 750 ml isvand; methylenchloridfasen skilles fra, og den vandige fase ekstraheres med endnu 2 x 200 ml methylenchlorid. De forenede methylenchloridfaser vaskes med 1200 ml vand, tørres under natriumsulfat og inddampes. For at fjerne den dannede benzylbromid bliver der til den olieagtige remanens tilsat hexan, som dekanteres af. Herved fis 2'-fluor-35 4-hydroxy-3-methoxybenzophenon som en gullig olie, som kan anvendes direkte i det efterfølgende reaktionstrin.c) To 42.4 g of 4- (benzyloxy) -2'-fluoro-3-methoxybenzophenone dissolved in 450 ml of methylene chloride is added at 20-25 ° C and in 20 minutes 170 ml of 33% hydrobromic acid in glacial acetic acid. After stirring for 1.5 hours at 20 ° C, the reaction mixture is poured into 750 ml of ice water; the methylene chloride phase is separated off and the aqueous phase is extracted with a further 2 x 200 ml of methylene chloride. The combined methylene chloride phases are washed with 1200 ml of water, dried under sodium sulphate and evaporated. To remove the benzyl bromide formed, hexane is added to the oily residue, which is decanted off. This gives 2'-fluoro-35-4-hydroxy-3-methoxybenzophenone as a yellowish oil which can be used directly in the subsequent reaction step.

På analog måde fås følgende: 69 DK 175069 B1 cl) Ud fra 4-{benzyloxy)'3’-fluor-3-methoxybenzophenon fås 3‘-fluor-4-hydroxy-3-methoxybenzophenon med smeltepunkt 133-135°C (af methylenchlorid/petroleumsether ts.); 5 c2) Ud fra 4-(benzyloxy)-4’-fluor-3-methoxybenzophenon fis 4’-fiuor-4-hydroxy-3-methoxybenzophenon med smeltepunkt 139-141°C (af ether); c3) Ud fra 4-(benzyloxy)-2’,6'-difluor-3-methoxybenzophenon fås 2*,6’-difluor-4-hydroxy- 3-methoxybenzophenon med smeltepunkt 130-132°C (af methylenchlorid/petroleumsether 10 ts.); c4) Ud fra 4-{benzyloxy)-2’-chlor-3-methoxybenzophenon fås 2'-chlor-4-hydroxy-3-methoxybenzophenon som amorft fast stof; 15 c5) Ud fra 4-(benzyloxy)*3’-chlor-3-methoxybenzophenon fås 3‘-chlor-4-hydroxy-3-methoxybenzophenon med smeltepunkt 136-138^0 (af methylenchlorid); c6) ud fra 4-(benzyloxy)-4'-chlor-3-methoxybenzophenon fås 4’-chlor-4-hydroxy-3-methoxybenzophenon med smeltepunkt 114-116°C (af methylenchlorid/petroleumsether 20 ts.); c7) ud fra 4-(benzyloxy)-3-methoxy-2'-methylbenzophenon fås 4-hydroxy-3-methoxy-2'-methylbenzophenon med smeltepunkt 103-105°C (af isopropylether); 25 c8) ud fra 4-(benzyloxy)-3-methoxy-4'-methylbenzophenon fås 4-hydroxy-3-methoxy-4'-methylbenzophenon med smeltepunkt 103-105°C (af ether/petroleumsether ts.); c9) ud fra 4-(benzyloxy)-2'-cyano-3-methoxybenzophenon fås 2’-cyano-4-hydroxy-3-methoxybenzophenon med smeltepunkt 124-126°C (af ether/n-hexan) og 30 clO) ud fra 4-(benzyloxy)-3-methoxy-2'-(trifluormethyl)benzophenon fås 4-hydroxy-3-methoxy-2‘-(trifluormethyl)benzophenon med smeltepunkt 115-117°C (af ether).In an analogous manner the following is obtained: 69 DK 175069 B1 cl) From 4- (benzyloxy) '3'-fluoro-3-methoxybenzophenone 3'-fluoro-4-hydroxy-3-methoxybenzophenone with melting point 133-135 ° C (of methylene chloride / petroleum ether ts.); C2) From 4- (benzyloxy) -4'-fluoro-3-methoxybenzophenone fis 4'-fluoro-4-hydroxy-3-methoxybenzophenone, m.p. 139-141 ° C (of ether); c3) From 4- (benzyloxy) -2 ', 6'-difluoro-3-methoxybenzophenone there is obtained 2 *, 6'-difluoro-4-hydroxy-3-methoxybenzophenone with melting point 130-132 ° C (of methylene chloride / petroleum ether 10 ts.); c4) From 4- (benzyloxy) -2'-chloro-3-methoxybenzophenone, 2'-chloro-4-hydroxy-3-methoxybenzophenone is obtained as an amorphous solid; C5) From 4- (benzyloxy) * 3'-chloro-3-methoxybenzophenone there is obtained 3'-chloro-4-hydroxy-3-methoxybenzophenone, m.p. 136-138 ° C (of methylene chloride); c6) from 4- (benzyloxy) -4'-chloro-3-methoxybenzophenone, 4'-chloro-4-hydroxy-3-methoxybenzophenone with a melting point of 114-116 ° C (of methylene chloride / petroleum ether 20 tsp) is obtained; c7) from 4- (benzyloxy) -3-methoxy-2'-methylbenzophenone is obtained 4-hydroxy-3-methoxy-2'-methylbenzophenone, m.p. 103-105 ° C (of isopropyl ether); C8) from 4- (benzyloxy) -3-methoxy-4'-methylbenzophenone there is obtained 4-hydroxy-3-methoxy-4'-methylbenzophenone, m.p. 103-105 ° C (of ether / petroleum ether, etc.); c9) from 4- (benzyloxy) -2'-cyano-3-methoxybenzophenone there is obtained 2'-cyano-4-hydroxy-3-methoxybenzophenone with melting point 124-126 ° C (of ether / n-hexane) and 30 clO) from 4- (benzyloxy) -3-methoxy-2 '- (trifluoromethyl) benzophenone is obtained 4-hydroxy-3-methoxy-2' - (trifluoromethyl) benzophenone, m.p. 115-117 ° C (of ether).

d) Til 29,4 g 2'-fluor-4-hydroxy-3-methoxybenzophenon opløst i 450 ml eddikesyre 35 dryppes der i løbet af 20 minutter ved 20°C 7,8 ml 65% saltpetersyre. Efter 1,5 times omrøring hældes reaktionsbiandingen ud i 2 I isvand, og det dannede bundfald filtreres fra, vaskes med vand og opløses i methylenchlorid. Methylenchloridopløsningen vaskes med vand, tørres over natriumsulfat og inddampes. Remanensen omkrystalliseres til methanol.d) To 29.4 g of 2'-fluoro-4-hydroxy-3-methoxybenzophenone dissolved in 450 ml of acetic acid 35, 7.8 ml of 65% hydrochloric acid are added dropwise over 20 minutes at 20 ° C. After stirring for 1.5 hours, the reaction mixture is poured into 2 l of ice water and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methanol.

Herved fås 2’-fluor-4-hydroxy-3-methoxy-5-nitrobenzophenon med smeltepunkt 127-This gives 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone, m.p.

LM\ I / U ILM \ I / U I

70 129°C.70 129 ° C.

Pi analog mide fis følgende: 5 dl) Ud fra 3'-fluor-4-hydroxy-3-methoxybenzophenon fis 3'-fluor-4-hydroxy-3-methoxy- 5-nitrobenzophenon med smeltepunkt 168-170°C (af methanol); d2) ud fra 4*-fluor-4-hydroxy-3-methoxybenzophenon fis 4’-fluor-4-hydroxy-3-methoxy- 5-nitrobenzophenon med smeltepunkt 126-128°C (af ether); 10 d3) ud fra 2',6'-difluor-4-hydroxy-3-methoxybenzophenon fis 2',6'-difluor-4-hydroxy*3-methoxy-5-njtrobenzophenon med smeltepunkt 147-149eC (af methanol); d4) ud fra 2'*chlor-4-hydroxy-3-methoxybenzophenon fis 2‘-chlor-4-hydroxy-3-methoxy-15 5-nitrobenzophenon med smeltepunkt 123-125°C (af ether); d5) ud fra 3'-chlor-4-hydroxy-3-methoxybenzophenon fis 3'-chlor-4-hydroxy-3-methoxy- 5-nitrobenzophenon med smeltepunkt 152-I54ec (af methanol); 20 d6) ud fra 4’-chlor-4-hydroxy-3-methoxybenzophenon fås 4‘-chlor-4-hydroxy-3-methoxy- 5-nitrobenzophenon med smeltepunkt 129-131°C (af methylenchlorid/petroleumsether); d7) ud fra 4-hydroxy-3-methoxy-2'-methylbenzophenon fås 4-hydroxy-3-methoxy-2‘-methyl-5-nitrobenzophenon med smeltepunkt 125-127°C (af ethanol); 25 d8) ud fra 4-hydroxy-3-methoxy-4’-methylbenzophenon fås 4-hydroxy-3-methoxy-4’-methyl-5-nitrobenzophenon med smeltepunkt 137-139°C (af methylenchlorid/ether); d9) ud fra 2’-cyano-4-hydroxy-3-methoxybenzophenon fås 2'-cyano-4-hydroxy-3-30 methoxy-5-nitrobenzophenon med smeltepunkt 163-164°C (af methanol); dlO) ud fra 4-hydroxy-3-methoxy-2’-(trifluormethyl)benzophenon fås 4-hydroxy-3-methoxy-5-nitro-2'-(trifluormethyl)benzophenon med smeltepunkt 138-140°C (af methylenchlorid/petroleumsether); 35 dl 1) ud fra 4-hydroxy-3,4’-dimethoxybenzophenon fås 4-hydroxy-3,4'-dimethoxy-5-nitrobenzophenon med smeltepunkt 134-l36eC (af methanol) og dl2) ud fra 4-hydroxy-3,3’,4,-trimethoxybenzophenon fås 4-hydroxy-5-nitro-3,3,,4'- 71 DK 175069 B1 trimethoxyben20phenon med smeltepunkt 178-180oC (af methanol).Pi analog mide fis the following: 5 dl) From 3'-fluoro-4-hydroxy-3-methoxybenzophenone fis 3'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone with melting point 168-170 ° C (of methanol ); d2) from 4 * -fluoro-4-hydroxy-3-methoxybenzophenone fis 4'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone, m.p. 126-128 ° C (of ether); D3) from 2 ', 6'-difluoro-4-hydroxy-3-methoxybenzophenone fis 2', 6'-difluoro-4-hydroxy * 3-methoxy-5-nitrobenzophenone with melting point 147-149 ° C (of methanol); d4) from 2 '* chloro-4-hydroxy-3-methoxybenzophenone fis 2'-chloro-4-hydroxy-3-methoxy-15 5-nitrobenzophenone, m.p. 123-125 ° C (of ether); d5) from 3'-chloro-4-hydroxy-3-methoxybenzophenone fis 3'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone, m.p. 152 DEG-154 DEG C. (of methanol); D6) from 4'-chloro-4-hydroxy-3-methoxybenzophenone there is obtained 4'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone, m.p. 129-131 ° C (of methylene chloride / petroleum ether); d7) from 4-hydroxy-3-methoxy-2'-methylbenzophenone is obtained 4-hydroxy-3-methoxy-2'-methyl-5-nitrobenzophenone, m.p. 125-127 ° C (of ethanol); D8) from 4-hydroxy-3-methoxy-4'-methylbenzophenone there is obtained 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone, m.p. 137-139 ° C (of methylene chloride / ether); d9) from 2'-cyano-4-hydroxy-3-methoxybenzophenone there is obtained 2'-cyano-4-hydroxy-3-30 methoxy-5-nitrobenzophenone, m.p. 163-164 ° C (of methanol); d10) from 4-hydroxy-3-methoxy-2 '- (trifluoromethyl) benzophenone, 4-hydroxy-3-methoxy-5-nitro-2' - (trifluoromethyl) benzophenone with a melting point of 138-140 ° C (of methylene chloride / petroleum ether); 35 dl 1) from 4-hydroxy-3,4'-dimethoxybenzophenone 4-hydroxy-3,4'-dimethoxy-5-nitrobenzophenone with melting point 134-136 ° C (of methanol) and dl2) from 4-hydroxy-3 , 3 ', 4, -trimethoxybenzophenone is obtained 4-hydroxy-5-nitro-3,3,, 4'-trimethoxybenzophenone, m.p. 178 DEG-180 DEG C. (from methanol).

e) 24,8 g 2'-fluor-4-hydroxy-3*methoxy-5-nitrobenzophenon opløst i 120 ml iseddikesyre, 100 ml 33% brombrintesyre i iseddike og 68 ml 48% vandig brombrintesyre 5 koges under tilbagesvaling i 4 timer. Derefter inddampes reaktionsblandingen under formindsket tryk og destilleres af med toluen. Remanensen opløses i methylenchlorid, vaskes med vand, tørres over natriumsulfat, filtreres og inddampes. Produktet krystalliseres af methylenchlorid/petroleumsether ts. Herved fås 2’-fluor-3,4-dihydroxy-5-nitrobenzophenon med smeltepunkt 169-171°C.e) 24.8 g of 2'-fluoro-4-hydroxy-3 * methoxy-5-nitrobenzophenone dissolved in 120 ml of glacial acetic acid, 100 ml of 33% hydrobromic acid in glacial acetic acid and 68 ml of 48% aqueous hydrobromic acid are boiled under reflux for 4 hours. The reaction mixture is then evaporated under reduced pressure and distilled off with toluene. The residue is dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The product is crystallized from methylene chloride / petroleum ether ts. This gives 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone, m.p. 169-171 ° C.

10 På analog måde fås følgende: el) Ud fra 3’-fluor-4-hydroxy-3-methoxy-5-nitrobenzophenon fås 3’-fluor-3,4-dihydroxy-5-nitrobenzophenon med smeltepunkt 124-126°C (af methylenchlorid); 15 e2) ud fra 4’-fluor-4-hydroxy-3-methoxy-5-nitrobenzophenon fis 4’-fluor-3,4-dihydroxy-5-nitrobenzophenon med smeltepunkt 171-173*0 (af methylenchlorid); e3) ud fra 2‘,6'-difluor-4-hydroxy-3-methoxy-5-nitrobenzophenon fås 2',6'-difluor-3,4-20 dihydroxy-5-nitrobenzophenon med smeltepunkt 194-196°C (af methanol); e4) ud fra 2'-chlor-4-hydroxy-3-methoxy-5*nitrobenzophenon fås 2’-chlor-3,4-dihydroxy-5-nitrobenzophenon med smeltepunkt 129-131°C (af methylenchlorid/petroleumsether ts.); 25 e5) ud fra 3'-chlor-4-hydroxy-3-methoxy-5-nitrobenzophenon fås 3'-chlor-3,4-dihydroxy-5-nitrobenzophenon med smeltepunkt 143-145°C (af methylenchlorid/petroleumsether ts.); 30 e6) ud fra 4'-chlor-4-hydroxy-3-methoxybenzophenon fås 4'-chlor-3,4-dihydroxybenzophenon med smeltepunkt 174-176°C (af methylenchlorid); e7) ud fra 4-hydroxy-3-methoxy-2'-methyl-5-nitrobenzophenon fås 3,4-dihydroxy-2'-methyl-5-nitrobenzophenon med smeltepunkt 164-166°C (af methylenchlorid); 35 e8) ud fra 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenon fås 3,4-dihydroxy-4‘-methyl-5-nitrobenzophenon med smeltepunkt 146-148°C (af methylenchlorid); e9) ud fra 2'-cyano-4-hydroxy-3-methoxy-5-nitrobenzophenon fås 2‘-cyano-3,4-In an analogous manner the following is obtained: el) From 3'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone 3'-fluoro-3,4-dihydroxy-5-nitrobenzophenone with melting point 124-126 ° C is obtained ( of methylene chloride); E2) from 4'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone fis 4'-fluoro-3,4-dihydroxy-5-nitrobenzophenone with melting point 171-173 * 0 (of methylene chloride); e3) from 2 ', 6'-difluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone there is obtained 2', 6'-difluoro-3,4-20 dihydroxy-5-nitrobenzophenone, m.p. 194-196 ° C ( of methanol); e4) from 2'-chloro-4-hydroxy-3-methoxy-5 * nitrobenzophenone, 2'-chloro-3,4-dihydroxy-5-nitrobenzophenone with a melting point of 129-131 ° C (of methylene chloride / petroleum ether ts.) is obtained. ; E5) from 3'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone 3'-chloro-3,4-dihydroxy-5-nitrobenzophenone with melting point 143-145 ° C (of methylene chloride / petroleum ether ts) is obtained. ); E6) from 4'-chloro-4-hydroxy-3-methoxybenzophenone, 4'-chloro-3,4-dihydroxybenzophenone with a melting point of 174-176 ° C (of methylene chloride) is obtained; e7) from 4-hydroxy-3-methoxy-2'-methyl-5-nitrobenzophenone there is obtained 3,4-dihydroxy-2'-methyl-5-nitrobenzophenone, m.p. 164-166 ° C (of methylene chloride); E8) from 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone there is obtained 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, m.p. 146-148 ° C (of methylene chloride); e9) from 2'-cyano-4-hydroxy-3-methoxy-5-nitrobenzophenone 2'-cyano-3,4-

Ul\ I I tM/Uø U IUl \ I I tM / Uø U I

72 dihydroxy-5-nitrobenzophenon med smeltepunkt 159-1610C (af methanol); elO) ud fra 4-hydroxy-3-methoxy-5-nitro-2’-(trifluormethyl)-benzophenon fås 3,4-dlhydroxy-5-nitro-2’-(trifluormethyl)-benzophenon med smeltepunkt 146-148eC (af 5 methanol); ell) ud fra 4-hydroxy-3,4’-dimethoxy-5-nitrobenzophenon fås 5-nitro-3,4,4'-trihydroxybenzophenon med smeltepunkt 212-214°C (af methanol/methylenchlorid) og 10 el2) ud fra 4-hydroxy-5-nitro-3,3’,4'-trimethoxybenzophenon fås 5-nitro-3,3’,4,4‘-tetrahydroxybenzophenon med smeltepunkt 222-224°C (af ether).72 dihydroxy-5-nitrobenzophenone, m.p. 159 DEG-161 DEG C. (of methanol); 10) from 4-hydroxy-3-methoxy-5-nitro-2 '- (trifluoromethyl) -benzophenone, 3,4-dihydroxy-5-nitro-2' - (trifluoromethyl) -benzophenone with a melting point of 146-148 ° C is obtained. Methanol); ell) from 4-hydroxy-3,4'-dimethoxy-5-nitrobenzophenone 5-nitro-3,4,4'-trihydroxybenzophenone with melting point 212-214 ° C (of methanol / methylene chloride) and 10 or 2) from 4-Hydroxy-5-nitro-3,3 ', 4'-trimethoxybenzophenone There is obtained 5-nitro-3,3', 4,4'-tetrahydroxybenzophenone, m.p. 222-224 ° C (of ether).

EKSEMPEL 77 15EXAMPLE 77 15

Til en suspension af 13,8 g 2-brom-3'-4,-dihydroxy-5,-nitroacetophenon sættes der 9,0 g l-(phenethyl)-2-thiourinstof i 150 ml n-butanol og opvarmes til kogning i 3 timer under tilbagesvaling. Efter afkøling til stuetemperatur suges krystallerne fra og omkrystatliseres af n-butanol. Herved fås 3-nitro-5-[2-(phenethyl-amino)-4-thiazolyl]pyrocatechol-20 hydrobromid med smeltepunkt 249-251°C.To a suspension of 13.8 g of 2-bromo-3'-4, -dihydroxy-5, -nitroacetophenone is added 9.0 g of 1- (phenethyl) -2-thiourea in 150 ml of n-butanol and heated to boiling in 3 hours under reflux. After cooling to room temperature, the crystals are filtered off with suction and recrystallized from n-butanol. This gives 3-nitro-5- [2- (phenethylamino) -4-thiazolyl] pyrocatechol hydrobromide, m.p. 249-251 ° C.

EKSEMPEL 78 25 Ud fra 2-brom-3‘,4'-dihydroxy-5'-nitroacetophenon og 2-aminobenzophenon fås analogt med eksempel 38 2-(3,4-dihydroxy-5-nitrobenzoyl)-3-phenylindol med smeltepunkt 196-198°C (af isopropanol).EXAMPLE 78 From 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone and 2-aminobenzophenone are obtained analogously to Example 38 2- (3,4-dihydroxy-5-nitrobenzoyl) -3-phenylindole, m.p. -198 ° C (of isopropanol).

30 EKSEMPEL 79EXAMPLE 79

Til en suspension af 8,3 g 2-brom-3‘,4'-dihydroxy-5’-nitroacetophenon sættes 1-(1-adamantyl)-2-thiourinstof i 90 ml n-butanol og opvarmes til kogning i 4 timer under tilbagesvaling. Efter afkøling til stuetemperatur suges krystallerne fra og omkrystalliseres 35 af n-butanol. Herved fås 5-[2-(l-adamantylamino)-5-thiazolyl]-3-nitropyrocatechol-hy-drobromid med smeltepunkt 245-247°C.To a suspension of 8.3 g of 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone is added 1- (1-adamantyl) -2-thiourea in 90 ml of n-butanol and heated to boiling for 4 hours under reflux. After cooling to room temperature, the crystals are filtered off with suction and recrystallized from n-butanol. This gives 5- [2- (1-adamantylamino) -5-thiazolyl] -3-nitropyrocatechol hydrobromide, m.p. 245-247 ° C.

EKSEMPEL 80 73 DK 175069 B1EXAMPLE 80 73 DK 175069 B1

En suspension af 2,6 g (3,4-dihydroxy-5-nitrobenzoyl)methylacetat i 20 ml ethanol og 20 ml IN saltsyre opvarmes til kogning i 5 timer under tilbagesvaling. Derefter inddampes reaktionsblandingen og afdestilleres videre med toluen, og remanensen omkrystalliseres af 5 ethanol. Herved fås 2,3,,4,-trihydroxy-5'-nitroacetophenon med smeltepunkt 208-210eC.A suspension of 2.6 g (3,4-dihydroxy-5-nitrobenzoyl) methyl acetate in 20 ml of ethanol and 20 ml of 1N hydrochloric acid is heated to reflux for 5 hours. The reaction mixture is then evaporated and further distilled off with toluene and the residue is recrystallized from ethanol. This gives 2,3,4,4-trihydroxy-5'-nitroacetophenone, m.p. 208 DEG-210 DEG.

EKSEMPEL 81 10 En opløsning af 4,0 g 3,4-dihydroxy-5-nitrophenyl-glyoxylsyre-n-hexylester og 1,5 g diaminomaleonitril i 35 ml ethanol opvarmes til kogning i 24 timer under tilbagesvaling.EXAMPLE 81 A solution of 4.0 g of 3,4-dihydroxy-5-nitrophenyl-glyoxylic acid n-hexyl ester and 1.5 g of diaminomaleonitrile in 35 ml of ethanol is heated to boiling for 24 hours under reflux.

Derefter destilleres alkoholen af, og remanensen opløses i ether, vaskes med vand, tørres over natriumsulfat, filtreres og inddampes. Herved fas 6-hydroxy-5-(3,4-dihydroxy-5-nitrophenyl)-2,3-pyrazindicarbonitril med smeltepunkt >300eC (af ether/methylenchlorid).The alcohol is then distilled off and the residue is dissolved in ether, washed with water, dried over sodium sulphate, filtered and evaporated. Hereby phase 6-hydroxy-5- (3,4-dihydroxy-5-nitrophenyl) -2,3-pyrazinedicarbonitrile with melting point> 300 ° C (of ether / methylene chloride).

15 EKSEMPEL 82 a) Til 4,2 g 5-(bromacetyl)-2,3-dimethoxybenzonitril opløst i 150 ml methylenchlorid 20 sættes der 8,9 ml bortribromid. Reaktionsblandingen omrøres i 18 timer ved 20°C.EXAMPLE 82 a) To 4.2 g of 5- (bromoacetyl) -2,3-dimethoxybenzonitrile dissolved in 150 ml of methylene chloride is added 8.9 ml of boron tribromide. The reaction mixture is stirred for 18 hours at 20 ° C.

Derefter hældes blandingen ud i 220 ml mættet natriumhydrogencarbonatopløsning og 100 g is, justeres til pH 6 ved hjælp af iseddike og ekstraheres med ethylacetat. Den organiske fase vaskes med vand, tørres over natriumsulfat og inddampes. Herved fås 5-(bromacetyl)-2,3-dihydroxybenzonitril som amorft fast stof.The mixture is then poured into 220 ml of saturated sodium bicarbonate solution and 100 g of ice, adjusted to pH 6 with glacial acetic acid and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. This gives 5- (bromoacetyl) -2,3-dihydroxybenzonitrile as an amorphous solid.

25 b) Til 3,8 g 5-(bromacetyl)-2,3-dihydroxybenzonitril opløst i 25 ml N,N-dimethylformamid sættes der N-phenylthiourinstof, og der omrøres i 5 timer ved 100°C.B) To 3.8 g of 5- (bromoacetyl) -2,3-dihydroxybenzonitrile dissolved in 25 ml of N, N-dimethylformamide is added N-phenylthiourea and stirred for 5 hours at 100 ° C.

Derefter dampes opløsningsmidlet af. Der tilsættes 200 ml IN natriumcarbonatopløsning til remanensen, og der ekstraheres med 3 x 100 ml methylenchlorid. De forenede organiske 30 faser vaskes med vand, tørres over natriumsulfat og inddampes. Remanensen chromatograferes på 30 g silicagel med ethylacetat. Til det således vundne råprodukt sættes 40 ml IN saltsyre, inddampes og krystalliseres af acetone. Herved fås 5-(2-anilino- 4-thiazolyl)-2,3-dihydroxybenzonitril-hydrochlorid med smeltepunkt 245-247°C.Then evaporate the solvent. Add 200 ml of 1N sodium carbonate solution to the residue and extract with 3 x 100 ml of methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 30 g of silica gel with ethyl acetate. To the crude product thus obtained is added 40 ml of 1N hydrochloric acid, evaporated and crystallized from acetone. This gives 5- (2-anilino-4-thiazolyl) -2,3-dihydroxybenzonitrile hydrochloride, m.p. 245-247 ° C.

35 EKSEMPEL 83 a) Til 10 g 4-(benzyloxy)-3*methoxy-brombenzen opløst i 100 ml tetrahydrofuran dryppes der ved -70°C og i løbet af 10 minutter 25 ml af en 1,4M opløsning af 74 DK 175069 B1 tert.butyllithiumopløsning i hexan. Efter 1 times omrøring ved -70°C tildryppes der i løbet af 30 minutter 5 g chinolin-4-carbaldehyd opløst i 50 ml tetrahydrofuran.EXAMPLE 83 a) To 10 g of 4- (benzyloxy) -3 * methoxy-bromobenzene dissolved in 100 ml of tetrahydrofuran is added dropwise at -70 ° C and in 10 minutes 25 ml of a 1.4M solution of 74 DK 175069 B1 tert.butyllithium solution in hexane. After stirring for 1 hour at -70 DEG C., 5 g of quinoline-4-carbaldehyde dissolved in 50 ml of tetrahydrofuran are added dropwise over 30 minutes.

Reaktionsblandingen omrøres i 1 time ved -40eC og i 1 time ved -5eC, hældes ud i 200 ml vand og justeres til pH 4 ved hjælp af iseddike. Blandingen ekstraheres med 3 x 50 ml 5 ether. De forenede etherfaser vaskes med vand, tørres over natriumsulfat og inddampes.The reaction mixture is stirred for 1 hour at -40 ° C and for 1 hour at -5 ° C, poured into 200 ml of water and adjusted to pH 4 with glacial acetic acid. The mixture is extracted with 3 x 50 ml of ether. The combined ether phases are washed with water, dried over sodium sulfate and evaporated.

Herved fås a-[4-(benzyloxy)-3-methoxhyphenyl]-4-chinolinmethanol som amorft fast stof.This gives α- [4- (benzyloxy) -3-methoxyhyphenyl] -4-quinolinemethanol as an amorphous solid.

b) Til 9,4 g a-[4-(benzyloxy)-3-methoxyphenyl]-4-chinolin-methanol opløst i 200 ml methylenchlorid sættes der 6,5 g pyridiniumchlorchromat, hvorpå der omrøres i 3 timer 10 ved stuetemperatur. Derefter filtreres de uopløselige bestanddele fra. Filtratet inddampes, og remanensen chromatograferes på 150 g silicagel med ethylacetat. Herved fås 4-(benzy!oxy)-3-methoxyphenyl-4-chinolylketon som amorft fast stof.b) To 9.4 g of α- [4- (benzyloxy) -3-methoxyphenyl] -4-quinolin-methanol dissolved in 200 ml of methylene chloride is added 6.5 g of pyridinium chlorochromate, then stirred for 3 hours at room temperature. The insoluble constituents are then filtered off. The filtrate is evaporated and the residue is chromatographed on 150 g of silica gel with ethyl acetate. This gives 4- (benzyloxy) -3-methoxyphenyl-4-quinolyl ketone as an amorphous solid.

c) Til 7,5 g 4-(benzyloxy)-3-methoxyphenyl-4-chinolytketon opløst i 150 ml 15 methylenchlorid dryppes der ved stuetemperatur og i løbet af 5 minutter 15 ml 33% brombrintesyre i iseddike. Efter 4,5 timers omrøring ved 20°C hældes reaktionsblandingen portionsvis ud i 250 ml mættet natriumhydrogencarbonatopløsning. Methylenchloridfasen skilles fra; den vandige fase ekstraheres med endnu 2 x 100 ml methylenchlorid. De forenede methylenchloridfaser tørres over natriumsulfat og inddampes. Remanensen 20 omkrystalliseres af methylenchlorid/hexan. Herved fås 4-hydroxy-3-methoxyphenyl-4-chinolylketon med smeltepunkt 190-192°C.c) To 7.5 g of 4- (benzyloxy) -3-methoxyphenyl-4-quinolyl ketone dissolved in 150 ml of methylene chloride are added dropwise at room temperature and over 5 minutes 15 ml of 33% hydrobromic acid in glacial acetic acid. After stirring for 4.5 hours at 20 ° C, the reaction mixture is poured portionwise into 250 ml of saturated sodium bicarbonate solution. The methylene chloride phase is separated; the aqueous phase is extracted with a further 2 x 100 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue 20 is recrystallized from methylene chloride / hexane. This gives 4-hydroxy-3-methoxyphenyl-4-quinolyl ketone, m.p. 190-192 ° C.

d) Til 1,3 g 4-hydroxy-3-methoxyphenyl-4-chinolylketon opløst i 25 ml iseddike dryppes der ved stuetemperatur 0,37 ml 65% saltpetersyre. Efter 3 timers omrøring hældes 25 reaktionsblandingen ud i isvand, hvorpå den justeres til pH 6 ved hjælp af koncentreret ammoniak, og det dannede bundfald filtreres fra. Den således vundne remanens opvarmes i 20 ml acetonitril under tilbagesvaling, hvorpå krystallerne filtreres fra ved 0°C. Herved fås 4- hydroxy-3-methoxy-5-nitrophenyl-4-chinolylketon med smeltepunkt 246-248°C.d) To 1.3 g of 4-hydroxy-3-methoxyphenyl-4-quinolyl ketone dissolved in 25 ml of glacial acetic acid, 0.37 ml of 65% nitric acid are added dropwise at room temperature. After stirring for 3 hours, the reaction mixture is poured into ice water, then adjusted to pH 6 with concentrated ammonia and the precipitate formed is filtered off. The residue thus obtained is heated in 20 ml of acetonitrile under reflux, whereupon the crystals are filtered off at 0 ° C. This gives 4-hydroxy-3-methoxy-5-nitrophenyl-4-quinolyl ketone, m.p. 246-248 ° C.

30 e) 1 g 4-hydroxy-3*methoxy-5-nitrophenyl-4-chinolylketon opløst i 30 ml 48% vandigt brombrintesyre omrøres i 18 timer ved 100°C. Efter afkøling til stuetemperatur fortyndes reaktionsblandingen med 30 ml vand, og bundfaldet suges fra. Herved fås 3,4-dihydroxy- 5- nitrophenyl-4-chinolylketon-hydrobromid med smeltepunkt 273-275°C (af acetonitril).E) 1 g of 4-hydroxy-3 * methoxy-5-nitrophenyl-4-quinolyl ketone dissolved in 30 ml of 48% aqueous hydrobromic acid is stirred for 18 hours at 100 ° C. After cooling to room temperature, the reaction mixture is diluted with 30 ml of water and the precipitate is filtered off with suction. This gives 3,4-dihydroxy-5-nitrophenyl-4-quinolyl ketone hydrobromide, m.p. 273-275 ° C (of acetonitrile).

35 EKSEMPEL 84 a) Til 4,03 g thiophen opløst i 40 ml tetrahydrofuran dryppes der ved -50°C og i løbet af 10 minutter 18,8 ml afen 1,6M opløsning af n-butyllithium i hexan. Efter 30 minutters 75 DK 175069 B1 omrøring ved -50eC tildryppes der i løbet af 30 minutter 6,3 g 3,4-dimethoxy-5-nitrobenzaldehyd opløst i 100 ml tetrahydrofuran. Reaktionsblandingen omrøres i 1 time ved -50°C og 30 minutter ved 0°C og hældes ud i 100 ml 2N-svovlsyre. Blandingen ekstraheres med 3 x 100 ml ether; de forenede etherfaser vaskes med kogsaltopløsning, 5 tørres over natriumsulfat, filtreres og inddampes. Herved fås a-(3,4-dimethoxy-5- nitrophenyl)-2-thiophenmethanol med smeltepunkt 79-81°C (af methylenchlorid/hexan).EXAMPLE 84 a) To 4.03 g of thiophene dissolved in 40 ml of tetrahydrofuran, drop at -50 ° C and in 10 minutes 18.8 ml of a 1.6 M solution of n-butyllithium in hexane. After stirring for 30 minutes at -50 ° C, 6.3 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 100 ml of tetrahydrofuran are added dropwise over 30 minutes. The reaction mixture is stirred for 1 hour at -50 ° C and 30 minutes at 0 ° C and poured into 100 ml of 2N-sulfuric acid. The mixture is extracted with 3 x 100 ml of ether; the combined ether phases are washed with brine, dried over sodium sulphate, filtered and evaporated. This gives α- (3,4-dimethoxy-5-nitrophenyl) -2-thiophenemethanol, m.p. 79-81 ° C (of methylene chloride / hexane).

b) Til 9,9 g a-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenmethanol opløst i 300 ml acetone sættes der 90 g brunsten og opvarmes i 4 timer under tilbagesvaling. Derefter 10 suges brunstenen fra, og filtratet inddampes. Herved fås 3,4-dimethoxy-5-nitrophenyl-2-thienylketon med smeltepunkt 102-104°C (af methylenchlorid/hexan).b) To 9.9 g of α- (3,4-dimethoxy-5-nitrophenyl) -2-thiophenemethanol dissolved in 300 ml of acetone is added 90 g of the rut and heated for 4 hours under reflux. Then the sulfur is sucked off and the filtrate is evaporated. This gives 3,4-dimethoxy-5-nitrophenyl-2-thienyl ketone, m.p. 102-104 ° C (of methylene chloride / hexane).

c) 2 g 3,4-dimethoxy-5-nitrophenyl-2-thienylketon omrørtes i 8 timer ved 100°C i en blanding af 20 ml 30-33% brombrintesyre i iseddike og 20 ml 48% vandig brombrintesyre.c) 2 g of 3,4-dimethoxy-5-nitrophenyl-2-thienyl ketone were stirred for 8 hours at 100 ° C in a mixture of 20 ml of 30-33% hydrobromic acid in glacial acetic acid and 20 ml of 48% aqueous hydrobromic acid.

15 Derefter inddampes reaktionsblandingen til tørhed. Remanensen tages op i ethylacetat, vaskes med vand, tørres over natriumsutfat og filtreres, og filtratet inddampes. Efter omkrystallisering af ethylacetat/hexan fas 3,4-dihydroxy-5-nitrophenyl-2-thienylketon med smeltepunkt 155-157°C.Then the reaction mixture is evaporated to dryness. The residue is taken up in ethyl acetate, washed with water, dried over sodium hydroxide solution and filtered and the filtrate is evaporated. After recrystallization from ethyl acetate / hexane phase 3,4-dihydroxy-5-nitrophenyl-2-thienyl ketone, m.p. 155-157 ° C.

2020

EKSEMPEL AEXAMPLE A

Gelatine-stikkapsler med følgende sammensætning kan fremstilles på i og for sig kendt måde: 25Gelatin capsules with the following composition can be prepared in a manner known per se: 25

Bestanddele Mængde i mg/kapsel L-dopa 100 30 Benserazid-hydrochlorid 29,3 3,4-dihydroxy-5-nitrophenyl-4-pyridylketon 25Ingredients Amount in mg / capsule L-dopa 100 30 Benserazide hydrochloride 29,3 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone 25

Gelatine 1Gelatin 1

Mg-stearat 1Mg stearate 1

Avicel 93,7 35 Mannit 100Avicel 93.7 35 Mannit 100

Kapselpåfyldningsvægt 350 mg mgCapsule filling weight 350 mg mg

Claims (18)

1. Forbindelser med den almene formel HOx Λ Ia H° XRb 5 hvor Ra er nitro eller cyano, Rb er hydrogen eller halogen, Rc er halogen, nitro, cyano eller gruppen -(A)n-(Q)m-R* eller -(A)n-Q-R2, A er eventuelt med lavere alkyl substitueret vinylen, n er 0 eller 1, m er 0 eller 1, R1 er gruppen -COR3, aryl eller heteroaryl, R2 er hydrogen eller en mættet eller delvist umættet lavere carbonhydridrest, som er usubstitueret eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, 10 lavere alkylamino, di(lavere alkyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)-carbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, R3 er hydroxy, amino, en mættet eller delvist umættet lavere carbonhydridrest, som er 15 usubstitueret eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, lavere alkylamino, di(lavere alkyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, og som 20 er bundet via et oxygenatom eller en imino- eller lavere alkyliminogruppe, eller en 4-morpholinyl-, 1-pyrrolidinyl- eller l-azetidinylgruppe, som er usubstitueret eller monoeller disubstitueret med lavere alkyl, hydroxy, lavere alkoxy, lavere alkanoyloxy, lavere hydroxyalkyl, lavere alkoxyalkyl, lavere alkanoyloxyalkyl, lavere alkoxycarbonyl, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, oxo og/eller lavere 25 alkylendioxy, Q er gruppen -CO- eller >C=N-(Z)P-R\ Z er et oxygenatom eller en imino-gruppe, p er 0 eller 1, og R4 er hydrogen eller en mættet eller delvist umættet lavere carbonhydridrest, som er usubstitueret eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, lavere alkylamino, di(lavere alkyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere 30 alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)-carbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino 77 DK 175069 B1 eller lavere alkylthio, og som eventuelt er bundet via en carbonylgruppe, idet aryl er en phenyl- eller naphthylgruppe, som er usubstitueret eller mono- eller disubstitueret med halogen, trifluormethyl, nitro, amino, mono- eller di(lavere alkyl)amino, lavere alkyl, lavere alkoxy, lavere alkylthio, lavere alkanoyl, lavere alkoxycarbonyl, carboxy, hydroxy, 5 cyano, lavere alkanoyloxy, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, lavere alkylendioxy, lavere alkanoylamino eller lavere alkoxycarbonylamino, heteroaryl er en heterocyklisk gruppe valgt fra gruppen bestående af pyridyl, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, benzoxazinyl, quinoxalinyl, benzopyranyl, 10 benzimidazolyl, indolyl, imidazothiazolyl, imidazothiadiazolyl, imidiazopyridyi, benzothiazinyl, benzoquinoxalinyl og imidazobenzothiazolyl, som er bundet via et carbonatom, og som er usubstitueret eller mono-, di- eller trisubstitueret med halogen, trifluormethyl, nitro, carboxy, amino, arylamino, lavere alkyl, lavere alkoxy, hydroxy, lavere alkoxycarbonyl, lavere alkanoyl, lavere alkanoyloxy, oxo, lavere alkylendioxy, 15 mercapto, lavere alkylthio, lavere alkylamino, di(lavere alkyl)amino, 03.7-cycloalkylamino, C8.10-bicydoalkylamino, lavere alkanoylamino, lavere alkoxycarbonylamino, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, cyano, aryl, aryl-lavere alkyl, aryl-lavere alkylamino, heteroaryl, heteroaryl-lavere alkyl, heteroarylamino eller C3.7-cycloalkyl, og lavere betegner rester med op til 7 carbonatomer, under fysiologiske betingelser hydroliserbare 20 ester- og etherderivater, og farmaceutisk acceptable salte deraf til anvendelse som terapeutisk aktive stoffer.Compounds of the general formula HOx Λ Ia H ° XRb 5 wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is halogen, nitro, cyano or the group - (A) n- (Q) mR * or - ( A) nQ-R 2, A is optionally lower alkyl substituted vinylene, n is 0 or 1, m is 0 or 1, R 1 is the group -COR 3, aryl or heteroaryl, R 2 is hydrogen or a saturated or partially unsaturated lower hydrocarbon residue which is unsubstituted or mono- or disubstituted by hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl , mono- or di (lower alkyl) -carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio, R 3 is hydroxy, amino, a saturated or partially unsaturated lower hydrocarbon residue which is unsubstituted or mono- or disubstituted with hydroxy, cyano o, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio, and which are bonded via an oxygen atom or an imino or lower alkylimino group, or a 4-morpholinyl, 1-pyrrolidinyl or 1-azetidinyl group which is unsubstituted or mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, oxo and / or lower alkylenedioxy , Q is the group -CO- or> C = N- (Z) PR \ Z is an oxygen atom or an imino group, p is 0 or 1 and R4 is hydrogen or a saturated or partially unsaturated lower hydrocarbon. est which is unsubstituted or mono- or disubstituted by hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) -carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino 77 or lower alkylthio, and optionally bonded via a carbonyl group, aryl being a phenyl- or naphthyl group which is unsubstituted or mono- or disubstituted by halogen, trifluoromethyl, nitro, amino, mono- or di (lower alkyl) amino, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, carboxy, hydroxy, cyano, lower alkanoyloxy, carbamoyl, mono- or di (lower alkyl) carbamoyl, lower alkylenedioxy, lower alkanoylamino or lower alkoxycarbonylamino, heteroaryl is a heterocyclic group of choice t from the group consisting of pyridyl, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, benzoxazinyl, quinoxazylyl, quinoxylinyl benzothiazinyl, benzoquinoxalinyl and imidazobenzothiazolyl which are attached via a carbon atom and which are unsubstituted or mono-, di- or trisubstituted by halogen, trifluoromethyl, nitro, carboxy, amino, arylamino, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto, lower alkylthio, lower alkylamino, di (lower alkyl) amino, 03,7-cycloalkylamino, C8-10 bicydoalkylamino, lower alkanoylamino, lower alkoxycarbonylamino, carbamoyl, mono- or di (lower alkyl) carbamoyl, cyano, aryl, aryl-lower alkyl, aryl-lower alkylamino, heteroaryl, heteroaryl-lower alkyl, heteroarylamino or C3,7-cycloalkyl, and lower denotes residues having up to 7 carbon atoms, under physiological conditions hydrolysable 20 ester and ether derivatives, and pharmaceutically acceptable salts thereof for use as therapeutically active substances. 2. Forbindelser med den almene formel ?a HV\ Λν-«*· Ib H0 s-\b 1 2 3 4 5 6 hvor Ra er nitro eller cyano, Rb er hydrogen eller halogen, 2 Rc' er nitro, cyano eller gruppen -(A)n-(Q)m-Rn eller -(A)n-Q-R21, A er eventuelt med lavere 3 alkyl substitueret vinylen, n er 0 eller 1, m er 0 eller 1, R11 er gruppen -COR3\ aryl eller 4 heteroaryl, R21 er en mættet eller delvist umættet lavere carbonhydridrest, som er 5 usubstitueret eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, 6 lavere alkylamino, di(lavere alkyl )armno, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di( lavere alkyl)carbamoyl, lavere alkylendioxy, trifluormethyl, L/r\ i f gugs D i 78 carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, R31 er hydroxy, amino, en mættet eller delvist umættet lavere carbonhydridrest, som er usubstitueret eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, lavere alkylamino, di(lavere alkyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, 5 arylaminocarbonyl, arylcarbonyl, arylcarbonylamlno, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, og som er bundet via et oxygenatom eller en imino- eller lavere alkyliminogruppe, eller en 4-morpholinyl-, 1-pyrrolidinyl- eller 1-azetidinylgruppe, som er usubstitueret eller mono-10 eller disubstitueret med lavere alkyl, hydroxy, lavere alkoxy, lavere alkanoyloxy, lavere hydroxyalkyl, lavere alkoxyalkyl, lavere alkanoyloxyalkyl, lavere alkoxycarbonyl, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, oxo og/eller lavere alkylendioxy, Q er gruppen -CO- eller >C=N-(Z)P-R\ Z er et oxygenatom eller en iminogruppe, p er 0 eller 1, og R4 er hydrogen eller en mættet eller delvist umættet lavere carbonhydridrest, 15 som er usubstitueret eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, lavere alkylamino, di(lavere a!kyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, og som 20 eventuelt er bundet via en carbonylgruppe, idet Ra er cyano, hvis Rc’ er cyano eller nitro, og R31 har en betydning forskellig fra hydroxy, når m er 0, og idet aryl betegner en phenyl-eller naphthylgruppe, som er usubstitueret eller mono- eller disubstitueret med halogen, trifluormethyl, nitro, amino, mono- eller di(lavere alkyl)amino, lavere alkyl, lavere alkoxy, lavere alkylthio, lavere alkanoyl, lavere alkoxycarbonyl, carboxy, hydroxy, cyano, lavere 25 alkanoyloxy, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, lavere alkylendioxy, lavere alkanoylamino eller lavere alkoxycarbonylamino, heteroaryl er en heterocyklisk gruppe valgt fra gruppen bestående af pyridyl, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, benzoxazinyl, quinoxalinyl, benzopyranyl, benzimidazolyl, indolyl, 30 imidazothiazolyl, imidazothiadiazolyl, imidiazopyridyl, benzothiazinyl, benzoquinoxalinyl og imidazobenzothiazolyl, som er bundet via et carbonatom, og som er usubstitueret eller mono-, di- eller trisubstitueret med halogen, trifluormethyl, nitro, carboxy, amino, arylamino, lavere alkyl, lavere alkoxy, hydroxy, lavere alkoxycarbonyl, lavere alkanoyl, lavere alkanoyloxy, oxo, lavere alkylendioxy, mercapto, lavere alkylthio, lavere 35 alkylamino, di(lavere alkyl)amino, C3.7-cydoalkylamino, C8-io'bicycloalkylamino, lavere alkanoylamino, lavere alkoxycarbonylamino, carbamoyl, mono- eller di(lavere alkyl)car-bamoyl, cyano, aryl, aryl-lavere alkyl, aryl-lavere alkylamino, heteroaryl, heteroaryl-lavere alkyl, heteroarylamino eller C3.7-cycloalkyl, og lavere betegner rester med op til 7 79 DK 175069 B1 carbonatomer, under fysiologiske betingelser hydroliserbare ester- og etherderivater, og farmaceutisk acceptable salte deraf.Compounds of the general formula? A HV \ Λν - «* · Ib H0 s- \ b 1 2 3 4 5 6 wherein Ra is nitro or cyano, Rb is hydrogen or halogen, 2 Rc 'is nitro, cyano or the group - (A) n- (Q) m -Rn or - (A) nQ-R21, A is optionally lower alkyl substituted vinylene, n is 0 or 1, m is 0 or 1, R11 is the group -COR3 \ aryl or 4 heteroaryl, R 21 is a saturated or partially unsaturated lower hydrocarbon radical which is unsubstituted or mono- or disubstituted by hydroxy, cyano, nitro, halogen, amino, 6 lower alkylamino, di (lower alkyl) armno, lower alkoxy, lower alkoxycarbonyl , aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, lower alkylenedioxy, trifluoromethyl, L / r \ if gugs D in 78 carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio, R 31 is hydroxy, amino, a saturated or partially unsaturated lower hydrocarbon residue which is unsubstituted or mono or disubstituted with hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio, and which are bonded via an oxygen atom or an imino or lower alkylimino group, or a 4-morpholinyl-, 1-pyrrolidinyl- or 1-azetidinyl group which is unsubstituted or mono-10 or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, oxo and / or lower alkylenedioxy, Q is the group -CO- or> C = N- (Z) PR \ Z is an oxygen atom or an imino group, p is 0 or 1 and R4 is hydrogen or a saturated e or partially unsaturated lower hydrocarbon residue which is unsubstituted or mono- or disubstituted by hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio, optionally bonded via a carbonyl group, Ra being cyano , if Rc 'is cyano or nitro, and R31 has a meaning different from hydroxy when m is 0, and aryl represents a phenyl or naphthyl group which is unsubstituted or mono- or disubstituted by halogen, trifluoromethyl, nitro, amino, mono- or di (lower alkyl) amino, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, carboxy, hydroxy, cyano, lower alkanoyloxy, carbamoyl, mono- or di ( lower alkyl) carbamoyl, lower alkylenedioxy, lower alkanoylamino or lower alkoxycarbonylamino, heteroaryl is a heterocyclic group selected from the group consisting of pyridyl, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, thetazoline, dihydroisoquinolinyl, benzoxazinyl, quinoxalinyl, benzopyranyl, benzimidazolyl, indolyl, imidazothiazolyl, imidazothiadiazolyl, imidiazopyridyl, benzothiazinyl, benzoquinoxalinyl and imidazobenzothiazolyl, which is tritubin or mono- , carboxy, amino, arylamino, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto, lower alkylthio, lower alkylamino, di (lower alkyl) amino, C 3-7 cycloalkylamino , C8-10 bicycloalkylamino, lower alkanoylamino, lower alkoxycarbonylamino, carbamoyl, mono- is di (lower alkyl) carbamoyl, cyano, aryl, aryl-lower alkyl, aryl-lower alkylamino, heteroaryl, heteroaryl-lower alkyl, heteroarylamino or C 3-7 cycloalkyl, and lower denotes residues of up to 7 79 DK 175069 B1 carbon atoms, under physiological conditions hydrolysable ester and ether derivatives, and pharmaceutically acceptable salts thereof. 3. Forbindelser ifølge krav 2, kendetegnet ved, at Rb sidder i p-stilling i forhold til 5 Ra.Compounds according to Claim 2, characterized in that Rb is in the p-position relative to 5 Ra. 4. Forbindelser ifølge krav 2 eller 3, k e n d e t e g n e t v e d, at Ra er nitro.Compounds according to claim 2 or 3, characterized in that Ra is nitro. 5. Forbindelser ifølge et hvilket som helst af kravene 2-4, kendetegnet ved, at Rb 10 er hydrogen, chlor eller fluor.Compounds according to any one of claims 2-4, characterized in that Rb 10 is hydrogen, chlorine or fluorine. 6. Forbindelse ifølge krav 5, kendetegnet ved, at Rb er hydrogen.A compound according to claim 5, characterized in that R b is hydrogen. 7. Forbindelser ifølge et hvilket som helst af kravene 2-6, hvor Rc‘ er gruppen -CO-R1, og 15 Rn er en phenylgruppe, som er usubstitueret eller mono- eller disubstitueret med halogen, trifluormethyl, nitro, amino, mono- eller di(lavere alkyl)amino, lavere alkyl, lavere alkoxy, lavere alkylthio, lavere alkynoyl, lavere alkanoyl, lavere alkoxycarbonyl, carboxy, hydroxy, cyano, lavere alkanoyloxy, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, lavere alkylendioxy, lavere alkanoylamino eller lavere alkoxycarbonylamino eller en heterocyklisk 20 gruppe valgt fra gruppen bestående af pyridyl, pyrazinyl, triazinyl, pyrazolyl og imidazolyl, som er usubstitueret eller mono-, di- eller trisubstitueret med halogen, trifluormethyl, nitro, carboxy, amino, arylamino, lavere alkyl, lavere alkoxy, hydroxy, lavere alkoxycarbonyl, lavere alkanoyl, lavere alkanoyloxy, oxo, lavere alkylendioxy, mercapto, lavere alkylthio, lavere alkylamino, di(lavere alkyl)amino, C3.7-cycloalkylamino, Ce-ur 25 bicycloalkylamino, lavere alkanoylamino, lavere alkoxycarbonylamino, carbamoyl, monoeller di(lavere aikyl)carbamoyl, cyano, aryl, aryl-lavere alkyl, aryl-lavere alkylamino, heteroaryl, heteroaryl-lavere alkyl, heteroarylamino eller C3.7-cycloalkyl, og som er bundet via et carbonatom.Compounds according to any one of claims 2-6, wherein R c 'is the group -CO-R 1 and R 11 is a phenyl group which is unsubstituted or mono- or disubstituted by halogen, trifluoromethyl, nitro, amino, mono- or di (lower alkyl) amino, lower alkyl, lower alkoxy, lower alkylthio, lower alkynoyl, lower alkanoyl, lower alkoxycarbonyl, carboxy, hydroxy, cyano, lower alkanoyloxy, carbamoyl, mono- or di (lower alkyl) carbamoyl, lower alkylenedioxy, lower alkanoylamino or lower alkoxycarbonylamino or a heterocyclic group selected from the group consisting of pyridyl, pyrazinyl, triazinyl, pyrazolyl and imidazolyl which is unsubstituted or mono-, di- or trisubstituted by halogen, trifluoromethyl, nitro, carboxy, amino, alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto, lower alkylthio, lower alkylamino, di (lower alkyl) amino, C 3-7 cycloalkylamino, Ce-ur 25 bicycloal kylamino, lower alkanoylamino, lower alkoxycarbonylamino, carbamoyl, mono or di (lower alkyl) carbamoyl, cyano, aryl, aryl-lower alkyl, aryl-lower alkylamino, heteroaryl, heteroaryl-lower alkyl, heteroarylamino or C 3-7 cycloalkyl, and which are bound via a carbon atom. 8. Forbindelser ifølge krav 7, k e n d e t e g n e t v e d, at R1 er en phenylgruppe, der eventuelt er mono- eller disubstitueret med halogen, trifluormethyl, cyano, hydroxy eller lavere alkyl, eller en pyridylgruppe. 9. 3,4-Dihydroxy-4*-methyl-5-nitrobenzophenon. 35 10. 2‘-Fluor-3,4-dihydroxy-5-nitrobenzophenon. 3,4-Dihydroxy-5-nitrophenyl-4-pyridylketon. m m * ww%r i 80Compounds according to claim 7, characterized in that R 1 is a phenyl group which is optionally mono- or disubstituted by halogen, trifluoromethyl, cyano, hydroxy or lower alkyl, or a pyridyl group. 9. 3,4-Dihydroxy-4 * -methyl-5-nitrobenzophenone. 35 10. 2′-Fluoro-3,4-dihydroxy-5-nitrobenzophenone. 3,4-Dihydroxy-5-nitrophenyl-4-pyridyl ketone. m m * ww% r i 80 12. Forbindelser ifølge et hvilket som helst af kravene 2*11 til anvendelse som terapeutisk aktive stoffer.Compounds according to any one of claims 2 * 11 for use as therapeutically active substances. 13. Forbindelser ifølge et hvilket som helst af kravene 1-11 til anvendelse som aktive 5 stoffer, som inhiberer catechol-O-methyl-transferase.Compounds according to any one of claims 1-11 for use as active substances which inhibit catechol-O-methyl-transferase. 14. Fremgangsmåde til fremstilling af forbindelser ifølge et hvilket som helst af kravene 2-11, af under fysiologiske betingelser hydroliserbare ester* og etherderivater, og af farmaceutisk acceptable salte deraf, kendetegnet ved, at 10 a) den/de lavere alkylethergrupper i en forbindelse med den almene formel II fa R0\ ,\ \ $-Rc· 11 R'O Rb hvor et af symbolerne R og R‘ er lavere alkyl, og det andet er hydrogen eller lavere alkyl, og Ra, Rb og Rc' har de i krav 2 anførte betydninger, fraspaltes eller 15 b) en forbindelse med den almene formel Ib’ fa HV\ /\w"‘(A)n'cO-cH2-X 15 HO . Rb hvor X betegner en fraspaltelig enhed, og Ra, Rb, A og n har de i krav 2 anførte betydninger, omsættes med et thioamid, thiourinstof, thiocarbonsyrehydrazid, thiosemi-carbazid, amidin, guanidin, amidrazon, aminoguanidin, cyclisk amidin, 1,2-diamin, 1,2-aminothiol eller en 1,2-aminoalkohol, og det vundne cyclokondensationsprodukt om 20 ønsket dehydrogeneres, eller 81 DK 175069 B1 c) en forbindelse med den almene formel Ib2 HV'· / %V*"iA)n-C0-C00R" Ib ho n Rb hvor R" er lavere alkyl, og Ra, Rb, A og n har de i krav 2 anførte betydninger, omsættes med en 1,2-diamin, 1,2-aminothiol, 1,2-aminoalkohol, semicarbazid, thiosemicarbazid, amidrazon eller en aminoguanidin, og det vundne cydokondensationsprodukt om ønsket 5 dehydrogeneres, eller d) en forbindelse med den ovennævnte formel Ib1 omsættes med en β-aminocar-bonylforbindelse, eller 10 e) i en forbindelse med den almene formel III, la2 eller IV CHO CN 9H0 H0\ H0\ f\ n odeE H°n.^ \ ,n' Λΐ» Ia «A't* IV hvor Rc’" er nitro, cyano eller gruppen -(A)n-R12, og R32 er gruppen -COR31, aryl eller heteroaryl, og Ra, Rb, A, n og R33 har de i krav 2 anførte betydninger, eller i et di-O-lavere alkanoyldenvat deraf, carboxaldehydgruppen/grupperne omdannes til cyanogruppen/grupperne, eller 15 82 DK 175069 Bl f) et di-O-lavere afkanoylderivat af en carboxylsyre med den ålmene formel lå3 eller Ib3 Ra Ht\ A , 3 *\ Λ \ Is oder i 3 ' /\V-<A>n-C00H m/\ \-Wn-c°-COOH Ib H0 ‘te Rb hvor Ra, Rb, A og n har de i krav 2 anførte betydninger, i nærværelse af et kondensationsmiddel eller et reaktivt derivat af di-O-lavere alkanoylderivat af en carboxylsyre med formlen la3 eller Ib3 omsættes med en forbindelse med den almene formel V 5 eller VI HO-Rs V eller HNR6R7 VI hvor Rs er en mættet eller delvist umættet lavere carbonhydridrest, som er usubstitueret 10 eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, ammo, lavere alkylamino, di(lavere alkyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)carbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, R6 er 15 hydrogen eller lavere alkyl, og R7 er hydrogen eller en mættet eller delvist umættet, lavere carbonhydridrest, som er usubstitueret eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, lavere alkylamino, di{lavere alkyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)-carbamoyl, lavere 20 alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, eller R6 og R7 tilsammen med nitrogenatomet er en 4-morpholinyl, 1-pyrrolidinyl- eller 1-azetidinylgruppe, som er usubstitueret eller mono- eller disubstitueret med lavere alkyl, hydroxy, lavere alkoxy, lavere alkanoyloxy, lavere hydroxyalkyl, lavere alkoxyalkyl, lavere alkynoyloxyalkyl, lavere alkoxycarbonyl, lavere alkanoyl, carbamoyl, 25 mono- eller di(lavere alkyl)carbamoyl, oxo og/eller lavere alkylendioxy, eller DK 175069 B1 83 g) en forbindelse med den ovennævnte formel Ib2 eller med den almene formel Ib4 8 ROw\ . 8 Λ J-»c· Ib rbo Rb hvor R8 er lavere alkanoyl, og Ra, Rb og Rc* har de i krav 2 anførte betydninger, hydrolyseres, eller 5 h) en forbindelse med den almene formel Ib5 ?a H<\ s -Αχ*-«" Ib H0 · Rb hvor Ra og Rb har de i krav 2 anførte betydninger, og Rm er hydrogen eller lavere alkyl eller et di-O-lavere alkanoylderivat deraf i nærværelse af en sekundær amin, omsættes 10 med en forbindelse med den almene formel VII CH3CO-R23 VII hvor R23 er en mættet eller delvist umættet lavere carbonhydridrest, som er usubstitueret 15 eller mono- eller disubstitueret med hydroxy, cyano, nitro, halogen, amino, lavere alkylamino, di(lavere alkyl)amino, lavere alkoxy, lavere alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lavere alkanoyloxy, lavere alkanoyl, carbamoyl, mono- eller di(lavere alkyl)-carbamoyl, lavere alkylendioxy, trifluormethyl, carboxy, lavere alkanoylamino, lavere alkoxycarbonylamino eller lavere alkylthio, eller 20 Lsrv i f >;vu« u i 84 i) en forbindelse med den almene formel Ib6 ?a HOl /· , \ 6 /\V'L(A)n"CO,_CH2-COOR" 1,0 · Rb hvor Ra, Rb, A og n har de i krav 2 anførte betydninger, og R" har den ovenfor anførte betydning, omsættes med en hydrazin eller en amidin, eller 5 j) en forbindelse med den ovennævnte formel Ib, hvor m er 1, og Q er gruppen -CO-, omsættes med en forbindelse med den almene formel VIII H2N-(Z)p-R* VIII 10 hvor Z, p og R4 har de i krav 2 anførte betydninger, og om ønsket k) en forbindelse med den ovennævnte formel Ib omdannes til et under fysiologiske 15 betingelser hydroliserbart ester- og etherderivat, eller et farmaceutisk acceptabelt salt deraf.Process for the preparation of compounds according to any one of claims 2-11, of ester * and ether derivatives which can be hydrolysed under physiological conditions, and of pharmaceutically acceptable salts thereof, characterized in that a) the lower alkyl ether group (s) in a compound with the general formula II fa R0 \, \ \ $ -Rc · 11 R'O Rb where one of the symbols R and R 'is lower alkyl and the other is hydrogen or lower alkyl, and Ra, Rb and Rc' have the (b) a compound of the general formula Ib 'fa HV \ / \ w "' (A) n'cO-cH2-X 15 HO. Rb wherein X represents a leaving group, and Ra Rb, A and n have the meanings given in claim 2, are reacted with a thioamide, thiourea, thiocarboxylic acid hydrazide, thiosemi-carbazide, amidine, guanidine, amidrazone, aminoguanidine, cyclic amidine, 1,2-diamine, 1,2-aminothiol or a 1,2-amino alcohol, and the cyclocondensation product obtained, if desired, is dehydrogenated, or c) a for compound of the general formula Ib2 HV '· /% V * "iA) n-CO-COR" Ib ho n Rb where R "is lower alkyl and Ra, Rb, A and n have the meanings given in claim 2, are reacted with a 1,2-diamine, 1,2-aminothiol, 1,2-amino alcohol, semicarbazide, thiosemicarbazide, amidrazone or an aminoguanidine, and the cydocondensation product obtained is dehydrated if desired, or d) a compound of the above formula Ib1 is reacted with a β-aminocarbonyl compound, or e) in a compound of the general formula III, Ia2 or IV CHO CN 9H0 H0 \ H0 \ f \ n odeE H ° n. ^ \, n 'Λΐ »Ia« A't IV wherein Rc '"is nitro, cyano or the group - (A) n -R12, and R32 is the group -COR31, aryl or heteroaryl, and Ra, Rb, A, n and R33 have the meanings given in claim 2, or in a di-O-lower alkanoyl denevate thereof, the carboxaldehyde group (s) is converted to the cyano group (s), or f) a di-O-lower decanoyl derivative of a carboxylic acid having the general formula la3 or Ib3 Ra Ht \ A, 3 * \ Λ \ Is ode ri 3 '/ \ V- <A> n-COOH m / \ \ -Wn-c ° -COOH Ib H0' te Rb where Ra, Rb, A and n have the meanings given in claim 2, in the presence of a condensing agent or a reactive derivative of di-O-lower alkanoyl derivative of a carboxylic acid of formula Ia3 or Ib3 is reacted with a compound of general formula V5 or VI HO-Rs V or HNR6R7 VI wherein Rs is a saturated or partially unsaturated lower hydrocarbon residue which is unsubstituted or mono- or disubstituted by hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamo , mono- or di (lower alkyl) carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio, R 6 is hydrogen or lower alkyl and R 7 is hydrogen or a saturated or partially unsaturated lower hydrocarbon radical which is unsubstituted or mono- or disubstituted with hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) -carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio, or R 6 and R 7 together with the nitrogen atom are a 4-morpholinyl, 1-pyrrolidinyl or 1-azetidinyl group which is unsubstituted or mono- or disubstituted with lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkynoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, oxo and / or lower alkylenedioxy, or DK 175069 B1 83 g) a compound of the above formula Ib2 or of the general formula Ib4 8 ROw \. -J- »c · Ib rbo Rb where R8 is lower alkanoyl and Ra, Rb and Rc * have the meanings given in claim 2, hydrolyzed, or 5 h) a compound of the general formula Ib5? A H <\ s Wherein H 1 and R 2 have the meanings given in claim 2 and R m is hydrogen or lower alkyl or a di-O-lower alkanoyl derivative thereof in the presence of a secondary amine, is reacted with a compound with the general formula VII CH3CO-R23 VII wherein R23 is a saturated or partially unsaturated lower hydrocarbon residue which is unsubstituted or mono- or disubstituted by hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di (lower alkyl) amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di (lower alkyl) -carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or 20 Lsrv if>; vu «ui 84 i) en for compound of the general formula Ib6? a HOl / ·, \ 6 / \ V'L (A) n "CO, _CH2-COOR" 1,0 · Rb where Ra, Rb, A and n have the meanings given in claim 2 , and R "has the meaning given above, is reacted with a hydrazine or an amidine, or 5 j) a compound of the above formula Ib, wherein m is 1 and Q is the group -CO-, is reacted with a compound of the general formula VIII H2N- (Z) pR * VIII wherein Z, p and R4 have the meanings given in claim 2, and if desired k) a compound of the above formula Ib is converted into a ester and ether derivative hydrolysable under physiological conditions, or a pharmaceutically acceptable salt thereof. 15. Lægemiddel, der indeholder en forbindelse ifølge et hvilket som helst af kravene 1-11 og et terapeutisk inert bærermateriale. 20A medicament containing a compound according to any one of claims 1-11 and a therapeutically inert carrier material. 20 16. Middel til inhtbering af catechol-O-methyl-transferase, hvilket middel indeholder en forbindelse ifølge et hvilket som helst af kravene 1-11 og et terapeutisk inert bærermateriale.An agent for inhibiting catechol-O-methyl transferase, which agent contains a compound according to any one of claims 1-11 and a therapeutically inert carrier material. 17. Middel til behandling af Parkinsons sygdom indeholdende L-dopa, en perifer decarboxylaseinhibitor, en forbindelse ifølge et hvilket som helst af kravene 1-11 og et terapeutisk inert bærermateriale.A agent for the treatment of Parkinson's disease comprising L-dopa, a peripheral decarboxylase inhibitor, a compound according to any one of claims 1-11 and a therapeutically inert carrier material. 18. Lægemiddelkombination til behandling af Parkinsons sygdom, hvilken kombination 30 indeholder et middel ifølge krav 16 og et middel indeholdende L-dopa, en perifer decarboxylaseinhibitor og et terapeutisk inert bærermateriale. 85 DK 175069 B1A drug combination for the treatment of Parkinson's disease, which combination contains an agent according to claim 16 and an agent containing L-dopa, a peripheral decarboxylase inhibitor and a therapeutically inert carrier material. 85 DK 175069 B1 19. Anvendelse af forbindelser ifølge et hvilket som helst af kravene 1-11 til fremstilling af midler, der inhiberer catechol-O-methy(transferase.Use of compounds according to any one of claims 1-11 for the preparation of agents that inhibit catechol-O-methyl (transferase). 20. Anvendelse af forbindelser ifølge et hvilket som helst af kravene 1-11 til fremstilling af et middel til behandling af Parkinsons sygdom i kombination med L-dopa og en perifer . decarboxylaseinhibitor.Use of compounds according to any one of claims 1-11 for the manufacture of an agent for the treatment of Parkinson's disease in combination with L-dopa and a peripheral. decarboxylase inhibitor. 21. Anvendelse af forbindelser ifølge et hvilket som helst af kravene 1-11 til fremstilling af 10 lægemiddelkombinationer ifølge krav 18.Use of compounds according to any one of claims 1-11 for the preparation of 10 drug combinations according to claim 18.
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