IE870609L - 3,5-disubstituted pyrocatechol derivatives - Google Patents

3,5-disubstituted pyrocatechol derivatives

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Publication number
IE870609L
IE870609L IE870609A IE60987A IE870609L IE 870609 L IE870609 L IE 870609L IE 870609 A IE870609 A IE 870609A IE 60987 A IE60987 A IE 60987A IE 870609 L IE870609 L IE 870609L
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IE
Ireland
Prior art keywords
signifies
hydroxy
nitro
group
alkyl
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IE870609A
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IE61316B1 (en
Inventor
Karl Bernauer
Janos Borgulya
Hans Bruderer
Prada Mose Da
Gerhard Zuercher
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Hoffmann La Roche
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Publication of IE870609L publication Critical patent/IE870609L/en
Publication of IE61316B1 publication Critical patent/IE61316B1/en

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Abstract

The use of substd. catechol derivs. of formula (Ia), their physiologically hydrolysable esters and ethers, and pharmaceutically acceptable salts as therapeutic agents is new. Ra = NO2 or CN; Rb = H or halo; Rc = halo, NO2, CN, -(A)n-(Q)m-R1 or -(A)n-Q-R2; A = vinylene, opt. substd. by lower alkyl; n and m = zero or 1; R1 = COR3, aromatic carbocyclic gp. or, bonded via a C atom, an aromatic or partially unsatd. heterocycle; R2 = H or lower hydrocarbyl, opt. substd., satd. or partially unsatd.; R3 = OH; NH2; lower hydrocarbyl (opt. substd., satd. or partially unsatd.) bonded via O, imino or lower alkylimino; or an N-bound, satd. N-contg. heterocyclyl; Q = CO or C=N-(Z)p-R4; Z = O or imino; P = zero or 1; R4 = H or a satd. or partially unsatd. lower hydrocarbyl, opt. substd. and opt. bound via carbonyl gp. (Ia) are new cpds. when R = NO2, CN, -(A)n-(Q)m-R1 or -(A)n-Q-R21; R21 is as R2, excluding H; provisos: Ra = CN if Rc = CN or NO2; R3 is other than OH when m = zero. The catechol derivatives of the formula …<IMAGE>… in which Ra, Rb and Rc have the meaning given in Claim 1,… the ester and ether derivatives which can be hydrolysed under physiological conditions and the pharmaceutically acceptable salts thereof have useful pharmacological properties. They inhibit, in particular, the enzyme catechol o-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transfer of the methyl group from S-adenosylmethionine to a catechol substrate, the corresponding methyl ethers being formed. Suitable substrates which are O-methylated by COMT and thus deactivated are, for example, extraneuronal catecholamines and exogenously administered therapeutic active compounds having a catechol structure. …<??>The above formula Ia comprises both novel and known compounds, it being possible to prepare the novel compounds by methods which are known per se. [EP0237929A1]

Description

/ 6o 16 - i - Description The chatecho1 derivatives of the general formula HOwX i 'i-Rc la HQ * \b wherein Ha signifies nitro or cyano, Rb signifies 5 hydrogen or halogen* He signifies halogen, nitro. cyano or the group -(A)^-(Q),-B1 or _ G&l -(&)p-Q-H *„ A signifies vinylene optionally substituted by lower alkyl. n signifies the number O or 1, m signifies the number 0 or 1, R" signifies 3 10 the group -COH , a carbocyclic, aromatic group or an aromatic or partially unsaturated, heterocyclic aroup 2 attached via a carbon atom, S signifies hydrogen or an optionally substituted, saturated or partially 3 unsaturated, lower hydrocarbon residue, H signifies 15 hydroxy,, amino, an optionally substituted, saturated or partially unsaturated, lower hydrocarbon residue attached via an oxygen atom or an imino or lower alkylimino group or a saturated. N-containing heterocyclic group attached via a ring nitrogen atom, Q 2o signifies the group -CO- or >C=N-(Z)^-a , z signifies an oxygen atom or an imino group, p signifies the number O or 1 and S signifies hydrogen or a saturated or partially unsaturated, lower hydrocarbon residue which is optionally _c substituted and which is optionally attached via a Z D carbonyl group,, the ester and ether derivatives which are hydrolyzable under physiological conditions and the pharmaceutical^ acceptable salts thereof possess valuable pharmacological 30 properties,, In particular. these compounds inhibit the enzyme catechol-0-methylt.cansf erase (COMT),, a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adenosyliaethionine to a catechol substrate,, thereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are. for example,,, extra,neuronal catecholamines and exogenously-administered therapeutically active substances having a catechol structure.
The compounds of formula la above can accordingly be used in the prevention or control of illnesses in which a deactivation of extraneuronal catecholamines by COMT plays a role, for example in the prevention or control of depressions. In this case the compounds of formula la above can be used as individual compounds or in combination with other therapeutically active substances which favourably influence the course of the illness. The compounds of formula la can, however. also be used as comedications with other therapeutically active substances.
The compounds of formula la can, however, also be used to improve the prevention or control of illnesses with therapeutically active substances which have a catechol structure. The treatment of Parkinson's disease and of parkinsonism with L-dopa, a therapeutically active substances having the catechol structure, can be mentioned as an example. In such cases the compounds of formula la can be used in the form of a cornedication or as combination preparations.
The field! of diagnostics offers a further possibility for the use of the compounds of formula la above. After 1 8 the administration of C F]-6-fluoro-L-dopa, •j Q f F]-dopamine in the brain can be visualised with the aid of positron emission tomography. By adding a cosapo\«sd - 3 - of formula la above the COMT is inhibited and thus the IB f orraacioo. of [ F]-3-O-methyldopa is prevented„ In the i 3 absence of a COMT-inhibitor, the [* F]-3-O-metty1d o pa would penetrate into the bcain and lead to a greatly 5 increased background which would make the diagnosis very sauch more difficult. 10 Formula la above embraces not only knowne but also novel compounds. The compounds of formula la which are known per se fall under the general formula Ea H°\ ! 3-RC" 1s" „,/ ^ x KC H0 * Rb wherein Ra signifies nitro or cyano, Rb signifies hydrogen or halogen. He" signifies nitro, eyeno or the group - (A)^-COOH or - (A)q-Q-H, A signifies vinylene optionally substituted by lower alkyl. a 1c signifies the number O or 1. 0 signifies the group -CO- or >c=38-(E)^-H , Z signifies an oxygen atom or an imino group, p signifies the number O or 1 and 4 R signifies hydrogen or a saturated or partially unsaturated,, lower hydrocarbon residue which is 2Q optionally substituted and which is optionally attached via a carbony1 group, whereby Ha signifies nitro when He" signifies cyano or nitro, ester and ether derivatives which are hydrolyzable under physiological conditions and pharmaceutical^ acceptable 25 salts thereof.
Similar phenylethvlamines have been published ia EP-A-142283. 3.5-Dinitropyrocar.echol has been described in GB-A-2038819 in connection with the manufacture of explosives. 5-Chloro-2.3-dihydroxybenzonitrile and 4,5-dichloro-2.3-dihydroxybenzonitrile, later alia„ have been published in Chem. Abstr„ 92, 146461k. The preparation and reduction of 3,4-dihydroxy-5-nitrobenzoic acid have been described in J. Antibiot. 35.. 1361-1366 (1982), Chen. Abstr, 29, 54421 (1935) relates to the preparation of 3,4-dihydroxy-5-nitro-cinnamic acid.
The novel compounds of formula la are the compounds of the general formula H0\ i il , . »-Rc lb H0 Rb wherein Ha signifies aitro or cyano, Rb signifies hydrogen or halogen. He' signifies nitro, cyano or the group -(A)n-(Q)m-H11 or ~(A)n-Q-R21. A signifies vinylene optionally substituted by lower alkyl, n signifies the number O or 1, ro signifies the it 31 number O or 1, H~~ signifies the group -COR a carbocyclic. aromatic group or an aromatic or partially unsaturated, heterocyclic group attached via a carbon atom, B'~ signifies an optionally substituted. saturated or partially unsaturated,, lower 31 hydrocarbon residue,, S ~ signifies hydroxy, amino, an optionally substituted, saturated or partially unsaturated, lower hydrocarbon residue attached via an oxygen atom or an imino or lower alkyliaino group or a saturated, N-containisng heterocyclic group attached via a ring nitrogen atom, Q signifies the group 4 -CO- or >C=M-(Z) -3 , 2 signifies an oxygen atom 0 or an isiino group, p signifies the number 0 or 1 and 4 R' signifies hydrogen or a saturated or partially unsaturated, lower hydrocarbon residue which is optionally substituted and which is optionally - 5 - attached via a carbonyl group,, whereby Ha signifies 31 cyano when Rc' signifies cyano or nitro and H ~ has a significance different from hydroxy when m signifies the number o„ 5 and the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutical^ acceptable salts thereof.
Objects of the present invention are; the above compounds of formula la and the mentioned derivatives 10 thereof for use as therapeutically active substances; medicaments based on these compounds and derivatives: the manufacture of sueh medicaments: the use of the compounds and derivatives in question.'in the prevention or control of illnesses; the use of the compounds and derivatives in 15 question for the manufacture of medicaments which in a given case inhibit the enzyme COMT in the sens® of a desired side-effect: the compounds of lb above and the mentioned derivatives thereof per ss; the manufacture of these compounds and derivatives: as well as intermediates 20 for their manufacture.
The tec® "lower" denotes residues and compounds with a maximum of 7, preferably a maximum of 4, carbon atoms. The term "alkyl", taken alone or in combinations such as "alkyl group". "alkoscy", "alkylthio" and "alkylinino", 25 denotes straight-chain or branched, saturated hydrocarbon residues such as methyl, ethyl, propyl, isopcopyl, n-butyl. s-butyl, i-butyl and t-butyl. The term "saturated or partially unsaturated, lower hydrocarbon residue" denotes open-chain and cyclic groups and combinations 30 thereof. Examples of saturated and partially unsaturated lower hydrocarbon residues are: lower alkyl groups such as those defined above: lower alkenvl groups such as 2-propenyl. 2-butenyl. 3-butenyl and 2-methyl-2-propenyl; C3 7-cycloalkyl and Cg Q-bicycloalkyl groups optionally substituted by lower alkyl groups such as cyclopropyl. cyclopentyl» 2~methylcyclopentyl, cyclohexyl and 3-methylcycXohexyX: lower cycloalkenyl groups optionally substituted by lower alkyl groups such as 3-cyclopentenyl. X-methyX-3-cyclopentenyl and 3-cycXohexenyX; lower alkyl or aXkenyX groups substituted by lower cycXoaXkyl or cycloalkenyl groups such as cyclopropyXmethyX, cycXopro- pylethyl, cycXopentyXaethyX. cyclohexylmethyX,„ 2-cyclo- hexenylraethyl and 3-cyclopropyl-2-propenyl. The lower alkenyl groups preferably contain 2-4 carbon atoms; the cycloalkyl and cycloalkenyl groups preferably contain 3-6 carbon atoms.
The follouring come into consideration as suhstituents for the above lower hydrocarbon residues: hydroxy,, cyano. nitro„ halogen, amino, lower alkylaaino, di(lower alkyl)-amino, lower alkoxy. lower alkoxycarbonyl, aryl, arylaminocarbonyl. arylcarbonyl, arylcarbonylamino, lower aXkanoyXoxy, lower aXkanoyX, carbamoyl,, no no- or di( lower alkyl)carbamoyl, lower alkylenedioxy. trifluoromethyl, carboxy. lower aXkanoyXamino. lower aXkoxycarbonyXaaino and lower aXkyXthio. The saturated or partially unsaturated,, lower hydrocarbon residues are preferably unsubstituted or mono- or disubstituted.
The term "aryl" denotes cacbocycXic aromatic groups, preferably aoao- or bicvclic groups. Especially preferred carbocycXic aromatic groups are phenyl and naphthyX groups. especiaXXy phenyl groups. These groups are optionally substitued by: halogen, trifXuoroaethyX, nitro, amino, mono- or di(Xower aXkyl)aaino, lower alkyl, lower alkoxy, lower alkylthio, Xower alkanoyl, lower alkoxycarbonyl, carboxy, hydroxy, cyano, lower aXkanoyXoxy, carbamoyl, saono- or di(lower alkyl)carbamoyl, lower alkylenedioxy, lower alkanoylamino or lower aXkoxycarbonyXamino. The carbocycXic aromatic groups are - 7 - preferably unsubstituted or: mono- or disubstituted.
The term "aromatic or partially unsaturated,, heterocyclic group" preferably denotes a mono-. di- or tricyclic, aromatic or partially unsaturated, heterocyclic 5 group with up to 5 hetero atoms from the group consisting of nitrogen, sulphur and oxygen. These heterocyclic groups preferably contain l-« nitrogen atoms and/or an oxygen or sulphur atom. They are preferably mono- or bicvclic. The hetero atoms are preferably distributed oa one or two -|0 rings,, whereby nitrogen atoms can simultaneously also be components of 2 rings. The heterocyclic groups are preferably aromatic. They can be substituted,, whereby in • this case they are preferably mono- . di- or trisubsti-tuted. As substituents there come into considerations halogen, trifluoromethyl, nitro, carboxy, amino, aryl-amino, lower alkyl, lower alkoxy. hydroxy, lower alkoxy-carbonyl, lower alkanoyl. lower alkanoyloxy, oxo. lower alkylenedioxy. mercapto. lower alkylthio. lower alkyl-amino, di(lower alkyl)amino. C"3 ^-cycloalkylamino, 20 Ce^o-bicycloalkylamino, lower alkanoylamino, lower alkoxycarbonylamino, carbamoyl, mono- or di(lower alkyl)-carbamoyl, cyano, aryl, aryl-lower alkyl. acyl-lower alkylamino, hetecoaryl. heteroaryl-lower alkyl. hetero-arylamino and C37-cvcloalkyl. The monocyclic hetero-25 cyclic groups are preferably 5- or 6-membered and contain a maximum of four hetero atoms. The bicyclic heterocyclic groups are preferably S- to 10-membered. whereby the individual rings are preferably S- or 6-membered.
The following are to be mentioned as examples of such 30 heterocyclic groups: pyridyl, pyrazinyl. triazinyl. thiadazinyl, thiazolyl. oxazolyl. oxadiazolyl, pyrazolyl, tetrazolyl. iaidazolyl. thienyl, quinolinyl, isoguinolinyl. dihydroisoquinolinyl. benzoxazinyl, quinoxalinyl. benzopyranyl, benzimidazolyl. indolyl. - 8 - imidazothiazolyl. imidazothiadia2olyl» imidazopyridyl. benzothiazinyl. benzoquinoxalinyl and imidazo-benzochiazolyl.
The term "heteroaryl" denotes aromatic, heterocyclic 5 groups as defined above.
The teria "a saturated, M-containing heterocyclic group attached via a ring nitrogen atom" preferably denotes a 3- to 7-membered. preferably 4- to S-membeced, saturated N-heterocycXe which, in addition to the said nitrogen atom, can contain an oxygen, sulphur or nitrogen atom as a second hetero atom. These saturated N-heterocycles can be mono- or disubstituted hvt lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower aXkoxyaXkyX. lower aXkanoyXoxyaXkyX, lower aXkoxycarbonyX, lower alkanoyl,, carbamoyl, mono- or di(lower alkyl)-carbamoyl. oxo and/or lower alkylenedioxy.
The following are to be mentioned as examples of such N-containing heterocyclic groups: 4-aorphoXinyX, 1-pyrroXidinyX and 1-azetidinyl.
The ester and ether derivatives which are hydroXyzable under physiological conditions are preferably compounds of formula Xa in which at least one of the two phenolic hydroxy groups is acylated by a lower fatty acid or ether ified by a lower X-aXkoxycarbonyXoxy-l-aXkyX, lower 1-aXkanoyloxy-X-aXfcyl oe by a lower 2-oxo-l-aXfcyX group.
The substituent la preferably signifies nitro. The substituent Sb is preferably situated in the p-position to the substituent Ha and preferably signifies hydrogen., chlorine or fXuorine. whereby the meaning hydrogen is especiaXXy preferred. The substituent EC preferably signifies the group -CO-H"" in which a"" signifies an 10 15 20 25 _ 9 - ©comatic» nosonuclear earbocyclic group or an aromatic, mononuclear heterocyclic group with 1-3 nitrogen, atoms as the hetero ring member(s) which is attached via a carbon 11 atom. In an especially preferred embodiment R "* signifies a phenyl group optionally mono- or disubstituted by halogen,, trifluoromethyl. cyano, hydroxy or lower alkyl or a pyridyl group.
Particularly preferred compounds in the scope of the present invention ares 3,f-Dihydroxy-S-nitrobenzophenone. 2 1 -fluoro-3,4-dihydroxy-5-nitEobenzophenone and 3„4-dihydcoxy-S-nitrophenyl 4-pyridyl ketone.
The compounds of formula lb. the ester and ether derivatives which are hydrolyzable under physiological 15 conditions and the pharmaceutical^ acceptable salts thereof can be manufactured in accordance with the invention by a) cleaving off the lower alkyl ether group(s) in a compound of the general formula fa EO^ ^\ ! - — Rc" II 20 ^ X a"0 * Rb wherein one of the symbols H and S' signifies lower alkyl and the other signifies hydrogen or lower alkyl and Ha, Sb and Be have the above significance. or b) reacting a compound of the general formula - 10 - V 5 10 15 20 HO, HO X Axi-lA)n~C°~CH2~X Ibl Rb wherein X signifies a leaving group and Ha„ Rb, A and n have the above significance. with a thioamide, thiourea, thiocarboxylic acid hydrazide, thiosemicarbazide, amidine. guanidine, aaidrazone, arainoguanidine, cyclic amidine, 1.2-diamine. 1,2-amino-thiol or a 1,2-arainoalcohol and, if desired, dehydrogen-ating the cyclocondensation product obtained. or c) reacting a compound of the general formula Ha ! 'i-tA) -CO-COOR* lb2 HO wherein R" signifies lower alkyl and Ha, Hb„ A and n have the above significance, with a 1,2-diamine. 1,2-aminothiol, 1.2-aminoalcohol, semicarbazide, thiosemicarbazide. aaidrazone or an amino-guanidine and, if desired, dehydrogenating the cyclocon-densation product obtained, or ■a d) reacting a compound of formula lb"" above with a B-aminocarbonyl compound, or e) converting the carboxaldehyde group(s) in a compound of the general formula - 11 - CHO CN I 'i -COR"9 IbS / ^ V HO • ^ HU Rb wherein Ha and Hb have the above significance and R"' signifies hydrogen or lower alkyl, or a di-O-lower alkanoyl derivative thereof in the presence of a secondary amine ^ith a compound of the general formula CH3CO-R23 VII 23 wherein H signifies an optionally substituted, saturated or partially unsaturated, lower hydrocarbon residue, or i) reacting a compound of the general formula - 13 - 10 hon /X •v ® hq/^ "(A)n-CO-CH2-COOR" tb6 wherein Ra, Rb. A, n and H" have the above significance, with a hydrazine or an amidine, or j) reacting a compound of formula lb above in which m signifies the number 1 and Q signifies the group -CO- with a compound of the general focrawla H2N-(Z)p-R4 ¥1X1 4 wherein Z„ p and R have the above significance,, and, if desired. k) converting a compound of formula lb above into an ester or ether derivative which is hydrolyzable under physiological conditions or into a pharmaceutical!:/ acceptable salt thereof. 15 In accordance with process variant a) the compounds of formula lb can be manufactured by cleaving the ether group(s) in a compound of formula II. This ether cleavage-can be carried out according to methods which are known per se and which ace familiar to any person skilled in the 20 art. The ether cleavage can be carried out. Cor example, by treatment with hydrogen bromide in a suitable solvent. Suitable solvents are, for example, water. acetic acid and mixtures thereof. The reaction is preferably carried out at an elevated temperature, for example in a temperature 25 range of about 100®C to the boiling temperature of the reaction mixture. There are preferably used 48 percent hydrobromic acid or mixtures thereof with acetic acid. - 14 - The ether cleavage can also be carried out by treatment with boron tribromide in a suitable solvent at temperatures of about -SO°C to about room temperature. Suitable solvents are ©specially halogenated lower hydrocarbons such as methylene chloride, chloroform and the like. Further suitable methods are: treatment with pyridinium hydrochloride at temperatures of about 150®C to about 250°C and treatment with sodium iodide/silicon tetrachloride in an inert organic solvent at an elevated temperature,, for example at the reflux temperature of the reaction mixture. Suitable solvents for the latter process are, for example, acetonitrile. aromatic hydrocarbons such as benzene or toluene, mixtures thereof and the like.
In accordance with process variant b) there can be manufactured compounds of the general formula H<\ ^ ' " im n1 Ib' ho'XX"1"1*-0 Rb wherein Ra. Rb. A and n have the above significance and, Q1 signifies a group of the formula .Re -NHRf ( "s ;-R* -< >-NHft£ - -s (O, N--s' (d) /Re ' NHRf ,N=: ✓Nsi \4h (e)" >..1H (£)- (9)' (h) ■ -N - 15 - M /Rg ^Rg /N-« (x) g /"-Rh (k) or --»/ *V._£h (k")„ "-N. X»=N/ Rf r ■* »9 _,Rg ■f ")-Rh (1) °* (n)< "-o »-0 He signifies hydrogen,, C37-alkyl. C3 7~ -cycloalkyl, aryl, heteroaryl,, aryl-lower alkyl or heteroaryl-lower alkyl,, Hf signifies hydrogen,, aryl,, aryl-lower alkyl,, lower alkyl,, lower alkoxycarbonyl, heteroaryl, heteroacyl-lower alkyl. Cg nQ-bicyclo- alkyl or -cycloalkyl. Eg and Rh each signify hydrogen, cyano. lower alkyl. ^-cycloalkyl* aryl, aryl-lower alkyl. heteroaryl or heteroaryl-lower alkyl or Eg and Rh together with the two carbon atoms to which they are attached signify a carboxycyclic aromatic group or an aromatic or partially unsaturated,, heterocyclic group, the dotted line 4 signifies an optional bond and Q together with the carbon atom and the nitrogen atom signify an aromatic or partially unsaturated, heterocyclic group which contains at least one nitrogen atom as a hetero ring member.
Suitable solvents for this process aspect are lower alcohols such as ethanol, n-butanol, n-hexanol and ethylene glycol. open-chain and cyclic ethers which can contain free hydroxy groups such as tetrahydrofuran. dioxan. t-butyl methyl ether, ethylene glycol dimethyl ether. diethylene glycol dimethyl ether, ethylene glycol monomethyl ether and diethylene glycol monomethyl ether, acetonitrile, dimethylformamide, distethylacetamide and dimethyl sulphoxide. The desired reaction can also be carried out without a solvent by dry heating the reaction partners. The reaction is preferably carried out at an elevated temperature, for example in a range of about 50®C - 16 - to 150°C» whereby it is preferably carried out at the boiling temperature of the solvent insofar as it is carried out in the presence of a solvent and the boiling point lies in the previously mentioned range.
In accordance with process variant c) there can be manufactured compounds of the general formula h°n /' ^ V " ~ ^ n~^ HO N-\b in which Rae Rb, A and n have the above significance 2 and Q" signifies a group of the formula 10 /Rg Bh ■- /--Rh »-Nn or Rf (n) /N- / "Si, N«-s/ J Rg -Rh (o) 0' o \ N- —0 Rg -Rh (P) , I-N >-n' (/ \l -OH (q) , N-N - -SH H (r), - ✓ N-Nv y \ o/ NH -Re (s) or /N-Ns -NHRf (t) •/"■Si in which He,, Rf. Rg* Rh and the dotted line have the above significance. 15 The reaction in accordance with process variant c) can b® carried out under the sane reaction conditions as process variant b). - 3.7 - In accordance with process variant d) there can be manufactured compounds of the general formula a « * H0\ /"v < 'i-(A) -Q3 lb9 / xv v ' n H° *Rb 3 wherein Q signifies the group of the formula Rf n.A/1^ fi l] (u) Re/ XRh and Ra. Rb. Re. If. Rg, Rh. A. n and the dotted line have the above significance.
Process variant d) can also be carried out under the same reaction conditions as process variant b). 10 In accordance with process variant e) there can be manufactured compounds of formula lb in which Ra signifies cyano,, EC signifies nitro. cyano or the group -(A)n-R12 and R~2 signifies the group -COR31, a carbocyclic. aromatic group ok an aromatic or partially i et unsaturated, heterocyclic aroup attached via a carbon atom 3"1 and Rb» A. n and B" have the above significance. The conversion or the carboxaldehyde group(s) into the cyano group(s) can be effected according to methods which are known per se and which ace familiar to any person skilled 2o in the art. For example, a compound of formula la2. III or IV can be treated with hydroxylamine O-sulphonic acid at an elevated temperature, whereby water is preferably used as the solvent. The reaction can be carried out in a temperature rang® of about 505C to about 100°C.
In accordance with process variant f) there can be manufactured di-O-lower alkanoyl derivatives of compounds of formula lb in which EC signifies the group - (A) n~ (CO)a-C°R32 and H32 signifies amino,, an optionally substituted,, saturated or partially unsaturated,, lower hydrocarbon residue attached via an oxygen atom or an imino or lower alkylimino group or a saturated, '^-containing heterocyclic group attached via a ring nitrogen atom and A. a and m have the above significance. This reaction can also be carried out according to methods which are known per se and which are familiar to any person skilled in the art. Lower alkyl esters can be manufactured, for example, by treating the carboxylic acid with the corresponding lower alcohol in the presence of an acid, whereby the corresponding lower alcohol is preferably used as the solvent. Suitable acids are, for example, mineral acids such as hydrogen chloride and organic sulphonic acids such as p-toluenesulphonic acid. The reaction temperature preferably lies in a range of room temperature to the boiling temperature of the chosen solvent.
The remaining esters and the amides are preferably manufactured starting from reactive carboxylic acid derivatives. Suitable reactive carboxylic acid derivatives are, for example, the corresponding carboxylic acid halides. especially the carboxylic acid chlorides, corresponding carboxylic acid anhydrides and missed anhydrides (e.g. with trifluoroacetic acid and organic sulphonic acids such as tnesitylenesulphonic acid and p-toluenesulphonic acid), corresponding carboxylic acid imidazolines and the like- The reaction is conveniently carried out in the presence of an acid-binding agent and in an inert organic solvent. Suitable acid-binding agents are, for example, tertiary amines such as tciethylamine and pyridine. Xn the manufacture of amides, excess amine - 19 - of formula VI can also be used as the acid-bindlag agent. Suitable solvents ace, foe example. open-chain and cyclic ethers such as tetrahydrofuran. diethyl ether, t-butyl methyl ether, dioxan, ethylene glycol, dimethyl ether or 5 the like, halogenated hydrocarbons such as methylene chloride, chloroform and 1.2-dichloroethane, acetonitrile and dimethylfomamidle. 4 The hydrolysis of compounds of formula lb to the corresponding catechol decivatives in accordance with 10 process variant g) can also be carried out according to methods which are known per se and which are familiar to any person skilled in the art. The hydrolysis can be carried out„ for example, by treatment with an alkali metal hydroxide such as sodium hydroxide or potassium 15 hydroxide in a suitable solvent. Suitable solvents are, for example, lo^er alcohols such methanol and water or mixtures thereof. The hydrolysis can be carried out, for example, in a temperature range of about 0°C to the boiling temperature of the solvent,, whereby, however, it is preferably carried out at room temperature. 20 In accordance with process variant h) there can be manufactured compounds of the general formula HO A \ S \ y"~c (H"1 =CH-CO-R23 1 b 10 H0 Rb ty 3 wherein Ha, Hb, a"' and 3" have the above signifi-25 cance, and the corresponding di-O-lower alkanoyl derivatives thereof. Cyclic amines such as pyrrolidine, piperidine. morpholine and thioaorpholine are preferably used as the secondary amine. Suitable solvents for this process are. - 20 - for example, open-chain and cyclic ethers such as tetrahydrof uran, diethyl ether, t-butyl methyl ether. dioxan, ethylene glycol and dimethyl ether, halogenated hydrocarbons such as methylene chloride, chloroform and 5 1,2-dichlocoethane. acetonitrile and dimethylsocmamide.
The reaction temperature conveniently lies in a raage of about 0°C to the boiling temperature of the chosen solvent whereby the reaction is preferably carried out at room temperature. In an especially preferred embodiment the 10 reaction is carried out in the presence of an acid, preferably a carboxylic acid such as acetic acid.
In accordance with process variant i) there can be manufactured compounds of the general formula HQWx > " mi n5 lhl1 „0/Vx"(A,n-° HO Rb 15 wherein Q5 signifies the group \ / Rf (V) or D \ N- OH / Re N (w) OH and Ha, Hb, He. Hf, A and n have the above significance .
Suitable solvents for this process are. for example, lower alcohols such as methanol and ethanol. open-chain and cyclic ethers such as tetrahydrofuran. diethyl ether, t-butyl methyl ether, dioxan, ethylene glycol and dimethyl ether, acetonitrile and dimethyIformamide. The reaction is preferably carried out at an elevated temperature, for example in a range of about 50°C to the boiling - 21 - temperature of the chosen solvent„ whereby it is preferably carried out at the boiling temperature of the chosen solvent.
In accordance with process variant j) there can be manufactured compounds of the general formvia "V>V Ri / Ih12 H0,%X^'n-CV(2)p.R, wherein Hi signifies the group -COR310 a carbocyclic* aromatic group or an aromatic or partially unsaturated,, heterocyclic group attached via a carbon atom or an optionally substituted,, saturated or partially unsaturated, louer hydrocarbon residue 31 4. and Ra, Rb, R R", A, Z, n and p have the above significance.
This process can also be carried out according to methods which are known per se and which are familiar to any person skilled in the art. Suitable solvents are, for example, lower alcohols such as methanol and ethanol. dimethylformamide and water. The reaction is conveniently carried out at room temperature.
In accordance with process variant k) the compounds of formula lb can be converted into ester oe ether derivatives which are hydrolyzable under physiological conditions. Suitable ester derivatives which are hydrolyzable under physiological conditions are especially the compounds of formula lb ia which at least one of the two phenolic hydroxy groups is acylated by a lower fatty acid. These can be manufactured according to methods which are known per se and which are familiar to any person skilled in the art. In a preferred embodiment the - 22 - acylation is carried out with the corresponding lower fatty acid anhydride in the presence of a catalytic amount of a strong acid, whereby excess fatty acid anhydride is preferably used as the solvent. Suitable acids are,, for 5 example, sulphuric acid and organic sulphonic acids such as p-toluenesulphonic acid.
Suitable ether derivatives which are hydrolyzable under physiological conditions are,, for example, compounds of formula lb ia which at least one of the two phenolic hydroxy groups is ethecified by a lower 1-alkoxycarbonyl-oxy-l-alkyl, lower 1-alkanoyloxv-1-alkyl or by a lower 2-oxo-l-alkyl group. The ether ification can be carried out according to methods which are known per se and which are familiar to any person skilled in the art. For example, a compound of formula lb can be reacted with a lower 1-alkoxy car bony loxy-1-alkyl halide,, a lower 1-alkanoyloxy--1-alkyl halide or a lower 2-oxo-l-alkyl halide, whereby this ether ification is conveniently carried owt in the presence of a base. ?is halides there come into consideration, in particular. the iodides. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates such as sodium hydroxide and sodium carbonate.
In accordance with process variant k) compounds of formula lb above can. also be converted into pharmaceut-ically acceptable salts. As salts there come into consideration, in particular. salts with pharmaceutically acceptable bases. As examples of such salts there are to be mentioned the alkali metal salts such as the sodium and potassium salts. These salts can be manufactured according to methods which are known per se and which are familiar to any person skilled in the art.
The various compounds which are used as starting materials are known or can be prepared according to 10 15 20 - 23 - methods known pee se. The following Examples contain detailed information concerning the preparation of these starting materials. as mentioned earlier, the compounds of formula la inhibit the enzyme COMT. This activity can he determined quantitatively as follows: Eat liver homogenate is incubated in the presence of a suitable substrate as described in J. Peurochem. 38„ 191-195 (1982) and the COMT activity is measured. In a second series of experiments the incubation is carried out in the presence of a compound of formula la» The can then be calculated from the difference of the COMT activity which is determined. The IC^0 is given in nmol/1 and is that coneen- tration in the incubation mixture which is required to reduce the COMT activity by 50%, The values for some compounds of formula la are given in the following Table. Moreover, this Table contains data concerning the acute toxicity of these compounds (LD^^ in sag/kg in the case of single oral administration to mice).
Compound of formula la ~C50 nrtt0~/'~ L^50 mg/kg ».o. 3„4-Dihydroxy-5-nit£ophenyl 2-pyridyl ketone 3,4-Dihydroxy-5-nitrophenvl 3-pyridyl ketone 3„4-Dihydroxy-5-nitrophenvl 4-pyridyl ketone n-Butyl 3„4-dihydroxy-5--nicrobenzoate n-Butyl 3.4-dihydroxy-5--nitrocinnamate 20.0 25.9 67.0 53.4 H7.0 2500-5000 1000-2000 1250-2500 1000-2000 312- 625 Ethyl 3,4-dihydroxy-5--nitrophenylglyoxylate 3.4-Dihydroxy-5-nitrobenzo-phenone 3.5-Dinitropyrocatechol 2 '-Fluoro-3.4-dihydroxy-5- nitroben^ophenone 48.1 1250-2500 48.0 500-1000 36.9 500-1000 $2.0 312- 625 The described substances can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral or parenteral administration. The compounds of formula la can be administered,, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules. solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, or parenteral!1/, e.g. in the form of injection solutions.
The manufacture of the pharmaceutical preparations can be effected in a manner which is familiar to any person skilled in the art by bringing the compounds of formula la, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and. if desired, the usual pharmaceutical adjuvants. as carrier materials there are suitable not only inorganic carrier materials, but also organic carrier materials. Thus, tor tablets, coated tablets, dragees and hard gelatine capsules there can be used as carrier materials, for example, lactose, maize starch or derivatives thereof,,, talc, stearic acid or its salts. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substances no carriers are, however, required ia the case - 25 - of soft gelatins capsules). Suitable carrier materials for the manufacture of solutions and syirups are. for example, water* polyols„ saccharose, invert sugar and glucose. Suitable carrier materials for injection solutions are. 5 for example0 water, alcohols, polyols, glycerine and vegetable oils. Suitable carrier materials for suppositories are. for example natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
As pharmaceutical adjuvants there come into considera-10 tion the usual preserving agents,, solubilisers. stabilizing agents, wetting agents, emulsifying agents, flavour-improving agents such as sweetening agents and flavouring agents, colouring agents, salts for varyin$?.the osmotic pressure,, buffers, coating agents and antioxidants.
The dosage of the described substances can vary within wide limits depending on the illness to be treated, the age and the individual condition of the patient and on the mode of administration and will, of course, be fitted to the individual requirements in each particular case. In 20 the improvement of the treatment of Parkinson's disease and of parkinsonism with L-dopa a daily dosage of 25 mg to about 1000 mg. especially about 100 mg to about 300 sag, comes into consideration. Depending on the dosage it is convenient to administer the daily dosage ia several 25 dosage units.
The pharmaceutical preparations ia accordance with the invention conveniently contain about 25 »g to about 300 mg, preferably about 50 mg to about 130 mg, of a compound of formula la or of an ester or ether derivative 30 which is hydrolyzable under physiological conditions or of a pharmaceutical^ acceptable salt thereof.
The following Examples are intended to illustrate the - 26 - present invention in more detail,, but are not intended to limit its scope in any manner. All temperatures are given in degrees Celsius.
Example 1 5 a) 17.1 g (86.7 ffisaol) of «-hydroxy-3-aethoxy-5-nitro- benzaldehyde are treated with 170 ml of constant-boiling hydrobromic acid and heated under reflux for 3.5 hours. After cooling the separated precipitate is filtered off under suction, washed twice with ice-water and taken up in 10 ethyl acetate. The organic phase is washed twice with 50 ml of sodium chloride solution each time, dried over magnesium sulphate and evaporated in a water-jet vacuum. The crystals obtained are taken up in methylene chloride, whereupon the solution is filtered over a ten-fold amount 15 of silica gel. The material obtained is crystallized from ethyl acetate/isopropyl ether. There is obtained 3,4-dihydroxy-S-nitrobenzaldehyde in the form of yellow crystals of m.p. 142-143°. b) A solution of 1.7 g (15 mmol) of hydroxvlamine O-2o -sulphonic acid in S ml of water is added to a solution of 1.83 g (10 mmol) of 3,4-dihydroxy-5-nitrobenzaldehyde in 25 ml of water,, subsequently stirred at 65® for 3.5 hours, cooled,, the separated precipitate is filtered off under suction and taken up in ethyl acetate. The organic phase 25 is dried over sodium sulphate and evaporated in a water- -jet vacuum. The crystals obtained are recrystallized from ethyl acetate/n~hexane. There is obtained 3.4-dihydroxy-S--nitrobenzonitrile in the fora of yellow crystals of m.p. 194-195°.
Example 2 aa) 10 ml of tert.butyl lithium solution (1.4M in hexane) - 27 - are added dropwise at -70° within 10 sain, to 4.1 g of «-(benzyloxy)-3-methoxy-browiobenzene dissolved in 40 ml of tetrahydrofuran. After stirring at -70° for 2 hrs. 1 ®1 of pyridine-3-carbaldehyde is added within 5 Mia. The 5 reaction mixture is stirred at -70® for 1 hr. and at 0° for 2 hrs. and poured into 100 ml of IN hydrochloric acid.„ The mixture is extracted three times with 50 ml of ether each time. The combined ether phases are washed with 100 ml of IN hydrochloric acid and 20 ml of water. The 1Q combined aqueous phases are saade alkaline with aqueous ammonia solution and extracted three times with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulphate and evaporated. There is obtained alpha-[4-(benzyloxy)-3-15 -methoxyphenyl]-3-pyridinemethanol as an oil. ab) in an analogous manner, using pycidine-4-cacbaldehyde there is obtained alpha-[4-(benzyloxy)-3-methoxyphenylJ-4--pyridinemethanol as an oil. ba) 3.2 g of alpha-f4-(benzyloxy)-5-methoxyphenyl]-3--pyridinemethanol suspended in 50 ml of water are treated with 2.5 g of potassium permanganate, whereupon the mixture is stirred at 90° for 30 min. Af tec adding a further 1.0 g of potassium permanganate and stirring for a further 30 min. at 90® the mixture is cooled to room temperature and extracted twice with 150 ml of ethyl acetate each time. The combined ethyl acetate phases are washed with sodium chloride solution,, dried over sodium sulphate and evaporated. The thus-obtained residue is chromatography on 50 g of silica gel with ethyl acetate. Aftec recrystallization from methylene chloride/hexane there is obtained 4-(ben2yloxy)-3-»ethoxyphenyl 3-pycidyl ketone of m.p. 76®. 20 25 30 bb) In an analogous manner. from alpha-[4-(benzyloxy)-3--methoxyphenyl)-4-pyridinemethanol there is obtained 4-(benzyloxy)-3-methoxyphenyl 4-pyridyl ketone of m.p. 85-87° (methylene chlori<3e/hexane). ca) 50 sd of 33 percent hydrobromic acid in acetic acid are added dropwise within 15 min. at 10° to 20 g of 4-(benzyloxy)-3-methoxyphenyl 3-pyridfl ketone dissolved in 200 ml of methylene chloride. After stirring at 20° for 3 hrs. the reaction mixture is poured into a mixture of 100 ill of conc. aqueous ammonia and ice. The pH is adjusted to 6 by adding acetic acid. The methylene chloride phase is separated; the aqueous phase is extracted a further twice with 100 sal of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulphate and evaporated. The residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone of m.p. 150-151°. cb) In an analogous manner, from 4-(benzyloxy)-3-methoxy-phenyl 4-pyridyI ketone there is obtained 4-hydroxy-3--methoxyphenyl 4-pyridyl ketone of m.p. 215-218° (acetonitrile). da) 0.38 ml of 65 percent nitric acid are added dropwise at room temperature to 1.15 g of 4-hydEoxy-3-methoxyphenyl 3-pyridyl ketone dissolved in 15 ml of acetic acid. After stirring for 2 hrs. the reaction mixture is poured into 120 ml of ice-water, whereupon the mixture is adjusted to pH 5 with conc. ammonia and the precipitate formed is filtered off. The thus-obtained residue is heated under reflurc in 20 ml of acetonitrile. whereupon it is again filtered off. There is obtained 4-hydroxy-3-methoxy-5--nitrophenyl 3-pyridyl ketone as brown crystals of m.p. - 29 - db) In. an analogous manner, from 4-hydroxy-3-methoxyphenyl 4-pyridyl ketone there Is obtained 4-hydroxy-3-methoxy-5- -nitrophenyl 4-pyridyl ketone of m.p. 240s I® e) 3.5 g of 4-hydroxy-3-methoxy-5-nitrophenyl 3-pyridyl 5 ketone dissolved in 70 ml of 48 percent aqueous hydro- bromic acid are stirred at 100° toe 18 hrs. The reaction mixture is subsequently evaporated under reduced pressure. The residue is recrystallized from water. There is obtained 3,4-dihydroxy-5-nitrophenyl 3-pyridyl ketone 10 hydEobromide of m.p. 265°. f) In an analogous manner, from 4-hydroxy-3-methoxy-5--nitrophenyl 4-pyridyl ketone there is obtained 3,4-dihydroxy-5-nitrophenyl 4-pyridyl ketone of m.p. 246° (from water). 15 g) 13.2 g of 3.4-dihydroxy-5-nitrophenyl 4-pyridyl ketone are suspended in 500 ml of methanol and treated while stirring with €.88 g of inethanesulphonic acid. The suspension is heated under reflux for 50 minutes. It is subsequently cooled to 10°. the crystals are filtered off 20 under suction and Mashed twice with 30 ml of methanol each time. There is obtained 3.4-dihydroxy-5-nitrophenyl 4-pyridyl ketone methanesulphonate of m.p. 260-261° (dec.).
Example 3 a) A solution of 2.5 g (12.2 «»ol) of 4-hydroxy-3-25 -methoxy-5-nitrobenzoic acid ia 2a ml of constant-boiling hydrobromic acid is heated under reflux for 2 hours. After cooling the solvent is distilled off in a water-jet vacuum. The crystalline residue is recrystallized from 50 ml of water at boiling temperature. There is obtained 30 3.4-dihydroxy-5-nitrobenzoic acid, in the form of yellow crystals of m.p. 224-226°. b) 1.0 g (5 mmol) of 3.4-dihydroxy-5-nitrobenzoic acid is treated %?ith 20 ml of methanolic hydrochloric acid. stirred at 45° for 3 hours and, after removing the solvent, the residue is taken up in methylene chloride. The organic phase is washed with sodium chloride solution.,, dried over sodium sulphate and evaporated. The crystalline product obtained is taken up in methylene chloride and filtered over a ten-fold amount of silica gel. The material obtained is recrystallized from ethyl acetate/n--hexane. There is obtained methyl 3.4-dihydroxy-5-nitro-benzoate in the form of yellow crystals of a.p. 144-145°.
The following esters are obtained in an analogous manner starting from 3,4-dihydroxy-5-nitrobenzoic acid; c) Ethyl 3 ,4-d ihydroxy-5-nitrobenzoate of m.p. 106-107° (from ethyl acetate/n-hexane). d) n-butyl 3.4-dihydroxy-5-nitrobenzoate of m.p. 73-74° (from methylene chloride) and e) n-hexyl 3,4-dihydroxy-5-nitrobenzoate of m.p. 44-45° (from isopropyl ether).
Example 4 a) 25 ml of 2M phenyl lithium solution (in benzene/ether (7:3)) are added dropwise within 15 sain. to 10.0 g of 3„4-dimethoxy-5-nitrobenzaldehyde dissolved in 150 ml of tetrahydrofuran and the mixture is stirred at 0° for 1 hr. and at 20° for 2 hrs. The mixture is subsequently treated with 150 ml of 2N sulphuric acid and extracted three times with 150 ml of ether. The combined ether phases are washed with sodium chloride solution, dried over sodium sulphate and evaporated. The thus-obtained residue is chromato-graphed on 180 g of silica gel with methylene chloride. There is obtained 3„4-dimethoxy-5-nitrobenzohydrol as an amorphous solid. b) 2.5 g of 3. i-dimethoxy-5-nitrobenzoiiydrol dissolved in 50 ml of methylene chlor ids ace treated with 2.2 g of pyr idiniuso chlorochromate„ whereupon the mixture is stirred at room tesapeeatu.ee for 2 hrs. The insoluble constituents ace subsequently filtered off. The filtrate is evaporated and the residue is chromatographed on SO g of silica gel with methylene chloride. Mter crystallization from methylene chloride/hexane there is thus obtained 3.4-dimethoxy-5-nitrobenzophenone of m.p. 78-80°. c) 0.5 g of 3,4-diraechojcy-5-nitrobenzophenon® are stirred at 110° for 30 hrs. in a mixture of 4 ml of acetic acid and 4 ml of 48 percent aqueous hydrobromic acid. The reaction mixture is subsequently evaporated to dryness. The residue is taken up in methylene chloride. It is washed with water, dried over sodium sulphate and evaporated. After recrystallization from methylene chloride/ hexane there is obtained 3,4-dihydroxy-5-nitrobenzophenone of m.p. 132°.
Example 5 a) 4.9 g (0.2 mol) of magnesium are suspended in 15 ml of absolute ethanol and,, after adding 1 ml of carbon tetrachloride,, warmed until the reaction starts. A solution of 31.8 g (0.2 mol) of diethyl nalonate in 19.9 ml of absolute ethanol and 80 ©1 of absolute toluene is then added dropwise while stirring so that the temperature lies between. 50® and SO®. It is subsequently stirred at this temperature for a further 1 hour, whereupon the reaction mixture is cooled to -5® and a solution of 49*3 g (0.2 mol) of 3,4-dimethoxy-5-nitrobenzoyl chloride (m.p. 82-85®) ia 300 ml of absolute toluene and 50 ral of absolute tetrahydrofuran is added dropwise so that the temperature does not exceed -5°. The mixture is subsequently stirred at room temperature overnight. Mter - 32 - distillation of the solvent the residue is dissolved in 500 ml of ethyl acetate. The solution is treated "while stirring and cooling with ice with an ice-cold solution of 12 ml of concentrated sulphuric acid in 80 ml of water. 5 The organic phase is washed with sodium chloride solution, dried over magnesium sulphate and evaporated. The oil obtained is chromatographed on a ten-fold amount of silica gel with methylene chloride. The crystalline material obtained is recrystallized from isopropyl ether. There is 10 obtained diethyl 3,4-dimethoxy-S-nitcobenzoylraalonate in the form of pale beige crystals of m.p. 70®. b) 19.0 g (51.4 mmol) of diethyl 3,,4-dimethoxy-5-nitro- benzoylmalonate are dissolved in 100 ml of glacial acetic acid,, 5 drops of concentrated sulphuric acid are added thereto and the mixture is heated under reflux for 16 hours. The acetic acid is distilled off at 60° in a water--jet vacuum and the residue is treated three times with 2S0 ml of toluene each time,, whereby it is evaporated 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 chromatographeti on a 30-fold amount of silica gel with toluene. The crystalline material obtained is recrystallized from isopropyl ether. There is obtained 3.4-dimethoxy-5•-nitroacetophenone ia the form of yellowish crystals of s. p. 86-87®. c) 2 g (8.9 ©mol) of 3',41-dimethoxy-5'-nitroacetophenone are treated with 30 al of constant-boiling hydrobromic acid and stirred at 140° for 2.5 hours. After cooling the mixture is poured into 200 sal of ice-water and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed twice with 25 al of sodium chloride solution each time, dried over sodium sulphate and evaporated. Th® product obtained is filtered with 15 20 25 ethyl acetate over a 20-fold amount of silica gel. By recrystallization of the material obtained from water there is obtained 3',%'-dihydroxy-5'-nitroacetophenone in the foca of yellow crystals of M.p. 159-160°.
The same compound is obtained starting from 4 ' -hydroxy-3 ' -methoxy-5 ' -nitroacetopheaone by treatment with hydrobromic acid at the boiling temperature.
Example 6 a) 100 g (0.8 mol) of guaiacol are dissolved in 136.4 g (0.86 mol) of isobutyric anhydride, treated with 120 g (0.88 mol) of anhydrous sine chloride (whereby all passes into solution), the reaction mixture is heated to 155° and cooled after three minutes. The residue is firstly subjected to a steam distillation in order to remove readily volatile constituents and is then extracted three times with 500 ml of ether each time, the organic phase is washed twice with 250 ul of water each time, once with 150 ml of saturated bicarbonate solution and again with 250 ml of water„ dried over sodium sulphate and evaporated in a water-jet vacuum. The brown resin obtained is distilled in a high vacuum. The distillate of b.p. 105-120° (6.67 Pa) is dissolved in ether, whereupon the solution is treated with n-hexane until crystallization begins. The crystals obtained are recrystallized fro® ether/hexane. There is obtained 4'-hydroxy-3'-methoxy-2--methyl-propiophenone in the form of colourless crystals of jtt.p. 86-87°. b) 15.0 g (77.2 mmol) of «'-hydroxv-3'-methoxy-2-methyl- -propiophenone are dissolved in 300 ml of glacial acetic acid and 7.65 ml of 50.5 percent nitric acid (11.2W) in 40 ml of glacial acetic acid are added dropwise thereto while stiring within 15 minutes. Mter 15 mints,tes the reaction mixture is poured into ice-water and the separated crystals are filtered off under suction,, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulphate and evaporated. The crude product obtained is taken up in methylene chloride and filtered over 100 g of silica gel. The thus-obtained crystals are recrystallized from methylene chloride/ n-hexane. There is obtained 4'-hvdroxy-3•-methoxy-2--methyl-51-nitropropiophenone in the form of yellow crystals of m.p. 85-87°. c) 8.0 g (33.4 sirjio 1) of 4 1 -hydroxy-3 ' -methoxy-2-methyl- -5'-nitropropiophenone are treated with 64 g of pyridine hydrochloride and stirred at 180° for 45 minutes. After cooling the reaction mixture is poured into 500 sal of ice-water, whereupon it is made acid with 20 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase is washed with water,, dried over sodium sulphate and evaporated in a water-jet vacuum. Af tec crystallization from methylene chloride/n-hexane there is obtained 3' ,4• -dihydcoxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 98-99°.
Example 7 a) 100 g (805.5 Mmol) of guaiacol are dissolved ia 136.4 g (86.2 mmol) of butyric anhydride, treated with 120 g (880 mmol) of zinc chloride, heated for 3 minutes as given, in Example 6.a and then worked-up as described there. The crude product obtained after high vacuum distillation is chcomatogcaphed with toluene on 600 g of silica gel. Mter recrystallization from ether/n-hexane there is obtained 4'-hydroxy-3'-raethoxy-butycophenone in the form of colourless crystals of m.p. 4.0-41®. b) 5.5 lal of 11.2N nitr ic acid are added dropwise to a solution of 12.7 g (65.4 mmol) of 4 '-hydroxy-3 ' -methoxy- butyrophenone ia 250 ml of glacial acetic acid while stilting within 10 minutes. It is subsequently stirred foe 15 minutes, the reaction mixtw.ee is poured into ice--water. the separated precipitate is filtered off under suction,, washed with ice-water and taken up in methylene chloride. The methylene chloride solution is filtered over 50 g of silica gel. The material obtained is recrystallized from methylene chloride/n-hexane. There is obtained 41-hydroxy-31-methoxy-51-nitrobutyrophenone in the form of yellow crystals of m.p. 92-93°, c) 10.2 g (42.6 mmol) of 4 1 -hydroxy-3 '-methoxy-5 '-nitrobutyrophenone are treated with 80 g of pyridine hydrochloride and stirred at 200° for 40 minutes. After cooling the reaction mixture is poured into 500 ml of ice-water. The mixture is treated with 30 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated. The crude product obtained is chromatographed with methylene chloride on ISO g of silica gel. The material obtained is recrystallized from methylene chloride/n-hexane. There is obtained 3'.4'-dihydroxy-5'-nitrobutyrophenone in the form of yellow crystals of m.p. 88-90°.
Example 8 a) 2.25 g (10 mmol) of 3,4-dihydroxy-5-nitrocinnamic acid are dissolved in 50 al of methanol and hydrochloric acid gas is introduced into this solution for 10 minutes, after 1 hour 50 lal of isopropyl ether are added thereto, and the separated precipitate is filtered off under suction and washed with isopropyl ether. After recrystallization from methanol/ether there is obtained methyl 3.4-dihydroxy-5--nitrocinnamate in the form of yellow crystals of m.p. 186-187°. b) In an analogous manner, £ com 3. 4-dihydroxy-5-nitro-cinnamic acid and butanolic hydrochloric acid solution there is obtained n-butyl 3„4-dihydroxy-5-nitrocinnamate in the form of yellowish crystals of m.p. 129-130°„ Example 9 5.0 g (13.5 mmol) of diethyl 3,4-dimethoxy-5-nitro-benzoyl malonate are dissolved in 50 ml of absolute methylene chloride. After cooling to -20° a solution of 16.9 g (67.5 mmol) of boron tribromide in 30 ml of methylene chloride is added dropwise thereto while stirring so that the temperature does not exceed -20°, The mixture is subsequently stirred at room temperature overnight. After adding 80 ml of ethanol the mixture is stirred at room temperature for 30 minutes and the solvent is subsequently distilled off in a water-jet vacuum. The residue is treated with water and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate 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. There is obtained ethyl 3,4-dihydrojcy-5-nitro-benzoylacetate ia the form of yellow crystals of m.p. 141-142°.
Example 10 a) A solution of 1.49 g {12.3 mmol) of 2-phenylethylamine in 100 ml of methylene chloride is treated with 1.26 g of triethylamine. A solution of 3.0 g of 3,4-diaethoxy-5--nitcobenzoyl chloride ia 100 ml of methylene chloride is added dropwise thereto while stirring, whereupon the mixture is stirred for a further 15 minutes. The organic phase is then extracted twice with 50 ml of ice-water each time, dried over sodium sulphate and evaporated in a - 37 - water-jet vacuum. After recrystallization from methylene chloride/n-hexane there is obtained 3»4-dimethoxy-5-nitro--N-phenethylbenzamide in the form of pale beige needles of m.p. 121-122°. 5 b) 3.6 g (10.9 mmol) of 3.4-dimethoxy-5-nitro-N- -phenethylbenzamide are heated under reflux with 36 ail of phosphorus oxychloride under a nitrogen atmosphere for 96 hours. After distilling off the excess phosphorus oxychloride in a water-jet vacuum at 60° the residue is 1 q treated three times with 100 ml of toluene each time, whereby the solvent is distilled off each time. The residue is taken up in methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated in a water-jet vacuum. The red resin obtained is chroraatographed on 120 g of silica gel with methylene chloride/ethyl acetate (1:1). There is obtained l-(3»€--dimethoxy-5-nitrophenyl)-3»€-dihydroisoquinoline in the form of a yellow resin. c) 1.4 g (4.5 mmol) of 1-(3»4-tiimethoxy-5-nitcophenyl)-2Q -3.4-dihydroisoquinoline are treated with IS ml of constant-boiling hydrobcomic acid and heated to boiling under reflux under a nitrogen atmosphere for 1.5 hours. After distilling off the hydcobcomic acid in a water-jet vacuum the crystalline residue is recrystallized from 25 acetone. There is obtained 5-(3.4-dihydro-l- -isoquinolinyl)-3-nitropyrocatechol hydrobromide ia the form of yellow crystals of m.p. >250° (decomposition).
Example 11 a) 5.0 g (27.7 mmol) of 4-hydEOxy-5-methoxy-isophthal- 30 aldehyde are treated with 50 ml of constant-boiling hydrobcomic acid and heated to boiling under reflux and while stirring under an argon atmosphere for 3 hours.
After cooling 50 ml of ice-water are added thereto,, and the separated precipitate is filtered off wader suction and washed with water. The crude product is taken up ia ethyl acetate and filtered over 50 g of aluminium oxide (activity grade II). The crystalline material obtained is recrystallized from ethyl acetate/n-hexane. There is obtained 4.5-dihydroxyisophthalaldehyde in the form of slightly orange crystals of m.p. 201-202°. b) A solution of 3.27 c (28.9 mmol) of hydroxylamine Q--sulphonic acid in 12 ml of water is added dropwise at 30° while stirring to a solution of 2.0 g (12.0 mmol) of 4,5-dihydroxyisophthalaldehyde in 20 lal of water, whereupon the mixture is held at 65° for 10 hours. After cooling the separated precipitate is filtered off under suction, washed with water and taken up in ethyl acetate. The organic phase is washed with water,, dried over sodium sulphate and evaporated in a water-jet vacuum. After recrystallization from ethyl acetate there is obtained 4«, 5-dihydroxvisophthalonitrile in the form of yellow crystals which decompose above 300°.
Examol® 12 a) A solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid is added dropwise while stirring and within 30 minutes at 20-25® to a solution of 112.5 g of 2-bromo-4'-hydroxy-3'-aethoxyacetophenone ia 560 ml of glacial acetic acid. Ye How-brown crystals thereby separate. Mter 90 minutes the reaction mixture is poured on to 300 g of ice. The crystals are filtered off under suction, washed with 1000 ml of water and dissolved in 1000 sal of methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate,, filtered and the filtrate is evaporated at 50° ia a water-jet vacuum until crystallisation begins.
The crystallizate. cooled to room temperature, is filtered! off under suction and cashed with a small amount of methylene chloride. There is obtained 2-broiao-«'-hydroxy--3'-methoxy-5'-nitroacetophenone of m.p. 147-149°. b) Method A: ba) A suspension of 580.1 mg of 2-bromo-4'-hydroxy-3'- -methoxy-5'-nitroacetophenone in 10 ml of ethanol is treated with 4.43.8 mg of selenium dioxide and heated under reflux for 71 hours. Thereafter., the reaction mixture is filtered off from selenium and the filtrate is evaporated. The residue is dissolved in methylene chloride, washed with saturated sodium chloride solution, dried over sodium sulphate,, filtered and evaporated. There is obtained ethyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of a.p. 165-167° (from ethanol).
In an analogous manner: hb) From 2-bromo-4'-hydroxy-3'-methoxy-51-nitroaceto-phenone and n-butanol there is obtained n-butyl 4-hydroxy--3-methoxy-5-nitrophenylglyoxylate of m.p. 105-107° (from ethanol) and be) from 2-bromo-4•-hydroxy-31-methoxy-5'-nitroacetophenone and n-hexanol there is obtained hexyl 4-hydroxy-3--methoxy-5-nitrophenylglyoxylate of m.p. 103-105 •» (from n-hexanol/petroleum ether). c) Method B: ca) A suspension of 29.01 g of 2-bromo-4'-hydroxy-3'--methoxy-5■-nitroacetophenone ia 300 ml of tert.butanol is treated with 27.74 g of selenium dioxide and heated to boiling under reflux for 18 hours. The hot reaction mixture is suction filtered through a filter aid of diatoraaceous earth while rinsing with methylene chloride. The filtrate is evaporated and the residue is suspended ia 150 ml of hot methylene chloride. The crystalline precipitate is filtered off under suction and washed with a small amount of Methylene chloride. There is obtained 4-hydEOxy-3-methoxy-5-nitEophenylglyoxylic acid of m.p. 159-171°. 2.42 g of 4-hydEoxy-3-methoxy-5-nitEophenylglyoxylic acid are dissolved in 25 ml of dry N.N-dimethylformamide, treated at room temperature with 50 mg of 4-dimethylamino-pyridine and 920 mg of dry methanol„ subsequently cooled to 0° with an ice-bath and 2.27 g of N.N-dicyclohexyl-carbodiimide are added thereto. After 10 minutes the ice-bath is removed and the reaction mixture is stirred for a further one hour at room temperature. The mixture is subsequently evaporated. The residue is dissolved in ethyl acetate,, thereupon insoluble urea is filtered off, the filtrate is washed four times with water, dried over sodium sulphate,, filtered and evaporated. There is obtained methyl 4-hydroxy-3-methoxy-5-nitEophenyl-glyoxylate of m.p. 155-157° (from methylene chloride/ ethet).
In an analogous manner: cb) From 4-hydroxy-3-methoxy-5-nitEophenylglyoxylic acid and ethanol there is obtained ethyl 4-hydcoxy-3-nethoxy-5--nitrophenylglyoxlate of m.p. 165-167° (from ethanol) and cc) From 4-hydroxy-3-aethoxy-5-aitEophenylglyoxylic acid and isopropanol there is obtained i-pEopyl 4-hydtoxy-3--methoxy-5-nitEophenylglyoxylate of m.p. 99-101° (from isopropanol). - 41 - d) A suspension of 17.2 g of ethyl «-hydroxy-3-methoxy-5--nitrophenylglyoxylate in 100 ml of dry acetonitrile and 100 ml of dry toluene is treated with 10.53 g of sodium iodide and 11.9 g of silicon, tetrachloride and heated 5 under reflux for 47 hours. The reaction mixture is then evaporated and the residue is distilled six times with 200 ml of toluene each time. The residue obtained is partitioned between water and ether and filtered through a filter aid of diatomaceous earth. The ethereal phase is 10 washed with four times with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The oily residue is treated three times with ether and active carbon. There is obtained ethyl 3.4-dihydroxy-5-nitrophenylglyoxylate of m.p. 77-79° (from 15 ether/n-hexane).
In an. analogous manner: e) From methyl «-hydroxy-3-methoxy-5-nitrophenyl-glyoxylate there is obtained methyl 3.4-dihydroxv-5-nitro-phenylglyoxylate as a yellow distillate at 145-150° and 20 10.67 Pa. f) from isopropyl 4-hydroxy-3-methoxy-5-nitrophenyl-glyoxylate there is obtained isopropyl 3,4-dihydroxy-5--nitrophenylglyoxylate as a yellow distillate at 155-160° and 12.0 Pa. 25 g) from n-butyl 4-hydroxy-3-methoxy-5-nitrophenyl- glvoxylate there is obtained n-butyl 3.4-dihydroxv-5--nitrophenylglyoxylate as a yellow distillate at 160-165° and 10.67 Pa and h) from n-hexyl 4-hydroxy-3-methoxy-5-nitrophenyl-30 glyoxylate there is obtained hexyl 3,4-dihydroxy-5-nitro- phenylglyoxvlate as a yellow distillate at 165-1/0® aad 12.0 Pa.
Example 13 236.1 mg of n-hexyl 3,4-dihvdroxy-nitrophenyl-glyoxylate are dissolved in 15 ml of ethanol and treated with 7.59 ml of 0.IN sodium hydroxide solution. Mter one hour the reddish-yellow solution is evaporated. The resulting sodium salt of the n-hexyl 3,4-dihydroxy-5--nitrophenylglyoxylate its crystallised from water and has a m.p. of ~ 300°.
Example 14 h solution of 3.18 g of n-hexyl 3„4-dihydroxy-5-nitro-phenylglyoxylate ia 47.5 ml of ethanol is treated with 1.11 g of O-methylhydroxylamine hydrochloride. 1.95 g of sodium acetate and 2.5 ml of water and heated to boiling under reflux for 5 hours. Thereafter. the reaction mixture is evaporated and the residue is treated with ether and water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed oa silica gel with methylene chloride. There is obtained a 7:3 mixture of n-hexyl E- and Z-3.4-dihydroxy-5-nitrophenyl-glyoxylate O-methyl oxiae as a reddish oil; 80 MHz NMR spectrum (CDCl^): signal for O-methvl at 3.96 and 4.05 ppm.
Bxamole 15 A solution of 5.1 g of ethyl 34-dihydroxy~5-nifcro-phenylglyoxylate ia dry methylene chloride is treated dropwise at -10® within 15 minutes with 25 g of boron tcibroiiide. The mixture is then stirred at -10° for one hour and subsequently at rooa temperature for 17 hours. Thereafter, the reaction mixture is evaporated, the residue is treated cautiously with water and stirred at - 43 - 50° for a further 30 minutes,, Mter cooling to room temperature the flocculent precipitate is filtered off under suction. The aqueous phase is acidified with 10 ml of IN hydrochloric acid, extracted four times with ether, 5 the combined organic extracts are washed four times with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The crude product is filtered three tiiaes ia succession in ether through a filter aid of diatomaceous earth. There is obtained 10 3,4-dihydroxy-5-nitEophenylglyoxylic acid of m.p. 172-174' (from isopropyl ether).
Example 16 a) A mixture of 3.93 g of n-hexyl 3.4-dihydroxy-5-nitro-phenylglyoxylate and 1.30 cj of 2-aminophenol are malted at 15 120° while stirring. The melt crystallises after 5 minutes. After 2 hours it is cooled and recrystallized from methanol. There is obtained 3-(3,4-dihyd£oxy-5-nitro-phenyl)-2H-1.4-benzoxazin-2-one of m.p. 202-204,°.
In an analogous manner: 2Q b) From n-hexyl 3,4-dihyd£Oxy-5-nit£ophenylglyoxylate and 2-amino-p-cresol there is obtained 3-(3.4-dihydroxv-5--nitrophenyl)-6-methyl-2H-l.4-benzoxazin-2-one of ®.p. 233-235° (from methanol/methylene chloride),, c) from n-hexyl 3.4-dihyd£Oxy-5~nitrophenylglyoxylate and 25 2-amino-4-pEopylphenol there is obtained 3- {3.4-dihydroxy- ~5-nit£ophenyl)-6-propyl-2H-l„4-benzoxazin-2-one of m.p. 200-202° (from methanol) „ d) from n-hexyl 3.4-dihydroxy-5-nitrophenylglyoxylate and 3-amino-4-hyd£Oxybenzoic acid there is obtained 3-(3.4-■a0 -dihydroxy-5-nit£ophenyl)-2-oxo-2H-1.4-benzoxazine-6- -carboxylic acid of sn.p. 286-287° (from acetone/petroleum ether)» e) from n-hexyl 3.4-dihvdroxy-5-nitrophenylglyoxylate and 2-amino-4-chloEophenoX there is obtained S-ehloro-3- - (3«, 4 -dihydroxy-5-nitr ©phenyl )-2H-l. 4-ben2oxazin-2-one of m.p. 241-2«3° (from methanol). f) from n-hexyl 3»4-dihydEoxy-5-nitEophenylgXyoxyXate and 2-amino-4„S-dichlorophenol there is obtained 6,8-dichloro--3-(3,4-dihydroxy-S-nitEophenyl)-2H-l.4-benzoxazin-2-one of m.p. 237-239° (from ethanol/ether) and g) from n-hexyl 3.4-dihydroxy-5-nitrophenylglyoxylate and 2-amino-5~nitrophenol there is obtained 3-(3,4-dihydroxy- -5-nitrophenyl)-7-nitco-2H-l,4-benzoxazin-2-ome of m.p. 253-255° (from acetonicrile/ethamol).
Example 17 a) A mixture of 396.0 mg of n-hexyX 3.4-dihydroxy-5--nitrophenylglyoxylate and 137.6 mg of 1.2-phenylene-diamine is heated to 120° for SO minutes. Thereafter, the mixture is suspended ia methanol, filtered off under suction and recrystallized from N.N-diotethylformamide/ water. There is obtained 3-(3,4-dihydroxy-5-nitEophenyX)~ -2(lH)-guinoxaXinone o£ a.p. >300°.
In an analogous manner: b) From n-hexyl 3,4-dihydroxy-S-nittophenylgXyoxyXate and N-methyX-1.2-phenyXene diamine there is obtained 1-aethyl--3-(3.4-dihydEoxy-5-nitEophenyl)-2(lH)-quinoxalinone of ia.p. 271-273° (from methanol). - 45 - c) from n-hexyl 3,.4-dihydroxy-5-nitrophenylglyoxylate and N-propyl-1.2-phenylene diamine there is obtained 1-propyl--3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone of M.p. 183-185° (from methanol),. d) from n-hexyl 3»4-dihydroxy-5-nitrophenylglyoxylate and 4,5-dimethyl-l.2-phenylenediamine there is obtained 3-(3.4-dihydroxy-5-nitrophenyl)-6,7-dimethy1-2(1H)--quinoxalinone of m.p„ >300° (from N»N-dimethylformamide/ water), e) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 4,5-dichloco-la2-phenyl©nediamine there is obtained 6„7-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)-2(IK)--quinoxalinone of m.p. >300° (frora M»,B5-dimethyXf ormamide/ water). f) from n-hexyl 3„4-dihydroxy-5-nitrophenylglyoxylate and 3-chloro-5-trifluoromethyl-1„2-phenylenediamine there is obtained a 1*1 mixture of 8(and 5)-chloro-3-(3,4--dihydroxy-5-nitrophenyl)-6 (and 7)-trifluoromethyl-2(IB)--quinoxalinone of m.p. >300° (froa N,N-dimethylformamide/ water). g) from n-hexyl 3.4-dihydroxy-5-nitrophenylglyoxylate and 4-methoxy-l,2-phenylenediamine there is obtained a 1:1 mixture of 3-(3»4-dihydroxy-5-nitrophenyl)-6(and 7)-?aethoxy-2(1H)-quiooica 1 inone of a.p. >300° (from ethanol/ether). h) from n-hexyl 3.4-dihydroxy-5-nitrophenylglyoacylate and 4-nitro-l.2-phenylenediamine there is obtained 1:1 mixture of 3 - (3 „4-dihydcoxy-5-nitrophenyl)-6(and 7)-nitro-2(lH)--quinoxalinone of m.p. >300° (fro® N.N-dimethylforaamide/ water) and - 46 - i) from n-hexyl 3,«-dihydroxy-5-nitrophenylglyoxylate and N-hexyl-1.2-phenvlenediamine there is obtained l-hexyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(IK)-quinoxalinone of is.p. 152-154° (fcoiR methanol). 5 Example 18 A solution of 1.07 g of n-hexyl 3.fl-dihydroxy-S-ttitro-phenylglyoxylate and 696.3 sng of 2.3-diaainonaphthalene in 3 ml of 1-hexanol is heated to boiling under reflux for 3 hours. The reaction mixture is then cooled and diluted 10 with methanol. The crude product is filtered off under suction and recrystallized from N.N-diaethylformamide/ water. There is obtained 3-(3,,4-dihydroxy-5-nitrophenyl)-benzo[g]auinoxalin-2(IH)-one of m.p. >300°.
Example 19 15 A suspension of 2.05 g of n-hexyl 3.4-dihydcoxy-5- -nitrophenylglyoxylate and 600.8 Big of thiosemicarbazide is stirred intensively at 90° for 30 'minutes. The mixture is then cooled to 40° and treated with a solution of 870.1 mg of sodium hydroxide in 15 al of water. The 20 solution is subsequently heated to 90® for 30 minutes,, the reaction mixture is cooled to room temperature and treated dropwise with 2 ml of conc. hydrochloric acid. The crysta Hi zed-out product is filtered off under suction and then dissolved in ethyl acetate. The solution is washed 25 with saturated sodium chloride solution, dried over sodium sulphate,, filtered and evaporated. There is obtained 6--(3,4-dihydroxy-5-nitrophenyl)-3 -meccapto-X.2,^-triaaia--5(4K)-one of m.p. 282-28(fro© ethanol).
Example 20 30 aaa) A suspension of 2.9 g of 2-broao-«•-hydroxy-3'- - 47 - -methoxy-s' -nitroacetophenone and 761.2 rag of thiourea in 170 ml of ethanol is treated at 60° with 320.3 rag of sodium acetate and stirred foe S hours. The reaction mixture is then evaporated, the residue is treated with 170 ml of water aad heated to 60® for 30 minutes. Mter cooling the product is filtered off under suction and washed with Mater. There is obtained <*-(2=-aiadao~4--thiazolyl)-2-®ethoxy-6-nitrophenol of m.p. 248-250° (from ethanol).
In an analogous manner: aab) From 2-bromo-§'-hydroxy-3'-methoxy-5'-aitroaceto-phenone and K-phenylthiourea there is obtained 4-(2-anilino-4-thiazolyl)-2-methoxy-6-nitrophenol of m.p. 105-107° (from ether). aba) 50 ul of 1.2-dichloroethane aad 3.56 g of calcium carbonate are added to a solution of 4.80 g of S-amino-4'--(trifluoromethyl)-hexanilide hydrochloride ia 70 ml of water. The suspension is treated within 60 minutes while stirring at room temperature with a solution of 2.6 g of thiophosgene in 1.7 ml of toluene. After 16 hours the precipitate is filtered off under suction and the organic phase is washed with IN hydrochloric acid and water. After drying over sodium sulphate aad filtration the filtrate is evaporated. There is obtained crude 4■-(tr iflmoroaethyl)-hexananilide-6-isothiocyanate. abb) A solution of 5.2 g of crude 41 -(trifiluoro-methyl)hexananilide-6-isothiocyanate in 60 ml of ethanol is treated with 100 ml of conc. ammonia solution. After 30 minutes the reaction mixture is evaporated. The residue is dissolved ia ethyl acetate,, washed with Mater., dried over sodium sulphate,, filtered and evaporated. There is obtained 1-[5-[(a, a,a-1r i fluoro-p-tolyl)ca rbamoyl]-pentyl]-2-thiourea of m.p. 140-142" (from ethanol). abc) A suspension of 666.7 mg of 1-[5-[e,a„a--trifluoro-p-tolyl)carbamoyl]pentyl3-2-thiourea and 580.2 mg of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroaceto-phenone in 50 ml of ethanol is treated at 60° with 164.2 mg of sodium acetate. & reddish-yellow solution thereby results. Mter 90 minutes the reaction mixture is evaporated. the residue is treated with water, the precipitate is filtered off under suction and washed four times with 10 ml of water each time. There is obtained 6-[[4-(4-hydroxy-3-methoxy-5-nitrophenyl)-2 -thiazolylJ-amino]-41 -(trifluoroaethyl)hexananilide of m.p. 160-162® (from ethanol). ac) A solution of 29.0 g of 2-be onto-4 • - hydroxy- 3 1 -methoxy--5'-nitroacetophenone and 13.5 g of 2-aminoacetophenone in 250 ml of dry N.N-dimethylformamide is stirred at 90® for 16 hours. The reaction mixture is then evaporated to about two thirds and poured on to ice. The separated crystals are filtered off under suction and dissolved in methylene chloride. The solution is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. There is obtained 2-(4-hydroxy-3-methoxy--5-nitrobenzoyl)-3-methylindole of a.p. 195-197® (from methylene chloride/aethanol). ada) A suspension of 14.5 g of 2-bromo-4'-hydroxy-3'--methoxy-5'-nitroacetophenone aad 5.41 g of 1,2-phenylene-diaaine ia 350 al of methanol is treated with 4.92 g of sodium acetate and the mixture is heated to boiling under reflux for 22 hours. The reaction mixture is then evaporated. the residue is dissolved ia methylene chloride, this solution is washed four times with water,, dried over sodium sulphate, filtered and evaporated. There is obtained 2-(4-hydroxy-3-aettooxy~S-nitrophenyl)quino5caline of a.p. 195-197° (from methylene chloride/methanol). - 49 - In an analogous manner: adb) From 2-bromo-4'-hydroxy-3'-methoxy-51-nitroaceto-phenone aad 4.5-di»ethyX-X,2-phenylenediamine there is obtained 6.7-dimethyl-2-(4-hydroxy-3-aethoxy-5 -nitro-phenyl)quinoxaline of m.p. 207-209° (from. methylene chlorida/methanol). b) a suspension of 267.3 tag of 4-(2-amino-4-thiazolyX)-2--methoxy-6-nitrophenol in 10 ml of dry methylene chloride is treated at -20° with 1.25 g of boron tribromide. After the addition the mixture is stirred at -20° for a further one hour and at room temperature without cooling for 18 hours. The reaction mixture is then evaporated, the residue is treated cautiously with water and stirred at 50° for 30 minutes. Mter cooling to roouj temperature the mixture is suction filtered and the crude product is filtered off and washed with a small amount of water.
There is obtained 5-(2-amino-4-thiazolyl)-3-nitropyro-catechol hydrobromide of m.p. 244-246° (from methanol).
In an analogous manner: c) From 4-(2-anilino-4-thiazolyl)-2-metboxy-6-nitrophenol there is obtained 5-(2-anilino-4-thiazolyl)-3-nitropyro-catechol of a.p. 202-204® (from methanol), d) from 6-[4-(4-hrb.enyl)-2--thiazolyX)aaino]-4,-(trif XuoroaethyXJhexananilide there is obtained S-[[4-(3,4-dihydroxy-5-nitropheny1)-2--thiazoXyl]arainoJ-4'-(trifluoromethy1)hexananiXide of m.p. 214-216" (from methanoX). e) from 2-(4-hydroxy-3-»ethoxy-5-nitrobenzoyl)-3- -methvlindole there is obtained 5-bromo-2-{3.4-dihydroxy--5-nitrobenzoyl)-3~methylindole of m.p. 265-267* (from methanol)« £) from 2-(«-hydroxy-3-methoxy-5-nitrophenyl)quinoxaline there is obtained 2- (3,«-dihydroxy-5-nitrophenyl)- quinojcaline of m.p. 241-243° (from methanol) and g) from 67-dime thy 1-2-(4-hydroxy-3-®ethoxy-5-nitro-phenyl)auinoxaline there is obtained 6.7-dimethyl-2-(3.4--dihydroxy-5-nitrophenyl)quinoscaline of m.p. 274-276® (from methanol).
Example 21 ft mixture of 3.12 g of 2-bromo-3 '.4 ' -dihydroxy-5' - -nitroacetophenone and 849.3 sag of thioacetamide are heated to boiling under reflux for 18 hours in 40 ml of ethanol. After cooling the crystals are filtered off under suction and recrystallized from methanol/isopropanol.
There is obtained 5-(2-methyl-4-thiazolyl)-3-nitropyro-catechol hydrobromide of m.p. 280-282°.
Example 22 A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'--nitroacetophenone and 461 mg of thiosemicarbazide in 20 ml of n-butanol is heated to boiling under reflux for SO minutes. After cooling to room temperature the crystals are filtered off under suction and recrystallized from n-butanol. There is obtained 5-(2-amino-6H-l.3.4--thiadiazin-5-yl)-3-nitropyrocatechol hydrobromide of m.p. 265-267°.
Example 23 A solution of 1.38 g of 2-bromo-33.4•-dihydroxy-5'--nitroacetophenone and 505.7 tag of 2-amino-l, 3.4--thiadiazole in 25 al of n-butanol is heated to boiling under reflux for 7 houcs. The reaction mixture is then cooled to room teiaperatur© and the separated crystals are filtered off under suction. There is obtained 5-(imidazo-[2.1-b]-l,3»4-thiadiazo1-6-y1)-3-nitropyrocatecho1 of m.p. 278-280° (from methanol).
Example 24 A mixture of 2.78 g of 2-brorao-3'„«•-dihydroxy-5'--nitroacetophenone. 1.01 g of 2 - a m i no t h i a 2 o 1 -e and 40 ill of ethanol is heated to boiling under reflux for 23 hours. The reaction raiactura is then cooled to room temperature and the crystals are filtered off under suction. There is obtained 5-(itnidazo[2.1-b]thiazol-6-yl)-3-nitropyro-. catechol hydrobromide of as.p. 286-288° (from methanol).
Example 25 A ®ixture of 1.95 g of 2-bromo-3',4'-dihydroxy-5'- -nitroacetophenone, 1.06 g of 2-aminobenzothiazol@ and 50 ml of ethanol is heated to boiling under reflux for 17 hours. The reaction mixture is then cooled to room temperature,, whereupon the crystals are filtered off under suction. There is obtained 5-(imidazo[2»1-b]benzothiazol--2-y1)- 3-nitropyrocatechol of m.p. 303-305° (from N,N-dimethylformaraide/methanol).
Sxaraole 26 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 boiliag under reflux for one hour. The reaction mixture is thea cooled to room temperature,, whereupon the crystals are filtered off under suction. There is obtained 5-(2H-l,4-benzothiazin-3-yl)-3-nitro-pyrocatechol of is.p. 302-304° (from N,N-dinethyl-formamide/methanol).
Example 27 A mixture of 987.5 sag of 2-bromo-3 ' , 4 ' -dihydroxy-5 ' - -n i t r oa ce t o phe no ne and 1.01 g of 2-aainopyridine is melted at 110°. After 30 minutes the laelt is treated with 15 ml of ethanol and heated to boiling under reflux for 3 hours. The reaction mixture is then cooled to toon teaperature and the crystals ace filtered off under suction. There is obtained 5-(imidazo[l.2-a]pyridin-3-yl)-3-nitropyrocatechol of m.p. 250-252® (from N.N-dimethylformamide/ methanol).
Example 28 a) 8.9 g of 1,1'-carbonyIdiimidazole are added to a solution of 10.7 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 500 ml of dry tetrahydrofuran and the reaction mixture is subsequently heated to 65-70° for 5 hours. It is then cooled to zoom temperature and a solution of 21.6 g of 6-aminohexyl-t-butylcarbaaate ia 50 al of dry tetrahydrofuran is added dropwise thereto within 15 minutes. The reaction mixture is then heated to 65-70° for 18 hours, evaporated, the residue is suspended ia ethyl acetate, suction filtered and the suction filtered material is chroaatographed on silica gel with acetone/methylene chloride £3:1). There is obtained [6-(4-hydroxy-5-nitro-a-anisaaido)hexyl]-t-butylcarbaaate of a.p. 145-147° (from isopropanol). b) 5.8 ml of hydrobromic acid in glacial acetic acid (~33 percent) are added at room temperature to a solution of €.1 g o£ [6-(4-hydroxy-5-nitE0-a-anisaaido)-hexyl]-t-butylcarbamate in 30 sal of glacial acetic acid.
The mixture is stirred for 2 hours, the separated crystals are filtered off under suction and washed with ether.
There is obtained N-(6-aainohexyl)-4-hyd£oxy-5-nitro-n- -anisamide hydcobroraide of m.p. 207-209° (fro® isopropanol). c) 1.25 g of bo cod, tribromide are added -20° to a suspension of 392.3 mg of N-(6-aminohexyl)-4-hydroxy-5- -nitto-m-anisamide hydrobromide in 25 ml of dry methylene ehloride„ After the addition Che mixture is stirred at -20° for one hour and subsequently at room temperature for 17 hours. The reaction mixture is then evaporated, the residue is treated vie si 10 ml of skater and stirred at room temperature for one hoar. After evaporating the water the residue is chromatographed on Sephadex LH 20 with toluene/ethanol (1:1). There is obtained N-6-arainohexyl--3 „ 4-dihydroxy-5-nitrobenzamide hydrobromide of m.p. 205-207° (from ethanol).
Example 29 aa) a solution of 4.93 g of 5-nitrovani11 in and 2.7 g of 1,2-phenylenediamine in 45 sal of methanol and 15 ml of nitrobenzene is heated to boiling under reflux. After 15 minutes crystals begin to separate 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 filtered off under suction and washed with methanol. There is obtained 4-(2-benzimidazolyl)-2--methoxy-6-nitrophenol of sr.p. 198-200° (from N,N-dimethylformamide/methanol).
In an analogous manner: at) Fross 5-nitrovanillin aad <5. 5-dichloro-l. 2-phenylenediamine there is obtained 4-(5,S-dichloro-2-benK-imidazolyl)-2-methoxy-6-nitrophenol of m.p. 258-260° (from N.N-dimethylformamide/ether). b) A suspension of 860.1 mg of (2-ben2imidazolyl)-2--methoxy-6-nitrophenol ia 10 ml of glacial acetic acid and 10 sal of 48 pesceat hydrobromic acid is heated to boiling under reflux for 72 hours. The mixture is then evaporated aad the residue is treated four times with 50 ml of toluene each time, which is again distilled off each time. There is obtained 5-(2-benzimiaazolyl)-3-nitropyrocatechol of m.p. >300° (from acetone/water).
In an analogous manner: c) From 4-(5.6-dichloro-2-benzimidazolyl)-2-methoxy-6--nitrophenol there is obtained 5-(5„S-dichloro-2--benzimidazolyl)-3-nitropvrocatechol of m.p. 282-284° (from acetone/water).
Example 30 A suspension of 29.0 g of 2-bromo-41 -hydroxy-3 '--methoxy-5'-nitroacetophenone in 700 ml of dry methylene chloride is treated at -20° within 30 minutes with a solution of 125.3 g of boron tcibroajide in 300 ml of dry methylene chloride. Mter the addition the mixture is stirred at -20° for a further one hour and at room temperature for IS hours, then evaporated, the residue is treated cautiously with water while cooling with ice aad stirred at 50° for 30 tainutes. After cooling the mixture is extracted with ether,, the ethereal phase is Hashed with water, dried over sodium sulphate,, filtered aad evaporated. There is obtained 2-&romo-31.4'-dihydroxv-s'-nitroacetophenone of m.p. 138-140° (from methylene chloride).
Example 31 a) A solution of 3.S g of ethyl 3.4-dihydroxy-S-nitro- phenylglyoxylate in 30 ml of acetic anhydride is heated at 110° for 30 minutes in the presence of a catalytic amount of conc. sulphuric acid, cooled to room temperature,, the reaction mixture is poured into 150 ml of water and stirred for 60 minutes. The mixture is extracted with ether, Mashed with saturated sodium chloride solution,, the combined organic extracts are dried sodium sulphate, filtered and evaporated. There is obtained ethyl 3,4-diacetoxy-5-nitrophenvlglyoxylate of m.p. 37-89° (from ether/petroleum ether).
In an analogous manner: b) From 3 - (3»4-dihydroxy-5-nitrophenyl) -2H-1,4--benzoxazin-Z-one there is obtained 3-(3,4-diacetoxy-5--n i t r o phe ny1)-2H-1,4-be nz oxa x i n-2-o ne of m.p. 186-188° (from methylene chlorida/methanol)„ c) from 3-(3„4-dihydEoxy-5-nitEophenyl)-2(lH)- -quinoxalinone there is obtained 3-(3„4-diacetoxy-5-nitro-phenyl)-2(lH)-quinoxalinone of m.p. 241-243® (from methylene chloride/methaaol), d) from 3.4-dihvdroxy-5-nitrobenzophenone there is obtained 3,4-diacetoxy-5-nitrobenzophenone of m.p. 141-143° (from methylene chloride/ether). e) from 21-fluoro-3,4-dihydroxy-5-nitEobenzophenone there is obtained 3„4-diacetoxv-2'-fluoro-S-nitrobenzophenone of m.p. 122-124° (from ether) and £) from 3,4-dihydE0xy-5-nitE0phenyl 4-pyridyl ketone there is obtained 3«4-diacetoxy-5-nitcoph@nyl 4-pyridyl ketone of m.p. 148-150° (from methylene chloride/ether). - 56 - Example 32 a) A solution of 2.0 g of 3,5-dinitropyrocatechol in 25 sal of propionic anhydride is heated at 110° for 18 hours in the presence of a catalytic amount of conc. 5 sulphuric acid, the excess anhydride is distilled off at 70° ia a high vacuum (1.33 Pa)„ the residue is dissolved in methylene chloride, washed with water,, dried over sodium sulphate, filtered and evaporated. There is obtained 1,2-dipropionyloxy-3,5-dinitrobenzene of m.p, 10 74-76° (from methylene chloride/petroleum ether).
In an analogous manner: b) From 3-(3,4-dihydroxy-5-nitrophenyl)-6-methy1-2H-1.4--benzoxazin-2-one there is obtained 3-(34-dipropionyloxy--5-nitrophenyl)-6-methyl-2H-l.4-benzoxazin-2-one of m.p. 15 158-160° (from methylene chloride), c) from 6-chloro-3-(3.4-dihydroxy-5-nitrophenyl)-2H-l,4--benzoxazin-2-one there is obtained 5-(6~chloro-2-oxo-2H--1.4-benzoxazin-3-yl)-3-nitro-o-phenylene-dipropionate of m.p. 148-150° (from methylene chloride/ether). 20 d) from 3-(3.4-dihydroxy-5-nitrophenyl)-7-nitro-2H-l,4- -benzoxazin-2-one there is obtained 3-nitro-5-(7-nitro-2--OXO-2H-1„4-benzoxazin-3-yl)~o-phenylene~dipropionate of st.p. 177-179° (from methanol), e) from 3-(3.4-dihydroxy-5-nitrophenyl)-2-oxo-2H-l.4-25 -benzoxazine-6-carboxylie acid there is obtained 3-[3„4- -bis(propionyloxy)-5-nitrophenyl3-2-oxo-2H-1.4-benzoxazine--6-carboxylic acid of ta.p. 192-194* (from methylene chloride). - 37 - f) from 3-nitro-5- (2-quinoxalinyl)py.c ©catechol these is obtained 3-nitro-5-(2-quinoxalinyl)-o-phenylene--dipropionate of m.p. 152-154° (fcom methylene ehloride/-ether, 5 g) from 5-(2-benzimidazolyl)-3-nitropyrocatechol there is obtained 5-(2-benzimidazolyl)-3-nitro-o-phenylene--dipropionate of m.p. 179-101° (from ether), h) from 6.7-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)--2(lH)-quinoxalinone there is obtained 5- (6 ,,7-dichloro- 10 - 3,4-dihydro- 3-os:o-2-quinoxal i&yl )-3-nitro-o-phenylene- -dipropionate of m.p. 260-262° (from methylene chloride), i) from 5-brorao-2-(3„i-di hydro scy-5-nitr obenzoyl)-3--methylindole there is obtained 5-brorao-2-(3,4--dipropionyloxy-5-nitrobenzoyl)-3-methylindole of m.p. 15 196-198° (from ether) and j) from 6-(3,4-dihydroxy-5-nitEophenyl)-3-mercapto-l,2,4--triazin-5(4H)-one there is obtained 3-nitro-5-(2„3,4.5--tetrahydro-5-oxo-3-thioxo-as-triazin-6-yl)-o-phenylene- -dipropionate of m.p. 237-239° (from ether)„ 20 Example 33 a) A solution of 1.09 g of ethyl 3.4-dihydroxy-5-nitro-phenylglyoxylate in 6 ml of isobutvric anhydride is heated at 110° for 17 hours ia the presence of a catalytic amount of conc. sulphuric acid. The reaction Mixture is then 25 treated ten tiiaes with 10 Ml of toluene each time, whereby it is evaporated each time at 80° and 18.7 nbar. The oily residue is distilled ia a bulb-tube at 175-100° and 8.0 Pa. There is obtained ethyl 3.4-diisobutyryloxy-5--nitrophenylglyoxylate. - 58 - In an analogous manner: b) From 3,5-dinitropyrocatechol there is obtained 1,2--diisobutyryloxy-3«S-dinitrobenzene of a. p. 78-80° (from ether)» 5 c) from 3-(3.4-dihydroxy-5-nitrophenvl)-6-methyl-2H-1,4- -benzoxazin-2-one there is obtained 3-(3.4-diisobutyryl-oxy-5-nitrophenyl)-6-methyl-2H-l.,4-benzoxazin-2-one of m.p. 142-144° (from ether). d) from 2 - (3,4 -d ihydroxy- 5-ni tr ophenyl )quinoxaline there 10 is obtained 2-(3.4-diisobutyryloxy-5-nitrophenyl)- quinoxaline of m.p. 155-157° (from ether), e) from l-methyl~3-(3*4-dihydroxy-5-nitrophenyl)-2(IH)--quinoxalinone there is obtained l-methyl-3-(3»4--diisobutyryloxy-5-nitrophenyl)-2(IH)-quinoxalinone of m.p. 138-1~0° (from ether), \ b £) from 5-(imida20[2„l-b]-1.3,4-thiadiazol-6-yl)-3-nitro-pyrocatechol there is obtained 5-(imidazo[2,l-b]-l,3,4--thiadiazol-6-yl)-3-nitro-o-phenylene diisobutyrate of m.p. 169-171° (from methylene chloride). 10 9) from 2-bromo-3'.4'-dihydroxy-5'-nitroacetophenone there is obtained 5-(bromoacetyl)-3~nitro-o-phenylene diisobutyrate of m.p. 56-58® (from methylene chloride/ hexane), h) from 5-(2-amino-4-thiazolyl)-3-aitropyr©catechol 15 hydrobromide there is obtained 3-nitro-5-(2-isobutyramido- -4-thiazolyl)-o-phenvlene diisobutyrate of m.p. 157-159° (from methylene chloride/ether). - 59 - i) from 5-(2-amino-SH-l»3,$-thiadiazin-5-yl)-3-nitro-pyrocatechol hydrobromide there is obtained 3-nitro-5-(2--isobutyramido-4-isobutyryl-1,3,4-thiadiazin-5-yl)-o- -phenylene diisobutyrate of m.p. 177-179° (from ether), 5 j) f roia 3 - (3 „ 4-d ihydroxy- 5-ni tr ophenyl) - 6-propy1-2H-1,4- -benzoxazin-2-one there is obtained 3-nitro-5-(2-oxo-S--propyl-2H-l.4-benzoxazin-3-yl)-o-phenylene diisobutyrate of m.p. 131-133° (from methanol). k) from 5-(imidazofl„2-aJpyridin-3-jl)-3-nitropyto-10 catechol there is obtained 5-(imidazo[ 1,2-a]pyridin-3-yl)- -3-nitco-o-phenylene diisobutyrate of m.p. 137-139° (from ether). 1) from 5-(imidazo[2„l-b]benzothia2o!-2-yl)-3-nitropyro-catechol there is obtained 5-(iaidazo[2» l-bjbenxothiasiol-15 -2-yl)-3-nitro-o-phenylene diisobutyrate of m.p. 197-199° (from methylene chloride/ethec and m) from 3,4-dihydroxy-5-nitrophenyl 2-pyridyl ketone hydrobromide there is obtained 3-nitro-5-(2-pyridyl-carbonyl)-o-phenylene diisobutyrate of m.p. 83-85° (from 20 ether/hexane).
Example 34 a) A solution of 613.0 Hag of ethyl 3,4-dihydroxy-5-nitro-phenylglyoxylate in 4 ml of pivaloyl anhydride is heated, to 100° for 17 hours in the presence of a catalytic amount 25 of conc. sulphuric acid,, the cooled solution is diluted with ether, washed with saturated sodium solution, olcied over sodium sulphate., filtered aad evaporated. The residue is treated ten times with 10 ml of toluene,, whereby it is evaporated again each time, Mter bulb-tube distillation 30 (air-bath) at 175-180° and 4.0 Pa there is obtained ethyl 3.4-dipivaloxyloxy-5-nitrophenylglyoxylate.
In an analogous manner: b) From 3- (3„4-dihydroxy-5-nitrophenyl)-6-methyl-2H-l,4--ben2oxazin-2-on® there is obtained 3-(3„4-dipivaloyloxy--5-nitrophenyl)-S-raethyl-2H-l.4-benzoxazin-2-one of m.p. 180-192° (from ether), c) from 3.4-dihydroxy-5-nitrobenzophenone there is obtained 3,4-dipivaloyloxy-5-nitrobenzophenone of m.p. 101-103° (from t-butyl methyl ether) and d) from 2'-fluoro-3„4-dihydroxy-5-nitrobenzophenone there is obtained 3.4-dipivaloyloxy-2'-fluorobenzophenone of mi.p. 74-76° (from low-boiling petroleum ether).
Example 35 A solution of 1.7 g of 3-(3„4-dihydroxy-5-nitro-phenyl)-2(IH)-quinoxalinone in 17 ml of oenanthic anhydride is heated to 110° for 17 hours in the presence of a catalytic amount of conc. sulphuric acid, the excess anhydride is then distilled off in a high vacuum, the residue is dissolved in methylene chloride, the organic solution is washed with water, dried over sodium sulphate, filtered and evaporated. There is obtained 5-(1,2-dihydro--2-oxo-3-auinoxalinyl)-3-nitro-o-phenylene diheptanoate of m.p. 186-183° (from methylene chloride/ether).
Example 36 a) 1.26 g of sodium acetate are added to a solution of 1.35 g of 2-bcomo-3',4'-dihydroxy-5'-nitroacetophenone in 25 ml of alcohol and heated to boiling under reflux. After 6 hours the reaction mixture is filtered off from separated sodium bromide and evaporated. The residue is dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated at 50°. There is obtained (3. 4 - d ihy dr oxy-5-n i t r obenz oy1)mechy1 acetate of 166-150° (from ethyl acetate/ether)- In an analogous manner: b) from 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and sodium isobutyrate there is obtained (3„4-dihydroxy-5--nitrobenzoyl)methyl isobutyrate of m.p. 120-122® (from ethyl acetate/ether) and c) from 2-bromo-3'.4'-dihydroxy-51-nitroacetophenone and sodium 3„4-dihydroxy-5-nitrophenylglyoxylate the.ce is obtained 3„4-dihydroxy-5-nitrophenacyl (3,4-dihydroxy-5--nitrobenzoyl)£ormate of m.p. 224-226° (from methanol/ ethyl acetate).
Example 37 A suspension of 2.51 g of 2-b.como-3 ' „ 4 ' -dihydroxy-5 ' --nitroacetophenone is treated with 1.31 g of thionicotin- amide in 50 ml of alcohol and heated to boiling under reflux for 2 hours. Mter cooling to room temperature the crystals are filtered off under suction and recrystallized from N,N-dimethyl£ormamide/alcohol. There is obtained 3-nitro-5-[2-(3-pyridyl)-4-thiazolyl]pyr©catechol of m.p. 279-281® .
Example 38 A solution of 5.52 g of 2-broao-3'.4'-dihydroxy-5'- -nitroacetophenone and 2.7 g of 2-aminoacetophenone ia 100 ml of dry N,N-dimethyIformamxde is stirred, at 90* for 24 hours. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate,, washed with water, dried over sodium sulphate,, filtered and evaporated. There is obtained 2-(3„4-dihydroxy-5-nitr©benzoyl)-3-methylindole of m.p. 212-214° (from n-butanol).
Examole 39 h suspension of 7,32 g of 2-bromo-3'.4'-dihydroxy-5'--nitroacetophenone is treated with 4.06 g of 1-(3--pyridinyl)-2-thiourea in 100 ©1 of n-butanol and heated to boiling under Kef lux for 3 hours. Mter cooling to roo.a temperature the crystals are filtered off under suction and recrystallized from n-butanol. There is obtained 3-nitro-5-[2-(3-pyridylamino)-4-thiazolyl]pyrocatechol hydrobromide of m.p. >300°.
Example 40 h suspension of 6.35 g of 2-bro«o-3'.4'-dihydroxy-51 --nitroacetophenone is treated with 4.68 g of l-(3--quinolinyl)-2-thiourea in 150 ml of n-butanol and heated to boiling under reflux for 3 hours. Mter cooling to room temperature the crystals are filtered off under suction and recrystallized from n-butanol. There is obtained 3-nitro-5-[2-(3-quinolinylamino)-4-thiazolyl)pyrocatechol hydrobromide of m.p. >300°.
Example 41 A suspension of 8.28 g of 2-bromo-3'»4'-dihydroxy-5'- -nitroacetophenone is treated with 6.37 g of rac-l-(2-exo--bornyl)-2-thiourea in 100 ml of a-butajaol and heated to boiling under reflux for 3 hours. After cooling to room temperature the crystals are filtered off under suction and recrystallized from n-butanol. There is obtained cac-3-nitro-5-[2-(2-exo-bornylamino)-4-thiazolyi]-pyro-cacechol hydrobromide of m.p. 262-264°.
- S3 - Example 42 0.075 ml of pyrrolidine in 35 ml of tetrahydrofuran is treated at 5° with 0.605 ml of acetic acid aad subsequently with 1.73 g of 3.4-dihydroxy-5-nitrobenz- 5 aldehyde and 2.87 g of 6-oxo-4'-(trifluoromethyl)- heptananilide and stirred at 23° under argon for 56 hours. The residue obtained after evaporating the reaction mixture is partitioned between ethyl acetate and IN sodium hydroxide solution. The combined sodium hydroxide extracts 10 are made acid with conc. hydrochloric acid, extracted with ethyl acetate,, the combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried over sodium sulphateevaporated and the residue is chromato-graphed on 120 g of silica gel with methylene chloride/ 15 methanol (91:9). After recrystal1ization from ethyl acetate/petroleum ether there is obtained (£)-3-(3 e--dihydroxy-5-nitrophenyl)-6-oxo-4'-(trifluoromethyl)-7--octenanilide of m.p. 194-197°.
Example 4 3 2o a) 25.0 g of 2-chloro-3-hydroxy-p-anisaldehvde are dissolved ia 400 ml of acetic anhydride and S ml of pyridine. The solution is stirred at 80° for 8 hours, the reaction Mixture is subsequently evaporated, the residue is partitioned between ice-water and methylene chloride,, 25 the organic phase is dried over sodium sulphate, evapor ated and the residue is recrystallized from methylene chloride/petroleum ether. There is obtained 2-chloro-3--formyl-6-methoxyphenyl acetate of m.p. 48-50®. b) 38 g of 2-chloro-3-£ormv1-6-methoxyphenyl acetate are 3Q introduced portionwise at -5® to -10® within 15 minutes into 150 si of 98 percent nitric acid. Mter stirring at -59 for 30 ainutes the reaction mixture is poured into - 64 - 1.5 1 of ice-water and extracted three times with 500 ml of methylene chloride. The combined ocganic phases are washed with ice-water, dried over sodium sulphate and evaporated. The residue is crystallized from ether. There 5 is obtained 2-chloro-3-forayl-6-methoxy-5-nitrophenyl acetate of m.p. 84-85°. c) 35.8 g of 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate are dissolved ia 300 al of methanol. After adding 145 sal of IN sodium hydroxide solution the mixture is 10 stirred at 23° for 1 hour. After evaporation of the methanol the residue is diluted with ice-water, made acid with 2N hydrochloric acid and extracted twice with €00 ml of ethyl acetate each time. The organic phases are washed with saturated sodium chloride solution,, dried over sodium 15 sulphate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. There is obtained 2-chloro-3-hydEOxy-5-nitro-p-anisaldehyde of m.p. 130°. d) 1.3 g of 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde are dissolved in 80 ml of methylene chloride, treated with 20 0.82 ml of boron tribromide, stirred at 23® for 18 hours, the reaction mixture is treated with 5 sal of methanol while cooling with ice,, evaporated, the residue is dried ia a high vacuum, digested in water, filtered and recrystallized from acetonitrile. There is obtained 25 2-chloro-3,4-dihydroxy-5-nitrobenzaldehyde of a.p. 193-195°.
Examole 14 a) A Mixture of 30 g of 2-chloro~3-hydroxy-p-anisaldehyde aad 230 al of ethanol is stirred at 70° for 4 hours in the 3Q presence of 12.3 g of hydroxylamine hydrochloride, the reaction mixture is subsequently evaporated, the residue is dried in a high vacuum and recrystallized from methanol/wacer. There is obtained 2-chloro-3-hydroxy-p--anisaldehyde oxime of sa.p. 17€-176°„ b) 21 g of 2-chloEo-3-hydEoxy-p-anisaldehyde oxime are heated under reflux for 20 hours together with 400 al of acetic anhydride. Thereupon, the reaction mixture is evaporated, the residue is treated with 300 ml of ice-water, stirred for 1 hour, decanted, the thus-cooled residue is partitioned between methylene chloride and water, the organic phase is dried over sodium sulphate, evaporated,, the residue is dried in a high vacuum, chromatographed on 200 g of silica gel with methylene chloride and recsystallized f.cos methylene chloride/ petroleum ether. There is obtained 2-chloro-3-cyaao-6- -methoxyphenyl acetate of m.p. 97-99®. c) In analogy to Examples 43b and 43c, from 2-chloro-3--cyano-6-methoxyphenyl acetate there is obtained 2-chloro--3-hydroxy-5-nitEO-p-anisonitrile of m.p. 157-159° (methylene chloride/hexane). d) In analogy to Example 43d, from 2-chloro-3-hydroxy-5--nitro-p-anisonitrile there is obtained 2-chloro-3.4--dihydE0xy-5-nitE0-benz0nitEile of m.p. 180° (acetonitrile) .
Example 4.5 a) 5.5 g of c-chloro-2-fluoro-3,4-dimethoxytoluene aad 4.05 g of potassium acetate are stirred at SO® for 25 hours ia 50 ml of dinethylformamide. The reaction mixture is subsequently poured into 150 al of ice-water aad extracted with ether. The ether phases are washed with sodium chloride solution, dried over sodium sulphate and evaporated. 2-?luoro-3,-a-dimethoxybenzyl acetate is obtained as an oil. b) 5.4 of of 2-fluoro-3.4-dimethoxybenzyl acetate are heated to 80° for 1.5 hours together with 50 Ml of methanol and 50 ml of IN sodium hydroxide solution. After evaporation of the methanol the residue is extracted with methylene chloride. The coabined extracts are washed with water. dried over sodium sulphate and evaporated. The residue is chcomatographed on 80 g of silica gel with methylene chloride/methanol (95:5). 2-Fluoro-3.4--disaethoxy benzyl alcohol is obtained as an oil. c) 3.0 g of 2-fluoro-3.4-dimethoxvbenzyl alcohol and 5.0 g of manganese dioxide are heated under reflux for 1 hour together with 50 ml of benzene. The insoluble constituents are subsequently filtered off while washing with methylene chloride. The filtrate is evaporated and the residue is recrystallized from methylene chloride/ hexane. There is obtained 2-fluoro-3.4-dimethoxybenz-aldehyde of m.p. 52-54°. d) 4.4 g of 2-fluoro-3.4-dimethoxybenzaldehyde and 1.8 3 g of hydroscylamine hydrochloride are heated under reflux for 5 hours together with 30 ml of ethanol.. The reaction mixture is subsequently evaporated and the residue, dried in a high vacuum at 23®, is introduced into 40 al of phosphorus oxychloride. After stirring at 23® for 2.5 hours the reaction mixture is evaporated, the residue is treated with ice-water, the precipitate which thereby forms is filtered off. washed with water, taken up in methylene chloride, the methylene chloride solution is dried over sodium sulphate and evaporated. By reccystall- isation of the residue from methylene chloride/hexane there is obtained 2-fluoro-3,4-dimethoxybenzonitrile of m.p. 64-65°. e) 2.0 g o£ 2-fluoro-3,4-dimethoxybenzonitrile are dissolved! in 60 ml of methylene chloride, treated with - 67 - 1.1 ml of boron tribromide„ stirred at 23° foe 1 hour* subsequent If treated with a further 1.0 ml of boron tribromide and stirred at 23° for a further 80 minutes. Thereupon., the reaction mixture is poured into 100 ml of ice-cold saturated sodium hydrogen carbonate solution, whereupon the mixture is extracted twice with 300 al of ether, the combined ether phases are washed twice with sodium chloride solution, dried over sodium sulphate, evaporated aad the residue is chromatographed oa 50 g of silica gel with methylene chloride aad methylene chloride/methanol (97;3). There is obtained 2-£luoro-3--hydroxy-p-anisonitrile of m.p. 198-200®. 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, whereupon the mixture is stirred at 120® for 2 hours. The reaction mixture is subsequently evaporated and the residue is partitioned between ice-water aad methylene chloride. The organic phase is dried over sodium sulphate aad evaporated,, and the residue is recrystallized from methylene chloride/hexane. There is obtained 3-cyano-2--fluoro-6-methoxyphenyl acetate of m.p. 90-91®. g) 0.8 g of 3-cyano-2-£luoro-6-methoxyphenyl acetate are introduced in three portions at -15° into 5 ml of 96 percent nitric acid, whereupon the mixture is stirred at -10° for 1 hour. Thereupon, the reaction mixture is poured on to 50 g of ice. The mixture is extracted twice with 70 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The thus--obtained residue is dissolved in 50 ml ©£ IN sodium carbonate solution and 50 ml of methanol, whereupon the solution is stirred at 23* for 1 hour and the methanol is distilled off. The residal aqueous phase is adjusted to pH 2 at 0° with conc. hydrochloric acid and extracted - 68 - twice with 100 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution., dried over sodium sulphate and evaporated, and the residue is chromatographed on 45 g of silica gel with methylene 5 chloride/aethanol (97.*3). Mter recrystallization from ether/hexane the.ee is obtained 2~fluoro-3-hydroxy-5-nitro--p-anisonitrile of m.p. 112-113®. h) 550 ag of 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile are dissolved in 30 sal of methylene chloride, whereupon 1Q the solution is treated vith 0.44 al of boron tribromide.
After stirring at 23° foe 6 hours a further 0.1 'al of boron tribromide are added thereto, whereupon the mixture is stirred at 23° for a further 1.5 hours. Thereupon, 3 ml of ethanol are added thereto at -15°. The reaction aixture 15 is evaporated and the residue is dried ia a high vacuum at 23°. By recrystallization from ether/hexane there is obtained 2-fluoro-3.4-dihydroxy-5-nitrobenzonitrile of m.p. 154°.
Example 46 20 a) 9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid are suspended in 95 al of thionyl chloride. The suspension is stirred at 80° for 1 hour. By two-fold evaporation with the addition of absolute toluene there are obtained 10 g of 3,4-diaethoxy-5-nitrobenzoyl chloride which is 25 dissolved ia 100 sal of tetrahydrof uran. This solution is added dropwise to 300 ml of 28 percent aqueous aamonia. The aixture is subsequently stirred at 40* for 2 hours and cooled to 5®, The crystalline precipitate is filtered off. There is obtained 3„4-diaethoxy~5~nitrobenzaaide of ».p. 30 182-185°. b) 2.46 g' of chlorine are introduced while cooling with ice into a aixture of 8.0 g of sodium hydroxide, so al of water and 30 g of ice. Thereupon. 6.5 g of 3.4-dimethoxy- -5-nitrobenzamide suspended in 5 ml of tetrahydrofuran are slowly added thereto. The reaction mixture is heated to 70° within 30 minutes, stirred at 70° for 1 hour, cooled to 5° and the separated crystals are filtered off. There is obtained 3,4-dimethoxy-5-nitroaniline of m.p. 129-131°, By extraction of the filtrate with ethyl acetate, drying the extract over sodium sulphate, concentration and crystallization of the residue with the addition of ether there can be obtained a further portion of 3,4-dimethoxy-- fs-ni t r oa ni11ne. c) 10 g of finely powdered 3„4-dimethoxy-5-nitroaniline are suspended in 15 sal of 12N hydrochloric acid and 40 ml 'i • of water, whereupon the suspension is stirring at 30° for 1 hour. Thereupon. 3.8 g of sodium nitrite dissolved in 20 ml of water are added dropwise thereto at -5° within 15 minutes. The solution is stirred at -5° for 30 minutes and the cold diazonium salt solution is added dropwise within 45 minutes to 100 rail of pyridine of 40°. The mixture is subsequently stirred at 70° for 1 hour. The reaction mixture is evaporated and the residue is taken up in 300 ml of ethyl acetate. It is extracted three tines with 200 ml of 2N hydrochloric acid each time. The acidic--aqueous phase is adjusted to pH 9 with coac. ammonia and extracted with methylene chloride. The combined methylene chloride extracts are dried over sodium sulphate and evaporated,, and the residue is chromatographed oa 250 g of silica gel with ethyl acetate. After crystallisation from methylene chloride/hexane there is obtained 2-(3»4--dimethoxy-5-nitrophenyl)pyridine of m.p. 89-90*. d) 1.5 g of 2-(3,4-dimethoxy-S-miitrophenyl) pyridine are dissolved in 30 ml of 48 percent aqueous hydrobrosaic acid. The reaction mixture is stirred at 100° for 16 hours and .at 23® for 18 hours. The precipitate which thereby forms is filtered off and recrystallized from methanol/ether. There is obtained 3-nitto-5-(2-pyridyl)pyrocatechol hydrobromide of m.p. 239-240°.
Example 47 a) 2.76 ml of 2-bromopyridine dissolved in 30 ml of absolute tetrahydrofuran are treated -60° within 30 minutes with 19.2 al of l.SM n-butyl lithium solution (in hexane), whereupon the mixture is stirred at -60° for 30 minutes. 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 50 ml of tetrahydrofuran are then added dropwise thereto at -40° within 30 minutes. The reaction mixture is warmed to 0° within 2 hours. poured into ice-water and extracted with ethyl acetate. The combined extracts are dried over sodium sulphate and evaporated,, and the residue is chromatographed on 200 g of silica gel with ethyl acetate. There is obtained a-(3,4-dimethoxy--5-nitrophenyl)-2-pyzidinemethanoX as a brown oil. b) 7 g of manganese dioxide and added portionwise to 4.0 g of a-(3.4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol dissolved ia 100 ml of acetone while constantly heating under reflux over a period of 2.5 hours.
Thereupon, the mixture is heated under reflux for a further 2 hours. The manganese salts are subsequently filtered off and the residue obtained after evaporation is recrystallized from ether/hexane. These is obtained 3,4-dimethoxy-5-nitrophenyl 2-pyridyl ketone of a.p. 113°. c) 1.5 g of 3,4-diaethoxy-5-nitrophenyl-2-pyridyl ketone dissolved ia 30 ml of 48 percent hydrobEoaic acid are stirred at 100° for IS hours. Thereupon, the reaction mixture is evaporated and the residue is recrystallized from acetonitrile/methanol. There is obtained 3,4-dihydros:y-5-nitrophenyl 2-pyr idyl ketone hydrobromide of m.p. 213°. - 71 - bkaiapl® 43 a) 11.3 g of tin dichloride dihydrate are added to 2.25 g of 3 ', 41-dimethoxy-5'-nitroacetophenone dissolved ia 50 al of ethanol. whereupon the aixture is stirred at 75° for 30 5 minutes. Thereupon, the reaction mixture is poured on to 100 g of ice, neutralized with about 300 al of saturated sodium hydrogen carbonate solution and treated with 150 ml of Methylene chloride. The mixture is filtered and the Methylene chloride phase is separated. This is dried over ■jq sodiua sulphate and evaporated, and the residue is recrystallized from ether/petroleua ether. There is obtained 5'-araino-31„4'-diaethoxyacetophenone of m.p. 63-65°. b) A solution of 5.2 g of sodium nitrite in 20 ml of 15 water is added dropwise at o°' within 20 minutes to 14.0 g of 5*-amino-3'.4'-diaethoxyacetophenone dissolved ia 155 ml of in hydrochloric acid. After stirring at -2* for 30 minutes the cold diazonium salt solution is added dropwise within 30 minutes at 5-10° to a solution of 8.7 g 20 of copper(I) cyanide and 5.45 g of potassium cyanide in SO ml of water. After completion of the addition 200 ml of methylene chloride are added. and the reaction aixture is stirred at 23° for 3 hours and then filtered. The organic phase is separated, washed with water, dried over sodium 25 sulphate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. There is obtained S '-cyano-3 ' 4 ' -diaethoxyacetophenone of m.p. 125-126° . c) 3.75 g of aluainiua powder aad 28.5 g of iodine are heated under reflux for 2 hours in 160 ml of absolute 30 benzene. 3.0 g of 5'-cyano-3',4'-diaethoxyacetophenone and 0.5 g of tetra-n-butylaamonium iodide are then added at 20°, whereupon the aixture is heated under reflux for 1 hour. Thereupon, the mixture is treated at 2©® with 50 g of ice aad filtered. The residue is washed with ethyl acetate. The phases are separated and the aqueous phase is extracted a further twice with ethyl acetate. The combined organic phases ace washed with 20 percent sodium thio-sulphate solution, dried over sodiua sulphate aad evaporated. The thus-obtained residue is dissolved ia 20 al of acetic anhydride and 0.5 ml of pyridine aad stirred at 120° for 6 hours. The Mixture is subsequently evaporated and the residue is partitioned between methylene chloride and ice-water. The methylene chloride phase is dried over sodium sulphate and evaporated, and the residue is chromatographed on 100 g of silica gel with methylene chloride. After recrystallization from ether there is obtained 5 '-cyano-3 ', 4 ' -diacetoxyacetophenone of Ba.p. 76-79°.
Example 49 0.33 g of 5'-cvano-3'„4'-diacetoxyacetophenone dissolved in 3.3 al of methanol are treated with 2.7 al of 1.0N sodiua hydroxide solution and the reaction aixture is stirred at 23° for 45 ainutes. The aixture is subsequently acidified with 2N hydrochloric acid, diluted with 5 al of saturated sodiua chloride solution and extracted twice with 30 al of ethyl acetate each tiae. The coabined ethyl acetate phases are dried over sodiua sulphate and evaporated . The residue is recrystallized froa toluene/aceto-nitrile. There is obtained 5'-cyano-3 0.4'-dihydroxvaceto-phenone as brownish crystals which decompose above 215®.
Example 50 a) 3.48 g of phenyltrimethylaaaoniua bromide dibromide dissolved in 30 al of tetrahydrofuran are added dropwise at room temperature within 45 ainutes to 1.9 g of 5'-cyano-3',4'-dimethoxyacetophenone dissolved in 30 al of - 73 - tetrahydrofuran. whereupon the mixture is stirred for 30 minutes. Thereupon, the reaction mixture is poured into 120 ml of ice-water and extracted three times with 70 Ml of methylene chloride. The combined methylene chloride phases are washed with 2K sulphuric acid, dried over sodium sulphate and evaporated. The residue is chromatographed oa 20 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane there is obtained 5-(bromoacetyl)-2.3-dimethoxybenzo-nitrile of m.p. 138-141®. b) 1.45 g of 5- (bromoaceti/1 )-2,3-dimethoayhensonitrile and 1.12 g of selenium dioxide are stirred at 120° for 18 hours in 10 ml of n-hexanol. After cooling to room temperature the mixture- is diluted with 20 ml of methylene chloride and filtered. The filtrate is washed with water, dried over sodium sulphate aad evaporated. The residue is chromatographed oa 70 g of silica gel with hexane/ether (2:1). There is obtained hexyl (3-cyano-4.5-dimethoxy-phenyUglyoxvlate as an oil. c) 4.8 ml of boron tribromide dissolved in 20 ml of methylene chloride are added dropwise while cooling with ice within 20 minutes to 4.0 g of hexyl (3-cyano-4,5--dimethoxyphenyl)glyoxylate dissolved in 100 ml of methylene chloride and the reaction aixture is stirred at room temperature for 13 hours. 40 ml of methanol are subsequently added dropwise thereto at -60°. the mixture is stirred at room temperature for 1 hour and evaporated. The residue is taken up in methanol. It is heated under reflux for 10 minutes, evaporated to dryness and dried in a high vacuum. The thus-obtained crude product is recrystallized from acetonitrile. There is obtained methyl (3-cyano-4.5-dihydroxyphenyl)glyoxylate of m.p. 252®.
Example 51 1.075 g of methyl (3-cyano-4,5-dihydroxyphenyl)-glyoxylate and 0.60 g of 2-amino-p-cresol are stirred at 120° for 70 ainutes ia 2 ul of dimethylforaamide. The mixture is subsequently cooled to room temperature and diluted with 15 ml of water. The precipitate is filtered off and dried in a Mater-jet vacuum at 80° for S hours. After recrystallization from acetonitrile there is obtained 2, 3-dihydroxy-5- (S-methyl-2-oxo-2B-l„ 4--benzoxazin-3-yl)benzonitrile of m.p. 278-280®.
Example 52 a) A solution of 2.5 g (10.2 mmo1) of 3,4-dimethoxy-5--nitrobenzovl chloride in 10 ml of absolute tetrahydrofuran is treated with 1.1 ml of ethyl isocyanoacetate and subsequently with a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran and stirred at roo® temperature for 48 hours. After distillation of the solvent the residue is extracted with ethyl acetate/water. The crude product obtained after evaporation is chromatographed on a 20-fold amount of silica gel with ethyl acetate. After recrystallization from ethyl acetate/hexane there is obtained ethyl 5-(3 „4-dimethoxv-5-nitrophenyl)-4-oxazole-carboxylate in the for® of yellow crystals of a.p. 109-110°. b) 1.0 g (3.1 Mmol) of ethyl 5-(3,4-dimethoxy-5-nitro-phenyl)-4-oxazolecarboxylate are treated with 10 ml of constant-boiling hydrobromic acid and stirred at 140® for 2 hours. Mter distillation of the excess hydrobromic acid the yellow residue is recrystallized from ethanol/acetone. There is obtained 2-amino-3'.4•-dihydroxy-5'-nitroacetophenone hydrobromide in the form of yellow crystals of m.p. >250° (dec.). - 75 - Example 53 a) 10 g (34 mmol) of ethyl (3,4-dimethoxy-5-nitro-benzoyl)acetate are suspended in 100 ml of ethanol,, treated with 1.7 g (37 mmol) of aethylhydrazine and heated 5 under reflux for IS hours. After distillation of about 50 sal of ethanol the aixture is cooled to 0® aad the separated precipitate is filtered off under suction. After recrystallization from ethanol there is obtained 3- (3,4--dimethoxy-5-nitrophenyl)-l-methylpyrazol-5-ol in the foria 10 of fellow crystals of a. p. 200-202°. b) 2.0 g (7.2 mmol) of 3-(3,4-diaethoxy-5-nitrophenyl)-l- -iaethylpyrazol-5-ol are suspended in 100 ml of methylene chloride. After cooling to -40° a solution of s.9 ml of boron tribromide in 60 ml of Methylene chloride is added 15 dropwise thereto within one hour. The mixture is subsequently stirred at room temperature for 16 hours, cooled to -20° and treated within 30 minutes with 100 ml of ethanol. After stirring at room temperature for one hour the solvent is distilled off in a water-jet vacuua at 20 40°. The residue is treated three times with a mixture of 100 ml of ethanol/toluene each tine, whereby the solvent is distilled off each time. The residue is recrystallized from ethanol. There is obtained 5-(S-hydroxy-l-aethyl-pyrazol-3-yl)-3-nitropyrocatechol hydrobromide in the for,a 25 of yellow crystals of m.p. >250®.
Example 54 a) 16.3 g (0.7 g-atoa) of aagnesiua are treated with 15 ml of ethanol and. after adding 2 al of carbon tetra-3Q chloride, the reaction is initiated by heating. A solution of 130.3 g of tert.butyl ethyl aalonate ia 70 al of ethanol aad S00 al of absolute ether is .added dropwise thereto while stirring within about 30 ainutes so that the reaction proceeds at the reflux temperature. The mixture is subsequently stirred at 50° for a further 3 hours and the solvent is distilled off at 40° in a water-jet vacuum. The residue is dissolved in §00 ml of tetrahydrofuran. To this solution is added dropwise while stirring at 50° a solution of 170 g (0.7 naol) of 3.4-dimethoxy-5-nitro-benzoyl chloride in 700 ml of absolute tetrahydrofuran and the mixture is stirred at the reflux temperature for one hour. The solvent is distilled off at 40° ia a water-jet vacuum. The residue is treated with X 1 of ether. 260 al of 3N sulphuric acid are added thereto while cooling and stirring and the mixture is stirred for 30 minutes. The aqueous phase is extracted twice with 600 ml of ether each time. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated. The brown oil obtained is filtered over 1 kg of silica gel with toluene. The resulting mixture., consisting of ethyl tert.butyl (3.4-dimethoxy-5-nitrobenzoyl)malonate and ethyl C3,4-dimethoxy-5-nitrobenzoyl)acetate, is dissolved ia 600 ml of methylene chloride aad treated while stirring within about 30 minutes with 193 ml of trifluoroacetic acid. The mixture is subsequently stirred at 40® for 2 hours and then evaporated at 40° ia a water-jet vacuum. The oil obtained is extracted with ether/water. The organic phase is dried over sodium sulphate aad evaporated. Mter dissolution ia diisopcopyl ether/hexane and cooling the separated crystals are filtered off under suction and recrystallized from diisopropyl ©ther. There is obtained ethyl {3.4-dimethoxy-5-nitrobenzoyl)acetate in the form of slightly yellowish crystals of a.p. 87-68®°. b) 10.0 g (33.6 mmol) of ethyl (3.4-dimethoxy-S-nitro-benzoyl)acetate are reacted with 4..Q g (37 euro!) of phenylhydrazine in analogy to Example 53a. Mter recryst-allization from methylene chloride/ethanol there is obtained 3- (3,4-disaethoxy-5-nitrophenyl)-l-phenyl-2- -pyra2o1in-5-one in the for® of fellow crystals of m.p. 190-192°. c) In analogy to Example 53b, with botoa tribromide there is obtained therefrom 5-(5-hydroxy-l-phenylpyrazol-3-yl)--3-nitropveoeatecho1 hydrobromide ia the form of yellow crystals of m.p. >220® (dec.). 20.1 g of diethyl l3»4-dimethoxy-5-nitrobenzoyl)- malonate are dissolved in 200 al of wetlay 1 si).a chlor ide, whereupon the solution is cooled to -20° aad at this temperature there is added dropwise while stirring within 15 minutes a solution of 88.1 g of boron tribromide in 120 ml of methylene chloride. The mixture is subsequently stirred at room temperature overnight, after cooling to -20° the mixture is treated with 300 §al of ethanol and stirred at room temperature for 30 minutes. The solvent is distilled off in a water-jet vacuum at 40°. The residue is treated with 300 ml of ice-water and methylene chloride. The organic phase is washed with water, dried, over sodium sulphate and evaporated. The etude product obtained is chromatographed on a 10-fold amount of silica gel with toluene. Mter crystallization from methylene chloride/ hexane there is obtained ethyl (3,4-dihydcoxy-5-nitrobenzoyl )acetate in the fora of yellow crystals of m.p. 136-137°.
Example 56 2.0 g (7.« mmol) of ethyl (3»4-dihydro2ey-5-nitro-benzoy1)acetate ate suspended in 50 *1 of ethanol. After treatment with 0.4 g of hydrazine hydrate the mixture is held at the reflux temperature for 16 hours. Mter distillation of the solvent the residue is held at the boiling temperature for 5 minutes with 50 ml of ethyl acetate. The separated precipitate is filtered off under suction and the filtrate is concentrated to 10 ml. The crystals, which separate ia the cold,, are filtered off under suction. There is obtained 5-(5-hydcoxypyi:azol-3--yl)-3-nitropyrocatechol in form of orange crystals of m.p. 228® (dec.).
Example 57 7.3 g (35*66 mmol) of 3.4-dihydroxy-5-nitrobenzoic acid are treated with 30 ml of acetic anhydride, whereupon the mixture is held at the reflux temperature for 8 hours. The reaction mixture is poured on to ice. The separated precipitate is filtered off under suction,, washed with water and taken up in methylene chloride. The organic phase is dried over sodium sulphate aad evaporated. The residue obtained is recrystallized fro® methylene chloride/n-hexane in the cold. There is obtained 3.4-diacetoxy-5-nitrobenzoic acid in the form of colourless crystals of m.p. 126-127®.
Example 58 a) 9.7 g (32.2 mmol) of 3„4-diacetoxy-5-nitrobenzoic acid are treated with 12.5 ml of thionyl chloride, whereupon the mixture is stirred at 100® for 1.5 hours. After distillation of the excess thionyl chloride the 5-(chloro-carbonyl)-2-nitro-o-phenylene diacetate is distilled, b.p. 160° (25-7 Pa). b) 3.2 g (10.6 mmol) of 5-(chlorocarbonyl)-2-nitro-o--phenylene diacetate are dissolved in 50 ml of dimethyl-formaraide. The ice-cold solution is treated while stirring with a solution of 2.2 ml of diethylamine in 20 ml of dimetkyIformamide. The 'aixture is subsequently stirred at - 79 - room temperature foe one hour„ whereupon the solvent is distilled off in a water- jet vacuum at 50°. The residue obtained is treated with water and methylene chloride. The organic phase is dried over sodium sulphate and evaporated. The yellow resin obtained is crystallised from methylene chloride/ether. There is obtained N.N-diethyl--3.4-dihydroxy-5-nitrobeazamide in the foe* of yellow crystals of m.p. 145-146°.
Example 59 3.2 g (10.6 mmol) of 5-(chlorocarbonyl)-2-nitro-o--phenylenediacetate are dissolved in 50 sal of dimethyl-formamide, whereupon the solution is treated at 0-5° while stirring and within SO minutes with a solution of 3.02 ml of 2.2-diethylaminoethylamine in 30 ml of dimethyl-forraamide. The mixture is subsequently stirred at room temperature for 30 minutes. The solvent is distilled off in a water-jet vacuum at 60°. The residue is extracted twice with 20 ml of ethanol each time, dissolved in hot ethanol and treated with an excess of ethanolic hydrochloric acid, whereupon the mixture is evaporated. After recrystallization from ethanol/ethyl acetate there is obtained N-[2-(diethylamino)ethylJ-3.4-dihydroxy-5--nitrobenzamide hydrochloride in the forsa of yellow crystals of a.p. 139® (dec.). example so 25 a) 10.0 g (47.4 mmol) of 2.3-dimethoxy-5-nitrobenz-aldehyde are treated with 50 ml of glacial acetic acid and 50 ml of constant-bo i1ing hydrobromic acid and held at the reflux temperature for 7 hours. After treatment with ice 30 the separated precipitate is filtered off under suction, washed with water and taken up in ethyl acetate. The organic phase is dried over sodium sulphate aad evapor10 15 20 ated. The crude product obtained is filtered over silica gel with ethyl acetate. Mter crystallization from ethyl acetate/hexane there is obtained 2,3-dihydroxy-5-nitro-benzaldehyde in the form of brownish crystals of m.p. 22S-2289. b) 4.5 g of 2,3-d ihydroxy-5-nitrobenzaldehvde are suspended in 75 sal of water. After treatment with €.2 g of hydroxylaaine o-sulphonic acid the mixture is stirred at 65° for IS hours. Mter cooling the separated crystals are filtered off under suction and washed with water. The filtrate is extracted with ethyl acetate. The crystals and the dried organic phase are combined,, whereupon the mixture is evaporated and the residue is recrystallized fro® diisopropyl ether. There is obtained 2.3~dihydroxy-5--nitrobenzonitrile in the form of yellow crystals of m.p. 186-188°.
Example 61 a) 4.0 g (19.2 mmol) of 3.4»diaethoxy-5-nitro-benzo-nitrile are dissolved in 50 ®1 of diaethylformamide, whereupon the solution is treated with 1.66 g of ammonium chloride and 2.02 g of sodium aside aad stirred at 125° for 31 hours. Mter in each case 8 and 15 hours the same amounts of ammonium chloride and sodium aside are added thereto. Mter cooling the aixture is poured oa to ice. The separated precipitate is filtered off under suction,, washed with water and dried. There is obtained 2-aethoxy--6-nitro-4-(lH-tetrazol-5-yl)phenol ia the form of orange crystals of a.p. >240° (dec.). b) «.0 g (16.9 aaol) of 2-aethoxy-6-nitto-4-(lH-teti:azol--5~yl)phenol ace created with 40 al of constant-boiling hydrobromic acid, whereupon -the aixture is stirred at 140* for ® hours under a nitrogen atmostphere. After cooling the aixture is poured oa to ice. The separated precipitate is filtered oft under suction and recrystallized from ether. There is obtained 3-nitro-5-(lH-tetcasol-5-yl)-pyrocatechol in the form of orange crystals of m.p. >240® (dec.).
Example 62 A total o£ 7.2 g (40 itaraol) of 3.4-dihydroxy-5-nitro- benzonitrile are introduced portionwise iato 130 ml of conc, sulphuric acid while stirring within 10 minutes, whereupon the aixture is stirred at 50° for 4 hours. The reaction mixture is poured iato 800 ml of ice-water. The separated precipitate is filtered off under suction, «?ashsd with water and taken up in ethyl acetate. The organic phase is dried over sodium sulphate and evaporated. After recrystallization from acetone/ethyl acetate there is obtained 3.4-dihydroxy-5-nitrobenzamide in the form of orange crystals of m.p. 235-236°.
Example 63 a) A solution of 11.25 g (82.6 mmol) of 2-hydroxyaceto-phenone in 100 ml of absolute dimethyIformamide is added dropwise under an argon atmosphere within 15 minutes to a suspension of 3.6 g (82.5 unol) of a 55 percent sodium hydride dispersion ia 50 al of absolute dimethylformamide and the mixture is stirred at room temperature for one hour. Mter cooling to 0° a solution of 20.3 g (82.6 mmol) of 3.4-dimethoxy-5-nitrobens5oyl chloride in 100 ml of absolute dimethylformamide is added dropwise thereto within 20 minutes and the mixture is stirred at room temperature overnight. The reaction mixture is poured iato ice-water, whereupon cine mixture is extracted twice with 250 ml of ethyl acetate each time. The organic phase is extracted twice with 100 ml of sodium chloride solution - 82 - each time, dried over sodium sulphate and evaporated. Tha brown oil obtained is heated ia 100 ml of toluene. The separated precipitate is filtered off under suction and the filtrate is chromatographed ©a a 30-fold amount of silica gel with toluene/ethvl acetate («:1). Mter recrystallization fro® ethyl acetate/hexane there is obtained o-acetylphenyl 3.4-dimethoxy-5-nitrobenzoate ia the form of yellowish crystals of a.p. 108-109®. h) 10.0 g (29 amol) of o-acetylphenyl 3,4-dimethoxy~5--nitrobenzoate are dissolved in 50 ml of pyridine. After treatment with 8.12 g (144 mmol) of powdered and dried potassum hydroxide the mixture is stirred at 80® for 5 minutes. Mter cooling the mixture is poured oa to ice. The aqueous solution is made acid by treatment with 3N hydrochloric acid. The separated precipitate is filtered off under suction. Mter recrystallization from ethyl acetate/hexane there is obtained 1-(o-hydroxyphenyl)-3--(3, 4-dimethoxy-5-nitrophenyl)-l,3-propanedione ia the form of yellowish crystals of ra.p. 188-189°. c) A solution of 1.02 g {0.7 al) of boron tribromide in 20 ml of methylene chloride is added dropwise within about 20 minutes to a solution of 500 mg (1.45 mmol) of l-(o-hydroxyphenyl)-3-(3,4-dimethoxy-S-nitrophenyl)-1.3-- propanediols.® in 50 sal of methylene chloride while 25 stirring and under an argon atraosphere at -20®. whereupon the mixture is stirred at room temperature overnight.
After cooling to -20° the aixture is treated dropwise with 25 ml of ethanol and evaporated at 40* ia a water-jet vacuum. After recrystallization from ethanol there is 30 obtained l-(3,4-dihydroxy-5-nitrophenyl)-3- -(o-hydroxyphenyl)-1,3-propanedione ia the for® of yellow crystals of a.p. 251-252°. 10 15 - 83 - Example 64, a) A solution of 2.0 g (5.79 Piiaol) of o-acetylphenyl 3.4-dimethoxy-5-nitrobenzoate ia 12.5 al of glacial acetic acid is treated with 0.94, g of sodiua acetat© aad held at 5 the reflux temperature foe 4 hours. Mter cooling the mixture is poured iato ice-water. The separated crystals ace filtered off under suction. Mter recrystallization from ethyl acetate/hexane there is obtained 2-(3,4--dimethoxy-5-nittophenyl)-4H-l-benzopyran-4-one in the 10 form of colourless crystals of M.p. 216-217®. b) Jk solution of 10 al of boron tribromide in 50 ml of methylene chloride are added dropwise within 30 minutes at -10° to a solution of 1.0 g (2.9 mmol) of 2-(3.4--dimethoxy-5-nitrophenyl)-4H-l-benzopyran-4-one in 100 ml 15 of methylene chloride under an argon atmosphere, whereupon the mixtu.ce is stirred at room temperature overnight.
After cooling to -20° 20 ml of ethanol are added dropwise thereto. The mixture is then evaporated in a water-jet vacuum. The yellow residue obtained is extracted with 20 water/ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. After recrystallization from ethanol/ethyl acetate there is obtained 2-(3.4-dihydroxy-5-nitrophenyl)-4H-l-benzopyran--4-one in the form of yellow crystals of n.p. >240® (dec.). or Example 65 Z 5 a) 92 ml of a-butyl lithium solution (1.6M in hexane) are added dropwise at -70" within 20 minutes to 33.0 g of 4-bromobenzotrifluoride (dissolved in 150 ml of tetrahydrofuran) . After stirring at -70° for 45 minutes 36 g of 30 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 100 al of tetrahydrofuran) are added dropwise thereto at between. -70° and -60®. The reaction mixture is stirred at -70a for 2 hours and at 0° for 1 hour, poured iato a mixture of ice and 100 sal of 2N sulphuric acid and extracted twice with 500 ail of ether. The combined ether phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. There is obtained 4-(benzyloxy)--3-methoxy-4 ' - (tr ifluoromethyl) benzhydrol which can be used directly in the subsequent reaction step. b) 52.6 g of 4-{benzyloxy)-3-methoxy-4 ' -(trif luoro-methyl)benzhydrol (dissolved in 500 al of methylene chloride) are treated within 10 minutes at 20® with 30.6 g of pyridiniua chlorochrornate and stirred at 20® for 2 hours. The precipitate forced is subsequently 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 there is obtained 4-(benzyloxy)-3-methoxy-4'-(trifluoro»ethyl)benzophenone of melting point 101®. c) 70 ml of 33 percent hydrobromic acid ia aeetic acid ace added within 15 ainutes at 10® to 20 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoroaethyl)benzophenone (dissolved in 150 ml of methylene chloride), after stirring at 20® for 1.5 hours the reaction mixture is poured iato 600 ml of ice-water: the methylene chloride phase is separated aad the aqueous phase is extracted a further twice with 100 ml of methylene chloride. The combined methylene chloride phases are washed with 600 ml of water, dried over sodium sulphate and evaporated. The residue is chromatogcaphed on 150 g of silica gel with ©ethylene chloride. Mter recrystallization from methylene chlor ide/hexane there is obtained 4-hydrojcy-3-saethoxy-4' --(trifluoromethyl)benzophenone of melting point 97®. - 85 - d) 3.2 ml of 65 percent nitric acid ace added dropwise within 10 minutes at 20° to 12.8 g o£ 4-hydroxy-3-methoxy--4'-(tri£luoroaethyl)benzophenone (dissolved ia ISO ml of acetic acid). Mter stirring for 1.5 hours the reaction mixture is poured iato 600 al of ice-water, aad the precipitate formed Is filtered off. washed with water and dissolved in methylene chloride. The methylene chloride solution is dried over sodium sulphate aad evaporated, and the residue is recrystallized from methylene chloride/ hexane. Thece is obtained 4-hydroxy-3-aethoxy-5-nitro-4' --(trifluoro.sa®ctoFl)b@usop,heao.oie of Belting point 172®. e) 2.0 g ot 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoro-methy1)benzophenone (dissolved in 20 ml of 33 percent hydrobromic acid in glacial acetic acid) are stirred at 90° for 18 hours. Thereupon. 20 ml of 48 percent aqueous hydrobromic acid are added thereto, whereupon the mixture is stirred at 110® for a further 18 hours. The reaction mixture is subsequently evaporated under reduced pressure and the residue is recrystallized from water. There is obtained 3.4-dihydroxy-5-ni"ro-4'-{trifluoEomethyl)benzophenone of melting point 116-118°.
Example 66 a) 18.7 g of 4-hydroxy-3-aethoxy-5-nitro-4'-(trifluoro-methy1)benzophenone (dissolved in 250 al of tetrahydrofuran) ace treated at room temperature with 27.5 al oi 2N potassium hydroxide solution, whereupon the mixture is evaporated. The residue is treated with 200 al of toluene, whereupon the aixture is again evaporated. Thereupon, the aixture is heated with 400 al of toluene for 4 hours with the separation of water and under reflux. 100 al of toluene are distilled off and 10 sal of diaethylforaaaide and 20 al of diaethyl sulphate (freshly distilled) are added, whereupon the aixture is heated under reflux for 5 hours. 300 ml of IN sodium hydroxide solution are subsequently added at 20°. The reaction mixture is stirred for 30 ainutes and treated with 200 ml of ether. The organic phase is separated; the aqueous phase is extracted a further twice with 100 ml of ether: the combined ether phases are dried over sodium sulphate and evaporated,, and the residue is chromatographed on 70 g of silica gel with methylene chloride. Mter recrystallization from methylene chlor ide/hexane there is obtained 3.4-dimethoxy-5-nitro--4 ' -(trifluoromethyl)benzophenone of melting point 113°. b) 49.5 g of tin dichloside dihydrate ace added to 16.0 g of 3,4-dimethoxy-5-nitro-4•-(trifluoromethyl)benzophenone (dissolved in 300 ml of ethanol), whereupon the mixture is stirred at 75° for 30 minutes. Thereupon, the reaction mixture is poured into 800 ml of ice-watec. It is neutralized with 28 percent sodium hydroxide solution and extracted three times with 600 ml of methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulphate and evaporated. After recrystallization fro® methylene chloride/hexane there is obtained 5-amino-3.4-dimethoxy-4'-Cteifluoromethyl)benzophenone of melting point 95-95°. c) 3.25 g of 5-amino-3.4-dimethoxy-4'-(trifluoEomethyl)-benzophenone (dissolved in 50 sal of acetone) are evaporated under reduced pressure after the addition of 15 al of 2N sulphuric acid. The thus-obtained residue is suspended in 20 al of acetic acid* diluted with 100 ml of water and treated! at 5® with a solution of 700 mg of sodium nitrite ia 10 ml o£ water. It is stirred at 5® for one hour. Thereupon, the diazonium salt solution is filtered, added at 5® to a solution of 2.0 g of sodiua cyanide and 1.0 g of copper(X) cyanide in 20 ml of water and stirred at 5® for 1 hour. Thereupon. 200 ml of methylene chloride are added thereto. Insoluble constituents are filtered off.
The phases are separated; the aqueous phase is extracted a further twice with 100 ml of Methylene chloride. The combined methylene chloride phases ace Mashed with water* dried over sodium sulphate and evaporated. The residue is chEomatographed oa 30 g of silica gel with methylene chloride. Mter recrystallization from methylene chloride/hexane there is obtained 5-cyano-3,4-dimethoxy--4'-(trifluocomethyl)benzophenone of melting point 130®. d) 1.5 g of 5-cyano-3,, 4-diaethoxy-.fi'-Ctrifluoromethyl)-benzophenone (dissolved ia 75 ©1 of methylene chloride) are treated at 5® with 2.18 ml of boron tribromide, whereupon the mixture is stirred at rooia temperature for 18 hours. The reaction mixture is subsequently diluted with 50 ml of methylene chloride. The aixture is heated under reflux for a further 4. hours, treated at -70° with 15 ml of methanol, stirred at room temperature for 2 hours, evaporated,, the residue is dried in vacuo and partitioned between ethyl acetate and ice-water. The aqueous phase is extracted a further twice with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulphate and evaporated. The thus-obtained material is stirred at 130® for 6 hours 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 ©ethylene chloride phase is dried over sodium sulphate aad evaporated, aad the residue is chromatographed oa 30 g of silica gel with methylene chloride. The thus-obtained diacetate is dissolved in 10 al of methanol. The solution is treated with 4.2 al of IN sodium hydroxide solution, stirred at 0* for 1 hour, neutralized with acetic acid, evaporated and partitioned between ethyl acetate and saturated sodium chloride solution. The ethyl acetate phases are dried over sodium sulphate and evaporated, and the residue is recrystallized from methylene chloride. There is obtained S-cyano-3.4- - 88 - -dihydroxy-4'-(trifluoromethyl)benzophenone of melting point 204-206°.
In an analogous saanner: al) From 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone there is obtained 3,4-diaethoxy-2 • -fluoro-5-aitrobenzo-phenone of m.p. 86-88° (from ether/low-boiling petroleum ether). bl) from 3.4-dimethoxy-2'-fluoro-5-nitrobenzophenone there is obtained 5-amino-3.4-dimethoxv-2'-fluorobenzophenone of m.p. 93-95° (from ether/low-boiling petroleum ether), cl) from 5-amino-3„4-dimethoxy-2'-fluorobenzophenone there is obtained 5-benzoyl-2.3-dimethoxy-21-£luorobenzonitrile of m.p. 132-134° (from methylene chloride/low-boiling petroleum ether) and dl) from 5-benzoyl-2.3-diaethoxy-2'-fluorobenzonitrile there is obtained 5-benzoyl-2. 3-dihydroasy-20-f luorobenzo-nitrile of m.p. 228-230° (frost ether/low-boiling petroleum ether).
In an analogous manner: b2) from 3.4-di:aethoxy-5-nitr©benzopheaone there is obtained S-amino-3,4-dimethoxybenzophenone as aa amorphous solid,, c2) from 5-a»im>-3.4-dinethoxybenzopheaone there is obtained 5-benzoyl-2,3-diaethoxybenzonitrile of a.p. 98-100® (fro® ether/hexaae) and d2) from 5-benzoyl-2.3~diiaiethoxybenzonitrile there is .obtained 5-benzoyl-2.3-dlhydroxybenzonitrile of m.p. 212-214° (from ethyl acetate/ether). - 89 - Example 57 a) A solution of 16.0 g (65.14 mmol) of 3,4-diffl,ethoxy-5--nitrobenzoyl chloride la 80 ml of pyridine is added dropwise to a solution of 2.68 g (32.64 mmol) of 1-methyl- 5 imidazole and 6.6 g (65.14 aaol) of triethylamine in 80 ail of pyridine,, whereupon the mixture is stirred at 60° for 3 hours. Mter treatment with 1.70 sal of 3N sodium hydroxide solution the mixture is stirred for a further 1 hour and subsequently poured into ice-water. The separated grey 1Q crystals are filtered off under suction aad taken up la ethyl acetate, whereupon the organic phase is dried over magnesium sulphate and the solvent is distilled off. Mter recrystallization from ethyl acetate/hexane there is obtained 3,4-dimethoxy-5-nitrophenyl (l-methylimidazol-2-15 -yl) ketone in the form of colourless crystals of m.p. 114-1450. b) 5.0 g (17.17 mmol) of 3,4-dimethoxy-5-nitrophenyl (X-methylimidazol-2-yl) ketone are treated with 50 ml of hydrobromic acid (48%), whereupon the mixture is stirred 20 und,r retlux "operature for 2 hours. Mter cooling the separated precipitate is filtered off under suction. washed with ice-water and recrystallized from ethanol. There is obtained 3,4-dihydroxy-5-nitrophenyl (1-methyl-imidazol-2-yl) ketone hydrobromide in the form of yellow 25 crystals of decomposition point >240®. example 68 In analogy to Example 67, from 3,4-dimethoxy-5-nitro-benzoyl chloride and x-benzylimidazole there is obtained 1-benzylimidazoI-2-yl (3.4-dimethoxy-5-nitrophenyl) ketone 30 in the form of colourless crystals of ©. p. 134-135° (from methylene chlor ide/hexane) and therefrom with hydrogen bromide there is obtained l-benzylimidazol-2-yi - 90 - (3.4-dihydroxy-5-nitrophenyl) ketone hydnobcomide as yellow crystals of m.p. 218-219° (dec.).
Example 69 a) A solution of 10.0 g (S3.13 mmol) of l-[ (beaaylojcy)-methyl]imidazole in 50 al of acetonitrile is added dropwise within 10 ainutes while cooling with ice to a solution of 13.0 g (53.13 mmol) of 3,4-dimethoxy-5-nitro-benzoyl chloride and 5.4 g (53.13 samol) of triethylamine in 80 ml of acetonitrile so that the temperature does aot exceed 25®. The mixture is subsequently stirred for a further 3 hours, whereupon the solvent is distilled off. After treatment with water the aixture is extracted vith ethyl acetate. After two-fold washing with water the organic phase is dried over sodium sulphate and evaporated . The resulting oil is chromatographed on SOO g of silica gel with toluene/ethyl acetate (95:5). There is obtained 1- [ (benzyloxy)methyl J isaidazol-2-yl (3.4-diaethoxy-5-nitrophenyl) ketone as a yellowish oil. b) In analogy to Example 67b) there is obtained after treatment with hydrobromic acid 3,4-dihydroxy-5-nitro-phenyl (iaidazol-2-yl) ketone hydrobromide as yellow crystals of m.p. 247-248°.
Example 70 a) A solution of 25.0 g ({120-16 mmol) of 3-broaoquinoline are dissolved in 200 al of dry ether and cooled to -SO®. At this temperature there are added dropwise within IS ainutes 75.1 ml (120.16 mmol) of a 1.6 molar solution of n-butyllithiua. whereupon the aixture is stirred for 10 ainutes. A solution of 26.5 g (109.2 aaol) of vanillin benzyl ether in 250 al of dry ether is added dropwise thereto at -60°. the mixture ie subsequently stirred at - 91 - room temperature for 3 hours, poured iato about I.S 1 of ice-water and extracted three times with 600 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulphate aad evaporated. The resulting 5 oil is chromatographed on 1 kg of silica gel with methylene chloride/ethyl acetat® (Xil). The crystalline crude product obtained is recrystallized fro© ethyl acetate. There is obtained a-^-(benzyloxyJ-S-methoxy-phenylj-S-quinolinemethanol in the form of colourless 10 crystals of m.p. 12«-125°. b) A solution of a.2 g (IS.7 saraol) of c-C4-(benzyloxy)--3-methoxyphenyl]-3-quinoiinemethanol in 200 ml of methylene chloride is treated with 62 g of manganese dioxide and stirred at the reflux temperature for 2 hours. Mter cooling the precipitate is filtered off under suction and washed with methylene chloride. The filtrate is evaporated and the oil obtained is dissolved ia hot ether, whereupon the solution is treated with a small amount of pentane. The separated crystals are filtered off 2Q under suction. There is obtained 4-(benzyloxy)-3-methoxy- phenyl (3-quinolinyl) ketone in the form of colourless crystals of m.p. 110-111®. c) 11.0 g (29.78 mmol) of 4-(benzyloxy)-3-methoxyphenyl (3-quinolinyl) ketone are treated with SO al of trifluoroacetic acid, whereupon the mixture is stirred at room temperature for 2 hours. After distillation of the trifluoroacetic acid the residue is treated twice with 50 ml of ethanol each time and the solvent is distilled off each time. The oil obtained crystallizes tupon 30 treatment with ethanol. Mtsc recrystallisation from ethanol there is obtained 4-hydroxy-3-methoxyphenyl (3-quinolinyl) ketone in the form of yellowish crystals of m.p. 196-197°. d) A solution of 1.91 sal of 65 percent nitric acid ia 20 ml of glacial acetic acid is added dropwise to a solution of 5.5 g (19.69 aaol) of 4-hydroxy-3-raethoxy-phenyl (3-quinolinyl) ketone in 300 al of glacial acetic acid at 150° aad the aixture is thea stirred at this temperature for a further 2 Eiowrs. The isixtuiee is thea poured iato ice-water and extracted three tiiaes with 300 ml of ethyl acetate each time. The organic phase is washed five times with 100 al of water each time, dried over sodiua sulphate and evaporated. After treatment of the residue with ethyl acetate there is obtained 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone in the form of yellow crystals of m.p. 220-221® (dec.). e) 820 mg (2.53 mmol) of 4-hydroxy-3-methoxy-5-nitro-phenyl (3-quinolinyl) ketone ace treated with 50 ®1 of 48 percent hydrobromic acid and held at the reflux temperature for 3 hours. After distillation of the hydrobromic acid at 50* the residue is treated with 70 al of hot water and the insoluble constituent is filtered off under suction. There is obtained 3„4-dihydroxy-5~nitrophenyl (3-quinolinyl) ketone hydrobromide in the form of yellow crystals of m.p. 270° (dec.).
Example 71 In analogy to Example 70 there is obtained benzyloxy)-3-oettooxypheayl3-4-quinolinemethanol as colourless crystals of a.p. 117-118° {ethyl acetate), therefrom with manganese dioxide there is obtained 4-(benzyloxy)-3-aethoxyphenyi (4-isoquinolinyl) ketone as colourless crystals of n.p. 126.5-127.5®, therefrom with trifluoroacetic acid there is obtained 4-hydroxy-3--methoxyphenyl (4-isoquinolinyl) ketone as yellow crystals of m.p. 197.5-198.5* aad therefrom by aitratioa with nitric acid in glacial acetic acid and subsequent - 93 - treatment with hydrobromic acid there is obtaiaed 3.4-dihydroxy-5-nitrophenyl (4-isoouiaolinyl) ketone hydrobromide as yellow crystals of a.p. 25S® (dec.).
Example 72 la analogy to Example 70 there is obtained a-[4-(benzyloxy)-3-methoxyphenylJ-2-oaphthalenemethano1 as colourless crystals (ethyl acetate/hexane) of m.p. 113-114®. therefrom with manganese dioxide there is obtaiaed 4-(benzyloxy)-3-methoxyphenyl (2-naphthyl) ketone as colourless crystals (ethyl acetate/hexane) of a.p. 104-105®. therefrom by treatment with trifluoroacetic acid aad nitration with nitric acid in glacial acetic acid there is obtaiaed 4-hydroxy-3-methoxy-5-nitrophenyl (2-naphthyl) ketone as yellow crystals o£ m.p. 137-108° and therefrom by treatment with hydrobromic acid there is obtained 3,4-dihydroxy-5-nitrophenyl (2-naphthyl) ketone as yellow crystals of m.p. 184-185*.
Example 73 a) A solution of 20.0 g (100.5 ©mol) of 3-phenylpropyl bromide in 300 sal of ether is treated at -60® while stirring within 15 minutes with a solution of 71.8 ml (100.5 mmol) of tert.butyllithium (1.4 molar) in pentane. After 10 minutes there is added dropwise at this temperature within 15 ainutes a solution of 22.14 g (91.36 mmol) of vanillic benzyl ether ia 200 ml of ether,, whereupon the mixture is stirred tfoc a fuirthesc 2 hours. The mixture is poured into 1 1 of ice-water and extracted three times with 500 al of ethyl acetate each time. The organic phase is washed twice with 200 ml of water each time, dried over sodium sulphate and evaporated. The oil obtained is chromatographed on 1 kg of silica gel with methylene chloride. The crystals obtained are recrystallized from - 94 - ether/pentane. There is obtained 4-(benzyloxy)-3-methoxy--a-(3-phenylpropyl)benzyl alcohol ia the for® of colourless crystals of m.p. 71-73°. b) A solution of 9.0 g (24.33 aaol) of 4-(benzyloxy)-3--methoxy-c-(3-phenylpropyl)benzyl alcokiol ia 250 ml of methylene chloride is treated with 90 g of aanganese dioxide and held at the reflux temperature for 2 hours. Mter cooling the precipitate is filtered off under suction and washed with methylene chloride. The filtrate is evaporated aad the residue is recrystallized frost ethyl acetate/ether. There is obtained 4'-(benzyloxy)-31 --methoxy-4-phenylbutvrophenone in the forn of colourless crystals of in.p. 81-32®. c) A solution of 7.0 g (19.42 mmol) of 4'-{benzyloxy)-3'--aethoxy-4-phenylbutyrophenone in 40 ml of 33 percent hydrobromic acid in glacial acetic acid Is stirred at room temperature for 5 hours and subsequently poured into 500 ml of ice-water. The solution is adjusted to pH 6.0 by the addition of conc. ammonia and extracted three times with 250 ail of ethyl acetate each time. The organic phase is washed three times with 50 ml of water each time, dried over sodium sulphate and evaporated. The oil obtained is dissolved in 20 sal of etfo.ee* whereupon the solution is treated with hexane until it becomes turbid and is left to crystallize out. There is obtained colourless 4'-hydroxy--3•-aethoxy-4-phenylbutyrophenone of m.p. 91-92°. d) A solution of 0.79 ml of 65 percent nitric acid in 25 ml of glacial acetic acid is added dropwise to a solution of 2.2 g (8.14 mmol) of 4'-hydroxy-3"-raethoxy-4--phenylbutyrophenone in 25 ml of glacial acetic acid and the aixture is stirred at room temperature for a further 2 hours. The mixture is poured into 150 al of ice-water and, after treatment with 20 al of 3N hydrochloric acid. 15 20 25 - 95 - extracted three times with 75 al of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulphate and evaporated. The crude product obtained is taken up in ethyl acetate and filtered over 7b g ot 5 silica gel. Mter recrystallization fro® acetonitrile there is obtained 4'-hydroxy-3•-methoxy-5•-aitro-4-phenyl-butyrophenone ia the for* of fellow crystals of a.p. 12O-1210. e) 1.0 g (3.2 mmol) of 4'-hydroxy-3'-methoxy-5'-nitro-4-1q -phenylbutyrophenone is held at 200° for 1 hour with 8 g of pyridine hydrochloride. The reaction aixture is poured while still warm into ice-water and extracted with ethyl acetate. The organic phase is washed with IN hydrochloric acid and subsequently with water, dried over sodium •]5 sulphate and evaporated. The dark residue obtained is chroaatographed on a 30-fold amount of silica gel with ethyl acetate. From aethylene chlor ide/hexane there is obtained 3'.4'-dihydroxy-5'-nitro-4-phenylbutyrophenone in the for® of yellow crystals of a.p. 118-119°. 2q Example 74 a) a solution of 14.68 g (225.4 aaol) of potassium cyanide in 20 al of water is added to a solution of 10,0 g (47.4 aaol) of 3,4-diaethoxy-5-nitrobenzaldehyde in 100 al of dioxan. 18.31 al (190.76 aaol) of 37 percent hydro-chloric acid are now added dropwise thereto within 30 ainutes while stirring vigourouslv. Mter the addition of 120 al of ether the excess hydrogen cyanide gas is driven off by passiag argoa through the aixture. The reaction mixture is filtered over s siliceous earth filter aid, and 30 the organic phase is washed with water dried over sodiua sulphate and evaporated. The «-hydroxy-3*4-diaethoxy-phenylacetonitrile (yellowish oil) which is formed is dissolved ia 200 al of ether, whereupon the solution is treated with 20 al of ethanol, cooled to 0® and hydrochloric acid gas is passed in foe 30 ainutes. Mter 3 hours the separated colourless precipitate is filtered off under suction aad recrystallized from ethanol/ether. Titer® is obtained ethyl (3.4-diaethoxy-5-nitrophenyl)hydroxy-acetiaidate hydrochloride. b) 19.7 g (61.46 aaol) of ethyl (3.4~diaethoxy-5-nitro-phenylJhydroxyacetiaidate are dissolved ia 500 al of ethanol, 6.73 g (61.46 msao!) of o-phenylenediamine are added, the mixture is stirred at cooa temperature for 2 hours and subsequently held at the reflux temperature overnight. After distillation of the solvent the residue is treated with 50 al of water, made alkaline with sodium carbonate solution and extracted twice with 250 al of methylene chloride each tine. The organic phase is washed with water, dried over sodium sulphate and evaporated. The orange residue obtaiaed is chroaatographed on ^00 g of silica gel with methylene chloride/ethyl acetate (Isl). From ether/hexane there is obtaiaed c-(3,4-dimethoxy-5--nitrophenyl)-2-benziaida20leaethanol in the fora of yellowish crystals of m.p, SO'9 (dec.). c) 13 .2 g (40.1 aaol) of a- (3,4-diaethoxy-5-nitro-phenyl)-2-benzimidazolemethanol are dissolved in 200 ml of methylene chloride and. after treatment with 130 g of manganese dioxide, the mixture is stirred at the reflux temperature for 2 hours. After filtration the solvent is distilled off. There is obtaiaed 2-benziaidazolyl (3,4-dimethoxy-5-iaitrophenyl) ketone ia the fora of yellowish crystals of m.p. 212-213°. d) 1.0 g (3.05 mmol) of 2-benzimidazolyl (3.4-dimethoxy--5-nitcophenyl) ketone and 8.0 g of pyridine hydrochloride are held at 200® for 60 minutes. The dark solution is poured while still warm into ice-water aad extracted three - 97 - times with 100 nl of ethyl acetate each tiae. The organic phase is washed with water, dried over sodiua sulphate and evaporated. Mter recrystallization from ethyl acetate/ hexane there is obtaiaed 2-benzimidazolyl (3.4-dihydroxy--5-nitrophenyl) ketone ia the fora of yellow crystals of ©.p. 245-250°.
Example 75 a) 30.0 g (132 arool) of 3,4-dimethoxy-5-nitr©benzoic acid are dissolved in 250 nl of tetrahydrofuran and. after the addition of 21.85 g (135 mmol) of 1.l'-carbonyl-diimidazol®, the mixture is stirred at the reflux temperature for 2 hours. The aixture is poured into 300 al of ice-water aad the precipitated crystals are filtered off under suction after stirring for 30 ainutes. The crystals are taken up in methylene chloride, whereupon the organic phase is washed with water, dried over sodiua sulphate and evaporated. Mter crystallization from aethylene chlor ide/hexane there is obtained 1-(3.4-dinethoxy-5--nitrobenzoyl)imidazole in the fora of colourless crystals of m.p. 136-137°. b) 10.0 g (36.1 aaol) of l-(3.4-diaethoxy-5-nitro-benzoyl)iaidazole in 50 al of diaethylforaanide are treated with 6.95 g (93.8 aaol) of acetaaidoxiae, whereupon the aixture is stirred at 70* for 1 hour. After cooling the aixture is poured into 500 al of ice-water and stirred for 30 ainutes. The separated crystals are filtered off under suction aad washed with water. After crystallization from ethyl acetate there is obtaiaed M' - [ (3.4-diaethoxy-5-ai trobenzoyl)oxyjjacetanidine ia the for® of colourless crystals of m.p. 165-166'°. c) 2.0 § (7.2 aaol) of !"-[(3.4-diroethoxy-5~nitro-benzoyl)oxy]acetaaidine are held at reflux temperature tor - 98 - 1 hour ia 20 ml of glacial acetic acid. Mter distillation of the acetic acid the crystalline residue is recrystallized from ether/hexane. There is obtained 5-(3.4--dimethoxy-5-nitrophenyl)-3-methy1-1,2,4-oxadiazole in the form of colourless crystals of a.p. 111®. d) 2.5 g (9.43 mmol) of 5-(3,4-dimethoxy-5-nitrophenyl)--3-methy1-1.2.4-oxadiazole are dissolved ia 70 ml of methylene chloride. Mter cooling to -60° there is added dropwise thereto within 20 minutes while stirring a solution of 23.62 g (94.3 tamol) of boron tribromide ia BO ml of methylene chloride, whereupon the mixture is held at the reflux temperature for 48 hours. Mter cooling to -60° the mixture is treated with SO ml of ethanol and subsequently stirred at room temperature for 30 minutes. The yellow solution is evaporated to dryness, whereupon the residue is treated three times with 100 ml of toluene/ethanol (1*1) each time aad. the solvent is distilled off each time. Mter crystallization from ethanol there is obtained 5-(3-methyl-l,2.4-oxadiazol-5--yl)-3-nitropyrocatechol in the form of yellow crystals of m.p. 201-202°.
Example 76 a) l«3.8 ml of n-butyllithium solution (1.53M in hexane) are addled dropwise at -70® within 30 minutes to 35.0 g of l-bromo-2-fluorobenzene (dissolved in 600 ml of tetrahydrofuran). After stirring at -70* for 60 minutes 48.5 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved ia 450 ml of tetrahydrofuran) are added dropwise thereto during 30 minutes. The reaction aixture is stirred at -70* for 2 hours and at 0"* for 30 minutes, poured iato a aixture of ice and 150 ml of 2N sulphuric acid aad extracted three times with SOO ml of ether. Tile combined ether phases are washed with saturated sodium chloride solution, dried over sodiua sulphate and evaporated. There is obtained 4-(benzyloxy)-2'-£luoro-3'-methoxybenzhydEol as a yellowish oil which can be used directly in the subsequent reaction step.
In aa analogous manner: al) Frosa 3-methoxy-4-benzyloxybenzaldehyde and l-bromo-3--fluocobenzene there is obtained 4-(benzyloxy)-3'--fluoco-3-methoxybenzhydEol as an oil: a2) fEora 3-methoxy-4-benzyloxybenzaldehyde and l-foromo-4--fluorobenzene these is obtained 4-(benzyloxy)-4'-fluoro--3-methoxybenzhydEol as an oil: a3) fcoa 3-nethoxy-4-benzyloxybenzaldehyde and 1-bEomo--2.6-difluorobenzene there is obtained. 4-(benzyloxv)--21,,S'-difIuoeo-3-wethoxybenzhydrol as an oil: a4) from 3-methoxy-4-benzyloxybenzaldehyde and l-brosao-2--chloEobenzene there is obtained 4-(benzyloxy)-2'-chloro--3-methoxybenzhydrol as an oil: aS) from 3-methoxy-4-benzyloxybenzaldehyde and l-bromo-3--chlorobenzene there is obtained 4-(benzyloxv)-3'-chloro--3-methoxybenzhvdrol as an oil: a6) from 3-Bethoxy-4-benzyloxybenzaldehyde and l-broao-4--chlorobenzene there is obtained 4-(benzyloxy)->4'-chloro--3~methoxybenzhyd£ol as an oil: a?) from 4-benzyloxy~3-methoxybenzaldehyde and 2-bromotoluene there is obtained 4-(beazyloxy)-3-methoxy--21 -tnethylbenzhydrol as an oil: - 100 - a8) from 3-methoxy-4-benzyloxybenzaldehyde and 4-bromotoluene there is obtained 4-(benzyloxy)-3-methoxy--4 1-methylbenzhydrol as an oil: a9) fcom 3-methoxy-4-benzyloxybenzaldehyde aad 1-bromobenzonitrile there is obtained 4-(benzyloxy)-2'--cyano-3-methoxybenzhydcol as aa oil and alO) from 3-methoxy-4-benzyioxybenzaldehyde and 1-bromo-2-trifluoromethylbenzene there is obtaiaed 4- (benzyloxy)-3-snethoxy-2 1 - (trif luoromethyl) benzhydrol as aa oil. b) 69.8 g of 4-(benzyloxy)-21-fluoro-3-nethoxybenzhydrol (dissolved in 600 ml of methylene chloride) are treated Hithin 30 ainutes at 20° with 45.3 g of pyridinium chlorochromate and stirred at 20° for 3 hours. The precipitate formed is subsequently filtered off aad washed with methylene chloride. The filtrate is evaporated and the residue is filtered oa 100 g of silica gel with ether. After recrystallization from ether there is obtaiaed 4-(benzyloxy)-2'-£luoro-3-aethoxybenzophenone of a.p. 118-120°.
In an analogous manner: bl) From 4-(benzyloxy)-3 g~fluoEO-3-aethoxybenzhydrol thece is obtained 4-(benzyloxy)-3'-fluoco-3-aethoxybenzophenone as an amorphous solid: b2) from 4-(benzyloxy)-4•~£luoco-3-aethoxybenzhydrol there is obtained 4-{benzyloxy)-4"-£luoco-3-aethoxybenzophenoae of m.p. 99-101° {from ether/hexane): b3) from 4-(benzvloxy)-2',6'~di£luoEO-3-methoxybenzhydEo! there is obtained 4-(benzyloxy)~21.S'-difluoro-3-methoxy- - 101 - benzophenone of a.p. 139-141® (from methylene chloride/ether); b4) from 4-(benzyloxy)-2 ' -chloro-3-methoxybenzhvdrol thece is obtaiaed 4-(benzyloxy)-20 -chloro-3-methoxybenzophenone 5 of m.p. 120-130° (fro® ether); b5) from 4-(benzyloxy)-3 '-chloro-3-methoxybenzhydrol thece is obtained 4-(benzyloxy)-3 '-chloro-3-methoxybenzophenone as an amorphous solid; b6) from 4-(benzyloxy)-4'-chloro-3-methoxybenzhydrol there 1q. is obtained 4-(benzyloxy)-48-chloro-3-methoxybenzophenone of m.p. 106-108° (frow methylene chloride/hexane): b7) fro® 4-(benzyloxy)-3-methoxy-2'-methylbenzhydrol there is obtained 4-(benzyloxy)-3-saethoxy-21-aethylbenzophenone of m.p. 86-88° (from isopropyl ether): 15 b8) from 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol thece is obtained 4-(benzyloxy)-3-methoxy-4'-aethylbenzophenone of m.p. 79-81° (from ether/hexane): b9) from 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol there is obtaiaed 4-(benzyloxy)-21-cyano-3-methoxybenzophenone 20 as an amorphous solid and t>10) from 4-(benzyloxy)-3-methoxy-2"-(trifluoromethyl )benzhydrol there is obtained 4-(benzyloxy)-3--methoxy-21 - (trif luoromethyl) benzophenone of m.p. 103-105® (from ether). 25 e) 170 ml of 33 percent hydrobromic acid in glacial acetic acid are added at 20-25° within 20 minutes to 42.4 g of (benzyloxy)-2'-fluoro-3-methoxybenzophenone (dissolved in 450 nl of methylene chloride). Mter - 102 - stirring at 20° tor 1.5 hours the reaction aixture is poured into 750 nl of ice-^ater; the methylene chloride phase is separated and the aqueous phase is extracted a further twice with 200 ml of methylene chloride. The combined Methylene chloride phases are washed with 1200 Ml of water. dried over sodium sulphate aad evaporated. In order to remove the resulting benzyl bromide,, the oily residue is treated with hexane aad decanted off. There is obtaiaed 2'-£luoro-4-hydroxy-3-®ethoxybenzophenone as a yellowish oil which can be used directly ia the subsequent reaction step.
In an analogous manner: cl) Frosa 4- (benzyloxy)-3 ' -f luoro-3-methoxybenzophenone there is obtained 3 1 -£luoro-4-hydroxy-3-methoxybenzo-phenone of m.p. 133-135® (from methylene chloride/low--boiling petroleum ether); c2) from 4-(benzyloxy)-4'-fluoro-3-raethoxybenzophenone there is obtained 4'-£luoro-4-hydroxy-3-methoxybenzo-phenone of m.p. 139-141® (from ether): c3) from 4-(benzyloxy)-2'*6'-difluoro-3-aethoxybenzophenone there is obtained 2'„6'-difluoro-4-hydroxy-3--jaethoxvbenzophenone of a.p. 130-132® (from methylene chloride/low-boiliag petroleum ether): c4) from 4-Cbenzyloxy)-21-chloro-3-methoxybenzophenone there is obtained 2'-chlojr©-4-hydroxy~3-me£hoxybenzo-phenone as an amorphous solid: c5) frosa «-(benzyloxy)-3'-chloro-3-iaethoxybenzophenone there is obtained 3•-chloro-4-hydroxy-3-methoxybenzo-phenone of a.p. 136-138® (from methylene chloride); c6) from 4-(benzyloxy)-4 '-chXo£o-3-meth©xyben2:o!Phanone thece is obtained 4'-chloro-4-hydroxy-3~methoxybenzo-phenone of m.p. 114-116° (fro* methylene chloride/low- -boiling petroleum ether): c7) from 4-(benzyloxy)-3-methoxy-2'-methylbenzophenone there is obtained 4-hydroxy-3-methoxy-2'-methylbenzo-phenone of m.p. 103-105° (from isopropyl ether): c8) fcom 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone there is obtained 4-hydroxy-3-methoxy-4'-methylbenzophenone of m.p. 103-105° (from ether/low-boiling petroleum ether): c9) from 4-(benzyloxy)-21-cyano-3-methoxybenzophenone there is obtained 2'-cyano-4-hydroxy-3-methoxybenzophenone of m.p. 124-126° (from ether/n-hexane) aad clO) from 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl) benzophenone there is obtained 4-hydroxy-3-methoxy--2(trifluoromethyl)benzophenone of m.p. 115-117° (from ether). d) 7.8 ml of 65 percent nitric acid are added dropwise at 20° within 20 sai mites to 29.4 g of 2'-f luoro-4-hydroxv-3--nethoxybenzophenone (dissolved in 450 ml of acetic acid). Mter stirring for 1.5 hours the reaction mixture is poured into 2 1 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 sulphate and evaporated. The residue is recrystallized from methanol. There is obtained 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone of m.p. 127-129°.
In an analogous manner: - 104 - dl) From 31-fIuoeo-4-hydroxy-3-methoxybenzophenone there is obtained 3'-£luoro-4-hydroxy-3-methoxy-5-nitrobenzo- phenone of ».p. 168-170° (from methanol); d2) from 4• -fluoro-4-hydrojcy-3-oethoxybenzophenone there 5 is obtaiaed 41'~fluoro-4-hydEOxy-3~methoxy-5-nitEobenzo- phenone of m.p. 126-128° (from ether); d3) from 2'.S 8-dif luora-4-faydEox:y-3-metI&oxybeazophenone there is obtained 2 • „ 6 ' -dif luoro-4-laydEQxy-3~methoxy-5--nitrobenzophenone of m.p. 147-149® (from methanol); .j0 d4) from 2 1 ~ c h 1 o r o - 4 - hy d r o xy - 3 - me t ho xy be nz o p he no ne there is obtained 2'-chloro-4-hydroxy-3-methoxy-5-nitrobenzo-phenone of m.p. 123-125° (from ether); d.5) from 31-chloro-4-hydroxy-3-methoxybenzophenone there is obtained 3'-chloEO-4-hydcoxy-3-methoxy-5-nit£obenzo~ phenone of m.p. 152-154® (from methanol): do) from 4'-chloEO-4-hydroxy-3-methoxybenzophenone there is obtained 4 ' -chlOEO-4-hydroxy-3-»ethoxy-5-nitrobenzo-phenone of m.p. 129-131" (from methylene chloride/low--boiling petEoleum ether); 20 d7) from 4-hyd£©xy-3-methoxy-2'-methvlbenzophenone there is obtained 4-hydEQxy-3-methoxy-2'-methyl-S-nitcobeazo- phenone of m.p. 125-127® (from ethanol); d8) from 4-hydEoxy-3-aethoxy-4'-methvlbenzophenone there is obtaiaed 4-hydEoxy-3-methoxy-4 1 -aietlayl-5-nittEobenzo-25 phenone of a.p. 137-139® (from methylene chloci.de/ether); d9) from 2•-cyano-4-hydroxy-3-»ethojcybeazoptaenone there is obtained 2'-cyano-4-hydEoxy-3-methoxy-5-aitcobenzophenone of m.p. 163-164® (from Methanol): - 105 - d10) £roffi 4-hydcoxy-3-methoxy-2'-(trifluoromethy1)-benzophenone there is obtaiaed 4-hydroxy-3-methoxy-5--nitro-2 ' - (trif luoromethyl)benzophenone of a.p. 138-14,0° (from methylene chlor ide/low-boi1ing petroleum ether): dll) from 4-hydroxy-3.4'-dimethoxybenzophenone there is obtained 4-hydroxy-3 '. 4 '-diaethoxy-5-nir.robenzophenone of n.p. 134-136° (f ros# methanol) and dl2) from 4-hydroxy-33',4'-trimethoxybenzophenone there is obtaiaed 4-hydroxy-5-nitro-3,3',4'-triaethoxy- benxophenone of m.p. 178-100® (from, methanol). e) 2«.8 g of 2 '-fluoro-4-hydroxy~3-methoxy-5-aitrobenzo-phenone (dissolved in 120 ©1 of glacial acetic acid, 100 sal of 33 percent hydrobromic acid in glacial acetic acid and 53 nil of 4,8 percent aqueous hydrobroralc acid) are boiled under reflux for 4 hours. The reaction mixture is subsequently evaporated under reduced pressure and the residue is distilled with toluene. The residue is dissolved in ©ethylene chloride,, washed with water, dried over sodium sulphate, filtered and evaporated. The product is crystallised from methylene chloride/low-boiling petroleum ether. There is obtained 2'-fluoro-3.4--dihydroxy-5-nitrobenzophenone of m.p. 169-171°.
In an analogous manner: el) From 3'-fluoro-4-toydroxy-3-raethoxy~5-nitr©benzophenone there is obtained 3'-fluoro-3.4-dihydroxy-5-nitrobenzo-phenone of m.p. 124-126° (from methylene chloride): e2) from 4'-fluoro-4-hydroxy-3-aethoxy-5-nitrobenzophenone there is obtaiaed 4'-fluoro-3.4-dihydroxy-5-aitrobenzo-phenone of m.p. 171-173° (from methylene chloride): e3) from 2'.6'-difiuoro-4-hydroxy-3-methoxy-5-nitrobenzo-phenone there is obtained 2•,6'-difluoro-3.4-dihydroxy-5--nitrobenzophenone of m.p. 194-196° (tzon methanol): ©4) froa 21-chloro-4-hydroxy-3-methoxy-5-nitrobenzo-phenone these is obtained 2' -chloro-3.4~dihydroxy-5-aitro-benzophenone of m.p. 129-131®' CfiroiR ©ethylene chloride/ low-boiling petroleum ether): @5) from 3 ' -chloro-4-hydroxy-3-methoxy-5~nitrobenzo-phenone there is obtaiaed 3 • -chloro-3.4~dihydroxy-5-nitro-benzophenone of at.p. 143-145° (from methylene chloride/ low-boiling petroleum ether); e6) from 4 1 -chloro-4-hydroxy-3-methoxybenzophenone there is obtained 4•-chloro-3,4-dihydroxybenzophenone of a.p. 174-176° (frosa methylene chloride); e7) from 4-hydcoxy-3-methoxy-2'-methy1-5-nitrobenzo-phenone there is obtained 3,4-dihydroxy-2'-aethyl-5-nitro-benzophenonte of m.p. 164-166° (froa methylene chloride); e8) from 4-hydroxy-3-ii»ethoxy-4 • -methyl-5-nitrobenzo-phenone there is obtained 3„4-dihydroxy-4'-methyl~5-nitro-benzophenone of a.p. 146-148® (froa methylene chloride); e9) froa 2■ -cyano-4-hydroxy-3-raethoxy-5-nitrobenzophenone there is obtained 2'-cyano-3,4-dihydroxy-5-nitrobea2o-phenone of m.p. 159-161° (from methanol): elO) from 4-hydroxy-3-methoxy-5-nitEo~2'-(tri£luoro-methy1)benzophenone there is obtaiaed 3,4-dihydroxy-5- -nitro-2,- Example 77 A suspension of 13.8 g of 2-broaio-3 ', 4' -dihydroxy-5 ' --nitroacetophenone is treated with 9.0 g of l-(phenethyl)--2-thiourea in 150 nl of n-butanol and the mixture Is 10 heated to boiling wader reflux for 3 hours. After cooling to room temperature the crystals are filtered off under suction aad crystallized from n-butanol. There is obtained 3-nitco-5-[2-(phenethylamino)~4-thiazolyl]pyrocatecho1 hydrobromide of m.p. 249-251°. q 5 Example 78 In analogy to Example 38, from 2-bromo-3' , 4' --dihydroxy-5'-nitroacetophenone and 2-aninobenzophenone there is obtained 2-(3.4-dihydroxy-5-nitrobenzoyl)-3--phenylindole of m.p. 195-198° (from isopropanol).
Example 79 20 A suspension of 8.3 g of 2~brono~3•, 4'-dihydroxy-5•--nitroacetophenone is treated with X-(1-adanantyl)-2--thiourea in 90 nl of n-butanol and the mixture is heated to boiling under reflux for 4 hours. After cooling to room 25 temperature the crystals are filtered off under suction and recrystallized froa n-butanol. There is obtained 5-12-C1-adamantylamino)-5-thiazolyl]-3-aitropyrocatechol hydrobromide of m.p. 245-247®. - 108 - Example 80 A suspension of 2.6 g of (3.4-dihydroxy-5-nitro-benzoyl)methyl acetate in 20 ml of ethanol aad 20 al of IN hydrochloric acid is heated to boillag under reflux for 5 hours. The reaction mixture is then evaporated, the residue is distilled with toluene aad thea recrystallized fcon ethanol. There is obtained 2,3*,«'-trihydroxy-5'--nitroacetophenone of m.p. 208-210®.
Example 81 A solution of 4.0 g of n-hexyl 3,4-dihydroxy-5-nitro-phenylglyoxylate and 1.5 g of diaainoaaleonitcile ia 35 ml of ethanol is heated to boiling under reflux for 24 hours. The alcohol is then distilled off,, the residue is dissolved in ether, washed with water, dried over sodium sulphate, filtered and evaporated. There is obtained 6 - hy d r o xy- 5 - (3,«. - d i hy d r oxy- 5 - n i t r opheny 1) - 2,3 - py r a z i ne— dicarbonitrile of a.p. >300° (froea ether/aethylene chloride).
Exaaple 92 a) 4.2 g of 5-(broaoacetyl)-2,3-diaethoxybenzonitcile dissolved in 150 al of methylene chloride are treated with 8.9 al of boron tribcoaide. The reaction aixture is stirred at 20® for 18 feousrs. It is subsequently poured into 220 nal of saturated sodiua hydrogen carbonate solution and 100 g of ice, adjusted to pH 6 with glacial acetic acid and extracted with ethyl acetate. The ocganic phase is washed with watec, dried ovec sodiua sulphate and evaporated. Thece is obtained 5~ Example 83 a) 25 ml of tert.-butyllithium solution (1.4H in hexane) are added dropwise at -70® within 10 minutes to 10 g of 4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 100 ml of tetrahydrofuraa. Mter stirring at -70° for 1 hour 5 g of quinoline-4-carbaldehyde dissolved ia 50 ml of tetrahydrofuraa are added dropwise within 30 minutes. The reaction aixture is stirred at -4.0® for 1 hour aad at -5® for 1 hour, poured into 200 al of water and adjusted to pH 4 with glacial acetic acid. The mixture is extracted three times with SO ml of ether each time. The combined ether phases are washed with water, dried over sodium sulphate and evaporated. There is obtained c-£4-(benzyloxy ) - 3~methoxyphenyl ]-4-quinolinemethanol as a,a amorphous solid. b) 9.4 g of a-[4-(benzyloxy5-3-methoxyphenyl3-4--quinolinemethanol dissolved ia 200 al of methylene chloride are treated with 6.5 g of pyridinium chloro-.chromate, whereupon the mixture is stirred at room temperature for 3 hones. The insoluble constituents are subsequently filtered off. The filtrate is evaporated aad the residue is chromatogr&phed oa 150 g of silica gel with ethyl acetate. There is thus obtained 4-(benzyloxy)-3--aethoxy 4-quinolyl Stetoa© as an amorphous solid. c) 15 nl of 33 percent hydrobromic acid in glacial acetic acid are added dropwise within 5 minutes at room temperature to 7.5 g ot 4-(benzyloxy)-3-aethoxy 4-quinolyl ketone dissolved in 150 al of methylene chloride. After stirring at 20° for 4.5 hours 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 a further twice with 100 al of methylene chloride each time. The combined methylene chloride phases are dried over sodiua sulphate and evaporated. The residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone of a.p. 190-192°. d) 0.37 al of 65 percent nitric acid is added dropwise at room temperature to 1.3 g of 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone. After stirring for 3 hours the reaction mixture is poured into ice-water. adjusted to pH 6 with conc. ammonia aad the precipitate formed is filtered off. The thus-obtained residue is heated under reflux in 20 ml of acetonitEile. whereupon the crystals are filtered off at 0®. These is obtaiaed 4-hydroxy-3-aethoxy-5-nitrophenvl 4-quinolyl ketone of a.p. 246-248*. e) 1 g of 4-bydEoxy-3-aethoxy-5-nitropheayl 4-quinolyl ketone dissolved in 30 al of 4§ percent aqueous hydrobromic acid is stirred at lOO* for 18 hours. After cooling to room temperature the reaction mixture is diluted with 30 al of water and the precipitate is filtered off under suction,. There is obtained 3,4-dihYd.roKf-5-p.itrophe.nFl 4-quinolyl ketone hydrobromide of. m.p. 273-275° (from acetonitrile).
Example 84 a) IB.8 al of n-butyllithium solution (1.6M ia hexane) ace added, dropwise at -50® within 10 minutes to 4..,03 g of thiophene dissolved in 40 ml of tetrahydrofuran. After stirring at -50° for 30 minutes 6.3 g of 3.4-di»etfcoxy-5--nitrobenzaldehyde dissolved ia 100 ml of tetrahydrofuran are added dropwise within 30 minutes. The reaction mixture is stirred at -50° for 1 hour at 0° for 30 minutes and poured into 100 ©1 of 2N sulphuric acid. The mixture is extracted three times with 100 ml of ether each time,? the combined ether phases are washed -with sodium chloride solution, dried over sodium sulphate,, filtered and evaporated. There is obtained a-(3,4-dimethoxy-5--nitrophenyl)-2-thiophenemethanol of m.p. 79-81° (from methylene chloride/hexane). b) 9.9 g of a-(3.4-dimethoxy-5-nitrophenyl)-2- -thiophenemethanol dissolved ia 300 ml of acetone are treated with 90 g of manganese dioxide aad heated under reflux for 4 hours. The manganese dioxide is removed by suction filtration and the filtrate is evaporated. There is obtained 3,4-dimethoxy-5-siitrophenyl 2-thienyl ketone of m.p. 102-104® (from methylene chloride/hexane). c) 2 g of 3,4-dimethoxy-5-nitrophenyl 2-thienyl ketone are stirred at 100® for 8 hours in a mixture of 20 al of 30-33 percent hydrobromic acid in glacial acetic acid and 20 ml of 48 percent aqueous hydrobromic acid. The reaction mixture is subsequently evaporated to dryness. The residue is taken up in ethyl acetate, washed with water, dried over sodium sulphate and filtered, and the filtrate is - 112 - evaporated. After cecrystallization from ethyl acetate/ hexane there Is obtained 3,4-dihydroxy-5-nitrophenyl 2-thienyl ketone of m.p. 155-157®.
Example A The interlocking gelatine capsules of the following composition can be nanufactuced in ra manner known pes se: Ingredients Aaount ia aa/capsules L-Dopa 100 Benserazide hydrochloride 29.3 10 3,S-Dihydroxy-S-nitrophenyl <-pyridyl ketone 25 Gelatine 1 Fig stearate 1 Avicel 93.7 Mannitol 100 15 Capsule till weight 350 rag -1 1 3-

Claims (27)

Claims
1. Compounds of £he general formula HO \ 4 \ I ii HO - Rc Rb ia wherein Ra signifies nitro or cifa.no, Hb signifies 5 hydrogen or halogen, He signifies halogen, nitro,, cyano ok the group -(A) -(Q) -H1 or -(A) -Q-R - A signifies vinylene optionally substituted by lower alkyl, a signifies the number O -114- 10 15 or 1, a signifies the number O or L B1 signifies 3 2 the group -COE » aryl or heteroaryl, E signifies hydrogen or a saturated or partially unsaturated,, lower hydrocarbon residue which is unsubstituted or aoao- or disubstituted by hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di(lower alkyl)- amino, lower alkoxy. lower alkoxycarbonvl. aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy. trifluoromethyl. car boxy,, lower alkanoylamino. lower alkoxycarbonylamino or lower alkylthio. H3 signifies hydroxy, amino, a saturated or partially unsaturated, lower hydrocarbon residue which is unsubstituted or mono- or disubstituted hy hydroxy., cyano,, nitro,, halogen,, amino,, lower alkylamino, di(lower alkyl)- amino, lower alkoxy. lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcacbonylanino, lower alkanoyloxy. lower alkanoyl, carbanoyl. mono- or di(lowec alkyl)carbamoyl, lower alkylenedioxy, trifluoronethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylthio and which is attached via am oxygen atom or an imino or lower alkylimino group or 4-mocpholinyl, l~pyrrolidinyl or 25 l-azetidinyl group which is unsubstituted oc mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl. lower alkoxy- alkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl. carbamoyl, mono- or di(lower alkyl)- carbamoyl, oxo and/or lower alkylenedioxy 0 signifies 4 the group -CO- or >c«N-(2) -B „ z signifies an oxygen atom or an imino group,, p signifies the number O or l and H' signifies 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. 20 30 35 di(lower alkyl)amino. lower alkoxy,, lower alkoxycarbonyl,, aryl, arylaminocarbonyl„ arylcarbonyl. arylcar-bonylamino. lower alkanoyloxy,, lower alkanoyl, carbamoyl, isono- or di(lover alkylJcarbamoyl. lower alkylenedioxy, trifluoromethyl. carboxy. lover alkanoylamino, lower alkoxycarbonylamino or lower alkylthio and which is optionally attached via a carbonyl group, whereby aryl denotes a phenyl or . naphthyl group which is unsubstituted or mono- or disubstituted by halogen, trif luoromethyl, nitro,, amino, mono- or di dower alkyl)amino. lower alkyl, lowec alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, carboxy,, hydroxy, cyano. lover alkanoyloxy. carbamoyl, »oo.o- or di(lower alkyl)carbamoyl, lower alkylenedioxy. lower alkanoylamino or lower alkoxycarbonylamino, heteroaryl denotes a heterocyclic group selected from the group consisting of pyridyl, pyrazinyl. triazinyl. thiadiazinyl, thiazolyl, oxazolyl. oxadiazolvl, pyrazolyl. tetrazolvl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinvl. benzoxazinyl. quinoxalinvl. benzopyranyl, benzimidazolyl, indolyl, imidazothia-zolyl. imidazothiadiazolyl, iaidiazopyridyl. benzo-thiazinyl, benzoquinoxalinyl aad imidazobenzothiazolyl which is attached via a cacbon atom and which is unsubstituted or mono-, di- or trisubstituted by halogen,, tr if luoromethyl. nitro, carboxy, amino, arylamino. lower alkyl, lower alkoxy. hydroxy,, lower alkoxycarbonyl. lower alkanoyl. lower alkanoyloxy. oxo. lower alkylenedioxy, mercapto. lower alkylthio. lower alkylamino. didower alkyl)amiao. C ^-cyclo-alkylamino, 1 -bicycloalkylamino. lower alkanoylamino, lower alkoxycarbonylamino. carbamoyl, mono- ©sc die lower alkyl)carbamoyl, cyano. aryl, aryl-lower alkyl. aryl-lower alkylamino. heteroaryl, heteroaryl-lower alkyl. heteroarylamino or -116- C3 7~cycloalkyl, and lower denotes residues with up to 7 carbon atoms,, ester and ether derivatives which are hydrolyzable umder physiological conditioas aad pharmaceutical^ acceptable salts thereof for use as therapeutically active substances.
2. Compounds of the general formula H0\ jTx i «_nr. lb / ^ X H0 " Eb wherein Ha signifies nitro or cyano, Sb signifies 10 hydrogen or halogen, EC signifies nitro, cyano or the group -(A) -(Q) -R11 or -(A) -Q-H21, A JU Ml HI signifies vinylene optionally substituted by lower alkyl. n signifies the number O or 1, a signifies the li 3i number O or 1, E signifies the group -COE 15 aryl or heteroaryl. a"" signifies a saturated or partially unsaturated, lower hydrocarbon residue which is unsubstituted or aono- or disubstituted by hydroxy, cyano, nitro, halogen, amino, lower alkylamino. di(lower alkyl)amino, lower alkoxy, lower 20 alkoxycarbonyl, aryl, arylaainocacbonyl, arylcarbonyl. acylcarbonylaaino, lower alkanoyloxy, lower alkanoyl. carbamoyl, aono- or die lower alkyl)carbamoyl, lower alkylenedioxy. trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylaaino or lower 31 25 alkylthio, s ~ signifies hydroxy, aaiao, a saturated or partially unsaturated, lower hydrocarbon residue which is unsubstituted or aono- or disubstituted by hydroxy, cyano. nitro. halogen, amino, lower alkylamino. di(lower alkyljamino, lower alkoxy, lower 30 alkoxycarbonyl, aryl, arylaainocacbonyl. arylcarbonyl. -117- aryl carbonylamino. lower alkanoyloxy,, lower alkanoyl. carbamoyl, rno.no- or di(lowe,c alkyl)carbamoyl, lower alkylenedioxy, trifluoromethyl. carboxy. lower alkanoylamino. lower alkoxvcarbonylamino or lower 5 alkylthio, aad which is attached via an oxygen atom or an imino or lower alkyliaino group or a 4-aorpholinyl. 1-pyrrolidinyl or 1-azetidinyl group which ia unsubsticuted or iono- or disubstituted by lower alkyl, hydroxy, lover alkoxy, lower alkanoyloxy. lower 10 hydroxyalkyl. lower alkoxyalkyl. lover alkanoyloxyalkyl. lover alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)-carbamoyl, oxo and/or lower alkylenedioxy Q signifies 4 the group -CO- or >C»N-(Z) -H , Z signifies an P 15 oxygen atom or an imino group, p signifies the number O or 1 and H* signifies hydrogen or a saturated or partially unsaturated, lower hydrocarbon residue which is unsubstituted or aono- or disubstituted by hydroxy, cyano. nitro. halogen, amino, lower alkylamino. 2o di(lower alkyl)amino, lower alkoxy. lower alkoxycar bonyl . aryl. aeylaninocarbonyl. arylcarbonyl. arylcar-bonylaaino. lower alkanoyloxy. lower alkanoyl. carbamoyl. mono- or diJ lower alkyl)carbamoyl, lower alkylenedioxy. trifluoromethyl. carboxy, lower 25 alkanoylamino, lower alkoxvcarbonylaaiao or lo&?er alkylthio and which is optionally attached via a carbonyl group, whereby Ha signifies cyano when He' 31 signifies cyano or nitro and R "" has a significance different from hydroxy when a signifies the number O. and whereby aryl denotes a phenyl or naphthyl group which is unsubstituted or aono- or disubstituted by halogen, trifluoromethyl. nitro. amino, aono- or di(lower alkyl )amiato. lower alkyl. lower alkoxy.'lower alkylthio, lower alkanoyl. lower alkoxycarbonyl. 35 carboxy, hydroxy, cyano. lower alkanoyloxy. carbamoyl, mono- or di(lower alkyl)carbamoyl. lower -118- alkylenedioxy, lower alkanoylamino or lower alkoxycarbonylamino. heteroaryl denotes a heterocyclic group selected fro® the group consisting of pyridyl, pyrazinyl, triazinyl. thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl. pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl. benzoxazinyl, quiaoxalinyl, benzopvranyl, benzimidazolyl, indolyl, is&idazothia-zolyl, iraidazothiadiazolyl, imidiazopyridyl, benzo-thiazinyl, benzoquinoxalinyl aad imidazobenzothiazolyl which is attached via a cacboa atom aad which is unsubstituted or raoao-, di- or trisubstituted bf halogen, trifluoromethyl, nitro, carboxy, amino, arylamino, lower alkyl, lower alkoxy,, hydcoxy, lower i • alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo. lower alkylenedioxy. aercapto, lower alkylthio, lower alkylamino, di(lower alkyl)amino. C„ ,-cyclo- alkylamino, C-a ,_~bicycloalkyla»ino, lower jLO alkanoylamino, lower alkozycarbonylamiao. cacbamoyl, mono- or di(lower alkyl)carbamoyl, cyano, aryl, aryl-lower alkyl. aryl-lower alkylamino, heteroaryl, heteroaryl-lower alkyl,, heteroarylamino or C3?-cycloalkyl, aad lower denotes residues with up to 7 carboa atoms, and ester and ether derivatives which are hydrolyzable under physiological conditions and pharmaceutical^ acceptable salts thereof.
3. Compounds according to !S i. <8l !> 2. wherein Eb is situated in the p-position to Ea.
4. Compounds according to claim 2 ot 3, wherein Ha signifies aitro.
5. Compounds according to any oae of claims 2-4, wherein Hb signifies hydrogen, chlorine or fluorine. -119-
6. Compounds according to claim 5, wherein Rb signifies hydrogen.
7. Compounds according to any on® of claims 2-6 „ 11 i i wherein Re' signifies the group -CO-E and R 5 signifies a phenyl group which is unsubstituted or aono- or disubstituted by halogen, trifluoromethyl, nitro,, amino,„ mono- or di(lo*?er alkyl)amino, lower alkyl, lower alkoxy, lower alkylthio, lower alkynoyl, lower alkoxy, lower alkylthio, lower alkanoyl,, lover alkoxycarbonyl, 10 carboxy, hydroxy* cyano, lower alkanoyloxy, carbamoyl, mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy. lower alkanoylamino oir lower alkoxycarbonylamino or a heterocyclic group selected from the group cons it in, g of pyridyl, pyrazinyl, triazinyl. pyrazolyl and 15 imidazolyl which is unsubstituted or mono-, di- or tr isubstituted by halogen, trif luoromethyl. nitro,, carboxy, amino,,, arylamino, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto, lower 20 alkthythio, lower alkylamino, di(lower alkyl)amino, C3 7-cycl°alkylamino. Cg_1^-bicycloalkylamino, lower alkanoylamino, lower alkoxycarbonylamino, carbamoyl, mono-or di (lower alkyl) car bamoyl. cyano, aryl, aryl-lower alkyl, aryl-lower alkylamino, heteroaryl, heteroaryl-lower 25 alkyl, heteroarylamino or C^ ^-cycloalkyl which is attached via a carbon atom.
8. Compounds according to claim 7, wherein signifies a phenyl group optionally mono- or disubstituted by halogen, trifluoromethyl. cyano. hydroxy or lower alkyl 30 or a pyridyl group.
9. 3,4-Dihydroxy-«1-methyl-5-nitrobenzophenone.
10. 21-Fluoro-3,«-dihydroxy-5-nitrobenzophenone. -120-
11. 3„41-Dihydroxy-5-nitrophenyl «-pyridyl ketone.
12. Compounds according to any one of claims 2-11 for use as therapeutically active substances.
13. Compounds according to any one of claims 1-11 for use as active substances which iahlbit catechol-O-methyl-transferase.
14. A process for the manufacture of compounds according to any one of claims 2-11. of ester aad ether derivatives which are hydrolyzable under physiological conditions and of phacmaceutically acceptable salts thereof, characterized by a) cleaving off the lower alkyl ether group(s) in a compound of the general formula V W > I LRc« ix ron S~\ / \ X R?0 "VRb wherein one of the symbols E and H' signifies lower alkyl and the other signifies hydrogea or lower alkyl aad Ha. Eb aad 3c' have the sigaificakice given ia claim 2, b) reacting a compound of the general formula fa H(VX AX"(A^"C0"CH2 HQ7 *-X bU Rb -X -121- 10 wherein 1 signifies a leaving group and Ha, Rb. A and n have the significance given in claim 2, with a thioamide, thiourea, thiocarboxylic acid hydrazide, thiosemicarbazide. amidine, guanidine, amidrazone. aminoguanidine, cyclic amidine. 1,2-diamine, l.2-amino-thiol or a 1,2-aminoalcohol and, if desired, dehydrogen-ating the cyclocondensation product obtained, or c) reacting a compound of the general formula HV\. /K V"~ (A) n"CO-COORL" Ib2 BO n Rb wherein E" signifies lower alkyl and Ha, Rb. A and n have the significance given in claim 2, with a 1,2-diamine, 1,2-aminothiol. 1,2-aminoalcohol, semicarbazide, thiosemicarbazide. amidrazone or an aminoguanidine and, if desired, dehydrogenating the cyclocon-15 densation product obtained, or 1 d) reacting a compound of formula Xb above with a B-aminocarbonyl compound, or e) converting the carboxaldehyde group(s) in a compound of the general formula CHO CN 9H0 HOwX _ hox H0\/X 20 I \ » r„o Ia2 OE i » - -CHO IV / v KC -vv-~cmo / ^ y H0 - Rb «0/ *-\b HO Rb wherein Rc"' signifies nitro, cyano or the group -(A) -R12 and. S'2 signifies the -COE3",, tea ^ « aryl or heteroaryl and Ra, Hb, A. a and R"*" have the -122- significance given ia claim 2, or in a di-O-lower alkanoyl derivative thereof into the cyano group(s). or £) reacting a di-O-lower alkanoyl derivative of a carboxylic acid of the general formula Ra Ra HOv /- HOv /'v \ V \ ... -a \ 7 \ 3 • - ia3 or » - IbJ /•v V" - (&) p-COOH .-v v'~
15. A medicament containing a compound according to any one of claims 1-11 aad a therapeutically inert carrier material.
16. A medicament Cor inhibiting catechol-O-methyl-transferase, containing a compound according to any one of claims 1-11 and a therapeutically inert carrier material.
17. A medicament for the treatment of Parkinson's disease and of parkinsonism, containing L-dopa, a peripheral decarboxylase inhibitor. a compound according to any oa© of claims 1-11 and a therapeutically inert carrier material.
18. A medicament pack for the treatment of Parkinson's disease and of parkinsonism, consisting of a medicament according to claim 16 and a medicament containing L-dopa. a peripheral decarboxylase inhibitor and a therapeutically inert carrier material.
19. The use of compounds according to any oae of claims 1-11 foe the manufacture of medicaments which inhibit catechol-O-anethyl transferase.
20. The use of compounds according to any one of claims l-ll for the Manufacture of medicament for the treatment of Parkinson's disease and of parkinsonism in combination with L-dopa and a peripheral decarboxylase inhibitor. -126-
21. The nss of compounds according to any one of claims 1-11 £ot the manufacture of Medicament packs according to claim 18.
22. A compound of the general formula Ia given and defined in Claim 1 or an ester or ether derivative thereof which is hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof which is any one of those specifically hereinbefore mentioned-
23. A process for the manufacture of a compound of the general formula ia given and defined in Claim 1 or a ester or ether derivative thereof which is hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof,, substantially as hereinbefore described with particular reference to Examples 1-84 of the accompanying Examples.
24. A compound of the general formula la given and defined in Claim 1 or an ester or ether derivative thereof which is hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof whenever manufactured by a process claimed in Claim 23.
25. A medicament according to any one of claims 15-17, substantially as hereinbefore described with particular reference to Example A of the accompanying Examples -
26. A medicament pack according to Claim 18, substantially as hereinbefore described.
27. Use according to any one of Claims 19-21, substantially as hereinbefore described with particular reference to Example A of the accompanying Examples. F. R- KELLY & CO., AGENTS FOR THE APPLICANTS.
IE60987A 1986-03-11 1987-03-10 3,5-disubstituted pyrocatechol derivatives IE61316B1 (en)

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