DK145822B - 3,4-DIMETHOXY-6- (4- (2-FUROYL) -1-PIPERAZINYLTHIOCARBAMIDO) BENZONITRIL USED AS INTERMEDIATE IN THE PREPARATION OF 6,7-DIMETHOXY-4-AMINO-2- (4- (2-FURO) 1-piperazinyl) quinazoline - Google Patents
3,4-DIMETHOXY-6- (4- (2-FUROYL) -1-PIPERAZINYLTHIOCARBAMIDO) BENZONITRIL USED AS INTERMEDIATE IN THE PREPARATION OF 6,7-DIMETHOXY-4-AMINO-2- (4- (2-FURO) 1-piperazinyl) quinazoline Download PDFInfo
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- DK145822B DK145822B DK558377AA DK558377A DK145822B DK 145822 B DK145822 B DK 145822B DK 558377A A DK558377A A DK 558377AA DK 558377 A DK558377 A DK 558377A DK 145822 B DK145822 B DK 145822B
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- dimethoxy
- furoyl
- piperazinyl
- amino
- piperazinylthiocarbamido
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
(19) DANMARK(19) DENMARK
|p (12) FREMLÆGGELSESSKRIFT <n) H5822B| p (12) PUBLICATION <n) H5822B
DIREKTORATET FOR PATENT- 06 VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT 06 BRAND
(21) Ansøgning nr. 5583/77 (51) |nt.CI.3 C 07 0 307/68 (22) Indleveringsdag ^ ^ * ^ec * ^ 977 (24) Løbedag 1^· ^ec* 1977 (41) Aim. tilgængelig 1^· Jun* 1978 (44) Fremlagt 1^· mar· 1983 (86) International ansøgning nr. “ (86) International indleveringsdag " (85) Videreførelsesdag “ (62) Stamansøgning nr. “(21) Application No. 5583/77 (51) | nt.CI.3 C 07 0 307/68 (22) Date of filing ^^^ ec * ^ 977 (24) Running day 1 ^ · ^ ec * 1977 (41) Aim. available June 1, 1978 (44) Submitted March 1, 1983 (86) International Application No. "(86) International Filing Day" (85) Continuation Day "(62) Stock Application No."
(30) Prioritet 15· dec. 1976, 763614, PI(30) Priority 15 · Dec. 1976, 763614, PI
(71) Ansøger ORION-ΥΗΤΐΜΑΈ ΟΥ, 00510 Helsinki 51 i PI.(71) Applicant ORION-ΥΗΤΐΜΑΈ ΟΥ, 00510 Helsinki 51 in PI.
(72) Opfinder Erkki Juhani Honkanen, PI: Aino Kyllikki Pippurij FI.(72) Inventor Erkki Juhani Honkanen, PI: Aino Kyllikki Pippurij FI.
(74) Fuldmægtig Ingeniørfirmaet Lehmann & Ree.(74) Associate Engineer Lehmann & Ree.
(54) 3i4-Dimethoxy-6-(4-(2-furoyl)-l -pip er azinylthi o carbamido)b enz0= nitril til anvendelse som mellem= produkt ved fremstillingen af 6,7-dimethoxy-4-amino-2-(4-(2-furoyl)-1 -piperazinyl)quinazolin.(54) 3,4-Dimethoxy-6- (4- (2-furoyl) -1-pip is azinylthio carbamido) benzo = nitrile for use as intermediate product in the preparation of 6,7-dimethoxy-4-amino-2 - (4- (2-furoyl) -1-piperazinyl) quinazoline.
Opfindelsen angår det hidtil ukendte 3,4-dimethoxy-6-[4- (2-furoyl)-l-piperazinylthiocarbamido]benzonitril til anvendelse som mellemprodukt ved fremstillingen af 6,7-dimethoxy-4-amino-2-[4-(2- furoyl)-l-piperazinyl]quinazolin, hvis generiske betegnelse eller to trivialnavn er prazosin, og som har blodtrykssænkende virkning.This invention relates to the novel 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile for use as an intermediate in the preparation of 6,7-dimethoxy-4-amino-2- [4- ( 2-furoyl) -1-piperazinyl] quinazoline, whose generic term or two trivial names are prazosin and which have antihypertensive effect.
<N Det er velkendt, at denne forbindelse, som har formlen:<N It is well known that this compound having the formula:
<N<N
oOIsland Island
LDLD
-d" ___ - ca3° yy " oc -γ°\-d "___ - ca3 ° yy" and -γ ° \
O 3 ^ YO 3 ^ Y
nh2 2 145822 er i besiddelse af en særlig kraftig blodtrykssænkende virkning (Cohen, Journal of Clinical Pharmacology, 10 (1970)).nh2 2 145822 possesses a particularly potent blood pressure lowering effect (Cohen, Journal of Clinical Pharmacology, 10 (1970)).
I beskrivelsen til USA-patent nr. 3.511.836 nævnes en række fremgangsmåder til fremstilling af 6,7-dimethoxy-4-amino-2-[4-substitueret-l-piperazinyl]quinazoliner. Ved en af disse fremgangsmåder til fremstilling af prazosin omsættes 6,7-dimethoxy-4-amino-2-chlorquinazolin med (2-furoyl)-l-piperazin ifølge nedenstående reaktionsskema: ch3°vVn VC1 K ) · _y°\ N + HN N “ 0C ^ CH3° T W W (X) m2In the disclosure of U.S. Patent No. 3,511,836, a number of methods for preparing 6,7-dimethoxy-4-amino-2- [4-substituted-1-piperazinyl] quinazolines are mentioned. In one of these processes for the preparation of prazosin, 6,7-dimethoxy-4-amino-2-chloroquinazoline is reacted with (2-furoyl) -1-piperazine according to the following reaction scheme: ch3 ° Vn VC1 K) · y ° \ N + HN N “CC CH CH ° TWW (X) m2
Ovennævnte reaktionsskema illustrerer den foretrukne fremgangsmåde ifølge ovennævnte USA-patentskrift. I patentskriftet er følgende andre fremgangsmåder anført som spekulative alternativer: Omsætning af 2-(4-(2-furoyl)-l-piperazinyl)-4-chlor-6,7-dimethoxyquinazolin med ammoniak; omsætning af 2-methylthio-4-amino-6,7-dimethoxyquinazolin med 4-(2-furoyl)piperazin; omsætning af 2-(l-piperazinyl)-4-amino-6,7-dimethoxyquinazolin med 2-furoylchlorid; omsætning af 3,4-dimethoxy- 6-aminobenzonitril med l-amidino-4-(2-furoyl)piperazin; omsætning af 3.4- dimethoxy-6-chlorbenzonitril med l-amidino-4-(2-furoyl)piperazin; omsætning af 2-amidino-4,5-dimethoxyanilin med l-amidino-4-(2-furoyl)-piperazin; omsætning af 2-(4-(2-furoyl)-l-piperazinyl)-4,6,7-trimeth-oxyquinazolin med ammoniak; og omsætning af 2-(4-(2-furoyl)-l-pipera-zinyl)-4-methylthio-6,7-dimethoxyquinazolin med ammoniak.The above reaction scheme illustrates the preferred process of the above-mentioned United States patent. The patent discloses the following other methods as speculative alternatives: Reaction of 2- (4- (2-furoyl) -1-piperazinyl) -4-chloro-6,7-dimethoxyquinazoline with ammonia; reaction of 2-methylthio-4-amino-6,7-dimethoxyquinazoline with 4- (2-furoyl) piperazine; reaction of 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline with 2-furoyl chloride; reaction of 3,4-dimethoxy-6-aminobenzonitrile with 1-amidino-4- (2-furoyl) piperazine; reaction of 3,4-dimethoxy-6-chlorobenzonitrile with 1-amidino-4- (2-furoyl) piperazine; reaction of 2-amidino-4,5-dimethoxyaniline with 1-amidino-4- (2-furoyl) -piperazine; reaction of 2- (4- (2-furoyl) -1-piperazinyl) -4,6,7-trimethoxyquinazoline with ammonia; and reaction of 2- (4- (2-furoyl) -1-piperazinyl) -4-methylthio-6,7-dimethoxyquinazoline with ammonia.
I beskrivelsen til hollandsk pat.ans.nr. 7206067 omtales en anden fremgangsmåde til fremstilling bl.a. af prazosin, ifølge hvilken 3.4- dimethoxy-6-aminobenzonitril bringes til omsætning med 1-cyano- 4-(2-furoyl)-piperazin ifølge nedenstående reaktionsskema: CH3°WNI12 /-\ /°\ KJ I + NC-N N-OC—< /)--In the description of Dutch Pat. 7206067 discloses another method of preparation including of prazosin according to which 3,4-dimethoxy-6-aminobenzonitrile is reacted with 1-cyano-4- (2-furoyl) -piperazine according to the following reaction scheme: CH3 ° WNI12 / - \ / ° \ KJ I + NC-N N- OC - </) -
Cl^O'^'cN W \J (I) 145822 3 I beskrivelsen til tysk offentliggørelsesskrift nr. 2.457.911 omtales endnu en fremgangsmåde til fremstilling af bl.a. prazosin, hvilken fremgangsmåde illustreres af nedenstående reaktionsskema: CH-,0. .NHU , _ ·—w-“-o—^In the specification of German Patent Specification No. 2,457,911, another method for the preparation of, inter alia, prazosin, which is illustrated by the reaction scheme below: CH-, 0. .NHU, _ · —w - “- o— ^
.NH ^NH ^NH.NH ^ NH ^ NH
hvor Q =CN eller C' og A = CN, C eller Cwhere Q = CN or C 'and A = CN, C or C
^nii2 OR xSR^ nii2 OR xSR
hvor R = en alkylgruppe med 1-6 carbonatomer, dog således, at r.år Qwherein R = an alkyl group having 1-6 carbon atoms, however, such that r is Q
er CN, er Ais CN, is A
^NH ^NH^ NH ^ NH
C ellerC or
X0R XSRX0R XSR
Fælles for disse kendte fremgangsmåder er, at slutproduktet dannes ved reaktion mellem to særskilte molekyler. Af de kendte fremgangsmåder turde den i eksempel 6 i beskrivelsen til den hollandske pat.ans.nr. 7206067 beskrevne fremgangsmåde være den mest hensigtsmæssige, og ifølge denne fremgangsmåde kan prazosin fremstilles i et udbytte på ca. 30%. Som følge af den mellem to forskellige molekyler foregående reaktion fremkommer der urenheder, hvis fjernelse fra slutproduktet har vist sig særligt vanskelig. Det fremkomne råprodukt må således omkrystalliseres flere gange, inden det opfylder de renhedskrav, som forlanges af et farmaceutisk råmateriale. Herved falder udbyttet af det rene produkt.Common to these known methods is that the final product is formed by the reaction of two separate molecules. Of the known methods, in Example 6 of the description of the Dutch Pat. 7206067 is the most convenient, and according to this method prazosin can be prepared in a yield of approx. 30%. As a result of the reaction between two different molecules, impurities appear which are particularly difficult to remove from the final product. Thus, the resulting crude product must be recrystallized several times before meeting the purity requirements demanded by a pharmaceutical raw material. This reduces the yield of the pure product.
Med mellemproduktet ifølge den foreliggende opfindelse kan prazosin derimod fremstilles ved en fremgangsmåde, som er baseret på en intramolekylær cykliseringsreaktion. Denne intramolekylære cyklise-ringsreaktion foranlediger ikke fremkomst af urenheder, som det er vanskeligt at fjerne fra slutproduktet, og udbyttet af det rene slutprodukt bliver derfor 50-60% højere end ved den ovenfor nævnte, kendte fremgangsmåde. Med mellemproduktet ifølge den foreliggende opfindelse kan ren prazosin således fremstilles i et betydeligt bedre udbytte, end hvad der har været muligt ved den bedste af de hidtil kendte frem-gangsgmåder. Mellemproduktet ifølge opfindelsen er endvidere let at fremstille og med godt udbytte. Mellemproduktet ifølge opfindelsen er 4 165822 3,4-dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]benzonitril og har formlen: CH,Ov. /v. JXE- C - N ^s— oc—\ 1 w ^ CH30^ cnBy contrast, with the intermediate of the present invention, prazosin can be prepared by a method based on an intramolecular cyclization reaction. This intramolecular cyclization reaction does not cause the emergence of impurities which are difficult to remove from the final product and therefore the yield of the pure final product is 50-60% higher than in the above-known known method. Thus, with the intermediate of the present invention, pure prazosin can be prepared in a significantly better yield than has been possible in the best of the known methods. Furthermore, the intermediate according to the invention is easy to manufacture and in good yield. The intermediate of the invention is 4,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile and has the formula: CH, Ov. / V. JXE- C - N ^ s— oc— \ 1 w ^ CH30 ^ cn
Fremstilling af prazosin (I) ud fra mellemproduktet ifølge opfindelsen kan gennemføres således, at 3,4-Dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]benzonitril omsættes med methyliodid til dannelsen af methyl-N-(3,4-dimethoxy-6-cyano-phenyl)-[4-(2-furoyl)-l-piperazinyl]thioformamidet med formlen:Preparation of prazosin (I) from the intermediate of the invention can be carried out so that 3,4-Dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile is reacted with methyl iodide to form methyl N- (3 (4-Dimethoxy-6-cyano-phenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamide of the formula:
CHjO-yy K - c - f~j- oc XIICHjO-yy K - c - f ~ j- oc XII
ch3o/^/Lxcn 3 og denne forbindelse cykliseres ved ophedning af samme sammen med ammoniak i et polært opløsningsmiddel i nærværelse af alkalimetalamid.CH 3 O / Lxcn 3 and this compound is cyclized by heating the same together with ammonia in a polar solvent in the presence of alkali metal amide.
Mellemproduktet (II) ifølge opfindelsen og prazosinet kan fremstilles kontinuerligt i ét og samme opløsningsmiddel uden fraskillelse af mellemprodukter, hvilket gør fremstillingen særlig enkel.The intermediate (II) of the invention and the prazosin can be prepared continuously in one and the same solvent without separation of intermediates, making the preparation particularly simple.
Mellemproduktet (II) ifølge opfindelsen kan fremstilles ved en fremgangsmåde, ved hvilken 3,4-dimethoxy-6-aminobenzonitril med formlen: -XT2The intermediate (II) of the invention may be prepared by a process in which 3,4-dimethoxy-6-aminobenzonitrile of the formula: -XT2
CH30 / CNCH30 / CN
omsættes med thiophosgen til dannelse af 3,4-dimethoxy-6-isothio-cyanatobenzonitril med formlen: 5 145822react with thiophosgene to give 3,4-dimethoxy-6-isothio-cyanatobenzonitrile of formula:
CH3°-s^v^ NCSCH3 ° -s ^ v ^ NCS
aa v 'aa v '
CH30X ^ CNCH30X ^ CN
og denne forbindelse omsættes med l-(2-furoyl)-piperazin med formlen: 0 oc ~\_/ vi f til dannelse af omhandlede mellemprodukt (II), eller l-(2-furoyl)-piperazin med formlen (VI) omsættes med thiophosgen til dannelse af 4-(2-furoyl)piperazinylthiocarbonylchlorid med formlen: / \ /0and this compound is reacted with 1- (2-furoyl) -piperazine of the formula: 0 and 6 to form the intermediate (II), or 1- (2-furoyl) -piperazine of formula (VI) is reacted with thiophosgene to form 4- (2-furoyl) piperazinylthiocarbonyl chloride of formula:
Cl-C-N N—OC —(λ" > „TTCl-C-N N-OC - (λ ">" TT
il V_/ VI1 s og denne forbindelse omsættes med 3,4-dimethoxy-6-aminobenzonitril med formlen IV til dannelse af mellemproduktet (II).and V this compound is reacted with 3,4-dimethoxy-6-aminobenzonitrile of formula IV to give the intermediate (II).
Opfindelsen belyses nærmere ved de efterfølgende eksempler, hvor eksempel 1-2 illustrerer fremstillingen af mellemproduktet (II), medens eksempel 3-4 illustrerer dets videre omdannelse til prazosin.The invention is further illustrated by the following Examples, in which Examples 1-2 illustrate the preparation of the intermediate (II), while Examples 3-4 illustrate its further conversion to prazosin.
145822 6145822 6
Eksempel 1 a) 3,4-dimethoxy-6-isothiocyanatobenzonitril (V) 27,0 g (0,15 mol) 3,4-dimethoxy-6-aminobenzonitril (IV) opløses i 150 ml 1,2-dichlorethan og tilsættes lidt efter lidt ved 0 -5°C til en blanding af 23,0 g (0,2 mol) thiophosgen, 100 ml 1,2-dichlorethan, 20,0 g (0,2 mol) kalciumcarbonat samt 200 ml vand. Efter tilsætningen fortsættes omrøring i endnu 1 time ved 0 - 5°C, derefter i 16 timer ved 20°C, og endelig i 1 time ved 35°C. Reaktionsblandingen filtreres, og dichlorethanlaget fraskilles, vaskes med fortyndet saltsyre samt vand og tørres med MgSO^. Opløsningsmidlet fjernes i vacuum, og den krystallinske rest (smeltepunkt 126 - 127°C) anvendes som sådan til de efterfølgende trin. Der fås 31,0 g (94% af det teoretiske udbytte) 3,4-dimethoxy-6-isothiocyanatobenzonitril.Example 1 a) 3,4-Dimethoxy-6-isothiocyanatobenzonitrile (V) 27.0 g (0.15 mol) of 3,4-dimethoxy-6-aminobenzonitrile (IV) are dissolved in 150 ml of 1,2-dichloroethane and added slightly. after a little at 0 -5 ° C to a mixture of 23.0 g (0.2 mole) of thiophosgene, 100 ml of 1,2-dichloroethane, 20.0 g (0.2 mole) of calcium carbonate and 200 ml of water. After the addition, stirring is continued for another hour at 0 - 5 ° C, then for 16 hours at 20 ° C, and finally for 1 hour at 35 ° C. The reaction mixture is filtered and the dichloroethane layer is separated, washed with dilute hydrochloric acid and water and dried over MgSO4. The solvent is removed in vacuo and the crystalline residue (mp 126 - 127 ° C) is used as such for the subsequent steps. 31.0 g (94% of theory) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile are obtained.
C10HgN2O2S Beregnet: C = 54,53 Fundet: C = 53,43 H = 3,66 H = 3,78 N = 12,72 N = 12,18 S = 14,56 S = 12,79 b) 3,4-dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]-benzo-nitril (II) 11,2 g (0,051 mol) 3,4-dimethoxy-6-isothiocyanatobenzonitril (V) opløses i 65 ml ethylacetat og tilsættes under omrøring ved 0°C lidt efter lidt til en opløsning af 9,2 g (0,051 mol) 1-(2-furoyl)-pi-perazin i 65 ml ethylacetat. Opløsningen får lov at henstå natten over ved -25°C, hvorved produktet udkrystalliseres. En filtrering gennemføres, og krystallerne vaskes med koldt ethylacetat samt tørres.C10HgN2O2S Calculated: C = 54.53 Found: C = 53.43 H = 3.66 H = 3.78 N = 12.72 N = 12.18 S = 14.56 S = 12.79 b) 3.4 -dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile (II) 11.2 g (0.051 mol) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile (V) dissolved in 65 ml of ethyl acetate and added with stirring at 0 ° C little by little to a solution of 9.2 g (0.051 mol) of 1- (2-furoyl) -piperazine in 65 ml of ethyl acetate. The solution is allowed to stand overnight at -25 ° C to crystallize the product. A filtration is carried out and the crystals are washed with cold ethyl acetate and dried.
Der fås 16,3 g (80% af det teoretiske udbytte) 3,4-dimethoxy-6-[4-(2--furoyl)-1-piperazinylthiocarbamido]-benzonitril. Smeltepunkt 178 -180°C.16.3 g (80% of theoretical yield) of 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile are obtained. Melting point 178-180 ° C.
^19^20^4^4^ Beregnet; C = 56,99 Fundet: C = 57,41 H « 5,03 H = 5,39 N = 13,99 N = 14,14 S = 8,01 S = 7,68 7 145822^ 19 ^ 20 ^ 4 ^ 4 ^ Calculated; C = 56.99 Found: C = 57.41 H + 5.03 H = 5.39 N = 13.99 N = 14.14 S = 8.01 S = 7.68 7 145822
Eksempel 2 3,4-dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]-benzonitril (II) 5.0 g (0,028 ml) 1-(2-furoyl)-piperazin (VI) og 2,83 g (0,028 mol) triethylamin opløses i 60 ml dichlormethan. Denne opløsning tilsættes under omrøring ved ca. 0°C til en blanding af 3,86 g (0,0336 mol) thiophosgen i 50 ml dichlormethan. Efter tilsætningen omrøres i 2 timer ved 0°C og i 3 timer ved stuetemperatur. Triethyl-aminhydrochloridet frafiltreres, og opløsningen inddampes i vacuum. Remanensen, 4-(2-furoyl)-piperazinylthiocarbonylchlorid (VII) opløses på ny i 50 ml dichlormethan og tilsættes under omrøring ved 0°C til en opløsning af 4,98 g (0,028 mol) 3,4-dimethoxy-6-aminobenzonitril (IV) og 2,83 g (0,028 mol) triethylamin i 60 ml dichlormethan. Der blandes i 2 timer ved 0°C og derefter i 2 - 3 timer ved stuetemperatur. Triethylaminhydrochloridet frafiltreres, og opløsningen vaskes med vand, tørres med MgSO^ og inddampes til tørhed i vacuum. Der fås 6,2 g (55% af det teoretiske udbytte) 3,4-dimethoxy-6-[4-(2-furoyl)--1-piperazinylthiocarbamido]benzonitril. Smeltepunkt 175 - 178°C.Example 2 3,4-Dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile (II) 5.0 g (0.028 ml) 1- (2-furoyl) -piperazine (VI) and 2.83 g (0.028 mol) of triethylamine is dissolved in 60 ml of dichloromethane. This solution is added with stirring at ca. To a mixture of 3.86 g (0.0336 mole) of thiophosgene in 50 ml of dichloromethane. After the addition, stir for 2 hours at 0 ° C and for 3 hours at room temperature. The triethylamine hydrochloride is filtered off and the solution is evaporated in vacuo. The residue, 4- (2-furoyl) -piperazinylthiocarbonyl chloride (VII) is redissolved in 50 ml of dichloromethane and added with stirring at 0 ° C to a solution of 4.98 g (0.028 mol) of 3,4-dimethoxy-6-aminobenzonitrile (IV) and 2.83 g (0.028 mol) of triethylamine in 60 ml of dichloromethane. Mix for 2 hours at 0 ° C and then for 2 - 3 hours at room temperature. The triethylamine hydrochloride is filtered off and the solution is washed with water, dried with MgSO4 and evaporated to dryness in vacuo. 6.2 g (55% of theoretical yield) of 3,4-dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile are obtained. Melting point 175 - 178 ° C.
Eksempel 3 a) Methyl-N-(3,4-dimethoxy-6-cyanophenyl)-[4-(2-furoyl)-1-piperazi-nyl]-thioformamidat-hydroiodid (III·ΗΙ) 20.0 g (0,05 mol) 3,4-dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido] benzonitril opløses i 200 ml bis-methoxyethylether (diglym) og tilsættes 14,2 g (0,1 mol) methyliodid. Blandingen opvar- o mes under tilbagesvali ng i 9 timer ved 60 C. Opløsningen nedkøles til stuetemperatur og filtreres. Det krystallinske reaktionsprodukt vaskes med ether og tørres. Der fås 24,6 g (90% af det teoretiske udbytte) methyl-N-(3,4-dimethoxy-6-cyanophenyl)-[4-(2-furoyl) -1-piperazinyl]thioformamidat-hydroiodid. Smeltepunkt 163°C.Example 3 a) Methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamidate hydroiodide (III · ΗΙ) 20.0 g (0.05 Mole) 3,4-Dimethoxy-6- [4- (2-furoyl) -1-piperazinylthiocarbamido] benzonitrile is dissolved in 200 ml of bis-methoxyethyl ether (diglyme) and 14.2 g (0.1 mole) of methyl iodide are added. The mixture is heated at reflux for 9 hours at 60 ° C. The solution is cooled to room temperature and filtered. The crystalline reaction product is washed with ether and dried. 24.6 g (90% of theory) of methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamidate hydroiodide are obtained. Melting point 163 ° C.
C20H23IN4°4S Beregneti C = 44,29 Pundet: C = 44,25 H = 4,27 H = 4,26 I = 23,39 I = 22,93 N = 10,33 N = 9,61 S = 5,91 S = 5,58 8 145822 b) Methyl-N-(3,4-dimethoxy-6-cyanopheny1)-[4-(2-furoyl)-1-piperazinyl] thioformamidat (III) 62.0 g (0,114 mol) methyl-N-(3,4-dimethoxy-6-cyanophenyl)--[4-(2-furoyl)-1-piperazinyl]thioformamidat-hydroiodid opløses ved 0 - 5°C i 350 ml methanol, og under omrøring tilsættes 186 ml 25% ammoniakopløsning. Der omrøres i 2 timer ved 0°C, produktet frafiltreres og vaskes med ether. Der fås 42,7 g (90% af det teoretiske udbytte) methyl-N-(3,4-dimethoxy-6-cyanophenyl)-[4-(2-furoyl)-1-piperazinyl]-thioformamidat. Smeltepunkt 105 - 107°C.C20H23IN4 ° 4S Calculated C = 44.29 Pounds: C = 44.25 H = 4.27 H = 4.26 I = 23.39 I = 22.93 N = 10.33 N = 9.61 S = 5, 91 S = 5.58 8 145822 b) Methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamidate (III) 62.0 g (0.114 mol) methyl -N- (3,4-Dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamidate hydroiodide is dissolved at 0 - 5 ° C in 350 ml of methanol and with stirring is added 186 ml 25% ammonia solution. Stir for 2 hours at 0 ° C, filter the product and wash with ether. 42.7 g (90% of theory) of methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1-piperazinyl] thioformamidate are obtained. Melting point 105 - 107 ° C.
C20H22N4°4S Beregnet; C = 57,95 Pundet*. C = 58,01 H = 5,36 H = 5,54 N = 13,52 N = 13,73 S = 7,73 S = 7,53 c) 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-1-piperazinyl]-quinazolin (I) 7.0 g (0,017 mol) methyl-N-(3,4-dimethoxy-6-cyanophenyl)- -[4-(2-furoyl)-1-piperazinyl]thioformamidat opløses i 100 ml formamid og tilsættes 2,0 g (0,051 mol) natriumamid. Opløsningen mættes med NHg-gas ved 0°C. Opløsningens temperatur hæves langsomt til 120°C, og opløsningen holdes over en periode på 24 timer opvarmet til denne temperatur under samtidig tilførsel af NHg-gas. Den afkølede reaktions-blanding udhældes i 100 ml isvand og ekstraheres 6-7 gange med 50 ml chloroform. Chloroformekstrakten vaskes 4 gange med 50 ml vand, tørres og inddampes til tørhed i vacuum. Produktet udkrystalliseres fra ethanol/vand-blandingen (50:15). Der fås 6,7-dimethoxy-4-amino-2--[4-(2-furoyl)-1-piperazinyl]quinazolin. Smeltepunkt 262 - 264°C. Produktets IR- og NMR-spektre er identiske med spektre for forbindelsen fremstillet ifølge tidligere publicerede fremgangsmåder.C20H22N4 ° 4S Calcd; C = 57.95 Pounds *. C = 58.01 H = 5.36 H = 5.54 N = 13.52 N = 13.73 S = 7.73 S = 7.53 c) 6,7-Dimethoxy-4-amino-2- [ 4- (2-Furoyl) -1-piperazinyl] -quinazoline (I) 7.0 g (0.017 mol) of methyl N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2-furoyl) -1 -piperazinyl] thioformamidate is dissolved in 100 ml of formamide and 2.0 g (0.051 mol) of sodium amide is added. The solution is saturated with NH 3 gas at 0 ° C. The temperature of the solution is slowly raised to 120 ° C, and the solution is heated to this temperature over a period of 24 hours with simultaneous supply of NHg gas. The cooled reaction mixture is poured into 100 ml of ice water and extracted 6-7 times with 50 ml of chloroform. The chloroform extract is washed 4 times with 50 ml of water, dried and evaporated to dryness in vacuo. The product is crystallized from the ethanol / water mixture (50:15). 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline is obtained. Melting point 262 - 264 ° C. The product's IR and NMR spectra are identical to the spectra of the compound prepared according to previously published methods.
C19H21N5O4 Beregnet: C = 59,52 Pundet: C = 59,28 H = 5,52 H = 5,88 N = 18,27 N = 17,99 9 145822C19H21N5O4 Calculated: C = 59.52 Pound: C = 59.28 H = 5.52 H = 5.88 N = 18.27 N = 17.99 9 145822
Eksempel 4 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-l-piperazinyl]quinazolin (I) 17,6 g (0,044 mol) 3,4-dimethoxy-6-[4-(2-furoyl)-l-pipera-zinylthiocarbamido]benzonitril opløses i 100 ml formamid og tilsættes 12,5 g (0,088 mol) methyliodid og opvarmes i 9 timer til 60°C. Overskudsmængden af methyliodid afdampes, og opløsningen mættes med NH3-gas ved 0°C, og til opløsningen sættes 6,9 g (0,176 mol) natriumamid. Temperaturen hæves til 120-140°C, og opløsningen holdes ved opvarmning på denne temperatur i 24 timer under samtidig tilførsel af NH3-gas. Den afkølede reaktionsblanding udhældes i isvand (ca. 150ml) og ekstraheres med chloroform (8x50 ml), chloro-formekstrakten vaskes med vand, behandles med aktivt kul, tørres og inddampes til tørhed i vacuum. Resten udkrystalliseres af ethanol/ vand-blandingen (50:15). Der fås 6,7-dimethoxy-4-amino~2-[4-(2-furoyl)-l-piperazinyl]quinazolin. Smeltepunkt 263-265°C.Example 4 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline (I) 17.6 g (0.044 mole) of 3,4-dimethoxy-6- [4- (2-Furoyl) -1-piperazinylthiocarbamido] benzonitrile is dissolved in 100 ml of formamide and 12.5 g (0.088 mol) of methyl iodide is added and heated for 9 hours to 60 ° C. The excess amount of methyl iodide is evaporated and the solution is saturated with NH 3 gas at 0 ° C and 6.9 g (0.176 mole) of sodium amide are added to the solution. The temperature is raised to 120-140 ° C and the solution is maintained by heating at this temperature for 24 hours while simultaneously adding NH 3 gas. The cooled reaction mixture is poured into ice water (about 150ml) and extracted with chloroform (8x50ml), the chloroform extract is washed with water, treated with activated carbon, dried and evaporated to dryness in vacuo. The residue is crystallized by the ethanol / water mixture (50:15). 6,7-Dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline is obtained. Melting point 263-265 ° C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI763614 | 1976-12-15 | ||
| FI763614A FI58124C (en) | 1976-12-15 | 1976-12-15 | NY MELLANPROTUKT 3,4-DIMETOXY-6- (4- (2-FUROYL) -1-PIPERAZINYLTHOUREA) -BENONITRIL FOR FRAMSTAELLNING AV 6,7-DIMETOXY-4-AMINO-2- (4- (2-FUROYL) -1 -PIPERAZINYL) QUINAZOLINE WITH BLODTRYCKSSAENKANDE VERKAN |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK558377A DK558377A (en) | 1978-06-16 |
| DK145822B true DK145822B (en) | 1983-03-14 |
| DK145822C DK145822C (en) | 1983-08-29 |
Family
ID=8510504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK558377A DK145822C (en) | 1976-12-15 | 1977-12-14 | 3,4-DIMETHOXY-6- (4- (2-FUROYL) -1-PIPERAZINYLTHIOCARBAMIDO) BENZONITRIL USED AS INTERMEDIATE IN THE PREPARATION OF 6,7-DIMETHOXY-4-AMINO-2- (4- (2-FURO) 1-piperazinyl) quinazoline |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS5387375A (en) |
| AT (1) | AT358047B (en) |
| BE (1) | BE861822A (en) |
| CA (1) | CA1102332A (en) |
| CH (1) | CH630624A5 (en) |
| CS (1) | CS197312B2 (en) |
| DD (1) | DD134226A1 (en) |
| DE (1) | DE2755638A1 (en) |
| DK (1) | DK145822C (en) |
| FI (1) | FI58124C (en) |
| HU (1) | HU174048B (en) |
| NL (1) | NL7713703A (en) |
| NO (1) | NO146239C (en) |
| PL (1) | PL106201B1 (en) |
| SE (1) | SE424993B (en) |
| SU (1) | SU923370A3 (en) |
| ZA (1) | ZA777222B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI67699C (en) * | 1979-01-31 | 1985-05-10 | Orion Yhtymae Oy | PROCEDURE FOR THE FRAMSTATION OF AV 6,7-DIMETOXY-4-AMINO-2- (4- (2-FUROYL) -1-PIPERAZINYL) QUINAZOLINE HYDROCHLORIDE WITH BLODTRYCKSSAENKANDE VERKAN |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3935213A (en) * | 1973-12-05 | 1976-01-27 | Pfizer Inc. | Process for hypotensive 4-amino-2-(piperazin-1-yl) quinazoline derivatives |
-
1976
- 1976-12-15 FI FI763614A patent/FI58124C/en not_active IP Right Cessation
-
1977
- 1977-11-24 CH CH1438277A patent/CH630624A5/en not_active IP Right Cessation
- 1977-11-25 SE SE7713377A patent/SE424993B/en not_active IP Right Cessation
- 1977-12-05 AT AT867177A patent/AT358047B/en not_active IP Right Cessation
- 1977-12-05 ZA ZA00777222A patent/ZA777222B/en unknown
- 1977-12-11 NL NL7713703A patent/NL7713703A/en not_active Application Discontinuation
- 1977-12-12 NO NO774263A patent/NO146239C/en unknown
- 1977-12-13 PL PL1977202898A patent/PL106201B1/en unknown
- 1977-12-13 HU HU77OI217A patent/HU174048B/en not_active IP Right Cessation
- 1977-12-14 BE BE183425A patent/BE861822A/en not_active IP Right Cessation
- 1977-12-14 DE DE19772755638 patent/DE2755638A1/en not_active Ceased
- 1977-12-14 CA CA293,066A patent/CA1102332A/en not_active Expired
- 1977-12-14 DK DK558377A patent/DK145822C/en not_active IP Right Cessation
- 1977-12-14 SU SU772555751A patent/SU923370A3/en active
- 1977-12-15 JP JP15157177A patent/JPS5387375A/en active Granted
- 1977-12-15 CS CS778433A patent/CS197312B2/en unknown
- 1977-12-15 DD DD77202667A patent/DD134226A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5387375A (en) | 1978-08-01 |
| DE2755638A1 (en) | 1978-06-22 |
| DD134226A1 (en) | 1979-02-14 |
| DK558377A (en) | 1978-06-16 |
| CA1102332A (en) | 1981-06-02 |
| ATA867177A (en) | 1980-01-15 |
| BE861822A (en) | 1978-03-31 |
| SU923370A3 (en) | 1982-04-23 |
| PL202898A1 (en) | 1978-08-28 |
| DK145822C (en) | 1983-08-29 |
| NO774263L (en) | 1978-06-16 |
| FI58124B (en) | 1980-08-29 |
| PL106201B1 (en) | 1979-12-31 |
| NO146239B (en) | 1982-05-18 |
| CH630624A5 (en) | 1982-06-30 |
| NL7713703A (en) | 1978-06-19 |
| ZA777222B (en) | 1978-09-27 |
| SE7713377L (en) | 1978-06-16 |
| AT358047B (en) | 1980-08-11 |
| SE424993B (en) | 1982-08-23 |
| CS197312B2 (en) | 1980-04-30 |
| FI58124C (en) | 1980-12-10 |
| NO146239C (en) | 1982-08-25 |
| HU174048B (en) | 1979-10-28 |
| JPS6225145B2 (en) | 1987-06-01 |
| FI763614A (en) | 1978-06-16 |
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