NO783086L - PROCEDURE FOR PREPARING NEW PYRIMIDINE DERIVATIVES - Google Patents

PROCEDURE FOR PREPARING NEW PYRIMIDINE DERIVATIVES

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Publication number
NO783086L
NO783086L NO783086A NO783086A NO783086L NO 783086 L NO783086 L NO 783086L NO 783086 A NO783086 A NO 783086A NO 783086 A NO783086 A NO 783086A NO 783086 L NO783086 L NO 783086L
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methyl
pyrimidine
hydrogen
lower alkyl
pyrazolo
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NO783086A
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Norwegian (no)
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Uwe D Treuner
Hermann Breuer
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Squibb & Sons Inc
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Priority claimed from US05/833,103 external-priority patent/US4124764A/en
Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc
Publication of NO783086L publication Critical patent/NO783086L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings 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
    • C07D231/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

"Fremgangsmåte for fremstilling"Procedure of manufacture

av nye pyrimidinderivater" of new pyrimidine derivatives"

U.S.-patent 4.053.474 utstedt 11. oktober 1977 beskriver en gruppe 3-merkapto-7H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]-pyrimidiner som er usubstituert eller lavere-alkyl-substituert i 7- og/eller 9-stillingene, og derivater hvor svovelatomet i 3-stilling bærer forskjellige substituenter. Disse tidligere beskrevne forbindelser fremstilles i henhold til en metode fra et 1- og/eller 3-usubstituert eller substituert 4-halogen-pyrazolot3,4-d]pyrimidin ved behandling i rekkefølge med hydrazin og 1,1-tiokarbonyldiimidazol. Disse forbindelser har formelen U.S. Patent 4,053,474 issued October 11, 1977 discloses a group of 3-mercapto-7H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]-pyrimidines which are unsubstituted or lower -alkyl-substituted in the 7- and/or 9-positions, and derivatives where the sulfur atom in the 3-position carries different substituents. These previously described compounds are prepared according to a method from a 1- and/or 3-unsubstituted or substituted 4-halo-pyrazolo3,4-d]pyrimidine by treatment in sequence with hydrazine and 1,1-thiocarbonyldiimidazole. These compounds have the formula

hvor R, og R9hver er hydrogen eller lavere alkyl; R_ er hydrogen, et salt-dannende ion, lavere alkyl eller substituert lavere alkyl hvor substituenten på lavere alkyl er hydroksy, cyano, fenyl, wherein R 1 and R 9 are each hydrogen or lower alkyl; R_ is hydrogen, a salt-forming ion, lower alkyl or substituted lower alkyl where the substituent on lower alkyl is hydroxy, cyano, phenyl,

R4er lavere alkyl eller fenyl; R5og R^er hver R 4 is lower alkyl or phenyl; R 5 and R 5 are each

hydrogen eller lavere alkyl, eller R^ ogR^sammen med nitrogen-atomet danner et av de heterocykliske radikaler pyrrolidino, piperidino, morfolino eller piperazino; og R^og Rg er hver hydrogen eller lavere alkyl. hydrogen or lower alkyl, or R^ and R^ together with the nitrogen atom form one of the heterocyclic radicals pyrrolidino, piperidino, morpholino or piperazino; and R 1 and R 8 are each hydrogen or lower alkyl.

Det er nu funnet at behandling av det samme usubstituerte eller substituerte 4-halogenpyrazolo[3,4-d]pyrimidin med et mono-substituert hydrazin istedenfor hydrazin og derefter med 1,1-tiokarbonyldiimidazol gir et 1,7-dihydro-l-substituert-3H-pyrazolot 4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-tion meso-ionisk didehydro-derivat, et indre salt eller meso-ionisk form hvor svovelatomet har en negativ ladning og et nitrogen har en positiv ladning, og substituenten på den opprinnelige hydrazin-reagens er nu i 1-stilling. De samme meso-ioniske derivater kan også oppnås ved å anvende karbondisulfid istedenfor 1,1-tiokarbonyldiimidazol. Når 1,1-karbonyldiimidazol anvendes istedenfor 1,1-tiokarbonyldiimidazol, får man på tilsvarende måte de analoge oksygenholdige forbindelser. It has now been found that treatment of the same unsubstituted or substituted 4-halopyrazolo[3,4-d]pyrimidine with a mono-substituted hydrazine instead of hydrazine and then with 1,1-thiocarbonyldiimidazole gives a 1,7-dihydro-l-substituted -3H-pyrazolot 4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-thione meso-ionic didehydro derivative, an inner salt or meso-ionic form in which the sulfur atom has a negative charge and a nitrogen has a positive charge, and the substituent on the original hydrazine reagent is now in the 1-position. The same meso-ionic derivatives can also be obtained by using carbon disulphide instead of 1,1-thiocarbonyldiimidazole. When 1,1-carbonyldiimidazole is used instead of 1,1-thiocarbonyldiimidazole, the analogous oxygen-containing compounds are obtained in a similar way.

De nye 1,7-dihydro-l-substituerte-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-tion eller -3-on meso-ioniske didehydro-derivater som fremstilles ifølge oppfinnelsen, har den generelle formel The new 1,7-dihydro-1-substituted-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-thione or -3-one meso-ionic didehydro derivatives produced according to the invention have the general formula

hvor er hydrogen, lavere alkyl, fenyl-lavere alkyl, hydroksy-lavere alkyl eller cyklo-lavere alkyl; R er hydrogen eller lavere alkyl; R^ er lavere alkyl, cyklo-lavere alkyl eller hydroksy-lavere alkyl; og X er svovel eller oksygen. where is hydrogen, lower alkyl, phenyl-lower alkyl, hydroxy-lower alkyl or cyclo-lower alkyl; R is hydrogen or lower alkyl; R 1 is lower alkyl, cyclo-lower alkyl or hydroxy-lower alkyl; and X is sulfur or oxygen.

De lavere alkylgrupper betegnet med R^, R_ og R^er lineære eller forgrenede alifatiske hydrokarbonradikaler med opp til 7 karbonatomer. C^-C^-gruppene, og særlig C^-C^-gruppene foretrekkes. Illustrerende lavere alkylgrupper er metyl, etyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl og lignende. The lower alkyl groups denoted by R₁, R₂ and R₂ are linear or branched aliphatic hydrocarbon radicals with up to 7 carbon atoms. The C^-C^ groups, and especially the C^-C^ groups, are preferred. Illustrative lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl and the like.

Hydroksy-lavere-alkyl-gruppene er tilsvarende grupper som bærer en hydroksysubstituent, fortrinnsvis på ende-karbonatomet, f.eks. hydroksymetyl, 2-hydroksyetyl, 3-hydroksypropyl o.l. De samme preferanser som ovenfor gjelder. The hydroxy-lower alkyl groups are corresponding groups bearing a hydroxy substituent, preferably on the terminal carbon atom, e.g. hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc. The same preferences as above apply.

Tilsvarende har fenyl-lavere-alkyl-gruppene en fenyl-substituent på alkylkjeden, fortrinnsvis på ende-karbonatomet. Igjen foretrekkes de grupper som har ett til fire karbonatomer i alkylkjeden, særlig ett eller to, slik som i fenylmetyl og fenyl-etyl. Cyklo-lavere-alkyl-gruppene har opp til 7 karbonatomer, fortrinnsvis Cc-Cr. Similarly, the phenyl lower alkyl groups have a phenyl substituent on the alkyl chain, preferably on the terminal carbon atom. Again, those groups which have one to four carbon atoms in the alkyl chain are preferred, especially one or two, such as in phenylmethyl and phenylethyl. The cyclo-lower alkyl groups have up to 7 carbon atoms, preferably Cc-Cr.

DD DD

Det foretrekkes forbindelser med formel I hvor og R^hver er lavere alkyl, særlig C]_-C4 alkyl, og R2ér hydrogen, og X er spesielt svovel. Eksemplene illustrerer spesielle fore-trukne utførelsesformer. Preference is given to compounds of formula I where and R 1 are each lower alkyl, especially C 1 -C 4 alkyl, and R 2 is hydrogen, and X is especially sulphur. The examples illustrate particular preferred embodiments.

De nye forbindelser fremstilles i henhold til oppfinnelsen fra et 4-halogenpyrazolo[3,4-d]pyrimidin med formelen The new compounds are prepared according to the invention from a 4-halopyrazolo[3,4-d]pyrimidine with the formula

hvor hal betyr halogen, fortrinnsvis klor. 4-halogenpyrazolo[3,4-d]pyrimidinet omsettes først med et substituert, hydrazin med formelen i en alkohol så som etanol eller propanol, fortrinnsvis ved om-trentlig omgivelsestemperatur. Denne reaksjon resulterer i et mellomprodukt som har formelen where hal means halogen, preferably chlorine. The 4-halopyrazolo[3,4-d]pyrimidine is first reacted with a substituted hydrazine of the formula in an alcohol such as ethanol or propanol, preferably at approximately ambient temperature. This reaction results in an intermediate product having the formula

Når mellomproduktet med formel IV derefter omsettes med 1,1-tiokarbonyldiimidazol eller med karbondisulfid i et inert organisk reaksjonsmedium så som dimetylformamid, etylacetat, diglym eller lignende, fortrinnsvis ved forhøyet temperatur, f.eks. ca. 80°C, får man et produkt med formel I hvor X er svovel. Når 1,1-karbonyldiimidazol anvendes i stedet, får man et produkt med formel I hvor X er oksygen. When the intermediate product of formula IV is then reacted with 1,1-thiocarbonyldiimidazole or with carbon disulphide in an inert organic reaction medium such as dimethylformamide, ethyl acetate, diglyme or the like, preferably at an elevated temperature, e.g. about. 80°C, a product of formula I is obtained where X is sulphur. When 1,1-carbonyldiimidazole is used instead, a product of formula I is obtained where X is oxygen.

Når er hydrogen eller hydroksy-lavere alkyl, bør hen-holdsvis 1-stillingen eller hydroksy-funksjonen beskyttes, f.eks. som i U.S.-patent 3.828.057, før omsetning med diimidazolet, hvor-efter den beskyttende gruppe fjernes. When hydrogen or hydroxy is lower alkyl, the 1-position or the hydroxy function, respectively, should be protected, e.g. as in U.S. Patent 3,828,057, before reaction with the diimidazole, after which the protecting group is removed.

Utgangsmaterialene kan fremstilles som beskrevet i vårt innledningsvis angitte patent, i U.S.-patent 3.720.674 utstedt 13. mars 1973, 3.732.225 utstedt 8. mai 1973 og 3.873.556 utstedt 25. mars 1975, og J. Org. Chem. 21, 1240 (1956). The starting materials may be prepared as described in our preamble, U.S. Patents 3,720,674 issued March 13, 1973, 3,732,225 issued May 8, 1973, and 3,873,556 issued March 25, 1975, and J. Org. Chem. 21, 1240 (1956).

De nye forbindelser fremstilt ifølge oppfinnelsen har antiinflammatoriske egenskaper og er nyttige som antiinflammatoriske midler, for eksempel for bekjempelse av lokale inflamma-toriske tilstander slik som de som er av en ødematøs natur eller skyldes utbredelse av bindevev i forskjellige pattedyr-arter så som rotter, hunder og lignende, ved oral administrering i doser på ca. 1 til 100 mg/kg/dag, fortrinnsvis 3 til 20 mg/kg/dag, i en enkelt eller 2 til 4 delte doser, som angitt av Mouse Active Arthus Assay. Den aktive forbindelse tilberedes i et preparat så som tablett, kapsel, oppløsning eller.suspensjon inneholdende opp til 500 mg pr. enhetsdose av en forbindelse eller en blanding av forbindelser med formel I. Materialet blandes på vanlig måte med et fysiologisk forlikelig bæremiddel, hjelpestoff, bindemiddel, konserveringsmiddel, stabiliseringsmiddel, smaksstoff osv., efter-som hva som er nødvendig i henhold til vanlig farmasøytisk praksis. Topiske' preparater inneholdende ca. 0,01 til 3 vektprosent aktiv forbindelse i en vanlig væske, krem eller salve, kan også anvendes. The new compounds produced according to the invention have anti-inflammatory properties and are useful as anti-inflammatory agents, for example for combating local inflammatory conditions such as those which are of an oedematous nature or due to proliferation of connective tissue in various mammalian species such as rats, dogs and the like, by oral administration in doses of approx. 1 to 100 mg/kg/day, preferably 3 to 20 mg/kg/day, in a single or 2 to 4 divided doses, as indicated by the Mouse Active Arthus Assay. The active compound is prepared in a preparation such as a tablet, capsule, solution or suspension containing up to 500 mg per unit dose of a compound or a mixture of compounds of formula I. The material is mixed in the usual way with a physiologically compatible carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc., as required according to normal pharmaceutical practice. Topical preparations containing approx. 0.01 to 3% by weight of active compound in a common liquid, cream or ointment can also be used.

De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere<q>g tjene som modell for fremstilling av andre forbindelser ved å anvende andre passende substituerte reak-sjonskomponenter. Alle temperaturer er i grader celsius. The following examples shall serve to further illustrate the invention and serve as a model for the preparation of other compounds by using other suitably substituted reaction components. All temperatures are in degrees Celsius.

Eksempel 1 Example 1

1, 7- dihydro- l, 7- dimetyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo[ 4, 3- c]-pyrimidin- 3- tion meso- ionisk didehydro- derivat 1, 7- dihydro- 1, 7- dimethyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo[ 4, 3- c]- pyrimidine- 3- thione meso- ionic didehydro- derivative

A. 1- metyl- 4- karboetoksy- 5- aminopyrazolA. 1- methyl- 4- carboethoxy- 5- aminopyrazole

320 g etoksymetylen-cyanoeddiksyreester oppløses i 2 liter . absolutt etanol. 87 g metyl-hydrazin tilsettes dråpevis under omrøring. Temperaturen stiger til 35°. Reaksjonsblandingen til-bakeløpsbehandles derefter i 12 timer. Efter avdestillering av oppløsningsmidlet krystalliseres det faste residuum fra litt metanol for å gi 162 g (95,8%) l-metyl-4-karboetoksy-5-aminopyrazol, sm.p. 92-93°. Dissolve 320 g of ethoxymethylene-cyanoacetic acid ester in 2 litres. absolute ethanol. 87 g of methylhydrazine are added dropwise while stirring. The temperature rises to 35°. The reaction mixture is then refluxed for 12 hours. After distilling off the solvent, the solid residue is crystallized from a little methanol to give 162 g (95.8%) of 1-methyl-4-carboethoxy-5-aminopyrazole, m.p. 92-93°.

B. 5-[( etoksynretylen) amino]- l- metyl- lH- pyrazol- 4-karboksylsyre- etylestér B. 5-[(ethoxynethylene)amino]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

84,6 g l-metyl-4-karboetoksy-5-aminopyrazol og 74,1 g ortomaursyre-trietylester oppvarmes sammen inntil avspaltningen av etanol er opphørt. Det oljeaktige residuum destilleres under oljepumpe-vakuum for å gi 5-[(etoksymetylen)amino]-1-metyl-lH-pyrazol-4-karboksylsyre-etylester, k.p. 98-102°; sm.p. 32-34° 84.6 g of 1-methyl-4-carboethoxy-5-aminopyrazole and 74.1 g of orthoformic acid triethyl ester are heated together until the separation of ethanol has ceased. The oily residue is distilled under oil pump vacuum to give 5-[(ethoxymethylene)amino]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, m.p. 98-102°; sm.p. 32-34°

(utbytte 87%).(yield 87%).

C. 1- metyl- l, 5- dihydro- 4H- pyrazolo[ 3, 4- d] pyrimidin- 4- on 57,2 g 5-[(etoksymetylen)amino]-l-metyl-lH-pyrazol-4-karboksylsyre-etylester oppløses i 200 ml etanol, 4,4 g ammoniakk tilsettes, og reaksjonsblandingen autoklaveres ved 60° i 40 timer. Efter avkjøling filtreres blandingen, og det gjenværende 1-metyl-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidin-4-on krystalliseres fra dimetylformamid, sm.p. 289-290° (utbytte 31 g - 80,7%). C. 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 57.2 g 5-[(ethoxymethylene)amino]-1-methyl-1H-pyrazol-4- carboxylic acid ethyl ester is dissolved in 200 ml of ethanol, 4.4 g of ammonia is added, and the reaction mixture is autoclaved at 60° for 40 hours. After cooling, the mixture is filtered, and the remaining 1-methyl-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidin-4-one is crystallized from dimethylformamide, m.p. 289-290° (yield 31 g - 80.7%).

D. l- metyl- 4- klorpyrazolo[ 3, 4- d] pyrimidinD. 1-methyl-4-chloropyrazolo[3,4-d]pyrimidine

80 g 1-metyl-l ,,5-dihydro-4H-pyrazolo[ 3 , 4^d] -pyrimidin-4-on settes til 300 ml fosforoksyklorid, og blandingen tilbake-løpsbehandles. Efter avdestillering av overskudd av fosforoksyklorid ekstraheres det halvfaste residuum med 3 x 100 ml kokende benzen.Benzenekstraktene samles og konsentreres til halvt volum og settes derefter til petroleter. , Efter henstand 12 timer i kjøleskap filtreres det utfelte l-metyl-4-klorpyrazolo-[3,4-d]pyrimidin under sugning og omkrystalliseres fra.cykloheksan for å gi 54 g hvite krystaller, sm.p. 93-96° (utbytte 60,5%). E. ' l- metyl- 4-( 1- metylhydrazino) pyrazolot 3, 4- d] pyrimidin 81 g l-metyl-4-klorpyrazolo[3,4-d]pyrimidin oppløses.i 1 liter n-propanol. 45 g metylhydrazin tilsettes dråpevis ved romtemperatur, og blandingen omrøres i 35 timer. Reaksjonsblandingen filtreres, og det gjenværende l-metyl-4-(1-metylhydrazino) pyrazolot 3 , 4-d] pyrimidin omkrystalliseres to ganger fra dimetylformamid med tilsatt aktivt kull for å gi 67,2 g hvitt, krystallinsk produkt, sm.p. 214° (utbytte 84%). F. 1, 7- dihydro- l, 7- dimetyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4-triazolo[ 4, 3- c] pyrimidin- 3- tion meso- ionisk didehydro-derivat 31 g l-metyl-4-(1-metylhydrazino)pyrazolot3,4-d]pyrimidin oppløses i 100 ml dimetylformamid, og 30 g 1,1-tiokarbonyldiimidazol oppløst i 20 ml dimetylformamid tilsettes alt på en gang. Reaksjonsblandingen omrøres i 12 timer ved romtemperatur.Bunnfallet filtreres under sugning, og sammen med residuet som erholdes ved konsentrering av filtratet, krystalles det fra dimetylformamid med tilsatt aktivt kull. Man får 2 9 g 1,7-dihydro-1,7-dimetyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]-pyrimidin-3-tion meso-ionisk didehydro-derivat som gulaktige, filt-lignende krystaller, sm.p. >270° (utbytte 75,4%). 80 g of 1-methyl-1,5-dihydro-4H-pyrazolo[3,4^d]-pyrimidin-4-one are added to 300 ml of phosphorus oxychloride, and the mixture is refluxed. After distilling off excess phosphorus oxychloride, the semi-solid residue is extracted with 3 x 100 ml of boiling benzene. The benzene extracts are collected and concentrated to half the volume and then added to petroleum ether. After standing for 12 hours in a refrigerator, the precipitated 1-methyl-4-chloropyrazolo-[3,4-d]pyrimidine is filtered with suction and recrystallized from cyclohexane to give 54 g of white crystals, m.p. 93-96° (yield 60.5%). E. 1-methyl-4-(1-methylhydrazino)pyrazolo3,4-d]pyrimidine 81 g of 1-methyl-4-chloropyrazolo[3,4-d]pyrimidine are dissolved in 1 liter of n-propanol. 45 g of methylhydrazine are added dropwise at room temperature, and the mixture is stirred for 35 hours. The reaction mixture is filtered and the remaining 1-methyl-4-(1-methylhydrazino)pyrazolo 3 , 4- d ]pyrimidine is recrystallized twice from dimethylformamide with added activated charcoal to give 67.2 g of white crystalline product, m.p. 214° (yield 84%). F. 1, 7- dihydro- 1, 7- dimethyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4-triazolo[ 4, 3- c] pyrimidine- 3- thione meso- ionic didehydro derivative 31 g of 1-methyl-4-(1-methylhydrazino)pyrazolo3,4-d]pyrimidine are dissolved in 100 ml of dimethylformamide, and 30 g of 1,1-thiocarbonyldiimidazole dissolved in 20 ml of dimethylformamide are added all at once. The reaction mixture is stirred for 12 hours at room temperature. The precipitate is filtered with suction, and together with the residue obtained by concentrating the filtrate, it is crystallized from dimethylformamide with added activated carbon. 29 g of 1,7-dihydro-1,7-dimethyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]-pyrimidine-3-thione meso- ionic didehydro derivative as yellowish, felt-like crystals, m.p. >270° (yield 75.4%).

Eksempel 2 Example 2

1, 7- dihydro- l- metyl- 7- metyletyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo-[ 4, 3- c] pyrimidin- 3- tion meso- ionisk didehydro- derivat 1, 7- dihydro- l- methyl- 7- methylethyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo-[ 4, 3- c] pyrimidine- 3- thione meso- ionic didehydro- derivative

A. l- metyletyl- 4- karboetoksy- 5- aminopyrazolA. 1- methylethyl- 4- carboethoxy- 5- aminopyrazole

Ved å anvende isopropylhydrazin istedenfor metylhydrazin ved fremgangsmåten ifølge eksempel IA, får man l-metyletyl-4-karboetoksy-5-aminopyrazol, k.p. Q05mm 123-127°. By using isopropylhydrazine instead of methylhydrazine in the method according to example IA, 1-methylethyl-4-carboethoxy-5-aminopyrazole is obtained, b.p. Q05mm 123-127°.

B. 5-[( etoksymetylen) amino]- 1-( metyletyl)- lH- pyrazol-4- karboksylsyre- etylester B. 5-[(ethoxymethylene)amino]-1-(methylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

Ved å anvende produktet fra del A ved fremgangsmåten ifølge eksempel 1(B), får man 5-[(etoksymetylen)amino]-1-(metyletyl)-lH-pyrazol-4-karboksylsyre-etylester, k.p. Q Ql 98-103°.By using the product from part A by the method according to example 1(B), 5-[(ethoxymethylene)amino]-1-(methylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester is obtained, b.p. QQ1 98-103°.

C. 1- isopropyl- l, 5- dihydro- 4H- pyrazolo[ 3, 4- d] pyrimidin-4- on C. 1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Ved å anvende produktet fra del B ved fremgangsmåten ifølge eksempel 1(C), får man 1-isopropyl-l,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidin-4-on, sm.p. 193°. By using the product from part B by the method according to example 1(C), 1-isopropyl-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidin-4-one is obtained, m.p. 193°.

D. 4- klor- l- metyletylpyrazolo[ 3, 4- d] pyrimidinD. 4-chloro-1-methylethylpyrazolo[3,4-d]pyrimidine

Ved å anvende produktet fra del (C) ved fremgangsmåten ifølge eksempel 1(D), får man 4-klor-l-metyletylpyrazolo[3,4-d]-pyrimidin, sm.p. 47-49°. By using the product from part (C) by the method according to example 1(D), 4-chloro-1-methylethylpyrazolo[3,4-d]pyrimidine is obtained, m.p. 47-49°.

E. 1-( metyletyl)- 4-( 1- metylhydrazino) pyrazolof 3, 4- d]-pyrimidin E. 1-(methylethyl)-4-(1-methylhydrazino)pyrazolof 3,4-d]-pyrimidine

Ved å anvende produktet fra del (D) ved fremgangsmåten ifølge eksempel 1(E), får man 1-(metyletyl)-4-(1-metylhydrazino)-pyrazolo[3,4-d]pyrimidin, sm.p. 105-108°. By using the product from part (D) by the method according to example 1(E), 1-(methylethyl)-4-(1-methylhydrazino)-pyrazolo[3,4-d]pyrimidine is obtained, m.p. 105-108°.

F. 1, 7- dihydro- l- metyl- 7- metyletyl- 3H- pyrazolo[ 4, 3- e]-1, 2, 4- triazolo[ 4, 3- c] pyrimidin- 3- tion meso- ionisk didehydro- derivat F. 1, 7- dihydro- l- methyl- 7- methylethyl- 3H- pyrazolo[ 4, 3- e]-1, 2, 4- triazolo[ 4, 3- c] pyrimidine- 3- thione meso- ionic didehydro - derivative

Ved å anvende produktet fra del E ved fremgangsmåten ifølge eksempel 1(F), får man 1,7-dihydro-l-metyl-7-metyletyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-tion meso-ionisk didehydro-derivat, sm.p. 290-292°. By using the product from part E by the method according to example 1(F), 1,7-dihydro-1-methyl-7-methylethyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo is obtained [4,3-c]pyrimidine-3-thione meso-ionic didehydro derivative, m.p. 290-292°.

Eksempel 3 Example 3

1- butyl- l, 7- dihydro- 7- metyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo-[ 4, 3- c] pyrimidin - 3- tion meso- ionisk didehydro- derivat 1- butyl- 1, 7- dihydro- 7- methyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo-[ 4, 3- c] pyrimidine - 3- thione meso- ionic didehydro- derivative

A. 4-( 1- butylhydrazino)- l- metyl- lH- pyrazolo[ 3, 4- d]-• A. 4-(1-Butylhydrazino)-1-methyl-1H-pyrazolo[3,4-d]-•

pyrimidinpyrimidine

Ved å anvende butylhydrazin istedenfor metylhydrazin ved fremgangsmåten ifølge eksempel 1(E), får man 4-(1-butylhydrazino)-1-metyl-lH-pyrazolo[3,4-d]pyrimidin, sm.p. 68-72°. By using butylhydrazine instead of methylhydrazine in the method according to example 1(E), 4-(1-butylhydrazino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine is obtained, m.p. 68-72°.

B. 1- butyl- l, 7- dihydro- 7- metyl- 3H- pyrazolo[ 4, 3- e]-1, 2, 4- triazolo[ 4, 3- c] pyrimidin- 3- tion meso- ionisk didehydro- derivat B. 1- butyl- 1, 7- dihydro- 7- methyl- 3H- pyrazolo[ 4, 3- e]-1, 2, 4- triazolo[ 4, 3- c] pyrimidine- 3- thione meso- ionic didehydro - derivative

Ved å anvende produktet fra del A ved fremgangsmåten^ifølge eksempel 1(F), får man 1-butyl-l,7-dihydro-7-metyl-3H-pyrazolot 4, 3-e] -1, 2 , 4-triazolo[ 4, 3-c ] pyrimidin-^3-tion meso-ionisk didehydro-derivat, sm.p. 272-275°. By using the product from part A by the method according to example 1(F), 1-butyl-1,7-dihydro-7-methyl-3H-pyrazolo 4,3-e]-1,2,4-triazolo is obtained [ 4, 3-c ] pyrimidine-^3-thione meso-ionic didehydro derivative, m.p. 272-275°.

Eksempel 4 Example 4

1, 7- dihydro- l- metyletyl- 7- metyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo-[ 4, 3- c] pyrimidin- 3- tion meso- ionisk didehydro- derivat 1, 7- dihydro- l- methylethyl- 7- methyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo-[ 4, 3- c] pyrimidine- 3- thione meso- ionic didehydro- derivative

A. ' 4-( 1- metyletylhydrazino)- l- metyl- lH- pyrazolo[ 3, 4- d]-pyrimidin A. ' 4-(1-Methylethylhydrazino)-1-methyl-1H-pyrazolo[3,4-d]-pyrimidine

Ved å anvende isopropylhydrazin istedenfor metylhydrazin ved fremgangsmåten ifølge eksempel 1(E), får man 4-(1-metyletyl-hydrazino)-1-metyl-lH-pyrazolot3,4-d]pyrimidin, sm.p. 57°. By using isopropylhydrazine instead of methylhydrazine in the method according to example 1(E), 4-(1-methylethyl-hydrazino)-1-methyl-1H-pyrazolo3,4-d]pyrimidine is obtained, m.p. 57°.

B. 1, 7- dihydro- l- metyletyl- 7- naetyl- 3H- pyrazolo[ 4, 3- e] - B. 1, 7- dihydro- 1- methylethyl- 7- naethyl- 3H- pyrazolo[ 4, 3- e] -

1, 2, 4- triazolo[ 4, 3- c] pyrimidin- 3- tion meso- ionisk didehydro- derivat 1, 2, 4- triazolo[ 4, 3- c] pyrimidine- 3- thione meso- ionic didehydro- derivative

Ved å anvende produktet fra del A ved fremgangsmåten ifølge eksempel 1(F), får man 1,7-dihydro-l-metyletyl-7-métyl-3H-pyrazolot 4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-tion meso-ionisk didehydro-derivat, sm.p. 316-317°. By using the product from part A by the method according to example 1(F), one obtains 1,7-dihydro-1-methylethyl-7-methyl-3H-pyrazolo 4,3-e]-1,2,4-triazolo[ 4,3-c]pyrimidine-3-thione meso-ionic didehydro derivative, m.p. 316-317°.

Eksempel 5 Example 5

1, 7- dihydro- l, 7- dimetyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo[ 4, 3- c] - pyrimidin- 3- tion meso- ionisk didehydro- derivat 1, 7- dihydro- 1, 7- dimethyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo[ 4, 3- c]- pyrimidine- 3- thione meso- ionic didehydro- derivative

A. l- metyl- 4-( 1- metylhydrazino) pyrazolot 3, 4- d]- pyrimidin 1,7 g metylhydrazin oppløses i 30 ml etanol. 3,3 g 4-klor-l-metylpyrazolo[3,4-d]pyrimidin tilsettes porsjonsvis. Blandingen tilbakeløpsbehandles i 30 minutter og får derefter stå i kjøleskap natten over. Blandingen filtreres, og produktet, l-metyl-4-(1-metylhydrazino)pyrazolo[3,4-d]pyrimidin, omkrystalliseres fra etanol-metanol, sm.p. 213-215° (utbytte 4,2 g). A. 1-methyl-4-(1-methylhydrazino)pyrazolot 3,4-d]-pyrimidine Dissolve 1.7 g of methylhydrazine in 30 ml of ethanol. 3.3 g of 4-chloro-1-methylpyrazolo[3,4-d]pyrimidine are added in portions. The mixture is refluxed for 30 minutes and then allowed to stand in the refrigerator overnight. The mixture is filtered and the product, 1-methyl-4-(1-methylhydrazino)pyrazolo[3,4-d]pyrimidine, is recrystallized from ethanol-methanol, m.p. 213-215° (yield 4.2 g).

B. 1, 7- dihydro- l, 7- dimetyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4-triazolo[ 4, 3- c] pyrimidin- 3- tion meso- ionisk didehydro-derivat B. 1, 7- dihydro- 1, 7- dimethyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4-triazolo[ 4, 3- c] pyrimidine- 3- thione meso- ionic didehydro derivative

0,5.g av produktet fra del A oppløses i 10 ml dimetylformamid. 0,22 g karbondisulfid tilsettes dråpevis. Reaksjonsblandingen oppvarmes derefter ved 80° i to timer. Produktet, 1,7-dihydro-l,7-dimetyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]-pyrimidin-3-tion meso-ionisk didehydro-derivat, krystalliseres i løpet av omsetningen. Reaksjonsblandingen avkjøles og filtreres for å gi 0,5 g av produktet, sm.p. 300°. Dissolve 0.5 g of the product from part A in 10 ml of dimethylformamide. 0.22 g of carbon disulphide is added dropwise. The reaction mixture is then heated at 80° for two hours. The product, 1,7-dihydro-1,7-dimethyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]-pyrimidine-3-thione meso-ionic didehydro- derivative, crystallizes during turnover. The reaction mixture is cooled and filtered to give 0.5 g of the product, m.p. 300°.

Eksempel 6'Example 6'

1, 7- dihydro- l, 7- dimetyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo[ 4, 3- c]-pyrimidin- 3- on meso- ionisk didehydro- derivat 1, 7- dihydro- 1, 7- dimethyl- 3H- pyrazolo[ 4, 3- e]- 1, 2, 4- triazolo[ 4, 3- c]-pyrimidin- 3- one meso- ionic didehydro- derivative

1,7 g l-metyl-4-(1-metylhydrazino)pyrazolot3,4-d]-pyrimidin og 1,62 g 1,1-karbonyldiimidazol i 20 ml dimetylformamid omrøres ved 80° i flere minutter. Produktet, 1,7-dihydro-l,7-dimetyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-on meso-ionisk didehydro-derivat, utfelles i form av filt-lignende nåler. Produktet omkrystålliseres fra dimetylformamid, 1.7 g of 1-methyl-4-(1-methylhydrazino)pyrazolo3,4-d]-pyrimidine and 1.62 g of 1,1-carbonyldiimidazole in 20 ml of dimethylformamide are stirred at 80° for several minutes. The product, 1,7-dihydro-1,7-dimethyl-3H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-one meso-ionic didehydro deriv. , precipitates in the form of felt-like needles. The product is recrystallized from dimethylformamide,

sm.p. 303-306° (utbytte 1,6 g).sm.p. 303-306° (yield 1.6 g).

De følgende ytterligere forbindelser fremstilles ved fremgangsmåten ifølge eksempel 1 ved å danne det passende (R^og R2) substituerte aminopyrazol (i henhold til del A og B), og anvende det passende (R2) substituerte hydrazin (i henhold til delE), (og eksempel 6 istedenfor eksempel 1(F) for forbindelser hvor X er oksygen). The following additional compounds are prepared by the method of Example 1 by forming the appropriate (R 1 and R 2 ) substituted aminopyrazole (according to parts A and B), and using the appropriate (R 2 ) substituted hydrazine (according to part E), ( and example 6 instead of example 1(F) for compounds where X is oxygen).

Claims (13)

1. Fremgangsmåte for fremstilling av en forbindelse med formelen 1. Procedure for preparing a compound of the formula hvor er hydrogen, lavere alkyl,. f enyl-lavere-alkyl, cyklo-lavere-alkyl eller hydroksy-lavere-alkyl;R2 er hydrogen eller lavere alkyl;R^ er lavere alkyl, cyklo-lavere-alkyl eller hydroksy-lavere-alkyl; og X er svovel eller oksygen, karakterisert ved at en forbindelse med formelen where is hydrogen, lower alkyl, . f phenyl-lower-alkyl, cyclo-lower-alkyl or hydroxy-lower-alkyl; R 2 is hydrogen or lower alkyl; R 1 is lower alkyl, cyclo-lower-alkyl or hydroxy-lower-alkyl; and X is sulfur or oxygen, characterized in that a compound of the formula omsettes med et substituert hydrazin med formelen R^-NH-NE^ (III) for å danne et mellomprodukt med formelen is reacted with a substituted hydrazine of the formula R^-NH-NE^ (III) to form an intermediate of the formula og derefter omsettes dette mellomprodukt med 1,1-karbonyldiimidazol for å danne et produkt hvor X er oksygen; eller nevnte mellomprodukt omsettes med 1,1-tiokarbonyldiimidazol eller karbon disulfid for å danne et produkt hvor X er .svovel.and then this intermediate is reacted with 1,1-carbonyldiimidazole to form a product where X is oxygen; or said intermediate is reacted with 1,1-thiocarbonyldiimidazole or carbon disulfide to form a product where X is .sulphur. 2. Fremgangsmåte som angitt i krav 1, karakterisert ved at R2 er hydrogen.2. Method as stated in claim 1, characterized in that R2 is hydrogen. 3* Fremgangsmåte som angitt i krav 1, karakterisert ved at R, er lavere alkyl og R2 er hydrogen.3* Process as stated in claim 1, characterized in that R is lower alkyl and R 2 is hydrogen. 4. Fremgangsmåte som angitt i krav 1, karakterisert ved at X er svovel.4. Method as stated in claim 1, characterized in that X is sulphur. 5. Fremgangsmåte som angitt i krav 1, karakterisert ved at X er oksygen.5. Method as stated in claim 1, characterized in that X is oxygen. 6. Fremgangsmåte som angitt i krav 4, karakterisert ved at R^ og-R hver er lavere alkyl og R2 er hydrogen.6. Process as stated in claim 4, characterized in that R 1 and R 2 are each lower alkyl and R 2 is hydrogen. 7. Fremgangsmåte som angitt i krav 5, karakterisert ved at R, og R, hver er lavere alkyl og R2 er hydrogen.7. Process as stated in claim 5, characterized in that R, and R, are each lower alkyl and R2 is hydrogen. 8. Fremgangsmåte som angitt i krav 4, karakterisert ved at R, og R^ hver er metyl og R2 er hydrogen.8. Method as stated in claim 4, characterized in that R, and R^ are each methyl and R2 is hydrogen. 9. Fremgangsmåte som angitt i krav 4, karakterisert ved at R^ er metyl, R2 er hydrogen ogR^ er metyletyl.9. Process as stated in claim 4, characterized in that R 1 is methyl, R 2 is hydrogen and R 2 is methylethyl. 10. Fremgangsmåte som angitt i krav 4, karakterisert ved at R^ er metyletyl, R2 er hydrogen og R^ er metyl.10. Process as stated in claim 4, characterized in that R 1 is methylethyl, R 2 is hydrogen and R 1 is methyl. 11. Fremgangsmåte som angitt i krav 4, karakterisert ved at R^ er metyl, R2 er hydrogen og R^ er n-butyl.11. Process as stated in claim 4, characterized in that R 1 is methyl, R 2 is hydrogen and R 2 is n-butyl. 12. Fremgangsmåte som angitt i krav 5, karakterisert ved atR^ og R^ hver er metyl og R2 er hydrogen.12. Process as stated in claim 5, characterized in that R 1 and R 2 are each methyl and R 2 is hydrogen. 13. Fremgangsmåte som angitt i krav 1, karakterisert ved at R^ er hydrogen eller hydroksy-lavere alkyl, og reaksjonskomponenten med formel IV har gruppen R^ i beskyttet form.13. Method as set forth in claim 1, characterized in that R^ is hydrogen or hydroxy-lower alkyl, and the reaction component with formula IV has the group R^ in protected form.
NO783086A 1977-09-13 1978-09-12 PROCEDURE FOR PREPARING NEW PYRIMIDINE DERIVATIVES NO783086L (en)

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