NO147715B - 2,4-DIAMINOPYRIMIDINE COMPOUND FOR USE IN THE PREPARATION OF DIAMINOBENZYLPYRIMIDINES - Google Patents
2,4-DIAMINOPYRIMIDINE COMPOUND FOR USE IN THE PREPARATION OF DIAMINOBENZYLPYRIMIDINES Download PDFInfo
- Publication number
- NO147715B NO147715B NO77771463A NO771463A NO147715B NO 147715 B NO147715 B NO 147715B NO 77771463 A NO77771463 A NO 77771463A NO 771463 A NO771463 A NO 771463A NO 147715 B NO147715 B NO 147715B
- Authority
- NO
- Norway
- Prior art keywords
- benzodiazepine
- chloro
- phenyl
- methyl
- base
- Prior art date
Links
- -1 2,4-DIAMINOPYRIMIDINE COMPOUND Chemical class 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 2
- 239000002585 base Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 2
- 229940049706 benzodiazepine Drugs 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 229910002651 NO3 Inorganic materials 0.000 description 8
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 5
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 3
- 235000011130 ammonium sulphate Nutrition 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910021653 sulphate ion Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000001166 ammonium sulphate Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 1
- XBWAZCLHZCFCGK-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-3,4-dihydro-2h-1,4-benzodiazepin-1-ium;chloride Chemical compound [Cl-].C12=CC(Cl)=CC=C2[NH+](C)CCN=C1C1=CC=CC=C1 XBWAZCLHZCFCGK-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- CYBAWVCMEUZAGR-UHFFFAOYSA-N N1N=CC=CC2=C1C=CC=C2.[N+](=O)(O)[O-] Chemical compound N1N=CC=CC2=C1C=CC=C2.[N+](=O)(O)[O-] CYBAWVCMEUZAGR-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical group 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
Fremgangsmåte til rensning av 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on. Process for the purification of 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one.
7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on er en forbindelse som anvendes som sedativ, muskelrelakserende middel og antikonvulsivt middel. Som be-kjent må forbindelser av denne art ha en meget høy renhetsgrad. Ved den tekniske fremstilling av ovennente forbindelse faller det ut et produkt som i stor grad er forurenset av ledsagerstoffer, og hvis rensning hittil har vært forbundet med stort arbeide. 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one is a compound used as a sedative, muscle relaxant and anticonvulsant. As is known, compounds of this nature must have a very high degree of purity. In the technical preparation of the above compound, a product is precipitated which is largely contaminated by accompanying substances, and the purification of which has hitherto been associated with considerable work.
Nærværende oppfinnelse vedrører en fremgangsmåte som gjør det mulig å rense 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on på enkel måte. The present invention relates to a method which makes it possible to purify 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one in a simple way.
Fremgangsmåten er karakterisert ved at man behandler rått 7-klor-l-methyl-5-f enyl-1,4-3H-benzodiazepin-2 (1H) -on med vandig saltsyre, skiller de ikke oppløselige bestanddeler fra, tilsetter den oppstående oppløsning salpeter- eller svovelsyre, isolerer det utfallende benzodiazepin-syreaddisjonssalt, oppvarmer i nærvær av en lavalifatisk alkohol med en base til en temperatur som sikrer fullstendig omdannelse av syreaddisjonssaltet til den frie base, avkjø-ler den oppstående oppløsning og isolerer det utfallende rensede 7-klor-l-methyl-5-f enyl-1,4-3H-benzodiazepin-2 (1H) -on. The method is characterized by treating crude 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2 (1H)-one with aqueous hydrochloric acid, separating the insoluble components, adding the resulting solution nitric or sulfuric acid, isolates the precipitated benzodiazepine acid addition salt, heats in the presence of a low aliphatic alcohol with a base to a temperature which ensures complete conversion of the acid addition salt to the free base, cools the resulting solution and isolates the precipitated purified 7-chloro -1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one.
Den rå base, som faller ut ved syntesen The crude base, which precipitates during the synthesis
av en blanding etter fjerning av oppløs-ningsmidlet, f. eks. ved inndampning, inneholder ved siden av de i løpet av syntesen dannede forurensninger også ledsagerstoffer som ble tatt med av utgangsmaterialene. of a mixture after removal of the solvent, e.g. by evaporation, in addition to the impurities formed during the synthesis, also contain accompanying substances that were brought along by the starting materials.
Basen kan på her ikke krevet måte f. eks. fremstilles ved at man kondenserer 5-klor-2-amino-benzofenon med amino-eddiksyreethylester i nærvær av pyridin til 7-klor-5-fenyl-l,4-3H-benzodiazepin-2-(lH)-on. Kondensasjonsproduktet omdan-nes ved methylering til 7-klor-l-metbyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on. The base cannot, in a manner not required here, e.g. is prepared by condensing 5-chloro-2-amino-benzophenone with amino-acetic acid ethyl ester in the presence of pyridine to 7-chloro-5-phenyl-1,4-3H-benzodiazepine-2-(1H)-one. The condensation product is converted by methylation into 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one.
I det første trinn av rensningsprosessen overføres det rå 7-klor-l-methyl-5-fe-nyl-1,4-3H-benzodiazepin-2 (1H) -on ved innvirkning av fortynnet saltsyre til det oppløselige 7-klor-1 -methyl-5-f enyl-1,4-3H-benzodiazepin-2(lH)-on-hydroklorid. Kjensgjerningen, at en rekke av forurens-ningene som hefter til den rå base ikke danner noen oppløselige salter, muliggjør fraskillelsen av disse ledsagerstoffer. In the first step of the purification process, the crude 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one is transferred by the action of dilute hydrochloric acid to the soluble 7-chloro-1 -methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one hydrochloride. The fact that a number of the contaminants that adhere to the raw base do not form any soluble salts, enables the separation of these companion substances.
Syrebehandlingen gjennomføres fortrinnsvis ved romtemperatur som har vist seg som den mest hensiktsmessige arbeids-temperatur. Anvendelsen av en 3 n vandig saltsyre har her vist seg som gunstig. De uoppløste ledsagerstoffer fjernes på vanlig måte, f. eks. ved filtrering av oppløsningen som inneholder hydrokloridet av 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2-(lH)-on. The acid treatment is preferably carried out at room temperature, which has proven to be the most appropriate working temperature. The use of a 3 N aqueous hydrochloric acid has proven beneficial here. The undissolved accompanying substances are removed in the usual way, e.g. by filtering the solution containing the hydrochloride of 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2-(1H)-one.
I det følgende trinn av rensningsmetoden etter oppfinnelsen tilsettes oppløsnin-gen av benzodiazepin-hydrokloridet, som er forurenset med ytterligere ledsagerstoffer, salpeter- eller svovelsyre. Som det er forklart nedenfor anvendes ifølge oppfinnelsen fortrinnsvis salpetersyre, hensiktsmessig 70 %'ig salpetersyre. In the following step of the purification method according to the invention, the solution of the benzodiazepine hydrochloride, which is contaminated with additional accompanying substances, nitric or sulfuric acid, is added. As explained below, nitric acid is preferably used according to the invention, preferably 70% nitric acid.
De nevnte mineralsyrer danner med benzodiazepinderivatet uoppløselige syre-addisjonssalter. Etter tilsetning av salpetersyre faller 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2 (1H) -on-nitratet ut, ved tilsetning av svovelsyre det tilsvarende sulfat. The mentioned mineral acids form insoluble acid addition salts with the benzodiazepine derivative. After the addition of nitric acid, the 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2 (1H)-one nitrate precipitates, upon addition of sulfuric acid the corresponding sulfate.
Ved denne, fortrinnsvis ved romtemperatur gjennomførte syrebehandling, oppnåes, da det ble fastslått at bestemte forurensninger forblir i oppløsning, en ytterligere rensningseffekt. Det i salpeter- eller svovelsyre uoppløselige benzodiazepin-nitrat eller -sulfat kan på enkel måte, f. eks. ved filtrering, skilles fra moderluten med de i oppløsning forblivende forurensninger. With this acid treatment, preferably carried out at room temperature, when it was determined that certain contaminants remain in solution, a further cleaning effect is achieved. The nitric or sulfuric acid insoluble benzodiazepine nitrate or sulphate can be easily, e.g. by filtration, separated from the mother liquor with the impurities remaining in solution.
Det på denne måte isolerte faste 7-klor-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on-nitrat eller -sulfat ble derpå i nærvær av en lavalifatisk alkohol tilsatt en base. Blandingen oppvarmes til en temperatur som er tilstrekkelig til fullstendig å spalte det dannede syreaddisjonssalt. Den innførte base forbinder seg ved dette under frigivelse av 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on med nitratet eller sulfatet til de tilsvarende salter. Ble f. eks. ammoniakk anvendt som base så danner ammoniumnitrat eller -sulfat seg. The thus isolated solid 7-chloro-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one nitrate or sulphate was then added to a base in the presence of a low aliphatic alcohol. The mixture is heated to a temperature sufficient to completely decompose the acid addition salt formed. The introduced base thereby combines to release 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one with the nitrate or sulfate of the corresponding salts. Was e.g. ammonia used as a base then ammonium nitrate or -sulphate is formed.
Som det ble anført foran innføres ved fremgangsmåten etter oppfinnelsen fortrinnsvis salpetersyre. De gode oppløselig-hetsegenskaper for ammoniumnitratet som danner seg i lavalifatiske alkoholer tillater nemlig en lett og enkel fraskillelse av den frigjorte i lavere alifatiske alkoholer uopp-løselige, organiske base. As was stated above, nitric acid is preferably introduced in the method according to the invention. The good solubility properties of the ammonium nitrate which is formed in low aliphatic alcohols allow an easy and simple separation of the insoluble organic base released in lower aliphatic alcohols.
Innsettes ved rensningsprosessen der-imot svovelsyre som mineralsyre, og ammoniakk deretter anvendes som base, dan-nes ammoniumsulfat som er uoppløselig i lavalifatiske alkoholer. Ammoniumsulfatet, som i motsetning til 7-klor-l-methyl-5-fe-nyl-l,4-3H-benzodiazepin-2(1H) -on forblir uoppløst i lavalifatiske alkoholer også i varme, kan fjernes fra blandingen med den dannede frie organiske base etter be-handling med en varm lavalifatisk alkohol som uoppløselig bestanddel fra oppløsnin-gen. 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-onet som løser seg i lavalifatiske alkoholer i varmen skiller seg etter avkjøling krystallinsk ut fra oppløsningen. Av de lavalifatiske alkoholer anvendes fortrinnsvis den (på markedet vanlige ethylalkohol. If, on the other hand, sulfuric acid is introduced during the purification process as a mineral acid, and ammonia is then used as a base, ammonium sulphate is formed which is insoluble in low aliphatic alcohols. The ammonium sulfate, which, unlike 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one, remains insoluble in low-aliphatic alcohols even in heat, can be removed from the mixture with the formed free organic base after treatment with a hot low aliphatic alcohol as an insoluble component from the solution. The 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one which dissolves in low aliphatic alcohols in the heat separates out crystalline from the solution after cooling. Of the low aliphatic alcohols, ethyl alcohol (common on the market) is preferably used.
Som foran anført oppvarmes blandingen av 7-klor-l-methyl-5-fenyl-l,4-3H- As stated above, the mixture of 7-chloro-1-methyl-5-phenyl-1,4-3H-
benzodiazepin-2(lH)-on-nitrat eller -sulfat med en base i en lavalifatisk alkohol til en temperatur som sikrer den angitte dobbelte omsetning av reaksjonsdeltagerne. Denne temperatur skal imidlertid ikke ligge så høyt, at bestanddeler av den som oppløs-ningsmiddel innførte lavalifatiske alkohol forflyktiger seg. Innføres f. eks. ethylalkohol så oppvarmes blandingen hensiktsmessig til en temperatur mellom 50 og 70°. Etter en fortrukken utførelsesform for fremgangsmåten etter oppfinnelsen innføres som base fortrinnsvis en vandig ammoni-akkoppløsning, hvis salpetersyre ble anvendt tidligere. Som anført danner ammoniakk et lett oppløselig nitrat. Nærvær av vann øker på den ene side oppløseligheten av ammoniumnitratet som danner seg i den lavalifatiske alkohol og senker på den an-nen side oppløseligheten av det ønskede 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on. benzodiazepine-2(1H)-one nitrate or sulfate with a base in a low aliphatic alcohol at a temperature that ensures the indicated double conversion of the reaction participants. However, this temperature must not be so high that components of the low aliphatic alcohol introduced as a solvent volatilize. Introduced e.g. ethyl alcohol then the mixture is suitably heated to a temperature between 50 and 70°. According to a preferred embodiment of the method according to the invention, an aqueous ammonia solution is preferably introduced as a base, if nitric acid was previously used. As stated, ammonia forms an easily soluble nitrate. The presence of water on the one hand increases the solubility of the ammonium nitrate which forms in the low aliphatic alcohol and on the other hand lowers the solubility of the desired 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine- 2(1H)-one.
Ved den foran beskrevne dobbelte omsetning av et syreaddisjonssalt med en base i varmen oppstår en oppløsning fra hvilken 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on skiller seg ut krystallinsk etter avkjøling. Den frie base lar seg lett filtrere fra og godt og hurtig vaske ut. Opp-løsningen kan avkjøles ved enkel henstand ved romtemperatur. Kjølingen kan dog fremskyndes ved andre almindelig anvend-te metoder, f. eks. ved avkjøling i et isbad. Det slik erholdte krystallinske 7-klor-l-me-thyl-5-fenyl-l,4-3H -benzodiazepin -2 (1H) - on er også fritt for de forurensende ledsagerstoffer fra råbasen. Basen kan ennå, for å befri den fullstendig fra de siste rester av det i siste trinn av rensningsmetoden dannede salt, f. eks. ammoniumnitrat, vaskes med vann fordi krystallene for den isolerte base bare har liten tendens til å bake seg sammen eller klebe seg sammen, og lar seg derfor lett og hurtig vaske ut og egner seg således for utvaskningsprosessen. In the above-described double reaction of an acid addition salt with a base in the heat, a solution results from which 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one separates out crystalline after cooling. The free base can be easily filtered out and washed out well and quickly. The solution can be cooled by simple standing at room temperature. However, the cooling can be accelerated by other commonly used methods, e.g. by cooling in an ice bath. The crystalline 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one thus obtained is also free of the contaminating accompanying substances from the crude base. The base can still, in order to free it completely from the last remains of the salt formed in the last step of the purification method, e.g. ammonium nitrate, is washed with water because the crystals of the isolated base have little tendency to cake together or stick together, and can therefore be easily and quickly washed out and are thus suitable for the leaching process.
Etter foranbeskrevne fremgangsmåte oppnåes 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on i renset form. Den beskrevne metode, kan modifiseres i mange henseender. Således kan f. eks. de uopp-løselige forbindelser på ny vaskes ut med de utfallende moderluter, hvorved fremde-les vedheftende oppløselige bestanddeler løses ut fullstendig. Following the procedure described above, 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one is obtained in purified form. The described method can be modified in many respects. Thus, e.g. the insoluble compounds are washed out again with the precipitated mother liquors, whereby any still adhering soluble components are completely dissolved.
Eksempel: Example:
100 g rått 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on, ca. 90% rent med et smeltepunkt på 115—120° (ukorrigert) oppløses ved romtemperatur under omrøring i 300 ml ca. 3 n vandig saltsyre. Den oppstående oppløsning filtreres av og de på filteret tilbakeblivende uoppløselige bestanddeler vaskes ut med ytterligere 50 ml ca. 3 n vandig saltsyre. Det sterkt far-vede filtrat forenes med vaskevæsken og tlisettes under omrøring langsomt 50 ml 70 %'s salpetersyre. Ved dette skiller nitratet av 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on seg spontant ut i krystallinsk form. 100 g raw 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one, approx. 90% pure with a melting point of 115-120° (uncorrected) dissolve at room temperature with stirring in 300 ml approx. 3 n aqueous hydrochloric acid. The resulting solution is filtered off and the insoluble components remaining on the filter are washed out with a further 50 ml approx. 3 n aqueous hydrochloric acid. The strongly colored filtrate is combined with the washing liquid and, while stirring, slowly 50 ml of 70% nitric acid is added. In this case, the nitrate of 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one separates spontaneously in crystalline form.
Med svovelsyre lar seg på analog måte utvinne det tilsvarende sulfat. With sulfuric acid, the corresponding sulfate can be extracted in an analogous way.
Det erholdte 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2(lH)-on-nitrat sus-penderes derpå i 300 ml ethylalkohol og tilsettes under omrøring 20 ml 26 %'s vandig ammoniakk. Blandingen går etter oppvar-ming til 65—70° fullstendig i oppløsning. Den svakt gule til ravfarvede oppløsning rystes med 2 g avfarvningskull i to like deler og filtreres av over kiselgur (Hyflo). Etter avkjøling skiller 7-klor-l-methyl-5-f enyl-l,4-3H-benzodiazepin-2 (1H) -on seg ut av filtratet i godt utformede krystaller. The obtained 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one-nitrate is then suspended in 300 ml of ethyl alcohol and, with stirring, 20 ml of 26% aqueous ammonia is added . The mixture dissolves completely after heating to 65-70°. The slightly yellow to amber colored solution is shaken with 2 g of decolorizing charcoal in two equal parts and filtered off over diatomaceous earth (Hyflo). After cooling, 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2(1H)-one separates from the filtrate in well-formed crystals.
Krystallgrøten røres igjennom en time ved romtemperatur, filtreres derpå av og vaskes to ganger, hver gang med 25 ml ethylalkohol. Derpå vaskes krystallisatet ut, for å befri det for de siste spor av ut-krystallisert ammoniumnitrat, med 200 ml varmt vann. Den fra ethylalkohol omkrys-talliserte base danner prismer og smelter ved 129—130,5° (ukorrigert). Stoffet viser i tynnsjiktkromatogram bare en eneste flekk identisk med 7-klor-l-methyl-5-fe-nyl-l,4-3H-benzodiazepin-2 (1H) -on. The crystal slurry is stirred for one hour at room temperature, then filtered off and washed twice, each time with 25 ml of ethyl alcohol. The crystallisate is then washed out, to rid it of the last traces of crystallized ammonium nitrate, with 200 ml of warm water. The base recrystallized from ethyl alcohol forms prisms and melts at 129-130.5° (uncorrected). The substance shows in a thin-layer chromatogram only a single spot identical to 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2 (1H)-one.
Rensningsgraden for basen kan ytterligere økes ved omkrystallisering: 50 g base oppløses under omrøring varmt i 150 ml ethylalkohol. Den oppstående oppløsning rystes igjennom to ganger, hver gang med 500 mg avfarvningskull, og filtreres av over kiselgur (Hyflo). Det klare filtrat røres igjennom etter avkjøling til romtemperatur ytterligere en time. Den utfallende krys-tallgrøt suges av og vaskes to ganger ved romtemperatur, hver gang med 10 ml ethylalkohol. Det slik erholdte rene 7-klor-l-methyl-5-fenyl-l,4-3H-benzodiazepin-2 (lH)-on danner prismer og smelter ved 130 —131° (ukorrigert). Det ved en prøve etter den i U. S. Pharmakopoe angitte metode bestemte smeltepunkt er 131,5—134,5°. The degree of purification of the base can be further increased by recrystallization: dissolve 50 g of base while stirring hot in 150 ml of ethyl alcohol. The resulting solution is shaken twice, each time with 500 mg of decolorizing charcoal, and filtered off over diatomaceous earth (Hyflo). The clear filtrate is stirred through after cooling to room temperature for a further hour. The precipitated crystal slurry is suctioned off and washed twice at room temperature, each time with 10 ml of ethyl alcohol. The pure 7-chloro-1-methyl-5-phenyl-1,4-3H-benzodiazepine-2 (1H)-one thus obtained forms prisms and melts at 130-131° (uncorrected). The melting point determined by a sample according to the method specified in the U.S. Pharmacopoeia is 131.5-134.5°.
Som foran nærmere anført skal ved spaltningen av syreaddisjonssaltet med en base i nærvær av en lavalifatisk alkohol en temperatur holdes, som sikrer en fullstendig omdannelse. As stated in more detail above, during the cleavage of the acid addition salt with a base in the presence of a low aliphatic alcohol, a temperature must be maintained which ensures a complete conversion.
Ved spaltningen av nitratet med ammoniakk danner oppløselig ammoniumnitrat seg. Reaksjonsblandingen må i dette tilfelle oppvarmes så sterkt inntil alle be-standeler er gått i oppløsning. Ved spaltningen av sulfatet oppstår ved innvirkning av ammoniakk uoppløselig ammoniumsulfat. Det er i dette tilfelle hensiktsmessig å anvende et overskudd av ammoniakk. When the nitrate is split with ammonia, soluble ammonium nitrate is formed. In this case, the reaction mixture must be heated so strongly until all ingredients have dissolved. During the splitting of the sulphate, insoluble ammonium sulphate is produced by the action of ammonia. In this case, it is appropriate to use an excess of ammonia.
Claims (3)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO771463A NO147715C (en) | 1971-10-12 | 1977-04-27 | 2,4-DIAMINOPYRIMIDINE COMPOUND FOR USE IN THE PREPARATION OF DIAMINOBENZYLPYRIMIDINES |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4749271A GB1413471A (en) | 1971-10-12 | 1971-10-12 | 2,4-diamino-5-benzylpyrimidines and a process for their preparation |
GB5751271 | 1971-12-10 | ||
NO3624/72A NO137093C (en) | 1971-10-12 | 1972-10-10 | PROCEDURES FOR THE PREPARATION OF 2,4-DIAMINO-5-BENZYLPYRIMIDINES |
NO771463A NO147715C (en) | 1971-10-12 | 1977-04-27 | 2,4-DIAMINOPYRIMIDINE COMPOUND FOR USE IN THE PREPARATION OF DIAMINOBENZYLPYRIMIDINES |
Publications (3)
Publication Number | Publication Date |
---|---|
NO771463L NO771463L (en) | 1973-04-13 |
NO147715B true NO147715B (en) | 1983-02-21 |
NO147715C NO147715C (en) | 1983-06-01 |
Family
ID=27448995
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO771463A NO147715C (en) | 1971-10-12 | 1977-04-27 | 2,4-DIAMINOPYRIMIDINE COMPOUND FOR USE IN THE PREPARATION OF DIAMINOBENZYLPYRIMIDINES |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO147715C (en) |
-
1977
- 1977-04-27 NO NO771463A patent/NO147715C/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO771463L (en) | 1973-04-13 |
NO147715C (en) | 1983-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPS5935381B2 (en) | Method for resolving (+)- and (-)-6-methoxy-α-methyl-2-naphthaleneacetic acid | |
EP2985275B1 (en) | Beta-hydroxy-beta-methylbutyric acid purification method | |
JPH0643400B2 (en) | A process for the stable transformation of torasemide. | |
NO147715B (en) | 2,4-DIAMINOPYRIMIDINE COMPOUND FOR USE IN THE PREPARATION OF DIAMINOBENZYLPYRIMIDINES | |
US3102116A (en) | Process for the purification of y-chloeo- | |
US3397231A (en) | Refining of alpha-6-deoxy-5-oxytetracycline | |
US2382288A (en) | Method for separation of hydroxy carboxylic acids | |
US2905662A (en) | Preparation of tetracycline-urea compound | |
US1954389A (en) | Process of manufacturing optically active mono-hydroxyphenyl methylamino-ethanols-1 | |
US1940146A (en) | Process of purifying phenolphthalein | |
Harris et al. | CXXII.—iso Quinoline and the iso quinoline-reds | |
Johnson et al. | RESEARCHES ON PYRIDINES. LXXXVIII. THE SYNTHESIS OF CYTOSINE ALDEHYDE. | |
DE2843040C2 (en) | ||
AT239244B (en) | Process for the purification of 7-chloro-1-methyl-5-phenyl-1, 4-3H-benzodiazepin-2 (1H) -one | |
US2577076A (en) | Purification of benzhydryl ethers | |
US2069546A (en) | Separation of chloranisidine isomers | |
US2302204A (en) | Process for the manufacture and purification of uric acid | |
US2033515A (en) | Apocupreine and apocupreine derivatives | |
US2018354A (en) | Method of purifying and decolorizing cinchophen | |
US2708198A (en) | Pentaerythrite-dichlorhydrine monosulfurous acid esters | |
US2250256A (en) | Method of producing trimethylolnitromethane | |
US2829154A (en) | Method for the esterification of 2-hydroxy-4-amino-benzoic acid with phenols | |
SU405861A1 (en) | METHOD FOR ISOLATING ACID AND ADIPINIC ACIDS | |
US631757A (en) | Xanthin derivative and process of making same. | |
US2032035A (en) | Purification of trinitrotoluene |