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【结 构 式】 
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【分子编号】43972 【品名】4-(N-Boc-aminomethyl)aniline;tert-butyl (4-aminophenyl)carbamate;tert-butyl 4-aminophenylcarbamate 【CA登记号】 |
【 分 子 式 】C11H16N2O2 【 分 子 量 】208.26032 【元素组成】C 63.44% H 7.74% N 13.45% O 15.36% |
合成路线1
该中间体在本合成路线中的序号：(IV)Elinogrel potassium is prepared as follows. Condensation of methyl 2-amino-4,5-difluorobenzoate (I) with 4-nitrophenyl chloroformate (II) in refluxing CH2Cl2 gives the 4-nitrophenyl carbamate (III), which is condensed with 4-(Boc-amino)aniline (IV) in the presence of Et3N in THF at 60-70 °C to yield the diaryl urea (V), which, without isolation, is cyclized to the quinazoline-2,4-dione (VI) upon treatment with methanolic NaOMe or DBU. Alternatively, diaryl urea (V) is prepared by treatment of anthranilate (I) with COCl2 in toluene to yield isocyanate (VII) and/or carbamoyl chloride (VIII), which are then condensed with 4-(Boc-amino)aniline (IV) in the presence of Et3N in DMF . Deprotection of the amino group in compound (VI) by removal of the Boc group by means of HCl in dioxane provides 3-(4-aminophenyl)-6,7-difluoroquinazoline-2,4(1H,3H)-dione hydrochloride (IX), which undergoes selective fluoride displacement with methylamine (X) in DMSO at 110 °C to provide 3-(4-aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione (XI). Subsequent carbamoylation of the primary amino group of quinazoline (XI) with ethyl N-(5-chlorothien-2-ylsulfonyl)carbamate (XII) in refluxing DMSO or acetonitrile yields elinogrel (XIII) , which is finally converted to its potassium salt by treatment with KOH in acetonitrile/H2O at 45-55 °C .
| 【1】 Scarborough, R.M., Pandey, A., Yiannikouros, G.P., Cruskie, M., White, D.C., Mehrotra, M. (Portola Pharmaceuticals, Inc.). Substituted-(quinazolinyl)phenyl thiophenyl-sulfonylureas, methods for making and intermediates thereof. US 2007208045, WO 2007056167. |
| 【2】 Huang, W., Mehrotra, M., Zhang, X., Cannon, H., Grant, C.M. (Portola Pharmaceuticals, Inc.). [4-(6-Halo-7-substituted-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureas and forms and methods related thereto. EP 1951254, JP 2009515836, US 2007123547, WO 200705619. |
| 【3】 Sharp, E., Quegan, L.J., Pandey, A., Wang, J., Nieder, M., Huang, W. (Portola Pharmaceuticals, Inc.). [4-(6-Fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, in different crystalline forms, pharmaceutical compositions thereof. EP 2076510, JP 2010526105, WO 2008137809. |
| 【4】 Sharp, E., Quegan, L.J., Pandey, A., Wang, J., Nieder, M., Huang, W. (Portola Pharmaceuticals, Inc.). [4-(6-Fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, forms and methods related thereto. US 2009156620, WO 2010054020. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 69088 | methyl 2-amino-4,5-difluorobenzoate;2-Amino-4,5-difluorobenzoicacid methyl ester | 207346-42-7 | C8H7F2NO2 | 详情 | 详情 |
| (II) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (III) | 69089 | methyl 4,5-difluoro-2-(((4-nitrophenoxy)carbonyl)amino)benzoate | C15H10F2N2O6 | 详情 | 详情 | |
| (IV) | 43972 | 4-(N-Boc-aminomethyl)aniline;tert-butyl (4-aminophenyl)carbamate;tert-butyl 4-aminophenylcarbamate | C11H16N2O2 | 详情 | 详情 | |
| (V) | 69090 | methyl 2-(3-(4-((tert-butoxycarbonyl)amino)phenyl)ureido)-4,5-difluorobenzoate | C20H21F2N3O5 | 详情 | 详情 | |
| (VI) | 69091 | tert-butyl (4-(6,7-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)carbamate | C19H17F2N3O4 | 详情 | 详情 | |
| (VII) | 69092 | methyl 4,5-difluoro-2-isocyanatobenzoate | C9H5F2NO3 | 详情 | 详情 | |
| (VIII) | 69093 | methyl 2-((chlorocarbonyl)amino)-4,5-difluorobenzoate | C9H6ClF2NO3 | 详情 | 详情 | |
| (IX) | 69094 | 3-(4-aminophenyl)-6,7-difluoroquinazoline-2,4(1H,3H)-dione hydrochloride | C14H9F2N3O2.HCl | 详情 | 详情 | |
| (X) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (XI) | 69095 | 3-(4-aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione | C15H13FN4O2 | 详情 | 详情 | |
| (XII) | 69097 | ethyl N-(5-chlorothien-2-ylsulfonyl)carbamate;[(5-Chlorothien-2-yl)sulfonyl]carbamic acid ethyl ester;Ethyl[(5-chlorothiophen-2-yl)sulfonyl]carbamate;N-[(5-chloro-2-thienyl)sulfonyl]- | 849793-87-9 | C7H8ClNO4S2 | 详情 | 详情 |
| (XIII) | 69096 | 5-chloro-N-((4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)carbamoyl)thiophene-2-sulfonamide | C20H15ClFN5O5S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Lithiation of 5-benzyloxy-2-bromobenzaldehyde dimethyl acetal (I), followed by addition to N,N-dimethyl-3,4,5-trimethoxybenzamide (II), gave rise to benzophenone (III). After acetal hydrolysis using an acidic ion exchange resin, the resulting aldehyde (IV) was oxidized to carboxylic acid (V) by means of sodium chlorite. Condensation of this keto acid (V) with diethyl bromomalonate (VI), followed by acidic treatment, furnished the isocoumarin derivative (VII). Subsequent addition of water to the double bond upon treatment with NaOH in aqueous methanol produced (VIII). This compound was condensed with N-Boc-p-phenylenediamine (IX) in the presence of N-methylmorpholine in hot 1,3-dimethyl-2-imidazolinone to afford the isoquinolinone (X). The methyl ester (XI) was prepared by reaction of carboxylic acid (X) with iodomethane and K2CO3.
| 【1】 Ikeo, T.; Ukita, T.; Omori, K. (Tanabe Seiyaku Co., Ltd.); Isoquinolinone derivs., process for preparing the same, and their use as phosphodiesterase inhibitors. JP 1998298164; WO 9838168 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 43965 | 4-(benzyloxy)-1-bromo-2-(dimethoxymethyl)benzene; benzyl 4-bromo-3-(dimethoxymethyl)phenyl ether | C16H17BrO3 | 详情 | 详情 | |
| (II) | 43966 | 3,4,5-trimethoxy-N,N-dimethylbenzamide | C12H17NO4 | 详情 | 详情 | |
| (III) | 43967 | [4-(benzyloxy)-2-(dimethoxymethyl)phenyl](3,4,5-trimethoxyphenyl)methanone | C26H28O7 | 详情 | 详情 | |
| (IV) | 43968 | 5-(benzyloxy)-2-(3,4,5-trimethoxybenzoyl)benzaldehyde | C24H22O6 | 详情 | 详情 | |
| (V) | 43969 | 5-(benzyloxy)-2-(3,4,5-trimethoxybenzoyl)benzoic acid | C24H22O7 | 详情 | 详情 | |
| (VI) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (VII) | 43970 | 7-(benzyloxy)-1-oxo-4-(3,4,5-trimethoxyphenyl)-1H-isochromene-3-carboxylic acid | C26H22O8 | 详情 | 详情 | |
| (VIII) | 43971 | 7-(benzyloxy)-3-hydroxy-1-oxo-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-isochromene-3-carboxylic acid | C26H24O9 | 详情 | 详情 | |
| (IX) | 43972 | 4-(N-Boc-aminomethyl)aniline;tert-butyl (4-aminophenyl)carbamate;tert-butyl 4-aminophenylcarbamate | C11H16N2O2 | 详情 | 详情 | |
| (X) | 43973 | 7-(benzyloxy)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylic acid | C37H36N2O9 | 详情 | 详情 | |
| (XI) | 43974 | methyl 7-(benzyloxy)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylate | C38H38N2O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The mono-Boc-protected 1,4-phenylenediamine (I) was acylated with 1,2,3-thiadiazole-4-carbonyl chloride (II) to produce amide (III). After Boc group cleavage in (III) by means of trifluoroacetic acid, the resultant amine (IV) was condensed with 3,5-bis(trifluoromethyl)phenyl isothiocyanate (V) to afford the title thiourea.
| 【1】 Feld, B.; Bloom, J.; Norton, E.; Dushin, R.; Di Grandi, M.J.; Curran, K.; Jones, T.; Potent novel thioureas as inhibitors of human cytomegalovirus. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2001, Abst 1895. |
| 【2】 Bloom, J.D.; Ross, A.A.; O'Hara, B.M.; Curran, K.J.; DiGrandi, M.J.; Dushin, R.G.; Lang, S.A.; Norton, E.B. (Wyeth); Thiourea inhibitors of herpes viruses. EP 1137632; JP 2002531545; WO 0034238 . |
| 【3】 Jones, T.R.; Bloom, J.D.; Ross, A.A.; O'Hara, B.M.; Curran, K.J.; DiGrandi, M.J.; Dushin, R.G.; Lang, S.A.; Terefenko, E.A. (Wyeth); Heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses containing a substd. phenylenediamine group. JP 2002533301; US 6166028; WO 0034261 . |
| 【4】 Bloom, J.D.; O'Hara, B.M.; DiGrandi, M.J.; Dushin, R.G.; Lang, S.A. (Wyeth); Thiourea inhibitors of herpes viruses. EP 1137647; JP 2002531557; WO 0034268 . |
| 【5】 Bloom, J.D.; Ross, A.A.; O'Hara, B.M.; Curran, K.J.; DiGrandi, M.J.; Dushin, R.G.; Lang, S.A.; Norton, E.B. (Wyeth); alpha-Methylbenzyl-containing thiourea inhibitors of herpes viruses containing a phenylenediamine group. JP 2002531555; WO 0034260 . |
| 【6】 Jones, T.R.; Bloom, J.D.; Ross, A.A.; O'Hara, B.M.; Curran, K.J.; DiGrandi, M.J.; Dushin, R.G.; Lang, S.A.; Terefenko, E.A. (Wyeth); Heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses containing phenylenediamine group. JP 2002531554; WO 0034258 . |
| 【7】 Bloom, J.D.; O'Hara, B.M.; DiGrandi, M.J.; Dushin, R.G.; Lang, S.A. (Wyeth); Thiourea inhibitors of herpes viruses. EP 1140913; JP 2002531558; WO 0034269 . |
| 【8】 Bloom, J.D.; O'Hara, B.M.; DiGrandi, M.J.; Dushin, R.G.; Lang, S.A. (Wyeth); Acetamide and substd. acetamide-containing thiourea inhibitors of herpes viruses. JP 2002531544; WO 0034237 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 43972 | 4-(N-Boc-aminomethyl)aniline;tert-butyl (4-aminophenyl)carbamate;tert-butyl 4-aminophenylcarbamate | C11H16N2O2 | 详情 | 详情 | |
| (II) | 58777 | 1,2,3-thiadiazole-4-carbonyl chloride | C3HClN2OS | 详情 | 详情 | |
| (III) | 58778 | tert-butyl 4-[(1,2,3-thiadiazol-4-ylcarbonyl)amino]phenylcarbamate | C14H16N4O3S | 详情 | 详情 | |
| (IV) | 58779 | N-(4-aminophenyl)-1,2,3-thiadiazole-4-carboxamide | C9H8N4OS | 详情 | 详情 | |
| (V) | 58780 | 3,5-Bis(trifluoromethyl)phenyl isothiocyanate | 23165-29-9 | C9H3F6NS | 详情 | 详情 |