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【结 构 式】

【药物名称】Elinogrel Potassium;PRT-060128;PRT-128

【化学名称】N-[4-[6-Fluoro-7-(methylamino)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]phenyl]-N'-(5-chlorothien-2-ylsulfonyl)urea potassium salt

【CA登记号】936501-01-8;936500-94-6 (free acid);936540-26-0 (sodium salt)

【 分 子 式 】C20H14ClFKN5O5S2

【 分 子 量 】562.0350

【开发单位】Portola Pharmaceuticals, Inc. (US); licensed to Novartis Pharma AG (DE)

【药理作用】P2Y12 Receptor Antagonist; Antiplatelet Therapy

合成路线1

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

Key intermediate (XII) is prepared by chlorosulfonation of 2-chlorothiophene (XIV) with ClSO3H and PCl5 to give 5-chlorothien-2-ylsulfonyl chloride (XV), which by treatment with NH4OH in H2O/THF yields sulfonamide derivative (XVI). Finally, sulfonamide (XVI) is condensed with ethyl chloroformate (XVII) by means of Cs2CO3 in THF .

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
(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
(XIV) 69098 2-chlorothiophene;2-Thienyl chloride 96-43-5 C4H3ClS 详情 详情
(XV) 61418 5-Chlorothiophene-2-sulfonyl chloride; 5-Chlorothiophene-2-sulfonyl chloride; 5-Chlorothiophene-2-sulphonyl chloride; 5-Chlorothiophene-2-sulphonyl chloride (Light & heat sensitive); 5-Chlorothiophene-2-sulphonylchloride; 5-Chlorothiophenesulphonyl chloride; 2,3-Dimethylthiophene 2766-74-7 C4H2Cl2O2S2 详情 详情
(XVI) 69099 5-chlorothiophene-2-sulfonamide   C4H4ClNO2S2 详情 详情
(XVII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
Extended Information