Elinogrel Potassium;PRT-060128;PRT-128, -Drug Synthesis Database

【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 合成路线2

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 .

参考文献中间体

【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 .

参考文献中间体

【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

Drug NewChemical Entity Original Patent(2)