SL-65.0472, -Drug Synthesis Database

【结构式】

【药物名称】SL-65.0472

【化学名称】2-[7-Fluoro-2-oxo-4-[2-[4-(thieno[3,2-c]pyridin-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinolin-1-yl]acetamide

【CA登记号】189003-92-7, 189003-46-1 (diHCl)

【分子式】C₂₄H₂₄FN₅O₂S

【分子量】465.55358

【开发单位】Sanofi-synthélabo (Originator)

【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Hypertension, Treatment of, 5-HT1B Antagonists, 5-HT2A Antagonists

合成路线1 合成路线2

合成路线1

Condensation of 3-fluoroaniline (I) with the cyclic anhydride (II) in AcOH gave amide (III). Subsequent cyclization of (III) in hot H2SO4 produced quinolineacetic acid (IV). After esterification of (IV) with methanol in the presence of SOCl2, the resulting methyl ester (V) was reduced to alcohol (VI) using NaBH4 in refluxing THF. Treatment of alcohol (VI) with SOCl2 afforded chloride (VII), which was condensed with 4-(1-piperazinyl)thieno[3,2-c]pyridine (VIII) yielding adduct (IX), isolated as the dihydro-chloride salt. Finally, alkylation of the quinoline N atom of (IX) with bromoacetamide (A) under phase-transfer conditions furnished the title compound.

参考文献中间体

【1】 McCort, G.; et al.; Synthesis and SAR of 3- and 4-substituted quinolin-2-ones: Discovery of mixed 5-HT1b/5-HT2A receptor antagonists. Bioorg Med Chem 2001, 9, 8, 2129.
【2】 Demarquay, D.; Lavergne, O.; Bailly, C.; et al.; Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins. J Med Chem 2000, 43, 11, 2285.
【3】 Mc Cort, G.; Hoornaert, C.; Dellac, G.; Aletru, M. (Sanofi-Synthelabo ); Quinolein-2(1H)-one derivs. as serotonin antagonists. EP 0850235; FR 2738822; FR 2739100; JP 1999514982; US 5958924; WO 9710238 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	38747	2-bromoacetamide	683-57-8	C₂H₄BrNO	详情	详情
(I)	20697	3-fluoroaniline; 3-fluorophenylamine	372-19-0	C₆H₆FN	详情	详情
(II)	40692	2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate		C₇H₆O₅	详情	详情
(III)	40693	(Z)-3-(acetoxy)-5-(3-fluoroanilino)-5-oxo-2-pentenoic acid		C₁₃H₁₂FNO₅	详情	详情
(IV)	40694	2-(7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl)acetic acid		C₁₁H₈FNO₃	详情	详情
(V)	40695	methyl 2-(7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl)acetate		C₁₂H₁₀FNO₃	详情	详情
(VI)	40696	7-fluoro-4-(2-hydroxyethyl)-2(1H)-quinolinone		C₁₁H₁₀FNO₂	详情	详情
(VII)	40697	4-(2-chloroethyl)-7-fluoro-2(1H)-quinolinone		C₁₁H₉ClFNO	详情	详情
(VIII)	40698	4-(1-piperazinyl)thieno[3,2-c]pyridine		C₁₁H₁₃N₃S	详情	详情
(IX)	40699	7-fluoro-4-[2-(4-thieno[3,2-c]pyridin-4-yl-1-piperazinyl)ethyl]-2(1H)-quinolinone		C₂₂H₂₁FN₄OS	详情	详情

合成路线2

The alkylation of 3-fluoroaniline (I) with 2-bromoacetamide (II) by means of KOH and Bu4NBr in THF gives 2-(3-fluorophenylamino)acetamide (III), which is condensed with 4-acetoxy-3,6-dihydro-2H-pyran-2,6-dione (IV) in Ac-OH to yield intermediate (V). The cyclization of (V) by means of H2SO4 or Ms-OH at 100?C affords the quinolone (VII), which is esterified with SOCl2 and methanol to provide the corresponding methyl ester (VII). The reduction of (VII) with NaBH4 in refluxing THF furnishes the 2-hydroxyethyl quinolone (VIII), which is treated with SOCl2 in refluxing CHCl3 to give the 2-chloroethyl derivative (IX). Finally, this compound is condensed with the arylpiperazine (X) by means of K2CO3 and KI in hot DMF to afford the desired quinolone.

参考文献中间体

【1】 McCort, G.; et al.; Synthesis and SAR of 3- and 4-substituted quinolin-2-ones: Discovery of mixed 5-HT1b/5-HT2A receptor antagonists. Bioorg Med Chem 2001, 9, 8, 2129.

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)	20697	3-fluoroaniline; 3-fluorophenylamine	372-19-0	C₆H₆FN	详情	详情
(II)	38747	2-bromoacetamide	683-57-8	C₂H₄BrNO	详情	详情
(III)	50951	2-(3-fluoroanilino)acetamide		C₈H₉FN₂O	详情	详情
(IV)	40692	2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate		C₇H₆O₅	详情	详情
(V)	50952	(Z)-3-(acetoxy)-5-[(2-amino-2-oxoethyl)-3-fluoroanilino]-5-oxo-2-pentenoic acid		C₁₅H₁₅FN₂O₆	详情	详情
(VI)	50953	2-[1-(2-amino-2-oxoethyl)-7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl]acetic acid		C₁₃H₁₁FN₂O₄	详情	详情
(VII)	50954	methyl 2-[1-(2-amino-2-oxoethyl)-7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl]acetate		C₁₄H₁₃FN₂O₄	详情	详情
(VIII)	50955	2-[7-fluoro-4-(2-hydroxyethyl)-2-oxo-1(2H)-quinolinyl]acetamide		C₁₃H₁₃FN₂O₃	详情	详情
(IX)	50956	2-[4-(2-chloroethyl)-7-fluoro-2-oxo-1(2H)-quinolinyl]acetamide		C₁₃H₁₂ClFN₂O₂	详情	详情
(X)	40698	4-(1-piperazinyl)thieno[3,2-c]pyridine		C₁₁H₁₃N₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)