DC-756, -Drug Synthesis Database

【结构式】

【药物名称】DC-756

【化学名称】(3S,4S)-7-[3-Amino-4-(fluoromethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

【CA登记号】218281-25-5

【分子式】C₁₉H₂₁F₂N₃O₄

【分子量】393.39372

【开发单位】Daiichi Pharmaceutical (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones

合成路线1 合成路线2 合成路线3

合成路线1

The condensation of itaconic acid (I) with (R)-1-phenylethylamine (II) produced a mixture of diastereomeric pyrrolidinones (III). The desired isomer (IV) was then isolated after conversion to the corresponding methyl ester. Introduction of the fluorine atom to give (VI) was achieved by either treatment with diethylaminosulfur trifluoride (DAST) or via conversion to the corresponding mesylate and further displacement by tetrabutylammonium fluoride. Hydroxylation of the lithium enolate of (VI) by means of O2 and (EtO)3P afforded the trans-3-hydroxy-4-(fluoromethyl)pyrrolidinone (VII). This was converted to mesylate (VIII) and subsequently displaced by NaN3 to provide the cis azide (IX). Hydrogenation of the azido group of (IX) over Pd/C in the presence of di-tert-butyl dicarbonate produced the Boc-protected amine (X). The pyrrolidinone ring was then reduced to pyrrolidine (XI) with borane in THF, and further hydrogenation over Pd/C at 50 C removed the alpha-methylbenzyl group, yielding (XII). Optionally, acid deprotection of the Boc group of (XII) provided intermediate (XIII).

参考文献中间体

【1】 Takahaski, H.; et al.; DC-756: A new methoxyquinolone: Synthesis and in vitro activity of 7-(3-amino-4-substituted-pyrrolidin-1-yl) derivatives. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-73.
【2】 Takeda, T.; Kimura, K.; Ohki, H.; Takahashi, H.; Miyauchi, R.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); Cis-substd. fluoromethylpyrrolidine derivs.. EP 0995744; WO 9858923 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	36288	(3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid		C₁₃H₁₅NO₃	详情	详情
(IIIb)	36289	(3S)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid		C₁₃H₁₅NO₃	详情	详情
(I)	27493	2-methylenesuccinic acid	97-65-4	C₅H₆O₄	详情	详情
(II)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(IV)	36290	methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylate		C₁₄H₁₇NO₃	详情	详情
(V)	36291	(4R)-4-(hydroxymethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone		C₁₃H₁₇NO₂	详情	详情
(VI)	36292	(4R)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone		C₁₃H₁₆FNO	详情	详情
(VII)	36293	(3R,4S)-4-(fluoromethyl)-3-hydroxy-1-[(1R)-1-phenylethyl]-2-pyrrolidinone		C₁₃H₁₆FNO₂	详情	详情
(VIII)	36294	(3R,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinyl methanesulfonate		C₁₄H₁₈FNO₄S	详情	详情
(IX)	36295	(3S,4S)-3-azido-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone		C₁₃H₁₅FN₄O	详情	详情
(X)	36296	tert-butyl (3S,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate		C₁₈H₂₅FN₂O₃	详情	详情
(XI)	36297	tert-butyl (3S,4S)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate		C₁₈H₂₇FN₂O₂	详情	详情
(XII)	36298	tert-butyl (3S,4S)-4-(fluoromethyl)pyrrolidinylcarbamate		C₁₀H₁₉FN₂O₂	详情	详情
(XIII)	36299	(3S,4S)-4-(fluoromethyl)-3-pyrrolidinamine; (3S,4S)-4-(fluoromethyl)pyrrolidinylamine		C₅H₁₁FN₂	详情	详情

合成路线2

Condensation of the protected pyrrolidine (XII) with either the BF2-chelate (XVIa) or the B(OAc)2-chelate (XIVb) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid provided the 7-(pyrrolidinyl)quinoline (XV). The boron chelate of (XV) was then removed upon refluxing with Et3N in aqueous EtOH to give the quinolinecarboxylic acid (XVI). Finally, treatment of (XVI) with concentrated HCl cleaved the Boc protecting group.

参考文献中间体

【1】 Takahaski, H.; et al.; DC-756: A new methoxyquinolone: Synthesis and in vitro activity of 7-(3-amino-4-substituted-pyrrolidin-1-yl) derivatives. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-73.
【2】 Takeda, T.; Kimura, K.; Ohki, H.; Takahashi, H.; Miyauchi, R.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); Cis-substd. fluoromethylpyrrolidine derivs.. EP 0995744; WO 9858923 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIVa)	36300	1-cyclopropyl-3-[[(difluoroboryl)oxy]carbonyl]-6,7-difluoro-8-methoxy-4(1H)-quinolinone	C₁₄H₁₀BF₄NO₄	详情	详情
(XIVb)	36301	diacetyl (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinyl)carbonyl borate	C₁₈H₁₆BF₂NO₈	详情	详情
(XVa)	36302	tert-butyl (3S,4S)-1-(1-cyclopropyl-3-[[(difluoroboryl)oxy]carbonyl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-7-quinolinyl)-4-(fluoromethyl)pyrrolidinylcarbamate	C₂₄H₂₈BF₄N₃O₆	详情	详情
(XVb)	36303	tert-butyl (3S,4S)-1-[3-([[bis(acetoxy)boryl]oxy]carbonyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-7-quinolinyl]-4-(fluoromethyl)pyrrolidinylcarbamate	C₂₈H₃₄BF₂N₃O₁₀	详情	详情
(XII)	36298	tert-butyl (3S,4S)-4-(fluoromethyl)pyrrolidinylcarbamate	C₁₀H₁₉FN₂O₂	详情	详情
(XVI)	36304	7-[(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-(fluoromethyl)pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid	C₂₄H₂₉F₂N₃O₆	详情	详情

合成路线3

In a further procedure, the deprotected pyrrolidine (XIII) was condensed with the fluoroquinoline (XIV) to give (XVII). The boron chelate of (XVII) was then deprotected with Et3N in EtOH-H2O at 50 C.

参考文献中间体

【1】 Takeda, T.; Kimura, K.; Ohki, H.; Takahashi, H.; Miyauchi, R.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); Cis-substd. fluoromethylpyrrolidine derivs.. EP 0995744; WO 9858923 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIVa)	36300	1-cyclopropyl-3-[[(difluoroboryl)oxy]carbonyl]-6,7-difluoro-8-methoxy-4(1H)-quinolinone	C₁₄H₁₀BF₄NO₄	详情	详情
(XIVb)	36301	diacetyl (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinyl)carbonyl borate	C₁₈H₁₆BF₂NO₈	详情	详情
(XVIIa)	36305	7-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidinyl]-1-cyclopropyl-3-[[(difluoroboryl)oxy]carbonyl]-6-fluoro-8-methoxy-4(1H)-quinolinone	C₁₉H₂₀BF₄N₃O₄	详情	详情
(XVIIb)	36306	diacetyl [7-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinyl]carbonyl borate	C₂₃H₂₆BF₂N₃O₈	详情	详情
(XIII)	36299	(3S,4S)-4-(fluoromethyl)-3-pyrrolidinamine; (3S,4S)-4-(fluoromethyl)pyrrolidinylamine	C₅H₁₁FN₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)