ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】15129

【品名】ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate

【CA登记号】

【分子式】C₁₅H₁₁ClF₃NO₃

【分子量】345.7051896

【元素组成】C 52.12% H 3.21% Cl 10.26% F 16.49% N 4.05% O 13.88%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(V)

The condensation of 3-chloro-2,4,5-trifluorobenzoylacetic acid ethyl ester (I) with (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) and ethyl orthoformate (II) in hot acetic anhydride gives (1R,2S)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(2-fluorocyclopropylamino)acrylic acid ethyl ester (IV). The cyclization of (IV) by means of NaH yields the quinolone (V), which is hydrolyzed with HCl to the free acid (VI). The condensation of (VI) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) by means of triethylamine in refluxing acetonitrile affords the protected final product (VIII), which is finally deprotected with trifluoroacetic acid and anisole.

参考文献中间体

合成目标

【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 .
【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827.

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)	11681	ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate	101987-86-4	C₁₁H₈ClF₃O₃	详情	详情
(II)	11927	5-Sulfanyl-1,3,4-thiadiazol-2-ylhydrosulfide; 1,3,4-Thiadiazole-2,5-dithiol	1072-71-5	C₂H₂N₂S₃	详情	详情
(III)	15127	tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate	127199-16-0	C₈H₁₄FNO₂	详情	详情
(IV)	15128	ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-[[(1R,2S)-2-fluorocyclopropyl]amino]-2-propenoate		C₁₅H₁₂ClF₄NO₃	详情	详情
(V)	15129	ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₅H₁₁ClF₃NO₃	详情	详情
(VI)	15130	8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid	127199-27-3	C₁₃H₇ClF₃NO₃	详情	详情
(VII)	15131	N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester	127199-45-5	C₁₁H₂₀N₂O₂	详情	详情
(VIII)	15132	7-[(7S)-7-(carboxyamino)-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid		C₂₀H₁₈ClF₂N₃O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

A new synthesis of DU-6859 has been described: This compound is obtained by condensation of 8-chloro-6,7-difluoro-1-[2(S)-fluoro-1(R)-cyclopropyl]-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (I) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (II) by means of triethylamine in refluxing acetonitrile, followed by deprotection with 35% aqueous HCl. The starting compounds (I) and (II) are obtained as follows: 1) The reaction of (+/-)-cis-2-fluorocyclopropane-1-carboxylic acid (III) with 1(R)-phenylethylamine (IV) by means of N,N'-carbonyldiimidazole (CDI) gives the corresponding amide (V) as a mixture of diastereomers, which is submitted to preparative HPLC yielding 2(S)-fluorocyclopropane-1(R)-carboxylic acid 1(R)-phenylethylamide (VI). Hydrolysis of (VI) with hot 35% HCl affords the corresponding free acid (VII), which by reaction with diphenyl phosphorazidate in tert-butanol is converted to 1(R)-(tert-butoxycarbonylamino)-2(S)-fluorocyclopropane (VIII). The deprotection of (VIII) with trifluoroacetic acid gives the corresponding free amine as trifluoroacetate (IX), which is condensed with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (X) by means of triethylamine in dichloromethane to yield the chiral 3-aminoacrylate (XI). The cyclization of (XI) by means of NaH in dioxane affords 8-chloro-6,7-difluoro-1-[2(S)-fluoro-1(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XII), which is finally saponified to the desired acid (I) with hot 35% HCl.

参考文献中间体

合成目标

【1】 Kimura, Y.; Atarashi, S.; Kawakami, K.; Hayakawa, I.; Sato, K.; (Fluorocyclopropyl)quinolones. 2. Synthesis and stereochemical structure-activity relationships of chiral 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone antibacterial agents. J Med Chem 1994, 37, 20, 3344.

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)	15130	8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid	127199-27-3	C₁₃H₇ClF₃NO₃	详情	详情
(II)	15193	tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate		C₁₁H₂₀N₂O₂	详情	详情
(III)	15140	(1S,2S)-2-fluorocyclopropanecarboxylic acid		C₄H₅FO₂	详情	详情
(IV)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(V)	15139	(1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₂H₁₄FNO	详情	详情
(VI)	15139	(1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₂H₁₄FNO	详情	详情
(VII)	15140	(1S,2S)-2-fluorocyclopropanecarboxylic acid		C₄H₅FO₂	详情	详情
(VIII)	15127	tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate	127199-16-0	C₈H₁₄FNO₂	详情	详情
(IX)	15146	(1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine		C₃H₆FN	详情	详情
(X)	11682	ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate		C₁₄H₁₂ClF₃O₄	详情	详情
(XI)	15190	ethyl (E)-2-(3-chloro-4,5-difluorobenzoyl)-3-[[(1R,2S)-2-fluorocyclopropyl]amino]-2-propenoate		C₁₅H₁₃ClF₃NO₃	详情	详情
(XII)	15129	ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₅H₁₁ClF₃NO₃	详情	详情

Extended Information