(1S,2S)-2-fluorocyclopropanecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】15140

【品名】(1S,2S)-2-fluorocyclopropanecarboxylic acid

【CA登记号】

【分子式】C₄H₅FO₂

【分子量】104.0809032

【元素组成】C 46.16% H 4.84% F 18.25% O 30.74%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XVI)

The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) is obtained as follows: 1) The cyclization of butadiene (IX) with dibromofluoromethane by means of BuONa, followed by oxidation with KMnO4, esterification with ethanol - sulfuric acid and reduction with tributyltin hydride gives 2-fluorocyclopropanecarboxylic acid ethyl ester as a cis/trans mixture (X), which is separated by crystallization. The cis-racemic-isomer (XI) is hydrolyzed with NaOH to the corresponding acid (XII), which is condensed with (R)-alpha-methylbenzylamine (XIII) by means of diphenyl chlorophosphate to give the mixture of diastereomers (XIV). This mixture is separated by crystallization, yielding pure (1S,2S)-2-fluoro-N-[alpha(R)-methylbenzyl]cyclopropanecarboxamide (XV), which is hydrolyzed with HCl to the corresponding free acid (XVI). Finally, this compound is converted into (III) by treatment with diphenylphosphoryl azide in refluxing tert-butanol.

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.
【3】 Sato, K.; Saito, T.; Hayakawa, I.; Sato, M.; Yafune, T.; Atarashi, S.; Une, T.; Kimura, Y.; Kawakami, K.; Design and structure-activity relationship of new N1-cis-2-fluorocyclopropyl quinolones. 31st. 31st Intersci Conf Antimicrob Agents Chemother (Sept 29-Oct 2, Chicago) 1991, Abst 1504.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIVa)	15139	(1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₂H₁₄FNO	详情	详情
(XIVb)	63959	(1S,2R)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₂H₁₄FNO	详情	详情
(III)	15127	tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate	127199-16-0	C₈H₁₄FNO₂	详情	详情
(IX)	11579	1,3-Butadiene; Butadiene	106-99-0	C₄H₆	详情	详情
(X)	15134	ethyl 2-fluorocyclopropanecarboxylate		C₆H₉FO₂	详情	详情
(XI)	63960	cis-rac[ethyl (1S,2S)-2-fluorocyclopropanecarboxylate]		C₆H₉FO₂	详情	详情
(XII)	63958	cis-rac(1S,2S)-2-fluorocyclopropanecarboxylic acid		C₄H₅FO₂	详情	详情
(XIII)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(XV)	15139	(1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₂H₁₄FNO	详情	详情
(XVI)	15140	(1S,2S)-2-fluorocyclopropanecarboxylic acid		C₄H₅FO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

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

合成路线3

该中间体在本合成路线中的序号：(III)

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