|
【结 构 式】 
|
【分子编号】15139 【品名】(1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide 【CA登记号】 |
【 分 子 式 】C12H14FNO 【 分 子 量 】207.2477032 【元素组成】C 69.55% H 6.81% F 9.17% N 6.76% O 7.72% |
合成路线1
该中间体在本合成路线中的序号：(XV)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.
| 【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：(XIVa)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.
| 【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3
该中间体在本合成路线中的序号：(V)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.
| 【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4
该中间体在本合成路线中的序号：(VI)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.
| 【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 |