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【结 构 式】 
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【分子编号】15146 【品名】(1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine 【CA登记号】 |
【 分 子 式 】C3H6FN 【 分 子 量 】75.0857832 【元素组成】C 47.99% H 8.05% F 25.3% N 18.65% |
合成路线1
该中间体在本合成路线中的序号：(XXII)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 2) The cyclization of (1S,2R)-2-amino-1,2-diphenylethanol (XVII) with trichloromethyl chloroformate and triethylamine in dichloromethane gives (4R,5S)-4,5-diphenyloxazolidin-2-one (XVIII), which is treated with 1,1-dimethoxyethane and an acid catalyst, yielding the 1-methoxyethyl derivative (XIX). The heat treatment (150 C) of (XIX) affords the corresponding vinyl derivative (XX), which is cyclized with fluorodiiodomethane and diethyl zinc (a fluorocarbenoid compound) in a preferentially cis-way to afford the cyclopropyl-oxazolidinone (XXI), purified by column chromatography. The hydrogenolysis of (XXI) with H2 over Pd/C in acetic acid gives (1R,2S)-2-fluorocyclopropylamine (XXII), which is finally converted into (III) by reaction with tert-butoxycarbonyl anhydride and triethylamine in THF.
| 【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【2】 Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani, K.; Kamada, M.; Hayakawa, I.; Akiba, T.; Terashima, S.; Asymmetric synthesis of (1R,2S)-2-fluorocyclopropylamine, the key intermediate of the new generation of quinolonecarboxylic acid, DU-6859. Tetrahedron Lett 1992, 33, 24, 3487-90. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (XVII) | 15141 | (1R,2S)-(-)-2-Amino-1,2-diphenylethanol; (1S,2R)-2-amino-1,2-diphenyl-1-ethanol | 23190-16-1 | C14H15NO | 详情 | 详情 |
| (XVIII) | 15142 | (4R,5S)-4,5-Diphenyl-1,3-oxazolan-2-one; (4S,5R)-(-)-4,5-Diphenyl-2-oxazolidinone | 86286-50-2 | C15H13NO2 | 详情 | 详情 |
| (XIX) | 15143 | (4R,5S)-3-[(1R)-1-Methoxyethyl]-4,5-diphenyl-1,3-oxazolan-2-one | C18H19NO3 | 详情 | 详情 | |
| (XX) | 15144 | (4R,5S)-4,5-diphenyl-3-vinyl-1,3-oxazolan-2-one | C17H15NO2 | 详情 | 详情 | |
| (XXI) | 15145 | (4R,5S)-3-[(1R,2S)-2-fluorocyclopropyl]-4,5-diphenyl-1,3-oxazolan-2-one | C18H16FNO2 | 详情 | 详情 | |
| (XXII) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXII)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 3) A study of the influence of different substituents in the cis/trans ratio of the cyclopropanation process has been performed. The general method is as follows: the reaction of benzylamine (XXIII) with acetaldehyde and trichloromethyl chloroformate gives the N-benzyl-N-vinylcarbamoyl chloride (XXIV), which by treatment with alcohol yields the N-vinylcarbamate (XXV). The cyclopropanation of (XXV) with fluorodiiodomethane and diethyl zinc as before preferentially affords the cis-N-(2-fluorocyclopropyl)carbamate (XXVI), which is purified by crystallization. The hydrogenolysis of (XXVI) with H2 over Pd/C in acetic acid gives cis-racemic-2-fluorocyclopropylamine (XXVII), which is submitted to optical resolution with L-menthyl chloroformate to afford pure (1R,2S)-isomer (XXII). Finally, this compound is converted into (III) with tert-butoxycarbonyl anhydride as before.
| 【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【2】 Kobayashi, Y.; Hashimoto, M.; Tamura, O.; Terashima, S.; Katoh, T.; Hayakawa, I.; Akiba, T.; Nakatani, K.; Kamada, M.; Synthesis and optical resolution of dl-cis-2-fluorocyclopropylamine, the key component of the new generation of quinolonecarboxylic acid, DU-6859. Tetrahedron Lett 1992, 33, 24, 3483-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XXIIIb) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (XXIIIc) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
| (XXIVa) | 15150 | N-benzyl-N-vinylcarbamic chloride | C10H10ClNO | 详情 | 详情 | |
| (XXIVb) | 15151 | N-(1-phenylethyl)-N-vinylcarbamic chloride | C11H12ClNO | 详情 | 详情 | |
| (XXIVc) | 15152 | N-benzhydryl-N-vinylcarbamic chloride | C16H14ClNO | 详情 | 详情 | |
| (XXVa) | 15153 | benzyl N-benzyl-N-vinylcarbamate | C17H17NO2 | 详情 | 详情 | |
| (XXVb) | 15154 | benzyl N-(1-phenylethyl)-N-vinylcarbamate | C18H19NO2 | 详情 | 详情 | |
| (XXVc) | 15155 | benzyl N-benzhydryl-N-vinylcarbamate | C23H21NO2 | 详情 | 详情 | |
| (XXVd) | 15156 | butyl N-benzyl-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
| (XXVe) | 15157 | butyl N-(1-phenylethyl)-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
| (XXVf) | 15158 | butyl N-benzhydryl-N-vinylcarbamate | C20H23NO2 | 详情 | 详情 | |
| (XXVIa) | 15159 | benzyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C18H18FNO2 | 详情 | 详情 | |
| (XXVIb) | 15160 | benzyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C19H20FNO2 | 详情 | 详情 | |
| (XXVIc) | 15161 | benzyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C24H22FNO2 | 详情 | 详情 | |
| (XXVId) | 15162 | butyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C15H20FNO2 | 详情 | 详情 | |
| (XXVIe) | 15163 | butyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C16H22FNO2 | 详情 | 详情 | |
| (XXVIf) | 15164 | butyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C21H24FNO2 | 详情 | 详情 | |
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (XXII) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (XXVII) | 63957 | rac-(1R*,2S*)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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：(V)The quinolone intermediate (X) has been obtained as follows: Acid chloride (I), prepared from 3-methyl-2,4,5-trifluorobenzoic acid (II) and SOCl2, was condensed with ethyl 3-(dimethylamino)acrylate (III) to produce the enamino keto ester (IV). Displacement of the dimethylamino group of (IV) with the cyclopropylamine (V) gave rise to (VI), which was further cyclized to the quinolone (VII) under basic conditions. Acid hydrolysis of ethyl ester (VII) provided carboxylic acid (VIII). Electrophilic nitration of the quinoline ring of (VIII) by means of nitronium fluoroborate yielded the nitro derivative (IX), which was finally reduced to the target aminoquinolone (X) by catalytic hydrogenation (See scheme no. 27170201a, intermediate (X)).
| 【1】 Takahashi, H.; et al.; DQ-113 (D61-1113), a potent fluoroquinolone against multi-drug resistance Gram-positive bacteria: Practical synthesis, and in vitro and in vivo activities. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-550. |
| 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) | 51094 | 2,4,5-trifluoro-3-methylbenzoic acid | C8H5F3O2 | 详情 | 详情 | |
| (II) | 55746 | 2,4,5-trifluoro-3-methylbenzoyl chloride | C8H4ClF3O | 详情 | 详情 | |
| (III) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
| (IV) | 55742 | ethyl 1-{4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-3-yl}cyclopropanecarboxylate | C18H20FNO3 | 详情 | 详情 | |
| (V) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (VI) | 55748 | ethyl (Z)-3-{[(1R,2S)-2-fluorocyclopropyl]amino}-2-(2,4,5-trifluoro-3-methylbenzoyl)-2-propenoate | C16H15F4NO3 | 详情 | 详情 | |
| (VII) | 55749 | ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H14F3NO3 | 详情 | 详情 | |
| (VIII) | 55750 | 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H10F3NO3 | 详情 | 详情 | |
| (IX) | 55751 | 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-5-nitro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H9F3N2O5 | 详情 | 详情 | |
| (X) | 44232 | 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H11F3N2O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The reaction of 2,4,5-trifluoro-3-methoxybenzoic acid (I) with SOCl2 in toluene gives the corresponding acyl chloride (II), which is condensed with 3-(dimethylamino)acrylic acid ethyl ester (III) by means of TEA to yield 3-(dimethylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylic acid ethyl ester (IV). The cyclization of (IV) with 2-fluorocyclopropylamine (V) by means of TEA and K2CO3 in DMF affords the quinolone-3-carboxylate (VI), which is hydrolyzed with HCl in HOAc to provide the carboxylic acid (VII). The reaction of (VII) with BF3/Et2O in diethyl ether gives the boronic ester (VIII), which is condensed with the spiropyrrolidine (IX) by means of TEA in ethanol. Finally, the boronic ester of (IX) is hydrolyzed with HCl to afford the target quinolone-3-carboxylic acid.
| 【1】 Kawakami, K.; et al.; DK-570k, a new 8-methoxyquinolone: Synthesis and biological evaluation of 7-[(3-amino-4-substituted)pyrrolidin-1-yl] derivatives. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-546. |
| 【2】 Suzuki, T.; Takahashi, H.; Hayakawa, I.; Takemura, M.; Ohtani, T.; Kawakami, K.; Itoh, M.; Miyauchi, R.; Sekiguchi, M. (Daiichi Pharmaceutical Co., Ltd.); Quinolonecarboxylic acid deriv.. WO 0172738 . |
| 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) | 12258 | 2,4,5-Trifluoro-3-methoxybenzoic acid | 112811-65-1 | C8H5F3O3 | 详情 | 详情 |
| (II) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
| (III) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
| (IV) | 53193 | ethyl (Z)-3-(dimethylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | n/a | C15H16F3NO4 | 详情 | 详情 |
| (V) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (VI) | 53194 | ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C16H14F3NO4 | 详情 | 详情 |
| (VII) | 53195 | 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | n/a | C14H10F3NO4 | 详情 | 详情 |
| (VIII) | 53196 | 3-{[(difluoroboryl)oxy]carbonyl}-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4(1H)-quinolinone | n/a | C14H9BF5NO4 | 详情 | 详情 |
| (IX) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (X) | 53197 | tert-butyl (7S)-5-{3-{[(difluoroboryl)oxy]carbonyl}-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-7-quinolinyl}-5-azaspiro[2.4]hept-7-ylcarbamate | n/a | C25H28BF4N3O6 | 详情 | 详情 |