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【结 构 式】 
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【分子编号】15127 【品名】tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate 【CA登记号】127199-16-0 |
【 分 子 式 】C8H14FNO2 【 分 子 量 】175.2031032 【元素组成】C 54.84% H 8.05% F 10.84% N 7.99% O 18.26% |
合成路线1
该中间体在本合成路线中的序号：(III)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.
| 【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：(III)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：(III)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4
该中间体在本合成路线中的序号：(III)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5
该中间体在本合成路线中的序号：(VIII)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 |