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【结 构 式】 
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【分子编号】55742 【品名】ethyl 1-{4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-3-yl}cyclopropanecarboxylate 【CA登记号】 |
【 分 子 式 】C18H20FNO3 【 分 子 量 】317.3601432 【元素组成】C 68.12% H 6.35% F 5.99% N 4.41% O 15.12% |
合成路线1
该中间体在本合成路线中的序号：(IX)The intermediate fluoropyrrolidine (XIV) was obtained as follows: Alkylation of ethyl acetoacetate (I) with 1,2-dibromoethane (II) led to the cyclopropane derivative (III). Bromination of (III) provided bromo ketone (IV), which was condensed with (S)-1-phenylethylamine (V), yielding amino ketone (VI). Acylation of amine (VI) with (diethylfosfonyl)fluoroacetyl chloride (VII) gave amide (VIII). Intramolecular Wadsworth-Emmons condensation of keto phosphonate (VIII) in the presence of potassium tert-butoxide produced the pyrrolinone (IX). Catalytic hydrogenation of the pyrroline double bond of (IX), followed by separation of the resultant diastereomeric mixture, furnished pyrrolidinone (X). After saponification of the ethyl ester group of (X), the resulting acid (XI) was subjected to Curtius rearrangement in the presence of DPPA and t-BuOH, giving rise to carbamate (XII). Lactam (XII) reduction by means of borane in THF afforded pyrrolidine (XIII). The N-phenylethyl group of (XIII) was then removed by hydrogenation over Pd/C to furnish the required intermediate pyrrolidine (XIV) (See scheme no. 27170201a, intermediate (IX)).
| 【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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 15171 | ethyl 1-acetylcyclopropanecarboxylate | C8H12O3 | 详情 | 详情 | |
| (IV) | 15172 | ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate | C8H11BrO3 | 详情 | 详情 | |
| (V) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VI) | 55739 | ethyl 1-(2-{[(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (VII) | 55740 | diethyl 2-chloro-1-fluoro-2-oxoethylphosphonate | C6H11ClFO4P | 详情 | 详情 | |
| (VIII) | 55741 | ethyl 1-(2-{[2-(diethoxyphosphoryl)-2-fluoroacetyl][(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate | C22H31FNO7P | 详情 | 详情 | |
| (IX) | 55742 | ethyl 1-{4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-3-yl}cyclopropanecarboxylate | C18H20FNO3 | 详情 | 详情 | |
| (X) | 44225 | ethyl 1-[(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate | C18H22FNO3 | 详情 | 详情 | |
| (XI) | 55743 | 1-{(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropanecarboxylic acid | C16H18FNO3 | 详情 | 详情 | |
| (XII) | 55744 | tert-butyl 1-{(3R,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate | C20H27FN2O3 | 详情 | 详情 | |
| (XIII) | 55745 | tert-butyl 1-{(3R,4S)-4-fluoro-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate | C20H29FN2O2 | 详情 | 详情 | |
| (XIV) | 44231 | tert-butyl 1-[(3R,4S)-4-fluoropyrrolidinyl]cyclopropylcarbamate | C12H21FN2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |