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【结 构 式】

【分子编号】44228

【品名】benzyl (3S,4S)-3-[1-(ethoxycarbonyl)cyclopropyl]-4-fluoro-1-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C18H22FNO4

【 分 子 量 】335.3754232

【元素组成】C 64.46% H 6.61% F 5.66% N 4.18% O 19.08%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VI)

The chiral pyrrolidinone derivative (I) was fluorinated to (II) by means of N-fluoro benzenesulfonimide in the presence of LDA at -78 C. The trans-fluoroderivative (II) was then epimerized to the cis-isomer (III) upon enolization with LDA in cold THF, followed by reprotonation with 2,6-di-tert-butylphenol. After conversion of (III) to the corresponding thiolactam (IV) using Lawesson’s reagent, desulfurization of (IV) in the presence of Raney-Ni yielded pyrrolidine (V). The 1-phenylethyl group of (V) was then removed by dealkylation with benzyl chloroformate, yielding carbamate (VI). Ester hydrolysis of (VI) and subsequent carbonyldiimidazole-mediated condensation with ammonia gave rise to amide (VII). Hofmann rearrangement of amide (VII) in the presence of lead tetraacetate and tert-butanol generated the tert-butyl carbamate (VIII). The N-benzyloxycarbonyl protecting group of (VIII) was then removed by hydrogenolysis over Pd/C to give amine (IX), which was condensed with the difluoroquinolone (X) to provide adduct (XI). The N-Boc group of (XI) was finally cleaved by treatment with aqueous HCl.

1 Takemura, M.; Kimura, Y.; Takahashi, H.; Kimura, K.; Miyauchi, S.; Ohki, H. (Daiichi Pharmaceutical Co., Ltd.); Substd. aminocycloalkylpyrrolidine derivs.. EP 0911328; WO 9719072 .
2 Takahashi, H.; Sugita, K.; Miyauchi, R.; Miyauchi, S.; Ohki, H.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); cis-Disubstd. aminocycloalkyl-pyrrolidine derivs.. EP 1020459; WO 9852939 .
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) 44223 ethyl 1-[(3S)-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate C18H23NO3 详情 详情
(II) 44224 ethyl 1-[(3S,4R)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate C18H22FNO3 详情 详情
(III) 44225 ethyl 1-[(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate C18H22FNO3 详情 详情
(IV) 44226 ethyl 1-[(3S,4S)-4-fluoro-1-[(1S)-1-phenylethyl]-5-thioxopyrrolidinyl]cyclopropanecarboxylate C18H22FNO2S 详情 详情
(V) 44227 ethyl 1-[(3S,4S)-4-fluoro-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate C18H24FNO2 详情 详情
(VI) 44228 benzyl (3S,4S)-3-[1-(ethoxycarbonyl)cyclopropyl]-4-fluoro-1-pyrrolidinecarboxylate C18H22FNO4 详情 详情
(VII) 44229 benzyl (3S,4S)-3-[1-(aminocarbonyl)cyclopropyl]-4-fluoro-1-pyrrolidinecarboxylate C16H19FN2O3 详情 详情
(VIII) 44230 benzyl (3R,4S)-3-[1-[(tert-butoxycarbonyl)amino]cyclopropyl]-4-fluoro-1-pyrrolidinecarboxylate C20H27FN2O4 详情 详情
(IX) 44231 tert-butyl 1-[(3R,4S)-4-fluoropyrrolidinyl]cyclopropylcarbamate C12H21FN2O2 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
(XI) 44233 5-amino-7-((3R,4S)-3-[1-[(tert-butoxycarbonyl)amino]cyclopropyl]-4-fluoropyrrolidinyl)-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C26H31F3N4O5 详情 详情
Extended Information