ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】15172

【品名】ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate

【CA登记号】

【分子式】C₈H₁₁BrO₃

【分子量】235.07754

【元素组成】C 40.88% H 4.72% Br 33.99% O 20.42%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXXIV)

b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 1) The cyclopropanation of ethyl acetoacetate (XXXI) with 1,2-dibromoethane (XXXII) by means of K2CO3 in DMF gives 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII), which is brominated with Br2 in ethanol yielding the bromoacetyl derivative (XXXIV). The cyclization of (XXXI) with (R)-alpha-methylbenzylamine (XIII) by means of triethylamine affords 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), which by reaction with hydroxylamine is converted into the monooxime (XXXVI). The reduction of (XXXVI) with H2 over RaNi in methanol affords 7-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one as a diastereomeric mixture (XXXVII) + (XXXVIII), which is separated by column chromatography. The reduction of the (7S)-isomer (XXXVIII) with LiAlH4 in THF gives 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXXIX), which is protected in the usual way to the tert-butoxycarbonyl derivative (XL). Finally, this compound is debenzylated to (VII) by hydrogenation with H2 over Pd/C in ethanol.

参考文献中间体

合成目标

【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
(XXXIX))	15177	(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine		C₁₄H₂₀N₂	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
(XIII)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(XXXI)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(XXXII)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情
(XXXIII)	15171	ethyl 1-acetylcyclopropanecarboxylate		C₈H₁₂O₃	详情	详情
(XXXIV)	15172	ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate		C₈H₁₁BrO₃	详情	详情
(XXXV)	15173	5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione		C₁₄H₁₅NO₂	详情	详情
(XXXVI)	15174	5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime		C₁₄H₁₆N₂O₂	详情	详情
(XXXVII)	15175	(7R)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one		C₁₄H₁₈N₂O	详情	详情
(XXXVIII)	15176	(7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one		C₁₄H₁₈N₂O	详情	详情
(XL)	15178	N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamic acid		C₁₅H₂₀N₂O₂	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 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)).

参考文献中间体

合成目标

【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

Extended Information