tert-butyl (2S)-2-bromo-4-methylpentanoate -Drug Synthesis Database

【结构式】

【分子编号】26059

【品名】tert-butyl (2S)-2-bromo-4-methylpentanoate

【CA登记号】

【分子式】C₁₀H₁₉BrO₂

【分子量】251.16366

【元素组成】C 47.82% H 7.62% Br 31.81% O 12.74%

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：(XXVI)

4) The deamination of L-leucine (XXIV) with NaNO2, NaBr and H2SO4 gives 2(S)-bromo-4-methylpentanoic acid (XXV), which is esterified with tert-butyl acetate and BF3.AcOH to yield the tert-butyl ester (XXVI). The condensation of (XXVI) with the sodium salt of diethyl malonate affords the substituted malonic ester (XXVII), which is selectively hydrolyzed at the tert-butyl ester group with formic acid, giving the monoacid (XXVIII). The decarboxylative reduction of (XXVIII) with BH3 and SMe2 provides 3(S)-isobutylbutano-4-lactone (XXIX). Lactone (XXIX) is submitted to ring opening by treatment with trimethylsilyl iodide in ethanol, yielding 3(S)-(iodomethyl)-5-methylhexanoic acid ethyl ester (XXX). The reaction of (XXX) with sodium azide yields azide (XXXI), which is hydrolyzed with KOH in ethanol/water to afford the free acid (XVII). Finally, this compound is reduced to pregabalin by treatment with H2 over Pd/C.

参考文献中间体

合成目标

【1】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348.
【2】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	26051	(3S)-3-(azidomethyl)-5-methylhexanoic acid		C₈H₁₅N₃O₂	详情	详情
(XXIV)	26057	L-Leucine	61-90-5	C₆H₁₃NO₂	详情	详情
(XXV)	26058	(2S)-2-bromo-4-methylpentanoic acid		C₆H₁₁BrO₂	详情	详情
(XXVI)	26059	tert-butyl (2S)-2-bromo-4-methylpentanoate		C₁₀H₁₉BrO₂	详情	详情
(XXVII)	26060	2-(tert-butyl) 1,1-diethyl (2S)-4-methyl-1,1,2-pentanetricarboxylate		C₁₇H₃₀O₆	详情	详情
(XXVIII)	26061	(2S)-2-[2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]-4-methylpentanoic acid		C₁₃H₂₂O₆	详情	详情
(XXIX)	26062	(4S)-4-isobutyldihydro-2(3H)-furanone		C₈H₁₄O₂	详情	详情
(XXX)	26063	ethyl (3S)-3-(iodomethyl)-5-methylhexanoate		C₁₀H₁₉IO₂	详情	详情
(XXXI)	26064	ethyl (3S)-3-(azidomethyl)-5-methylhexanoate		C₁₀H₁₉N₃O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Esterification of (S)-2-bromo-4-methylpentanoic acid (I) with isobutylene in the presence of H2SO4 affords the corresponding tert-butyl ester (II). Subsequent alkylation of dibenzyl malonate with bromoester (II) gives triester (III). After acidic tert-butyl group cleavage in (III), the resultant acid (IV) is coupled with L-phenylglycine-N-methylamide (V), yielding diamide (VI). Transfer hydrogenolysis of the dibenzyl ester (VI) with ammonium formate and Pd/C produces diacid (VII). Mannich reaction of malonic acid (VII) with formaldehyde and piperidine, with concomitant decarboxylation, leads to the alpha-methylene carboxylic acid (VIII), which is further coupled to O-benzyl hydroxylamine giving hydroxamate (IX). Simultaneous double bond hydrogenation and O-debenzylation of (IX) then produces a diastereomeric mixture of alpha-methyl hydroxamic acids, from which the desired diastereoisomer is isolated by preparative HPLC.

参考文献中间体

合成目标

【2】 Hirayama, R.; Tsukida, T.; Yamamoto, M.; Ikeda, S.; Sakamoto, F.; Obata, Y.; Matsuo, K. (Kanebo Pharmaceuticals, Ltd.); Acylphenylglycine deriv. and preventive and remedy for diseases caused by increased collagenase activity containing said cpd. as active ingredient. EP 0712838; JP 1995101925; US 5795891; WO 9504715 .
【1】 Hirayama, R.; et al.; Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors. Bioorg Med Chem 1997, 5, 4, 765.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	26058	(2S)-2-bromo-4-methylpentanoic acid	C₆H₁₁BrO₂	详情	详情
(II)	26059	tert-butyl (2S)-2-bromo-4-methylpentanoate	C₁₀H₁₉BrO₂	详情	详情
(III)	16014	1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate	C₂₇H₃₄O₆	详情	详情
(IV)	56999	(2R)-2-{2-(benzyloxy)-1-[(benzyloxy)carbonyl]-2-oxoethyl}-4-methylpentanoic acid	C₂₃H₂₆O₆	详情	详情
(V)	57000	(2S)-2-amino-N-methyl-2-phenylethanamide	C₉H₁₂N₂O	详情	详情
(VI)	57001	dibenzyl 2-[(1R)-3-methyl-1-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)butyl]malonate	C₃₂H₃₆N₂O₆	详情	详情
(VII)	57002	2-[(1R)-3-methyl-1-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)butyl]malonic acid	C₁₈H₂₄N₂O₆	详情	详情
(VIII)	57003	2-[(1R)-3-methyl-1-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)butyl]acrylic acid	C₁₈H₂₄N₂O₄	详情	详情
(IX)	57004	(2R)-N~4~-(benzyloxy)-2-isobutyl-N~1~-[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]-3-methylenebutanediamide	C₂₅H₃₁N₃O₄	详情	详情

Extended Information