(2S)-2-bromo-4-methylpentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】26058

【品名】(2S)-2-bromo-4-methylpentanoic acid

【CA登记号】

【分子式】C₆H₁₁BrO₂

【分子量】195.05614

【元素组成】C 36.95% H 5.68% Br 40.96% O 16.4%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XXV)

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：(I)

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

合成路线3

该中间体在本合成路线中的序号：(I)

(R)-2-Bromo-4-methylpentanoic acid (I) was protected as the benzyl ester (II) and subsequently condensed with benzyl tert-butyl malonate (III) in the presence of potassium tert-butoxide to furnish the triester (IV) as an epimeric mixture. Alkylation of (IV) with cinnamyl bromide (V) produced adduct (VI). The key intermediate (VII) was then obtained by catalytic hydrogenation of the benzyl esters and olefin double bond of (VI), followed by thermal malonate decarboxylation.

参考文献中间体

合成目标

【1】 Fujisawa, T.; Odake, S.; Morita, Y.; Hongo, T.; Ito, H.; Yasuda, J.; Suda, E.; Igeta, K.; Morikawa, T. (Fuji Yakuhin Kogyo Co., Ltd.); Highly water-soluble metalloproteinase inhibitor. EP 0832875; WO 9633968 .

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)	26058	(2S)-2-bromo-4-methylpentanoic acid		C₆H₁₁BrO₂	详情	详情
(II)	60695	benzyl (2R)-2-bromo-4-methylpentanoate		C₁₃H₁₇BrO₂	详情	详情
(III)	60696	1-benzyl 3-(tert-butyl) malonate		C₁₄H₁₈O₄	详情	详情
(IV)	60697	1,2-dibenzyl 1-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate		C₂₇H₃₄O₆	详情	详情
(V)	21131	1-[(E)-3-bromo-1-propenyl]benzene	4392-24-9	C₉H₉Br	详情	详情
(VI)	60698	4,5-dibenzyl 4-(tert-butyl) (E,5R)-7-methyl-1-phenyl-1-octene-4,4,5-tricarboxylate		C₃₆H₄₂O₆	详情	详情
(VII)	60699	(2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-phenylhexanoic acid		C₂₁H₃₂O₄	详情	详情

Extended Information