(2R)-2-bromo-3-methylbutyric acid -Drug Synthesis Database

【结构式】

【分子编号】33158

【品名】(2R)-2-bromo-3-methylbutyric acid

【CA登记号】565-74-2

【分子式】C₅H₉BrO₂

【分子量】181.02926

【元素组成】C 33.17% H 5.01% Br 44.14% O 17.68%

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：(XIV)

The N-protection of 1-aminocyclopentane-1-carboxylic acid (I) with PhCH2-OCOCl and NaOH in tert-butyl methyl ether gives the carbamate (VII), which is condensed with L-tyrosine ethyl ester (VIII) by means isobutyl chloroformate and triethylamine in THF yielding the protected dipeptide (IX). The methylation of (IX) with dimethyl sulfate and K2CO3 in ethyl acetate affords the protected 4-O-methyl dipeptide (X). The deprotection of (X) with HCO2H and Pd/C in ethyl acetate affords the previously reported free dipeptide (V), which is condensed with 2(R)-bromo-3-methylbutyryl chloride (XI) by means of NMM in toluene giving the acylated dipeptide (XII). Finally, this compound is treated with thioacetic acid and K2CO3 in ethyl acetate. The intermediate 2(R)-bromo-3-methylbutyryl chloride (XI) has been obtained by reaction of D-valine (XIII) with NaNO2 and HBr giving the 2(R)-bromo-3-methylbutyric acid (XIV), which is then treated with SOCl2 and DMF to afford the target intermediate (XI).

参考文献中间体

合成目标

【1】 Johnson, E.P.; et al.; Efficient large scale preparation of neutral endopeptidase/angiotensin-converting enzyme dual inhibitor CGS30440. Org Process Res Dev 1998, 2, 4, 238.

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)	33149	1-aminocyclopentanecarboxylic acid	52-52-8	C₆H₁₁NO₂	详情	详情
(V)	33152	ethyl (2S)-2-[[(1-aminocyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate		C₁₈H₂₆N₂O₄	详情	详情
(VII)	33154	1-[[(benzyloxy)carbonyl]amino]cyclopentanecarboxylic acid		C₁₄H₁₇NO₄	详情	详情
(VIII)	33155	ethyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	949-67-7	C₁₁H₁₅NO₃	详情	详情
(IX)	33156	ethyl (2S)-2-[[(1-[[(benzyloxy)carbonyl]amino]cyclopentyl)carbonyl]amino]-3-(4-hydroxyphenyl)propanoate		C₂₅H₃₀N₂O₆	详情	详情
(X)	33157	ethyl (2S)-2-[[(1-[[(benzyloxy)carbonyl]amino]cyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate		C₂₆H₃₂N₂O₆	详情	详情
(XI)	33159	(2R)-2-bromo-3-methylbutanoyl chloride		C₅H₈BrClO	详情	详情
(XII)	33160	ethyl (2S)-2-[[(1-[[(2R)-2-bromo-3-methylbutanoyl]amino]cyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate		C₂₃H₃₃BrN₂O₅	详情	详情
(XIII)	21056	(R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid	640-68-6	C₅H₁₁NO₂	详情	详情
(XIV)	33158	(2R)-2-bromo-3-methylbutyric acid	565-74-2	C₅H₉BrO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The protected 4-pyrimidinylphenylalanine (III) was prepared by palladium-catalyzed coupling of the boronophenylalanine (I) with the 5-halopyrimidine (II). After acidic cleavage of the N-Boc protecting group of (III), the resultant amino ester (IV) was coupled with N-Boc-cycloleucine (V) to provide dipeptide (VI). Further acidic treatment of (VI) removed the N-Boc group to yield amine (VII). The chiral bromo acid (IX) was obtained by diazotization of D-valine (VIII) in the presence of HBr and KBr. Acylation of the racemic amine (VII) with bromo acid (IX) furnished the corresponding amide (X) as an epimeric mixture. The bromo group of (X) was finally displaced with potassium thioacetate to give the title thioacetate ester.

参考文献中间体

合成目标

【1】 Gude, C.; Chan, K.; Firooznia, F.; et al.; Synthesis and biological activity of novel potent endothelin-converting enzyme-1 inhibitors. Bioorg Med Chem Lett 2001, 11, 3, 375.

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)	47701	methyl 2-[(tert-butoxycarbonyl)amino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate		C₂₁H₃₂BNO₆	详情	详情
(II)	38987	5-bromopyrimidine	4595-59-9	C₄H₃BrN₂	详情	详情
(III)	47702	methyl 2-[(tert-butoxycarbonyl)amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate		C₁₉H₂₃N₃O₄	详情	详情
(IV)	47703	methyl 2-amino-3-[4-(5-pyrimidinyl)phenyl]propanoate		C₁₄H₁₅N₃O₂	详情	详情
(V)	30890	1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid		C₁₁H₁₉NO₄	详情	详情
(VI)	47704	methyl 2-[([1-[(tert-butoxycarbonyl)amino]cyclopentyl]carbonyl)amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate		C₂₅H₃₂N₄O₅	详情	详情
(VII)	47705	methyl 2-[[(1-aminocyclopentyl)carbonyl]amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate		C₂₀H₂₄N₄O₃	详情	详情
(VIII)	21056	(R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid	640-68-6	C₅H₁₁NO₂	详情	详情
(IX)	33158	(2R)-2-bromo-3-methylbutyric acid	565-74-2	C₅H₉BrO₂	详情	详情
(X)	47706	methyl 2-[[(1-[[(2R)-2-bromo-3-methylbutanoyl]amino]cyclopentyl)carbonyl]amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate		C₂₅H₃₁BrN₄O₄	详情	详情

Extended Information