(2S)-2-amino-N-methyl-2-phenylethanamide -Drug Synthesis Database

【结构式】

【分子编号】57000

【品名】(2S)-2-amino-N-methyl-2-phenylethanamide

【CA登记号】

【分子式】C₉H₁₂N₂O

【分子量】164.20716

【元素组成】C 65.83% H 7.37% N 17.06% O 9.74%

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：(V)

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2

该中间体在本合成路线中的序号：(VII)

An alternative, stereoselective synthesis has been reported. The alkylation of the chiral N-acyl oxazolidinone (I) with benzyl L-2-[(trifluoromethylsulfonyl)oxy]propionate (II) leads to the succinic acid derivative (III). After hydrogenolysis of the benzyl ester group of (III), the resultant carboxylic acid (IV) is esterified with isobutylene and H2SO4 to afford the tert-butyl ester (V). Removal of the chiral auxiliary group of (V) is then effected by hydrolysis with lithium peroxide, yielding acid (VI). Subsequent coupling of (VI) with L-phenylglycine-N-methylamide (VII) provides diamide (VIII). Acidic tert-butyl ester cleavage in (VIII) gives acid (IX), which is condensed with O-benzyl hydroxylamine to furnish hydroxamate (X). The O-benzyl group of (X) is finally removed by catalytic hydrogenolysis over Pd/C.

参考文献中间体

合成目标

【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)	25391	(4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one	C₁₆H₂₁NO₃	详情	详情
(II)	43504	benzyl (2S)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate	C₁₁H₁₁F₃O₅S	详情	详情
(III)	57005	benzyl (2S,3R)-3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2,5-dimethylhexanoate	C₂₆H₃₁NO₅	详情	详情
(IV)	57006	(2S,3R)-3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2,5-dimethylhexanoic acid	C₁₉H₂₅NO₅	详情	详情
(V)	57007	tert-butyl (2S,3R)-3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2,5-dimethylhexanoate	C₂₃H₃₃NO₅	详情	详情
(VI)	57008	(2R)-2-[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]-4-methylpentanoic acid	C₁₃H₂₄O₄	详情	详情
(VII)	57000	(2S)-2-amino-N-methyl-2-phenylethanamide	C₉H₁₂N₂O	详情	详情
(VIII)	57009	tert-butyl (2S,3R)-2,5-dimethyl-3-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)hexanoate	C₂₂H₃₄N₂O₄	详情	详情
(IX)	57010	(2S,3R)-2,5-dimethyl-3-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)hexanoic acid	C₁₈H₂₆N₂O₄	详情	详情
(X)	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