methyl (2S,3R)-2-amino-3-hydroxybutanoate -Drug Synthesis Database

【结构式】

【分子编号】42026

【品名】methyl (2S,3R)-2-amino-3-hydroxybutanoate

【CA登记号】

【分子式】C₅H₁₁NO₃

【分子量】133.14728

【元素组成】C 45.1% H 8.33% N 10.52% O 36.05%

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：(II)

D-Threonine (I) was esterified by means of thionyl chloride in methanol, and the resultant amino ester (II) was subsequently acylated with 3,5-dinitrobenzoyl chloride (III) to afford amide (IV). Conversion of (IV) to the acetoacetate ester (VI) was effected by reaction with the diketene precursor 2,2,6-trimethyl-4H-1,3-dioxin-4-one (V) in boiling xylene. Treatment of keto ester (V) with ammonia in the presence of p-toluenesulfonic acid produced the aminocrotonate ester (VI). Dihydropyridine (IXa-b) was then obtained as a diastereomeric mixture by a modified Hantzsh condensation between enamine (VI), 2-trifluoromethylbenzaldehyde (VII) and nitroacetone. After chromatographic separation of the isomers, the chiral auxiliary group was removed by methanolysis in the presence of DBU. The desired (+)-(S)-dihydropyridinecarboxylic acid (X) was finally converted to the nitrooxyethyl ester by reaction with 2-bromoethyl nitrate (XI).

参考文献中间体

合成目标

【1】 Shan, R.; Knaus, E.E.; Howlett, S.E.; Syntheses, calcium channel agonist-antagonist modulation activities, nitric oxide release, and voltage-clamp studies of 2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate enantiomers. J Med Chem 2002, 45, 4, 955.
【2】 Knaus, E.E.; Shan, R.; The design of (-)-(S)-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate: A cardioselective positive inotropic derivative of Bay K 8644. Bioorg Med Chem Lett 1999, 9, 17, 2613.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIII)	30332	2-(trifluoromethyl)benzaldehyde	447-61-0	C₈H₅F₃O	详情	详情
(IXa)	59607	(1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (4S)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylate		C₂₇H₂₄F₃N₅O₁₁	详情	详情
(IXb)	59608	(1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (4R)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylate		C₂₇H₂₄F₃N₅O₁₁	详情	详情
(I)	28908	L-Threonine; (2R,3S)-2-amino-3-hydroxybutyric acid	632-20-2	C₄H₉NO₃	详情	详情
(II)	42026	methyl (2S,3R)-2-amino-3-hydroxybutanoate		C₅H₁₁NO₃	详情	详情
(III)	12053	3,5-Dinitrobenzoyl chloride	99-33-2	C₇H₃ClN₂O₅	详情	详情
(IV)	59604	methyl (2R,3S)-2-[(3,5-dinitrobenzoyl)amino]-3-hydroxybutanoate		C₁₂H₁₃N₃O₈	详情	详情
(V)	13327	2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid	5394-63-8	C₇H₁₀O₃	详情	详情
(VI)	59605	methyl (2R,3S)-3-(acetoacetyloxy)-2-[(3,5-dinitrobenzoyl)amino]butanoate		C₁₆H₁₇N₃O₁₀	详情	详情
(VII)	59606	(1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (E)-3-amino-2-butenoate		C₁₆H₁₈N₄O₉	详情	详情
(X)	59609	(4S)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylic acid		C₁₅H₁₃F₃N₂O₄	详情	详情
(XI)	59610	1-bromo-2-(nitrooxy)ethane		C₂H₄BrNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Synthesis of intermediate (XII): The protection of 2-hydroxy-5-methoxybenzoic acid (VI) with benzyl bromide and K2CO3 in DMF gives 2-(benzyloxy)-5-methoxybenzoic acid (VII), which is condensed with L-threonine methyl ester (VIII) by means of (OEt)2P(O)CN (DEPC) and TEA in DMF yielding the corresponding benzamide (IX). The oxidation of (IX) with DMP, followed by cyclization by means of PPh3 and TEA affords 2-[2-(benzyloxy)-5-methoxyphenyl]-5-methyloxazole-4-carboxylic acid methyl ester (X) which is debenzylated with H2 over Pd/C in methanol to the corresponding phenol (XI). Finally the ester group of (XI) is hydrolyzed with NaOH in THF/water to afford the acid intermediate (XII).

参考文献中间体

合成目标

【1】 Yokokawa, F.; et al.; Total synthesis of amamistatin A, an antiproliferative linear peptide from an actinomycete. Tetrahedron 2000, 56, 19, 3027.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	42020	2-hydroxy-5-methoxybenzoic acid	2612-02-4	C₈H₈O₄	详情	详情
(VII)	42021	2-(benzyloxy)-5-methoxybenzoic acid		C₁₅H₁₄O₄	详情	详情
(VIII)	42026	methyl (2S,3R)-2-amino-3-hydroxybutanoate		C₅H₁₁NO₃	详情	详情
(IX)	42022	methyl (2S,3R)-2-[[2-(benzyloxy)-5-methoxybenzoyl]amino]-3-hydroxybutanoate		C₂₀H₂₃NO₆	详情	详情
(X)	42023	methyl 2-[2-(benzyloxy)-5-methoxyphenyl]-5-methyl-1,3-oxazole-4-carboxylate		C₂₀H₁₉NO₅	详情	详情
(XI)	42024	methyl 2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylate		C₁₃H₁₃NO₅	详情	详情
(XII)	42025	2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylic acid		C₁₂H₁₁NO₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The heterocyclic amino acid precursor (VI) was synthesized as follows. Coupling between N-Boc-D-alanine (I) and L-threonine methyl ester (II) in the presence of DCC and HOBt gave dipeptide (III). Cyclization of (III) using Burgess reagent provided the oxazoline (IV) as a mixture of diastereoisomers. Subsequent dehydrogenation of (IV) by means of bromotrichloromethane and DBU afforded the protected oxazole amino acid (V). Basic hydrolysis of the ethyl ester group then yielded the intermediate acid (VI).

参考文献中间体

合成目标

【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IVa)	48360	methyl (4S,5R)-2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate		C₁₃H₂₂N₂O₅	详情	详情
(IVb)	48361	methyl (4S,5S)-2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate		C₁₃H₂₂N₂O₅	详情	详情
(I)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(II)	42026	methyl (2S,3R)-2-amino-3-hydroxybutanoate		C₅H₁₁NO₃	详情	详情
(III)	48359	methyl (2S,3R)-2-([(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-3-hydroxybutanoate		C₁₃H₂₄N₂O₆	详情	详情
(V)	48362	methyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazole-4-carboxylate		C₁₃H₂₀N₂O₅	详情	详情
(VI)	48363	2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-5-methyl-1,3-oxazole-4-carboxylic acid		C₁₂H₁₈N₂O₅	详情	详情

Extended Information