methyl (2R)-2,3-dihydroxypropanoate -Drug Synthesis Database

【结构式】

【分子编号】20916

【品名】methyl (2R)-2,3-dihydroxypropanoate

【CA登记号】

【分子式】C₄H₈O₄

【分子量】120.10512

【元素组成】C 40% H 6.71% O 53.28%

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)

This compound can be prepared by two related ways: 1) The diazotation of L-serine methyl ester (I) with NaNO2 - HCl gives methyl (S)-glycerate (II), which by reaction with 2,2-dimethoxypropane and p-toluenesulfonic acid (or acetone and ZnCl2) is converted to methyl (S)-O-isopropylideneglycerate (III). The reduction of (III) with LiAlH4 in refluxing ether affords (S)-2,3-O-isopropylideneglycerol (IV), which by reaction with tosyl chloride in pyridine is converted to the corresponding tosylate (V). The partial hydrolysis of (V) with HCl in acetone affords (S)-glycerol-1-tosylate (VI), which is finally condensed with 1-phenylpiperazine (VII) in refluxing benzene. 2) The partial hydrolysis of (S)-2,3-epoxypropyl tosylate (VIII) with HCl as before gives the glycerol tosylate (VI), already obtained.

参考文献中间体

合成目标

【1】 Borsa, M.; Tonon, G.; Malandrino, S. (Dompé Farm. SpA); Optically active compounds with antitussive and central sedative activity, a process for the preparation thereof and compositions containing the same. EP 0147847; US 4699911; US 4764515 .
【2】 Giani, R.; Marione, E.; Melillo, G.; Borsa, M.; Tonon, G.C.; Synthesis and pharmacological screening of new phenylpiperazinepropane derivatives and their enantiomers. Arzneim-Forsch Drug Res 1988, 38, 8, 1139-41.
【3】 Prous, J.; Castaner, J.; LEVDROPROPIZINE < Rec INN >. Drugs Fut 1989, 14, 6, 522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10272	[[Amino(imino)methyl]sulfanyl]methane	2986-19-8	C₂H₆N₂S	详情	详情
(I)	20915	methyl (2S)-2-amino-3-hydroxypropanoate	5680-80-8	C₄H₉NO₃	详情	详情
(II)	20916	methyl (2R)-2,3-dihydroxypropanoate		C₄H₈O₄	详情	详情
(III)	20917	methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate	52373-72-5	C₇H₁₂O₄	详情	详情
(IV)	12709	[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol	22323-82-6	C₆H₁₂O₃	详情	详情
(V)	20919	[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate	23788-74-1	C₁₃H₁₈O₅S	详情	详情
(VI)	20920	(2R)-2,3-dihydroxypropyl 4-methylbenzenesulfonate		C₁₀H₁₄O₅S	详情	详情
(VII)	10756	N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine	92-54-6	C₁₀H₁₄N₂	详情	详情
(VIII)	16242	(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate	113826-06-5	C₁₀H₁₂O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

An efficient synthesis of the optically active compound has been reported. Acid hydrolysis of the chiral acetonide (I) gave dihydroxy ester (II), which was selectively protected at the primary hydroxyl group as the O-trityl derivative (III). The beta-keto thioester (V) was obtained by condensation of palmitic acid (IV) with the magnesium salt of [(tert-butylthio)carbonyl]acetic acid via activation with carbonyl diimidazole. Silver salt-promoted condensation of thioester (V) with hydroxy ester (III) gave adduct (VI). The 3-acyltetronic acid system (VII) was obtained by cyclization of (VI) in the presence of tetrabutylammonium fluoride. Finally, deprotection of the trityl group using 1 N HCl afforded the title compound.

参考文献中间体

合成目标

【1】 Sodeoka, M.; et al.; Asymmetric synthesis of a 3-acyltetronic acid derivative, RK-682, and formation of its calcium salt during silica gel column chromatography. Chem Pharm Bull 2001, 49, 2, 206.

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)	20917	methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate	52373-72-5	C₇H₁₂O₄	详情	详情
(II)	20916	methyl (2R)-2,3-dihydroxypropanoate		C₄H₈O₄	详情	详情
(III)	46955	methyl (2R)-2-hydroxy-3-(trityloxy)propanoate		C₂₃H₂₂O₄	详情	详情
(IV)	27918	palmitic acid	57-10-3	C₁₆H₃₂O₂	详情	详情
(V)	46956	S-(tert-butyl) 3-oxooctadecanethioate		C₂₂H₄₂O₂S	详情	详情
(VI)	46957	(1R)-2-methoxy-2-oxo-1-[(trityloxy)methyl]ethyl 3-oxooctadecanoate		C₄₁H₅₄O₆	详情	详情
(VII)	46958	(5R)-3-palmitoyl-5-[(trityloxy)methyl]-2,4(3H,5H)-furandione		C₄₀H₅₀O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Ketal exchange between the chiral acetonide (I) and 2-(benzoyloxy)acetaldehyde (II) under acidic conditions affords the 2-(benzoyloxymethyl) dioxolane (III) as a diastereomeric mixture. Alternatively, diazotization of D-serine (IV) in the presence of NaNO2 and H2SO4 produces D-glyceric acid (V), which is further esterified with methanol to afford the methyl ester (VI). Condensation of dihydroxy ester (VI) with 2-(benzoyloxy)acetaldehyde dimethyl acetal (VII) then gives dioxolane (III).

参考文献中间体

合成目标

【1】 Nguyen-Ba, N. (Shire BioChem Inc.); Antiviral nucleoside analogues. EP 1140937; JP 2002533470; US 6358963; WO 0039143 .
【2】 Cimpoia, A.; Janes, L.; Kazlauskas, R. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0047759 .
【3】 Cimpoia, A.; Wang, Y.-F. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0158894 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	57514	methyl (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate		C₁₃H₁₄O₆	详情	详情
(IIIb)	57515	methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate		C₁₃H₁₄O₆	详情	详情
(I)	20917	methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate	52373-72-5	C₇H₁₂O₄	详情	详情
(II)	15605	2-oxoethyl benzoate		C₉H₈O₃	详情	详情
(IV)	15728	(+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine	312-84-5	C₃H₇NO₃	详情	详情
(V)	57516	(2R)-2,3-dihydroxypropanoic acid		C₃H₆O₄	详情	详情
(VI)	20916	methyl (2R)-2,3-dihydroxypropanoate		C₄H₈O₄	详情	详情
(VII)	57517	2,2-dimethoxyethyl benzoate		C₁₁H₁₄O₄	详情	详情

Extended Information