(2S,3S)-3-(benzyloxy)-1,2,4-butanetriol -Drug Synthesis Database

【结构式】

【分子编号】43826

【品名】(2S,3S)-3-(benzyloxy)-1,2,4-butanetriol

【CA登记号】

【分子式】C₁₁H₁₆O₄

【分子量】212.24564

【元素组成】C 62.25% H 7.6% O 30.15%

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：(II)

A new synthesis of (3R,4S)-1-benzyl-4-phenyl-3-(triethylsilyloxy)azetidin-2-one (XIII), a precursor of the side chain of paclitaxel, has been described: The reaction of ethyl L-tartrate (I) with benzaldehyde and TsOH followed, by reduction with LiAlH4 and AlCl3 gives the monobenzylated tretraol (II), which is submitted to an oxidative cleavage of the alpha-diol bond with NaIO4 to yield the aldehyde (III). Reaction of (III) with benzylamine affords the imine (IV), which is submitted to a Grignard addition of phenylmagnesium bromide in ether providing a 1:9 mixture of aminoalcohols (VI) and (VII) separated by chromatography. Oxidation of the desired major isomer (VII) with CrO3/H2SO4 gives the corresponding acid (VIII), which is then esterified with TMS-Cl in refluxing methanol to the methyl ester (IX). Deprotection of compound (IX) by hydrogenolysis with reluxing HCO2H over Pd/C yields 3(S)-amino-2(R)-hydroxy-3-phenylpropionic acid methyl ester (X), which is silylated at the OH group of with TES-Cl and TEA in ether/THF to afford the silyl ether (XI). Cyclization of (XI) by means of LHMDS in THF provides the beta-lactam (XII), which is finally benzoylated with benzoyl chloride and TEA in the usual way.

参考文献中间体

合成目标

【1】 Kim, H.-K.; Kim, S.-C.; Synthesis of new Taxol side chain precursor from L-tartaric ester. Bull Korean Chem Soc 2000, 21, 10, 1047.

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)	16696	Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate	87-91-2	C₈H₁₄O₆	详情	详情
(II)	43826	(2S,3S)-3-(benzyloxy)-1,2,4-butanetriol		C₁₁H₁₆O₄	详情	详情
(III)	43827	(2S)-2-(benzyloxy)-3-hydroxypropanal		C₁₀H₁₂O₃	详情	详情
(IV)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(V)	43828	(2R)-3-(benzylimino)-2-(benzyloxy)-1-propanol		C₁₇H₁₉NO₂	详情	详情
(VI)	43829	(2R,3R)-3-(benzylamino)-2-(benzyloxy)-3-phenyl-1-propanol		C₂₃H₂₅NO₂	详情	详情
(VII)	43830	(2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenyl-1-propanol		C₂₃H₂₅NO₂	详情	详情
(VIII)	43831	(2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenylpropionic acid		C₂₃H₂₃NO₃	详情	详情
(IX)	43832	methyl (2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenylpropanoate		C₂₄H₂₅NO₃	详情	详情
(X)	43833	methyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoate		C₁₀H₁₃NO₃	详情	详情
(XI)	43834	methyl (2R,3S)-3-amino-3-phenyl-2-[(triethylsilyl)oxy]propanoate		C₁₆H₂₇NO₃Si	详情	详情
(XII)	10685	(3R,4S)-4-Phenyl-3-[(triethylsilyl)oxy]-2-azetidinone		C₁₅H₂₃NO₂Si	详情	详情
(XIII)	10490	(3R,4S)-1-Benzoyl-4-phenyl-3-[(triethylsilyl)oxy]-2-azetanone		C₂₂H₂₇NO₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).

参考文献中间体

合成目标

【1】 Al-Hakim, A.H.; et al.; Synthesis of 1,2-O-isopropylidene-L-threitol and its conversion to (R)-1,2-O-isopropylideneglycerol. Synthesis 1985, 207.
【2】 Katoh, T.; Terashima, S.; Total synthesis of antitumor antibiotic FR900482. Yuki Gosei Kagaku Kyokaishi 1997, 55, 11, 946.
【3】 Ohno, M.; et al.; An enantioselective synthesis of platelet-activating factors, their enantiomers, and their analogues from D- and L-tartaric acids. Chem Pharm Bull 1985, 33, 2, 572.
【4】 Yoshino, T.; et al.; Total synthesis of natural (+)-FR900482. 2. Efficient syntheses of the aromatic and the optically active aliphatic fragments. Tetrahedron Lett 1996, 37, 20, 3475.
【5】 Yoshino, T.; et al.; Total synthesis of an enantiomeric pair of FR900482. 2. Syntheses of the aromatic and the optically active aliphatic segments. Tetrahedron 1997, 53, 30, 10239.

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)	28476	dimethyl (2S,3S)-2,3-dimethylbutanedioate		C₆H₁₀O₆	详情	详情
(II)	47374	dimethyl (4R,5R)-2-phenyl-1,3-dioxolane-4,5-dicarboxylate	38270-72-3	C₁₃H₁₄O₆	详情	详情
(III)	43826	(2S,3S)-3-(benzyloxy)-1,2,4-butanetriol		C₁₁H₁₆O₄	详情	详情
(IV)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(V)	47375	(2S)-2-(benzyloxy)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol		C₁₄H₂₀O₄	详情	详情
(VI)	47376	(4S)-4-[(1S)-1-(benzyloxy)-2-[(4-methoxybenzyl)oxy]ethyl]-2,2-dimethyl-1,3-dioxolane; benzyl (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl ether		C₂₂H₂₈O₅	详情	详情
(VII)	47377	(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl methanesulfonate		C₁₆H₂₄O₇S	详情	详情
(VIII)	47378	(1S,2S)-2,3-dihydroxy-1-[[(4-methoxybenzyl)oxy]methyl]propyl methanesulfonate		C₁₃H₂₀O₇S	详情	详情
(IX)	47379	((2S,3R)-3-[[(4-methoxybenzyl)oxy]methyl]oxiranyl)methanol		C₁₂H₁₆O₄	详情	详情
(X)	47380	(2R,3S)-2-azido-4-[(4-methoxybenzyl)oxy]-1,3-butanediol		C₁₂H₁₇N₃O₄	详情	详情
(XI)	47381	(2S,3R)-3-azido-4-[[tert-butyl(diphenyl)silyl]oxy]-1-[(4-methoxybenzyl)oxy]-2-butanol		C₂₈H₃₅N₃O₄Si	详情	详情
(XII)	47382	(2S,3R)-3-amino-4-[[tert-butyl(diphenyl)silyl]oxy]-1-[(4-methoxybenzyl)oxy]-2-butanol		C₂₈H₃₇NO₄Si	详情	详情
(XIII)	47383	2,2,2-trichloroethyl (1R,2S)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2-hydroxy-3-[(4-methoxybenzyl)oxy]propylcarbamate		C₃₁H₃₈Cl₃NO₆Si	详情	详情
(XIV)	47384	2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-[[(4-methoxybenzyl)oxy]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₃₄H₄₂Cl₃NO₆Si	详情	详情
(XV)	47385	2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₂₆H₃₄Cl₃NO₅Si	详情	详情
(XVI)	47386	2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,2-dimethyl-5-([[(trifluoromethyl)sulfonyl]oxy]methyl)-1,3-oxazolidine-3-carboxylate		C₂₇H₃₃Cl₃F₃NO₇SSi	详情	详情

Extended Information