[(2-chloro-2-oxoacetyl)oxy]methyl pivalate -Drug Synthesis Database

【结构式】

【分子编号】17199

【品名】[(2-chloro-2-oxoacetyl)oxy]methyl pivalate

【CA登记号】

【分子式】C₈H₁₁ClO₅

【分子量】222.62504

【元素组成】C 43.16% H 4.98% Cl 15.92% O 35.93%

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：(XII)

2) The esterification of 2(R)-[4-oxo-3(S)-[1(R)-(trimethylsilyloxy)ethyl]azetidin-2(S)-yl]propionic acid (X) with the previously obtained pyrrolidinone (V) gives the expected thiopropionic ester (XI), which is acylated with oxalic acid monochloride monopivaloyloxymethyl ester (XII) by means of trimethylsilylchloride and triethylamine yielding the condensation product (XIII). The cyclization of (XIII) by means of methylphosphonic acid diethyl ester affords silylated CS-834 (XIV), which is finally deprotected with 1N HCl.

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, R.M.; Castañer, J.; Leeson, P.; CS-834. Drugs Fut 1998, 23, 3, 261.
【2】 Yasuda, H.; Kuwahara, S.; Kawamoto, I.; Miyauchi, M.; Endo, R.; Hisaoka, M.; CS-834, a new oral carbapenem: I. Structure-activity relationships of 2-substituted 1beta-methylcarbapenems. 36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996, Abst F105.
【3】 Oita, S.; Mori, M. (Sankyo Co., Ltd.); Carbapenem ester preparation. JP 1996059663 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	17192	(4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one	157429-42-0	C₄H₇NOS	详情	详情
(X)	17197	(2R)-2-[(2S,3R)-3-isopropyl-4-oxoazetidinyl]propionic acid		C₉H₁₅NO₃	详情	详情
(XI)	17198	S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3R)-3-isopropyl-4-oxoazetidinyl]propanethioate		C₁₃H₂₀N₂O₃S	详情	详情
(XII)	17199	[(2-chloro-2-oxoacetyl)oxy]methyl pivalate		C₈H₁₁ClO₅	详情	详情
(XIII)	17200	([2-[(2S,3R)-3-isopropyl-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxopyrrolidinyl]sulfanyl]ethyl)-4-oxoazetidinyl]-2-oxoacetyl]oxy)methyl pivalate		C₂₁H₃₀N₂O₈S	详情	详情
(XIV)	17201	[(2,2-dimethylpropanoyl)oxy]methyl (4R,5S,6R)-6-isopropyl-4-methyl-7-oxo-3-[[(3R)-5-oxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₁H₃₀N₂O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

A short-step synthesis of CS-834 has been described: The condensation of azetidinone (I) with pyrrolidinone (II) by means of CDI gives the thioester (III), which is desilylated with BF3/Et2O to the alcohol (IV). In order to have a more labile protecting group, alcohol (IV) is resilylated with TMS-Cl (or TES-Cl) and triethylamine affording the silyl ether (V), which is protected again at the pyrrolidine nitrogen with TES-Cl, affording the disilylated azetidinone (VI). The condensation of (VI) with the oxalyl chloride (VII) by means of triethylamine in dichloromethane gives the expected oxalylazetidinone (VIII), which is treated with diethyl ethylphosphonite in toluene yielding the ylide (IX). This compound, without isolation, is cyclized in refluxing mesitylene to afford the protected carbapenem intermediate (X), which is finally desilylated with HCl in acetonitrile. The cyclization of azetidinone (VIII) to carbapenem (X) can also be performed with triethyl phosphite instead of diethyl ethylphosphonite. The oxalyl chloride (VII) is obtained by monoesterification of oxalic acid (XI) with pivaloyloxymethyl iodide (XII) by means of triethylamine yielding monoester (XIII), which is finally converted to intermediate (VII) by treatment with oxalyl chloride in dichloromethane.

参考文献中间体

合成目标

【1】 Oida, S.; Mori, M.; A short-step synthesis of orally active carbapenem antibiotic CS-834. Chem Pharm Bull 2000, 48, 1, 126.

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)	30029	(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid		C₁₄H₂₇NO₄Si	详情	详情
(II)	17192	(4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one	157429-42-0	C₄H₇NOS	详情	详情
(III)	33402	S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanethioate		C₁₈H₃₂N₂O₄SSi	详情	详情
(IV)	33403	S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]propanethioate		C₁₂H₁₈N₂O₄S	详情	详情
(V)	33404	S-[(3R)-5-oxopyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate		C₁₅H₂₆N₂O₄SSi	详情	详情
(VI)	33405	S-[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate		C₂₁H₄₀N₂O₄SSi₂	详情	详情
(VII)	17199	[(2-chloro-2-oxoacetyl)oxy]methyl pivalate		C₈H₁₁ClO₅	详情	详情
(VIII)	33406	[[2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)-2-oxoacetyl]oxy]methyl pivalate		C₂₉H₅₀N₂O₉SSi₂	详情	详情
(IX)	33407	[[2-[diethoxy(ethyl)phosphoranylidene]-2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)acetyl]oxy]methyl pivalate		C₃₅H₆₅N₂O₁₀PSSi₂	详情	详情
(X)	33408	[(2,2-dimethylpropanoyl)oxy]methyl (4R,5S,6S)-4-methyl-7-oxo-3-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₉H₅₀N₂O₇SSi₂	详情	详情
(XI)	15713	Oxalic acid	144-62-7	C₂H₂O₄	详情	详情
(XII)	11159	iodomethyl pivalate		C₆H₁₁IO₂	详情	详情
(XIII)	33409	2-[[(2,2-dimethylpropanoyl)oxy]methoxy]-2-oxoacetic acid		C₈H₁₂O₆	详情	详情

Extended Information