(3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one -Drug Synthesis Database

【结构式】

【分子编号】30150

【品名】(3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one

【CA登记号】137391-68-5

【分子式】C₁₇H₁₈N₄O₇

【分子量】390.35268

【元素组成】C 52.31% H 4.65% N 14.35% O 28.69%

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：(IX)

The condensation of (3R,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilylioxy)ethyl)azetidin-2-one (I) with benzyl 2-bromopropionate (II) by means of diethylaluminum chloride in hexane - THF gives the isomeric mixture (III), (IIIa), which is separated by column chrornatography and the correct isomer (III) is treated with tert-butyldimethylsilyl chloride to yield the silylated azetidine (IV). The reductive debenzylation of (IV) with H2 over Pd/C in methanol affords the protected free acid (V), which is condensed with magnesium 4-nitrobenzylmalonate (VI) by means of carbonyldiimidazole (CDI) in hot acetonitrile to give the protected ketoester (VII). Partial hydrolysis of (VII) with HCl in methanol affords the free ketoester (VIII), which is treated with p-toluenesulfonylazide in acetonitrile yielding the diazo compound (IX). The cyclization of (IX) by means of rhodium acetate in refluxing toluene gives 6alpha-[1(R)-hydroxyethyl)-1beta-methyl-2-oxo-1-dethia-1-carba-2-penem-3-car boxylic acid 4-nitrobenzyl ester (X), which is condensed with diphenyl chlorophosphate (XI) by means of diisopropylethylamine in acetonitrile, yielding the enol ester (XII).

参考文献中间体

合成目标

【1】 Fukasawa, M.; Inoue, T.; Kato, M.; Matsumura, H.; Sunagawa, M. (Sumitomo Pharmaceuticals Co., Ltd.); Thiopyrrolidinyl-beta-lactam derivs.. EP 0126587; ES 8600305; JP 1985001186; JP 1985019787; JP 1991041066; US 4933333; US 4943569; US 5122604 .
【2】 Prous, J.; Castaner, J.; SM-7338. Drugs Fut 1988, 13, 6, 534.

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)	22568	benzyl (2S)-2-[(2S,3S)-3-(1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate		C₂₁H₃₃NO₄Si	详情	详情
(I)	22565	methyl (2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxo-2-azetidinecarboxylate		C₁₃H₂₅NO₄Si	详情	详情
(II)	16074	Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate	2524-64-3	C₁₂H₁₀ClO₃P	详情	详情
(II)	22566	benzyl 2-bromopropanoate	3017-53-6	C₁₀H₁₁BrO₂	详情	详情
(III)	22567	benzyl 2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate		C₂₁H₃₃NO₄Si	详情	详情
(IV)	22569	benzyl 2-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoate		C₂₇H₄₇NO₄Si₂	详情	详情
(V)	22570	2-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid		C₂₀H₄₁NO₄Si₂	详情	详情
(VI)	22571	3-[(4-nitrobenzyl)oxy]-3-oxopropanoate		C₁₀H₈MgNO₆	详情	详情
(VII)	22572	4-nitrobenzyl 4-[(2R,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate		C₂₉H₄₈N₂O₇Si₂	详情	详情
(VIII)	22573	4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate		C₁₇H₂₀N₂O₇	详情	详情
(IX)	30150	(3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one	137391-68-5	C₁₇H₁₈N₄O₇	详情	详情
(X)	22575	4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₁₇H₁₈N₂O₇	详情	详情
(XII)	22577	4-nitrobenzyl (5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₉H₂₇N₂O₁₀P	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Azetidineacetic acid derivative (I) was activated with 1,1'-carbonyldiimidazole and then condensed with p-nitrobenzyl malonate magnesium salt (II) to afford ketoester (III). Desilylation of (III) with methanolic HCl then gave alcohol (IV). Dodecylbenzenesulfonyl azide (VI) was prepared by treatment of sulfonyl chloride (V) with NaN3. Reaction of (IV) with sulfonyl azide (VI) provided diazo ester (VII). Ring closure of (VII) in the presence of rhodium diacetate in hot cyclohexane, followed by condensation with diphenylphosphoric chloride furnished carbapenem phosphate (VIII).

参考文献中间体

合成目标

【1】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 .

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)	33039	magnesium 2-(4-nitrobenzyl)malonate		C₁₀H₇MgNO₆	详情	详情
(III)	33040	4-nitrobenzyl (4R)-4-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate		C₂₃H₃₄N₂O₇Si	详情	详情
(IV)	22573	4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate		C₁₇H₂₀N₂O₇	详情	详情
(V)	33041	4-dodecylbenzenesulfonyl chloride		C₁₈H₂₉ClO₂S	详情	详情
(VI)	33042	4-dodecylbenzenesulfonyl azide		C₁₈H₂₉N₃O₂S	详情	详情
(VII)	30150	(3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one	137391-68-5	C₁₇H₁₈N₄O₇	详情	详情
(VIII)	13224	4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	90776-59-3	C₂₉H₂₇N₂O₁₀P	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXXVIII)

Diazoketone (XXXIX), prepared by silyl protection of the precursor (XXXVIII), was cyclized in the presence of Rh(II) catalyst to produce oxocarbapenem (XL). Treatment of (XL) with Tf2O and 2,2,6,6-tetramethylpiperidine yielded vinyl triflate (XLI). Hydroxymethylation of (XLI) was then achieved by cross coupling with tributylstannylmethanol in the presence of Pd catalyst to furnish (XLII).

参考文献中间体

合成目标

【1】 Yasuda, N.; et al.; Preparation of anti-MRS carbapenem L-786,392. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-31.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXVIII)	30150	(3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one	137391-68-5	C₁₇H₁₈N₄O₇	详情	详情
(XXXIX)	30151	2-Diazo-3-oxo-4(R)-[3(S)-[1(R)-(triethylsilyloxy)ethyl]-4-oxoazetidin-2(R)-yl]pentanoic acid 4-nitrobenzyl ester		C₂₃H₃₂N₄O₇Si	详情	详情
(XL)	30152	(4R,5R,6S)-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]heptane-3,7-dione		C₂₃H₃₂N₂O₇Si	详情	详情
(XLI)	30153	(4R,5R,6S)-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl trifluoromethanesulfonate		C₂₄H₃₁F₃N₂O₉SSi	详情	详情
(XLII)	30154	(4S,5R,6S)-3-(hydroxymethyl)-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-7-one		C₂₄H₃₄N₂O₇Si	详情	详情

Extended Information