4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate -Drug Synthesis Database

【结构式】

【分子编号】22573

【品名】4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate

【CA登记号】

【分子式】C₁₇H₂₀N₂O₇

【分子量】364.35508

【元素组成】C 56.04% H 5.53% N 7.69% O 30.74%

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：(VIII)

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：(XVI)

Reaction of 3-(benzyloxy)propionic acid (I) with 4(R)-isopropyl-1,3-thiazolidine-2-thione (II) in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and DMAP gives 3-[3-(benzyloxy)propanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (III), which by treatment with tin(II) trifluoromethanesulfonate and excess acetaldehyde affords 3-[(2S,3R)-2-(benzyloxymethyl)-3-hydroxybutanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (IV). Protection of the hydroxy group of (IV) with tert-butyldimethylsilyl chloride in the presence of imidazole yields 3-[(2S,3R)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)butanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (V), which is treated with p-anisidine to afford (2S,3R)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)-N-(4-methoxyphenyl)butylamide (VI). Deprotection of (VI) by hydrogenation with Pd/C in methanol-acetic acid gives (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)-N-(4-methoxyphenyl)butylamide (VII), which is mesylated with methanesulfonyl chloride in the presence of triethylamine to yield (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-[(methanesulfonyloxy)methyl]-N-(4-methoxyphenyl)butylamide (VIII). Cyclization of (VIII) with sodium hydride in CH2Cl2-DMF affords 3(S)-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-1-(4-methoxyphenyl) azetidin-2-one (IX), the nitrogen atom of which is deprotected with cerium ammonium nitrate (CAN) in a mixture of acetonitrile-water to yield 3(S)-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (X). Compound (X) is stereoselectively converted to (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one (XI) on treatment with peracetic acid and ruthenium(III) chloride. Compound (XI) and 4(S)-ethyl-3-propionyl-1,3-thiazolidine-2-thione (XII) give, on treatment with tin(II) trifluoromethanesulfonate, (3S,4R)-3-[1(R)-(tert-butyldimethysilyloxy)methyl]-4-[1(R)-[4(S)-ethyl-2-thioxo-1,3-thiazolidin-3-ylcarbonyl]ethyl]azetidin-2-one (XIII) as the major diastereoisomer. Reaction of (XIII) with imidazole in acetonitrile gives (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(R)-(imidazol-1-ylcarbonyl)ethyl]azetidin-2-one (XIV), which is treated with Mg(O2CH2CO2PNB)2 in acetonitrile to yield (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (XV). Compound (XV) is deprotected with hydrochloric acid in methanol to give (3S,4R)-3-[1(R)-hydroxyethyl]-4-[1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (XVI), which on diazotization with dodecylbenzenesulfonyl azide in acetonitrile yields (3S,4R)-4-[3-diazo-1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-3-[1(R)-hydroxyethyl]azetidin-2-one (XVII). Treatment of compound (XVII) with rhodium(II) octanoate in ethylacetate gives p-nitrobenzyl (1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate (XVIII), which is reacted with diphenylchlorophosphate and diisopropylethylamine to afford p-nitrobenzyl (1R,5R,6S)-2-[(diphenylphosphono)oxy]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (XIX).

参考文献中间体

合成目标

【1】 Kumagai, T.; Matsunaga, H.; Machida, Y.; Nagase, Y.; Hikida, M.; Nagao, Y. (Lederle (Japan), Ltd.); (1R,5S,6S)-2-(Substd. thio)-6-[(R)-1-hydroxy-ethyl]-1-methyl-carbapenem-3-carboxylic-acid derivatives. AU 8814428; EP 0289801; JP 1989025779; US 4925836 .
【2】 Abe, T.; Matsunaga, H.; Kumagai, T.; Nagase, Y. (Lederle (Japan), Ltd.); Method of preparation of carbapenem cpds. JP 1990088578 .
【3】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631.
【4】 Hayashi, T.; Shimada, O.; Inoue, Y.; Nagao, Y.; Matsunaga, H.; Nagase, Y.; Kumagai, T.; Abe, T.; beta-Lactams. 3. Asymmetric total synthesis of new non-natural 1beta-methylcarbapenems exhibiting strong antimicrobial activities and stability against human renal dehydropeptidase-. J Org Chem 1992, 57, 15, 4243-9.

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)	13189	3-(Benzyloxy)propionic acid		C₁₀H₁₂O₃	详情	详情
(II)	13190	(4R)-4-Isopropyl-1,3-thiazolidine-2-thione		C₆H₁₁NS₂	详情	详情
(III)	13191	3-(Benzyloxy)-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-propanone		C₁₆H₂₁NO₂S₂	详情	详情
(IV)	13192	(2S,3R)-2-[(Benzyloxy)methyl]-3-hydroxy-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-butanone		C₁₈H₂₅NO₃S₂	详情	详情
(V)	13193	(2S,3R)-2-[(Benzyloxy)methyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-butanone		C₂₄H₃₉NO₃S₂Si	详情	详情
(VI)	13194	(2S,3R)-2-[(Benzyloxy)methyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-N-(4-methoxyphenyl)butanamide		C₂₅H₃₇NO₄Si	详情	详情
(VII)	13195	(2S,3R)-3-[[tert-Butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-N-(4-methoxyphenyl)butanamide		C₁₈H₃₁NO₄Si	详情	详情
(VIII)	13196	(2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxyanilino)carbonyl]butyl methanesulfonate		C₁₉H₃₃NO₆SSi	详情	详情
(IX)	13197	(3S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-1-(4-methoxyphenyl)-2-azetidinone		C₁₈H₂₉NO₃Si	详情	详情
(X)	13198	(3S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-2-azetidinone		C₁₁H₂₃NO₂Si	详情	详情
(XI)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate		C₁₃H₂₅NO₄Si	详情	详情
(XII)	13200	1-[(4S)-4-Ethyl-2-thioxo-1,3-thiazolidin-3-yl]-1-propanone		C₈H₁₃NOS₂	详情	详情
(XIII)	13201	(3S,4S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-[(4S)-4-ethyl-2-thioxo-1,3-thiazolidin-3-yl]-1-methyl-2-oxoethyl]-2-azetidinone		C₁₉H₃₄N₂O₃S₂Si	详情	详情
(XIV)	13202	(3S,4S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-(1H-imidazol-1-yl)-1-methyl-2-oxoethyl]-2-azetidinone		C₁₇H₂₉N₃O₃Si	详情	详情
(XV)	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
(XVI)	22573	4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate		C₁₇H₂₀N₂O₇	详情	详情
(XVII)	38749	4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate		C₁₇H₁₈N₄O₇	详情	详情
(XVIII)	37720	4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₁₇H₁₈N₂O₇	详情	详情
(XIX)	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：(IV)

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

Extended Information