Meropenem, ICI-194660, SM-7338, Meropen, Meronem, Merrem, -Drug Synthesis Database

【结构式】

【药物名称】Meropenem, ICI-194660, SM-7338, Meropen, Meronem, Merrem

【化学名称】(4R,5S,6S)-3-[5(S)-(N,N-Dimethylcarbamoyl)pyrrolidin-3(S)-ylsulfanyl]-6-[1(R)-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
　　　　　　(1R,5S,6S)-2-[5(S)-(N,N-Dimethylcarbamoyl)pyrrolidin-3(S)-ylsulfanyl]-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid

【CA登记号】96036-03-2, 119478-56-7 (trihydrate)

【分子式】C₁₇H₂₅N₃O₅S

【分子量】383.4699

【开发单位】AstraZeneca (Orphan Drug), Sumitomo Pharmaceuticals (Originator), AstraZeneca (Licensee)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

The mercaptopyrrolidine (XIII) is prepared as follows: trans-4-hydroxy-L-proline (XV) is protected with 4-nitrobenzyl chloride (XVI) giving trans 4-hydroxy-N-(4-nitrobenzyloxycarbonyl)-L-proline (XVII), which is esterified with 4-methoxy benzyl chloride (XVIII) to the corresponding ester (XIX). The reaction of (XIX) with thioacetic acid by means of diethyl azodicarboxylate arid triphenyl-phosphine in THF affords the 4-acetylthio derivative (XX), which is partially hydrolyzed with trifluoroacetic acid and anisole to 4beta-(acetylthio)-N-(4-nitrobenzyloxycarbonyl)pyrrolidine-2beta-carboxylic acid (XXI). The condensation of (XXI) with dimethylamine by means of dicyclohexylcarbodiimide (DCC) gives the fully protected dimethylamide (XXII), which is deacetylated with NaOH in water to atford the desired product (XIII).

参考文献中间体

【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
	12893	Ethanethioic S-acid		C₂H₄OS	详情	详情
(XIII)	22578	4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate		C₁₅H₁₉N₃O₅S	详情	详情
(XV)	14489	(2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline	51-35-4	C₅H₉NO₃	详情	详情
(XVI)	22580	1-(chloromethyl)-4-nitrobenzene	100-14-1	C₇H₆ClNO₂	详情	详情
(XVII)	22581	(2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid		C₁₃H₁₄N₂O₇	详情	详情
(XVIII)	11910	4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether	824-94-2	C₈H₉ClO	详情	详情
(XIX)	22583	2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate		C₂₁H₂₂N₂O₈	详情	详情
(XX)	22584	2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4S)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate		C₂₃H₂₄N₂O₈S	详情	详情
(XXI)	18241	(2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid		C₁₅H₁₆N₂O₇S	详情	详情
(XXII)	22586	4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(dimethylamino)carbonyl]-1-pyrrolidinecarboxylate		C₁₇H₂₁N₃O₆S	详情	详情

合成路线3

The condensation of (XII) with 1-(4-nitrobenzyloxycarbonyl)-2beta-(dimethylaminocarbonyl)-4beta-mercaptopyrrolidine (XIII) in acetonitrile affords the di(4-nitrobenzyl) derivative (XIV), which is finally debencilated by hydrogenation with H2 over Pd/C in THF.

参考文献中间体

【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	分子式	供应商	用于合成
(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
(XIII)	22578	4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate	C₁₅H₁₉N₃O₅S	详情	详情
(XIV)	22587	4-nitrobenzyl (5S,6S)-3-[((3S,5S)-5-[(dimethylamino)carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₃₂H₃₅N₅O₁₁S	详情	详情

Extended Information