Tomopenem, CS-023, R-115685, R-1558，Ro-4098463, -Drug Synthesis Database

【结构式】

【药物名称】Tomopenem, CS-023, R-115685, R-1558，Ro-4098463

【化学名称】(1R,5S,6S)-2-[5(S)-[3(S)-(2-Guanidinoacetamido)pyrrolidin-1-ylcarbonyl]-1-methylpyrrolidin-3(S)-ylsulfanyl]-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid

【CA登记号】222400-20-6

【分子式】C₂₃H₃₅N₇O₆S

【分子量】537.6427

【开发单位】Sankyo (Originator), Roche (Licensee)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Carbapenems

合成路线1 合成路线2

合成路线1

The pyrrolidine intermediate (VII) has been obtained as follows: The acylation of N-Boc-pyrrolidine-3(R)-amine (I) with chloroacetyl chloride (II) and TEA in dichloromethane gives the acetamide (III), which by treatment with ammonia in methanol/water yields the glycinamide (IV). The reaction of (IV) with protected S-methylisothiourea (V) in methanol affords the protected guanidine (VI). The N-Boc deprotection of (VI) by means of HCl in ethyl acetate/acetonitrile affords the target pyrrolidine intermediate (VII).

参考文献中间体

【1】 Kanno, O.; Shibayama, T.; Ohya, S.; Shimoji, Y.; Kuwahara, S.; Ishikawa, K.; Kojima, K.; Kawamoto, I.; R-115685, a novel parenteral carbapenem: Synthesis and structure-activity relationships. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1229.

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)	53603	tert-butyl (3S)-3-amino-1-pyrrolidinecarboxylate	n/a	C₉H₁₈N₂O₂	详情	详情
(II)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(III)	53604	tert-butyl (3S)-3-[(2-chloroacetyl)amino]-1-pyrrolidinecarboxylate	n/a	C₁₁H₁₉ClN₂O₃	详情	详情
(IV)	53605	tert-butyl (3S)-3-[(2-aminoacetyl)amino]-1-pyrrolidinecarboxylate	n/a	C₁₁H₂₁N₃O₃	详情	详情
(V)	53606	1-({[imino(methylsulfanyl)methyl]amino}carbonyl)-4-nitrobenzene	n/a	C₉H₉N₃O₃S	详情	详情
(VI)	53607	tert-butyl (3S)-3-{[2-({imino[(4-nitrobenzoyl)amino]methyl}amino)acetyl]amino}-1-pyrrolidinecarboxylate	n/a	C₁₉H₂₆N₆O₆	详情	详情
(VII)	53608	2-({imino[(4-nitrobenzoyl)amino]methyl}amino)-N-[(3S)pyrrolidinyl]acetamide	n/a	C₁₄H₁₈N₆O₄	详情	详情

合成路线2

The reaction of the hydroxyproline 4-methoxybenzyl ester (VIII) with Ms-Cl and DIEA in THF gives the mesylate (IX), which is treated with thioacetic acid and Cs2CO3 in DMA to yield the acetylsulfanyl derivative (X). The Boc deprotection of (X) with 4N HCl in ethyl acetate, followed by methylation with HCHO/HCOOH and simultaneous ester hydrolysis, affords the methylated proline (XI), which is activated with pivaloyl chloride and DIEA in acetonitrile to the mixed anhydride (XII). The condensation of (XII) with the intermediate pyrrolidine (VII) by means of DIEA in acetonitrile provides the adduct (XIII), which is further condensed with the carbapenem (XIV) by means of NaOMe in methanol to give the intermediate (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in THF/water to furnish the target 1-beta-methyl carbapenem.

参考文献中间体

【1】 Kanno, O.; Shibayama, T.; Ohya, S.; Shimoji, Y.; Kuwahara, S.; Ishikawa, K.; Kojima, K.; Kawamoto, I.; R-115685, a novel parenteral carbapenem: Synthesis and structure-activity relationships. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1229.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	53608	2-({imino[(4-nitrobenzoyl)amino]methyl}amino)-N-[(3S)pyrrolidinyl]acetamide	n/a	C₁₄H₁₈N₆O₄	详情	详情
(VIII)	53609	1-(tert-butyl) 2-(4-methoxybenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate	n/a	C₁₈H₂₅NO₆	详情	详情
(IX)	53610	1-(tert-butyl) 2-(4-methoxybenzyl) (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate	n/a	C₁₉H₂₇NO₈S	详情	详情
(X)	53611	1-(tert-butyl) 2-(4-methoxybenzyl) (2S,4S)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate	n/a	C₂₀H₂₇NO₆S	详情	详情
(XI)	53612	(2S,4S)-4-(acetylsulfanyl)-1-methyl-2-pyrrolidinecarboxylic acid	n/a	C₈H₁₃NO₃S	详情	详情
(XII)	53613	(2S,4S)-4-(acetylsulfanyl)-1-methyl-2-pyrrolidinecarboxylic 1,1-dimethylpropanoic anhydride	n/a	C₁₃H₂₁NO₄S	详情	详情
(XIII)	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
(XIV)	53614	S-{(3S,5S)-5-[((3S)-3-{[2-({imino[(4-nitrobenzoyl)amino]methyl}amino)acetyl]amino}pyrrolidinyl)carbonyl]-1-methylpyrrolidinyl} ethanethioate	n/a	C₂₂H₂₉N₇O₆S	详情	详情
(XV)	53615	4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({(3S,5S)-5-[((3S)-3-{[2-({imino[(4-nitrobenzoyl)amino]methyl}amino)acetyl]amino}pyrrolidinyl)carbonyl]-1-methylpyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	n/a	C₃₇H₄₃N₉O₁₁S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)