合成路线:1) The mesylation of 4(S)-hydroxypyrrolidin-2-one (I) with mesyl chloride and triethylamine in pyridine gives the corresponding ester (II),which is treated with potassium thioacetate (III) in refluxing acetonitrile yielding 4(R)-(acetylsulfanyl)pyrrolidin-2-one (IV).The hydrolysis of (IV) with sodium methoxide in methanol followed by acidification with aqueous HCl affords 4(R)-sulfanylpyrrolidin-2-one (V),which is condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VI) by means of ethyldiisopropylamine in acetonitrile to give (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[5-oxopyrrolidin-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VII).The hydrogenolysis of (VII) with H2 over Pd/C in THF/aqueous phosphate buffer yields the sodium salt (VIII),which is finally esterified with pivaloyloxymethyl iodide (IX) in dimethylacetamide.
参考文献标题:Crystalline carbapenem deriv
文献作者:Kawamoto,I.; Miyauchi,M.; Endo,R.(Sankyo Co.,Ltd.)
参考来源:EP 0599512; JP 1995165759
合成路线: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.
参考文献标题:Carbapenem ester preparation
文献作者:Oita,S.; Mori,M.(Sankyo Co.,Ltd.)
参考来源:JP 1996059663
合成路线:1) The mesylation of 4(S)-hydroxypyrrolidin-2-one (I) with mesyl chloride and triethylamine in pyridine gives the corresponding ester (II),which is treated with potassium thioacetate (III) in refluxing acetonitrile yielding 4(R)-(acetylsulfanyl)pyrrolidin-2-one (IV).The hydrolysis of (IV) with sodium methoxide in methanol followed by acidification with aqueous HCl affords 4(R)-sulfanylpyrrolidin-2-one (V),which is condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VI) by means of ethyldiisopropylamine in acetonitrile to give (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[5-oxopyrrolidin-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VII).The hydrogenolysis of (VII) with H2 over Pd/C in THF/aqueous phosphate buffer yields the sodium salt (VIII),which is finally esterified with pivaloyloxymethyl iodide (IX) in dimethylacetamide.
合成路线: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.
参考文献标题:CS-834,a new oral carbapenem: I.Structure-activity relationships of 2-substituted 1beta-methylcarbapenems
文献作者:Yasuda,H.; Kuwahara,S.; Kawamoto,I.; Miyauchi,M.; Endo,R.; Hisaoka,M.
参考来源:36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18,New Orleans) 1996,Abst F105
合成路线:1) The mesylation of 4(S)-hydroxypyrrolidin-2-one (I) with mesyl chloride and triethylamine in pyridine gives the corresponding ester (II),which is treated with potassium thioacetate (III) in refluxing acetonitrile yielding 4(R)-(acetylsulfanyl)pyrrolidin-2-one (IV).The hydrolysis of (IV) with sodium methoxide in methanol followed by acidification with aqueous HCl affords 4(R)-sulfanylpyrrolidin-2-one (V),which is condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VI) by means of ethyldiisopropylamine in acetonitrile to give (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[5-oxopyrrolidin-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VII).The hydrogenolysis of (VII) with H2 over Pd/C in THF/aqueous phosphate buffer yields the sodium salt (VIII),which is finally esterified with pivaloyloxymethyl iodide (IX) in dimethylacetamide.
参考文献标题:Synthesis and structure-activity relationships of a novel oral carbapenem,CS-834
文献作者:Miyauchi,M.; Endo,R.; Hisaoka,M.; Yasuda,H.; Kawamoto,I.
参考来源:J Antibiot 1997,50(5),429-39
合成路线:1) The mesylation of 4(S)-hydroxypyrrolidin-2-one (I) with mesyl chloride and triethylamine in pyridine gives the corresponding ester (II),which is treated with potassium thioacetate (III) in refluxing acetonitrile yielding 4(R)-(acetylsulfanyl)pyrrolidin-2-one (IV).The hydrolysis of (IV) with sodium methoxide in methanol followed by acidification with aqueous HCl affords 4(R)-sulfanylpyrrolidin-2-one (V),which is condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VI) by means of ethyldiisopropylamine in acetonitrile to give (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[5-oxopyrrolidin-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VII).The hydrogenolysis of (VII) with H2 over Pd/C in THF/aqueous phosphate buffer yields the sodium salt (VIII),which is finally esterified with pivaloyloxymethyl iodide (IX) in dimethylacetamide.
合成路线: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.
参考文献标题:CS-834
文献作者:Graul,A.; Castar,R.M.; Castar,J.; Leeson,P.
参考来源:Drugs Fut 1998,23(3),261
合成路线: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.
参考文献标题:A short-step synthesis of orally active carbapenem antibiotic CS-834
文献作者:Mori,M.; Oida,S.
参考来源:Chem Pharm Bull 2000,48(1),126
产品链接: CAS No. 157542-49-9›› 产品链接: CAS No.193811-33-5››