合成路线1

The reaction of (1R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-methoxybenzyl ester (I) with diphenyl chlorophosphate (II) and ethyl diisopropylamine in acetonitrile gives the corresponding penem diphenylphosphate (III), which is condensed with 1-(tert-butoxycarbonyl)-2(S)-sulfamoylaminomethyl)pyrrolidine-4(S)-thio l (IV) by means of ethyl diisopropylamine in the same solvent, yielding compound (V), which is finally treated with AlCl3 to eliminate the protecting groups to obtain S-4661.

合成路线2

A new synthesis of S-4661 has been reported: The esterification of trans-4-hydroxy-L-proline (I) with methanol/HCl gives the corresponding methyl ester (II), which is N-protected as trans-N-(4-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline methyl ester (III). The mesylation of (III) with methanesulfonyl chloride and triethylamine in dichloromethane affords the 4-O-mesylate (IV), which is treated with sodium triphenylmethylsulfide giving cis-N-(4-methoxybenzyloxycarbonyl)-4-(triphenylmethylsulfanyl)-L-prolin e methyl ester (V). The reduction of (V) with LiBH4 in THF yields the corresponding methanol (VI), which is mesylated as before affording (VII). The reaction of (VII) with potassium phthalimide (VIII) gives the adduct (IX), which is cleaved with hydrazine yielding (2S,4S)-2-(aminomethyl)-1-(4-methoxybenzyloxycarbonyl)-4-(triphenylmeth ylsulfanyl)pyrrolidine (X). The condensation of (X) with N-(4-methoxybenzyl)sulfamoyl chloride (XI) by means of triethylamine affords the corresponding protected sulfamide (XII). Deprotection of the trityl group of (XII) by treatment with silver nitrate and pyridine affords compound (XIII) with a free SH group. The reaction of (XIII) with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-methoxybenzyl ester (XIV) by means of diisopropylethylamine yields the protected final product (XV), which is finally treated with AlCl3 in anisole to eliminate the protecting groups.

合成路线3

A new synthesis of S-4661 has been reported: The protection of trans-4-hydroxy-L-proline with tert-butoxycarbonyl anhydride gives N-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (II), which is successively treated with ethyl chloroformate, mesylated with mesyl chloride and reduced with NaBH4 yielding (2S,4R)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)-4-(methanesulfonyloxy)pyrrolidine (III). The reaction of (III) with potassium thioacetate affords Compound (IV), which is condensed with N-(tert-butoxycarbonyl)sulfamide (V) by means of diethyl azodicarboxylate and triphenylphosphine to give the protected pyrrolidinesulfamide (VI). The deacetylation of (VI) with sodium methoxide yields (2S,4S)-1-(tert-butoxycarbonyl)-2-[N-(tert-butoxycarbonyl)-N-sulfamoylaminomethyl]-4-sulfanylpyrrolidine (VII), which is then condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid diphenylmethyl ester (VIII) by means of diisopropylethylamine to afford the protected final product (IX). Finally, this compound is deprotected with AlCl3 in anisole.

合成路线4

合成路线5

合成路线6

合成路线7

合成路线8

合成路线9

合成路线10

合成路线11