合成路线1

The reaction of methyl 3-hydroxythiophene-2-carboxylate (I) with PCl5 in refluxing CCl4 gives 3-chlorothiophene-2-carboxylic acid (II), which by treatment with NaHSO3 and Cu in basic water at 143 C in a pressure vessel is converted into 3-sulfothiophene-2-carboxylic acid (III). The esterification of (III) with refluxing methanol affords methyl 3-sulfothiophene-2-carboxylate (IV), which by reaction with refluxing SOCl2 yields methyl-3-chlorosulfonylthiophene-2-carboxylate (V). The condensation of (V) with sarcosine ethyl ester (VI) in hot CHCl3 gives methyl-3-(N-ethoxycarbonyl-methyl-N-methylsulfamoyl)thiophene-2-carboxylate (VII), which is cyclized by treatment with sodium methoxide in refluxing methanol affording 3-ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazine-1,1-dioxide (VIII). Finally, this compound is condensed with 2-aminopyridine (IX) in refluxing toluene.

合成路线2

The tripeptide building block (XXVII) is prepared as follows. Cyclization of N-Boc-L-serine (XIX) to the beta-lactone (XX) is achieved by treatment with DEAD and PPh3. Subsequent ring opening with diphenyldiselenide in the presence of a reducing agent leads to selenide (XXI). Aminoacid (XXI) is then coupled to sarcosine ethyl ester (XXII) to afford dipeptide (XXIII). After acidic Boc group cleavage in (XXIII), the resultant carboxylic acid (XXIV) is coupled to N-Boc-D-aminobutyric acid (XXV) to give (XXVI). The N-Boc group of (XXVI) is then deprotected with trifluoroacetic acid, producing intermediate (XXVII).

合成路线3