合成路线1

The thiazolopyridine derivatives (II) and (III) can be obtained in several ways. Treatment of N-Boc-4-piperidinone (XXXVI) with pyrrolidine in the presence of p-TsOH·H2O in refluxing cyclohexane, followed by cyclization of the resulting enamine with cyanamide and elemental sulfur in MeOH gives 2-amino-5-Boc-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XXXVII), which by Sandmeyer reaction with CuBr2 and t-BuONO in DMF at 40 °C affords the 2-bromo compound (XXXVIII). After removal of the N-Boc-protecting group of intermediate (XXXVIII) with TFA, reductive methylation of the deprotected amine (XXXIX) with formaldehyde and NaBH(OAc)3 in the presence of AcOH and Et3N in CH2Cl2 yields 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XL) , optionally isolated as the corresponding tosylate salt (1). Alternatively, cyclization of 1-methyl-4-piperidinone (XLI) with cyanamide and sulfur in the presence of pyrrolidine in i-PrOH at 50 °C yields 2-amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XLII), which is converted to the corresponding bromide (XL) by diazotization with NaNO2 in the presence of HBr in H2O. Metalation of the bromo derivative (XL) with BuLi in THF at –78 °C, followed by quenching with CO2 affords the lithium carboxylate (II) , which is converted to the carboxylic acid (III) by treatment with HCl in EtOH. Alternatively, cyanation of bromide (XL) with NaCN/CuCN in DMAc at 150 °C yields nitrile (XLIII), which is hydrolyzed to carboxylate (II) using LiOH in EtOH . In one further method, deamination of intermediate (XXXVII) by diazotization with NaNO2 and H2SO4 in the presence of hypophosphorous acid in H2O gives 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XLIV) , which is carboxylated to compound (II) by metalation with BuLi in THF at –78 °C and subsequent quenching with CO2 , or by acylation with trichloroacetyl chloride and Et3N in toluene, followed by haloform reaction of the resultant trichloromethyl ketone in the presence of LiOH .
The tetrahydrothiazolopyridine intermediate (XLIV) can also be prepared by a different procedure. After protection of 4-aminopyridine (XLV) as the N-Boc derivative (XLVI) with Boc2O in THF, treatment with BuLi in cold THF, followed by elemental sulfur yields the 3-sulfanylpyridine (XLVI). Cyclization of the Boc-protected amino thiol (XLVI) with formic acid at reflux, followed by KOH in H2O or Et2O leads to thiazolo[5,4-c]pyridine (XLVII), which is converted to the target intermediate (XLIV) by quaternization with iodomethane in DMF at 80 °C and then reduction with NaBH4 in MeOH .