合成路线1

Protection of pyrrolidine (I) with Boc2O in MTBE provides the corresponding N-Boc derivative (II) , which after metalation with sec-BuLi in THF and quenching with B(OMe)3 gives N-Boc-boroproline (III) . Condensation of racemic boronic acid (III) with (+)-pinanediol (IV) in isopropyl acetate or MTBE affords the boronate ester (V) as a diastereomeric mixture. After deprotection by removing the Boc group with HCl in i-PrOH or Et2O , the 2(R)-boroproline pinanediol ester hydrochloride (VI) diastereomer is separated by recrystallization from i-PrOH (1-3). Acylation of compound (VI) with 2-chloroacetyl chloride (VII) in the presence of NMM in CH2Cl2 provides the 2-chloroacetamide (VIII), which is then condensed with 3(R)-amino-1-Boc-pyrrolidine (IX) by means of K2CO3 in THF to give the glycinamide derivative (X). Finally, simultaneous hydrolysis of the N-Boc and boronate ester groups in compound (X) using phenylboronic acid in H2O/hexane provides dutogliptin free base (XI) .
Alternatively, coupling of the 2(R)-boroproline derivative (VI) with either the diprotected N-(benzyloxycarbonyl)-N-[1-(benzyloxycarbonyl)-3(R)-pyrrolidinyl]glycine (XII) via activation as the corresponding mixed anhydride with isobutyl chloroformate and NMM in 2-MeTHF , or by means of EDC, HOBt and NMM in CH2Cl2 , or also with the dicyclohexylamine salt (XIII) in the presence of EDC, HOBt and NMM , affords amide (XIV), which is deprotected by catalytic hydrogenolysis over Pd/C in MeOH to give diamine (XV). Finally, diamine (XV) undergoes boronate ester cleavage by means of phenylboronic acid in the presence of L-tartaric acid in H2O/MTBE to afford dutogliptin tartrate .