Process for the preparation of dipeptidylpeptidase inhibitors
The present invention provides a process for the preparation of linagliptin, a compound of Formula I, the process comprising deprotecting a compound of Formula II wherein R 1 and R 2 together with the nitrogen to which they are attached form a phthalimido group, wherein the aromatic ring of the phthalimido group is substituted with one or more R 3 substituents selected from the group consisting of halogen, alkyl, nitro and amino; or R 1 is H and R 2 is selected from the group consisting of trialkylsilyl, 2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl, 9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl, diphenylphosphine and sulfonylethoxycarbonyl.
1. Crystalline linagliptin dibenzoyl-D-tartaric acid salt.
2. The linagliptin dibenzoyl-D-tartaric acid salt of claim 1 in crystalline form characterized by an XRD pattern having peak reflections at 6.35, 7.52, 14.05±0.2 degrees 2 theta.
3. The linagliptin dibenzoyl-D-tartaric acid salt of claim 1 in crystalline form characterized by a 1 H NMR spectrum having peaks at δ 1.03-1.04 (d, 2H), 1.57 (m, 2H), 1.76-1.77 (s, 3H,), 1.93 (m, 1H), 2.88 (s, 3H), 3.0-3.12 (m, 2H), 3.32-3.33 (m, 1H), 3.46-3.49 (dd, 1H), 3.65-3.67 (dd, 1H), 4.83-4.95 (m, 2H), 5.33 (s, 2H), 5.66 (s, 2H), and 7.47-8.28 (4+10H).
4. The crystalline linagliptin dibenzoyl-D-tartaric acid salt of claim 1 , characterized by Differential Seaming calorimetric (DSC) thermogram having an endotherm peak at 233±0.2° C.
5. A process for the preparation of crystalline linagliptin dibenzoyl-D-tartaric acid salt comprising reacting linagliptin with dibenzoyl-D-tartaric acid.