Development and Scale-Up of an Asymmetric Synthesis Process for Alogliptin

Abstract

Alogliptin (1) benzoate is a potent, highly selective inhibitor of serine protease dipeptidyl-peptidase IV, approved by US FDA for the treatment of type 2 diabetes. Herein, we report a more cost-effective process that includes ruthenium-catalyzed asymmetric hydrogenation followed by Hofmann rearrangement of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1­(2H)-yl)­methyl)­benzonitrile (10) to introduce a chiral amino moiety at a late stage. Use of an inexpensive and readily available nicotinamide (6) for a chiral aminopiperidine core and iodobenzene diacetate (PIDA) under mild and specific conditions allowed us to access 1 with excellent total yield and comparable quality to that manufactured by the original process.

Enantioselective Transformations in the Synthesis of Therapeutic Agents

“…Application of this reaction can be found in the production of alogliptin ( 138 ). The Ru/BINAP catalyzed asymmetric hydrogenation of prochiral tetrahydropyridine salt 136 , which was obtained from nicotinamide by Pd/C -catalyzed hydrogenation, led to chiral intermediate 137 in 68% yield and 99.7% ee after recrystallization (Scheme a) …”

“…The Ru/ BINAP catalyzed asymmetric hydrogenation of prochiral tetrahydropyridine salt 136, which was obtained from nicotinamide by Pd/C -catalyzed hydrogenation, led to chiral intermediate 137 in 68% yield and 99.7% ee after recrystallization (Scheme 29a). 87 Enantiomerically pure fluoro-containing molecules are important intermediates for the synthesis of active pharmaceutical ingredients due to their improved physiological properties. In the synthesis of AZD9742 (141) containing a cis-4-amino-3fluoropiperidine moiety, the asymmetric hydrogenation was performed on tetrasubstituted enamide 139, which was obtained from the reduction of the corresponding pyridinium salt with NaBH 4 (Scheme 29b).…”

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…Nitrogen-containing heterocycles are present in several valuable bioactive compounds, such as piracetam ( 50) [132], anisomycin (51) [133], and alogliptin (52) [134] (Scheme 20A).…”

(4 + 2) Annulation of Cl–NH3+CH2SiMe2CH2Cl and Propynones for the Synthesis of 1,3-Azasilinones

“…Asymmetric hydrogenation of 6b using RuCl 2 (s-binap) as the catalyst led to amido ester 14 in 65% yield with 95:5 er. 17 Removal of the Boc group followed by N-alkylation with homoallylic bromide delivered 15 in 72% yield. Subsequent hydrolysis of the ester group and treatment with aqueous HCl gave sila-tiagabine 16 in 85% yield with 95:5 er, indicating that both silicon and chiral carbon moieties were well-tolerated under a series of strongly basic and acidic conditions in this approach.…”

“…We further carried out the synthesis of the sila analogue of tiagabine, a well-known antiepileptic drug. Asymmetric hydrogenation of 6b using RuCl 2 (s-binap) as the catalyst led to amido ester 14 in 65% yield with 95:5 er . Removal of the Boc group followed by N -alkylation with homoallylic bromide delivered 15 in 72% yield.…”