Efficient synthesis of sitagliptin phosphate, a novel DPP-IV inhibitor, via a chiral aziridine intermediate

Practical Asymmetric Synthesis of Sitagliptin Phosphate Monohydrate

“…( R )- tert -butyl 4-hydroxy-1-2,4,5-trifluorobenzylbutan-2-ylcarbamate 9b was prepared from 4b (333 mg, 1 mmol) according to the procedure of the synthesis of 9a , and 9b was obtained as a white solid (316 mg, 99%): 1 H-NMR (400 MHz, CDCl 3 ) δ 7.03–7.10 (m, 1H), 6.90–6.96 (m, 1H),4.49 (d, J = 12.5 Hz, 1H), 4.57 (d, J = 12.6 Hz, 1H), 4.00–4.06 (m, 1H), 3.69 (d, J = 4.2 Hz, 1H), 2.75–2.82 (m, 2H), 1.84–1.92 (m, 2H), 1.42 (s, 9H) [ 13 ].…”

“…In this process, the key structure of sitagliptin was installed via rare-metal catalyzed asymmetric hydrogenation, biocatalytic asymmetric reduction or transaminase-catalyzed asymmetric synthesis [ 4 , 5 ]. Generally, most of synthetic routes including the latest reported methods focus on constructing key chiral fragment by employing diverse metal catalysts [ 6 , 7 , 8 ], chiral auxiliary [ 9 , 10 , 11 , 12 ] or chiral starting materials [ 13 , 14 ].…”

Improved Synthesis of (R)‐3‐(t‐Butoxycarbonylamino)‐4‐(2,4,5‐trifluorophenyl)butanoic Acid as a Key Intermediate for the Synthesis of Sitagliptin

“…Recently, Pan et al . synthesized compound 1 from l ‐homoserine by the nucleophilic ring opening reaction of a chiral N ‐Boc aziridino alcohol derivative with Grignard reagent (2,4,5‐trifluorophenylmagnesium bromide) in 33% overall yield, then prepared sitagliptin via a total of 12 longest linear steps with overall 26% yield (Scheme ) . Although this method has shown good overall yield (33%) for the synthesis of compound 1 , the relatively long reaction steps (six isolation steps) and the use of sodium hydride for ring formation of aziridine ring were not suitable for scale‐up production.…”

“…mp: 124.2 °C (Ref. 123–125 °C); IR: 3358, 1683, 1521, 1161/cm; 1 H NMR (CDCl 3 , 600 MHz): δ 7.08–7.00 (m, 1H), 6.92–6.86 (m, 2H), 5.09 (d, J = 9 Hz, 1H), 4.19–4.02 (m, 1H), 2.92–2.82 (m, 2H), 2.63–2.42 (m, 2H), 1.35 (s, 9H); 13 C NMR (CDCl 3 , 150 MHz): δ 176.4, 175.1, 157.0, 155.4, 155.2, 149.8, 149.7, 149.6, 148.1, 148.0, 147.4, 145.7, 121.2, 121.1, 119.3, 119.1, 119.0, 105.5, 105.4, 105.3, 105.2, 81.4, 79.9, 48.8, 47.6, 38.3, 38.0, 33.9, 33.0, 28.2, 28.0; HRMS (ESI) m / z : calculated for C 15 H 18 F 3 NO 4 Na + [M + Na] + : 356.1086, found: 356.1137; ee: 99.9%.…”

Lipase B from Candida antarctica Immobilized on Epoxy-functionalized Hollow Silica Microspheres: Efficient Biocatalysts for Enantiomer Selective Acylation of Alcohols and Amines

“…Chirality is a key property of organic fine chemicals in the field of agrochemical [1], pharmaceutical [2,3] and food industries [4,5]. Consequently, there is an ever increasing demand for optically pure final products especially by active pharmaceutical ingredients [6][7][8] where particularly hydroxyl [9,10] and amine [11] functions or their derivatives [12] are bound to the center of asymmetry. Asymmetric techniques, such as aldol reaction [13], epoxide opening [14], ketone reduction [15] or kinetic resolution of racemic mixtures [16] are well known methods to produce pure enantiomers of alcohols.…”