Home > News > Januvia – Sitagliptin Synthesis

News

Januvia – Sitagliptin Synthesis
2015-05-10 07:06:42

Januvia – Sitagliptin Synthesis 捷诺维 – 磷酸西格列汀制备方法
Chemical Structure of Sitagliptin Phosphate - Januvia  - Merck - Type II Diabetes 磷酸西格列汀片-捷诺维化学结构

Manufacture of Sitagliptin phosphate, an active ingredient in JANUVIA and JANUMET (a fixed dose combination with the antidiabetic agent metformin) for the treatment of type 2 diabetes, represents one of the best examples of sustainable chemistry (Green Chemistry) in the pharmaceutical industry via three generations of process research and development.

Sitagliptin (previously known as MK-0431), developed and marketed by Merck in 2006, is the first oral selective dipeptidyl peptidase-4 (DPP-IV) inhibitor to enter the market.

Chemical Name: (7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tet-rahydro-[3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine Phosphate (1:1) Monohydrate (Sitagliptin Phosphate monohydrate)
CAS No.  654671-78-0 (Sitagliptin Phosphate)
CAS No. 486460-32-6 (Sitagliptin)
通用名称:磷酸西格列汀片
商品名称:捷诺维
英文名称:JANUVIA (Sitagliptin Phosphate)
化学名】7-[(3R)~3-氨基-1-氧-4~(2,4,5-三氟苯基)丁基]-5,6,7,8-四氢-3-(三氟甲基)~1,2,4-三唑并[4,3-a]吡嗪磷酸盐(1:1)

The first generation process was used to prepare for the early safety and clinical studies. It involes a beta-lactam route with EDC(N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride)coupling/Mitsunobu reaction with diisopropyl azodicarboxylate (DIAD).

Both EDC coupling and Mitsunobu reaction with the use of energetic reagent DIAD have poor atom economy leading to significant amount of waste.

Merck, in collabaration with Solvias and Codexis, was able to develop the second and third commercial processes of sitagliptin phosphate.The 2nd generation process outlined in Scheme below has received the 2006 Presidential Green Chemistry Challenge Award for Greener Synthetic Pathways and the 2005 IChemE Astra-Zeneca Award for Excellence in Green Chemistry and Engineering. The 3rd generation process has received the 2010 Presidential Green Chemistry Challenge Award for Greener Reaction Conditions.

The Key feature in the second generation synthesis of sitagliptin involves dehydrositagliptin enamine formation in three steps in one pot followed by asymmetric hydrogenation at high pressure (250 psi) using a rhodium-based chiral catalyst [Rh(COD)Cl]2 dimer/tBu JOSIPHOS, providing  sitagliptin in 97% e.e.Following the reduction, 90–95% of the rhodium was recovered for recycling using an Ecosorb C-941 adsorbant. Recrystallization to upgrade e.e. followed by phosphate salt formation provides sitagliptin phosphate. This environmentally friendly, ‘green’ synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams.

The third generation synthesis of sitagliptin features direct amination of prositagliptin ketone via a highly evolved transaminase biocatalyst to provide enantiopure sitagliptin, followed by phosphate salt formation to provide sitagliptin phosphate. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.

First Generation  Manufacture of Sitagliptin phosphate (Januvia)

Synthetic scheme for the first generation manufacture of Sitagliptin phosphate (Januvia) 捷诺维-磷酸西格列汀-第一代制备方法

Sitagliptin - Januvia manufacture-1st gen syn-beta lactam route 捷诺维-磷酸西格列汀-第一代制备方法

Synthetic conditions for the first generation manufacture of Sitagliptin phosphate (Januvia)

1)1,1′-Carbonyldiimidazole (CDI), potassium methyl malonate, magnium chloride, triethylamine, 86% yield
reference:  Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem., Int. Ed. Engl.1979, 18,72-73.
2)(S)-BinapRuCl2 triethylamine complex, HBr, MeOH,90 psi H2, 80°C, 10h
3)sodium hydroxide, MeOH/H2O, 83% yield(two steps)
4)O-benzylhydroxy amine hydrochloride, EDC.HCl, LiOH, THF/H2O
5)diisopropyl azodicarboxylate(DIAD),triphenyl phosphine, THF, 81% yield (two steps)
6)LiOH, THF/water
7)trizole HCl salt (see below for its synthesis), EDC, N-methylmorpholine,acetonitrile, 0°C, 2h
8)10% Pd/C, Ethanol, 40 psi H2, 50°C, 16-18 h
9)85 wt% phosphoric acid, 78% yield (five steps)

References for the first generation manufacture of Sitagliptin phosphate (Januvia)

Karl B. Hansen,Jaume Balsells, Spencer Dreher, Yi Hsiao, Michele Kubryk, Michael Palucki, Nelo Rivera, Dietrich Steinhuebel, Joseph D. Armstrong III, David Askin, and Edward J. J. Grabowski; First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin; Organic Process Research & Development 2005, 9, 634−639

Detailed Procedures for the first generation manufacture of Sitagliptin phosphate (Januvia)

Preparation of 4-(2,4,5-Trifluorophenyl)-3(S)-hydroxybutanoic Acid

A solution of ketoester 9 (2.5 kg, 10.2 mol) and HBr (115 mL, 48 wt % solution in water, 1.01 mol, 0.1 equiv) in 11.5 L of methanol was degassed by bubbling N2 through the solution for 20 min and then transferred to a stirred autoclave. 21.5 g of (S)-BinapRuCl2 triethylamine complex was dissolved in1Lofmethanol which had been degassed as above and transferred to the autoclave. Following addition of the catalyst solution, the entire reaction solution was further degassed by five vacuum purge/N2 back-fill cycles. The mixture was then subjected to 90 psig H2 at 80 °C for 10 h at which point <1% ketoester remained by HPLC assay. The solution was removed from the vessel with a methanol rinse. The solution was assayed to contain 2.51 kg of hydroxy ester(99.3% yield) which was 90.8% ee by chiral HPLC analysis.

A solution of hydroxy ester (5.00 kg, 20.15 mol) in 25 L of methanol was charged to a round-bottom flask equipped with an overhead stirrer, steam bath, and thermocouple. A solution of aqueous NaOH (0.89 kg, 22.16 mol, 1.1 equiv) dissolved in 25 L of water was charged to the methanol solution. The mixture was aged for1hatwhich point HPLC assay indicated complete consumption of ester starting material. The methanol was removed by distillation in vacuo, and the resulting solution was transferred to an extractor. 12 N HCl (3.8 L, 34.3 mol, 1.7 equiv) and 15 L of MTBE were added to the solution with cooling. The layers were separated, and the aqueous layer was back-extracted with 15 L of MTBE. The combined MTBE layers were switched to toluene by distillation at 50-60 °C, and upon complete removal of MTBE, the volume was adjusted to 50 L. The solution was then allowed to cool to room temperature. At ˘37 °C the product began to crystallize from solution. The mixture was aged overnight at room temperature (˘18 h). The crystals were isolated by filtration and washed with5Loftoluene. Following drying at 40 °C, 4.08 kg of title compound which was 94% ee and 96.7 wt % pure were isolated in 83% yield.(Chiracel AD-H, 95% hexanes, 5% IPA, 1% TFA, 1 mL/min, 35 °C, tr ) 20.3 min (S-11), 22.9 (R-11)). Mp: 84 °C. 1H NMR: (CDCl3, 400 MHz) δ(ppm): 7.11 (m, 1H), 6.92 (m, 1H), 4.27 (m, 1H), 2.82 (d, J ) 6.1 Hz, 2H), 2.61 (dd, J ) 3.4, 16.8 Hz, 1H), 2.52 (dd, J ) 8.7, 16.8 Hz, 1H). 13C NMR:(CD3OD, 100 MHz)  δ(ppm): 173.7, 156.3 (dd, JC-F ) 9.3, 243.1 Hz), 148.7 (ddd, JC-F ) 12.8, 27.3, 248.0 Hz), 146.2 (ddd, JC-F ) 3.6, 12.4, 242.5 Hz), 122.1 (ddd, JC-F ) 4.4, 5.4, 18.3 Hz), 119.2 (dd, JC-F ) 6.2, 19.3 Hz), 104.7 (dd, JC-F ) 21.1, 29.3), 67.6, 41.1, 35.1. 19F NMR: (CDCl3, 376 MHz) -119.7 (dd, JF-F ) 3.2, 15.5 Hz), -136.0 (dd, JF-F ) 3.2, 21.0 Hz), -133.3 (dd, JF-F ) 15.5, 21.0 Hz). [R]D )+16.3°(c ) 1.0, CHCl3). Anal. Calcd for C10H9F3O3: C, 51.29; H,3.87. Found: C, 50.59; H, 3.62.

Preparation of N-Benzyloxy-4(R)-[1-methyl-(2,4,5-trifluorophenyl)]-2-oxoazetidine

To a slurry of hydroxyacid (4.0 kg, 17.1 mol, 1.0 equiv), O-benzylhydroxy amine hydrochloride (3.0 kg, 18.8 mol, 1.1 equiv), and LiOH (0.72 kg, 17.1 mol, 1.0 equiv) in 10 L of THF and 30 L of water at 20 °C was added EDC-HCl (4.26 kg, 22.2 mol, 1.3 equiv). The solution was aged for1hat which point <1% hydroxy acid was present by HPLC assay. 32 L of MTBE were added, and the phases were separated. The organic layer was then vacuum distilled and dried by flushing first with MTBE and then with THF until all of the MTBE had been removed and the water content was <2000 ppm as judged by Karl Fisher titration. The final volume was adjusted to 17 L, and the solution was then used directly in the next step. In a separate vessel, DIAD (3.70 L, 18.8 mol, 1.1 equiv) was charged slowly via addition funnel to a solution of PPh3 (4.93 kg, 18.8 mol, 1.1 equiv) at 0 °C such that the temperature did not rise above 10 °C. A slurry of white solids formed during the addition. The THF solution of hydroxamate was then added slowly to the slurry keeping the reaction temperature below 10 °C. Upon completion of the addition, the reaction was warmed to 20 °C and then aged overnight (18 h). The reaction was assayed by HPLC at which point <1% area percent starting material remained. Acetic acid (51.6 g, 0.86 mol) was charged to the solution which was then solvent switched to methanol. Crystals formed upon complete removal of THF. The final volume of the mixture was adjusted to 43 L with methanol, and then water (2.8 L) was added. The mixture was heated to 35 °C to redissolve all of the solids and then slowly cooled to -20 °C. After1hat-20 °C, the slurry was filtered and then washed with 2  4.5 L of 10% v/v water/methanol cooled to -20 °C. 4.7 kg of title compound (93 wt % purity by HPLC) were isolated as a crystalline solid after drying at room temperature in vacuo (82% yield over two steps). The material was assayed by chiral HPLC to be 99.7% ee.(Chiracel AD-RH, 60% CH3CN/40% H2O, 0.6 mL/min, 20 °C, tr ) 9 min (R-5), 11 min (S-5). Mp: 80 °C. 1H NMR (CDCl3, 400 MHz):  δ(ppm): 7.37 (m, 5H), 6.90 (m, 2H), 4.92 (m, 2H), 3.63 (m, 1H), 2.86 (dd, J ) 5.0, 14.3 Hz, 1H), 2.67 (m, 2H), 2.33 (dd, J ) 2.2, 13.8 Hz, 1H). 13C NMR (CDCl3, 400 MHz):  δ(ppm): 163.6, 155.9 (dd, JC-F ) 10.6, 244.2 Hz), 149.1 (dd, JC-F ) 12.5, 250.9 Hz), 146.6 (ddd, JC-F ) 3.7, 12.5, 231.3 Hz), 135.3, 129.3, 129.1, 128.6, 119.7 (ddd, JC-F ) 4.4, 5.1, 18.4 Hz), 118.8 (dd, JC-F ) 6.5, 19.2 Hz), 105.5 (dd, JC-F ) 20.8, 28.5 Hz), 78.2, 57.0, 37.6, 31.0. 19F NMR (CDCl3, 377 Hz):  δ(ppm): -119.4 (dd, JF-F ) 3.2, 15.1 Hz), -135.5 (dd, JF-F ) 3.2, 21.6 Hz), -147.7 (dd, JF-F ) 14.9, 21.5 Hz). [R]D )+ 26.2° (c ) 1.04, CHCl3). Anal. Calcd for C17H14F3NO2: C, 63.55; H, 4.39; N, 4.36. Found: C, 63.55; H, 4.27; N, 4.33.

Preparation of Sitagliptin Phosphate (Januvia)

A solution of lactam (4.65 kg, 93 wt %purity, 13.4 mol, 1.0 equiv) and LiOH monohydrate (0.84 kg, 20 mol, 1.5 equiv) in 14 L of THF and 14 L of water was aged for 1.5 h at 20 °C at which point <1% starting material was present by HPLC assay. Methanesulfonic acid (1.30 L, 20 mol, 1.5 equiv) was slowly added to the reaction with cooling such that the temperature stayed below 20 °C. MTBE (28 L) was charged, and the phases were mixed well and then separated. The organic layer was then concentrated by vacuum distillation and then distilled at constant volume while the solvent was replaced with acetonitrile. The volume was then adjusted to 43 L with acetonitrile. Triazole HCl salt (see below for its synthesis,3.81 kg, 16.7 mol, 1.25 equiv) was charged, and the mixture was then cooled to 0 °C. N-Methyl morpholine (1.35 kg, 13.4 mol, 1.0 equiv) was then charged to the slurry followed by EDC-HCl (3.85 kg, 20.07 mol, 1.5 equiv). The reaction was aged for2hat0 °C at which point <1% 2b remained by HPLC assay. The mixture was quenched with 20 L of water and 40 L of MTBE. After warming to 15 °C, the layers were separated and the organic layer was washed with 1 x 20 L of 10% KHCO3 and 1 x 20 L of 20% NaCl solution. The organic layer was then concentrated by vacuum distillation, and the solvent was switched to ethanol. The volume was adjusted to 36 L with ethanol, and 4Lof water were charged. The solution was hydrogenated at 40 psi and 50 °C with 1.00 kg of 10% Pd on carbon as catalyst. The reactions were complete after 16-18 h as judged by complete consumption of starting material by HPLC assay. The catalyst was removed by filtration of the reaction through cellulose which was washed with ethanol. The combined filtrate and wash was combined and assayed to contain 4.71 kg of Sitagliptin free base (86% yield).

The ethanol solution was concentrated by vacuum distillation to a volume of 25 L. 5.5 L of water were added, and the mixture was heated to 50°C. Phosphoric acid (85 wt %, 1.33 kg, 11.5 mol, 1.0 equiv) was then added in one portion, and the temperature of the solution raised to 70-74 °C. The solution temperature was lowered to 65 °C, and it was then seeded with sitagliptin H3PO4 salt. The slurry was aged for 1 h and then slowly cooled to rt. 75 L of EtOH were added slowly to the slurry, which was then aged for 18 h at room temperature. The crystals were isolated by filtration and washed with 2 x 10 L of ethanol. The solids were dried in a40°C vacuum oven with a nitrogen sweep to afford 5.30 kg of sitagliptin phosphate (78% yield from 5). The optical purity was assayed to be >99.5% ee. Chiralpak AD-H, 60% (2% H2O, 2% diethylamine, 96% hexanes), 40% (2% H2O, 2% diethyl-amine, 96% EtOH), 0.8 mL/min, 35 °C, tr ) 13 min (S-1), 15 min (R-1). Mp ) 215-217 °C. 1H NMR (D2O, 600 MHz)  δ(ppm): 7.06 (m, 1H, major and minor), 6.91 (m, 1H, major and minor), 4.76 (s, 2H, minor), 4.75 (d, J ) 17.6 Hz, 1H, major), 4.70 (d, J ) 17.6 Hz, 1H, major), 4.11 (m, 2H, major), 4.07 (m, 1H, minor), 4.02 (m, 1H, minor), 3.83 (m, 1H minor and 2H major), 3.79 (m, 2H, major), 2.91 (m, 1H, both), 2.83 (m, 2H, major and minor), 2.79 (dd, J ) 17.0, 4.9 Hz, 1H, major), 2.68 (m, 1H, major and minor). 13C NMR: (D2O, 151 MHz)  δ(ppm): 170.4 (minor), 170.3 (major), 156.5 (m, major and minor), 151.2 (major), 150.7 (minor), 149.4 (m, major and minor), 146.6 (m, major and minor), 144.0 (q, JC-F ) 40.6 Hz, minor), 143.9 (q, JC-F ) 40.7 Hz, major), 119.3 (m, major and minor), 118.6 (m, major and minor), 117.8 (q, JC-F ) 270.1 Hz, major), 117.8 (q, JC-F ) 270.2 Hz, minor), 106.0 (dd, JC-F ) 28.6, 21.2, major and minor), 48.4 (major and minor), 43.6 (major), 43.3 (minor), 42.0 (minor), 41.3 (major), 38.9 (major), 38.2 (minor), 33.9 (major), 33.8 (minor). [R]D )-74.4° (c ) 1.0, H2O). Anal. Calcd for C16H18F6N5O5P: C, 38.03; H, 3.59; O, 13.86. Found: C, 38.08; H, 3.30; N, 13.77.

 

Synthetic scheme for the preparation of  3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride salt (precursor for Sitagliptin)

Synthetic conditions for the preparation of  3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride salt (precursor for Sitagliptin)

a)35 wt% hydrazine, 63-65 °C
b)trifluoroacetic anhydride, isopropyl acetate, 49% yield (two steps)
c)superphosphoric acid, 75 °C, 5 h
d)10% Pd/C, EtOH, 50 psig, 45 °C
e)isopropyl alcohol, HCl, 51% yield (three steps)

References for the preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride salt

Karl B. Hansen,Jaume Balsells, Spencer Dreher, Yi Hsiao, Michele Kubryk, Michael Palucki, Nelo Rivera, Dietrich Steinhuebel, Joseph D. Armstrong III, David Askin, and Edward J. J. Grabowski; First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin; Organic Process Research & Development 2005, 9, 634−639

Detailed Procedures for the preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride salt

Preparation of (1,2)-Bis-trifluoroacetyl-1-pyrazinylhydrazide 

2-Chloropyrazine (3.9 L, 5.0 kg, 43.7 mol, 1 equiv) was added dropwise to 22.2 L of 35 wt % aqueous solution of hydrazine (245 mol, 5.6 equiv) at 63-65 °Cover4h.The addition rate was carefully monitored to ensure that the reaction temperature did not exceed 65 °C. Following the addition, the reaction mixture was aged for 11-13hat65 °C, at which point <1% chloropyrazine was observed by GC area percent assay. The reaction mixture was cooled to 30 °C and then extracted 5 times with 10% (v/v) 2-propanol/CH2Cl2.

The extracts were then concentrated by distillation and flushed with IPAc (isopropyl acetate) until <1 vol% of IPA (2-propanol) remained as judged by GC assay. The solution was diluted with IPAC to a total volume of 51 L at which point the mixture was a slurry of white solids. The solution was cooled to 5 °C, and trifluoroacetic anhydride (19.6 L, 29.2 kg, 139.1 mol, 3.94 equiv) was added while maintaining the reaction temperature below 20 °C by controlling the addition rate (˘1 h total addition time). Upon complete addition, the reaction was assayed by HPLC and contained <1 area percent 7. Heptane (22 L) was added to the slurry, and the product was isolated by filtration. The solids were washed with 9L of 10% (v/v) IPAC/heptane. After drying at ambient temperature under a vacuum/nitrogen sweep, 6.44 kg of a yellow solid (49% yield) was isolated. 1H NMR (DMSO-d6, 400 MHz)  δ(ppm): 13.30 (s, 1H), 9.30 (s, 1H), 8.66 (d, J ) 2 Hz, 1H), 8.64 (m, 1H). 13C NMR (DMSO-d6, 100 MHz) δ(ppm): 157.6 (q, JC-F ) 37.8 Hz), 157.3 (q, JC-F ) 37.6 Hz), 146.1, 143.6, 143.1, 139.3, 115.4 (q, JC-F ) 288 Hz). 19F NMR (DMSO-d6, 376 MHz) δ(ppm): -74.5, -71.3.

Preparation of  3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride salt

4.8 kg (15.8 mol, 1 equiv) of 8 were charged to 19.2 L of superphosphoric acid. The viscous slurry was heated to an internal temperature of 75 °C at which point the color became dark red and the mixture became homogeneous. After 5 h, the reaction was cooled to 30 °C and sampled for conversion by HPLC. Water (19.2 L) was added over 1.5 h to the reaction mixture while maintaining the temperature below 40 °C. NH4OH (28.8 L) was carefully added to the mixture (gas evolution and strong exotherm) while keeping the temperature below 40 °C, until a pH of 8-9 was achieved. The slurry was extracted with 2  29 L and then 1  14 L of IPAC. The solids present were partitioned with the aqueous phase during each separation. The combined organic layers were treated with 0.5 kg of DARCO KB for1hand then filtered through cellulose. The waste cake was washed with 9.6 L of IPAC.

The combined organic extracts were then solvent switched into EtOH by vacuum distillation, and upon complete removal of IPAC, the volume was adjusted to 36 L with EtOH. The solution was then hydrogenated in three 12 L batches using 200 g of 10% Pd/C (each batch) at 50 psig H2 and 45 °C. The combined hydrogenation mixtures were then treated with 200 g of DARCO G-60 and then filtered through cellulose. The cake was washed with ethanol, and the combined filtrate and wash was assayed to contain 1.87 kg of piperazine.

The solvent was then switched into IPA by vacuum distillation until <2 vol % ethanol remained. The volume was adjusted to 8 L, and then 2.4 L of a 3.7 M solution of HCl in IPA (8.8 mol, 1.01 equiv, prepared by diluting concentrated HCl with IPA, charge based on assay yield of the slurry, and the mixture was aged for1hat20 °C and then filtered. The cake was washed with 4L of 13 vol% IPA in IPAC and then dried under vacuum with a nitrogen sweep. 1.8 kg (8.01 mol, 51% yield) of
3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride salt as a white solid were obtained. m.p. 264 °C (decomp); Anal., Calc. for C6H8ClF3N4: C: 31.52%, H: 3.53%, N: 24.51%, Cl: 15.51%; F: 24.93%; Found: C: 31.38%, H: 3.37%, N: 24.35%, Cl: 15.51%; F: 25.21%; IR(KBr):3016, 2947, 1572, 1518, 1499, 1271, 1210, 1181 cm-1; MS (ES): 192 (M+); HRMS(ES+) calc. for (M+H)+: 193.0701, found: 193.0702 (0.5 ppm); 1H-NMR (400.13 MHz, DMSO), δ(ppm): 3.61 (t, 2H), 4.40 (t, 2H), 4.66 (s, 2H), 10.62 (br, 2H). 13C-NMR (100.62 MHz, DMSO), δ(ppm): 39.4, 39.6, 41.0, 118.6 (q, J = 260 Hz), 142.9 (q, J = 40 Hz), 148.8.

Second Generation  Manufacture of Sitagliptin phosphate (Januvia)

The 2nd generation process outlined in Scheme below has received the 2006 Presidential Green Chemistry Challenge Award for Greener Synthetic Pathways and the 2005 IChemE Astra-Zeneca Award for Excellence in Green Chemistry and Engineering.

Synthetic scheme for the second generation manufacture of Sitagliptin phosphate (Januvia) 捷诺维-磷酸西格列汀-第二代制备方法

Sitagliptin - Januvia manufacture-2nd gen synthesis-asymmetric hydrogenation route捷诺维-磷酸西格列汀-第二代制备方法

Synthetic conditions for the second generation manufacture of Sitagliptin phosphate (Januvia)

a)Meldrum’s acid, iPr2NEt, DMAP(cat), pivaloyl chloride, acetonitrile
b)triazole hydrochloride, trifluoroacetic acid
c)ammonium acetate,MeOH, MeCN, 82% yield (three steps)
d)[Rh(COD)Cl]2 dimer (0.15 mol%), tBu-JOSIPHOS(0.155 mol%), NH4Cl(0.15 mol%), H2, 250 psig, 500C, 16-18 h; EcosorbC-941 (Graver Technologies, Glasgow, DE, 19702) ) for Rh removal, 98% yield, 95% ee
e)45% wt phosphoric acid, isopropanol, water, 81% yield, >99.9% ee, >99.9% purity

References for the second generation manufacture of Sitagliptin phosphate (Januvia)

Karl B. Hansen, Yi Hsiao, Feng Xu,Nelo Rivera,Andrew Clausen,Michele Kubryk,Shane Krska,Thorsten Rosner,Bryon Simmons,Jaume Balsells,Nori Ikemoto,Yongkui Sun,Felix Spindler,Christophe Malan,Edward J. J. Grabowski, and Joseph D. Armstrong III.; Highly Efficient Asymmetric Synthesis of Sitagliptin; J. Am. Chem. Soc; 2009, 131, 8798-8804

This manufacturing process received the Presidential Green Chemistry Challenge Award (2006) for alternative synthetic pathways and the IChemE Astra-Zeneca Award for excellence in green chemistry and chemical engineering (2005).

Detailed Experimental Procedures for the second generation manufacture of Sitagliptin phosphate (Januvia)

Preparation of (Z)-3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-but-2-en-1-one

2,4,5-Trifluorophenylacetic acid (11, 2.5 kg, 13.15 mol), Meldrum’s acid (10, 2.09 kg, 14.46 mol), DMAP (128.5 g, 1.052 mol), and acetonitrile (7.5 L) were charged into a 50 L three-neck flask. N,N-Diisopropylethylamine (4.92 L, 28.27 mol) was added in portions at room temperature while maintaining the temperature below 50°C. Pivaloyl chloride (1.78 L, 14.46 mol) was added dropwise over 1-2 h while maintaining the temperature below 55 °C. The reaction was aged at 45-50 °C for 2-3 h. Triazole hydrochloride (3.01kg, 13.2 mol) was added in one portion at 40-50 °C. Trifluoroacetic acid (303 mL, 3.95 mol) was added dropwise, and the reaction solution was aged at 50-55 °C for 6 h. 90% solution assay yield of ketoamide (4.81 kg).

A solution of NH4OAc (0.91 kg, 11.81 mol) in MeOH (27 L) was heated to 45 °C. About 10% of the above ketoamide crude solution was then added dropwise over 30 min. The reaction mixture was stirred at 45 °C for 1.5 h, and the batch was then seeded with 9 (140 g). After 30 min at 45 °C, the remaining of the crude 14 solution was added dropwise over 3-6 h. After additional 3 h age, MeOH (12 L) was charged over 2 h while maintaining the batch temperature at 40-45 °C. The slurry was then cooled to 0-5 °C over 3-4 h and aged for an additional 1 h before filtration. The wet cake was washed with 29 L of cold methanol (0 °C) and dried at ambient temperature in a vacuum oven to afford 4.37 kg of white crystalline 9 (99.6 wt %). 82% yield. 1H-NMR (400 MHz, DMSO-d6): δ 8.48 (s, br, 1H), 7.50 (m, 2H), 6.82 (s, br, 1 H), 4.90 (s, 1H), 4.85 (s, 2H), 4.14 (t, J ) 5.1 Hz, 2H), 3.90 (t, J ) 5.1 Hz, 2H), 3.44 (s, 2H). 13C-NMR (100 MHz, CDCl3): δ 168.9, 160.1, 155.6 (ddd, J ) 243.7, 10.0, 1.7 Hz), 151.4, 148.1 (dt, J ) 247.4, 13.9 Hz), 145.9 (ddd, J ) 241.5, 12.1, 3.3 Hz), 142.4 (q, J ) 38.9 Hz), 121.9 (ddd, J ) 18.6, 6.3, 4.2 Hz), 118.6 (dd, J ) 19.7, 5.5 Hz), 118.5 (q, 270.6 Hz), 105.6 (dd, J ) 28.9, 21.4 Hz), 81.0, 43.5, 34.1. Anal. Calcd for C16H13F6N5O: C, 47.41; H, 3.23; N, 17.28; Found: C, 47.42; H, 3.16; N, 17.20.

Preparation of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tet-rahydro-[3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine Phos-phate (1:1) Monohydrate (Sitagliptin Phosphate)

To a slurry of (Z)-3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-but-2-en-1-one (405.3 g, 1.0 mol) and ammonium chloride (80 mg, 1.5 mmol) in methanol (3.25 L) was added 18 (52 mg, 1.55 mmol) followed by [(COD)RhCl]2 dimer (23 mg, 1.5 mmol). The slurry was N2 degassed and aged with agitation for 1 h, then heated to 50 °C and hydrogenated under 250 psig hydrogen pressure. After 15-17 h, the reaction mixture was cooled to ambient temperature. Ecosorb C-94117 (40.5 g, Graver Technologies, Glasgow,DE 19702) was charged to the batch. The slurry was aged at ambient temperature for 1 h before filtration. The wet cake was washed with methanol (1.2 L). The filtrate was solvent-switched to isopropanol via distillation under reduced pressure to a final volume of ∼1.1 L, while maintaining the batch temperature below 40 °C. After the distillation, the batch was maintained at 40 °C for 1 h, and then cooled to 20-15 °C. Heptane (3.2 L) was added dropwise over 3-4 h. After filtration, the wet cake was washed with 20%isopropanol in heptane (1.2 L) and dried in vacuo at 40 °C to afford free-base Sitagliptin in 82% yield (332 g) and >99.9% ee.

To a solution of free-base sitagliptin (407.3 g, 1.0 mol) in isopropanol (1.73 L) and water (0. 45 L) was added 45 wt % H3PO4 (1.15 mol) dropwise. The resulting slurry was heated to 70-80 °C to dissolve the solids. The batch solution was then cooled to 60-65 °C and seeded with milled phosphate monohydrate 1 (3 g). The batch was agitated for3hat60-65 °C and cooled to ambient temperature over 6 h. Isopropanol (1.26 L) was added dropwise to the batch over 1-2 h. The slurry was then filtered, and the wet cake was washed with aqueous isopropanol (20 wt % water, 1.2 L). The wet cake was dried at ∼40 °C in vacuo to give 390 g of phosphate monohydrate 1 in 96% yield (corrected for seed charged). 1H NMR (600 MHz, D2O): In D2O solution, 1 exists as a 4:3 mixture of amide rotamers. Severe overlap of signals does not permit unequivocal assignment of each rotamer. Assignments are grouped (when necessary) and rotamers (major/minor/both) denoted in parentheses. δ 7.06 (overlapping m, 1 H, both), 6.92 (overlapping m, 1 H, both), 4.76 (s, 2 H, minor), 4.75 (d, J ) 17.6 Hz, 1 H, major), 4.70 (d, J ) 17.6 Hz, 1 H, major), 4.11 (m, 2 H, major), 4.08 (m, 1 H, minor), 4.03 (m, 1 H, minor), 3.89-3.78 (overlapping m, 2 H, minor; 1 H, both), 3.79 (m, 2 H, major), 2.92 (m, 2 H, both), 2.86-2.79 (overlapping m, 1 H, both; 1 H, minor), 2.79 (dd, J ) 17.1, 4.9 Hz, 1 H, major), 2.68 (overlapping m, 1 H, both). 13C-NMR (150 MHz, D2O): 170.37 (1C, minor), 170.29 (1C, major), 119.26 (overlapping m, 1C, both), 156.44 (overlapping m, 1C, both), 151.24 (1C, major), 150.70 (1C, minor), 149.39 (overlapping m, 1C, both), 146.64 (overlapping m, 1C, both), 143.97 (q, JCF ) 40.8 Hz, 1C, minor), 143.86 (q, JCF ) 40.7 Hz, 1C, major), 118.60 (overlapping m, 1C, both), 117.80 (q, JCF ) 270.1 Hz, 1C, major), 117.78 (q, JCF ) 270.2 Hz, 1C, minor)105.96 (dd, JCF ) 28.6, 21.2 Hz, 1C, both), 48.38 (1C, both), 43.57 (1C, major), 43.28 (1C, minor), 41.98 (1C, minor), 41.33 (1C, major), 38.89 (1C, major), 38.19 (1C, minor), 33.92 (1C, major), 33.85 (1C, minor), 31.14 (1C, major), 31.04 (1C, minor). HRMS: Calcd for C16H15N5OF6 [M + H]+ 408.1259; Found 408.1264.

Third Generation  Manufacture of Sitagliptin phosphate (Januvia)

The 3rd generation process has received the 2010 Presidential Green Chemistry Challenge Award for Greener Reaction Conditions.

Previous   [Return Home] [Print] [Go Back]   Next