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With phosphoric acid In water; isopropyl alcohol at 70 - 80℃; for 2 h;
At room temperature, 8.14 g of sitagliptin was added to the reactor.16.3 mL of isopropyl alcohol, 7.3 mL of water, and then dropwise added 1.73 mL of an 85percent by volume aqueous phosphoric acid solution; the temperature was raised to 80 ° C, dissolved into a transparent liquid; and cooled to 70 ° C.The reaction was stirred for 2 hours. After that, the mixture was cooled to 54 ° C with a cooling rate of 8 ° C per hour, and then cooled to 22 ° C with a cooling rate of 16 ° C per hour.A large amount of white solid was precipitated. Add 57 mL of isopropanol in 40 minutes.Then, the mixture was stirred for 15 minutes; suction-filtered, washed twice with 40.7 mL of an isopropanol-water (V/V = 11:1) system; and dried at a vacuum of -0.08 MPa at 25 ° C for 5.5 hours.Obtained 10.22 g of a white crystalline solid, which was tested.HPLC (percent): 99.91percent; moisture: 3.54percent; molar yield: 97.7percent.
95%
With phosphoric acid; water In isopropyl alcohol at 20 - 75℃;
In IPA (17mL) and H2O (7.2mL), compound 6 (8.0g,19.7mmol) was dissolved and 85percent H3PO4 (2.27g,19.7mmol) was added dropwise. The mixture was heated to 75. to dissolve the solids. The batch was then cooled to 60-65. and seeded with phosphate monohydrate 1. The batch was aged for 1h and cooled to ambient temperature for 16h. IPA (56mL) was added and the batch was stirred for 1h. The batch was filtered, and the wet cake was washed with IPA (5mL). The wet cake was dry at 60. to give 9.83g of sitagliptin phosphate monohydrate 1 (95.0percent) with a purity of 99.93percent and ee>99.94percent. HPLC purity: 99.93percent: Waters Symmetry, 25percent CH3CN, 75percent H2O (0.1percent TFA), f=1mL/min, T=40.. ee >99.94percent: Chiralpak IC-3, 40percent hexanes(0.1percent diethylamine), 60percent hexanes(0.1percent diethylamine), f=0.5mL/min, T=30.. Anal. Calcd for C16H20F6N5O6P: C 36.72percent, H 3.85percent, N 13.38percent, F 21.78. Found: C 36.59percent, H 3.83percent, N 13.45percent, F 21.78. Figures S1~S7 show the identifications of 1 through 1H-NMR, MS, HPLC, chiral HPLC, DSC and TGA. The data of 1H-NMR were consistent with that reported in the reference
With phosphoric acid; In water; isopropyl alcohol; at 70 - 80℃; for 2h;
At room temperature, 8.14 g of sitagliptin was added to the reactor.16.3 mL of isopropyl alcohol, 7.3 mL of water, and then dropwise added 1.73 mL of an 85% by volume aqueous phosphoric acid solution; the temperature was raised to 80 C, dissolved into a transparent liquid; and cooled to 70 C.The reaction was stirred for 2 hours. After that, the mixture was cooled to 54 C with a cooling rate of 8 C per hour, and then cooled to 22 C with a cooling rate of 16 C per hour.A large amount of white solid was precipitated. Add 57 mL of isopropanol in 40 minutes.Then, the mixture was stirred for 15 minutes; suction-filtered, washed twice with 40.7 mL of an isopropanol-water (V/V = 11:1) system; and dried at a vacuum of -0.08 MPa at 25 C for 5.5 hours.Obtained 10.22 g of a white crystalline solid, which was tested.HPLC (%): 99.91%; moisture: 3.54%; molar yield: 97.7%.
95%
With phosphoric acid; water; In isopropyl alcohol; at 20 - 75℃;
In IPA (17mL) and H2O (7.2mL), compound 6 (8.0g,19.7mmol) was dissolved and 85% H3PO4 (2.27g,19.7mmol) was added dropwise. The mixture was heated to 75. to dissolve the solids. The batch was then cooled to 60-65. and seeded with phosphate monohydrate 1. The batch was aged for 1h and cooled to ambient temperature for 16h. IPA (56mL) was added and the batch was stirred for 1h. The batch was filtered, and the wet cake was washed with IPA (5mL). The wet cake was dry at 60. to give 9.83g of sitagliptin phosphate monohydrate 1 (95.0%) with a purity of 99.93% and ee>99.94%. HPLC purity: 99.93%: Waters Symmetry, 25% CH3CN, 75% H2O (0.1% TFA), f=1mL/min, T=40.. ee >99.94%: Chiralpak IC-3, 40% hexanes(0.1% diethylamine), 60% hexanes(0.1% diethylamine), f=0.5mL/min, T=30.. Anal. Calcd for C16H20F6N5O6P: C 36.72%, H 3.85%, N 13.38%, F 21.78. Found: C 36.59%, H 3.83%, N 13.45%, F 21.78. Figures S1~S7 show the identifications of 1 through 1H-NMR, MS, HPLC, chiral HPLC, DSC and TGA. The data of 1H-NMR were consistent with that reported in the reference
With phosphoric acid; water; In isopropyl alcohol; at 75℃;
A 250 mL round bottom flask equipped with an overhead stirrer, heating mantle and thermocouple, was charged with 31.5 mL of isopropanol (IPA), 13.5 mL water, 15.0 g (36.9 mmol) of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine freebase and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid. The mixture was heated to 75 0C. A thick white precipitate formed at lower temperatures but dissolved upon reaching 75 0C. The solution was cooled to 68 0C and then held at that temperature for 2 h. A slurry bed of solids formed during this age time [the solution can be seeded with 0.5 to 5 wt% of small particle size (alpine milled) monohydrate]. The slurry was then cooled at a rate of 4 C/h to 21 0C and then held overnight. 105 mL of IPA was then added to the slurry. After 1 h the slurry was filtered and washed with 45 mL IPA. The solids were dried on the frit with open to air. The solids were found to greater than 99.8% pure by EtaPLC area percentage (EtaPLC conditions same as those given above).
With phosphoric acid; water; In water; isopropyl alcohol; for 0.25h;
Example 9 Preparation of Sitagliptin Phosphate Monohydrate [0204] Sitagliptin (58 g), IPA (105 ml) and water (45 ml) were charged to a 1 L round bottom flask and the solution was stirred for 15 min. To this, 85% aqueous phosphoric acid (16.5 g) was added and the mixture was heated to 75 C. to get a clear solution. The clear solution was cooled to 65-68 C. and held at that temperature for 2 hours. The slurry was cooled to 55 C. gradually and seeded with Sitagliptin phosphate monohydrate. The slurry was cooled to 25 C., and to this IPA (350 ml) was added and stirred for 12 hours. The obtained solid was filtered, washed with IPA (2×100 ml) and dried to obtain 50 g of Sitagliptin phosphate monohydrate.
With phosphoric acid; water; In isopropyl alcohol; at 68 - 75℃; for 2h;
A 250 ML round bottom flask equipped with an overhead stirrer, heating mantle and thermocouple, was charged with 31.5 mL of isopropanol (IPA), 13.5 ML water, 15.0 g (36.9 mmol) of (2R)-4-OXO-4- [3- (TRIFLUOROMETHYL)-5, 6-dihydro [1, 2,4] triazolo [4,3-a] pyrazin-7 (8H)-YL]-1-(2, 4,5- trifluorophenyl) butan-2-amine freebase and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid. The mixture was heated to 75 C. A thick white precipitate formed at lower temperatures but dissolved upon reaching 75 C. The solution was cooled to 68 C and then held at that temperature for 2 h. A slurry bed of solids formed during this age time [the solution can be seeded with 0.5 to 5 wt% of small particle size (alpine milled) monohydrate]. The slurry was then cooled at a rate of 4 C/H to 21 C and then held overnight. 105 mL of IPA was then added to the slurry. After 1 h the slurry was filtered and washed with 45 mL IPA (solids can also be washed with a water/IPA solution to avoid turnover to other crystal forms). The solids were dried on the frit with open to air. 18.6 g of solids were recovered. The solids were found to greater than 99.8% pure by HPLC area percentage (HPLC conditions same as those given above). The particle size distribution analysis of the isolated solids showed a mean PSD of 80 microns with 95% less than 180 microns. The crystal form of the solids was shown to be monohydrate by X-ray powder diffraction and thermogravimetric analysis.
With phosphoric acid; In water; isopropyl alcohol;Reflux;
In a 1000 mL round bottom flask,Add (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (69.2 g, 0.17 mol) and isopropanol 110g,Stir,Add 61.2 g of purified water,Phosphoric acid 19.4g,Plus,Heated to reflux,After cooling the reaction system to room temperature,Filter to give a white solid.That is, sitagliptin phosphate,HPLC content = 99.8%,Ee=99.5%,Among them, 17.451 minutes is impurity A,The purity is 0.038%,It is about 0.04%.The spectrum is shown in Figure 8.
The above crystalline monohydrate was dissolved in water at a concentration of approximately 50 mg/mL. The mixture was agitated until no solid material was apparent, and the solution was filtered through a 0.2 mum filter into a clean container. The solution was then frozen using a dry ice/methanol bath. The sample was pulled under vacuum to remove the solvent and leave a fluffy, white amorphous solid. The solid displays no reflections when analyzed be X-ray powder diffraction.
at 58 - 140℃; for 1 - 8h;
Form IV was prepared by heating the above monohydrate at 120 C for about 2 h or by heating the monohydrate above 58 C for about 8 h. Form IV is metastable and converts into the crystalline monohydrate slowly under ambient conditions and rapidly under high relative humidity (98%) at room temperature. Form IV can also be converted to anhydrate Form I in about 1 h at a temperature above 140 C.
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