5-1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione

2, 4, 5-Trifluorophenylacetic acid (2-1) (available from several commercial supplers) (25 g, 0.132 mol), Meldrum's acid (21 g, 0.145 mol), and DMAP (1.29 g, 0.0011 mol) were charged into a 1000 mL three-neck flask. Acetonitrile (75 mL) was added in one portion at room temperature. N, N-diisopropylethylamine (49.2 mL, 0.283 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (17.8 mL, 0.145 mol) was added dropwise over 1 to 2 h while maintaining the temperature below 50 C. The reaction was aged at 45-50 C for 2-3 h and cooled to 0 C. 1N HCl (300 mL) was added dropwise over 1 h while the Meldrum's adduct 2-2 was crystallized out. The product was collected by filtration and washed with 20percent MeCN/ water. After drying, 36.5 g of the Meldrum's acid adduct was obtained (88percent yield). 1H-NMR (400 MHz, CDCl3): δ 15.50 (s, 1H), 7.14 (m, 1H), 6.96 (m, 1H), 4.45 (s, 2H), 1.76 (s, 6H) ppm. 13C-NMR (100 MHz, CDCl3): δ 192.76, 170.66, 160.42, 156.47 (ddd, J CF = 245.7, 9.6, 2.4 Hz), 149.79 (ddd, J CF = 251.4, 14.5, 12.0 Hz), 146.90 (ddd, J CF = 244.9, 12.0, 3.2 Hz), 119.40 (dd, J CF = 19.3, 5.6 Hz), 117.41 (ddd, J CF = 18.5, 5.6, 4.0 Hz), 105.80 (dd, J CF = 28.1, 20.9 Hz), 105.63, 91.99, 34.59, 27.06 ppm.Under ice bath conditions, To a 2 L three-necked reaction flask equipped with 800 mL of acetonitrile, 2, 4, 5-trifluorophenylacetic acid was added(285.2 g, 1.5 mol, 1 eq), Pivaloyl chloride(199.0 g, 1.65 mol, 1.1 eq), DMAP (1.8 g, 0.015 mol, 0.01 eq), DIPEA (387.6 g, 3.0 mol, 2.0 eq), Stirred at room temperature for 45min, Meldrum's acid (237.8, 1.65 mol, 1.1 eq) was added and the temperature was raised to 45 ° C. to react overnight.TLC detection of the reaction process. After the reaction was completed, cooled to room temperature, 1M hydrochloric acid was slowly added, Solid generation. The resulting solid was washed with water and recrystallized from acetonitrile-water to give a white solid, Yield 85percent.2, 4, 5-Trifluorophenylacetic acid (2-1) (11.4 g, 60 mmol) was dissolved in THF (60 mL) and 1, 1'-carbonyldiimidazole (10.7 g, 66 mmol) was added over 5 min. The mixture was warmed to 51 C, Meldrum's acid (9.51 g, 66 mmol) was added, and the mixture was aged for 3 h. The reaction mixture was diluted with IPAc (60 mL) and water (60 mL), and the pH was adjusted to 2.4 with concentrated hydrochloric acid (11.5 mL). The aqueous layer was separated, and the orgnic layer was washed at 36 C with 0.1 N HCl (60 mL). The organic layer was concentrated, flushed with IPAc, and the residue was slurried in 2:1 heptane/IPAc (70 mL). the mixture was cooled over an ice-bath, then filtered, rinsing the solid with 2:1 heptane/IPAc. After drying, the Meldrum's acid adduct was obtained as a solid (15.1 g) in 80percent yield. The Meldrum's acid adduct (22.1 g, 70 mmol) and the triazole hydrochloride 1-4 (16.0 g, 70 mmol) were sluuried in IPAc (220 mL) and N, N-diisopropylethylamine (12.8 mL) was added. After aging for 3.5 h at 85 C, water (175 mL) was added and the mixture was transferred to a separatory funnel with a 40-mL rinse with IPAc. The aqueous layer was separated and the organic layer was washed with water (100 mL). The organic layer was partially concentrated under reduced pressure to give a 65 g of solution of the ketoamide 2-3 in IPAc. n-Heptane (30 mL) was added at roo temperature, followed by seed crystals of ketoamide. Additional heptane (20 mL) was added dropwise, and the mixture was stirred overnight. Additional heptane (50 mL) was added slowly and after aging for 2 h, the solids were filtered and washed with 2.2:1 heptane/IPAc (30 mL). After drying, the ketoamide 2-3 was obtained in 92percent yield (26.3 g).Under nitrogen protection, Compound A was added sequentially to a 1000 mL three-necked flask(100 g, 0.524 mol), Compound B (84 g, 0.583 mol), DMAP (5.2 g, 0.042 mol), Acetonitrile (250 mL), Cooling to 0 ~ 5 .Temperature control 0 ~ 30 , Triethylamine was added dropwise to the system(150 mL, 1.079 mol).Cooling to 0 ~ 5 , To the system, pivaloyl chloride was added dropwise(76 mL, 1.17 mol), Dropping temperature below 30 , plus complete, And the temperature was raised to 40 to 45C. 3 to 5 hours later, At the end of the reaction, Cooling to 25 ~ 30 .filter, The filter cake was washed twice with 200 mL of methyl tert-ether, The solvent was distilled off under reduced pressure (<30C) to 3-fold volume (viscous).600 mL of methylene chloride was added, The mixture was stirred for 5 minutes (25 to 30 ° C)Approximately 300 mL of 1.5 M hydrochloric acid was added dropwise over 15 minutes, Adjust the pH = 2 ~ 3.The DCM phase was washed with 100 mL of saturated brine, and the organic phase was evaporated in vacuo for 2 times the volume of the solvent (<15C)200 mL of n-heptane was added, The solvent was distilled off under reduced pressure (<15C)50 mL of ethyl acetate was added, Heptane 300 mL was beaten for 2 hours.Filtration, 100 ml (n-heptane:Ethyl acetate = 10: 1)Dried to obtain 134.23 g of product, Yield 80.7percent.Meldrum's Adduct (19)2, 4, 5-Trifluorophenylacetic acid (500.0 gm, 2.63 mol) (18) was suspended in tetrahydrofuran (5.26 vol, 2.63 Ltr) at 25-30° C. and the reaction mixture was stirred for 10-15 minutes. To this clear solution, 1, 1'-carbonyldiimidazole (1.5 eq, 639.68 gm) was charged in four lots and the reaction mixture was stirred for 2-3 hours at 25-30° C. After 2-3 hours stirring, Meldrum's acid (1.2 eq, 454.87 gm) was charged and the reaction mixture was heated for 6 hours at 50-55° C. After 6 hours heating at 50-55° C., the tetrahydrofuran was distilled out completely at 50-55° C. under reduced pressure to give a dark yellow coloured residue. The dark yellow residue was acidified by using a 1:1 mixture of 35percent hydrochloric acid:water (0.5 vol, 250.0 ml) at 0-5° C. The product was extracted from the aqueous solution by using dichloromethane (3.x.5.0 vol, 3.x.2.5 Ltr). The combined dichloromethane layers were further washed with water (3.x.10.0 vol, 3.x.5.0 Ltr). After water washing, the dichloromethane was completely distilled under reduced pressure to give a dark yellow fluffy solid. The product was further washed with methanol (2.0 vol, 1.0 Ltr) at 0-5° C.Molar Yield: 60-65percent (505.0 gm)Chemical Purity: 98-99.5percent (as measured by HPLC)2, 4, 5-trifluorophenylacetic acid (30 g), tetrahydrofuran (360 ml_), 1 , 1 -carbonyl diimidazole (25.5 g) at about 5OMeldrum's adduct (19)2, 4, 5-Trifluorophenylacetic acid (500.0 gm, 2.63 mol) (18) was suspended in tetrahydrofuran (5.26 vol, 2.63 Ltr) at 25-30°C and the reaction mixture was stirred for 10- 15 minutes. To this clear solution, l, r-carbonyldmidazole (1.5 eq, 639.68 gm) was charged in four lots and the reaction mixture was stirred for 2-3 hours at 25-30

5-[1-Hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione is an impurity of the DPP-IV inhibitor Sitagliptin (S491000).

Molecular Weight:316.23
XLogP3:3.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:2
Exact Mass:316.05585793
Monoisotopic Mass:316.05585793
Topological Polar Surface Area:72.8
Heavy Atom Count:22
Complexity:495
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes