Chemical Properties
Off-white solid
Uses
Methyl 3-Oxo-4-(2,4,5-trifluorophenyl)butanoate is a useful synthetic intermediate in the synthesis of Sitagliptin (S491000); a trizolopyrazine dipeptidyl peptidase (DPP) IV inhibitor for the treatment of type II diabetes.
Preparation
The preparation of methyl 3-Oxo-4-(2,4,5-trifluorophenyl)butanoate is as follows:Stage 1: (2,4,5-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In acetonitrile for 3.5h;Stage 2: monomethyl monopotassium malonate With triethylamine; magnesium chloride In acetonitrile at 50℃; for 8h;Stage 3: In acetonitrile at 30℃; for 26h.
Synthesis
Step-1: Preparation of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate (formula III)
Potassium monomethylmalonic acid salt (MMMKS; 122.8 g), triethylamine (264 mL) and acetonitrile (1200 mL) were added to a 3 L round bottom flask (RBF), the unit was equipped with a condenser, nitrogen inlet, thermometer casing and overhead stirrer. MgCl2 (65.2 g) was added in batches for 15-20 min at 30 °C, followed by stirring the mixture for 10 min. The reaction mixture was heated to 50 °C at the same temperature and maintained for 8 hours. Upon completion of the reaction, the mixture was cooled to 30 °C and labeled as Part A.
To another 2 L RBF, 1,1'-carbonyldiimidazole (CDI) (110 g) and acetonitrile (250 mL) were added to a unit equipped with a nitrogen inlet, thermometer casing, addition funnel and overhead stirrer. A solution of 2,4,5-trifluorophenylacetic acid (100 g) in acetonitrile (600 mL) was slowly added dropwise at 30 °C for 30 min, followed by stirring of the reaction mixture at 30 °C for 3 h. The reaction mixture was labeled as part B. The reaction mixture was then stirred for 2 h at 30 °C for 2 min.
The part B solution was added dropwise to the part A slurry over 2 h at 30 °C and the mixture was stirred. The progress of the reaction was monitored by TLC (mobile phase: n-hexane:ethyl acetate = 50:50).After 12 h, TLC analysis showed less than 5% unreacted feedstock. The reaction mixture was concentrated under reduced pressure at 50-55°C to obtain a thick slurry. Water (1000 mL) was added to the slurry and cooled to 10-15 °C before continuing to concentrate. HCl (220.6 mL) was added slowly at less than 20°C. MTBE (700 mL) was added and the mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with MTBE (200 mL). The organic layers were combined and washed sequentially with 7% aqueous NaHCO3 (400 mL) and brine (200 mL). The organic layer was dried with sodium sulfate and concentrated under vacuum at 50 °C to give an oil (120 g).
The resulting oily substance was diluted with isopropanol (400 mL) and cooled to 20 °C. Water (800 mL) was slowly added at 18-20 °C for 4 hours. The slurry was then stirred for 4 hours and filtered. The filter cake was washed with water (100 mL) and dried to give the free solid of the title product.
Yield: 115 g (83%); Melting point: 37-39 °C; HPLC purity: >95%.
1H NMR (CDCl3): δ 3.64 (s, 3H), 3.75 (s, 2H), 3.85 (s, 2H), 6.88-7.11 (m, 2H).
MS: 247 [M+H]+.
References
[1] Tetrahedron Asymmetry, 2006, vol. 17, # 2, p. 205 - 209
[2] Patent: WO2012/25944, 2012, A2. Location in patent: Page/Page column 29-30
[3] Patent: US2013/158265, 2013, A1. Location in patent: Paragraph 0156; 0157; 0158; 0159; 0160
