A kind of synthetic method of cinacalcet hydrochloride intermediate
A technology for cinacalcet hydrochloride and an intermediate, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of unstable acid chloride of the intermediate, not easy to store, and high production cost, achieves short synthesis route, avoids hydrogenation reaction, and has strong operability Effect
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Embodiment 1
[0051] Example 1 Synthesis of 2,2-dimethyl-5-(3-(trifluoromethyl)benzyl)-1,3-dioxo-4,6-dione
[0052] L-Proline (4.07 g, 35.0 mmol) was added to a mixture of 3-trifluoromethylbenzaldehyde (30.3 g, 174 mmol) and Michaelis acid (25.6 g, 174 mmol) in ethanol (996 mL) at room temperature middle. After 40 minutes, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (44.1 g, 174 mmol) was added in one portion, followed by ethanol (125 mL). After stirring overnight, the mixture was concentrated under reduced pressure to give a yellow solid. Add isopropanol (300mL) and beat at room temperature for 3h. The mixture was filtered, and the filter cake was washed with isopropanol. The solids were collected and dried in vacuo to obtain 47.9 g of white solids with a yield of 91%.
Embodiment 2
[0053] Example 2 Synthesis of 2,2-dimethyl-5-(3-(trifluoromethyl)benzyl)-1,3-dioxo-4,6-dione
[0054] D,L-Proline (4.07g, 35.0mmol) was added to 3-trifluoromethylbenzaldehyde (30.3g, 174mmol) and Michaelis acid (25.6g, 174mmol) in acetonitrile (300mL) at room temperature in the mixture. After 40 minutes, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (44.1 g, 174 mmol) was added in one portion. After stirring overnight, the mixture was concentrated under reduced pressure to give a yellow solid. Add ethyl acetate (300mL), extract twice with 150mL 5% aqueous sodium hydroxide solution, cool the collected lye in an ice bath, carefully adjust the pH to about 4 with 6N hydrochloric acid, a white solid precipitates, and let it stand for 5 Minutes later, the solid was collected and dried in vacuo to obtain 50.0 g of a white solid with a yield of 95%.
Embodiment 3
[0055] Example 3 Synthesis of 2,2-dimethyl-5-(3-(trifluoromethyl)benzyl)-1,3-dioxo-4,6-dione
[0056] Under stirring, potassium phosphate (1.3 g, 6.0 mmol) was added to a solution of Metric acid (4.3 g, 30.0 mmol) in ethanol (100 mL), followed by 3-trifluoromethylbenzaldehyde (5.2 g, 30.0 mmol). After reacting at room temperature for 6 h, it was cooled in an ice bath, sodium borohydride (2.4 g, 62.0 mmol) was added in portions, and the mixture was raised to room temperature for another 2 h. The reaction solution was concentrated to about 20 mL, added 100 mL of 1N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, then slurried with isopropanol (30 mL), filtered the mixture, and washed the filter cake with isopropanol . The solids were collected and dried in vacuo to obtain 6.8 g of white solids with a yield of 75%.
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