New method for synthesizing nateglinide
A technology of nateglinide and a new method, which is applied in the field of synthesizing nateglinide, can solve the problems of high cost of nateglinide raw materials, few deep-processed products, and low selectivity, and achieve rich raw materials, few method steps, The effect of cheap raw materials
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Embodiment 1
[0021] Embodiment one, the preparation of notopine acid (2)
[0022] Dissolve 4g of sodium hydroxide and 39.5g of potassium permanganate in 450mL of 30% aqueous pyridine solution, and add 14.2g of 96% β-pinene in batches under vigorous stirring. Use a water bath to maintain the reaction temperature at 25-30°C, react for 3-5 hours, and finish the reaction with potassium permanganate as the end point. The precipitated manganese dioxide was filtered off and washed several times with water. The filtrate was concentrated to 150 mL by evaporation under reduced pressure, and left overnight in the refrigerator. Filtrate under reduced pressure and wash with a small amount of ice water to obtain white norpinate sodium crystals.
[0023] Add the sodium pinoleate obtained above into a mixture of 20 mL of water and 25 mL of dichloromethane, adjust to strong acidity with 6 mol / L hydrochloric acid solution, separate the dichloromethane, wash the aqueous phase three times with 7 mL of dichl...
Embodiment 2
[0024] Embodiment two, the preparation of dihydrocuminic acid (3)
[0025] 8.0g norpine acid and 400mL 20% H 2 SO 4 Put it into a reaction flask, and react with magnetic stirring at a constant temperature of 80° C. for 6 hours. After cooling, the crystals were filtered and recrystallized with 50% ethanol aqueous solution to obtain 5.6 g of white needle crystals of dihydrocuminic acid with a yield of 82.4% and a melting point of 132-134°C.
Embodiment 3
[0026] Embodiment three, the preparation of trans-4-isopropylcyclohexanecarboxylic acid (5)
[0027] 8.0g of dihydrocuminic acid, 400mL of methanol and 1.6g of 7.5% Pd / C were put into the reaction flask, and stirred and reacted for 5 hours at room temperature with hydrogen gas. The catalyst was recovered by filtration, and the filtrate was distilled under reduced pressure to recover methanol to obtain 8.0 g of a colorless liquid, which was a mixture of cis and trans isomers of p-isopropylcyclohexanecarboxylic acid. Put 8.0g of the product from the previous step, 200mL of p-cymene and 4.2g of potassium hydroxide into the reaction flask, heat to 145°C under nitrogen protection, and stir for 6 hours. Cool, add a mixed solution of 80mL water and 80mL methanol, separate the lower layer (water / alcohol phase) after standing for layers, and use 6mol·L -1 Acidify with hydrochloric acid to pH 2; stir at low temperature for 1 hour, filter out the precipitate, and recrystallize twice fro...
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