Nateglinide preparing process

Abstract

The nateglinide preparing process includes condensation between trans-4-isopropyl cyclohexane formyl chloride and D-phenylalanine to obtain crude type-B nateglinide crystal; dissolving the crude type-B nateglinide crystal in mixture solution comprising emthanol, amino methane and water in the volume ratio of 60 to 20 to 20; heating at 40-60 deg.c, decolorizing with active carbon in 2 % for 7-15 min, filtering, cooling to 10 deg.c to separate solid, filering, washing with 40 % concentration ethanol solution to neutral and drying to obtain nateglinide product in H-type crystal form while re-crystallizing the mother liquid to obtain also nateglinide product in H-type crystal form. The present invention has the features of high nateglinide yield, environment friendship, low production cost, etc.

Description

technical field

[0001] The invention relates to a preparation process of nateglinide, which belongs to the synthesis process of raw materials in the field of medicine and chemical industry. Background technique

[0002] Nateglinide is an effective drug for treating diabetes, and it has various crystal forms. In US4816484; US5488150 patents and published articles by Zhu Xueyan et al. The synthesis of nateglinide has been introduced in detail.

[0003] At present, the synthesis of nateglinide is based on 4-isopropylbenzoic acid as a starting material, and the mixture of cis-trans isomers of 4-isopropylcyclohexanecarboxylic acid is obtained through catalytic hydrogenation (ratio of cis-trans isomers is 3:1), the cis and trans isomers are separated to obtain trans-4-isopropylcyclohexanecarboxylic acid, and then reacted with thionyl chloride to obtain trans-4-isopropylcyclohexanecarbonyl chloride . Trans-4-isopropylcyclohexanecarbonyl chloride is acylated with D-phenylalanine...

Examples

Embodiment 1

[0016] Add 500ml of 0.5N sodium hydroxide solution, 35g of phenylalanine, 300ml of acetone, 50ml of aminomethane and keep stirring at 25°C in the reaction flask, then slowly drop trans-4-isopropylcyclohexanecarbonyl chloride into the reaction flask in the liquid. After dropping, lower the temperature to 15-18°C, adjust the pH to 2 with 1N hydrochloric acid, and filter and wash to neutral after crystallization. The crude product of nateglinide (type B) was obtained, and the crude product was heated and dissolved in 350 ml of methanol aminomethane solution (methanol: aminomethane: water = 60:20:20), and then decolorized by adding activated carbon. Filter and cool to 10°C with solid precipitation. Filter, wash with 40% ethanol until neutral, and dry. 46g of nateglinide (type H) was obtained. Mp138-140°C.

[0017] The mother liquor was concentrated and distilled under reduced pressure, filtered, dissolved in 50% ethanol, decolorized, and the filtrate was placed in a refrigerat...

Embodiment 2

[0019] 42 g of trans-4-isopropylcyclohexanecarbonyl chloride was dissolved in 100 ml of acetone. Take another reaction bottle and add 33g of D-phenylalanine, 100ml (0.1mol) of 1N sodium hydroxide, 50ml of aminomethane solution, stir, and add the above-mentioned acetone solution. Cool down to 10°C and react for 3 hours, adjust the pH to 2-3 with 1N hydrochloric acid, filter and wash until neutral to obtain 56 g of the crude product of type B, with a yield of 88%. The crude type B was dissolved in a solution of methanol:aminomethane:water=60:20:20. After dissolving, decolorize and filter, and crystallize out after cooling. After filtration, washing and drying, 44 g of the H-form product was obtained, with a yield of 78%.

Embodiment 3

[0021] Take 20g of D-phenylalanine, dissolve in 100ml of 10% sodium hydroxide, 100ml of acetone, and add 50ml of aminomethane. Add trans-4-isopropylcyclohexanecarbonyl chloride solution (25g dissolved in 60ml acetone) dropwise, cool to 5-10°C, and keep stirring for 30 minutes. Adjust with 10% sodium hydroxide solution, keep the pH of the reaction solution = 10, react for 2 hours, then acidify with 2N hydrochloric acid to pH = 2, filter and wash the crystals to obtain the crude product of type B, and dissolve the crude product of type B in methanol:aminomethane: Water=60:20:20 solution. After dissolving, decolorize and filter, and crystallize out after cooling. After filtration, washing and drying, 29 g of type H product was obtained with a yield of 81%.

technical field

[0001] The invention relates to a preparation process of nateglinide, which belongs to the synthesis process of raw materials in the field of medicine and chemical industry. Background technique

[0002] Nateglinide is an effective drug for treating diabetes, and it has various crystal forms. In US4816484; US5488150 patents and published articles by Zhu Xueyan et al. The synthesis of nateglinide has been introduced in detail.

[0003] At present, the synthesis of nateglinide is based on 4-isopropylbenzoic acid as a starting material, and the mixture of cis-trans isomers of 4-isopropylcyclohexanecarboxylic acid is obtained through catalytic hydrogenation (ratio of cis-trans isomers is 3:1), the cis and trans isomers are separated to obtain trans-4-isopropylcyclohexanecarboxylic acid, and then reacted with thionyl chloride to obtain trans-4-isopropylcyclohexanecarbonyl chloride . Trans-4-isopropylcyclohexanecarbonyl chloride is acylated with D-phenylalanine...

Examples

Embodiment 1

[0016] Add 500ml of 0.5N sodium hydroxide solution, 35g of phenylalanine, 300ml of acetone, 50ml of aminomethane and keep stirring at 25°C in the reaction flask, then slowly drop trans-4-isopropylcyclohexanecarbonyl chloride into the reaction flask in the liquid. After dropping, lower the temperature to 15-18°C, adjust the pH to 2 with 1N hydrochloric acid, and filter and wash to neutral after crystallization. The crude product of nateglinide (type B) was obtained, and the crude product was heated and dissolved in 350 ml of methanol aminomethane solution (methanol: aminomethane: water = 60:20:20), and then decolorized by adding activated carbon. Filter and cool to 10°C with solid precipitation. Filter, wash with 40% ethanol until neutral, and dry. 46g of nateglinide (type H) was obtained. Mp138-140°C.

[0017] The mother liquor was concentrated and distilled under reduced pressure, filtered, dissolved in 50% ethanol, decolorized, and the filtrate was placed in a refrigerat...

Embodiment 2

[0019] 42 g of trans-4-isopropylcyclohexanecarbonyl chloride was dissolved in 100 ml of acetone. Take another reaction bottle and add 33g of D-phenylalanine, 100ml (0.1mol) of 1N sodium hydroxide, 50ml of aminomethane solution, stir, and add the above-mentioned acetone solution. Cool down to 10°C and react for 3 hours, adjust the pH to 2-3 with 1N hydrochloric acid, filter and wash until neutral to obtain 56 g of the crude product of type B, with a yield of 88%. The crude type B was dissolved in a solution of methanol:aminomethane:water=60:20:20. After dissolving, decolorize and filter, and crystallize out after cooling. After filtration, washing and drying, 44 g of the H-form product was obtained, with a yield of 78%.

Embodiment 3

[0021] Take 20g of D-phenylalanine, dissolve in 100ml of 10% sodium hydroxide, 100ml of acetone, and add 50ml of aminomethane. Add trans-4-isopropylcyclohexanecarbonyl chloride solution (25g dissolved in 60ml acetone) dropwise, cool to 5-10°C, and keep stirring for 30 minutes. Adjust with 10% sodium hydroxide solution, keep the pH of the reaction solution = 10, react for 2 hours, then acidify with 2N hydrochloric acid to pH = 2, filter and wash the crystals to obtain the crude product of type B, and dissolve the crude product of type B in methanol:aminomethane: Water=60:20:20 solution. After dissolving, decolorize and filter, and crystallize out after cooling. After filtration, washing and drying, 29 g of type H product was obtained with a yield of 81%.