A kind of preparation method of fodosteine

A technology of fudosteine ​​and cysteine, which is applied in the field of medicine, can solve the problems of short reaction time, low purity, and easy residual heavy metals, and achieve the effects of mild reaction conditions, simple process, and high atom utilization rate

Active Publication Date: 2018-04-17
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] For example, Chinese patent 200510059733.3 adopts this method to prepare fudosteine ​​with L-cysteine ​​and propenyl alcohol under thermally induced conditions. Although this process is relatively simple, the product has many impurities and low purity (≤95%). The yield is also low (70-80%); Chinese patent application 200910244823.8 uses microwave method to synthesize fudosteine, the method has short reaction time and high yield, but microwave method is not suitable for industrial production; Synthesis of the drug fudosteine" and others used ultraviolet light catalyzed free radical reaction to prepare fudosteine. The synthesis conditions of this method are mild and the product yield is high, but the photoreaction also has the problem of being difficult to industrialize; Chinese patent 201310040183.5 uses metal Catalytic synthesis of fudosteine ​​with peroxide, this method has the characteristics of high yield and high product purity, but it is easy to leave heavy metals, resulting in excessive heavy metals in the product

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] At room temperature, dissolve 20 g of L-cysteine ​​in 200 mL of water, add 7.2 g of sodium hydroxide, stir for 1 hour, cool to 0-10°C, and add 12.5 g of oxetane dropwise to the reaction system After dripping and raising to room temperature and stirring for 2 hours, heating to 40-50°C and stirring for 6 hours, cooling to room temperature, adjusting pH to 6 with 6mol / L hydrochloric acid, distillation under reduced pressure to 1 / 10 of the original volume, and heating to 80°C Hot filter, slowly add 600mL of 95% ethanol to the filtrate, after the addition, cool to 0-10℃ and stir for 2 hours, filter, rinse the filter cake with 30mL of ethanol, and dry with air blow at 40-50℃ to obtain 29.0g of crude product. Add the obtained crude product to a 1000ml four-necked flask, add 570mL of 20% ethanol aqueous solution, heat up to 50-60℃, and after all is dissolved, gradually reduce the temperature to room temperature and stir for 1h, reduce the temperature to 0-10℃, stir for 2h, filter...

Embodiment 2

[0023] At room temperature, dissolve 20 g of L-cysteine ​​in 200 mL of water, add 4.0 g of sodium hydroxide, stir for 1 hour, cool to 0-10°C, and add 19.2 g of oxetane dropwise to the reaction system After dripping, raise to room temperature and stir for 2 hours, warm to 40-50°C and stir for 8 hours, cool to room temperature, adjust pH to 6 with 6mol / L hydrochloric acid, distill under reduced pressure to 1 / 10 of the original volume, and warm to 80°C Hot filter, slowly add 600mL of 95% ethanol to the filtrate, after the addition, cool to 0-10℃ and stir for 2 hours, filter, rinse the filter cake with 30mL of ethanol, and dry with air at 40-50℃ to obtain 27.9g of crude product. Add the obtained crude product to a 1000ml four-necked flask, add 550mL of 15% ethanol aqueous solution, heat up to 50-60℃, and after all is dissolved, gradually reduce the temperature to room temperature and stir for 1h, reduce the temperature to 0-10℃, stir for 2h, filter, 40 Air-dried at -50°C to constan...

Embodiment 3

[0025] At room temperature, dissolve 20g of L-cysteine ​​in 100mL of water, add 9.0g of sodium hydroxide, stir for 1 hour, cool to 0-10°C, and add 10.5g of oxetane dropwise to the reaction system After dripping and raising to room temperature and stirring for 2 hours, heating to 40-50°C and stirring for 5 hours, cooling to room temperature, adjusting pH to 6 with 6mol / L hydrochloric acid, distillation under reduced pressure to 1 / 6 of the original volume, and heating to 85°C Hot filter, slowly add 300mL 95% ethanol to the filtrate, cool to 0-10°C and stir for 2 hours after addition, filter, rinse the filter cake with 30mL ethanol, and dry with air blow at 40-50°C to obtain 28.4g crude product. Add the obtained crude product to a 1000ml four-necked flask, add 560mL 30% ethanol aqueous solution, heat up to 50-60℃, and after all is dissolved, gradually reduce the temperature to room temperature and stir for 1h, reduce the temperature to 0-10℃, stir for 2h, filter, 40 Air-dried at -...

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Abstract

The invention relates to a preparation method of fudosteine, which comprises the following steps: by using L-cysteine and trimethylene oxide as raw materials, heating under alkaline conditions to promote the completion of the reaction, adding 95% ethanol into the product to precipitate, and recrystallizing to obtain the fine product fudosteine, wherein the product yield is greater than or equal to 90%, the HPLC (high performance liquid chromatography) purity is greater than or equal to 99.5%, and the maximum single impurity content is less than or equal to 0.1%. The whole process is easy to control, simple to operate and suitable for industrial production, and is a synthesis route capable of satisfying the demands of the market for fudosteine active pharmaceutical ingredients.

Description

Technical field [0001] The invention relates to a preparation method of Fudosteine, belonging to the technical field of medicine. Background technique [0002] Fudosteine, chemical name: (-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid, developed by Mitsubishi Pharmaceutical Co., Ltd. and SSP Pharmaceutical Co., Ltd., in 2001 It was first launched in Japan in October. It is a cysteine ​​derivative that has multiple pharmacological effects on chronic respiratory diseases: inhibiting the excessive secretion of airway mucus, inhibiting the excessive formation of goblet cells; having mucus repairing effects; serous airway hypersecretion and anti-inflammatory effects. Due to its strong efficacy, low side effects, wide indications and great market potential, Fudosteine ​​will become the first choice for the expectorant of chronic respiratory diseases. [0003] At present, the synthetic methods of this compound are mainly divided into two types: [0004] (1) Under alkaline condition...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C319/14C07C323/58
CPCC07C319/14C07C323/58
Inventor 王宁宁苗华明梁松军何田
Owner 迪嘉药业集团股份有限公司
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