Preparation method of fudosteine

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

Active Publication Date: 2016-04-06
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 heat-initiated 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" etc. used ultraviolet light catalyzed free radical reaction to prepare fudosteine. This method has mild synthesis conditions and high product yield, 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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Examples

Experimental program
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Effect test

Embodiment 1

[0022] At room temperature, dissolve 20g of L-cysteine ​​in 200mL of water, add 7.2g of sodium hydroxide, stir for 1 hour, cool down to 0-10°C, and drop 12.5g of oxetane into the reaction system , after dropping, rise to room temperature and stir for 2 hours, heat up to 40-50°C and stir for 6 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 heat up to 80°C Filtrate hot, slowly add 600mL of 95% ethanol to the filtrate, cool down to 0-10°C and stir for 2 hours after addition, filter, rinse the filter cake with 30mL of ethanol, blow dry at 40-50°C until constant weight to obtain 29.0g of crude product. Add the obtained crude product into a 1000ml four-neck flask, add 570mL of 20% ethanol aqueous solution, heat up to 50-60°C, after all dissolve, gradually cool down to room temperature and stir for 1h, cool down to 0-10°C, stir for 2h, filter, 40 Blast drying at -50°C to constant weight...

Embodiment 2

[0024] At room temperature, dissolve 20g of L-cysteine ​​in 200mL of water, add 4.0g of sodium hydroxide, stir for 1 hour, cool down to 0-10°C, and drop 19.2g of oxetane into the reaction system , dropwise rise to room temperature and stir for 2 hours, heat up 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, heat up to 80°C After hot filtration, slowly add 600mL of 95% ethanol to the filtrate, cool down to 0-10°C and stir for 2 hours after addition, filter, rinse the filter cake with 30mL of ethanol, and blow dry at 40-50°C until constant weight to obtain 27.9g of crude product. Add the obtained crude product into a 1000ml four-neck flask, add 550mL of 15% ethanol aqueous solution, heat up to 50-60°C, after all dissolve, gradually cool down to room temperature and stir for 1h, cool down to 0-10°C, stir for 2h, filter, 40 Blast drying at -50°C to constant weigh...

Embodiment 3

[0026] At room temperature, dissolve 20g of L-cysteine ​​in 100mL of water, add 9.0g of sodium hydroxide, stir for 1 hour, cool down to 0-10°C, and drop 10.5g of oxetane into the reaction system , dropwise rise to room temperature and stir for 2 hours, heat up to 40-50°C and stir for 5 hours, cool to room temperature, adjust pH to 6 with 6mol / L hydrochloric acid, distill under reduced pressure to 1 / 6 of the original volume, heat up to 85°C After hot filtration, slowly add 300mL of 95% ethanol to the filtrate, cool down to 0-10°C and stir for 2 hours after addition, filter, rinse the filter cake with 30mL of ethanol, blow dry at 40-50°C until constant weight to obtain 28.4g of crude product. Add the obtained crude product into a 1000ml four-neck flask, add 560mL of 30% ethanol aqueous solution, heat up to 50-60°C, after all dissolve, gradually cool down to room temperature and stir for 1h, cool down to 0-10°C, stir for 2h, filter, 40 Blast drying at -50°C to constant weight yie...

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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, which belongs 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 Launched in Japan for the first time in October. As a cysteine ​​derivative, it has multiple pharmacological effects on chronic respiratory diseases: inhibiting the excessive secretion of airway mucus, inhibiting the excessive formation of goblet cells; it has the effect of mucus repair; the effect of hypersecretion of serous airway and anti-inflammation. Due to its strong efficacy, few side effects, wide indications and great market potential, fudosteine ​​will become the first choice drug for expectorant in chronic respiratory diseases. [0003] At present, the synthesis method of this compound is mainly divided into two kinds: [0004] (1)...

Claims

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Application Information

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Patent Type & Authority Applications(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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