CN110922345B

CN110922345B - Synthesis method of fudosteine

Info

Publication number: CN110922345B
Application number: CN201911219657.6A
Authority: CN
Inventors: 韩浩吉; 王秋芬; 郑庚修; 高令峰; 张启龙
Original assignee: University of Jinan
Current assignee: University of Jinan
Priority date: 2019-12-03
Filing date: 2019-12-03
Publication date: 2021-06-11
Anticipated expiration: 2039-12-03
Also published as: CN110922345A

Abstract

The invention relates to a synthesis method of fudosteine, belonging to the field of biological medicine industry. Taking L-cysteine and acrolein as raw materials, carrying out Michael addition reaction in an acidic aqueous solution, then adding sodium borohydride for reduction, synthesizing fudosteine by a one-pot method, and recrystallizing to obtain high-purity fudosteine. The preparation method has mild and controllable reaction conditions, the product yield is 95 percent, and the liquid phase purity is 99.8 percent.

Description

Synthesis method of fudosteine

Technical Field

The invention relates to a synthesis method of high-purity fudosteine, belonging to the field of biological medicine industry.

Background

Fudosteine (Fudosteine), a cysteine derivative with expectorant effect, which is developed by Mitsubishi pharmaceutical corporation and S.S. pharmaceutical corporation and has a basic skeleton of Staten (steine), has multiple pharmacological effects on chronic respiratory diseases: inhibiting airway epithelial cell proliferation, normalizing trehalose/sialic acid ratio in phlegm, recovering cilium transport gas channel secretion state, and resisting inflammation; has the advantages of strong drug effect, small side effect, wide adaptation diseases, large market potential and the like, and is suitable for eliminating phlegm of chronic respiratory system diseases such as bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, emphysema, atypical mycobacterium infection, diffuse bronchiolitis and the like. Fudosteine, chemical name (-) - (R) -2-amino-3- (3-hydroxypropylthio) propanoic acid, molecular weight 179.24, CAS: 13189-98-5, molecular formula C₆H₁₃NO₃S, the structural formula is as follows:

。

the current methods for synthesizing fudosteine according to literature reports are mainly four:

(1) reacting L-cysteine with halopropanol under alkaline conditions

。

Chinese patent (CN 101851185) reports a method for synthesizing fudosteine by reacting L-cysteine with halopropanol under alkaline conditions. Compared with acrolein, the raw material of the high-purity halopropanol used in the method is expensive, the cost is increased, and inorganic salts generated by the reaction are difficult to mix with products. Refining for many times, reducing the yield of fudosteine and being not suitable for industrial production.

(2) Reaction of L-cysteine with allyl alcohol

。

Chinese patents (CN 103113273A, CN 105968035A) and the like adopt L-cysteine and allyl alcohol as raw materials to synthesize fudosteine under the condition of free radical initiators such as light or peroxide and the like. The salt impurities obtained in the product by the method are more, and the quality risk exists.

(3) Reaction of L-cysteine with Oxetane

。

Chinese patent (CN 105461603A) reports a method for synthesizing fudosteine by taking L-cysteine and oxetane as raw materials and heating to promote reaction under alkaline conditions, wherein the method needs strong acid to adjust the pH value, has long reaction time and is complex to operate.

(4) Reaction of L-cysteine with halopropyl acetate

。

In Chinese patent (CN 108586298A), L-cysteine and halopropyl acetate are used as raw materials, strong acid is needed to adjust the pH value in the reaction process, the dosage of an extraction solvent is large, and the halopropyl acetate is expensive, so that the cost is increased.

Disclosure of Invention

Aiming at the defects in the preparation of fudosteine, the invention provides a method for synthesizing high-purity fudosteine by a one-pot method, which has the advantages of simple process, mild and controllable reaction conditions.

The technical scheme of the invention is a method for synthesizing fudosteine, which is characterized in that L-cysteine and acrolein are used as raw materials, and the raw materials are subjected to Michael addition and sodium borohydride is added in a one-pot method to reduce and synthesize the fudosteine.

The invention discloses a more detailed method for preparing fudosteine, which comprises the following steps:

(1) michael addition reaction: at the temperature of 25-35 ℃, taking L-cysteine into a four-mouth bottle, adding water, dropwise adding acid under mechanical stirring, dropwise adding acrolein after dropwise adding, continuously stirring for a period of time, and controlling the liquid phase until the reaction is finished.

(2) Reduction reaction: adding metered sodium borohydride into the system, and stirring at 15-25 ℃ until the reaction is finished. Concentrating the solvent to obtain crude fudosteine, and recrystallizing with ethanol water solution to obtain high-purity fudosteine.

In the invention, preferably, the acid in the addition reaction is acetic acid; the pH value range is 3.0-3.5.

According to the invention, the molar ratio of L-cysteine to acrolein is preferably from 1:1.5 to 2.0.

According to the invention, the mol ratio of L-cysteine to sodium borohydride in the reduction reaction is preferably 1: 0.8-1.

According to the invention, the addition reaction temperature is preferably 25-35 ℃; the reduction reaction temperature is 15-25 ℃.

The invention has the beneficial effects that: the L-cysteine and the acrolein are used as raw materials, the cost is low, the process is simple, the reaction condition is mild and controllable, the L-cysteine and the acrolein are synthesized by a one-pot method, the yield is 95%, and the purity is 99.8%; chinese patent (CN 101851185) reports that in the method for synthesizing fudosteine by taking L-cysteine and 3-chloro-1-propanol as raw materials, the yield is only 90%, and the purity is 99%.

Detailed Description

Example 1:

adding L-cysteine (24.2 g, 0.2 mol) into a 250 mL four-mouth bottle at 25-35 ℃, adding 60 mL of water, dropwise adding acetic acid under mechanical stirring, adjusting the pH =3.2, reacting for 1 h, dropwise adding acrolein (16.8 g, 0.3 mol) into the system, reacting for 10 h after the dropwise adding is finished, and controlling the liquid phase until the reaction is finished; adding sodium borohydride (7.6 g, 0.2 mol) into the system in batches at 15-25 ℃, continuously stirring for 2 h, adjusting the pH value to be =6 by using a NaOH solution, and concentrating a solvent to obtain a crude product fudosteine; and adding 300 mL of ethanol water solution in a certain proportion into the crude product, heating to 45 ℃, completely dissolving and stirring for 30 min, cooling at room temperature, stirring for 30 min, filtering, leaching a filter cake with ethanol, and drying the filter cake to obtain 34.3g of refined fudosteine with the purity of 99.7% and the yield of 95.8%.

Example 2:

adding L-cysteine (24.2 g, 0.2 mol) into a 250 mL four-mouth bottle at 25-35 ℃, adding 60 mL of water, dropwise adding acetic acid under mechanical stirring, adjusting the pH =3.2, reacting for 1 h, dropwise adding acrolein (22.4 g, 0.4 mol) into the system, reacting for 10 h after the dropwise adding is finished, and controlling the liquid phase until the reaction is finished; adding sodium borohydride (7.6 g, 0.2 mol) into the system in batches at 15-25 ℃, continuously stirring for 2 h, adjusting the pH value to be =6 by using a NaOH solution, and concentrating a solvent to obtain a crude product fudosteine; and adding 300 mL of ethanol water solution in a certain proportion into the crude product, heating to 45 ℃, completely dissolving and stirring for 30 min, cooling at room temperature, stirring for 30 min, filtering, leaching a filter cake with ethanol, and drying the filter cake to obtain 33.8g of refined fudosteine with the purity of 99.8% and the yield of 94.4%.

Example 3:

adding L-cysteine (24.2 g, 0.2 mol) into a 250 mL four-mouth bottle at 25-35 ℃, adding 60 mL of water, dropwise adding acetic acid under mechanical stirring, adjusting the pH =3.2, reacting for 1 h, dropwise adding acrolein (19.6 g, 0.35 mol) into the system, reacting for 10 h after dropwise adding, and controlling the liquid phase until the reaction is finished; adding sodium borohydride (7.6 g, 0.2 mol) into the system in batches at 15-25 ℃, continuously stirring for 2 h, adjusting the pH value to be =6 by using a NaOH solution, and concentrating a solvent to obtain a crude product fudosteine; and adding 300 mL of ethanol water solution in a certain proportion into the crude product, heating to 45 ℃, completely dissolving and stirring for 30 min, cooling at room temperature, stirring for 30 min, filtering, leaching a filter cake with ethanol, and drying the filter cake to obtain 34.5g of refined fudosteine with the purity of 99.8% and the yield of 96.3%.

Example 4

Adding L-cysteine (24.2 g, 0.2 mol) into a 250 mL four-mouth bottle at 25-35 ℃, adding 60 mL of water, dropwise adding acetic acid under mechanical stirring, adjusting the pH =3.2, reacting for 1 h, dropwise adding acrolein (19.6 g, 0.35 mol) into the system, reacting for 10 h after dropwise adding, and controlling the liquid phase until the reaction is finished; adding sodium borohydride (6.1 g, 0.16 mol) into the system in batches at 15-25 ℃, continuously stirring for 2 h, adjusting the pH value to be =6 by using a NaOH solution, and concentrating a solvent to obtain a crude product fudosteine; and adding 300 mL of ethanol water solution in a certain proportion into the crude product, heating to 45 ℃, completely dissolving and stirring for 30 min, cooling at room temperature, stirring for 30 min, filtering, leaching a filter cake with ethanol, and drying the filter cake to obtain 34.0g of refined fudosteine with the purity of 99.7% and the yield of 95.0%.

Example 5

Adding L-cysteine (24.2 g, 0.2 mol) into a 250 mL four-mouth bottle at 25-35 ℃, adding 60 mL of water, dropwise adding acetic acid under mechanical stirring, adjusting the pH =3.2, reacting for 1 h, dropwise adding acrolein (19.6 g, 0.35 mol) into the system, reacting for 10 h after dropwise adding, and controlling the liquid phase until the reaction is finished; adding sodium borohydride (6.8 g, 0.18 mol) into the system in batches at 15-25 ℃, continuously stirring for 2 h, adjusting the pH value to be =6 by using a NaOH solution, and concentrating a solvent to obtain a crude product fudosteine; and adding 300 mL of ethanol water solution in a certain proportion into the crude product, heating to 45 ℃, completely dissolving and stirring for 30 min, cooling at room temperature, stirring for 30 min, filtering, leaching a filter cake with ethanol, and drying the filter cake to obtain 34.2g of refined fudosteine with the purity of 99.8% and the yield of 95.6%.

Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Claims

1. The synthesis method of fudosteine comprises the following steps:

a, addition reaction: adding acid into the aqueous solution to adjust the pH value to a certain range, and carrying out addition reaction on L-cysteine and acrolein to obtain an intermediate F-1, wherein the acid in the addition reaction is acetic acid; the pH value range is 3.0-3.5, and the molar ratio of the L-cysteine to the acrolein is 1: 1.5-2.0;

b, reduction reaction: and reducing the F-1 by sodium borohydride to obtain fudosteine, wherein the molar ratio of the sodium borohydride to the L-cysteine in the reduction reaction is 1: 0.8-1.