阅读说明：本技术 一种***二酚的合成方法 (Method for synthesizing cannabidiol ) 是由 朱常成 席亮 尹子丽 金毅 廖荣 李之恒 甘昌敏 杨金芳 谢富兰 于 2020-07-16 设计创作，主要内容包括：本发明属于化学制药领域,具体公开一种大麻二酚的合成制备方法,包括如下步骤：S1,以2,4-二甲氧基-6-戊基苯甲酸甲酯为原料,在路易斯酸的催化条件下与(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇进行偶联反应得到中间体(I)；S2,将制备得到的中间体(I)在强碱的作用下高温脱羧,制备得到中间体(II)；S3,将制备得到的中间体(II)在三溴化硼的作用下脱出甲基得到最终产物大麻二酚。本发明所得到的大麻二酚的纯度为99.90—99.99%；最后制得的合格纯度原料药时总产率最高可达60～80％,工艺明显提高,其具有很好的工业应用前景。(The invention belongs to the field of chemical pharmacy, and particularly discloses a method for synthesizing cannabidiol, which comprises the following steps: s1, taking methyl 2, 4-dimethoxy-6-pentylbenzoate as a raw material, and carrying out coupling reaction with (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol under the catalysis of Lewis acid to obtain an intermediate (I); s2, decarboxylating the prepared intermediate (I) at high temperature under the action of strong alkali to prepare an intermediate (II); s3, removing methyl from the prepared intermediate (II) under the action of boron tribromide to obtain the final product, namely the cannabidiol. The purity of the cannabidiol obtained by the invention is 99.90-99.99%; the total yield of the finally prepared raw material medicine with qualified purity can reach 60-80% at most, the process is obviously improved, and the method has good industrial application prospect.)

1. The method for synthesizing cannabidiol is characterized by comprising the following steps:

s1, taking methyl 2, 4-dimethoxy-6-pentylbenzoate as a raw material, and carrying out coupling reaction with (1S, 4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol under the catalysis of Lewis acid to obtain an intermediate (I);

s2, decarboxylating the prepared intermediate (I) at high temperature under the action of strong alkali to prepare an intermediate (II);

s3, removing methyl from the prepared intermediate (II) under the action of boron tribromide to obtain the final product, namely the cannabidiol.

2. The method of claim 1, wherein the step of S1 comprises the steps of:

s11, carrying out a coupling reaction on the raw material methyl 2, 4-dimethoxy-6-pentylbenzoate and (1S, 4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-ol under the catalysis of boron trifluoride diethyl etherate;

s12, wherein the reaction solvent is one of DMF, dichloromethane or tetrahydrofuran;

s13, the acid used in the post-reaction treatment is one of hydrochloric acid, sulfuric acid or acetic acid.

The method of claim 1, wherein the step of S2 comprises the steps of:

s21, the alkali used in the reaction is: one of sodium hydroxide, potassium hydroxide or potassium carbonate;

s22, heating the reaction at 60-200 ℃.

4. The method of claim 1, wherein the step of S3 comprises the steps of:

s31, the solvent used in the reaction is: one of ethyl acetate, dichloromethane, tetrahydrofuran or toluene;

s32, the alkali used in the reaction is: one of sodium hydroxide, potassium hydroxide or potassium carbonate;

s33, the solvent for recrystallization is: at least one of methanol, ethanol or acetone.

5. Cannabidiol prepared according to any of the methods of claims 1-4.

6. A pharmaceutical composition comprising the cannabidiol of claim 5.

7. Use of cannabidiol as claimed in claim 5 as active ingredient in the manufacture of a medicament for the treatment of epilepsy, rheumatoid arthritis, insomnia, cancer.

8. Use of cannabidiol as claimed in claim 5 as an active ingredient in the manufacture of a daily use product or health product.

Technical Field

The invention belongs to the field of chemical pharmacy, and particularly relates to a method for synthesizing cannabidiol.

Background

Cannabis has been used in traditional medicine for thousands of years and first introduced to western medicine in the 30's 19 th century. The initial uses were analgesic, sedative, anti-inflammatory, antispasmodic and anticonvulsant effects. After more than 100 years, cannabis has shifted from the drugs listed for medical treatment to narcotic drugs due to concerns about its safety, and was classified as a drug of appendix I in the United states before 1970, which means that it has not been accepted for medical use.

Cannabidiol is also called levo-trans-Cannabidiol, and is called (-) -Cannabdiol, and is a very valuable raw material medicine, and the structural formula of the compound is as follows:

at present, cannabidiol is mainly applied to nerve protection, spasm resistance, inflammation resistance, anxiety resistance and the like. In 2015, uk GW biopharmaceutical company announced: the clinical trial data of the pure cannabidiol for the intractable child epilepsy is updated, the medicine has been approved by the US FDA rare disease medicine and the fast channel approval in 2014, and is used for treating the infant severe myoclonic epilepsy, so that the market prospect of the medicine becomes wider. Low cost, high efficiency and simple operation, is suitable for industrial production, and has great promotion effect on the application of cannabidiol.

US20090036523a1 uses olive alcohol as a starting material, and uses p-toluenesulfonic acid for catalysis, and obtains a target product by a one-step method, which specifically comprises the following steps:

however, the reaction system is complex, has more isomers and dimers, is troublesome in post-treatment, needs column chromatography for purification, has low yield of only 24 percent, and is not suitable for large-scale production.

WO2006053766A1 utilizes zinc chloride catalysis to synthesize the target product. This document reports a process for obtaining the product without column purification, but the product purity is only 97.1% and the yield is only 22%. Repeated experiments are carried out on the document to find that the maximum single impurity in the reaction process is a dimer and reaches more than 20%, and the impurity can be reduced to be within 0.1% by more than 3 times of crystallization (meeting the requirement of the index of the raw material medicine). Finally, the total yield of the qualified raw material medicine is only 13%, and the process cost is high.

US20100298579a1 starts from methyl 2, 4-dihydroxy-6-pentanenylbenzoate and catalyzes the preparation of the coupled methyl ester intermediate (I) with boron trifluoride in diethyl etherate in slightly higher purity than the one-step process, and with significantly less isomers and dimers than the one-step process. However, after the coupling, the methyl ester intermediate is still only about 75% pure after acid-base treatment, and the melting point of the compound is possibly low, so that the compound cannot be crystallized (the intermediate I is not reported to have a melting point, and cannot be precipitated into a solid finally even if the intermediate I with the purity of 98% obtained by column chromatography is crystallized). The methyl ester intermediate I cannot be recrystallized and purified by a conventional method, so that the requirements of chemical purity and single impurity index of a key intermediate serving as a raw material medicament cannot be met.

In addition to the above two chemical synthesis methods, some documents report that cannabidiol is obtained by biological extraction, but the steps of the methods are complicated, and the industrial production is limited too much.

Disclosure of Invention

The present invention mainly aims to solve the above technical problems and provide a method for synthesizing cannabidiol.

The purpose of the invention is realized by the following technical scheme:

a method for synthesizing cannabidiol, the reaction formula of which is shown as follows,

The method comprises the following steps:

s1, taking methyl 2, 4-dimethoxy-6-pentylbenzoate as a raw material, and carrying out coupling reaction with (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol under the catalysis of Lewis acid to obtain an intermediate (I).

S2, decarboxylating the prepared intermediate (I) at high temperature under the action of strong alkali (such as potassium hydroxide) to prepare an intermediate (II);

s3, removing methyl from the prepared intermediate (II) under the action of boron tribromide to obtain the final product, namely the cannabidiol.

Preferably, the S1 includes the following steps:

s11, carrying out a coupling reaction on the raw material methyl 2, 4-dimethoxy-6-pentylbenzoate and (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-ol under the catalysis of boron trifluoride diethyl etherate;

s12, the reaction solvent is preferably one of DMF, dichloromethane and tetrahydrofuran;

s13, the acid used for the post-reaction treatment is preferably one of hydrochloric acid, sulfuric acid and acetic acid.

Preferably, the S2 includes the following steps:

s21, the base used in the reaction is preferably: one of sodium hydroxide, potassium hydroxide and potassium carbonate;

s22, the reaction heating temperature is preferably 60-200 ℃;

s23, the crude product of the intermediate (II) is a key intermediate for synthesizing the high-purity cannabidiol product through solvent recrystallization.

Preferably, the S3 includes the following steps:

s31, the solvent used for the reaction is preferably: one of ethyl acetate, dichloromethane, tetrahydrofuran and toluene;

s32, the base used in the reaction is preferably: one of sodium hydroxide, potassium hydroxide and potassium carbonate;

s33, the solvent for recrystallization is preferably: at least one solvent selected from methanol, ethanol and acetone; cannabidiol prepared by any of the above methods.

A pharmaceutical composition comprises cannabidiol obtained by the above preparation method.

The cannabidiol obtained by the preparation method is used as an active ingredient for preparing medicines for treating epilepsy, rheumatoid arthritis, insomnia and cancer.

The cannabidiol obtained by the preparation method is used as an active ingredient in the preparation of daily necessities or health care products.

The invention has the beneficial effects that: the raw materials and reagents in the method are low in price and easy to obtain commercially, and the cannabidiol with high yield and high quality can be obtained through three steps of coupling, decarboxylation and demethylation. The intermediate of each step of the process can be purified by recrystallization, the single impurity can reach the index of the intermediate of the raw material medicine, and the purity of the cannabidiol obtained by the invention is 99.90-99.99%; the total yield of the finally prepared raw material medicine with qualified purity can reach 60-80% at most, the process is obviously improved, and the method has good industrial application prospect.

Drawings

FIG. 1 schematic representation of the cannabidiol reaction scheme.

Detailed Description

The method of the present invention is described below with reference to specific examples to make it easier to understand and understand the technical solution of the present invention, but the present invention is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available without special instructions, and the reagents are purchased in analytical purity.

A method for synthesizing cannabidiol, the reaction formula of which is shown as follows,

the method comprises the following steps:

s1, taking methyl 2, 4-dimethoxy-6-pentylbenzoate as a raw material, and carrying out coupling reaction with (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol under the catalysis of Lewis acid to obtain an intermediate (I).

S2, decarboxylating the prepared intermediate (I) at high temperature under the action of strong alkali (such as potassium hydroxide) to prepare an intermediate (II);

s3, removing methyl from the prepared intermediate (II) under the action of boron tribromide to obtain the final product, namely the cannabidiol.