阅读说明：本技术 一种槟榔碱的合成方法 (Method for synthesizing arecoline ) 是由 董万荣 孙慧娟 杨波勇 郇利刚 张雷雷 于 2020-12-30 设计创作，主要内容包括：本发明公开了一种槟榔碱的合成方法。该合成方法以3-溴丙酸甲酯为起始原料,依次经甲醇钠克莱森酯缩合,甲胺关环,硼氢化钠还原以及碱性条件下脱水,得到槟榔碱。本发明使用3-溴丙酸甲酯和甲胺醇溶液为原料,避免N甲基化步骤使用成本高的碘甲烷或者剧毒品硫酸二甲酯,从源头上控制安全问题。(The invention discloses a method for synthesizing arecoline. The synthesis method comprises the steps of using 3-bromomethyl propionate as a starting material, and sequentially carrying out sodium methoxide claisen ester condensation, methylamine cyclization, sodium borohydride reduction and dehydration under an alkaline condition to obtain the arecoline. The invention uses methyl 3-bromopropionate and methylamine alcohol solution as raw materials, avoids using methyl iodide or highly toxic dimethyl sulfate with high cost in the N methylation step, and controls the safety problem from the source.)

1. A method for synthesizing arecoline is characterized by comprising the following steps:

1) taking 3-bromomethyl propionate as a starting material, and refluxing in a methanol solution of sodium methoxide to perform claisen ester condensation reaction to obtain a compound M1;

2) under the catalysis of KI, reacting a compound M1 with methylamine to close a ring to obtain a compound M2;

3) reducing the compound M2 by sodium borohydride to obtain a compound M3;

4) dehydrating a compound M3 under an alkaline condition by taking methanol as a solvent to obtain arecoline;

2. the method for synthesizing arecoline according to claim 1, wherein the reaction temperature in step 2) is 35-45 ℃.

3. The method for synthesizing arecoline according to claim 1, wherein the reaction temperature in step 3) is 0-10 ℃.

4. The method for synthesizing arecoline according to claim 1, wherein the alkaline condition of step 3) is sodium hydroxide or sodium methoxide.

5. The method for synthesizing arecoline according to any one of claims 1 to 4, comprising the steps of:

1) heating, refluxing and reacting 3-bromomethyl propionate and sodium methoxide for 5-6 hours by using methanol as a solvent, cooling after the reaction is finished, dropwise adding formic acid, and filtering out impurities to obtain a methanol solution of M1;

2) adding methylamine and a catalyst KI into the methanol solution of M1 in the step 1), reacting for 7-8 hours at 35-45 ℃, and carrying out post-treatment to obtain a compound M2;

3) adding the compound M2 into a solvent methanol, adding sodium borohydride in batches, controlling the temperature to be 0-10 ℃, reacting for 1-3 hours, and carrying out aftertreatment to obtain a compound M3;

4) adding the compound M3 and sodium hydroxide or sodium methoxide into solvent methanol for reflux reaction for 6-8 hours, and carrying out post-treatment to obtain the compound arecoline.

6. The method for synthesizing arecoline according to claim 5, wherein the post-treatment of step 2) is: and after the reaction is finished, cooling to 10-20 ℃, adding water, extracting with dichloromethane, washing, and distilling under reduced pressure to obtain a compound M2.

7. The method for synthesizing arecoline according to claim 5, wherein the post-treatment of step 3) is: quenching with 8-15% dilute hydrochloric acid, adding water, extracting with dichloromethane, washing, drying, and distilling under reduced pressure to obtain compound M3.

8. The method for synthesizing arecoline as claimed in claim 5, wherein methanol is distilled off and new methanol is added during the reaction of step 4).

9. The method for synthesizing arecoline according to claim 5, wherein the post-reaction treatment in step 4) is: cooling to 10-20 deg.C after reaction, stirring, filtering to remove impurities, and distilling under reduced pressure to obtain arecoline.

Technical Field

The invention relates to a method for synthesizing arecoline, belonging to the technical field of organic synthesis.

Background

Arecoline with the chemical name of 1,2,5, 6-tetrahydro-1-methyl-3-picolinic acid methyl ester is a compound with great medicinal value. Arecoline is a cholinomimetic drug, can reduce pupil size and intraocular pressure, and can be used for treating glaucoma. The arecoline has stronger paralysis effect on tapeworm muscles, so that the tapeworm muscles lose the ability of climbing the intestinal wall, and in addition, the medicament has a muscarinic effect on a host, so that the intestinal peristalsis is strengthened, the secretion of a chemical book from digestive glands is increased, and the rapid elimination of the paralytic worm is facilitated.

US2506458A describes the synthesis of arecoline by using 3, 3-iminodipropionitrile as raw material and through methylation, hydrolysis, ester condensation and reduction (using catalyst PtO)₂) And refining to obtain arecoline, wherein the synthetic route is shown as follows. The synthesis method has the advantages of insufficient market supply of raw materials, expensive reduced catalyst, high hydrogenation risk and poor controllability.

In addition, most routes at home and abroad take nicotinic acid as a starting material, methyl iodide or dimethyl sulfate is taken as a methylating agent after esterification, and arecoline is prepared by reduction and refining of sodium borohydride or sodium borohydride acetate, wherein the synthetic route is shown as follows. The methyl iodide used in the synthesis method has high toxicity and price, dimethyl sulfate is extremely toxic, the yield of the reduction step is only about 30%, and the yield of the single step is too low.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a method for synthesizing arecoline. The synthesis method comprises the steps of using 3-bromomethyl propionate as a starting material, and sequentially carrying out sodium methoxide claisen ester condensation, methylamine cyclization, sodium borohydride reduction and dehydration under an alkaline condition to obtain the arecoline. The invention uses methyl 3-bromopropionate and methylamine alcohol solution as raw materials, avoids using methyl iodide or highly toxic dimethyl sulfate with high cost in the N methylation step, and controls the safety problem from the source.

The technical scheme of the invention is as follows: a method for synthesizing arecoline is characterized in that,

1) taking 3-bromomethyl propionate (SM1) as a starting material, refluxing in a methanol solution of sodium methoxide to perform a claisen ester condensation reaction to obtain a compound M1;

2) under the catalysis of KI, reacting a compound M1 with methylamine to close a ring to obtain a compound M2;

3) reducing the compound M2 by sodium borohydride to obtain a compound M3;

4) dehydrating compound M3 under alkaline condition with methanol as solvent to obtain arecoline (M4).

The reaction temperature of the step 2) is 35-45 ℃. The reaction temperature of the step 3) is 0-10 ℃.

The alkali adopted under the alkaline condition is sodium hydroxide or sodium methoxide.

The reaction equation is as follows:

the method specifically comprises the following steps:

1) heating, refluxing and reacting 3-bromomethyl propionate and sodium methoxide for 5-6 hours by using methanol as a solvent, cooling after the reaction is finished, dropwise adding formic acid, and filtering out impurities to obtain a methanol solution of M1;

2) adding methylamine and a catalyst KI into the methanol solution of M1 in the step 1), reacting for 7-8 hours at 35-45 ℃, and carrying out post-treatment to obtain a compound M2;

3) adding the compound M2 into a solvent methanol, adding sodium borohydride in batches, controlling the temperature to be 0-10 ℃, reacting for 1-3 hours, and carrying out aftertreatment to obtain a compound M3;

4) adding the compound M3 and sodium hydroxide or sodium methoxide into solvent methanol for reflux reaction for 6-8 hours, and carrying out post-treatment to obtain the compound arecoline.

Preferably, the molar ratio of the methyl 3-bromopropionate in the step 1) to the sodium methoxide to the formic acid is 1:1.0-1.5: 1.0-1.5.

Preferably, the molar ratio of the methyl 3-bromopropionate in the step 2) to the methylamine is 1:0.9-1.1, and the KI is used in a catalytic amount, so that the catalytic effect can be realized.

Preferably, the molar ratio of the compound M2 in the step 3) to the sodium borohydride is 1: 1.2-2.0.

Preferably, the molar ratio of the compound M3 in the step 4) to sodium hydroxide or sodium methoxide is 1: 1.0-1.5.

The post-treatment of the step 2) comprises the following steps: and after the reaction is finished, cooling to 10-20 ℃, adding water, extracting with dichloromethane, washing, and distilling under reduced pressure to obtain a compound M2.

The post-treatment of the step 3) comprises the following steps: quenching with 8-15% dilute hydrochloric acid, adding water, extracting with dichloromethane, washing, drying, and distilling under reduced pressure to obtain compound M3.

During the reaction of said step 4), methanol is distilled off and new methanol is added. The post-reaction treatment is as follows: cooling to 10-20 deg.C after reaction, stirring, filtering to remove impurities, and distilling under reduced pressure to obtain arecoline.

The invention has the beneficial effects that:

1) the invention uses methyl 3-bromopropionate and methylamine alcohol solution as raw materials, avoids using methyl iodide or highly toxic dimethyl sulfate with high cost in the N methylation step, and controls the safety problem from the source.

2) The preparation method is simple, the product purity is high (more than or equal to 99 percent), the yield is high (more than or equal to 55 percent), and the method is suitable for industrial production.

Detailed Description

Example 1

1) Synthesis of M1

Adding 50g (0.299mol) of methyl 3-bromopropionate, 54g of methanol solution (30 wt%) of sodium methoxide and 150ml of methanol into a reaction bottle, heating and refluxing for 5 hours, cooling to 20-30 ℃ after reaction is finished, dropwise adding 15g of formic acid, dropwise adding for 1.5 hours, stirring for half an hour, performing suction filtration (precipitated impurities such as sodium formate), and washing a filter cake to obtain the methanol solution of M1.

2) Synthesis of M2

A methanol solution of M1, 28g of methylamine in methanol (30 wt%) and 0.4g of KI were added to the reaction flask and reacted at 35-45 ℃ for 7.5 h. After the reaction, the temperature was decreased to 10 to 20 ℃, 15ml of water was added, extraction was performed with dichloromethane, washing was performed with 15ml of 10% diluted hydrochloric acid, washing was performed with 15ml of saturated brine, and dichloromethane was distilled under reduced pressure to dryness to obtain 38.4g of compound M2, yield: 75.01% purity: 98.22 percent.

3) Synthesis of M3

Adding 35g (0.204mol) of compound M2, 150ml of methanol and 11.7g of sodium borohydride into a reaction bottle, adding the mixture into the reaction bottle by 10 times, controlling the temperature to be 0-10 ℃ for reaction for 2.5 hours, quenching the mixture by 10% diluted hydrochloric acid, adding 50ml of water, extracting the mixture by 50ml of methylene chloride, washing the mixture by 50ml of saturated saline solution, drying the mixture for 0.5 hour by anhydrous sodium sulfate, filtering the dried mixture by suction, and distilling the filtered mixture under reduced pressure to obtain 29.4g of compound M3, wherein the yield is as follows: 83.03% and the purity is 97.82%.

4) Synthesis of arecoline (M4)

20g (0.116mol) of Compound M3, 100ml of methanol and 4.4g of ground sodium hydroxide were added to a reaction flask, and the mixture was refluxed for 7 hours, and methanol was distilled off after 3 hours of the reaction, and fresh methanol was added. Cooling to 10-20 deg.C after reaction, stirring for 1 hr, vacuum filtering to separate out impurities (such as sodium hydroxide), and vacuum distilling to dry to obtain arecoline oil 16.6g, with yield: 92.52% purity: 99.47 percent.

Example 2:

1) synthesis of M1

Adding 50g (0.299mol) of methyl 3-bromopropionate and 74g of sodium methoxide methanol solution (30 wt%) into a reaction bottle, heating and refluxing for 6 hours, cooling to 20-30 ℃ after reaction, dropwise adding 15g of formic acid for 1 hour, stirring for half an hour, then carrying out suction filtration, and washing a filter cake to obtain M1 methanol solution.

2) Synthesis of M2

A methanol solution of M1 and 28g of methylamine in methanol (30 wt%) were added to a reaction flask, and 0.4g of KI was added thereto to conduct reaction at 35 to 45 ℃ for 7 hours. After the reaction, the temperature was reduced to 10 to 20 ℃, a fixed amount of water (15 ml) was added, extraction was performed with dichloromethane, washing was performed with 15ml of 10% diluted hydrochloric acid solution, washing was performed with saturated brine, and dichloromethane was distilled to dryness to obtain 38.7g of compound M2, yield: 75.59 percent; purity: 98.16 percent.

3) Synthesis of M3

Adding 35g (0.204mol) of compound M2, 150ml of methanol and 11.7g of sodium borohydride into a reaction bottle, adding the mixture into the reaction bottle by 10 times, controlling the temperature to be 0-10 ℃ for reaction for 2 hours, quenching the mixture by using 10% diluted hydrochloric acid, adding 50ml of water, extracting the mixture by using 50ml of methylene chloride, washing the mixture by using 50ml of saturated saline solution, drying the mixture for 0.5 hour by using anhydrous sodium sulfate, filtering the dried mixture by suction, and distilling the dried mixture under reduced pressure to obtain 29.1g of compound M3, wherein the yield is as follows: 82.35% and 98.42% purity.

4) Synthesis of arecoline (M4)

20g (0.116mol) of Compound M3, 100ml of methanol and 4.4g of pulverized sodium methoxide were put into a reaction flask, and the mixture was refluxed for 6.5 hours, and methanol was distilled off after 3 hours of the reaction, and fresh methanol was added. Cooling to 10-20 deg.C after reaction, stirring for 1 hr, vacuum filtering, and distilling under reduced pressure to dry to obtain arecoline 16.0 g. Yield: 88.88% purity: 99.56 percent.