阅读说明：本技术 一种古豆碱的制备方法 (Preparation method of gulconine ) 是由 马小燕 胡新军 于 2019-10-18 设计创作，主要内容包括：本发明提供了一种古豆碱的制备方法,其制备方法为：将N-甲基脯氨酸溶于有机溶剂中,依次发生羟基氯代反应、氰化反应、氰基水解反应、甲酯化反应、胺解反应和亲核加成反应,最终得到古豆碱。本发明所需原料价格低廉,制备工艺便于操作控制,有效解决了操作困难不易控制、收率较低、成本较高和环境污染大的问题。(The invention provides a preparation method of gulicine, which comprises the following steps: dissolving N-methylproline in an organic solvent, and sequentially carrying out hydroxyl chlorination reaction, cyanidation reaction, cyano hydrolysis reaction, methyl esterification reaction, aminolysis reaction and nucleophilic addition reaction to finally obtain the gulconine. The raw materials needed by the invention are low in price, the preparation process is convenient to operate and control, and the problems of difficult operation, low yield, high cost and great environmental pollution are effectively solved.)

1. The preparation method of the gulicine is characterized by comprising the following steps:

(1) hydroxyl chlorination reaction: dissolving N-methyl proline in an organic solvent I, dropwise adding a thionyl chloride solution at the temperature of 0 ℃, stirring at room temperature for 1-3 hours, refluxing for 20-40 min, concentrating under reduced pressure, adding ethanol and diethyl ether, mixing, filtering, and cleaning to obtain a compound I; the molar ratio of the N-methyl proline to the thionyl chloride solution is 4-6: 5-7; the volume ratio of the ethanol to the diethyl ether is 1-3: 40-60 during filtering;

(2) cyanidation reaction: dissolving the compound I obtained in the step (1) in an organic solvent II, dropwise adding a sodium bicarbonate solution at the temperature of 0 ℃, stirring for 10-20 min, then adding sodium cyanide, refluxing for 20-40 min, extracting for 2-4 times after decompression and concentration, combining obtained organic phases, washing with water, and drying to obtain a compound II; the molar ratio of the compound I, the sodium bicarbonate solution and the sodium cyanide is 4-6: 6-8;

(3) and (3) cyano hydrolysis reaction: adding concentrated hydrochloric acid into the compound II obtained in the step (2), refluxing for 1-3 h, and concentrating under reduced pressure to obtain a compound III; the concentration of the compound II in concentrated hydrochloric acid is 160-180 mg/mL;

(4) methyl esterification reaction: dissolving the compound III obtained in the step (3) in an organic solvent III, dropwise adding a thionyl chloride solution, heating to 60-70 ℃, refluxing for 5-7 h, cooling to room temperature, concentrating under reduced pressure, adding water for diluting at 0 ℃, adjusting the pH value to 8-9, extracting for 2-4 times, combining the obtained organic phases, and drying to obtain a compound IV; the molar ratio of the compound III to the thionyl chloride solution is 1: 4-6;

(5) and (3) aminolysis reaction: mixing the compound IV obtained in the step (4) with dimethylhydroxylamine hydrochloride, dissolving the mixture in an organic solvent IV, adding isopropyl magnesium chloride at the temperature of minus 20 ℃, stirring for 15-25 min, adding water for quenching, extracting for 2-4 times, combining the obtained organic phases, drying and carrying out chromatography to obtain a compound V; the mol ratio of the compound IV to the dimethylhydroxylamine hydrochloride to the isopropyl magnesium chloride is 1-3: 2-4: 5-7;

(6) nucleophilic addition reaction: dissolving the compound penta obtained in the step (5) in an organic solvent IV, dropwise adding methyl magnesium chloride at the temperature of 0 ℃, stirring for 1-3 h, cooling to-25-15 ℃, adding water for quenching, extracting for 2-4 times, combining obtained organic phases, and drying to obtain the gulconine; the molar ratio of the compound five to the methyl magnesium chloride is 1: 2-4.

2. The method of claim 1, wherein said first organic solvent is chloroform, said second organic solvent is aqueous ethanol, said third organic solvent is methanol, and said fourth organic solvent is dry tetrahydrofuran.

3. The process for producing gulconine according to claim 1, wherein in step (2), extraction is carried out with ethyl acetate, washing with saturated brine, and drying with anhydrous sodium sulfate.

4. The method of claim 1, wherein in step (2), the drying is followed by purification using a silica column, wherein the volume ratio of petroleum ether to ethyl acetate in the silica column is 1: 1.

5. The process for the preparation of gulconine as claimed in claim 1, wherein in step (4) the pH is adjusted with saturated sodium carbonate solution.

6. The process for the preparation of gulicine according to claim 1, wherein in steps (4) - (6), extraction is carried out with a mixed extractant, and drying is carried out with anhydrous sodium sulfate;

wherein the mixed extracting agent is dichloromethane and methanol according to the volume ratio of 10: 1, and mixing the components.

7. The process for the preparation of gulconine according to claim 1, wherein the drying in steps (4) - (5) is followed by purification using a silica column with a volume ratio of dichloromethane to methanol of 20: 1.

8. The process for the preparation of gulconine as claimed in claim 1, wherein step (6) is dried and purified using a silica column with a volume ratio of dichloromethane to methanol of 30: 1.

9. The process for the preparation of gulconine as claimed in claim 1, wherein the concentration of organic solvent two in step (2) in steps (5) - (6) is 80%.

Technical Field

The invention belongs to the technical field of preparation of gulicine, and particularly relates to a preparation method of gulicine.

Background

Gudourine is a pyrrolidine alkaloid present in various plants including coca leaves, has central sedative and peripheral anticholinergic effects, is less active than atropine, but has a relatively strong effect in inhibiting gastrointestinal motility and gastric fluid secretion. It also has the effects of dilating peripheral blood vessels, increasing coronary blood flow, and relieving asthma, and is commonly used for treating spastic pain caused by gastric ulcer and various gastrointestinal diseases. However, at present, the conventional preparation process of the gulconine with good effect is not available, most processes are difficult to operate, the reaction is difficult to control, the yield is low, reaction raw materials and reagents are expensive, the production cost is high, and each reagent or intermediate product has great pollution to the environment, and is not beneficial to long-time contact of operators and influences the physical and psychological health of the operators.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides the preparation method of the gulutinine, which has the advantages of low price of the required raw materials and convenient operation and control of the preparation process, and effectively solves the problems of difficult operation, low yield, high cost and great environmental pollution.

In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows: provides a preparation method of the gulicine, which comprises the following steps:

(1) hydroxyl chlorination reaction: dissolving N-methyl proline in an organic solvent I, dropwise adding a thionyl chloride solution at the temperature of 0 ℃, stirring at room temperature for 1-3 hours, refluxing for 20-40 min, concentrating under reduced pressure, adding ethanol and diethyl ether, mixing, filtering, and cleaning to obtain a compound I; the molar ratio of the N-methyl proline to the thionyl chloride solution is 4-6: 5-7; the volume ratio of the ethanol to the diethyl ether is 1-3: 40-60 during filtering;

(2) cyanidation reaction: dissolving the compound I obtained in the step (1) in an organic solvent II, dropwise adding a sodium bicarbonate solution at the temperature of 0 ℃, stirring for 10-20 min, then adding sodium cyanide, refluxing for 20-40 min, extracting for 2-4 times after decompression and concentration, combining obtained organic phases, washing with water, and drying to obtain a compound II; the molar ratio of the compound I, the sodium bicarbonate solution and the sodium cyanide is 4-6: 6-8;

(3) and (3) cyano hydrolysis reaction: adding concentrated hydrochloric acid into the compound II obtained in the step (2), refluxing for 1-3 h, and concentrating under reduced pressure to obtain a compound III; the concentration of the compound II in concentrated hydrochloric acid is 160-180 mg/mL;

(4) methyl esterification reaction: dissolving the compound III obtained in the step (3) in an organic solvent III, dropwise adding a thionyl chloride solution, heating to 60-70 ℃, refluxing for 5-7 h, cooling to room temperature, concentrating under reduced pressure, adding water for diluting at 0 ℃, adjusting the pH value to 8-9, extracting for 2-4 times, combining the obtained organic phases, and drying to obtain a compound IV; the molar ratio of the compound III to the thionyl chloride solution is 1: 4-6;

(5) and (3) aminolysis reaction: mixing the compound IV obtained in the step (4) with dimethylhydroxylamine hydrochloride, dissolving the mixture in an organic solvent IV, adding isopropyl magnesium chloride at the temperature of minus 20 ℃, stirring for 15-25 min, adding water for quenching, extracting for 2-4 times, combining the obtained organic phases, drying and carrying out chromatography to obtain a compound V; the mol ratio of the compound IV to the dimethylhydroxylamine hydrochloride to the isopropyl magnesium chloride is 1-3: 2-4: 5-7;

(6) nucleophilic addition reaction: dissolving the compound penta obtained in the step (5) in an organic solvent IV, dropwise adding methyl magnesium chloride at the temperature of 0 ℃, stirring for 1-3 h, cooling to-25-15 ℃, adding water for quenching, extracting for 2-4 times, combining obtained organic phases, and drying to obtain the gulconine; the molar ratio of the compound five to the methyl magnesium chloride is 1: 2-4.

Further, the first organic solvent is trichloromethane, the second organic solvent is an ethanol water solution, the third organic solvent is methanol, and the fourth organic solvent is dried tetrahydrofuran.

Further, in the step (2), extraction was performed with ethyl acetate, washing with saturated saline, and drying over anhydrous sodium sulfate.

Further, in the step (2), after drying, purifying by using a silica column, wherein the volume ratio of petroleum ether to ethyl acetate in the silica column is 1: 1.

Further, in the step (4), a saturated sodium carbonate solution is adopted to adjust the pH value.

Further, in the steps (4) to (6), a mixed extracting agent is adopted for extraction, and anhydrous sodium sulfate is dried;

wherein the mixed extracting agent is dichloromethane and methanol according to the volume ratio of 10: 1, and mixing the components.

Further, after drying in steps (4) to (5), purifying by using a silica column in which the volume ratio of dichloromethane to methanol is 20: 1.

Further, after drying in the step (6), purifying by using a silica column, wherein the volume ratio of dichloromethane to methanol in the silica column is 30: 1.

Further, the concentration of the second organic solvent in the step (2) was 80%.

Further, in the steps (5) to (6), 5 to 15mL of water is added for quenching.

Further, in the steps (1) to (4), chloroform, ethanol, water and methanol were removed by concentration under reduced pressure.

The gulicine is prepared by the preparation method of the gulicine.

In summary, the invention has the following advantages:

1. in the preparation process of the gulconine, N-methyl proline is dissolved in an organic solvent, hydroxyl chlorination reaction is carried out under the action of thionyl chloride solution to generate hydrochloride of 2- (chloromethyl) -1-methyl pyrrolidine, then cyanidation reaction is carried out under the action of sodium cyanide and sodium bicarbonate solution to generate 2- (1-methyl pyrrolidine-2-yl) acetonitrile, cyano group is hydrolyzed into carboxylic acid under acidic condition to generate hydrochloride of 2- (1-methyl pyrrolidine-2-yl) acetic acid, methyl esterification reaction is carried out to generate 2- (1-methyl pyrrolidine-2-yl) methyl acetate, and aminolysis is carried out to generate N-methoxy-N-methyl-2- (1-methyl pyrrolidine-2-yl) acetamide, finally, the nucleophilic addition reaction is carried out to obtain the gulconine, and the process route is as follows:

2. compared with the existing preparation method of the gulconine, the preparation method has the advantages that the used raw materials are easy to obtain and low in price, the intermediate product and the final product contain fewer impurities, the environmental pollution is small, the reaction operation in each step is simple, the control is easy, the preparation route is simple, the gulconine can be quickly prepared, and the yield is high.

Drawings

FIG. 1 is a drawing of Compound I¹H NMR spectrum;

FIG. 2 is a drawing of Compound I¹³C NMR spectrum;

FIG. 3 shows the preparation of compound II¹H NMR spectrum;

FIG. 4 shows the preparation of compound II¹³C NMR spectrum;

FIG. 5 is a drawing of Compound III¹H NMR spectrum;

FIG. 6 is a drawing of Compound III¹³C NMR spectrum;

FIG. 7 is a drawing of Compound No. IV¹H NMR spectrum;

FIG. 8 is a drawing of Compound four¹³C NMR spectrum;

FIG. 9 is a drawing of Compound five¹H NMR spectrum;

FIG. 10 is a drawing of Compound five¹³C NMR spectrum;

FIG. 11 is a drawing of Compound five¹³C-dept135 NMR spectrum;

FIG. 12 is a representation of a salt of gulconine¹H NMR spectrum;

FIG. 13 is a representation of a salt of gulconine¹³C NMR spectrum;

FIG. 14 is a representation of a salt of gulconine¹³C-dept135 NMR spectrum.

Detailed Description