阅读说明：本技术 一种维格列汀的合成方法 (Synthetic method of vildagliptin ) 是由 孙学喜 杨会来 毛杰 于 2020-06-15 设计创作，主要内容包括：本发明公开了一种维格列汀的合成方法,通过将L-谷氨酸和乙醇进行酯化反应,制得L-谷氨酸-γ-乙酯,将L-谷氨酸-γ-乙酯在钾硼氢的作用下还原制得L-脯氨酸,将L-脯氨酸和氯甲酸乙酯混合反应得到酸酐,酸酐进一步与胺反应得到酰胺,酰胺在五氧化二磷的作用下进行脱水制得中间体1,将中间体1与氯乙酰氯进行取代反应制得中间体2,中间体2与3-氨基-1-金刚烷醇进一步反应制得维格列汀,该方法制备维格列汀的过程中出现的杂质较少,且制备出的维格列汀产率高,且与现有工艺相比,工艺更加简单,大大降低了维格列汀的制备成本。(The invention discloses a synthetic method of vildagliptin, which comprises the steps of carrying out esterification reaction on L-glutamic acid and ethanol to prepare L-glutamic acid-gamma-ethyl ester, reducing the L-glutamic acid-gamma-ethyl ester to prepare L-proline under the action of potassium borohydride, mixing the L-proline and ethyl chloroformate to react to obtain anhydride, further reacting the anhydride with amine to obtain amide, dehydrating the amide under the action of phosphorus pentoxide to obtain an intermediate 1, carrying out substitution reaction on the intermediate 1 and chloroacetyl chloride to obtain an intermediate 2, further reacting the intermediate 2 with 3-amino-1-adamantanol to prepare vildagliptin, wherein the method has the advantages of less impurities in the vildagliptin preparation process, high yield of the prepared vildagliptin and simpler process compared with the prior art, greatly reduces the preparation cost of vildagliptin.)

1. A synthetic method of vildagliptin is characterized by comprising the following steps: the method specifically comprises the following steps:

step S1: adding glutamic acid and ethanol into a reaction kettle, stirring at the rotation speed of 200-3 ℃ at 300r/min and the temperature of 1-3 ℃ until the glutamic acid and the ethanol are uniformly mixed, dropwise adding a sulfuric acid solution, continuously stirring for 1-1.5 hours at the temperature of 3-5 ℃, heating to 25-30 ℃, continuously reacting for 1-1.5 hours, cooling to 15-20 ℃, adding sodium carbonate until the pH value is 8-8.5, and preparing L-glutamic acid-gamma-ethyl ester;

step S2: adding the L-glutamic acid-gamma-ethyl ester prepared in the step S1 and deionized water into a reaction kettle, stirring at the rotation speed of 200-300r/min and the temperature of 3-5 ℃ until the L-glutamic acid-gamma-ethyl ester is completely dissolved, adding potassium borohydride, reacting at the temperature of 25-30 ℃ for 1-1.5h, heating to 45-50 ℃, reacting for 3-4h, adding a hydrochloric acid solution until the pH value is 4-4.5, cooling to 0 ℃, and filtering to obtain L-proline;

step S3: adding the L-proline prepared in the step S2 and dichloromethane into a reaction kettle, stirring until the L-proline is completely dissolved, adding ethyl chloroformate and triethylamine into the reaction kettle, reacting for 1.5-2h at the temperature of-10-5 ℃, adding ammonia water, and reacting for 30-40min at the temperature of 25-30 ℃ to prepare an intermediate 1;

step S4: mixing the intermediate 1 prepared in the step S3 with tetrahydrofuran to prepare a mixed solution, adding chloroacetyl chloride and dichloromethane into a reaction kettle, continuously stirring the mixture until the mixture is uniformly mixed under the conditions that the rotation speed is 200-300r/min and the temperature is 0-3 ℃, dropwise adding the mixed solution, reacting for 30-40min, heating the mixture to 40-45 ℃, and carrying out reflux reaction for 2-2.5h to prepare an intermediate 2;

step S5: and (4) adding the intermediate 2, the 3-amino-1-adamantanol and the dimethylformamide prepared in the step (S4) into a reaction kettle, stirring until the intermediate 2 and the 3-amino-1-adamantanol are completely dissolved, adding cesium carbonate and potassium carbonate powder, and reacting for 3-5h under the conditions that the rotation speed is 200-300r/min and the temperature is 40-60 ℃ to prepare the vildagliptin.

2. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: the dosage ratio of the glutamic acid solution, the ethanol solution and the sulfuric acid solution in the step S1 is 15 g: 100mL of: 8mL, and the mass fraction of the sulfuric acid solution is 75-80%.

3. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: the dosage ratio of the L-glutamic acid-gamma-ethyl ester, the deionized water and the potassium borohydride in the step S2 is 7 g: 35mL of: 2g, the mass fraction of the hydrochloric acid solution is 20-30%.

4. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: the dosage ratio of the L-proline, the dichloromethane, the ethyl chloroformate, the triethylamine and the ammonia water in the step S3 is 1.5 g: 10mL of: 1.5 g: 2 mL.

5. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: the dosage ratio of the intermediate 1 and the tetrahydrofuran in the step S4 is 1 g: 2mL, and the volume ratio of the dosage of the chloracetyl chloride to the dosage of the dichloromethane to the mixed solution is 3: 16: 10.

6. the method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: the using amount ratio of the intermediate 2, 3-amino-1-adamantanol, dimethylformamide, cesium carbonate and potassium carbonate in the step S5 is 10 g: 30g of: 50mL of: 1 g: 1g of the total weight of the composition.

Technical Field

The invention belongs to the technical field of chemical drugs, and particularly relates to a synthetic method of vildagliptin.

Background

Vildagliptin is used for treating type 2 diabetes, the type 2 diabetes is named as adult onset diabetes, the onset of the vildagliptin is mostly after 35-40 years of age, the vildagliptin accounts for more than 90% of diabetics, the capability of insulin production in the bodies of the type 2 diabetics is not completely lost, and some patients even produce excessive insulin in the bodies, but the action effect of the insulin is poor, so that the insulin in the bodies of the patients is relatively deficient, the secretion of the insulin in the bodies can be stimulated through some oral medicines, but some patients still need to be treated by the insulin in the later period.

According to the traditional vildagliptin synthesis method, a large amount of impurities are generated in the re-synthesis process, so that a large amount of cost is consumed for impurity removal of crude vildagliptin, the yield of vildagliptin is low, the traditional vildagliptin synthesis process is complicated in steps, and the synthesis cost of vildagliptin is increased.

Disclosure of Invention

The invention aims to provide a synthetic method of vildagliptin.

The technical problems to be solved by the invention are as follows:

according to the traditional vildagliptin synthesis method, a large amount of impurities are generated in the re-synthesis process, so that a large amount of cost is consumed for impurity removal of crude vildagliptin, the yield of vildagliptin is low, the traditional vildagliptin synthesis process is complicated in steps, and the synthesis cost of vildagliptin is increased.

The purpose of the invention can be realized by the following technical scheme:

a synthetic method of vildagliptin specifically comprises the following steps:

step S1: adding L-glutamic acid and ethanol into a reaction kettle, stirring at the rotation speed of 200-300r/min and the temperature of 1-3 ℃ until the L-glutamic acid and the ethanol are uniformly mixed, dropwise adding a sulfuric acid solution, continuously stirring for 1-1.5 hours at the temperature of 3-5 ℃, heating to the temperature of 25-30 ℃, continuously reacting for 1-1.5 hours, cooling to the temperature of 15-20 ℃, and adding sodium carbonate until the pH value is 8-8.5 to prepare L-glutamic acid-gamma-ethyl ester;

the reaction process is as follows:

step S2: adding the L-glutamic acid-gamma-ethyl ester prepared in the step S1 and deionized water into a reaction kettle, stirring at the rotation speed of 200-300r/min and the temperature of 3-5 ℃ until the L-glutamic acid-gamma-ethyl ester is completely dissolved, adding potassium borohydride, reacting at the temperature of 25-30 ℃ for 1-1.5h, heating to 45-50 ℃, reacting for 3-4h, adding a hydrochloric acid solution until the pH value is 4-4.5, cooling to 0 ℃, and filtering to obtain L-proline;

the reaction process is as follows:

step S3: adding the L-proline prepared in the step S2 and dichloromethane into a reaction kettle, stirring until the L-proline is completely dissolved, adding ethyl chloroformate and triethylamine into the reaction kettle, reacting at-10-5 ℃ for 1.5-2h, adding ammonia water, reacting at 25-30 ℃ for 30-40min, adding phosphorus pentoxide, and reacting at 60-65 ℃ for 30-40min to obtain an intermediate 1;

the reaction process is as follows:

step S4: mixing the intermediate 1 prepared in the step S3 with tetrahydrofuran to prepare a mixed solution, adding chloroacetyl chloride and dichloromethane into a reaction kettle, continuously stirring the mixture until the mixture is uniformly mixed under the conditions that the rotation speed is 200-300r/min and the temperature is 0-3 ℃, dropwise adding the mixed solution, reacting for 30-40min, heating the mixture to 40-45 ℃, and carrying out reflux reaction for 2-2.5h to prepare an intermediate 2;

the reaction process is as follows:

step S5: and (4) adding the intermediate 2, the 3-amino-1-adamantanol and the dimethylformamide prepared in the step (S4) into a reaction kettle, stirring until the intermediate 2 and the 3-amino-1-adamantanol are completely dissolved, adding cesium carbonate and potassium carbonate powder, and reacting for 3-5h under the conditions that the rotation speed is 200-300r/min and the temperature is 40-60 ℃ to prepare the vildagliptin.

The reaction process is as follows:

further, the dosage ratio of the glutamic acid solution, the ethanol solution and the sulfuric acid solution in the step S1 is 15 g: 100mL of: 8mL, and the mass fraction of the sulfuric acid solution is 75-80%.

Further, the dosage ratio of the L-glutamic acid- γ -ethyl ester, the deionized water, and the potassium borohydride in the step S2 is 7 g: 35mL of: 2g, the mass fraction of the hydrochloric acid solution is 20-30%.

Further, in step S3, the ratio of the amounts of L-proline, dichloromethane, ethyl chloroformate, triethylamine, ammonia water, and phosphorus pentoxide is 1.5 g: 10mL of: 1.5 g: 2mL of: 1g of the total weight of the composition.

Further, the amount of the intermediate 1 and tetrahydrofuran in the step S4 is 1 g: 2mL, and the volume ratio of the dosage of the chloracetyl chloride to the dosage of the dichloromethane to the mixed solution is 3: 16: 10.

further, the intermediate 2, 3-amino-1-adamantanol, dimethylformamide, cesium carbonate and potassium carbonate described in step S5 were used in an amount ratio of 10 g: 30g of: 50mL of: 1 g: 1g of the total weight of the composition.

The invention has the beneficial effects that: the invention prepares L-glutamic acid-gamma-ethyl ester by carrying out esterification reaction on L-glutamic acid and ethanol, reduces the L-glutamic acid-gamma-ethyl ester under the action of potassium borohydride to prepare L-proline, mixes the L-proline and ethyl chloroformate to react to obtain anhydride, further reacts the anhydride with amine to obtain amide, dehydrates the amide under the action of phosphorus pentoxide to prepare an intermediate 1, carries out substitution reaction on the intermediate 1 and chloroacetyl chloride to prepare an intermediate 2, further reacts the intermediate 2 with 3-amino-1-adamantanol to prepare vildagliptin, the method has less impurities in the process of preparing the vildagliptin, and the prepared vildagliptin has high yield, compared with the prior art, the process is simpler, and the preparation cost of vildagliptin is greatly reduced.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.