CN111635379A

CN111635379A - Synthesis process of blood sugar reducing medicine repaglinide

Info

Publication number: CN111635379A
Application number: CN202010703015.XA
Authority: CN
Inventors: 王建; 朱向宏; 谢西平; 黄鹿; 叶刚; 刘毅
Original assignee: Jiangxi Boya Seehot Pharmaceutical Co ltd
Current assignee: Jiangxi Boya Seehot Pharmaceutical Co ltd
Priority date: 2020-07-21
Filing date: 2020-07-21
Publication date: 2020-09-08

Abstract

The invention discloses a synthesis process of a hypoglycemic medicine repaglinide, which comprises the following steps: a) the method comprises the following steps of (1) dissociating a compound II regoramine glutamate serving as a raw material by using alkali, and directly condensing an obtained organic phase containing the compound III regoramine with a compound IV regorac acid in the presence of an acylation reagent and alkali without concentration; b) refining the crude product of the compound V regel ester obtained after condensation by using an alkane solvent; c) then hydrolyzing in the presence of an alcohol solvent and an inorganic base, acidifying after treatment at a proper temperature, and purifying the obtained crude repaglinide compound I by using an alcohol-water mixed solvent to obtain a refined repaglinide product. The synthesis process provided by the invention simplifies the synthesis steps, has the advantages of environmental protection, simple operation, high yield, low cost and the like, and is suitable for industrial mass production.

Description

Synthesis process of blood sugar reducing medicine repaglinide

Technical Field

The invention relates to a synthesis process of a hypoglycemic medicine repaglinide, belonging to the technical field of medicine synthesis.

Background

Repaglinide (repaglinide), trade name Prandin (Chinese name: noh and long). The prodrugs of repaglinide were developed by doctor Karl Thomae GmbH, German scientist, and were purchased from Boehringer Ingelheim, Germany (Chinese name: Boringer Invitrogen) in 1990. Repaglinide was successfully developed and successfully licensed to Boehringer Ingelheim (chinese name: nordanide), a world-leading biopharmaceutical company with nordanide, who is the world leading position in the development and production of insulin for the treatment of diabetes, and was filed with repaglinide IND by nordanide in 1992 to the us FDA, filed with NDA in 1997 in 7 months, approved in 1997 in 12 months, and first marketed in the us in 1998.

Repaglinide is chemically known as S (+) -2-ethoxy-4- [ N- {1- (2-piperidinylphenyl) -3-methyl-1-butyl } aminocarbonylmethyl ] benzoic acid and has the structural formula:

repaglinide is a novel oral hypoglycemic medicament of methylbenzylamine benzoic acid (CBMA) family, is a non-sulfonylurea insulin secretagogue, and is mainly clinically used for treating type II diabetes (non-insulin-dependent) patients who cannot effectively control hyperglycemia through diet control and exercise. Different from the binding site of beta-cells and sulfonylureas drugs, the compound has the characteristics of quick absorption, quick response and short action time, can simulate physiological insulin secretion in type II diabetic patients, effectively control postprandial hyperglycemia, is mainly metabolized in the liver, mostly excreted by feces, has higher protein binding rate, can not accumulate in tissues, has better safety, and has synergistic effect with biguanides drugs, for example, when metformin is used alone cannot effectively control hyperglycemia, repaglinide can be used together with metformin. Therefore, in patients with type II diabetes with ineffective diet therapy, the compound antidiabetic can be used as a first-line antidiabetic medicament to be singly applied, and can also be used together with other antidiabetic medicaments to increase the curative effect, thereby becoming a new treatment means for type II diabetes.

Many documents report the synthesis of repaglinide, which is prepared by condensing a compound of formula (III) with a compound of formula (IV) to obtain a compound (V), and hydrolyzing to obtain a product (I), wherein the process flow is as follows:

various methods and routes for synthesizing the compound V have been reported in various literatures, but the use of trimethylacetyl chloride (also referred to as pivaloyl chloride) as a condensing agent is a route suitable for industrial production in view of product cost and quality.

CN108047163A preparation method of repaglinide, which comprises the steps of carrying out dissociation reaction on regetamine glutamate under the action of sodium hydroxide, extracting with petroleum ether, repeatedly washing with water for several times, and concentrating under reduced pressure to obtain a compound III; using triethylamine as an acid-binding agent, dropwise adding a toluene solution of trimethyl acetyl chloride into a mixed solution of a compound IV and toluene at the temperature of-5 ℃ for acylation, adding a toluene solution dissolved with the compound III after the reaction is finished for condensation reaction, washing with water for a plurality of times, concentrating, and refining with petroleum ether to obtain a condensation product with the purity of only 79%; and (3) carrying out hydrolysis reaction on the condensation product under the action of sodium hydroxide to obtain a repaglinide crude product, and refining with acetone to obtain a qualified product.

CN105175361A improved repaglinide production process, which comprises the steps of carrying out dissociation reaction on regoramine glutamic acid under the action of ammonia water, and carrying out series post-treatment to obtain a compound III; using triethylamine as an acid-binding agent, dropwise adding a toluene solution of trimethyl acetyl chloride into a mixed solution of regenic acid and toluene at the temperature of-5-0 ℃ for acylation, adding a toluene solution dissolved with the compound III after the reaction is finished for condensation reaction, performing series post-treatment, and refining with toluene to obtain a condensation product, wherein the yield is 65-80%; and (3) carrying out hydrolysis reaction on the condensation product under the action of sodium hydroxide to obtain a repaglinide crude product, and then refining with ethanol/water to obtain a qualified product.

Although the reaction routes are reasonable, the methods have the defects of low product yield and purity, complex post-treatment operation, flammable, explosive and volatile solvent, increased production cost, low production safety coefficient and the like.

For example, in the dissociation step of CN108047163A, petroleum ether is used as a reaction solvent and an extractant, and since compound III has poor solubility in petroleum ether, the extraction efficiency is low, which leads to a problem of low yield of the final product, and further, petroleum ether has a low flash point and a low boiling point, which is extremely dangerous in use; similar disadvantages also exist when the crude repaglinide product of the final product is refined by acetone.

In the CN105175361A dissociating step, ammonia water with pungent odor is used as an acid-binding agent, so that the workshop environment and the health of workers are influenced to a certain extent; since the compound V has a high solubility in toluene, toluene is used as a purification solvent in the condensation step, and the yield is low.

Disclosure of Invention

Aiming at various defects of the existing repaglinide preparation method, the invention aims to provide a method for synthesizing the repaglinide raw material medicine, which has the advantages of simple process, safety, reliability, stable quality, low cost, high yield, suitability for industrial mass production and great social, economic and environmental benefits.

In order to solve the technical problems, the invention is realized by adopting the following technical scheme.

The technical scheme is as follows:

a synthesis process of a hypoglycemic medicine repaglinide comprises the following steps: a) the method comprises the following steps of (1) dissociating a compound II regoramine glutamate serving as a raw material by using alkali, and directly condensing an obtained organic phase containing the compound III regoramine with a compound IV regorac acid in the presence of an acylation reagent and alkali without concentration; b) refining the crude product of the compound V regel ester obtained after condensation by using an alkane solvent; c) then, hydrolyzing in the presence of an alcohol solvent and an inorganic base, acidifying after treatment at a proper temperature, and purifying the obtained repaglinide crude product of the compound I by using an alcohol-water mixed solvent to obtain a repaglinide refined product;

further, in the synthesis of the compound III, toluene is used as a reaction solvent, and an organic phase obtained after post-treatment is washed by water and directly enters the next reaction without concentration; in the synthesis of the compound V, toluene is used as a reaction solvent, and the toluene is recycled in the post-treatment process; the crude product of the compound V is refined by using n-heptane as a solvent, and the n-heptane solvent is recycled and reused in the post-treatment process.

Further, the method sequentially comprises the following steps:

first step of dissociation

Adding a reaction solvent and a certain amount of alkali into a reaction container, adding a compound II at a certain temperature, and keeping the temperature for reaction for a period of time after the addition;

secondly, post-treatment: after the reaction is finished, layering, washing with water, and directly putting the organic phase of the compound III into the next reaction without concentration;

the second step is that: condensation of

Adding a compound IV, a reaction solvent and an acid-binding agent into a reaction container, dripping a certain amount of an acylating agent, acylating, and preserving heat for reacting for a period of time after dripping;

dropping the organic phase of the compound III in the previous step into the reaction container for condensation, and then preserving the temperature for reaction for a period of time;

thirdly, post-processing: after the reaction is finished, washing with water, and concentrating under reduced pressure to obtain a crude product of the compound V;

and fourthly, refining: adding an alkane solvent into a concentration and refining container filled with the crude compound V, dissolving and crystallizing at a certain temperature, filtering and drying to obtain a refined compound V;

the third step: hydrolysis

Putting a compound V and a reaction solvent into a reaction container, dropwise adding alkali at a certain temperature, and carrying out heat preservation reaction for a period of time;

secondly, post-treatment: after the reaction is finished, reducing the temperature to a certain temperature, regulating the pH value to a certain range by hydrochloric acid, reducing the temperature to a certain temperature, preserving the temperature for a period of time to ensure that crystallization is complete, and filtering to obtain a crude wet product of the compound I;

refining: and putting the crude wet product of the compound I and a reaction solvent into a refining container, dissolving and crystallizing at a certain temperature, filtering and drying to obtain a refined product of the compound I.

Furthermore, in the first step, the feeding molar ratio of the regoramine glutamate to the alkali is 1: 1-5;

further, in the first step, the reaction solvent is aromatic hydrocarbon or halogenated hydrocarbon solvent, and comprises one or two or more of toluene, xylene, dichloromethane, chloroform and dichloroethane;

further, in the first step, the base used is an inorganic base or an organic base, and comprises one or two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonia water or triethylamine, pyridine, diisopropylamine, diisopropylethylamine, N-dimethylaniline and N, N-diethylaniline;

further, in the first step, the reaction temperature is 0-50 ℃;

further, in the first step, the reaction time is kept at 0.5-5 hours.

Further, in the second step, the acid-binding agent is inorganic base or organic base, and comprises one or two or more of sodium carbonate, potassium carbonate, or triethylamine, pyridine, diisopropylamine, diisopropylethylamine, N-dimethylaniline and N, N-diethylaniline;

further, in the second step, the acylating reagent is alkane acyl chloride or sulfonyl chloride, including one or two or more of pivaloyl chloride, oxalyl chloride, p-toluenesulfonyl chloride and thionyl chloride;

further, in the second step, the reaction solvent is aromatic hydrocarbon or halogenated hydrocarbon solvent, including one or two or more of toluene, xylene, dichloromethane, chloroform and dichloroethane;

further, in the second step, the feeding molar ratio of the compound III to the compound IV to the acylating agent to the acid-binding agent is 1: 1-1.5: 1-2.0;

further, in the second step, the acylation reaction temperature is minus 20 ℃ to 50 ℃;

further, in the second step, the acylation reaction time is 0.5-5 hours;

further, in the second step, the condensation reaction temperature is minus 20 ℃ to 50 ℃;

further, in the second step, the condensation reaction time is 0.5-5 hours;

further, in the second step, the solvent adopted for refining is alkane solvent, including one or two or more of n-hexane, n-heptane and cyclohexane;

further, in the second step, the refining, dissolving and heat preservation temperature is 60-120 ℃;

furthermore, in the second step, the refining crystallization temperature is 0-30 ℃.

Further, in the third step, the hydrolysis reaction solvent is alcohol or a mixture of alcohol and water, including methanol, ethanol/water or methanol/water;

further, in the third step, the alkali used in the hydrolysis reaction is alkali metal hydroxide, including sodium hydroxide or potassium hydroxide;

further, in the third step, the hydrolysis reaction temperature is 20-100 ℃;

further, in the third step, the hydrolysis reaction time is 0.5-5 hours;

further, in the third step, the acidification temperature is 0-100 ℃;

further, in the third step, the pH range after acidification is 1.0-4.0-6.0;

further, in the third step, the crystallization temperature after acidification is 0-40 ℃;

further, in the third step, the solvent used for refining is alcohol or a mixture with water, and comprises methanol, ethanol or 95% ethanol;

further, in the third step, the refining, dissolving and heat preservation temperature is 60-120 ℃;

further, in the third step, the refining crystallization temperature is 0-50 ℃.

The second technical proposal is that: the repaglinide bulk drug prepared by the repaglinide synthesis process is applied to hypoglycemic drugs.

The third technical scheme is as follows: an oral hypoglycemic medicament is prepared by using the repaglinide pure product obtained by the method through the traditional technology and auxiliary materials.

In summary, compared with the prior art, the invention comprises the following components:

compared with CN108047163A, the method has the advantages that regoramine glutamate is subjected to a free reaction under the action of sodium hydroxide, regoramine and toluene are mixed for condensation reaction, re-washing and crystallization, wherein a crystallization solvent is a mixed solution of toluene and petroleum ether, and petroleum ether is mainly used as a reaction solvent and an extracting agent;

CN105175361A uses regranamine glutamate as a main material to prepare chiral amine by adjusting pH, then the chiral amine is condensed with regranol acid, and finally the repaglinide finished product is obtained by hydrolysis, the compound (S) - (+) -3-methyl-1- (2-piperidyl-phenyl) butylamine-N-acetyl-L-glutamic acid (1) is added into the mixed solution of water and toluene, then ammonia water is added to be stirred to be fully dissolved, an organic layer is extracted after reaction, and the organic layer is dried, filtered and concentrated under reduced pressure to obtain the compound (S) - (+) -3-methyl-1- (2-piperidyl-phenyl) butylamine (2); in this step, ammonia water used as an acid-binding agent in the liberation step has an irritant odor.

The invention provides a method for preparing a compound of regoramine glutamate, which uses regoramine glutamate as a raw material, and carries out dissociation by using alkali, but the obtained organic phase is directly condensed with regoramine acid in the presence of an acylating agent and alkali without concentration; refining with alkane solvent; then the repaglinide is hydrolyzed and acidified in the presence of alcohol solvent and inorganic base, and finally purified to obtain the repaglinide refined product.

The method specifically comprises the following steps:

(1) in the synthesis of the compound III, toluene is used as a reaction solvent, and an organic phase obtained after the post-treatment is simply washed by water and directly enters the next reaction without concentration, so that the operation process is simplified, and the production efficiency is improved;

(2) in the synthesis of the compound V, toluene is still used as a reaction solvent, and after the reaction is carried out for a short time, the recovered toluene can be returned to the next batch for reuse after the post-treatment; the n-heptane is used as a solvent for refining the crude compound V, the obtained refined product has high purity and yield, the solvent recovery rate is high, and the refined product can be reused for the next reaction, so that the production cost is reduced.

In summary, the inventive process technology is as follows:

(1) the synthesis of the compound I has high product purity and yield and simple operation. As a raw material medicine, the medicine for reducing blood sugar prepared by the method has better quality and stable finished product quality.

(2) The invention overcomes the defects in the prior art, and provides the synthesis process of the blood sugar lowering medicine repaglinide, which has the advantages of simple process, safety, reliability, high yield, stable quality of intermediates and finished products, suitability for industrial mass production and great social, economic and environmental benefits.

Drawings

FIG. 1 is an HPLC chromatogram of compound V (regesterate), a repaglinide intermediate;

Detailed Description

The technical solution of the present invention will be described in detail with reference to the following embodiments.

Example 1:

the first step is as follows: free form

Adding 60g of 10% sodium hydroxide aqueous solution and 180g of toluene into a 500L reaction bottle in sequence, adding 33g of regoramine glutamate (compound II) powder solid at 5-10 ℃, and keeping the temperature for reaction for 0.5 hour after the addition is finished; standing and layering after the reaction is finished, collecting an organic phase, washing the organic phase once by using 35g of drinking water, and directly carrying out the condensation reaction of the obtained regoramine (compound III) toluene solution in the next step.

The second step is that: condensation of

Adding 180g of toluene, 19g of regic acid (compound IV) and 17g of triethylamine into a 1000ml reaction bottle in sequence, dropwise adding a mixed solution of 10g of pivaloyl chloride and 35g of toluene at 10-15 ℃, and preserving heat at 10-15 ℃ for reaction for 1 hour after dropwise adding.

Dropwise adding the toluene solution of regoramine (compound III) obtained in the first step at 10-15 ℃, heating to 40-45 ℃ after dropwise adding, and carrying out heat preservation reaction for 1 hour; and (5) sampling and controlling.

After the reaction is finished, adding 250g of drinking water into the reaction kettle to quench the reaction, standing for layering, washing with 62g of saturated sodium bicarbonate solution and 85g of drinking water in sequence, and concentrating the organic phase under reduced pressure to recover toluene; adding 112g of n-heptane into the concentrated residue, heating and refluxing for 2 hours, cooling to 0-5 ℃ for crystallization, filtering and drying to obtain 31.9g of off-white regorate refined product with HPLC purity of 99.81% and molar yield of 87% (calculated as compound II).

The third step: hydrolysis

Adding 365g of 95% ethanol, 31.9g of regel ester and 30g of 10% sodium hydroxide aqueous solution into a 1000ml reaction kettle in sequence, and heating and carrying out reflux reaction for 3-4 hours; carrying out sampling reaction central control;

after the reaction is finished, cooling to 15-20 ℃, dropwise adding hydrochloric acid to adjust the pH to 4.0-6.0, and carrying out heat preservation and crystallization for 1 hour; filtering, and barreling the filtrate to recover ethanol; the filter cake is washed by a proper amount of purified water and then enters a refining process.

Refining: adding 65g of 95% ethanol, 65g of purified water and a repaglinide crude wet product into a 500ml reaction kettle in sequence, and heating to reflux; carrying out hot filtration through a positive pressure filter, and enabling filtrate to enter a clean area crystallization kettle; cooling the filtrate to 10-15 ℃, and stirring for 1 hour under the condition of heat preservation; filtering and drying to obtain 113g of white crystalline powder repaglinide refined product, the molar yield is 96 percent, and the HPLC purity is 100 percent.

Example 2:

the first step is as follows: free form

Sequentially adding 2.4kg of 10% sodium hydroxide aqueous solution and 6.65kg of toluene into a 20L reaction kettle, adding 1.33kg of regoramine glutamate (compound II) powder solid at 5-10 ℃, and keeping the temperature for 0.5 hour after the addition; standing and layering after the reaction is finished, collecting an organic phase, washing the organic phase once by using 1.35kg of drinking water, and directly carrying out the condensation reaction of the obtained regoramine (compound III) toluene solution in the next step.

The second step is that: condensation of

6.65kg of toluene, 0.79kg of regic acid (compound IV) and 0.67kg of triethylamine are sequentially added into a 50L reaction kettle, a mixed solution of 0.40kg of pivaloyl chloride and 1.35kg of toluene is dripped at the temperature of 10-15 ℃, and after dripping, the temperature is kept at 10-15 ℃ for 1 hour of reaction.

After the reaction is finished, 9.04kg of drinking water is added into the reaction kettle to quench the reaction, the reaction kettle is kept stand for layering, 2.45kg of saturated sodium bicarbonate solution and 3.01kg of drinking water are sequentially used for washing, and the organic phase is decompressed and concentrated to recover toluene; and adding 5.04kg of n-heptane into the concentrated residue, heating and refluxing for 2 hours, cooling to 0-5 ℃ for crystallization, filtering and drying to obtain 1.25kg of off-white regorate refined product, wherein the HPLC purity is 99.80%, and the molar yield is 85% (calculated as a compound II).

The third step: hydrolysis

Adding 14.61kg of 95% ethanol, 1.25kg of regel ester and 1.2kg of 10% sodium hydroxide aqueous solution into a 50L reaction kettle in sequence, and heating and carrying out reflux reaction for 3-4 hours; carrying out sampling reaction central control;

Refining: sequentially adding 2.65kg of 95% ethanol, 2.65kg of purified water and a repaglinide crude wet product into a 20L reaction kettle, and heating to reflux; carrying out hot filtration through a positive pressure filter, and enabling filtrate to enter a clean area crystallization kettle; cooling the filtrate to 10-15 ℃, and stirring for 1 hour under the condition of heat preservation; filtering and drying to obtain 1.11kg of white crystalline powder repaglinide refined product, the molar yield is 94 percent, and the HPLC purity is 100 percent.

In the synthesis of the compound I in the two embodiments, the purity of the regoramate HPLC is 99.80% and 99.81% (fig. 1-the purity of the intermediate regoramate is 99.81%), and the purity of the repaglinide can reach 100%;

in the prior art, the HPLC purity of the regel ester obtained by the CN108047163A condensation reaction is only 79%; although CN105175361A does not indicate how pure the obtained regenamate is, the listed yield is only 65-80%, and the purity of the obtained repaglinide is more than 99.00%.

Meanwhile, flammable and explosive solvents such as petroleum ether, acetone and the like are used in the documents, and the toluene used in the embodiment is relatively safer and has high recovery rate.

The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and do not limit the concept and the protection scope of the present invention, and the ordinary skilled person of the present invention can modify the technical solutions of the present invention or substitute the equivalent without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.

Claims

1. A synthesis process of a hypoglycemic medicine repaglinide is characterized by comprising the following steps: a) the method comprises the following steps of (1) dissociating a compound II regoramine glutamate serving as a raw material by using alkali, and directly condensing an obtained organic phase containing the compound III regoramine with a compound IV regorac acid in the presence of an acylation reagent and alkali without concentration; b) refining the crude product of the compound V regel ester obtained after condensation by using an alkane solvent; c) then, hydrolyzing in the presence of an alcohol solvent and an inorganic base, carrying out post-treatment and acidification, and purifying the obtained repaglinide crude product of the compound I by using an alcohol-water mixed solvent to obtain a refined repaglinide product;

2. the process for synthesizing repaglinide according to claim 1, wherein toluene is used as a reaction solvent in the synthesis of the compound III, and an organic phase obtained after the post-treatment is washed with water and directly enters the next reaction without being concentrated; in the synthesis of the compound V, toluene is used as a reaction solvent, and the toluene is recycled in the post-treatment process; the crude product of the compound V is refined by using n-heptane as a solvent, and the n-heptane solvent is recycled and reused in the post-treatment process.

3. Process for the synthesis of repaglinide according to claim 1 or 2, characterized by comprising the following steps in sequence:

first step of dissociation

Adding a reaction solvent and alkali into a reaction container, adding a compound II, and carrying out heat preservation reaction after the addition is finished;

the second step is that: condensation of

Adding a compound IV, a reaction solvent and an acid-binding agent into a reaction container, dripping an acylating agent for acylation, and carrying out heat preservation reaction after dripping;

dropping the organic phase of the compound III in the previous step into the reaction container for condensation, and then preserving the temperature for reaction;

the third step: hydrolysis

Putting a compound V and a reaction solvent into a reaction container, dropwise adding alkali and carrying out heat preservation reaction;

secondly, post-treatment: after the reaction is finished, cooling, regulating the pH value by hydrochloric acid, cooling again, keeping the temperature to ensure that crystallization is complete, and filtering to obtain a crude wet product of the compound I;

refining: and putting the crude wet product of the compound I and a reaction solvent into a refining container, dissolving and crystallizing, filtering and drying to obtain a refined product of the compound I.

4. The repaglinide synthesis process of claim 3, wherein:

in the first step, the feeding molar ratio of regoramine glutamate to alkali is 1: 1-5;

in the first step, the reaction solvent is aromatic hydrocarbon or halogenated hydrocarbon solvent, including one or two or more of toluene, xylene, dichloromethane, chloroform and dichloroethane;

in the first step, the used base is inorganic base or organic base, and comprises one or two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonia water or triethylamine, pyridine, diisopropylamine, diisopropylethylamine, N-dimethylaniline and N, N-diethylaniline;

in the first step, the reaction temperature is 0-50 ℃;

in the first step, the reaction time is kept at 0.5-5 hours.

5. The repaglinide synthesis process of claim 3, wherein:

in the second step, the acid-binding agent is inorganic base or organic base, and comprises one or two or more of sodium carbonate, potassium carbonate or triethylamine, pyridine, diisopropylamine, diisopropylethylamine, N-dimethylaniline and N, N-diethylaniline;

in the second step, the acylating reagent is alkane acyl chloride or sulfonyl chloride, including one or two or more of pivaloyl chloride, oxalyl chloride, p-toluene sulfonyl chloride and thionyl chloride;

in the second step, the reaction solvent is aromatic hydrocarbon or halogenated hydrocarbon solvent, including one or two or more of toluene, xylene, dichloromethane, chloroform and dichloroethane;

in the second step, the feeding molar ratio of the compound III to the compound IV to the acylating agent to the acid-binding agent is 1: 1-1.5: 1-2.0;

in the second step, the acylation reaction temperature is minus 20 ℃ to 50 ℃;

in the second step, the acylation reaction time is 0.5-5 hours;

in the second step, the condensation reaction temperature is minus 20 ℃ to 50 ℃;

in the second step, the condensation reaction time is 0.5-5 hours;

in the second step, the refining solvent is alkane solvent, including one or two or more of n-hexane, n-heptane and cyclohexane;

in the second step, the refining, dissolving and heat preservation temperature is 60-120 ℃;

in the second step, the refining crystallization temperature is 0-30 ℃.

6. The repaglinide synthesis process of claim 3, wherein:

in the third step, the hydrolysis reaction solvent is alcohol or a mixture of alcohol and water, and comprises methanol, ethanol/water or methanol/water;

in the third step, the alkali used in the hydrolysis reaction is alkali metal hydroxide, including sodium hydroxide or potassium hydroxide;

in the third step, the hydrolysis reaction temperature is 20-100 ℃;

in the third step, the hydrolysis reaction time is 0.5-5 hours;

in the third step, the acidification temperature is 0-100 ℃;

in the third step, the pH range after acidification is 1.0-4.0-6.0;

in the third step, the crystallization temperature after acidification is 0-40 ℃;

in the third step, the solvent used for refining is alcohol or a mixture of alcohol and water, and comprises methanol, ethanol or 95% ethanol;

in the third step, the refining, dissolving and heat preservation temperature is 60-120 ℃;

in the third step, the refining crystallization temperature is 0-50 ℃.

7. The repaglinide bulk drug prepared by the repaglinide synthesis process according to claim 1 is applied to a hypoglycemic drug.

8. An oral hypoglycemic drug is characterized in that the repaglinide pure product is prepared into the oral hypoglycemic drug by using the traditional technology and auxiliary materials.