CN116693540A

CN116693540A - Synthesis method of sitagliptin intermediate

Info

Publication number: CN116693540A
Application number: CN202310581566.7A
Authority: CN
Inventors: 卢文才; 苏建; 吴鹏森; 周子敬; 陈恬
Original assignee: Jiangsu Baju Pharmaceutical Co ltd
Current assignee: Jiangsu Baju Pharmaceutical Co ltd
Priority date: 2023-05-23
Filing date: 2023-05-23
Publication date: 2023-09-05

Abstract

The invention relates to a synthesis method of sitagliptin intermediate, belonging to the technical field of synthesis of pharmaceutical intermediate. In order to solve the existing problem of being not friendly to the environment and low in yield, a synthesis method of sitagliptin intermediate is provided, the method comprises the steps of reacting raw materials of chloroacetonitrile, ethanol and acetyl chloride in a water-insoluble organic solvent to obtain intermediate compound of ethyl chloroethylimine ethyl hydrochloride; in an alcohol solvent I, carrying out cyclization reaction on a compound shown in a formula I and a trifluoro-acethydrazide shown in a formula II to obtain an intermediate compound shown in a formula III; carrying out condensation reaction on a compound of a formula III and ethylenediamine to obtain an intermediate compound of a formula IV; and adding hydrochloric acid to react to obtain the final product of the compound shown in the formula V. The method has the advantages of high product purity and yield, no need of purification, and can be directly used for the next reaction, thereby being beneficial to simplifying the operation and improving the reaction efficiency.

Description

Synthesis method of sitagliptin intermediate

Technical Field

The invention relates to a synthesis method of sitagliptin intermediate, belonging to the technical field of synthesis of pharmaceutical intermediate.

Background

Sitagliptin is a novel anti-type 2 diabetes drug developed by Merck corporation in the United states, is the first dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes, and is often used as a medicament in the form of phosphate, and the structural formula of sitagliptin is shown in the formula I.

Wherein 3-trifluoromethyl-5, 6,7, 8-tetrahydro-1, 2, 4-triazole [4,3-a ] pyrazine hydrochloride is a key intermediate in sitagliptin synthesis, and the structural formula of the 3-trifluoromethyl-5, 6,7, 8-tetrahydro-1, 2, 4-triazole [4,3-a ] pyrazine hydrochloride is shown as follows.

Currently, in the synthesis of this intermediate (3-trifluoromethyl-5, 6,7, 8-tetrahydro-1, 2, 4-triazole [4,3-a ] pyrazine hydrochloride), the following synthetic routes are mainly reported in the literature. If hydrazine hydrate, ethyl trifluoroacetate and chloroacetyl chloride are used for generating an intermediate, the intermediate is subjected to phosphorus oxychloride condensation reaction, then reacts with ethylenediamine at low temperature, and then reacts with hydrochloric acid to obtain a product, wherein the reaction route is as follows:

however, when the ethyl trifluoroacetate reacts with the hydrazine hydrate, two amino groups of the hydrazine hydrate are easy to react with the ethyl trifluoroacetate with high activity, and the impurity N, N' -di (trifluoroacetyl) hydrazine can be generated, and the impurity is not separated in the reaction route and is always brought into the subsequent process to participate in the reaction, so that the impurity is easy to generate, and the purity quality of the product is influenced; meanwhile, a large amount of phosphorus-containing wastewater is generated due to the adoption of phosphorus oxychloride, so that the environment friendliness is poor; and the phosphorus oxychloride is used for dehydration condensation, so that a large amount of impurities are generated, and the yield of the step is lower. Is not beneficial to industrial production.

The other synthetic route is that 2-chloropyrazine is used as raw material, and reacts with hydrazine hydrate and trifluoroacetic anhydride, and then phosphoric acid is dehydrated to form a ring, palladium-carbon catalytic hydrogenation is used for reduction, and hydrochloride is formed to prepare the compound of the formula II. The method uses the catalyst noble metal palladium carbon, the total yield of the product only reaches about 25 percent, and the yield is low, so that the synthetic cost of the route is high, and the method is not beneficial to industrial production.

Disclosure of Invention

Aiming at the problems existing in the prior art, the invention provides a synthesis method of sitagliptin intermediates, and solves the problems of how to effectively realize green and environment protection and high product yield.

The invention aims at realizing the following technical scheme, namely a synthesis method of sitagliptin intermediate, which comprises the following steps:

A. in a water-insoluble organic solvent, raw materials of chloroacetonitrile, ethanol and acetyl chloride are reacted to obtain an intermediate compound of the formula I, namely chloroethylimine ethyl ester hydrochloride;

B. in an alcohol solvent I, carrying out cyclization reaction on a compound shown in a formula I and a trifluoro-acethydrazide shown in a formula II to obtain an intermediate compound shown in a formula III;

C. carrying out condensation reaction on a compound of a formula III and ethylenediamine to obtain an intermediate compound of a formula IV; adding hydrochloric acid to react to obtain a final product of the compound of the formula V;

the intermediate compound of the formula I, namely the ethyl chloroimine ethyl ester hydrochloride, is synthesized by taking chloroacetonitrile as a raw material and then reacts with trifluoroacetyl hydrazine, so that more impurities generated in the reaction process can be effectively avoided without using phosphorus tri-hydroxide, the intermediate impurity content is low, the intermediate product has the advantages of high purity and high conversion rate, the product has high yield, and the subsequent purification treatment is not needed, so that the method can be directly used for the next reaction, the operation is greatly simplified, and the production efficiency is improved; meanwhile, the problem of environmental pollution caused by adopting phosphorus oxychloride is solved, and the method is environment-friendly; then reacts with ethylenediamine, the ethylenediamine is adopted to participate in the raw materials of the reaction, and can directly act as an acid binding agent, thereby being beneficial to better reducing the generation of impurities in the reaction process, hydrochloric acid can be added for cyclization reaction after the reaction, the hydrochloride form of the final product is formed, and the overall product yield is high, and the liquid phase purity reaches more than 99%.

In the above synthesis method of sitagliptin intermediate, preferably, the alcohol solvent in the step B is one or more selected from methanol, ethanol, propanol and isopropanol. The alcohol solvent has the advantages of mild reaction conditions, high safety, contribution to better improving the purity quality of intermediate products, better reducing impurities, and easy recovery of the alcohol solvent, and better reduction of production cost.

In the above synthesis method of sitagliptin intermediate, preferably, the molar ratio of the compound of formula i to the compound of formula ii in step B is 1:1.0 to 1.2. The method is beneficial to better utilizing the raw materials, reducing the waste of the raw materials, improving the utilization rate of the raw materials, reducing the production cost, realizing more sufficient reaction and improving the conversion rate and the purity quality of the intermediate product. As a further preference, the molar ratio of the compound of formula i to the compound of formula ii is 1:1.0 to 1.08.

In the above synthesis method of sitagliptin intermediate, preferably, the water-insoluble organic solvent in step a is one or more selected from dichloromethane, chloroform and ethyl acetate. Can effectively make the raw materials fully dissolved, is favorable for reaction, makes the reaction mild, is favorable for subsequent separation, and can better ensure the quality of intermediate products.

In the above synthesis method of sitagliptin intermediate, preferably, the molar ratio of chloroacetonitrile, ethanol and acetyl chloride in step a is 1:1.0 to 1.1:1.0 to 1.5. The method is beneficial to more fully utilizing the raw materials, ensuring the reaction to be fully carried out, reducing the waste of the raw materials and reducing the production cost.

In the above-mentioned synthesis method of sitagliptin intermediate, preferably, the reaction in the step a is carried out at-10 to 10 ℃; the cyclization reaction in step B is carried out under reflux. After the reaction in the step A is finished, a large amount of solid intermediate products are separated out, which is favorable for production operation, and in the step B, the reaction is favorable for full progress in a reflux state. Further preferably, the reaction described in step A is carried out at a temperature of from-5℃to 5 ℃.

In the above synthesis method of sitagliptin intermediate, preferably, after the cyclization reaction in the step B is finished, the method further comprises a post-treatment, wherein the post-treatment specifically comprises:

and distilling the reaction liquid to remove the first alcohol solvent, adding an extraction solvent and water into the residue, extracting, standing for layering, collecting an organic layer, and removing the solvent to obtain the corresponding intermediate compound of the formula III. The impurities can be better removed through post-treatment, and the purity and quality of the intermediate product are improved. As a further preferred aspect, the post-treatment is specifically:

after the reaction is finished, the reduced pressure distillation is carried out at the temperature of 40-50 ℃, the first alcohol solvent is recovered, after the reduced pressure distillation is finished, the concentrate is cooled to 0-25 ℃, then water and the extraction solvent are added for extraction, layering is carried out, the collected organic phase is washed by sodium bicarbonate aqueous solution, standing and layering are carried out, the collected organic phase is dried by sodium sulfate and filtered, and the collected organic phase is subjected to reduced pressure concentration distillation at the temperature of 30-40 ℃ to remove the solvent until the solvent is dried, thus obtaining the corresponding intermediate compound of formula III.

The extraction solvent is preferably selected from one or more of dichloromethane, dichloroethane and methyl tert-butyl ether. The method is favorable for better extracting the intermediate product into the organic phase, is favorable for extraction and separation, better removes water-soluble impurities, and can better ensure the purity and quality of the intermediate product.

In the above synthesis method of sitagliptin intermediate, preferably, the compound of formula ii, trifluoroacethydrazide, in step B is synthesized by the following method:

the trifluoro-acethydrazide compound of the formula II in the step B is synthesized by the following method:

ethyl trifluoroacetate and hydrazine hydrate are used as raw materials for reaction, after the reaction is finished, sodium chloride aqueous solution is added into the reaction solution for washing, standing and layering are carried out, the collected organic layer is distilled and concentrated to dryness, then n-hexane and/or n-heptane are added, and crystallization is carried out, thus obtaining the corresponding compound trifluoro acethydrazide shown in the formula II. Because ethyl trichloroacetate reacts with hydrazine hydrate to generate N, N' -di (trifluoroacetyl) hydrazine as an impurity, and unreacted hydrazine hydrate also reacts with acetyl chloride to generate corresponding impurities. After the reaction is finished, the method adopts the aqueous solution of sodium chloride to carry out salt washing, and separates the solid intermediate product through crystallization, so that the impurities can be better removed, the purity and quality of the intermediate product are ensured, and the conversion rate of the subsequent reaction is improved. As a further preferred aspect, the reaction of ethyl trifluoroacetate with hydrazine hydrate is preferably carried out in one or more of an alcohol solvent, an ether solvent and an ester solvent, wherein the alcohol solvent may be selected from methanol, ethanol, propanol, isopropanol, etc.; the ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, etc., and the ester solvent is selected from ethyl acetate, etc. Replaces the acetonitrile solvent with high price, is more beneficial to reducing the cost and is suitable for industrial production. Further preferably, the molar ratio of ethyl trifluoroacetate to hydrazine hydrate is 1:1.05 to 1.2. The temperature of the reaction can be further controlled between 0 and 30 ℃.

In the above synthesis method of sitagliptin intermediate, the compound of formula III in step C is used as raw material, and the compound is reacted with ethylenediamine to synthesize according to the existing method, and then concentrated hydrochloric acid is added to carry out cyclization to form corresponding product hydrochloride. Preferably, the condensation reaction in step C is carried out in an alcoholic solvent two. The alcohol solvent II is preferably selected from lower alcohol solvents such as methanol, ethanol or isopropanol; the molar ratio of the compound of formula III to ethylenediamine in step C is 1:2.8 to 3.6.

The reaction is carried out in an alcohol solvent, and excessive ethylenediamine is adopted, so that the reaction is participated in and is also used as an acid binding agent, and the reaction is more effectively carried out. And the ethylenediamine raw material is adopted, and after the reaction is finished, unreacted ethylenediamine can be recovered, so that ethylenediamine in the mother solution can be recovered, and the cost can be greatly reduced. The reaction is carried out in the alcohol solvent, so that the reaction is facilitated, the alcohol solvent II can be recovered, and the method is suitable for industrialization and greatly reduces the cost. The temperature of the condensation reaction in step C is preferably-10℃to-20℃and preferably-10℃to-15 ℃.

The synthesis method of the sitagliptin intermediate can be represented by the following reaction equation:

wherein, the raw material trifluoro-acethydrazide can be represented by the following reaction equation:

in summary, compared with the prior art, the invention has the following advantages:

1, the corresponding intermediate chloroethylimine ethyl ester hydrochloride is generated under the action of chloroacetyl chloride by adopting raw materials of chloroacetonitrile and ethanol, and then the reaction is carried out with trifluoroacetyl hydrazine to synthesize a product, so that phosphorus oxychloride which has large equipment corrosion and is difficult to treat waste gas and waste water is not required; the defect that more impurities can be generated by adopting phosphorus oxychloride cyclization dehydration is avoided, the method has the advantages of high product purity and high yield, and can be directly used for the next reaction without purification, thereby being beneficial to simplifying the operation and improving the reaction efficiency.

2. The method has the advantages of small impurity of the intermediate, high yield, simple operation, high total yield (calculated by ethyl trifluoroacetate, and total yield reaching more than 60 percent), low cost of auxiliary materials used in the whole reaction route, and low total production cost, and solves the problem of three wastes (phosphorus oxychloride) in difficult places.

Detailed Description

The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.

Example 1

Synthesis of trifluoroacetyl hydrazine:

adding 1000. 1000m l g (1.05 mol) of methanol solvent and 61.76g (1.0 mol) of hydrazine hydrate with the mass percentage of 85% into a clean reaction kettle, cooling to 0-10 ℃ under stirring, starting to slowly dropwise add 142g (1.0 mol) of ethyl trifluoroacetate serving as a raw material, controlling the temperature to 25-30 ℃, continuing stirring and preserving heat at 25-30 ℃ for 3 hours after the completion of dropwise addition, adding 50g of saturated sodium chloride aqueous solution into the reaction liquid after the completion of preserving heat, stirring for 30 minutes, standing for layering, concentrating the collected organic layer under reduced pressure to remove the solvent until the solvent is dry, adding 800ml of n-hexane into the residue, heating to 30-40 ℃, stirring for 1 hour, slowly cooling to 0-10 ℃, preserving heat and crystallizing for 0.5-1 hour, filtering, and drying the obtained solid wet product to obtain 122.5g of intermediate trifluoroacetyl hydrazine, wherein the molar yield is 95.7%, and the liquid phase purity is 99.4%.

Synthesis of intermediate compound chloroethylimine ethyl ester hydrochloride of formula I:

adding 75.5 (1.0 mol) chloroacetonitrile, 46g (1.0 mol) ethanol and 200. 200m l methylene dichloride solvent into a clean reaction kettle, cooling to-5 ℃, dropwise adding 86.35g (1.1 mol) acetyl chloride, controlling the temperature to-5 ℃, carrying out heat preservation reaction for 3 hours at-5 ℃ after the dropwise adding is finished, precipitating a large amount of solid, finishing heat preservation, filtering, drying the obtained solid intermediate to obtain 148.6g of intermediate compound chloroethylimine ethyl ester hydrochloride, wherein the molar yield of the step is 94%, and the liquid phase purity is 99.5%.

Example 2

Synthesis of intermediate compounds of formula iii:

the intermediate trifluoroacetyl hydrazine synthesized by the method in example 1 above and the ethyl chloroethylimine hydrochloride of formula I were used. The method comprises the following steps: 128g (1 mol) of trifluoroacethydrazide (II) as a raw material and 158g (1 mol) of chloroethylimine ethyl ester hydrochloride (a compound of the formula I) as a raw material are put into another clean reaction kettle, methanol 800-m l is added, the temperature is raised to reflux under stirring, the mixture is kept at the reflux condition for reaction for 4 hours, after the heat preservation is finished, the temperature is reduced, reduced pressure distillation is carried out to recover the methanol, 500ml of dichloromethane is added into the concentrate, the mixture is stirred for 5 minutes, the temperature is slowly reduced to 0-25 ℃, 200ml of water is added, the mixture is stirred for 5 minutes, the mixture is left to stand for layering, the collected organic layer is washed by 100ml of sodium bicarbonate aqueous solution with the mass percentage of 5%, the mixture is left to stand for layering, 20g of anhydrous sodium sulfate is put into the organic layer for drying, the mixture is filtered, the collected filtrate is distilled under reduced pressure at the temperature of 30-40 ℃ until no liquid is obtained, the concentrate is 162g of the compound of the intermediate formula III, and the molar yield of the step is 86.9% (the liquid phase purity is 98%), and the gas phase purity is 97.5%).

Synthesis of intermediate compounds of formula iv:

adding 1200ml of methanol and 168g (2.8 mol) of 1, 2-ethylenediamine into a clean reaction kettle, slowly cooling to-10 ℃ to-15 ℃, dropwise adding 186.5g (1.0 mol) of compound of formula III, controlling the temperature of a reaction system between-10 ℃ and-15 ℃ in the dropwise adding process, continuously carrying out heat preservation reaction for 2h at-10 ℃ to-15 ℃ after the dropwise adding is finished, filtering after the reaction is finished, drying a filter cake, and obtaining 182g of compound of intermediate product formula IV, wherein the molar yield of the step is 86.67%.

Further, the filtered filtrate can be recovered, the filtrate is cooled to 0-10 ℃ under stirring, and sodium methoxide solid is slowly added: 64.8g (1.2 mol), controlling the temperature to be 0-30 ℃, stirring for 1h, cooling to be 0-10 ℃, filtering, obtaining sodium chloride as a filter cake, rectifying the filtrate at normal pressure, and obtaining 1100ml of recovered methanol, wherein the gas phase purity is 99.5%. 91g of ethylenediamine was recovered.

Adding 1400 g of ethanol m l into a clean reaction kettle, adding 210g (1.0 m l) of a compound of formula IV into 120ml of concentrated hydrochloric acid at a stirring control temperature of 0-30 ℃, heating to 50-60 ℃ under stirring after the addition, preserving heat and stirring for 4h,

after the reaction is finished, slowly cooling to 0-10 ℃, filtering, and drying the obtained filter cake to obtain 189g of finished product of compound of formula V, wherein the molar yield of the step is 82.7%, and the liquid phase purity is 99.2%.

Example 3

Synthesis of trifluoroacetyl hydrazine:

adding 1000ml of methyl tertiary butyl ether and 70.59g (1.2 mol) of 85% hydrazine hydrate into a clean reaction kettle, cooling to 0-10 ℃ under stirring, slowly dropwise adding 142g (1.0 mol) of ethyl trifluoroacetate, controlling the temperature to 0-15 ℃, stirring and preserving heat for 4h at 15-20 ℃ after the completion of dropwise adding, adding 50g of saturated sodium chloride aqueous solution into the reaction solution, stirring for 30 min, standing for layering, concentrating the collected organic layer under reduced pressure to remove the solvent until dryness, adding 800m l n-heptane into the residue, heating to 30-40 ℃, stirring for 1h, cooling to 0-10 ℃, preserving heat for 1.0h, filtering, drying the obtained solid wet product to obtain 120g of intermediate trifluoroacetyl hydrazine, wherein the step yield is 93.75%, and the liquid phase purity is 99.5%.

adding 75.5 (1.0 mol) chloroacetonitrile, 47g (1.02 mol) ethanol and 200ml dichloromethane into a clean reaction kettle, cooling to-5 ℃, dropwise adding 86.35g (1.5 mol) acetyl chloride, controlling the temperature to-5 ℃, carrying out heat preservation reaction for 3 hours at-5 ℃ after the dropwise adding is finished, separating out a large amount of solids, ending the heat preservation, filtering, drying a solid intermediate product to obtain 150.3g of an intermediate compound chloroethylimine ethyl ester hydrochloride with the formula I, wherein the molar yield is 95.1%, and the liquid phase purity is 99.5%.

Example 4

Synthesis of intermediate compounds of formula iii:

the intermediate trifluoroacetyl hydrazine synthesized by the method described in example 3 above and the ethyl chloroiminoester hydrochloride of formula I were employed. The method comprises the following steps: adding 128g (1 mol) of trifluoroacethydrazide and 158g (1 mol) of chloroethylimine ethyl ester hydrochloride which is a compound of formula I into a clean reaction kettle, adding 800ml of ethanol, heating to reflux under stirring, keeping the mixture at reflux for 4 hours, cooling and distilling under reduced pressure to recover the ethanol after the heat preservation is finished, adding 500ml of dichloromethane into the concentrate, stirring for 5 minutes, cooling to 0-25 ℃, adding 200. 200m l of water, stirring for 5 minutes, standing for layering, washing the collected organic layer with 100ml of 5% sodium bicarbonate aqueous solution, standing for layering, and collecting an organic layer; then 20g of anhydrous sodium sulfate is added into the organic layer for drying, filtration is carried out, the collected filtrate is distilled under reduced pressure at 30-40 ℃ until no liquid is discharged, the concentrate is 173g of an intermediate compound of formula III, and the molar yield of the step is 92.7% (the liquid phase purity is 98.5%, and the gas phase purity is 97.8%).

Synthesis of intermediate compounds of formula iv:

adding 1200ml of methanol and 216g (3.6 mol) of 1, 2-ethylenediamine into a clean reaction kettle, slowly cooling to-15 ℃ to-20 ℃, dropwise adding 186.5g (1.0 mol) of a compound of formula III, controlling the temperature of a reaction system to be-15 ℃ to-20 ℃ in the dropwise adding process, continuously keeping the temperature to be-15 ℃ to-20 ℃ for heat preservation reaction for 3 hours after the dropwise adding is finished, filtering, and drying a filter cake to obtain 184.5g of an intermediate compound of formula IV, wherein the molar yield of the step is 87.85%.

Further, the filtrate of this step may be subjected to recovery treatment. Cooling the filtrate to 0-10 ℃ under stirring, slowly dropwise adding 216g of 30% sodium methoxide methanol solution (1.2 mol of sodium methoxide), controlling the temperature to 0-30 ℃, stirring for 1h, cooling to 0-10 ℃, filtering, and rectifying the filter cake at normal pressure to obtain recovered methanol 1150m l with gas phase purity: 99.5%; 125g of recovered ethylenediamine.

Adding 1400 g of ethanol m l into a clean reaction kettle, dropwise adding 210g (1.0 m l) of a compound of formula IV into 120ml of concentrated hydrochloric acid at a temperature of 0-30 ℃ under stirring, heating to 50-60 ℃ under stirring after the dropwise adding is finished, preserving heat and stirring for 3 hours, cooling to 0-5 ℃ after the reaction is finished, filtering, and drying the obtained filter cake to obtain 188g of a compound of formula V, wherein the molar yield of the step is 82.3%, and the liquid phase purity is 99.3%.

Example 5

Synthesis of trifluoroacetyl hydrazine:

adding 1000m L of ethyl acetate and 70.59g (1.2 mol) of 85% hydrazine hydrate into a clean reaction kettle, cooling to 0-5 ℃ under stirring, starting to slowly dropwise add 142g (1.0 mol) of ethyl trifluoroacetate serving as a raw material, controlling the temperature to 5-15 ℃, continuing stirring and heat preservation at 5-15 ℃ after the dropwise addition is completed, reacting for 5 hours under heat preservation, adding 50g of saturated sodium chloride aqueous solution into the reaction solution after heat preservation, stirring for 30 minutes, standing and layering, concentrating the collected organic layer under reduced pressure until dryness, adding 800-m l n-hexane into the solid residue, stirring and heating to 30-40 ℃, controlling the temperature and stirring for 1 hour, slowly cooling to 0-5 ℃, preserving heat and crystallizing for 1 hour, filtering and drying to obtain 123g of an intermediate trifluoroacetyl hydrazine, wherein the molar yield of the step is 96%, and the liquid phase purity is 99.3%.

75.5 g (1.0 mol) of chloroacetonitrile, 46.9g (1.02 mol) of ethanol and 220ml of dichloromethane are put into a clean reaction kettle, the temperature is controlled to be between minus 5 ℃ and 5 ℃, 80.6g (1.4 mol) of acetyl chloride is dropwise added at the temperature of between minus 5 ℃ and 5 ℃, the temperature is kept for 4 hours after the dropwise addition, a large amount of solids are separated out, the heat preservation is finished, the filtration is carried out, the obtained solid intermediate product is dried, the intermediate compound chloroethylimine ethyl hydrochloride 146g is obtained, the molar yield of the step is 92.4%, and the liquid phase purity is 99.6%.

Example 6

Synthesis of intermediate compounds of formula iii:

the intermediate trifluoroacetyl hydrazine synthesized by the method of example 5 above and the ethyl chloroiminoester hydrochloride of formula I were employed. The method comprises the following steps: 128g (1 mol) of trifluoroacethydrazide and 158g (1 mol) of chloroethyliminoethyl hydrochloride which is a compound of formula I are put into a reaction kettle, 800ml of isopropanol is stirred and heated to reflux, the temperature is kept for 6h after the heat preservation is finished, the temperature is reduced, reduced pressure distillation is carried out to recover the isopropanol, 500ml of methyl tertiary butyl ether is added into concentrate, the mixture is stirred for 5 minutes, the temperature is slowly reduced to 10-15 ℃, 200ml of saturated sodium chloride aqueous solution is added, the mixture is stirred for 5 minutes, the mixture is stood for layering, the collected organic layer is washed with 100ml of sodium bicarbonate aqueous solution with the mass fraction of 5%, the mixture is stood for layering, the organic layer is collected, 20g of anhydrous sodium sulfate is put into the organic layer for drying, the mixture is filtered, the collected filtrate is distilled under reduced pressure at the temperature of 35-40 ℃ until no liquid is produced, the concentrate is 164.5g of an intermediate compound III, and the molar yield of the step is 88.2% (the liquid phase purity is 98.3%) and the gas phase purity is 97.5%).

Synthesis of intermediate compounds of formula iv:

adding 1100ml of ethanol and 180g (3.0 mol) of 1, 2-ethylenediamine into a clean reaction kettle, slowly cooling to-10 ℃ to-15 ℃, dropwise adding 186.5g (1.0 mol) of a compound of formula III, controlling the temperature of a reaction system to be-10 ℃ to-15 ℃ in the dropwise adding process, continuously carrying out heat preservation reaction for 3h at-10 ℃ to-15 ℃ after the dropwise adding is finished, filtering after the reaction is finished, drying a filter cake, and obtaining 180g of an intermediate compound of formula IV, wherein the molar yield of the step is 85.72%.

Adding 1400 g of ethanol m l into a clean reaction kettle, dropwise adding 210g (1.0 m l) of a compound of formula IV into 120ml of concentrated hydrochloric acid at the temperature of 0-10 ℃, heating to 55-60 ℃ under stirring after the dropwise adding, preserving heat and stirring for 4 hours, slowly cooling to 0-5 ℃ after the reaction is finished, filtering, and drying the obtained filter cake to obtain 191g of a compound of formula V, wherein the molar yield of the step is 83.6%, and the liquid phase purity is 99.1%.

Example 7

75.5 (1.0 mol) of chloroacetonitrile, 50.6g (1.1 mol) of ethanol and 300ml of dichloromethane solvent are put into a clean reaction kettle, the temperature is reduced to-5-0 ℃, 86.35g (1.1 mol) of acetyl chloride is dropwise added, the temperature is controlled to-5-0 ℃, after the dropwise addition is finished, the heat preservation reaction is carried out for 3.5 hours under the condition of-5-0 ℃, a large amount of solids are separated out, the heat preservation is finished, the filtration is carried out, the obtained solid intermediate is dried, 147g of intermediate compound chloroethylimine ethyl hydrochloride with the formula I is obtained, the molar yield of the step is 93%, and the liquid phase purity is 99.3%.

Example 8

Synthesis of intermediate compounds of formula iii:

intermediate trifluoroacetyl hydrazine synthesized by the method described above in example 1 and intermediate ethyl chloroiminoethyl ester hydrochloride of compound of formula I synthesized by the method described in example 7 were employed. The method comprises the following steps: 153.6g (1.2 mol) of trifluoroacethydrazide and 158g (1 mol) of chloroethylimine ethyl ester hydrochloride as a compound of formula I are put into another clean reaction kettle, 1000ml of propanol is added, the temperature is raised to reflux under stirring, the mixture is kept at the reflux condition for 3 hours of thermal insulation reaction, after the thermal insulation is finished, the temperature is reduced, reduced pressure distillation is carried out to recover the propanol, 500ml of dichloromethane is added into the concentrate, the mixture is stirred for 5 minutes, the temperature is slowly reduced to 0-10 ℃, 200ml of water is added, the mixture is stirred for 5 minutes, the mixture is stood for layering, the collected organic layer is washed by 100ml of sodium bicarbonate aqueous solution with the mass percent of 5%, the mixture is stood for layering, the collected organic layer is put into 20g of anhydrous sodium sulfate for drying, the mixture is filtered, the collected filtrate is distilled under reduced pressure under the condition that the temperature is 35-40 ℃ until no liquid exists, the concentrate is 163.3g of the compound of the intermediate formula III, and the molar yield of the step is 87.6% (the liquid phase purity is 98.4 percent, and the gas phase purity is 98.1%).

Synthesis of intermediate compounds of formula iv:

1000ml of methanol and 216g (3.6 mol) of 1, 2-ethylenediamine are put into a clean reaction kettle, then the temperature is slowly reduced to minus 10 ℃ to minus 15 ℃, 186.5g (1.0 mol) of compound of formula III is dripped, in the dripping process, the temperature of a reaction system is controlled to minus 10 ℃ to minus 15 ℃, the dripping is finished, the reaction is continuously carried out for 3 hours under the condition of minus 10 ℃ to minus 15 ℃, after the reaction is finished, the filtration and the drying of a filter cake are carried out, 184g of compound of intermediate product formula IV are obtained, and the molar yield of the step is 87.62 percent.

1400ml of ethanol is added into a clean reaction kettle, 210g (1.0 ml) of the compound of the formula IV obtained by the method is added, 130ml of concentrated hydrochloric acid is dripped into the reaction kettle at the temperature of 10-15 ℃ under stirring, the temperature is raised to 50-60 ℃ under stirring after the dripping is finished, the reaction kettle is kept at the temperature for 4 hours under stirring, the temperature is slowly lowered to 0-10 ℃ after the reaction is finished, the filtration is carried out, the obtained filter cake is dried, 191.5g of the compound of the formula V is obtained, the molar yield of the step is 83.8%, and the liquid phase purity is 99.4%.

The specific embodiments described herein are offered by way of illustration only. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

1. A method for synthesizing a sitagliptin intermediate, comprising the steps of:

2. the method for synthesizing sitagliptin intermediate according to claim 1, wherein in step B, the alcohol solvent is one or more selected from the group consisting of methanol, ethanol, propanol and isopropanol.

3. The process for the synthesis of sitagliptin intermediates according to claim 1, wherein the molar ratio of the compound of formula i to the compound of formula ii in step B is 1:1.0 to 1.2.

4. The method for synthesizing sitagliptin intermediate according to claim 1, wherein the water-insoluble organic solvent in step a is one or more selected from the group consisting of dichloromethane, chloroform and ethyl acetate.

5. The process for the synthesis of sitagliptin intermediate according to any one of claims 1 to 4, wherein the molar ratio of chloroacetonitrile, ethanol and acetyl chloride in step a is 1:1.0 to 1.1:1.0 to 1.5.

6. The process for the synthesis of sitagliptin intermediate according to any one of claims 1 to 4, wherein the temperature of the reaction in step a is-10 ℃ to 10 ℃; the cyclization reaction in step B is carried out under reflux.

7. The method for synthesizing sitagliptin intermediate according to any one of claims 1 to 4, wherein after the cyclization reaction in step B is completed, further comprising a post-treatment, wherein the post-treatment specifically comprises:

and distilling the reaction liquid to remove the solvent, adding an extraction solvent and water into the residue, extracting, standing for layering, collecting an organic layer, and removing the solvent to obtain the corresponding intermediate compound of the formula III.

8. The method for synthesizing sitagliptin intermediate according to claim 7, wherein the extraction solvent is one or more selected from the group consisting of dichloromethane, dichloroethane and methyl tert-butyl ether.

9. The process for the synthesis of sitagliptin intermediates according to any one of claims 1 to 4, wherein in step B the compound of formula ii trifluoroacetyl hydrazine is synthesized by:

ethyl trifluoroacetate and hydrazine hydrate are used as raw materials for reaction, after the reaction is finished, sodium chloride aqueous solution is added into the reaction solution for washing, standing and layering are carried out, the collected organic layer is distilled and concentrated to dryness, then n-hexane and/or n-heptane are added, and crystallization is carried out, thus obtaining the corresponding compound trifluoro acethydrazide shown in the formula II.

10. The process for the synthesis of sitagliptin intermediates according to any one of claims 1 to 4, wherein the condensation reaction in step C is carried out in an alcohol solvent two; the molar ratio of the compound of formula III to ethylenediamine is 1:2.8 to 3.6.