WO2024119985A1

WO2024119985A1 - Method for preparing sitagliptin intermediate pyrazine hydrochloride

Info

Publication number: WO2024119985A1
Application number: PCT/CN2023/121912
Authority: WO
Inventors: 周魏魏; 缪炳林; 徐龙; 张盛荣; 鲍佳莲
Original assignee: 台州达辰药业有限公司
Priority date: 2022-12-07
Filing date: 2023-09-27
Publication date: 2024-06-13

Abstract

The present invention relates to the technical field of pharmaceutical intermediate synthesis, and relates to a method for preparing sitagliptin intermediate pyrazine hydrochloride. In order to solve the problem of poor yield and output in the prior art, the present invention provides a method for preparing sitagliptin intermediate pyrazine hydrochloride, which is characterized by comprising: by using N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacethydrazide as a raw material to carry out a cyclization reaction by heating or heating in an organic solvent medium; after the reaction is finished, concentrating and distilling to remove water from the system, and then filtering to obtain a compound of formula I, i.e., 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a] pyrazine in a free state; and then adding an anhydrous hydrogen chloride reagent to carry out a salt forming reaction to obtain the corresponding compound of formula I, i.e., 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a] pyrazine hydrochloride. The effects of high product yield and purity are achieved.

Description

A preparation method of pyrazine hydrochloride, an intermediate of sitagliptin

Technical Field

The invention relates to a method for preparing pyrazine hydrochloride, an intermediate of sitagliptin, and belongs to the technical field of drug intermediate synthesis.

Background technique

Sitagliptin phosphate is a new hypoglycemic drug for the treatment of type II diabetes developed by Merck and approved by the U.S. FDA in October 2006. Among them, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride is a key intermediate of the diabetes treatment drug sitagliptin. The product has an off-white to white crystalline solid appearance, is easily soluble in water, slightly soluble in ethanol, and easily soluble in alkali metal hydroxide or carbonate solutions. Its structure is shown in the following formula I compound:

At present, there are many literature reports on the synthesis of the sitagliptin phosphate intermediate 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (referred to as sitagliptin intermediate pyrazine hydrochloride). For example, the reaction disclosed in the international patent application (publication number: WO2004087650A2) is to use methanol and hydrochloric acid aqueous solution for ring closing operation, and after the conversion is completed, methyl tert-butyl ether is added dropwise for crystallization to obtain the product.

This route uses aqueous hydrochloric acid for ring closure, but the product is extremely soluble in water. Although methyl tert-butyl ether is used for crystallization operation, the yield is still low, and the presence of water makes subsequent treatment of the product difficult. The product is highly water-soluble, and water exists simultaneously with the precipitated solid product. If the crystallization is carried out directly without removing water, the product yield will be reduced. If dehydration is required after the reaction is completed, it will be more difficult to remove water in this state. Long-term water removal is likely to cause unnecessary impurities to be generated during the treatment process, and will also affect the final quality of the product, such as yellowing of the appearance, etc.

As reported in Yunnan Chemical Technology, Jul. 2019, Vol. 46, No. 7, 95% ethanol aqueous solution was used as the solvent, hydrochloric acid ethanol solution was added dropwise and the temperature was raised to perform ring closure, and then the product was obtained by hot filtration and cooling and crystallization.

This route also has the problem of residual water. In this state, it is more difficult to remove water. Long-term water removal can easily lead to the generation of unnecessary impurities during the treatment process, and will also affect the final quality of the product, such as yellowing appearance and reduced yield.

Summary of the invention

The present invention aims at the above problems existing in the prior art and provides a method for preparing pyrazine hydrochloride, an intermediate of sitagliptin, which solves the problem of how to avoid the influence of water on product quality and improve product purity and yield quality.

The object of the present invention is achieved by the following technical scheme: a method for preparing pyrazine hydrochloride, an intermediate of sitagliptin, characterized in that the method comprises the following steps:

A. Using the compound of formula II, N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine, as a raw material, a cyclization reaction is carried out by direct heating or heating in an organic solvent medium. After the reaction is completed, the water present in the system is removed by concentrated distillation, and then filtered to obtain a concentrate of the compound of formula I, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in free form;

B. Add anhydrous hydrogen chloride reagent to the above concentrate to carry out salt formation reaction to obtain the corresponding compound of formula I, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride;

The present invention heats the raw material formula II compound N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine to form a free product by cyclization, and then distills to remove water. The free product is formed at a reaction temperature that allows the raw material to form a cyclization, which is equivalent to the temperature conditions that allow the raw material formula II compound to form a closed ring under heating conditions. The free product is liquid, so that the small molecular water produced in the cyclization reaction can be effectively removed during the concentration and distillation process, avoiding the water generated in the reaction process from being brought into the salt-forming reaction. When an organic solvent medium is added to the system, the free product can be removed together with the solvent medium during the concentration and distillation performed on the free product, thereby effectively avoiding the presence of water in the subsequent salt-forming reaction system, and in the formation The hydrochloride is treated with water removal before being prepared, which is more convenient in operation, has high water removal efficiency, and will not be affected by the presence of water causing a decrease in product yield; and by first forming a free state, the concentrated product can be filtered after water removal, and the organic salt (ethylenediamine hydrochloride) and solid impurities in the system can be effectively removed, and the effect of ensuring product quality can be more effectively achieved; then, the free state of the compound of formula I 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine is allowed to enter the next step to react with an anhydrous hydrogen chloride reagent to form a salt, and the salt quality is high, and there is basically no water in the salt forming system, so that the hydrochloride (sitaglin) of the compound of formula I 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine is subsequently formed. After the intermediate pyrazine hydrochloride (pyrazine hydrochloride) is solid, there is no need to consider the problem of dehydration after the salt formation reaction, which ensures the overall yield and purity quality of the product, and has the advantages of convenient operation and high production efficiency.

The structural formula of the above-mentioned free-state compound of formula I, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, is shown below:

In the above-mentioned preparation method of the intermediate pyrazine hydrochloride of sitagliptin, preferably, the organic solvent medium in step A is selected from a benign organic solvent that can dissolve the free state of the compound 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine of formula I. This can make the cyclization reaction proceed better, and in the subsequent water removal process, the water is removed by evaporating the solvent during the concentrated distillation, and the small molecular water formed by the reaction in the system or the water introduced by the solvent used is removed more efficiently, so that the water present in the system can be removed more thoroughly and efficiently.

As a further preference, the above-mentioned benign organic solvent that can dissolve the free state of the compound of formula I 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine and the organic solvent that can dissolve the product can achieve the present purpose. In order to better ensure the realization of the reaction purpose, it is best to make the mass ratio of the compound of formula II to the above-mentioned benign organic solvent be 1:2 to 5. Further, the benign organic solvent capable of dissolving the free state of the compound of formula I, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, can be any solvent that can effectively disperse the solute. It is best to make the benign organic solvent selected from one or more of C ₁ -C ₅ alcohol solvents, water-insoluble organic solvents, nitrile solvents and ether solvents. These solvents can achieve the purpose of the present invention when used as solvents. In order to better illustrate the preferred scheme of the solvent, and considering factors such as cost and achieving a better choice for the product, as a further preferred embodiment, the C ₁ -C ₅ alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and isopentanol; the water-insoluble organic solvent is selected from one or more of C 1 -C 5 alcohol solvents, water-insoluble organic solvents, nitrile solvents and ether solvents. The organic solvent is selected from one or more of toluene, xylene, chlorobenzene, dichlorobenzene, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane and chloroform; the nitrile solvent is selected from acetonitrile; the ether solvent is selected from one or more of methyl tert-butyl ether, tetrahydrofuran and dioxane. Further, the amount of the above-mentioned benign organic solvent can be adjusted according to the amount of solvent used in the general reaction and is not limited.

In the above-mentioned preparation method of the intermediate pyrazine hydrochloride of sitagliptin, the reaction temperature in step A can form the structure of the free compound of formula I as long as the reaction temperature can make the hydrazide structure in the raw material compound of formula II form a ring-closed reaction temperature. In order to better control the reaction temperature and make the reaction more effective, the reaction can be controlled at a temperature below the boiling point (including the reflux temperature) of the benign organic solvent used in the reaction system, and the above-mentioned cyclization reaction can be further controlled at a reaction temperature above 30°C. Preferably, the temperature of the cyclization reaction in step A is 35°C to 80°C. The cyclization reaction temperature can also be further controlled to react at 50°C to 75°C, and the cyclization reaction time is preferably controlled to be 3 to 8h.

In the above-mentioned preparation method of the sitagliptin intermediate pyrazine hydrochloride, preferably, the anhydrous hydrogen chloride reagent in step B is selected from hydrogen chloride or a hydrogen chloride organic solvent mixed solution. Further preferably, the hydrogen chloride organic solvent mixed solution is selected from hydrogen chloride methanol, hydrogen chloride ethanol, hydrogen chloride isopropanol or hydrogen chloride ethyl acetate. The use of these anhydrous hydrogen chloride solvent mixed solutions can effectively obtain hydrochloride by reaction, and can effectively control the presence of water in the system, without considering the dehydration operation after the salt formation reaction is completed, thereby improving the quality of the product, ensuring the purity and yield quality of the product, and improving production efficiency.

In the above-mentioned preparation method of the intermediate pyrazine hydrochloride of sitagliptin, the salt-forming reaction in step B is carried out in an anhydrous organic solvent system, and it is best to make the solvent system in an anhydrous organic solvent system that can dissolve the free form of the compound of formula I. Preferably, the salt-forming reaction in step B is carried out in an alcohol solvent or an ester solvent, and the alcohol solvent is preferably a C1-C5 alcohol solvent, and the ester solvent is preferably an ester solvent formed by the reaction of a C1-C5 carboxylic acid and a C1-C5 alcohol. As a further preference, the alcohol solvent The solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol, and the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, and butyl acetate.

The reaction flow chart of the preparation method of the sitagliptin intermediate pyrazine hydrochloride of the present invention can be represented by the following reaction equation:

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

1. The free state product is formed by heating and cyclization first. The free state is liquid, so that the water generated by the reaction and the water brought in by the added organic solvent can be effectively removed by concentration to avoid being brought into the subsequent salt-forming reaction system. The water removal effect is more efficient, and the obtained product has the advantages of high purity and high yield, and avoids the subsequent water removal factors. The operation is simpler, the processing efficiency is high, and the effect is excellent. In addition, the free state can be filtered in a liquid state to remove organic salts and solid impurities, and the requirements for improving the purity and quality of the product are more effectively achieved.

2. By re-adding alcohol solvent or ester solvent in the salt-forming reaction and then forming salt with the added hydrogen chloride, the moisture content of the system can be more effectively controlled, which is more conducive to significantly improving the yield of the product.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an HPLC spectrogram analysis of the product obtained in Example 1 of the present invention.

Detailed ways

The technical solution of the present invention is further specifically described below through specific embodiments and drawings, but the present invention is not limited to these embodiments.

Example 1

Add 900 g of ethanol solvent and raw material N-[(2Z)-piperazine into a clean reaction bottle. -2-subunit]-2,2,2-trifluoroacetylhydrazine 300g, then, under stirring, the temperature is raised to 65℃～70℃, the temperature is controlled and the reaction is kept warm for 3～4h. After the reaction is finished, the solvent and water in the reaction system are distilled off, and the water content in the sampling analysis system is less than 0.5%. The liquid concentrate is filtered, and then 900g of anhydrous ethanol solvent is added to the filtered concentrate, and then 200g of 30% by mass hydrogen chloride ethanol solution is added dropwise. After the addition is completed, the temperature is lowered to 0～5℃, stirred and fully crystallized, and then filtered to obtain a solid product wet product. The wet product is dried to obtain 310g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which has the appearance of white crystals, the yield is 95.0%, and the HPLC purity detection is 100.0%. The HPLC spectrum analysis of the product is shown in Figure 1.

Example 2

900 g of toluene solvent and 300 g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine were added to a clean reaction bottle, and then the temperature was raised to 65°C to 70°C under stirring, and the temperature was controlled and the reaction was kept warm for 6 to 8 hours. After the reaction was finished, the solvent and water in the reaction system were distilled off, and the water content in the sampling analysis system was less than 0.5%. The liquid concentrate was filtered, and 900 g of anhydrous ethanol solvent was added to the filtered concentrate, and 200 g of 30% by mass hydrogen chloride ethanol solution was added dropwise. After the addition was completed, the temperature was lowered to 0 to 5°C, and after stirring and fully crystallizing, a solid product was obtained by suction filtration. The wet product was dried to obtain 308 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which appeared as white crystals, with a yield of 94.4% and a purity of 100.0% by HPLC.

Example 3

Add 1000g of methanol solvent and 300g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine into a clean reaction bottle, then heat to 50°C to 55°C under stirring, control the temperature and carry out insulation reaction for 3 to 4 hours. After the insulation reaction is completed, distill to remove the solvent and water in the reaction system, sample and analyze the water content in the system <0.5%, filter the liquid concentrate, add 900g of anhydrous ethanol solvent to the filtered concentrate, and then drop 230g of 30% hydrochloric acid by mass. After the ethanol solution was added dropwise, the temperature was lowered to 0-5°C, stirred and fully crystallized, and then filtered to obtain a wet solid product. The obtained solid product was dried to obtain 307 g of dry 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which appeared as white crystals, with a yield of 94% and a purity of 100.0% by HPLC.

Example 4

The specific preparation method of the product 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride in this example is the same as that in Example 1, except that the solvent in the cyclization reaction is replaced by acetonitrile in the same amount, and the amount of acetonitrile added is 900 g to obtain the corresponding solid product wet product, and the solid product 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 305 g after the wet product is dried has the appearance of white crystals, the yield is 93.4%, and the HPLC purity detection is 100.0%.

Example 5

Directly add 300 g of the raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine into a clean reaction bottle, directly heat to 65°C-70°C without adding a solvent, control the temperature and carry out insulation reaction for 4 hours. After the insulation reaction is completed, distill to remove the water produced by the reaction in the reaction system, sample and analyze the water content in the system <0.5%, filter the liquid concentrate, add 900 g of anhydrous ethanol solvent to the filtered concentrate, and then drop 210 g of a 30% by mass hydrogen chloride ethanol solution. After the dropwise addition is completed, cool to 0-5°C, stir to fully crystallize, and filter to obtain a wet solid product. The obtained solid product is dried to obtain 303.7 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which appears as white crystals, has a yield of 93.0%, and a purity of 99.8% as determined by HPLC.

Example 6

Add 900g of dioxane solvent and 300g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine to a clean reaction bottle, then heat to 65°C-70°C under stirring, control the temperature and keep warm for 3.5h. After the insulation reaction is completed, distill to remove the solvent and water in the reaction system, and take samples for analysis. The water content in the system is less than 0.5%. The liquid concentrate is filtered, and 900g of anhydrous ethanol solvent is added to the filtered concentrate. Then 230g of a 30% by mass hydrogen chloride ethanol solution is added dropwise. After the addition is completed, the temperature is lowered to 0-5°C, stirred and fully crystallized, and then filtered to obtain a wet solid product. The obtained solid product is dried to obtain 312g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which has a white appearance, a yield of 95.5%, and a purity of 100.0% by HPLC.

Example 7

Add 900g of tetrahydrofuran solvent and 300g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine to a clean reaction bottle, then heat to 50°C to 55°C under stirring, control the temperature and carry out insulation reaction for 4h. After the insulation reaction is completed, distill to remove the solvent and water in the reaction system, sample and analyze the water content of the system <0.5%, filter the liquid concentrate, and add 90 0g of anhydrous isopropanol solvent, and then 220g of a 30% by mass hydrogen chloride isopropanol solution was added dropwise. After the addition was completed, the temperature was lowered to 0-5°C, stirred and fully crystallized, and then filtered to obtain a wet solid product. The obtained solid product was dried to obtain 309g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which was white in appearance, had a yield of 94.7%, and was 100.0% by HPLC purity detection.

Example 8

800 g of isopropanol solvent and 300 g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine were added to a clean reaction bottle, and then the temperature was raised to reflux state under stirring, the temperature was controlled and the reaction was kept warm for 4.5 hours. After the reaction was finished, the isopropanol solvent and water in the reaction system were distilled off, and the water content in the sampling analysis system was less than 0.5%. The liquid concentrate was filtered, and 900 g of anhydrous ethanol solvent was added to the filtered concentrate, and 200 g of 30% by mass hydrogen chloride ethanol solution was added dropwise. After the addition was completed, the temperature was lowered to 0-5°C, stirred and fully crystallized, and then filtered to obtain a wet solid product. The obtained solid product was dried to obtain 308.5 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which appeared as white crystals, with a yield of 94.5% and a purity of 100.0% by HPLC.

Example 9

900 g of ethyl acetate solvent and 300 g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine were added to a clean reaction bottle, and then heated to 70°C-75°C under stirring, the temperature was controlled and the reaction was kept warm for 5 hours. After the reaction was completed, the solvent and water in the reaction system were distilled off, and the water content in the sampling analysis system was <0.5%. The liquid concentrate was filtered, and 900 g of anhydrous ethyl acetate solvent was added to the filtered concentrate, and 220 g of 30% by mass hydrogen chloride ethyl acetate solution was added dropwise. After the addition was completed, the temperature was lowered to 0-5°C, stirred and fully crystallized, and then filtered to obtain a wet solid product. The obtained solid product was dried to obtain 307.6 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which was white in appearance, with a yield of 94.3% and a purity of 100.0% by HPLC.

Example 10

900 g of dichloromethane and 300 g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine were added to a clean reaction bottle, and then the temperature was raised to reflux under stirring, the temperature was controlled and the reaction was kept warm for 8 hours. After the reaction was finished, the solvent and water in the reaction system were distilled off, and the water content in the sampling analysis system was less than 0.5%. The liquid concentrate was filtered, and 900 g of anhydrous ethanol solvent was added to the filtered concentrate, and 200 g of 30% by mass hydrogen chloride ethanol solution was added dropwise. After the addition was completed, the temperature was lowered to 0-5°C, stirred and fully crystallized, and then filtered to obtain a wet solid product. The obtained solid product was dried to obtain 308 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which appeared as white crystals, with a yield of 94.4% and a purity of 100.0% by HPLC.

Embodiment 11

Add 900g of chlorobenzene and 300g of the raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine to a clean reaction bottle, then heat to 75°C to 80°C under stirring, control the temperature and carry out insulation reaction for 5h. After the insulation reaction is completed, distill to remove the solvent and water in the reaction system, sample and analyze the water content of the system <0.5%, filter the liquid concentrate, and add the filtered concentrate to 900g of anhydrous isopropanol solvent was added dropwise with 200g of 30% by mass hydrogen chloride isopropanol solution. After the addition was completed, the temperature was lowered to 0-5°C, stirred and fully crystallized, and then filtered to obtain a wet solid product. The obtained solid product was dried to obtain 306g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which appeared as white crystals with a yield of 93.8% and a purity of 100.0% by HPLC.

Comparative Example 1

Add 900g of 95% ethanol solvent and 100g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine to a clean reaction bottle, heat to 65-70°C, directly drop 67g of 30% hydrogen chloride ethanol solution, keep warm and stir for 1-2 hours, filter while hot, cool to 0-5°C, stir and crystallize sufficiently, filter to obtain a solid wet product, dry to obtain 95.6g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, with a yield of 87.8% and HPLC purity detection of 100.0%.

Comparative Example 2

Add 400g of methanol and 100g of the raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine to a clean reaction bottle, then heat to 55-60°C under stirring, drop 67g of 30% by mass hydrogen chloride methanol solution, stir and react for 1-2 hours, filter while hot, cool to 0-5°C, fully crystallize, filter to obtain a solid wet product, dry to obtain 89.9g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, with a yield of 82.6% and HPLC purity detection of 100.0%.

Comparative Example 3

Add 900g of 95% ethanol solvent and 100g of raw material N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine to a clean reaction bottle, heat to 65-70°C, directly drop 67g of 30% hydrogen chloride ethanol solution, keep warm and stir for 1-2 hours, filter while hot, concentrate the filtrate to half volume, then reduce the temperature to 0-5°C, stir and crystallize sufficiently, filter to obtain a solid wet product, dry to obtain 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 99.3g, the yield is 91.2%, and the HPLC purity test is 99.2%.

In order to better illustrate the advantages of the product obtained by the method of the present invention, which is simple to operate and easy to handle, a comparative description is given below of the control process of drying the wet product obtained by the method of the present invention and the product obtained in the comparative example.

The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

A method for preparing pyrazine hydrochloride, an intermediate of sitagliptin, characterized in that the method comprises the following steps:

A. Using the compound of formula II, N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine, as a raw material, a cyclization reaction is carried out by direct heating or heating in an organic solvent medium. After the reaction is completed, the water present in the system is removed by concentrated distillation, and then filtered to obtain a concentrate of the compound of formula I, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in free form;

B. Add anhydrous hydrogen chloride reagent to the above concentrate to carry out salt formation reaction to obtain the corresponding compound of formula I, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride;
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to claim 1 is characterized in that the organic solvent medium in step A is selected from a benign organic solvent that can dissolve the free state of the compound of formula I 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine.
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to claim 2, characterized in that the benign organic solvent is selected from one or more of C 1 to C 5 alcohol solvents, water-insoluble organic solvents, nitrile solvents and ether solvents.
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to claim 3, characterized in that the C 1 -C 5 alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and isopentanol; the water-insoluble organic solvent is selected from toluene, xylene, chlorobenzene, dichlorobenzene, ethyl acetate The solvent is selected from one or more of ester, isopropyl acetate, butyl acetate, dichloromethane and chloroform; the nitrile solvent is selected from acetonitrile; the ether solvent is selected from one or more of methyl tert-butyl ether, tetrahydrofuran and dioxane.
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to any one of claims 1 to 4, characterized in that the temperature of the cyclization reaction in step A is 35° C. to 80° C.
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to any one of claims 1 to 4, characterized in that the anhydrous hydrogen chloride reagent in step B is selected from hydrogen chloride or a mixed solution of hydrogen chloride and an organic solvent.
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to claim 6, characterized in that the hydrogen chloride organic solvent mixed solvent is selected from hydrogen chloride methanol, hydrogen chloride ethanol, hydrogen chloride isopropanol or hydrogen chloride ethyl acetate.
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to claim 6, characterized in that the salt-forming reaction in step B is carried out in an alcohol solvent or an ester solvent.
The method for preparing the sitagliptin intermediate pyrazine hydrochloride according to claim 8, characterized in that the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol, and the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, and butyl acetate.