Preparation method of sitagliptin intermediate

Abstract

The invention relates to the technical field of synthesis of sitagliptin intermediates, and discloses a preparation method of a sitagliptin intermediate. According to the preparation method, ethyl trifluoroacetate is subjected to a new intermediate IV (5-(iodometyl)-2-(triflurometyl)-1, 3, 4-oxadiazole, 5-iodomethyl-2-trifluoromethyl-1, 3, 4-oxadiazole) which does not obtain a CAS number, so that the yield of the intermediate N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacethydrazide can be effectively improved, and the product yield is further improved. The preparation method of the novel intermediate IV is mild in reaction condition, convenient to operate and easy to industrially amplify, and has obvious economic benefits and social benefits.

Description

Technical Field

[0001] The present invention relates to the technical field of sitagliptin intermediate synthesis, and in particular to a method for preparing a sitagliptin intermediate. Background Art

[0002] Sitagliptin is a new anti-type 2 diabetes drug developed by Merck in the United States. It is the first dipeptidyl peptidase 4 (DPP4) inhibitor used to treat type 2 diabetes and is commonly used in the form of a phosphate salt. 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (TAP-4) is a key intermediate of sitagliptin. The main industrial synthesis routes are:

[0003] Representative literature for this synthetic route includes Organic Letters, 2005, 7(6), 1039-1042; WO2005097733A1. The advantage of this route is that the starting materials are inexpensive and readily available. However, the disadvantage is that the synthesis step of the intermediate N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine has a low yield and many by-products, resulting in a low product yield. Summary of the Invention

[0004] In order to solve the technical problem of low product yield mentioned above, the present invention provides a method for preparing a sitagliptin intermediate, which uses a new intermediate that has not yet obtained a CAS number, and can effectively improve the yield of the intermediate N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine, thereby improving the product yield.

[0005] The specific technical solution of the present invention is: a method for preparing a sitagliptin intermediate, comprising the following steps: Step 1: iodination reaction is carried out between a 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole (III) solution and an iodine reagent to obtain a mixed solution containing 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole (IV); Step 2: Mixing a mixed solution containing 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole (IV) with an ethylenediamine solution to undergo a nucleophilic substitution reaction to obtain N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine (V).

[0006] The preparation method of the present invention adds an iodination reaction step to the existing synthesis route to prepare an active intermediate 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole (5-(iodomethyl)-2-(trifluoromethyl)-1,3,4-oxadiazole), which has not been reported yet. The intermediate can be directly used in subsequent synthesis without purification, thereby significantly improving the yield of N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine, and thus improving the product yield. This breaks the conventional perception that adding reaction steps will lead to a decrease in yield, demonstrating the innovation of the present invention.

[0007] Optionally, in step 1, the iodine reagent is at least partially dissolved in a solvent, and the solvent used for 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole (III) and the iodine reagent is one or more of alcohols, benzenes, nitriles, and ethers; or, in step 2, the solvent used for ethylenediamine is one or more of alcohols, benzenes, nitriles, and ethers.

[0008] Optionally, in step 1, the solvent used for the 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole (III) is toluene or chlorobenzene; the solvent used for the iodination reagent is methanol, ethanol, acetonitrile or isopropanol.

[0009] Optionally, in step 2, the solvent used for the ethylenediamine is methanol, ethanol, acetonitrile or isopropanol.

[0010] Optionally, in step 1, the reaction temperature of the iodination reaction is -5-40°C; or, the reaction time of the iodination reaction is 2-4h.

[0011] Optionally, in step 1, the iodination reagent is one or more of sodium iodide, potassium iodide, cesium iodide, and elemental iodine; or, the molar ratio of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole (III) to the iodination reagent is 1:1.1-2.0.

[0012] Optionally, in step 2, the reaction temperature of the nucleophilic substitution reaction is -5-20°C; or, the reaction time of the nucleophilic substitution reaction is 1-2h.

[0013] Optionally, the molar ratio of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole (III) to ethylenediamine is 1:1.5-3.5.

[0014] Optionally, in step 1, the preparation method of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole (III) comprises the following steps: S1: Starting from ethyl trifluoroacetate (I), it reacts with hydrazine hydrate and acetyl chloride to obtain 1-chloroacetyl-2-(trifluoroacetyl)hydrazine (II); S2: 1-Chloroacetyl-2-(trifluoroacetyl)hydrazine and phosphorus oxychloride undergo dehydration cyclization reaction to obtain 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole (III).

[0015] Optionally, a method for preparing a sitagliptin intermediate further comprises the following steps: Step 3: N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine (V) reacts with hydrogen chloride to obtain the product 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (VI).

[0016] The reaction scheme of the above-mentioned method for preparing the sitagliptin intermediate of the present invention is:

[0017] Compared with the prior art, the present invention has at least the following advantages: 1) The preparation method of the present invention adds an iodination step to the existing synthetic route to prepare an active intermediate 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole (IV), which has not yet obtained a CAS number and has not been reported. The intermediate does not need to be purified and is directly used in the subsequent synthesis, thereby significantly improving the yield of N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine (V), thereby improving the product yield. The combined yield of steps one and two can reach more than 80%, and can reach up to 85%. This is a significant improvement compared to the yield of only 65% in a process without iodination. This is because the radius of the iodine atom is significantly larger than that of the chlorine atom, which makes the electron cloud overlap of the C-I bond lower than that of the C-Cl bond, resulting in a longer C-I bond length and lower bond energy. The lower bond energy makes the iodide more easily substituted in the nucleophilic substitution reaction, which can significantly increase the main reaction rate and reduce the occurrence of side reactions; 2) The N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine (V) prepared by the present invention has a high purity of up to 99.2%. Due to the high purity of the intermediate V, the final product has good quality; 3) The preparation method of the present invention has mild reaction conditions, is easy to operate, is easy to scale up industrially, and has obvious economic and social benefits. DETAILED DESCRIPTION

[0018] The present invention is described below by way of specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit and scope of the inventive concept, any changes and advantages that can be imagined by those skilled in the art are included in the present invention, and the scope of protection of the present invention is defined by the appended claims and any equivalents thereof.

[0019] Unless otherwise defined, all technical terms and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present disclosure belongs. Unless otherwise specified, the raw materials and equipment used in the present invention are conventional raw materials and equipment in the art and can be obtained from conventional commercial channels; unless otherwise specified, the methods used in the present invention are conventional methods in the art. It should be noted that, in accordance with the IUPAC naming rules, both 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole (5-(iodomethyl)-2-(trifluoromethyl)-1,3,4-oxadiazole) and 2-iodomethyl-5-trifluoromethyl-1,3,4-oxadiazole (2-(iodomethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole) are acceptable. In this application, the expression 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole (5-(iodomethyl)-2-(trifluoromethyl)-1,3,4-oxadiazole) is uniformly adopted.

[0020] The following explanations are given for each compound in the following examples: Compound 1: ethyl trifluoroacetate; Compound II 1-chloroacetyl-2-(trifluoroacetyl)hydrazine; Compound III 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole; Compound IV 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole; Compound V N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazide; Compound VI 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride.

[0021] A method for preparing a sitagliptin intermediate of the present invention comprises the following steps: (1) Starting from ethyl trifluoroacetate (I), it reacts with hydrazine hydrate and acetyl chloride to obtain compound II; (2) Compound II and phosphorus oxychloride undergo a dehydration cyclization reaction to obtain compound III; (3) Compound III is subjected to iodination reaction to obtain compound IV; (4) Compound IV reacts with ethylenediamine through a nucleophilic substitution reaction to obtain compound V; (5) Compound V reacts with hydrogen chloride in alcohol to obtain compound VI (product).

[0022] The present invention focuses on adding an iodination reaction step based on the existing synthesis route. The above steps (1), (2) and (5) are existing synthetic processes that have been disclosed. Since the experimental operation procedures and process parameters of these existing steps have been fully disclosed in relevant technical literature, in order to avoid redundancy, this patent will no longer elaborate on them. The following examples will focus on the newly added process steps (3) and (4) of the present invention.

[0023] In the following examples, the yield of compound V is the combined yield of step 1 and step 2, calculated as follows: yield = amount of compound V / amount of compound III.

[0024] The purity analysis method of Compound V in the following Examples and Comparative Examples is as follows: Methanol (HPLC), sodium hydroxide (AR), phosphoric acid (AR), purified water; Chromatographic conditions: Chromatograph: High performance liquid chromatograph with DAD or VWD detector; Chromatographic column: ChromCore C18, 4.6×250mm, 5μm or similar; Mobile phase A: 0.1% phosphoric acid aqueous solution, adjusted to pH 7.0 with 30% sodium hydroxide solution Mobile phase B: methanol Diluent: Mobile phase A: Mobile phase B = 70:30 Detection wavelength (UV): 215 nm; flow rate: 1.0 ml / min; injection volume: 10 μl; column temperature: 25°C; The running gradient table is shown in Table 1.

[0025] Table 1. Run gradient table. Time / min Mobile phase A / % Mobile phase B / % 0 95 5 20 85 15 40 10 90 45 10 90 46 95 5 55 95 5

[0026] Example 1: A method for preparing a sitagliptin intermediate comprises the following steps: Synthesis of Compound IV: 65 g of methanol and 80 g (0.538 mol) of solid sodium iodide were added to a four-necked flask; after the addition, the mixture was stirred at room temperature until the sodium iodide was not completely dissolved; 300 g of a toluene solution of Compound III (the actual effective amount of Compound III in the solution was 50 g, 0.269 mol) was quickly added to carry out an iodination reaction, and the reaction temperature was controlled to 25° C. and stirred for 4 hours. After the reaction was completed, the mixture was naturally heated to room temperature to obtain a mixed solution of Compound IV. The mixed solution did not require purification operations such as distillation and extraction and could be directly used in subsequent synthetic reactions.

[0027] Synthesis of compound V: Add 270g of methanol and 56.6g of ethylenediamine (0.941mol) to a four-necked flask; after the addition is completed, move the mixture into a refrigerator and stir, control the temperature inside the refrigerator to -5°C, and after the temperature inside the refrigerator drops to this temperature, slowly add the mixed solution of the above-mentioned compound IV dropwise to carry out a nucleophilic substitution reaction. After the addition is completed, keep warm and stir for 2h, then filter the product, rinse with a small amount of ethanol, place the filter cake in a vacuum oven, and dry it at 40°C to constant weight to obtain compound V.

[0028] After detection and analysis, the mass of compound V was 48.0 g, the amount of substance was 0.228 mol, the yield was 85%, and the purity was 99.5%.

[0029] The obtained compound IV was analyzed by high resolution mass spectrometry (HRMS) using electrospray ionization mode (ES + ), the calculated molecular ion plus proton peak ([M+H] + ) has a theoretical mass-to-charge ratio of 278.9237, while the mass-to-charge ratio obtained in the actual test is 278.9234. The measured value is highly consistent with the theoretical calculated value. This result shows that the molecular mass of the prepared or tested compound is consistent with the expected molecular weight of 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole.

[0030] The obtained compound IV was subjected to nuclear magnetic resonance hydrogen spectrum ( 1 H NMR analysis was performed using a 400 MHz instrument with deuterated DMSO (dimethyl sulfoxide) as the solvent. The spectrum showed only a single peak (s) at a chemical shift δ (ppm) of 4.72, with the integrated area corresponding to two hydrogen atoms (2H). This peak was attributed to the hydrogen atoms on the iodomethyl group (-CH2I) in the structure of 2-iodomethyl-5-trifluoromethyl-1,3,4-oxadiazole. The appearance of the single peak indicated that the two hydrogen atoms on the iodomethyl group were in exactly the same chemical environment, which was consistent with the structural characteristics of the target compound and further confirmed the structural correctness of the compound.

[0031] Example 2: A method for preparing a sitagliptin intermediate comprises the following steps: Synthesis of Compound IV: 65 g of ethanol and 49 g (0.296 mol) of solid potassium iodide were added to a four-necked flask; after the addition, the mixture was stirred at room temperature until the sodium iodide was not completely dissolved; 300 g of a chlorobenzene solution of Compound III (the actual effective amount of Compound III in the solution was 50 g, 0.269 mol) was quickly added to carry out an iodination reaction. The reaction temperature was controlled to 40° C. and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature to obtain a mixed solution of Compound IV. The mixed solution did not require purification operations such as distillation and extraction and could be directly used in subsequent synthetic reactions.

[0032] Synthesis of compound V: 270 g of ethanol and 24.3 g of ethylenediamine (0.404 mol) were added to a four-necked flask; after the addition was completed, the mixture was moved into a refrigerator and stirred, and the temperature inside the refrigerator was controlled to 20°C. After the temperature inside the refrigerator dropped to this temperature, the mixed solution of the above-mentioned compound IV was slowly added dropwise to carry out a nucleophilic substitution reaction. After the addition was completed, the mixture was kept warm and stirred for 1 hour, and then the product was filtered, rinsed with a small amount of ethanol, and the filter cake was placed in a vacuum oven and dried at 40°C to constant weight to obtain compound V.

[0033] After detection and analysis, the mass of compound V was 45.1 g, the amount of substance was 0.214 mol, the yield was 80%, and the purity was 99.3%.

[0034] Example 3: A method for preparing a sitagliptin intermediate comprises the following steps: Synthesis of Compound IV: 65 g of acetonitrile and 140 g (0.538 mol) of solid cesium iodide were added to a four-necked flask; after the addition of the materials, the mixture was stirred at room temperature until the cesium iodide was not completely dissolved; 300 g of a toluene solution of Compound III (the actual effective amount of Compound III in the solution was 50 g, 0.269 mol) was quickly added to carry out an iodination reaction, and the reaction temperature was controlled to 10° C. and stirred for 3 hours. After the reaction was completed, the mixture was naturally heated to room temperature to obtain a mixed solution of Compound IV. The mixed solution did not require purification operations such as distillation and extraction and could be directly used in subsequent synthetic reactions.

[0035] Synthesis of compound V: 270 g of acetonitrile and 45.3 g of ethylenediamine (0.753 mol) were added to a four-necked flask; after the addition was completed, the mixture was moved into a refrigerator and stirred, and the temperature inside the refrigerator was controlled to 10°C. After the temperature inside the refrigerator dropped to this temperature, the mixed solution of the above-mentioned compound IV was slowly added dropwise to carry out a nucleophilic substitution reaction. After the addition was completed, the mixture was kept warm and stirred for 2 hours, and then the product was filtered, rinsed with a small amount of ethanol, and the filter cake was placed in a vacuum oven and dried at 40°C to constant weight to obtain compound V.

[0036] After detection and analysis, the mass of compound V was 46.3 g, the amount of substance was 0.22 mol, the yield was 82%, and the purity was 99.2%.

[0037] Example 4: A method for preparing a sitagliptin intermediate comprises the following steps: Synthesis of Compound IV: 65 g of isopropanol and 60 g (0.400 mol) of solid sodium iodide were added to a four-necked flask; after the addition, the mixture was stirred at room temperature until the sodium iodide was not completely dissolved; 300 g of a toluene solution of Compound III (the actual effective amount of Compound III in the solution was 50 g, 0.269 mol) was quickly added to carry out an iodination reaction, and the reaction temperature was controlled to -5°C, stirred at this temperature for 4 hours, and after the reaction was completed, the mixture was naturally heated to room temperature to obtain a mixed solution of Compound IV. The mixed solution did not require purification operations such as distillation and extraction and could be directly used in subsequent synthetic reactions.

[0038] Synthesis of compound V: 270 g of isopropanol and 56.6 g of ethylenediamine (0.941 mol) were added to a four-necked flask; after the addition was completed, the mixture was moved into a refrigerator and stirred, and the temperature inside the refrigerator was controlled to -5°C. After the temperature inside the refrigerator dropped to this temperature, the mixed solution of the above-mentioned compound IV was slowly added dropwise to carry out a nucleophilic substitution reaction. After the addition was completed, the mixture was kept warm and stirred for 2 hours, and then the product was filtered, rinsed with a small amount of ethanol, and the filter cake was placed in a vacuum oven and dried at 40°C to constant weight to obtain compound V.

[0039] After detection and analysis, the mass of compound V was 46.9 g, the amount of substance was 0.223 mol, the yield was 83%, and the purity was 99.3%.

[0040] Comparative Example 1 The difference between this comparative example and Example 1 is: Synthesis of Compound V: 270 g of methanol and 65 g of ethylenediamine (1.08 mol) were added to a four-necked flask. After the addition was complete, the mixture was placed in a refrigerator with stirring and the internal temperature was controlled at -20°C. After the internal temperature dropped to this temperature, the mixed solution of Compound IV was slowly added dropwise to carry out a nucleophilic substitution reaction. After the addition was completed, the mixture was stirred at this temperature for 2 hours. The resultant was then filtered and rinsed with a small amount of ethanol. The filter cake was placed in a vacuum oven at 40°C and dried to constant weight to obtain Compound V. Analysis showed that the mass of Compound V prepared in this comparative example was 39.6 g, the amount of substance was 0.188 mol, and the yield was 70%.

[0041] Comparative Example 2 The difference between this comparative example and Example 1 is: Synthesis of Compound IV: 65 g of methanol and 100 g (0.667 mol) of solid sodium iodide were added to a four-necked flask; after the addition of the materials, the mixture was stirred at room temperature until the sodium iodide was not completely dissolved; 300 g of a toluene solution of Compound III (the actual effective amount of Compound III in the solution was 50 g, 0.269 mol) was quickly added to carry out an iodination reaction, and the reaction temperature was controlled to -10°C, stirred at this temperature for 4 hours, and after the reaction was completed, the mixture was naturally heated to room temperature to obtain a mixed solution of Compound IV. The mixed solution does not require purification operations such as distillation and extraction and can be directly used in subsequent synthetic reactions.

[0042] After detection and analysis, the mass of the compound V prepared in this comparative example was 41.8 g, the amount of substance was 0.199 mol, and the yield was 74%.

[0043] Comparative Example 3: This comparative example adopts the existing synthesis process to directly synthesize compound V from compound III, and the steps are as follows: Synthesis of Compound V: Add 270 g of methanol and 56.6 g of ethylenediamine (0.941 mol) to a four-necked flask; after adding the materials, move it into a refrigerator with stirring and cool it to an internal temperature of -5°C; after cooling, slowly add dropwise 300 g of a toluene solution of Compound III (the actual effective amount of Compound III in the solution is 50 g, 0.269 mol), and after the addition is complete, keep warm and stir for 6 hours; filter, rinse with a small amount of ethanol, place the filter cake in a vacuum oven, and dry it at 40°C to constant weight to obtain Compound V.

[0044] After detection and analysis, the mass of compound V prepared in this comparative example was 36.7 g, 0.174 mol, the yield was 65%, and the purity was 98.5%.

[0045] Comparing the test results of Examples 1-4 and Comparative Example 3, it can be seen that the yield of Compound V prepared in Examples 1-4 can reach more than 80%, and can reach up to 85%, while the yield of Comparative Example 3 without iodination reaction is only 65%. It can be proved that the preparation method of the present invention adds an iodination reaction step on the basis of the existing synthesis route, which can significantly improve the yield of Compound V.

[0046] Comparing the test results of Example 1 and Comparative Examples 1-2, it can be seen that the yield of Compound V obtained beyond the process range is significantly reduced, which can be proved that the preparation method of the present invention can significantly improve the yield of Compound V by precisely controlling the process parameters.

[0047] Unless otherwise specified, the raw materials and equipment used in the present invention are commonly used in the art; the methods used in the present invention are conventional methods in the art unless otherwise specified.

[0048] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent transformation made to the above embodiment based on the technical essence of the present invention still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing a sitagliptin intermediate, characterized in that: The following steps are involved: Step 1: iodination reaction is carried out between a 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole solution and an iodine reagent to obtain a mixed solution containing 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole; Step 2: Mixing a mixed solution containing 5-iodomethyl-2-trifluoromethyl-1,3,4-oxadiazole with an ethylenediamine solution to carry out a nucleophilic substitution reaction to obtain N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine.

2. The method for preparing a sitagliptin intermediate according to claim 1, wherein In step 1, the iodination reagent is at least partially dissolved in a solvent, and the solvent used for 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole and the iodination reagent is one or more of alcohols, benzenes, nitriles, and ethers; or, in step 2, the solvent used for ethylenediamine is one or more of alcohols, benzenes, nitriles, and ethers.

3. The method for preparing a sitagliptin intermediate according to claim 2, wherein In step 1, the solvent used for the 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole is toluene or chlorobenzene; the solvent used for the iodination reagent is methanol, ethanol, acetonitrile or isopropanol.

4. The method for preparing a sitagliptin intermediate according to claim 2, wherein In step 2, the solvent used for the ethylenediamine is methanol, ethanol, acetonitrile or isopropanol.

5. The method for preparing a sitagliptin intermediate according to claim 1, wherein In step 1, the reaction temperature of the iodination reaction is -5-40° C.; or, the reaction time of the iodination reaction is 2-4 h.

6. The method for preparing a sitagliptin intermediate according to claim 1, wherein In step 1, the iodination reagent is one or more of sodium iodide, potassium iodide, cesium iodide, and elemental iodine; or the molar ratio of the 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole to the iodination reagent is 1:1.1-2.

0.

7. The method for preparing a sitagliptin intermediate according to claim 1, wherein In step 2, the reaction temperature of the nucleophilic substitution reaction is -5-20° C.; or, the reaction time of the nucleophilic substitution reaction is 1-2 h.

8. The method for preparing a sitagliptin intermediate according to claim 1, wherein The molar ratio of the 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole to ethylenediamine is 1:1.5-3.

5.

9. The method for preparing a sitagliptin intermediate according to any one of claims 1 to 8, characterized in that: In step 1, the preparation method of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole The following steps are involved: S1: Starting from ethyl trifluoroacetate, it reacts with hydrazine hydrate and acetyl chloride to obtain 1-chloroacetyl-2-(trifluoroacetyl)hydrazine; S2: 1-Chloroacetyl-2-(trifluoroacetyl)hydrazine and phosphorus oxychloride undergo a dehydration cyclization reaction to obtain 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole.

10. The method for preparing a sitagliptin intermediate according to any one of claims 1 to 8, characterized in that: The following steps are also included: Step 3: N-[(2Z)-piperazine-2-ylidene]-2,2,2-trifluoroacetylhydrazine is reacted with hydrogen chloride to obtain the product 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride.

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