Method for industrially preparing saxagliptin

Abstract

The invention provides a method for industrially preparing saxagliptin. The method comprises the following steps: reacting a compound I with acyl chloride in a solvent A under the action of an acid-binding agent to obtain a compound II; under the action of a dehydrating agent, carrying out dehydration reaction on the compound III to obtain a compound IV; reacting the compound II with a compound IV in a solvent C under the action of an acid-binding agent to obtain a compound V; in a solvent D, under the action of acid, the compound V is subjected to a deprotection reaction, and saxagliptin is obtained. The saxagliptin is prepared through four-step reaction, and the preparation method is simple; used reagents are high in industrialization degree, cheap and easy to obtain, and the whole route meets industrialization requirements and is green, safe and environmentally friendly; the reaction selectivity is high, side reactions are few, and the target product yield and purity are high.

Description

Technical Field

[0001] The invention relates to a method for industrially preparing saxagliptin, and belongs to the technical field of drug synthesis. Background Art

[0002] Saxagliptin, whose chemical name is (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile monohydrate, is a potent and selective dipeptidyl peptidase inhibitor jointly developed by Bristol-Myers Squibb and AstraZeneca Pharmaceuticals for the treatment of type II diabetes. Its chemical structure is shown below.

[0003]

[0004] In recent years, the demand for saxagliptin has increased, and the preparation technology of saxagliptin has received widespread attention. At present, the synthesis method of saxagliptin is mainly chemical synthesis. Saxagliptin is a derivative of two unnatural amino acids.

[0005] The peptidomimetic formed by connecting (S)-(3-hydroxyadamantan-1-yl)glycine (adamantane part) and (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (cyclopropylpyrrolidine part) through an amide bond. The synthesis of saxagliptin adopts the method of splicing two fragments: synthesizing the azabicyclohexane derivative fragment and the adamantane derivative fragment separately. The main synthetic route is as follows:

[0006] Patents WO2004052850, WO2013175395 and the document Preparation of Saxagliptin, a Novel DPP-IV Inhibitor. Organic Process Research & Development 2009, 13, 1169-1176 report the following synthesis method of saxagliptin:

[0007]

[0008] The method uses (S)-N-tert-butyloxycarbonyl-(3-hydroxyadamantan-1-yl)glycine and (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methanesulfonate or hydrochloride as raw materials, and undergoes a condensation reaction under EDC / HOBt conditions to obtain (S)-2-{(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3,1,0]hexane-2-yl}-1-[(3-hydroxyadamantan-1-yl)glycine. The method comprises the following steps: preparing (S)-2-{(1S,3S,5S)-3-cyano-2-azabicyclo[3,1,0]hexane-2-yl}-1-[(3-hydroxyadamantan-1-yl)-2-oxoethyl]tert-butoxyformamide, dehydrating the tert-butoxyformamide with trifluoroacetic anhydride or trichloroacetyl chloride and deprotecting the tert-butoxyformamide under alkaline conditions, and finally removing the protecting group with hydrochloric acid or trifluoroacetic acid, and obtaining saxagliptin after alkalization. The total yield is 46.71%.

[0009] Patent WO2005094323 discloses another method for synthesizing saxagliptin:

[0010]

[0011] The method uses (S)-(3-hydroxyadamantan-1-yl)glycine as a raw material, firstly, under the action of ethyl trifluoroacetate and trifluoroacetic anhydride, the amino group and the hydroxyl group are protected respectively to generate a compound (S)-2-trifluoroacetylamino-2-[3-(trifluoroacetoxy)adamantan-1-yl]acetic acid, then reacts with a Vilsmeier reagent to obtain an acyl chloride, and then reacts with (1S, 3S, 5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride to obtain a condensation product, and finally hydrolyzes and removes the protective group on the oxygen under alkaline conditions, and reduces and removes the amino protective group with sodium borohydride to finally obtain saxagliptin. The total yield is 37.87%.

[0012] The synthesis method of saxagliptin reported in patents US8664443 and WO2013179297:

[0013]

[0014] The method uses Cbz or Bn protected S-3-hydroxyadamantane glycine as a raw material, condenses with (1S, 3S, 5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide, then dehydrates with trifluoroacetic anhydride, hydrolyzes under alkaline conditions, and finally removes the amino protecting group by catalytic hydrogenation to obtain saxagliptin. The total yield is 68.4%.

[0015] The disadvantages of the above method are that the reagents used are expensive, for example, expensive EDC / HOBt is used as a condensation reagent, trifluoroacetic anhydride is used as a dehydration reagent and an amino protection reagent, and Vilsmeier reagent is used as an acylation reagent; at the same time, the use of precious metal catalytic hydrogenation is a high-risk reaction, the process risk is large, and the total yield is low. The overall route cost is high and the industrialization of the process is not utilized.

[0016] Therefore, it is of great significance to develop an industrial method for preparing saxagliptin with low raw material cost, simple preparation process, safety, environmental protection and high product yield. Summary of the invention

[0017] In view of the deficiencies of the prior art, the present invention provides a method for industrially preparing saxagliptin. The present invention prepares saxagliptin through four-step reactions, and the preparation method is simple; the reagents used are highly industrialized, cheap and easily available, the overall route meets industrialization requirements, and is green, safe and environmentally friendly; the reaction selectivity is high, the side reactions are few, and the target product yield and purity are high.

[0018] The technical solution of the present invention is as follows:

[0019] A method for industrial preparation of saxagliptin comprises the steps of:

[0020] (1) In solvent A, in the presence of an acid-binding agent, compound I reacts with an acyl chloride to obtain compound II;

[0021]

[0022] (2) Under the action of a dehydrating agent, compound III undergoes a dehydration reaction to obtain compound IV;

[0023]

[0024] (3) Compound II and compound IV react in solvent C under the action of an acid-binding agent to obtain compound V;

[0025]

[0026] (4) In solvent D, under the action of an acid, compound V undergoes a deprotection reaction to obtain saxagliptin VI;

[0027]

[0028] According to the preferred embodiment of the present invention, the solvent A in step (1) is one or a mixture of ethyl acetate, acetonitrile or dichloromethane, preferably dichloromethane; the volume ratio of the molar amount of compound I to solvent A is 0.1-1 mol / L, preferably 0.3 mol / L.

[0029] According to the preferred embodiment of the present invention, the acid binding agent in step (1) is an inorganic base or an organic base; the inorganic base is selected from potassium carbonate or sodium hydroxide; the organic base is selected from diethylamine or triethylamine; preferably, the acid binding agent is triethylamine; and the molar ratio of the acid binding agent to compound I is 3-5:1.

[0030] Preferably, according to the present invention, the acyl chloride in step (1) is a combination of acetyl chloride and oxalyl chloride or a combination of acetyl chloride and thionyl chloride; preferably, the acyl chloride is a combination of acetyl chloride and oxalyl chloride, wherein the molar ratio of acetyl chloride to compound I is 1-1.05:1, preferably 1:1, and the molar ratio of oxalyl chloride to compound I is 1-2:1, preferably 1:1.

[0031] Preferably, according to the present invention, in step (1), the acyl chloride is added dropwise into the system under stirring conditions; the dropping time is 1-3 hours.

[0032] Preferably, according to the present invention, the reaction temperature in step (1) is 0-50°C; the reaction time is 1-5h; and the reaction is carried out under stirring conditions.

[0033] Preferably, in step (1), after the reaction is completed, the post-treatment step of the obtained reaction solution is: the reaction solution is subjected to reduced pressure distillation to obtain compound II.

[0034] Preferably, the dehydration reaction in step (2) is carried out in solvent B or in the absence of solvent; the solvent B is acetonitrile, DMF or DMSO; the mass ratio of compound III to solvent B is 5-10:1 g / mL. Preferably, the dehydration reaction is carried out in the absence of solvent.

[0035] According to the preferred embodiment of the present invention, the dehydrating agent in step (2) is thionyl chloride; the molar ratio of the dehydrating agent to compound III is 1-20:1, preferably 5-10:1, and more preferably 10:1.

[0036] Preferably, according to the present invention, the reaction temperature in step (2) is 20-80° C., and the reaction time is 1-12 h; the reaction is carried out under stirring conditions.

[0037] Preferably, in step (2), after the reaction is completed, the post-treatment step of the obtained reaction solution is: the reaction solution is subjected to reduced pressure distillation to obtain compound IV.

[0038] According to the preferred embodiment of the present invention, the solvent C in step (3) is ethyl acetate, acetonitrile or dichloromethane, preferably ethyl acetate; the volume ratio of the molar amount of compound II to the solvent C is 0.1-0.5 mol / L.

[0039] According to the preferred embodiment of the present invention, the acid binding agent in step (3) is an inorganic base or an organic base; the inorganic base is selected from potassium carbonate or sodium hydroxide; the organic base is selected from diethylamine or triethylamine; preferably, the acid binding agent is triethylamine; the molar ratio of the acid binding agent to compound II is 1-5:1, preferably 3:1.

[0040] Preferably, in step (3), the acid-binding agent is added dropwise into the system under stirring conditions; the addition time is 0.5-2h.

[0041] Preferably according to the present invention, the molar ratio of compound II to compound IV in step (3) is 1:1-1.2.

[0042] Preferably, according to the present invention, the reaction temperature in step (3) is room temperature, the reaction time is 1-5h; and the reaction is carried out under stirring conditions.

[0043] Preferably, in step (3), after the reaction is completed, the post-treatment step of the obtained reaction solution is: the reaction solution is washed with water, washed with saturated brine, dried, and concentrated to obtain compound V.

[0044] Preferably according to the present invention, the solvent D in step (4) is one or a combination of two of isopropanol, ethanol, water or methanol, preferably a mixture of isopropanol and water, wherein the volume ratio of isopropanol to water is 1-5:1, preferably 1:1; the mass ratio of compound V to the volume ratio of solvent D is 1:5-30 g / mL.

[0045] Preferably, in step (4), the acid is a hydrochloric acid aqueous solution with a concentration of 1-5 mol / L; the mass ratio of compound V to the acid is 1:0.5-5 g / mL; the acid is added dropwise to the system under stirring; and the dropwise addition rate is 1-10 ml / min.

[0046] Preferably, according to the present invention, the temperature of the deprotection reaction in step (4) is 0-80° C., and the reaction time is 1-5 h; the reaction is carried out under stirring conditions.

[0047] Preferably, according to the present invention, the post-treatment step of the reaction solution obtained by the deprotection reaction in step (4) is: adding water to the reaction solution, adjusting the pH of the system to 9-10 with an aqueous sodium hydroxide solution, extracting with dichloromethane to obtain an organic phase, concentrating the organic phase under reduced pressure, dissolving the concentrate in methanol, and then cooling and crystallizing, solid-liquid separation, and drying to obtain saxagliptin.

[0048] According to a preferred embodiment of the present invention, the method for industrial preparation of saxagliptin comprises the steps of:

[0049] (1) Dissolve compound I in solvent A at 0-50°C, add an acid binding agent, and stir to mix evenly; then add acetyl chloride dropwise at 0-50°C with stirring, and after the addition, stir to react at 0-50°C for 0.5-2h; add oxalyl chloride dropwise at 0-50°C with stirring, and after the addition, stir to react at 0-50°C for 0.5-3h; then remove the solvent from the obtained reaction solution by distillation under reduced pressure to obtain compound II;

[0050] (2) mixing compound III and a dehydrating agent uniformly, subjecting the mixture to a dehydration reaction, and then subjecting the mixture to reduced pressure distillation to obtain a compound of formula IV;

[0051] (3) Compound II and compound IV are dissolved in solvent C, stirred evenly, and triethylamine is added dropwise under stirring. After the addition is completed, stirring is continued to react. After the reaction is completed, deionized water is added and stirred for washing, and the upper organic phase is separated by standing and layering. Saturated salt water is added and stirred for washing, and the upper organic phase is separated by standing and layering. Anhydrous sodium sulfate is added for drying, and the dried organic phase is concentrated to remove the solvent to obtain compound V;

[0052] (4) Compound V is dissolved in solvent D, and aqueous hydrochloric acid solution is added dropwise. After the addition is completed, the mixture is stirred for reaction; water is then added, and aqueous sodium hydroxide solution is added to adjust the pH value to 9-10. The organic phase is extracted with dichloromethane and collected, and concentrated under reduced pressure. Methanol is then added to dissolve the mixture by heating, and the temperature is lowered for crystallization. The suspension is centrifuged and dried to obtain saxagliptin.

[0053] The synthetic route of the present invention is as follows:

[0054]

[0055] The technical features and beneficial effects of the present invention are as follows:

[0056] 1. The present invention prepares saxagliptin through four-step reactions, and the preparation method is simple; the raw materials used are all reagents with high industrialization degree, cheap and easily available, avoiding the use of expensive EDC / HOBt, trifluoroacetic anhydride, Vilsmeier and other reagents; no high-risk reaction of noble metal catalytic hydrogenation is used, and the process is safe; the overall route of the present invention has low cost and is green, safe and environmentally friendly, and meets industrialization requirements.

[0057] 2. The preparation method provided by the present invention can realize industrial production by selecting different raw materials and reaction reagents and changing the process route. The method of the present invention has high reaction selectivity, few side reactions, and high yield and purity of saxagliptin. It can be seen that the present invention can realize low-cost, large-scale preparation of high-purity saxagliptin, with good economic benefits.

[0058] 3. The present invention adopts a convergent synthesis route, wherein the adamantane part and the cyclopropylpyrrolidine part are first modified and then condensed, and the step with high reaction difficulty is placed in the front, which greatly improves the molecular utilization rate and the total yield.

[0059] 4. The adamantane synthesis part of the present invention uses the conventional raw material N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-D-glycine as the starting material, and cleverly combines carboxyl activation and hydroxyl protection, which not only improves the reaction efficiency of condensation, but also improves the reaction selectivity, avoids the formation of impurities, and ensures the yield and quality.

[0060] 5. In the cyclopropylpyrrolidine synthesis part of the present invention, the cyano reaction uses thionyl chloride, a large conventional material, as both a dehydrating agent and a reaction solvent. After the reaction is completed, the thionyl chloride is directly evaporated, thereby realizing the recovery and utilization of the thionyl chloride, and improving the process technology from the aspects of cost and environmental protection.

[0061] 6. The dehydration reagent used in the cyano reaction of the present invention has a low boiling point and is easy to recycle, thereby reducing environmental pressure and cost pressure. In the condensation reaction step, the present invention adopts a route of first protecting the hydroxyl group, activating the carboxyl group, and then condensing. Compared with not protecting the hydroxyl group and directly using relatively expensive trichloro-s-triazine as a condensation agent, the condensation selectivity is better, the impurities are less, the yield is higher, and the cost advantage is greater. DETAILED DESCRIPTION

[0062] The present invention will be further described below with reference to specific embodiments, but is not limited thereto.

[0063] Unless otherwise specified, the raw materials used in the examples are all common commercial products; the methods described are all commonly used methods in the art unless otherwise specified.

[0064] Preparation of compound II:

[0065]

[0066] Example 1

[0067] Preparation of Compound II

[0068] At 0-5°C, compound I (0.10 mol) was dissolved in 330 ml of dichloromethane, triethylamine (0.40 mol) was added, and the mixture was stirred evenly. Acetyl chloride (0.10 mol) was slowly added dropwise under stirring for 1 hour, and the reaction was continued with stirring for 1 hour. Oxalyl chloride (0.10 mol) was slowly added dropwise for 1 hour, and the mixture was heated to room temperature and stirred for 2 hours. The reaction solution was distilled under reduced pressure to remove the solvent to obtain compound II with a molar yield of 98.5% and a purity of 99.20%.

[0069] Example 2

[0070] Preparation of Compound II

[0071] At 0-5°C, compound I (0.10 mol) was dissolved in 330 ml of dichloromethane, triethylamine (0.50 mol) was added, and the mixture was stirred evenly. Acetyl chloride (0.10 mol) was slowly added dropwise under stirring for 1 hour, and the reaction was continued with stirring for 1 hour. Oxalyl chloride (0.10 mol) was slowly added dropwise for 1 hour, and the mixture was heated to room temperature and stirred for 2 hours. The reaction solution was distilled under reduced pressure to remove the solvent to obtain compound II with a molar yield of 98.6% and a purity of 99.15%.

[0072] Example 3

[0073] Preparation of Compound II

[0074] At 0-5°C, compound I (0.10 mol) was dissolved in 330 ml of dichloromethane, triethylamine (0.40 mol) was added, and the mixture was stirred evenly. Acetyl chloride (0.10 mol) was slowly added dropwise under stirring for 1 hour, and the reaction was continued with stirring for 1 hour. Sulfonyl chloride (0.10 mol) was slowly added dropwise for 1 hour, and the mixture was heated to room temperature and stirred for 2 hours. The reaction solution was distilled under reduced pressure to remove the solvent to obtain compound II with a molar yield of 95.8% and a purity of 97.20%.

[0075] Preparation of compound IV:

[0076]

[0077] Example 4

[0078] Preparation of Compound IV

[0079] At room temperature, compound III (0.10 mol) was added to 1 mol of thionyl chloride, the temperature was raised to 80°C and stirred for reaction for 2 h, and the reaction liquid was distilled under reduced pressure to remove unreacted thionyl chloride to obtain compound IV with a molar yield of 98.4% and a purity of 98.50%.

[0080] Example 5

[0081] Preparation of Compound IV

[0082] At room temperature, compound III (0.10 mol) was added to 1 mol of thionyl chloride, the temperature was raised to 60°C and stirred for reaction for 2 h, and the reaction liquid was distilled under reduced pressure to remove unreacted thionyl chloride to obtain compound IV with a molar yield of 85.2% and a purity of 85.45%.

[0083] Example 6

[0084] Preparation of Compound IV

[0085] At room temperature, compound III (0.10 mol) was added to 0.5 mol of thionyl chloride, the temperature was raised to 80°C and stirred for reaction for 2 h, and the reaction liquid was distilled under reduced pressure to remove unreacted thionyl chloride to obtain compound IV with a molar yield of 95.5% and a purity of 94.39%.

[0086] Preparation of Compound V:

[0087]

[0088] Example 7

[0089] Preparation of Compound V

[0090] At room temperature, compound II (0.1 mol) prepared according to the method of Example 1 and compound IV (0.12 mol) prepared according to the method of Example 4 were dissolved in 500 ml of ethyl acetate and stirred evenly. Triethylamine (0.30 mol) was added dropwise under stirring for 0.5 h. The reaction was continued with stirring for 3 h. After the reaction was completed, 200 ml of deionized water was added and stirred for washing. The upper organic phase was separated by standing and stratification. 200 ml of saturated brine was added and stirred for washing. The upper organic phase was separated by standing and stratification. 20.00 g of anhydrous sodium sulfate was added for drying. The dried organic phase was concentrated to remove the solvent to obtain compound V with a molar yield of 98.0% and a purity of 99.35%.

[0091] Example 8

[0092] Preparation of Compound V

[0093] At room temperature, compound II (0.1 mol) prepared according to the method of Example 1 and compound IV (0.12 mol) prepared according to the method of Example 4 were dissolved in 500 ml of dichloromethane and stirred evenly. Triethylamine (0.30 mol) was added dropwise under stirring for 0.5 h. The reaction was continued with stirring for 3 h. After the reaction was completed, 200 ml of deionized water was added and stirred for washing. The lower organic phase was separated by standing and stratification. 200 ml of saturated brine was added and stirred for washing. The lower organic phase was separated by standing and stratification. 20.00 g of anhydrous sodium sulfate was added for drying. The dried organic phase was concentrated to remove the solvent to obtain compound V with a molar yield of 96.7% and a purity of 99.02%.

[0094] Preparation of Saxagliptin:

[0095]

[0096] Example 9

[0097] Preparation of Saxagliptin

[0098] 20 g of compound V prepared according to the method of Example 7 was weighed and dissolved in a mixed solution formed by 200 mL of water and isopropanol (volume ratio of 1:1). Aqueous hydrochloric acid solution (20 ml, 3 mol / L) was added dropwise under stirring at 55 ° C. for 5 min. The reaction was stirred at 40 ° C for 2 hours, and then 100 mL of water was added. The pH value of the mixed solution was adjusted to 9-10 by a 5% sodium hydroxide aqueous solution. The organic phase was extracted with dichloromethane (100 ml*3) and collected, and concentrated under reduced pressure. 50 ml of methanol was added to dissolve by heating, cooled to 0-5 ° C. for crystallization for 3 h, and the suspension was centrifuged and the filter cake was dried to obtain saxagliptin with a molar yield of 98.2% and an HPLC purity of 99.87%.

[0099] Example 10

[0100] Preparation of Saxagliptin

[0101] 20 g of compound V prepared according to the method of Example 7 was weighed and dissolved in a mixed solution formed by 200 mL of water and isopropanol (volume ratio of 1:2). Aqueous hydrochloric acid solution (20 ml, 3 mol / L) was added dropwise under stirring at 55 ° C. for 5 min. The reaction was stirred at 40 ° C for 2 hours, and then 100 mL of water was added. The pH value of the mixed solution was adjusted to 9-10 by a 5% sodium hydroxide aqueous solution. The organic phase was extracted with dichloromethane (100 ml*3) and collected, and concentrated under reduced pressure. 50 ml of methanol was added to dissolve by heating, cooled to 0-5 ° C. for crystallization for 3 h, and the suspension was centrifuged and the filter cake was dried to obtain saxagliptin with a molar yield of 93.3% and an HPLC purity of 99.89%.

Claims

1. A method for industrial preparation of saxagliptin, comprising the steps of: (1) In solvent A, in the presence of an acid-binding agent, compound I reacts with an acyl chloride to obtain compound II; (2) Under the action of a dehydrating agent, compound III undergoes a dehydration reaction to obtain compound IV; (3) Compound II and compound IV react in solvent C under the action of an acid-binding agent to obtain compound V; (4) In solvent D, under the action of an acid, compound V undergoes a deprotection reaction to obtain saxagliptin VI; 2. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (1), one or more of the following conditions are included: i. Solvent A is one or a mixture of ethyl acetate, acetonitrile or dichloromethane, preferably dichloromethane; the volume ratio of the molar amount of compound I to solvent A is 0.1-1 mol / L, preferably 0.3 mol / L; ii. The acid-binding agent is an inorganic base or an organic base; the inorganic base is selected from potassium carbonate or sodium hydroxide; the organic base is selected from diethylamine or triethylamine; preferably, the acid-binding agent is triethylamine; the molar ratio of the acid-binding agent to compound I is 3-5:1; iii. The acyl chloride is one or a combination of two of acetyl chloride, thionyl chloride or oxalyl chloride; preferably, the acyl chloride is a combination of acetyl chloride and oxalyl chloride or a combination of acetyl chloride and thionyl chloride; further preferably, the acyl chloride is a combination of acetyl chloride and oxalyl chloride, wherein the molar ratio of acetyl chloride to compound I is 1-1.05:1, preferably 1:1, and the molar ratio of oxalyl chloride to compound I is 1-2:1, preferably 1:1; iv. Acid chloride is added dropwise into the system under stirring; the addition time is 1-3h.

3. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (1), one or more of the following conditions are included: i. The reaction temperature is 0-50°C; the reaction time is 1-5h; the reaction is carried out under stirring; ii. After the reaction is completed, the post-treatment step of the obtained reaction solution is as follows: the reaction solution is distilled under reduced pressure to obtain compound II.

4. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (2), one or more of the following conditions are included: i. The dehydration reaction is carried out in solvent B or in the absence of solvent; the solvent B is acetonitrile, DMF or DMSO; the mass ratio of compound III to solvent B is 5-10:1 g / mL; preferably, the dehydration reaction is carried out in the absence of solvent; ii. The dehydrating agent is thionyl chloride; the molar ratio of the dehydrating agent to compound III is 1-20:1, preferably 5-10:1, and more preferably 10:

1.

5. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (2), one or more of the following conditions are included: i. The reaction temperature is 20-80°C, and the reaction time is 1-12h; the reaction is carried out under stirring conditions; ii. After the reaction is completed, the post-treatment step of the obtained reaction solution is as follows: the reaction solution is subjected to reduced pressure distillation to obtain compound IV.

6. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (3), one or more of the following conditions are included: i. Solvent C is ethyl acetate, acetonitrile or dichloromethane, preferably ethyl acetate; the volume ratio of the molar amount of compound II to solvent C is 0.1-0.5 mol / L; ii. The acid-binding agent is an inorganic base or an organic base; the inorganic base is selected from potassium carbonate or sodium hydroxide; the organic base is selected from diethylamine or triethylamine; preferably, the acid-binding agent is triethylamine; the molar ratio of the acid-binding agent to compound II is 1-5:1, preferably 3:1; iii. The acid-binding agent is added dropwise into the system under stirring conditions; the addition time is 0.5-2h; iv. The molar ratio of compound II to compound IV is 1:1-1.

2.

7. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (3), one or more of the following conditions are included: i. The reaction temperature is room temperature, and the reaction time is 1-5h; the reaction is carried out under stirring; ii. After the reaction is completed, the post-treatment steps of the obtained reaction solution are: the reaction solution is washed with water, washed with saturated brine, dried, and concentrated to obtain compound V.

8. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (4), one or more of the following conditions are included: i. Solvent D is one or a combination of isopropanol, ethanol, water or methanol, preferably a mixture of isopropanol and water, wherein the volume ratio of isopropanol to water is 1 to 5:1, preferably 1:1; the mass ratio of compound V to the volume ratio of solvent D is 1:5-30 g / mL; ii. The acid is a hydrochloric acid aqueous solution with a concentration of 1-5 mol / L; the mass ratio of compound V to the acid is 1:0.5-5 g / mL; the acid is added dropwise to the system under stirring; the dropping rate is 1-10 ml / min.

9. The method for industrial preparation of saxagliptin according to claim 1, characterized in that: In step (4), one or more of the following conditions are included: i. The temperature of the deprotection reaction is 0-80°C, and the reaction time is 1-5h; the reaction is carried out under stirring conditions; ii. The post-treatment step of the reaction solution obtained by the deprotection reaction is as follows: adding water to the reaction solution, adjusting the pH of the system to 9-10 with an aqueous sodium hydroxide solution, extracting with dichloromethane to obtain an organic phase, concentrating the organic phase under reduced pressure, dissolving the concentrate in methanol, and then cooling and crystallizing, solid-liquid separation, and drying to obtain saxagliptin.

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