A method for industrial production of saxagliptin

Abstract

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

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 2 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 non-natural amino acids.

[0005] The peptidomimetic is formed by linking (S)-(3-hydroxyadamantan-1-yl)glycine (adamantane moiety) and (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (cyclopropylpyrrolidine moiety) via an amide bond. The synthesis of saxagliptin is achieved by combining two fragments: an azabicyclohexane derivative fragment and an adamantane derivative fragment are synthesized 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 product is dehydrated with trifluoroacetic anhydride or trichloroacetyl chloride and deprotected under alkaline conditions to obtain (S)-2-{(1S,3S,5S)-3-cyano-2-azabicyclo[3,1,0]hexan-2-yl}-1-[(3-hydroxyadamantan-1-yl)-2-oxoethyl]tert-butoxycarboxamide. The protecting groups are then removed with hydrochloric acid or trifluoroacetic acid, and saxagliptin is obtained after alkalization. The total yield is 46.71%.

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

[0010]

[0011] This method uses (S)-(3-hydroxyadamantan-1-yl)glycine as the raw material. First, the amino and hydroxy groups are protected in the presence of ethyl trifluoroacetate and trifluoroacetic anhydride to generate the compound (S)-2-trifluoroacetylamino-2-[3-(trifluoroacetoxy)adamantan-1-yl]acetic acid. This is then reacted with a Vilsmeier reagent to obtain an acyl chloride, which is then reacted with (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride to obtain a condensation product. Finally, the oxygen protecting group is hydrolyzed under alkaline conditions, and the amino protecting group is removed by reduction with sodium borohydride to obtain saxagliptin. The total yield is 37.87%.

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

[0013]

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

[0015] The above method has the disadvantages of using expensive reagents, such as expensive EDC / HOBt as a condensation reagent, trifluoroacetic anhydride as a dehydration reagent and amino protection reagent, and Vilsmeier reagent as an acylation reagent. Furthermore, the method uses a high-risk reaction of noble metal catalytic hydrogenation, which results in high process risks and a low overall yield. 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 industrialized method for preparing saxagliptin with low raw material cost, simple preparation process, safety, environmental protection and high product yield. Summary of the Invention

[0017] To address the shortcomings of the prior art, the present invention provides a method for industrially preparing saxagliptin. The present invention prepares saxagliptin through a four-step reaction, resulting in a simple preparation method. The reagents used are highly industrialized, inexpensive, and readily available. The overall route meets industrialization requirements and is environmentally friendly, safe, and environmentally friendly. The reaction has high selectivity, few side reactions, and a high yield and purity of the target product.

[0018] The technical solutions of the present invention are as follows:

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

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

[0021]

[0022] (2) Compound III undergoes a dehydration reaction under the action of a dehydrating agent 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 present invention, preferably, in step (1), 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; and the molar ratio of the acid binding agent to compound I is 3-5:1.

[0030] According to the present invention, preferably, 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 to the system under stirring conditions; the addition time is 1-3 hours.

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

[0033] According to a preferred embodiment of the present invention, in step (1), after the reaction is completed, the post-treatment step of the reaction solution is as follows: the reaction solution is subjected to reduced pressure distillation to obtain compound II.

[0034] According to the present invention, preferably, the dehydration reaction in step (2) is carried out in solvent B or in the absence of a solvent; the solvent B is acetonitrile, DMF, or DMSO; and 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 a 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] According to the preferred embodiment of the present invention, the reaction temperature in step (2) is 20-80° C., the reaction time is 1-12 h, and the reaction is carried out under stirring conditions.

[0037] According to a preferred embodiment of the present invention, 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 solvent C is 0.1-0.5 mol / L.

[0039] According to the present invention, preferably, in step (3), 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; and the molar ratio of the acid binding agent to compound II is 1-5:1, preferably 3:1.

[0040] According to the preferred embodiment of the present invention, in step (3), the acid binding agent is added dropwise to 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] According to the preferred embodiment of the present invention, the reaction temperature in step (3) is room temperature, the reaction time is 1-5 hours, and the reaction is carried out under stirring conditions.

[0043] According to a preferred embodiment of the present invention, in step (3), after the reaction is completed, the post-treatment step of the reaction solution is as follows: the reaction solution is washed with water, washed with saturated brine, dried, and concentrated to obtain compound V.

[0044] According to the present invention, preferably, 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 solvent D is 1:5-30 g / mL.

[0045] Preferably, according to the present invention, the acid in step (4) 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 conditions; the dropwise addition rate is 1-10 ml / min.

[0046] According to the preferred embodiment of 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] According to the preferred embodiment of the present invention, the post-treatment step of the reaction solution obtained by the deprotection reaction in step (4) is as follows: water is added to the reaction solution, the pH of the system is adjusted to 9-10 with an aqueous sodium hydroxide solution, and an organic phase is extracted with dichloromethane. The organic phase is concentrated under reduced pressure, and the concentrate is dissolved in methanol, and then cooled for crystallization, 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 stir at 0-50°C for 0.5-2h; then add oxalyl chloride dropwise at 0-50°C with stirring, and stir at 0-50°C for 0.5-3h; then remove the solvent from the resulting reaction solution by distillation under reduced pressure to obtain compound II;

[0050] (2) Compound III and a dehydrating agent are uniformly mixed, subjected to a dehydration reaction, and then subjected 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 complete, the reaction is continued with stirring. After the reaction is completed, deionized water is added and stirred for washing. The upper organic phase is separated by standing and layering. Saturated saline is added and stirred for washing. The upper organic phase is separated by standing and layering. Anhydrous sodium sulfate is added for drying. 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 completion of the addition, the mixture is stirred for reaction. Water is then added, and an aqueous sodium hydroxide solution is added to adjust the pH 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, cooling the mixture for crystallization, and 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 a four-step reaction, which is simple. The raw materials used are all highly industrialized, cheap and readily available reagents, avoiding the use of expensive EDC / HOBt, trifluoroacetic anhydride, Vilsmeier reagents, etc.; the high-risk reaction of precious metal catalytic hydrogenation is not used, and the process is safe. The overall route of the present invention is low-cost, green, safe and environmentally friendly, and meets industrial requirements.

[0057] 2. The preparation method provided by the present invention can realize industrialized 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. The adamantane part and the cyclopropylpyrrolidine part are first modified and then condensed. The step with high reaction difficulty is placed at the front, which greatly improves the molecular utilization rate and total yield.

[0059] 4. The adamantane synthesis portion 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 with hydroxyl protection, thereby improving both the condensation reaction efficiency and the reaction selectivity, avoiding the formation of impurities, and ensuring yield and quality.

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

[0061] 6. The dehydrating agent used in the cyano reaction of the present invention has a low boiling point and is easily recyclable, reducing environmental and cost pressures. 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 unprotecting the hydroxyl group and directly using the relatively expensive trichloro-s-triazine as the condensing agent, the condensation selectivity is better, the impurities are reduced, the yield is higher, and it has a greater cost advantage. 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; unless otherwise specified, the methods described are all commonly used methods in the art.

[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 temperature was raised to room temperature and stirred for 2 hours. The reaction liquid 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 temperature was raised to room temperature and stirred for 2 hours. The reaction liquid 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 temperature was raised to room temperature and stirred for 2 hours. The reaction liquid 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] Compound III (0.10 mol) was added to 1 mol of thionyl chloride at room temperature, and the temperature was raised to 80°C with stirring for 2 h. The reaction liquid was then 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] Compound III (0.10 mol) was added to 1 mol of thionyl chloride at room temperature, and the temperature was raised to 60°C with stirring for 2 h. The reaction liquid was then 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] Compound III (0.10 mol) was added to 0.5 mol of sulfurous acid chloride at room temperature, and the reaction was stirred at 80 °C for 2 h. The unreacted sulfurous acid chloride was removed by distillation under reduced pressure to obtain compound IV at 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] 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 at room temperature, and triethylamine (0.30 mol) was added dropwise under stirring for 0.5 h. After the completion of the dropwise addition, the reaction was stirred for 3 h. After the completion of the reaction, 200 ml of deionized water was added to the reaction mixture, and the mixture was stirred and washed. The upper organic layer was separated by standing. 200 ml of saturated brine was further added to the reaction mixture, and the mixture was stirred and washed. The lower organic layer was separated by standing. 20.00 g of anhydrous sodium sulfate was added to the separated organic layer to dry the same. The dried organic layer was concentrated to remove the solvent to obtain compound V at a molar yield of 98.0% and a purity of 99.35%.

[0091] Example 8

[0092] Preparation of compound V

[0093] 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 at room temperature, and triethylamine (0.30 mol) was added dropwise under stirring for 0.5 h. After the completion of the dropwise addition, the reaction was stirred for 3 h. After the completion of the reaction, 200 ml of deionized water was added to the reaction mixture, and the mixture was stirred and washed. The lower organic layer was separated by standing. 200 ml of saturated brine was further added to the reaction mixture, and the mixture was stirred and washed. The lower organic layer was separated by standing. 20.00 g of anhydrous sodium sulfate was added to the separated organic layer to dry the same. The dried organic layer was concentrated to remove the solvent to obtain compound V at 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 of 200 mL of water and isopropanol (volume ratio of 1:1). Aqueous hydrochloric acid solution (20 ml, 3 mol / L) was added dropwise at 55 ° C with stirring for 5 min. The mixture was stirred at 40 ° C for 2 hours, and then 100 mL of water was added. The pH value of the mixture was adjusted to 9-10 with a 5% mass concentration of sodium hydroxide aqueous solution. The organic phase was extracted with dichloromethane (100 ml * 3) and collected, concentrated under reduced pressure, and then 50 ml of methanol was added to dissolve the mixture by heating. The temperature was lowered to 0-5 ° C for crystallization for 3 h. 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 of 200 mL of water and isopropanol (volume ratio of 1:2). Aqueous hydrochloric acid solution (20 ml, 3 mol / L) was added dropwise at 55 ° C with stirring for 5 min. The mixture was stirred at 40 ° C for 2 hours, and then 100 mL of water was added. The pH value of the mixture was adjusted to 9-10 by 5% sodium hydroxide aqueous solution. The organic phase was extracted with dichloromethane (100 ml * 3) and collected, concentrated under reduced pressure, and then 50 ml of methanol was added to dissolve the mixture by heating. The temperature was lowered to 0-5 ° C for crystallization for 3 h. 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, compound I reacts with acyl chloride in the presence of an acid-binding agent to obtain compound II; Solvent A is one or a mixture of ethyl acetate, acetonitrile or dichloromethane; the acid-binding agent is an inorganic base or an organic base; the acyl chloride is a combination of acetyl chloride and oxalyl chloride or a combination of acetyl chloride and thionyl chloride; I II (2) Under the action of a dehydrating agent, compound III undergoes a dehydration reaction to obtain compound IV; The dehydrating agent is thionyl chloride; the reaction temperature is 80°C; III IV (3) In solvent C, under the action of an acid-binding agent, compound II and compound IV react to obtain compound V; Solvent C is ethyl acetate, acetonitrile or dichloromethane; the acid binding agent is an inorganic base or an organic base; V (4) In solvent D, under the action of acid, compound V undergoes a deprotection reaction to obtain saxagliptin VI; Solvent D is one or a combination of isopropanol, ethanol, water or methanol; VI.

2. The method for industrial preparation of saxagliptin according to claim 1, wherein In step (1), one or more of the following conditions are included: i. Solvent A is dichloromethane; the volume ratio of the molar amount of compound I to solvent A is 0.1-1 mol / L; ii. the inorganic base is selected from potassium carbonate or sodium hydroxide; the organic base is selected from diethylamine or triethylamine; the molar ratio of the acid binding agent to compound I is 3-5:1; iii. Acid chloride is added dropwise to the system under stirring; the addition time is 1-3 hours.

3. The method for industrial preparation of saxagliptin according to claim 1, wherein 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, and the molar ratio of oxalyl chloride to compound I is 1-2:

1.

4. The method for industrial preparation of saxagliptin according to claim 1, wherein 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.

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 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; ii. The molar ratio of the dehydrating agent to compound III is 1-20:

1.

6. 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 time is 1-12h; 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 IV.

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. Solvent C is ethyl acetate; the volume ratio of the molar amount of compound II to solvent C is 0.1-0.5 mol / L; ii. The inorganic base is selected from potassium carbonate or sodium hydroxide; the organic base is selected from diethylamine or triethylamine; the molar ratio of the acid binding agent to compound II is 1-5:1; iii. The acid binding agent is added dropwise to the system under stirring conditions; the addition time is 0.5-2h; The molar ratio of compound iv, compound II and compound IV is 1:1-1.

2.

8. 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, 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.

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. Solvent D is a mixture of isopropanol and water, wherein the volume ratio of isopropanol to water is 1 to 5:1; and the mass ratio of compound V to solvent D is 1:5-30 g / mL; ii. The acid is a 1-5 mol / L aqueous hydrochloric acid solution; 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 dropwise addition rate is 1-10 ml / min.

10. 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 deprotection reaction temperature 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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