A method for the synthesis of sitagliptin

Abstract

The application belongs to the technical field of chemical pharmacy, and particularly relates to a synthesis method of sitagliptin, which comprises five steps: S1, preparation of intermediate I; S2, preparation of intermediate II; S3, preparation of intermediate III; S4, preparation of intermediate IV; and S5, preparation of sitagliptin. The synthesis process is more concise and clear, the synthesis line is short, the reaction steps are significantly reduced compared with the existing synthesis method, the operation process is simplified, the production efficiency is greatly improved, so that the whole synthesis process is more efficient and controllable, the synthesis difficulty and cost are greatly reduced, the cost and environmental problems caused by the use of precious metal catalysts and toxic and dangerous chemical reagents are solved, the reaction by-products are few, the product purity can reach more than 99%, the total yield can reach more than 85%, the industrial operation and popularization are easier, and the idea of green chemistry and sustainable development is met.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical pharmacy, and particularly relates to a synthesis method of Sitagliptin. BACKGROUND

[0002] Sitagliptin is an oral DPP-IV (dipeptidyl peptidase-IV) inhibitor with the chemical name of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyrazine, which is widely used for treating type II diabetes. Its unique mechanism of action is to inhibit the activity of DPP-4 enzyme, prolong the half-life of GLP-1 (glucagon-like peptide-1) in vivo, enhance the protective effect of GLP-1 on beta cells, promote the secretion of insulin, and inhibit the release of glucagon, so as to ultimately achieve the effect of reducing blood glucose, and its structural formula is as follows:

[0003] .

[0004] There are related reports on the synthesis method of Sitagliptin. For example, US2021 / 24667 and Tetrahedron, 28(1), 34-40, 2017 disclose that 2,4,5-trifluorophenyl acetaldehyde is used as a starting material, which is first condensed with (R)-(+)-tert-butylsulfinamide to synthesize the corresponding imine compound, and then subjected to asymmetric addition, decarboxylation, hydrolysis, condensation and hydrolysis to obtain the corresponding Sitagliptin compound, and the synthesis route is as follows:

[0005] ;

[0006] This method has the defects of long steps, low yield, expensive raw materials and complex preparation process, which limits the industrial application of the method to some extent.

[0007] For example, WO2021 / 250702, US2020206221, WO2020 / 109938, US2016 / 229859, EP2789616 and the like disclose the following synthesis route:

[0008] ;

[0009] This method also has the defects of long steps, low yield and purity, complex preparation and the need for noble metal reducing agent for reduction, which also limits the industrial application of the method to some extent.

[0010] The prior art has a study on low yield in the synthesis process of sitagliptin, such as patent application CN116478169A - a synthesis method of sitagliptin, which is obtained by reacting compound III, compound IV and trifluoromethylation reagent with alkaline reagent under the action of chiral catalyst to obtain compound V, and then reducing compound V by hydrogen to obtain sitagliptin, and the synthesis route is as follows:

[0011] ;

[0012] The synthesis method has relatively complex overall steps, uses chiral catalyst and precious palladium-carbon catalyst (Pd / C), the cost of these catalysts is high, which is easy to cause negative impact on the environment, and the hydrogen reduction reaction needs to be carried out in a high-pressure reaction kettle in the second step, which increases the operation difficulty and safety hazard, and is easy to produce by-products in the synthesis process, resulting in low total yield, so that the actual application is also limited to a certain extent. Therefore, a new technical solution is needed to solve the above technical problems. SUMMARY

[0013] The purpose of the present application is to provide a synthesis method of sitagliptin to solve the problems of using precious metal reagents, producing impurities, low yield, high cost, harmful substance emission affecting environmental protection and the like in the current synthesis process of sitagliptin.

[0014] To achieve the above purpose, the present application provides the following technical solution: a synthesis method of sitagliptin, comprising the following specific steps:

[0015] S1, preparation of intermediate I: methyl acetate and 2,4,5-trifluorobenzene acetaldehyde are used as starting materials, dissolved in a reaction solvent, and an aldol condensation reaction occurs under the catalysis of proline to obtain intermediate I, wherein the molar ratio of 2,4,5-trifluorobenzene acetaldehyde, methyl acetate and proline is 1:1.0-2.0:1.0-5.0, and the reaction solvent is acetonitrile;

[0016] S2, preparation of intermediate II: intermediate I obtained in S1 is dissolved in a reaction solvent, and a carboxylic acid ester ammonolysis reaction occurs with an ammonolysis reagent to obtain intermediate II, wherein the ammonolysis reagent is one of ammonia, methanol ammonia and ethanol amine, and the reaction solvent is one or a mixture of several of methanol, tetrahydrofuran, acetonitrile, ethanol, dioxane and acetone;

[0017] S3, preparation of intermediate III: intermediate II obtained in S2 is dissolved in a reaction solvent, and a β-lactam condensation cyclization occurs with a condensing agent under the action of a catalyst to obtain an intermediate III transition state, wherein the catalyst is tetrabutylammonium fluoride, the condensing agent is N,O-bis(trimethylsilyl)acetamide, and the reaction solvent is one or a mixture of several of toluene, tetrahydrofuran, acetonitrile, ethanol, dioxane, acetone and isopropyl acetate.

[0018] S4, preparation of intermediate IV: the transition state of intermediate III obtained in S3 is subjected to hydrolysis reaction with a basic reagent to obtain intermediate IV, wherein the basic reagent is one or a mixture of several of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide;

[0019] S5, preparation of sitagliptin: intermediate IV obtained in S4 is dissolved in a reaction solvent, and subjected to acylation reaction with intermediate V and a condensing agent under the action of a basic catalyst to obtain the final product sitagliptin, wherein the molar ratio of intermediate IV to intermediate V is 1:1.0-2.0, the molar ratio of intermediate IV to the condensing agent is 1:0.5-2.5, and the molar ratio of intermediate IV to the basic catalyst is 1:1.0-10.0, wherein the condensing agent is O-benzotriazol-tetramethyluronium hexafluorophosphate, the basic catalyst is N-methylimidazole, and the reaction solvent is one or a mixture of several of toluene, tetrahydrofuran, acetonitrile, isopropyl acetate, dioxane, dimethylbenzene, and acetone;

[0020] According to the above specific synthesis steps, the overall synthesis route of sitagliptin is as follows:

[0021] .

[0022] Compared with the prior art, the beneficial effects of the present application are:

[0023] 1. The present application adopts a five-step synthesis process of aldol condensation-ammonolysis of carboxylic acid ester-β-lactam condensation and cyclization-hydrolysis-acylation, which makes the synthesis process of sitagliptin more concise and clear, effectively shortens the synthesis route of sitagliptin, significantly reduces the reaction steps compared with the existing synthesis method, simplifies the operation process, and greatly improves the production efficiency, so that the entire synthesis process is more efficient and controllable, greatly reduces the synthesis difficulty and cost, effectively avoids the use of precious metal catalysts and toxic and dangerous chemical reagents (such as palladium-carbon catalysts) by optimizing the reaction conditions and selecting suitable catalysts, reaction solvents, etc., effectively reduces the production cost, reduces the emission of harmful substances, is more friendly to the environment, and also makes the synthesis reaction conditions of sitagliptin more mild, without the need for extreme conditions such as high pressure or high temperature, reduces the operation difficulty and safety risk, reduces the generation of reaction byproducts, thereby effectively improving the purity of sitagliptin product to more than 99%, and also making the total yield more than 85%, which is more easy for industrial operation and promotion, in line with the concept of green chemistry and sustainable development;

[0024] 2.The application adopts proline of natural amino acid as the catalyst of aldol condensation reaction, which has higher biocompatibility and environmental friendliness compared with traditional metal catalyst or organic base catalyst, is conducive to reducing environmental pollution in the production process, utilizes the good chemical stability of acetonitrile to make the aldol condensation reaction not easy to have side reactions with reactants, thereby ensuring the smooth progress of the reaction, controls the molar ratio among 2, 4, 5-trifluorobenzeneacetaldehyde, methyl acetate and proline to make the aldol condensation reaction can provide sufficient flexibility and operability, which is conducive to optimizing the reaction conditions and improving the production efficiency, so that the synthesis of sitagliptin can be carried out under relatively mild conditions, which is conducive to reducing energy consumption and production cost, and helps to reduce the generation of by-products, improve the yield and purity of intermediate I;

[0025] 3.The application can realize effective control of the reaction process by adjusting the types and amounts of ammonolysis reagent and alkaline reagent, the types and proportions of reaction solvents, and reaction temperature and time, which is conducive to optimizing the reaction conditions and improving the yield and quality of intermediate II and intermediate IV, and the use of low-toxicity and environmentally friendly ammonolysis reagents, alkaline reagents and corresponding reaction solvents is conducive to reducing environmental pollution in the production process, easy to recycle and handle, and meets the concept of green chemistry and sustainable development;

[0026] 4.The application utilizes the catalytic activity of tetrabutylammonium fluoride to make intermediate II can effectively condense with N, O-bis (trimethylsilyl) acetamide under relatively mild conditions to generate intermediate III transition state, which helps to maintain the activity of the catalyst and condensing agent, reduces the generation of by-products, and is conducive to reducing energy consumption and production cost and improving the yield and quality of intermediate III;

[0027] 5.The application effectively reduces the number of intermediate conversions and the generation of by-products by reasonably designing the reaction steps and selecting suitable catalysts and condensing agents, effectively avoids waste treatment and resource waste, ensures the consistency of product quality, and also improves the stability and reliability of the synthesis process, which is conducive to further optimizing product quality and production cost and enhancing the feasibility of industrial application. DETAILED DESCRIPTION

[0028] The following examples are used to further illustrate the content of the application and do not limit the application of the application. Example 1:

[0029] Firstly, methyl acetate and 2,4,5-trifluorobenzene acetaldehyde are selected as starting materials, proline is selected as catalyst for preparing intermediate I, acetonitrile is selected as reaction solvent for preparing intermediate I, ammonia is selected as aminating reagent for preparing intermediate II, ethanol is selected as reaction solvent for preparing intermediate II, tetrabutylammonium fluoride (TBAF) is selected as catalyst for preparing intermediate III, N,O-bis(trimethylsilyl)acetamide (BSA) is selected as condensing agent for preparing intermediate III, toluene is selected as reaction solvent for preparing intermediate III, lithium hydroxide is selected as basic reagent for preparing intermediate IV, N-methyl imidazole (NMI) is selected as basic catalyst for preparing sitagliptin, O-benzotriazol-tetramethyluronium hexafluorophosphate (HBTU) is selected as condensing agent for preparing sitagliptin, acetonitrile is selected as reaction solvent for preparing sitagliptin.

[0030] Secondly, in a four-port reaction bottle equipped with a thermometer and a stirrer and under the protection of nitrogen, 300 ml of acetonitrile, 2,4,5-trifluorobenzene acetaldehyde (66 g, 0.38 mol) and methyl acetate (35 g, 0.5 mol) are first added, and proline acetonitrile mixture (87 g, 0.75 mol) is added dropwise at 20-30°C to carry out aldol condensation reaction, after which the reaction is concentrated and then slurried with water to obtain intermediate I in the form of white solid, 86 g, with a yield of 92% and a purity of 98%.

[0031] Thirdly, in a four-port reaction bottle equipped with a thermometer and a stirrer, 200 ml of ethanol is first added, and then intermediate I (55 g, 0.22 mol) is added, and ammonia water (55 ml) is added dropwise at 20-30°C, and white solid is precipitated after stirring for 10-15 hours, and intermediate II in the form of white solid is obtained by filtration, 49 g, with a yield of 95% and a purity of 98%.

[0032] Then, in a four-port reaction bottle equipped with a thermometer and a stirrer and under the protection of nitrogen, 200 ml of toluene is first added, and then TBAF (0.8 g, 0.003 mol) and intermediate II (42 g, 0.18 mol) are added, and the temperature is raised to 30-40°C while stirring, and then BSA (42 g, 0.21 mol) is added dropwise, and after the dropwise addition is completed, the temperature is raised to 40-50°C, and the reaction is carried out for 5-6 hours, and after the reaction is completed, the reaction is concentrated, and then intermediate III is obtained, and after the concentration, intermediate III is directly added into 200 ml of ethanol to be stirred and dissolved, and then the hydrolysis is carried out with lithium hydroxide aqueous solution (10 g, 0.42 mol), and after extraction with isopropyl acetate, 41 g of intermediate IV in the form of oil is obtained, with a yield of 98% and a purity of 97%.

[0033] Finally, in a four-necked flask equipped with a thermometer, a stirrer and under nitrogen protection, 200 ml of acetonitrile was added, followed by stirring and dissolving of intermediate IV (40 g, 0.17 mol) and intermediate V (36 g, 0.18 mol), then NMI (28 g, 0.34 mol) and HBTU (33 g, 0.09 mol) were added, the temperature was raised to 70-80 °C, and the reaction was carried out for 8-10 hours. After the reaction was completed, water was added for washing, and then concentrated and refined with isopropyl alcohol to obtain sitagliptin 66 g of white solid, with a yield of 95%, a purity of 99.9%, and ee > 99%.

[0034] The hydrogen spectrum and carbon spectrum data of sitagliptin prepared in this example are as follows:

[0035] 1) Hydrogen spectrum:

[0036] 1H-NMR (600 MHz, DMSO d6):

[0037] δ 7.32 (m, 1H), 7.16 (m, 1H), 5.03 (s, 1H), 4.97 (s, 1H), 4.37-4.22

[0038] (m, 2H), 4.11-4.05 (m, 3H), 3.22-2.89 (m, 4H);

[0039] 2) Carbon spectrum:

[0040] 13C-NMR (300 MHz, CDCI3): 171.60 (s, 1C), 159.47 (m, 1C), 156.

[0041] 14 (m, 1C), 152.57 (m, 1C), 149.43 (m, 1C), 146.20 (m, 1C), 144.91 (m,

[0042] 1C), 120.47 (m, 1C), 120.15 (q, 1C), 107.20 (dd, 1c), 49.69 (s, 1C)

[0043] , 44.93 (s, 1C), 42.69 (s, 1C), 40.22 (s, 1C), 35.24 (s, 1C), 32.46 (s, 1C).

[0044] MS: [M+H]+: 408.1266. Example 2:

[0045] Firstly, methyl acetate and 2,4,5-trifluorobenzene acetaldehyde are selected as starting materials, proline is selected as catalyst for preparing intermediate I, acetonitrile is selected as reaction solvent for preparing intermediate I, methanol ammonia is selected as ammonolysis reagent for preparing intermediate II, ethanol is selected as reaction solvent for preparing intermediate II, TBAF is selected as catalyst for preparing intermediate III, BSA is selected as condensing agent for preparing intermediate III, toluene is selected as reaction solvent for preparing intermediate III, sodium hydroxide is selected as alkaline reagent for preparing intermediate IV, NMI is selected as alkaline catalyst for preparing sitagliptin, HBTU is selected as condensing agent for preparing sitagliptin, acetonitrile is selected as reaction solvent for preparing sitagliptin.

[0046] Secondly, in a four-port reaction bottle equipped with a thermometer and a stirrer and under the protection of nitrogen, 300 ml of acetonitrile, 2,4,5-trifluorobenzene acetaldehyde (66 g, 0.38 mol) and methyl acetate (35 g, 0.5 mol) are first added, and proline acetonitrile mixture (66 g, 0.57 mol) is added dropwise at 20-30°C to carry out Aldol aldol condensation reaction, and after concentration, the obtained intermediate I is slurried with water to obtain white solid 82 g, with a yield of 88% and a purity of 98%.

[0047] Thirdly, in a four-port reaction bottle equipped with a thermometer and a stirrer, 200 ml of ethanol is first added, and then intermediate I (55 g, 0.22 mol) is added, and methanol ammonia (55 ml) is added dropwise at 20-30°C, and white solid is precipitated after stirring for 10-15 hours, and the obtained intermediate II is filtered to obtain white solid 45 g, with a yield of 90% and a purity of 98%.

[0048] Then, in a four-port reaction bottle equipped with a thermometer and a stirrer and under the protection of nitrogen, 200 ml of toluene is first added, and then TBAF (0.8 g, 0.003 mol) and intermediate II (42 g, 0.18 mol) are added, and the temperature is increased to 30-40°C under stirring, and then BSA (42 g, 0.21 mol) is added dropwise, and the temperature is increased to 40-50°C after the dropwise addition is completed, and the reaction is carried out for 5-6 hours, and then the reaction is concentrated to obtain intermediate III, and then the obtained intermediate III is directly added into 200 ml of ethanol for stirring and dissolving, and then sodium hydroxide aqueous solution (10 g, 0.25 mol) is used for hydrolysis, and then acetic acid isopropyl ester is used for extraction, and then the obtained 37 g of intermediate IV is concentrated to obtain oil, with a yield of 88% and a purity of 95%.

[0049] Finally, in a four-necked flask equipped with a thermometer, a stirrer and under nitrogen protection, 200 ml of acetonitrile was added, followed by stirring and dissolving of intermediate IV (40 g, 0.17 mol) and intermediate V (36 g, 0.18 mol), then NMI (28 g, 0.34 mol) and HBTU (80 g, 0.21 mol) were added, the temperature was raised to 70-80 °C, and the reaction was carried out for 8-10 hours. After the reaction was completed, water was added for washing, and then concentrated and refined with isopropyl alcohol to obtain sitagliptin 66 g of white solid, with a yield of 95%, a purity of 99.7%, and ee > 99%.

[0050] The hydrogen spectrum and carbon spectrum data of sitagliptin prepared in this example are as follows:

[0051] 1) Hydrogen spectrum:

[0052] 1H-NMR (600 MHz, DMSO d6):

[0053] δ 7.32 (m, 1H), 7.16 (m, 1H), 5.03 (s, 1H), 4.97 (s, 1H), 4.37-4.22

[0054] (m, 2H), 4.11-4.05 (m, 3H), 3.22-2.89 (m, 4H);

[0055] 2) Carbon spectrum:

[0056] 13C-NMR (300 MHz, CDCI3): 171.60 (s, 1C), 159.47 (m, 1C), 156.

[0057] 14 (m, 1C), 152.57 (m, 1C), 149.43 (m, 1C), 146.20 (m, 1C), 144.91 (m,

[0058] 1C), 120.47 (m, 1C), 120.15 (q, 1C), 107.20 (dd, 1c), 49.69 (s, 1C)

[0059] , 44.93 (s, 1C), 42.69 (s, 1C), 40.22 (s, 1C), 35.24 (s, 1C), 32.46 (s, 1C).

[0060] MS: [M+H]+: 408.1266. Example 3:

[0061] Firstly, methyl acetate and 2,4,5-trifluorobenzene acetaldehyde are selected as starting materials, proline is selected as catalyst for preparing intermediate I, acetonitrile is selected as reaction solvent for preparing intermediate I, ethanolamine is selected as ammonolysis reagent for preparing intermediate II, ethanol is selected as reaction solvent for preparing intermediate II, TBAF is selected as catalyst for preparing intermediate III, BSA is selected as condensing agent for preparing intermediate III, toluene is selected as reaction solvent for preparing intermediate III, lithium hydroxide is selected as basic reagent for preparing intermediate IV, NMI is selected as basic catalyst for preparing sitagliptin, HBTU is selected as condensing agent for preparing sitagliptin, acetonitrile is selected as reaction solvent for preparing sitagliptin.

[0062] Secondly, in a four-port reaction bottle equipped with a thermometer and a stirrer and under the protection of nitrogen, 300 ml of acetonitrile, 2,4,5-trifluorobenzene acetaldehyde (66 g, 0.38 mol) and methyl acetate (53 g, 0.76 mol) are first added, and proline acetonitrile mixture (87 g, 0.75 mol) is added dropwise at 20-30°C to carry out Aldol aldol condensation reaction, and after concentration, the obtained intermediate I is slurried with water to obtain white solid 86 g, with a yield of 92% and a purity of 97%.

[0063] Thirdly, in a four-port reaction bottle equipped with a thermometer and a stirrer, 200 ml of ethanol is first added, and then intermediate I (55 g, 0.22 mol) is added, and ethanolamine (55 ml) is added dropwise at 20-30°C, and white solid is precipitated after stirring for 10-15 hours, and the obtained intermediate II is filtered to obtain white solid 47 g, with a yield of 92% and a purity of 98%.

[0064] Then, in a four-port reaction bottle equipped with a thermometer and a stirrer and under the protection of nitrogen, 200 ml of toluene is first added, and then TBAF (0.8 g, 0.003 mol) and intermediate II (42 g, 0.18 mol) are added, and the temperature is raised to 30-40°C, and then BSA (73 g, 0.36 mol) is added dropwise, and after the addition is completed, the temperature is continuously raised to 40-50°C, and the reaction is carried out for 5-6 hours, and after the reaction is completed, the obtained intermediate III is concentrated, and then 200 ml of ethanol is added to dissolve the intermediate III, and then the obtained intermediate III is hydrolyzed with lithium hydroxide aqueous solution (10 g, 0.42 mol), and then acetic acid isopropyl ester is extracted to obtain 41.5 g of intermediate IV oil, with a yield of 99% and a purity of 95%.

[0065] Finally, in a four-necked flask equipped with a thermometer, a stirrer and under nitrogen protection, 200 ml of acetonitrile was added, followed by stirring and dissolving of intermediate IV (40 g, 0.17 mol) and intermediate V (65 g, 0.34 mol), then NMI (70 g, 0.85 mol) and HBTU (33 g, 0.09 mol) were added, the temperature was raised to 70-80 °C, and the reaction was carried out for 8-10 hours. After the reaction was completed, water was added for washing, and then concentrated and refined with isopropyl alcohol to obtain sitagliptin 66 g of white solid, with a yield of 95%, a purity of 99.9%, and ee > 99%.

[0066] The hydrogen spectrum and carbon spectrum data of sitagliptin prepared in this example are as follows:

[0067] 1) Hydrogen spectrum:

[0068] 1H-NMR (600 MHz, DMSO d6):

[0069] δ 7.32 (m, 1H), 7.16 (m, 1H), 5.03 (s, 1H), 4.97 (s, 1H), 4.37-4.22

[0070] (m, 2H), 4.11-4.05 (m, 3H), 3.22-2.89 (m, 4H);

[0071] 2) Carbon spectrum:

[0072] 13C-NMR (300 MHz, CDCI3): 171.60 (s, 1C), 159.47 (m, 1C), 156.

[0073] 14 (m, 1C), 152.57 (m, 1C), 149.43 (m, 1C), 146.20 (m, 1C), 144.91 (m,

[0074] 1C), 120.47 (m, 1C), 120.15 (q, 1C), 107.20 (dd, 1c), 49.69 (s, 1C)

[0075] , 44.93 (s, 1C), 42.69 (s, 1C), 40.22 (s, 1C), 35.24 (s, 1C), 32.46 (s, 1C).

[0076] MS: [M+H] + : 408.1266.

Claims

1. A process for the synthesis of sitagliptin, characterized in that, The specific steps include: S1, preparation of intermediate I: methyl acetate and 2,4,5-trifluorobenzene acetaldehyde as starting material, dissolved in reaction solvent, in the presence of proline catalysis aldol condensation reaction to obtain intermediate I; S2, preparation of intermediate II: intermediate I obtained in S1 is dissolved in reaction solvent, and carboxylic acid ester ammonolysis reaction with ammonia solution reagent to obtain intermediate II; S3, preparation of intermediate III: intermediate II obtained in S2 is dissolved in reaction solvent, and β-lactam condensation cyclization with condensing agent in the presence of catalyst to obtain intermediate III transition state; S4, preparation of intermediate IV: intermediate III transition state obtained in S3 is hydrolyzed with alkaline reagent to obtain intermediate IV; S5, preparation of sitagliptin: intermediate IV obtained in S4 is dissolved in reaction solvent, acylation reaction with intermediate V and condensing agent in the presence of basic catalyst to obtain the final product sitagliptin; The synthetic route is as follows: 。 2. The method of synthesis of sitagliptin as claimed in claim 1 wherein, In S1, the molar ratio of 2,4,5-trifluorobenzene acetaldehyde, methyl acetate and proline is 1:1.0-2.0:1.0-5.

0.

3. The process for synthesis of sitagliptin as claimed in claim 1, wherein, In S1, the reaction solvent is acetonitrile.

4. The process for synthesis of sitagliptin as claimed in claim 1, wherein, In S2, the reaction solvent is one or a mixture of several of methanol, tetrahydrofuran, acetonitrile, ethanol, dioxane and acetone.

5. The process for synthesis of sitagliptin as claimed in claim 1, wherein, In S2, the ammonolysis reagent is one of ammonia, methanol ammonia and ethanol amine.

6. The method of synthesis of sitagliptin as claimed in claim 1 wherein, In S3, the catalyst is tetrabutylammonium fluoride, and the condensing agent is N,O-bis(trimethylsilyl)acetamide.

7. The method of synthesis of sitagliptin as claimed in claim 1 wherein, In S3, the reaction solvent is one or a mixture of several of toluene, tetrahydrofuran, acetonitrile, ethanol, dioxane, acetone and isopropyl acetate. 8.The method of claim 1, wherein the step of reacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of 60-80℃. In S4, the alkaline reagent is one or a mixture of several of lithium hydroxide, sodium hydroxide, potassium hydroxide and magnesium hydroxide.

9. The method of synthesis of Sitagliptin as claimed in claim 1 wherein, In S5, the molar ratio of intermediate IV to intermediate V is 1:1.0-2.0, the molar ratio of intermediate IV to condensing agent is 1:0.5-2.5, and the molar ratio of intermediate IV to basic catalyst is 1:1.0-10.0, wherein the condensing agent is O-benzotriazole-tetramethylurea hexafluorophosphate, and the basic catalyst is N-methylimidazole.

10. The method of synthesis of sitagliptin as claimed in claim 1 wherein, In S5, the reaction solvent is one or a mixture of several of toluene, tetrahydrofuran, acetonitrile, isopropyl acetate, dioxane, xylene and acetone.

Images