Sitagliptin derivative as well as preparation method and application thereof in blood glucose reduction

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a sitagliptin derivative, a preparation method thereof and application of the sitagliptin derivative in blood glucose reduction. The chemical structural formula of the sitagliptin derivative is shown in the specification, in the formula, R is propionyl, valeryl, hexanoyl, heptanoyl, capryloyl, isobutyryl, 3, 3-dimethyl butyryl or isovaleryl; the hypoglycemic activity of the Sd-05 prepared from hexanoyl chloride is obviously superior to that of sitagliptin, the acute safety is high, the Sd-05 can obviously improve the glucose tolerance of normal mice under the low-dosage condition, and the Sd-05 is obviously superior to that of existing sitagliptin in the aspects of improving glucose metabolism disorder and maintaining blood glucose stability.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a sitagliptin derivative, its preparation method, and its application in lowering blood sugar. Background Technology

[0002] DPP-4 inhibitors are targets for the treatment of type 2 diabetes. The DPP-4 enzyme hydrolyzes and inactivates GLP-1 in the body. When GLP-1 levels are high, in diabetic patients with elevated blood glucose levels, GLP-1 can increase cAMP concentration, enhance pancreatic β-cell synthesis, and promote insulin secretion, thus restoring blood glucose to normal levels. In 2006, Merck's first DPP-4 inhibitor, sitagliptin, was approved by the FDA. This drug opened up a new market for DPP-4 inhibitors, further promoting their development, and subsequently, more DPP-4 inhibitors were launched.

[0003] Although many DPP-4 inhibitors have been marketed, some researchers are still studying the developed DPP-4 inhibitors and modifying their structures in hopes of finding clinical candidates with better activity and safety, thus providing more options for the development of drugs to treat diabetes.

[0004] A patent published by a research group at Xi'an Jiaotong University discloses a method for preparing and applying a type of sitagliptin-nitrate hybrid. This compound, ω-NA-SG, has a significant and sustained hypoglycemic effect on a streptozotocin (STZ)-induced diabetic mouse model. It can rapidly reduce blood glucose and, by releasing NO, increase serum NO levels, improve NO function deficit in diabetic states, protect vascular endothelial function, and thus delay the occurrence and development of related complications. However, the preparation process of this compound is cumbersome, time-consuming, and requires harsh reaction conditions (the reaction needs to be protected from light). The final product needs to be obtained by column chromatography, making it difficult to achieve industrial production.

[0005] Chinese patent CN 115304604 A discloses a dual-target sitagliptin derivative. This compound can improve oral glucose tolerance in normal mice under low-dose conditions, but its activity is comparable to that of the DPP-4 inhibitor sitagliptin, and its activity needs further improvement. Therefore, it is necessary to optimize the existing sitagliptin structure and provide a sitagliptin derivative with a simple and feasible preparation process and stronger hypoglycemic activity. Summary of the Invention

[0006] In view of the shortcomings and deficiencies of the existing technology, the purpose of this invention is to provide a sitagliptin derivative with a simple and feasible preparation process and stronger hypoglycemic activity. By reacting fatty acyl chloride with sitagliptin amino group, the structure of sitagliptin is modified by forming fatty amides with different chain lengths, resulting in a compound with stronger hypoglycemic activity.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A sitagliptin derivative has the following chemical structural formula:

[0009]

[0010] Wherein, R is propionyl, valeryl, hexanoyl, heptanyl, octanoyl, isobutyryl, 3,3-dimethylbutyryl or isovaleryl.

[0011] The present invention also provides a method for preparing the above-mentioned sitagliptin derivative, wherein sitagliptin and a chelating agent are dissolved in an organic solvent, and then propionyl chloride, valeryl chloride, hexanoyl chloride, heptanyl chloride, octanoyl chloride, isobutyryl chloride, 3,3-dimethylbutyryl chloride or isovaleryl chloride are added to react.

[0012] As a preferred embodiment of the present invention, the molar ratio of sitagliptin to the acid-binding agent is 1:1-3; the molar ratio of sitagliptin to propionyl chloride, valeryl chloride, hexanoyl chloride, heptanyl chloride, octanoyl chloride, isobutyryl chloride, 3,3-dimethylbutyryl chloride or isovaleryl chloride is 1:1-3.

[0013] As a preferred embodiment of the present invention, the organic solvent is dichloromethane or tetrahydrofuran, and the acid-binding agent is potassium carbonate or triethylamine.

[0014] The sitagliptin derivatives provided by this invention have hypoglycemic activity. The hypoglycemic activity of Sd-06 is comparable to that of the positive control drug sitagliptin, while the hypoglycemic activity of Sd-05 is significantly better than that of sitagliptin. Moreover, Sd-05 can significantly improve glucose tolerance in normal mice under low-dose conditions, and its activity is superior to that of the sitagliptin group. This proves that the sitagliptin derivative Sd-05 exhibits a good hypoglycemic effect and is significantly better than the existing sitagliptin in improving glucose metabolism disorders and maintaining blood glucose stability. Therefore, it can be used in the preparation of drugs for treating diabetes.

[0015] Advantages and beneficial effects of the present invention:

[0016] (1) There are no reports of introducing fatty acyl groups on the amino N of sitagliptin, and there are no reports on how to further improve the activity of sitagliptin. This invention is the first to react fatty acyl chloride with the amino group of sitagliptin to modify the structure of sitagliptin by forming fatty amides with different chain lengths. The results show that all of the 10 new compounds designed and synthesized have hypoglycemic activity except for Sd-02 and Sd-03. Among them, the hypoglycemic activity of Sd-06 is comparable to that of the positive control drug sitagliptin, and the hypoglycemic activity of Sd-05 is significantly better than that of sitagliptin.

[0017] (2) The Sd-05 synthesized in this invention can significantly improve glucose tolerance in normal mice under low-dose conditions, and its activity is superior to that of the sitagliptin group, proving that the sitagliptin derivative Sd-05 exhibits good hypoglycemic effect and is significantly superior to the existing sitagliptin in improving glucose metabolism disorder and maintaining blood glucose stability.

[0018] (3) The preparation method provided by this invention significantly improves the yield by optimizing the organic solvent, acid-binding agent, and the amount of each substance added, while controlling the post-treatment pH value to 5-6. In addition, the method has mild reaction conditions, is environmentally friendly, produces readily available final products, and has a controllable and easy-to-operate synthesis process, making it suitable for industrial production.

[0019] (4) The maximum lethal dose of the new compound designed and synthesized in this invention is >1000mg / kg, and it has high acute safety, which is expected to provide a safer and more effective hypoglycemic drug for diabetic patients. Attached Figure Description

[0020] Figure 1 This is a bar chart showing the hypoglycemic effect of the sitagliptin derivative of this invention;

[0021] Figure 2 The effect of low-dose Sd-05 and sitagliptin on oral glucose tolerance in mice. Detailed Implementation

[0022] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments of the present invention are not limited thereto. For process parameters not specifically specified, conventional techniques can be referred to. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field.

[0023] This invention synthesized a total of 10 new compounds. A type 2 diabetes mouse model was established using streptozotocin (STZ). Pharmacodynamic studies of the synthesized compounds were conducted by measuring indicators such as diet, water intake, urine output, and fasting blood glucose in the mice. Target compounds meeting the expected criteria were screened, providing candidate drugs for future research and development of new hypoglycemic agents for the treatment of type 2 diabetes. The synthesis process and hypoglycemic pharmacodynamic experiments of sitagliptin derivatives are described in detail below.

[0024] I. Synthesis Process of Sitagliptin Derivatives

[0025] 1. Test equipment and materials

[0026] 1.1 Test Equipment

[0027] AVANCE NEO 400MHz liquid superconducting nuclear magnetic resonance spectrometer (Bruker, Switzerland), 400M nuclear magnetic resonance spectrometer (JEOL JNM-ECZL400S, Japan), Thermo Fisher Q Exactive high-resolution mass spectrometer (Thermo Fisher Scientific, USA), MPA100 fully automated melting point apparatus (Optimelt, USA).

[0028] 1.2 Reagents and Tests

[0029] Sitagliptin (chemical grade, purity ≥99%, Hubei Weideli Chemical Reagent Co., Ltd., product batch: HEW220803-5); propionyl chloride, acetyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride, heptanyl chloride, octanoyl chloride, isobutyryl chloride, isovaleryl chloride, 3,3-dimethylbutyryl chloride (purity: >99%, all purchased from Chengdu Huaxia Chemical Reagent Co., Ltd.); dichloromethane, ethanol (analytical grade, Beijing Chemical Plant); potassium carbonate (analytical grade, Tianjin Guangfu Technology Development Co., Ltd.); tetrahydrofuran, toluene (Sinopharm Chemical Reagent Co., Ltd.), triethylamine, DIPEA (analytical grade, Beijing Chemical Plant).

[0030] 2. Experimental Section

[0031] 2.1 Preparation of (R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)propionamide (Sd-01):

[0032]

[0033] Molar ratio of feed ingredients: sitagliptin: propionyl chloride: potassium carbonate = 1:1.08:1.5

[0034] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.22 g (13.26 mmol) propionyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic (pH 5-6) with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to obtain 3.98 g of white solid, yield: 70.0%.

[0035] 2.2 Preparation of (R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)acetamide (Sd-02):

[0036]

[0037] Molar ratio of feed ingredients: Sitagliptin: Acetyl chloride: Potassium carbonate = 1:1.08:1.5

[0038] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.04 g (13.26 mL) acetyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to obtain 3.98 g of white solid, yield: 72.3%.

[0039] 2.3 Preparation of (R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)butyramide (Sd-03):

[0040]

[0041] Molar ratio of feed ingredients: Sitagliptin: Butyryl chloride: Potassium carbonate = 1:1.08:1.5;

[0042] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.41 g (13.26 mmol) n-butyryl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 3.94 g of white solid, yield: 66.0%.

[0043] Preparation of 2,4(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)pentanamide (Sd-04):

[0044]

[0045] Molar ratio of feed ingredients: sitagliptin: valerate chloride: potassium carbonate = 1:1.08:1.5

[0046] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.6 g (13.26 mmol) of n-valeryl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 3.86 g of white solid, yield: 64.0%.

[0047] Preparation of 2.5(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)hexamamide (Sd-05):

[0048]

[0049] Molar ratio of feed ingredients: sitagliptin: hexanoyl chloride: potassium carbonate = 1:1.08:1.5

[0050] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.78 g (13.26 mmol) hexanoyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 4.03 g of white solid, yield: 65.0%.

[0051] Preparation of 2,6(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)heptanamide (Sd-06):

[0052]

[0053] Molar ratio of feed ingredients: sitagliptin: heptayl chloride: potassium carbonate = 1:1.08:1.5

[0054] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.97 g (13.26 mmol) heptanyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 4.20 g of white solid, yield: 65.9%.

[0055] Preparation of 2.7(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)octylamide (Sd-07):

[0056]

[0057] Molar ratio of feed ingredients: Sitagliptin: Octanoyl chloride: Potassium carbonate = 1:1.08:1.5

[0058] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 2.16 g (13.26 mmol) octanoyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 3.97 g of white solid, yield: 60.6%.

[0059] Preparation of 2,8(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)isobutyramide (Sd-08):

[0060]

[0061] Molar ratio of feed ingredients: sitagliptin: isobutyryl chloride: potassium carbonate = 1:1.08:1.5

[0062] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.41 g (13.26 mmol) isobutyryl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 2.78 g of white solid, yield: 47.4%.

[0063] Preparation of 2.9(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)isovaleramide (Sd-09):

[0064]

[0065] Molar ratio of feed ingredients: sitagliptin: isovaleryl chloride: potassium carbonate = 1:1.08:1.5

[0066] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.60 g (13.26 mmol) isovaleryl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 2.27 g of white solid, yield: 37.6%.

[0067] 2.10(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-yl)3,3-dimethylbutyramide (Sd-10):

[0068]

[0069] Molar ratio of feed ingredients: sitagliptin: 3,3-dimethylbutyryl chloride: potassium carbonate = 1:1.08:1.5

[0070] 5 g (12.28 mmol) sitagliptin and 2.54 g (18.41 mmol) potassium carbonate were dissolved in 50 mL of anhydrous dichloromethane. The solution was cooled to below 0 °C, and 1.78 g (13.26 mmol) of 3,3-dimethylbutyryl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to give 1.48 g of white solid, yield: 23.8%.

[0071] 3. Optimization of synthesis conditions:

[0072] 3.1 Screening of reaction solvents:

[0073] Sitagliptin and potassium carbonate were dissolved in the three solvents listed in Table 1, respectively. The solution was cooled to below 0°C, and hexanoyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated, and an appropriate amount of water was added to the reaction flask. The pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol.

[0074] Table 1

[0075]

[0076] As shown in the table above, using dichloromethane as the reaction solvent results in a higher product yield.

[0077] 3.2 Screening of acid-binding agents:

[0078] Sitagliptin and different types of antacids were dissolved separately in anhydrous dichloromethane according to the prescribed dosage. The solution was cooled to below 0°C, and hexanoyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol.

[0079] Table 2

[0080]

[0081] As shown in the table above, using potassium carbonate as an acid-binding agent results in a higher product yield.

[0082] 3.3 Investigate the effect of acid-binding agent dosage on reaction yield:

[0083] Sitagliptin and potassium carbonate were dissolved separately in anhydrous dichloromethane according to the prescribed dosage. The solution was cooled to below 0°C, and hexanoyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol.

[0084] Table 3

[0085]

[0086]

[0087] As shown in the table above, the appropriate dosage of potassium carbonate should be 1.5 eq.

[0088] 3.4 Investigate the effect of acyl chloride dosage on reaction yield:

[0089] Sitagliptin and potassium carbonate were dissolved separately in anhydrous dichloromethane according to the prescribed dosage. The solution was cooled to below 0°C, and hexanoyl chloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, and the pH of the solution was adjusted to weakly acidic with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated to obtain the crude product. The crude product was recrystallized from anhydrous ethanol.

[0090] Table 4

[0091]

[0092] As shown in the table above, the yield was highest when the amount of acetyl chloride was 1.08 eq. Further increasing the amount did not significantly change the product yield, so the amount of n-hexanoyl chloride should be 1.08 eq.

[0093] 4. Structural characterization:

[0094] Sd-01:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)propionamide

[0095]

[0096] White solid (70.0% yield); mp183.3-183.5℃; 1 H NMR(400MHz, DMSO-d6)δ7.69(t,J=8.9Hz,1H),7.49–7.28(m,2H),4.99(s,1H),4.86(s,1H),4.36–4.20(m,2H),4. 12–3.87(m,3H),2.89(dd,J=13.6,5.7Hz,1H),2.76–2.62(m,3H),1.99–1.78(m,2H),0.83(t,J=11.1,7.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ169.80,169.14,156.36(dd,J=243.0,9.8Hz),151.38(d,J=13 .7Hz), 148.23 (dd, J=245.0, 13.7Hz), 146.12 (dd, J=240.0, 12.9Hz), 142.98 (q, J=39.6 Hz), 123.21 (d, J = 18.6Hz), 119.50 (dd, J = 19.5, 6.3Hz), 118.92 (q, J = 271.7Hz), 105.88 (dd,J=29.4,21.0Hz),46.56,44.03,43.44,42.51,41.59,37.93,32.86,22.90.MS-ESI m / z:C 20 H 21 F6N5O2:486.1331[M+Na]+ .

[0097] Sd-02:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)acetamide

[0098]

[0099] White solid(72.3%yield);m.p.159.6-169.1℃; 1 H NMR(400MHz,DMSO-d6)δ7.78(t,J=8.6Hz,1H),7.50–7.30(m,2H),4.98(s,1H),4.86(d,J=3.1Hz,1H),4.31–4.22(m,2H),4.10–4.06(m,1H),3.95(dt,J=14.1,5.1Hz,2H),2.87(dt,J=13.8,6.8Hz,1H),2.75–2.57(m,3H),1.65(d,J=32.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ172.93,169.86(d,J=6.4Hz),156.42(dd,J=243.4,9.9Hz),151.45(d,J=12.9Hz),148.25(dd,J=247.5,13.7Hz),146.12(dd,J=240.0,12.5Hz),143.04(q,J=38.8Hz),123.32(d,J=18.5Hz),119.66(ddd,J=27.1,18.7,6.5Hz),118.99(q,J=270.7Hz),105.81(dd,J=47.3,27.3Hz),46.42,43.79,42.61,41.69,32.99,29.03,10.27.MS-ESI m / z:C 20 H 21 F6N5O2:472.1175[M+Na] + .

[0100] Sd-03:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)butyramide

[0101]

[0102] White solid(66.0%yield);m.p.168.4-169.1℃; 1 H NMR(400MHz,DMSO-d6)δ7.71(t,J=9.4Hz,1H),7.51–7.28(m,2H),5.07–4.93(m,1H),4.85(s,1H),4.45–3.83(m,5H),2.89(d,J=13.9Hz,1H),2.75–2.60(m,3H),1.90(t,J=7.2Hz,1H),1.81(dt,J=10.8,7.2Hz,1H),1.33(dq,J=13.2,7.0,6.6Hz,2H),0.67(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ171.94,169.83(d,J=4.6Hz),156.40(dd,J=243.1,9.8Hz),151.45(d,J=11.8Hz),148.25(dd,J=247.5,13.6Hz),146.14(dd,J=242.4,12.9Hz),143.03(q,J=38.9Hz),123.33(d,J=17.0Hz),119.64(dd,J=19.3,6.2Hz),118.99(q,J=270.7Hz),105.94(dd,J=29.5,20.9Hz),46.38,44.09,43.49,42.62,41.71,37.92,33.04,19.00,13.69.MS-ESI m / z:C 20 H 21 F6N5O2:500.1486[M+Na] + .

[0103] Sd-04:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)pentanamide

[0104]

[0105] White solid(64.0%yield);m.p.179.3-180.5℃; 1 H NMR(400MHz,DMSO-d6)δ7.71(dd,J=11.1,8.7Hz,1H),7.49–7.39(m,1H),7.38–7.30(m,1H),5.07–4.93(m,1H),4.86(s,1H),4.41–4.19(m,2H),4.13–3.85(m,3H),2.89(dt,J=14.2,4.5Hz,1H),2.68(td,J=13.9,11.6,5.0Hz,3H),1.92(t,J=7.3Hz,1H),1.88–1.76(m,1H),1.34–1.18(m,2H),1.09–0.98(m,2H),0.75(td,J=7.3,2.7Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ172.08,169.83(d,J=3.8Hz),156.41(dd,J=243.0,9.7Hz),151.45(d,J=11.1Hz),148.27(dd,J=247.5,13.6Hz),146.13(dd,J=242.4,12.1Hz),143.02(q,J=39.1Hz),123.32(d,J=18.4Hz),119.68(dd,J=19.0,6.1Hz),118.99(q,J=270.7Hz),105.93(dd,J=29.4,21.0Hz),46.34,44.10,43.49,42.63,41.71,35.57,33.07,27.79,21.96,14.01.MS-ESI m / z:C 20 H 21 F6N5O2:514.1644[M+Na] + .

[0106] Sd-05:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)hexanamide

[0107]

[0108] White solid(65.0%yield);m.p.161.7-162.5℃; 1 H NMR(400MHz,DMSO-d6)δ7.71(t,J=9.8Hz,1H),7.49–7.40(m,1H),7.38–7.28(m,1H),5.07–4.93(m,1H),4.86(s,1H),4.37–4.19(m,2H),4.14–3.85(m,3H),2.90(dd,J=14.1,4.1Hz,1H),2.71–2.62(m,3H),1.91(t,J=7.3Hz,1H),1.81(q,J=7.0Hz,1H),1.30(dt,J=12.6,6.9Hz,2H),1.21–1.10(m,2H),1.09–0.91(m,2H),0.78(t,J=7.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ172.12,169.82(d,J=4.6Hz),156.39(dd,J=243.0,9.6Hz),151.43(d,J=11.9Hz),148.27(dd,J=247.5,13.6Hz),146.13(dd,J=242.4,12.3Hz),143.02(q,J=39.3Hz),123.30(d,J=18.5Hz),119.67(td,J=19.9,18.7,9.2Hz).118.79(q,J=270.7Hz),105.85(dd,J=47.1,29.1Hz),46.32,43.79,42.63,41.72,35.90,33.02,31.50,28.55,25.63,22.38,14.25.MS-ESI m / z:C 20 H 21 F6N5O2:528.1799[M+Na] + .

[0109] Sd-06:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)heptanamide

[0110]

[0111] White solid(65.9%yield);m.p.162。0.-163.0℃; 1 H NMR(400MHz,DMSO-d6)δ7.71(t,J=9.9Hz,1H),7.47–7.39(m,1H),7.38–7.30(m,1H),5.07–4.93(m,1H),4.86(s,1H),4.37–4.19(m,2H),4.10–3.87(m,3H),2.89(dt,J=14.2,4.2Hz,1H),2.71–2.62(m,3H),1.91(t,J=7.2Hz,1H),1.88–1.73(m,1H),1.40–0.94(m,8H),0.81(t,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ172.12,169.82(d,J=4.6Hz),156.39(dd,J=243.0,9.6Hz),151.43(d,J=11.9Hz),148.27(dd,J=247.5,13.6Hz),146.14(dd,J=242.4,12.3Hz),143.02(q,J=39.3Hz),123.30(d,J=18.5Hz),119.67(td,J=19.9,18.7,9.2Hz),118.79(q,J=270.7Hz),105.85(dd,J=47.1,29.1Hz),46.32,43.79,42.63,41.72,38.31,35.90,33.02,31.50,28.55,25.63,22.38,14.25.MS-ESI m / z:C 20 H 21 F6N5O2:542.1951[M+Na] + .

[0112] Sd-07:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)octanamide

[0113]

[0114] White solid(60.6%yield);m.p.163.3.-164.1℃; 1 H NMR(400MHz,DMSO-d6)δ7.71(t,J=9.9Hz,1H),7.49–7.28(m,2H),5.07–4.93(m,1H),4.86(s,1H),4.40–4.21(m,2H),4.13–3.81(m,3H),2.90(dd,J=14.0,4.3Hz,1H),2.71–2.63(m,3H),1.91(t,J=7.3Hz,1H),1.81(q,J=7.2Hz,1H),1.37–0.95(m,10H),0.84(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ172.11,169.82(d,J=4.8Hz),156.39(dd,J=243.1,9.6Hz),151.43(d,J=11.7Hz),148.27(dd,J=247.5,13.6Hz),146.14(dd,J=242.4,12.9Hz),143.02(q,J=38.9Hz),123.29(d,J=18.5Hz),119.64(dd,J=19.3,6.2Hz),118.98(q,J=270.7Hz),105.93(dd,J=48.5,28.3Hz),46.30,43.79,42.63,41.72,38.81,38.10,35.87,33.02,31.60,28.90,25.67,22.55,14.31.MS-ESI m / z:C 20 H 21 F6N5O2:556.2110[M+Na] + .

[0115] Sd-08:(R)-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)isobutyramide

[0116]

[0117] White solid(47.4%yield);m.p.208.6-209.8℃; 1 H NMR(400MHz,DMSO-d6)δ7.65(t,J=9.0Hz,1H),7.49–7.27(m,2H),5.01(s,1H),4.85(s,1H),4.44–4.19(m,2H),4.06(d,J=5.4Hz,1H),4.00–3.90(m,2H),2.93–2.85(m,1H),2.72–2.58(m,3H),2.25–2.07(m,1H),0.87–0.75(m,6H). 13 C NMR(101MHz,DMSO-d6)δ176.05,169.91,156.39(dd,J=242.8,9.7Hz),151.44(d,J=12.9Hz),148.22(dd,J=247.5,13.6Hz),146.08(dd,J=241.4,12.0Hz),143.04(q,J=39.0Hz),123.34(d,J=19.6Hz),119.76(dq,J=19.1,11.1,9.1Hz),118.98(q,J=271.7Hz),105.85(dd,J=45.5,29.3Hz),46.16,43.78,42.20,38.32,34.52,33.01,19.86,19.56.MS-ESI m / z:C 20 H 21 F6N5O2:500.1487[M+Na] + .

[0118] Sd-09:(R)-3-methyl-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)butanamide

[0119]

[0120] White solid(37.6%yield);m.p.208.6-209.8℃; 1 H NMR(400MHz,DMSO-d6)δ7.71(t,J=9.6Hz,1H),7.50–7.25(m,2H),5.08–4.93(m,1H),4.85(s,1H),4.44–4.22(m,2H),4.13–3.83(m,3H),2.89(dd,J=13.7,4.3Hz,1H),2.76–2.63(m,3H),1.85–1.72(m,2H),1.70(d,J=5.6Hz,1H),0.73–0.68(d,J=6.1Hz,3H),0.65(d,J=6.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ171.40,169.83,156.38(dd,J=243.2,9.4Hz),151.44(d,J=11.0Hz),148.26(dd,J=247.5,13.7Hz),146.14(dd,J=241.4,11.6Hz),143.03(q,J=38.9Hz),123.30(dd,J=18.5,5.1Hz),119.67(ddd,J=27.8,19.0,6.5Hz),118.98(q,J=271.7Hz),106.03(dd,J=27.2,18.9Hz),46.37,45.19,43.80,42.46,41.73,38.45,33.07,25.87,22.38.MS-ESI m / z:C 20 H 21 F6N5O2:514.1643[M+Na] + .

[0121] Sd-10:(R)-3,3-dimethyl-N-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)butanamide

[0122]

[0123] White solid (23.8% yield); mp151.1-151.8℃; 1 H NMR(400MHz, DMSO-d6)δ7.66(t,J=8.7Hz,1H),7.49–7.30(m,2H),5.09–4.93(m,1H),4.92–4.77(m,1H),4.39(d,J=10.3Hz,1H), 4.32–4.18(m,1H),4.14–3.80(m,3H),2.87(dd,J=14.0,4.5Hz,1H),2.76–2.57(m,3H),1.90–1.62(m,2H),0.76(d,J=2.7Hz,9H). 13 C NMR (101MHz, DMSO-d6) 13 C NMR(101MHz,DMSO-d6)δ170.74,169.80,156.39(dd,J=243.2,9.8Hz),151.43(d,J=9.0Hz ),148.25(dd,J=247.5,13.6Hz),146.16(dd,J=242.4,13.1Hz),143.02(q,J=38.8Hz),12 3.29(d,J=18.7Hz),119.69(dd,J=18.7,6.1Hz),118.98(q,J=271.7Hz),105.89(dd,J=29 .4,21.0Hz),49.29,46.33,43.79,42.20,38.80,38.09,33.00,30.60,29.81.MS-ESIm / z:C 20 H 21 F6N5O2:528.1799[M+Na] + .

[0124] II. Hypoglycemic Pharmacodynamics of Sitagliptin Derivatives

[0125] 1. Experimental Materials

[0126] 1.1 Medicines and Materials

[0127] Ten sitagliptin derivatives were synthesized and provided by this invention; the positive control drug sitagliptin was purchased from Hubei Weideli Chemical Reagent Co., Ltd. (chemical grade, content ≥99%, product batch: HEW220803-5); streptozotocin (STZ, Wuhan Saiweier Biotechnology Co., Ltd., batch number: CR2410070); basal maintenance feed (Liaoning Changsheng Biotechnology Co., Ltd., batch number: 2107632500015257); high-fat feed (Yushu Biotechnology (Shanghai) Co., Ltd., batch number: QC202502152125011); anhydrous citric acid (Meilun Biotechnology Co., Ltd., batch number: J00121B); trisodium citrate dihydrate (Beijing Chemical Plant, batch number: 20130109); sodium carboxymethyl cellulose (China Pharmaceutical Shanghai Chemical Reagent Co., Ltd., batch number: F20020928).

[0128] 1.2 Animals

[0129] Kunming mice, SPF grade, weighing 18-20g, were provided by Liaoning Changsheng Biotechnology Co., Ltd., certificate number 210726250100354. The animal experiments and methods were approved by the Experimental Animal Ethics Committee of Jilin Provincial Institute of Pharmaceutical Research, animal experiment approval number: 2025001.

[0130] 1.3 Instruments

[0131] Blood glucose meter (Jiuzhoutong Medical Devices Group Co., Ltd., model: GLM-77); Blood glucose test strips (Jiuzhoutong Medical Devices Group Co., Ltd., batch number: 77-2306061-44)

[0132] 2. Experimental Methods

[0133] 2.1 Preparation of reagents and feed

[0134] Preparation of 0.1 mol / L pH 4.5 citrate buffer: Solution A (0.1 mol / L citric acid aqueous solution): Add 2.10 g of hydrated citric acid to distilled water to a final volume of 100 ml. Solution B (0.1 mol / L trisodium citrate aqueous solution): Add 2.94 g of trisodium citrate dihydrate to distilled water to a final volume of 100 ml. Mix the 0.1 mol / L citric acid aqueous solution and the 0.1 mol / L trisodium citrate aqueous solution at a volume ratio of 1:1.44 to prepare the 0.1 mol / L pH 4.5 citrate buffer.

[0135] STZ solution preparation: Dissolve in 0.1 mol / L pH 4.5 citrate buffer to prepare a 5 mg / ml solution, place on ice, protect from light, and inject within half an hour.

[0136] Preparation of sitagliptin suspension: Disperse 250 mg sitagliptin evenly in 50 ml of 0.25% sodium carboxymethyl cellulose solution to prepare a suspension with a concentration of 5 mg / ml. Sitagliptin derivative suspensions are prepared using the same method.

[0137] High-fat feed formulation: 47.2% basal feed, 15% lard, 20% sucrose, 10% casein, 2% laboratory animal premix, 1.9% microcrystalline cellulose, 2% dicalcium phosphate, 5% limestone powder, 1.2% cholesterol, and 0.2% sodium cholate. Energy sources include: 19.21% protein, 17.09% fat, and 45.15% carbohydrates.

[0138] 2.2 Establishment of a type II diabetic mouse model

[0139] Kunming mice, half male and half female, were used. All animals had free access to food and water and were not restricted in their activity. The animal room temperature was maintained at 20-25℃, and the humidity at 40-70%. An acclimatization diet was introduced for 3 days. Ten mice were selected as a blank control group and fed a normal diet throughout. The remaining mice were used to establish a diabetic model by feeding them a high-fat diet for 4 weeks. Changes in body weight and physical appearance of the mice in each group were observed and recorded during the experiment, such as coat color, motor function, whether metabolites were normal, and the presence of abnormal secretions, to assess the general condition of the animals.

[0140] After 4 weeks of feeding, the high-fat diet group was fasted for 12 hours and then injected intraperitoneally with streptozotocin (STZ) at a dose of 50 mg / kg for 5 consecutive days. After another week of feeding, the mice were fasted for 12 hours but allowed free water. Blood was collected by tail amputation, and blood glucose was measured using a glucometer. Blood glucose was measured every other day for a total of three measurements. Mice with a blood glucose level ≥11.11 mol / L were considered to have successfully established a stable hyperglycemic model. Mice with a blood glucose level <11.11 mol / L were considered unqualified and discarded.

[0141] 2.3 Maximum Dead Quantity

[0142] Normal mice were acclimatized for 3 days and then administered the drug by gavage at a dose of 1000 mg / kg. The condition of the mice was observed.

[0143] 2.4 Screening of hypoglycemic activity of sitagliptin derivatives

[0144] Mice that successfully modeled the disease were grouped according to their blood glucose levels, with the average blood glucose level in each group being calculated. The groups were: model group, sitagliptin group, and sitagliptin derivative groups (Sd-01, Sd-02, Sd-03, Sd-04, Sd-05, Sd-06, Sd-07, Sd-08, Sd-09, and Sd-10), with 10 mice in each group (half male and half female). All mice were fed a high-fat diet. The control group continued to be fed a normal diet.

[0145] Mice in the sitagliptin group were administered sitagliptin suspension daily by gavage, while mice in the sitagliptin derivative group were administered sitagliptin derivative suspension daily. The dosage for both groups was 50 mg / kg (equivalent to 0.1 ml suspension per 10 g mouse). The model group and the blank control group were administered 0.1 ml / 10 g of 0.25% sodium carboxymethyl cellulose solution. All animals had free access to food and water throughout the day and were allowed free movement. The administration was continued for 7 days. Fasting was enforced on the evening of the 7th day, and fasting blood glucose was measured using a glucometer on the morning of the 8th day. The average fasting blood glucose levels before administration and on the 8th day are shown in Table 5.

[0146] Table 5. Average fasting blood glucose levels of mice in each group before drug administration and on day 8.

[0147]

[0148] Note: * This indicates that, compared to the model group, the p-value is <0.05. ** This indicates that the p-value is <0.01 compared to the model group. ▲▲ This indicates that compared with the sitagliptin group, the P value was <0.01, which is statistically significant.

[0149] Oral glucose tolerance test of 2.5Sd-05

[0150] Kunming mice, weighing 18–20 g, with an equal number of males and females, were randomly divided into three groups of 10 mice each. Before the experiment, the mice were fasted for 12 hours but allowed free access to water. The control group received a blank solvent (0.25% sodium carboxymethyl cellulose), the sitagliptin group received sitagliptin suspension by gavage at a dose of 50 mg / kg, and the Sd-05 group received Sd-05 suspension by gavage at a dose of 30 mg / kg. After administration, blood was collected by tail amputation, and blood glucose levels were measured (recorded as -30 min). Blood glucose levels measured 30 min after administration were recorded as 0 min. Immediately afterwards, glucose solution (concentration 2 mg / ml) was administered by gavage at a dose of 20 mg / kg, and blood glucose levels were measured at 30, 60, 90, and 120 min. The results are shown in Table 6.

[0151] Table 6. Effects of each group on oral glucose tolerance in mice

[0152]

[0153] Note: ▲▲ indicates that the p-value is <0.01 compared with the sitagliptin group.

[0154] 3. Results

[0155] (1) After being fed a high-fat diet for 4 weeks, the mice developed dull fur and also exhibited the symptoms of "three more and one less", namely, excessive drinking, excessive eating, excessive urination, and weight loss.

[0156] (2) Maximum lethal dose: The mice were in normal condition after administration, indicating that the maximum lethal dose of sitagliptin derivative Sd-01~10 is >1000mg / kg, and the acute safety is high.

[0157] (3) The results of the screening experiment on hypoglycemic activity showed that all of the 10 new compounds designed and synthesized except for Sd-02 and Sd-03 had hypoglycemic activity. Among them, the hypoglycemic activity of Sd-06 was comparable to that of the positive control drug sitagliptin, and the hypoglycemic activity of Sd-05 was significantly better than that of sitagliptin.

[0158] (4) The oral glucose tolerance test results showed that Sd-05 could significantly improve the glucose tolerance of normal mice under low-dose conditions, and its activity was significantly better than that of the sitagliptin group, proving that the sitagliptin derivative Sd-05 showed good hypoglycemic effect and was significantly better than the existing sitagliptin in improving glucose metabolism disorder and maintaining blood glucose stability.

[0159] The above-described specific examples are for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various simple deductions, modifications, or substitutions based on the principles of this invention. Therefore, the scope of protection of this invention should be determined by the scope of the claims.

Claims

1. A sitagliptin derivative, characterized in that, The chemical structural formula is: Wherein, R is propionyl, valeryl, hexanoyl, heptanyl, octanoyl, isobutyryl, 3,3-dimethylbutyryl or isovaleryl.

2. The method for preparing the sitagliptin derivative according to claim 1, characterized in that, This method involves dissolving sitagliptin and a chelating agent in an organic solvent, followed by the addition of propionyl chloride, valeryl chloride, hexanoyl chloride, heptanyl chloride, octanoyl chloride, isobutyryl chloride, 3,3-dimethylbutyryl chloride, or isovaleryl chloride for reaction.

3. The preparation method according to claim 2, characterized in that, The molar ratio of sitagliptin to the acid-binding agent is 1:1-3; the molar ratio of sitagliptin to propionyl chloride, valeryl chloride, hexanoyl chloride, heptanyl chloride, octanoyl chloride, isobutyryl chloride, 3,3-dimethylbutyryl chloride or isovaleryl chloride is 1:1-3.

4. The preparation method according to claim 2 or 3, characterized in that, The organic solvent is dichloromethane or tetrahydrofuran, and the acid-binding agent is potassium carbonate or triethylamine.

5. The use of the sitagliptin derivative of claim 1 in the preparation of a medicament for treating diabetes.

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