Preparation method of high-purity vildagliptin

A high-purity, crude product technology, applied in the direction of organic chemistry, can solve the problems of low acetylation yield, difficulty in removing by-products, and small residual amount of 3-amino-1-adamantanol, so as to reduce the content and reduce the The effect of impurity content

Inactive Publication Date: 2015-11-25
NANJING UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The advantage of the L-proline route is that the price of L-proline is low, and the disadvantage is that the first step in the synthesis step is due to the poor solubility of L-proline, and the yield of acetylation is not high.
In the second step, the carboxylic acid is converted into an amide, and the condensing agent DCC is required. The reaction operation described in the literature requires strict anhydrous operation, and will produce DC

Method used

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  • Preparation method of high-purity vildagliptin
  • Preparation method of high-purity vildagliptin
  • Preparation method of high-purity vildagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (1) Synthesis of vildagliptin crude product

[0036] Add 500ml of tetrahydrofuran and 92g of 3-amino-1-adamantanol into a 1L three-necked flask, stir to dissolve the solid, then add 138g of potassium carbonate and 1.7g of potassium iodide, stir to cool down to 0°C to 5°C, add (2S)- 86.3 g of 1-(2-chloroacetyl)-2-pyrrolidinecarbonitrile. The temperature was controlled and the reaction was stirred for 10 hours, and the oil was obtained after post-treatment. Vildagliptin crude product 114.2g was obtained by crystallization of 2-butanone, with a yield of 75.3%. The HPLC and GC spectra of the crude product are respectively shown in the attached figure 1 And attached image 3 .

[0037] (2) Crude refined

[0038] Add the crude product (100g) into 2-butanone (1.6L) and isopropanol (0.64L), heat to 60-70°C to dissolve the solid, filter, cool to 0-10°C to crystallize for 6 hours, and filter with suction. Dry under reduced pressure at 50°C to obtain 67.4g of refined product o...

Embodiment 2

[0040] (1) Synthesis of vildagliptin crude product

[0041] Add 1000ml of tetrahydrofuran and 192.3g of 3-amino-1-adamantanol into a 2L three-necked flask, stir to dissolve the solid, then add 276g of potassium carbonate and 3.4g of potassium iodide, stir to cool down to 0°C to 5°C, add (2S) - 172.6 g of 1-(2-chloroacetyl)-2-pyrrolidinecarbonitrile. The reaction was carried out under temperature control and stirring for 10 hours, and after treatment, an oily substance was obtained, and 218.8 g of crude vildagliptin was obtained by crystallization with isopropanol, with a yield of 72.1%.

[0042] (1) Crude refined

[0043] Add the crude product (200g) to 2-butanone (3.4L) and isopropanol (1.3L), heat to 60-70°C to dissolve the solid, filter, cool to 0-10°C to crystallize for 6 hours, and filter with suction. Drying under reduced pressure at 50°C yielded 138.4 g of white crystal refined product with a yield of 69.2%.

Embodiment 3

[0045] (1) Synthesis of vildagliptin crude product

[0046] Add 120ml of dichloromethane and 21g of 3-amino-1-adamantanol into a 500ml three-necked flask, stir to dissolve the solid, then add 33g of anhydrous potassium carbonate and 0.4g of potassium iodide, stir to cool down to 5°C-10°C, add 20.6 g of (2S)-1-(2-chloroacetyl)-2-pyrrolidinecarbonitrile. The reaction was carried out under temperature control and stirring for 12 hours, and post-treatment was carried out to obtain an oily product, which was crystallized with 2-butanone to obtain 25.5 g of crude vildagliptin, with a yield of 70.5%.

[0047] (2) Crude refined

[0048]Add the crude product (20g) to 2-butanone (300ml) and isopropanol (120ml), heat to 60-70°C to dissolve the solid, filter, cool to 0-10°C to crystallize for 6 hours, suction filter, 50°C After drying under reduced pressure, 13.7 g of white crystalline refined product was obtained, with a yield of 68.7%.

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Abstract

The invention discloses a preparation method of high-purity vildagliptin, which comprises the following steps: carrying out nucleophilic substitution reaction on an intermediate (2S)-1-(2-chloracetyl)-2-pyrrolidine formonitrile and 3-amino-1-adamantanol in a certain reaction solvent by using potassium iodide as a catalyst and potassium carbonate as an acid-binding agent, carrying out after-treatment to obtain grease, and carrying out solvent crystallization to obtain a vildagliptin crude product; and refining the vildagliptin crude product by using a purified solvent to obtain the refined product. The synthesis method by controlling the vildagliptin crude product obtains favorable technical effects, and can obviously lower the impurity content in the vildagliptin crude product. A refinement technique different from the documents is adopted, and isopropanol and 2-butanone impurity removal is performed to obtain favorable technical effects, thereby obviously lowering the content of the main impurity 3-amino-1-adamantanol and vildagliptin bis-substituted impurity in the vildagliptin crude product. The vildagliptin purity detected by HPLC (high performance liquid chromatography) and GC (gas chromatography) is up to 99.8% or above, and the contents of the two impurities are respectively lower than 0.1%.

Description

field of invention [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation process of high-purity vildagliptin. Background technique [0002] Vildagliptin is a highly selective substrate-like enzyme inhibitor that more thoroughly inhibits DPP-4 enzyme activity and can obtain more active GLP-1 compared with competitive inhibitors (such as sitagliptin) . Vildagliptin is covalently bound to the catalytic site of DPP-4, acting quickly and slowly dissociated, so it can quickly and persistently increase the level of active GLP-1 in the body, effectively covering the mealtime and fasting periods, and is more conducive to the patient's HbA1c level reaching the standard. Due to the unique mechanism of action of vildagliptin, its hypoglycemic effect is significant, and it is glucose concentration-dependent hypoglycemic, so it is less hypoglycemic, does not increase body weight, and is safer. Vildagliptin simultaneously improves α an...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 孔杜林林强
Owner NANJING UNIV OF SCI & TECH
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