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Preparation method of vildagliptin

A technology of aminoadamantanol and formonitrile, which is applied in chemical instruments and methods, compounds of Group 4/14 elements of the periodic table, organic chemistry, etc., can solve problems such as reducing production efficiency and increasing production costs, and achieves improved efficiency. , improve the yield, improve the effect of crude product purity

Active Publication Date: 2020-01-03
烟台万润药业有限公司
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  • Claims
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Problems solved by technology

[0010] CN201510283346.1 reported a high-efficiency synthesis method of vildagliptin. In this method, the chlorination of L-prolineamide and the subsequent dehydration are completed in one pot, which improves the efficiency, and 3-aminoadamantanol is used when participating in the reaction. The acid-binding agent is replaced by an organic base, which improves the reaction effect and reduces the by-product Ⅰ to a certain extent a The generation of , so that the efficiency of the entire preparation process has been significantly improved, but the by-product I a The content in the primary refined product is still higher than 0.1%, and it needs to be refined again, which increases the production cost and reduces the production efficiency

Method used

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  • Preparation method of vildagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] (1) Preparation of 3-aminoadamantanol protected by silyl groups:

[0041] Add 117.8g (0.7299mol) 1,1,1,3,3,3-hexamethyldisilazane (HMDS for short), 116.3g (0.6954mol) 3-aminoadamantanol, 3.52 g (0.03479mol) triethylamine, 348.9g dichloromethane, heated to 35-40°C, and kept at 35-40°C for 1-6h. ) to steam off HMDS and solvent to obtain 217.0g (theoretical yield 216.7g) of light yellow liquid, yield 100.1%, GC purity 96.0%, MS spectrogram data see figure 1 , [M]=311, that is, the crude product of silyl-protected 3-aminoadamantanol.

[0042] (2) Preparation of Vildagliptin:

[0043] In a 2L three-necked flask, add 216.7g (0.6954moL) of silyl-protected 3-aminoadamantanol, 73.2g (0.7234moL) of triethylamine, 5.7g (0.03434moL) of potassium iodide and 650.0g of acetonitrile, and heat to 75 -80°C, add 118.8g (0.6883moL) (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile (dissolved in 356.4g acetonitrile) dropwise, 2h dropwise, 75-80°C Insulated and stirred for 1 h; T...

Embodiment 2

[0045] (1) Preparation of 3-aminoadamantanol protected by silyl groups:

[0046] Add 123.5g (0.7652mol) 1,1,1,3,3,3-hexamethyldisilazane (HMDS for short), 116.3g (0.6954mol) 3-aminoadamantanol, 4.93 g (0.04872mol) triethylamine, 465.2g dichloromethane, heated to 35-40°C, and kept at 35-40°C for 1-6h. ) to distill off HMDS and solvent to obtain 217.3 g of light yellow liquid (theoretical yield 216.7 g), yield 100.3%, GC purity 97.5%, ie the crude product of silyl-protected 3-aminoadamantanol.

[0047] (2) Preparation of Vildagliptin:

[0048] In a 2L three-necked flask, add 216.7g (0.6954moL) of silyl-protected 3-aminoadamantanol, 76.3g (0.7540moL) of triethylamine, 7.6g (0.04578moL) of potassium iodide and 650.0g of acetonitrile, and heat to 75 -80°C, add dropwise 113.2g (0.6558moL) (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile (dissolved in 339.6g acetonitrile), 2h dropwise, 75-80°C Stir under insulation for 1 h; TLC detects that the reaction is complete, add 3...

Embodiment 3

[0050] (1) Preparation of 3-aminoadamantanol protected by silyl groups:

[0051] Add 129.1g (0.7999mol) 1,1,1,3,3,3-hexamethyldisilazane (HMDS for short), 116.3g (0.6954mol) 3-aminoadamantanol, 7.04 g (0.06957mol) triethylamine, 581.5g dichloromethane, heated to 35-40°C, and kept at 35-40°C for 1-6h. ) to distill off HMDS and solvent to obtain 219.3 g of light yellow liquid (theoretical yield 216.7 g), yield 101.2%, GC purity 98.7%, ie the crude product of silyl-protected 3-aminoadamantanol.

[0052] (2) Preparation of Vildagliptin:

[0053] In a 2L three-necked flask, add 216.7g (0.6954moL) of silane-protected 3-aminoadamantanol, 114.4g (0.8852moL) of diisopropylethylamine, 10.5g (0.06325moL) of potassium iodide, 650.0g of acetonitrile, and stir Heated to 75-80°C, added dropwise 109.1g (0.6321moL) (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile (dissolved in 327.3g acetonitrile), and the dropwise addition was completed after 2h, 75 Stir at -80°C for 1 hour; TLC d...

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Abstract

The invention relates to a preparation method of vildagliptin. The preparation method comprises the following steps: (1) adding 1,1,1,3,3,3-hexamethyldisilazane, 3-aminoadamantanol, a catalyst and dichloromethane into a reactor, carrying out heating, carrying out a heat-preserved reaction, and after the reaction is completed, evaporating out 1,1,1,3,3,3-hexamethyldisilazane and the solvent to obtain a silicyl-protected 3-aminoadamantanol crude product; and (2) adding potassium iodide, organic alkali and acetonitrile into the reactor filled with the silicyl-protected 3-aminoadamantanol crude product, carrying out heating, dropwise adding (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile dissolved in acetonitrile, carrying out a reaction for 1-6 h, adding ethanol with a concentrationof 95%, continuing stirring for 0.5-2 h, and successively performing cooling, filtering, desolventizing and recrystallizing after the stirring reaction is finished so as to obtain vildagliptin. The preparation method can significantly reduce the generation of the impurity Ia, improve yield and reduce the cost, and is beneficial for industrial production.

Description

technical field [0001] The invention relates to a preparation method of vildagliptin, which belongs to the technical field of chemical synthesis. Background technique [0002] Vildagliptin, chemical name (S)-1-[[3-hydroxy-1-adamantylamine)amino]acetyl]-2-cyanopyrrolidine, structural formula as shown in I. It is a new oral hypoglycemic drug developed by Novartis, which was approved by the European Food and Drug Administration in 2008. Vildagliptin is an oral hypoglycemic drug belonging to type Ⅳ dipeptidyl peptidase (DPP-Ⅳ) inhibitors. Its mechanism of action is to inhibit the activity of this enzyme by combining with DPP-Ⅳ to form a complex. The concentration of blood glucose-like peptide Ⅰ (GLP-1) promotes the production of insulin by the pancreatic beta cells and at the same time reduces the concentration of glucagon, thereby reducing blood sugar. It has a very obvious hypoglycemic effect when used alone or in combination with metformin and insulin, and has many advantag...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07F7/18
CPCC07D207/16C07F7/188C07F7/1892
Inventor 杜体建唐春超乔仁国徐力丰袁明亮夏晓丽林培森易朝辉
Owner 烟台万润药业有限公司
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