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Vildagliptin preparation method

A technology for chloroacetyl and cyanopyrrolidine, which is applied in the field of preparation of pyrrolidine heterocyclic compounds, can solve the problems of low purity index of the final product, complicated operation procedures, long synthesis routes, etc. The effect of stable conditions and short reaction times

Inactive Publication Date: 2015-08-19
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are some problems and defects in the preparation method of vildagliptin, which are mainly reflected in the following points: the synthetic route is long and the yield is not high; the reaction time is long and the energy consumption is high; the operation process is relatively complicated; The purity index is not high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A preparation method of vildagliptin, comprising the following steps:

[0033] (1) Preparation of S-1-chloroacetyl-2-cyanopyrrolidine acetonitrile solution: Dissolve 20 kg (0.116mol) S-1-chloroacetyl-2-cyanopyrrolidine in 62 kg acetonitrile (ie 79 L of acetonitrile, the volume of acetonitrile used in liters is 3.95 times the number of kilograms of S-1-chloroacetyl-2-cyanopyrrolidine), stirred for 15 min, dissolved and set aside;

[0034] (2) Nucleophilic substitution reaction: Add 120 kg of acetonitrile (ie 153 L of acetonitrile, the volume of acetonitrile used is 7.65 times the number of kilograms of S-1-chloroacetyl-2-cyanopyrrolidine) into a 500 L reactor ), start stirring, add 25 kg (0.149mol) of 3-amino-1-adamantanol, 56 kg of potassium carbonate (0.405mol) and 1.5 kg (0.009mol) of potassium iodide, and heat the system to 65-70°C , add dropwise the above-prepared S-1-chloroacetyl-2-cyanopyrrolidine acetonitrile solution to the system, after the dropwise addition, ...

Embodiment 2

[0041] A preparation method of vildagliptin, comprising the following steps:

[0042] (1) Preparation of S-1-chloroacetyl-2-cyanopyrrolidine acetonitrile solution: Dissolve 20 kg (0.116mol) S-1-chloroacetyl-2-cyanopyrrolidine in 31.4 kg acetonitrile (ie 40 L of acetonitrile, the number of liters used for acetonitrile is twice the number of kilograms of S-1-chloroacetyl-2-cyanopyrrolidine), stirred, dissolved and set aside;

[0043] (2) Nucleophilic substitution reaction: Add 235.8 kg of acetonitrile into a 500 L reactor (that is, 300 L of acetonitrile, the volume of acetonitrile used is 15 times the number of kilograms of S-1-chloroacetyl-2-cyanopyrrolidine ), start stirring, add 20.4 kg (0.122mol) of 3-amino-1-adamantanol, 40.1 kg (0.29mol) of potassium carbonate and 3.8 kg (0.023mol) of potassium iodide, and heat the system to 55-60°C , add dropwise the above-prepared S-1-chloroacetyl-2-cyanopyrrolidine acetonitrile solution to the system, after the dropwise addition, conti...

Embodiment 3

[0050] A preparation method of vildagliptin, comprising the following steps:

[0051] (1) Preparation of S-1-chloroacetyl-2-cyanopyrrolidine acetonitrile solution: Dissolve 20 kg (0.116mol) S-1-chloroacetyl-2-cyanopyrrolidine in 78.6 kg acetonitrile (ie 100 L of acetonitrile, the number of liters used for acetonitrile is 5 times the number of kilograms of S-1-chloroacetyl-2-cyanopyrrolidine), stirred, dissolved and set aside;

[0052] (2) Nucleophilic substitution reaction: Add 94.3 kg of acetonitrile to a 500 L reactor (that is, 120 L of acetonitrile, the volume of acetonitrile used is 6 times the number of kilograms of S-1-chloroacetyl-2-cyanopyrrolidine ), start stirring, add 58.2 kg (0.348mol) of 3-amino-1-adamantanol, 24 kg (0.174mol) of potassium carbonate and 1.0 kg (0.006mol) of potassium iodide, and heat the system to 45-50°C , add dropwise the above-prepared S-1-chloroacetyl-2-cyanopyrrolidine acetonitrile solution to the system, after the dropwise addition, continue ...

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Abstract

The invention discloses a vildagliptin preparation method, and relates to the technical field of preparation of pyrrolidine heterocyclic compounds. The method comprises the following steps: 1, preparing an acetonitrile solution of S-1-chloroacetyl-2-cyanpyrrolidine; 2, adding acetonitrile into a reaction kettle, stirring, adding 3-amino-1-adamantanol, potassium carbonate and potassium iodide, heating, adding the acetonitrile solution of S-1-chloroacetyl-2-cyanpyrrolidine in a dropwise manner, and carrying out a heat insulation reaction after the dropwise addition until the reaction is completely carried out; and 3, post-processing: cooling, stirring, centrifuging, collecting the obtained filter cake, adding dichloromethane into the kettle, stirring, adding the filter cake, stirring, centrifuging, collecting the obtained filtrate, concentrating the filtrate to obtain a concentrate, re-crystallizing the concentrate by using isopropanol to obtain a crude product, carrying out hot washing on the crude product by using isopropanol, cooling, and centrifuging to obtain a product. The product is obtained through the one-step reaction by using the method, the yield is high, the chemical purity and the chiral purity are respectively greater than 99%, and the method has the advantages of short reaction time, low energy consumption and simple operation.

Description

technical field [0001] The invention relates to the technical field of preparation of pyrrolidine heterocyclic compounds. Background technique [0002] Diabetes is the fourth most common disease in the world after cardiovascular and cerebrovascular diseases, cancer and AIDS. According to the World Health Organization report in 2011, 346 million people worldwide suffer from diabetes. According to the Asian Diabetes Society, as of 2012, the total number of people suffering from diabetes in China has reached 92.4 million, and the incidence of diabetes is as high as 9.7%. The current situation of diabetes is very serious. [0003] Diabetes can be divided into type 1 diabetes and type 2 diabetes. Type 1 diabetes is caused by the absolute deficiency of insulin due to the loss of pancreatic β-cell function. Type 2 diabetes is characterized by insulin resistance, which is manifested by the progressive failure of pancreatic β-cells, which leads to insufficient insulin secretion aft...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 张少平张基勇王平周文峰张伟
Owner CANGZHOU SENARY CHEM SCI TEC
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