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A kind of purification method of vildagliptin crude product

A purification method and crude product technology, which is applied in the field of purification of vildagliptin crude product, can solve the problem of low yield and achieve the effect of increasing yield and reducing cost

Active Publication Date: 2016-03-30
苏州正济药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The post-treatment adopts the method of washing with water, which can remove the raw material, but the yield is not high (41%), and there is the introduction of the impurity vildagliptin amide (that is, the formula ( ))risks of

Method used

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  • A kind of purification method of vildagliptin crude product
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  • A kind of purification method of vildagliptin crude product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: A kind of purification method of vildagliptin crude product

[0026] Add acetone (1000ml), 3-amino-1-adamantanol (100g), potassium iodide (4.87g), and potassium carbonate (123g) into the reaction flask, and heat to 60~65°C. Slowly add (S)-1-(2-chloroacetyl)pyrrole-2-carbonitrile (77.4g) in acetone (500ml) solution dropwise, keep warm for 5h after dropping, after the reaction is complete, filter, evaporate the solvent under reduced pressure, Add acetone (800ml) to dissolve the residue, add silica gel (209.6g), stir at 30-40°C for 60 minutes, filter, wash the filter residue with acetone (100ml*2), combine the filtrates and concentrate under reduced pressure to about 400ml of the system, and then the system Cool slowly to 0~5°C to crystallize, filter, wash with cold acetone (50ml*2), and dry in vacuum to obtain the product (102g, yield 74.8%, purity by HPLC 99.92%, GC (content of formula II) 0.02%) .

Embodiment 2

[0027] Embodiment 2: A kind of purification method of vildagliptin crude product

[0028] Add acetone (1000ml), 3-amino-1-adamantanol (100g), potassium iodide (4.87g), and potassium carbonate (123g) into the reaction flask, and heat to 60~65°C. Slowly add (S)-1-(2-chloroacetyl)pyrrole-2-carbonitrile (77.4g) in acetone (500ml) solution dropwise, keep warm for 5h after dropping, after the reaction is complete, filter, evaporate the solvent under reduced pressure, Add methanol (800ml) to dissolve the residue, add silica gel (309.6g), stir at 30-40°C for 30 minutes, filter, wash the filter residue with methanol (100ml*2), combine the filtrates and concentrate under reduced pressure to about 300ml of the system, and then the system Cool slowly to 0~5°C to crystallize, filter, wash with cold methanol (20ml*2), and dry in vacuo to obtain the product (95g, yield 69.7%, purity by HPLC 99.82%, GC (content of formula II) 0.04%) .

Embodiment 3

[0029] Embodiment 3: A kind of purification method of vildagliptin crude product

[0030] Add acetone (1000ml), 3-amino-1-adamantanol (100g), potassium iodide (4.87g), and potassium carbonate (123g) into the reaction flask, and heat to 60~65°C. Slowly add (S)-1-(2-chloroacetyl)pyrrole-2-carbonitrile (77.4g) in acetone (500ml) solution dropwise, keep warm for 5h after dropping, after the reaction is complete, filter, evaporate the solvent under reduced pressure, Add dichloromethane (500ml) to dissolve the residue, add silica gel (350g), stir at 30-40°C for 30 minutes, filter, wash the filter residue with dichloromethane (100ml*2), combine the filtrates and concentrate under reduced pressure to about 200ml of the system. Ethyl acetate (400ml) was added to co-crystallize, the system was slowly cooled to 0~5°C, filtered, washed with cold ethyl acetate (50ml*2), and dried in vacuo to obtain the product (85g, yield 62.3%, purity by HPLC: 99.95%, GC (Formula II content) N.D.).

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Abstract

The invention relates to a purification method of a vildagliptin crude product, which is characterized by comprising the following steps: adding a vildagliptin crude product obtained by reacting (S)-1-(2-chloracetyl)pyrryl-2-formonitrile and 3-amino-1-adamantanol disclosed as Formula (II) into a solvent to form a reaction mother solution, adding silica gel into the reaction mother solution, and stirring uniformly at 30-40 DEG C, wherein the solvent is any one of aromatic hydrocarbons, hydrochloric ethers, C1-C5 carboxylates, ketones and alcohols, and the weight ratio of the silica gel to the (S)-1-(2-chloracetyl)pyrryl-2-formonitrile is 0.5:1-6:1; filtering to obtain a filtrate; and finally, recrystallizing to obtain the vildagliptin pure product disclosed as Formula (I), wherein the content of the 3-amino-1-adamantanol raw material disclosed as Formula (II) in the vildagliptin pure product is lower than 0.05%. The purification method can lower the content of the impurity disclosed as Formula (II) to 0.05%, has satisfactory yield, and can implement large-scale application in industry.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for purifying crude vildagliptin. Background technique [0002] Vildagliptin (English name: Vildagliptin), chemical name (-)-(2S)-1-[[(3-hydroxytricyclo[3.3.1.1[3,7]]decane-1-yl)amino ] Acetyl] pyrrolidine-2-carbonitrile, the structural formula is as shown in formula (I), [0003] [0004] It is a diabetes drug used to treat type 2 diabetes. [0005] The synthetic method of vildagliptin reported in the literature, the main route is as follows: [0006] [0007] The original compound patent WO0034241A1 provides a preparation method of vildagliptin, the reaction route of which is as follows: [0008] [0009] According to the method described in WO0034241A1 patent, vildagliptin is synthesized using potassium carbonate as base, (S)-1-(2-chloroacetyl)pyrrole-2-carbonitrile (ie formula (Ⅲ)) and 3-amino -1-Adamantanol (formula (II)) was sti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 沈巍巍马春鸣徐敏
Owner 苏州正济药业有限公司
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