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Vildagliptin diketopiperazine and preparation method thereof

A technology for vildagliptin diketopiperazine and diketopiperazine, which is applied in the field of medicinal chemistry, can solve the problems of many reaction steps, many side reactions, complicated processes and the like, achieves mild and easy controllable reaction conditions, reduced synthesis cost, The effect of the simple method of synthesis

Pending Publication Date: 2021-10-22
重庆医科大学附属大学城医院
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0004] Vildagliptin diketopiperazine (2-(3-hydroxyadamantan-1-yl) hexahydropyrrole[1,2-a]piperazine-1,4-dione, its structure is shown in formula II ) is a specific degraded impurity of vildagliptin in the preparation, and its source mainly has the following two ways: (1) extracting from the preparation of vildagliptin, the extraction process in this method is complicated, the operation is difficult, and the cost is extremely high High; (2) Using L-proline and 3-amino-1-adamantanol as raw materials, it is synthesized through 5 steps of chloroacetylation, methylation, substitution, demethylation, and dehydration condensation. There are many steps, the process is complicated and unfavorable for operation, and the price of ethyl chloroformate used in the route is relatively expensive, and there are many side reactions, which are not conducive to post-treatment and purification;

Method used

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  • Vildagliptin diketopiperazine and preparation method thereof
  • Vildagliptin diketopiperazine and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A preparation method of vildagliptin diketopiperazine, comprising the following steps:

[0030] S1, the synthesis of compound 1

[0031] Add 5g (0.044mol) of L-proline and 50ml (0.62mol) of tetrahydrofuran into a 150ml three-necked flask and stir, slowly add 5.04ml (0.067mol) of chloroacetyl chloride dropwise under ice-bath conditions, and heat to 40 Reflux at ℃ for 2h, cool, add 100ml of saturated sodium bicarbonate to wash; then add 100ml of ethyl acetate for extraction, the aqueous layer is extracted with ethyl acetate (20ml×3), the combined organic layers are dried with anhydrous sodium sulfate for 10h, and concentrated under reduced pressure A light yellow oil was obtained, which was recrystallized by slowly adding isopropyl ether dropwise in an ice bath, filtered, and the filter cake was dried to obtain 7.34 g of a white solid, with a yield of 87.5%, mp: 106-108°C;

[0032] S2, the synthesis of compound 2

[0033] 4.79g (0.025mol) of compound 1 was added in 20ml...

Embodiment 2

[0037] A preparation method of vildagliptin diketopiperazine, comprising the following steps:

[0038] S1, the synthesis of compound 1

[0039] Add 5g (0.044mol) of L-proline and 50ml of ethyl acetate into a 150ml three-neck flask and stir, slowly add 5.04ml (0.067mol) of chloroacetyl chloride dropwise under ice-bath conditions, and heat to reflux at 40°C after dropping 2h, cooled, added 100ml of saturated sodium bicarbonate for washing; then added 100ml of ethyl acetate for extraction, the aqueous layer was extracted with ethyl acetate (20ml×3), the combined organic layers were dried over anhydrous sodium sulfate for 10h, concentrated under reduced pressure to obtain Yellow oil, recrystallized by slowly adding isopropyl ether dropwise in ice bath, filtered, and dried the filter cake to obtain 7.50 g of white solid, yield 89.0%, mp: 106.5~107.5°C;

[0040] S2, the synthesis of compound 2

[0041]4.5g (0.023mol) of compound 1 was added in 20ml of acetonitrile to make a soluti...

Embodiment 3

[0045] A preparation method of vildagliptin diketopiperazine, comprising the following steps:

[0046] S1, the synthesis of compound 1

[0047] Add 10g (0.087mol) of L-proline and 100ml of tetrahydrofuran into a 250ml three-neck flask and stir, slowly add 8.5ml (0.114mol) of chloroacetyl chloride dropwise under ice-bath conditions, and heat to reflux at 40°C for 2h after dropping. Cool, add 200ml of saturated sodium bicarbonate to wash; then add 200ml of ethyl acetate to extract, the aqueous layer is extracted with ethyl acetate (20ml×3), the combined organic layer is dried with anhydrous sodium sulfate for 10h, and concentrated under reduced pressure to obtain a light yellow oil Recrystallized by slowly adding isopropyl ether dropwise in an ice bath, filtered, and dried the filter cake to obtain 15.20 g of white solid, yield 91.20%, mp: 106-108°C;

[0048] S2, the synthesis of compound 2

[0049] Add 3g (0.015mol) of compound 1 to 20ml of dimethylformamide to prepare a solu...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a vildagliptin impurity, namely vildagliptin diketopiperazine, and a preparation method thereof. The preparation method comprises the following steps: (1) dissolving L-proline, mixing with chloroacetyl chloride, and reacting to generate a compound 1; (2) carrying out substitution reaction on the compound 1 and 3-amino-1-adamantanol under an alkaline condition to generate a compound 2; and (3) cyclizing the compound 2 under an alkaline condition to obtain vildagliptin diketopiperazine. According to the preparation method of vildagliptin diketopiperazine provided by the invention, L-proline is used as a raw material, and is synthesized through three steps of reaction of chloroacetylation, substitution and dehydration, the synthesis method is simple, the reaction conditions are mild and easy to control, the raw materials are cheap, the synthesis cost is effectively reduced, and the product purity reaches 98.0% or above, accords with the provisions of the Chinese Medicine Biological Product Institute, and can be used as an impurity reference substance for quality control.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a vildagliptin impurity, vildagliptin diketopiperazine, and a preparation method thereof. Background technique [0002] Vildagliptin (structure shown in formula I), is a reversible, competitive and selective dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Novartis, which was approved by the European Union in 2007 In 2011, CFDA officially approved its listing in China. Clinically, vildagliptin is mainly used orally for the treatment of type 2 diabetes mellitus. It has a significant hypoglycemic effect when used alone or in combination with biguanides, thiazolidinediones, sulfonylureas and other drugs. The main hypoglycemic mechanism is: Glucose-dependent glucagon-like peptide-1 (GLP-1) and insulinotropic polypeptide (GIP) are two important incretin hormones in the human body, but GLP-1 and GIP in the human body will be destroyed within a few minutes....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 袁誉铭张明
Owner 重庆医科大学附属大学城医院
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