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New crystal form and preparation method of highly pure trelagliptin

A high-purity, crystalline technology, applied in organic chemistry and other directions, can solve the problems of undisclosed impact on the quality of the final product, difficult industrial production of purification methods, and limited production capacity improvement, and achieves low-cost, easy recovery, and improved production efficiency. Effect

Inactive Publication Date: 2016-06-22
SHANGHAI INST OF PHARMA IND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] 1. The disclosed method does not carry out in-depth research on positional isomers, and does not reveal its impact on the quality of the final product;
[0016] 2. The disclosed purification methods (such as preparative HPLC purification) are difficult to realize industrial production, which reduces production efficiency and limits the improvement of production capacity;

Method used

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  • New crystal form and preparation method of highly pure trelagliptin
  • New crystal form and preparation method of highly pure trelagliptin
  • New crystal form and preparation method of highly pure trelagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1, the synthesis of compound trexagliptin:

[0068] Compound 1 (10g, 34mmol), (R)-3-aminopiperidine dihydrochloride (8.0g, 47mmol) and sodium bicarbonate (13g, 154mmol) were stirred at reflux in ethanol (200ml) for 3 hours; filtered while hot , the filter cake was washed with ethanol (50ml), and a large amount of solids were precipitated from the filtrate, and the filtrate was stirred for 1 hour in an ice bath. The solid was filtered out, and the solid was recrystallized from ethanol to obtain 10 g of high-purity trexagliptin crystals (yield: 82.1%).

Embodiment 2

[0069] Embodiment 2, the synthesis of compound Trexagliptin:

[0070]Compound 4 (10g, 34mmol), (R)-3-aminopiperidine dihydrochloride (8.0g, 4.7mmol) and sodium bicarbonate (13g, 154mmol) were stirred under reflux in isopropanol (250ml) for 2.5 hours; Filtration while hot, the filter cake was washed with Virahol alcohol (50ml), the filtrate was stirred in an ice bath for 1 hour, and the solid was filtered out, and the solid was recrystallized with Virahol to obtain 10.4g of high-purity Trexagliptin crystals (yield: 85.4%).

Embodiment 3

[0071] Embodiment 3, the synthesis of compound trexagliptin:

[0072] Compound 4 (10g, 34mmol), (R)-3-aminopiperidine dihydrochloride (8.0g, 47mmol) and potassium bicarbonate (21g, 152mmol) were stirred at reflux in ethanol (200ml) for 3.5 hours; filtered while hot , the filter cake was washed with ethanol (50ml), the filtrate was stirred in an ice bath for 1 hour, the solid was filtered off, and the solid was recrystallized with isopropanol to obtain 9.7g of high-purity trexagliptin crystals (80.2% yield).

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Abstract

The invention provides a novel high-purity trexagliptin crystal. The high-purity trexagliptin prepared by the present invention can form a salt with an acid to obtain a high-purity trexagliptin salt, and at the same time provide a high-purity trexagliptin crystal preparation and purification crystallization process, including the following steps: Step 1: Condensation reaction, that is, compound 1 and (R)-3-aminopiperidine dihydrochloride 2 are used as raw materials, and are heated to reflux in an organic solvent and in the presence of a base to undergo a condensation reaction to obtain the crude product of trexagliptin; Step 2: Recrystallization, that is, recrystallize the crude trexagliptin obtained in step 1 in an organic solvent to obtain high-purity trexagliptin. The method of the invention has the advantages of simple operation, high yield and low cost, and is very suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of chemical drug synthesis, and in particular relates to a new high-purity crystal form of trexagliptin, a hypoglycemic drug, and its preparation and application. Background technique [0002] Diabetes Mellitus (DM) is a metabolic disease with multiple etiologies, which is caused by an absolute or relative deficiency of insulin, resulting in an increase in blood sugar and causing metabolic disorders in the body. It can be divided into insulin-dependent diabetes mellitus (insulin-dependent diabetes mellitus, IDDM, also known as type 1 diabetes) and non-insulin-dependent diabetes mellitus (NIDDM, also known as type 2 diabetes), of which type 2 diabetes is the most common, accounting for More than 90% of patients. Dipeptidyl peptidase IV (DPP-IV) is a serine protease expressed in many tissues in the body, such as intestine, liver, lung, kidney, etc., as well as in circulating T lymphocytes. It is responsible for the me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 陈武刘相奎于净平胡宏亮朱雪焱袁哲东顾红梅王祥建
Owner SHANGHAI INST OF PHARMA IND
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