Method for producing saxagliptin

A technology for products and compounds, applied in the direction of organic chemistry, etc., can solve the problems of reduced total yield and cumbersome operation

Inactive Publication Date: 2013-08-28
SHANGHAI TWISUN BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this reaction process, through three-step treatment, the total yield is reduced, and...

Method used

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  • Method for producing saxagliptin
  • Method for producing saxagliptin
  • Method for producing saxagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] refer to figure 1 , the method for synthesizing saxagliptin in the present embodiment is as follows:

[0039] Compound d was synthesized by referring to the method of J.Med.Chem, 2005, 48:5025-5037.

[0040] Compound d (384g), isopropanol (384ml), water (384ml) and 36% hydrochloric acid (126ml) were put into the reaction bottle, heated to an internal temperature of 65°C, and stirred for 1.5h; TLC tracking confirmed that the reaction was complete.

[0041] Concentrate the reaction solution in a 65°C water bath; add water (500ml) and methylene chloride (3.0L) to the concentrate, adjust the pH value of the upper layer to 9-10 with 20% potassium carbonate solution under stirring, add sodium chloride (480g ), stirred for 30 min; allowed to stand, the upper layer was extracted with dichloromethane (3.0L), and discarded after TLC showed no product; the lower layers were combined, washed with water (3.0L), and filtered to remove mechanical impurities.

[0042] Concentrate to ...

Embodiment 2

[0044] Provides compound d.

[0045] Compound d (350g), isopropanol (385ml), water (385ml) and 36% hydrochloric acid (125ml) were put into the reaction flask, heated to an internal temperature of 65°C, and stirred for 1.5h; TLC tracking confirmed that the reaction was complete.

[0046] Concentrate the reaction solution in a 65°C water bath; add water (500ml) and methylene chloride (3.0L) to the concentrate, adjust the pH value of the upper layer to 9-10 with 20% potassium carbonate solution under stirring, add sodium chloride (480g ), stirred for 30 min; the upper layer was extracted with dichloromethane; the lower layers were combined, washed with water (3.0 L), and filtered to remove mechanical impurities.

[0047]Concentrate to about 500ml, add ethyl acetate (1.2L), stir slowly; after 0.5h, add 3ml of water, stir for 0.5h, add 3ml of water again, stir at room temperature for 0.5h; remove residual dichloromethane in the system; stir at room temperature for 15h ; Filter, wa...

Embodiment 3

[0049] refer to figure 2 , the method for synthesizing saxagliptin in the present embodiment is as follows:

[0050] Preparation of compound a

[0051] In a four-necked flask, compound a-1 (150g, 0.667mol, (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0], CAS: 361440-67-7), Isopropanol Isopropanol (1.5L), methanesulfonic acid (83.2g, 0.866mol), heated to an internal temperature of 65°C under stirring, kept stirring for 3h, cooled the reaction solution to 0-5°C, kept stirring for 1h, A large amount of solid precipitated, filtered, washed with 200ml of isopropanol, and dried at 55°C for 8h to obtain off-white solid a (142.5g).

[0052] Preparation of compound c

[0053] At room temperature, put a (142.5g), b (204.5g, N-tert-butoxycarbonyl-3-hydroxy-1-adamantyl-D-glycine, CAS: 361442-00-4), HOBT into the reaction bottle (86.6g, CAS: 80029-43-2), EDC·HCl (131.3g, CAS: 25952-53-8), DIPEA (170.5g, CAS: 7087-68-5) with acetonitrile (520ml), ethyl acetate The ester (500ml) w...

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Abstract

The invention provides a method for producing saxagliptin. The method comprises the following steps of: 1, providing a compound d; and 2, reacting the compound d, isopropanol and concentrated hydrochloric acid at the temperature of between 50 and 80 DEG C, and collecting the product to obtain the saxagliptin. Compared with the prior art, the method has the advantages that the compound d is directly converted into the target product, so that the reaction rate is greatly improved, the reaction yield is improved, the post treatment method is simplified, and industrial wastewater is greatly reduced.

Description

technical field [0001] The invention relates to a compound synthesis method, in particular to a method for producing saxagliptin. Background technique [0002] Saxagliptin is a novel dipeptidyl peptidase-IV (DPP-IV, endogenous incretin) inhibitor jointly developed by Bristol-Myers Squibb and AstraZeneca. By selectively inhibiting DPP-4, it can increase the levels of endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thereby regulating blood sugar. In March 2010, the US FDA approved saxagliptin for the treatment of hyperglycemia in adults with type 2 diabetes; and in May 2011, it was officially approved by SFDA in China. The drug can be used as a monotherapy, or in combination with metformin on the basis of poor control of metformin. Clinical studies have confirmed that saxagliptin has the advantages of outstanding curative effect and long-lasting effect. [0003] The chemical structure of saxagliptin is as follows: [0004]...

Claims

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Application Information

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IPC IPC(8): C07D209/52
Inventor 李维宏沈建刚龚洪泉李悌聪胡静波
Owner SHANGHAI TWISUN BIO PHARM
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