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Method for preparing saxagliptin

A technology of compound and condensing agent, which is applied in the field of preparation of saxagliptin, can solve the problems that it is not suitable for industrial operation, difficult to remove ethyl nicotinate, etc., achieve good economic benefits, reduce the requirements of reaction conditions, and simplify the process steps.

Active Publication Date: 2020-05-29
连云港恒运药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] As can be seen from the above-mentioned saxagliptin synthetic route, ethyl nicotinate is used when formula IV is prepared from the compound of formula VII in this process, and ethyl nicotinate is difficult to remove. In this process, it is necessary to add tetramethylethylenediamine ( TMEDA), wash with water to remove trifluoroacetic acid, then add dilute hydrochloric acid to wash to remove ethyl nicotinate, after repeated extractions, ethyl nicotinate can be removed, which is not suitable for industrial operation; and use trifluoroacetic anhydride and ethyl nicotinate There will be more by-products, including trifluoroacetic anhydride and hydroxyl to form ester groups, or products from the removal of tert-butoxycarbonyl

Method used

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  • Method for preparing saxagliptin
  • Method for preparing saxagliptin
  • Method for preparing saxagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] At room temperature, the compound of formula I (22.63g, 0.10mol) was dissolved in 75ml of ethyl acetate, pyridine (18.98g, 0.24mol) and benzenesulfonyl chloride (17.66g, 0.10mol) were added, and the reaction was stirred for 3 hours, Generate the compound of formula II, add hydrochloric acid solution (50ml, 3mol / L), stir and separate layers, extract the aqueous layer with dichloromethane (60ml×3), combine the organic phases, concentrate under reduced pressure, then place the organic phase concentrate in hydrochloric acid (50ml, 3mol / L) and diethyl ether (300ml) mixed solution, stirred for 8 hours, and the solvent was removed by distillation under reduced pressure, and the solid residue was redissolved in anhydrous ether, filtered and washed with anhydrous ether, and vacuum-dried. 12.11 g of the compound of formula II was obtained with a molar yield of 98.3% and a purity of 99.50%.

Embodiment 2

[0047]At room temperature, the compound of formula I (18.10 g, 0.08 mol) was dissolved in 75 ml of ethyl acetate, pyridine (15.82 g, 0.20 mol) and benzenesulfonyl chloride (14.13 g, 0.08 mol) were added, and the reaction was stirred for 3 hours, Generate the compound of formula II, add hydrochloric acid solution (50ml, 3mol / L), stir and separate layers, extract the aqueous layer with dichloromethane (60ml×3), combine the organic phases, concentrate under reduced pressure, then place the organic phase concentrate in hydrochloric acid (50ml, 3mol / L) and diethyl ether (300ml) mixed solution, stir 8 hours, adopt decompression distillation to remove solvent, solid residue is dissolved in ethyl acetate, obtain 30ml formula II compound ethyl acetate solution, set aside;

[0048] Dissolve the compound of formula III (34.74g, 0.10mol) in 75ml of acetonitrile, dissolve 20.7g of DIEA in 50ml of ethyl acetate, add the mixed solution of DIEA / ethyl acetate to the acetonitrile solution of the...

Embodiment 3

[0050] Take by weighing 20g of the compound of formula IV prepared in Example 2, then dissolve it in the mixed solution formed by water and isopropanol, add hydrochloric acid (20ml, 3mol / L) dropwise at 55°C, finish the dropwise addition in 5min, and keep the temperature Stir the reaction at 60°C for 2 hours, then add water, adjust the pH value of the mixture to 9-10 through sodium hydroxide and potassium carbonate solution, extract with dichloromethane (100ml×3), collect the organic phase, and concentrate under reduced pressure , to obtain 20.18 g of the compound of formula V, namely saxagliptin, with a molar yield of 96.7% and an HPLC purity of 99.85%.

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Abstract

The invention discloses a method for preparing saxagliptin, and belongs to the technical field of drug synthesis. The method comprises the following steps: (a) converting amide on a compound shown ina formula I into cyano and removing Boc groups to obtain a compound shown in a formula II; (b) condensing the compound shown in the formula II and a compound shown in a formula III to obtain a compound shown in a formula IV; and (c) removing Boc groups on the compound shown in the formula IV to obtain a compound shown in a formula V. According to the method, different raw materials and reaction reagents are selected, and a process route is changed, so that four procedures of salifying, condensing, cyanating and de-protecting are shortened into three procedures of cyanating, condensing and de-protecting; meanwhile, cyanating and condensation reaction are realized at the room temperature, the requirements on reaction conditions are reduced, and industrial production can be realized.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing saxagliptin. Background technique [0002] Saxagliptin (Saxagliptin), trade name Onglyza, chemical name (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7Jdecane -1-yl)acetyl]-2-azabicyclo[3.1.O]hexane-3-carbonitrile, jointly developed by Bristol-Myers Squibb Company and Astra Zeneca Company, approved by FDA in July 2009, is a A highly selective and reversible competitive dipeptidyl peptidase IV (DPP-IV) inhibitor, which is well tolerated and does not cause obesity, and is clinically used for the treatment of type 2 diabetes. [0003] There are many reports on the synthesis method of saxagliptin. Most of the literature on its synthesis mainly adopts the amidation reaction of adamantane amino acid derivatives and carbamoyl tetrahydropyrrole derivatives, and the primary amide group is dehydrated by trifluoroacetic anhydride to fo...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 嵇海澄陈刚胜王佩李佳
Owner 连云港恒运药业有限公司
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