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Preparation method of medication saxagliptin for treating diabetes

A synthesis method and compound technology, applied in the field of preparation of drug saxagliptin, can solve the problems of saxagliptin cumbersome reaction route, expensive raw materials, harsh reaction conditions, etc., and achieve high yield, shortened reaction route, side effects The effect of product reduction

Active Publication Date: 2019-05-17
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved in the present invention is aimed at the problems in the prior art that the reaction route of saxagliptin is relatively cumbersome, some reaction conditions are relatively harsh, the reaction route is long, the price of raw materials is relatively expensive, and the yield is low, and the product purity is not high.

Method used

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  • Preparation method of medication saxagliptin for treating diabetes
  • Preparation method of medication saxagliptin for treating diabetes
  • Preparation method of medication saxagliptin for treating diabetes

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preparation example Construction

[0029] The invention discloses a preparation method of saxagliptin, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. It needs to be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention, and relevant personnel can obviously make changes without departing from the content, spirit and scope of the present invention. Changes or appropriate changes and combinations are made to the content described herein to realize and apply the technology of the present invention.

[0030] In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art.

Embodiment 1

[0032] Embodiment 1: the preparation of cyclization compound

[0033]

[0034] In 120mL tetrahydrofuran, under nitrogen protection, add 7.65g (45mmol) diethyl butynedioate and 10.91g (45mmol) (S)-N-Boc-3-amino-3-cyano-propionic acid ethyl ester, 0.22g (1.2mmol) PdCl 2 and 0.65g (1.2mmol) chiral ligand L 1 And 8.21g (100mmol) sodium acetate, 18.53g (80mmol) Ag 2O was used as an oxidizing agent, stirred at 40° C. for 3 hours, and TLC monitored the reaction process. After the reaction was completed, water was added to separate the layers, and the organic phase was dried overnight over anhydrous magnesium sulfate, concentrated under reduced pressure, and obtained cyclized compound 17.93g (43.7 mmol), the yield was 97%, e.e.>99.9%.

[0035] 1 H NMR (CHCl 3 -d,400M)δ: 5.25(d,1H),4.26(m,2H),4.15(m,2H),4.05(m,2H),3.67(d,1H),1.55(s,9H),1.24 (m,3H),1.19(m,3H),1.11(m,3H); 13 C NMR (CHCl 3 -d,400M)δ:171.1,167.8,165.1,148.2,135.5,122.1,118.9,87.6,67.1, 61.6,43.8,38.5,26.9,14.1; ...

Embodiment 2

[0036] Example 2: Preparation of (S)-N-Boc-2-cyano-2,3-dihydro-1H-pyrrole

[0037]

[0038] In a 150mL Schlenk reaction tube, add 4.10g (10mmol) of the cyclized compound and 100mL of xylene, 6.33g of solid sodium hydroxide, nitrogen protection, seal the tube and heat to 180 ° C, react for 10 hours, cool to room temperature, filter, wash with water, reduce The solvent was removed under pressure, and 1.57 g (8.1 mmol) of compound (S)-N-Boc-2-cyano-2,3-dihydro-1H-pyrrole was obtained by column chromatography with a yield of 81%.

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Abstract

The invention provides a preparation method of saxagliptin with a shorter synthetic route. (S)-3-amino-3-cyano-propionic ether protected by diethyl acetylenedicarboxylate and an amino group is used asa starting material in the presence of an organic phosphine ligand and a palladium catalyst, and is subjected to cyclization, decarboxylation and cyclopropanation to obtain an intermediate product (1S, 3S, 5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile p-toluenesulfonate, and then the intermediate product is reacted with carboxyl-activated (S)-N-t-butyloxycarboryl-(3-hydroxyadamantane-1-yl)glycineto increase the reaction rate and obtain a saxagliptin product with a high yield and high purity, the reaction route is greatly shortened, the yield in each step is high, the reaction time is short, the production cost is reduced, and industrial production is facilitated.

Description

technical field [0001] The application relates to a preparation method of saxagliptin, a medicine for treating diabetes, and belongs to the field of western medicine synthesis. Background technique [0002] In recent years, the incidence of diabetes has increased year by year, and diabetes has become another non-communicable disease that seriously threatens human health after cardiovascular diseases and malignant tumors. The type II incidence of diabetes accounts for 90%, and the pathogenesis of type II diabetes is mainly caused by the human body's resistance to insulin and insulin and cell function defects. Clinically used drugs for the treatment of type II diabetes mainly include insulin secretion promoters, sulfonylureas, meglitinides, insulin sensitizers, insulin and insulin receptor agonists and dipeptidyl peptidase-4 inhibitors . [0003] Saxagliptin, chemical name (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-nitrogen Heterobicyclo[3.1.0]hexane-3-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
Inventor 阎德文谭回左馨
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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