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Novel synthesis method of ticagrelor intermediate (1R,2R)-2-(3,4-difluorophenyl) cyclopropane nitrile

A technology of difluorophenyl and ticagrelor, which is applied in the fields of organic chemistry methods, chemical instruments and methods, preparation of sugar derivatives, etc. It can solve the problems of heavy environmental pollution, poor atom economy, difficult recycling and reuse in the production process, etc. , to achieve the effect of improving the production environment, mild reaction conditions, and easy separation and purification

Active Publication Date: 2017-09-08
TAIZHOU VOCATIONAL & TECHN COLLEGE
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  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned technical route has disadvantages such as long route, low yield, resolution of chiral products and the use of expensive chiral substances as chiral induction centers, which lead to (1R, 2R)-2-(3,4-di The production cost of fluorophenyl) cyclopropane nitrile improves greatly, and the space for the improvement of original process route technology is limited
2). The preparation process is not environmentally friendly and the atom economy is poor
The by-products in the above process route are difficult to recycle and reuse, the three wastes are produced in a large amount, and the production process causes great environmental pollution

Method used

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  • Novel synthesis method of ticagrelor intermediate (1R,2R)-2-(3,4-difluorophenyl) cyclopropane nitrile
  • Novel synthesis method of ticagrelor intermediate (1R,2R)-2-(3,4-difluorophenyl) cyclopropane nitrile
  • Novel synthesis method of ticagrelor intermediate (1R,2R)-2-(3,4-difluorophenyl) cyclopropane nitrile

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-2

[0036] Example 1-2. N-[2,3,4,6-Tetra-O-(3,4,5-tribenzyloxy)benzoyl-β-D-glucopyranosyl]-(2E) Synthesis of -3-(3,4-difluorophenyl)acrylamide

[0037] Add N-[2,3,4,6-tetra-O-(3,4,5-tribenzyloxy)benzoyl-β-D-glucopyranosyl]amine in a 500mL four-necked flask I (36.1g, 0.02mol), toluene (200mL) and triethylamine (3.03g, 0.03mol), placed at 0℃, slowly add (2E)-3-(3,4-difluorophenyl) dropwise ) Acrylic acid chloride toluene solution (4.44g(2E)-3-(3,4-difluorophenyl)acrylic acid chloride dissolved in 100 mL of toluene), after dripping, the temperature is raised to 65℃ and the reaction is kept warm. The reaction is detected by TLC and the reaction is over After cooling to room temperature, use 5% NaCl solution and 6% NaHCO 3 The solution was washed with purified water and distilled under reduced pressure to obtain 37.64 g of pale yellow solid. The product yield is 95.5%, and the HPLC content is 99.0%. Example 1-3. N-(2,3,4,6-Tetra-O-pivaloyl-β-D-glucopyranosyl)-(2E)-3-(3,4-difluorophenyl...

Embodiment 1-3

[0038] Add N-[2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl]amine I (10.3g, 0.02mol), toluene (200mL) to a 500mL four-necked flask. ) And pyridine (2.37g, 0.03mol), placed at 0℃, slowly add (2E)-3-(3,4-difluorophenyl)acryloyl chloride toluene solution (4.44g(2E)-3- (3,4-Difluorophenyl)acryloyl chloride dissolved in 100 mL of toluene). After the addition, the temperature is raised to 65°C and the reaction is kept warm. The reaction is detected by TLC. After the reaction is completed, it is cooled to room temperature, and 5% NaCl solution is used. 6% NaHCO 3 The solution was washed with purified water and distilled under reduced pressure to obtain 13.35 g of off-white solid. The product yield is 98.0%, and the HPLC content is 99.6%.

Embodiment 1-4

[0039] Example 1-4. N-(2,3,4,6-Tetra-O-pivaloyl-β-D-glucopyranosyl)-(2E)-3-(3,4-difluorophenyl ) Synthesis of acrylamide

[0040] Add N-[2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl]amine I (10.3g, 0.02mol), toluene (200mL) to a 500mL four-necked flask. ) And pyridine (2.84g, 0.036mol), placed at 0℃, slowly add dropwise (2E)-3-(3,4-difluorophenyl)acryloyl chloride toluene solution (0.024mol(2E)-3- (3,4-Difluorophenyl)acryloyl chloride dissolved in 100 mL of toluene). After the addition, the temperature is raised to 60°C and the reaction is kept warm. The reaction is detected by TLC. After the reaction is completed, it is cooled to room temperature and 5% NaCl solution is used. 6% NaHCO 3 The solution was washed with purified water and distilled under reduced pressure to obtain 13.28 g of off-white solid. The product yield is 97.5%, and the HPLC content is 99.5%.

[0041] Then, the glucosyl α, β-unsaturated amide compound II prepared in any of the above embodiments 1-1 to 1-4 is u...

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Abstract

The invention discloses a novel synthesis method of a ticagrelor intermediate (1R,2R)-2-(3,4-difluorophenyl) cyclopropane nitrile. The novel synthesis method comprises the following steps: firstly, carrying out amination reaction on a glucose molecule chiral auxiliary reagent and (2E)-3-(3,4-diflurophenyl) acryloyl chloride; secondly, carrying out cyclopropanation reaction on a reactant and a sulfur ylide reagent to obtain a N-glucosyl (1R,2R)-2-(3,4-diflurophenyl) cyclopropanecarboxamide; thirdly, carrying out beta-N-glycosylation reaction on the N-glucosyl(1R,2R)-2-(3,4-diflurophenyl) cyclopropanecarboxamide under the action of PPh3, CBr4, AgOTf and NH3 water. The novel method has the characteristics of shorter process route, low-priced and easily-obtained starting materials, high yield, good stereoselectivity, good enantioselectivity and the like; the production cost is reduced to a great extent and better benefits in economy are obtained.

Description

Technical field [0001] The invention belongs to the technical field of organic synthesis and chemical medicine preparation, and relates to a method for synthesizing (1R, 2R)-2-(3,4-difluorophenyl) cyclopropane nitrile, specifically a method for preparing anticoagulant Synthetic method of important intermediate (1R, 2R)-2-(3,4-difluorophenyl) cyclopropane nitrile of blood drug ticagrelor. [0002] technical background [0003] Ticagrelor / Brilinta is a new type of small molecule anticoagulant developed by AstraZeneca. It is the first reversible, direct-acting, orally administered platelet adenosine diphosphate P2Y12 Receptor antagonist. The recently published PLATO (a randomized, double-blind, multi-center parallel controlled clinical trial conducted by 862 centers in 43 countries) showed that compared with clopidogrel, ticagrelor caused cardiovascular death, myocardial infarction or stroke to be the main component The relative risk of the composite endpoint was significantly reduc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/20C07C255/46
CPCC07B2200/07C07C253/20C07H1/00C07H13/06C07H13/08C07C255/46
Inventor 管月清
Owner TAIZHOU VOCATIONAL & TECHN COLLEGE
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