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A kind of preparation method of ticagrelor key intermediate

A technology of ticagrelor and chiral intermediates, which is applied in the field of medicine, can solve problems such as unsuitability for industrial production, difficulty in controlling chiral purity, and poor atom economy, so as to reduce labor and raw material costs, and avoid material loss and cost Effects of pressure, shortening of reaction steps

Active Publication Date: 2021-11-23
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In summary, the existing technologies generally face problems such as long reaction routes, low yields, poor atom economy, unfriendly environment, and difficult control of chiral purity, which are not suitable for industrial production.

Method used

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  • A kind of preparation method of ticagrelor key intermediate
  • A kind of preparation method of ticagrelor key intermediate
  • A kind of preparation method of ticagrelor key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Formula I compound obtains formula II compound through coupling reaction

[0041]

[0042] Cyclopropylmethyl ketone (1.68g, 20mmol), palladium acetate (0.22g, 1mmol), L-valine (0.23g, 2mmol), 2-hydroxy-5-nitropyridine (0.28g, 2mmol), Add 3,4-difluoroiodobenzene (2.40g, 10mmol), trifluoroacetic acid (1.71g, 15mmol), and silver phosphate (2.76g, 10mmol) into 25mL of isopropanol, heat to reflux, keep the reaction overnight, and detect by TLC The starting material was completely converted. An appropriate amount of silica gel was added, concentrated to dryness at 45°C under reduced pressure, and 1.70 g of the compound of formula II was obtained by column chromatography. The purity was 98.5% by HPLC, the yield was 85.0%, and the ee value was >99%. 1 H NMR (500MHz, CDCl 3 )δ7.03(ddd, J=8.9,7.5,5.6Hz,1H),6.99-6.92(m,1H),6.89(dddd,J=7.6,5.7,2.0,1.0Hz,1H),2.60-2.51( m,1H),2.36(q,J=7.0Hz,1H),2.19(s,3H),1.71(td,J=7.0,5.0Hz,1H),1.39(td,J=6.9,4.9Hz,1H ).

Embodiment 2

[0044]Cyclopropylmethyl ketone (1.68g, 20mmol), tetrakis(triphenylphosphine) palladium (0.23g, 0.2mmol), L-proline (0.12g, 1mmol), 2-hydroxy-5-trifluoroform Pyridine (0.06g, 0.4mmol), 3,4-difluoroiodobenzene (3.60g, 15mmol), trifluoroacetic acid (4.56g, 40mmol), silver acetate (0.47g, 4mmol) were added into 30mL acetonitrile and heated to Reflux, keep the reaction overnight, and TLC detects that the starting material is completely converted. An appropriate amount of silica gel was added, concentrated to dryness at 45°C under reduced pressure, and 1.67 g of the compound of formula II was obtained by column chromatography. The purity was 97.6% by HPLC, the yield was 83.0%, and the ee value was >99%.

Embodiment 3

[0046] The compound of formula II is prepared by a one-pot method of configuration inversion and haloform reaction to compound of formula III

[0047]

[0048] Dissolve the compound of formula II (1.96g, 10mmol) in 10mL of 1,4-dioxane, add aqueous sodium hydroxide solution (5mL, 80mmol), heat up to 40°C, keep stirring overnight, and TLC monitors that the configuration is completely inverted. Cool down to 0-5°C, slowly add bromine (6.39g, 40mmol) dropwise, and control the temperature not to exceed 5°C; after dropping, keep warm for 6h, add sodium thiosulfate (3.16g, 20mmol), stir at room temperature for 30min, and react The solution was adjusted to pH 3-4 with 2N hydrochloric acid. Extracted with 10mL*3 ethyl acetate, layered, washed with 10mL*2 water, the organic layer was dried with anhydrous sodium sulfate, filtered, and an appropriate amount of silica gel was added to the filtrate , concentrated to dryness at 45°C under reduced pressure, and obtained 1.94 g of the compou...

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Abstract

The present invention relates to the field of medical technology, in particular to a method for preparing a key intermediate of ticagrelor, comprising the following steps: dissolving the compound of formula I and 3,4-difluoroiodobenzene in a solvent, adding a catalyst, the first compound Body, second ligand, acid and metal salt catalyst, heat reaction to obtain the compound of formula II; dissolve the compound of formula II and alkali in the solvent, stir the reaction, add bromine dropwise, continue the reaction after dropping, and add thiosulfuric acid Sodium, the compound of formula III is obtained after the reaction is finished. The preparation method of the ticagrelor chiral intermediate provided by the invention has a short and novel route, mild reaction conditions, economical and effective, and a higher yield than the existing preparation method, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of a key intermediate of ticagrelor. Background technique [0002] Ticagrelor, developed by AstraZeneca, was approved by the FDA on July 20, 2011 to reduce the occurrence of thrombotic events in patients with acute coronary syndrome (ACS). It is a novel, selective anticoagulant drug and the first reversible binding P2Y12 adenosine diphosphate receptor (ADP) antagonist that can reversibly act on vascular smooth muscle cells (VSMC) Purine 2 receptor subtype P2Y12 has obvious inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. In 2012, Ticagrelor (or Ticagrelor), trade name Belinda, has obtained the import drug license issued by the State Food and Drug Administration (SFDA), which means that this drug for acute coronary syndrome ( The drug for patients with ACS) has bee...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C45/68C07C49/567C07C51/093C07C61/40
CPCC07B2200/07C07C45/68C07C51/093C07C2601/02C07C49/567C07C61/40
Inventor 于立国王兵张云然孙光祥俞风山周文
Owner CHANGZHOU PHARMA FACTORY
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