Preparation method of ticagrelor medicinal crystal form II

A technology of ticagrelor and crystal form, applied in the field of preparation of ticagrelor, can solve the problems of high toxicity of the crystallization solvent chloroform, unsuitable for large-scale production, uneven crystal particles, etc., and achieves small particle size and high purity. , the effect of simple process preparation

Pending Publication Date: 2019-09-03
BEIJING JIMEITANG MEDICINE RES CO LTD
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

Among the above-mentioned crystal forms, type II crystal has the best stability, and it is also the crystal form of the drug marketed by the original research unit, but the crystallization solvent of type II crystal, chloroform, is highly

Method used

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  • Preparation method of ticagrelor medicinal crystal form II
  • Preparation method of ticagrelor medicinal crystal form II
  • Preparation method of ticagrelor medicinal crystal form II

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0031] Example 1

[0032] In a 1L reaction flask, add toluene (300ml), 2-(3AR, 4S, 6R, 6AS)-6-(5-amino-6-chloro-2-propylthio-4-pyrimidinyl) amino tetra Hydrogen-2,2-dimethyl-4H-cyclopenteno-1,3-dioxolol-4-yl]oxy]-ethanol (Intermediate 1) (62.6g, 149mmol), acetic acid ( 50.0g, 834mmol), stirred and cooled to 0-10°C, and added dropwise an aqueous sodium nitrite solution (10.8g sodium nitrite / 25ml water). After dripping, the temperature was raised to 20-30° C., stirred for 10 min, and potassium carbonate aqueous solution (61.8g potassium carbonate / 125ml water) was added dropwise to adjust pH=7-8, the system was allowed to stand for liquid separation, and the organic phase was ready for use (Intermediate 2).

[0033] In a 3L reaction flask, add the organic phase of the previous step, stir and cool to 0-10°C, add dropwise a mixture of pre-cooled concentrated hydrochloric acid and methanol (271.9g concentrated hydrochloric acid / 250ml methanol), stir and react for 5min, then stand for li...

Example Embodiment

[0036] Example 2

[0037] The preparation method of ticagrelor organic phase solution is the same as in Example 1.

[0038] Add n-heptane dropwise to the organic phase in a 2L reaction flask. After dripping, reduce to 0-10°C, stir for 48h, centrifuge, and dry the filter cake under vacuum at 40-45°C to constant weight (the difference in weight is less than 0.5%) to obtain White solid, yield range: 60-65%.

[0039] The purity of the product is 99.2% by HPLC; the sample is crystal form II by DSC and XRD; the particle size range of Malvern particle size analyzer is less than 20um.

Example Embodiment

[0040] Example 3

[0041] The preparation method of ticagrelor organic phase solution is the same as in Example 1.

[0042] Concentrate the organic phase in a 2L reaction flask at 40-45°C to about 0.5L remaining. The residue is heated to 60-70°C, and cyclohexane is added dropwise to control the temperature. After the drop is completed, it is reduced to 0-10°C, stirred for 3h, and centrifuged. , The filter cake is vacuum dried at 40-45°C to a constant weight (the difference in weight is less than 0.5%) to obtain an off-white solid. The yield range is 75-80%.

[0043] The purity of the product is 99.5% by HPLC; the sample is crystal form II by DSC and XRD; the particle size range is 30-40um by the Malvern particle size analyzer.

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Abstract

The invention relates to a preparation method of ticagrelor, in particular to a preparation method of a ticagrelor medicinal crystal form II. The invention provides a new method of preparing the ticagrelor medicinal crystal form II from 2-(3AR, 4S, 6R, 6AS)-6-(5-amino-6-chloro-2-propylthio-4-pyrimidinyl)amino tetrahydro-2, 2-dimethyl-4H-cyclopenteno-1, 3-dioxolane-4-yl]oxo]-ethanol. The method hasthe characteristics of stable process, high crystal form purity, small and uniform particle size, and is easy for large-scale production.

Description

technical field [0001] The present invention relates to a preparation method of ticagrelor, in particular to a preparation method of ticagrelor pharmaceutical II crystal form, specifically, the present invention relates to the preparation of high-purity ticagrelor through the selection of crystallization conditions. Crystal form, the process is stable, the yield is relatively high, and no special equipment and reagents are used in the process. [0002] Background of the invention [0003] Ticagrelor (Ticagrelor, see formula Ⅰ for chemical structure) belongs to cyclopentyl triazolopyrimidine compounds, and is a new type of small molecule anticoagulant developed by AstraZeneca to selectively treat acute coronary syndrome (ACS). Blood drug, can reversibly act on the purine 2 receptor (P2) subtype P2Y12 on vascular smooth muscle cells, without metabolic activation, has obvious inhibitory effect on platelet aggregation caused by adenosine diphosphate, has rapid onset, high curativ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/13
Inventor 张翔郑士彬
Owner BEIJING JIMEITANG MEDICINE RES CO LTD
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