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
  • Claims
  • Application Information

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 toxic and is not suitable for large-scale production; and the crystal particles are not uniform, There are large particles (40-60um), which need to be pulverized first when preparing the preparation, and the cost of the preparation is high

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

Embodiment 1

[0032] In a 1L reaction flask, sequentially add toluene (300ml), 2-(3AR,4S,6R,6AS)-6-(5-amino-6-chloro-2-propylthio-4-pyrimidinyl)amino tetra Hydrogen-2,2-dimethyl-4H-cyclopenta-1,3-dioxolan-4-yl]oxy]-ethanol (Intermediate 1) (62.6 g, 149 mmol), acetic acid ( 50.0g, 834mmol), stirring and cooling down to 0-10°C, and adding sodium nitrite aqueous solution (10.8g sodium nitrite / 25ml water) dropwise. After dropping, the temperature was raised to 20-30°C, stirred for 10 minutes, and an aqueous solution of potassium carbonate (61.8g potassium carbonate / 125ml water) was added dropwise to adjust the pH to 7-8.

[0033] In a 3L reaction bottle, add the organic phase of the previous step, stir and cool down to 0-10°C, add the pre-cooled concentrated hydrochloric acid and methanol mixture (271.9g concentrated hydrochloric acid / 250ml methanol) dropwise, stir for 5 minutes, and let stand to separate the liquid . Add 1L of purified water and 0.5L of ethyl acetate to the aqueous phase, co...

Embodiment 2

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

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

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

Embodiment 3

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

[0042] Concentrate the organic phase in a 2L reaction bottle at 40-45°C to the remaining about 0.5L, raise the temperature of the residue to 60-70°C, add cyclohexane dropwise under temperature control, after the drop is completed, lower it to 0-10°C, stir for 3 hours, and centrifuge , the filter cake was vacuum-dried at 40-45° C. to constant weight (the difference in weight was less than 0.5%) to obtain an off-white solid with a yield range of 75-80%.

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

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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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