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1,2-diol compound single crystal preparation method

A technology of compounds and diols, applied in the field of medicinal chemistry, can solve problems such as lack and easy occurrence of mixed crystal forms

Pending Publication Date: 2019-11-12
SHANGHAI HUILUN BIOLOGICAL TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to solve the current lack of a simple and efficient way to obtain (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl) Cyclopropyl]amino}-5-(propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy) ring Penta-1,2-diol type II single crystal problem, the inventors of the present invention unexpectedly found that in the preparation of (1S,2S,3R,5S)-3-(7-{[(1R,2S)- 2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl) -5-(2-hydroxyethoxy) cyclopenta-1,2-diol type II crystallization, the content of the specific impurity formula 1 in the starting reactant has a significant impact on (1S, 2S, 3R, 5S)-3- (7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylmercapto)-3H-1,2,3-triazolo[4 , 5-d] pyrimidin-3-yl)-5-(2-hydroxyethoxy) cyclopenta-1,2-diol type II crystallization has an impact on the unity, and the reduction of formula I content will lead to the preparation of II Type crystals are prone to mixed crystal forms, such as mixed with type I, type III crystals or amorphous; on the contrary, the singleness of type II crystals is better

Method used

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  • 1,2-diol compound single crystal preparation method
  • 1,2-diol compound single crystal preparation method
  • 1,2-diol compound single crystal preparation method

Examples

Experimental program
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Embodiment 1

[0037] In a 100L reactor, add (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5 -(Propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopenta-1,2-diol 5.50kg, 27.5L of ethyl acetate, 110g of the compound of formula I (proportion 2.0%) was added, stirred and dissolved. Heat to 50-55°C, add dropwise 33L of n-heptane preheated to the corresponding temperature, control the temperature at 45-52°C during the process, keep it warm for 1h after dropping; then cool down to 10-15°C and keep it for 1h, filter, and use 0 -5°C Ethyl acetate / n-heptane 20kg (mass ratio 1:1) was washed 2-3 times and dried to obtain (1S,2S,3R,5S)-3-(7-{[(1R,2S) -2-(3,4-Difluorophenyl)cyclopropyl]amino}-5-(propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl )-5-(2-hydroxyethoxy)cyclopenta-1,2-diol crystal form 5.42 kg (yield 98.5%), with Figure 4 As shown in the DSC diagram (the tangent temperature is 137.41°C, the peak value is 139.16°C), the crystal form ...

Embodiment 2

[0039] In a 100L reactor, add (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5 -(Propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopenta-1,2-diol 5.50kg, add 17L of ethyl acetate, then add 220g of the compound of formula I (proportion 4%), stir to dissolve. Heat to 50-55°C, add dropwise 38L of n-hexane preheated to the corresponding temperature, keep it at 45-52°C for 1h after dropping; then cool down to 10-15°C and keep it for 1h, filter, and use Wash with 20kg of n-hexane (mass ratio 1:1), and dry to obtain (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl) ring Propyl]amino}-5-(propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopenta -1,2-diol crystal form 5.39 kg (98.0% yield), with Figure 4 As shown in the DSC figure, the crystal form has the following figure 1 The XRD diffraction pattern shown proves that it is (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino} -5-...

Embodiment 3

[0041] In a 100L reactor, add (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5 -(Propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopenta-1,2-diol 5.50kg, add 17L of ethyl acetate, then add 5.5g of the compound of formula I (proportion 0.1%), stir to dissolve. Heat to 50-55°C, add dropwise 38L of n-hexane preheated to the corresponding temperature, keep it at 45-52°C for 1h after dropping; then cool down to 10-15°C and keep it for 1h, filter, and use Wash with 20kg of n-hexane (mass ratio 1:1), and dry to obtain (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl) ring Propyl]amino}-5-(propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopenta -1,2-diol crystal form 5.40 kg (yield 98.2%), with Figure 6 As shown in the DSC spectrum, the crystal form has image 3 The XRD diffraction pattern shown proves that it is (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino} -5-(Propylmer...

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Abstract

The invention provides a 1,2-diol compound type II single crystal preparation method, which comprises: dissolving (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol and a compound represented by a formula I in an organic solvent, adding an anti-solvent, and crystallizing. Accordingto the present invention, the preparation method has simple operation, and the obtained product has a single crystal form, does not contain other non-target crystal forms, and has high application prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl ]amino}-5-(propylmercapto)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopenta-1 , The preparation method of 2-diol type II crystal form. Background technique [0002] The chemical name is (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylmercapto )-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopenta-1,2-diol, antiplatelet The aggregated drug, developed by AstraZeneca, was approved by the European Medicines Agency in 2010 and approved by the US FDA in 2011. It has the following structure: [0003] [0004] Patent CN1817883 discloses (1S,2S,3R,5S)-3-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propane I, Type II, III and IV crystals and methods for their preparation. Among the four crystal forms, type II crystals are more stable, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04G01N25/20
CPCC07D487/04G01N25/20C07B2200/13
Inventor 李文华刘海珠朱明辉
Owner SHANGHAI HUILUN BIOLOGICAL TECH CO LTD
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