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Novel crystal form of ibrutinib and preparation method of novel crystal form

A technology of ibrutinib and crystal form, applied in the field of chemical pharmacy, can solve the problems of solubility, stability difference, influence on drug bioavailability, curative effect and safety, etc., achieve low cost, good clinical application value, guarantee The effect of stability

Inactive Publication Date: 2017-10-24
SHANGHAI SUNTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, different crystal forms of drug molecules have different physical and chemical properties, and their solubility and stability may have significant differences, which will affect the bioavailability, efficacy and safety of drugs. Therefore, it is necessary to look for more excellent physical and chemical properties. Crystal form is of great significance to improve the effectiveness, safety and quality controllability of drugs

Method used

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  • Novel crystal form of ibrutinib and preparation method of novel crystal form
  • Novel crystal form of ibrutinib and preparation method of novel crystal form
  • Novel crystal form of ibrutinib and preparation method of novel crystal form

Examples

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Effect test

Embodiment 1

[0120] Example 1: Preparation of Ibrutinib powder used as raw material for the preparation of the new crystal form (crystal form 1) of the present invention

[0121] Prepared by the same method as CN101610676A Example 1b: add 3.86g of intermediate (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H to a 200mL three-necked flask -pyrazolo[3,4-d]pyrimidin-4-amine and 35ml of dichloromethane, start stirring. Add 4.2 mL of triethylamine, slowly add 1 mL of acryloyl chloride dropwise, and continue the reaction for 2 hours after the addition. After the reaction, the organic phase was washed with 5% citric acid and saline solution to separate layers. MgSO for organic layer 4 After drying, the residue was purified by column chromatography (dichloromethane / methanol=25 / 1) to obtain 2.15 g of ibrutinib powder.

Embodiment 2

[0122] Example 2: Ibrutinib (1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one) new crystal form (crystal form 1)

[0123] Add 500 mg of the ibrutinib powder prepared in Example 1 into 4 ml of methanol, heat to 60° C. and stir for 1 hour to obtain a clear solution. The solution was cooled to 25°C, 2 mL of water was added dropwise, and after stirring at 25°C for 1 hour, the temperature was lowered to 5°C within 1 hour and stirring was continued for 48 hours, filtered, and the solid was collected and vacuum dried at 50°C for 18 hours to obtain 466mg of crystal form 1, its XRPD pattern is as follows figure 1 shown.

Embodiment 3

[0124] Embodiment 3: Preparation of ibrutinib crystal form 1

[0125]Add 500 mg of the ibrutinib powder prepared in Example 1 into 4 ml of methanol, heat to 50° C. and stir for 2 hours to obtain a clear solution. The solution was cooled to 25°C, 2 mL of water was added dropwise, and after stirring at 25°C for 2 hours, the temperature was lowered to 5°C within 1 hour and stirring was continued for 16 hours, filtered, and the solid was collected and vacuum-dried at 50°C for 18 hours to obtain 458 mg of crystal form 1, the XRPD pattern of which is the same as that of the product prepared in Example 2.

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Abstract

The invention provides a novel crystal form of ibrutinib. The novel crystal form is named as a crystal form 1; the 2-theta value of the X-ray powder diffraction pattern of the novel crystal form has characteristic peaks at 5.8 degrees + / - 0.2 degree, 10.8 degrees + / - 0.2 degree, 19.2 degrees + / - 0.2 degree, and 21.6 degrees + / - 0.2 degree; the novel crystal form has a heat absorption peak when being heated to about 150.3 DEG C; the novel crystal form is an anhydrous substance and is non-hygroscopic. The crystal form I of ibrutinib provided by the invention is good in solubleness, beneficial to improvement of oral bioavailability of medicines and relatively good in clinical application values. The crystal form I of ibrutinib is good in stability and almost has no hygroscopicity, so that stability of the medicines in the storage and transportation process and the safety in clinical application are ensured. The crystal form I of ibrutinib provided by the invention is simple in preparation method operation, low in cost, free of special requirement on production equipment, easy in industrial production and relatively great in application value.

Description

technical field [0001] The present invention relates to chemical pharmacy, in particular to drug preparation, especially ibrutinib, 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[ A new crystal form of 3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one and a preparation method thereof. Background technique [0002] Ibrutinib (Ibrutinib) is a targeted inhibitor that selectively inhibits Bruton's tyrosine kinase (Btk), developed by Pharmacyclics in the United States. Its chemical name is 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine -1-yl)prop-2-en-1-one. Structure is as shown in formula I: [0003] [0004] Bruton's tyrosine kinase (Btk), a non-receptor tyrosine kinase, is an important mediator necessary for the formation, differentiation, information transmission and survival of B-lymphocytes. Inhibiting the activity of Bruton's tyrosine kinase (Btk) can effectively inhibit the proliferation and survival of tumor cells. On Nove...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07B2200/13C07D487/04
Inventor 刘学军陈春根陈晓冬程吉
Owner SHANGHAI SUNTECH PHARMA
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