Crystallization form of BTK inhibitor, and preparation method thereof

A crystallization and solvent technology, applied in the field of crystal form and preparation of BTK kinase inhibitor, can solve the problems of easy agglomeration, poor product stability, difficult filtration, etc., and achieves repeatable and controllable production process, good crystal form stability, The effect of stable production process

Active Publication Date: 2017-07-11
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.

Method used

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  • Crystallization form of BTK inhibitor, and preparation method thereof
  • Crystallization form of BTK inhibitor, and preparation method thereof
  • Crystallization form of BTK inhibitor, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (R)-1-(3-(4-Amino-3-(4-(2,6-difluorophenoxy)phenyl)-7-hydroxy-1H-pyrrolo[2,3-d]pyridine Synthesis of oxazin-1-yl)piperidin-1-yl)propyl-2-en-1-one

[0038] The first part: the preparation of compound 1e

[0039]

[0040] Step A

[0041] Sodium acetate ethanol solution (160ml, mass fraction 21%, 0.49mmol) was added to 110ml ethanol, and diethyl oxalate (64ml, 0.47mol) was added under ice-bath condition. The mixture was stirred for 30 min. A solution of (16 g, 0.15 mmol) (E)-hex-3-enenitrile 1a in (30 ml) ethanol was then added to the mixture. Stir overnight at room temperature. After cooling in an ice bath, the suspension was filtered. The solid was washed with a small amount of ethanol, then dissolved in 380 ml of water, and acidified to pH 4 with hydrochloric acid. A large amount of solid precipitated out which was filtered, washed with water and dried to give 11.9 g of yellow solid 1b.

[0042] Step B

[0043] To (2.3g, 7.5mmol) 1b in (120ml) ethyl acetate s...

Embodiment 2

[0069] Take 300mg of the compound represented by formula (I) (prepared according to Example 1) in a 25ml single-necked bottle, add 2ml of ethanol, heat to dissolve, cool down to crystallize, and stir overnight. The next day, it was suction filtered and dried to obtain 241 mg of solid, with a yield of 80.3%. For the X-ray diffraction of this crystalline sample see image 3 , where at about 4.29(20.56), 6.58(13.42), 7.58(11.66), 10.07(8.78), 10.72(8.24), 11.68(7.57), 12.49(7.08), 13.74(6.44), 14.12(6.26), 15.86 There are characteristic peaks at (5.58) and 19.98 (4.44). See the DSC spectrum Figure 4 , there is a melting endothermic peak around 141°C, and this crystal form is defined as I crystal form.

Embodiment 3

[0071] Take a 300 mg sample of the compound represented by formula (I) (prepared according to Example 1) in a 25 ml single-necked bottle, add 3 ml of methanol, heat to dissolve, cool down to crystallize, and stir overnight. The next day, it was filtered with suction and dried to obtain 165 mg of solid, with a yield of 55.0%. The X-ray diffraction and DSC patterns of the crystalline sample are studied and compared, and it is determined that the product is the I crystal form.

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Abstract

The invention relates to a crystallization form of a BTK inhibitor, and a preparation method thereof, and concretely relates to a type I crystal of (R)-1-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-7-hydroxy-1H-pyrrolo[2,3-d]pyridazine-1-yl)piperidine-1-yl)propyl-2-ene-1-one (compound of formula (I)), and a preparation method thereof. The type I crystal of the compound (I) obtained in the invention has the advantages of good chemical stability and crystal form stability, and a crystallization solvent used in the invention has low toxicity and low residual, so the type I crystal of the compound (I) can be well used in clinic treatment.

Description

technical field [0001] The present invention relates to a crystalline form and preparation method of a BTK kinase inhibitor, in particular to (R)-1-(3-(4-amino-3-(4-(2,6-difluorophenoxy)benzene Base)-7-hydroxyl-1H-pyrrolo[2,3-d]pyridazin-1-yl)piperidin-1-yl)propyl-2-en-1-one type I crystal and its preparation method. Background technique [0002] Bruton's tyrosine kinase (BTK) is a non-receptor cytoplasmic tyrosine kinase belonging to the Tec family of kinases, of which Tec family kinase members also include Tec, Itk, Txk and Bmx, most of these kinases are mainly expressed in hematopoiesis cell. BTK is critical for B cell development, differentiation, maturation and signaling. Loss-of-function mutations in BTK cause X-linked agammaglobulinemia (XLA) in humans and X-related immunodeficiency in mice. XLA patients have a normal population of pre-B cells in their bone marrow, but these cells fail to mature and enter circulation. Consequently, these patients also essentially ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 武乖利张全良边林卢韵
Owner JIANGSU HENGRUI MEDICINE CO LTD
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