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Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof

A formal, crystalline technique applied to (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5 Crystalline form of ,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, its preparation and application fields, can solve the problems of low stability and difficult handling

Active Publication Date: 2019-11-15
BEIGENE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The amorphous form of compound 1 poses some challenges for pharmaceutical formulation due to its low stability and difficult handling

Method used

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  • Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof
  • Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof
  • Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof

Examples

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[0077] Also disclosed herein are methods for the preparation of Compound 1, such as the procedure described in Scheme 1. The new synthetic method and crystallization / recrystallization procedure for Compound A via Form A or B disclosed herein overcomes many of the problems associated with previously reported methods, such as the preparation of key chiral intermediates with >98% optical purity, improved The purity of compound 1 can meet the acceptance criteria in the specification, control the impurities in compound 1 and provide more advantages than existing methods. Notably, the method disclosed herein is particularly suitable for the reproducible commercial-scale production of compound 1 with high quality and good yield. In an alternative approach, BG-9 in Scheme 1 or its analogs can be asymmetrically reduced with low to excellent enantioselectivities (5% ee. to 95% ee). The procedure for the other steps is similar to the steps listed in Scheme 1. The absolute configuration...

Embodiment 1

[0161] Example 1: (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra Preparation of Hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 1)

[0162] Step 1: Synthesis of BG-2

[0163]

[0164] Under nitrogen atmosphere, EtOAc (5v), HOBT (1.2 equiv), EDCI (1.2 equiv), 4-phenoxybenzoic acid (BG-1, 80Kg, 1.0 equiv) and malononitrile (1.2 equiv) were added at 10°C. ) was added TEA (2.4 equiv). The mixture was then stirred at room temperature until the reaction was complete. The mixture was then centrifuged and the filter cake was washed with EtOAc. filtrate with NaHCO 3 Wash twice with aqueous solution and wash with NH 4 Cl wash. The organic phase was washed with 1.5N H 2 SO 4 Wash twice and stir. The mixture was concentrated and precipitated from methanol and purified water. The solid was collected by centrifugation and dried under vacuum to yield 79.9 Kg of BG-2. 1 H NMR (DMSO-d 6 )δ7.62(d, J=8.6Hz, 2H), 7.46-7.38(m, 2H), 7.18(t, J=7.4Hz, ...

Embodiment 2

[0206] Example 2: Preparation of Form A of Compound 1

[0207] The crude compound 1 prepared in Example 1 above was dissolved in 5.0 volumes of DCM. The resulting solution was washed with water (3.0 vol*2). The organic phase was concentrated and exchanged into EtOAc (not to exceed 2 volumes). Further EtOAc was added to this solution up to 4.5 volumes. 27.5% w / w n-heptane / EtOAc (12.0 v) (v / v ratio of EtOAc:n-heptane about 2:1) was added dropwise to the system while maintaining the temperature at room temperature. The system was then stirred at room temperature for at least 24 hours, centrifuged and the filter cake collected to obtain the resulting product, which was in solid form.

[0208] The solid was then subjected to various characterizations including XRPD ( Figure 2A ), TGA / DSC ( Figure 2B )and 1 H NMR ( Figure 2C ). 1 H-NMR (DMSO-d 6 ( m, 2H), 4.09-3.95(m, 1H), 3.33-3.26(m, 2H), 3.17-2.95(m, 1H), 2.70-2.52(m, 1H), 2.36-2.18(m, 1H), 2.00 (s, 3H), 2.12-1.85...

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Abstract

The present invention relates to a crystalline form of (S) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyri midine-3-carboxamide for inhibitingBtk, methods of preparation thereof and pharmaceutical compositions, and use of the crystalline form above in the treatment of a disease, or in the manufacturing of a medicament for the treatment of adisease.

Description

[0001] This application claims the benefit of International Patent Application No. PCT / CN2017 / 072553 filed on January 25, 2017, the disclosure of which is hereby incorporated by reference in its entirety for all purposes. technical field [0002] Disclosed herein is (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro Crystalline form of pyrazolo[1,5-a]pyrimidine-3-carboxamide (hereinafter referred to as Compound 1); Process for preparing the crystalline form of Compound 1; Comprising the crystalline form of Compound 1 and a pharmaceutically acceptable carrier Pharmaceutical compositions; and methods of using a crystalline form of Compound 1 as a Btk inhibitor for treating or preventing a disease. Background technique [0003] Bruton's tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361:226-233, 1993; Bradshaw, Cell Signal.22:1175-84, 2010). Btk is mainly expressed in most hematopoietic cells such as B cells, m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/551A61P35/00A61P37/00
CPCC07D487/04A61P35/00A61P37/00A61P29/00C07B2200/13
Inventor 郭运行于得胜王志伟
Owner BEIGENE