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A kind of crystal form of cyclopropanecarboxamide derivative and preparation method thereof

A technology of cyclopropanecarboxamide and derivatives, which is applied in organic chemistry methods, drug combinations, bone diseases, etc., can solve problems such as instability and unfavorable hygroscopicity of cyclopropanecarboxamide derivatives, and achieve excellent high temperature stability, Good bioavailability, low hygroscopic effect

Active Publication Date: 2017-07-25
SHANGHAI SUNTRONG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The problem to be solved by the present invention is that problems such as instability, hygroscopicity and easy conversion into stable crystal forms of existing cyclopropanecarboxamide derivatives are unfavorable for pharmaceutical processing and use in pharmaceutical compositions. Cyclopropanecarboxamide derivatives The problem of providing more qualitative and quantitative information for the curative effect research of solid drugs

Method used

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  • A kind of crystal form of cyclopropanecarboxamide derivative and preparation method thereof
  • A kind of crystal form of cyclopropanecarboxamide derivative and preparation method thereof
  • A kind of crystal form of cyclopropanecarboxamide derivative and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1 to 15

[0033] Preparation of Embodiment 1 to 15 Cyclopropanecarboxamide Derivative A Crystal Form

[0034] Weigh 500 mg of the cyclopropanecarboxamide derivative raw material into a container, add 100 ml of the solvent (analytical grade) in Table 1, suspend at 35° C. for 48 hours, filter, and vacuum-dry to obtain off-white powder. Weigh to calculate its yield.

[0035] Table 1 Preparation of crystal form A of cyclopropanecarboxamide derivatives

[0036] Example solvent yield 1 n-propanol 76％ 2 Isopropanol 78％ 3 sec-butanol 79％ 4 Butyl acetate 66％ 5 n-heptane 86％ 6 n-Hexane 85％ 7 Cyclohexane 88％ 8 acetone 73％ 9 Ether 88％ 10 isopropyl ether 77％ 11 methyl tert-butyl ether 76％ 12 toluene 86％ 13 p-xylene 84％ 14 Tetrahydrofuran 76％ 15 Dichloromethane 76％

Embodiment 16

[0037] Example 16. Characterization of cyclopropanecarboxamide derivative A crystal form by XRPD pattern

[0038] The measurement of the X-ray powder diffraction (XRPD) pattern is carried out using the Rigaku UltimaIV model combined multifunctional X-ray diffractometer, and the specific collection information is as follows: Cu anode (40kV, 40mA), scanning speed 20° / min, scanning range (2θ range )3~45°, scan step size 0.02, slit width 0.01. Samples were processed using glass slides pressed directly onto the test plate. Subsequent XRPD patterns all adopt similar measurement methods.

[0039]Determination of the XRPD spectrum of the cyclopropanecarboxamide derivative A crystal form prepared according to the method described in Example 1, at 2θ=8.3, 8.702, 10.62, 11.94, 13.101, 13.699, 16.217, 16.659, 19.218, 20.1, 20.939, 21.34, There are diffraction peaks at 21.597, 22.72, 23.32, 25.098, 25.841, 27.62, 28.542, 29.541, 30.739, 32.06, 32.6, 34.14, 35.621, 36.261, 37.12, and 37.5...

Embodiment 17

[0041] Example 17. Investigation of High Temperature Stability of Crystal Form A of Cyclopropanecarboxamide Derivatives

[0042] The cyclopropanecarboxamide derivative A crystal sample was placed in a 60°C oven, and after 5 days and 10 days, the sample was taken out for XRPD testing (such as figure 2 and Figure 5 Shown), in order to investigate the stability of the crystal form of the sample to temperature. The results show that the crystal form A sample is stable under high temperature conditions.

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Abstract

The invention provides a cyclopropanecarboxamide derivative A crystal form (please see the specification for the formula) in the formula (I). According to the XRPD illustration of the crystal form, diffraction peaks exist when 2Q is equal to 8.3, 8.702, 10.62, 11.94, 13.101, 13.699, 16.217, 16.659, 19.218, 20.1, 20.939, 21.34, 21.597, 22.72, 23.32, 25.098, 25.841, 27.62, 28.542, 29.541, 30.739, 32.06, 32.6, 34.14, 35.621, 36.261, 37.12 and 37.5, and the error range of the 2Q value is + / -0.2. The cyclopropanecarboxamide derivative A crystal form has good high-temperature stability, high-humidity stability and illumination stability. Moreover, low moisture absorption performance and excellent solubility are achieved. The cyclopropanecarboxamide derivative A crystal form can be applied to drugs for treatment or prevention of JAK-participated inflammation and autoimmunity diseases, proliferative diseases, graft rejective reactions and congenital cartilage deformation or diseases caused by IL6 oversecretion, and good bioavailability is achieved. Meanwhile, qualitative and quantitative information is provided, which is of important significance to further studying the curative effect of the solid drugs.

Description

technical field [0001] The present invention relates to a polymorphic form of a cyclopropanecarboxamide derivative as a JAK inhibitor, in particular to a crystal form A of a cyclopropanecarboxamide derivative and a preparation method thereof. Background technique [0002] JAK, Janus Kinase, is a non-receptor tyrosine protein kinase and a non-transmembrane tyrosine kinase. This is because JAK can not only phosphorylate the cytokine receptors associated with it, but also phosphorylate multiple signaling molecules containing specific SH2 domains. The JAK protein family consists of four members: JAK1, JAK2, JAK3 and TYK2, which have seven JAK homology domains (JAK homology domain, JH) in structure, of which the JH1 domain is the kinase domain and the JH2 domain is the " The "pseudo" kinase domain, JH6 and JH7, are receptor binding regions. [0003] TYK2 is a potential target for immunoinflammatory diseases, which has been confirmed by human genetics and mouse knockout studies ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/541A61P37/02A61P29/00A61P35/00A61P37/06A61P19/08
CPCC07B2200/13C07D471/04
Inventor 弋东旭陈金瑶于迎渌
Owner SHANGHAI SUNTRONG BIOTECH
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