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Crystal form of JAK inhibitor and preparation method thereof

A crystal form and solvent technology, applied in organic chemical methods, anti-inflammatory agents, pharmaceutical formulations, etc., can solve problems affecting drug absorption and bioavailability, differences in clinical efficacy, solubility and stability, etc.

Active Publication Date: 2016-09-07
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Different crystal forms of solid chemical drugs can cause different solubility and stability, which will affect the absorption and bioavailability of drugs, and will lead to differences in clinical efficacy
However, there is currently no relevant report on the crystal form of the compound of formula (I), therefore, it is necessary to carry out a comprehensive and systematic polymorphic screening of the compound of formula (I) to select the most suitable crystal form for development.

Method used

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  • Crystal form of JAK inhibitor and preparation method thereof
  • Crystal form of JAK inhibitor and preparation method thereof
  • Crystal form of JAK inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] The preparation method of formula (I) compound crystal form I:

[0139] Add 39.5 mg of the compound of formula (I) to 1.5 mL of acetone to obtain a suspension, place the suspension in a constant temperature incubator at 50°C and stir for 100 minutes, then filter while it is hot to obtain a clear solution, at a rate of 0.1°C per minute The temperature was slowly lowered to 5°C, and solids were precipitated. The solids in the lower layer were taken by centrifugation, and dried overnight at a constant temperature of 25°C. After testing, the obtained solids were crystal form I.

[0140] Table 1 shows the X-ray powder diffraction data of the crystal forms obtained in this example. Its XRPD pattern is as follows figure 1 , and its DSC graph is shown in figure 2 , and its TGA figure is shown in image 3 .

[0141] Table 1

[0142]

[0143]

Embodiment 2

[0145] The preparation method of formula (I) compound crystal form I:

[0146] 5.16 mg of the compound of formula (I) was dissolved in 1.80 mL of dichloromethane, evaporated at room temperature, and the obtained solid was detected as crystal form I.

[0147] The X-ray powder diffraction data of the crystal forms obtained in this example are shown in Table 2.

[0148] Table 2

[0149]

[0150]

Embodiment 3

[0152] The preparation method of formula (I) compound crystal form II:

[0153] 106.3 mg of the compound of formula (I) was dissolved in 1.0 mL of glacial acetic acid, and slowly evaporated at room temperature, and the obtained solid was detected as crystal form II.

[0154] The X-ray powder diffraction data of the crystal forms obtained in this example are shown in Table 3. Its XRPD pattern is as follows Figure 5 , and its DSC graph is shown in Image 6 , and its TGA figure is shown in Figure 7 ,That 1 H-NMR picture as Figure 8 , 1 The H-NMR data are as follows:

[0155] 1 H-NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.92(s,1H),8.71(s,1H),8.47(s,1H),7.62(dd,J 1 =2.4Hz,J 2 =3.2Hz,1H),7.08(dd,J 1 =1.2Hz,J 2 =3.2Hz,1H),4.60(d,J=9.2Hz,2H),4.24(d,J=9.2Hz,2H),3.69(s,2H),3.23(q,J=7.2Hz,2H), 1.90(s, 3H), 1.25(t, J=7.2Hz, 3H).

[0156] table 3

[0157]

[0158]

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Abstract

The invention relates to a novel crystal form of a JAK inhibitor and a preparation method thereof. The novel crystal form provided by the invention can be used for treating autoimmune diseases, especially rheumatoid arthritis. The novel crystal form provided by the invention has good stability, obvious process purification effect, and the solubility and moisture in conformity with the requirement of medicine usage. The preparation method of the novel crystal form is simple and low in cost, and is of great value to the optimization and development of the medicine in the future.

Description

technical field [0001] The present invention relates to the field of chemical medicine, in particular to {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -Crystal form of azetidin-3-yl}acetonitrile and preparation method thereof. Background technique [0002] JAK (Janus kinase) kinases are a family of intracellular non-receptor tyrosine kinases that mediate the signals produced by cytokines and pass them on through the JAK-STAT signaling pathway. There are currently four known JAK family members: JAK kinase 1 (JAK1), JAK kinase 2 (JAK2), JAK kinase 3 (JAK3) and tyrosine kinase 2 (Tyrosine Kinase, TYK2). JAK-dependent cytokines are involved in the pathogenesis of various inflammatory and autoimmune diseases, and JAK inhibitors may be widely used in the treatment of various inflammatory diseases. [0003] Baricitinib is a selective JAK1 and JAK2 inhibitor jointly developed by Lilly and Incyte. In kinase assays, Baricitinib exhibited higher inhibitory s...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P19/02A61P29/00A61P37/06
CPCC07B2200/13C07D487/04
Inventor 陈敏华张炎锋刁小娟夏楠张晓宇
Owner ELI LILLY & CO
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