阅读说明：本技术 固体形式的fgfr抑制剂化合物及其制备方法 (Solid form of FGFR inhibitor compounds and methods of making the same ) 是由 付志飞 罗妙荣 孙继奎 张杨 黎健 陈曙辉 于 2020-02-14 设计创作，主要内容包括：本发明公开了式(I)化合物的固体形式、结晶形式、A晶型及其制备方法、B晶型及其制备方法,还包括所述固体形式、结晶形式、A晶型、B晶型在制备用于治疗与FGFR相关疾病的药物中的应用。(The invention discloses a solid form, a crystal form A and a preparation method thereof, a crystal form B and a preparation method thereof of a compound shown in a formula (I), and further discloses application of the solid form, the crystal form A and the crystal form B in preparation of medicaments for treating FGFR related diseases.)

A compound of formula (I) in solid form

The compound of formula (I) in solid form according to claim 1, in crystalline form.

A compound of formula (I) in solid form according to claim 1 or 2, in the form of form a of compound of formula (I), having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.37 +/-0.2 degrees, 9.90 +/-0.2 degrees and 19.07 +/-0.2 degrees.

Form a of the compound of formula (I) according to claim 3 having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.37 +/-0.2 degrees, 9.90 +/-0.2 degrees, 12.74 +/-0.2 degrees, 13.35 +/-0.2 degrees, 14.26 +/-0.2 degrees, 16.31 +/-0.2 degrees, 19.07 +/-0.2 degrees and 21.83 +/-0.2 degrees.

The crystalline form a of the compound of formula (I) according to claim 4 having an XRPD pattern as shown in figure 1.

Form A of compound of formula (I) according to any one of claims 3 to 5 having a differential scanning calorimetry curve with an endothermic peak at 141.05 ℃ ± 5 ℃.

The compound of formula (I) in crystal form A according to claim 6, which has a DSC pattern as shown in figure 2.

Form A of the compound of formula (I) according to any one of claims 3 to 7, having a thermogravimetric analysis curve with a weight loss of 1.232% at 124.65 ± 3 ℃.

The crystalline form a of the compound of formula (I) according to claim 8 having a TGA profile as shown in figure 3.

A process for preparing form a of the compound of formula (I) according to any one of claims 3 to 9 comprising:

(a) adding a compound of formula (I) to a nitrile or ester solvent;

(b) stirring for 40-55 hours at 30-50 ℃;

(c) isolating to obtain the compound of formula (I) in form A.

The production method according to claim 10, wherein the nitrile-based solvent is selected from acetonitrile, propionitrile, and butyronitrile.

The preparation method according to claim 10, wherein the ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, ethyl isopropyl ester, and ethyl formate.

A compound of formula (I) in solid form according to claim 1 or 2, in the form of form B of the compound of formula (I), having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles:

9.14±0.2°，15.07±0.2°。

form B of the compound of formula (I) according to claim 13 having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 9.14 +/-0.2 degrees, 11.05 +/-0.2 degrees, 13.25 +/-0.2 degrees, 15.07 +/-0.2 degrees, 16.47 +/-0.2 degrees, 18.31 +/-0.2 degrees and 22.29 +/-0.2 degrees.

The crystalline form B of the compound of formula (I) according to claim 14 having an XRPD pattern as shown in figure 4.

Form B of a compound of formula (I) according to any one of claims 13 to 15 having a differential scanning calorimetry curve with an onset of an endothermic peak at 174.09 ℃ ± 5 ℃.

Form B of the compound of formula (I) according to claim 16 having a DSC profile as shown in figure 5.

Form B of a compound of formula (I) according to any one of claims 13 to 17 having a thermogravimetric analysis curve with a weight loss of 0.432% at 169.70 ± 3 ℃.

A crystalline form B of the compound of formula (I) according to claim 18 having a TGA profile as shown in figure 6.

A process for preparing form B of a compound of formula (I) according to any one of claims 13 to 19, comprising:

(a) adding the crystal form A of the compound shown in the formula (I) into an alcohol solvent or a mixed solvent of alcohol and water;

(b) stirring for 5-30 hours at 30-50 ℃;

(c) standing for 3-10 hours at 10-20 ℃;

(d) isolating to obtain the B crystal form of the compound of formula (I).

The method of claim 20, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol and isopropanol.

The production method according to claim 20, wherein the mixed solvent of an alcohol and water is selected from the group consisting of a mixed solvent of methanol and water, a mixed solvent of ethanol and water, and a mixed solvent of isopropyl alcohol and water.

Use of a compound of formula (I) according to claim 1 in solid form, a compound of formula (I) according to claim 2 in crystalline form, form a of a compound of formula (I) according to any one of claims 3 to 9, or form B of a compound of formula (I) according to any one of claims 13 to 19 for the manufacture of a medicament for the treatment of a FGFR-related disease.

The use of claim 23, wherein the FGFR-related disease is a solid tumor.