阅读说明：本技术 瑞卢戈利新晶型及其制备方法 (Rugosril new crystal form and preparation method thereof ) 是由 张富昌 郭万成 段永立 段雄鹏 王国平 于 2021-02-02 设计创作，主要内容包括：本发明涉及瑞卢戈利新晶型及制备方法。具体地,本发明提供了瑞卢戈利(式I化合物)的三种新晶型APTI-I、APTI-II、APTI-III及其制备方法。本发明的晶型APTI-II、APTI-III除杂效果好。三种晶型均易于制备、操作简便,均适用于工业化大生产。(The invention relates to a new Ruugeli crystal form and a preparation method thereof. Specifically, the invention provides three new crystal forms of APTI-I, APTI-II and APTI-III of Ruogeli (a compound shown in a formula I) and a preparation method thereof. The crystal forms APTI-II and APTI-III have good impurity removal effect. The three crystal forms are easy to prepare, simple and convenient to operate and suitable for industrial mass production.)

1. A crystalline form of a compound of formula I,

the crystal form is a crystal form APTI-II;

and the X-ray powder diffraction pattern of the crystal form APTI-II has characteristic peaks at one or more positions with 2 theta values of 7.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.6 +/-0.2 degrees, 15.7 +/-0.2 degrees and 20.7 +/-0.2 degrees.

2. The crystalline form of claim 1, wherein the crystalline form APTI-II is a hemiacetonate crystalline form of the compound of formula I.

3. The crystalline form of claim 1, wherein the crystalline form APTI-II further has a characteristic peak in its X-ray powder diffraction pattern at any one or more of 2 Θ values of 4.7 ± 0.2 °,5.7 ± 0.2 °,8.8 ± 0.2 °, 11.1 ± 0.2 °,12.3 ± 0.2 °, 13.0 ± 0.2 °,14.1 ± 0.2 °,17.8 ± 0.2 °,19.1 ± 0.2 °, and 20.0 ± 0.2 °.

4. The crystalline form of claim 1, wherein the crystalline form APTI-II further has one or more of the following characteristics:

a. the X-ray powder diffraction pattern of the crystal form APTI-II is basically as shown in figure 6;

b. the differential scanning calorimetry (DSC chart) of the crystal form APTI-II has an endothermic peak within the range of 178-195 ℃;

c. the Differential Scanning Calorimetry (DSC) chart of the crystal form APTI-II has the initial value of 180.8 +/-2 ℃ and/or the peak value of 190.23 +/-2 ℃;

d. the Differential Scanning Calorimetry (DSC) of the crystal form APTI-II is basically shown as figure 7;

e. the infrared absorption spectrum of the crystal form APTI-II is 3250 +/-10, 3211 +/-10, 3055 +/-10, 2978 +/-10, 1717 +/-10, 1678 +/-10 and 1526 +/-10 cm^-1Has an absorption peak;

f. the infrared absorption spectrum of the crystal form APTI-II is basically shown in figure 8;

g. the crystalline form APTI-II has a thermogravimetric analysis (TGA) profile with a weight loss of about 0.15 + -0.2% over the range of 0 deg.C to 60 + -3 deg.C;

e. the thermogravimetric analysis (TGA) profile of the crystalline form APTI-II is substantially as shown in figure 9.

5. A process for preparing a crystalline form of claim 1, comprising the steps of:

II-a) providing a mixture of the compound of formula I starting material in acetone;

II-b) stirring the mixture of step II-a); and

II-c) collecting the solid in the mixture and drying to obtain the crystal form APTI-II.

6. A solvate of a compound of formula I,

characterized in that the solvate is a hemiacetonate of the compound of formula I.

7. A method of preparing the solvate of claim 6, comprising the steps of:

s-a) providing a mixture of the compound of formula I starting material in acetone;

s-b) stirring the mixture of step S-a); and

s-c) collecting the solid in the mixture and drying to obtain the semi-acetonide of the compound of the formula I.

8. A crystalline form of a compound of formula I,

the crystal form is a crystal form APTI-III;

and the X-ray powder diffraction pattern of the crystal form APTI-III has characteristic peaks at 2 theta values of 7.2 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees and 19.0 degrees +/-0.2 degrees.

9. A process for preparing a crystalline form according to claim 8, comprising the steps of:

III-a) providing a solution a of a compound of formula I starting material in a solvent A;

III-B) adding the solution a of step 3a) to a solvent B;

III-c) optionally cooling to 0-10 ℃ and stirring; and

III-d) collecting precipitated solid, and drying to obtain the crystal form APTI-III.

10. Use of the crystalline form of claim 1, the solvate of claim 6 or the crystalline form of claim 8 for the preparation of a highly pure pharmaceutically acceptable crystalline form of a compound of formula I.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a new crystal form of Ruogeli and a preparation method thereof.

Background

Ruogeli is a once-a-day, oral, gonadotropin releasing hormone (GnRH) receptor antagonist that inhibits the production of testosterone in the testes, which stimulates the growth of prostate cancer. In addition, Ruugolili also reduces the level of female ovarian-produced estrogen and male testosterone production by blocking GnRH receptors in the pituitary gland, reducing ovarian estradiol production, and reducing the release of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH).

Ruogo is approved by the Japan pharmaceutical and medical device integration institution (PMDA) in 2019, 1 month and 8 days, and is sold in the markets by Wutian and Aska pharmaceutical under the trade name of40 mg/tablet approved for the treatment and symptom relief of uterine fibroids; the Food and Drug Administration (FDA) of 18 U.S. at 12 months of 2020, is approved for marketing under the trade name ORGOVYX, 120 mg/tablet, and has the following structural formula:

WO2014051164 reports crystal forms of tetrahydrofuran solvate of rilogelide and crystal forms of rilogelide (hereinafter referred to as crystal form I), and discloses that wherein the crystal forms of tetrahydrofuran solvate are used for purifying rilogelide, a crude product with a purity of 99.37% can be purified to obtain a product with a purity of 99.75%, and an impurity RS-1 in the crude product can be reduced from 0.1% to 0.04%, an impurity RS-2 in the crude product is reduced from 0.16% to 0.07%, and an impurity RS-3 in the crude product is reduced from 0.08% to 0.02%. From the purification process, the whole purification effect is not good, and the product purity is only improved by 0.38%. In addition, after repeating the WO2014051164 process, the inventors of the present invention found that no matter the tetrahydrofuran solvate crystal form or the product crystal form I, the impurity k and the product cannot be separated from each other in the HPLC analysis pattern, and actually, the tetrahydrofuran solvate crystal form and the product crystal form I both contain more than 0.15% of the impurity k.

WO2019178304 reports crystalline form F, crystalline form G, crystalline form H, and crystalline form J of rilogeli. The crystal form F is a homogeneous polycrystalline form with three forms of anhydrous, semi-hydrated and monohydrate, is not easy to control in production, and is not easy to measure in subsequent preparation processes. The crystal form G and the crystal form H are prepared from the same solvent system (dichloromethane), and mixed crystals are very easy to obtain. The crystal form J is a triclinic crystal system, can be a solvate, and can also be a hydrate, and the crystal form J cannot be accurately characterized and is not suitable for a preparation. In addition, the yield of the crystal forms is only about 40 to 50 percent, and the crystal forms are not suitable for process amplification.

In view of the above, there is an urgent need in the art to develop a new crystal form of Ruugeli suitable for industrial production and having better pharmaceutical performance or purification capability.

Disclosure of Invention

The invention aims to provide a new Ruugeli crystal form or solvate which is suitable for industrial production and has better patent drug performance or purification capability.

In a first aspect of the invention, there is provided a crystalline form of the compound of formula I,

wherein the crystal form is a crystal form APTI-II;

and the X-ray powder diffraction pattern of the crystal form APTI-II has characteristic peaks at one or more positions with 2 theta values of 7.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.6 +/-0.2 degrees, 15.7 +/-0.2 degrees and 20.7 +/-0.2 degrees.

In another preferred embodiment, the crystal form APTI-II is a hemiacetonate crystal form of the compound of the formula I.

In another preferred embodiment, the crystalline form APTI-II also has an X-ray powder diffraction pattern having characteristic peaks at any one or more of 2 θ values of 4.7 ± 0.2 °,5.7 ± 0.2 °,8.8 ± 0.2 °, 11.1 ± 0.2 °,12.3 ± 0.2 °, 13.0 ± 0.2 °,14.1 ± 0.2 °,17.8 ± 0.2 °,19.1 ± 0.2 °, and 20.0 ± 0.2 °.

In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form APTI-II has characteristic peaks at 2 theta values of 4.7 +/-0.2 degrees, 5.7 +/-0.2 degrees, 7.0 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.6 +/-0.2 degrees, 11.1 +/-0.2 degrees, 12.3 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.1 +/-0.2 degrees, 15.7 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.1 +/-0.2 degrees, 20.0 +/-0.2 degrees and 20.7 +/-0.2 degrees.

In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form APTI-II is basically as shown in figure 6.

In another preferred embodiment, the differential scanning calorimetry (DSC chart) of the crystal form APTI-II has an endothermic peak within the range of 178-195 ℃.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) chart of the APTI-II crystal form has an initial value of 180.8 +/-2 ℃ and/or a peak value of 190.23 +/-2 ℃.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) of the crystal form APTI-II is substantially as shown in figure 7.

In another preferred embodiment, the crystal form APTI-II has an infrared absorption spectrum at 3250 +/-10, 3211 +/-10, 3055 +/-10, 2978 +/-10, 1717 +/-10, 1678 +/-10 and 1526 +/-10 cm^-1Has an absorption peak.

In another preferred embodiment, the infrared absorption spectrum of the crystal form APTI-II is basically as shown in figure 8.

In another preferred embodiment, the crystal form APTI-II has a weight loss of about 0.15 +/-0.2% in a thermogravimetric analysis chart (TGA chart) in the range of 0 ℃ to 60 +/-3 ℃.

In another preferred embodiment, the thermogravimetric analysis (TGA) of the crystalline form APTI-II is substantially as shown in figure 9.

In a second aspect of the present invention, there is provided a process for the preparation of the crystalline form as described in the first aspect, wherein the process comprises the steps of:

II-a) providing a mixture of the compound of formula I starting material in acetone;

II-b) stirring the mixture of step II-a); and

II-c) collecting the solid in the mixture and drying to obtain the crystal form APTI-II.

In another preferred embodiment, the compound of formula I is amorphous or crystalline.

In another preferred embodiment, the starting compound of formula I is an amorphous form of the compound of formula I or a crystalline form of the compound of formula I, APTI-I (the crystalline form of APTI-I is as defined in the seventh aspect).

In another preferred embodiment, the purity of the compound of formula I starting material is < 98%; preferably, < 97%.

In another preferred embodiment, in step II-a), the weight volume of the starting compound of formula I to acetone (g: mL) ratio of 1:1 to 20; preferably, 1: 5-15; more preferably 1: 10. + -. 3.

In another preferred embodiment, in step II-b), the temperature is controlled at 30-50 deg.C (preferably, 35-50 deg.C; more preferably, 30 to 40 ℃ under stirring.

In another preferred example, in the step II-b), the stirring time is 0.5-5 hours; preferably, 1 to 5 hours; more preferably, 1 to 3 hours.

In another preferred embodiment, the step II-b) further comprises the step of optionally cooling the mixture to a temperature of 25 ℃ or less (preferably, 15 to 25 ℃) after stirring.

In another preferred embodiment, in step II-c), the solid in the mixture is collected by filtration.

In another preferred embodiment, in step II-c), the drying temperature T of the drying is T <40 ℃.

In a third aspect of the invention, there is provided a solvate of a compound of formula I,

the solvate is a hemiacetonate of the compound of formula I.

In another preferred embodiment, the nuclear magnetic results of the solvates are as follows:

1H-NMR(300MHz,CDCl3)δ:2.13(6H,s),2.17(3H,s),3.40～3.79(2H,br.), 3.81(3H,s),4.18(3H,s),5.34(2H,br.),6.85～7.00(2H,t,J＝8.1Hz),7.10～7.18 (1H,d,J＝9.0Hz),7.20～7.38(1H,m),7.40(1H,d,J＝9.1Hz),7.40～7.70(5H,m), 7.70(1H,s).

in another preferred embodiment, the nuclear magnetic results of the solvate are substantially as shown in fig. 10.

In a fourth aspect of the present invention, there is provided a process for the preparation of a solvate as defined in the seventh aspect, comprising the steps of:

s-a) providing a mixture of the compound of formula I starting material in acetone;

s-b) stirring the mixture of step S-a); and

s-c) collecting the solid in the mixture and drying to obtain the semi-acetonide of the compound of the formula I.

In another preferred embodiment, said starting compound of formula I is as defined in the second aspect.

In another preferred embodiment, in step S-a), the weight volume of the starting compound of formula I and acetone (g: mL) ratio of 1:1 to 20; preferably, 1: 5-15; more preferably 1: 10. + -. 3.

In another preferred embodiment, in step S-b), the temperature is controlled at 30-50 deg.C (preferably, 35-50 deg.C; more preferably, 30 to 40 ℃ under stirring.

In another preferred example, in the step S-b), the stirring time is 0.5-5 hours; preferably, 1 to 5 hours; more preferably, 1 to 3 hours.

In another preferred embodiment, step S-b) optionally includes a step of cooling the mixture to a temperature of 25 ℃ or less (preferably, 15 to 25 ℃) after stirring.

In another preferred embodiment, in step S-c), the solids in the mixture are collected by filtration.

In another preferred embodiment, in step S-c), the drying temperature T of the drying is T <40 ℃.

In a fifth aspect of the invention, there is provided a crystalline form of the compound of formula I,

the crystal form is a crystal form APTI-III;

and the X-ray powder diffraction pattern of the crystal form APTI-III has characteristic peaks at 2 theta values of 7.2 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees and 19.0 degrees +/-0.2 degrees.

In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form APTI-III also has characteristic peaks at any one or more of 2 theta values of 4.9 +/-0.2 degrees, 5.8 +/-0.2 degrees, 9.0 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 14.3 +/-0.2 degrees, 16.4 +/-0.2 degrees, 18.0 +/-0.2 degrees, 20.0 +/-0.2 degrees and 20.6 +/-0.2 degrees.

In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form APTI-III has characteristic peaks at 2 theta values of 4.9 +/-0.2 degrees, 5.8 +/-0.2 degrees, 7.2 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.7 +/-0.2 degrees, 10.7 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.4 +/-0.2 degrees, 18.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.0 +/-0.2 degrees and 20.6 +/-0.2 degrees.

In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form APTI-III is basically as shown in figure 11.

In another preferred embodiment, the differential scanning calorimetry (DSC chart) of the crystal form APTI-III has an endothermic peak within the range of 169 ℃ to 190 ℃.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) diagram of the form APTI-III has an onset value (onset) of 171.4 + -2 ℃ and/or a peak value of 183.4 + -2 ℃.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) chart of the crystal form APTI-III is substantially as shown in figure 12.

In another preferred embodiment, the crystal form APTI-III has an infrared absorption spectrum with absorption peaks at 3248 +/-10, 3210 +/-10, 3110 +/-10, 2946 +/-10, 1718 +/-10, 1678 +/-10 and 1526 +/-10 cm-1.

In another preferred embodiment, the infrared absorption spectrum of the crystal form APTI-III is basically as shown in figure 13.

In another preferred embodiment, the crystal form APTI-III has a weight loss of about 0.48 +/-0.2% in a thermogravimetric analysis chart (TGA chart) in the range of 0 ℃ to 60 +/-3 ℃.

In another preferred embodiment, the thermogravimetric analysis (TGA) of the crystalline form APTI-III is substantially as shown in figure 14.

In another preferred embodiment, the crystalline form of APTI-III is a crystalline form of the compound of formula I in free form.

In a sixth aspect of the present invention, there is provided a process for preparing the crystalline form of the fifth aspect, comprising the steps of:

III-a) providing a solution a of a compound of formula I starting material in a solvent A;

III-B) adding the solution a of step 3a) to a solvent B;

III-c) optionally cooling to 0-10 ℃ and stirring; and

III-d) collecting precipitated solid, and drying to obtain the crystal form APTI-III.

In another preferred example, in the step III-a), the temperature of the solution a is 30-50 ℃.

In another preferred embodiment, in step III-a), the solvent a is selected from the group consisting of: DMSO, DMF, NMP, DMAC, or a combination thereof.

In another preferred embodiment, in step III-B), the solvent B is selected from the group consisting of: alcohol solvent, wherein the alcohol solvent (preferably, (C)_1-6Fatty alcohol)).

In another preferred embodiment, in step III-B), the solvent B is selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, n-butanol, or a combination thereof.

In another preferred embodiment, in step III-a), the weight volume of the starting compound of formula I to solvent a (g: mL) ratio of 1: 1-10; preferably, 1:1 to 3.

In another preferred embodiment, in the step III-B), the weight/volume ratio of the compound of formula I starting material to the solvent B is 1: 3-20.

In another preferred embodiment, the compound of formula I is amorphous or crystalline.

In another preferred embodiment, the purity of the compound of formula I starting material is < 98%; preferably, < 97%.

In a seventh aspect of the invention, there is provided a crystalline form of the compound of formula I,

wherein the crystal form is a crystal form APTI-I;

and the X-ray powder diffraction pattern of the crystal form APTI-I has characteristic peaks at 2 theta values of 5.2 +/-0.2 degrees, 10.5 +/-0.2 degrees, 15.3 +/-0.2 degrees and 19.1 +/-0.2 degrees.

In another preferred embodiment, the crystalline form APTI-I further has an X-ray powder diffraction pattern having characteristic peaks at any one or more of 2 Θ values of 6.4 ± 0.2 °, 8.0 ± 0.2 °, 12.5 ± 0.2 °, 15.9 ± 0.2 °, and 21.1 ± 0.2 (e.g., 1, 2, 3, 4, or 5).

In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form APTI-I has characteristic peaks at 2 theta values of 5.2 +/-0.2 degrees, 6.4 +/-0.2 degrees, 8.0 +/-0.2 degrees, 10.5 +/-0.2 degrees, 12.5 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 19.1 +/-0.2 degrees and 21.1 +/-0.2 degrees.

In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form APTI-I is basically as shown in figure 1.

In another preferred embodiment, the differential scanning calorimetry (DSC chart) of the crystal form APTI-II has an endothermic peak within the range of 133-152 ℃.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) graph of the crystalline form APTI-I has an initial (onset) value of 135.08 + -2 ℃ and/or a peak value of 143.23 + -2 ℃.

In another preferred embodiment, the Differential Scanning Calorimetry (DSC) chart of the crystal form APTI-I is substantially as shown in figure 2.

In another preferred embodiment, the crystal form APTI-I has an infrared absorption spectrum at 3311 + -10, 3168 + -10, 3062 + -10, 1719 + -10, 1673 + -10, 1524 + -10 and 1410 + -10 cm^-1Has an absorption peak.

In another preferred embodiment, the infrared absorption spectrum of the crystal form APTI-I is basically as shown in figure 3.

In another preferred embodiment, the crystalline form of APTI-I has a thermogravimetric analysis (TGA) profile with a weight loss of about 0.94 ± 0.2% in the range of 0 ℃ to 60 ± 3 ℃ and a weight loss of about 1.98 ± 0.2% in the range of 60 ± 3 ℃ to 140 ± 3 ℃.

In another preferred embodiment, the thermogravimetric analysis (TGA) of the crystalline form APTI-I is substantially as shown in figure 4.

In an eighth aspect of the present invention, there is provided a process for preparing the crystalline form of the seventh aspect, wherein the process comprises the steps of:

i-a) providing a solution of a compound of formula I starting material in an organic solvent 1;

i-b) adding water to the solution of step I-a) to precipitate a solid in the solution, and optionally continuing stirring; and

i-c) collecting the precipitated solid and drying to obtain the crystalline form.

In another preferred example, in the step I-b), the stirring time is 1-3 hours.

In another preferred example, in the step I-a), the temperature of the solution is 15-30 ℃.

In another preferred example, the temperature of the step I-b) is reduced to 0-10 ℃, water is dripped into the system until solid is separated out, and the mixture is kept under the condition of heat preservation and stirred for 1-3 hours; or dripping water into the system under the condition of heat preservation until solid is separated out, and continuously stirring for 1-3 hours.

In another preferred embodiment, the organic solvent 1 is selected from the group consisting of: a nitrogen or sulfur containing highly polar aprotic solvent, a ketone solvent, an alcohol solvent, an ester solvent, an ether solvent, or a combination thereof.

In another preferred example, the organic solvent 1 is a high-polarity aprotic solvent containing nitrogen or sulfur, or a mixed solvent of a high-polarity aprotic solvent containing nitrogen or sulfur and a solvent selected from the group consisting of: ketone solvents and/or alcohol solvents, ester solvents, ether solvents, or combinations thereof.

In another preferred embodiment, the volume content of the nitrogen-or sulfur-containing highly polar aprotic solvent in the organic solvent 1 is 50 to 100%.

In another preferred embodiment, the nitrogen or sulfur containing highly polar aprotic solvent comprises: DMSO, DMF, NMP, acetonitrile, or a combination thereof; preferably, it is selected from the group consisting of: DMSO, DMF, NMP, or a combination thereof.

In another preferred embodiment, the ketone solvent includes: acetone, methyl ethyl ketone, butanone, methyl isobutyl ketone, or a combination thereof; preferably, acetone.

In another preferred embodiment, the alcohol solvent is an aliphatic alcohol having 1 to 6 carbon atoms; preferably, it is selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, n-butanol, or a combination thereof.

In another preferred embodiment, the ester solvent includes: ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate, or a combination thereof.

In another preferred embodiment, the ethereal solvent includes: tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1, 4-dioxane, or a combination thereof; preferably, it is selected from the group consisting of: tetrahydrofuran, 1, 4-dioxane, or a combination thereof.

In another preferred embodiment, the organic solvent 1 is selected from the group consisting of: DMSO, DMF, NMP, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, aliphatic alcohols of 1-6 carbon atoms (including methanol, ethanol, propanol, or combinations thereof), ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1, 4-dioxane, or combinations thereof.

In another preferred example, the organic solvent 1 is a high-polarity aprotic solvent selected from nitrogen or sulfur, or a mixed solvent of a high-polarity aprotic solvent containing nitrogen or sulfur and a solvent selected from the group consisting of: acetone, methyl ethyl ketone, methyl isobutyl ketone, aliphatic alcohols of 1-6 carbon atoms (including methanol, ethanol, propanol, or combinations thereof), ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1, 4-dioxane, or combinations thereof; wherein the highly polar aprotic solvent containing nitrogen or sulfur is selected from: DMSO, DMF, NMP, acetonitrile, or a combination thereof.

In another preferred embodiment, in step I-a), the weight volume of the compound of formula I with organic solvent 1 (g: mL) ratio of 1:1 to 20; preferably, 1: 2-6.

In another preferred embodiment, in step I-b), the weight volume of the starting compound of formula I to water (g: mL) ratio of 1: 1-20; preferably, 1: 2-20; more preferably, 1: 2-10.

In another preferred embodiment, the compound of formula I is amorphous or crystalline.

In a ninth aspect of the invention, there is provided a crystalline form according to the first aspect, a solvate according to the third aspect or a crystalline form according to the fifth aspect for use in the preparation of a highly pure pharmaceutically acceptable form of a compound of formula I.

In another preferred example, the medicinal crystal form is the crystal form I of WO 2014051164.

In another preferred embodiment, the purity of the pharmaceutically acceptable crystalline form is > 99.5% (preferably, > 99.8%).

In another preferred embodiment, the content of the impurity and/or the impurity RS-1 and/or the impurity RS-2 and/or the impurity RS-3 in the medicinal crystal form is less than 0.1% (preferably, less than 0.05%).

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows a PXRD pattern for a typical example of crystalline form APTI-I;

FIG. 2 shows a DSC profile of a typical example of crystalline form APTI-I;

FIG. 3 shows the IR spectrum of a typical example of crystalline form APTI-I;

FIG. 4 shows a TGA profile of a representative example of crystalline form APTI-I;

FIG. 5 shows the 1H-NMR spectrum of a typical example of crystalline form APTI-I;

FIG. 6 shows a PXRD pattern for a typical example of crystalline form APTI-II;

FIG. 7 shows a DSC profile of a typical example of crystalline form APTI-II;

FIG. 8 shows the IR spectrum of a typical example of crystalline form APTI-II;

FIG. 9 shows a TGA profile of a representative example of crystalline form APTI-II;

FIG. 10 shows the 1H-NMR spectrum of a typical example of crystalline form APTI-II

FIG. 11 shows a PXRD pattern for a typical example of crystalline form APTI-III;

FIG. 12 shows a DSC profile of a representative example of crystalline form APTI-III;

FIG. 13 shows an IR spectrum of a typical example of crystalline form APTI-III;

FIG. 14 shows a TGA profile of a representative example of crystalline form APTI-III;

FIG. 15 shows the 1H-NMR spectrum of a typical example of crystalline form APTI-III.

Detailed Description

Have been studied extensively and intensively. The inventors surprisingly found a new crystal form and a new solvate of Ruugeli as shown in formula I, which are simple to prepare and have very excellent impurity removal effect. The crystal forms (especially the crystal forms APTI-II) and the solvates (hemiacetonates) have excellent removal effects on impurities RS-1, RS2, RS-3 and k in Rulugol, so that the purity of the crystal forms and the solvates is more than 99.5 percent, and the content of each single impurity is basically less than 0.1, and further the medicinal crystal forms prepared from the crystal forms and the solvates have the purity of more than 99.8 percent and the content of the single impurity of less than 0.05 percent. Based on this, the inventors have completed the present invention.

The structures of the impurities are as follows:

new crystal form of Ruogeli and preparation method thereof

The first object of the invention is to provide a new Ruugeli (formula I) crystal form APTI-I, which uses Cu-Kalpha radiation and has characteristic peaks in diffraction angle 2 theta values of 5.2 degrees +/-0.2 degrees, 10.5 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees by X-ray powder diffraction.

Furthermore, the Ruogeli crystal form APTI-I provided by the invention has characteristic peaks at 2 theta values of 5.2 +/-0.2 degrees, 6.4 +/-0.2 degrees, 8.0 +/-0.2 degrees, 10.5 +/-0.2 degrees, 12.5 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 19.1 +/-0.2 degrees, 21.1 +/-0.2 degrees in an X-ray powder diffraction pattern.

Furthermore, the Ruogeli crystal form APTI-I provided by the invention has X-ray powder diffraction data shown in table 1;

TABLE 1

NO.	2θ(°)	Relative Strength (%)
			1	5.2±0.2°	100
2	6.4±0.2°	21.8
			3	8.0±0.2°	13.5
4	10.5±0.2°	30.1
			5	12.5±0.2°	12.8
6	15.3±0.2°	26.5
			7	15.9±0.2°	11.5
8	19.1±0.2°	46.7
			9	21.1±0.2°	24.0

Furthermore, the X-ray powder diffraction pattern of the Ruogeli crystal form APTI-I provided by the invention is basically shown in figure 1.

Furthermore, the Differential Scanning Calorimetry (DSC) of the Ruogeli crystal form APTI-I provided by the invention has the initial onset and peak values of 135.08 +/-2 ℃ and 143.23 +/-2 ℃ respectively.

Furthermore, a Differential Scanning Calorimetry (DSC) chart of the Ruugeli crystal form APTI-I is basically shown in figure 2.

Furthermore, the Ruogeli crystal form APTI-I provided by the invention has absorption peaks at 3311 +/-10, 3168 +/-10, 3062 +/-10, 1719 +/-10, 1673 +/-10, 1524 +/-10 and 1410 +/-10 cm < -1 > in an infrared absorption spectrum.

Furthermore, the infrared absorption spectrum of the Ruogeli crystal form APTI-I provided by the invention is basically shown in figure 3.

Furthermore, the Ruugeli crystal form APTI-I thermogravimetric analysis chart (TGA) provided by the invention has the weight loss of about 0.94 +/-0.2% at the temperature of 0-60 +/-3 ℃, has the weight loss of about 1.98 +/-0.2% at the temperature of 60-140 +/-3 ℃,

furthermore, a thermogravimetric analysis (TGA) of the Ruugeli crystal form APTI-I provided by the invention is basically shown in figure 4.

Furthermore, the crystal form APTI-I is determined to be Ruogeli through nuclear magnetism, and basically as shown in figure 5, the nuclear magnetism result is as follows:

1H-NMR(300MHz,CDCl3)δ:2.13(6H,s),3.40～3.79(2H,br.),(3.80(3H,s), 4.18(3H,s),5.10～5.64(2H,br.),6.85～7.00(2H,t,J＝8.1 8.1Hz),7.10～7.18(1H,d, J＝9.0Hz),7.20～7.38(1H,m),7.40(1H,d,J＝9.1Hz),7.40～7.60(6H,m),7.73 (1H,s).

the second purpose of the invention is a preparation method of Ruogeli crystal form APTI-I, which comprises the following steps:

i-a) dissolving a Ruugeli (formula I) raw material in an organic solvent 1 at 15-30 ℃ to obtain a Ruugo solution in the organic solvent 1;

i-b) optionally cooling to 0-10 ℃, adding (such as dropwise) water to the Ruugeli-containing mixture, and continuing to stir for 1-3 hours under heat preservation; or

Adding dropwise water into the Ruogeli-containing mixture at the constant temperature, and continuously stirring for 1-3 hours;

i-c) filtering and drying to obtain Ruogeli crystal form APTI-I.

Further, the organic solvent 1 described in step I-a is selected from nitrogen-or sulfur-containing highly polar aprotic solvents (DMSO, DMF, NMP, acetonitrile), ketones (acetone, methyl ethyl ketone, methyl isobutyl ketone) solvents, alcohols (aliphatic alcohols having 1 to 6 carbon atoms), esters (ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate) solvents, ethers (tetrahydrofuran, methyl t-butyl ether, isopropyl ether, anisole, 1, 4-dioxane) solvents, or a mixture of any two or more thereof.

Further, the organic solvent 1 is a nitrogen-or sulfur-containing highly polar aprotic solvent (DMSO, DMF, NMP, acetonitrile), or a mixed solvent of a nitrogen-or sulfur-containing highly polar aprotic solvent (DMSO, DMF, NMP, acetonitrile) and a solvent selected from the group consisting of: ketone (acetone, methyl ethyl ketone, methyl isobutyl ketone) solvents, alcohols (aliphatic alcohols containing 1 to 6 carbon atoms), ester (ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate) solvents, and ether (tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1, 4-dioxane) solvents.

Furthermore, the volume content of the nitrogen or sulfur-containing high-polarity aprotic solvent (DMSO, DMF, NMP, acetonitrile) in the organic solvent 1 is 50-100%.

Furthermore, the nitrogen or sulfur containing high polar aprotic solvent is preferably one or more of DMSO, DMF and NMP, and the alcoholic solvent is preferably one or more of methanol, ethanol, isopropanol, n-propanol or n-butanol; the ketone solvent is preferably acetone; the ether solvent is preferably one or more of tetrahydrofuran and 1, 4-dioxane.

Further, the weight volume ratio of the raw material Ruugeli to the organic solvent 1 in the step I-a is 1: 1-20.

Further, in step I-b, the weight-to-volume ratio of the raw material rilogeli to water is 1: 4-20.

The third object of the invention provides a new Ruugeli crystal form APTI-II, which uses Cu-Kalpha radiation, and has characteristic peaks in diffraction angle 2 theta values of 7.0 degrees +/-0.2 degrees, 9.5 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 15.7 degrees +/-0.2 degrees and 20.7 degrees +/-0.2 degrees in X-ray powder diffraction.

Furthermore, the Ruogeli crystal form APTI-II provided by the invention has characteristic peaks at 2 theta values of 4.7 +/-0.2 degrees, 5.7 +/-0.2 degrees, 7.0 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.6 +/-0.2 degrees, 11.1 +/-0.2 degrees, 12.3 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.1 +/-0.2 degrees, 15.7 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.1 +/-0.2 degrees, 20.0 +/-0.2 degrees and 20.7 +/-0.2 degrees in an X-ray powder diffraction pattern.

Furthermore, the Ruogeli crystal form APTI-II provided by the invention has X-ray powder diffraction data shown in a table 2;

TABLE 2

Furthermore, the X-ray powder diffraction pattern of the Ruogeli crystal form APTI-II provided by the invention is basically shown in figure 6. PXRD showed that this structure is different from that reported in the patent publication.

Furthermore, the initial value and the peak value of a Differential Scanning Calorimetry (DSC) chart of the Ruogeli crystal form APTI-II provided by the invention are 180.8 +/-2 ℃ and 190.23 +/-2 ℃; the Differential Scanning Calorimetry (DSC) chart is substantially as shown in FIG. 7.

Furthermore, the Ruogeli crystal form APTI-II provided by the invention has absorption peaks at 3250 +/-10, 3211 +/-10, 3055 +/-10, 2978 +/-10, 1717 +/-10, 1678 +/-10 and 1526 +/-10 cm < -1 > in an infrared absorption spectrum.

Furthermore, the infrared absorption spectrum of the Ruogeli crystal form APTI-II provided by the invention is basically shown in figure 8.

Furthermore, the Ruugeli crystal form APTI-II thermogravimetric analysis chart (TGA) provided by the invention has the weight loss of about 0.15 +/-0.2% at the temperature of 0-60 +/-3 ℃.

Furthermore, a thermogravimetric analysis (TGA) of the Ruugeli crystal form APTI-II provided by the invention is shown in figure 9.

Furthermore, the crystal form APTI-II is determined to be Ruogeli hemiacetonate through nuclear magnetism. The nuclear magnetic results are as follows and are shown in FIG. 10:

1H-NMR(300MHz,CDCl3)δ:2.13(6H,s),2.17(3H,s),3.40～3.79(2H,br.), 3.81(3H,s),4.18(3H,s),5.34(2H,br.),6.85～7.00(2H,t,J＝8.1Hz),7.10～7.18 (1H,d,J＝9.0Hz),7.20～7.38(1H,m),7.40(1H,d,J＝9.1Hz),7.40～7.70(5H,m), 7.70(1H,s).

the fourth purpose of the invention is to provide a preparation method of Ruogeli crystal form APTI-II, which comprises the following steps:

II-a) adding the Ruugeli starting material to acetone, optionally heating to 30-50 ℃, thereby obtaining a mixture of Ruugeli (formula I) starting material in acetone;

II-b) stirring, e.g. stirring for 1-5 hours, optionally reducing the temperature to < 25 ℃ (preferably, 15-25 ℃);

II-c) filtering and drying to obtain the crystal form APTI-II of Ruogeli.

Further, in the step II-a, the weight volume ratio of the raw material Ruugeli to acetone is 1: 1-20.

The fifth purpose of the invention is to provide a new Ruugeli crystal form APTI-III, which uses Cu-Kalpha radiation, and has characteristic peaks in diffraction angle 2 theta values of 7.2 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees and 19.0 degrees +/-0.2 degrees by X-ray powder diffraction.

Furthermore, the crystal form APTI-III of Ruogeli provided by the invention has characteristic peaks at 2 theta values of 4.9 +/-0.2 degrees, 5.8 +/-0.2 degrees, 7.2 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.7 +/-0.2 degrees, 10.7 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.4 +/-0.2 degrees, 18.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.0 +/-0.2 degrees and 20.6 +/-0.2 degrees in an X-ray powder diffraction pattern.

Furthermore, the Ruogeli crystal form APTI-III provided by the invention has X-ray powder diffraction data shown in a table 3;

TABLE 3

NO.	2θ(°)	Relative Strength (%)
			1	4.9±0.2°	17.2
2	5.8±0.2°	14.3
			3	7.2±0.2°	81.1
4	9.0±0.2°	30.4
			5	9.7±0.2°	79.2
6	10.7±0.2°	100
			7	11.2±0.2°	41.8
8	12.6±0.2°	32.1
			9	13.1±0.2°	58.4
10	14.3±0.2°	7.2
			11	15.8±0.2°	46.5
12	16.4±0.2°	5.6
			13	18.0±0.2°	24.2
14	19.0±0.2°	44.3
			15	20.0±0.2°	28.1
16	20.6±0.2°	39.5

Furthermore, the X-ray powder diffraction pattern of the crystalline form APTI-III of the Ruogeli provided by the invention is basically shown in figure 11. PXRD showed that this structure is different from that reported in the patent publication.

Furthermore, the peak values of the Differential Scanning Calorimetry (DSC) chart of the crystal form APTI-III of Ruogeli provided by the invention are 171.4 +/-2 ℃ and 183.4 +/-2 ℃; the Differential Scanning Calorimetry (DSC) chart is substantially as shown in FIG. 12.

Furthermore, the crystal form APTI-III of Ruogeli provided by the invention has absorption peaks at 3248 +/-10, 3210 +/-10, 3110 +/-10, 2946 +/-10, 1718 +/-10, 1678 +/-10 and 1526 +/-10 cm < -1 > in an infrared absorption spectrum.

Furthermore, the infrared absorption spectrum chart of the crystal form APTI-III of Ruogeli provided by the invention is basically shown in figure 13.

Furthermore, the crystal form APTI-III thermogravimetric analysis chart (TGA) of the Ruugeli provided by the invention has the weight loss of about 0.48 +/-0.2% at the temperature of 0-60 +/-3 ℃.

Furthermore, the thermogravimetric analysis (TGA) of the crystalline form APTI-III of Ruugeli provided by the invention is basically shown in figure 14.

Furthermore, it was confirmed by nuclear magnetism that the crystal form APTI-III is rilogeli, as shown in fig. 15, the nuclear magnetism data is as follows:

1H-NMR(300MHz,DMSO-d6)δ:2.04(6H,s),3.40～3.70(2H,br.),3.64(3H, s),4.09(3H,s),5.10～5.50(2H,br.),7.10～7.20(2H,t,J＝8.2Hz),7.40-7.60(4H,m), 7.80～7.92(3H,m),9.10(1H,s),9.63(1H,s).

the sixth purpose of the invention is to provide a preparation method of Ruogeli crystal form APTI-III, which comprises the following steps:

III-a) adding a Ruugeli raw material into a solvent A, and heating to 30-50 ℃ under stirring to obtain a solution a;

III-B) dropwise adding the solution a into a solvent B, and separating out solids;

III-c) optionally cooling to 0-10 ℃ after dripping, and continuously stirring for 1-3 hours;

III-d) filtering and drying to obtain the Ruogeli crystal form APTI-III.

Further, in the step III-a, the solvent A is one or a combination of DMSO, DMF, NMP and DMAC. The organic solvent B is selected from alcohol (fatty alcohol containing 1-6 carbon atoms) solvent, wherein the alcohol solvent is preferably methanol, ethanol, isopropanol, n-propanol or n-butanol.

In the step a III-, the weight-to-volume ratio of the raw material Ruugeli to the organic solvent is 1: 1-10; and/or

In the step III-B, the weight-to-volume ratio of the raw material Ruogeli to the solvent B is 1: 3-20.

Raw materials and general procedure:

1. in the examples, the raw material used was prepared by Ruogeli amorphous reference WO2004067535, and the purity was 96.1%.

2. XRPD pattern determination method

X-ray powder diffraction instrument: BRUKER AXS D2 PHASER X-ray powder diffractometer; radiation source:the intensity ratio α 1/α 2 was 0.5; generator (Generator) kv: 30.0 kv; generator (Generator) mA: 10.0 mA; initial 2 θ: 2.000 °, scan range: 2.0000-40.000 degree.

DSC measurement method

METTLEER DSC1 differential scanning calorimeter temperature program: the temperature is raised by 10 ℃ per minute at 25-210 ℃.

TGA determination method

The instrument model is as follows: METTLEER TGA/DSC1 thermogravimetric analyzer temperature program: the temperature is raised by 10 ℃ per minute at 25-400 ℃.

5. Infrared absorption measuring method

The instrument model is as follows: perkinelmer Spectrun Two Fourier transform Infrared Spectroscopy Potassium bromide pellet scanning range 4400 and 450cm-1 resolution were 4cm-1 scans 4 times.

HPLC detection conditions:

the instrument comprises the following steps: agilent 1260series HPLC.

A chromatographic column: waters XSelect CSH C18,4.6mm X250 mm,5 μm

Column temperature 10 deg.C

The temperature of the sample chamber is 5 DEG C

Mobile phase A phosphate buffer solution with pH 2

Mobile phase B of chromatographic pure acetonitrile

Flow rate: 1.0 ml/min

Measuring time: 68 minutes

Detection wavelength: 230 nm.

The main advantages of the invention include:

(1) the crystal form APTI-II and the crystal form APTI-III have good impurity removal effect, and the purity of the product can be easily improved from 96% to more than 99.5%.

(2) The preparation methods of the three new crystal forms are simple and convenient to operate and easy for industrial production.

(3) The crystal form and the solvate (such as the crystal form APTI-II) can effectively remove impurities such as RS-1, RS2, RS-3 and impurity k in Ruogeli.

(4) The crystal form (such as crystal form APTI-II) and the solvate of the invention are easy to be converted into medicinal crystal forms, thereby obtaining the medicinal crystal form with high purity.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

Example 1: crystal form APTI-I for preparing Ruogeli

Dissolving 30.0g of Ruogeli solid amorphous substance in 80ml of DMSO (dimethylsulfoxide) at 15-25 ℃, adding 60ml of ethanol, cooling to 0-10 ℃, dropwise adding 80ml of water into the solution, stirring for 2 hours at 0-10 ℃, filtering, drying a filter cake to obtain 24.6g of solid, wherein the purity is 96.62% according to HPLC (high performance liquid chromatography) detection, and the yield is 82.0%.

The obtained solid was subjected to XRPD test, and X-ray powder diffraction data thereof are shown in Table 1, and an X-ray powder diffraction pattern thereof is shown in FIG. 1; performing DSC test, and the spectrum is shown in figure 2; performing an IR test, wherein the spectrogram is shown in figure 3; TGA testing was performed with the spectrum shown in figure 4; h NMR measurement is carried out, and the spectrogram is shown in figure 5 and is Ruugeli crystal form APTI-I.

Example 2: crystal form APTI-I for preparing Ruogeli

Dissolving Ruogeli amorphous 1.0g in DMSO 2ml and isopropanol 0.5ml at 15-25 deg.C, dropping 5ml water into the solution at 0-10 deg.C, stirring at 0-10 deg.C for 2 hr, filtering, and drying the filter cake to obtain solid 0.89g with purity 96.34% and yield 89.0%.

The resulting solid was subjected to XRPD testing, the X-ray powder diffraction pattern of which is shown in figure 1; performing DSC test, and the spectrum is shown in figure 2; performing an IR test, wherein the spectrogram is shown in figure 3; TGA testing was performed with the spectrum shown in figure 4; h NMR measurement was carried out, and the spectrum is shown in FIG. 5, and the solid was crystalline form APTI-I of Ruogeli.

Example 3: crystal form APTI-I for preparing Ruogeli

Dissolving Ruogeli amorphous 1.0g in DMF 2ml at 15-25 deg.C, dropping 10ml water into the solution at 15-25 deg.C, stirring at 15-25 deg.C for 2 hr, filtering, and drying the filter cake to obtain solid 0.92g with purity 96.10% and yield 92.0%.

The resulting solid was subjected to XRPD testing, the X-ray powder diffraction pattern of which is shown in figure 1; performing DSC test, and the spectrum is shown in figure 2; performing an IR test, wherein the spectrogram is shown in figure 3; TGA testing was performed with the spectrum shown in figure 4; h NMR measurement was carried out, and the spectrum is shown in FIG. 5, and the solid was Ruugeli crystal form APTI-I.

Example 4: crystal form APTI-II for preparing Ruogeli

Taking 15.0g of the crystal form APTI-I obtained in the example 1 (with water content of 30 percent), adding the crystal form APTI-I into 120ml of acetone, pulping for 2 hours at the temperature of 35-40 ℃, cooling to 25 ℃, filtering, drying at the temperature T <40 ℃ to obtain 9.6g of solid, and detecting the purity by HPLC (high performance liquid chromatography) to be 99.71 percent, and the yield is 91.4 percent.

The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 2, and its X-ray powder diffraction pattern is shown in FIG. 1; performing DSC test, and the spectrum is shown in figure 7; performing an IR test, wherein the spectrogram is shown in FIG. 8; TGA testing was performed with the spectrum shown in figure 9; h NMR measurement was carried out, and the spectrum is shown in FIG. 10, and the solid is crystalline form APTI-II of Ruogeli.

Example 5: crystal form APTI-II for preparing Ruogeli

Taking Ruogeli amorphous 1.0g, adding into 10ml acetone, pulping at 30-35 deg.C for 1.5 hr, cooling to 15 deg.C, filtering, drying at T <40 deg.C to obtain solid 0.90g, purity 99.67% by HPLC detection, and yield 90%.

The resulting solid was subjected to XRPD testing, the X-ray powder diffraction pattern of which is shown in figure 1; performing DSC test, and the spectrum is shown in figure 7; performing an IR test, wherein the spectrogram is shown in FIG. 8; TGA testing was performed with the spectrum shown in figure 9; h NMR test is carried out, the spectrum is shown in figure 10, and the solid is Ruugeli crystal form APTI-II.

Example 6: crystal form APTI-II for preparing Ruogeli

Taking Ruogeli amorphous 6.0g, adding into 50ml acetone, pulping at 35-40 deg.C for 2 hr, cooling to 20 deg.C, filtering, drying at T <40 deg.C to obtain solid 5.5g, purity 99.64% by HPLC detection, and yield 91.7%.

The resulting solid was subjected to XRPD testing, the X-ray powder diffraction pattern of which is shown in figure 1; performing DSC test, and the spectrum is shown in figure 7; performing an IR test, wherein the spectrogram is shown in FIG. 8; TGA testing was performed with the spectrum shown in figure 9; h NMR test is carried out, the spectrum is shown in figure 10, and the solid is Ruugeli crystal form APTI-II.

Example 7: crystal form APTI-III for preparing Ruogeli

Taking 2.0g of Ruogeli amorphous, adding into 4ml of DMSO, dissolving at 30-40 ℃, dropwise adding into 15 ml of ethanol, preserving heat at 30-40 ℃ for 2 hours, cooling to 5 ℃, filtering, and drying to obtain 1.81g of solid, wherein the purity is 99.68% by HPLC detection, and the yield is 90.5%.

The solid obtained was subjected to XRPD testing, and its X-ray powder diffraction data are shown in Table 3, and its X-ray powder diffraction pattern is shown in FIG. 11; performing DSC test, and the spectrum is shown in figure 12; performing an IR test, wherein the spectrum is shown in FIG. 13; TGA testing was performed with the spectrum shown in figure 14; h NMR test is carried out, the spectrum is shown in figure 15, and the solid is Ruugeli crystal form APTI-III.

Example 8: preparation of Ruogeli patent crystal form I

The temperature is controlled at 30-40 ℃, 30 ml of ethanol is dripped into 7.5ml of DMSO solution of Ruogeli (5.0 g of APTI-II obtained in example 6), the temperature is kept for 2 hours at 30-40 ℃ after dripping, the temperature is reduced by 5 ℃, and the solid is obtained by filtering and drying, the purity is 99.88 percent by HPLC detection, and the yield is 92.0 percent.

The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data matched that of form I in document WO 2014051164.

Therefore, the crystal form APTI-II can be conveniently converted into a medicinal preparation crystal form (namely, the crystal form I) by taking the crystal form APTI-II as a raw material.

Comparative example 9: pulping the amorphous crude product in ethyl acetate for purification

Pulping 2.0g of Ruogeli amorphous solid in 10ml of ethyl acetate at 45-60 ℃ for 2 hours, cooling to 25 ℃, filtering, drying at the temperature T <40 ℃ to obtain 1.90g of solid, wherein the purity is 97.14% by HPLC detection, and the yield is 95%.

Comparative example 10: pulping the amorphous crude product in ethanol for purification

Pulping 2.0g of Ruogeli amorphous solid in 10ml of ethanol at 45-60 ℃ for 2 hours, cooling to 25 ℃, filtering, and drying at the temperature T <40 ℃ to obtain 1.78g of solid, wherein the purity is 96.67% by HPLC detection, and the yield is 89%.

Comparative example 11: pulping the amorphous crude product in methanol for purification

Pulping 2.0g of Ruogeli amorphous solid in 10ml of methanol at 45-60 ℃ for 2 hours, cooling to 25 ℃, filtering, and drying at the temperature T <40 ℃ to obtain 1.72g of solid, wherein the purity is 96.85% by HPLC detection, and the yield is 86%.

Comparative example 12: pulping the amorphous crude product in acetonitrile for purification

Pulping 2.0g of Ruogeli amorphous solid in 10ml of acetonitrile at 45-60 ℃ for 2 hours, cooling to 25 ℃, filtering, drying at the temperature T <40 ℃ to obtain 1.76g of solid, wherein the purity is 99.01% by HPLC detection, and the yield is 88%.

Comparative example 13: pulping the amorphous crude product in methyl tert-butyl ether

Taking 2.0g of Ruogeli amorphous product, respectively pulping in 10ml of methyl tert-butyl ether at 35-45 ℃ for 2 hours, cooling to 25 ℃, filtering, drying at T <40 ℃ to obtain 1.90g of solid, wherein the purity is 97.03% by HPLC detection, and the yield is 95%.

Comparative example 14: pulping the amorphous crude product in methyl isobutyl ketone

Taking 2.0g of Ruogeli amorphous product, pulping in 10ml of methyl isobutyl ketone at 35-45 ℃ for 2 hours, cooling to 25 ℃, filtering, drying at T <40 ℃ to obtain 1.80g of solid, wherein the purity is 98.23% by HPLC detection, and the yield is 90%.

Comparative example 15: pulping the amorphous crude product in dichloromethane/ethyl acetate for purification

Taking 2.0g of Ruogeli amorphous, pulping in 10ml of dichloromethane/ethyl acetate (volume ratio of 7/3) at 35-45 ℃ for 2 hours, cooling to 25 ℃, filtering, drying at T <40 ℃ to obtain 1.72g of solid, and detecting the purity by HPLC (high performance liquid chromatography) to be 99.01 percent and the yield to be 86 percent.

In addition, the corresponding solvate is obtained in ethyl acetate, acetonitrile, methyl tert-butyl ether and methyl isobutyl ketone through experiments; dichloromethane/ethyl acetate gave ethyl acetate solvate and ethyl acetate could not be removed during attempts to convert the solvate to the proprietary crystalline form I.

The contents of the compound of the formula I and related substances in each of the crystals obtained in examples 1 to 15 were determined by HPLC, and the results are shown in table 4.

TABLE 4

Sample (I)	Compound of formula I (%)	RS-1(％)	RS2(％)	RS-3(％)	Impurity k
						Amorphous raw material	96.18	0.63	0.86	0.28	0.13
EXAMPLE 1 crystalline form APTI-I	96.62	0.55	0.80	0.12	0.13
						Example 2 crystalline form APTI-I	96.34	0.60	0.81	0.22	0.13
EXAMPLE 3 crystalline form APTI-I	96.10	0.61	0.82	0.25	0.12
						Example 4 crystalline form APTI-II	99.71	0.04	0.05	0.07	0.04
Example 5 crystalline form APTI-II	99.67	N.D.	0.08	0.06	0.05
						Example 6 crystalline form APTI-II	99.64	N.D.	0.05	0.06	0.04
Example 7 crystalline form APTI-III	99.68	0.03	0.12	0.08	0.05
						Example 8 form I	99.88	N.D.	0.03	0.04	0.03
Comparative example 9	97.14	0.45	0.60	0.13	0.11
						Comparative example 10	96.67	0.50	0.62	0.11	0.12
Comparative example 11	96.85	0.51	0.58	0.20	0.12
						Comparative example 12	99.01	0.12	0.25	0.13	0.08
Comparative example 13	97.03	0.48	0.46	0.12	0.12
						Comparative example 14	98.23	0.25	0.35	0.14	0.09
Comparative example 15	99.01	0.10	0.23	0.05	0.12

As can be seen from Table 4, the crystal forms APTI-II and APTI-III of the invention have good impurity removal effect, especially the crystal forms APTI-II have excellent impurity removal effect, and the impurities RS-1, RS-2, RS-3 and k can be reduced to below 0.1%. In addition, the purity of the crystal form I prepared by the crystal form of the invention is as high as 99.88 percent, and the content of each impurity is below 0.05 percent.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it will be appreciated that various changes or modifications may be made by those skilled in the art after reading the above teachings of the invention, and such equivalents will fall within the scope of the invention as defined in the appended claims.