CN108026043A - A kind of crystal form of naphthalene cycle compound - Google Patents

Abstract

The present invention provides a kind of crystal form of naphthalene cycle compound, belong to medicinal chemistry art.The crystal form is crystal form 1, crystal form 2, crystal form 3, crystal form 4, crystal form 5, crystal form 6, crystal form 7, crystal form 8, crystal form 9, or crystal form 10, and various crystal forms have different X ray powder diffraction characteristic peaks.The crystal form is non-hygroscopic, has preferable property in stability or mobility etc., can be used for the medicine for preparing treatment hyperuricemia or gout.Present invention also offers the preparation method of various crystal forms, by different solvent or operating method, can obtain different crystal form products.

Description

A kind of crystal form of naphthalene cycle compound Technical field

The present invention relates to a kind of crystal forms of naphthalene cycle compound and preparation method thereof for treating gout, belong to field of medicinal chemistry.

Background technique

Compound 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid, in the present invention also referred to as compound (1), it is a kind of 1 inhibitor of lithate anion transport body, it can be used for treating hyperuricemia and gout, shown in structure such as formula (1):

Patent application WO2011159839 and WO2013067425 disclose the preparation method of compound (1), purposes etc., but the undisclosed relevant information of its crystal form.It is an important factor for influencing drug quality because polymorph in pharmaceuticals is the common phenomenon in drug research and development.The different crystal forms of same drug might have dramatically different in terms of the physicochemical properties such as appearance, mobility, solubility, storage stability, bioavilability, there may be huge differences, can generate different influences to store transfer, application, stability, curative effect etc. of drug；Effectively it is conducive to the crystal form of pharmaceutical preparation in order to obtain, needs comprehensively to investigate the crystallization behavior of drug, to obtain the crystal form for meeting production requirement.

Summary of the invention

Summary of the invention

The present invention provides the novel crystal forms and preparation method thereof of compound (1).

Term definition

Term "comprising" or " comprising " are open language, that is, include content specified by the present invention, but otherwise content is not precluded.

Term " crystal form " is used to describe the existence of solid chemical compound, describes ion, atom or the molecular composition of crystals, the different kinds of parameters aggregate of symmetric property and periodic arrangement rule.

Term " relative intensity " refer to by the strength definition at the last the first peak in one group of diffraction maximum for belonging to a certain crystal form be 100% when, other peaks The ratio of intensity and the intensity at the last the first peak.

In the context of the present invention, 2 θ in X-ray powder diffraction figure (also known as 2theta or diffraction maximum) value is with degree (°) for unit.

When referring to data in map and/or figure, term " diffraction maximum " refers to that those skilled in the art will not belong to a feature of background noise.

The X-ray powder diffraction peak of the crystal form, 2 θ of its X-ray powder diffraction collection or the measurement of diffraction maximum have experimental error, between a machine and another machine and between a sample and another sample, 2 θ of X-ray powder diffraction collection or the measurement of diffraction maximum may slightly have difference, the numerical value of the experimental error or difference may be +/- 0.2 unit or +/- 0.1 unit or +/- 0.05 unit, thus 2 θ or the numerical value of diffraction maximum cannot be considered as it is absolute.

The differential scanning calorimetric curve (DSC) of the crystal form has experimental error, between a machine and another machine and between a sample and another sample, the position of endothermic peak and peak value may slightly have difference, the numerical value of experimental error or difference is likely less than equal to 5 DEG C, or it is less than or equal to 4 DEG C, or be less than or equal to 3 DEG C, or be less than or equal to 2 DEG C, or be less than or equal to 1 DEG C, therefore the peak position of the DSC endothermic peak or the numerical value of peak value cannot be considered as it is absolute.

The thermogravimetric analysis (TGA) of the crystal form has experimental error, between a machine and another machine and between a sample and another sample, weightless temperature and weightless amount may slightly have difference, the numerical value of experimental error or difference may be about +/- 0.1 unit, about +/- 0.05 unit, or about +/- 0.01 unit, therefore the weightless temperature and the numerical value of weightless amount cannot be considered as it is absolute.

In the context of the present invention, wordings such as " about " or " about " whether or not using, all numbers being disclosed are approximation.The numerical value of each number is possible to will appear the differences such as 1%, 2% or 5%.

" room temperature " refers to temperature at about 15 DEG C -32 DEG C or about 20 DEG C -30 DEG C or about 23 DEG C -28 DEG C or about 25 DEG C.

Term " good solvent " can be single solvent or mixed solvent, refer to that sample is greater than 1g/L in the solubility of the single solvent or in the mixed solvent, or be greater than 2g/L, or be greater than 3g/L, or it is greater than 4g/L, or be greater than 5g/L, or be greater than 6g/L, or be greater than 7g/L, or it is greater than 8g/L, or be greater than 9g/L, or be greater than 10g/L, or it is greater than 15g/L, or be greater than 20g/L, or be greater than 30g/L, or it is greater than 40g/L, or be greater than 50g/L, or be greater than 60g/L, or it is greater than 70g/L, or be greater than 80g/L, or be greater than 100g/L.In some embodiments, solubility of the sample in good solvent is bigger than poor solvent；In some embodiments, good solvent and poor solvent are about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% to the difference of the solubility of sample；In some embodiments, good solvent is bigger than poor solvent to the solubility of sample, is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

Term " poor solvent " refers to the solvent that solution can be promoted to reach supersaturation state or crystallization.In some embodiments, solubility of the sample in poor solvent is less than 0.001g/L, or is less than 0.01g/L, or is less than 0.1g/L, or it is less than 0.2g/L, or be less than 0.3g/L, or be less than 0.4g/L, or be less than 0.5g/L, or it is less than 0.6g/L, or be less than 0.8g/L, or be less than 1g/L, or it is less than 2g/L, or be less than 3g/L, or be less than 4g/L, or it is less than 5g/L, or be less than 6g/L, or be less than 7g/L, or it is less than 8g/L, or be less than 9g/L, or be less than 10g/L.

Detailed description of the invention

In a first aspect, inventor passes through the novel crystal forms for having researched and developed compound (1), referred to as crystal form 1.

The crystal form 1 of compound (1) has the property that in its X-ray powder diffraction figure there is diffraction maximum in the position that 2 θ are 10.36,13.89,17.50,24.17 degree.

In some embodiments, there is diffraction maximum in the position that 2 θ are 10.36,13.89,17.51,19.41,22.46,24.17 degree in the X-ray powder diffraction figure of the crystal form 1 of compound (1).

In some embodiments, there is diffraction maximum in the position that 2 θ are 7.48,10.36,13.89,17.51,19.41,20.62,22.46,24.17,28.96,29.39 degree in the X-ray powder diffraction figure of the crystal form 1 of compound (1).

In some embodiments, there is diffraction maximum in the position that 2 θ are 10.38,13.92,17.54,24.20,28.15 degree in the X-ray powder diffraction figure of the crystal form 1 of compound (1).

In some embodiments, there is diffraction maximum in the position that 2 θ are 10.38,13.92,17.54,19.48,20.65,22.51,24.20,28.15 degree in the X-ray powder diffraction figure of the crystal form 1 of compound (1).

In some embodiments, in the X-ray powder diffraction figure of the crystal form 1 of compound (1) 2 θ be 7.48,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17, there is diffraction maximum in 26.51,28.96,29.39,33.79,34.85 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 1 of compound (1) 2 θ be 7.48,8.30,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17,25.81,26.51,28.96,29.39,31.29, there is diffraction maximum in 32.4,33.79,34.85 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 1 of compound (1) 2 θ be 7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,19.41,20.62,21.73,22.46,24.17,25.36,25.81,26.51,28.96,29.39, there is diffraction maximum in 31.29,32.4,33.79,34.85 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 1 of compound (1) 2 θ be 7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,19.41,20.62,21.73,22.46,23.76,24.17,25.36,25.81,26.51,28.96,29.39,30.19,31.29, there is diffraction maximum in 32.0,32.4,33.79,34.85 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 1 of compound (1) is as shown in Figure 1, wherein the relative intensity at the peak that 2 θ are 13.89 degree is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

In some embodiments, the X-ray powder diffraction figure of the crystal form 1 of compound (1) is as shown in Figure 1.

The crystal form 1 of the compound (1) also has the property that its differential scanning calorimetric curve (DSC) has endothermic peak at 200 DEG C -220 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 1 of compound (1) has endothermic peak at 205 DEG C -215 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 1 of compound (1) has endothermic peak at 209 DEG C -213 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 1 of compound (1) has endothermic peak, endothermic peak summit value at 210 DEG C -212 DEG C It is 212 DEG C.In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form 1 of compound (1) is as shown in Figure 2.

In one embodiment, the X-ray powder diffraction figure of the crystal form 1 of compound (1) is as shown in Figure 3.

Crystal form 1 of the present invention is studied, discovery crystal form 1 is non-hygroscopic, and good performance is all had in terms of stability, mobility, is conducive to storage, shifts, operates in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 1 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

Second aspect, the present invention provides the methods for the crystal form 1 for preparing the compound (1).

A kind of method preparing crystal form 1 includes: that compound (1) is mixed with the first solvent, stirs in certain temperature, then separates solid, obtain crystal form 1.First solvent is methyl tertiary butyl ether(MTBE), hexamethylene, normal heptane, isopropyl ether or tetrahydrofuran；Or first solvent is the mixed solvent of methanol with methyl tertiary butyl ether(MTBE) (MTBE), hexamethylene, isopropyl acetate or normal heptane；Or first solvent is the mixed solvent of tetrahydrofuran and n-hexane or hexamethylene.The temperature is reflux temperature of the room temperature to solvent.The time of the stirring is -6 hours 0.5 hour.

In some embodiments, compound (1) is mixed with methyl tertiary butyl ether(MTBE), hexamethylene, normal heptane, isopropyl ether or tetrahydrofuran, is stirred at room temperature -5 hours 3 hours, and solid is then separated, and is removed solvent, is obtained crystal form 1.

In some embodiments, compound (1) stirs -5 hours 1 hour in certain temperature in the in the mixed solvent of methanol and MTBE, hexamethylene, isopropyl acetate or normal heptane, separates solid, obtain crystal form 1.

On the other hand, a kind of method preparing crystal form 1 includes: that compound (1) is mixed with the second solvent, and heating makes it completely dissolved, and is then cooled to -10 DEG C of arbitrary temps for arriving room temperature, and crystallization separates solid, obtains crystal form 1.Second solvent be glycol dimethyl ether, methanol, ethyl alcohol, isopropanol, acetonitrile, acetone, water, toluene, or combinations thereof.

In some embodiments, second solvent is the mixed solvent of glycol dimethyl ether with methanol, acetone, water or toluene.

In some embodiments, second solvent is the mixed solvent or water of water and methanol and the mixed solvent of acetone.

In some embodiments, second solvent is methanol, ethyl alcohol, isopropanol or acetonitrile.

On the other hand, a kind of method preparing crystal form 1 includes: that compound (1) is dissolved in glycol dimethyl ether, is then mixed with the first poor solvent, stirring and crystallizing, separates solid, obtains crystal form 1；First poor solvent is normal heptane or isopropyl acetate.

On the other hand, a kind of method preparing crystal form 1 includes: that compound (1) is dissolved in third solvent, the second poor solvent is then added, it is dry that opening evaporates into solvent, obtains crystal form 1.The third solvent is glycol dimethyl ether, methanol, ethyl alcohol, acetonitrile, ethyl acetate, isopropanol.Second poor solvent is water, methylene chloride, methyl tertiary butyl ether(MTBE), toluene, acetonitrile, n-hexane, ethyl acetate, acetone or isopropanol.

In some embodiments, the third solvent is glycol dimethyl ether, and second poor solvent is water, methylene chloride, methyl tertiary butyl ether(MTBE) or toluene.In some embodiments, the third solvent is methanol, and second poor solvent is water, methyl tertiary butyl ether(MTBE), acetonitrile, methylene chloride, toluene or acetone.In some embodiments, the third solvent is ethyl alcohol, and second poor solvent is water, toluene, n-hexane, methylene chloride, ethyl acetate, methyl tertiary butyl ether(MTBE), acetone or isopropanol.In some embodiments, the third solvent is isopropyl Alcohol, second poor solvent are methylene chloride, methyl tertiary butyl ether(MTBE), toluene or n-hexane.In some embodiments, the third solvent is acetonitrile, and second poor solvent is water.In some embodiments, the third solvent is ethyl acetate, and second poor solvent is methylene chloride.

The third aspect, the present invention provides the novel crystal forms of compound (1), referred to as crystal form 3.

The crystal form 3 of compound (1) has the property that in its X-ray powder diffraction figure there is diffraction maximum in the position that 2 θ are 10.41,13.13,13.89,15.27,16.58,20.06,24.17 degree.

In some embodiments, there is diffraction maximum in the position that 2 θ are 10.41,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,22.31,24.17 degree in the X-ray powder diffraction figure of the crystal form 3 of compound (1).

In some embodiments, in the X-ray powder diffraction figure of the crystal form 3 of compound (1) 2 θ be 9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06, there is diffraction maximum in 20.80,21.31,22.31,23.73,24.17 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 3 of compound (1) 2 θ be 9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,24.17,27.56, there is diffraction maximum in 28.34,29.41,31.35 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 3 of compound (1) 2 θ be 6.89,7.54,9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,23.05,23.73,24.17,26.32,27.56, there is diffraction maximum in 28.34,29.41,31.35,32.97 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 3 of compound (1) is as shown in Figure 4, wherein the relative intensity at the peak that 2 θ are 16.58 degree is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

In some embodiments, the X-ray powder diffraction figure of the crystal form 3 of compound (1) is as shown in Figure 4.

Crystal form 3 of the present invention is studied, discovery crystal form 3 is non-hygroscopic, and good performance is all had in terms of mobility, is conducive to storage, shifts, operates in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 3 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

Fourth aspect, the present invention provides the preparation methods of the crystal form 3 of the compound (1).

A kind of method preparing crystal form 3 includes: that compound (1) is dissolved in glycol dimethyl ether, and methyl tertiary butyl ether(MTBE) is then added, and is stirred -6 hours 3 hours, and solid is separated, and removes solvent, obtains crystal form 3.

When compound (1) is dissolved in glycol dimethyl ether, can take plus thermally or ultrasonically or it is other be conducive to dissolution method.

A kind of method preparing crystal form 3 includes: that compound (1) is dissolved in ethyl acetate, methyl tertiary butyl ether(MTBE) is then added, opening evaporates into solvent dry after mixing, obtains crystal form 3.

A kind of method preparing crystal form 3 includes: that compound (1) is mixed with chloroform or isopropanol, and heating forms solution, then methyl tertiary butyl ether(MTBE) is added dropwise；Then it stirs or stirring to the solid that cools down is precipitated, stirring and crystallizing -12 hours 0.1 hour, separate solid, remove solvent, obtain 3 product of crystal form.

5th aspect, the present invention provides the novel crystal forms of compound (1), referred to as crystal form 4.

The crystal form 4 of compound (1) has the property that in its X-ray powder diffraction figure there is diffraction maximum in the position that 2 θ are 9.79,13.20,13.85,15.94,17.46,20.32,23.06,28.68 degree.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 4 of compound (1) 2 θ be 9.79,11.35,13.20,13.85,15.94,17.46,19.81,20.32,20.72, there is diffraction maximum in 21.66,22.70,23.06,25.56,28.68 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 4 of compound (1) 2 θ be 9.79,11.35,13.20,13.85,15.94,16.47,17.07,17.46,19.81,20.32,20.72,21.66,22.70,23.06,24.03,25.56,27.91, there is diffraction maximum in 28.68,29.64,32.44 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 4 of compound (1) 2 θ be 8.00,9.79,11.35,12.05,13.20,13.85,15.94,16.47,17.07,17.46,18.79,19.81,20.32,20.72,21.66,22.12,22.70,23.06,24.03,24.50,25.56,27.91,28.68 there is diffraction maximum in 29.64,32.44,35.22 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 4 of compound (1) is as shown in Figure 5, wherein the relative intensity at the peak that 2 θ are 23.06 degree is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

In some embodiments, the X-ray powder diffraction figure of the crystal form 4 of compound (1) is as shown in Figure 5.

The crystal form 4 of the compound (1) also has the property that its differential scanning calorimetric curve (DSC) has endothermic peak at about 200 DEG C -215 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 4 of compound (1) has endothermic peak at about 202 DEG C -213 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 4 of compound (1) has endothermic peak at about 203 DEG C -210 DEG C, and endothermic peak summit value is 208 DEG C.In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form 4 of compound (1) is as shown in Figure 6.

Crystal form 4 of the present invention to be studied, discovery crystal form 4 is non-hygroscopic, and it is with good performance in terms of mobility, but crystal form 4 changes after being placed at room temperature for certain time to crystal form 1.The crystal form 4 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

6th aspect, the present invention provides the preparation methods of the crystal form 4 of the compound (1).

A kind of method preparing crystal form 4 includes: that compound (1) is dissolved in ethyl acetate, toluene is then added, opening evaporates into solvent dry after mixing, obtains crystal form 4.

A kind of method preparing crystal form 4 includes: that compound (1) heating is dissolved in 2- methyltetrahydrofuran, and n-hexane, hexamethylene, normal heptane or combinations thereof solvent are then added dropwise at room temperature, solid is precipitated, stirring and crystallizing -8 hours 0.5 hour, solid is separated, solvent is removed, obtains the production of crystal form 4 Object.

7th aspect, the present invention provides the novel crystal forms of compound (1), referred to as crystal form 5.

The crystal form 5 of compound (1) has the property that in its X-ray powder diffraction figure there is diffraction maximum in the position that 2 θ are 8.77,17.55,19.82,23.74,27.33,35.48 degree.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 5 of compound (1) 2 θ be 8.77,11.09,12.48,15.38,16.16,17.55,18.89,19.82,20.97, there is diffraction maximum in 22.22,23.74,27.33,28.88,35.48 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 5 of compound (1) is as shown in Figure 7, wherein the relative intensity at the peak that 2 θ are 17.55 degree is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

In some embodiments, the X-ray powder diffraction figure of the crystal form 5 of compound (1) is as shown in Figure 7.

The crystal form 5 of the compound (1) also has the property that its differential scanning calorimetric curve (DSC) has endothermic peak at about 130 DEG C -155 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 5 of compound (1) has endothermic peak at about 132 DEG C -150 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 5 of compound (1) has endothermic peak at about 132 DEG C -149 DEG C, and endothermic peak summit value is 148.6 DEG C.

Crystal form 5 of the present invention is studied, discovery crystal form 5 is also non-hygroscopic, stability, in terms of all have good performance, be conducive to storage, transfer, operate in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 5 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

Eighth aspect, the present invention provides the preparation methods of the crystal form 5 of the compound (1).

In some embodiments, a kind of method preparing crystal form 5 includes: that compound (1) at 40 DEG C -60 DEG C is dissolved in glycol dimethyl ether, then 30 DEG C -60 DEG C of temperature control, hexamethylene is added, it finishes, mixed liquor stirs -6 hours 4 hours at 10 DEG C -40 DEG C, separates solid, obtained solid removes solvent, obtains crystal form 5.

In some embodiments, a kind of method preparing crystal form 5 includes: that compound (1) is mixed with chloroform, is thermally formed solution, then hexamethylene is added dropwise at room temperature, there is solid precipitation, continues stirring -8 hours 0.5 hour, then solid is separated, solvent is removed, obtains 5 product of crystal form.

9th aspect, the present invention provides the crystal form A of the mono-sodium salt of the compound (1), mono-sodium salt.The crystal form A of the mono-sodium salt of the compound (1), which has the property that in its X-ray powder diffraction figure, has diffraction maximum in the position that 2 θ are 10.15,13.04,15.42,16.88,20.07,21.86,24.62,26.69,31.11,34 .47 degree.

In some embodiments, in the X-ray powder diffraction figure of the crystal form A of the mono-sodium salt of compound (1) 2 θ be 10.15,12.19,13.04,15.42,15.64,16.88,18.67,19.23,20.07,21.86,22.93,23.57,24.62,25.81,26.69,27.13,28.72 29.23 31.11,34.47 there is diffraction maximum in the position of degree.

In some embodiments, in the X-ray powder diffraction figure of the crystal form A of the mono-sodium salt of compound (1) 2 θ be 7.10,10.15,12.19,13.04,15.42,15.64,16.88,18.67,19.23,20.07,20.91,21.43,21.86,22.52,22.93,23.57,24.62,25.81,26.69,27.13,28.72,29.23,29.59, there is diffraction maximum in 31.11,31.69,32.97,34.47 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form A of the mono-sodium salt of compound (1) 2 θ be 5.15,7.10,10.15,12.19,13.04,14.24,15.42,15.64,16.88,18.25,18.67,19.23,20.07,20.55,20.91,21.43,21.86,22.52,22.93,23.57,24.62,25.81,26.69,27.13,27.63,28.72,29.23,29.59,31.11, there is diffraction maximum in 31.69,32.00,32.41,32.97,34.47,39.05 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form A of the mono-sodium salt of compound (1) is as shown in figure 8, wherein, relative intensity at the peak that 2 θ are 13.04 degree is greater than 50%, or is greater than 70%, or is greater than 80%, or it is greater than 90%, or be greater than 99%.

In some embodiments, the X-ray powder diffraction figure of the crystal form A of the mono-sodium salt of compound (1) is as shown in Figure 8.

The crystal form A of the mono-sodium salt of the compound (1) also has the property that its differential scanning calorimetric curve (DSC) has at 100 DEG C -125 DEG C at endothermic peak and 165 DEG C -195 DEG C and has endothermic peak.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form A of the mono-sodium salt of compound (1) at 105 DEG C -120 DEG C at endothermic peak and 170 DEG C -190 DEG C have endothermic peak.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form A of the mono-sodium salt of compound (1) has endothermic peak at 110 DEG C -120 DEG C, endothermic peak summit value is 120 DEG C, has endothermic peak at 175 DEG C -190 DEG C, and endothermic peak summit value is 186 DEG C.In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form A of the mono-sodium salt of compound (1) is as shown in Figure 9.

The crystal form A of the mono-sodium salt of compound of the present invention (1) is studied, it was found that the crystal form A of the mono-sodium salt of compound (1) has preferable solubility in water, and crystal form A is non-hygroscopic, stability, in terms of all have good performance, be conducive to storage, shift, operated in production technology, can be used for preparing pharmaceutical preparation.

The crystal form A of the mono-sodium salt of the compound (1) can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

Tenth aspect, the present invention provides the preparation methods of the crystal form A of the mono-sodium salt of the compound (1).

A kind of method of the crystal form A of the mono-sodium salt of prepare compound (1) includes: that the mono-sodium salt of compound (1) is soluble in water, subsequently into solid sodium chloride, it is stirred at room temperature -15 hours 3 hours, then solid is separated, obtained solid removes residual solvent, obtain crystal form A, wherein the mass ratio of sodium chloride and water is not higher than 20%.In some embodiments, wherein the mass ratio of sodium chloride and water is 1%-10%.In some embodiments, wherein the mass ratio of sodium chloride and water is 1%-5%.In some embodiments, wherein the mass ratio of sodium chloride and water is 5%-10%.

Tenth on the one hand, and the present invention provides the novel crystal forms of the compound (1), referred to as crystal form 6.The crystal form 6 of the compound (1) has the property that in its X-ray powder diffraction figure in the position that 2 θ are 13.84,14.52,16.01,18.41,18.82,21.30,22.00,24.37,25.36 degree It is equipped with diffraction maximum.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 6 of compound (1) 2 θ be 10.30,10.57,13.84,14.52,16.01,17.08,17.45,18.41,18.82,19.76,20.12,21.30,22.00,23.49,24.37, there is diffraction maximum in 25.36,32.49,39.23 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 6 of compound (1) is as shown in Figure 10.

The crystal form 6 of compound (1) also has the property that its differential scanning calorimetric curve (DSC) has at 130 DEG C -150 DEG C at endothermic peak and 210 DEG C -220 DEG C and has endothermic peak.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 6 of compound (1) at 135 DEG C -145 DEG C at endothermic peak and 215 DEG C -219 DEG C have endothermic peak.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 6 of compound (1) has endothermic peak at 140 DEG C -145 DEG C, endothermic peak summit value is 144 DEG C, has endothermic peak at 215 DEG C -219 DEG C, and endothermic peak summit value is 218 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 6 of compound (1) is as shown in figure 11.

The crystal form 6 of compound (1) also has the property that its thermal gravimetric analysis curve (TGA) is shown in 100 DEG C -150 DEG C and has weightlessness, and weight loss is about 8%-10%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 6 of compound (1), which is shown in 100 DEG C -150 DEG C, weightlessness, and weight loss is about 10%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 6 of compound (1) is as shown in figure 12.

Crystal form 6 of the present invention is studied, crystal form 6 is non-hygroscopic, stability and in terms of all have good performance, be conducive to storage, transfer, operate in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 6 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

12nd aspect, the present invention provides the preparation methods of the crystal form 6 of the compound (1).

A kind of method preparing crystal form 6 includes: that compound (1) is mixed with glacial acetic acid, is heated to reflux, and water then is added to gained mixed liquor, mixed liquor has been cooled to solid precipitation, insulated and stirred；Then mixed liquor is cooled to room temperature, insulated and stirred；Separation solid simultaneously removes solvent, obtains 6 product of crystal form.

13rd aspect, the present invention provides the novel crystal forms of the compound (1), referred to as crystal form 7.The crystal form 7 of the compound (1), which has the property that in its X-ray powder diffraction figure, has diffraction maximum in the position that 2 θ are 10.30,13.83,14.87,16.06,18.06,19.76,21.03,23.02,24.18,25 .25 degree.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 7 of compound (1) 2 θ be 8.25,10.30,13.83,14.87,16.06,16.97,18.06,19.76,20.31,20.67,21.03,23.02,24.18,25.25, there is diffraction maximum in 28.43,29.06,31.66 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 7 of compound (1) is as shown in figure 13, wherein the relative intensity at the peak that 2 θ are 13.83 degree is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

In some embodiments, the X-ray powder diffraction figure of the crystal form 7 of compound (1) is as shown in figure 13.

The crystal form 7 of compound (1) also has the property that its differential scanning calorimetric curve (DSC) has endothermic peak at 215 DEG C -225 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 7 of compound (1) has endothermic peak at 215 DEG C -219 DEG C, and endothermic peak summit value is 217 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 7 of compound (1) is as shown in figure 14.

The crystal form 7 of compound (1) also has the property that its thermal gravimetric analysis curve (TGA) is shown in 100 DEG C -150 DEG C and has weightlessness, and weight loss is about 0.5%-2%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 7 of compound (1), which is shown in 100 DEG C -150 DEG C, weightlessness, and weight loss is about 1.8%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 7 of compound (1) is as shown in figure 15.

Crystal form 7 of the present invention is studied, discovery crystal form 7 is non-hygroscopic, be easy to be separated by filtration, stability, in terms of all have good performance, be conducive to storage, transfer, operate in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 7 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

Fourteenth aspect, the present invention provides the preparation methods of the crystal form 7 of the compound (1).

A kind of method preparing crystal form 7 includes: that compound (1) is mixed with glacial acetic acid, is heated to reflux；Then water is added into gained mixed liquor, is cooled to room temperature or is cooled to 0 DEG C -5 DEG C, insulated and stirred；Separation solid simultaneously removes solvent, obtains 7 product of crystal form.

15th aspect, the present invention provides the novel crystal forms of the compound (1), referred to as crystal form 8.The crystal form 8 of the compound (1), which has the property that in its X-ray powder diffraction figure, has diffraction maximum in the position that 2 θ are 10.26,13.83,14.31,19.08,19.46,20.14,21.91,23.87,24.19,29 .10 degree.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 8 of compound (1) 2 θ be 7.52,10.26,13.83,14.31,15.01,16.06,16.91,17.48,18.61,19.08,19.46,20.14,21.91,22.49, there is diffraction maximum in 23.87,24.19,29.10 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 8 of compound (1) is as shown in figure 16.

The crystal form 8 of compound (1) also has the property that its differential scanning calorimetric curve (DSC) has endothermic peak at 206 DEG C -215 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 8 of compound (1) has endothermic peak at 207 DEG C -212 DEG C, and endothermic peak summit value is 210.5 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 8 of compound (1) is as shown in figure 17.

The crystal form 8 of compound (1) also has the property that its thermal gravimetric analysis curve (TGA) is shown in 100 DEG C -150 DEG C and has weightlessness, and weight loss is about 2.5%-4.5%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 8 of compound (1), which is shown in 100 DEG C -150 DEG C, weightlessness, and weight loss is about 4%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 8 of compound (1) is as shown in figure 18.

Crystal form 8 of the present invention is studied, discovery crystal form 8 is non-hygroscopic, in terms of all have good performance, be conducive to storage, transfer, operate in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 8 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

16th aspect, the present invention provides the preparation methods of the crystal form 8 of the compound (1).

A kind of method preparing crystal form 8 includes: that compound (1) is dissolved in chloroform, and or mixtures thereof normal heptane or hexamethylene is then added, and solid is precipitated, then stirring and crystallizing separates solid, removes solvent, obtains 8 product of crystal form.

17th aspect, the present invention provides the novel crystal forms of the compound (1), referred to as crystal form 9.The crystal form 9 of the compound (1), which has the property that in its X-ray powder diffraction figure, has diffraction maximum in the position that 2 θ are 9.97,12.66,15.56,16.54,17.69,18.31,21.80,25.14,25.67 degree.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 9 of compound (1) 2 θ be 9.97,12.66,14.92,15.56,16.54,17.69,18.31,19.19,20.77,21.80, there is diffraction maximum in 22.84,25.14,25.67,27.36,30.12 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 9 of compound (1) 2 θ be 6.79,9.97,12.66,13.54,14.92,15.56,16.54,17.32,17.69,18.31,19.19,19.79,20.77,21.80,22.84,24.27,25.14,25.67,26.23,27.36, there is diffraction maximum in 27.94,28.60,29.61,30.12 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 9 of compound (1) is as shown in figure 19, wherein the relative intensity at the peak that 2 θ are 12.66 degree is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

In some embodiments, the X-ray powder diffraction figure of the crystal form 9 of compound (1) is as shown in figure 19.

The crystal form 9 of compound (1) also has the property that its differential scanning calorimetric curve (DSC) has endothermic peak at 155 DEG C -175 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 9 of compound (1) has endothermic peak at 155 DEG C -170 DEG C, and endothermic peak summit value is 165 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 9 of compound (1) is as shown in figure 20.

The crystal form 9 of compound (1) also has the property that its thermal gravimetric analysis curve (TGA) is shown in 100 DEG C -150 DEG C and has weightlessness, and weight loss is about 5%-7%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 9 of compound (1), which is shown in 100 DEG C -150 DEG C, weightlessness, and weight loss is about 6.6%.In one embodiment, the thermal gravimetric analysis curve (TGA) of the crystal form 9 of compound (1) is as shown in figure 21.

Crystal form 9 of the present invention is studied, discovery crystal form 9 is non-hygroscopic, in terms of all have good performance, be conducive to storage, transfer, operate in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 9 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

18th aspect, the present invention provides the preparation methods of the crystal form 9 of the compound (1).

A kind of method preparing crystal form 9 includes: that compound (1) is dissolved in n,N-Dimethylformamide, and methyl tertiary butyl ether(MTBE) to solid is added and is precipitated, is cooled to -5 DEG C of -5 DEG C of stirring and crystallizings, then separates solid, remove solvent, obtain 9 product of crystal form.

19th aspect, the present invention provides the novel crystal forms of the compound (1), referred to as crystal form 10.The crystal form 10 of the compound (1) has such as Lower characteristic: there is diffraction maximum in the position that 2 θ are 10.38,13.44,13.95,16.31,17.62,20.48,22.50,22.86,24.26 degree in its X-ray powder diffraction figure.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 10 of compound (1) 2 θ be 9.90,10.38,13.44,13.95,16.02,16.31,16.58,16.96,17.62,20.48, there is diffraction maximum in 22.50,22.86,24.26,25.79,32.20 degree of position.

In some embodiments, in the X-ray powder diffraction figure of the crystal form 10 of compound (1) 2 θ be 7.49,8.22,9.90,10.38,11.17,13.44,13.95,15.06,16.02,16.31,16.58,16.96,17.62,19.78,20.48,22.50,22.86, there is diffraction maximum in 24.26,25.79,32.20 degree of position.

In some embodiments, the X-ray powder diffraction figure of the crystal form 10 of compound (1) is as shown in figure 22.

The crystal form 10 of compound (1) also has the property that its differential scanning calorimetric curve (DSC) has endothermic peak at 209 DEG C -215 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 10 of compound (1) has endothermic peak at 209 DEG C -212 DEG C, and endothermic peak summit value is 211.5 DEG C.In one embodiment, the differential scanning calorimetric curve (DSC) of the crystal form 10 of compound (1) is as shown in figure 23.

Crystal form 10 of the present invention is studied, discovery crystal form 10 is non-hygroscopic, stability, in terms of all have good performance, be conducive to storage, transfer, operate in production technology, can be used for preparing pharmaceutical preparation.

The crystal form 10 of the compound (1) or be prepared into after salt can be with pharmaceutically acceptable auxiliary material, such as filler, adhesive, disintegrating agent, or the mixing such as lubricant, it is prepared into various dosage forms, such as tablet, capsule, the suitable dosage form such as granule, for treating hyperuricemia or gout etc..

20th aspect, the present invention provides the preparation methods of the crystal form 10 of the compound (1).

A kind of method preparing crystal form 10 includes: that compound (1) is mixed with tetrahydrofuran, isopropanol, dioxane or combinations thereof solvent, heating, form solution, methyl tertiary butyl ether(MTBE), hexamethylene, n-hexane, normal heptane, isopropyl acetate or its mixed solvent is added into solution at room temperature to there is solid precipitation, it is stirred at room temperature -12 hours 0.1 hour, then solid is separated, solvent is removed, obtains 10 product of crystal form.

Detailed description of the invention

Fig. 1 shows the X-ray powder diffraction figure of the crystal form 1 of compound (1).

Fig. 2 shows the differential scanning calorimetric curve figure (DSC) of the crystal form 1 of compound (1).

Fig. 3 shows a kind of X-ray powder diffraction figure of the crystal form 1 of compound (1) in embodiment.

Fig. 4 shows the X-ray powder diffraction figure of the crystal form 3 of compound (1).

Fig. 5 shows the X-ray powder diffraction figure of the crystal form 4 of compound (1).

Fig. 6 shows the differential scanning calorimetric curve figure (DSC) of the crystal form 4 of compound (1).

Fig. 7 shows the X-ray powder diffraction figure of the crystal form 5 of compound (1).

Fig. 8 shows the X-ray powder diffraction figure of the crystal form A of the mono-sodium salt of compound (1).

Fig. 9 shows the differential scanning calorimetric curve figure (DSC) of the crystal form A of the mono-sodium salt of compound (1).

Figure 10 shows the X-ray powder diffraction figure of the crystal form 6 of compound (1).

Figure 11 shows the differential scanning calorimetric curve figure (DSC) of the crystal form 6 of compound (1).

Figure 12 shows the thermal gravimetric analysis curve figure of the crystal form 6 of compound (1).

Figure 13 shows the X-ray powder diffraction figure of the crystal form 7 of compound (1).

Figure 14 shows the differential scanning calorimetric curve figure (DSC) of the crystal form 7 of compound (1).

Figure 15 shows the thermal gravimetric analysis curve figure (TGA) of the crystal form 7 of compound (1).

Figure 16 shows the X-ray powder diffraction figure of the crystal form 8 of compound (1).

Figure 17 shows the differential scanning calorimetric curve figure (DSC) of the crystal form 8 of compound (1).

Figure 18 shows the thermal gravimetric analysis curve figure (TGA) of the crystal form 8 of compound (1).

Figure 19 shows the X-ray powder diffraction figure of the crystal form 9 of compound (1).

Figure 20 shows the differential scanning calorimetric curve figure (DSC) of the crystal form 9 of compound (1).

Figure 21 shows the thermal gravimetric analysis curve figure (TGA) of the crystal form 9 of compound (1).

Figure 22 shows the X-ray powder diffraction figure of the crystal form 10 of compound (1).

Figure 23 shows the differential scanning calorimetric curve figure (DSC) of the crystal form 10 of compound (1).

Specific embodiment

In order to make those skilled in the art more fully understand technical solution of the present invention, disclosing some non-limiting embodiments further below, the present invention is described in further detail.

Reagent used in the present invention is available on the market or can be prepared by the method for the prior art or described method is prepared through the invention.

In the present invention, DEG C expression degree Celsius, g expression gram, mL expression milliliter.

Instrument parameter

Except making separate stipulations in nonparametric, all analyses all carry out at room temperature below.

X-ray powder diffraction (XRPD)

X-ray powder diffraction (XRPD) is carried out using the x'celerator detector equipped with the 2 θ ranges with 120 ° to analyze.It is 3 ° in 2 θ using Cu-K α radiation to start to collect real time data with 0.01672 θ resolution ratio.Tube voltage and amperage are respectively set as 45kV and 40mA.Antiscatter slits are set as 6.6mm, and divergent slit is 1 degree.Show the pattern of 3 ° of -40 ° of 2 θ.It takes suitable crystal form samples to be placed at zero Background Samples frame circular groove, is gently pressed with clean glass slide, obtain a smooth plane, and zero Background Samples frame is fixed to get sample being placed on automatic sampling apparatus, successively sample introduction.Instrument calibration is carried out with reference to standard specimen using silicon.Experiment XRPD is collected according to cGMP specification in SSCI, Inc. to scheme.In X-ray powder diffraction figure, ordinate is the diffracted intensity indicated with (counts) is counted, and abscissa is 2 θ of the angle of diffraction that expenditure (°) indicates.

Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) is carried out using TA Instruments differential scanning calorimetry (DSC) Q2000.Sample is put into aluminium DSC disk and accurately records weight.The disk is covered with lid, is then crimped.Sample cell is balanced and is heated under nitrogen purge with the rate of 10 DEG C/min at 25 DEG C 300 DEG C of final temperature.Use indium metal as calibration sample.In DSC figure, abscissa expression temperature (Temperature, DEG C), ordinate indicates the heat flow (Heat Flow, W/g) that the substance of unit mass is released.

Thermogravimetry (TGA)

Thermogravimetric analysis is carried out using thermogravimetric analyzer Q500, appropriate amount of sample is placed in platinum sample disc, under nitrogen atmosphere, is heated up with 10 DEG C/min of rates, temperature range is 25 DEG C to 300 DEG C.In TGA figure, abscissa expression temperature (Temperature, DEG C), ordinate indicates mass percent (Weight, %).

Embodiment 1

(1) 0.3 gram of compound is added in 10mL methyl tertiary butyl ether(MTBE), mashing 4 hours is stirred at room temperature；Filtering, obtained solid are dried under vacuum to dry at 50 DEG C, obtain solid 0.24g, detect solid, are crystal form 1, referring to Fig. 1 and Fig. 2.

Methyl tertiary butyl ether(MTBE) is substituted with hexamethylene, normal heptane or isopropyl ether 10mL, same operation obtains 1 product of crystal form.

Embodiment 2

(1) 0.3 gram of compound is added in 3mL tetrahydrofuran, mashing 4 hours is stirred at room temperature；Filtering, obtained solid are dried under vacuum to dry at 50 DEG C, obtain solid 0.24g, detect, and are crystal form 1.

Embodiment 3

(1) 0.4 gram of compound is added in the mixed solution (volume ratio 1:1) of 8mL methanol and methyl tertiary butyl ether(MTBE), 50 DEG C heating stirring 4 hours；Then 10 DEG C -20 DEG C are cooled to, filtering, obtained solid is dried under vacuum to dry at 50 DEG C, obtains solid 0.35g, detects, is crystal form 1.

The methanol hexamethylene mixed liquor for being 1:1 with volume ratio, methanol acetic acid isopropyl ester mixed liquor, methanol normal heptane mixed liquor 8mL substitute the mixed solution of methanol and methyl tertiary butyl ether(MTBE), same to operate, and obtain 1 product of crystal form.

It is same to operate with the mixed solution of tetrahydrofuran n-hexane mixed liquor or tetrahydrofuran hexamethylene mixed liquor 6mL substitution methanol and methyl tertiary butyl ether(MTBE) that volume ratio is 1:5, obtain 1 product of crystal form.

Embodiment 4

Glycol dimethyl ether 1mL and methanol 15mL is added in compound (1) 0.5g, stirring is warming up to 60 DEG C of stirring clarifications；Then it is cooled to 0 DEG C, filtering, obtained solid is dried in vacuo at 50 DEG C, is obtained product 0.38g, is crystal form 1 after testing.

Glycol dimethyl ether 1mL and methanol 15mL is substituted with glycol dimethyl ether 1mL and methanol 15mL or glycol dimethyl ether 3mL and acetone 20mL or glycol dimethyl ether 3mL and toluene 20mL, it is same to operate, obtain 1 product of crystal form.

Embodiment 5

Glycol dimethyl ether 2mL, stirring and dissolving are added in compound (1) 0.5g；Normal heptane 12mL is added dropwise, solid is precipitated, is stirred at room temperature 4 hours.Filtering, obtained solid are dried in vacuo at 50 DEG C, obtain 1 product 0.37g of crystal form.

Normal heptane is substituted with isopropyl acetate, it is same to operate, obtain 1 product of crystal form.

Embodiment 6

4mL water and 40mL methanol are added in compound (1) 4.0g, is heated to reflux to being completely dissolved；Then by mixed liquor slow cooling to 5 DEG C, stirring is filtered after 2 hours, and obtained solid is dried under vacuum to dry at 50 DEG C, obtains 1 product 3.1g of crystal form.

Methanol is substituted with acetone or glycol dimethyl ether, it is same to operate, obtain 1 product of crystal form.

Embodiment 7

Methanol 5mL is added in compound (1) 0.2g, is heated to reflux to being completely dissolved；Then solution is cooled to 0 DEG C -5 DEG C, is precipitated solid, filtering, obtained solid is dried under vacuum to dry at 50 DEG C, obtains 1 product 0.15g of crystal form.

With ethyl alcohol, isopropanol or acetonitrile substitute methanol, same to operate, and obtain 1 product of crystal form.

Embodiment 8

It will be dissolved in 6mL ethyl alcohol under compound (1) 0.1g ultrasound condition, 6mL ethyl acetate be then added, stirred 10 minutes, no solid is precipitated.Then solution stand opening is placed in air, after solvent volatilization is dry, obtains dried powder 0.1g, crystal form 1 is confirmed as in detection.

Embodiment 9

10mL isopropyl acetate is added in compound (1) 0.3g, mashing 4 hours is stirred at room temperature, filtering, obtained solid is dried under vacuum to dry at 50 DEG C, obtains powder 0.2g, confirms after testing, is crystal form 1 shown in Fig. 3, referring to Fig. 3.

Isopropyl acetate is substituted with n-hexane, it is same to operate, obtain 1 product of crystal form.

Embodiment 10

Compound (1) 0.5g is mixed with 2mL glycol dimethyl ether, and dissolution is stirred at room temperature；Methyl tertiary butyl ether(MTBE) 12mL is added dropwise, solid is precipitated, is stirred at room temperature 4 hours, then filters, and obtained solid is dried in vacuo 12 hours at 50 DEG C, obtains product 0.35g, is crystal form 3, referring to fig. 4 after testing.

Embodiment 11

Compound (1) 0.3g is added into 3mL chloroform, and stirring is heated to flowing back, has a small amount of solid insoluble, filter while hot；Methyl tertiary butyl ether(MTBE) 18mL is added dropwise into gained filtrate, drop finishes to be precipitated without solid.Continue stirring to start to be precipitated to solid, be stirred for 6 hours；Then it filters, 50 DEG C of obtained solid are dried in vacuo 12 hours, obtain 3 product 0.2g of crystal form.

Embodiment 12

The mixing of compound (1) 0.3g and 3mL isopropanol, being heated to 85 DEG C dissolves solid.Stop heating, reaction system is transferred at room temperature, and methyl tertiary butyl ether(MTBE) 18mL is slowly added dropwise into solution, and drop finishes to be precipitated without solid.It is cooled to 0 DEG C, stirring had solid precipitation after 1.5 hours, continued stirring 6 hours.Then it filters, 50 DEG C of obtained solid are dried in vacuo 12 hours, obtain 3 product 0.2g of crystal form.

Embodiment 13

Compound (1) 0.1g is dissolved in 8mL ethyl acetate under ultrasound condition, and methyl tertiary butyl ether(MTBE) 8mL is added, is stirred at room temperature 30 minutes, and no solid is precipitated.Solution room temperature opening is statically placed in air, solution evaporation obtains dried powder 0.1g, be confirmed as crystal form 3 after testing to doing.

Embodiment 14

Compound (1) 0.1g is dissolved in 8mL ethyl acetate under ultrasound condition, and toluene 8mL is added, is stirred at room temperature 30 minutes, and no solid is precipitated.Solution room temperature opening is statically placed in air, solution evaporation obtains dried powder 0.11g, be confirmed as crystal form 4 after testing, referring to figs. 5 and 6 to doing.

Embodiment 15

Compound (1) 0.25g is dissolved in the 2- methyltetrahydrofuran with 3mL under the conditions of 40 DEG C -60 DEG C, and solution is then cooled to 25 DEG C -30 DEG C；N-hexane 18mL is added dropwise into solution, there is solid precipitation, finishes and continues stirring 6 hours；Then it filters, obtained solid is dried in vacuo 12 hours at 50 DEG C, obtains 4 product 0.16g of crystal form.

N-hexane is substituted with hexamethylene or normal heptane, it is same to operate, also obtain 4 product of crystal form.

Embodiment 16

Compound (1) 0.5g is added into 4mL glycol dimethyl ether, is stirred at room temperature insoluble, is heated to 40 DEG C -60 DEG C.After solid dissolution, thiacyclohexane 24mL is added dropwise within the scope of 30 DEG C -60 DEG C into above-mentioned system, during which there is solid precipitation, drop finishes, continue stirring -6 hours 4 hours, filtering at 10 DEG C -40 DEG C, obtained solid is dried in vacuo at 50 DEG C, dried powder 0.4g is obtained, crystal form 5 is confirmed as after testing, referring to Fig. 7.

Embodiment 17

Compound (1) 0.3g is added into 3mL chloroform, and heating has fraction solids insoluble, filters while hot；Hexamethylene 18mL is added dropwise into gained filtrate at room temperature, there is solid precipitation during being added dropwise；It finishes, continues stirring 6 hours；Then it filters, obtained solid is dried in vacuo 12 hours at 50 DEG C, obtains 5 product 0.17g of crystal form.

Embodiment 18

The mono-sodium salt 10g of compound (1) is dissolved in 100mL water, it is slowly added to solid sodium chloride 5g, (25 DEG C) of room temperature stirrings, this process has solid to be precipitated and gradually increases, it is filtered after stirring 12h, obtained solid is dried in vacuo at 60 DEG C, obtains product 8.5g, it is detected as the mono-sodium salt crystal form A of compound (1), referring to Fig. 8 and Fig. 9.

The mono-sodium salt mono-sodium salt crystal form A of gained compound (1) is beaten 4 hours with methyl tertiary butyl ether(MTBE), thiacyclohexane, normal hexane, isopropyl acetate in room temperature, is detected after filtration drying, crystal form has no variation, remains as crystal form A.

Embodiment 19

Compound (1) 2.0g and glacial acetic acid 12mL mixing, are heated to flowing back, and solid all dissolves.Stop heating, water 3mL, 5mL, 3mL is added portionwise to being formed by solution, system is still clarified.Lower slow cooling is stirred, has a small amount of solid to be precipitated when temperature is 80 DEG C, insulated and stirred 3 hours.Then stirring drops to room temperature, crystallization is stirred at room temperature 6 hours, filters, and obtained solid is dried in vacuo 12 hours at 50 DEG C, obtains product 1.6g, is crystal form 6, referring to Figure 10, Figure 11 and Figure 12 after testing.

Embodiment 20

In reaction flask, compound (1) 2.0g is added, glacial acetic acid 12mL is heated to flowing back, and solid all dissolves.Stop heating, water 3mL, 5mL, 3mL is added portionwise to being formed by solution, system is still clarified.Then reaction flask is moved in 5 DEG C of ice-water baths and is stirred, there is solid precipitation；Stirring and crystallizing 6 hours, filtering, obtained solid was dried in vacuo 12 hours at 50 DEG C, obtained product 1.6g, was crystal form 7, referring to Figure 13, Figure 14 and Figure 15 after testing.

Embodiment 21

Compound (1) 2.0g and glacial acetic acid 12mL mixing, are heated to flowing back, and solid all dissolves.Stop heating, water 3mL, 5mL, 3mL is added portionwise to being formed by solution, system is still clarified.Then mixed liquor is stirred in air and is cooled to room temperature, there is solid precipitation, stirring and crystallizing 6 hours, filtering, obtained solid was dried in vacuo 12 hours at 50 DEG C, obtained 7 product 1.5g of crystal form.

Embodiment 22

Compound (1) 0.3g and chloroform 3mL mixing, heating still have a small amount of solid insoluble, filter to obtain clear solution while hot, and normal heptane 18mL is slowly added dropwise into gained filtrate, have solid precipitation during being added dropwise, finish, and continue stirring 6 hours；Filtering, obtained solid are dried in vacuo 12 hours at 50 DEG C, and obtained product 0.15g is confirmed as crystal form 8, referring to Figure 16, Figure 17 and Figure 18 after testing.

Normal heptane is substituted with n-hexane, it is same to operate, also obtain 8 product of crystal form.

Embodiment 23

Compound (1) 0.4g, which is stirred at room temperature, to be dissolved in 2mL N,N-dimethylformamide.Methyl tertiary butyl ether(MTBE) 20mL is slowly added dropwise into solution, no solid is precipitated；It is cooled to 0 DEG C, stirring has a small amount of solid to be precipitated for 1 hour, adds methyl tertiary butyl ether(MTBE) 6mL, then be cooled to -5 DEG C and stir 3 hours, filtering, obtained solid are dried in vacuo 12 hours at 60 DEG C, obtain product 0.3g, it is confirmed as crystal form 9 after testing, referring to Figure 19, Figure 20 and Figure 21.

Embodiment 24

Compound (1) 0.4g and tetrahydrofuran 2mL mixing, are heated to 40 DEG C -50 DEG C, solid is completely dissolved.Acquired solution is down to room temperature, Methyl tertiary butyl ether(MTBE) 12mL is slowly added dropwise, there is solid precipitation, finishes and continues stirring 6 hours；Filtering, obtained solid are dried in vacuo 12 hours at 50 DEG C, obtain product 0.3g, be confirmed as crystal form 10 after testing, referring to fig. 22 and Figure 23.

Embodiment 25

Compound (1) 0.3g and isopropanol 3mL mixing, are heated to 85 DEG C, solid is completely dissolved.Acquired solution is transferred in room temperature environment, and hexamethylene 18mL is slowly added dropwise thereto, and drop, which finishes, solid precipitation, continues to be stirred at room temperature 6 hours；Filtering, obtained solid are dried in vacuo 12 hours at 50 DEG C, obtain 10 product of crystal form, 0.2g.

Embodiment 26

Compound (1) 0.4g and dioxane 4mL mixing, are heated to flowing back, and solid all dissolves.Acquired solution is transferred in room temperature environment, and normal heptane 20mL is slowly added dropwise thereto, there is solid precipitation, continues to be stirred at room temperature 6 hours；Filtering, obtained solid are dried in vacuo 12 hours at 50 DEG C, obtain 10 product 0.3g of crystal form.

Normal heptane is substituted with isopropyl acetate, methyl tertiary butyl ether(MTBE), n-hexane or hexamethylene, it is same to operate, also obtain 10 product of crystal form.

Embodiment 27

Compound (1) 0.3g and dioxane 5mL mixing, 50 DEG C -60 DEG C are heated to solid and all dissolve.Stop heating, solution is stirred be cooled to room temperature in air, stirring and crystallizing 6 hours；Filtering, obtained solid are dried in vacuo 12 hours at 50 DEG C, obtain 10 product 0.2g of crystal form.

28 stability test of embodiment

Method: sample sets monolayer polyethylene bag (PE bags) tying, then sets in aluminium foil bag and seal；The environment for being placed in 60 DEG C of relative humidity 75% is placed 3 months, respectively the 0th day and the 91st day sample detection.

As a result: HPLC (high performance liquid chromatography) test sample purity, discovery purity, impurity content are unchanged, and discovery crystal form variation is as follows:

The crystal form of compound (1)	0 day	91st day
Crystal form 1	Crystal form 1	Crystal form 1
Crystal form 3	Crystal form 3	Crystal form 1
Crystal form 4	Crystal form 4	Crystal form 1
Crystal form 5	Crystal form 5	Crystal form 5
Crystal form 6	Crystal form 6	Crystal form 6
Crystal form 7	Crystal form 7	Crystal form 7
Crystal form 8	Crystal form 8	Crystal form 1
Crystal form 9	Crystal form 9	Crystal form 9
Crystal form 10	Crystal form 10	Crystal form 10
Mono-sodium salt crystal form A	Mono-sodium salt crystal form A	Mono-sodium salt crystal form A

It can be seen that according to testing result, crystal form 1, crystal form 5, crystal form 6, crystal form 7, crystal form 9, crystal form 10 and mono-sodium salt crystal form A are in test-strips Crystal form is unchanged under part, relatively stable；And there is crystal transfer in crystal form 3, crystal form 4, crystal form 8, become crystal form 1.

Method of the invention is described by preferred embodiment, and related personnel obviously can within that content, spirit and scope of the present invention be modified or appropriate changes and combinations method described herein and application, carrys out implementation and application the technology of the present invention.Those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications are apparent to those skilled in the art, they are considered as being included in the present invention.

Claims (30)

1. A kind of crystal form of 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid, the crystal form are crystal form 1, crystal form 3, crystal form 4, crystal form 5, crystal form 6, crystal form 7, crystal form 8, crystal form 9 or crystal form 10；Wherein, there is diffraction maximum in the position that 2 θ are 10.36,13.89,17.50,24.17 degree in the X-ray powder diffraction figure of crystal form 1；There is diffraction maximum in the position that 2 θ are 10.41,13.13,13.89,15.27,16.58,20.06,24.17 degree in the X-ray powder diffraction figure of crystal form 3；There is diffraction maximum in the position that 2 θ are 9.79,13.20,13.85,15.94,17.46,20.32,23.06,28.68 degree in the X-ray powder diffraction figure of crystal form 4；There is diffraction maximum in the position that 2 θ are 8.77,17.55,19.82,23.74,27.33,35.48 degree in the X-ray powder diffraction figure of crystal form 5；There is diffraction maximum in the position that 2 θ are 13.84,14.52,16.01,18.41,18.82,21.30,22.00,24.37,25.36 degree in the X-ray powder diffraction figure of crystal form 6；There is diffraction maximum in the position that 2 θ are 10.30,13.83,14.87,16.06,18.06,19.76,21.03,23.02,24.18,25 .25 degree in the X-ray powder diffraction figure of crystal form 7；There is diffraction maximum in the position that 2 θ are 10.26,13.83,14.31,19.08,19.46,20.14,21.91,23.87,24.19,29 .10 degree in the X-ray powder diffraction figure of crystal form 8；There is diffraction maximum in the position that 2 θ are 9.97,12.66,15.56,16.54,17.69,18.31,21.80,25.14,25.67 degree in the X-ray powder diffraction figure of crystal form 9；There is diffraction maximum in the position that 2 θ are 10.38,13.44,13.95,16.31,17.62,20.48,22.50,22.86,24.26 degree in the X-ray powder diffraction figure of crystal form 10.
2. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 12 θ be 10.36,13.89,17.51,19.41,22.46,24.17 degree of position have in diffraction maximum or the X-ray powder diffraction figure of crystal form 12 θ be 7.48,10.36,13.89,17.51,19.41,20.62,22.46, there is diffraction maximum in 24.17,28.96,29.39 degree of position, or in the X-ray powder diffraction figure of crystal form 12 θ be 10.38,13.92,17.54,19.48,20.65, there is diffraction maximum in 22.51,24.20,28.15 degree of position；Or in the X-ray powder diffraction figure of crystal form 12 θ be 7.48,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17,26.51,28.96,29.39,33.79,34.85 degree of position have in diffraction maximum or the X-ray powder diffraction figure of crystal form 12 θ be 7.48,8.30,10.36,13.89,14.94,16.51,17.51,19.41,20.62,22.46,24.17,25.81,26.51,28.96,29.39,31.29,32.4, there is diffraction maximum in 33.79,34.85 degree of position, or brilliant In the X-ray powder diffraction figure of type 12 θ be 7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,19.41,20.62,21.73,22.46,24.17,25.36,25.81,26.51, there is diffraction maximum in 28.96,29.39,31.29,32.4,33.79,34.85 degree of position, or in the X-ray powder diffraction figure of crystal form 12 θ be 7.48,8.30,10.36,12.42,13.89,14.94,15.29,16.17,16.51,17.51,18.58,1 9.41,20.62,21.73,22.46,23.76,24.17,25.36,25.81,26.51,28.96,29.39,30.19,31.29,32.0,32.4,33.79,34.85 degree of position has diffraction maximum or the X-ray powder diffraction figure of crystal form 1 as shown in Figure 1 or 2.
3. Crystal form described in claim 1, wherein the differential scanning calorimetric curve of crystal form 1 has endothermic peak at 209 DEG C -213 DEG C.
4. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 32 θ be 10.41,13.13,13.89,15.27,16.58,17.57,19.16,20.06, there is diffraction maximum in 20.80,22.31,24.17 degree of position, or in the X-ray powder diffraction figure of crystal form 32 θ be 9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31, there is diffraction maximum in 22.31,23.73,24.17 degree of position, or in the X-ray powder diffraction figure of crystal form 32 θ be 9.54,10.41,10.8 There are diffraction maximum or crystal form 3 in 8,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,24.17,27.56,28.34,29.41,31.35 degree of position X-ray powder diffraction figure in 2 θ be 6.89,7.54,9.54,10.41,10.88,13.13,13.89,15.27,16.58,17.57,19.16,20.06,20.80,21.31,22.31,23.05,23.73,24.17,26.32,27.56,28.34,29.41,31.35,32.97 degree of position has diffraction maximum or the X-ray powder diffraction figure of crystal form 3 as shown in Figure 4.
5. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 42 θ be 9.79,11.35,13.20,13.85,15.94,17.46,19.81,20.32,20.72,21.66, there is diffraction maximum in 22.70,23.06,25.56,28.68 degree of position, or in the X-ray powder diffraction figure of crystal form 42 θ be 9.79,11.35,13.20,13.85,15.94,16.47,17.07,17.46,19.81,20.32,20.72,21.66,22.70,23.06,24.03,25.56,27.91,28.68,29.64,3 2.44 degree of position have in diffraction maximum or the X-ray powder diffraction figure of crystal form 42 θ be 8.00,9.79,11.35,12.05,13.20,13.85,15.94,16.47,17.07,17.46,18.79,19.81,20.32,20.72,21.66,22.12,22.70,23.06,24.03,24.50,25.56,27.91,28.68,29.64,32.44,35.22 degree of position has diffraction maximum or the X-ray powder diffraction figure of crystal form 4 as shown in Figure 5.
6. Crystal form described in claim 1, wherein the differential scanning calorimetric curve of crystal form 4 has endothermic peak at 203 DEG C -210 DEG C.
7. Crystal form described in claim 1, wherein have diffraction maximum in the position that 2 θ are 8.77,11.09,12.48,15.38,16.16,17.55,18.89,19.82,20.97,22.22,23.74,27.33,28.88,35.48 degree in the X-ray powder diffraction figure of crystal form 5.
8. A method of preparing any crystal form 1 of claim 1-3, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is mixed with the first solvent, it is stirred in certain temperature, then separates solid, obtain crystal form 1；First solvent is methyl tertiary butyl ether(MTBE), hexamethylene, normal heptane, isopropyl ether or tetrahydrofuran；Or first solvent is the mixed solvent of methanol with methyl tertiary butyl ether(MTBE), hexamethylene, isopropyl acetate or normal heptane；Or first solvent is the mixed solvent of tetrahydrofuran and n-hexane or hexamethylene；The temperature is reflux temperature of the room temperature to solvent；Or

   A method of preparing any crystal form 1 of claim 1-3, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is mixed with the second solvent, heating makes it completely dissolved, then -10 DEG C of arbitrary temps for arriving room temperature are cooled to, crystallization, solid is separated, crystal form 1 is obtained；Second solvent be glycol dimethyl ether, methanol, ethyl alcohol, isopropanol, acetonitrile, acetone, water, toluene, or combinations thereof；Or

   A method of preparing any crystal form 1 of claim 1-3, include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is dissolved in glycol dimethyl ether, is then mixed with the first poor solvent, stirring and crystallizing, solid is separated, crystal form 1 is obtained；First poor solvent is normal heptane or isopropyl acetate.
9. A method of preparing the crystal form 3 of claim 1 or 4, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is dissolved in glycol dimethyl ether, then methyl tertiary butyl ether(MTBE) is added, stirring -6 hours 3 hours, separate solid, solvent is removed, crystal form 3 is obtained.
10. A method of preparing claim 1 or 5 or 6 crystal forms 4, comprising: compound (1) heating is dissolved in 2- methyltetrahydrofuran, and n-hexane, hexamethylene, normal heptane or combinations thereof solvent are then added dropwise at room temperature, solid is precipitated, stirring and crystallizing -8 hours 0.5 hour, separate solid Solvent is removed, 4 product of crystal form is obtained.
11. A method of preparing the crystal form 5 of claim 1 or 7, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid at 40 DEG C -60 DEG C is dissolved in glycol dimethyl ether, then 30 DEG C -60 DEG C of temperature control, hexamethylene is added, it finishes, mixed liquor stirs -6 hours 4 hours at 10 DEG C -40 DEG C, separates solid, obtained solid removes solvent, obtains crystal form 5.
12. The crystal form of 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid mono-sodium salt in 2 θ is 10.15,13.04,15.42 in X-ray powder diffraction figure, 16.88,20.07,21.86,24.62, there is diffraction maximum in 26.69,31.11,34.47 degree of position.
13. Crystal form described in claim 12 in 2 θ is 10.15,12.19,13.04,15.42,15.64 in X-ray powder diffraction figure, 16.88,18.67,19.23,20.07,21.86,22.93,23.57,24.62,25.81,26.69,27.13,28.72,29.23,31.11,34.47 degree of position have in diffraction maximum or its X-ray powder diffraction figure 2 θ be 7.10,10.15,12.19,13.04,15.42,15.64,16.88,18.67,19.23,20.07,20.91,21.43,21.86,22.52,22 .93,23.57,24.62,25.81,26.69,27.13,28.72,29.23,29.59,31.11,31.69,32.97,34.47 degree of position have in diffraction maximum or its X-ray powder diffraction figure 2 θ be 5.15,7.10 10.15,12.19,13.04,14.24,15.42,15.64,16.88 18.25,18.67,19.23,20.07,20.55,20.91,21.43,21.86,22.52,22.93,23.57,24.62,25.81,26.69,27.13,27.63,28.72,29 .23,29.59,31.11,31.69,32.00,32.41,32.97,34.47,39.05 degree of position has diffraction maximum or its X-ray powder diffraction figure as shown in Figure 8.
14. The crystal form of 2- described in claim 12 [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid mono-sodium salt, its differential scanning calorimetric curve has endothermic peak at 110 DEG C -120 DEG C, endothermic peak summit value is 120 DEG C, there is endothermic peak at 175 DEG C -190 DEG C, endothermic peak summit value is 186 DEG C.
15. A method of preparing any crystal form of claim 12-14, it include: that the mono-sodium salt of 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is mixed with solvent, stirring -5 hours 3 hours, separate solid, obtained solid removes residual solvent, obtains crystal；The solvent is methyl tertiary butyl ether(MTBE), thiacyclohexane, normal hexane or isopropyl acetate.
16. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 62 θ be 10.30,10.57,13.84,14.52,16.01,17.08,17.45,18.41,18.82,19.76,20.12,21.30,22.00,23.49,24.37, there is diffraction maximum in 25.36,32.49,39.23 degree of position；Or the X-ray powder diffraction figure of crystal form 6 is as shown in Figure 10.
17. Crystal form described in claim 1, wherein the differential scanning calorimetric curve of crystal form 6 at 135 DEG C -145 DEG C at endothermic peak and 215 DEG C -219 DEG C have endothermic peak.
18. A method of preparing claim 1,16 or 17 crystal forms 6, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is mixed with glacial acetic acid, it is heated to reflux, then water is added into gained mixed liquor, mixed liquor solid precipitation, insulated and stirred have been cooled to；Then mixed liquor is cooled to room temperature, insulated and stirred；Separation solid simultaneously removes solvent, obtains 6 product of crystal form.
19. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 72 θ be 8.25,10.30,13.83,14.87,16.06,16.97,18.06,19.76,20.31,20.67,21.03, there is diffraction maximum in 23.02,24.18,25.25,28.43,29.06,31.66 degree of position；Or the X-ray powder diffraction figure of crystal form 7 is as shown in figure 13.
20. Crystal form described in claim 1, wherein the differential scanning calorimetric curve of crystal form 7 has endothermic peak at 215 DEG C -219 DEG C.
21. A method of preparing crystal form 7 described in claim 1,19 or 20, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is mixed with glacial acetic acid, it is heated to reflux, then water is added into gained mixed liquor, it is cooled to room temperature or 0 DEG C -5 DEG C, insulated and stirred；Separation solid simultaneously removes solvent, obtains 7 product of crystal form.
22. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 82 θ be 7.52,10.26,13.83,14.31,15.01,16.06,16.91,17.48,18.61,19.08,19.46, there is diffraction maximum in 20.14,21.91,22.49,23.87,24.19,29.10 degree of position；Or the X-ray powder diffraction figure of crystal form 8 is as shown in figure 16.
23. Crystal form described in claim 1, wherein the differential scanning calorimetric curve of crystal form 8 has endothermic peak at 207 DEG C -212 DEG C.
24. A method of preparing crystal form 8 described in claim 1,22 or 23, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is dissolved in chloroform, then or mixtures thereof normal heptane or hexamethylene is added, solid is precipitated, stirring and crystallizing, then solid is separated, solvent is removed, obtains 8 product of crystal form.
25. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 92 θ be 9.97,12.66,14.92,15.56,16.54,17.69,18.31,19.19,20.77,21.80, there is diffraction maximum in 22.84,25.14,25.67,27.36,30.12 degree of position；Or in the X-ray powder diffraction figure of crystal form 92 θ be 6.79,9.97,12.66,13.54,14.92,15.56,16.54,17.32,17.69,18.31,19.19,19.79,20.77,21.80,22.84,24.27,25.14,25.67,26.23,27.36,27.94,28.60,29.61,30.12 there is diffraction maximum in the position of degree；Or the X-ray powder diffraction figure of crystal form 9 is as shown in figure 19.
26. Crystal form described in claim 1, wherein the differential scanning calorimetric curve of crystal form 9 has endothermic peak at 155 DEG C -170 DEG C.
27. A method of preparing crystal form 9 described in claim 1,25 or 26, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is dissolved in N, in dinethylformamide, methyl tertiary butyl ether(MTBE) to solid is added to be precipitated, it is cooled to -5 DEG C of -5 DEG C of stirring and crystallizings, then solid is separated, solvent is removed, obtains 9 product of crystal form.
28. Crystal form described in claim 1, wherein in the X-ray powder diffraction figure of crystal form 10 2 θ be 9.90,10.38,13.44,13.95,16.02,16.31,16.58,16.96,17.62,20.48, there is diffraction maximum in 22.50,22.86,24.26,25.79,32.20 degree of position；Or in the X-ray powder diffraction figure of crystal form 10 2 θ be 7.49,8.22,9.90,10.38,11.17,13.44,13.95,15.06,16.02,16.31,16.58,16.96,17.62,19.78,20.48,22.50,22.86,24.26,25.79,32.20 there is diffraction maximum in the position of degree；Or the X-ray powder diffraction figure of crystal form 10 is as shown in figure 22.
29. Crystal form described in claim 1, wherein the differential scanning calorimetric curve of crystal form 10 has endothermic peak at 209 DEG C -212 DEG C.
30. A method of preparing crystal form 10 described in claim 1,28 or 29, it include: that 2- [[3- (4- cyano naphthalene -1- base) pyridin-4-yl] is thio] -2 Methylpropionic acid is mixed with tetrahydrofuran, isopropanol, dioxane or combinations thereof solvent, heating, form solution, methyl tertiary butyl ether(MTBE), hexamethylene, n-hexane, normal heptane, isopropyl acetate or its mixed solvent is added into solution at room temperature to there is solid precipitation, it is stirred at room temperature -12 hours 0.1 hour, then solid is separated, solvent is removed, 10 product of crystal form is obtained.