CN108727417B

CN108727417B - Polycyclic compound sodium salt, and polycrystalline type, preparation method and application thereof

Info

Publication number: CN108727417B
Application number: CN201810449053.XA
Authority: CN
Inventors: 詹正云
Original assignee: AB Pharma Ltd
Current assignee: AB Pharma Ltd
Priority date: 2015-02-05
Filing date: 2016-02-05
Publication date: 2021-10-08
Anticipated expiration: 2036-02-05
Also published as: CN105859748A; CN105859748B; CN108727417A

Abstract

The invention disclosesA polycyclic compound sodium salt, a polymorphism thereof, a preparation method and application. The sodium salt of the polycyclic compound is crystal form G shown as formula II, has good stability and absorption, is easy to be crushed into powder with large surface area after being dried, and is easy to prepare and use the pharmaceutical composition.

Description

Polycyclic compound sodium salt, and polycrystalline type, preparation method and application thereof

The patent application is a divisional application of patent application with application number 2016100818508, the application date of the patent application is 2016, 2 and 5, and the patent application is named as polycyclic compound sodium salt and polymorphic form thereof, a preparation method and application thereof.

Technical Field

The invention relates to a polycyclic compound sodium salt, a polycrystalline type, a preparation method and application thereof.

Background

The polymorphism of a chemical drug refers to a chemical drug which can exist in more than one crystal form, and the bonding mode in the molecule or between molecules is changed due to the influence of various factors during crystallization, so that the molecules or atoms are arranged in different lattice spaces to form different crystal form structures. The same chemical drug has the same molecular structure but different crystal forms, and the crystals of different crystal forms may have significant differences in appearance, filterability, density, fluidity, solubility, dissolution rate, melting point (or initial melting temperature), etc., thereby affecting the stability, dissolution rate, bioavailability and therapeutic effect of the drug.

The phenomenon is particularly obvious in the aspect of oral solid preparations, and the polymorphism of chemical drugs is one of important factors influencing the quality and clinical curative effect of the drugs. Some polymorphic forms of chemical drugs are difficult to formulate due to shape or hygroscopicity. Therefore, the manufacturing process ensuring pharmaceutical active ingredients capable of producing single crystals with consistent purity levels is an important issue in pharmaceutical research. If a process for the manufacture of a pharmaceutical active ingredient produces polymorphs having varying degrees of polymorphic purity, or if the process does not control the interconversion between polymorphs, serious problems with dissolution and/or bioavailability of the pharmaceutical composition containing the active ingredient may result.

In the late stage of the last eighties, the solubility and bioavailability of the imitation drugs are poorer than those of original drugs due to different crystal forms of the imitation drugs, so that the American FDA has strict requirements on the forms, shapes, particle size distribution and the like of active ingredients of the drugs after accidents are caused by no curative effect.

(1S,4R,6S,14S,18R) -6, 8-dihydro- [1,3]-dioxolo [4,5-e]Isoindole-7-carboxylic acid-14-tert-butoxyamido-4-cyclopropylsulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0^4,6]Nineteen-carbon-7-en-18-yl ester with the molecular formula C₃₆H₄₇N₅O₁₁S has a molecular weight of 757.862 and a chemical structure shown in formula I (hereinafter referred to as compound of formula 1), and can be used for inhibiting hepatitis C virus protease and effectively treating hepatitis C virus infection. The synthesis method and the pharmaceutical activity of the compound of the formula I can be specifically referred to PCT patent application with publication number WO2011/091757(A1), US patent of US2011/0183895(A1) and Chinese patent application of CN 102140100A.

However, the physical and chemical properties of the compound of formula I, such as stability and solubility, are poor, and thus have a certain limitation in practical application.

Disclosure of Invention

The invention provides a polycyclic compound sodium salt, a polymorphism thereof, a preparation method and application, aiming at overcoming the defects that the compound of the formula I has poor stability and solubility and is not beneficial to practical application. The polycyclic compound sodium salt has the advantages of high polymorphic crystal purity, good stability and good solubility, and is easy for medicine dispersion, combination, configuration and use. The preparation method has the advantages of simple process, mild conditions and stable yield.

The invention solves the technical problems through the following technical scheme.

The invention provides a compound of formula II, which is a polycyclic compound sodium salt; wherein n is less than or equal to 5;

the chemical name of the compound of formula II and its anhydride is (1S,4R,6S,14S,18R) -6, 8-dihydro- [1,3]-dioxolo [4,5-e]Isoindole-7-carboxylic acid-14-tert-butoxyamido-4-cyclopropylsulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.04,6]Nonadeca-7-en-18-yl ester sodium salt with molecular formula C₃₆H₄₆N₅NaO₁₁S, molecular weight 779.84.

The invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps: mixing the compound of formula I with ethanol to obtain a mixture; and adding an ethanol solution of sodium ethoxide into the mixture under the stirring state, reacting, and concentrating to dryness to obtain the sodium ethoxide-containing water-soluble organic silicon dioxide.

Wherein, in the mixture, the proportion of the compound of the formula I and the ethanol is preferably (0.8-1.2) g, (4-6) mL; more preferably 1 g:5 mL.

The molar ratio of the sodium ethoxide to the compound of formula I is preferably 1.08:1 to 1.02:1, and more preferably 1.05: 1. In the ethanol solution of sodium ethoxide, the amount of ethanol can be the amount which is conventional in the field, so that the sodium ethoxide is at least completely dissolved. In the ethanol solution of sodium ethoxide, the dosage of the sodium ethoxide and the ethanol is preferably (0.9-1) g:50mL, and more preferably 0.942g:50 mL.

Wherein the reaction methods and conditions are conventional in the art. The reaction temperature is preferably 0 to 5 ℃. The reaction is generally carried out by an ice-water bath method. The end point of the reaction is based on the complete reaction, and the reaction is generally carried out until the reaction liquid is clear.

In the present invention, the crystal form of the compound of formula II may be an anhydrate crystal form of the compound of formula II, or a hydrate crystal form of the compound of formula II. The X-ray powder diffraction (XRPD) pattern of each crystalline form was taken using a penumbra X-ray powder diffraction analyzer from parnacco, the netherlands, at a wavelength of 1.54 angstroms, measured with the ka line of the Cu target, with 2 theta values ranging from 0 degrees to 40 degrees, with a reproducible range of 2 theta + -0.50 deg. (preferably 2 theta + -0.20 deg.). Differential Scanning Calorimetry (DSC) and Modulated Differential Scanning Calorimetry (MDSC) were collected on an us TA instruments Q200 differential scanning calorimeter with nitrogen blanket. Thermogravimetric analysis (TGA) was collected on a us TA instruments Q500 thermogravimetric analyzer with nitrogen blanket. Infrared Spectroscopy (IR) data acquisition was carried out by the Scimitar FTS2000, Varian corporation, USA, using potassium bromide tablet method at wave number 400cm^-1～4000cm^-1Scan interval 4cm^-1Scan time 32 s. Single crystal X-ray diffraction was collected on a Bruker APEX-II CCD, Bruker, Germany, and measured under the Ka line of the Mo target, resolved using 'SHELXS-97 (Shell drick, 2008)'.

The invention also provides an amorphous substance of the compound shown in the formula II, wherein the amorphous substance has no characteristic peak in a 2 theta spectrum of an X-ray powder diffraction spectrum; the amorphous material has an infrared spectrum of 3446cm^-1、2976cm^-1、2930cm^-1、2868cm^-1、1706cm^-1、1560cm^-1、1526cm^-1、1471cm^-1、1429cm^-1、1367cm^-1、1330cm^-1、1308cm^-1、1246cm^-1、1186cm^-1、1167cm^-1、1114cm^-1、1049cm^-1、1013cm^-1、972cm^-1、919cm^-1、891cm^-1、855cm^-1、797cm^-1、767cm^-1、699cm^-1And 580cm^-1The wavelength has an absorption peak.

The invention also provides crystal forms of the compound shown in the formula II, wherein the crystal forms of the compound shown in the formula II comprise a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form E, a crystal form G, a crystal form H, a crystal form I, a crystal form J or a crystal form K.

The 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form A has characteristic peaks at 3.70 +/-0.50 degrees, 7.48 +/-0.50 degrees, 11.36 +/-0.50 degrees, 19.87 +/-0.50 degrees and 25.60 +/-0.50 degrees, and the X-ray powder diffraction uses a Ka spectral line of a Cu target.

Wherein, the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form A preferably has characteristic peaks at 3.70 +/-0.20 degrees, 7.48 +/-0.20 degrees, 11.36 +/-0.20 degrees, 19.87 +/-0.20 degrees and 25.60 +/-0.20 degrees, and the X-ray powder diffraction uses the Ka spectral line of a Cu target.

Characteristic peaks are found at 4.4 +/-0.50 degrees, 5.32 +/-0.50 degrees, 6.38 +/-0.50 degrees, 8.69 +/-0.50 degrees, 13.31 +/-0.50 degrees, 14.45 +/-0.50 degrees, 15.52 +/-0.50 degrees, 17.57 +/-0.50 degrees and 21.11 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form B, and the X-ray powder diffraction uses a Kalpha spectrum line of a Cu target.

Wherein, in the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form B, the crystal form B preferably has characteristic peaks at 4.4 +/-0.20 degrees, 5.32 +/-0.20 degrees, 6.38 +/-0.20 degrees, 8.69 +/-0.20 degrees, 13.31 +/-0.20 degrees, 14.45 +/-0.20 degrees, 15.52 +/-0.20 degrees, 17.57 +/-0.20 degrees and 21.11 +/-0.20 degrees, and the X-ray powder diffraction uses the K alpha spectrum line of a Cu target.

Characteristic peaks are found at 3.22 +/-0.50 degrees, 6.26 +/-0.50 degrees, 14.61 +/-0.50 degrees, 15.624 +/-0.50 degrees, 18.82 +/-0.50 degrees and 20.17 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form C, and the X-ray powder diffraction uses a Ka spectral line of a Cu target.

Wherein, the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form C preferably has characteristic peaks at 3.22 +/-0.20 degrees, 6.26 +/-0.20 degrees, 14.61 +/-0.20 degrees, 15.624 +/-0.20 degrees, 18.82 +/-0.20 degrees and 20.17 +/-0.20 degrees, and the X-ray powder diffraction uses the Ka spectral line of a Cu target.

Characteristic peaks are found at 2.02 + -0.50 degrees, 4.769 + -0.50 degrees, 5.677 + -0.50 degrees, 8.41 + -0.50 degrees, 11.04 + -0.50 degrees, 16.57 + -0.50 degrees, 18.25 + -0.50 degrees, 19.36 + -0.50 degrees and 22.61 + -0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form D, and the X-ray powder diffraction uses a K alpha spectrum line of a Cu target.

Wherein, in the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form D, the crystal form D preferably has characteristic peaks at 2.02 +/-0.20 degrees, 4.769 +/-0.20 degrees, 5.677 +/-0.20 degrees, 8.41 +/-0.20 degrees, 11.04 +/-0.20 degrees, 16.57 +/-0.20 degrees, 18.25 +/-0.20 degrees, 19.36 +/-0.20 degrees and 22.61 +/-0.20 degrees, and the X-ray powder diffraction uses the Ka spectral line of a Cu target.

Characteristic peaks are found at 7.12 +/-0.50 degrees, 13.92 +/-0.50 degrees, 14.64 +/-0.50 degrees, 16.47 +/-0.50 degrees, 18.86 +/-0.50 degrees, 19.86 +/-0.50 degrees, 20.78 +/-0.50 degrees, 22.58 +/-0.50 degrees and 29.58 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form E, and the X-ray powder diffraction uses a K alpha spectral line of a Cu target.

Wherein, in the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form E, the crystal form E preferably has characteristic peaks at 7.12 +/-0.20 degrees, 13.92 +/-0.20 degrees, 14.64 +/-0.20 degrees, 16.47 +/-0.20 degrees, 18.86 +/-0.20 degrees, 19.86 +/-0.20 degrees, 20.78 +/-0.20 degrees, 22.58 +/-0.20 degrees and 29.58 +/-0.20 degrees, and the X-ray powder diffraction uses the K alpha line of a Cu target.

In the invention, the crystal form G is a monohydrate crystal form of the compound shown in the formula II. Characteristic peaks exist at 7.59 +/-0.50 degrees, 8.78 +/-0.50 degrees, 13.33 +/-0.50 degrees, 15.06 +/-0.50 degrees, 16.31 +/-0.50 degrees, 18.80 +/-0.50 degrees, 20.28 +/-0.50 degrees, 22.35 +/-0.50 degrees and 23.60 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form G, and the X-ray powder diffraction uses a K alpha spectral line of a Cu target; the infrared spectrum of the crystal form G is 3676cm^-1、3429cm^-1、3054cm^-1、2924cm^-1、2867cm^-1、2206cm^-1、1699cm^-1、1641cm^-1、1569cm^-1、1504cm^-1、1472cm^-1、1424cm^-1、1378cm^-1、1330cm^-1、1308cm^-1、1236cm^-1、1168cm^-1、1104cm^-1、1049cm^-1、970cm^-1、918cm^-1、894cm^-1、825cm^-1、767cm^-1、691cm^-1、582cm^-1、521cm^-1And 464cm^-1The wavelength has an absorption peak; in the crystal form G, n is 1.

Wherein, in the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form G, the crystal form G preferably has characteristic peaks at 7.59 +/-0.20 degrees, 8.78 +/-0.20 degrees, 13.33 +/-0.20 degrees, 15.06 +/-0.20 degrees, 16.31 +/-0.20 degrees, 18.80 +/-0.20 degrees, 20.28 +/-0.20 degrees, 22.35 +/-0.20 degrees and 23.60 +/-0.20 degrees, and the X-ray powder diffraction uses the K alpha spectrum line of a Cu target.

Characteristic peaks are found at 4.32 +/-0.50 degrees, 5.34 +/-0.50 degrees, 5.96 +/-0.50 degrees, 9.31 +/-0.50 degrees, 13.24 +/-0.50 degrees, 14.65 +/-0.50 degrees, 16.14 +/-0.50 degrees, 18.09 +/-0.50 degrees and 20.55 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form H, and the X-ray powder diffraction uses a Kalpha spectrum line of a Cu target.

Wherein, in the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form H, the crystal form H preferably has characteristic peaks at 4.32 +/-0.20 degrees, 5.34 +/-0.20 degrees, 5.96 +/-0.20 degrees, 9.31 +/-0.20 degrees, 13.24 +/-0.20 degrees, 14.65 +/-0.20 degrees, 16.14 +/-0.20 degrees, 18.09 +/-0.20 degrees and 20.55 +/-0.20 degrees, and the X-ray powder diffraction uses the K alpha spectrum line of a Cu target.

Characteristic peaks are found at 7.00 +/-0.50 degrees, 7.40 +/-0.50 degrees, 7.93 +/-0.50 degrees, 14.09 +/-0.50 degrees, 14.76 +/-0.50 degrees, 18.89 +/-0.50 degrees, 19.94 +/-0.50 degrees, 20.78 +/-0.50 degrees and 22.35 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form I, and the X-ray powder diffraction uses a Kalpha spectral line of a Cu target.

Wherein, in the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form I, the crystal form I preferably has characteristic peaks at 7.00 +/-0.20 degrees, 7.40 +/-0.20 degrees, 7.93 +/-0.20 degrees, 14.09 +/-0.20 degrees, 14.76 +/-0.20 degrees, 18.89 +/-0.20 degrees, 19.94 +/-0.20 degrees, 20.78 +/-0.20 degrees and 22.35 +/-0.20 degrees, and the X-ray powder diffraction uses the K alpha spectral line of a Cu target.

In the invention, the crystal form J is a hydrate crystal form of the compound shown in the formula II. Characteristic peaks exist at 5.97 +/-0.50 degrees, 6.52 +/-0.50 degrees, 9.42 +/-0.50 degrees, 11.03 +/-0.50 degrees, 11.63 +/-0.50 degrees, 15.59 +/-0.50 degrees, 16.61 +/-0.50 degrees, 19.91 +/-0.50 degrees and 22.46 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form J, and the X-ray powder diffraction uses a Ka spectral line of a Cu target; in the crystal form J, n is 1-5.

Wherein, in the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form J, the crystal form J preferably has characteristic peaks at 5.97 +/-0.20 degrees, 6.52 +/-0.20 degrees, 9.42 +/-0.20 degrees, 11.03 +/-0.20 degrees, 11.63 +/-0.20 degrees, 15.59 +/-0.20 degrees, 16.61 +/-0.20 degrees, 19.91 +/-0.20 degrees and 22.46 +/-0.20 degrees, and the X-ray powder diffraction uses the K alpha spectrum line of a Cu target.

Preferably, the crystal form J is a single crystal, and the unit cell parameters of the single crystal of the crystal form J are as follows:

α＝90°；

β＝90°；

γ is 90 °; the single crystal of form J has a unit cell volume of

The unit cell parameters and the unit cell volume of the single crystal of the crystal form J are determined by the measuring wavelength

Single crystal X-ray diffraction analysis of (a). In an XRPD spectrum obtained by single crystal diffraction simulation of the crystal form J, characteristic peaks exist at 5.91 +/-0.50 degrees, 6.01 +/-0.50 degrees, 6.51 +/-0.50 degrees, 8.94 +/-0.50 degrees, 9.44 +/-0.50 degrees, 11.66 +/-0.50 degrees, 15.70 +/-0.50 degrees, 21.04 +/-0.50 degrees and 21.75 +/-0.50 degrees, and the characteristic peaks are matched with a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form J.

Characteristic peaks exist at 6.475 +/-0.50 degrees, 9.575 +/-0.50 degrees, 10.81 +/-0.50 degrees, 11.743 +/-0.50 degrees, 15.446 +/-0.50 degrees and 20.714 +/-0.50 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form K, and the X-ray powder diffraction uses a Ka spectral line of a Cu target; the infrared spectrum of the crystal form G is 3447cm^-1、2976cm^-1、2930cm^-1、2869cm^-1、1773cm^-1、1700cm^-1、1654cm^-1、1636cm^-1、1560cm^-1、1525cm^-1、1471cm^-1、1430cm^-1、1367cm^-1、1329cm^-1、1308cm^-1、1246cm^-1、1187cm^-1、1167cm^-1、1116cm^-1、1049cm^-1、1013cm^-1、972cm^-1、919cm^-1、890cm^-1、843cm^-1、798cm^-1、766cm^-1、722cm^-1、700cm^-1And 581cm^-1The wavelength has an absorption peak.

Wherein, the 2 theta spectrum of the X-ray powder diffraction spectrum of the crystal form K preferably has characteristic peaks at 6.475 +/-0.20 degrees, 9.575 +/-0.20 degrees, 10.81 +/-0.20 degrees, 11.743 +/-0.20 degrees, 15.446 +/-0.20 degrees and 20.714 +/-0.20 degrees, and the X-ray powder diffraction uses the Ka line of a Cu target.

The inventors of the present invention have found through extensive studies that organic solvents that can be used to dissolve the compound of formula ii include one or more of the following due to the specific physical properties of the compound of formula ii: methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, toluene, and N, N-dimethylacetamide. Preferably, ethanol is selected to dissolve the compound of formula II.

The invention also provides a preparation method of the amorphous substance of the compound shown in the formula II, which comprises the following steps: mixing the compound of formula I with ethanol to obtain a mixture; adding an ethanol solution of alkali into the mixture under the stirring state, reacting, and concentrating to dryness to obtain the compound; wherein the alkali is sodium hydroxide and/or sodium ethoxide.

Wherein the molar ratio of the base to the compound of formula I is preferably 1.08:1 to 1.02:1, more preferably 1.05: 1. In the ethanol solution of the base, the amount of ethanol may be an amount conventionally used in the art, subject to at least complete dissolution of the base. In the ethanol solution of the alkali, the amount of the alkali and the ethanol is preferably (0.9-1) g:50mL, more preferably 0.942g:50 mL.

The invention also provides a preparation method of the amorphous substance of the compound shown in the formula II, which comprises the following steps: dissolving the compound of formula II in water, and drying to obtain the final product.

Wherein the amount of water is the amount conventionally used in the art, as long as the compound of formula II is dissolved away.

The drying method may be a method conventional in the art, as long as it can remove water and precipitate the compound of formula ii. The drying temperature is preferably 30 to 80 ℃, more preferably 55 ℃.

In the present invention, the amorphous form of the compound of formula II is obtained as a solid.

The invention also provides a preparation method of the crystal form of the compound shown in the formula II, which comprises the following steps:

the preparation method of the crystal form A comprises the following steps: dissolving a compound shown in a formula II in dichloromethane to obtain a mixed solution; adding ether into the mixed solution to form liquid phase layering; and collecting precipitated solid after the ether is diffused to the mixed solution, thus obtaining the product.

The volume-mass ratio of the dichloromethane to the compound of formula II is preferably 5-10 mL/g, more preferably 5 mL/g.

Wherein, according to the common knowledge in the field, the amount of the diethyl ether is more than that of the dichloromethane. The volume ratio of the diethyl ether and the dichloromethane is preferably 2 or more.

The invention also provides a preparation method of the crystal form B of the compound shown in the formula II, which comprises the following steps: dissolving a compound shown in a formula II in ethanol to obtain a mixed solution; adding ether into the mixed solution to form liquid phase layering; and collecting precipitated solid after the ether is diffused to the mixed solution, thus obtaining the product.

The volume-mass ratio of the ethanol to the compound of formula II is preferably 5-10 mL/g, more preferably 5 mL/g.

Wherein, according to the common knowledge in the field, the amount of the diethyl ether is more than the amount of the ethanol. The volume ratio of the ether to the ethanol is preferably 2 or more.

The preparation method I of the crystal form C comprises the following steps: dissolving a compound shown in a formula II in a mixed solvent of tetrahydrofuran and n-hexane at a temperature of 58-62 ℃ to obtain a mixed solution; cooling, and collecting precipitated solid.

Among them, the compound of formula II is preferably dissolved in a mixed solvent of tetrahydrofuran and n-hexane at 60 ℃.

Wherein, in the mixed solvent of the tetrahydrofuran and the normal hexane, the volume ratio of the tetrahydrofuran to the normal hexane is preferably 1: 1-1: 1.2. The volume mass ratio of the mixed solvent of tetrahydrofuran and n-hexane and the compound of formula II is preferably 5-10 mL/g, more preferably 6 mL/g.

Wherein, the method and condition for reducing the temperature can be the conventional method and condition in the field. The cooling rate is preferably 0.04-0.06 ℃/min. The target temperature of the temperature reduction is preferably 4 to 6 ℃, more preferably 5 ℃.

The preparation method II of the crystal form C comprises the following steps: dissolving a compound shown in a formula II in tetrahydrofuran to obtain a mixed solution; and diffusing the n-hexane into the mixed solution through gas diffusion, and collecting the precipitated solid to obtain the catalyst.

The volume-mass ratio of the tetrahydrofuran to the compound of formula II is preferably 5-10 mL/g, more preferably 6 mL/g.

Wherein, according to the common knowledge in the field, the amount of the normal hexane is more than that of the tetrahydrofuran. The volume ratio of the n-hexane to the tetrahydrofuran is preferably 5:1 to 10:1, and more preferably 5: 1.

The preparation method of the crystal form D comprises the following steps: dissolving a compound shown in a formula II in ethyl acetate to obtain a mixed solution; and diffusing the n-hexane into the mixed solution through gas diffusion, and collecting the precipitated solid to obtain the catalyst.

The volume-mass ratio of the ethyl acetate to the compound of formula II is preferably 5-10 mL/g, more preferably 6 mL/g.

Wherein, according to the common knowledge in the field, the amount of the normal hexane is more than the amount of the ethyl acetate. The volume ratio of the n-hexane to the ethyl acetate is preferably 5:1 to 10:1, and more preferably 5: 1.

The preparation method of the crystal form E comprises the following steps: dissolving a compound shown in a formula II in ethanol to obtain a mixed solution; and diffusing the n-hexane into the mixed solution through gas diffusion, and collecting the precipitated solid to obtain the catalyst.

The volume-mass ratio of the ethanol to the compound of formula II is preferably 5-10 mL/g, more preferably 6 mL/g.

Wherein, according to the common knowledge in the field, the dosage of the normal hexane is more than that of the ethanol. The volume ratio of the n-hexane to the ethanol is preferably 5:1 to 10:1, and more preferably 5: 1.

The preparation method of the crystal form G comprises the following steps: dissolving the compound shown in the formula II in ethanol, stirring for 1-8 hours at 20-70 ℃, carrying out suction filtration, and drying to obtain the compound.

Wherein the stirring is preferably carried out at 30 to 45 ℃. The stirring time is preferably 3 hours.

In the preparation method II of the crystal form G, the compound shown in the formula I is mixed with ethanol to obtain a mixture; and adding an ethanol solution of sodium hydroxide into the mixture under the stirring state, reacting until the mixture is clear, stirring for 1-8 hours at the temperature of 20-70 ℃, filtering, and drying to obtain the sodium hydroxide.

Wherein, in the mixture, the mass volume ratio of the compound of the formula I and the ethanol is preferably (0.8-1.2) g, (4-6) mL;

wherein the molar ratio of the sodium hydroxide to the compound of formula I is preferably 1.20:1 to 1.00: 1.

Wherein the dosage of the sodium hydroxide and the ethanol in the ethanol solution of the sodium hydroxide is (0.5-1) g:50 mL.

Wherein the reaction temperature is preferably 0-25 ℃.

Wherein, after the operation of reaction to clarification, the stirring is preferably carried out at 30 to 45 ℃. After the operation after the reaction to clarification, the stirring time is preferably 3 hours.

The preparation method of the crystal form G comprises the following steps: dissolving the compound shown in the formula II in a mixed solvent of ethanol and n-hexane, volatilizing the solvent at room temperature, and collecting precipitated solid to obtain the compound.

Wherein, in the mixed solvent of the ethanol and the n-hexane, the volume ratio of the ethanol to the n-hexane is preferably 1:1.

The volume mass ratio of the mixed solvent of ethanol and n-hexane to the compound of formula II is preferably 5-10 mL/g, more preferably 6 mL/g.

The preparation method of the crystal form H comprises the following steps: dissolving a compound shown in a formula II in ethanol to obtain a mixed solution; and dropwise adding the mixed solution into n-hexane under a stirring state, and collecting precipitated solids to obtain the catalyst.

The volume-mass ratio of the ethanol to the compound of formula II is preferably 5-8 mL/g, more preferably 6 mL/g.

Wherein, according to the common knowledge in the field, the dosage of the normal hexane is more than that of the ethanol. The volume ratio of the n-hexane to the ethanol is preferably 30:1 to 40:1, and more preferably 33: 1.

The method and conditions for the dropping may be those conventional in the art, among others. The dropping rate is preferably 0.1 mL/s.

A process for preparing form I, comprising the steps of: dissolving a compound shown in a formula II in ethanol to obtain a mixed solution; and (3) diffusing the ether into the mixed solution through gas diffusion, and collecting the precipitated solid to obtain the catalyst.

Wherein, according to the common knowledge in the field, the amount of the diethyl ether should be more than the amount of the ethanol. The volume ratio of the ethyl ether to the ethanol is preferably 5:1 to 10:1, more preferably 5: 1.

The preparation method of the crystal form J comprises the following steps: dissolving the compound shown in the formula II in a mixed system of ethyl acetate and water, stirring for 3-4 h at 0-30 ℃, crystallizing, and performing suction filtration to obtain the compound.

Wherein, according to the common knowledge in the field, the mixed system refers to a non-layered mixed solution, and the amount of the water is less than the maximum dissolving amount of the water in the ethyl acetate. The volume ratio of the water to the ethyl acetate is preferably 1:10 to 1: 40.

Wherein the stirring temperature is preferably 15 ℃.

The preparation method II of the crystal form J comprises the following steps: and placing the crystal form K in an environment with the humidity of more than or equal to 40% and the temperature of more than or equal to 30 ℃ for at least one day to obtain the crystal form J.

Wherein, the humidity is preferably 75%. The temperature is preferably 40 ℃. The time of said placing is preferably one week.

The preparation method of the crystal form J comprises the following steps: dissolving a compound shown in the formula II in a mixed system of ethyl acetate and water, and collecting and separating out solids after the solvent is volatilized at 10-30 ℃ to obtain the single crystal of the crystal form J.

The volume mass ratio of the ethyl acetate to the compound of the formula II is preferably 5-100 mL/g.

Wherein the amount of ethyl acetate may be an amount conventionally used in the art, as long as the compound of formula ii is completely dissolved. As is common in the art, the mixed system is referred to as a "non-stratified mixed solution" and the amount of water used should be less than the maximum amount of water dissolved in ethyl acetate. In the mixed system of ethyl acetate and water, the volume ratio of the water to the ethyl acetate is preferably 1:20 to 1: 100.

The preparation method of the crystal form K comprises the following steps: dissolving the compound shown in the formula II in a mixed system of ethyl acetate and water, stirring for 3-4 h at 15 ℃, filtering precipitates, and drying to obtain the compound.

Wherein, according to the common knowledge in the field, the mixed system means that the amount of the water used in the non-layered mixed solution is less than the maximum dissolving amount of the water in the ethyl acetate. The volume ratio of the water to the ethyl acetate is preferably 1:10 to 1: 40.

The drying method and conditions may be those conventional in the art, and preferably vacuum drying. The drying temperature is preferably 50 to 60 ℃.

Wherein, the solvent volatilization is the conventional meaning in the field, and means the solvent is free to volatilize.

In the present invention, the type of crystal form of the compound of formula II used in the above-described processes for preparing amorphous and polymorphic forms of the compound of formula II is not limited, according to common knowledge in the art. In the method for preparing the crystal form of the compound of formula II of the present invention, the compound of formula II as a starting material is preferably an amorphous form of the compound of formula II.

In the invention, the ethanol is absolute ethanol.

In the invention, the room temperature is the room temperature in the conventional sense in the field, and is generally 10-30 ℃.

The invention also provides the application of the compound shown in the formula II in preparing a medicament for treating diseases infected by the hepatitis C virus.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows:

1. the crystal form G of the compound shown in the formula II has high purity, good stability and good absorption, is easy to be crushed into powder with large surface area after being dried, and is easy to prepare and use the pharmaceutical composition.

2. The preparation method of the crystal form G of the compound shown in the formula II is simple and rapid, mild in preparation conditions, stable in yield, environment-friendly in solvent, extremely low in toxicity and suitable for large-scale production.

Drawings

FIG. 1 is an XRPD pattern of ZN2007Na amorphous substance.

FIG. 2 is a ZN2007Na amorphous modulated differential scanning calorimetry analysis chart.

FIG. 3 is an amorphous infrared spectrum of ZN2007 Na.

FIG. 4 is an XRPD pattern for form A of ZN2007 Na.

FIG. 5 is a differential scanning calorimetry and thermogravimetric analysis chart of form A of ZN2007 Na.

FIG. 6 is an XRPD pattern for form B of ZN2007 Na.

FIG. 7 is a differential scanning calorimetry and thermogravimetric analysis chart of form B of ZN2007 Na.

FIG. 8 is an XRPD pattern for form C of ZN2007 Na.

FIG. 9 is a differential scanning calorimetry analysis chart of form C of ZN2007 Na.

FIG. 10 is an XRPD pattern for form D of ZN2007 Na.

FIG. 11 is a differential scanning calorimetry analysis of form D of ZN2007 Na.

FIG. 12 is an XRPD pattern for form E of ZN2007 Na.

FIG. 13 is a differential scanning calorimetry analysis of form E of ZN2007 Na.

FIG. 14 is an XRPD pattern for form G of ZN2007 Na.

FIG. 15 is a differential scanning calorimetry analysis of form G of ZN2007 Na.

FIG. 16 is an infrared spectrum of form G of ZN2007 Na.

FIG. 17 is a HNMR spectrum of form G of ZN2007 Na.

FIG. 18 is a CNMR spectrum of form G of ZN2007 Na.

FIG. 19 is a conventional thermogravimetric analysis plot of form G of ZN2007 Na.

FIG. 20 is a N-pass of form G of ZN2007Na under the conditions of 25 ℃ and relative humidity of 0% RH₂Thermogravimetric analysis measured after gas purge.

FIG. 21 is an XRPD pattern for form H of ZN2007 Na.

FIG. 22 is a differential scanning calorimetry and thermogravimetric analysis plot of form H of ZN2007 Na.

FIG. 23 is an XRPD pattern for form I of ZN2007 Na.

FIG. 24 is a differential scanning calorimetry and thermogravimetric analysis plot of form I of ZN2007 Na.

FIG. 25 is an XRPD pattern for form J ZN2007 Na.

FIG. 26 is a thermogravimetric analysis diagram of form J of ZN2007 Na.

FIG. 27 is a differential scanning calorimetry of form J of ZN2007 Na.

FIG. 28 is a single crystal diffraction XRSD structural analysis diagram of form J ZN2007 Na.

FIG. 29 is a single crystal diffraction simulated XRPD pattern of ZN2007Na form J.

FIG. 30 is an XRPD pattern for form K of ZN2007 Na.

FIG. 31 is an infrared spectrum of form K of ZN2007 Na.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the examples below, the X-ray powder diffraction pattern (XRPD) was taken using a penny X-ray powder diffraction analyzer from Pasacaceae, the Netherlands, at a wavelength of 1.54 angstroms, measured using the Ka line of a Cu target, and having 2 θ values ranging from 0 degrees to 40 degrees.

Differential Scanning Calorimetry (DSC) and Modulated Differential Scanning Calorimetry (MDSC) were collected on an us TA instruments Q200 differential scanning calorimeter with nitrogen blanket.

Thermogravimetric analysis (TGA) was collected on a us TA instruments Q500 thermogravimetric analyzer with nitrogen blanket.

Infrared Spectroscopy (IR) data acquisition was carried out by the Scimitar FTS2000, Varian corporation, USA, using potassium bromide tablet method at wave number 400cm^-1～4000cm^-1Scan interval 4cm^-1Scan time 32 s.

Single crystal X-ray diffraction was collected on a Bruker APEX-II CCD, Bruker, Germany, and measured under the Ka line of the Mo target, resolved using 'SHELXS-97 (Shell drick, 2008)'.

In the following examples, the method used for substance purity detection was High Performance Liquid Chromatography (HPLC), and analysis was performed using a column packed with octadecylsilane chemically bonded silica, gradient elution was performed with a multi-component organic solvent, and the retention time of the chromatogram to the main component peak was recorded at 2 times, and the purity was calculated by an external standard method.

Example 1 preparation of ZN2007Na amorphous Material

Adding 10.0g of ZN2007 (namely the compound shown in the formula I) into a reaction bottle, adding 50mL of absolute ethyl alcohol, starting stirring, dissolving 0.942g (1.05eq) of sodium ethoxide into 50mL of absolute ethyl alcohol until the absolute ethyl alcohol is clear, keeping the temperature of the reaction bottle in an ice water bath at 10 ℃, dropwise adding an ethanol solution of the sodium ethoxide into the reaction bottle, and concentrating the reaction liquid until the reaction liquid is dry after the reaction liquid is clear to obtain an amorphous solid. Yield: 100%, purity: 98.0 percent.

Structure identification data:

(1) infrared absorption Spectrum (IR)

1-2 mg of the sample prepared in example 1 was weighed, 200mg of 200-mesh KBr powder was added, and infrared scanning measurement was performed by the KBr pellet method, and the spectrum of the sample was recorded. The results are shown in Table 1 below.

TABLE 1

As can be seen from the infrared absorption spectrum data, the molecular structure of the product contains characteristic functional groups such as amide, alkenyl, benzene ring, methyl, methylene, sulfonamide and the like, and the characteristic functional groups are consistent with the characteristic functional groups of the compound.

(2) Nuclear Magnetic Resonance (NMR)

The instrument used was a Brucker-400 NMR spectrometer. The test results were as follows:¹H NMR(400MHz,DMSO-d₆)δ7.81-7.83(d,1H,21),6.85-6.88(m,2H,J＝7.9Hz,34+3),6.71-6.80(m,1H,J＝7.9Hz,4),5.98-6.03(m,2H,10),5.43-5.48(t,1H,J＝10.0Hz,25),5.26-5.32(m,2H,16+26),4.54-4.55(m,4H,7+8),4.38-4.44(m,1H,18),4.12-4.15(m,2H,17a+32),3.85-3.90(m,1H,17b),2.56-2.60(m,1H,42),2.26-2.27(m,2H,19),2.23(m,1H,27a)1.98(m,1H,27b),1.83-1.85(m,1H,24),1.66(m,2H,23a+31a),1.51-1.54(m,2H,23b+31b),1.32(m,5H,28+29a+30),1.18-1.21(m,9H,37+38+39),1.07-1.09(m,1H,29b),0.75-0.78(m,2H,43),0.60-0.64(m,2H,44)ppm；¹³C NMR(100MHz,DMSO-d₆)δ174.05-174.12(40),172.07-172.16(33),170.70-170.81(20),155.63(35),153.76-153.88(14),147.08(1),141.88-141.95(2),131.71-132.30(6),129.59-129.79(26),129.40(25),117.56-118.18(5),115.62-115.72(4),108.32-108.41(3),101.75-101.79(10),78.24-78.85(36),74.38(16),59.49(18),53.25-53.36(17),52.19-52.24(32),51.67-52.04(8),48.94-49.26(7),44.31(22),34.68-34.73(19),31.66(31),30.27(42),28.50(24),28.36-28.41(37+38+39),27.80(28),26.75(29),25.55(27),22.34-22.39(30),20.94-21.12(23),4.60-4.78(43/44)ppm。

the measured NMR data are shown in Table 2.

TABLE 2

The NMR data are shown in Table 3.

TABLE 3

The results show that the structure of the product made in example 1 is as follows:

from the above structure identification data, it can be seen that the product obtained in example 1 is a compound of formula ii, hereinafter referred to as ZN2007 Na.

Other test results:

the XRPD of the product is shown in figure 1, and as can be seen from figure 1, the product is amorphous and has no characteristic peak in the 2 theta spectrum of the X-ray powder diffraction spectrum. The differential scanning calorimetry analysis of this product is shown in figure 2. The infrared spectrum of the product is shown in FIG. 3, and its infrared spectrum is 3446cm^-1、2976cm^-1、2930cm^-1、2868cm^-1、1706cm^-1、1560cm^-1、1526cm^-1、1471cm^-1、1429cm^-1、1367cm^-1、1330cm^-1、1308cm^-1、1246cm^-1、1186cm^-1、1167cm^-1、1114cm^-1、1049cm^-1、1013cm^-1、972cm^-1、919cm^-1、891cm^-1、855cm^-1、797cm^-1、767cm^-1、699cm^-1And 580cm^-1The wavelength has an absorption peak.

Example 2 preparation of ZN2007Na form a

Taking 10g of ZN2007Na prepared in example 1 as a raw material, adding 100mL of dichloromethane to dissolve and clarify, adding 200mL of diethyl ether into the upper layer of the solution to form a liquid phase, layering, slowly diffusing the diethyl ether into the sample solution to precipitate a solid, and collecting the precipitated solid. The yield thereof was 81%, and the purity thereof was 98.1%.

And (3) testing results:

the XRPD pattern of the product is shown in fig. 4, and it can be seen from fig. 4 that the product has characteristic peaks at 3.70 °, 7.48 °, 11.36 °, 19.87 ° and 25.60 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is the form a of ZN2007 Na. A differential scanning calorimetry and thermogravimetric analysis of this product is shown in FIG. 5.

Example 3 preparation of ZN2007Na form B

10g of the ZN2007Na raw material prepared in example 1 is taken, dissolved and clarified by 100mL of ethanol, 200mL of diethyl ether is added into the upper layer of the solution to form a liquid phase, the liquid phase is separated, the diethyl ether is slowly diffused into the sample solution to precipitate a solid, and the precipitated solid is collected. The yield is 90%, and the purity is 98.4%.

And (3) testing results:

the XRPD pattern of the product is shown in FIG. 6, and as can be seen from FIG. 6, the 2 theta spectrum of the X-ray powder diffraction spectrum of the product has characteristic peaks at 4.4 degrees, 5.32 degrees, 6.38 degrees, 8.69 degrees, 13.31 degrees, 14.45 degrees, 15.52 degrees, 17.57 degrees and 21.11 degrees, and the characteristic peaks are ZN2007Na crystal form B. A differential scanning calorimetry and thermogravimetric analysis of this product is shown in FIG. 7.

Example 4 preparation of ZN2007Na form C

10g of the ZN2007Na raw material prepared in example 1 was taken, dissolved and clarified by 100mL of tetrahydrofuran, separated and independently contained 500mL of n-hexane liquid was diffused into the sample solution by gas to precipitate a solid, and the precipitated solid was collected. The yield was 82%, and the purity was 98.0%.

And (3) testing results:

the XRPD pattern of the product is shown in fig. 8, and it can be seen from fig. 8 that the product has characteristic peaks at 3.22 °, 6.26 °, 14.61 °, 15.624 °, 18.82 ° and 20.17 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form C. The differential scanning calorimetry analysis of this product is shown in FIG. 9.

Example 5 preparation of ZN2007Na form D

10g of the ZN2007Na raw material prepared in example 1 was taken, dissolved and clarified by 100mL of ethyl acetate, separated and independently contained 500mL of n-hexane liquid was diffused into the sample solution by gas to precipitate a solid, and the precipitated solid was collected. The yield thereof was found to be 86% and the purity thereof was found to be 98.8%.

And (3) testing results:

the XRPD pattern of the product is shown in fig. 10, and as can be seen from fig. 10, the product has characteristic peaks at 2.02 °, 4.769 °, 5.677 °, 8.41 °, 11.04 °, 16.57 °, 18.25 °, 19.36 ° and 22.61 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form D. The differential scanning calorimetry analysis of this product is shown in FIG. 11.

Example 6 preparation of ZN2007Na form E

10g of ZN2007Na obtained in example 1 was taken as a raw material, dissolved and clarified by 100mL of ethanol, separated and independently contained 500mL of n-hexane liquid was diffused into a sample solution by gas to precipitate a solid, and the precipitated solid was collected. The yield is 85 percent, and the purity is 98.6 percent.

And (3) testing results:

the XRPD pattern of the product is shown in fig. 12, and as can be seen from fig. 12, the 2 θ spectrum of the X-ray powder diffraction spectrum of the product has characteristic peaks at 7.12 °, 13.92 °, 14.64 °, 16.47 °, 18.86 °, 19.86 °, 20.78 °, 22.58 ° and 29.58 °, which is ZN2007 form 2007Na E. The differential scanning calorimetry analysis of this product is shown in FIG. 13.

EXAMPLE 7 preparation of ZN2007Na form G

Taking 10g of ZN2007Na raw material prepared in example 1, adding 100mL of ethanol, starting stirring at room temperature to dissolve, heating to 35 ℃ after clarification, stirring for 3h to precipitate white solid, performing suction filtration, and performing vacuum drying at 55 ℃ to constant weight to obtain a product. The yield is 95 percent, and the purity is 98.5 percent.

And (3) testing results:

the XRPD pattern of the product is shown in fig. 14, and it can be seen from fig. 14 that the product has characteristic peaks at 7.59 °, 8.78 °, 13.33 °, 15.06 °, 16.31 °, 18.80 °, 20.28 °, 22.35 ° and 23.60 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form G. The differential scanning calorimetry analysis of this product is shown in FIG. 15.

Structure identification data:

(1) infrared absorption Spectrum (IR)

1-2 mg of the sample prepared in example 7 was weighed, 200mg of 200-mesh KBr powder was added, and infrared scanning measurement was performed by the KBr pellet method, and the recorded spectrum of the sample is shown in FIG. 16. The results are shown in Table 4 below.

TABLE 4

(2) Nuclear Magnetic Resonance (NMR)

The instrument used was a Brucker-400 NMR spectrometer. The structure of the product obtained in example 7 is explained as follows:

the HNMR spectrum of the recorded sample is shown in fig. 17, the CNMR spectrum of the recorded sample is shown in fig. 18, and the specific test results are summarized as follows:¹H NMR(400MHz,DMSO-d₆)δ7.81-7.83(d,1H,21),6.85-6.88(m,2H,J＝7.9Hz,34+3),6.71-6.80(m,1H,J＝7.9Hz,4),5.98-6.03(m,2H,10),5.43-5.48(t,1H,J＝10.0Hz,25),5.26-5.32(m,2H,16+26),4.54-4.55(m,4H,7+8),4.38-4.44(m,1H,18),4.12-4.15(m,2H,17a+32),3.85-3.90(m,1H,17b),2.56-2.60(m,1H,42),2.26-2.27(m,2H,19),2.23(m,1H,27a)1.98(m,1H,27b),1.83-1.85(m,1H,24),1.66(m,2H,23a+31a),1.51-1.54(m,2H,23b+31b),1.32(m,5H,28+29a+30),1.18-1.21(m,9H,37+38+39),1.07-1.09(m,1H,29b),0.75-0.78(m,2H,43),0.60-0.64(m,2H,44)ppm；¹³C NMR(100MHz,DMSO-d₆)δ174.05-174.12(40),172.07-172.16(33),170.70-170.81(20),155.63(35),153.76-153.88(14),147.08(1),141.88-141.95(2),131.71-132.30(6),129.59-129.79(26),129.40(25),117.56-118.18(5),115.62-115.72(4),108.32-108.41(3),101.75-101.79(10),78.24-78.85(36),74.38(16),59.49(18),53.25-53.36(17),52.19-52.24(32),51.67-52.04(8),48.94-49.26(7),44.31(22),34.68-34.73(19),31.66(31),30.27(42),28.50(24),28.36-28.41(37+38+39),27.80(28),26.75(29),25.55(27),22.34-22.39(30),20.94-21.12(23),4.60-4.78(43/44)ppm。

the conventional thermogravimetric analysis pattern of the product is shown in FIG. 19, and FIG. 20 shows that the crystal form G of ZN2007Na passes through N under the conditions of 25 ℃ and 0% RH of relative humidity₂Thermogravimetric analysis measured after gas purge. Fig. 20 shows that the moisture in form G of ZN2007Na was 1.9%, by this value,form G of ZN2007Na can be judged as monohydrate. Whereas the theoretical amount of water of more than 1 crystal water in FIG. 19 is adsorbed water.

EXAMPLE 8 preparation of ZN2007Na form H

Taking 10g of ZN2007Na raw material prepared in example 1, and adding 100mL of ethanol to completely dissolve the raw material; to 3300mL of n-hexane under stirring was added at a rate of 0.1mL/s, and the resulting solid was collected. The yield is 90 percent, and the purity is 98.5 percent.

And (3) testing results:

the XRPD pattern of the product is shown in FIG. 21, and as can be seen from FIG. 21, the 2 theta spectrum of the X-ray powder diffraction spectrum of the product has characteristic peaks at 4.32 degrees, 5.34 degrees, 5.96 degrees, 9.31 degrees, 13.24 degrees, 14.65 degrees, 16.14 degrees, 18.09 degrees and 20.55 degrees, which are ZN2007Na crystal form H. A differential scanning calorimetry and thermogravimetric analysis of this product is shown in FIG. 22.

Example 9 preparation of ZN2007Na form I

10g of ZN2007Na obtained in example 1 as a raw material was dissolved in 100mL of ethanol and clarified, 500mL of an ether liquid contained separately was used to precipitate a solid by gas diffusion into a sample solution, and the precipitated solid was collected. The yield is 92.0 percent, and the purity is 98.5 percent.

And (3) testing results:

the XRPD pattern of the product is shown in FIG. 23, and as can be seen from FIG. 23, the 2 theta spectrum of the X-ray powder diffraction spectrum of the product has characteristic peaks at 7.00 degrees, 7.40 degrees, 7.93 degrees, 14.09 degrees, 14.76 degrees, 18.89 degrees, 19.94 degrees, 20.78 degrees and 22.35 degrees, which are ZN2007Na crystal form I. A differential scanning calorimetry and thermogravimetric analysis of this product is shown in FIG. 24.

EXAMPLE 10 preparation of ZN2007Na form J

Taking 10g of ZN2007Na prepared in example 1 as a raw material, adding 100mL of ethyl acetate, adding 5mL of water, stirring at 25 ℃ until the mixture is clear, then cooling to 15 ℃, stirring for 3h, precipitating white solid, and filtering to obtain a product. The yield is 94% and the purity is 99.0%.

And (3) testing results:

the XRPD pattern of the product is shown in fig. 25, and it can be seen from fig. 25 that the product has characteristic peaks at 5.97 °, 6.52 °, 9.42 °, 11.03 °, 11.63 °, 15.59 °, 16.61 °, 19.91 ° and 22.46 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form J. The thermogravimetric analysis of the product is shown in FIG. 26, and the differential scanning calorimetry analysis of the product is shown in FIG. 27.

EXAMPLE 11 Single Crystal preparation of ZN2007Na form J

And (3) taking 1g of the ZN2007Na raw material prepared in the example 1, adding a mixed system of 100mL of ethyl acetate and 5mL of water, and collecting precipitated solids after the solvent is freely volatilized at 10-30 ℃ to obtain the zinc sulfide. The purity is 99.9%.

And (3) testing results:

FIG. 28 is a single crystal diffraction (XRSD) structure analysis of form J ZN2007Na by measuring the wavelength as

The single crystal X-ray diffraction analysis of (a) shows that the product has unit cell parameters of:

α＝90°；

β＝90°；

γ is 90 °; the crystal form L has a unit cell volume of

FIG. 29 is an XRPD spectrum from an cif file of single crystal data as simulated by software Mercury 1.4. from FIG. 29, the simulated X-ray powder diffraction spectrum of the product has characteristic peaks at 5.91 + -0.50 °, 6.01 + -0.50 °, 6.51 + -0.50 °, 8.94 + -0.50 °, 9.44 + -0.50 °, 11.66 + -0.50 °, 15.70 + -0.50 °, 21.04 + -0.50 ° and 21.75 + -0.50 °; compared with fig. 25, the main peak is similar, and the two crystal forms are confirmed to be the same crystal form.

EXAMPLE 12 preparation of ZN2007Na form K

Taking 10g of the ZN2007Na raw material prepared in the example 1, adding 100mL of ethyl acetate, adding 5mL of water, stirring at 25 ℃ until the mixture is clear, slowly cooling to 15 ℃, stirring for 3h, separating out white solid, performing suction filtration, and drying in vacuum at 55 ℃ until the weight is constant to obtain a product. The yield is 95 percent, and the purity is 98.5 percent.

And (3) testing results:

the XRPD pattern of the product is shown in FIG. 30, and as can be seen from FIG. 30, the 2 theta spectrum of the X-ray powder diffraction spectrum of the product has characteristic peaks at 6.475 degrees, 9.575 degrees, 10.81 degrees, 11.743 degrees, 15.446 degrees and 20.714 degrees, and the characteristic peaks are ZN2007Na crystal form K. The infrared spectrum of the product is shown in FIG. 31, and its infrared spectrum is 3447cm^-1、2976cm^-1、2930cm^-1、2869cm^-1、1773cm^-1、1700cm^-1、1654cm^-1、1636cm^-1、1560cm^-1、1525cm^-1、1471cm^-1、1430cm^-1、1367cm^-1、1329cm^-1、1308cm^-1、1246cm^-1、1187cm^-1、1167cm^-1、1116cm^-1、1049cm^-1、1013cm^-1、972cm^-1、919cm^-1、890cm^-1、843cm^-1、798cm^-1、766cm^-1、722cm^-1、700cm^-1And 581cm^-1The wavelength has an absorption peak.

Example 13 preparation of ZN2007Na amorphous form

Adding 10.0g of ZN2007 (namely the compound shown in the formula I) into a reaction bottle, adding 50mL of absolute ethanol, starting stirring, dissolving 0.554g (1.05eq) of sodium hydroxide into 50mL of absolute ethanol until the absolute ethanol is clear, keeping the temperature of the reaction bottle in an ice-water bath at 10 ℃, dropwise adding an ethanol solution of the sodium hydroxide into the reaction bottle, and concentrating the reaction solution until the reaction solution is dry after the reaction solution is clear to obtain an amorphous solid. Yield: 100%, purity: 98.0 percent.

And (3) testing results:

the XRPD pattern of this product is consistent with that of FIG. 1, and the 2 theta spectrum of its X-ray powder diffraction spectrum has no characteristic peak, and this product is amorphous. Differential scanning calorimetry analysis of the productAnd 2 are identical. The product has an infrared spectrum corresponding to that of FIG. 3, and an infrared spectrum of 3446cm^-1、2976cm^-1、2930cm^-1、2868cm^-1、1706cm^-1、1560cm^-1、1526cm^-1、1471cm^-1、1429cm^-1、1367cm^-1、1330cm^-1、1308cm^-1、1246cm^-1、1186cm^-1、1167cm^-1、1114cm^-1、1049cm^-1、1013cm^-1、972cm^-1、919cm^-1、891cm^-1、855cm^-1、797cm^-1、767cm^-1、699cm^-1And 580cm^-1The wavelength has an absorption peak.

EXAMPLE 14 preparation of ZN2007Na form C

Taking 10g of ZN2007Na raw material prepared in example 1, dissolving and clarifying at 60 ℃ by using 60mL of mixed solvent of tetrahydrofuran and n-hexane to obtain mixed solution, wherein the volume ratio of tetrahydrofuran to n-hexane is 1:1, cooling at the cooling rate of 0.06 ℃/min to 5 ℃, and collecting precipitated solid. The yield is 40 percent, and the purity is 98.8 percent.

And (3) testing results:

the XRPD pattern of this product is consistent with fig. 8, with characteristic peaks at 3.22 °, 6.26 °, 14.61 °, 15.624 °, 18.82 ° and 20.17 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form C. The differential scanning calorimetry analysis of this product is consistent with figure 9.

EXAMPLE 15 preparation of ZN2007Na form G

Adding 10.0g of ZN2007 (namely the compound shown in the formula I) into a reaction bottle, adding 50mL of absolute ethanol, starting stirring, dissolving 0.554g (1.05eq) of sodium hydroxide into 50mL of absolute ethanol until the absolute ethanol is clear, keeping the temperature of the reaction bottle in an ice water bath at 10 ℃, dropwise adding an ethanol solution of the sodium hydroxide into the reaction bottle, heating to 35 ℃ after the reaction solution is clear, stirring for 3 hours, precipitating white solids, stirring at room temperature, performing suction filtration, and drying at 55 ℃ in vacuum until the constant weight is achieved, thus obtaining the product. The yield was 93% and the purity 98.5%.

And (3) testing results:

XRPD pattern of this product is in phase with FIG. 14The crystal form G of ZN2007Na is consistent, and characteristic peaks exist at 7.59 degrees, 8.78 degrees, 13.33 degrees, 15.06 degrees, 16.31 degrees, 18.80 degrees, 20.28 degrees, 22.35 degrees and 23.60 degrees in a 2 theta spectrum of an X-ray powder diffraction spectrum of the crystal form G. The differential scanning calorimetry analysis of this product is consistent with figure 15. The product has an infrared spectrum corresponding to that of FIG. 16, and an infrared spectrum of 3676cm^-1、3429cm^-1、3054cm^-1、2924cm^-1、2867cm^-1、2206cm^-1、1699cm^-1、1641cm^-1、1569cm^-1、1504cm^-1、1472cm^-1、1424cm^-1、1378cm^-1、1330cm^-1、1308cm^-1、1236cm^-1、1168cm^-1、1104cm^-1、1049cm^-1、970cm^-1、918cm^-1、894cm^-1、825cm^-1、767cm^-1、691cm^-1、582cm^-1、521cm^-1And 464cm^-1The wavelength has an absorption peak.

EXAMPLE 16 preparation of ZN2007Na form G

10g of the ZN2007Na raw material prepared in example 1 was taken and dissolved in 60mL of a mixed solvent of ethanol and n-hexane, wherein the volume ratio of ethanol to n-hexane was 1:1, the solvent was volatilized at room temperature, and the precipitated solid was collected. The yield was 38% and the purity 98.6%.

And (3) testing results:

the XRPD pattern of this product is consistent with fig. 14, with characteristic peaks at 7.59 °, 8.78 °, 13.33 °, 15.06 °, 16.31 °, 18.80 °, 20.28 °, 22.35 ° and 23.60 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form G. The differential scanning calorimetry analysis of this product is consistent with figure 15. The product has an infrared spectrum corresponding to that of FIG. 16, and an infrared spectrum of 3676cm^-1、3429cm^-1、3054cm^-1、2924cm^-1、2867cm^-1、2206cm^-1、1699cm^-1、1641cm^-1、1569cm^-1、1504cm^-1、1472cm^-1、1424cm^-1、1378cm^-1、1330cm^-1、1308cm^-1、1236cm^-1、1168cm^-1、1104cm^-1、1049cm^-1、970cm^-1、918cm^-1、894cm^-1、825cm^-1、767cm^-1、691cm^-1、582cm^-1、521cm^-1And 464cm^-1The wavelength has an absorption peak.

EXAMPLE 17 preparation of ZN2007Na form J

The ZN2007Na crystal form K prepared in example 12 is placed in a stable box with the humidity of 75% and the temperature of 40 ℃, and the crystal form K is converted into the ZN2007Na crystal form J after being placed for one week.

And (3) testing results:

the XRPD pattern of the product is consistent with 25. as can be seen from fig. 25, the product has characteristic peaks at 5.97 °, 6.52 °, 9.42 °, 11.03 °, 11.63 °, 15.59 °, 16.61 °, 19.91 ° and 22.46 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form J. The thermogravimetric analysis of the product is consistent with fig. 26, and the differential scanning calorimetry analysis of the product is consistent with fig. 27.

EXAMPLE 18 preparation of ZN2007Na form K

And (3) carrying out vacuum drying on the ZN2007Na crystal form J prepared in example 10 at 55 ℃ to constant weight to obtain the ZN2007Na crystal form K.

The XRPD pattern of the product is consistent with fig. 30, and as can be seen from fig. 30, the product has characteristic peaks at 6.475 °, 9.575 °, 10.81 °, 11.743 °, 15.446 ° and 20.714 ° in the 2 θ spectrum of the X-ray powder diffraction spectrum, which is ZN2007Na form K. The infrared spectrum of the product is consistent with that of 31, and the infrared spectrum of the product is 3447cm^-1、2976cm^-1、2930cm^-1、2869cm^-1、1773cm^-1、1700cm^-1、1654cm^-1、1636cm^-1、1560cm^-1、1525cm^-1、1471cm^-1、1430cm^-1、1367cm^-1、1329cm^-1、1308cm^-1、1246cm^-1、1187cm^-1、1167cm^-1、1116cm^-1、1049cm^-1、1013cm^-1、972cm^-1、919cm^-1、890cm^-1、843cm^-1、798cm^-1、766cm^-1、722cm^-1、700cm^-1And 581cm^-1The wavelength has an absorption peak.

Experiments show that the crystal form J can be converted into the crystal form K after losing moisture, and the crystal form K can be converted into the crystal form J after obtaining moisture. The crystal form J is a pipeline hydrate and is easy to lose moisture, and when the crystallinity of the crystal form J is high, an XRPD peak shape is sharp; form J has a water content of between 1 and 5 waters of crystallization. The crystal form J loses crystal water under the condition of low humidity, so that the crystal form collapses, the crystallinity is reduced, and the crystal form is finally converted into a crystal form K, and as shown in a spectrogram 30, the peak shape is not obvious any more. Form K is an anhydrate form of the compound of formula ii. When the crystal form K is in a high-humidity environment, the pipeline is filled with water, the collapse part is supported, the crystallinity is high, and the crystal form K is converted into the crystal form J.

EXAMPLE 19 preparation of ZN2007Na amorphous form

A process for the preparation of an amorphous form of a compound of formula ii comprising the steps of: dissolving the compound of formula II in water, and vacuum drying at 55 deg.C to constant weight.

The crystal form of the compound of formula ii is not limited, and may be any crystal form or amorphous form of the compound of formula ii in the above embodiments.

Effect example 1 solubility of different forms

The amorphous form of ZN2007Na prepared in example 1, the crystalline form G and solubility of ZN2007Na prepared in example 7 and the crystalline form J of ZN2007Na prepared in example 10 were subjected to solubility test.

The definition of solubility is made according to the four-part normal x item referred to in pharmacopoeia 2015 and the specification that requires fifteen (2) solubility: very easy dissolution: means that 1g (ml) of solute can be dissolved in less than 1ml of solvent; easy dissolution: means that 1g (ml) of solute can be dissolved in 1m to 10ml of solvent; dissolving: means that 1g (ml) of solute can be dissolved in 10ml to 30ml of solvent; slightly dissolving: means that 1g (ml) of solute can be dissolved in 30ml to 100ml of solvent; slightly soluble: it means that 1g (ml) of solute can be dissolved in 1000ml to 10000ml of solvent; insolubilization: it means that 1g (ml) of solute could not be completely dissolved in 10000ml of solvent. The definition of solubility is herein after consistent.

The amorphous form of ZN2007Na prepared in example 1, the form G of ZN2007Na prepared in example 7, the form J of ZN2007Na prepared in example 10 and the form J of ZN2007 were subjected to solubility test at a solvent temperature of 25 ℃, and the standard was defined in pharmacopoeia of 2015 edition. The test results are shown in Table 5.

TABLE 5

As can be seen from Table 5, the amorphous form and crystalline form G of the compound of formula II according to the present invention have greater solubility in water, methanol and ethanol than the compound of formula I, and crystalline form J has greater solubility in methanol and ethanol than the compound of formula I.

The amorphous form of ZN2007Na prepared in example 1, the form G of ZN2007Na prepared in example 7, the form J of ZN2007Na prepared in example 10 and ZN2007 were subjected to solubility test at a solvent temperature of 50 ℃ according to the pharmacopoeia of the 2015 edition. The test results are shown in Table 6.

TABLE 6

Solvent(s)	EXAMPLE 1 amorphous Material	EXAMPLE 7 form G	Example 10 form J
				Water (W)	Is easy to dissolve	Is easy to dissolve	Slightly soluble
Methanol	Is very easy to dissolve	Is easy to dissolve	Is easy to dissolve
				Ethanol	Is very easy to dissolve	Dissolution	Is easy to dissolve

As can be seen from table 6, the solubility of amorphous form, form G and form J of the compound of formula ii of the present invention in water, methanol and ethanol also increases after the temperature is increased.

Effect example 2 stability

The content of the main component is determined by adopting high performance liquid chromatography and the detection of water KF.

The stability of the amorphous form of ZN2007Na obtained in example 1 was examined. The amorphous ZN2007Na stored for 2 years under the condition of normal temperature and light shielding has no characteristic peak or amorphous structure after being detected by XRPD. The main component is not changed compared with the reference substance by high performance liquid chromatography measurement. The amorphous form of the compound of formula ii of the present invention remains stable for periods of up to 24 months.

The stability of form G of ZN2007Na obtained in example 7 was examined. The stability test conditions were: the temperature was 25 ℃ and the relative humidity was 60%. The test results are shown in Table 7.

TABLE 7

Investigation time	Content of Main component (%)	Water content (%)
			0 month	98.92	3.20
3 month	99.11	4.11
			Month 5	99.03	4.40
6 month	99.15	4.00
			12 month	99.15	4.07

As can be seen from table 7, the compound of formula ii of the present invention, form G, remains stable for periods of up to 12 months.

Further detection results show that: ZN2007Na crystal form G is slightly hygroscopic, and the stable standing water content is less than or equal to 5%. Other properties of the ZN2007Na crystal form G are stable under the condition of RH 95% for 30 days, HPLC shows that ZN2007Na is not decomposed and is not added with impurities, and related substances are not changed; is stable for 30 days at the high temperature of 60 ℃; the product is stable for 5 days under the condition of strong light 4500Lx, and starts to degrade after 5 days; unstable under strongly oxidizing and acidic conditions; is stable under alkali condition.

Form G was heated in ethanol of different water contents (anhydrous, 1% water and 5% water) from 20 ℃ to different temperatures (20 ℃, 40 ℃, 50 ℃ and 60 ℃) and then cooled to 20 ℃ (four times), no crystal transformation was observed, and it was physically stable in the process.

The stability of form J of ZN2007Na obtained in example 10 was examined. The results show that: ZN2007Na crystal form J has water absorption of 11.8% at 25 ℃ and RH 80%; ZN2007Na crystal form J can reach 9% moisture content after long-term open placement, and the moisture content after drying is lower than 1%.

Stability at different humidity: dynamic moisture sorption (DVS) tests on ZN2007Na form J samples at 25 ℃ and 40 ℃ showed that the samples were stable for 3 hours in the range of 45% -80% RH during dehydration. At low humidity (RH 0%), ZN2007Na form J was dehydrated and the crystallinity of the sample decreased after DVS testing. The crystal form J has no change after being placed for 2 weeks under the conditions of 25 ℃ and RH 60% or 40 ℃ and RH 75%, which shows that the ZN2007Na crystal form J has good physical stability under the conditions. The crystallinity of the sample increased at 40 ℃ and RH 75%.

Effect example 3 dissolution and form transformation of ZN2007Na form J

About 90mg of the sample of form J ZN2007Na prepared in example 10 was weighed into a 20mL sample bottle, and 6mL of water and SGF (simulated gastric fluid) were added to the sample bottle to form a suspension. And (3) stirring the suspension in a constant temperature box at 37 ℃, filtering the suspension for 0.5h, 1h, 2h, 4h, 9h and 12h respectively, and taking a clear solution for HPLC test while taking a solid for XRPD test. The results show that the amorphous content of the sample increases and the solubility in water increases with increasing stirring time in water. Whereas ZN2007Na form J, which has a solubility in SGF below the minimum detection limit of the instrument (0.002mg/mL), was undetectable, indicating a gradual conversion of the sample to amorphous form in SGF.

Effect example 4 hygroscopicity of ZN2007 Potassium salt and ZN2007 calcium salt

The preparation method of ZN2007 potassium salt is as follows: weighing 3.1g of potassium tert-butoxide, dissolving in 50mL of ethanol, weighing 20.0g of ZN2007, dispersing in 100mL of ethanol, dropwise adding an ethanol solution of potassium tert-butoxide under the stirring of ice water bath, gradually clarifying the solution under the stirring, concentrating to remove ethanol, and drying to obtain the product.

ZN2007 calcium salt preparation method is as follows: weighing 98mg of calcium hydroxide, dissolving in 1mL of glycerol, weighing 2.0g of ZN2007, dispersing in 30mL of ethanol, dripping the calcium hydroxide glycerol solution while stirring, clarifying the solution gradually while stirring, concentrating to remove the ethanol, adding 40mL of ethyl acetate, stirring for dissolving, adding 150mL of petroleum ether, precipitating a solid, stirring, filtering, and drying to obtain the product.

The hygroscopicity (24 hours) of ZN2007 potassium salt and ZN2007 calcium salt was measured, and the results are shown in table 8.

TABLE 8

ZN2007 potassium salt and ZN2007 calcium salt have different moisture contents in different humidity environments.

The above embodiments are preferred embodiments of the present invention, but the implementation manner of the present invention is not limited by the above embodiments, and any other changes, modifications, substitutions, combinations, simplifications which do not depart from the spirit and principle of the present invention should be regarded as equivalent replacements within the protection scope of the present invention.

Claims

1. A crystalline form G of the compound of formula ii, characterized by characteristic peaks in the 2 Θ spectrum of its X-ray powder diffraction spectrum at 7.59 ± 0.50 °, 8.78 ± 0.50 °, 13.33 ± 0.50 °, 15.06 ± 0.50 °, 16.31 ± 0.50 °, 18.80 ± 0.50 °, 20.28 ± 0.50 °, 22.35 ± 0.50 ° and 23.60 ± 0.50 °, the X-ray powder diffraction using the ka spectrum line of the Cu target; the infrared spectrum of the crystal form G is 3676cm^-1、3429cm^-1、3054cm^-1、2924cm^-1、2867cm^-1、2206cm^-1、1699cm^-1、1641cm^-1、1569cm^-1、1504cm^-1、1472cm^-1、1424cm^-1、1378cm^-1、1330cm^-1、1308cm^-1、1236cm^-1、1168cm^-1、1104cm^-1、1049cm^-1、970cm^-1、918cm^-1、894cm^-1、825cm^-1、767cm^-1、691cm^-1、582cm^-1、521cm^-1And 464cm^-1The wavelength has an absorption peak; in the crystal form G, n is 1;

2. form G of the compound of formula II according to claim 1, having characteristic peaks, in terms of 2 θ, at 7.59 ± 0.20 °, 8.78 ± 0.20 °, 13.33 ± 0.20 °, 15.06 ± 0.20 °, 16.31 ± 0.20 °, 18.80 ± 0.20 °, 20.28 ± 0.20 °, 22.35 ± 0.20 ° and 23.60 ± 0.20 ° in the X-ray powder diffraction spectrum using the Ka line of the Cu target.

3. A process for the preparation of form G of the compound of formula II according to claim 1 or 2, comprising the following steps: dissolving the compound shown in the formula II in ethanol, stirring for 1-8 hours at 20-70 ℃, carrying out suction filtration, and drying to obtain the compound.

4. A process for the preparation of form G of the compound of formula II according to claim 3, wherein the stirring is carried out at 30-45 ℃; and/or the stirring time is 3 hours.

5. A process for the preparation of form G of the compound of formula ii according to claim 1 or 2, comprising the following steps: mixing the compound of formula I with ethanol to obtain a mixture; adding an ethanol solution of sodium hydroxide into the mixture under the stirring state, reacting until the mixture is clear, stirring for 1-8 hours at the temperature of 20-70 ℃, filtering, and drying to obtain the sodium hydroxide-containing organic fertilizer;

6. a process for preparing the compound of formula II in crystalline form G according to claim 5, wherein the mixture is such that the mass to volume ratio of the compound of formula I to ethanol in the mixture is (0.8-1.2) G (4-6) mL;

and/or the molar ratio of the sodium hydroxide to the compound of the formula I is 1.20: 1-1.00: 1;

and/or the dosage of the sodium hydroxide and the ethanol in the ethanol solution of the sodium hydroxide is (0.5-1) g:50 mL;

and/or the reaction temperature is 0-25 ℃;

and/or after the operation of reaction to clarification, stirring at 30-45 ℃; the stirring time was 3 hours.

7. A process for the preparation of form G of the compound of formula II according to claim 1 or 2, comprising the following steps: dissolving the compound shown in the formula II in a mixed solvent of ethanol and n-hexane, volatilizing the solvent at room temperature, and collecting precipitated solid to obtain the compound.

8. A process for preparing a crystalline form G of the compound of formula II according to claim 7, wherein in the mixed solvent of ethanol and n-hexane, the volume of ethanol and n-hexane is 1: 1;

and/or the volume-to-mass ratio of the mixed solvent of the ethanol and the n-hexane to the compound of the formula II is 5-10 mL/g.

9. The method according to claim 8, wherein the volume-to-mass ratio of the mixed solvent of ethanol and n-hexane to the compound of formula II is 6 mL/G.