CN110407837A - Salts of compounds, their crystal forms and their applications - Google Patents

Abstract

The invention belongs to pharmaceutical fields, provide compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide tartrate and its crystal form, hydrate and crystal form, unformed, its pharmaceutical composition, and its preparation method and application.

Description

Salts of compounds, their crystal forms and their applications

technical field

The invention belongs to the field of pharmacy and provides compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydro Pyrrolo[3,4-b]pyrrole-5(1H)-carboxamide tartrate and its crystal form, hydrate and crystal form, amorphous form, its pharmaceutical composition, and its preparation method and application.

Background technique

Binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR) activates tyrosine kinase activity, which initiates a response that leads to cell proliferation. Overexpression and/or overactivation of EGFR can lead to uncontrolled cell division, which can be a cause of cancer. Therefore, compounds that inhibit EGFR overexpression and/or overactivation are drug candidates for the treatment of cancer.

The related compound of the present invention (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3, 4-b] pyrrole-5(1H)-carboxamide, which can effectively inhibit the overexpression and/or overactivation of EGFR. Therefore, it can be used for the treatment of diseases related to the overexpression and/or overactivation of EGFR, such as the treatment of cancer.

The phenomenon that a compound can exist in two or more crystal structures is called polymorphism. Many compounds can exist in various crystalline forms, as well as in the form of an amorphous solid. Before the polymorphism of a compound is discovered, it is difficult to predict (1) whether a specific compound has polymorphism; (2) how to make these unknown polymorphs; (3) the properties of these polymorphs What will it be like, stability for example. See J. Bernstein "Polymorphism in Molecular Crystals", Oxford University Press, (2002).

Since the properties of a solid depend on the structure and the properties of the compound itself, different solid forms of a compound often exhibit different physical and chemical properties as well as different biopharmaceutical properties. Differences in chemical properties can be measured, analyzed and compared by means of various analytical techniques, and these differences can ultimately be used to distinguish the different solid forms that exist. Differences in physical properties such as stability, solubility and biopharmaceutical properties such as bioavailability are also important in describing the solid form of pharmaceutical compounds. Likewise, in pharmaceutical compounds such as the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydro New crystalline and amorphous forms of pharmaceutical compounds are also important in the development of pyrrolo[3,4-b]pyrrole-5(1H)-carboxamide.

Patent application CN102906086A discloses compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazole

Lin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide and its preparation method.

Contents of the invention

overview

After a lot of exploration and research, we found that the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrole And[3,4-b]pyrrole-5(1H)-carboxamide (abbreviated as the free base of formula A compound) can be prepared into tartrate, such as L-tartrate (abbreviated as formula A compound), the chemical structure is shown in the formula a. The research results show that the solubility of the compound of formula A relative to its free base is significantly increased, and there is no obvious acid-base dependence, which is conducive to improving the pharmacokinetic characteristics of the compound and increasing the bioavailability of the compound in vivo. We have also found that the compound of formula A can exist in different crystal forms. We have conducted a lot of research on the polymorphic form of the compound of formula A, and determined and prepared a crystalline form that meets the pharmaceutical requirements. Based on these studies, the present invention provides the compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydro Various crystalline forms of pyrrolo[3,4-b]pyrrole-5(1H)-carboxamide tartrate (they are respectively designated as Form I, Form II, Form IV and Form V) and its amorphous form things.

In one aspect, firstly, the present invention provides (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydro Tartrate salt of pyrrolo[3,4-b]pyrrole-5(1H)-carboxamide.

Secondly, the present invention provides (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl as shown in formula A -hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide tartrate, i.e. formula A compound, also provides the hydrate of formula A compound, the crystal form of formula A compound and hydrate thereof ( For example Form I, Form II, Form IV and Form V) and the amorphous form of the compound of formula A.

The compound of formula A and its polymorphic forms provided by the invention have the characteristics of high solubility, no obvious acid-base dependence of solubility, good crystallinity and stability.

In another aspect, the present invention provides the compound of formula A, its hydrate, the crystal form of the compound of formula A and its hydrate (such as crystal form I, crystal form II, crystal form IV and crystal form V) and the compound of formula A without Shaped preparation method. These preparation methods are reproducible and easy to operate.

In another aspect, the present invention provides a pharmaceutical composition containing an effective amount of a compound of formula A or a hydrate thereof or a crystal form of a compound of formula A or a hydrate thereof (such as crystal form I, crystal form II, One or more of crystal form IV and crystal form V) or the amorphous form of the compound of formula A, and at least one pharmaceutically acceptable carrier.

The present invention also provides methods of treating cancer. The method comprises administering to an individual in need thereof an effective amount of one or more compounds of formula A or hydrates thereof or crystalline forms of compounds of formula A or hydrates thereof (e.g., Form I, Form II, Form IV and crystal form V) or an amorphous form of a compound of formula A or a pharmaceutical composition according to the invention.

The present invention also provides a compound of formula A or a hydrate thereof or a crystal form (such as form I, form II, form IV and form V) of a compound of formula A or a hydrate thereof or an amorphous form of a compound of formula A for use in Use for the preparation of a medicament for treating cancer.

The present invention also provides the compound of formula A or its hydrate or the crystal form (such as crystal form I, crystal form II, crystal form IV and crystal form V) of the compound of formula A or its hydrate or the amorphous form of the compound of formula A, which Used to treat cancer.

Such cancers are, for example, lung cancer (including non-small cell lung cancer, non-small cell lung cancer with brain metastases), head and neck cancer, colorectal cancer, colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, brain cancer (including glioblastoma ), breast cancer, pharyngeal cancer, epidermoid cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, esophageal cancer, bone cancer and sarcomas such as soft tissue sarcoma and leukemia. The cancer may be a cancer responsive to inhibition of epidermal growth factor receptor overexpression and/or overactivity.

The present invention also provides a method for inhibiting the overexpression and/or overactivity of the epidermal growth factor receptor, which comprises making the epidermal growth factor receptor and an effective amount of one or more compounds of formula A of the present invention or a hydrate thereof or A crystalline form (eg, Form I, Form II, Form IV, and Form V) of a compound of formula A or a hydrate thereof or an amorphous form of a compound of formula A is contacted.

The present invention also provides a compound of formula A or a hydrate thereof or a crystal form (such as form I, form II, form IV and form V) of a compound of formula A or a hydrate thereof or an amorphous form of a compound of formula A for use in Use for the preparation of the free base of the compound of formula A, and a process for the preparation of the free base of the compound of formula A therefrom.

Description of drawings

Fig. 1 shows the powder X-ray diffraction pattern of the crystal form I of the compound of formula A, the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

Fig. 2 shows the differential scanning calorimetry diagram of the crystal form I of the compound of formula A, the horizontal axis (X-axis) is the temperature, and the vertical axis (Y-axis) is the heat flow.

Fig. 3 shows the thermogravimetric analysis diagram of the crystal form I of the compound of formula A, the horizontal axis (X-axis) is the temperature, and the vertical axis (Y-axis) is the weight percentage.

Fig. 4 shows the powder X-ray diffraction pattern of the crystal form II of the compound of formula A, the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

Fig. 5 shows the differential scanning calorimetry diagram of the crystal form II of the compound of formula A, the horizontal axis (X-axis) is temperature, and the vertical axis (Y-axis) is heat flow.

Fig. 6 shows the thermogravimetric analysis diagram of the crystal form II of the compound of formula A, the horizontal axis (X-axis) is the temperature, and the vertical axis (Y-axis) is the weight percentage.

Fig. 7 shows the powder X-ray diffraction pattern of the crystal form IV of the compound of formula A, the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

Fig. 8 shows the differential scanning calorimetry diagram of the crystal form IV of the compound of formula A, the horizontal axis (X-axis) is temperature, and the vertical axis (Y-axis) is heat flow.

Fig. 9 shows the thermogravimetric analysis diagram of the crystal form IV of the compound of formula A, the horizontal axis (X-axis) is the temperature, and the vertical axis (Y-axis) is the weight percentage.

Figure 10 shows the powder X-ray diffraction pattern of the crystal form V of the compound of formula A, the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

Figure 11 shows a differential scanning calorimetry diagram of Form V of the compound of formula A, the horizontal axis (X-axis) is temperature, and the vertical axis (Y-axis) is heat flow.

Fig. 12 shows the thermogravimetric analysis diagram of the crystal form V of the compound of formula A, the horizontal axis (X-axis) is the temperature, and the vertical axis (Y-axis) is the weight percentage.

Fig. 13 shows an amorphous powder X-ray diffraction pattern of the compound of formula A, the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

Figure 14 shows the dynamic moisture adsorption and desorption of the crystal form I of the compound of formula A, wherein the vertical axis (Y-axis) represents the percentage of mass change relative to the initial mass of the sample before testing.

Figure 15 shows the dynamic moisture adsorption and desorption of the crystal form II of the compound of formula A, wherein the vertical axis (Y-axis) represents the percentage of mass change relative to the initial mass of the sample before testing.

Figure 16 shows the dynamic moisture adsorption and desorption of the crystal form IV of the compound of formula A, wherein the vertical axis (Y-axis) represents the percentage of mass change relative to the initial mass of the sample before testing.

Fig. 17 shows the powder X-ray diffraction pattern of the product obtained in Example 23, the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

definition

Unless otherwise stated, the following abbreviations or terms used in this application (including the specification and claims) have the definitions given below. It must be noted that, as used in this specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise.

The "crystal form of the present invention" as used herein refers to the crystal form I, II, IV or V of the compound of formula A or its hydrate, or a mixture of several forms thereof. "Crystal form", "crystal form", "crystalline form" and "polymorph" are used interchangeably herein.

As used herein, "compound of formula A" refers to a compound having the following chemical structure of formula A (also referred to as compound A):

"Pure crystal" as used herein means that the crystal structure of the crystal form does not contain water molecules or other solvent molecules, that is, the crystal form is not a hydrate or a solvate.

As used herein, "C _1-6 alkyl alcohol" refers to a fully saturated straight or branched chain alkyl alcohol having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, n-hexanol, and the like.

As used herein, "haloalkane of less than three carbon atoms" refers to a fully saturated hydrocarbon having 1 or 2 carbon atoms, which is substituted with one or more halogen atoms selected from F, Cl, Br or I. Examples thereof include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like.

As used herein, "about" means deviating by up to ±10% from the specifically given numerical value.

As used herein, "substantially free of other crystal forms" means that the content of the other crystal forms accounts for less than 50%, preferably less than 40%, preferably less than 30%, preferably less than 20%, and preferably less than 20% of the total weight of the crystal form. Less than 10%, preferably less than 5%, preferably less than 1%.

As used herein, "solution" refers to a mixture of one or more solutes in one or more solvents for a certain use. Solution is meant to include homogeneous mixtures, and heterogeneous mixtures, such as beating liquors or other suspended mixtures containing insoluble matter.

As used herein, "organic solvent" broadly refers to any suitable organic solvent for a purpose herein.

As used herein, "water-miscible organic solvent" includes methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, dioxane, and mixtures thereof. "C _2-6 water-miscible organic solvent" refers to the above-mentioned water-miscible organic solvent, wherein the number of carbon atoms contained in the solvent molecule is 2, 3, 4, 5 or 6.

The "effective amount" of the compound of formula A and the crystal form of the compound of formula A, the hydrate of the compound of formula A and its crystal form, or the amorphous form of the compound of formula A refers to the effective amount administered to an individual that can effectively reduce or improve the effect on the inhibition of cancer. amount, and the administration object may be a human being or a subject such as an animal. The "effective amount" will vary with various factors such as the compound, the disease state being treated, the severity of the disease being treated, the age and related health condition of the individual, the route and form of administration, and the judgment of the attending physician or veterinary practitioner. .

"Cancer" as used herein may be, but is not limited to, lung cancer (including non-small cell lung cancer, non-small cell lung cancer with brain metastases), head and neck cancer, colorectal cancer, colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, brain cancer, Cancer (including glioblastoma), breast cancer, pharyngeal cancer, epidermoid cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, esophageal cancer, bone cancer and sarcomas such as soft tissue sarcoma and leukemia, etc., the cancer Can be a cancer responsive to epidermal growth factor receptor overexpression and/or overactivity.

As used herein, "individual" means both mammals and non-mammals. Mammal means any member of the mammalian class, including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits , dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds and the like. The term "individual" does not denote a particular age or gender.

Detailed description of the invention

The invention provides compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b]pyrrole-5(1H)-carboxamide tartrate and its crystalline and amorphous forms.

The crystal form of the present invention has the characteristics of good crystallinity, high solubility, no obvious acid-base dependence of solubility and good stability. The crystal form of the present invention has good reproducibility, and can realize repeated scale-up production; moreover, it is stable in common preparations, so it is convenient for preparation production and use in treating diseases. In addition, the crystal form of the present invention has high purity, less solvent residue, and meets the quality requirements of raw materials, such as the requirements of ICH Q3A.

Those skilled in the art can verify the above advantages of the crystalline form of the present invention based on the test methods disclosed in the Pharmacopoeia, their modification methods or conventional methods in the field.

As described herein, the crystalline forms of the present invention can be identified by one or several solid-state analysis methods. For example, the crystal form of the present invention can be detected by one or more methods, such as powder X-ray diffraction (PXRD), lattice parameters of single crystals, Fourier transform infrared (IR) spectroscopy, differential scanning calorimetry (DSC) ) data and/or thermogravimetric analysis (TGA) curves for identification. And if the identification analysis result of one of the methods is consistent with the crystal form of the present invention, it does not mean that the identification result of any other method is consistent with the crystal form of the present invention.

As described herein, new crystalline forms can be identified by powder X-ray diffraction spectroscopy. However, those skilled in the art know that the peak intensity and/or peak situation of powder X-ray diffraction may be different due to different experimental conditions, such as different diffraction test conditions and/or preferential orientations, etc. At the same time, due to the different accuracy of different instruments, the measured 2θ value will have an error of about ±0.2 2θ. However, it is known that the relative intensity values of the peaks are more dependent on certain properties of the sample being measured than the position of the peaks, such as the size of the crystals in the sample, the orientation of the crystals and the purity of the material being analysed, so the peaks shown Intensity deviations of about ±20% or greater are possible. However, despite the presence of experimental errors, instrumental errors and preferred orientations, etc., those skilled in the art can still obtain sufficient identification of crystal forms I, II, IV, V, amorphous forms and other crystal forms of the present invention from the PXRD data provided by the present invention. information.

Form I

The present invention provides the crystal form I of the compound of formula A.

In some embodiments, Form I of the compound of Formula A can be identified by powder X-ray diffraction. In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form I of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 6.4, 9.5, 14.1, 15.0 and 20.7 degrees, measured The 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form I of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.4, 7.4, 9.5, 13.4, 14.1, 15.0, 16.2 , 17.6 and 20.7 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form I of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.4, 7.4, 9.5, 13.4, 14.1, 15.0, 16.2 , 17.6, 19.1, 20.7, 22.2 and 23.9 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form I of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.4, 7.4, 9.5, 13.4, 14.1, 15.0, 16.2 , 17.6, 19.1, 20.7, 22.2, 23.9, 26.1 and 27.0 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form I of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.4, 7.4, 9.5, 12.9, 13.4, 14.1, 15.0 , 16.2, 17.6, 18.2, 19.1, 20.7, 22.2, 22.8, 23.9, 26.1 and 27.0 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the crystalline form I of the compound of formula A has a powder X-ray diffraction spectrum as shown in FIG. 1 .

In some embodiments, Form I of the compound of Formula A can be identified using differential scanning calorimetry analysis. In some embodiments, Form I of the compound of Formula A has a differential scanning calorimetry curve as shown in FIG. 2 . In the DSC spectrum, the endothermic peaks of the crystal form I of the compound of formula A are at about 47.6-83.8°C and about 172.6-180.5°C.

In some embodiments, Form I of the compound of Formula A can be identified using thermogravimetric analysis. In some embodiments, the crystalline form I of the compound of formula A has a thermogravimetric analysis curve as shown in Figure 3, which shows that the crystalline form I is a pure crystal.

In some embodiments, Form I of the compound of Formula A is substantially free of other forms described herein. For example, the weight content of the crystal form I of the compound of formula A is at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the weight content of the crystal form I of the compound of formula A reaches at least 70%, or at least 60%. Or further, the weight content of the crystal form I of the compound of formula A reaches at least 50%.

The preparation method of crystal form I

The present invention relates to a kind of preparation method of the crystal form I of compound of formula A, comprising:

(1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b] dissolving pyrrole-5(1H)-carboxamide and L-tartaric acid in methanol, heating and stirring, and reacting to form a salt;

(2) cooling the reaction solution obtained in step (1) to room temperature and stirring to promote salt precipitation;

(3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] pyrrole-5 (1H)-carboxamide tartrate crystal form I solid;

(4) Optionally, drying the resulting solid.

In some embodiments, the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo The molar ratio of [3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3.

In some embodiments, in the step (1), L-tartaric acid is dissolved in methanol, and compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7- Methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide.

In some embodiments, in the step (1), the heating temperature is about 40-55°C, such as about 50°C.

In some embodiments, in the steps (1) and (2), the stirring speed is medium speed, for example, from 50 rpm to 200 rpm.

In some embodiments, in the step (4), the drying temperature and drying time should be appropriate, so that the solid can be fully dried and maintain the required crystalline properties. In some embodiments, the drying temperature is 40°C.

The present invention relates to another preparation method of the crystal form I of the compound of formula A, comprising: preparing the crystal form I by transcrystallizing the crystal form I of the compound of formula A and the crystal form II of the compound of formula A in methanol. In this method, the crystallization can be carried out under heating and stirring, for example, the heating temperature is about 40-55°C, such as about 50°C.

Hydrate

The present invention also provides a hydrate of the compound of formula A.

In some embodiments, the hydrate of the compound of Formula A is the tetrahydrate.

In some embodiments, the tetrahydrate of the compound of Formula A is Form II.

In some embodiments, Form II of the tetrahydrate of the compound of Formula A can be identified by X-ray powder diffraction. The powder X-ray diffraction pattern of Form II (obtained by irradiation with CuKα) includes the following characteristic peaks represented by 2θ angles: 5.4, 6.1, 8.1, 14.2 and 16.3 degrees, and the measured 2θ values have an error of about ±0.2 2θ .

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form II of the tetrahydrate of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 5.4, 6.1, 8.1, 12.3, 14.2 , 16.3, 16.6, 19.7 and 20.5 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form II of the tetrahydrate of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 5.4, 6.1, 8.1, 10.7, 11.2 , 12.3, 14.2, 16.3, 16.6, 17.4, 19.7, 20.5 and 21.9 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form II of the tetrahydrate of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 5.4, 6.1, 8.1, 10.7, 11.2 .

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form II of the tetrahydrate of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 5.4, 6.1, 8.1, 10.7, 11.2 . .

In some embodiments, Form II of the tetrahydrate of the compound of Formula A has a diffraction pattern as shown in FIG. 4 .

In some embodiments, Form II of the tetrahydrate of the compound of Formula A can be identified using differential scanning calorimetry analysis. In some embodiments, Form II of the tetrahydrate of the compound of Formula A has a differential scanning calorimetry profile as shown in FIG. 5 . In the DSC spectrum, the endothermic peaks of the crystal form II of the tetrahydrate of the compound of formula A are at about 98.4-111.4°C and about 139.1-144.3°C.

In some embodiments, Form II of the tetrahydrate of the compound of Formula A can be identified using thermogravimetric analysis. In some embodiments, the crystal form II of the tetrahydrate of the compound of formula A has a thermogravimetric analysis curve as shown in FIG. 6 , which shows that the crystal form II is a tetrahydrate (containing 4 molecules of water).

In some embodiments, Form II of the tetrahydrate of the compound of Formula A is substantially free of other crystalline forms described herein. For example, the tetrahydrate of the compound of formula A has a weight content of Form II of at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the tetrahydrate of the compound of formula A has a weight content of Form II of at least 70%, or at least 60%. Or further, the tetrahydrate of the compound of formula A has a crystal form II weight content of at least 50%.

The preparation method of crystal form II

Method A

The present invention relates to a preparation method of the crystal form II of the tetrahydrate of the compound of formula A, comprising:

(1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b] dissolving pyrrole-5(1H)-carboxamide and L-tartrate in water, heating and stirring to make it react to form a salt;

(2) be cooled to room temperature and stir to promote salt precipitation;

(3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form II solid of pyrrole-5 (1H)-carboxamide tartrate;

(4) Optionally, drying the resulting solid.

In some embodiments, the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo The molar ratio of [3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3.

In some embodiments, in the step (1), the weight percentage of L-tartaric acid in water is about 2-7%, such as about 5%.

In some embodiments, in the step (1), L-tartaric acid is dissolved in water, and compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methyl Oxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide.

In some embodiments, in the step (1), the heating temperature is about 40-55°C, such as about 50°C.

In some embodiments, in the steps (1) and (2), the stirring speed is medium speed, for example, from 50 rpm to 200 rpm.

In some embodiments, in the step (4), the drying temperature and drying time should be appropriate, so that the solid can be fully dried and maintain the required crystalline properties.

Method B

The present invention relates to another preparation method of the crystal form II of the tetrahydrate of the compound of formula A, or a method for purifying the compound of formula A or its free base, comprising:

(1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] L-tartrate of pyrrole-5(1H)-carboxamide or (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazoline- 6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide and L-tartaric acid are added to a mixed solvent composed of a water-miscible organic solvent and water, heated and stir to dissolve;

(2) be cooled to room temperature and stir to promote salt precipitation;

(3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form II solid of pyrrole-5 (1H)-carboxamide tartrate;

(4) Optionally, drying the solid obtained in step (3).

In some embodiments, the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo The molar ratio of [3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3.

In some embodiments, the compound of formula A (ie, the L-tartrate salt) or its free base may be in crude form, eg, containing the s,s-isomer. Through the method of the present invention, the compound of formula A or its free base (eg crude product) can be purified, especially the content of s, s-isomer can be effectively reduced.

In some embodiments, the water-miscible organic solvent is selected from tetrahydrofuran or dioxane.

In some embodiments, the volume ratio of the water-miscible organic solvent to water in the mixed solvent is about 1:1 to 10:1. In some embodiments, the water-miscible organic solvent is tetrahydrofuran, and the volume ratio of tetrahydrofuran to water is about 1:1, or the water-miscible organic solvent is dioxane, and the volume ratio of dioxane to water is The ratio is about 10:1.

In some embodiments, in the step (1), the heating temperature is about 55-65° C., or heated to the reflux temperature of the solvent.

In some embodiments, in the steps (1) and (2), the stirring speed is medium speed, for example, from 50 rpm to 200 rpm.

In some embodiments, in the step (4), the drying temperature and drying time should be appropriate, so that the solid can be fully dried and maintain the required crystalline properties.

Method C

The present invention relates to a preparation method of the crystal form II of the tetrahydrate of the compound of formula A, comprising:

(1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b] adding pyrrole-5(1H)-carboxamide to a water-miscible organic solvent, adding an aqueous solution of L-tartrate to it, heating and stirring to make it react to form a salt;

(2) be cooled to room temperature and stir to promote salt precipitation;

(3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form II solid of pyrrole-5 (1H)-carboxamide tartrate;

(4) Optionally, drying the resulting solid.

In some embodiments, the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo The molar ratio of [3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3.

In some embodiments, in the aqueous solution of L-tartrate, the content of L-tartaric acid is about 2-7% (by weight), such as about 4%.

In some embodiments, the water-miscible organic solvent is selected from acetone, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, and mixtures thereof.

In some embodiments, the water-miscible solvent is mixed with water in an appropriate ratio, such as about 1:1 to 10:1 by volume; such as water/acetone (1/3 volume ratio), water/methanol (1/3 volume ratio), water/ethanol (1/3 volume ratio), water/isopropanol (1/3 volume ratio), water/acetonitrile (1/3 volume ratio), water/tetrahydrofuran (1/3 volume ratio or 1 /1 volume ratio).

In some embodiments, in the step (1), the heating temperature is about 40-55°C, such as about 50°C.

In some embodiments, in the steps (1) and (2), the stirring speed is medium speed, for example, from 50 rpm to 200 rpm.

In some embodiments, in the step (4), the drying temperature and drying time should be appropriate, so that the solid can be fully dried and maintain the required crystalline properties.

Form IV

The present invention also provides the crystal form IV of the compound of formula A.

In some embodiments, Form IV of the compound of Formula A can be identified by X-ray powder diffraction. In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form IV of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 6.5, 9.6, 12.2, 14.7 and 17.5 degrees, measured The 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form IV of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 6.5, 7.0, 7.3, 9.6, 12.2, 13.5, 14.7 , 17.5, 19.8 and 24.7 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form IV of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 6.5, 7.0, 7.3, 9.6, 12.2, 13.0, 13.5 , 14.0, 14.7, 17.5, 19.8, 21.2, 23.0 and 24.7 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form IV of the compound of formula A includes the following characteristic peaks represented by the following 2θ angles: 6.5, 7.0, 7.3, 9.6, 12.2, 13.0, 13.5 , 14.0, 14.7, 16.0, 17.0, 17.5, 19.8, 21.2, 22.5, 23.0, 24.7 and 26.9 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form IV of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.5, 7.0, 7.3, 9.6, 10.9, 12.2, 13.0 .

In some embodiments, Form IV of the compound of Formula A has a diffraction pattern as shown in FIG. 7 .

In some embodiments, Form IV of the compound of Formula A can be identified using differential scanning calorimetry analysis. In some embodiments, Form IV of the compound of Formula A has a differential scanning calorimetry profile as shown in FIG. 8 . In the DSC spectrum, the endothermic peaks of the crystal form IV of the compound of formula A are at about 42.0-74.9°C, about 146.0-150.7°C and about 178.8-184.3°C.

In some embodiments, Form IV of the compound of Formula A can be identified using thermogravimetric analysis. In some embodiments, the crystalline form IV of the compound of formula A has a thermogravimetric analysis curve as shown in Figure 9, which shows that the crystalline form IV is a pure crystal.

In some embodiments, Form IV of the compound of Formula A is substantially free of other forms described herein. For example, the weight content of Form IV of the compound of formula A is at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the weight content of Form IV of the compound of formula A is at least 70%, or at least 60%. Or further, the weight content of the crystalline form IV of the compound of formula A reaches at least 50%.

Preparation method of crystal form IV

Method A

The present invention relates to a preparation method of the crystal form IV of the compound of formula A, comprising:

(1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] pyrrole-5(1H)-carboxamide is dissolved in a mixed solvent of C _1-6 alkyl alcohol and halogenated alkanes with less than three carbon atoms, slowly adding an acetone solution of L-tartaric acid at room temperature, Stir to react to form a salt;

(2) isolated (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystalline form IV solid of pyrrole-5 (1H)-carboxamide tartrate;

(3) Optionally, drying the resulting solid.

In some embodiments, the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo The molar ratio of [3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3.

In some embodiments, the volume ratio of C _1-6 alkyl alcohol to halogenated alkanes with less than three carbon atoms in the mixed solution is about 1:1.

In some embodiments, the C _1-6 alkyl alcohol is methanol.

In some embodiments, the haloalkane of less than three carbon atoms is dichloromethane.

In some embodiments, in the acetone solution of L-tartaric acid, the weight-to-volume ratio of L-tartaric acid to acetone is about 10-20 mg/mL. In some embodiments, in the acetone solution of L-tartaric acid, the weight-to-volume ratio of L-tartaric acid to acetone is about 14-17 mg/mL.

In some embodiments, in the step (1), the stirring speed is medium speed, for example, from 50 rpm to 200 rpm.

In some embodiments, in the step (3), the drying temperature and drying time should be appropriate, so that the solid can be fully dried and the required crystalline properties can be maintained.

Method B

The present invention relates to another preparation method of the crystal form IV of the compound of formula A, comprising:

(1) Dissolve L-tartaric acid in C _2-6 water-miscible organic solvent, add compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazoline -6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, heated and stirred and kept in suspension, allowing it to react to form a salt;

(2) be cooled to room temperature and stir to promote salt precipitation;

(3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystalline form IV solid of pyrrole-5 (1H)-carboxamide tartrate;

(4) Optionally, drying the resulting solid.

In some embodiments, the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo The molar ratio of [3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3.

In some embodiments, the organic solvent is selected from ethanol, isopropanol, n-propanol, or acetone;

In some embodiments, in the step (1), the heating temperature is about 15-55°C, such as about 50°C.

In some embodiments, in the steps (1) and (2), the stirring speed is medium speed, for example, from 50 rpm to 200 rpm.

In some embodiments, in the step (4), the drying temperature and drying time should be appropriate, so that the solid can be fully dried and maintain the required crystalline properties.

Form V

The present invention also provides the crystal form V of the compound of formula A.

In some embodiments, Form V of the compound of Formula A can be identified by X-ray powder diffraction. In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form V of the compound of formula A includes characteristic peaks represented by the following 2θ angles: 6.5, 6.9, 7.8, 10.0 and 14.2 degrees, measured The 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form V of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.5, 6.9, 7.8, 9.5, 10.0, 12.7, 14.2 , 15.8 and 17.8 degrees, the measured 2θ value has an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form V of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.5, 6.9, 7.8, 9.5, 10.0, 12.7, 13.0 , 13.5, 14.2, 14.6, 15.8, 17.8 and 19.8 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form V of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.5, 6.9, 7.8, 9.5, 10.0, 12.7, 13.0 , 13.5, 14.2, 14.6, 15.8, 17.8, 19.8, 22.4 and 24.7 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction pattern (obtained by irradiation with CuKα) of the crystalline form V of the compound of formula A includes the following characteristic peaks represented by 2θ angles: 6.5, 6.9, 7.8, 9.5, 10.0, 12.7, 13.0 , 13.5, 14.2, 14.6, 15.8, 17.8, 19.8, 21.1, 22.4, 24.7 and 26.6 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, Form V of the compound of Formula A has a diffraction pattern as shown in FIG. 10 . .

In some embodiments, Form V of the compound of Formula A can be identified using differential scanning calorimetry analysis. In some embodiments, Form V of the compound of Formula A has a differential scanning calorimetry curve as shown in FIG. 11 . In the DSC spectrum, the endothermic peaks of the crystal form V of the compound of formula A are at about 150.7-162.1°C and about 174.1-181.3°C.

In some embodiments, Form V of the compound of Formula A can be identified using thermogravimetric analysis. In some embodiments, Form V of the compound of Formula A has a thermogravimetric analysis curve as shown in Figure 12, which shows that Form V is a pure crystal.

In some embodiments, Form V of the compound of Formula A is substantially free of other forms described herein. For example, the weight content of the crystal form V of the compound of formula A is at least 99%, at least 95%, at least 90%, or lower to 80%. Alternatively, the weight content of Form V of the compound of formula A is at least 70%, or at least 60%. Or further, the weight content of the crystal form V of the compound of formula A reaches at least 50%.

The preparation method of crystal form V

The present invention relates to the preparation method of the crystal form V of the compound of formula A, comprising:

(1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b]pyrrole-5(1H)-formamide is dissolved in a mixed solvent of C _1-6 alkyl alcohol and halogenated alkanes with less than three carbon atoms, slowly add L- A solution of tartaric acid in acetone, stirred to make it react to form a salt;

(2) Heat up to about 40-60°C, stir to make it continue to react to form a salt;

(3) be cooled to room temperature and stir to promote salt precipitation;

(4) isolated (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form V solid of pyrrole-5 (1H)-carboxamide tartrate;

(5) Optionally, drying the resulting solid.

In some embodiments, the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo The molar ratio of [3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3.

In some embodiments, the volume ratio of C _1-6 alkyl alcohol to halogenated alkanes with less than three carbon atoms in the mixed solution is about 1:1.

In some embodiments, the C _1-6 alkyl alcohol is methanol.

In some embodiments, the haloalkane of less than three carbon atoms is dichloromethane.

In some embodiments, in the acetone solution of L-tartaric acid, the volume ratio of L-tartaric acid to acetone is about 15-30 mg/mL.

In some embodiments, the stirring speed is moderate, for example, from 50 rpm to 200 rpm.

In some embodiments, in the step (5), the drying temperature and drying time should be appropriate, so that the solid can be fully dried and the required crystalline properties can be maintained.

not finalized

The present invention also provides an amorphous form of the compound of formula A.

In some embodiments, the amorphous form of the compound of formula A can be identified by X-ray powder diffraction. As stated in the text, the amorphous powder X-ray diffraction of the compound of formula A is characterized by no diffraction peaks in the range of 0-40 degrees 2Θ diffraction angle. The measured 2Θ values have an error of about ±0.2 degrees 2Θ.

In some embodiments, the amorphous form has a diffraction pattern similar to that shown in FIG. 13 .

Amorphous preparation method

The invention relates to a method for preparing an amorphous form of a compound of formula A, comprising: removing crystal water from a hydrate of the compound of formula A to obtain an amorphous form of the compound of formula A.

In some embodiments, the hydrate of the compound of formula A is the tetrahydrate of the compound of formula A.

In some embodiments, the hydrate of the compound of formula A is the tetrahydrate form II of the compound of formula A.

In some embodiments, the method for removing the water of crystallization is: rapidly heating the hydrate of the compound of formula A to remove the water of crystallization; the heating rate is about 8-12°C (for example, about 10°C), and heated to about 140- 160°C (eg about 150°C).

In some embodiments, the method for removing the water of crystallization is: placing the hydrate of the compound of formula A in an environment with a relative humidity of less than or equal to about 5%, until all the water of crystallization is removed.

Preparation of (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b ]Pyrrole-5(1H)-carboxamide method

The present invention also provides a method for preparing the free base of the compound of formula A, comprising: (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl )-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide tartrate, a compound of formula A or a hydrate thereof or a crystal form of a compound of formula A or a hydrate thereof (such as Form I, Form II, Form IV and Form V) or the amorphous form of the compound of formula A is converted to the free base of the compound of formula A.

In some embodiments, the method for preparing the free base of the compound of formula A comprises:

(3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b ]pyrrole-5(1H)-carboxamide tartrate, a compound of formula A or a hydrate thereof, or a crystal form of a compound of formula A or a hydrate thereof (such as crystal form I, crystal form II, crystal form IV and crystal form V) Or the amorphous compound of the formula A is suspended in a mixed solvent composed of a water-miscible organic solvent and water, an aqueous alkali solution is added, stirred until the solid is precipitated, and a solid product is obtained by separation, which is the free base of the compound of the formula A.

In some embodiments, in the mixed solvent composed of the water-miscible organic solvent and water, the volume ratio of the water-miscible organic solvent to water is about 1:5 to about 5:1.

In some embodiments, in the mixed solvent composed of the water-miscible organic solvent and water, the volume ratio of the water-miscible organic solvent to water is about 1:4. In some embodiments, in the mixed solvent composed of the water-miscible organic solvent and water, the volume ratio of ethanol to water is about 4:1.

In some embodiments, the water-miscible organic solvent is selected from acetone, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, and mixtures thereof.

In some embodiments, the water-miscible organic solvent is selected from methanol, ethanol, isopropanol, and mixtures thereof. In some embodiments, the water-miscible organic solvent is ethanol.

In some embodiments, the base is an inorganic base, eg, selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.

In some embodiments, the base is sodium carbonate.

In some embodiments, the free base of the compound of formula A is a crystal, and its powder X-ray diffraction characteristic diffraction angle (2θ) is 5.4, 6.5, 10.1, 12.2, 13.1, 16.2 degrees, and the measured 2θ value is about ±0.2 2θ error.

In some embodiments, the free base of the compound of formula A is a crystalline powder X-ray diffraction characteristic diffraction angle (2θ) of 5.4, 6.5, 8.0, 10.1, 10.8, 12.2, 13.1, 14.8, 16.2, 22.6, 25.4 degrees, the measured 2θ value has an error of about ±0.22θ.

In some embodiments, the free base of the compound of formula A is a crystalline powder X-ray diffraction characteristic diffraction angle (2θ) of 5.4, 6.5, 8.0, 10.1, 10.8, 12.0, 12.2, 13.1, 14.8, 16.2, 17.3, 18.1, 20.5, 22.6, 23.1, 25.4, 26.6 degrees, the measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the free base of the compound of formula A is a crystalline powder X-ray diffraction characteristic diffraction angle (2θ) of 5.4, 6.5, 8.0, 10.1, 10.8, 12.0, 12.2, 13.1, 14.8, 16.2, 17.3, 18.1, 18.8, 20.5, 21.1, 22.6, 23.1, 24.1, 25.4, 26.6, 27.2 degrees, the measured 2θ value has an error of about ±0.2 2θ.

In some embodiments, the free base of the compound of formula A is a crystalline powder X-ray diffraction characteristic diffraction angle (2θ) of 5.4, 6.5, 8.0, 10.1, 10.8, 12.0, 12.2, 13.1, 14.4, 14.8, 16.2, 17.3, 18.1, 18.8, 20.5, 21.1, 22.6, 23.1, 24.1, 25.4, 26.6, 27.2, 29.9, 30.7 degrees. The measured 2θ values have an error of about ±0.2 2θ.

In some embodiments, the free base of the compound of Formula A is crystalline, having a diffraction pattern as shown in FIG. 17 .

The various embodiments described in the present invention and the features in each embodiment should be understood as being able to be combined arbitrarily with each other, and the various solutions obtained by these mutual combinations are included in the scope of the present invention, just as specifically and one by one herein unless the context clearly indicates otherwise.

Pharmaceutical compositions and methods of treatment

The compound of formula A or its hydrate or the crystal form of the compound of formula A or its hydrate (such as crystal form I, crystal form II, crystal form IV and crystal form V) or the amorphous form of the formula A compound can be used for treating diseases, such as cancer .

Provided herein are methods of treating cancer comprising administering an active pharmaceutical ingredient formed from a compound of formula A, or a compound of formula A or a hydrate thereof or a crystalline form of a compound of formula A or a hydrate thereof (e.g., Form I, crystalline Form II, Form IV and Form V) or one or more of the amorphous form of the compound of formula A.

At least one selected from the compound of formula A or its hydrate or the crystal form (such as crystal form I, crystal form II, crystal form IV and crystal form V) of the compound of formula A or its hydrate or the amorphous form of the compound of formula A The amount of active pharmaceutical ingredient administered to achieve the desired physiological effect depends on various factors, for example, the purpose of use, the mode of administration, and the clinical condition of the patient. The daily dosage may, for example, range from 0.01 mg to 3 g per day (eg from 0.05 mg to 2 g per day, even from 100 mg to 1 g per day). Orally administrable unit dosage formulations include, for example, tablets or capsules.

In order to achieve the above-mentioned therapeutic purposes, a compound selected from formula A or a hydrate thereof or a crystal form of a compound of formula A or a hydrate thereof (such as crystal form I, crystal form II, crystal form IV and crystal form V) or formula A At least one active pharmaceutical ingredient in the amorphous form of the compound can be administered in the form of the compound itself, but usually they are all used in the form of a pharmaceutical composition with one or more pharmaceutically acceptable carriers, such as formulated administered in a suitable formulation.

A representative carrier should be compatible with the other ingredients of the composition and not endanger the health of the patient. The carrier can be solid or liquid, or both, and they are mixed with a compound of formula A or a hydrate thereof or a crystalline form of a compound of formula A or a hydrate thereof (for example, Form I, Form II, Form IV, and Form V) or an amorphous composition of a compound of formula A Pharmaceutical compositions or unit dosage forms (eg, tablets, capsules), which may contain 0.05% to 95% by weight of a compound of formula A. Carriers include excipients such as diluents, preservatives, disintegrants, lubricants, sweeteners, flavorants, colorants, dyes and emulsifiers. The pharmaceutical composition described in the present invention can be prepared by known pharmaceutical preparation methods, for example, the method includes mixing with a pharmaceutically acceptable carrier and the like.

In some examples, the compound of Formula A or a hydrate thereof or a crystalline form (e.g., Form I, Form II, Form IV, and Form V) of a compound of Formula A or a hydrate thereof, or an amorphous form of a compound of Formula A will not Transformation occurs upon formulation with one or more pharmaceutically acceptable carriers and/or adjuvants and/or diluents. In other examples, the compound of formula A or its hydrate or the crystal form of the compound of formula A or its hydrate (such as crystal form I, crystal form II, crystal form IV and crystal form V) or the amorphous form of the formula A compound is in When formulated with one or more pharmaceutically acceptable carriers and/or adjuvants and/or diluents, it may be transformed, wholly or partially, into one or more crystalline forms, including into non-solid forms. In some instances, the crystalline form I or other crystalline forms of the present invention can be dissolved when made into a pharmaceutical composition. Thus, in these "dissolved" instances, Form I or other crystalline forms no longer exist in their respective crystalline forms in the pharmaceutical composition.

The pharmaceutical compositions described in the present invention may be those suitable for oral and oral (such as sublingual) administration, as well as various parenteral dosage forms, and the appropriate administration may depend on each individual. The severity of the condition of the case and the treatment situation also depends on the crystal form selected from the compound of formula A or its hydrate or the compound of formula A or its hydrate (such as crystal form I, crystal form II, crystal form IV and crystal form V ) or the properties of the specific form of the pharmaceutically active ingredient in the amorphous form of the compound of formula A used in the preparation of the pharmaceutical composition.

At least one of the crystal forms (such as crystal form I, crystal form II, crystal form IV and crystal form V) of the compound of formula A or its hydrate or the compound of formula A or its hydrate or the amorphous form of the compound of formula A Suitable pharmaceutical compositions for oral administration may also be in unit dosage form such as capsules, cachets and tablets, including suckable tablets, each consisting of at least one of the The active pharmaceutical ingredient of the invention is prepared quantitatively; its formulation form can also be selected from powder, granule, solution, suspension in water or non-aqueous liquid, oil-in-water and water-in-oil emulsion. These compositions can also be prepared by any suitable method for the preparation of pharmaceutical preparations as described above. For example, these methods include the following steps: (eg, Form I, Form II, Form IV, and Form V) or at least one active pharmaceutical ingredient in an amorphous form of a compound of Formula A and a carrier are mixed together. These compositions can generally be selected from a compound of formula A or a hydrate thereof or a crystalline form (such as form I, form II, form IV and form V) of a compound of formula A or a hydrate thereof or an amorphous form of a compound of formula A It is prepared by uniformly and homogeneously mixing at least one active pharmaceutical ingredient and liquid or finely divided solid carrier, and its product can be made into a certain shape.

At least one selected from the compound of formula A or its hydrate or the crystal form (such as crystal form I, crystal form II, crystal form IV and crystal form V) of the compound of formula A or its hydrate or the amorphous form of the compound of formula A Active pharmaceutical ingredients may also be used in combination with one or more other active ingredients (eg, in synergistic therapy). When used in combination, the active ingredients may be separate compositions for simultaneous administration by the same or different routes of administration or separately (e.g., sequentially in any order) administration at different times in therapy, or they may be administered in the same administered together in a pharmaceutical composition.

In some examples, a compound selected from Formula A or a hydrate thereof or a crystalline form of a compound of Formula A or a hydrate thereof (such as Form I, Form II, Form IV, and Form V) or an amorphous form of a compound of Formula A At least one of the active pharmaceutical ingredients may be administered simultaneously with one or more other active ingredients known to have a therapeutic effect, such as for the treatment of cancer.

The "combined use" mentioned here is used to define the crystal form selected from the compound of formula A or its hydrate or the compound of formula A or its hydrate (such as crystal form I, crystal form II, crystal form IV and crystal form V) Or the combination of at least one active pharmaceutical ingredient in the amorphous form of the compound of formula A and one or more other active ingredients, such as in an anti-tumor method. Here, "anti-tumor method" may refer to any method aimed at treating cancer. Examples of anti-tumor methods include, but are not limited to: radiotherapy, immunization, DNA damaging chemotherapy, chemotherapy that disrupts cell replication. Drugs for DNA damaging chemotherapy and cell replication disrupting chemotherapy are known in the art, for example as described in patent application CN102906086A.

Thus, the methods described herein are not limited to the order of administration, and one or more of the other active ingredients may be administered concurrently or before or after administration. In the combination described above, at least one pharmaceutically active ingredient is derived from a compound of formula A or a hydrate thereof or a crystal form of a compound of formula A or a hydrate thereof (such as crystal form I, crystal form II, crystal form IV and crystal form V) or an amorphous form of a compound of formula A.

The following are non-limiting examples.

Experimental part

The compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[ 3,4-b]pyrrole-5(1H)-carboxamide raw material is prepared according to CN102906086A.

All reagents (except intermediates) used in the present invention are commercially available. All compound names (except reagents) were generated by the software ChemBioDraw Ultra 16.0.

Unless otherwise noted, powder X-ray diffraction spectra were obtained by German Bruker D8 ADVANCE (target: Cu (CuKα irradiation), voltage: 40kV, current: 40mA, scanning speed: 4 degrees/min, step size: 0.02 degrees , Measurement range: 3-45 degrees) measurement.

Differential scanning calorimetry was determined by Perkin Elmer's DSC7 (purge gas: nitrogen, flow rate: 50mL min ^-1 , heating rate: 5-10°C/min, measurement range: 25°C→200°C), the sample Measurements were made using perforated aluminum pans, with temperature correction using indium.

Thermogravimetric analysis was determined by TGA7 from Perkin Elmer (purge gas: nitrogen, flow rate: 50 mL min-1, heating rate: 10°C/min).

The preparation of the crystal form I of embodiment 1 formula A compound

At 50°C, 3.6g (24mmol, 1.2eq) of L-tartaric acid was dissolved in 60mL of methanol, and the compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino)-7-methoxy Quinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide 8.84g (20mmol) was added to the system, and stirred at 50°C for 4 hours , cooled to room temperature over 2 hours, and stirred overnight. Filtrate and dry in vacuum at 50°C for two days to obtain 11.03g of product, yield: 89.0%.

¹ H-NMR (399MHz, DMSO) δ9.66(s, 1H), 8.66(d, J=4.0Hz, 1H), 8.49(s, 1H), 7.86(dd, J=8.2, 1.2Hz, 1H) ,7.58(s,1H),7.35(t,J=7.9Hz,1H),7.24(s,1H),7.16(dt,J=7.6,1.2Hz,1H),4.21(s,2H),4.16( s,1H),3.99(s,3H),3.65(dd,J=15.5,6.6Hz,2H),3.40(dd,J=11.5,5.3Hz,1H),3.27(dd,J=10.2,6.3Hz ,1H),3.11(t,J=8.6Hz,1H),3.02–2.95(m,1H),2.87(s,1H),2.39(d,J=8.6Hz,1H),2.35(s,3H) ,2.03(dd,J＝13.0,7.0Hz,1H),1.67–1.56(m,1H).

The obtained powder sample is crystal form I, and its powder X-ray diffraction pattern is shown in FIG. 1 . The peaks selected from it have the following values: 6.4, 7.4, 9.5, 12.9, 13.4, 14.1, 15.0, 16.2, 17.6, 18.2, 19.1, 20.7, 22.2, 22.8, 23.9, 26.1 and 27.0 degrees, each with different angular errors ±0.2 degrees (2θ), where the characteristic peaks are: 6.4, 9.5, 14.1, 15.0 and 20.7 degrees.

DSC test showed that the crystal form I had endothermic peaks at 47.6-83.84° C. and 172.6-180.5° C., respectively, as shown in FIG. 2 .

The thermogravimetric analysis curve is shown in Figure 3, which shows that there is a small amount of weight loss in the thermogravimetric analysis curve, and the crystal form I is pure crystal.

The preparation of the crystal form I of embodiment 2 formula A compound

Mix 63mg of the crystalline form I sample of the compound of formula A (prepared according to the method described above) and 63mg of the crystalline form II sample of the compound of formula A (prepared according to the method described in the following example) in 1.26ml of methanol, and stir at 50°C for 30 Hours, a solid sample was obtained by filtration. It was determined that the powder X-ray diffraction spectrum of the obtained sample was consistent with that of the sample obtained in Example 1, which was crystal form I.

The preparation of the crystal form II of embodiment 3 formula A compound

At 50°C, 2.4g (16mmol, 1.2eq) of L-tartaric acid was dissolved in 51mL of water, and 6g (13.6mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino)-7 -Methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide was added to the system, and the system was clear. Stir to precipitate a solid, and keep stirring at 50° C. for 2 hours. After 1.5 hours, it was cooled to room temperature and stirred for 2 hours, filtered, and the filter cake was washed with ethanol/water mixed solvent (3/1, v/v), and vacuum-dried at 40°C overnight to obtain 9.0g product, yield: 99.9% (according to tetrahydrate).

¹ H NMR (399MHz, DMSO) δ9.67(s, 1H), 8.66(s, 1H), 8.49(s, 1H), 7.99(t, J=1.8Hz, 1H), 7.86(dd, J=8.2 ,1.2Hz,1H),7.59(s,1H),7.35(t,J=7.9Hz,1H),7.24(s,1H),7.18–7.14(m,1H),4.22(s,2H),4.16 (s,1H),3.99(s,3H),3.65(d,J=10.8Hz,2H),3.40(dd,J=11.5,5.3Hz,1H),3.27(dd,J=10.2,6.3Hz, 1H), 3.12(t, J=7.5Hz, 2H), 3.00(s, 1H), 2.87(s, 1H), 2.40(d, J=8.9Hz, 1H), 2.35(s, 3H), 2.05– 1.93(m,1H),1.67–1.57(m,1H).

The obtained powder sample is crystal form II, and its powder X-ray diffraction pattern is shown in FIG. 4 . The peaks selected from it have the following values: 5.4, 6.1, 8.1, 10.7, 11.2, 12.3, 13.2, 13.7, 14.2, 15.4, 15.8, 16.3, 16.6, 17.4, 18.7, 19.7, 20.5, 21.9, 23.8, 24.2, 25.6 , 26.8 and 27.8 degrees, each different angle error ±0.2 degrees (2θ), where the characteristic peaks are: 5.4, 6.1, 8.1, 12.3, 14.2, 16.3, 16.6, 19.7 and 20.5 degrees.

DSC test shows that Form II has endothermic peaks at about 98.4-111.4°C and about 138.1-144.3°C, respectively, as shown in FIG. 5 .

The thermogravimetric analysis curve is shown in Fig. 6, which shows that the crystal form II is a hydrate crystal form, containing four crystal waters (4H ₂ O).

The preparation of the crystal form II of embodiment 4 formula A compound

At 60°C, dissolve 500mg of the compound of formula A (prepared by reacting the free base of the compound of formula A with L tartaric acid) in 10mL of tetrahydrofuran/water=1/1 (v/v), naturally cool to 40°C and keep stirring 1 hour, then naturally cooled to room temperature and stirred overnight. After filtering, the filter cake was vacuum-dried overnight at room temperature, and then vacuum-dried at 50° C. for 4 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of embodiment 5 formula A compound

At 50°C, 18 mg (0.12 mmol) of L-tartaric acid was dissolved in 0.5 mL of water to form an aqueous solution of L-tartaric acid, and 45 mg (0.10 mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylaniline )-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-formamide was stirred in 1.5mL methanol; L -Aqueous solution of tartaric acid is added to compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[ 3,4-b] pyrrole-5(1H)-carboxamide in methanol solution, stirred overnight at 50°C. The temperature was lowered to room temperature over 1.5 hours, stirred for 6 hours, and filtered. After vacuum drying at room temperature overnight, vacuum drying at 50° C. for 4 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of embodiment 6 formula A compound

At 50°C, 18 mg (0.12 mmol, 1.2 eq) of L-tartaric acid was dissolved in 0.5 mL of water to form an aqueous solution of L-tartaric acid, and 45 mg (0.10 mmol) of compound (3aR, 6aR)-N-(4-(3-acetylene phenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide by adding 1.5 mL of isopropanol Stirring in the medium, adding L-tartaric acid aqueous solution to the compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl- A solution of hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide in isopropanol was stirred overnight at 50°C. Cool down to room temperature over 1.5 hours, stir at room temperature for 6 hours, filter, vacuum dry overnight at room temperature, and then vacuum dry at 50°C for 4 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of embodiment 7 formula A compound

At 50°C, 18 mg (0.12 mmol, 1.2 eq) of L-tartaric acid was dissolved in 0.5 mL of water to form an aqueous solution of L-tartaric acid, and 45 mg (0.10 mmol) of compound (3aR, 6aR)-N-(4-(3-acetylene Add phenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-formamide into 1.5mL tetrahydrofuran and stir , adding tartaric acid aqueous solution to the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo [3,4-b]pyrrole-5(1H)-carboxamide in tetrahydrofuran solution, stirred overnight at 50°C. Cool down to room temperature over 1.5 hours, stir at room temperature for 6 hours, filter, vacuum dry overnight at room temperature, and vacuum dry at 50°C for 4 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of embodiment 8 formula A compound

At 50°C, 18 mg (0.12 mmol, 1.2 eq) of L-tartaric acid was dissolved in 0.5 mL of water to form an aqueous solution of L-tartaric acid, and 45 mg (0.10 mmol) of compound (3aR, 6aR)-N-(4-(3-acetylene Add 1.5mL acetonitrile and stir , adding tartaric acid aqueous solution to the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo A solution of [3,4-b]pyrrole-5(1H)-carboxamide in acetonitrile was stirred overnight at 50°C. Cool down to room temperature over 1.5 hours, stir at room temperature for 6 hours, filter, vacuum dry overnight at room temperature, and vacuum dry at 50°C for 4 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of embodiment 9 formula A compound

At 50°C, 18 mg (0.12 mmol, 1.2 eq) of L-tartaric acid was dissolved in 0.5 mL of water to form an aqueous solution of L-tartaric acid, and 45 mg (0.10 mmol) of compound (3aR, 6aR)-N-(4-(3-acetylene Add 1.5mL acetone to 1.5mL acetone and stir , adding tartaric acid aqueous solution to the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo A solution of [3,4-b]pyrrole-5(1H)-carboxamide in acetone was stirred overnight at 50°C. Cool down to room temperature over 1.5 hours, stir at room temperature for 6 hours, filter, vacuum dry overnight at room temperature, and vacuum dry at 50°C for 4 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of the compound of formula A of embodiment 10

At 50°C, 18 mg (0.12 mmol, 1.2 eq) of L-tartaric acid was dissolved in 0.5 mL of water to form an aqueous solution of L-tartaric acid, and 45 mg (0.10 mmol) of compound (3aR, 6aR)-N-(4-(3-acetylene Add 1.5mL ethanol to 1.5mL ethanol and stir , adding tartaric acid aqueous solution to the compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo [3,4-b]pyrrole-5(1H)-carboxamide in ethanol solution, stirred overnight at 50°C. Naturally lowered to room temperature, stirred at room temperature for 6 hours, filtered, vacuum dried overnight at room temperature, and then vacuum dried at 50°C for 4 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of the compound of formula A of embodiment 11

Suspend 100mg of the compound of formula A (prepared by reacting the free base of the compound of formula A with L tartaric acid) in a mixed solvent consisting of 1,4-dioxane (30ml) and water (3ml), and heat to reflux to dissolve , then naturally cooled to room temperature, stirred overnight, 70 mg of solid precipitated out, yield: 70%. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form II of the compound of formula A of embodiment 12

The compound (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b] Add 1 g of crude pyrrole-5(1H)-carboxamide (containing about 1.76% of s, s-isomer) and 0.41 g of L-tartaric acid into a mixed solvent composed of tetrahydrofuran (12ml) and water (12ml), and stir Dissolve under heating. The mixture was cooled to room temperature from heat under stirring, and a solid precipitated out. Filter and dry to obtain 1.3 g of solid, yield 86.7%, purity: 99.4%, s, s-isomer impurity: 0.35%. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 3, which is crystal form II.

The preparation of the crystal form IV of the compound of formula A of embodiment 13

At room temperature, 5.96g (39.7mmol, 2.2eq) of L-tartaric acid was dissolved in 400mL of acetone, and 8g (18.1mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino) -7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide dissolved in 180mL methanol/dichloromethane=1 In /1 (v/v), the acetone solution of L-tartaric acid was slowly added to the methanol/dichloromethane solution of the compound, stirred overnight at room temperature, filtered, and the filter cake was washed with 16ml of acetone. Vacuum dried at 50°C overnight to obtain 11.6 g of product, yield: 93.0%.

¹ H NMR (399MHz, DMSO) δ9.67(s, 1H), 8.66(s, 1H), 8.49(s, 1H), 7.99(t, J=1.7Hz, 1H), 7.86(dd, J=8.3 ,1.2Hz,1H),7.60(s,1H),7.35(t,J＝7.9Hz,1H),7.25(d,J＝3.4Hz,1H),7.18–7.14(m,1H),4.23–4.21 (m,2H),4.16(s,1H),3.99(s,3H),3.65(dd,J=10.2,6.6Hz,2H),3.42(dd,J=11.5,5.4Hz,1H),3.28( dd,J＝10.3,6.2Hz,1H),3.18–3.10(m,1H),3.09–3.02(m,1H),2.89(s,1H),2.44(d,J＝8.6Hz,1H),2.38 (s,3H),2.09–2.02(m,1H),1.63(ddd,J=21.4,10.7,6.3Hz,1H).

The obtained powder sample is crystal form IV, and its powder X-ray diffraction pattern is shown in FIG. 7 . The peaks selected from it have the following values: 6.5, 7.0, 7.3, 9.6, 10.9, 12.2, 13.0, 13.5, 14.0, 14.7, 15.5, 16.0, 17.0, 17.5, 19.4, 19.8, 21.2, 22.1, 22.5, 23.0, 24.7 and 26.9 degrees, each with a different angle error of ±0.2 degrees (2θ), where the characteristic peaks are: 6.5, 9.6, 12.2, 14.7 and 17.5 degrees.

DSC test shows that Form IV has endothermic peaks at 42.0-74.9°C, 146.0-150.7°C and 178.8-184.3°C, respectively, as shown in Figure 8 .

The thermogravimetric analysis curve is shown in Figure 9, which shows that the crystal form IV is a pure crystal. It can be concluded from the experiment that the crystal form IV is hygroscopic, so there is a small amount of weight loss in the thermogravimetric analysis curve.

The preparation of the crystal form IV of the compound of formula A of embodiment 14

At 50°C, 36mg (0.24mmol, 1.2eq) of L-tartaric acid was dissolved in 4mL of ethanol, and 89mg (0.2mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino) was added -7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, stirred at 50°C for 1 hour, Naturally cooled to room temperature, stirred overnight at room temperature, filtered, and vacuum-dried at 50°C overnight to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 13, which is crystal form IV.

The preparation of the crystal form IV of the compound of formula A of embodiment 15

At 50°C, 66mg (0.44mmol, 2.2eq) of L-tartaric acid was dissolved in 4mL of acetone, and 89mg (0.2mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino) was added -7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, stirred overnight at 50°C, naturally Cool to room temperature, stir at room temperature for 4 hours, filter, and dry under vacuum at 50°C overnight to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 13, which is crystal form IV.

The preparation of the crystal form IV of the compound of formula A of embodiment 16

At 50°C, 66mg (0.44mmol, 2.2eq) of L-tartaric acid was dissolved in 6mL of isopropanol, and 89mg (0.2mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylphenyl Amino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, stirred at 50°C for 2 Hours, naturally cooled to room temperature, stirred overnight at room temperature, filtered, vacuum dried at room temperature over the weekend, and then vacuum dried at 50°C for 5 hours to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 13, which is crystal form IV.

The preparation of the crystal form IV of the compound of formula A of embodiment 17

At 50°C, dissolve 36mg (0.24mmol, 1.2eq) of L-tartaric acid in 6mL of n-propanol, add 89mg (0.2mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylphenyl Amino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, stirred at 50°C for 3 Hours, naturally cooled to room temperature, stirred overnight at room temperature, filtered, and dried under vacuum at 50°C overnight to obtain a solid sample. It has been determined that the powder X-ray diffraction spectrum of the sample obtained by this method is consistent with that of the sample obtained in Example 13, which is crystal form IV.

Preparation of Form V of Example 18 Compound of Formula A

At room temperature, 0.41g (2.73mmol, 1.2eq) of L-tartaric acid was dissolved in 18mL of acetone, and 1g (2.26mmol) of compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino) -7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide dissolved in 22mL methanol/dichloromethane=1 In /1 (v/v), the acetone solution of tartaric acid was slowly added to the methanol/dichloromethane solution of the compound, stirred at room temperature for 1 hour, raised to 50°C, stirred overnight, cooled naturally to room temperature, stirred for 4 hours, filtered . Vacuum dried at 50° C. over the weekend to obtain 1.33 g of product, yield: 96.3%.

¹ H NMR (399MHz, DMSO) δ9.66(s, 1H), 8.66(d, J=4.1Hz, 1H), 8.49(s, 1H), 7.99(t, J=1.8Hz, 1H), 7.86( dd,J=7.8,1.7Hz,1H),7.59(s,1H),7.35(t,J=7.9Hz,1H),7.24(d,J=3.0Hz,1H),7.17(dt,J=7.6 ,1.2Hz,1H),4.22(s,2H),4.16(s,1H),3.99(s,3H),3.66(t,J=10.4Hz,2H),3.40(dd,J=11.5,5.4Hz ,1H),3.27(dd,J=10.2,6.3Hz,1H),3.12(t,J=7.5Hz,1H),2.99(d,J=5.9Hz,1H),2.87(s,1H),2.40 (d,J=8.8Hz,1H),2.35(s,3H),2.07–1.99(m,1H),1.67–1.56(m,1H).

The obtained powder sample is crystal form V, and its powder X-ray diffraction pattern is shown in FIG. 10 . The peaks selected from it have the following values: 6.5, 6.9, 7.8, 9.5, 10.0, 12.7, 13.0, 13.5, 14.2, 14.6, 15.8, 17.8, 19.8, 21.1, 22.5, 24.7 and 26.6 degrees, each with different angular errors ±0.2 degrees (2θ), where the characteristic peaks are: 6.5, 6.9, 7.8, 10.0, 12.7, 14.2 degrees.

DSC test showed that Form V had endothermic peaks at 150.7-162.1°C and 174.1-181.3°C, respectively, as shown in Figure 11 .

The thermogravimetric analysis curve is shown in Figure 12, which shows that there is a small amount of weight loss in the thermogravimetric analysis curve, which is the adsorption of volatile substances, and the crystal form V is pure crystal.

The preparation of the amorphous form of the compound of formula A of embodiment 19

Put the crystal form II of the compound of formula A into the sample pan of the thermogravimetric instrument, and heat it at 10°C per minute to 150°C to lose crystal moisture, and obtain a solid sample, which is amorphous. Its PXRD is shown in FIG. 13 .

Embodiment 20: Hygroscopicity experiment

Determination method: put a certain amount of sample into the sample tray of a dynamic moisture adsorption instrument (DVS INTRINSIC, Surface Measurement System Ltd UK) and balance it to a constant weight at a relative humidity of 0%, and start the moisture adsorption-desorption test. The test conditions are as follows:

Temperature: 25°C

Humidity range: 0-95%RH

Humidity step: 5%RH

Results: The test results of Form I, Form II and Form IV are shown in Figure 14, Figure 15 and Figure 16, respectively.

Figure 14 shows that the crystal form I is stable when the relative humidity is below about 40%, and has no obvious hygroscopicity. When the relative humidity reaches about 45%, the hygroscopicity increases rapidly, and after the relative humidity reaches about 75%, the hygroscopicity increases significantly again and forms hydrate. Hydrates begin to lose water of crystallization below 5% relative humidity and are stable in the range of about 10% to about 85% relative humidity.

Figure 15 shows that the crystal form II sample rapidly absorbs water to form a hydrate when the relative humidity reaches 20% after equilibration. When the relative humidity is 5-95%, the moisture of the crystal form II will not be lost due to the change of humidity, so the crystal form II is stable in the relative humidity range of 10-95%.

Figure 16 shows that the crystal form IV is hygroscopic when the relative humidity is less than 70%, and the moisture absorption is 2.78%. When the relative humidity exceeds 70%, the hygroscopic ability is significantly enhanced and a hydrate is formed. The formed hydrate loses water during the desorption process when the relative humidity is lower than 5%.

Embodiment 21 stability test

Determination method: take 0.5g of crystal form I, crystal form II and crystal form IV of the test product, respectively, and place them in a petri dish, and place them in a sealed clean container with the opening exposed, at 60°C, 25°C and relative humidity Place it under the conditions of 92.5%±5% and illuminance of 4500lx±500lx for 5 days, take a sample on the 5th day, investigate the purity (tested by HPLC) and crystal form (tested by PXRD) of the sample, and compare and investigate As a result, the results are shown in Table 1 below.

Table 1 The experimental results of the influencing factors of crystal form I, crystal form II and crystal form IV

Conclusion: The crystal form I was placed under high temperature and light for 5 days, the crystal form remained unchanged, the purity did not decrease significantly, and the crystal form I was stable. Under high humidity conditions, the crystal form I transforms into the tetrahydrate crystal form II, but its chemical purity does not change significantly, and it has good chemical stability.

The crystal form II remains unchanged under the conditions of high temperature, light and high humidity, and the purity does not change significantly, and the crystal form II is stable under the experimental conditions.

The crystal form IV remains unchanged under high temperature and light conditions, the purity does not decrease significantly, and the crystal form IV is stable. Under high humidity conditions, most of the crystal form IV is transformed into crystal form II, and only a small amount of crystal form IV remains, indicating that its crystal form is unstable under high humidity conditions, but its chemical purity does not change significantly, and it has good chemical stability sex.

Embodiment 22 solubility comparison

Take an appropriate amount of compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3, 4-b] The sample of pyrrole-5(1H)-carboxamide and the crystal form II sample of the compound of formula A prepared by the method described in the above examples were placed in different pH buffers, stirred at 37°C for 3-4 hours, and the samples were taken Filter, test the solubility of the sample in the solution (tested by HPLC) and the crystal form of the residual sample in the solution (tested by PXRD), the results are shown in Table 2.

Table 2

Conclusion: The solubility of free base has a strong acid-base dependence. Under acidic conditions, the solubility of free base is slightly larger. Under alkaline and neutral conditions, free base is almost insoluble. The solubility of the crystal form II of the compound of formula A has no obvious acid-base dependence, and has relatively large solubility at various pHs.

Example 23 Preparation of free base with compound of formula A

Suspend 0.25 g of the compound of formula A (prepared by reacting the free base of the compound of formula A with L tartaric acid) in 7.5 ml of 20% ethanol/water mixed solvent, add aqueous sodium carbonate solution (2 equivalents) thereto, stir at room temperature for two days, Filtration and drying gave a solid sample. The powder X-ray diffraction spectrum of the sample obtained by this method is shown in FIG. 17 . The peaks selected from it had the following values: 5.4, 6.5, 8.0, 10.1, 10.8, 12.0, 12.2, 13.1, 14.4, 14.8, 16.2, 17.3, 18.1, 18.8, 20.5, 21.1, 22.6, 23.1, 24.1, 25.4, 26.6 , 27.2, 29.9, 30.7 degrees, each different angle error is ±0.2 degrees (2θ), and the characteristic peaks are: 5.4, 6.5, 10.1, 12.2, 13.1, 16.2 degrees.

Example 24 Preparation of free base with compound of formula A

Suspend 0.25 g of the compound of formula A (prepared by reacting the free base of the compound of formula A with L tartaric acid) in 7.5 ml of 80% ethanol/water mixed solvent, add aqueous sodium carbonate solution (2 equivalents) thereto, stir at room temperature for two days, Filtration and drying gave a solid sample. The powder X-ray diffraction spectrum of the sample obtained by this method is consistent with the sample obtained in Example 23.

It should be understood that the examples and implementations described herein are for illustrative purposes only, and various improvements or changes will be suggested to those skilled in the art in view of this, and they are included in the spirit and scope of the application and the appended within the scope of the claims. All publications, patents, and patent applications cited herein are incorporated by reference for all purposes.

Claims (15)

1. (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b] Tartrate salt of pyrrole-5(1H)-carboxamide. 2. (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo represented by formula A Tartrate of [3,4-b]pyrrole-5(1H)-carboxamide: 3. The salt of claim 2, wherein Said salt is crystal form I, and its powder X-ray diffraction pattern obtained by irradiation with CuKα includes characteristic peaks represented by the following 2θ angles: 6.4, 9.5, 14.1, 15.0 and 20.7 degrees, and each 2θ value has about ±0.2 ° error; or The salt is in the crystalline form IV, and its powder X-ray diffraction pattern obtained by irradiation with CuKα includes the following characteristic peaks represented by the following 2θ angles: 6.5, 9.6, 12.2, 14.7 and 17.5 degrees, each 2θ value has about ± 0.2 2θ error; or The salt is Form V, and its powder X-ray diffraction pattern obtained by irradiation with CuKα includes the following characteristic peaks represented by the following 2θ angles: 6.5, 6.9, 7.8, 10.0 and 14.2 degrees, each 2θ value has about ± 0.2 2θ error; or said salt is amorphous; or The salt is the tetrahydrate. 4. The salt according to claim 3, wherein the tetrahydrate is crystal form II, and the powder X-ray diffraction spectrum obtained by CuKα irradiation comprises the characteristic peaks represented by the following 2θ angles: 5.4, 6.1, 8.1, 14.2 and 16.3 degrees, each 2θ value has an error of about ±0.2°. 5. The salt according to any one of claims 2-4, characterized in that, The salt is crystal form I, and its powder X-ray diffraction pattern obtained by irradiation with CuKα includes the following characteristic peaks represented by 2θ angles: 6.4, 7.4, 9.5, 13.4, 14.1, 15.0, 16.2, 17.6 and 20.7 degrees, Each 2θ value has an error of approximately ±0.2°; or The salt is crystal form IV, and its powder X-ray diffraction pattern obtained by irradiation with CuKα includes the following characteristic peaks represented by 2θ angles: 6.5, 7.0, 7.3, 9.6, 12.2, 13.5, 14.7, 17.5, 19.8 and 24.7 degrees, with an error of approximately ±0.2° for each 2θ value; or The salt is crystal form V, and its powder X-ray diffraction pattern obtained by irradiation with CuKα includes the following characteristic peaks represented by 2θ angles: 6.5, 6.9, 7.8, 9.5, 10.0, 12.7, 14.2, 15.8 and 17.8 degrees, Each 2θ value has an error of approximately ±0.2°; or The salt is a tetrahydrate crystal form II, and its powder X-ray diffraction spectrum obtained by CuKα irradiation includes the following characteristic peaks represented by 2θ angles: 5.4, 6.1, 8.1, 12.3, 14.2, 16.3, 16.6, 19.7 and 20.5 degrees, with an error of approximately ±0.2° for each 2θ value; or The salt is amorphous, and its powder X-ray diffraction characteristic is that there is no diffraction peak in the range of 0-40 degrees 2θ diffraction angle. 6. The salt according to any one of claims 2-5, characterized in that, The salt is Form I, which is characterized by the powder X-ray diffraction spectrum shown in Figure 1; or The salt is Form IV, which is characterized by the powder X-ray diffraction spectrum shown in Figure 7; or The salt is Form V, which is characterized by the powder X-ray diffraction pattern shown in Figure 10; or The salt is tetrahydrate crystal form II, which is characterized by the powder X-ray diffraction spectrum shown in Figure 4; or The salt is amorphous, which is characterized by the powder X-ray diffraction pattern shown in FIG. 13 . 7. A pharmaceutical composition, characterized in that the pharmaceutical composition contains an effective amount of one or more of the salts according to any one of claims 1-6, and a pharmaceutically acceptable carrier. 8. Use of the salt according to any one of claims 1-6 in the preparation of a medicament, the medicament is used for the treatment of cancer, the cancer is for example selected from lung cancer, including non-small cell lung cancer, non-small cell lung cancer with brain Metastasis, head and neck cancer, colorectal cancer, colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, brain cancer, breast cancer, pharyngeal cancer, epidermoid cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, esophageal cancer, Bone cancers and sarcomas such as soft tissue sarcomas and leukemias. 9. A method for treating cancer, comprising administering to an individual in need thereof an effective amount of one or more salts according to any one of claims 1-6, said cancer being for example selected from lung cancer, including non-small cell Lung cancer, non-small cell lung cancer with brain metastases, head and neck cancer, colorectal cancer, colorectal cancer, rectal cancer, colon cancer, pancreatic cancer, brain cancer, breast cancer, pharyngeal cancer, epidermoid cancer, ovarian cancer, prostate cancer, gastric cancer, Kidney cancer, liver cancer, esophageal cancer, bone cancer and sarcomas such as soft tissue sarcomas and leukemia. 10. The salt according to any one of claims 1-6, for use in the treatment of cancer, such as selected from lung cancer, including non-small cell lung cancer, non-small cell lung cancer with brain metastases, head and neck cancer, colorectal cancer, Colorectal, rectal, colon, pancreas, brain, breast, pharynx, epidermoid, ovary, prostate, stomach, kidney, liver, esophagus, bone and sarcomas such as soft tissue sarcomas and leukemia. 11. A method of inhibiting overexpression and/or overactivity of epidermal growth factor receptor comprising contacting epidermal growth factor receptor with an effective amount of one or more salts according to any one of claims 1-6 . 12. The salt according to any one of claims 1-6 is used for the preparation of (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl Use of )-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide. 13. The preparation method of the salt described in any one in the claim 3-6, wherein: (a) The preparation method of the crystal form I of the salt comprises: (1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b] pyrrole-5(1H)-carboxamide and L-tartaric acid were dissolved in methanol, heated and stirred, and reacted to form a salt; wherein, Preferably, L-tartaric acid is dissolved in methanol, and compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl) is added thereto -1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide; and/or Preferably, the heating temperature is about 40-55°C, such as about 50°C; (2) cooling the reaction solution obtained in step (1) to room temperature and stirring to promote salt precipitation; (3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] pyrrole-5 (1H)-carboxamide tartrate crystal form I solid; (4) optionally, drying the resulting solid; or The crystalline form I is prepared by transcrystallizing the crystalline form I of the salt and the crystalline form II of the salt in methanol. Preferably, the crystallization can be carried out under heating and stirring, for example, the heating temperature is about 40-55 °C, for example about 50 °C; (b) The preparation method of the crystal form IV of the salt comprises: (1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] pyrrole-5(1H)-carboxamide is dissolved in a mixed solvent of C _1-6 alkyl alcohol and halogenated alkanes with less than three carbon atoms, slowly adding an acetone solution of L-tartaric acid at room temperature, Stir to allow it to react to form a salt; where, Preferably, the volume ratio of C _1-6 alkyl alcohol to halogenated alkanes with less than three carbon atoms in the mixed solution is about 1:1; Preferably, the C _1-6 alkyl alcohol is methanol; Preferably, the haloalkane with less than three carbon atoms is dichloromethane; and/or Preferably, in the acetone solution of L-tartaric acid, the weight-volume ratio of L-tartaric acid to acetone is about 10-20 mg/mL; more preferably, the weight-volume ratio of L-tartaric acid to acetone is about 14-17 mg/mL ; (2) isolated (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystalline form IV solid of pyrrole-5 (1H)-carboxamide tartrate; (3) Optionally, drying the resulting solid; or (1) Dissolve L-tartaric acid in C _2-6 water-miscible organic solvent, add compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazoline -6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, heating and stirring and keeping in suspension, allowing it to react to form a salt; wherein, Preferably, the organic solvent is selected from ethanol, isopropanol, n-propanol or acetone; and/or Preferably, the heating temperature is about 15-55°C, such as about 50°C; (2) be cooled to room temperature and stir to promote salt precipitation; (3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystalline form IV solid of pyrrole-5 (1H)-carboxamide tartrate; (4) optionally, drying the resulting solid; (c) The preparation method of the crystal form V of the salt comprises: (1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b]pyrrole-5(1H)-formamide is dissolved in a mixed solvent of C _1-6 alkyl alcohol and halogenated alkanes with less than three carbon atoms, slowly add L- Acetone solution of tartaric acid, stirred to make it react to form salt; wherein, Preferably, the volume ratio of C _1-6 alkyl alcohol to halogenated alkanes with less than three carbon atoms in the mixed solution is about 1:1; Preferably, the C _1-6 alkyl alcohol is methanol; Preferably, the haloalkane with less than three carbon atoms is dichloromethane; and/or Preferably, in the acetone solution of L-tartaric acid, the volume ratio of L-tartaric acid to acetone is about 15-30 mg/mL; (2) Heat up to about 40-60°C, stir to make it continue to react to form a salt; (3) be cooled to room temperature and stir to promote salt precipitation; (4) isolated (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form V solid of pyrrole-5 (1H)-carboxamide tartrate; (5) optionally, drying the resulting solid; (d) The preparation method of tetrahydrate or tetrahydrate crystal form II of the salt comprises: (1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b] pyrrole-5(1H)-carboxamide and L-tartrate are dissolved in water, heated and stirred to make it react to form a salt; wherein, Preferably, L-tartaric acid is dissolved in water, and compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)- 1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide; and/or Preferably, the weight percent of L-tartaric acid in water is about 2-7%, such as about 5%; (2) be cooled to room temperature and stir to promote salt precipitation; (3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form II solid of pyrrole-5 (1H)-carboxamide tartrate; (4) optionally, drying the resulting solid; or (1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] L-tartrate of pyrrole-5(1H)-carboxamide or (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazoline- 6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide and L-tartaric acid are added to a mixed solvent composed of a water-miscible organic solvent and water, heated and stirred to dissolve; where, Preferably, the L-tartrate salt or its free base may be in crude form, for example containing the s,s-isomer; Preferably, the water-miscible organic solvent is selected from tetrahydrofuran or dioxane; Preferably, the volume ratio of the water-miscible organic solvent to water in the mixed solvent is about 1:1 to 10:1; Preferably, the water-miscible organic solvent is tetrahydrofuran, more preferably the volume ratio of tetrahydrofuran to water is about 1:1, or the water-miscible organic solvent is dioxane, more preferably dioxane and Water in a volume ratio of about 10:1; and/or Preferably, the heating temperature is about 55-65 ° C, or heated to the solvent reflux temperature; (2) be cooled to room temperature and stir to promote salt precipitation; (3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form II solid of pyrrole-5 (1H)-carboxamide tartrate; (4) optionally, drying the resulting solid; or (1) Compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 ,4-b] adding pyrrole-5(1H)-carboxamide to a water-miscible organic solvent, adding an aqueous solution of L-tartrate to it, heating and stirring to make it react to form a salt; wherein, Preferably, in the aqueous solution of L-tartrate, the content of L-tartaric acid is about 2-7% (weight content), such as about 4%; Preferably, the water-miscible organic solvent is selected from acetone, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, dioxane and mixtures thereof; Preferably, the water-miscible solvent and water are mixed in a volume ratio of about 1:1 to 10:1; for example, water/acetone volume ratio: 1/3, water/methanol volume ratio: 1/3, water/ethanol volume ratio: 1/3, water/isopropanol by volume: 1/3, water/acetonitrile by volume: 1/3, water/THF by volume: 1/3 or 1/1; and/or Preferably, the heating temperature is about 40-55°C, such as about 50°C; (2) be cooled to room temperature and stir to promote salt precipitation; (3) isolated to obtain (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b] the crystal form II solid of pyrrole-5 (1H)-carboxamide tartrate; (4) optionally, drying the resulting solid; and / or (e) The preparation method of the amorphous form of the salt comprises: removing the crystal water from the hydrate of the salt to obtain the amorphous form of the salt; wherein, Preferably, the method for removing the water of crystallization is: rapidly heating the hydrate to remove the water of crystallization; the heating rate is about 8-12°C (for example, about 10°C), and heated to about 140-160°C (for example, about 150°C); Or place the hydrate in an environment with a relative humidity of less than or equal to about 5% until all the water of crystallization is removed; and/or Preferably, the hydrate is tetrahydrate; more preferably, the hydrate is the crystal form II according to any one of claims 4-6. 14. The preparation method according to claim 13, wherein: compound (3aR, 6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1- The molar ratio of methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide to L-tartaric acid is about 1:1 to 1:3. 15. (3aR,6aR)-N-(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b] the preparation method of pyrrole-5 (1H)-formamide, comprising: converting the salt described in any one of claims 1-6 into (3aR, 6aR)-N-(4-(3-ethynylbenzene Amino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, preferably the resulting compound is crystalline form.