阅读说明：本技术 一种金刚烷胺类化合物的晶型及其制备方法 (Crystal form of amantadine compound and preparation method thereof ) 是由 徐巾超 叶辉青 李英龙 张�杰 林碧悦 寇景平 陈勇 罗忠华 黄芳芳 于 2020-03-03 设计创作，主要内容包括：本发明涉及一种金刚烷胺类化合物的晶型及其制备方法,属于药物化学领域。本发明所述晶型在稳定性、溶解性、溶出、药理等方面具有良好的性能,可用于制备药物制剂生产中。(The invention relates to a crystal form of an amantadine compound and a preparation method thereof, belonging to the field of pharmaceutical chemistry. The crystal form has good performances in the aspects of stability, solubility, dissolution, pharmacology and the like, and can be used for preparing pharmaceutical preparations.)

1. A crystalline form A of a compound of formula (I):

characterized by having diffraction peaks at the following 2 theta angles by an X-ray powder diffractometer using Cu-Ka radiation: 6.83, 8.15, 10.89, 11.44, 14.87, 15.85, 16.58, 19.83 and 22.09.

2. Form A of the compound of formula (I) according to claim 1, characterized by having diffraction peaks at the following 2 θ angles by X-ray powder diffractometer using Cu-Ka radiation: 4.76, 6.83, 8.15, 10.89, 11.44, 12.32, 14.87, 15.85, 16.58, 19.83, 20.55, 20.81 and 22.09; or it has diffraction peaks at the following 2 θ angles: 5.44, 10.16, 13.65, 14.33, 17.13, 17.54, 18.81, 19.18, 22.70, 23.11, 34.73 and 36.38; or it has diffraction peaks at the following 2 θ angles: 4.76, 5.24, 5.70, 7.58, 9.61, 11.92, 12.32, 13.18, 15.31, 17.82, 18.14, 18.64, 20.55, 20.81, 21.85, 23.47, 24.06, 24.57 and 25.11; or it has diffraction peaks at the following 2 θ angles: 4.76, 5.24, 5.44, 5.70, 6.83, 8.15, 10.16, 10.89, 11.44, 12.32, 13.65, 14.33, 14.87, 15.31, 15.85, 16.58, 17.13, 17.82, 18.81, 19.18, 19.83, 20.55, 20.81, 22.09 and 23.47; or it has diffraction peaks at the following 2 θ angles: 4.76, 5.24, 5.44, 5.70, 6.83, 7.58, 8.15, 9.61, 10.16, 10.89, 11.44, 11.92, 12.32, 13.18, 13.65, 14.33, 14.87, 15.31, 15.85, 16.58, 17.13, 17.54, 17.82, 18.14, 18.64, 18.81, 19.18, 19.83, 20.55, 20.81, 21.85, 22.09, 22.70, 23.11, 23.47, 24.06, 24.57, 25.11, 34.73 and 36.38.

3. Form A of the compound of formula (I) according to claim 1 or 2, characterized in that it is present in a substantially water-free form or it has an endothermic peak at 35 ℃ -45 ℃ in its differential scanning calorimetry curve.

4. Form a of the compound of formula (I) according to any one of claims 1 to 3, wherein said form a has an X-ray powder diffraction pattern substantially as shown in figure 1 or said form a has a differential scanning calorimetry pattern substantially as shown in figure 2.

5. Form A of the compound of formula (I) according to any one of claims 1 to 4, having a form A content of at least 90%, or having a form A content of at least 95%, or having a form A content of at least 97%, or having a form A content of at least 98%, or having a form A content of at least 99% by mass ratio to the compound of formula (I).

6. A composition comprising the compound of formula (I) as defined in any one of claims 1 to 4 in crystalline form a and at least one pharmaceutically acceptable excipient, said composition comprising from 0.01% to 99% of crystalline form a, based on the total weight of the composition; wherein, the content of the crystal form A is at least 90 percent or the content of the crystal form A is not more than 0.01 to 10 percent in terms of the mass ratio of the crystal form A to the compound shown in the formula (I).

7. A process for preparing form a of a compound of formula (I) as defined in any one of claims 1 to 5, which comprises: under the room temperature or heating condition, mixing the compound shown in the formula (I) with a solvent to obtain a mixture, then continuously stirring the obtained mixture, and naturally volatilizing to obtain the crystal form A, or cooling, stirring and filtering the obtained mixture to obtain the crystal form A; or under room temperature or heating condition, mixing the compound shown in the formula (I) with a good solvent, then mixing with water, stirring, and filtering to obtain a crystal form A; wherein the content of the first and second substances,

the solvent is at least one of methanol, ethanol, trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, isobutanol, isoamyl alcohol, acetone, butanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl formate, methyl acetate, dimethyl carbonate, 1, 4-dioxane, toluene, methyl tert-butyl ether, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, cyclohexane, n-heptane and dichloromethane; or

The good solvent is at least one of methanol, ethanol, isopropanol, acetone, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether.

8. The method according to claim 7, wherein the temperature is 20-100 ℃ under heating; or the temperature is-20 ℃ to 20 ℃ in the cooling and stirring process.

9. The process according to claim 7, wherein the solvent is used in an amount of 1ml to 30ml per gram of the compound of formula (I); or the dosage of the good solvent is 1ml to 50ml per gram of the compound shown in the formula (I), and the volume ratio of the good solvent to water is 1:1 to 1: 4.

10. The method according to claim 7, wherein the stirring time is controlled to be 0.1 to 12 hours; or after filtration, drying the obtained crystal at room temperature or-5-20 ℃ to constant weight.

Technical Field

The invention relates to a crystal form of an amantadine compound and a preparation method thereof, belongs to the field of pharmaceutical chemistry, and particularly relates to crystal forms of (((((1R, 3R,5S,7R) -3, 5-dimethyl adamantane-1-yl) carbamoyl) oxy) methyl palmitate and (((((1R, 3R,5S,7R) -3, 5-dimethyl adamantane-1-yl) carbamoyl) oxy) methyl stearate and a preparation method thereof.

Background

Most of the transmission of synaptic excitation is rapid signaling with glutamate as neurotransmitter. N-methyl-D-aspartate receptors (NMDARs) are a class of ionotropic glutamate receptors whose function is primarily involved in the refinement of neural circuits during development and in triggering various forms of synaptic plasticity. Plays an important physiological role in the processes of learning, memory and emotion regulation. An increasing number of studies have shown that NMDAR is involved in a number of pathological processes, including stroke-induced brain cell death, neuropsychiatric disorders and neurological/psychiatric disorders such as schizophrenia and depression. Hyperexcitability of NMDAR leads to too high concentrations of Ca2+ in the neurosynaptic and to an increase in the background noise of signaling, so that changes in the information when learning and memory occur are not obvious or difficult to discern, manifesting as dementia. Chronic cranial nerve diseases such as senile dementia, huntington's disease, atrophic myelitis and AIDS dementia are all related to prolonged hyperexcitation of NMDAR due to excessive concentration of glutamic acid secreted in brain nerve cells for a long time. In addition, during cerebral ischemia and hypoxia, the secretion of glutamic acid is also increased sharply, and the hyperexcitation of the NMDAR is a main reason for the loss of brain cells after brain surgery and various brain diseases.

Alzheimer's Disease (AD) is a neurodegenerative disease, also known as alzheimer's disease, a common disease in the elderly. The disease affects memory, location, judgment and reasoning of the elderly, and shows clinical symptoms such as hypomnesis, cognitive dysfunction, behavioral abnormalities and social disturbance. Death caused by complications occurs in l0-20 years after the disease occurs, and the life quality of the human in later life is seriously influenced.

The amantadine compound is used as a micromolecule reversible antagonist of NMDAR, can effectively inhibit NMDA overexcitation, and has the function of protecting cortical nerves from being damaged. Due to noncompetitive antagonism at the N-methyl-D-aspartate receptor, part of the amantadine compounds have been used clinically in the treatment of moderate to severe Alzheimer's Disease (AD), such as: memantine hydrochloride, and the like. With the development of society, the aging speed of population is accelerated, the incidence rate of Alzheimer's disease is increased year by year, and the incidence situation is very severe. Therefore, it is important to develop more bioactive amantadine compounds, study that different salts and solid forms thereof may have different properties, and provide more excellent formulations by changing the properties of different salts and solid forms, for example, easy synthesis or handling, improved dissolution rate or improved stability and shelf life.

Biological experiments show that the compound shown as the formula (I) (((((1R, 3R,5S,7R) -3, 5-dimethyl adamantan-1-yl) carbamoyl) oxy) methyl palmitate and the compound shown as the formula (II) (((((1R, 3R,5S,7R) -3, 5-dimethyl adamantan-1-yl) carbamoyl) oxy) methyl stearate

Can be metabolized into memantine raw drug in vivo, has good slow release effect, and can be used for treating central nervous system diseases (see patent application WO 2017193870). The inventors have studied and found that the white solid of the compound represented by the formula (I) prepared by the method disclosed in example 7 of patent application WO2017193870 (compound 4) is a wax, and the microscopic morphology of the white solid cannot be detected and determined, and the wax is not favorable for transfer in production and research on pharmaceutical preparations, and is difficult to use in subsequent research and production and use processes. Although the process disclosed in example 5 of patent application WO2017193870 (compound 9) produces the aforementioned white solid of the compound of formula (II) as a crystal, it is still necessary to study the crystal form of the compound of formula (II), which is beneficial for the development and research of pharmaceutical preparations.

According to the invention, a large number of experimental researches are carried out on the compound shown in the formula (I) and the compound shown in the formula (II), and different solvents are used for recrystallization to obtain a plurality of new crystal forms of the two compounds with similar structures, so that the research on the crystal forms provides opportunities for improving the overall performance (easy synthesis or treatment, improved dissolution rate or improved stability and shelf life) of the medicinal product, and simultaneously, the variety of materials available for formulation scientists to design the medicinal preparation is enlarged, and the method is of great importance for the research and development of medicaments. The crystal form of the medicine is an important factor influencing the quality of the medicine, and different crystal forms of the same medicine molecule have obvious differences in the aspects of appearance, solubility, melting point, dissolution rate, bioavailability and other properties, so that the stability, bioavailability and curative effect of the medicine are directly influenced.

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a crystal form A of (((((1R, 3R,5S,7R) -3, 5-dimethyladamantan-1-yl) carbamoyl) oxy) methyl palmitate shown in a formula (I) and a preparation method thereof, wherein the crystal form has good characteristics such as stability. The invention also provides a crystal form B of ((((1R,3R,5S,7R) -3, 5-dimethyl adamantan-1-yl) carbamoyl) oxy) methyl palmitate and a preparation method thereof.

The crystal form of ((((1R,3R,5S,7R) -3, 5-dimethyl adamantan-1-yl) carbamoyl) oxy) methyl palmitate provided by the invention can be used for treating nervous system diseases.

The crystal forms are researched, and the crystal forms have good performances in the aspects of stability, solubility, dissolution, pharmacology and the like, and can be used for preparing pharmaceutical preparation production.

In one aspect, the invention provides a crystalline form a of a compound of formula (I):

form a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-ka radiation: 6.83, 8.15, 10.89, 11.44, 12.32, 14.87, 15.85, 16.58, 19.83, 20.55 and 22.09.

In some embodiments, the form a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 4.76, 6.83, 8.15, 10.89, 11.44, 12.32, 14.87, 15.85, 16.58, 19.83, 20.55, 20.81 and 22.09.

In some embodiments, the form a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 4.76, 5.24, 5.70, 7.58, 8.15, 9.61, 11.44, 11.92, 12.32, 13.18, 14.87, 15.31, 15.85, 16.58, 17.82, 18.14, 18.64, 19.83, 20.55, 20.81, 21.85, 22.09, 23.47, 24.06, 24.57 and 25.11.

In some embodiments, the form a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 5.44, 6.83, 10.16, 10.89, 13.65, 14.33, 17.13, 17.54, 18.81, 19.18, 22.70, 23.11, 34.73 and 36.38.

In some embodiments, the form a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 4.76, 5.24, 5.44, 5.70, 6.83, 8.15, 10.16, 10.89, 11.44, 12.32, 13.65, 14.33, 14.87, 15.31, 15.85, 16.58, 17.13, 17.82, 18.81, 19.18, 19.83, 20.55, 20.81, 22.09 and 23.47.

In some embodiments, the form a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 4.76, 5.24, 5.44, 5.70, 6.83, 7.58, 8.15, 9.61, 10.16, 10.89, 11.44, 11.92, 12.32, 13.18, 13.65, 14.33, 14.87, 15.31, 15.85, 16.58, 17.13, 17.54, 17.82, 18.14, 18.64, 18.81, 19.18, 19.83, 20.55, 20.81, 21.85, 22.09, 22.70, 23.11, 23.47, 24.06, 24.57, 25.11, 34.73 and 36.38.

In some embodiments, the form a has an X-ray powder diffraction pattern (XRD pattern) substantially as shown in figure 1.

In some embodiments, the differential scanning calorimetry curve of form a has an endothermic peak at 35 ℃ to 45 ℃. In some embodiments, the differential scanning calorimetry curve of form a has an endothermic peak at 39 ℃ ± 2 ℃ with a peak top value of 39 ℃.

In some embodiments, the form a has a differential scanning calorimetry curve (DSC profile) as shown in figure 2.

In some embodiments, the thermogravimetric analysis curve (TGA) of form a shows about 0.10% weight loss between 0 ℃ and 120 ℃, which can be considered substantially free of weight loss. In some embodiments, the crystalline form a has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 3. According to DSC and TGA detection results of the crystal form A, the crystal form A is considered to exist in a form which is basically free of water and is an anhydrous crystal form. The content of the crystal form A is higher, and the content of the crystal form A is at least 90 percent, or the content of the crystal form A is at least 95 percent, or the content of the crystal form A is at least 97 percent, or the content of the crystal form A is at least 98 percent, or the content of the crystal form A is at least 99 percent calculated by the mass ratio of the crystal form A to the compound shown in the formula (I).

In one aspect, the invention also provides a composition. The composition contains the crystal form A of the compound shown in the formula (I) and at least one pharmaceutically acceptable auxiliary material. In some embodiments, the composition contains 0.01% to 99% of form a and at least one pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the composition contains 0.01% to 95% of form a and at least one pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the composition contains 0.01% to 90% of form a and at least one pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the composition contains 0.1% to 90% of form a and at least one pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the composition contains 1% to 90% of form a and at least one pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the composition contains 5% to 90% form a and at least one pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the composition contains 10% to 90% form a and at least one pharmaceutically acceptable excipient, based on the total weight of the composition.

In some embodiments, the aforementioned composition has a crystalline form a content of at least 90%, or at least 95%, or at least 97%, or at least 99%, by mass ratio to the compound of formula (I). In some embodiments, the aforementioned composition comprises at least 0.1%, alternatively at least 0.5%, alternatively at least 1%, alternatively at least 5%, alternatively at least 10%, of form a by mass relative to the compound of formula (I).

In some embodiments, the amount of form a in the aforementioned composition is not more than 0.01% to 10%, alternatively not more than 0.1% to 10%, alternatively not more than 1% to 10%, alternatively not more than 5% to 10%, alternatively not more than 1% to 5%, by mass relative to the compound of formula (I). In some embodiments, the aforementioned composition contains no more than 5%, or 4%, or 3%, or 2%, or 1%, or 0.5%, or 0.1%, or 0.05%, or 0.01% of form a by mass relative to the compound of formula (I).

In some embodiments, the composition, comprising the aforementioned form a and at least one pharmaceutically acceptable excipient, comprises 0.01% to 99% form a; wherein, the content of the crystal form A is at least 90 percent or the content of the crystal form A is not more than 0.01 to 10 percent in terms of the mass ratio of the crystal form A to the compound shown in the formula (I). In some embodiments, the composition, comprising the aforementioned form a and at least one pharmaceutically acceptable excipient, comprises 0.01% to 99% form a; wherein, the content of the crystal form A is at least 95 percent or the content of the crystal form A is not more than 0.1 to 10 percent in terms of mass ratio to the compound shown in the formula (I). In some embodiments, the composition, comprising the aforementioned form a and at least one pharmaceutically acceptable excipient, comprises 0.01% to 99% form a; wherein, the content of the crystal form A is at least 95 percent or the content of the crystal form A is not more than 1 to 10 percent in terms of mass ratio to the compound shown in the formula (I). In some embodiments, the composition, comprising the aforementioned form a and at least one pharmaceutically acceptable excipient, comprises 0.01% to 99% form a; wherein, the content of the crystal form A is at least 95 percent or the content of the crystal form A is not more than 5 to 10 percent in terms of mass ratio to the compound shown in the formula (I).

In another aspect, the invention provides a crystalline form B of a compound of formula (I):

form B is characterized by having diffraction peaks at the following 2 θ (units: degrees, error. + -. 0.2 degrees) angles by using an XX ray powder diffractometer for Cu-Ka radiation: 5.09, 5.63, 7.07, 8.57, 9.76, 10.71, 12.65, 12.89, 14.62, 15.04, 15.35, 16.38, 17.74, 18.27, 19.90, 21.66, 21.86, 23.76 and 25.88.

In some embodiments, the form B has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 4.31, 6.41, 8.81, 9.28, 13.98, 14.22, 16.75, 17.23, 18.59, 18.88, 22.25, 27.16 and 37.79.

In some embodiments, the form B has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 4.31, 5.09, 5.63, 6.41, 7.07, 8.57, 8.81, 9.28, 9.76, 10.71, 12.65, 12.89, 13.98, 14.22, 14.62, 15.04, 15.35, 16.38, 16.75, 17.23, 17.74, 18.27, 18.59, 18.88, 19.90, 21.66, 21.86, 22.25, 23.76, 25.88, 27.16 and 37.79.

In some embodiments, the crystalline form B has an X-ray powder diffraction pattern (XRD pattern) substantially as shown in figure 4.

In some embodiments, the form B has a differential scanning calorimetry curve (DSC profile) as shown in figure 5.

In some embodiments, the crystalline form B has a thermogravimetric analysis curve (TGA) showing a weight loss of about 18.8% between 30 ℃ and 120 ℃.

In some embodiments, the crystalline form B has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 6.

In another aspect, the present invention provides a process for preparing form a of the compound of formula (I) as described above.

A process for preparing form a of the compound of formula (I) as hereinbefore described comprising: mixing a compound shown as a formula (I) with a solvent at room temperature or under a heating condition to obtain a mixture; then continuously stirring the obtained mixture, and naturally volatilizing to obtain the crystal form A, or cooling, stirring and filtering the obtained mixture to obtain the crystal form A; or mixing the compound shown in the formula (I) with a good solvent at room temperature or under a heating condition, then mixing with water, stirring, and filtering to obtain the crystal form A.

In some embodiments, a method of making a compound of formula (I) as described above in crystalline form a, comprises: mixing a compound shown as a formula (I) with a solvent at room temperature to obtain a mixture; then continuously stirring the obtained mixture, and naturally volatilizing to obtain a crystal form A; or mixing the compound shown in the formula (I) with a solvent at room temperature to obtain a mixture; and then cooling and stirring the obtained mixture, and filtering to obtain the crystal form A.

In some embodiments, a method of making a compound of formula (I) as described above in crystalline form a, comprises: under the heating condition, mixing a compound shown as a formula (I) with a solvent to obtain a mixture; then continuously stirring the obtained mixture, and naturally volatilizing to obtain a crystal form A; or under the heating condition, mixing the compound shown in the formula (I) with a solvent to obtain a mixture; and then cooling and stirring the obtained mixture, and filtering to obtain the crystal form A.

The solvent can be at least one selected from alcohol solvents, ketone solvents, ester solvents, ether solvents, alkane solvents, acetonitrile, tetrahydrofuran and 1, 4-dioxane. In some embodiments, the solvent is a mixed solvent of acetonitrile and at least one of alcohol solvents. In some embodiments, the solvent is a mixed solvent of alcoholic solvents. In some embodiments, the solvent may be at least one of methanol, ethanol, trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, isobutanol, isoamyl alcohol, acetone, butanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, isopropyl acetate, butyl formate, methyl acetate, dimethyl carbonate, methyl tert-butyl ether, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, cyclohexane, n-heptane, dichloromethane, toluene, and the like, or any mixture thereof.

Under the heating condition, the temperature can be 20-100 ℃, or 25-80 ℃, or 25-60 ℃, or 25-40 ℃, or 40-60 ℃; or 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.

The solvent is used in an amount of 1ml to 30ml per gram of the compound of formula (I). In some embodiments, the solvent is used in an amount of 3ml to 30ml per gram of the compound of formula (I). In some embodiments, the solvent is used in an amount of 3ml to 20ml per gram of the compound of formula (I). In some embodiments, the solvent is used in an amount of 5ml to 30ml per gram of the compound of formula (I). In some embodiments, the solvent is used in an amount of 5ml to 20ml per gram of the compound of formula (I). In some embodiments, the amount of the solvent is 10ml to 30ml per gram of the compound of formula (I), which facilitates obtaining form a.

In the cooling and stirring process, the temperature can be between-20 and 20 ℃. In some embodiments, the temperature may be-10 ℃ to 10 ℃ during the cooling and stirring process. In some embodiments, the temperature may be-5 ℃ to 5 ℃ during the cooling and stirring process. In some embodiments, the temperature may be-5 ℃ to 0 ℃ during the cooling and stirring process. In some embodiments, the temperature is 0 ℃ during the cooling and stirring process.

In some embodiments, a method of making a compound of formula (I) as described above in crystalline form a, comprises: mixing a compound shown in a formula (I) with a solvent at room temperature, continuously stirring, and naturally volatilizing to obtain a crystal form A, or mixing a compound shown in a formula (I) with a solvent at room temperature, cooling, stirring, and filtering to obtain a crystal form A; the solvent is at least one of methanol, ethanol, trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, isobutanol, isoamyl alcohol, acetone, butanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl formate, methyl acetate, dimethyl carbonate, 1, 4-dioxane, toluene, methyl tert-butyl ether, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, cyclohexane, n-heptane and dichloromethane.

In some embodiments, the solvent is a mixed solvent of methanol and acetonitrile. In some embodiments, the solvent is a mixed solvent of methanol and trifluoroethanol. In some embodiments, the solvent is a mixed solvent of ethanol and acetonitrile.

In some embodiments, a method of making a compound of formula (I) as described above in crystalline form a, comprises: mixing the compound shown in the formula (I) with a good solvent at room temperature or under a heating condition to obtain a mixture, then adding the mixture into water, or adding the water into the mixture, stirring and filtering to obtain the crystal form A. In some embodiments, a method of making a compound of formula (I) as described above in crystalline form a, comprises: mixing the compound shown in the formula (I) with a good solvent at room temperature to obtain a mixture, then adding the mixture into water, or adding water into the mixture, stirring and filtering to obtain the crystal form A. In some embodiments, a method of making a compound of formula (I) as described above in crystalline form a, comprises: under the heating condition, mixing the compound shown in the formula (I) with a good solvent to obtain a mixture, then adding the mixture into water, or adding water into the mixture, stirring and filtering to obtain the crystal form A.

The good solvent can be at least one of methanol, ethanol, isopropanol, acetone, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether. In some embodiments, the good solvent is ethanol or acetone, or a mixed solvent of ethanol and acetone.

Under the heating condition, the compound shown in the formula (I) is mixed with a good solvent, and the temperature can be 20-100 ℃, or 25-80 ℃, or 25-60 ℃, or 25-40 ℃, or 40-60 ℃ when the heating condition is adopted; or 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.

The volume ratio of the good solvent to the water can be 1:1 to 1: 4. In some embodiments, the volume ratio of the good solvent to water is 1: 2.

The dosage of the good solvent is 1ml to 50ml for each gram of the compound shown in the formula (I). In some embodiments, the good solvent is used in an amount of 3ml to 30ml per gram of the compound of formula (I). In some embodiments, the good solvent is used in an amount of 5ml to 30ml per gram of the compound of formula (I). In some embodiments, the amount of the good solvent is 10ml to 30ml per gram of the compound of formula (I). In some embodiments, the good solvent is used in an amount of 5ml to 20ml per gram of the compound of formula (I).

In the method, after filtration, the obtained crystal is dried at room temperature or-5-20 ℃, and forced air drying or vacuum drying or natural volatilization drying is adopted to constant weight, and then the crystal form A is obtained.

In the foregoing method, the stirring time may be controlled to be 0.1 hour to 12 hours, or 0.1 hour to 10 hours, or 0.1 hour to 8 hours, or 0.1 hour to 6 hours, or 0.1 hour to 4 hours, or 0.1 hour to 2 hours, or 0.1 hour to 1 hour, or 0.5 hour to 8 hours, or 0.5 hour to 4 hours, or 0.5 hour to 2 hours.

In some embodiments, a method of making a compound of formula (I) as described above in crystalline form a, comprises: under the condition of heating or room temperature, mixing the compound shown in the formula (I) with ethanol or acetone or a mixed solvent of ethanol and acetone to obtain a clear mixture, then adding the obtained mixture into water or adding water into the mixture under the condition that the temperature is controlled not to exceed 20 ℃, separating out a solid, stirring for 0.1-12 hours, filtering, and carrying out vacuum drying at room temperature to obtain the crystal form A.

In another aspect, the present invention provides a process for preparing form B of the compound of formula (I) as described above, comprising: under the condition of heating or room temperature, mixing the compound shown in the formula (I) with a solvent, cooling, stirring and filtering to obtain a crystal form B; the solvent can be dimethyl sulfoxide, or a mixed solvent of dimethyl sulfoxide and any one or more of methyl tert-butyl ether, methanol, N-dimethylformamide, acetone and toluene; in the cooling and stirring process, the temperature can be between 20 ℃ below zero and 20 ℃. In some embodiments, the temperature during the cooling and stirring process may be-10 ℃ to 10 ℃, or-5 ℃ to 5 ℃, or-5 ℃ to 0 ℃, or 0 ℃.

In some embodiments, a method of making the compound of formula (I) in crystalline form B, as described above, comprises: and (3) mixing the compound shown in the formula (I) with dimethyl sulfoxide at room temperature, and stirring for volatilization to obtain the crystal form B.

In some embodiments, a method of making the compound of formula (I) in crystalline form B, as described above, comprises: dissolving the compound shown in the formula (I) in dimethyl sulfoxide at room temperature, slowly cooling to 10-0 ℃ under stirring, filtering, and vacuum-drying at room temperature to obtain the crystal form B.

In some embodiments, after filtration, the obtained crystals are dried at room temperature or-5 ℃ to 20 ℃, and air drying or vacuum drying or natural evaporation drying is adopted to reach constant weight, and then the crystal form B is obtained.

The crystal form A provided by the invention has good stability and good powder fluidity, is easy to prepare and obtain, can be used for preparing a medicinal preparation, has a simple and convenient preparation method, is easy to operate and implement, and is beneficial to large-scale industrial production.

In another aspect, the invention also provides a crystal form of the compound shown in formula (II).

The inventors have studied and found that the compound of formula (II) is obtained as a white solid, in the form of a crystal, called crystalline form II-a, prepared according to the method disclosed in patent application WO2017193870 in example 5 (compound 9), having diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by means of an X-ray powder diffractometer using Cu-ka radiation: 4.75,5.15,6.76,9.23, 10.22, 11.52, 12.56, 13.67, 13.91, 14.63, 15.59, 15.90, 16.38, 17.20, 18.02, 18.37, 19.91, 20.57, 23.18, 23.52, 24.09, 25.52, 25.80, 28.11, 36.35.

In some embodiments, the crystalline form II-a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-K α radiation: 5.50,7.65, 11.02, 12.82, 14.27, 15.43, 16.60, 17.72, 18.74, 19.08, 20.83, 22.03, 25.08, 30.08, 34.78.

In some embodiments, the crystalline form II-a has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-K α radiation: 4.75,5.15,5.50,6.76,7.65,9.23, 10.22, 11.02, 11.52, 12.56, 13.67, 12.82, 13.67, 13.91, 14.27, 14.63, 15.43, 15.59, 15.90, 16.38, 16.60, 17.20, 17.72, 18.02, 18.37, 18.74, 19.08, 19.91, 20.57, 20.83, 22.03, 23.18, 23.52, 24.09, 25.08, 25.52, 25.80, 30.08, 34.78, 36.35.

In some embodiments, the crystalline form II-a has an X-ray powder diffraction pattern (XRD pattern) substantially as shown in figure 9.

In some embodiments, the differential scanning calorimetry curve of form II-a has an endothermic peak at 47 ± 2 ℃.

In some embodiments, the crystalline form II-a has a differential scanning calorimetry curve (DSC profile) as shown in figure 10.

In some embodiments, the crystalline form II-a has a thermogravimetric analysis curve (TGA) showing a weight loss of about 0.10% between 0 ℃ and 210 ℃ with substantially no weight loss.

In some embodiments, the crystalline form II-a has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 11.

The crystal form II-A has good stability and can be used for the crystal form of a pharmaceutical preparation.

The invention also provides a novel crystal form of the compound shown in the formula (II). The new crystal forms of the compound shown in the formula (II) are respectively named as a crystal form II-B, a crystal form II-C and a crystal form II-E.

The crystalline form II-B having diffraction peaks at the following 2 theta (unit: degree, error. + -. 0.2 degrees) angles by an X-ray powder diffractometer using Cu-Ka radiation: 6.08, 12.99, 14.31, 17.28, 19.88, 22.58, 25.97.

In some embodiments, the crystalline form II-B has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 8.18, 12.28, 13.97, 15.23, 16.22, 18.09, 21.82, 23.05.

In some embodiments, the crystalline form II-B has an X-ray powder diffraction pattern (XRD pattern) substantially as shown in figure 12.

In some embodiments, the differential scanning calorimetry curve of form II-B has an endothermic peak at 41 ± 2 ℃.

In some embodiments, the crystalline form II-B has a differential scanning calorimetry curve (DSC profile) as shown in figure 13.

In some embodiments, the crystalline form II-B has a thermogravimetric analysis curve (TGA) showing a weight loss between 30 ℃ and 150 ℃ of about 0% to about 15%.

In some embodiments, the crystalline form II-B has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 14.

The crystalline form II-C having diffraction peaks at the following 2 theta (unit: degree, error. + -. 0.2 degrees) angles by an X-ray powder diffractometer using Cu-Ka radiation: 4.57,6.12,7.38,7.70,9.10, 11.08, 11.42, 13.25, 14.95, 15.93, 16.47, 18.33, 19.30, 20.39, 20.63, 21.80, 22.63, 24.90, 25.26.

In some embodiments, the crystalline form II-C has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 4.99,6.81,9.60, 11.63, 12.32, 13.74, 17.24, 20.03, 21.32, 23.43, 39.62.

In some embodiments, the crystalline form II-C has an X-ray powder diffraction pattern (XRD pattern) substantially as shown in figure 15.

In some embodiments, the differential scanning calorimetry curve of form II-C has an endothermic peak at 36 ± 2 ℃.

In some embodiments, the crystalline form II-C has a differential scanning calorimetry curve (DSC profile) as shown in figure 16.

In some embodiments, the crystalline forms II-C have a thermogravimetric analysis curve (TGA) showing a weight loss between 30 ℃ and 150 ℃ of about 0% to 6.0%.

In some embodiments, the crystalline form II-C has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 17.

The crystalline form II-E having diffraction peaks at the following 2 theta (unit: degree, error. + -. 0.2 degrees) angles by an X-ray powder diffractometer using Cu-Ka radiation: 4.57,4.99,6.81,7.38,9.10,9.60, 11.08, 12.32, 13.25, 13.74, 14.95, 16.47, 17.24, 18.33, 20.39, 21.32, 23.43, 24.90, 25.26.

In some embodiments, the crystalline form II-E has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-K α radiation: 6.12,7.70, 11.42, 11.63, 15.93, 19.30, 20.03, 20.63, 21.80, 22.63, 39.62.

In some embodiments, the crystalline form II-E has an X-ray powder diffraction pattern (XRD pattern) substantially as shown in figure 18.

In some embodiments, the differential scanning calorimetry curve of form II-E has endothermic peaks at both 31 ± 2 ℃ and 44 ± 2 ℃.

In some embodiments, the crystalline form II-E has a differential scanning calorimetry curve (DSC profile) as shown in figure 19.

In some embodiments, the crystalline forms II-E have a thermogravimetric analysis curve (TGA) showing a weight loss between 30 ℃ and 100 ℃ of about 0% to 6%.

In some embodiments, the crystalline form II-E has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 20.

On the other hand, the invention also provides a preparation method of the crystal form II-A of the compound shown in the formula (II) and a new crystal form II-B, a crystal form II-C and a crystal form II-E thereof.

A process for preparing the compound of formula (II) as described above in crystalline form II-a, comprising: mixing a compound shown as a formula (II) with a solvent at room temperature or under a heating condition, continuously stirring, and naturally volatilizing to obtain a crystal form II-A; or comprises the following steps: mixing the compound shown in the formula (II) with a solvent at room temperature or under a heating condition, cooling, stirring and filtering to obtain a crystal form II-A; the solvent can be methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, isobutanol, isoamyl alcohol, cyclohexane, n-heptane, dichloromethane, acetone, butanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl formate, methyl acetate, dimethyl carbonate, 1, 4-dioxane, toluene, methyl tert-butyl ether, isopropyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether or a mixture thereof.

In some embodiments, the temperature may be-20 ℃ to 20 ℃ in the cooling process.

The invention also provides a method for preparing the compound shown in the formula (II) in the crystal form II-A, which comprises the following steps: mixing a compound shown as a formula (II) with a solvent at room temperature, then mixing with water, stirring, and filtering to obtain a crystal form II-A; the solvent can be methanol, ethanol, isopropanol, acetone, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether or a mixture thereof.

In another aspect, the present invention provides a process for preparing the aforementioned crystalline form II-B of the compound of formula (II), comprising: mixing the compound shown in the formula (II) with a solvent at room temperature or under a heating condition, cooling, stirring and filtering to obtain a crystal form II-B; the solvent can be dimethyl sulfoxide, ethanol, 1, 4-dioxane, trifluoroethanol, ethylene glycol monomethyl ether, N-dimethylformamide, acetone, ethyl acetate or a mixture thereof.

In some embodiments, in the method for preparing the crystal form II-B, the temperature can be between-20 ℃ and 20 ℃ in the cooling process.

The invention also provides a method for preparing the compound shown in the formula (II) in the crystal form II-B, which comprises the following steps: and (3) mixing the compound shown in the formula (II) with dimethyl sulfoxide at room temperature, naturally volatilizing the dry solvent under stirring, separating out crystals, and filtering to obtain the crystal form II-B.

In another aspect, the present invention provides a process for preparing the aforementioned crystalline form II-C of the compound of formula (II), comprising: mixing the compound shown in the formula (II) with a solvent at room temperature or under a heating condition, cooling, stirring and filtering to obtain a crystal form II-C; the solvent can be N, N-dimethylformamide, ethanol, 1, 4-dioxane, trifluoroethanol, ethylene glycol monomethyl ether, acetone, ethyl acetate or a mixture thereof.

In some embodiments, in the method for preparing the crystal form II-C, the temperature can be between-20 ℃ and 20 ℃ in the cooling process.

The invention also provides a method for preparing the compound shown in the formula (II) in the crystal form II-C, which comprises the following steps: and (3) mixing the compound shown in the formula (II) with N, N-dimethylformamide at room temperature, naturally volatilizing the dry solvent under stirring, separating out crystals, and filtering to obtain the crystal form II-C.

In another aspect, the present invention provides a process for preparing the aforementioned crystalline form II-E of the compound of formula (II), comprising: mixing the compound shown in the formula (II) with trifluoroethanol at room temperature, stirring, naturally volatilizing, and filtering to obtain a crystal form II-E; or comprises the following steps: and (3) mixing the compound shown in the formula (II) with trifluoroethanol and water at room temperature, stirring, cooling and crystallizing, and filtering to obtain the crystal form II-E.

Definition of terms

In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may differ by 1%, 2%, or 5%.

X-ray powder diffraction (XRD) can detect information such as change, crystallinity, crystal structure state and the like of the crystal form, and is a common means for identifying the crystal form. The peak positions of the XRD patterns depend mainly on the structure of the crystalline form and are relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRD pattern with certain peak positions, substantially as shown by the XRD pattern provided in the figures of the present invention. Also, the measurement of the 2 θ of the XRD pattern may have experimental errors, and the measurement of the 2 θ of the XRD pattern may be slightly different between different instruments and different samples, so that the value of the 2 θ cannot be regarded as absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.

The Differential Scanning Calorimetry (DSC) of the crystal form has experimental errors, the positions and peak values of endothermic peaks may slightly differ between one machine and another machine and between one sample and another sample, and the numerical value of the experimental errors or differences may be 10 ℃ or less, 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so that the peak positions or peak values of the DSC endothermic peaks cannot be regarded as absolute.

Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.

"room temperature" in the present invention means a temperature of from about 10 ℃ to about 30 ℃, alternatively 20 ℃ to 30 ℃, alternatively 23 ℃ to 28 ℃, alternatively 25 ℃.

In the present invention, "RH" is relative humidity.

Drawings

FIG. 1: an X-ray powder diffraction (XRD) pattern of a crystalline form A of the compound of formula (I).

FIG. 2: a Differential Scanning Calorimetry (DSC) curve of form a of a compound of formula (I).

FIG. 3: thermogravimetric analysis (TGA) profile of crystalline form a of the compound of formula (I).

FIG. 4: an X-ray powder diffraction (XRD) pattern of form B of the compound of formula (I).

FIG. 5: a Differential Scanning Calorimetry (DSC) curve of form B of the compound of formula (I).

FIG. 6: thermogravimetric analysis (TGA) profile of form B of the compound of formula (I).

FIG. 7: influence factor test spectrum of crystal form A of the compound shown in the formula (I).

FIG. 8: influence factor test spectrum of crystal form B of the compound shown in the formula (I).

FIG. 9: an X-ray powder diffraction (XRD) pattern of crystalline form II-A of the compound of formula (II).

FIG. 10: a Differential Scanning Calorimetry (DSC) curve of crystalline form II-A of the compound of formula (II).

FIG. 11: a thermogravimetric analysis (TGA) profile of crystalline form II-a of the compound of formula (II).

FIG. 12: an X-ray powder diffraction (XRPD) pattern of crystalline form II-B of the compound of formula (II).

FIG. 13: a Differential Scanning Calorimetry (DSC) curve of crystalline form II-B of the compound of formula (II).

FIG. 14: a thermogravimetric analysis (TGA) profile of crystalline form II-B of the compound of formula (II).

FIG. 15: an X-ray powder diffraction (XRD) pattern of crystalline form II-C of the compound of formula (II).

FIG. 16: a Differential Scanning Calorimetry (DSC) curve of crystalline form II-C of the compound of formula (II).

FIG. 17: a thermogravimetric analysis (TGA) profile of crystalline form II-C of the compound of formula (II).

FIG. 18: an X-ray powder diffraction (XRD) pattern of crystalline form II-E of the compound of formula (II).

FIG. 19: a Differential Scanning Calorimetry (DSC) curve of crystalline form II-E of the compound of formula (II).

FIG. 20: a thermogravimetric analysis (TGA) profile of crystalline form II-E of the compound of formula (II).

Detailed Description

Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

In the invention, g: g, Ml or Ml: ml, min: min, h: hour, DEG C: degree centigrade, mA: milliampere.

Test instrument and method

(1) Powder X-ray diffraction (XRD) study

Powder X-ray diffraction (XRD) X-ray powder diffraction (XRD) patterns were collected on a PANALYtic Empyrean X-ray diffractometer equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder using a radiation source of (Cu, K α, K α 1)1.540598；Kα21.544426, K α 2/K α 1 intensity ratio: 0.50), where the voltage is set at 45KV and the current is set at 40 mA.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 10mm. an effective 2 theta range of 3-40 deg. is obtained using a theta-theta continuous scanning mode.A suitable amount of sample is taken at a circular groove of a zero background sample holder under environmental conditions (about 18-32 deg.C), a flat plane is obtained by light pressing with a clean glass slide, and the zero background sample holder is fixed.A conventional XRD pattern is generated by scanning the sample at 0.0167 deg. in a range of 3-40 deg. 2 theta + -0.2 deg.C.the software for Data collection is Collector, and the Data is analyzed and presented by Data Viewer and HighScore Plus.

(2) Differential Scanning Calorimetry (DSC) analysis

DSC measurements were performed in a TA instruments model Q2000 using a sealed tray apparatus. Samples (approximately 1-3 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis.

(3) Thermogravimetric analysis (TGA) analysis

TGA measurements were performed in TA instruments model Q500. The operation steps are that the empty crucible is peeled, about 10mg of solid sample is taken and put in the peeled empty crucible, and the solid sample is spread evenly. After the instrument runs stably, data are collected at a heating rate of 10 ℃/min between room temperature and 300 ℃ under nitrogen purging, and a spectrum is recorded.

The crystal form samples prepared in the respective examples were respectively tested by using the above conditions.

Preparation of the Compound of formula (I) ((((1R,3R,5S,7R) -3, 5-Dimethyladamantan-1-yl) carbamoyl) oxy) methyl palmitate

Referring to the process disclosed in patent application WO2017193870, in a 1L single-neck bottle, 20.0g of chloromethyl ((1R,3R,5S,7R) -3, 5-dimethyladamantan-1-yl) carbamate, 19.8g of stearic acid, 8.9g of TEA (triethylamine), 5.5g of sodium iodide and 120mL of DMF (N, N-dimethylformamide) were added and the temperature was raised to 85 ℃. After the reaction is finished, cooling to 60 ℃, adding 300mL of water and 300mL of toluene, stirring for 30min, standing for layering, and separating an organic layer; the aqueous layer was extracted once with 300mL of toluene, the organic layers were combined, the organic layer was washed 2 times with water (300 mL of water each time), the organic layer was separated, the toluene was distilled off under reduced pressure to give a brown oil, the liquid was allowed to cool and solidify, 150mL of acetonitrile was added, the solid was precipitated by stirring, the mixture was filtered after stirring for 1 hour, the white filter cake was discarded, the filtrate was evaporated to dryness to give 11.0g of a pale yellow oil, and 2.0g of a white solid was obtained after column chromatography purification as a wax, and the microscopic morphology could not be determined.

1H NMR(600MHz,DMSO)7.28(s,1H),5.58(s,2H),2.31(t,J＝7.2Hz,2H),2.10–2.02(m,1H),1.69(s,2H),1.58–1.41(m,7H),1.26(d,J＝21.8Hz,27H),1.08(d,J＝12.8Hz,2H),0.86(t,J＝7.0Hz,3H),0.80(d,J＝6.4Hz,6H)。