WO2018141276A1 - Crystal form a of brivaracetam intermediate and preparation method thereof, and crystal form c of brivaracetam and preparation method thereof - Google Patents

Abstract

Disclosed are a novel crystal form of a brivaracetam intermediate compound (I) and preparation method thereof, and a novel crystal form of brivaracetam and preparation method thereof, specifically a crystal form A of a compound I and a crystal form C of brivaracetam. The crystal form A provided in the present invention has beneficial properties such as good stability, technologically developable property, and easy-to-treat property; moreover, the crystal form A features a simple preparation method and low costs, and is significantly valuable for the production, the purification, and the quality control of active ingredients of the drug. The crystal form C provided in the present invention has beneficial properties such as good stability, technologically developable property, and easy-to-treat property; moreover, the crystal form A features a simple preparation method and low costs, and is significantly valuable for future optimization and development of the drug.

Description

Form A of basistatin intermediate, preparation method thereof and crystal form C of bovistam and preparation method thereof Technical field

The invention relates to the field of chemical medicine, in particular to a crystalline form A of a basixamine intermediate, a preparation method thereof and a crystalline form C of bovistam and a preparation method thereof.

Background technique

Epilepsy is a common disease of the nervous system. The incidence rate in the population is 0.6% to 1.1%, and 60% to 70% of patients still have seizures when taking anti-epileptic drugs, causing some patients to stop taking drugs themselves. At present, there are about 6 million epilepsy patients in China, and 650,000 to 700,000 new epilepsy patients each year, and about 25% are refractory epilepsy. Although the current diagnosis and treatment of epilepsy has made great progress, the number of patients with refractory epilepsy is increasing. Generalized refractory epilepsy refers to the use of current anti-epileptic drugs (AEDs) to treat epilepsy and epilepsy syndrome that cannot be terminated or has been clinically proven to be refractory.

Bovasitan, English name: Brivaracetam, the structural formula is:

Bovasistatin is a novel high-affinity synaptophysin 2A ligand that inhibits neuronal voltage-dependent sodium channels and is used to treat partial seizures of refractory epilepsy. Phase II, phase III clinical trials of bovistam have a good effect. The incidence of major adverse events was similar to that of the placebo group, with mild to moderate fatigue, headache, nasopharyngitis, nausea, lethargy, and dizziness. No patients discontinued treatment due to adverse events. The results indicate that bovistam tablets are effective and well tolerated in the adjuvant treatment of patients with refractory epilepsy with a prevalence of 16 to 65 years of age. Overall, bovistam is a third-generation anti-epileptic drug with very good prospects after levetiracetam. It was approved for listing in the United States in February 2016.

So far, there have been no reports on the patent of bovistam in the country. In foreign countries, only the original patent US 6,784,197 published the X-ray powder diffraction pattern of Form A at 2theta values of 8.8, 9.8, 14.9, 15.0, 17.0, 17.1, 21.2, 21.4, 24.8; the X-ray powder diffraction pattern of Form B is The 2theta values are 6.50, 11.25, 19.22, 23.44, 28.47, 29.94.

Domestic patents on the synthesis of bovistam have not been reported. There are also a number of foreign related patent reports, such as the patents US 6,784,197, US 7,629, 474, US 8, 957, 226, US 8, 338, 621, US 8, 076, 493, and related patents, which disclose the synthesis of bosiracetam, wherein US 6,784,197, US 7,629,474 report some synthetic routes, The problems in the synthetic route mainly focus on the fact that the process route cannot selectively synthesize the target chiral molecules, and there are operations methods that require column chromatography purification, chiral high performance liquid chromatography purification, etc., which are not conducive to industrial scale production. Chiral HPLC purity separation requires expensive equipment and consumables and is not suitable for large scale production. In addition, in chiral HPLC purity separation, if the yield is to be increased and the cost is reduced, it will inevitably lead to the collection of more isomer components, and the quality will be reduced. The presence of a large amount of chiral impurities may cause adverse drug reactions and influence. The safety of the drug. In addition, the patent CN104892483A reports a method of asymmetric catalytic hydrogenation, but in which an expensive chiral ligand is used, the route is uneconomical. CN106279074A, CN106365986A, CN106432030A and CN105646319A report the synthesis of bovistam from a chiral raw material which is readily available at low cost, the route does not involve expensive chiral catalysts or ligands, and does not require chiral HPLC purity separation and purification of the final product, Among them, compound I is an intermediate for the synthesis of bovistam, which is essential for the successful synthesis of high purity, high chiral purity of bovistam. The structural formula of Compound I is:

The polymorph of a drug means that two or more different crystalline form states exist in the drug, and the polymorph of the compound means that two or more different crystalline form states exist in the compound. Polymorphism is widespread in drugs and organic compounds. Different crystal forms of the same drug or the same compound have significant differences in solubility, melting point, density, stability, etc., thereby affecting the stability and uniformity of the drug or compound to varying degrees, and affecting the drug for the drug. Bioavailability, efficacy and safety. In addition, the research on the crystal form and purification process of the drug intermediate compound is beneficial to reduce the production cost of the active ingredient of the drug, improve the quality of the active ingredient of the drug, and ensure the quality and safety of the drug preparation. Therefore, in drug development, comprehensive systematic polymorph screening of drugs and drug intermediates, and selection of the most suitable crystal form, is one of the important research contents that cannot be ignored.

Summary of the invention

The invention provides a new crystal form of the bovastatin intermediate compound I, named as the crystal form A, and the crystal form A provided by the invention has the significant improvement effect on the purification of the compound I, and has good stability and process development. With favorable properties such as easy handling, the preparation method of crystal form A is simple and low in cost, and has important value for the production, purification and quality control of compound I, and is essential for obtaining bovastatin bulk drug of high purity and high chiral purity. .

The invention also provides a new crystal form of basistatin, named as crystal form C, and the crystal form C provided by the invention has favorable properties such as good stability, process development and easy handling, and the preparation method is simple and the cost is Low cost and valuable for the development and formulation optimization of bovistam.

To achieve the above object, the present invention adopts the following technical solutions:

It is an object of the present invention to provide a crystalline form A of Compound I having an X-ray powder diffraction pattern at a 2theta value of 7.9 ° ± 0.2 °, 15.7 ° ± 0.2 °, 21.7 ° ± 0.2 °, 28.6 ° ± 0.2 ° With characteristic peaks,

Wherein the structure of the compound I is

Further, the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.4 ° ± 0.2 °, 25.5 ° ± 0.2 °, 28.1 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 14.0 ° ± 0.2 °, 19.1 ° ± 0.2 °, and 36.5 ° ± 0.2 °.

According to a particular and preferred aspect of the invention, the X-ray powder diffraction pattern is also 2theta value of 17.4 ° ± 0.2 °, 25.5 ° ± 0.2 °, 28.1 ° ± 0.2 °, 14.0 ° ± 0.2 °, 19.1 ° ± 0.2 ° , with characteristic peaks at 36.5 ° ± 0.2 °.

In a specific embodiment according to the scheme, its X-ray powder diffraction pattern is substantially identical to that of FIG.

Further, its purity is greater than 98.0%.

Further, its purity is greater than 99.0%.

Still further, its purity is greater than 99.5%.

Further, in the compound I, the content of the enantiomer and the diastereomer are not more than 2.5%.

Wherein the structure of the enantiomer of Compound I is

Diastereomers of Compound I include those represented by the following structural formula:

Further, the content of both the enantiomeric and diastereomers is not more than 1.0%.

Further, the content of both the enantiomeric and diastereomers is not more than 0.5%.

Most preferably, the content of both enantiomers and diastereomers is not more than 0.15%.

Another object of the present invention is to provide a process for the preparation of Form A of Compound I, which comprises adding a powder of Compound I to a mixed system of one or more solvents for crystallization.

Further, the crystallization method includes a suspension stirring method, a heating and cooling method, a volatilization method or an anti-solvent addition method.

Further, the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent. One or several.

Further, the solvent is a mixed system of an ether solvent and an aliphatic hydrocarbon solvent, preferably a mixed system of tetrahydrofuran and n-heptane.

According to a specific and preferred aspect of the present invention, the method of crystallization is a heating and cooling method, and the specific process comprises: adding the compound I powder to the first solvent, raising the temperature to 50 to 60 ° C, stirring, and then adding the second solvent. Cooling to 0-10 ° C, filtration, the obtained filter cake is dried to obtain the crystal form A, wherein the first solvent is water, alcohols, ethers, ketones, esters, aromatic hydrocarbons, halogen a mixed system of one or more of a hydrocarbon, a nitrile, a nitroalkane, an aliphatic hydrocarbon solvent; the second solvent is water, an alcohol, an ether, a ketone, an ester, an aromatic hydrocarbon, a halogen A mixed system of one or more of a hydrocarbon, a nitrile, a nitroalkane, and an aliphatic hydrocarbon solvent.

Further preferably, the first solvent and the second solvent are different solvents.

Still further preferably, the first solvent is a mixed system of one or more of an ether, a ketone, and a nitrile; and the second solvent is an aliphatic hydrocarbon, an ether, or one of water or Several hybrid systems.

More preferably, the first solvent is a mixed system of one or more of tetrahydrofuran, acetone, acetonitrile; the second solvent is n-heptane, methylcyclohexane, methyl t-butyl A mixed system of one or more of ether and water.

A third object of the present invention is to provide a use of the crystalline form A of the compound I as an intermediate for the synthesis of bovistam.

A fourth object of the present invention is to provide a crystalline form C of bovistam with an X-ray powder diffraction pattern having a value of 15.7 ° ± 0.2 °, 17.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 26.9 °. There is a characteristic peak at ±0.2°.

Further, the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 8.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, and 21.6 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 10.0 ° ± 0.2 °, 15.0 ° ± 0.2 °, and 25.0 ° ± 0.2 °.

According to a particular and preferred aspect of the invention, the X-ray powder diffraction pattern is also 2theta values of 8.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, 21.6 ° ± 0.2 °, 10.0 ° ± 0.2 °, 15.0 ° ± 0.2 ° , with characteristic peaks at 25.0 ° ± 0.2 °.

In a specific embodiment according to this embodiment, its X-ray powder diffraction pattern is substantially identical to that of FIG.

A fifth object of the present invention is to provide a process for preparing bovistam form C, which comprises adding bovistam powder to a mixed system of one or more solvents for crystallization.

Further, the method of crystallization includes a suspension stirring method, a heating and cooling method, a volatilization method or an anti-solvent addition method.

Further, the solvent is one selected from the group consisting of an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent. Mixed system of one kind or several kinds.

Further, the solvent is methyl tert-butyl ether.

A sixth object of the present invention is to provide a pharmaceutical composition comprising an effective amount of said crystalline form C of bovistam and a pharmaceutically acceptable excipient.

A seventh object of the present invention is to provide the use of said crystalline form C of bovistam or said pharmaceutical composition for the preparation of a pharmaceutical preparation for the treatment of epilepsy.

The beneficial effects of the invention are:

The new crystalline form (crystal form A) of the bovastatin intermediate compound I provided by the invention has remarkable purification effect and good stability;

The crystallization method of the crystal form A provided by the present invention can effectively control the enantiomeric and diastereomers in the compound I to 2.5% or less, further, 1.0% or less, further, 0.5% or less, further, 0.15. %the following;

The high chiral purity compound I obtained by the crystallization method provided by the invention can be used to produce bovastatin with high chiral purity, improve the chiral purity of the final active ingredient of the drug, and reduce the potential adverse reaction caused by chiral impurities. Thereby improving the safety of the drug;

The preparation method of the crystal form A provided by the invention is simple and reproducible, the solvent is not easy to remain, and the process is controllable, and is suitable for direct use in industrial production.

The novel crystalline form of Bevastatin (Form C) provided by the present invention is better than the crystalline forms A and B of Bovaciltam disclosed by U.S. Patent No. 6,784,197. Stability, suitable for long-term storage and industrial production, to provide more and better choice for the subsequent development of drugs.

The crystallization method of the crystal form C provided by the invention can effectively control the impurities to be less than 0.10%;

The crystallization of the process provided by the patent US 6,784,197 is carried out using isopropyl ether, which presents a potential hazard in industrial scale-up. The preparation method of the crystal form C provided by the invention is simple and reproducible, avoids the use of dangerous solvents, the solvent is not easy to remain, and the process is controllable, and is suitable for direct use in industrial production.

DRAWINGS

1 is an XRPD pattern of Compound I Form A of Example 1.

2 is a TGA chart and a DSC chart overlay of Compound I Form A of Example 1.

Figure 3 is an XRPD pattern of the Bovaxitan Form C.

detailed description

The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

In the following examples, the test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the compound I is prepared by the method of WO2016191435.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric Analysis

The X-ray powder diffraction pattern of the present invention was collected on a PANalytical Empyrean X-ray diffraction powder diffractometer.

XRPD scan parameter Start Position[°2Th.]:3.0056; End Position[°2Th.]:39.9906;Step Size[°2Th.]:0.0167;Scan Step Time[s]:17.8500;K-Alpha1

1.54060; K-Alpha2

1.54443; voltage: 40 mA; current: 45 kV.

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

Example 1

Preparation method of Compound I crystal form A:

30 g of Compound I (HPLC purity: 97.51%) was added to 180 mL of tetrahydrofuran, the temperature was raised to 60 ° C, stirred for 0.5 h, 360 mL of n-heptane was slowly added, the temperature was slowly lowered to 0-10 ° C, and the filter cake was placed at 50 ° C. Drying in a vacuum oven overnight, the obtained solid was determined to be Form A, yield 91%, HPLC purity 99.79%, chiral HPLC purity: Compound I was 99.98%, compound (R, S)-I was not detected, compound ( R, R)-I was 0.01%, and the compound (S, S)-I was 0.01%.

The XRPD data of the crystal form A obtained in this example is shown in Table 1.

Table 1

2theta	d interval	Relative Strength%
7.85	11.26	100.00
13.94	6.35	2.46
15.68	5.65	15.15
17.39	5.10	2.74
19.07	4.65	1.71
21.73	4.09	6.50
25.47	3.49	2.30
28.04	3.18	3.36
28.61	3.12	20.76
36.49	2.46	1.94

Example 2

Preparation method of Compound I crystal form A:

20 g of the compound I powder (HPLC purity: 98.89%) was added to 120 mL of tetrahydrofuran, the temperature was raised to 60 ° C, stirred for 0.5 h, 120 mL of n-heptane was slowly added, the temperature was slowly lowered to 0 to 10 ° C, and the filter cake was placed at 50. Drying in a vacuum oven at °C overnight, the obtained solid was detected as Form A, yield 80%, HPLC purity 99.85%, chiral HPLC purity: Compound I was 99.95%, compound (R, S)-I was not detected, compound (R, R)-I was not detected, and the compound (S, S)-I was 0.05%.

The XRPD data of the crystal form A obtained in this example is shown in Table 2.

Table 2

2theta	d interval	Relative Strength%
7.86	11.24	100.00
13.96	6.34	6.68
15.69	5.64	22.26
17.41	5.09	7.03
19.10	4.64	6.85
21.76	4.08	25.65
25.52	3.49	10.53
28.08	3.18	13.41
28.64	3.11	50.91

36.54

2.46

6.21

Example 3

Preparation method of Compound I crystal form A:

1.28 kg of Compound I powder (HPLC purity: 97.63%) was added to 7.7 L of tetrahydrofuran, the temperature was raised to 60 ° C, stirred for 0.5 h, 15.4 L of n-heptane was slowly added, and the temperature was slowly lowered to 0 to 10 ° C, and filtered to obtain a filter cake. After drying overnight in a vacuum oven at 50 ° C, the obtained solid was detected as Form A, the yield was 82%, the HPLC purity was 99.00%, the chiral HPLC purity: the compound I was 99.95%, and the compound (R, S)-I was not detected. Thus, the compound (R, R)-I was 0.03%, and the compound (S, S)-I was 0.02%.

The XRPD data of the crystal form A obtained in this example is shown in Table 3.

table 3

2theta	d interval	Relative Strength%
7.86	11.24	100.00
13.95	6.34	4.93
15.69	5.64	17.53
17.40	5.09	5.13
19.08	4.64	4.22
21.75	4.08	16.26
25.49	3.49	5.88
28.06	3.17	8.20
28.62	3.11	35.43
36.51	2.46	3.11

Example 4

Compound I recrystallization method:

500 mg of Compound I powder (HPLC purity: 95.70%) was added to 4.5 mL of acetone, and the temperature was raised to 50 ° C, stirred for 0.5 h, 6 mL of methylcyclohexane was slowly added, and the temperature was slowly lowered to 0 to 10 ° C, and filtered to obtain a filter cake. It was dried overnight in a vacuum oven at 50 ° C, the yield was 56.2%, and the HPLC purity was 97.48%.

Example 5

Compound I recrystallization method:

500 mg of Compound I powder (HPLC purity: 95.70%) was added to 4.5 mL of acetone, and the temperature was raised to 50 ° C, stirred for 0.5 h, 6 mL of n-heptane was slowly added, and the temperature was slowly lowered to 0 to 10 ° C, and the resulting filter cake was placed. It was dried overnight in a vacuum oven at 50 ° C, the yield was 57.5%, and the HPLC purity was 96.29%.

Example 6

Compound I recrystallization method:

500 mg of Compound I powder (HPLC purity 95.70%) was added to 4.5 mL of acetone, and the temperature was raised to 50 ° C, stirred for 0.5 h, 4 mL of methyl tert-butyl ether was slowly added, and the temperature was slowly lowered to 0 to 10 ° C, and filtered. The cake was dried overnight in a vacuum oven at 50 ° C in a yield of 51.2% and HPLC purity of 95.73%.

Example 7

Compound I recrystallization method:

500 mg of the compound I powder (HPLC purity 95.70%) was added to 3 mL of tetrahydrofuran, the temperature was raised to 60 ° C, stirred for 0.5 h, 5 mL of methylcyclohexane was slowly added, and the temperature was slowly lowered to 0 to 10 ° C, and the resulting filter cake was placed. It was dried overnight in a vacuum oven at 50 ° C, the yield was 63.4%, and the HPLC purity was 96.59%.

Example 8

Compound I recrystallization method:

500 mg of the compound I powder (HPLC purity 95.70%) was added to 3 mL of tetrahydrofuran, the temperature was raised to 60 ° C, stirred for 0.5 h, 5 mL of methyl tert-butyl ether was slowly added, and the temperature was slowly lowered to 0 to 10 ° C, and filtered to obtain a filter cake. It was dried overnight in a vacuum oven at 50 ° C, the yield was 56.8%, and the HPLC purity was 95.67%.

Example 9

Compound I recrystallization method:

500 mg of Compound I powder (HPLC purity 95.70%) was added to 4.5 mL of acetonitrile, the temperature was raised to 60 ° C, stirred for 0.5 h, 6 mL of water was slowly added, the temperature was slowly lowered to 0-10 ° C, and the filter cake was placed at 50 ° C. Dry overnight in a vacuum oven at a yield of 75.8% and HPLC purity of 96.68%.

Example 10

Compound I recrystallization method:

500 mg of Compound I powder (HPLC purity 95.70%) was added to 4.5 mL of acetone, and the temperature was raised to 50 ° C, stirred for 0.5 h, 6 mL of water was slowly added, and the temperature was slowly lowered to 0 to 10 ° C, and the resulting filter cake was placed at 50 ° C. Dry overnight in a vacuum oven at a yield of 80.5% and HPLC purity of 95.70%.

Example 11

500 mg of Compound I (0.60% (S, S) isomer in chiral HPLC) was added to 3 mL of tetrahydrofuran, heated to 60 ° C, stirred for 0.5 h, slowly added 6 mL of n-heptane, slowly cooled to 0 ~ 10 ° C After filtration, the obtained filter cake was dried in a vacuum oven at 50 ° C overnight, and the obtained solid was found to be crystal form A, the yield was 90.7%, and the compound (S, S)-I was 0.20%.

Example 12

500 mg of compound I (0.3% of the (S, S) isomer in chiral HPLC) was added to 3 mL of tetrahydrofuran, the temperature was raised to 60 ° C, stirred for 0.5 h, 6 mL of n-heptane was slowly added, and the temperature was slowly lowered to 0-10 ° C. After filtration, the obtained filter cake was dried in a vacuum oven at 50 ° C overnight, and the obtained solid was found to be crystal form A, the yield was 92.5%, and the compound (S, S)-I was 0.14%.

Example 13

Preparation method of basistatin crystal form C:

240 g of bovastatin powder (HPLC purity: 98.95% (R, R) + (S, S) isomer 0.23%) was added to 1.2 L of methyl tert-butyl ether, heated to 50 ° C dissolved completely, stirred 0.5h, slowly cooled to 0 ~ 10 ° C, filtered, the obtained filter cake was dried in a vacuum oven at 35 ° C overnight, the obtained solid was detected as Form C, (HPLC purity was 99.75%, chiral HPLC purity was 99.91%, The (R,R)+(S,S) isomer was 0.09%, and the (R,S) isomer was not detected).

The XRPD data of the crystal form C obtained in this example is shown in Table 4.

Table 4

2theta	d interval	Relative Strength%
8.90	9.93	100.00
10.05	8.80	3.21
15.03	5.89	6.31
15.74	5.62	4.46
17.35	5.10	4.06
17.85	4.96	4.33
19.17	4.62	15.55

21.61	4.11	12.67
24.98	3.56	5.03
26.90	3.31	4.37

Claims (29)

1. Form A of Compound I, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 7.9 ° ± 0.2 °, 15.7 ° ± 0.2 °, 21.7 ° ± 0.2 °, 28.6 ° ± 0.2 ° ,

   Wherein the structure of the compound I is

   
2. The crystal form A according to claim 1, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.4 ° ± 0.2 °, 25.5 ° ± 0.2 °, and 28.1 ° ± 0.2 °.
3. The crystal form A according to claim 1 or 2, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 14.0 ° ± 0.2 °, 19.1 ° ± 0.2 °, and 36.5 ° ± 0.2 °.
4. The crystal form A according to claim 1, wherein the X-ray powder diffraction pattern is substantially identical to that of FIG.
5. Form A according to claim 1 wherein the purity is greater than 98.0%.
6. Crystal Form A according to claim 5, characterized in that its purity is greater than 99.0%.
7. Crystal Form A according to claim 6, characterized in that its purity is greater than 99.5%.
8. The crystalline form A according to claim 1, wherein the content of the enantiomer and the diastereomer in the compound I is not more than 2.5%.

   Wherein the structure of the enantiomer of Compound I is

   

   Diastereomers of Compound I include those represented by the following structural formula:

   
9. The crystalline form A according to claim 8, wherein the enantiomeric and diastereomeric content is not more than 1.0%.
10. The crystalline form A according to claim 9, wherein the enantiomeric and diastereomeric content is not more than 0.5%.
11. The crystalline form A according to claim 10, wherein the enantiomeric and diastereomeric content thereof is not more than 0.15%.
12. A method for producing a crystalline form A of the compound I according to any one of claims 1 to 11, which comprises adding a powder of the compound I to a mixed system of one or more solvents for crystallization. .
13. The method according to claim 12, wherein the method of crystallizing comprises a suspension stirring method, a heating lowering method, a volatilization method or an anti-solvent addition method.
14. The preparation method according to claim 12, wherein the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, and a nitrile solvent. One or more of a nitroalkane solvent and an aliphatic hydrocarbon solvent.
15. The process according to claim 14, wherein the solvent is a mixed system of an ether solvent and an aliphatic hydrocarbon solvent, preferably a mixed system of tetrahydrofuran and n-heptane.
16. The preparation method according to claim 12, wherein the method of crystallization is a heating and cooling method, and the specific process comprises: adding the compound I powder to the first solvent, raising the temperature to 50 to 60 ° C, stirring, and then Adding a second solvent, cooling to 0-10 ° C, filtering, the obtained filter cake is dried to obtain the crystal form A, wherein the first solvent is water, alcohols, ethers, ketones, esters, a mixed system of one or more of an aromatic hydrocarbon, a halogenated hydrocarbon, a nitrile, a nitroalkane, an aliphatic hydrocarbon solvent; the second solvent is water, an alcohol, an ether, a ketone, an ester, A mixed system of one or more of an aromatic hydrocarbon, a halogenated hydrocarbon, a nitrile, a nitroalkane, and an aliphatic hydrocarbon solvent, wherein the first solvent and the second solvent are different solvents.
17. The preparation method according to claim 16, wherein the first solvent is a mixed system of one or more of an ether, a ketone, and a nitrile; and the second solvent is an aliphatic hydrocarbon. a mixed system of one or more of ethers and water.
18. The preparation method according to claim 17, wherein the first solvent is a mixed system of one or more of tetrahydrofuran, acetone and acetonitrile; and the second solvent is n-heptane or methyl. A mixed system of cyclohexane, methyl tert-butyl ether, or one or more of water.
19. Use of the crystalline form A of the compound I according to any one of claims 1 to 11 as an intermediate for the synthesis of bovistam.
20. A crystalline form C of bosiracetam characterized by having an X-ray powder diffraction pattern having a 2theta value of 15.7 ° ± 0.2 °, 17.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, and 26.9 ° ± 0.2 ° Characteristic peaks.
21. The crystal form C according to claim 20, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 8.9 ° ± 0.2 °, 19.2 ° ± 0.2 °, and 21.6 ° ± 0.2 °.
22. The crystal form C according to claim 20 or 21, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 10.0 ° ± 0.2 °, 15.0 ° ± 0.2 °, and 25.0 ° ± 0.2 °.
23. Crystalline Form C according to claim 20, characterized in that its X-ray powder diffraction pattern is substantially identical to that of Figure 1.
24. A method for preparing bovistam crystal form C according to any one of claims 20 to 23, which comprises adding bovisamane powder to a mixed system of one or more solvents, Crystallization is obtained.
25. The method according to claim 24, wherein the method of crystallizing comprises a suspension stirring method, a heating lowering method, a volatilization method or an anti-solvent addition method.
26. The preparation method according to claim 24, wherein the solvent is selected from the group consisting of an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, and a nitro group. A mixed system of one or more of an alkane solvent and an aliphatic hydrocarbon solvent.
27. The process according to claim 26, wherein the solvent is methyl tert-butyl ether.
28. A pharmaceutical composition comprising an effective amount of Form C of bosiracetam according to any one of claims 20 to 23 and a pharmaceutically acceptable excipient.
29. Use of a crystalline form C of bosiracetam or a pharmaceutical composition according to any of claims 20 to 23 for the preparation of a pharmaceutical preparation for the treatment of epilepsy.

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