CN112778387A - Molnupiravir crystal form A and preparation method thereof - Google Patents
Molnupiravir crystal form A and preparation method thereof Download PDFInfo
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention provides a Molnnapiarvir crystal form A, and an X-ray powder diffraction pattern 2Theta value obtained by Cu-Kalpha ray measurement has characteristic peaks at 3.26 +/-0.2 degrees, 6.52 +/-0.2 degrees, 13.09 +/-0.2 degrees, 16.38 +/-0.2 degrees, 21.33 +/-0.2 degrees and 31.69 +/-0.2 degrees. The crystal form has the advantages of simple preparation process, simple and convenient operation, good stability, easy preservation in the production and circulation process, and good selection for the preparation of the pharmaceutical preparation, which has very important significance for the development of the medicine.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a novel antiviral drug Molnopiravir crystal form A and a preparation method thereof.
Background
Molnupiarvir (code MK-4482 or EIDD-2801) is a small molecule antiviral drug of the cytidine family developed by Emersonid. The medicine is a SARS-CoV2 polymerase inhibitor, and research proves that in animal experiments, the Molnupiarvir can be used for treating ferrets infected with SARS-CoV-2, can effectively inhibit viruses and prevent the growth of new coronavirus within 24 hours, thereby inhibiting the spread of viruses. The research group believes that new coronary patients receiving this oral drug treatment can become non-contagious within a day if Molnupiravir also achieves similar effects in human trials. Currently, the Moshadong has begun to perform clinical trials for treating new coronavirus patients, and once successful, the market prospect is huge.
The Molnopiravir chemical name is: ((2R,3S,4R,5R) -3, 4-dihydro-5- (4- (hydroxyamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) methylisobutyl ester, of the formula:
it is known that different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability, etc., thereby affecting the stability, bioavailability and therapeutic effect of the drug, and the phenomenon is particularly obvious in the aspect of oral solid preparations. PCT patent WO2019113462A reports a chemical synthesis route of Molnupriarvir, and no report is made on a crystal form of the Molnupriarvir in the existing patent, and the inventor discovers that the Molnupriarvir has a new crystal form A in the experimental research process.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of the novel Molnnapiarvir crystal form A, which is simple in process route, low in cost and suitable for industrial production.
The invention aims to provide a novel Molnopiravir crystal form, which adopts the following technical scheme:
molnnupiravir crystal form A has characteristic peaks at 3.26 +/-0.2 degrees, 6.52 +/-0.2 degrees, 13.09 +/-0.2 degrees, 16.38 +/-0.2 degrees, 21.33 +/-0.2 degrees and 31.69 +/-0.2 degrees of a Theta value of an X-ray powder diffraction pattern 2 measured by using Cu-Kalpha rays.
Further, the X-ray powder diffraction pattern 2Theta values also have characteristic peaks at 17.08 + -0.2 degrees, 17.20 + -0.2 degrees, 18.10 + -0.2 degrees, 20.61 + -0.2 degrees, 28.08 + -0.2 degrees and 28.40 + -0.2 degrees.
Further, a Differential Scanning Calorimetry (DSC) graph shows that an endothermic peak appears when heated to 160-164 ℃.
Further, the thermogravimetric analysis (TGA) thereof shows that the decomposition starts at 195 ℃ to 200 ℃ and is completed at 490 ℃ to 500 ℃.
The invention also aims to provide a preparation method of the novel Molnbupiravir crystal form, which adopts the following technical scheme:
a preparation method of Molnopiravir crystal form A is characterized in that Molnopiravir is added into a solvent A, heated to a certain temperature and stirred for a period of time, a solvent B is added or not added, the obtained mixed solvent system or single solvent is stirred for a period of time, then slowly cooled to a certain temperature for crystallization, and kept warm and pulped to obtain a suspension, and the suspension is filtered and dried to obtain a white to off-white solid, namely the crystal form A;
preferably, the heating temperature is 35-110 ℃, and preferably 55-60 ℃; the cooling temperature is-20 to 30 ℃, and preferably 0 to 5 ℃.
Further, as a preference, the crystallization system used can be selected from the following three solvent systems:
the solvent system 1 is a single solvent system without adding a solvent B, wherein the solvent A is selected from water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone or acetonitrile.
Preferably, the volume dosage of the solvent A is 1-40 times of the mass dosage of the Molnnupiravir, and the preferred range is 2-15 times.
The solvent system 2 is a mixed solvent system with water as a selected solvent A and a selected solvent B, wherein the solvent A is selected from methanol, ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetone or acetonitrile, and the solvent B is water.
Preferably, the volume dosage of the solvent A is 1-40 times of the mass dosage of the Molnopiravir, and the preferred range is 2-5 times; the volume dosage of the water is 0.01-10 times of the mass dosage of the Molnnupiravir, and the preferred range is 0.1-3 times.
The solvent system 3 is a mixed solvent system of a selected solvent A and a selected solvent B, wherein the solvent A is selected from methanol, ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetone or acetonitrile, the solvent B is selected from ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, n-heptane, n-hexane, methyl tert-butyl ether or isopropyl ether, and the solvents A and B are different from each other.
Preferably, the volume dosage of the solvent A is 0.2-40 times of the mass dosage of the Molnnupiravir, and the preferred range is 1-10 times; the volume dosage of the solvent B is 0.2-40 times of the mass dosage of the Molnnupiravir, and the preferred range is 3-10 times.
Preferably, the solvent A is methanol, and the solvent B is isopropanol, so as to form a mixed solvent system of methanol and isopropanol; the solvent A is methanol, and the solvent B is ethyl acetate, so as to form a mixed solvent system of methanol and ethyl acetate; the solvent A is methanol, the solvent B is dichloromethane, and a mixed solvent system of the methanol and the dichloromethane is formed; the solvent A is ethyl acetate, and the solvent B is n-heptane, so that a mixed solvent system of ethyl acetate and n-heptane is formed.
The invention discovers a new crystal form of Molnnapiarvir, the preparation process of the crystal form is simple, the operation is simple and convenient, and the quality index of the obtained crystal form is basically kept unchanged in a stability acceleration experiment, which shows that the product crystal form A has good stability, is easy to store in the production and circulation process, provides good selection for the preparation of a pharmaceutical preparation thereof, and has very important significance for the development of medicaments.
Drawings
1. FIG. 1 is an XRPD pattern of crystalline form A of Molnupiarvir made in accordance with the present invention;
2. FIG. 2 is a DSC of crystalline form A of Molnupiarvir made by the present invention;
3. fig. 3 is a TGA profile of crystalline form a of Molnupiravir made by the present invention.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
In the examples described below, the test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer. The Molnnupiravir starting material is prepared according to the prior art, the preparation method can refer to WO2019113462 or Eur.J.org.chem.2020 page 6736 and 6739, and other raw materials and solvents are obtained commercially.
The X-ray powder diffraction pattern is collected on a D8ADVANCE X-ray powder diffractometer, the detection collection temperature is room temperature (about 25 ℃), and the detection method parameters are as follows:
a Differential Scanning Calorimetry (DSC) chart is acquired on TA Q2000, and the parameters of the detection method are as follows:
the thermogravimetric analysis (TGA) graph disclosed by the invention is collected on TA Q5000, and the detection method parameters are as follows:
example 1
Adding Molnnupiravir (1.0g, purity of 98.0%) and isopropanol (5 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A (0.90 g, purity of 99.8%, yield of 91.7%).
The X-ray powder diffraction data of form a obtained in this example are shown in table 1, with the XRPD pattern shown in fig. 1, the DSC pattern shown in fig. 2, and the TGA pattern shown in fig. 3.
TABLE 1
2THETA | d interval | Strength% |
3.26 | 27.07 | 100.00% |
6.52 | 13.54 | 6.10% |
9.80 | 9.02 | 0.80% |
13.09 | 6.76 | 3.20% |
16.38 | 5.41 | 3.30% |
17.08 | 5.19 | 2.60% |
17.20 | 5.15 | 2.70% |
18.10 | 4.90 | 1.60% |
19.49 | 4.55 | 0.90% |
19.67 | 4.51 | 1.20% |
19.90 | 4.46 | 0.70% |
20.38 | 4.35 | 0.70% |
20.61 | 4.31 | 1.20% |
21.33 | 4.16 | 3.20% |
23.39 | 3.80 | 0.70% |
24.06 | 3.70 | 0.70% |
27.37 | 3.26 | 1.00% |
28.08 | 3.17 | 2.20% |
28.40 | 3.14 | 1.50% |
28.93 | 3.08 | 0.80% |
30.15 | 2.96 | 0.60% |
31.69 | 2.82 | 9.70% |
34.02 | 2.63 | 0.80% |
Example 2
Adding Molnnupiravir (1.0g, purity of 98.0%) and 5mL of water into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain 0.82g of crystal form A (purity of 99.5%, yield of 83.3%).
The X-ray powder diffraction data of form a obtained in this example are shown in table 2,
TABLE 2
Example 3
Adding Molnnupiravir (1.0g, purity of 98.0%) and ethyl acetate 3mL into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain 0.93g of crystal form A (purity of 99.6%, yield of 94.5%).
The X-ray powder diffraction data of form a obtained in this example are shown in table 3,
TABLE 3
Example 4
Adding Molnnupiravir (1.0g, purity of 98.0%) and isopropyl acetate 3mL into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A0.94 g (purity of 99.7%, yield of 95.6%).
The X-ray powder diffraction data for form a obtained in this example are shown in table 4:
TABLE 4
Example 5
Adding Molnnupiravir (1.0g, purity of 98.0%) and dichloromethane (10 mL) into a three-neck flask, uniformly stirring, heating to 38-42 ℃, stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain the crystal form A (0.85 g, purity of 99.7%, yield of 86.4%).
The X-ray powder diffraction data for form a obtained in this example are shown in table 5:
TABLE 5
2THETA | d interval | Strength% |
3.23 | 27.40 | 100.00% |
6.49 | 13.64 | 6.50% |
9.75 | 9.08 | 1.10% |
13.06 | 6.78 | 3.00% |
16.36 | 5.42 | 3.20% |
17.07 | 5.19 | 4.70% |
17.12 | 5.17 | 5.30% |
18.04 | 4.92 | 2.40% |
19.45 | 4.56 | 1.80% |
19.61 | 4.52 | 1.60% |
19.84 | 4.47 | 1.30% |
20.35 | 4.36 | 1.80% |
20.60 | 4.32 | 2.40% |
21.26 | 4.18 | 6.10% |
23.33 | 3.81 | 0.70% |
24.02 | 3.70 | 1.00% |
26.35 | 3.38 | 0.30% |
27.56 | 3.24 | 0.30% |
28.09 | 3.19 | 4.30% |
28.86 | 3.08 | 1.50% |
30.12 | 2.97 | 0.90% |
31.63 | 2.82 | 2.90% |
33.94 | 2.64 | 0.80% |
34.37 | 2.62 | 0.70% |
Example 6
Adding Molnnupiravir (1.0g, purity of 98.0%) and acetone (10 mL) into a three-neck flask, uniformly stirring, heating to 38-42 ℃, stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain 0.78g of crystal form A (purity of 99.6%, yield of 79.2%).
The X-ray powder diffraction data for form a obtained in this example are shown in table 6:
TABLE 6
2THETA | d interval | Strength% |
3.24 | 27.40 | 100.00% |
6.48 | 13.64 | 5.90% |
9.74 | 9.07 | 1.20% |
13.08 | 6.78 | 4.50% |
16.38 | 5.44 | 3.80% |
17.04 | 5.19 | 4.20% |
17.14 | 5.17 | 5.10% |
18.07 | 4.91 | 3.40% |
19.46 | 4.56 | 1.20% |
19.62 | 4.52 | 1.20% |
19.87 | 4.47 | 1.70% |
20.36 | 4.37 | 2.10% |
20.62 | 4.30 | 2.00% |
21.30 | 4.18 | 0.40% |
23.40 | 3.80 | 0.40% |
26.38 | 3.38 | 0.20% |
28.16 | 3.16 | 0.40% |
28.43 | 3.14 | 0.60% |
29.72 | 3.01 | 0.40% |
31.68 | 2.82 | 3.80% |
33.12 | 2.70 | 0.40% |
33.52 | 2.68 | 0.40% |
34.05 | 2.63 | 0.80% |
Form A can likewise be obtained by the process of example 6, in which acetone is replaced by methanol, ethanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.
Example 7
Adding Molnnupiravir (1.0g, purity of 98.0%) and ethyl acetate 5mL into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water 0.3mL, stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A0.91 g (purity of 99.8%, yield of 92.7%).
The X-ray powder diffraction data for form a obtained in this example are shown in table 7:
TABLE 7
2THETA | d interval | Strength% |
3.29 | 26.81 | 100.00% |
6.54 | 13.51 | 6.90% |
9.79 | 9.03 | 0.80% |
13.06 | 6.77 | 2.40% |
16.36 | 5.42 | 2.60% |
17.05 | 5.20 | 0.20% |
17.20 | 5.15 | 0.20% |
19.66 | 4.51 | 1.10% |
20.58 | 4.31 | 0.10% |
21.28 | 4.17 | 0.50% |
22.99 | 3.86 | 0.20% |
23.38 | 3.80 | 0.20% |
26.37 | 3.38 | 0.40% |
28.13 | 3.17 | 0.20% |
28.41 | 3.14 | 0.50% |
29.70 | 3.01 | 0.20% |
31.67 | 2.82 | 3.70% |
33.10 | 2.70 | 0.30% |
33.51 | 2.67 | 0.20% |
34.02 | 2.63 | 0.40% |
Example 8
Adding Molnnupiravir (1.0g, purity of 98.0%) and ethanol (5 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water (0.3 mL), stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A (0.88 g, purity of 99.8%, yield of 89.6%). The X-ray powder diffraction data for form a obtained in this example are shown in table 8:
TABLE 8
Example 9
Adding Molnnupiravir (1.0g, purity of 98.0%) and isopropanol (3 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water (0.3 mL), stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A (0.86 g, purity of 99.9%, yield of 87.6%).
The X-ray powder diffraction data for form a obtained in this example are shown in table 9:
TABLE 9
Example 10
Adding Molnnupiravir (1.0g, purity of 98.0%) and tetrahydrofuran (3 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water (0.3 mL), stirring for 2-3 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A (0.88 g, purity of 99.7%, yield of 89.5%).
The X-ray powder diffraction data for form a obtained in this example are shown in table 10:
watch 10
2THETA | d interval | Strength% |
3.25 | 27.44 | 100.00% |
6.49 | 13.63 | 6.10% |
9.73 | 9.08 | 1.30% |
13.09 | 6.78 | 4.20% |
16.39 | 5.42 | 3.90% |
17.05 | 5.19 | 3.20% |
17.17 | 5.17 | 3.40% |
18.08 | 4.92 | 4.10% |
19.45 | 4.58 | 1.10% |
19.63 | 4.52 | 1.90% |
19.88 | 4.47 | 1.20% |
20.38 | 4.36 | 3.10% |
20.60 | 4.31 | 2.00% |
21.32 | 4.17 | 0.20% |
23.42 | 3.81 | 0.40% |
24.05 | 3.71 | 0.70% |
26.44 | 3.36 | 0.20% |
27.38 | 3.26 | 0.60% |
28.12 | 3.18 | 0.20% |
28.48 | 3.13 | 0.40% |
31.72 | 2.83 | 3.50% |
34.07 | 2.64 | 0.20% |
Form A can likewise be obtained by the process of example 10, in which tetrahydrofuran is replaced by methanol, n-butanol, isopropyl acetate, dichloromethane, 2-methyltetrahydrofuran, acetone or acetonitrile.
Example 11
Adding Molnnupiravir (1.0g, purity of 98.0%) and methanol (1 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 2-3 hours, slowly adding isopropanol (5 mL), slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A (0.87 g, purity of 99.9%, yield of 88.7%).
The X-ray powder diffraction data of form a obtained in this example are shown in table 11.
TABLE 11
2THETA | d interval | Strength% |
3.25 | 27.16 | 100.00% |
6.52 | 13.55 | 6.30% |
9.79 | 9.03 | 1.00% |
13.07 | 6.77 | 3.10% |
16.37 | 5.41 | 3.40% |
17.04 | 5.20 | 0.30% |
17.24 | 5.14 | 0.30% |
18.08 | 4.90 | 0.20% |
19.68 | 4.51 | 1.20% |
21.29 | 4.17 | 0.60% |
23.01 | 3.86 | 0.20% |
23.39 | 3.80 | 0.30% |
24.04 | 3.70 | 0.20% |
25.79 | 3.45 | 0.20% |
26.38 | 3.38 | 0.30% |
28.12 | 3.17 | 0.20% |
28.42 | 3.14 | 0.50% |
29.71 | 3.01 | 0.20% |
31.69 | 2.82 | 0.20% |
33.10 | 2.70 | 0.30% |
34.03 | 2.63 | 0.40% |
Example 12
Adding Molnnapiarvir (1.0g, purity 98.0%) and methanol (1 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 2-3 hours, slowly adding ethyl acetate (5 mL), slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A (0.89 g, purity 99.8%, yield 90.6%).
The X-ray powder diffraction data of form a obtained in this example are shown in table 12.
TABLE 12
2THETA | d interval | Strength% |
3.26 | 27.06 | 100.00% |
6.52 | 13.54 | 5.40% |
9.79 | 9.02 | 0.70% |
13.07 | 6.77 | 1.60% |
16.36 | 5.41 | 1.60% |
17.06 | 5.19 | 2.40% |
17.22 | 5.14 | 3.20% |
18.08 | 4.90 | 1.80% |
19.45 | 4.56 | 1.00% |
19.65 | 4.51 | 0.50% |
19.87 | 4.47 | 0.60% |
20.36 | 4.36 | 0.50% |
20.58 | 4.31 | 1.30% |
21.31 | 4.17 | 2.50% |
23.37 | 3.80 | 0.60% |
24.04 | 3.70 | 0.40% |
28.07 | 3.18 | 2.30% |
28.41 | 3.14 | 0.90% |
28.93 | 3.08 | 0.70% |
30.15 | 2.96 | 0.70% |
31.67 | 2.82 | 0.60% |
34.00 | 2.63 | 0.40% |
Example 13
Adding Molnnupiravir (1.0g, purity of 98.0%) and methanol (1 mL) into a three-neck flask, uniformly stirring, heating to 38-42 ℃, stirring for 2-3 hours, slowly adding dichloromethane (10 mL), slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A (0.68 g, purity of 99.9%, yield of 69.3%).
The X-ray powder diffraction data of form a obtained in this example are shown in table 13.
Watch 13
Example 14
Adding Molnnapiarvir (1.0g, purity 98.0%) and ethyl acetate 10mL into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 2-3 hours, slowly adding n-heptane 5mL, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 10-16 hours, centrifuging, and drying to obtain crystal form A0.96 g (purity 98.9%, yield 96.8%).
The X-ray powder diffraction data of form A obtained in this example are shown in Table 14, and the XRPD pattern thereof is shown in FIG. 1.
TABLE 14
The procedure of example 14 is followed, where ethyl acetate is replaced by methanol, ethanol, isopropanol, n-butanol, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone or acetonitrile; the n-heptane can be replaced by ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, n-heptane, n-hexane, methyl tert-butyl ether or isopropyl ether, and the two solvents are different, so that the crystal form A can be obtained.
Example 15
Taking the crystal form A obtained in example 1, example 7 and example 11 to perform a stability acceleration experiment, wherein the test conditions are as follows: the purity and moisture data of the product, measured at 40 ℃. + -. 2 ℃ and RH 75%. + -. 5%, are shown in Table 15, and the product exhibits very stable properties over a period of 2 months under accelerated conditions.
TABLE 15 accelerated stability test
Test results show that the crystal form A is stable for 1 month and 2 months under the conditions of 40 +/-2 ℃ and RH 75% +/-5%, and does not generate crystal form change and chemical degradation.
Claims (10)
1. A Molnnupiravir crystal form A is characterized in that an X-ray powder diffraction pattern 2Theta value obtained by Cu-Kalpha ray measurement has characteristic peaks at 3.26 +/-0.2 degrees, 6.52 +/-0.2 degrees, 13.09 +/-0.2 degrees, 16.38 +/-0.2 degrees, 21.33 +/-0.2 degrees and 31.69 +/-0.2 degrees.
2. Crystalline Molnupiravir a as claimed in claim 1, characterized by the X-ray powder diffraction pattern 2Theta values with characteristic peaks at 17.08 ± 0.2 °, 17.20 ± 0.2 °, 18.10 ± 0.2 °, 20.61 ± 0.2 °, 28.08 ± 0.2 ° and 28.40 ± 0.2 °.
3. Crystalline Molnnupiravir A as claimed in claim 1 or 2, characterized by a Differential Scanning Calorimetry (DSC) profile showing an endothermic peak at 160-164 ℃ heating.
4. Crystalline Molnnupiravir A according to claim 1 or 2, characterized in that its thermogravimetric analysis (TGA) profile shows that the decomposition starts at 195 ℃ -200 ℃ and is complete at 490 ℃ -500 ℃.
The preparation method of the Molnbupiarvir crystal form A is characterized by adding Molnbupiarvir into a solvent A, heating to a certain temperature, stirring for a period of time, adding or not adding a solvent B, stirring in an obtained mixed solvent system or a single solvent for a period of time, slowly cooling to a certain temperature for crystallization, carrying out heat preservation and pulping to obtain a suspension, filtering and drying to obtain a white to off-white solid, namely the crystal form A.
6. The method of claim 5, wherein the heating temperature is 35-110 ℃, preferably 55-60 ℃; the cooling temperature is-20 to 30 ℃, and preferably 0 to 5 ℃.
7. The method of claim 5, wherein the solvent system is a single solvent system without solvent B, and wherein solvent A is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, and acetonitrile.
8. The method according to claim 5, wherein the solvent system is a mixed solvent system selected from the group consisting of water, organic solvent A and solvent B, wherein the solvent A is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetone, and acetonitrile, and the solvent B is water.
9. The method according to claim 5, wherein the solvent A is selected from methanol, ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetone or acetonitrile, the solvent B is selected from ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, n-heptane, n-hexane, methyl tert-butyl ether or isopropyl ether, and the solvents A and B are different from each other.
10. The method of claim 9, wherein solvent a is methanol and solvent B is isopropanol to form a mixed solvent system of methanol and isopropanol; the solvent A is methanol, and the solvent B is ethyl acetate, so as to form a mixed solvent system of methanol and ethyl acetate; the solvent A is methanol, the solvent B is dichloromethane, and a mixed solvent system of the methanol and the dichloromethane is formed; the solvent A is ethyl acetate, and the solvent B is n-heptane, so that a mixed solvent system of ethyl acetate and n-heptane is formed.
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