CN112939876A - Crystal form I of Mavacamten and preparation method thereof - Google Patents
Crystal form I of Mavacamten and preparation method thereof Download PDFInfo
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- CN112939876A CN112939876A CN202110262843.9A CN202110262843A CN112939876A CN 112939876 A CN112939876 A CN 112939876A CN 202110262843 A CN202110262843 A CN 202110262843A CN 112939876 A CN112939876 A CN 112939876A
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- RLCLASQCAPXVLM-NSHDSACASA-N CC(C)n1c(=O)cc(N[C@@H](C)c2ccccc2)[nH]c1=O Chemical compound CC(C)n1c(=O)cc(N[C@@H](C)c2ccccc2)[nH]c1=O RLCLASQCAPXVLM-NSHDSACASA-N 0.000 title claims abstract description 61
- 229940069673 mavacamten Drugs 0.000 title claims abstract description 59
- 239000013078 crystal Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 95
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 72
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 60
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 57
- 239000002904 solvent Substances 0.000 claims description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 51
- 238000003756 stirring Methods 0.000 claims description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 25
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 24
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 24
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 24
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 24
- 229940011051 isopropyl acetate Drugs 0.000 claims description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 23
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000000354 decomposition reaction Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 229910017488 Cu K Inorganic materials 0.000 claims description 2
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- 238000010586 diagram Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 238000011161 development Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000005259 measurement Methods 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 25
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 102000013602 Cardiac Myosins Human genes 0.000 description 1
- 108010051609 Cardiac Myosins Proteins 0.000 description 1
- 102000002585 Contractile Proteins Human genes 0.000 description 1
- 108010068426 Contractile Proteins Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 210000002235 sarcomere Anatomy 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a Mavacamten crystal form I, and an X-ray powder diffraction pattern 2Theta value obtained by Cu-Kalpha ray measurement has characteristic peaks at 18.73 +/-0.2 degrees and 11.64 +/-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 crystal form I of a new medicine Mavacamten for treating hypertrophic cardiomyopathy and a preparation method thereof.
Background
Mavacamten (code No. MYK-461) is a cardiac myosin modulator developed by MyoKardia, Inc. USA, a heavy-duty basic study (A small-molecule inhibitor of myocardial contrast pathophysiological in the same) published in the Science journal of 2016, the theoretical basis of Mavacamten for the treatment of Hypertrophic Cardiomyopathy (HCM) was studied, and the first proposed attempt to make Mavacamten a small molecule inhibitor of sarcomere contractile proteins promising as a treatment for HCM. In 2020, MyoKardia announces mavacamten to reach the primary and all secondary endpoints in the third phase of clinical treatment of HCM patients and announces that it qualifies a breakthrough therapeutic drug for FDA approval in month 7, and the subsequent clinical studies are still in progress with a huge market prospect.
Mavacamten has the chemical name: (S) -3-isopropyl-6- ((1-phenylethyl) amino) pyrimidine-2, 4(1H,3H) -dione. The structural formula is as follows:
it is known that different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability and the like, thereby affecting the stability, bioavailability and curative effect of the drug, and the phenomenon is particularly obvious in the aspect of oral solid preparations, but the crystal form of Mavacamten is not reported in the existing patent. In the experimental research process, the inventor discovers that the crystal form I exists in the Mavacamten, and researches a preparation method of the crystal form, so that more choices are provided for the application of the Mavacamten.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a new medicine Mavacamten crystal form I for treating hypertrophic cardiomyopathy and a preparation method thereof.
The invention aims to provide a novel crystal form of Mavacamten, which adopts the following technical scheme:
a Mavacamten crystal form I having characteristic peaks at 11.64 ± 0.2 ° and 18.73 ± 0.2 ° in its X-ray powder diffractogram 2Theta value measured using Cu-K α radiation.
Further, the X-ray powder diffraction pattern 2Theta values also have characteristic peaks at 14.64 +/-0.2 degrees, 17.39 +/-0.2 degrees, 20.01 +/-0.2 degrees and 22.36 +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern 2Theta values also have characteristic peaks at 10.09 +/-0.2 degrees, 15.75 +/-0.2 degrees, 16.22 +/-0.2 degrees, 25.69 +/-0.2 degrees, 26.18 +/-0.2 degrees and 29.14 +/-0.2 degrees.
Further, the thermogravimetric analysis (TGA) of the inventive crystalline form I of Mavacamten shows that decomposition starts to be significant at around 250 ℃ and is complete at around 400 ℃.
The invention also aims to provide a preparation method of the novel crystal form of Mavacamten, which adopts the following technical scheme:
a preparation method of a Mavacamten crystal form I comprises the steps of adding Mavacamten 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, crystallizing, preserving heat, pulping to obtain a suspension, filtering, and drying to obtain a white to off-white solid, namely the crystal form I.
Preferably, the heating temperature is 35-110 ℃, and preferably 55-60 ℃; the cooling temperature is-20 to 30 ℃, and preferably 0 to 5 ℃.
Further, the crystallization system used may be selected from the following three solvent systems:
the solvent system 1 is a single solvent A system without adding a solvent B, and the solvent A is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile.
Preferably, the volume dosage of the solvent A is 0.5-40 times, preferably 5-20 times of the mass dosage of Mavacamten.
The solvent system 2 is a mixed solvent system in which an organic solvent A and a solvent B are selected from water, and specifically, the solvent A is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile.
Preferably, the volume dosage of the solvent A used in the method is 0.2-20 times of the dosage of the Mavacamten, preferably 2-10 times; the volume dosage of the water is 0.01-20 times of the mass dosage of the Mavacamten, and the optimal dosage is 3-10 times.
The solvent system 3 is a mixed solvent system consisting of a solvent A and a solvent B, wherein the solvent A is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile, the solvent B is selected from methanol, ethanol, isopropanol, N-butanol, N-heptane, N-hexane, petroleum ether, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile, and the solvents A and B are different from each other.
Preferably, the volume dosage of the solvent A used in the method is 0.2-40 times of the mass dosage of Mavacamten, and preferably 1-10 times; the volume dosage of the solvent B is 0.2-40 times of the mass dosage of the Mavacamten, and preferably 3-10 times.
More preferably, 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 ethanol, and the solvent B is n-heptane, so that a mixed solvent system of ethanol and n-heptane is formed.
The invention discovers a novel crystal form of Mavacamten, 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 I 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 the medicine.
Drawings
1. FIG. 1 is an XRPD pattern of form I of Mavacamten obtained in example 1;
2. FIG. 2 is a TGA profile of form I of Mavacamten obtained in example 1;
3. FIG. 3 is an XRPD pattern of form I of Mavacamten obtained in example 6;
4. FIG. 4 is an XRPD pattern of form I of Mavacamten obtained in example 11.
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.
Test conditions
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:
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 Mavacamten (1.0g, purity 98.0%) and anhydrous methanol 5mL into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 4-6 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain 0.81g of crystal form I (purity 99.9%, yield 82.6%).
The X-ray powder diffraction data of form I obtained in this example are shown in table 1, with an XRPD pattern as shown in figure 1, a DSC pattern as shown in figure 2, and a TGA pattern as shown in figure 3.
TABLE 1
In example 1, the anhydrous methanol may be replaced with ethanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile; the amount of methanol is in the range of 0.5-40 ml.
Example 2
Adding Mavacamten (1.0g, purity 98.0%) and 10mL of absolute ethyl alcohol into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 4-6 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain 0.86g of crystal form I (purity 99.8%, yield 87.6%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 2.
TABLE 2
In example 2, the anhydrous ethanol may be replaced with methanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile; the dosage of the ethanol is within the range of 0.5-40 ml.
Example 3
Adding Mavacamten (1.0g, purity 98.0%) and 10mL of isopropanol into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 4-6 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain 0.91g of crystal form I (purity 99.8%, yield 92.7%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 3.
TABLE 3
In example 3, isopropanol may be replaced with ethanol, methanol, N-butanol, ethyl acetate, isopropyl acetate, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone, or acetonitrile; the dosage of the isopropanol is within the range of 0.5-40 ml.
Example 4
Adding Mavacamten (1.0g, purity 98.0%) and ethyl acetate 20mL into a three-neck flask, uniformly stirring, heating to 55-60 ℃, stirring for 16-18 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain 0.91g of crystal form I (purity 99.7%, yield 92.6%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 4.
TABLE 4
In example 4, ethyl acetate may be replaced with isopropyl alcohol, ethanol, methanol, N-butanol, isopropyl acetate, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, or acetonitrile; the amount of ethyl acetate used is in the range of 0.5-40 ml.
Example 5
Adding Mavacamten (1.0g, purity 98.0%) and acetone (15 mL) into a three-neck flask, uniformly stirring, heating to 38-40 ℃, stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain 0.92g of crystal form I (purity 99.7%, yield 93.6%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 5.
TABLE 5
In example 5, acetone may be replaced with ethyl acetate, isopropyl alcohol, ethanol, methanol, N-butanol, isopropyl acetate, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile; the dosage of the acetone is within the range of 0.5-40 ml.
Example 6
Adding Mavacamten (1.0g, purity 98.0%) and methanol (3.0 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water (10.0 mL), stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain crystal form I (0.91 g, purity 99.9%, yield 92.8%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 6, with the XRPD pattern shown in figure 4.
TABLE 6
| 2THETA | d interval | Strength% |
| 10.02 | 8.82 | 4.30％ |
| 11.58 | 7.64 | 25.20％ |
| 13.70 | 6.46 | 1.30％ |
| 14.58 | 6.07 | 12.70％ |
| 15.69 | 5.64 | 6.10％ |
| 16.16 | 5.48 | 6.70％ |
| 17.33 | 5.11 | 12.30％ |
| 18.46 | 4.80 | 1.50％ |
| 18.67 | 4.75 | 100.00％ |
| 19.95 | 4.45 | 15.50％ |
| 22.30 | 3.98 | 7.30％ |
| 23.36 | 3.80 | 2.30％ |
| 23.81 | 3.73 | 1.70％ |
| 24.11 | 3.69 | 1.30％ |
| 24.51 | 3.63 | 1.60％ |
| 24.85 | 3.58 | 1.40％ |
| 25.63 | 3.47 | 3.00％ |
| 26.12 | 3.41 | 2.40％ |
| 27.33 | 3.26 | 1.20％ |
| 29.07 | 3.07 | 7.50％ |
| 29.93 | 2.98 | 1.40％ |
| 31.59 | 2.83 | 2.00％ |
| 31.81 | 2.81 | 0.70％ |
| 32.71 | 2.74 | 0.70％ |
| 37.89 | 2.37 | 1.20％ |
In example 6, methanol may be replaced with acetone, ethyl acetate, isopropyl alcohol, ethanol, N-butanol, isopropyl acetate, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile; the amount of methanol is in the range of 0.2-20 ml.
Example 7
Adding Mavacamten (1.0g, purity 98.0%) and ethanol (5.0 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water (5.0 mL), stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain crystal form I (0.93 g, purity 99.8%, yield 94.7%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 7.
TABLE 7
| 2THETA | d interval | Strength% |
| 10.02 | 8.84 | 6.50％ |
| 11.60 | 7.66 | 28.30％ |
| 13.70 | 6.48 | 1.10％ |
| 14.54 | 6.09 | 12.00％ |
| 15.69 | 5.64 | 10.00％ |
| 16.16 | 5.46 | 3.30％ |
| 17.31 | 5.13 | 16.60％ |
| 18.44 | 4.78 | 3.60％ |
| 18.69 | 4.77 | 100.00％ |
| 19.97 | 4.45 | 12.50％ |
| 22.30 | 3.98 | 9.70％ |
| 23.38 | 3.80 | 5.00％ |
| 23.81 | 3.75 | 2.80％ |
| 24.09 | 3.67 | 3.20％ |
| 24.49 | 3.63 | 5.90％ |
| 24.83 | 3.58 | 4.10％ |
| 25.63 | 3.47 | 5.30％ |
| 26.12 | 3.43 | 1.40％ |
| 27.35 | 3.26 | 0.50％ |
| 29.07 | 3.07 | 2.80％ |
| 29.97 | 2.98 | 1.70％ |
| 31.61 | 2.83 | 2.70％ |
| 31.81 | 2.83 | 2.30％ |
| 32.71 | 2.72 | 1.30％ |
| 37.93 | 2.35 | 6.00％ |
In example 7, ethanol may be replaced with methanol, acetone, ethyl acetate, isopropanol, N-butanol, isopropyl acetate, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile; the dosage of the ethanol is within the range of 0.2-20 ml; the amount of water is in the range of 0.01-20 ml.
Example 8
Adding Mavacamten (1.0g, purity 98.0%) and 6mL of dimethyl sulfoxide into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding 3mL of water, stirring for 4-6 hours, slowly cooling to 0-5 ℃ for crystallization, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain 0.72g of crystal form I (purity 99.9%, yield 73.4%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 8.
TABLE 8
| 2THETA | d interval | Strength% |
| 10.04 | 8.79 | 2.30％ |
| 11.61 | 7.63 | 40.20％ |
| 13.68 | 6.48 | 1.70％ |
| 14.62 | 6.07 | 4.60％ |
| 15.68 | 5.62 | 3.40％ |
| 16.16 | 5.48 | 6.60％ |
| 17.34 | 5.11 | 8.90％ |
| 18.29 | 4.87 | 0.80％ |
| 18.35 | 4.86 | 1.50％ |
| 18.66 | 4.73 | 100.00％ |
| 19.98 | 4.44 | 22.20％ |
| 21.23 | 4.17 | 1.00％ |
| 22.30 | 3.98 | 7.40％ |
| 23.40 | 3.80 | 1.50％ |
| 23.79 | 3.73 | 2.40％ |
| 24.10 | 3.71 | 6.40％ |
| 24.52 | 3.65 | 0.70％ |
| 24.81 | 3.58 | 2.10％ |
| 25.65 | 3.49 | 2.20％ |
| 26.12 | 3.41 | 1.50％ |
| 27.31 | 3.28 | 2.10％ |
| 29.11 | 3.05 | 9.50％ |
| 29.97 | 3.00 | 1.40％ |
| 31.58 | 2.81 | 5.10％ |
| 37.95 | 2.37 | 1.60％ |
In example 8, dimethyl sulfoxide can be replaced by ethanol, methanol, acetone, ethyl acetate, isopropanol, N-butanol, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or acetonitrile; the dosage of the dimethyl sulfoxide is within the range of 0.2-20 ml; the amount of water is in the range of 0.01-20 ml.
Example 9
Adding Mavacamten (1.0g, purity 98.0%) and tetrahydrofuran (10.0 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water (5.0 mL), stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain crystal form I (0.90 g, purity 99.8%, yield 91.7%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 9.
TABLE 9
| 2THETA | d interval | Strength% |
| 10.11 | 8.76 | 10.80％ |
| 11.64 | 7.58 | 31.70％ |
| 13.78 | 6.43 | 7.50％ |
| 14.66 | 6.05 | 27.80％ |
| 15.77 | 5.62 | 17.50％ |
| 16.24 | 5.48 | 17.30％ |
| 17.37 | 5.10 | 30.10％ |
| 18.73 | 4.73 | 100.00％ |
| 20.03 | 4.41 | 19.80％ |
| 20.14 | 4.41 | 3.80％ |
| 22.36 | 3.99 | 20.80％ |
| 23.44 | 3.81 | 6.30％ |
| 23.87 | 3.72 | 5.90％ |
| 24.18 | 3.68 | 2.70％ |
| 24.57 | 3.62 | 1.10％ |
| 24.92 | 3.57 | 8.00％ |
| 25.69 | 3.44 | 8.10％ |
| 26.22 | 3.38 | 5.10％ |
| 27.37 | 3.27 | 3.80％ |
| 27.82 | 3.20 | 4.00％ |
| 29.14 | 3.06 | 10.60％ |
| 29.98 | 2.98 | 5.20％ |
| 31.67 | 2.82 | 5.10％ |
| 32.79 | 2.73 | 0.70％ |
| 37.92 | 2.37 | 5.60％ |
In example 9, tetrahydrofuran may be replaced with dimethyl sulfoxide, ethanol, methanol, acetone, ethyl acetate, isopropyl alcohol, N-butanol, isopropyl acetate, methylene chloride, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or acetonitrile; the dosage of the tetrahydrofuran is within the range of 0.2-20 ml; the amount of water is in the range of 0.01-20 ml.
Example 10
Adding Mavacamten (1.0g, purity 98.0%) and isopropanol (10.0 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding water (5.0 mL), stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain crystal form I (0.92 g, purity 99.8%, yield 93.7%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 10.
Watch 10
| 2THETA | d interval | Strength% |
| 10.10 | 8.77 | 13.00％ |
| 11.63 | 7.62 | 36.00％ |
| 13.77 | 6.44 | 4.80％ |
| 14.63 | 6.03 | 40.70％ |
| 15.75 | 5.62 | 8.00％ |
| 16.22 | 5.44 | 14.80％ |
| 17.38 | 5.08 | 35.40％ |
| 18.70 | 4.72 | 100.00％ |
| 20.02 | 4.42 | 16.90％ |
| 20.17 | 4.40 | 2.40％ |
| 22.34 | 3.98 | 13.10％ |
| 23.44 | 3.80 | 5.80％ |
| 23.85 | 3.73 | 3.90％ |
| 24.14 | 3.66 | 2.40％ |
| 24.59 | 3.60 | 3.30％ |
| 24.91 | 3.57 | 4.80％ |
| 25.68 | 3.45 | 6.30％ |
| 26.15 | 3.40 | 11.00％ |
| 27.39 | 3.28 | 6.50％ |
| 27.77 | 3.21 | 2.00％ |
| 29.13 | 3.06 | 4.60％ |
| 29.98 | 2.96 | 0.80％ |
| 31.68 | 2.80 | 5.10％ |
| 31.82 | 2.79 | 4.40％ |
| 37.85 | 2.35 | 1.60％ |
In example 10, isopropanol may be replaced with tetrahydrofuran, dimethyl sulfoxide, ethanol, methanol, acetone, ethyl acetate, N-butanol, isopropyl acetate, dichloromethane, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or acetonitrile; the dosage of the isopropanol is within the range of 0.2-20 ml; the amount of water is in the range of 0.01-20 ml.
Example 11
Adding Mavacamten (1.0g, purity 98.0%) and methanol (2.0 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding ethyl acetate (10.0 mL), stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain crystal form I (0.88 g, purity 99.9%, yield 89.7%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 11, with the XRPD pattern shown in figure 4.
TABLE 11
| 2THETA | d interval | Strength% |
| 10.08 | 8.77 | 11.40％ |
| 11.63 | 7.60 | 34.60％ |
| 13.75 | 6.44 | 2.50％ |
| 14.63 | 6.05 | 36.30％ |
| 15.75 | 5.62 | 13.00％ |
| 16.22 | 5.46 | 19.60％ |
| 17.38 | 5.10 | 30.50％ |
| 18.72 | 4.74 | 100.00％ |
| 20.00 | 4.44 | 18.70％ |
| 20.15 | 4.40 | 2.10％ |
| 22.34 | 3.98 | 16.30％ |
| 23.42 | 3.80 | 2.90％ |
| 23.85 | 3.73 | 3.70％ |
| 24.16 | 3.68 | 2.60％ |
| 24.57 | 3.62 | 2.60％ |
| 24.91 | 3.57 | 3.30％ |
| 25.68 | 3.47 | 7.00％ |
| 26.17 | 3.40 | 7.60％ |
| 27.37 | 3.26 | 2.80％ |
| 27.81 | 3.21 | 1.70％ |
| 29.13 | 3.06 | 8.40％ |
| 29.96 | 2.98 | 3.40％ |
| 31.68 | 2.82 | 2.20％ |
| 31.82 | 2.81 | 2.50％ |
| 37.87 | 2.37 | 1.10％ |
In example 11, the methanol may be ethanol, isopropanol, N-butanol, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile, and the ethyl acetate may be ethanol, isopropanol, N-butanol, N-heptane, N-hexane, petroleum ether, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile; the dosage of the methanol is within the range of 0.2-40 ml; the amount of ethyl acetate is in the range of 0.2-40 ml.
Example 12
Adding Mavacamten (1.0g, purity 98.0%) and methanol (2.0 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding dichloromethane (10.0 mL), stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain crystal form I (0.67 g, purity 99.9%, yield 68.3%).
The X-ray powder diffraction data for form I obtained in this example are shown in table 12.
TABLE 12
| 2THETA | d interval | Strength% |
| 10.11 | 8.74 | 7.50％ |
| 11.64 | 7.58 | 33.60％ |
| 13.76 | 6.43 | 1.10％ |
| 14.66 | 6.03 | 19.50％ |
| 15.77 | 5.64 | 10.20％ |
| 16.20 | 5.46 | 16.80％ |
| 17.41 | 5.08 | 30.20％ |
| 18.71 | 4.71 | 100.00％ |
| 19.99 | 4.43 | 17.00％ |
| 20.14 | 4.43 | 1.90％ |
| 22.36 | 3.97 | 19.00％ |
| 23.42 | 3.77 | 2.30％ |
| 23.87 | 3.74 | 8.30％ |
| 24.20 | 3.70 | 4.30％ |
| 24.59 | 3.62 | 0.60％ |
| 24.94 | 3.55 | 0.90％ |
| 25.69 | 3.44 | 7.80％ |
| 26.16 | 3.40 | 4.60％ |
| 27.41 | 3.23 | 7.00％ |
| 27.82 | 3.20 | 4.90％ |
| 29.14 | 3.04 | 5.10％ |
| 29.98 | 3.00 | 5.80％ |
| 31.69 | 2.82 | 6.90％ |
| 32.75 | 2.73 | 3.40％ |
| 37.90 | 2.39 | 1.00％ |
In example 12, the methanol may be ethanol, isopropanol, N-butanol, isopropyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile, and the methylene chloride may be ethyl acetate, ethanol, isopropanol, N-butanol, N-heptane, N-hexane, petroleum ether, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile; the dosage of the methanol is within the range of 0.2-40 ml; the amount of dichloromethane is in the range of 0.2-40 ml.
Example 13
Adding Mavacamten (1.0g, purity 98.0%) and ethanol (10.0 mL) into a three-neck flask, uniformly stirring, heating to 55-60 ℃, slowly adding n-heptane (10.0 mL), stirring for 4-6 hours, slowly cooling to 0-5 ℃, crystallizing, keeping the temperature, stirring for 16-24 hours, centrifuging, and drying to obtain crystal form I (0.94 g, purity 99.5%, yield 95.4%).
The X-ray powder diffraction data of form I obtained in this example are shown in table 13.
Watch 13
In example 13, the ethanol may be methanol, isopropanol, N-butanol, isopropyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile, and the N-heptane may be dichloromethane, ethyl acetate, isopropanol, N-butanol, N-hexane, petroleum ether, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile; the dosage of the ethanol is within the range of 0.2-40 ml; the dosage of the n-heptane is within the range of 0.2-40 ml.
Accelerated test
Taking the crystal form I obtained in example 1, example 6 and example 11 to carry out 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 14, and the product exhibits very stable properties over a period of 2 months under accelerated conditions.
TABLE 14 accelerated stability test
Test results show that the crystal form I 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 Mavacamten crystal form I, which is characterized in that the X-ray powder diffraction pattern 2Theta value measured by using Cu-K alpha rays has characteristic peaks at 11.64 +/-0.2 degrees and 18.73 +/-0.2 degrees.
2. Form I of Mavacamten according to claim 1, characterized in that it further has characteristic peaks at 14.64 ± 0.2 °, 17.39 ± 0.2 °, 20.01 ± 0.2 ° and 22.36 ± 0.2 ° in its X-ray powder diffraction pattern 2Theta value.
3. Form I of Mavacamten according to claim 1, characterized in that it further has characteristic peaks in the X-ray powder diffraction pattern 2Theta values at 10.09 ± 0.2 °, 15.75 ± 0.2 °, 16.22 ± 0.2 °, 25.69 ± 0.2 °, 26.18 ± 0.2 ° and 29.14 ± 0.2 °.
4. The crystalline form of Mavacamten according to any one of claims 1 to 3, characterized in that the TGA diagram of the thermogravimetric analysis curve of the crystalline form I of Mavacamten shows a marked decomposition starting from heating to 250 ℃ and a complete decomposition at 400 ℃.
5. A process for the preparation of crystalline form I of Mavacamten as claimed in any of claims 1 to 3, which comprises adding Mavacamten to solvent a, heating to a certain temperature and stirring for a period of time, adding or not adding solvent B, stirring in the resulting mixed solvent system or single solvent for a period of time, slowly cooling to a certain temperature for crystallization, and slurrying at an elevated temperature to obtain a suspension, filtering and drying to obtain a white to off-white solid, i.e. crystalline form I.
6. The method for preparing the crystalline form I of Mavacamten according to claim 5, characterized in that the heating temperature is 35-110 ℃; the cooling temperature is-20 to 30 ℃.
7. The method for preparing Mavacamten crystal form I according to claim 5, wherein solvent system 1 is a single solvent a system selected without adding solvent B, wherein solvent a is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile; the volume dosage of the solvent A is 0.5-40 times of the mass dosage of the Mavacamten.
8. The method for preparing the crystal form I of Mavacamten according to claim 5, wherein the solvent system 2 is a mixed solvent system selected from organic solvent A and solvent B as water, and the solvent A is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile; the volume dosage of the solvent A used in the method is 0.2-20 times of the dosage of the Mavacamten; the volume dosage of the water is 0.01-20 times of the mass dosage of the Mavacamten.
9. The method for preparing Mavacamten crystal form I according to claim 5, characterized in that solvent system 3 is selected from the group consisting of solvent A and solvent B, wherein solvent A is selected from the group consisting of methanol, ethanol, isopropanol, N-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone or acetonitrile, and solvent B is selected from the group consisting of methanol, ethanol, isopropanol, N-butanol, N-heptane, N-hexane, petroleum ether, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, N-dimethylformamide, N-, Acetone or acetonitrile, and different solvents A and B; the volume dosage of the solvent A used in the method is 0.2-40 times of the mass dosage of Mavacamten; the volume dosage of the solvent B is 0.2-40 times of the mass dosage of the Mavacamten.
10. The method for preparing the crystal form I of Mavacamten according to claim 9, wherein 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 ethanol, and the solvent B is n-heptane, so that a mixed solvent system of ethanol and n-heptane is formed.
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| WO2022189599A1 (en) * | 2021-03-12 | 2022-09-15 | Sandoz Ag | Crystalline forms of mavacamten for the treatment of hcm |
| CN115515941A (en) * | 2020-01-28 | 2022-12-23 | 梯瓦制药国际有限责任公司 | Solid state forms of MAVACAMTEN and processes for their preparation |
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