CN116987013A - Crystal form of optically active diamine derivative and preparation method thereof - Google Patents
Crystal form of optically active diamine derivative and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000013078 crystal Substances 0.000 title abstract description 20
- 150000004985 diamines Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000012296 anti-solvent Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 238000007664 blowing Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 230000002349 favourable effect Effects 0.000 description 4
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 108010094028 Prothrombin Proteins 0.000 description 2
- 102100027378 Prothrombin Human genes 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940039716 prothrombin Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- PSMMNJNZVZZNOI-SJILXJHISA-N edoxaban tosylate hydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 PSMMNJNZVZZNOI-SJILXJHISA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
-
- 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
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a crystal form of an optically active diamine derivative and a preparation method thereof, the crystal form of a compound shown in a formula I,
Description
Technical Field
The present invention relates to a crystalline form of an optically active diamine derivative and a process for the preparation thereof.
Background
Elegance is a reversible factor Xa inhibitor, has high selectivity, can directly inhibit FXa, and as a result, can prolong Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT), and finally inhibit thrombosis. Factor Xa inhibitors are more potent than thrombin inhibitors because of the physiological effects of a factor Xa inhibitor molecule that inhibits 138 prothrombin molecules due to the chemical book amplification of biological signals present in the clotting process. Therapeutic dose irinotecan has an effect on PT, international Normalized Ratio (INR), and APTT, but varies less; peak concentrations (Cmax) were reached 1-2 h after oral administration.
The compound related by the invention is a key intermediate in the edoxaban, the existing production process is improved according to the patent CN102348688B, the oxalate of the compound is required to be prepared for purification, meanwhile, the oxalate is required to be dissociated in the next reaction, the whole production process is complex, the atom economy is poor, a large amount of waste water and waste liquid are generated, the conditions of lower product purity, poor product shape, easy disqualification of solvent residues and the like are met if the oxalate is not prepared in the normal process, the crystal system of the patent is adopted to obtain the crystal form of the patent, the product purity can be effectively improved, the product is better dispersed in the solvent system, the shape of the filtered product is uniform, the dissolved residue is less, the proportion of the solvent of the crystal system in the patent is a key process parameter, the good solvent is more, the solid cannot be separated out, and the reverse solvent is more, so that oily matters can be separated out. The compound with the crystal form of the patent synthesizes the idexaban API according to the experimental scheme in patent WO2019158550, and can obtain qualified high-quality idexaban.
Disclosure of Invention
The purpose of the invention is that: the preparation method has the advantages of low cost, stable process, high product purity, high chiral purity, green and environment-friendly production process and the like, and the crystal form of the X-ray powder diffraction pattern prepared by the specific process has high solubility, good stability at high temperature, difficult degradation of products and low hygroscopicity, so that the preparation is facilitated, and the compound is convenient for long-term storage. Meanwhile, the crystallization product is not subjected to oxalate purification, so that the sub-economy is greatly improved.
In order to achieve the above object, the present invention adopts the following method:
a crystalline form of a compound of formula I,
which in the X-ray powder diffraction pattern at diffraction angles: peaks at 6.4 °,9.5 °,11.1 °,13.2 °,17.5 °,18.6 °,19.1 °,19.8 °,20.5 °,24.2 °,27.3 ° (2θ±0.2°).
A crystalline form of a compound of formula I, characterized by: the crystalline form has an endothermic peak at a temperature of 124.08 ℃ to 125.95 ℃ when measured using differential scanning calorimetry.
A process for the preparation of a crystalline form of a compound of formula I, comprising the steps of: dispersing a compound shown in a formula I in any form in a good solvent, heating to a certain temperature to dissolve, preserving heat and stirring for 2-10h, adding an anti-solvent into the solution after dissolving, crystallizing, cooling, preserving heat and stirring for 4-48h.
Further, the good solvent is selected from one of ethyl acetate, isopropyl acetate, methyl tertiary butyl ether, methanol, ethanol, isopropanol and dichloromethane.
Further, the antisolvent is selected from the group consisting of water, petroleum ether, n-heptane, cyclohexane, n-hexane, and mixtures thereof.
Further, the ratio of good solvent to anti-solvent is: 1:1 to 30, preferably 1:5 to 1, more preferably 1:8.
further, the dissolution temperature of the compound shown in the formula I in a good solvent is 20-90 ℃, and the temperature of the crystallized compound after cooling and heat preservation is 0-40 ℃.
The beneficial effects of adopting the technical scheme are as follows:
the oxalate is required to be prepared in the traditional process, if the oxalate is not prepared, the conditions of lower product purity, poor product shape, easy disqualification of solvent residues and the like can be met, the crystal system of the patent is adopted to obtain the crystal form in the patent, the product purity can be effectively improved, the product is better dispersed in the solvent system, the filtered product is uniform in shape and less in solvent residues, the proportion of the solvent of the crystal system in the patent is a key technological parameter, more good solvents can lead to incapability of separating out solids, and more reverse solvents can separate out oily matters
Compared with the traditional process, the preparation method has the advantages of low cost, stable process, high product purity, high chiral purity, green and environment-friendly production process and the like, and the crystalline form of the X-ray powder diffraction pattern prepared by the specific process has high solubility (favorable for the next reaction), good stability at high temperature, difficult degradation of the product (favorable for storage) and low hygroscopicity (favorable for storage).
Drawings
Fig. 1 shows an X-ray diffraction pattern of a crystalline form of a compound of formula I according to an exemplary embodiment of the present invention.
Fig. 2 shows a thermogram of a crystalline form of the compound of formula I according to an exemplary embodiment of the present invention formed by DSC (differential scanning calorimetry).
Fig. 3 shows an HPLC purity profile of a compound of formula I according to an exemplary embodiment of the invention.
Detailed Description
The following describes a crystalline form of an optically active diamine derivative and a method for producing the same in the present invention.
A crystalline form of a compound of formula I, which has the following diffraction angles in an X-ray powder diffraction pattern: peaks at 6.4 °,9.5 °,11.1 °,13.2 °,17.5 °,18.6 °,19.1 °,19.8 °,20.5 °,24.2 °,27.3 ° (2θ±0.2°).
A crystalline form of a compound represented by formula I, characterized by: the crystalline form has an endothermic peak at a temperature of 124.08 ℃ to 125.95 ℃ when measured using differential scanning calorimetry.
A method of crystallizing a crystalline form of a compound represented by formula I, comprising: dispersing any form of compound represented by chemical formula I in a good solvent, heating to a certain temperature to dissolve, preserving heat and stirring for 2-10h, adding an anti-solvent into the solution after dissolving, crystallizing, cooling, preserving heat and stirring for 4-48h.
Wherein the good solvent can be ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, dichloromethane, etc., and the anti-solvent can be one of water, petroleum ether, n-heptane, cyclohexane, methyl tert-butyl ether, n-hexane, etc.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are for illustrative purposes only and the present invention should not be limited by these examples.
FIG. 1 shows an X-ray diffraction pattern of a crystalline form of the compound of formula I prepared in example 1.
FIG. 2 shows a thermogram of the crystalline form of the compound of formula I prepared in example 1 formed by DSC (differential scanning calorimetry).
FIG. 3 shows an HPLC purity profile of the compound of formula I prepared in example 1.
Example 1:
adding 25mL of methanol and 50.0g of compound I into a three-port reaction bottle, heating to 50-60 ℃ and stirring to dissolve, dropwise adding 400mL of MTBE into the reaction bottle, gradually precipitating solids in the dropwise adding process, keeping the temperature at 50-60 ℃ and stirring for 4-14h after 3h, reducing the internal temperature of the reaction bottle to 0-10 ℃, keeping the temperature and stirring for 2-5h, filtering, and drying by blowing at 40-50 ℃ to obtain 41.2g of white solid with the yield: 82.4% and 98.58% by HPLC.
An experimental powder X-ray diffraction Pattern (PXRD) is shown in figure 1. Diffraction peak data for the experimental PXRD pattern are shown in table 1.
TABLE 1
Table 1 continuation
| 29.1985 | 633.03 | 0.1535 | 3.05858 | 0.99 |
| 30.1847 | 912.56 | 0.1535 | 2.96086 | 1.43 |
| 30.5982 | 483.74 | 0.1535 | 2.92178 | 0.76 |
| 31.1869 | 995.86 | 0.1023 | 2.86797 | 1.56 |
| 31.7466 | 2250.16 | 0.1791 | 2.81867 | 3.52 |
| 32.8183 | 956.17 | 0.1535 | 2.72903 | 1.49 |
| 33.7368 | 460.01 | 0.1791 | 2.65681 | 0.72 |
| 35.2237 | 316.63 | 0.3070 | 2.54799 | 0.49 |
| 36.4562 | 230.42 | 0.3070 | 2.46463 | 0.36 |
| 37.0853 | 241.41 | 0.3070 | 2.42425 | 0.38 |
| 37.9019 | 538.38 | 0.2047 | 2.37388 | 0.84 |
| 38.8483 | 986.77 | 0.1791 | 2.31820 | 1.54 |
| 40.7532 | 499.80 | 0.2047 | 2.21413 | 0.78 |
| 41.7424 | 327.18 | 0.2047 | 2.16392 | 0.51 |
| 42.9862 | 798.15 | 0.2047 | 2.10415 | 1.25 |
| 45.4384 | 231.68 | 0.2047 | 1.99613 | 0.36 |
| 46.5256 | 607.22 | 0.1279 | 1.95199 | 0.95 |
| 47.1535 | 668.92 | 0.1535 | 1.92745 | 1.05 |
| 48.0386 | 380.00 | 0.2047 | 1.89399 | 0.59 |
Example 2:
25mL of DCM and 50.0g of compound I are added into a three-port reaction bottle, the temperature is raised to 50-60 ℃ and the solution is stirred, 400mL of MTBE is dripped into the reaction bottle, the solid is gradually separated out in the dripping process, the dripping process is completed, the temperature is kept at 50-60 ℃ and the mixture is stirred for 2-14h, the internal temperature of the reaction bottle is reduced to 0-10 ℃, the temperature is kept at 50-60 ℃ and the mixture is stirred for 2-5h, the mixture is filtered and dried by blowing at 40-50 ℃ to obtain 47.3g of white solid, and the yield is: 94.6% and 99.61% by HPLC.
Example 3:
25mL of DCM and 50.0g of compound I are added into a three-port reaction bottle, the temperature is raised to 50-60 ℃ and the solution is stirred, 400mL of n-heptane is dripped into the reaction bottle, the solid is gradually separated out in the dripping process, the dripping process is completed, the temperature is kept at 50-60 ℃ and the mixture is stirred for 2-14h, the internal temperature of the reaction bottle is reduced to 0-10 ℃, the temperature is kept at 50-60 ℃ and the mixture is stirred for 2-5h, the mixture is filtered and dried by blowing at 40-50 ℃ to obtain 48.8g of white solid, and the yield is: 97.6% and 98.93% by HPLC.
Example 4:
adding 25mL of ethyl acetate and 50.0g of compound I into a three-port reaction bottle, heating to 50-60 ℃ and stirring to dissolve, dropwise adding 400mL of n-heptane into the reaction bottle, gradually precipitating solids in the dropwise adding process, keeping the temperature at 50-60 ℃ and stirring for 2-14h after 3h, reducing the internal temperature of the reaction bottle to 0-10 ℃, keeping the temperature and stirring for 2-5h, filtering, and drying by blowing at 40-50 ℃ to obtain 43.9g of white solid with the yield: 87.8% and 98.65% by HPLC.
Example 5:
adding 25mL of isopropyl acetate and 50.0g of compound I into a three-port reaction bottle, heating to 50-60 ℃ and stirring to dissolve, dropwise adding 400mL of petroleum ether into the reaction bottle, gradually precipitating solids in the dropwise adding process, stirring for 2-14h at 50-60 ℃ after 3h, reducing the internal temperature of the reaction bottle to 0-10 ℃, stirring for 2-5h at the temperature, filtering, and drying by blowing at 40-50 ℃ to obtain 45.7g of white solid with the yield: 90.4% and 99.64% by HPLC.
Example 6: moisture permeability experiments of different crystal forms
The hygroscopicity has a considerable influence on the preservation of the medicine and the development of the preparation, the low hygroscopicity greatly prolongs the preservation time of the medicine, is favorable for storage, and the compound with higher hygroscopicity is difficult to formulate and has a great influence on the reproducibility, and the hygroscopicity of three different crystal forms is studied:
from the data in the table, it can be seen that the oxalate salt formed from the compound and oxalic acid dihydrate has a stronger hygroscopicity than the free base, which is detrimental to long-term storage.
The above table shows that the monohydrate crystal form has obviously changed color appearance under the irradiation of strong light, the white powder is changed into pale yellow powder, the chiral purity is greatly reduced, and the impurity is obviously increased. Although the color of the anhydrous crystal form I is not obviously changed, the enantiomer impurity is increased from 0.02% to 0.06%, potential risk points appear, the impurity is increased from 0.12% to 0.22%, the obvious increase is also caused, and the product is easy to be disqualified. The anhydrous crystal form II is free from detection of enantiomer impurities before and after illumination, and the impurities are increased, so that the anhydrous crystal form II has better light adaptability and better stability compared with other two crystal forms.
It will be evident to a person skilled in the art that the invention is not limited to the details of the example embodiments described above, but that the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that while the present description describes embodiments, not every embodiment is presented by way of example only, and that this description is provided for clarity only, and that the present disclosure is not limited to the embodiments described in the figures, as such, and that the embodiments described in the examples may be combined in any suitable manner to form other embodiments that will be apparent to those of skill in the art.
Claims (9)
1. A crystalline form of a compound of formula I, characterized by:
which in the X-ray powder diffraction pattern at diffraction angles: peaks at 6.4 °,9.5 °,11.1 °,13.2 °,17.5 °,18.6 °,19.1 °,19.8 °,20.5 °,24.2 °,27.3 ° (2θ±0.2°).
2. A crystalline form of a compound of formula I according to claim 1, characterized in that: the crystalline form has an endothermic peak at a temperature of 124.08 ℃ to 125.95 ℃ when measured using differential scanning calorimetry.
3. A process for the preparation of a crystalline form of a compound of formula I, characterized in that: the preparation method comprises the following steps: dispersing a compound shown in a formula I in any form in a good solvent, heating to a certain temperature to dissolve, preserving heat and stirring for 2-10h, adding an anti-solvent into the solution after dissolving, crystallizing, cooling, preserving heat and stirring for 4-48h.
4. A process for the preparation of a crystalline form of a compound of formula I according to claim 3, characterized in that: the good solvent is selected from one of ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol and dichloromethane.
5. A process for the preparation of a crystalline form of a compound of formula I according to claim 3, characterized in that: the anti-solvent is selected from one of water, petroleum ether, n-heptane, cyclohexane, MTBE and n-hexane.
6. A process for the preparation of a crystalline form of a compound of formula I according to claim 3, characterized in that: the ratio of the good solvent to the anti-solvent is as follows: 1:1 to 30.
7. The process for preparing a crystalline form of a compound of formula I according to claim 6, wherein: the ratio of the good solvent to the anti-solvent is as follows: 1:5 to 1.
8. A process for the preparation of a crystalline form of a compound of formula I according to claim 7, wherein: the ratio of the good solvent to the anti-solvent is as follows: 1:8.
9. a process for the preparation of a crystalline form of a compound of formula I according to claim 3, characterized in that: the dissolution temperature of the compound shown in the formula I in a good solvent is 20-90 ℃, and the temperature of the compound after crystallization is 0-40 ℃.
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