CN116621817A - Entecavir fumarate crystal form, preparation method, pharmaceutical composition and application thereof - Google Patents
Entecavir fumarate crystal form, preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- CN116621817A CN116621817A CN202310892033.0A CN202310892033A CN116621817A CN 116621817 A CN116621817 A CN 116621817A CN 202310892033 A CN202310892033 A CN 202310892033A CN 116621817 A CN116621817 A CN 116621817A
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- entecavir
- crystal form
- fumarate
- pharmaceutical composition
- crystalline form
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 100
- 229960000980 entecavir Drugs 0.000 title claims abstract description 93
- 239000013078 crystal Substances 0.000 title claims abstract description 91
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 86
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 77
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 239000012535 impurity Substances 0.000 claims abstract description 7
- 230000005855 radiation Effects 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000001530 fumaric acid Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- 238000001228 spectrum Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- 241000711573 Coronaviridae Species 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910017488 Cu K Inorganic materials 0.000 claims 2
- 229910017541 Cu-K Inorganic materials 0.000 claims 2
- 230000009286 beneficial effect Effects 0.000 abstract description 10
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000013112 stability test Methods 0.000 description 10
- QMPBBNUOBOFBFS-UHFFFAOYSA-N 6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione Chemical compound CN1N=C(C=C(C(/N=C(\NC(N2CC3=NN(C)C=N3)=O)/N(CC(C=C(C(F)=C3)F)=C3F)C2=O)=C2)Cl)C2=C1 QMPBBNUOBOFBFS-UHFFFAOYSA-N 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 7
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 7
- -1 6-chloro-2-methyl-2H-indazol-5-yl Chemical group 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 229910002483 Cu Ka Inorganic materials 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- LKDRXBCSQODPBY-JDJSBBGDSA-N D-allulose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O LKDRXBCSQODPBY-JDJSBBGDSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- 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
Abstract
The invention provides a crystal form of Entecavir fumarate, a preparation method, a pharmaceutical composition and application thereof, and belongs to the technical field of pharmaceutical chemistry. The crystal form of the invention is the crystal form of Entecavir fumarate shown in the formula I, cu-K alpha radiation is used, and characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in terms of 2 theta value plus or minus 0.2 DEG comprise 6.63, 9.67, 10.92, 12.04, 12.18, 12.78, 13.27, 13.48, 16.22, 17.57, 18.35, 19.93, 21.78, 22.10, 22.39,23.33, 23.72, 24.20, 24.56, 25.67, 26.05, 28.03, 32.99. The invention realizes the targets of high yield, high purity, less impurities, good quality and controllable reaction of the novel crystal form of Entecavir fumarate, and the preparation method has the advantages of low cost, less three wastes and environmental protection, is beneficial to industrialized amplified production and has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a crystal form of entecavir fumarate, a preparation method, a pharmaceutical composition and application thereof.
Background
Drug molecules typically have different solid forms including salts, polymorphs, co-crystals, amorphous, hydrates, solvates and the like; different crystal forms of the same drug molecule often have different physical properties including solubility, hygroscopicity, flowability, stability, bioavailability, etc., which can directly affect the efficacy and developability of the drug. The stable crystal form is beneficial to increasing the safety of the medicine in clinical application. Therefore, a drug molecule with high crystal form stability, convenient production and pharmaceutically acceptable property should be provided as much as possible in the commercial production of drugs.
Entecavir fumarate, chinese name: (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-e-2, 4-dioneA fumarate salt; english name: ensitrelvir Fumaric Acid; CAS:2757470-18-9; the molecular formula: c (C) 22 H 17 ClF 3 N 9 O 2 ·C 4 H 4 O 4 The method comprises the steps of carrying out a first treatment on the surface of the Molecular weight: 647.96; the structure of the compound is shown as formula I:
ensibrotevir (Ensibrelvir) is developed by the university of North sea and salt wild pharmaceutical together, is a novel coronavirus 3CL protease inhibitor, the active ingredient of which is Ensibrotevir fumarate, and is urgently approved in Japan for the treatment of novel coronaviruses, month 2022. It blocks the proliferation of new coronaviruses by selectively inhibiting 3CL protease. This mechanism of action is consistent with that of the previously approved psicose oral drug. According to the medicine intelligence data and the medicine clinic public data, ensitrelvir is the medicine with the best effectiveness, highest safety and longest action maintenance time compared with the new crown medicines of other companies. Has excellent performances in terms of nucleic acid conversion, virus elimination, hospitalization rate and death rate. The marketing of the medicine clearly brings great benefits to the control and treatment of new coronaviruses.
International patent application publication No. WO2023027198A1 discloses a crystalline form of entecavir fumarate prepared by adding fumaric acid and ethyl acetate to entecavir free base and stirring at room temperature, and taking the solid by filtration and drying. However, the crystalline form of Entecavir fumarate obtained in this manner is unknown in purity and stability. Chinese patent (publication No. CN 114591304B) discloses two crystal forms of Entecavir fumarate, and the preparation method of the crystal form A comprises the steps of adding Entecavir fumarate into a solvent to prepare a suspension, suspending and stirring for 3-7 days at room temperature, separating the suspension, and drying to obtain the final product. The crystal form has long preparation time and low production efficiency, is not beneficial to industrialized amplified production, and is consistent with the crystal form obtained by international patent application (publication number WO2023027198A 1) through data comparison. The other crystal form is a crystal form B obtained by stirring Entecavir free base and fumaric acid in ethyl acetate and filtering, but the purity of the crystal form obtained by the method is not high (97%), and the patent data show that the crystal form B has poor stability, is slightly agglomerated or agglomerated under high humidity conditions, is unstable under illumination and has color change. Therefore, a new crystal form of Entecavir fumarate and a preparation method thereof are required to be researched so as to meet the commercial production of the pharmaceutical market.
Disclosure of Invention
In order to overcome the problems of the existing Entecavir fumarate crystal forms, the invention provides an Entecavir fumarate crystal form, and a preparation method, a pharmaceutical composition and application thereof. The crystal form of the entecavir fumarate provided by the invention is completely different from the crystal form A and the crystal form B disclosed in the prior art. The invention prepares the new crystal form C of Entecavir fumarate by a more economical, simpler and more convenient and better-repeatability method, and the crystal form C obtained by the method has high purity and excellent product stability and is suitable for industrial production.
The present invention provides crystalline forms of entecavir fumarate of formula I using Cu-ka radiation, characterized diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2Θ values ± 0.2 ° including 6.63, 9.67, 10.92, 12.04, 12.18, 12.78, 13.27, 13.48, 16.22, 17.57, 18.35, 19.93, 21.78, 22.10, 22.39, 23.33, 23.72, 24.20, 24.56, 25.67, 26.05, 28.03, 32.99;
formula I.
Further, it uses Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include 15.09, 19.13, 20.64, 26.38, 28.40, 30.40, 34.15, 35.52, 37.47, 39.21.
Further, the X-ray powder diffraction pattern of the crystal form is shown in figure 1.
Further, the differential scanning calorimetric spectrum of the crystal form is shown in fig. 2;
the differential scanning calorimeter spectrum has two endothermic peaks, namely an endothermic peak with a peak value of 233+/-2 ℃ and an endothermic peak with a peak value of 268+/-2 ℃.
Further, the molar ratio of entecavir to fumaric acid in the crystal form is 1:1; the purity of the crystal form is more than 99%, and/or the content of single impurity is less than 0.1%.
The invention also provides a preparation method of the crystal form, which comprises the following steps:
dissolving Entecavir solid in a solvent, adding fumaric acid, stirring, precipitating crystals by using a poor solvent, and drying to obtain the final product.
Further, the solvent is one or more of dioxane, butanone, acetonitrile, ethyl formate, ethyl acetate, butyl formate, methylene chloride, chloroform, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, 4-methyl-2-pentanone and/or tetrahydrofuran;
and/or the poor solvent is one or more of dichloromethane, methanol and ethyl acetate;
and/or the drying temperature is 60-100 ℃.
Preferably, the solvent is dimethyl sulfoxide;
and/or the poor solvent is dichloromethane, methanol or ethyl acetate.
The invention also provides a pharmaceutical composition which comprises the crystal form and a pharmaceutically acceptable carrier.
Further, in the pharmaceutical composition, the weight percentage of the crystal form is 0.1% -85%.
The invention also provides application of the crystal form or the pharmaceutical composition in preparing medicines for treating novel coronaviruses.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel crystal form of Entecavir fumarate and a preparation method thereof. The obtained Entecavir fumarate crystal form has high purity (HPLC is more than 98.5%), high melting point, better stability compared with the existing Entecavir fumarate crystal form, meets the ICHQ3C solvent limit requirement, has higher quality, can effectively prolong the effective period of medicines when being used as medicine raw materials, can meet the pharmaceutical requirements of production, processing, transportation and storage, and is also beneficial to preservation and quality control at normal temperature. The invention realizes the targets of high yield, high purity, less impurities, good quality and controllable reaction of the novel crystal form of Entecavir fumarate, and the preparation method has the advantages of low cost, less three wastes and environmental protection, is beneficial to industrialized amplified production and has wide application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1 is an X-ray powder diffraction diagram of crystalline form C of entecavir fumarate prepared in example 1, with 2 theta degrees on the abscissa and intensity (counts) on the ordinate.
FIG. 2 is a Differential Scanning Calorimetric (DSC) spectrum of crystalline form C of Entecavir fumarate prepared in example 1.
Fig. 3 is an X-ray powder diffraction diagram of crystalline form C of entecavir fumarate prepared in example 2, with 2 theta degrees on the abscissa and intensity (counts) on the ordinate.
Fig. 4 is an X-ray powder diffraction diagram of crystalline form C of entecavir fumarate prepared in example 3, with 2 theta degrees on the abscissa and intensity (counts) on the ordinate.
Fig. 5 is an X-ray powder diffraction diagram of crystalline form a of entecavir fumarate prepared in comparative example 1, with 2 theta [ deg. ] on the abscissa and intensity (counts) on the ordinate.
Fig. 6 is an X-ray powder diffraction diagram of crystalline form B of entecavir fumarate prepared in comparative example 3, with 2 theta o on the abscissa and intensity (counts) on the ordinate.
Fig. 7 is an X-ray powder diffraction diagram of the entecavir fumarate crystal form C prepared in example 1 after 6 months of accelerated stability test, wherein the abscissa is 2θ [ deg. ], and the ordinate is intensity (count).
Fig. 8 is an HPLC profile of crystalline form C of entecavir fumarate prepared in example 1.
Fig. 9 is an HPLC profile of crystalline form C of entecavir fumarate prepared in example 1 after 6 months of accelerated stability test.
Fig. 10 is a Differential Scanning Calorimeter (DSC) profile of crystalline form C of entecavir fumarate prepared in example 1 after a 6 month accelerated stability test.
Fig. 11 is a GC chart of the solvent residue of crystalline form C of entecavir fumarate prepared in example 1.
Fig. 12 is a GC chart of the solvent residue of crystalline form a of entecavir fumarate prepared in comparative example 1.
Detailed Description
The compounds or reagents used in the embodiments of the invention are commercially available or may be prepared by conventional methods known to those skilled in the art; the laboratory apparatus used is commercially available.
Test instrument for experiments:
1. x-ray powder diffraction spectrum
Instrument model: PANalygraphic Empyrean (PANalygraphic, NL)
Rays: monochromatic Cu-Ka ray
Scanning mode: q/2q, scan range: 2 to 50
Voltage: 45kV; current flow: 40mA
2. DSC spectrum
Instrument model: TADiscovery2500 (TA, US)
Sweep gas: nitrogen gas
Rate of temperature rise: 10.0 K/min
Temperature range: 30-350 DEG C
3. High Performance Liquid Chromatography (HPLC)
Instrument model: agilenttechnologies1260 Informance
Chromatographic column: c18 column
Sample injection volume: 10 μl of
Mobile phase: water + acetonitrile; the volume ratio of water to acetonitrile 95:5 lasts for 5min, the volume ratio of water to acetonitrile 10:90 lasts for 15min, and the volume ratio of water to acetonitrile 95:5 lasts for 5min
Flow rate: 1.0ml/min
Column temperature: 30 DEG C
Detection wavelength: 260nm of
4. Gas chromatography (GC-RES)
A detector: FID (FID)
Chromatographic column: agilent DB-624 30m 0.32mm 1.80 μm
Heating program: maintaining at 40deg.C for 0min, and heating to 120deg.C at 20deg.C/min for 5min
Sample inlet temperature: 250 DEG C
Detector temperature: 300 DEG C
Carrier gas: n (N) 2
Pressure: (constant pressure)/flow (constant flow) 7.8 Psi (constant pressure)
Split ratio: 30:1
Heating box temperature: 80 DEG C
Quantitative ring temperature: 90 DEG C
Transmission line temperature: 100 DEG C
Sample bottle equilibration time: 15min
GC cycle time: 25min
EXAMPLE 1 preparation of Entecavir fumarate Crystal form C of the invention
(6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazole-3-yl) methyl ] -1- (2, 4, 5-trifluoro benzyl) -1,3, 5-triazin-E-2, 4-dione solid (1.0 g) is added into 3.0ml dimethyl sulfoxide to prepare a solution liquid, the solution liquid is heated and dissolved, 0.22g of fumaric acid is added while the solution is hot, stirred and reacted for 30min, the temperature is reduced to room temperature, 3.0ml of dichloromethane is dripped, white solid is separated out, and the solution is dried to obtain crystal form C (1.16 g) with the yield of 95%, the purity of HPCL is more than 99.9%, and the content of single impurity is lower than 0.1%.
The Entecavir fumarate crystal form C of the invention uses Cu-Ka radiation, the obtained X-ray powder diffraction diagram is shown in figure 1, the X-ray powder diffraction diagram is expressed by 2 theta angles + -2 and interplanar spacing (d), and specific diffraction peak parameters are shown in table 1.
TABLE 1 specific diffraction peak parameters for Entecavir fumarate form C
| Numbering device | 2θ[°] | d value | Relative strength% |
| 1 | 6.63 | 13.32 | 34.93 |
| 2 | 8.77 | 10.09 | 3.07 |
| 3 | 9.67 | 9.14 | 56.62 |
| 4 | 10.92 | 8.09 | 12.58 |
| 5 | 12.04 | 7.35 | 11.69 |
| 6 | 12.18 | 7.26 | 6.93 |
| 7 | 12.78 | 6.92 | 13.68 |
| 8 | 13.27 | 6.67 | 14.12 |
| 9 | 13.48 | 6.56 | 24.65 |
| 10 | 14.08 | 6.28 | 3.59 |
| 11 | 15.09 | 5.86 | 5.38 |
| 12 | 16.22 | 5.46 | 100.00 |
| 13 | 16.77 | 5.28 | 3.18 |
| 14 | 17.57 | 5.04 | 48.51 |
| 15 | 18.35 | 4.83 | 29.96 |
| 16 | 19.13 | 4.63 | 8.26 |
| 17 | 19.37 | 4.57 | 4.76 |
| 18 | 19.93 | 4.45 | 19.59 |
| 19 | 20.64 | 4.30 | 5.75 |
| 20 | 20.87 | 4.25 | 1.98 |
| 21 | 21.78 | 4.07 | 19.59 |
| 22 | 22.10 | 4.02 | 13.64 |
| 23 | 22.39 | 3.97 | 24.13 |
| 24 | 23.33 | 3.81 | 41.98 |
| 25 | 23.72 | 3.75 | 10.21 |
| 26 | 24.20 | 3.67 | 43.08 |
| 27 | 24.56 | 3.62 | 24.97 |
| 28 | 24.97 | 3.56 | 42.88 |
| 29 | 25.67 | 3.46 | 92.69 |
| 30 | 26.05 | 3.41 | 25.05 |
| 31 | 26.38 | 3.37 | 6.44 |
| 32 | 26.72 | 3.33 | 3.07 |
| 33 | 27.16 | 3.28 | 3.15 |
| 34 | 28.03 | 3.18 | 53.52 |
| 35 | 28.40 | 3.14 | 9.82 |
| 36 | 28.84 | 3.09 | 3.23 |
| 37 | 29.62 | 3.01 | 1.49 |
| 38 | 30.05 | 2.97 | 2.82 |
| 39 | 30.40 | 2.94 | 9.45 |
| 40 | 30.94 | 2.89 | 1.16 |
| 41 | 31.40 | 2.84 | 4.16 |
| 42 | 31.68 | 2.82 | 3.86 |
| 43 | 32.29 | 2.77 | 3.05 |
| 44 | 32.58 | 2.74 | 4.02 |
| 45 | 32.99 | 2.71 | 20.13 |
| 46 | 33.50 | 2.67 | 4.54 |
| 47 | 34.15 | 2.62 | 5.98 |
| 48 | 34.66 | 2.58 | 1.13 |
| 49 | 34.94 | 2.56 | 2.22 |
| 50 | 35.52 | 2.52 | 6.44 |
| 51 | 35.97 | 2.49 | 1.15 |
| 52 | 36.33 | 2.47 | 1.27 |
| 53 | 36.80 | 2.44 | 1.74 |
| 54 | 36.99 | 2.42 | 2.43 |
| 55 | 37.47 | 2.39 | 4.85 |
| 56 | 37.77 | 2.37 | 1.25 |
| 57 | 38.22 | 2.35 | 1.81 |
| 58 | 39.21 | 2.29 | 5.72 |
The Differential Scanning Calorimeter (DSC) spectrum of the Entecavir fumarate crystal form C is shown in figure 2, wherein the spectrum has two endothermic peaks, namely an endothermic peak with a peak value of 233+/-2 ℃ and an endothermic peak with a peak value of 268+/-2 ℃.
EXAMPLE 2 preparation of Entecavir fumarate Crystal form C of the invention
(6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione solid (1.0 g) was taken and added to 1.0ml of dimethyl sulfoxide to prepare a solution, the solution was heated and dissolved, 0.22g of fumaric acid was added while the solution was still hot, stirred and reacted for 30min, cooled to room temperature, 6.0ml of methanol was added dropwise, a white solid was precipitated, and dried to obtain crystalline form C (1.16 g) with a yield of 95% and an HPCL purity of 99.9%. The XRD pattern of form C obtained in this example (see fig. 3) was consistent with example 1, and it was confirmed that Entecavir fumarate form C was indeed obtained.
EXAMPLE 3 preparation of Entecavir fumarate Crystal form C of the invention
(6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione solid (1.0 g) was taken and added to 1.0ml of dimethyl sulfoxide to prepare a solution, the solution was dissolved in hot water, 0.22g of fumaric acid was added to the solution, stirred for 30 minutes, cooled to room temperature, 6.0ml of ethyl acetate was added dropwise, a white solid was precipitated, and dried to obtain crystalline form C (1.14 g) with a yield of 94% and an HPCL purity of 99.9%. The XRD pattern of form C obtained in this example (see fig. 4) is consistent with example 1, and it can be confirmed that it is Entecavir fumarate form C.
Example 4 kilogram-level product production
Taking (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazole-3-yl) methyl ] -1- (2, 4, 5-trifluoro benzyl) -1,3, 5-triazinane-2, 4-dione solid (3.4 kg), adding into 9.12L dimethyl sulfoxide to prepare a solution, heating to dissolve, adding 967.40g of fumaric acid while the solution is hot, stirring to react for 30min, cooling to room temperature, dropwise adding 9.12L of dichloromethane, precipitating white solid, drying to obtain crystal form C (3.8 kg), wherein the yield is 92%, the purity of HPCL is more than 99.9%, and the content of single impurity is lower than 0.1%. The XRD pattern of form C obtained in this example is consistent with that of example 1, and it can be confirmed that Entecavir fumarate form C is indeed obtained.
Comparative example 1 preparation of Entect fumarate Wei Jita Crystal form
(6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione solid (1.0 g) was taken and added to 1.0ml of dimethyl sulfoxide to prepare a solution, the solution was dissolved in hot water, 0.22g of fumaric acid was added, stirred for 30min, cooled to room temperature, 6.0ml of purified water was added dropwise, a white solid was precipitated, and dried to obtain crystalline form A (1.12 g) with a yield of 92% and an HPCL purity of 99.9%. The X-ray powder diffraction pattern of the obtained form a is shown in fig. 5.
Comparing examples 1-3 with comparative example 1, it was found that the solvents used were different, and that the resulting Entecavir fumarate crystalline form was different, such as salt formation with dimethyl sulfoxide as the solvent, crystallization with methanol, dichloromethane (DCM), ethyl Acetate (EA) as the poor solvent, and crystallization with purified water as the poor solvent, to give form C, but crystallization with form A was obtained.
Preparation method of crystal form A in patent with publication number CN114591304B in comparative example 2
An amorphous powder of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione fumaric acid (15.2, mg) was added to 1.0mL of ethyl acetate to prepare a suspension, which was stirred at room temperature for 3-7 days, the suspension was separated, and the solid was dried in vacuo to give a white solid as Entecavir fumarate form A (13.45 mg), yield 88.5%, and HPCL purity was 99.9%. The XRD pattern of form A obtained in this comparative example was identical to that of comparative example 1, and it was confirmed that Entecavir fumarate form A was indeed obtained.
Preparation method of crystal form B in patent with publication number CN114591304B in comparative example 3
(6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione (2.0 g) was mixed with fumaric acid (475.10 mg) in ethyl acetate (10 mL) and stirred at room temperature for 45 min. The suspension was filtered to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione fumaric acid as a white solid, form B (2.10 g), yield 85%, HPCL purity 98%. The X-ray powder diffraction pattern of the obtained form B is shown in fig. 6.
The beneficial effects of the present invention are demonstrated by specific test examples below.
Test example 1 stability study of Entecavir fumarate crystalline forms
(1) An accelerated stability test was performed for 6 months on the entecavir fumarate form C prepared in example 1, which was stored at a temperature of 40±2 ℃, humidity: in 75% ± 5% environment, the properties, moisture, melting point and purity were measured before (0 month) and after (6 months of acceleration) the accelerated stability test, and the crystal forms were observed by X-ray powder diffraction, and the results are shown in table 2.
TABLE 26 month accelerated stability test results of Entecavir fumarate form C prepared in EXAMPLE 1
The results in table 2 show that: entecavir fumarate crystal form C prepared in example 1 has good stability after 6 months of accelerated stability test, the appearance and purity are basically consistent with those of 0 month, and the crystal form is still crystal form C after 6 months of accelerated stability test, and no dissociation or crystal transformation occurs. The Differential Scanning Calorimetric (DSC) spectrum of the Entecavir fumarate crystal form C prepared in the example 1 after 6 months of accelerated stability experiments is shown in figure 10, and the results are consistent with those of figure 2, which also shows that the Entecavir fumarate crystal form C prepared in the invention has good stability.
(2) The stability of the entecavir fumarate form C prepared in example 1, the entecavir fumarate form a prepared in comparative example 1 and the entecavir fumarate form B prepared in comparative example 3 was investigated. Entecavir fumarate, form A, form B and form C were evenly distributed in an open petri dish, approximately 5mm thick, and placed under high temperature (60 ℃) and high humidity (92.5%, 25 ℃) and light (4500 lx.+ -. 500 lx) conditions, respectively, sampled for 5 days, 10 days and 30 days, and observed for appearance and purity, and compared with the results for 0 days, stability comparison results for form A, form B and form C are shown in Table 3.
TABLE 3 stability comparison results for form A, form B and form C
Table 3 the results show that: entecavir fumarate crystal form C has good stability at high temperature, high humidity and illumination, and keeps stable appearance and purity within 30 days. Although the appearance of the Entecavir fumarate crystal form A has no obvious change, the purity is reduced, which proves that the stability of the Entecavir fumarate crystal form C of the invention is superior to that of the Entecavir fumarate crystal form A. The Entecavir fumarate crystal form B has micro-caking or agglomeration under high humidity condition, is unstable under illumination, has color change and has the worst stability.
From the above results, it can be seen that: compared with the Entecavir fumarate Wei Jita crystal form, the Entecavir fumarate crystal form C prepared by the invention has very good stability, is beneficial to preparation, transportation and storage of medicines, and ensures the effectiveness and safety of the use of the medicines.
(3) Entecavir fumarate form C prepared in example 1, entecavir fumarate form A prepared in comparative example 1 and Entecavir fumarate form B prepared in comparative example 3 were subjected to an accelerated stability test for 6 months, and each form was stored at a temperature of 40.+ -. 2 ℃ and a humidity: 75% ± 5% of the environment. The appearance and purity of each crystal form was examined before the experiment (0 month), 1 month after the experiment, 2 months and 6 months after the experiment. The results are shown in Table 4.
TABLE 4 6 month accelerated stability test results for form A, form B and form C
The results in Table 4 show that Entecavir fumarate form C has good stability at 40+ -2deg.C and Relative Humidity (RH) 75% + -5%, and maintains stable appearance and purity over 6 months. Comparing the data of the Entecavir fumarate crystal form A and the Entecavir fumarate crystal form B accelerating for 6 months, the stability of the crystal form C is better than that of the Entecavir fumarate crystal form A and the Entecavir fumarate crystal form B.
(4) The invention also examines the solvent residue condition of the Entecavir fumarate crystal form C prepared in the examples 1-3, and adopts gas chromatography detection. The results of the solvent residue detection are shown in Table 5. Fig. 11 is a graph showing the residual solvent pattern of crystalline form C of entecavir fumarate prepared in example 1.
TABLE 5 solvent residual detection results of Entecavir fumarate form C of the present invention
The results in Table 5 show that the Entecavir fumarate crystal form C prepared by the invention has the solvent residue limit lower than ICHQ3C limit requirement and meets the quality requirement of the bulk drug. Fig. 12 is a graph showing the residual solvent pattern of crystalline form a of entecavir fumarate prepared in comparative example 1. The product obtained in the comparative example 1 has too high solvent residue to meet the quality requirements of the bulk drug, and fully demonstrates that the preparation method of the crystal form C is more superior.
The results of the above test example 1 illustrate that: compared with the existing Entecavir fumarate crystal form A and Entecavir fumarate crystal form B, the Entecavir fumarate crystal form C prepared by the invention has excellent stability. Meanwhile, the Entecavir fumarate crystal form C solvent residue prepared by the invention meets the quality requirements of raw material medicines. In addition, compared with the existing method for preparing the Entecavir fumarate crystal form C, the method for preparing the Entecavir fumarate crystal form C has the advantages of smaller volume of reaction solvent, simpler operation, convenient post-treatment, greatly shortened reaction time, higher yield and better product quality.
In summary, the invention provides the novel crystal form of Entecavir fumarate and the preparation method thereof, and the method for preparing the novel crystal form of Entecavir fumarate is simple and convenient, reduces the consumption of reaction solvents, shortens the reaction time, simplifies the post-treatment process and improves the reaction yield. The obtained Entecavir fumarate crystal form has high purity (HPLC is more than 98.5%), high melting point, better stability compared with the existing Entecavir fumarate crystal form, meets the ICHQ3C solvent limit requirement, has higher quality, can effectively prolong the effective period of medicines when being used as medicine raw materials, can meet the pharmaceutical requirements of production, processing, transportation and storage, and is also beneficial to preservation and quality control at normal temperature. The invention realizes the targets of high yield, high purity, less impurities, good quality and controllable reaction of the novel crystal form of Entecavir fumarate, and the preparation method has the advantages of low cost, less three wastes and environmental protection, is beneficial to industrialized amplified production and has wide application prospect.
Claims (10)
1. The crystal form of Entecavir fumarate shown in formula I is characterized in that: the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2 theta value plus or minus 0.2 degrees, which uses Cu-K alpha radiation, include 6.63, 9.67, 10.92, 12.04, 12.18, 12.78, 13.27, 13.48, 16.22, 17.57, 18.35, 19.93, 21.78, 22.10, 22.39, 23.33, 23.72, 24.20, 24.56, 25.67, 26.05, 28.03, 32.99;
formula I.
2. The crystalline form of claim 1, characterized by: the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2 theta values + -0.2 DEG using Cu-K alpha radiation also include 15.09, 19.13, 20.64, 26.38, 28.40, 30.40, 34.15, 35.52, 37.47, 39.21.
3. The crystalline form according to claim 1 or 2, characterized in that: the X-ray powder diffraction pattern of the crystal form is shown in figure 1.
4. The crystalline form according to claim 1 or 2, characterized in that: the differential scanning calorimeter spectrum has two endothermic peaks, namely an endothermic peak with a peak value of 233+/-2 ℃ and an endothermic peak with a peak value of 268+/-2 ℃.
5. The crystalline form according to claim 1 or 2, characterized in that: the molar ratio of Entecavir to fumaric acid in the crystal form is 1:1; the purity of the crystal form is more than 99%, and/or the content of single impurity is less than 0.1%.
6. The method for preparing a crystal form according to any one of claims 1 to 5, characterized in that: it comprises the following steps:
dissolving Entecavir solid in a solvent, adding fumaric acid, stirring, precipitating crystals by using a poor solvent, and drying to obtain the final product.
7. The method of manufacturing according to claim 6, wherein: the solvent is one or more of dioxane, butanone, acetonitrile, ethyl formate, ethyl acetate, butyl formate, methylene dichloride, chloroform, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, 4-methyl-2-pentanone and/or tetrahydrofuran;
and/or the poor solvent is one or more of dichloromethane, methanol and ethyl acetate;
and/or the drying temperature is 60-100 ℃.
8. A pharmaceutical composition characterized by: comprising the crystalline form of any one of claims 1-5 and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition of claim 8, wherein: in the pharmaceutical composition, the weight percentage of the crystal form of any one of claims 1-5 is 0.1% -85%.
10. Use of the crystalline form of any one of claims 1-5 or the pharmaceutical composition of claim 8 or 9 in the manufacture of a medicament for the treatment of novel coronaviruses.
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