CN117466914A - Novel crystal form of balo Sha Weizhi and method for purifying products by using novel crystal form - Google Patents
Novel crystal form of balo Sha Weizhi and method for purifying products by using novel crystal form Download PDFInfo
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- CN117466914A CN117466914A CN202210865894.5A CN202210865894A CN117466914A CN 117466914 A CN117466914 A CN 117466914A CN 202210865894 A CN202210865894 A CN 202210865894A CN 117466914 A CN117466914 A CN 117466914A
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- 239000013078 crystal Substances 0.000 title claims abstract description 73
- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000012535 impurity Substances 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 21
- 238000012360 testing method Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 238000002411 thermogravimetry Methods 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 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
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 229940095102 methyl benzoate Drugs 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 230000004580 weight loss Effects 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 3
- 230000002829 reductive effect Effects 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- ZVJWBAOEJGXYKJ-UHFFFAOYSA-N 2H-oxazine pyridine triazine Chemical group N1=CC=CC=C1.O1NC=CC=C1.N1=NN=CC=C1 ZVJWBAOEJGXYKJ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RZVPBGBYGMDSBG-GGAORHGYSA-N baloxavir marboxil Chemical compound COC(=O)OCOc1c2C(=O)N3CCOC[C@H]3N([C@H]3c4ccc(F)c(F)c4CSc4ccccc34)n2ccc1=O RZVPBGBYGMDSBG-GGAORHGYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- IYYZUPMFVPLQIF-ALWQSETLSA-N dibenzothiophene Chemical group C1=CC=CC=2[34S]C3=C(C=21)C=CC=C3 IYYZUPMFVPLQIF-ALWQSETLSA-N 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003892 spreading Methods 0.000 description 3
- 230000007480 spreading Effects 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229940123734 Endonuclease inhibitor Drugs 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940008411 baloxavir marboxil Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- -1 chloromethyl dimethyl carbonate Chemical compound 0.000 description 1
- MFSHZGFPADYOTO-UHFFFAOYSA-N chloromethyl methyl carbonate Chemical compound COC(=O)OCCl MFSHZGFPADYOTO-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- 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 discloses a crystal form E of balo Sha Weizhi and a method for purifying balo Sha Weizhi by using the crystal form E, wherein the purity of balo Sha Weizhi obtained by purifying the crystal form E is not lower than 99.5%, the content of impurity A is not higher than 0.20%, the content of other impurities is not higher than 0.10%, the purification process is simple to operate and can be industrially implemented, meanwhile, the crystal form E can be further prepared into a crystal form D with more stable medicinal value, the preparation yield is not lower than 95%, the refining yield of balo Sha Weizhi is greatly improved, and the production cost is reduced.
Description
Technical Field
The invention relates to a novel crystal form of balo Sha Weizhi and a method for purifying products by using the novel crystal form, and belongs to the technical field of pharmaceutical chemistry.
Background
Balo Sha Weizhi (Baloxavir Marboxil) is a new anti-influenza drug developed by the japanese salt wild-sense pharmaceutical (shimogi) company under the trade name Xofluza. Xofluza is an innovative Cap-dependent endonuclease inhibitor, also a novel oral drug for inhibiting the proliferation of influenza viruses, which can inhibit the Cap structure of the 5' end of host mRNA obtained from host cells aiming at the key link of the replication of influenza viruses, thereby inhibiting the transcription of the mRNA of the influenza viruses, is approved by Japan in 2018, 2 for the treatment of type A and type B influenza of adult and pediatric patients, and is approved by the FDA in 2018, 10 for the treatment of acute influenza patients with no complications of 12 years old and older than 48 hours.
Balo Sha Weizhi is a prodrug that hydrolyzes into the active substance balo Sha Wei in vivo, and has the following chemical structural formula:
the structure of the baluo Sha Weizhi compound comprises two parts of dibenzothiophene ring and oxazine pyridine triazine ring, which are disclosed in patent WO2010147068 and patent WO 2012039414. Patent WO2016175224 discloses a synthesis method of balo Sha Weizhi, wherein after two parts of a dibenzothiophene ring structure and an oxazine pyridine triazine ring structure are butted, benzyl protecting groups are removed, and then the benzyl protecting groups react with chloromethyl dimethyl carbonate to obtain balo Sha Weizhi. This route is the simplest and most straightforward method to obtain balo Sha Weizhi.
Patent WO2017221869 discloses a synthesis method, wherein before the oxazine pyridine triazine ring is in butt joint with the dibenzothiophene ring, the hydroxyl protecting agent on the oxazine pyridine triazine ring is replaced, the benzyl is replaced by the n-hexyl, and the conversion of crystallization induced diastereomers to products is realized by utilizing different steric hindrance and inducibility of different substituents. The selectivity of the method is improved after n-hexyl substitution, and the receiving rate is reported to be 85%.
In all routes for synthesizing the balo Sha Weizhi, the balo Sha Wei compound which is not esterified with chloromethyl methyl carbonate is a necessary intermediate and is also an active ingredient after in vivo metabolism, but in the balo Sha Weizhi raw material medicine, the balo Sha Wei compound exists as an impurity A, the solubility of the balo Sha Weizhi raw material medicine in each solvent is similar to that of the balo Sha Weizhi, the balo Sha Weizhi is difficult to remove, if the impurity is too high in the raw material medicine, the processes of granulating, dissolving out and the like of the preparation are influenced in the preparation process of the preparation, the processes are controlled within the limit, the yield is required to be lost, the yield of the obtained raw material medicine is low, and the cost of the raw material medicine is greatly increased.
Disclosure of Invention
In response to the foregoing problems and needs in the art, the present invention provides a form E of balo Sha Weizhi and, at the same time, provides a method for purifying balo Sha Weizhi using form E. The purification of the balo Sha Weizhi is carried out by utilizing the crystal form E, all impurities can be controlled within limit standards by simple operation, the method is easy to implement industrially, the yield of the purified product is up to 95%, the purity is not lower than 99.5%, and the quality requirement is met.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a first aspect of the present invention is to provide a form E of balo Sha Weizhi having an X-ray powder diffraction pattern with characteristic diffraction peaks at 7.3 °, 12.1 °, 17.3 °, 18.6 °, 22.7 °, 24.4 °, 26.2 ° and 31.2 ° with a test error of ±0.2 °.
In another preferred embodiment, the X-ray powder diffraction pattern of form E of balo Sha Weizhi further has characteristic diffraction peaks at 3.6 °, 7.3 °, 11.1 °, 12.1 °, 13.3 °, 14.7 °, 15.2 °, 16.2 °, 17.3 °, 18.6 °, 19.4 °, 20.0 °, 20.6 °, 21.0 °, 21.4 °, 22.3 °, 22.7 °, 24.4 °, 26.2 °, 30.0 °, 31.2 and 33.9 ° and a test error of ±0.2 °.
In another preferred embodiment, the X-ray powder diffraction pattern of form E of balo Sha Weizhi is substantially as shown in fig. 1.
In another preferred embodiment, the differential scanning calorimetry thermogram of form E of balo Sha Weizhi has endothermic peaks at 80-100 ℃ and 130-150 ℃.
In another preferred embodiment, the differential scanning calorimetry thermogram of form E of balo Sha Weizhi is substantially as shown in figure 2.
In another preferred embodiment, the thermogravimetric analysis of form E of balo Sha Weizhi shows a weight loss at 50 to 120 ℃ and 130 to 150 ℃.
In another preferred embodiment, the thermogravimetric analysis of form E of balo Sha Weizhi shows a weight loss of 15% to 25%, preferably 17% to 23% at 50 to 120 ℃ and 130 to 150 ℃.
In another preferred embodiment, the form E of balo Sha Weizhi is an N-methylpyrrolidone solvate of balo Sha Weizhi.
In another preferred embodiment, the thermogravimetric analysis of form E of balo Sha Weizhi is substantially as shown in fig. 3.
A second aspect of the invention is to provide a process for preparing form E of balo Sha Weizhi.
In another preferred embodiment, the method for preparing balo Sha Weizhi comprises the steps of:
a) Dissolving Ballon Sha Weizhi in N-methylpyrrolidone, and dripping poor solvent
b) Stirring for crystallization, cooling to room temperature, filtering, and collecting the precipitated crystals to obtain the Ballon Sha Weizhi crystal form E.
In another preferred example, the temperature of the baluo Sha Weizhi dissolved in the N-methyl pyrrolidone is 20-70 ℃; preferably, the temperature is 30-60 ℃; more preferably, the temperature is 40-50 ℃.
In another preferred example, the poor solvent is one or more of water, methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate; preferably, water, ethanol and or ethyl acetate; more preferably, water and/or ethanol.
In another preferred embodiment, the impurity a content in the prepared balo Sha Weizhi crystal form E is not higher than 0.20%, and the other impurity content is not higher than 0.10%.
In a third aspect of the invention, there is provided a process for purifying balo Sha Weizhi from form E of balo Sha Weizhi.
In another preferred embodiment, the method comprises the steps of:
1) The balo Sha Weizhi is dissolved in N-methyl pyrrolidone, and poor solvent is added dropwise;
2) Stirring for crystallization, cooling, filtering and collecting the precipitated crystals.
In another preferred example, the temperature of the baluo Sha Weizhi dissolved in the N-methyl pyrrolidone is 20-70 ℃; preferably, the temperature is 30-60 ℃; more preferably, the temperature is 40-50 ℃.
In another preferred example, the poor solvent is one or more of water, methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate; preferably, water, ethanol and/or ethyl acetate; more preferably, water and/or ethanol.
In another preferred embodiment, the precipitated crystals are form E of balo Sha Weizhi.
In another preferred embodiment, the impurity a content in the obtained balo Sha Weizhi form E is not higher than 0.20%, and the other impurity content is not higher than 0.10%.
In a fourth aspect of the invention, there is provided a process for preparing form D of balo Sha Weizhi using form E of balo Sha Weizhi.
In another preferred embodiment, the method comprises the steps of:
(I) Dissolving the balo Sha Weizhi crystal form E in dichloromethane solution, washing with water, layering, collecting dichloromethane layer, drying with anhydrous magnesium sulfate, and concentrating 40% dichloromethane;
(II) dropwise adding the methylene dichloride solution concentrated in the step (I) into a mixed solvent of methyl benzoate and n-heptane, and stirring at room temperature for 0.5-1 hour;
(III) filtering, leaching the filter cake by using n-heptane, and drying the filter cake to constant weight in a vacuum drying oven at 80 ℃ to obtain the balo Sha Weizhi crystal form D.
In another preferred example, form D of balo Sha Weizhi is an anhydrous, solvate-free form of balo Sha Weizhi having characteristic diffraction peaks at diffraction angles 2θ of 4.5 °, 8.8 °, 9.8 °, 10.8 °, 11.7 °, 13.2 °, 14.3 °, 14.8 °, 15.8 °, 16.2 °, 16.5 °, 17.3 °, 17.5 °, 17.8 °, 18.8 °, 20.2 °, 21.6 °, 21.9 °, 22.3 °, 24.2 °, 24.4 °, 26.5 °, 28.0 °, 28.3 °, 29.7 ° and 31.5 ° under X-ray powder diffraction, with a test error of ±0.2 °.
In another preferred embodiment, the X-ray powder diffraction pattern of form D of balo Sha Weizhi is substantially as shown in fig. 4.
In another preferred embodiment, the preparation method of the balo Sha Weijing type D comprises the following steps:
a-1) at a dissolution temperature of 20-50 ℃, the balo Sha Weizhi raw material is dissolved in a mixed solvent formed by methylene dichloride and an ester solvent according to a volume ratio of 1.0 (0.5-2.5) to obtain a clear solution;
a-2) then dropwise adding n-heptane into the system, and stirring to crystallize;
a-3) filtering and collecting precipitated crystals;
and A-4) vacuum drying the crystal obtained in the step c) at 50-100 ℃ for 6-15 hours to obtain the balo Sha Weizhi crystal form D.
Compared with the prior art, the invention has the following remarkable beneficial effects:
a new crystalline form E of balo Sha Weizhi is provided;
the crystal form E of the balo Sha Weizhi can be used for purifying the crude product of the balo Sha Weizhi;
the crystal form E of the balo Sha Weizhi can be converted into anhydrous solvent-free form by a simple process, is in an elongated needle shape, and can be used as a crystal form D of the balo Sha Weizhi of a medicinal crystal form;
the method for purifying the balo Sha Weizhi by using the crystal form E of the balo Sha Weizhi has simple operation process and good purification effect,
the content of impurity A in the purified product is not higher than 0.20%, and the content of other impurities is not higher than 0.10%.
Drawings
FIG. 1 shows an X-ray powder diffraction pattern (XRPD) of form E;
FIG. 2 shows a differential scanning calorimetric analysis profile (DSC) of form E;
FIG. 3 shows thermogravimetric analysis data (TGA) of form E;
FIG. 4 shows an X-ray powder diffraction pattern (XRPD) of form D;
FIG. 5 shows an X-ray powder diffraction pattern (XRPD) for form I;
FIG. 6 shows a High Performance Liquid Chromatography (HPLC) of crude Ballon Sha Weizhi purity;
FIG. 7 shows a High Performance Liquid Chromatogram (HPLC) of the resulting purity after refining crude Ballon Sha Weizhi using form E;
FIG. 8 shows a High Performance Liquid Chromatogram (HPLC) of the resulting purity after refining a crude product of baluo Sha Weizhi using form I;
fig. 9 shows a photograph of a crystal habit of form D of balo Sha Weizhi;
fig. 10 shows a photograph of a crystal habit of form I of balo Sha Weizhi.
Detailed Description
In the examples below, unless otherwise indicated, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer, and the starting materials and reagents shown are commercially available.
Test method
Unless otherwise indicated, all the solids produced in the examples were tested according to the following method:
the parameters for X-ray powder diffraction are as follows (XRPD):
x-ray powder diffractometer: a Brucker D8 advance X-ray powder diffractometer;
x-ray reflection parameters: copper targetScanning at room temperature:
voltage: 40 kilovolts (kv);
current flow: 40 milliamperes (mA);
scanning mode: continuous;
scanning range: 2.0-50.0 degrees;
step size: 0.020 °;
measuring time per step, namely 0.1 second/step;
the Differential Scanning Calorimeter (DSC) analysis method parameters are as follows:
differential Scanning Calorimeter (DSC) instrument: TA+ -Q2000 type;
temperature range: room temperature to 180 ℃;
scanning speed: 10 ℃/min;
protective gas: nitrogen, 50 ml/min;
thermogravimetric analysis (TGA) parameters were as follows:
thermogravimetric analysis (TGA) instrument: TGA type 55;
temperature range: room temperature to 180 ℃;
scanning speed: 10 ℃/min;
protective gas: nitrogen, 60 ml/min.
Example 1
10.0g of crude ballo Sha Weizhi (containing ballo Sha Wei, namely impurity a:3.31%, rrt=0.91, shown in fig. 6) is dispersed in 40ml of N-methylpyrrolidone solvent, the temperature is raised to 40 ℃, the solution is stirred and cleared, 50ml of ethanol is added dropwise, the temperature is kept and stirred for 1 hour after the dripping, the temperature of the system is reduced to 10-15 ℃, the temperature is kept and stirred for 0.5 hour, and the filtration is carried out, so as to obtain ballo Sha Weizhi solid with the purity of 99.69%, wherein the impurity a (rrt=0.91) is 0.08%, as shown in fig. 7.
The XRPD, DSC and TGA patterns of the solid obtained after the test are shown in figures 1, 2 and 3, respectively, as form E.
Example 2
10.0g of a crude product of the ballo Sha Weizhi is dispersed in 50ml of N-methylpyrrolidone solvent, the solution is stirred at room temperature, 50ml of water is dripped, the system is cooled to 10-15 ℃ after dripping, the temperature is kept for 1 hour, the temperature is kept for 0.5 hour, the stirring is continued, the filtration is carried out, the ballo Sha Weizhi solid with the purity of 99.62% is obtained, and the impurity A (RRT=0.91) is 0.12%.
The XRPD, DSC and TGA patterns of the solid obtained after the test are shown in figures 1, 2 and 3, respectively, as form E.
Example 3
10.0g of a crude product of ballo Sha Weizhi is dispersed in 50ml of N-methylpyrrolidone solvent, stirred at room temperature, 50ml of ethyl acetate is added dropwise, the mixture is stirred for 1 hour after the dripping, the system is cooled to 10-15 ℃, the mixture is stirred for 0.5 hour after the dripping, the mixture is filtered, and a solid of ballo Sha Weizhi with the purity of 99.55% is obtained, wherein the impurity A (RRT=0.91) is 0.08%.
The XRPD, DSC and TGA patterns of the solid obtained after the test are shown in figures 1, 2 and 3, respectively, as form E.
Example 4
The preparation method comprises the steps of dissolving a balo Sha Weizhi crystal form E in 30ml of dichloromethane solution, adding 10ml of 3-phase water to wash an organic layer, adding 2.0g of anhydrous magnesium sulfate to the dichloromethane layer for drying, filtering, concentrating the organic phase to 20ml, dripping the concentrated organic phase into a mixed solvent of 25ml of methyl benzoate and 100ml of n-heptane, stirring at room temperature for 0.5 hour after dripping, carrying out suction filtration, washing a filter cake by 10ml of n-heptane, drying a wet product in a vacuum drying oven at 80 ℃ until the weight is constant, obtaining a balo Sha Wei solid, and testing the XRPD spectrum of the obtained solid is shown in figure 4, wherein the XRPD spectrum of the obtained solid is the balo Sha Weizhi crystal form D.
Example 5
10.0g of a crude product of balo Sha Weizhi (containing balo Sha Wei, namely impurity A:3.31%, RRT=0.91 and shown in fig. 6) is dispersed in 60ml of dimethyl sulfoxide, dissolved and stirred at room temperature, 50ml of water is dripped, the system is stirred for 1 hour after dripping, the temperature is reduced to 15-20 ℃, stirring is continued for 3 hours after heating, the filtration is carried out, and balo Sha Weizhi solid of crystal form I is obtained, the purity is 98.37%, wherein impurity A (RRT=0.91) is 1.38%, as shown in fig. 8, and the XRPD spectrum of the solid obtained through testing is shown in fig. 5 and is balo Sha Weizhi crystal form I.
Example 6: stability test
According to the guidelines for pharmaceutical formulation stability testing, for form D (see example 4) prepared from form E of the present application and for known form I (see example 10 of patent WO2018030463, having XRPD spectra as shown in fig. 5, substantially identical to fig. 3 of WO 2018030463), influence factor experiments were performed, including high temperature, high humidity and intense light irradiation experiments, to examine stability conditions affecting the crystalline forms:
high temperature test: taking appropriate amounts of samples of the crystal form D and the crystal form I respectively, spreading the samples in a weighing bottle, placing the samples in a constant temperature and humidity box at 70 ℃ and RH75% for 10 days, taking about 100mg of the samples, and testing the crystal form conditions by adopting powder X-ray powder diffraction (XRPD), wherein the results are shown in Table 1;
high humidity test: taking appropriate amounts of samples of the crystal form D and the crystal form I respectively, spreading the samples in a weighing bottle, placing the samples in a constant temperature and humidity box at 25 ℃ and RH 92.5% for 10 days, taking about 100mg of the samples, and testing the crystal form conditions by adopting powder X-ray powder diffraction (XRPD), wherein the results are shown in Table 1;
illumination test: respectively taking appropriate amounts of samples of the crystal form D and the crystal form I, spreading the samples into a weighing bottle, and obtaining the crystal form I and the crystal form D in visible light 4500Lux (+ -)
After 10 days of standing in a constant temperature and humidity cabinet (25 ℃ C., RH60% + -5%) with 500Lux (VIS) and ultraviolet light of 1.7W h/m2 (UV), about 100mg of the above sample was taken, and the crystal form was tested by powder X-ray powder diffraction (XRPD), and the results are shown in Table 1.
TABLE 1 stability test results
As can be seen in combination with table 1, form D described herein has the same stability as form I.
Example 7: solubility test
The following solutions were formulated with reference to the japanese pharmacopoeia appendix:
ph1.2 solution: dissolving 2.0g of sodium chloride in a proper amount of water, adding 7mL of hydrochloric acid, diluting to 1000mL with water, and uniformly mixing to obtain the sodium chloride;
ph4.0 solution: mixing 0.05mol/L acetic acid solution with 0.05mol/L sodium acetate solution according to the proportion of 16.4:3.6 to obtain the catalyst;
phosphate buffer at ph 6.8: taking 1.7g of monopotassium phosphate and 1.775g of anhydrous disodium hydrogen phosphate, adding water for dissolution, and fixing the volume to 1000mL to obtain the aqueous solution.
And respectively taking a proper amount of crystal form D and crystal form I samples, respectively dissolving the samples into a pH1.2 solution, a pH4.0 solution and a pH6.8 phosphate buffer solution to prepare saturated solutions, centrifuging, carrying out HPLC content analysis on the supernatant, and calculating the corresponding solubility. The specific experimental results are shown in table 2.
TABLE 2 solubility test results
| Sample crystal form | Crystal form D | Crystal form I |
| PH1.2，37℃ | 22.68μg/mL | 20.6μg/mL |
| PH4.0，37℃ | 24.98μg/mL | 19.3μg/mL |
| PH6.8，37℃ | 23.54μg/mL | 18.9μg/mL |
The results shown in Table 2 can be seen: the balo Sha Weizhi crystal form D prepared from the crystal form E has better solubility than the existing crystal form I in the pH environment simulating gastrointestinal fluid, and is very favorable for absorption and utilization of oral preparations.
In addition, a proper amount of samples of the crystal form D and the crystal form I are taken respectively, and the crystal habit of the samples is obtained by observing the samples under a microscope and amplifying the samples by 100 times:
fig. 9 is a photograph of crystal form D, as can be seen from fig. 9: the crystal habit of the crystal form D is slender needle-shaped crystals, and the particles are good in dispersibility, so that the crystal form D has good fluidity and compressibility, and is very suitable for being used as a raw material of tablets;
fig. 10 is a photograph of a crystal habit of a known crystal form I, and can be seen from fig. 10: the crystal habit of the crystal form I is flaky, and flaky crystals are easy to wrap a solvent in the process of drying materials to form caking and agglomeration, so that the dried materials are hard, solvent residues are easy to exceed the standard, the solvent limit can be reached only by long drying time, and degradation impurities are easy to exceed the standard due to overlong drying time; in addition, after the materials are agglomerated, the fluidity of the product is poor, the particle size requirement is required to be achieved through physical crushing, the production and the preparation of the tablets are bothersome, and the product is not an ideal raw material for the preparation of the tablets.
Finally, it is pointed out here that: the above is only a part of the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention, and some insubstantial modifications and adaptations of the present invention based on the foregoing are within the scope of the present invention.
Claims (10)
1. A crystalline form E of baluo Sha Weizhi, characterized by: under X-ray powder diffraction, there were characteristic diffraction peaks at diffraction angles 2θ of 7.3 °, 12.1 °, 17.3 °, 18.6 °, 22.7 °, 24.4 °, 26.2 °, and 31.2 °, with test errors of ±0.2 °.
2. The crystalline form E of balo Sha Weizhi according to claim 1, characterized in that: under X-ray powder diffraction, there are characteristic diffraction peaks at diffraction angles 2θ of 3.6 °, 7.3 °, 11.1 °, 12.1 °, 13.3 °, 14.7 °, 15.2 °, 16.2 °, 17.3 °, 18.6 °, 19.4 °, 20.0 °, 20.6 °, 21.0 °, 21.4 °, 22.3 °, 22.7 °, 24.4 °, 26.2 °, 30.0 °, 31.2 and 33.9 °, and the test error is ±0.2 °.
3. Form E of balo Sha Weizhi according to claim 1, characterized in that the differential scanning calorimetry profile of form E has endothermic peaks at 80-100 ℃ and 130-150 ℃.
4. Form E of balo Sha Weizhi according to claim 1, characterized in that the thermogravimetric analysis of said form E shows a weight loss at 50-120 ℃ and 130-150 ℃.
5. A process for preparing form E of balo Sha Weizhi according to claim 1, characterized in that it comprises the steps of:
a) Dissolving Ballon Sha Weizhi in N-methylpyrrolidone, and dripping poor solvent
b) Stirring for crystallization, cooling to room temperature, filtering, and collecting the precipitated crystals to obtain the Ballon Sha Weizhi crystal form E.
6. The method according to claim 5, wherein: in step a), the temperature at which the baluo Sha Weizhi is dissolved in N-methylpyrrolidone is 20 to 70 ℃.
7. The method according to claim 5, wherein: in the step a), the poor solvent is one or more of water, methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate.
8. The method according to claim 5, wherein the impurity a content in the prepared balo Sha Weizhi crystal form E is not higher than 0.20% and the other impurity content is not higher than 0.10%.
9. A process for purifying balo Sha Weizhi using form E of balo Sha Weizhi as claimed in claim 1, comprising the steps of:
1) The balo Sha Weizhi is dissolved in N-methyl pyrrolidone, and poor solvent is added dropwise;
2) Stirring for crystallization, cooling, filtering and collecting the precipitated crystals.
Wherein the temperature of the baluo Sha Weizhi dissolved in the N-methyl pyrrolidone is 20-70 ℃; the poor solvent is one or more of water, methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate; the separated crystals are the crystal form E, and the content of the impurity A in the crystal form E ballo Sha Weizhi is not higher than 0.20 percent, and the content of other impurities is not higher than 0.10 percent.
10. A process for preparing form D of balo Sha Weizhi using form E of balo Sha Weizhi of claim 1, comprising: the method comprises the following steps:
(I) Dissolving the balo Sha Weizhi crystal form E in dichloromethane solution, washing with water, layering, collecting dichloromethane layer, drying with anhydrous magnesium sulfate, and concentrating 40% dichloromethane;
(II) dropwise adding the methylene dichloride solution concentrated in the step (I) into a mixed solvent of methyl benzoate and n-heptane, and stirring at room temperature for 0.5-1 hour;
(III) filtering, leaching the filter cake by using n-heptane, and drying the filter cake to constant weight in a vacuum drying oven at 80 ℃ to obtain the balo Sha Weizhi crystal form D.
Wherein, the form D of balo Sha Weizhi is an anhydrous and solvate-free form of balo Sha Weizhi, which has characteristic diffraction peaks at diffraction angles 2θ of 4.5 °, 8.8 °, 9.8 °, 10.8 °, 11.7 °, 13.2 °, 14.3 °, 14.8 °, 15.8 °, 16.2 °, 16.5 °, 17.3 °, 17.5 °, 17.8 °, 18.8 °, 20.2 °, 21.6 °, 21.9 °, 22.3 °, 24.2 °, 24.4 °, 26.5 °, 28.0 °, 28.3 °, 29.7 ° and 31.5 ° under X-ray powder diffraction, and a test error of ±0.2°.
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