CN114989106A - Novel crystal form of chlorobenzoic acid and preparation method thereof - Google Patents
Novel crystal form of chlorobenzoic acid and preparation method thereof Download PDFInfo
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- CN114989106A CN114989106A CN202110178547.0A CN202110178547A CN114989106A CN 114989106 A CN114989106 A CN 114989106A CN 202110178547 A CN202110178547 A CN 202110178547A CN 114989106 A CN114989106 A CN 114989106A
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- 239000013078 crystal Substances 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 title claims description 84
- 239000007787 solid Substances 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 111
- 238000001816 cooling Methods 0.000 claims description 63
- 238000003756 stirring Methods 0.000 claims description 63
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 54
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 229960000583 acetic acid Drugs 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- 239000012362 glacial acetic acid Substances 0.000 claims description 22
- RGISOLFSSBPMSO-UHFFFAOYSA-N 4-[(3,5-dichlorobenzoyl)amino]-3-hydroxybenzoic acid Chemical compound OC1=CC(C(=O)O)=CC=C1NC(=O)C1=CC(Cl)=CC(Cl)=C1 RGISOLFSSBPMSO-UHFFFAOYSA-N 0.000 claims description 20
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 20
- 238000002425 crystallisation Methods 0.000 claims description 19
- 230000008025 crystallization Effects 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 8
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- NGKNMHFWZMHABQ-UHFFFAOYSA-N 4-chloro-2h-benzotriazole Chemical compound ClC1=CC=CC2=NNN=C12 NGKNMHFWZMHABQ-UHFFFAOYSA-N 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- -1 chlorbenzpyrolic acid Chemical compound 0.000 abstract description 4
- 238000002441 X-ray diffraction Methods 0.000 description 18
- 239000011259 mixed solution Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- JONFYSWOLCTYFK-UHFFFAOYSA-N 2-(2,3-dichloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(Cl)=C1Cl JONFYSWOLCTYFK-UHFFFAOYSA-N 0.000 description 7
- 229950009130 clofenamic acid Drugs 0.000 description 7
- 238000010998 test method Methods 0.000 description 4
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
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- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000034846 Familial Amyloid Neuropathies Diseases 0.000 description 2
- 206010019889 Hereditary neuropathic amyloidosis Diseases 0.000 description 2
- CWFOCCVIPCEQCK-UHFFFAOYSA-N chlorfenapyr Chemical compound BrC1=C(C(F)(F)F)N(COCC)C(C=2C=CC(Cl)=CC=2)=C1C#N CWFOCCVIPCEQCK-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229960003291 chlorphenamine Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- TXEIIPDJKFWEEC-UHFFFAOYSA-N tafamidis Chemical compound O1C2=CC(C(=O)O)=CC=C2N=C1C1=CC(Cl)=CC(Cl)=C1 TXEIIPDJKFWEEC-UHFFFAOYSA-N 0.000 description 2
- 201000007905 transthyretin amyloidosis Diseases 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- OYNVQAUSTQRNHE-UHFFFAOYSA-N 4-chloro-2-phenyl-1,3-oxazole Chemical compound ClC1=COC(C=2C=CC=CC=2)=N1 OYNVQAUSTQRNHE-UHFFFAOYSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 206010007509 Cardiac amyloidosis Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 108010071690 Prealbumin Proteins 0.000 description 1
- 102000009190 Transthyretin Human genes 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 208000022256 primary systemic amyloidosis Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 229960001353 tafamidis Drugs 0.000 description 1
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- 230000000007 visual effect Effects 0.000 description 1
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- 208000027121 wild type ATTR amyloidosis Diseases 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to two new crystal forms A, B of chlorbenzpyrolic acid and a preparation method thereof, wherein the two crystal forms have good stability and small crystal granularity and are beneficial to the preparation of solid preparations; the two crystal forms are easy to prepare in a large scale, simple to operate, good in safety, easy to remove impurities, high in purity and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to two new crystal forms A, B of chlorobenzoic acid and a preparation method thereof.
Background
Chlorobenzoic acid (Tafamidis) with molecular formula C 14 H 7 Cl 2 NO 3 The chemical name is 6-carboxyl-2- (3, 5-dichlorophenyl) -benzoxazole, and the structural formula is as follows:
clofenamic acid is a drug used to treat transthyretin amyloid diseases, such as Senile Systemic Amyloidosis (SSA), Familial Amyloid Polyneuropathy (FAP), and Familial Amyloid Cardiomyopathy (FAC) in mammals.
The crystal forms of the chlorobenzoic acid reported in the prior literature are as follows: patent WO2016038500 discloses a crystal form 1, a crystal form 4 and preparation methods thereof; ② patent WO2019175263 discloses a crystal form of free acid of chlorobenzoic acid, acetic acid compound and a preparation method thereof; ③ WO2020232325 discloses amorphous chlorophenyloxazole acid and crystal forms I, II, III, IV and V and a preparation method thereof.
The prior art has the following problems: the crystal form 1 is obtained by adding isopropanol into a toluene feed liquid for suspension, the impurity removal effect of the crystal form is poor, the quality requirement of a raw material medicament can be met only by refining for many times, the residual solvent is difficult to remove, the crystal form needs to be dried at 60-70 ℃ for more than 18 hours, the drying difficulty can be further improved along with the scale expansion, and the industrial production is not facilitated; secondly, the crystal form 4 is obtained by dissolving the crystal form 1 in tetrahydrofuran and then adding the dissolved crystal form into ice toluene for standing overnight at-10 to-25 ℃, and is obtained by standing for crystallization for a long time at an extremely low temperature, so that the energy consumption is extremely high and the industrial production is not suitable; ③ acetic acid compounds are not suitable for pharmaceutical use; the free acid crystal form is obtained by adding the chlorobenzoic acid acetic acid compound into ethyl acetate/water for heating and dissolving, filtering and drying, and the chlorobenzoic acid is difficult to dissolve in the ethyl acetate or the water, so the chlorobenzoic acid is required to be prepared into an acetic acid addition product firstly, and the chlorobenzoic acid can be heated and dissolved in the ethyl acetate/water; crystal form I may be hydrate, the characteristic peak is consistent with the crystal form of free acid, the clofenamic acid is dispersed in acetone/water or methanol/water or water in an amorphous manner and slowly volatilizes for 33 days, and the industrial production is not facilitated; crystalline form II is obtained by dissolving clofenamic acid in 2-methyltetrahydrofuran at 61 deg.C and quenching to 7 deg.C; or the clofenamic acid is dissolved in the 2-methyltetrahydrofuran at room temperature and slowly volatilized for 7 days, and the preparation methods of the crystal form II are difficult to realize in industrial production; the crystal form III is an acetic acid compound and is obtained by dissolving chlorobenzoic acid in acetic acid at 118 ℃ and slowly volatilizing for 24 hours; or crushing the chlorobenzoic acid in a ball mill for 30min and then dropwise adding glacial acetic acid to obtain the clofenamic acid; or the clofenamic acid is dissolved in glacial acetic acid at the temperature of 92 ℃, and the clofenamic acid is obtained by rapidly cooling to 65 ℃, and the preparation methods of the crystal form III are not beneficial to industrial production; the crystalline form IV is obtained by dissolving chlorobenzoic acid in glacial acetic acid at 105 ℃, slowly (naturally) cooling to 89 ℃, stirring for 1h and then carrying out suction filtration, and industrialization is difficult to realize; ninthly, the crystal form V is a methanolic compound and is not suitable for medical use.
It is well known that polymorphic forms of a drug may exhibit different physical and mechanical properties, including hygroscopicity, particle shape, density, flowability, compressibility, and the like, which in turn may affect the preparation of drug substances and formulations. Different crystal forms of the same medicament may have obvious difference in aspects of appearance, solubility, melting point, dissolution rate, bioavailability and the like, so that the stability, bioavailability and curative effect of the medicament can be influenced, and the phenomenon is particularly obvious in the aspect of oral solid preparations.
Therefore, it is necessary to further develop a new crystal form of high-purity chlorobenzoic acid which is easy to prepare, suitable for industrial production, beneficial to the preparation of solid preparations, suitable for medical use and easy to remove impurities.
Disclosure of Invention
The inventors have surprisingly found, through a large number of experimental studies, novel crystal forms a and B of high-purity chlorobenzoic acid which are easy to prepare, suitable for industrial production, favorable for preparation of solid preparations, suitable for medical use and easy to remove impurities, and have completed the present invention based on the finding.
The invention provides a chlorphenamine crystal form A, which is characterized in that Cu-Ka radiation is used, and X-ray powder diffraction represented by a 2 theta angle is within 5.9 +/-0.2 degrees, 6.8 +/-0.2 degrees, 9.6 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.8 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 27.3 +/-0.2 degrees, and diffraction peaks are arranged at the positions.
Preferably, the Torizoic acid crystal form A has diffraction peaks at 5.9 +/-0.2 degrees, 6.8 +/-0.2 degrees, 9.6 +/-0.2 degrees, 12.8 +/-0.2 degrees, 14.0 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.8 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 23.8 +/-0.2 degrees, 25.7 +/-0.2 degrees, 27.3 +/-0.2 degrees, 31.5 +/-0.2 degrees, 36.4 +/-0.2 degrees and 42.9 +/-0.2 degrees by X-ray powder diffraction represented by 2 theta angles by using Cu-Ka radiation.
Specifically, the crystal form A of the chlorobenzoic acid has an X-ray powder diffraction pattern shown in figure 1.
Differential Scanning Calorimetry (DSC) of the crystal form A of the chlorobenzoic acid shows that the crystal form has an endothermic peak within 278-298 ℃; specifically, a Differential Scanning Calorimetry (DSC) pattern of the crystal form A of the chlorobenzoic acid is shown in figure 2.
Preferably, the thermogravimetric analysis (TGA) of crystalline form a of chlorobenzoic acid is shown in fig. 2, and the crystalline form has no weight loss, indicating that the crystalline form a is a non-solvate or a non-hydrate.
In a second aspect, the present invention provides a process for preparing crystalline clofenac form a according to the first aspect of the invention, comprising the steps of:
(a) adding the intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid (compound II) into glacial acetic acid, adding methane sulfonic acid, stirring and refluxing for reacting for 6-10 h;
(b) cooling the system to 60-70 ℃, adding a solvent, stirring and dissolving;
(c) cooling the system to 35-45 ℃, adding dichloromethane/methanol, stirring, cooling and crystallizing;
(d) filtering and drying to obtain a crystal form A of the chlorobenzoic acid;
wherein the solvent in step (b) is tetrahydrofuran, dioxane or a combination thereof; the volume amount of the solvent is 25-100 times, preferably 30-40 times, of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
the volume ratio of the dichloromethane to the methanol in the step (c) is 1: 0.5-10, preferably 1: 1-2;
in the step (c), the volume amount of the dichloromethane/methanol is 30-100 times, preferably 40-50 times of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
the crystallization temperature in the step (c) is-20-30 ℃, and preferably 0-10 ℃;
drying in the step (d) at the temperature of 30-90 ℃, preferably 50-70 ℃.
The purity of the crystal form A of the chlorobenzoic acid prepared by the method of the second aspect of the invention is up to more than 99.9 percent.
The invention provides a chlorphenamine crystal form B, which is characterized in that Cu-Ka radiation is used, and diffraction peaks exist at the positions of 6.4 +/-0.2 degrees, 9.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 13.5 +/-0.2 degrees, 18.3 +/-0.2 degrees in X-ray powder diffraction represented by a 2 theta angle.
Preferably, the chlorobenzene acid crystal form B has diffraction peaks at 6.4 +/-0.2 degrees, 9.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 13.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 18.3 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.4 +/-0.2 degrees, 22.7 +/-0.2 degrees, 24.9 +/-0.2 degrees, 27.5 +/-0.2 degrees, 28.8 +/-0.2 degrees, 31.7 +/-0.2 degrees and 32.8 +/-0.2 degrees by X-ray powder diffraction represented by an angle of 2 theta by using Cu-Ka radiation.
Specifically, the crystal form B of the chlorobenzoic acid has an X-ray powder diffraction pattern shown in figure 3.
Differential Scanning Calorimetry (DSC) analysis of the crystal form B of the chlorobenzoic acid shows that the crystal form has an endothermic peak within the range of 280-300 ℃; specifically, a Differential Scanning Calorimetry (DSC) pattern of the crystalline form B of chlorobenzoic acid is shown in fig. 4.
Preferably, the thermogravimetric analysis (TGA) of crystalline form B of chlorobenzoic acid is shown in fig. 4, and the crystalline form B has no weight loss, indicating that crystalline form B is a non-solvate or a non-hydrate.
In a fourth aspect, the present invention provides a process for preparing crystalline clofenac form B according to the third aspect of the invention, comprising the steps of:
(a) adding the crystal form A of the chlorobenzoic acid into a mixed solvent of dichloromethane and ethanol, and heating to 35-45 ℃ for dissolution;
(b) standing and volatilizing at 35-45 ℃ until a layer of film-shaped solid appears on the upper surface of the liquid, stirring, and cooling to 0-10 ℃;
(c) filtering and airing at room temperature to obtain a crystal form B of the chlorobenzoic acid;
wherein the crystal form A of the chlorobenzoic acid: dichloromethane: ethanol 1:100:100, unit g/ml/ml.
In a fifth aspect, the present invention provides another process for preparing crystalline clofenazole form B, according to the third aspect of the present invention, comprising the steps of:
(a) adding the intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid (compound II) into glacial acetic acid, adding methane sulfonic acid, stirring and refluxing for reacting for 6-10 h;
(b) cooling the system to 60-70 ℃, adding a solvent, stirring and dissolving;
(c) cooling the system to 35-45 ℃, adding dichloromethane or a mixture of dichloromethane and other solvents, stirring, cooling and crystallizing;
(d) filtering and drying to obtain a crystal form B of the chlorobenzoic acid;
wherein the solvent in step (b) is tetrahydrofuran, dioxane or a combination thereof; the volume amount of the solvent is 25-100 times, preferably 30-40 times of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
in the step (c), the volume amount of the dichloromethane or the mixed solvent of the dichloromethane and other solvents is 30-100 times, preferably 40-50 times of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
the other solvent in the step (c) is ethanol, isopropanol, propanol, ethyl acetate, isopropyl acetate, acetonitrile, acetone, butanone or a combination solvent thereof; the volume ratio of the dichloromethane to other solvents is 1: 0.5-10, preferably 1: 1-2;
the crystallization temperature in the step (c) is-20-30 ℃, and preferably 0-10 ℃;
drying in the step (d) at the temperature of 30-90 ℃, preferably 50-70 ℃.
The purity of the crystal form B of the chlorobenzoic acid prepared by the method in the fourth and fifth aspects of the invention is up to more than 99.9 percent.
The sixth aspect of the invention provides the use of the crystal form a of chlorobenzoic acid and the crystal form B of chlorobenzoic acid in the first aspect and the third aspect of the invention for preparing chlorobenzoic acid medicaments and preparations.
The novel crystal form of the chlorobenzoic acid solves the defects in the prior art, and has the following beneficial effects: (1) the crystal form stability is good, the crystal granularity is small, the crushing is not needed, the fluidity is good, the static electricity is avoided, the preparation difficulty of the solid preparation is obviously reduced, and the industrial production is facilitated; (2) the preparation method is easy for large-scale preparation, simple to operate, free of redundant steps, good in safety, free of uncontrollable hidden danger and suitable for industrial production; (3) is easy to remove impurities, has the purity of 99.9 percent, and can meet the quality requirement of the raw material medicaments without refining for many times.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline form A of chlorfenapyr of example 1;
FIG. 2 is a differential scanning calorimetry-thermogravimetric analysis of crystalline form A of chlorobenzoic acid of example 1;
FIG. 3 is an X-ray powder diffraction pattern of crystalline form B of chlorobenzoic acid of example 7;
FIG. 4 is a differential scanning calorimetry-thermogravimetric analysis of crystalline form B of chlorobenzoic acid of example 7;
FIG. 5 is a scanning electron micrograph of crystalline form A of chlorobenzoic acid of example 1;
FIG. 6 is a scanning electron micrograph of crystalline diclofenac B of example 7;
FIG. 7 is a scanning electron micrograph of crystalline chlorphenamine form 1 of comparative example 1.
Detailed Description
The above-mentioned aspects of the present invention are further described with reference to specific embodiments, but should not be construed as limiting the scope of the present invention, and all technical solutions implemented based on the above-mentioned aspects of the present invention are within the scope of the present invention. The present invention generally and/or specifically describes the materials used in the tests, as well as the test methods. The materials and methods of operation used in the present invention are well known in the art unless otherwise specified; the starting materials and solvents used in the present invention are commercially available or can be prepared by known methods.
The apparatus and method used in the present invention:
(1) x-ray powder diffractometer
The instrument model is as follows: PANALYtic X-ray powder diffractometer
The test method comprises the following steps: the ground sample (100mg) was filled in a groove of a glass plate, and after the flat surface thereof was flush with the glass surface by a glass slide, the sample was placed in a PANalytical X-ray powder diffractometer using a 40kV and 40mA copper X-ray source with a scanning range of 3 to 45 ° (2 θ) and a scanning speed of 8 °/min. The scan error is typically ± 0.2 degrees (2 θ).
(2) TGA/DSC1 synchronous thermal analyzer
The instrument model is as follows: METTLER TGA/DSC 1.
The test method comprises the following steps: samples weighing 10mg were placed in a closed aluminum pan with small pin holes, equilibrated at 30 ℃ and then heated to 400 ℃ at a scan rate of 10 ℃/min. Dry nitrogen was used as purge gas.
(3) Scanning electron microscope
The instrument model is as follows: ZEISS Sigma 300 scanning electron microscope
The test method comprises the following steps: taking a proper amount of a test article, uniformly spreading the test article on a conductive adhesive tape, spraying gold, and observing under the visual field of an electron microscope.
Example 1 preparation of crystalline form a of chlorobenzoic acid
Adding 50kg of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 500L of glacial acetic acid, adding 100kg of methanesulfonic acid, stirring and refluxing for 8h, cooling to 60-70 ℃, adding 1500L of dioxane, stirring for dissolving, cooling to 35-45 ℃, adding 1000L of mixed solution of dichloromethane/1000L of methanol, stirring for crystallization, cooling to 0-10 ℃, filtering, washing a filter cake with dichloromethane/methanol, drying in vacuum for 4h at 60 ℃, and keeping constant weight to obtain 40.5kg of chlorfenapyr, wherein the yield is 85.7%, and the purity is 99.91%; the X-RPD is shown in figure 1, and the DSC-TGA spectrum is shown in figure 2, which is the crystal form A.
Example 2 preparation of Crystal form A of Chlorobenzoic acid
Adding 15g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 150mL of glacial acetic acid, adding 30g of methanesulfonic acid, stirring for reflux reaction for 6h, cooling to 60-70 ℃, adding 525mL of dioxane, stirring for dissolution, cooling to 35-45 ℃, adding a mixed solution of 250mL of dichloromethane/500 mL of methanol, stirring for crystallization, cooling to-10-0 ℃, filtering and drying to obtain 12.1g of chlorobenzoic acid, wherein the yield is 85.4%, and the purity is 99.95%; the X-RPD profile was determined to be substantially in accordance with FIG. 1.
Example 3 preparation of crystalline form a of chlorobenzoic acid
Adding 15g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 150mL of glacial acetic acid, adding 30g of methanesulfonic acid, stirring and refluxing for 9h, cooling to 60-70 ℃, adding 450mL of tetrahydrofuran, stirring for dissolving, cooling to 35-45 ℃, adding a mixed solution of 300mL of dichloromethane/300 mL of methanol, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 11.8g of chlorobenzoic acid, wherein the yield is 83.3%, and the purity is 99.94%; the X-RPD profile was determined to be substantially identical to that of FIG. 1.
Example 4 preparation of crystalline form a of chlorobenzoic acid
Adding 15g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 150mL of glacial acetic acid, adding 30g of methanesulfonic acid, stirring and refluxing for 10h, cooling to 60-70 ℃, adding 525mL of tetrahydrofuran, stirring for dissolving, cooling to 35-45 ℃, adding a mixed solution of 250mL of dichloromethane/500 mL of methanol, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 12.3g of chlorobenzoic acid with the yield of 86.8% and the purity of 99.96%; the X-RPD profile was determined to be substantially in accordance with FIG. 1.
Example 5 preparation of crystalline form a of chlorobenzoic acid
Adding 15g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 150mL of glacial acetic acid, adding 30g of methanesulfonic acid, stirring and refluxing for reaction for 7h, cooling to 60-70 ℃, adding a mixed solution of 225mL of tetrahydrofuran/225 mL of dioxane, stirring and dissolving, cooling to 35-45 ℃, adding 250mL of dichloromethane/250 mL of methanol, stirring and crystallizing, cooling to 0-10 ℃, filtering and drying to obtain 12.0g of chlorobenzoic acid, wherein the yield is 84.7%, and the purity is 99.93%; the X-RPD profile was determined to be substantially in accordance with FIG. 1.
Example 6 preparation of crystalline form B of chlorobenzoic acid
Adding 10g of the crystal form A of the chlorobenzoic acid into a mixed solvent of 1000ml of dichloromethane and 1000ml of ethanol, heating to 35-45 ℃ for dissolution, keeping standing at 35-45 ℃ for continuous volatilization until a layer of membranous solid appears on the upper surface of liquid, stirring, cooling to 0-10 ℃, filtering, and drying at room temperature to obtain 8.3g of crystal form B of the chlorobenzoic acid, wherein an X-RPD (X-ray diffraction pattern) of the crystal form B of the chlorobenzoic acid is basically consistent with that shown in a figure 3.
Example 7 preparation of crystalline form B of chlorobenzoic acid
Adding 7.5kg of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 75L of glacial acetic acid, adding 15kg of methanesulfonic acid, stirring for reflux reaction for 8h, cooling to 60-70 ℃, adding 225L of dioxane, stirring for dissolution, cooling to 35-45 ℃, adding 300L of dichloromethane, stirring for crystallization, cooling to 0-10 ℃, filtering, and carrying out vacuum drying at 60 ℃ for 4h to achieve constant weight, thereby obtaining 6.1kg of chlorobenzoic acid, wherein the yield is 86.1% and the purity is 99.92%; the X-RPD is shown in figure 3, and the DSC-TGA spectrum is shown in figure 4, which is the crystal form B.
Example 8 preparation of Crystal form B of Chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methanesulfonic acid, stirring and refluxing for 10h, cooling to 60-70 ℃, adding 350mL of dioxane, stirring for dissolving, cooling to 35-45 ℃, adding 500mL of dichloromethane, stirring for crystallization, cooling to-10-0 ℃, filtering and drying to obtain 8.2g of chlorobenzoic acid, wherein the yield is 86.8%, and the purity is 99.96%; the X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 9 preparation of Crystal form B of Chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methanesulfonic acid, stirring and refluxing for 9h, cooling to 60-70 ℃, adding 300mL of tetrahydrofuran, stirring for dissolving, cooling to 35-45 ℃, adding 400mL of dichloromethane, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.0g of chlorobenzoic acid, wherein the yield is 84.7%, and the purity is 99.94%; the X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 10 preparation of crystalline form B of chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methanesulfonic acid, stirring for reflux reaction for 7h, cooling to 60-70 ℃, adding a mixed solution of 150mL of tetrahydrofuran and 150mL of dioxane, stirring for dissolution, cooling to 35-45 ℃, adding 450mL of dichloromethane, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.1g of chlorobenzoic acid, wherein the yield is 85.7%, and the purity is 99.95%; the X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 11 preparation of crystalline form B of chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methanesulfonic acid, stirring and refluxing for 6h, cooling to 60-70 ℃, adding 300mL of tetrahydrofuran, stirring for dissolving, cooling to 35-45 ℃, adding 200mL of dichloromethane/200 mL of ethanol mixed solution, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.0g of chlorobenzoic acid, wherein the yield is 84.7%, and the purity is 99.94%; the X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 12 preparation of Crystal form B of Chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methanesulfonic acid, stirring for reflux reaction for 6h, cooling to 60-70 ℃, adding 300mL of dioxane, stirring for dissolution, cooling to 35-45 ℃, adding 200mL of dichloromethane/200 mL of ethyl acetate mixed solution, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.1g of chlorobenzoic acid, wherein the yield is 85.7%, and the purity is 99.94%; the X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 13 preparation of Crystal form B of Chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methane sulfonic acid, stirring and refluxing for 10 hours, cooling to 60-70 ℃, adding 350mL of dioxane, stirring for dissolving, cooling to 35-45 ℃, adding 200mL of dichloromethane/200 mL of acetonitrile mixed solution, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.2g of chlorobenzoic acid, wherein the yield is 86.8%, and the purity is 99.90%; the X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 14 preparation of crystalline form B of chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methanesulfonic acid, stirring and refluxing for 10h, cooling to 60-70 ℃, adding 300mL of tetrahydrofuran, stirring for dissolving, cooling to 35-45 ℃, adding 200mL of dichloromethane/300 mL of acetone mixed solution, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.0g of chlorobenzoic acid, wherein the yield is 84.7%, and the purity is 99.90%; the X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 15 preparation of crystalline form B of chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methane sulfonic acid, stirring and refluxing for 10 hours, cooling to 60-70 ℃, adding 300mL of tetrahydrofuran, stirring for dissolving, cooling to 35-45 ℃, adding 200mL of dichloromethane/150 mL of propanol/150 mL of isopropanol mixed solution, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.1g of chlorobenzoic acid, wherein the yield is 85.7%, and the purity is 99.89%; (ii) a The X-RPD profile was determined to be substantially in accordance with FIG. 3.
Example 16 preparation of crystalline form B of chlorobenzoic acid
Adding 10g of intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of glacial acetic acid, adding 20g of methanesulfonic acid, stirring and refluxing for 10h, cooling to 60-70 ℃, adding 300mL of tetrahydrofuran, stirring for dissolving, cooling to 35-45 ℃, adding 200mL of dichloromethane/150 mL of isopropyl acetate/150 mL of butanone mixed solution, stirring for crystallization, cooling to 0-10 ℃, filtering and drying to obtain 8.2g of chlorobenzoic acid, wherein the yield is 86.8 percent, and the purity is 99.82 percent; (ii) a The X-RPD profile was determined to be substantially in accordance with FIG. 3.
Comparative example 1: preparation of form 1
Reference WO2016038500 example 1, which comprises adding 10g of 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid into 100mL of tetrahydrofuran, adding 3.4g of triethylamine, adding 40mL of purified water, keeping the mixture at 20-25 ℃, pulping for 1 hour, filtering, adding 4.7g of methanesulfonic acid into the filtrate, stirring, adding 200mL of toluene into a water separator, heating and stirring, reacting for 3 hours, then carrying out reflux reaction for 16 hours, cooling to 20 ℃, adding 50mL of isopropanol, pulping for 1 hour, filtering, washing the filter cake with 40mL of 2 isopropanol, drying the filter cake under vacuum at 65 ℃ for 20 hours, and keeping the weight constant to obtain 7.8g of chlorobenzoic acid, wherein the yield is 82.6% and the purity is 98.27%. The X-RPD map is basically consistent with the map described in figure 1 of WO2016038500 and is determined to be the crystal form 1.
Stability test
The samples prepared in examples 1 and 7 were placed at 40 ℃ and the stability at 1 month, 2 months, 3 months and 6 months was examined, and the results are shown in Table 1.
The specific stability investigation method can refer to the method in appendix XIX C of the second part of China pharmacopoeia 2020 edition; the HPLC method for purity determination can be referred to the method in appendix V D of the second part of the Chinese pharmacopoeia 2020.
TABLE 1 stability test results for inventive form A and form B samples
The experiments show that the purity and the crystal form of the crystal form A and the crystal form B of the chlorobenzoic acid prepared by the invention are not changed after 6-month stability tests, which shows that the crystal form A and the crystal form B of the chlorobenzoic acid provided by the invention are stable and have good chemical stability.
Crystal micro-morphology and its fluidity
TABLE 2 comparison of crystal microscopic morphologies of Crystal form A, Crystal form B, and Crystal form 1 of Chlorobenzoic acid
As BCS (biopharmaceutical classification system) is classified into 4 types: low solubility-low permeability drugs, making oral formulations difficult, often requiring micronization of the product. The crystal form A and the crystal form B of the chlorobenzoic acid prepared by the method have smaller granularity, do not need to be crushed, have good fluidity and no static electricity, avoid dust pollution caused by crushing and provide convenience for industrial production; the crystal form 1 has larger particles, stronger static electricity after being crushed and poor fluidity, and increases the preparation difficulty of the preparation.
Claims (10)
1. A crystal form of crystal form A of chlorobenzoic acid, which is characterized in that Cu-Ka radiation is used, and X-ray powder diffraction expressed by 2 theta angle has diffraction peaks at 5.9 +/-0.2 degrees, 6.8 +/-0.2 degrees, 9.6 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.8 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.5 +/-0.2 degrees and 27.3 +/-0.2 degrees.
2. The crystalline form of claim 1, wherein X-ray powder diffraction using Cu-Ka radiation, expressed in terms of 2 Θ angles, has diffraction peaks at 5.9 ± 0.2 °, 6.8 ± 0.2 °, 9.6 ± 0.2 °, 12.8 ± 0.2 °, 14.0 ± 0.2 °, 16.6 ± 0.2 °, 17.8 ± 0.2 °, 20.0 ± 0.2 °, 20.5 ± 0.2 °, 23.8 ± 0.2 °, 25.7 ± 0.2 °, 27.3 ± 0.2 °, 31.5 ± 0.2 °, 36.4 ± 0.2 °, 42.9 ± 0.2 °; specifically, it has an X-ray powder diffraction pattern as shown in FIG. 1.
3. The crystalline form of claim 1, characterized by a Differential Scanning Calorimetry (DSC) pattern with endothermic peaks at 278-298 ℃ respectively; specifically, it has a Differential Scanning Calorimetry (DSC) profile as shown in fig. 2.
4. A preparation method of the crystal form A of the chlorobenzoic acid according to claim 1 or 2, which comprises the following steps:
(a) adding the intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid (compound II) into glacial acetic acid, adding methane sulfonic acid, stirring and refluxing for reacting for 6-10 h;
(b) cooling the system to 60-70 ℃, adding a solvent, stirring and dissolving;
(c) cooling the system to 35-45 ℃, adding dichloromethane/methanol, stirring, cooling and crystallizing;
(d) filtering and drying to obtain crystal form A of the chlorobenzoic acid;
wherein the solvent in step (b) is tetrahydrofuran, dioxane or a combination thereof; the volume amount of the solvent is 25-100 times, preferably 30-40 times of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
the volume ratio of the dichloromethane to the methanol in the step (c) is 1: 0.5-10, preferably 1: 1-2;
in the step (c), the volume amount of the dichloromethane/methanol is 30-100 times, preferably 40-50 times of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
the crystallization temperature in the step (c) is-20 to 30 ℃, and preferably 0 to 10 ℃.
5. A crystal form of crystal form B of chlorobenzoic acid, which is characterized in that X-ray powder diffraction expressed by 2 theta angle by using Cu-Ka radiation has diffraction peaks at 6.4 +/-0.2 degrees, 9.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 13.5 +/-0.2 degrees and 18.3 +/-0.2 degrees.
6. The crystalline form of claim 5, wherein an X-ray powder diffraction using Cu-Ka radiation, expressed in terms of 2 θ, has diffraction peaks at 6.4 ± 0.2 °, 9.6 ± 0.2 °, 11.6 ± 0.2 °, 13.5 ± 0.2 °, 16.5 ± 0.2 °, 18.3 ± 0.2 °, 19.3 ± 0.2 °, 20.4 ± 0.2 °, 22.7 ± 0.2 °, 24.9 ± 0.2 °, 27.5 ± 0.2 °, 28.8 ± 0.2 °, 31.7 ± 0.2 °, 32.8 ± 0.2 °; specifically, it has an X-ray powder diffraction pattern as shown in fig. 3.
7. The crystalline form of claim 5, characterized by a Differential Scanning Calorimetry (DSC) pattern in which endothermic peaks occur in the range of 280-300 ℃ respectively; specifically, it has a Differential Scanning Calorimetry (DSC) profile as shown in fig. 4.
8. A preparation method of the crystal form B of the chlorobenzoic acid as claimed in claim 5 or 6, which comprises the following steps:
(a) adding the crystal form A of the chlorobenzoic acid into a mixed solvent of dichloromethane and ethanol, and heating to 35-45 ℃ for dissolution;
(b) standing and volatilizing at 35-45 ℃ until a layer of film-shaped solid appears on the upper surface of the liquid, stirring, and cooling to 0-10 ℃;
(c) filtering and airing at room temperature to obtain a crystal form B of the chlorobenzoic acid;
wherein the crystal form A of the chlorobenzotriazole acid: dichloromethane: ethanol is 1:100:100, unit g/ml/ml.
9. A preparation method of the crystal form B of the chlorobenzoic acid as claimed in claim 5 or 6, which comprises the following steps:
(a) adding the intermediate 4- [ (3, 5-dichlorobenzoyl) amino ] -3-hydroxybenzoic acid (compound II) into glacial acetic acid, adding methane sulfonic acid, stirring and refluxing for reacting for 6-10 h;
(b) cooling the system to 60-70 ℃, adding a solvent, stirring and dissolving;
(c) cooling the system to 35-45 ℃, adding dichloromethane or a mixture of dichloromethane and other solvents, stirring, cooling and crystallizing;
(d) filtering and drying to obtain the crystal form B of the chlorobenzoic acid.
10. The preparation method according to claim 9, wherein the solvent in step (b) is tetrahydrofuran, dioxane or a combination thereof; the volume amount of the solvent is 25-100 times, preferably 30-40 times of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
in the step (c), the volume amount of the dichloromethane or the mixed solvent of the dichloromethane and other solvents is 30-100 times, preferably 40-50 times of the mass of the compound II, and the corresponding units of the volume amount and the mass are ml and g respectively;
the other solvent in the step (c) is ethanol, isopropanol, propanol, ethyl acetate, isopropyl acetate, acetonitrile, acetone, butanone or a combination solvent thereof; the volume ratio of the dichloromethane to other solvents is 1: 0.5-10, preferably 1: 1-2;
the crystallization temperature in the step (c) is-20 to 30 ℃, and preferably 0 to 10 ℃.
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| WO2019175263A1 (en) * | 2018-03-13 | 2019-09-19 | Azad Pharma Ag | New polymorphs and new path to synthesize tafamidis |
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