CN111689897B - Preparation method of high-purity lenvatinib mesylate crystal form C - Google Patents
Preparation method of high-purity lenvatinib mesylate crystal form C Download PDFInfo
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- CN111689897B CN111689897B CN201910190726.9A CN201910190726A CN111689897B CN 111689897 B CN111689897 B CN 111689897B CN 201910190726 A CN201910190726 A CN 201910190726A CN 111689897 B CN111689897 B CN 111689897B
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- HWLFIUUAYLEFCT-UHFFFAOYSA-N lenvatinib mesylate Chemical compound CS(O)(=O)=O.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 HWLFIUUAYLEFCT-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960001429 lenvatinib mesylate Drugs 0.000 title claims abstract description 47
- 239000013078 crystal Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 11
- 229960003784 lenvatinib Drugs 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 19
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000004321 preservation Methods 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012453 solvate Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 3
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 2
- OFQLBCBNNWFEPV-UHFFFAOYSA-N 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C(Cl)=C1 OFQLBCBNNWFEPV-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 229940126163 KIT kinase inhibitor Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- RFJVQGMBFQGZPV-UHFFFAOYSA-N 4-amino-3-chlorophenol;hydrochloride Chemical compound Cl.NC1=CC=C(O)C=C1Cl RFJVQGMBFQGZPV-UHFFFAOYSA-N 0.000 description 1
- ZBTVNIDMGKZSGC-UHFFFAOYSA-N 4-chloro-7-methoxyquinoline-6-carboxamide Chemical compound C1=CC(Cl)=C2C=C(C(N)=O)C(OC)=CC2=N1 ZBTVNIDMGKZSGC-UHFFFAOYSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- SVWLIIFHXFGESG-UHFFFAOYSA-N formic acid;methanol Chemical compound OC.OC=O SVWLIIFHXFGESG-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and in particular relates to a preparation method of a lenvatinib mesylate crystal form C, which avoids conditions such as high temperature, acid serving as a solvent and the like, greatly reduces the content of impurities, has higher purity and better yield, the purity is over 99 percent, the yield is over 95 percent, and the method has the advantages of simple process, convenient operation, mild condition, no need of special reaction conditions, environmental friendliness and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a high-purity lenvatinib mesylate crystal form C.
Background
Lenvatinib mesylate (Lenvatinib mesylate) of formula I, having the chemical name 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide mesylate. It is known that lenvatinib mesylate has a strong c-Kit kinase inhibitory action, and is useful as a angiogenesis inhibitor or c-Kit kinase inhibitor having high pharmaceutical applicability, and has more excellent properties in terms of physical properties and kinetics.
Patent document WO2005063713 and its chinese counterpart CN100569753C disclose the crystallization of salts of 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide or solvates thereof and a process for its preparation. Crystalline forms a, B, C, F, I and dimethyl sulfoxide solvates of lenvatinib mesylate and methods of preparing the same are disclosed. Wherein, the crystal form C has better thermodynamic stability, higher cleanliness and lower hygroscopicity, and is more suitable for application in pharmaceutical preparations. The preparation of 4 crystalline forms C is described in this patent: (1) Heating the lenvatinib mesylate dimethyl sulfoxide solvate; (2) Mixing the crystalline form I of lenvatinib mesylate acetate and a solvent; (3) Mixing lenvatinib, acetic acid and methanesulfonic acid to dissolve the lenvatinib; (4) humidifying the crystalline form B of lenvatinib mesylate.
Numerous studies have shown that lenvatinib mesylate has poor thermal stability and stability under acidic conditions, and is easily degraded at high temperatures and under acidic conditions. Patent CN106660964a reports impurity a (formula II), which is a recognized strong mutagenic chemical substance, published on an occupational safety website in the department of health, labor and welfare (the Ministry of Health, labour and Welfare of Japan) of japan. The impurity a is partly derived from the residue of the starting material and partly from the decomposition of lenvatinib, which is difficult to remove by conventional column chromatography and crystallization methods.
The preparation method (1) of the crystal form C reported in WO2005063713 has the advantages that the impurity A is obviously increased after Wen Zhuaijing; acetic acid is used as a solvent in the method (2) and the method (3), so that degradation of the acetic acid is accelerated, and the method (3) is difficult to stir due to caking in the salt forming process; the method (4) is not suitable for industrial production.
In summary, the reported preparation method of the crystal form C still has the problems of high impurity content, low product purity, easy caking and inapplicability to industrial production. In view of the high applicability of lenvatinib as a pharmaceutical agent, an angiogenesis inhibitor or a c-Kit kinase inhibitor is excellent in physical properties and kinetics. Therefore, it is necessary to develop a preparation method of the crystalline form C of lenvatinib mesylate with low impurity content and higher purity.
Disclosure of Invention
In order to solve the technical problems in the report, the invention aims to provide a preparation method of the lenvatinib mesylate crystal form C, which has low impurity content and high purity and is easy for industrial production.
In order to achieve the technical aim, the invention adopts the following technical scheme:
a) Adding lenvatinib free base to a solvent;
b) Adding methanesulfonic acid into the solution obtained in the step a), suspending to form salt, stirring and reacting;
c) Filtering and drying to obtain the lenvatinib mesylate crystal form C;
in the step a), the solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran and methylene dichloride; preferably one or more of ethanol, ethyl acetate, acetone, tetrahydrofuran; most preferred is ethanol.
In step a), after the addition of the lenvatinib free base to the solvent, seed crystals C may be added to the system in an amount of 0 to 0.2 times, preferably 0.001 to 0.05 times, more preferably 0.005 to 0.015 times the mass of the lenvatinib.
In step b), the methanesulfonic acid may be added in the form of a methanesulfonic acid solution, and the solvent used to prepare the solution may be one or more selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and methylene chloride.
In the step a), the mass-volume ratio of the lenvatinib to the solvent is 1:2 g/mL-1: 200g/mL, preferably 1:5 g/mL-1: 50g/mL, more preferably 1:10 g/mL-1: 30g/mL.
In step b), the molar amount of methanesulfonic acid is 1 to 5 times, preferably 1 to 3 times, more preferably 1.1 to 1.5 times the molar amount of lenvatinib.
In step b), the salification temperature is from-20 to 40 ℃, preferably from-5 to 30 ℃, more preferably from 10 to 20 ℃; the salification time is 0.5-20h, preferably 2-3h.
In step C), crystalline form C of lenvatinib mesylate is obtained having an X-ray powder diffraction pattern as shown in fig. 1, a purity of 99% or more, 99.5% or more, 99.8% or more, as measured by HPLC.
It should be noted that the lenvatinib free base used in step a) of the present invention is prepared according to the method described in patent CN106660964a or the same method as it; the crystalline form C of the lenvatinib mesylate disclosed in the patent CN100569753C has an X-ray powder diffraction pattern shown in figure 2; the crystalline form C of lenvatinib mesylate, used in step a) of the present invention, was prepared according to the method described in patent CN 100569753C.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the lenvatinib mesylate crystal form C provided by the invention avoids harsh conditions such as high temperature, acid as a solvent and the like, greatly reduces the content of impurities, and the obtained lenvatinib mesylate crystal form C has higher purity and better yield; the method is simple, convenient to operate and suitable for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline form C of lenvatinib mesylate obtained by the process of the present invention;
figure 2 patent publication (CN 100569753C) shows an X-ray powder diffraction pattern of crystalline form C of lenvatinib mesylate.
FIG. 3 DSC-TGA spectrum of crystalline form C of lenvatinib mesylate obtained by the present invention;
Detailed Description
The foregoing is further elaborated by the following specific embodiments, which are not to be construed as limiting the claimed subject matter. The technical scheme obtained by simply improving the invention or adopting conventional means or components to perform equivalent substitution on the basis of the technical scheme of the invention belongs to the protection scope of the invention.
The inspection instrument and the method used in the invention are as follows:
(1) X-ray powder diffraction
Instrument model: PANalytical Empyrean X ray powder diffraction analyzer
The testing method comprises the following steps: the ground sample (100 mg) was filled in a groove of a glass plate, and after the plane of the sample was flush with the glass surface by a glass slide, the sample was placed in a PANalytical Empyrean X ray powder diffraction analyzer, and a 40kV and 40mA copper X-ray source was used, with a scanning range of 3 to 45 degrees (2. Theta.) and a scanning speed of 4 degrees/min for 6 minutes. The scan error is typically + -0.2 degrees (2 theta).
(2) TGA/DSC simultaneous thermal analysis
Instrument model: METTLER TGA/DSC 1.
The testing method comprises the following steps: samples weighing 10mg were placed in a closed aluminum pan with small pinholes, kept in equilibrium at 30 ℃ and then heated to 250 ℃ at a scan rate of 10 ℃/min. Dry nitrogen was used as the purge gas.
(3) HPLC high performance liquid chromatography (purity detection)
Instrument model: waters 2695
Chromatographic column: octadecylsilane chemically bonded silica is used as filler (YMC-Pack Pro C18,
4.6mm X250 mm,5 μm column or column of comparable performance
Mobile phase: water-acetonitrile-perchloric acid as mobile phase a; water-acetonitrile-perchloric acid as mobile phase B
A detector: ultraviolet detector
(4) LC-MS liquid chromatography-mass spectrometry (detection of impurity A)
Instrument model: AB Triple Quad 5500
Chromatographic column: octadecylsilane chemically bonded silica was used as filler (Waters Atlantis T, 2.1X)
100mm,3 μm or equivalent performance chromatographic column)
Mobile phase: 0.1% formic acid aqueous solution as mobile phase A and 0.1% formic acid methanol solution as mobile phase B
A detector: ultraviolet detector
Preparation example 1: preparation of lenvatinib free base
(a) Preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxy-quinoline-6-carboxamide:
a mixture of 4.35g of 4-amino-3-chlorophenol hydrochloride, 5.38g of aqueous potassium hydroxide (48.5 w/w%), 4.40g of 4-chloro-7-methoxy-quinoline-6-carboxamide and 40ml of dimethyl sulfoxide was stirred for 20h at 70℃under nitrogen. Acetone (22 ml)/water (44 ml) mixture was added at 55℃and cooled to 5-10℃and filtered, and the filter cake was washed with acetone/water and dried to give intermediate 5.87g in 92.1% yield.
(b) Preparation of lenvatinib free base:
to a mixture of 2.60g of 4- (4-amino-3-chlorophenoxy) -7-methoxy-quinoline-6-carboxamide, 1.32g of pyridine, 0.14g of water and 20ml of DMF at-20℃was added 2.66g of phenyl chloroformate under nitrogen protection, followed by stirring for 3 hours under heat preservation. Then further adding 1.94g of cyclopropylamine at the temperature of 5-10 ℃, and stirring for 15h under heat preservation. 1.3ml of water/26 ml of acetone mixed solution is added into the reaction solution, then the mixture is filtered, the filter cake is washed by acetone, and the crude product of the lenvatinib free base is obtained after drying. Then, the resulting mixture was crystallized from 36ml of 1, 3-dimethylimidazolidinone and 57.5ml of isopropyl alcohol to obtain 2.42g of lenvatinib free base in a yield of 75.4%.
Comparative example 1: crystal form C of lenvatinib mesylate
Crystalline form C of lenvatinib mesylate was prepared according to the method described in patent CN 100569753C:
1.0g of lenvatinib mesylate DMSO solvate is added into 20ml of n-butyl acetate, the temperature is controlled to be 115 ℃ and stirred for 10 hours, the temperature is reduced to room temperature, the temperature is kept and stirred for 1.5 hours, the suction filtration and the vacuum drying at 60 ℃ are carried out, and 0.81g of lenvatinib mesylate crystal form C is obtained, the yield is 81.0%, and the purity of HLPC is 99.4%. The X-ray powder diffraction pattern is shown in figure 1.
Comparative example 2: crystal form C of lenvatinib mesylate
Crystalline form C of lenvatinib mesylate was prepared according to the method described in patent CN 100569753C:
2.0g of lenvatinib free base is added into a mixed solvent of 14ml of acetic acid and methanesulfonic acid (0.37 ml), stirred and dissolved at the temperature of 40 ℃, then isopropanol (9 ml) and seed crystal C (0.1 g) are added, stirred for 20 minutes at a constant temperature, then isopropyl acetate (10 ml) is added dropwise over 30 minutes, the reaction solution is stirred for 1.5 hours, then stirred for 14 hours at 15 ℃, filtered by suction, dried in vacuum at 60 ℃ to obtain 2.2g of lenvatinib mesylate crystal form C, the yield is 90.2%, and the purity of HLPC is 99.5%. The X-ray powder diffraction pattern is shown in figure 1
Example 1: crystal form C of lenvatinib mesylate
Adding 1.0g of lenvatinib free base into 15ml of ethanol, controlling the temperature to 15-25 ℃, adding 0.27g of ethanol solution (5 ml) of methanesulfonic acid, stirring for 2 hours under heat preservation, filtering, and vacuum drying at 60 ℃ to obtain 1.17g of lenvatinib mesylate crystal form C, wherein the yield is 95.5%, and the purity of HLPC is 99.9%; the X-ray powder diffraction pattern is shown in figure 1, and the DSC-TGA pattern is shown in figure 3.
EXAMPLE 2 Crystal form C of lenvatinib mesylate
Adding 1.0g of lenvatinib free base into 20ml of ethanol, heating and dissolving, controlling the temperature to 15-25 ℃, adding 0.27g of methanesulfonic acid, stirring for 3 hours under heat preservation, filtering, and vacuum drying at 60 ℃ to obtain 1.14g of lenvatinib mesylate crystal form C, wherein the yield is 93.1%, and the purity of HLPC is 99.8%; the X-ray powder diffraction pattern was determined to be substantially in accordance with FIG. 1 and the DSC-TGA pattern was determined to be substantially in accordance with FIG. 3.
EXAMPLE 3 Crystal form C of lenvatinib mesylate
Adding 1.0g of lenvatinib free base into 15ml of ethanol, then adding 0.01g of seed crystal C, controlling the temperature to 15-25 ℃, adding 0.27g of ethanol solution (5 ml) of methanesulfonic acid, stirring for 3h under heat preservation, filtering, and vacuum drying at 60 ℃ to obtain 1.16g of lenvatinib mesylate crystal form C, wherein the yield is 94.7%, and the purity of HLPC is 99.9%; the X-ray powder diffraction pattern was determined to be substantially in accordance with FIG. 1 and the DSC-TGA pattern was determined to be substantially in accordance with FIG. 3.
Example 4: crystal form C of lenvatinib mesylate
Adding 1.0g of lenvatinib free base into 15ml of acetone, controlling the temperature to 15-25 ℃, adding 0.27g of acetone solution (5 ml) of methanesulfonic acid, stirring for 2 hours under heat preservation, filtering, and vacuum drying at 60 ℃ to obtain 1.10g of lenvatinib mesylate crystal form C, wherein the yield is 89.8%, and the purity of HLPC is 99.6%; the X-ray powder diffraction pattern was determined to be substantially in accordance with FIG. 1 and the DSC-TGA pattern was determined to be substantially in accordance with FIG. 3.
EXAMPLE 5 Crystal form C of lenvatinib mesylate
Adding 1.0g of lenvatinib free base into 15ml of ethyl acetate, controlling the temperature to 15-25 ℃, adding 0.27g of ethyl acetate solution (5 ml) of methanesulfonic acid, stirring for 2 hours under heat preservation, filtering, and vacuum drying at 60 ℃ to obtain 1.17g of lenvatinib mesylate crystal form C, wherein the yield is 95.5%, and the purity of HLPC is 99.6%; the X-ray powder diffraction pattern was determined to be substantially in accordance with FIG. 1 and the DSC-TGA pattern was determined to be substantially in accordance with FIG. 3.
EXAMPLE 6 Crystal form C of lenvatinib mesylate
Adding 5.0kg of lenvatinib free base into 75L of ethanol, then adding 25g of seed crystal C, controlling the temperature to 15-25 ℃, adding 1.35kg of ethanol solution (25L) of methanesulfonic acid, stirring for 3 hours at a constant temperature, filtering, and vacuum drying at 60 ℃ to obtain 5.87kg of lenvatinib mesylate crystal form C, wherein the yield is 95.8%, and the purity of HLPC is 99.8%; the X-ray powder diffraction pattern was determined to be substantially in accordance with FIG. 1 and the DSC-TGA pattern was determined to be substantially in accordance with FIG. 3.
Example 7 impurity A content and purity comparison
The content of impurity a in the above preparation method was measured using HPLC, and the comparison result is shown in table 1:
as shown in Table 1, the crystalline form C of lenvatinib mesylate prepared in examples 1,3 and 6 has the advantages of less impurity A content, less total impurity content and higher product purity. The crystalline form C of lenvatinib mesylate (comparative examples 1 and 2), prepared according to patent CN100569753C, was higher in both impurity a and total impurities.
Table 1: impurity A content and total impurity content at different preparation methods
| Preparation method | Impurity A (ppm) | Total impurity content (%) |
| Example 1 | 40 | 0.1％ |
| Example 3 | 60 | 0.1％ |
| Example 6 | 104 | 0.2％ |
| Comparative example 1 | 500 | 0.6％ |
| Comparative example 2 | 165 | 0.5％ |
Claims (5)
1. The preparation method of the high-purity lenvatinib mesylate crystal form C is characterized by comprising the following steps of:
a) Adding lenvatinib free base to a solvent;
b) Adding methanesulfonic acid into the solution obtained in the step a), suspending to form salt, stirring and reacting;
c) Filtering and drying to obtain the lenvatinib mesylate crystal form C;
in step a), the solvent is selected from ethanol; the methanesulfonic acid in step b) is added in the form of a methanesulfonic acid solution, the solvent for preparing said solution being selected from ethanol; in step b), the salt forming temperature is 15-25 ℃.
2. The process according to claim 1, wherein seed C is added to the system after the addition of the lenvatinib free base in step a) to the solvent in an amount of 0.005 to 0.015 times the mass of the lenvatinib.
3. The process according to claim 1, wherein in step a), the mass to volume ratio of lenvatinib to the solvent is 1:10 g/mL-1: 30g/mL.
4. The process according to claim 1, wherein in step b) the molar amount of methanesulfonic acid is 1.1 to 1.5 times the molar amount of lenvatinib.
5. The process of claim 1, wherein the crystalline form C of lenvatinib mesylate has an X-ray powder diffraction pattern as shown in fig. 1.
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| CN1890220A (en) * | 2003-12-25 | 2007-01-03 | 卫材株式会社 | A crystalline of the salt form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same |
| CN101001629A (en) * | 2004-09-17 | 2007-07-18 | 卫材R&D管理有限公司 | Medicinal composition |
| WO2016184436A1 (en) * | 2015-05-21 | 2016-11-24 | 苏州晶云药物科技有限公司 | New crystal form of lenvatinib methanesulfonate salt and preparation method thereof |
| WO2018196687A1 (en) * | 2017-04-25 | 2018-11-01 | 苏州科睿思制药有限公司 | New crystal form of lenvatinib methanesulfonate and preparation method thereof |
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| CN1890220A (en) * | 2003-12-25 | 2007-01-03 | 卫材株式会社 | A crystalline of the salt form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same |
| CN101001629A (en) * | 2004-09-17 | 2007-07-18 | 卫材R&D管理有限公司 | Medicinal composition |
| WO2016184436A1 (en) * | 2015-05-21 | 2016-11-24 | 苏州晶云药物科技有限公司 | New crystal form of lenvatinib methanesulfonate salt and preparation method thereof |
| WO2018196687A1 (en) * | 2017-04-25 | 2018-11-01 | 苏州科睿思制药有限公司 | New crystal form of lenvatinib methanesulfonate and preparation method thereof |
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