CN115572261A - Method for removing impurities of varlitinib mesylate - Google Patents
Method for removing impurities of varlitinib mesylate Download PDFInfo
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- CN115572261A CN115572261A CN202211023662.1A CN202211023662A CN115572261A CN 115572261 A CN115572261 A CN 115572261A CN 202211023662 A CN202211023662 A CN 202211023662A CN 115572261 A CN115572261 A CN 115572261A
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 239000012535 impurity Substances 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 26
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 title claims abstract description 23
- 229950006605 varlitinib Drugs 0.000 title claims abstract description 23
- 238000003756 stirring Methods 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 238000000967 suction filtration Methods 0.000 claims abstract description 10
- 238000001291 vacuum drying Methods 0.000 claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 8
- 238000010010 raising Methods 0.000 claims abstract description 4
- 239000012065 filter cake Substances 0.000 claims abstract description 3
- 238000004321 preservation Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- BNMGPDZKAHVEQH-UHFFFAOYSA-N phenyl n-[4-(6-carbamoyl-7-methoxyquinolin-4-yl)oxy-2-chlorophenyl]carbamate Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)OC1=CC=CC=C1 BNMGPDZKAHVEQH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229960001429 lenvatinib mesylate Drugs 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- -1 phenyl (4- ((6-carbamoyl-7-methoxyquinoline-4-yl) oxy) -2-chlorphenyl) carbamate Chemical compound 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000005303 weighing Methods 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 238000005406 washing Methods 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 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
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000011217 control strategy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 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 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for removing impurities in varlitinib mesylate, which comprises the following steps of (1) adding phenyl (4- ((6-carbamoyl-7-methoxyquinoline-4-yl) oxy) -2-chlorphenyl) carbamate serving as an intermediate for preparing the varlitinib mesylate into a first solvent, and heating and stirring; (2) Raising the temperature of the solution to 55-65 ℃, and dropwise adding a second solvent, wherein the temperature is controlled to be 55-65 ℃; (3) keeping the temperature and stirring for l-2h after the dropwise addition; (4) And after the heat preservation is finished, reducing the temperature to 25-45 ℃, preserving the heat for l-3h, carrying out suction filtration, stirring a filter cake by using a second solvent, and carrying out suction filtration and vacuum drying to obtain a white-like product. According to the invention, the intermediate product obtained by purification through the method is used for continuously synthesizing the varlitinib mesylate, so that the content of impurities in the varlitinib mesylate can be obviously reduced, and the medication safety of the varlitinib mesylate is ensured.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a method for removing impurities in varenib mesylate.
Background
Varenib mesylate is a tyrosine kinase (RTK) receptor inhibitor that inhibits the kinase activity of the Vascular Endothelial Growth Factor (VEGF) receptors VEGFR1 (FLT 1), VEGFR2 (KDR) and VEGFR3 (FLT 4), and additionally inhibits other RTKs associated with the pro-angiogenic and tumorigenic pathways, including Fibroblast Growth Factor (FGF), receptors FGFR1, 2, 3 and 4, platelet Derived Growth Factor (PDGF) receptors PDGFR α, KIT and RET. The indications are for unresectable hepatocellular carcinoma patients who have not received systemic treatment.
The chemical name of the varlitinib mesylate is as follows: 4- [ 3-chloro-4- (cyclopropylaminocarbonylamino) phenoxy ] -7-methoxy-6-quinolinecarboxamide methanesulfonate, having the following structural formula:
US7253286 discloses a process for the preparation of varenib mesylate by reacting 4-amino-3-chlorophenol hydrochloride with 4-chloro-7-methoxyquinoline-6-carboxamide, followed by reaction of phenyl chloroformate with the resulting 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide, isolation to give phenyl (4- ((6-carbamoyl-7-methoxyquinolin-4-yl) oxy) -2-chlorophenyl) carbamate, which is then reacted with cyclopropylamine to give the compound 4- [ 3-chloro-4- (cyclopropylaminocarbonylamino) phenoxy ] -7-methoxy-6-quinolinecarboxamide.
CN106660964 discloses se:Sub>A novel process for synthesizing ranvatinib, which can obtain ranvatinib with high purity, indicating that impurity C-1 is formed mainly by the subsequent conduction of C-se:Sub>A, se:Sub>A by-product formed in step 2, and the content of impurity C-1 in ranvatinib or se:Sub>A salt thereof is 0.10% by mass or less according to the guideline of ICH Q3 se:Sub>A, but se:Sub>A purification method capable of effectively reducing or removing the impurity or its precursor C-se:Sub>A has not been reported. The reaction is as follows:
the existing preparation process of the methane sulfonic acid lunvatinib can generate an impurity compound (an impurity C-1) which has the following chemical structural formula:
at present, the C-1 control strategy is mainly realized by controlling the generation of se:Sub>A precursor compound C-A of the impurity through reaction conditions, if the generated compound C-A exceeds the limit of 0.10% in the reaction in the multi-batch production process, the impurity C-1 is subsequently conducted to exceed the limit and is difficult to remove, the subsequent product quality of the varlitinib mesylate is influenced, and the medication safety of the varlitinib mesylate cannot be ensured. Therefore, it is required to develop se:Sub>A new purification control method of impurities C-1 or C-A.
Disclosure of Invention
The invention aims to provide se:Sub>A method for removing se:Sub>A varlitinib mesylate impurity, which controls the content of an impurity C-A in se:Sub>A finished product by controlling the content of the impurity C-A in an intermediate in se:Sub>A preparation process of the varlitinib mesylate, wherein the chemical structural formulse:Sub>A of the intermediate impurity C-A is as follows:
a method for removing an impurity of varlitinib mesylate comprises the following steps:
(1) Adding phenyl (4- ((6-carbamoyl-7-methoxyquinolin-4-yl) oxy) -2-chlorophenyl) carbamate, an intermediate for preparing the varlitinib mesylate, into a first solvent in an amount of 10 times by volume, and stirring with heating;
(2) Raising the temperature of the solution to 55-65 ℃, and dropwise adding a second solvent with the volume of 10 times of that of the intermediate, wherein the temperature is controlled to be 55-65 ℃;
(3) Keeping the temperature and stirring for l-2h after the dropwise adding is finished;
(4) After the heat preservation is finished, reducing the temperature to 25-45 ℃, preserving the heat for l-3h, carrying out suction filtration, stirring a filter cake by using a second solvent, and then carrying out suction filtration and vacuum drying to obtain a white-like product;
(5) The obtained off-white product was used for the preparation of varlitinib mesylate.
As a preferred embodiment, the first solvent includes one or more of N, N-dimethylformamide, N-dimethylacetamide and methylacetamide.
As a preferred embodiment, the second solvent comprises one or more of acetonitrile and ethyl acetate.
As a preferred embodiment, the first solvent is N, N-dimethylformamide and the second solvent is acetonitrile.
As a preferred embodiment, the temperature of heating, dropping and reacting in the step (2) is 65 ℃.
As a preferred embodiment, the temperature reduction and crystallization stirring in the step (4) is 35-45 ℃.
In a preferred embodiment, the temperature reduction and crystallization stirring in step (4) is 40 ℃.
As a preferred embodiment, the prepared pravastatin mesylate has an impurity C-1 content of less than 0.05% or is not detected.
The invention has the following beneficial effects:
the invention creatively provides se:Sub>A method for controlling the content of the impurity C-A by se:Sub>A purification method so as to effectively control the content of the impurity C-1 in the subsequent steps, thereby improving the product purity to meet the quality standard of the varlitinib mesylate and ensuring the medication safety of the varlitinib mesylate. Compared with the existing scheme, the formation of the compound C-A is inhibited only by reaction conditions, and the feasibility of mass production of the pravastatin mesylate is more stably and effectively guaranteed.
Detailed Description
The preparation route of the varlitinib mesylate is as follows:
example 1
In this example, during the preparation of varenib mesylate using crude phenyl (4- ((6-carbamoyl-7-methoxyquinolin-4-yl) oxy) -2-chlorophenyl) carbamate of compound 4, p-phenyl (4- ((6-carbamoyl-7-methoxyquinolin-4-yl) oxy) -2-chlorophenyl) carbamate was subjected to the following treatment step:
adding 42.5kg of DMF into se:Sub>A 100L kettle, starting stirring, weighing 4.5kg of crude varenib mesylate compound 4 (containing 0.42% of C-A), adding into se:Sub>A reaction kettle, heating and stirring, heating to 65 ℃, dropwise adding 35.5kg of acetonitrile, controlling the dropwise adding temperature to be 55-65 ℃, finishing dropwise adding, keeping the temperature for lh, cooling, reducing the temperature to 40 ℃, keeping the temperature for lh, centrifuging, mixing the obtained solid with 35.5kg of acetonitrile, adding into the 100L reaction kettle, pulping at 25-35 ℃, stirring and washing for 0.5h, centrifuging, vacuum drying the obtained solid at 35-40 ℃ for 12h, and collecting to obtain 4.2kg of white-like solid with the purity of 99.68% and the content of impurity C-A of 0.03%.
Adding 26.6kg of dimethyl sulfoxide into a 100L reaction kettle, starting stirring, weighing 2.92kg of the off-white solid, adding the off-white solid into the reaction kettle, uniformly stirring, weighing 327.5g of cyclopropylamine, slowly adding the cyclopropylamine into the reaction kettle, and controlling the internal temperature to be 20-30 ℃ to react L h. 10kg of acetone and 25kg of purified water are weighed and slowly added into the reaction solution, and stirred and crystallized for 1-1.5h at the temperature of 20-35 ℃ after the acetone and the purified water are completely added. Centrifuging, vacuum drying the obtained solid at 50-55 ℃ for 8h, and collecting to obtain 2.3kg of white solid Ranuncutinib with the purity of 99.91% and the content of impurity C-1 of 0.03%.
Example 2
Adding 50.2kg of DMF into se:Sub>A 200L kettle, starting stirring, adding 5.3kg of crude product of the methanesulfonic acid lunvatinib compound 4 (containing 0.39% of C-A) into se:Sub>A reaction kettle, heating and stirring, raising the temperature to 65 ℃, dropwise adding 41.3kg of acetonitrile, controlling the dropwise adding temperature to be 55-65 ℃, finishing dropwise adding, keeping the temperature for lh, cooling, lowering the temperature to 40 ℃, keeping the temperature for lh, centrifuging, mixing the obtained solid with 41.3kg of acetonitrile, adding into se:Sub>A 100L reaction kettle, pulping at 25-35 ℃, stirring and washing for 0.5h, centrifuging, vacuum drying the obtained solid at 35-40 ℃ for 12h, collecting to obtain 4.9kg of similar white solid with the purity of 99.73%, wherein the impurity C-A is not detected.
Adding 53.2kg of dimethyl sulfoxide into a 200L reaction kettle, starting stirring, weighing 4.8kg of the off-white solid, adding the off-white solid into the reaction kettle, uniformly stirring, weighing 654.9g of cyclopropylamine, slowly adding the cyclopropylamine into the reaction kettle, and controlling the internal temperature to be 20-30 ℃ to react L h. 19.2kg of acetone and 48.4kg of purified water are weighed and slowly added into the reaction solution, and stirred and crystallized for 1-1.5h at the temperature of 20-35 ℃ after the acetone and the purified water are completely added. Centrifuging, vacuum drying the obtained solid at 50-55 deg.C for 8h, collecting to obtain 3.5kg white solid Ranvatinib with purity of 99.93%, and no impurity C-1.
Adding 38.0kg of dimethyl sulfoxide into a 100L reaction kettle, starting stirring, weighing 3.4kg of Rankine, adding into the reaction kettle, heating to 20-30 ℃, weighing 935.1g of methanesulfonic acid, slowly adding into the reaction kettle, and controlling the temperature of the adding process to be 20-30 ℃. After the reaction liquid is clarified, 170.0g of active carbon is added, and after 0.5h of stirring, the reaction liquid is subjected to pressure filtration to a 100L reaction kettle. 46.7kg of ethyl acetate is weighed and slowly added into the reaction solution, and the temperature is controlled between 10 and 20 ℃ in the adding process. Stirring and crystallizing for 2h after the addition is finished, centrifuging the obtained solid, drying the solid for 12h in vacuum at the temperature of 50-55 ℃, and collecting to obtain 4.4kg of white solid varlitinib mesylate with the purity of 99.93 percent and no impurity C-1 detected.
Example 3
284.5g of DMF is added into se:Sub>A 1L reaction bottle, stirring is started, 30.0g of crude product of the methanesulfonic acid lunvatinib compound 4 (containing 0.50 percent of C-A) is added into se:Sub>A reaction kettle, heating and stirring are carried out, the temperature is increased to 65 ℃, 234.0g of acetonitrile is dripped, the temperature is controlled to 65 ℃, dripping is finished, the temperature is reduced to 40 ℃ after lh is kept, lh is kept for suction filtration, the obtained solid is pulped with 234.0g of acetonitrile at 30 ℃, stirred and washed for 0.5h, suction filtration is carried out, the obtained solid is dried for 12h in vacuum at 40 ℃, and 25.7g of white-like solid is obtained, the purity is 99.70 percent, and the content of the impurity C-A is 0.02 percent.
277.1g of dimethyl sulfoxide is added into a 1L reaction bottle, stirring is started, 25.0g of the solid is weighed and added into the reaction liquid, after uniform stirring, 3.41g of cyclopropylamine is weighed and added into the reaction liquid, and the internal temperature is controlled at 30 ℃ for reaction of L h. 100.0g of acetone and 250.0g of purified water are weighed and slowly added into the reaction solution, and stirred and crystallized for 1 hour at 30 ℃ after the complete addition. And (3) carrying out suction filtration, and carrying out vacuum drying on the obtained solid at the temperature of 50-55 ℃ for 8h to obtain 17.6g of white solid Ranuncutinib, wherein the purity of the solid Ranuncutinib is 99.89%, and the content of impurity C-1 is 0.02%.
Adding 190.0g of dimethyl sulfoxide into a 500mL reaction bottle, starting stirring, weighing 17.0g of Rankine, adding into the reaction bottle, heating to 30 ℃, weighing 4.67g of methanesulfonic acid, slowly adding into the reaction liquid, and controlling the temperature of the adding process to be 20-30 ℃. After the reaction liquid is clarified, 0.85g of activated carbon is added, the mixture is stirred for 0.5h and then is filtered, the filtrate is stirred, 233.5g of ethyl acetate is slowly dripped into the filtrate, and the temperature is controlled to be 10-20 ℃ in the adding process. Stirring and crystallizing for 2h after adding, and vacuum drying the obtained solid for 12h at 50-55 ℃ by suction filtration to obtain 20.2g of white solid varlitinib mesylate, wherein the purity is 99.90 percent, and the content of impurity C-1 is 0.01 percent.
As described above, the above embodiments are only illustrative of the preferred embodiments of the present invention, and do not include all the scope of the invention. Various changes and modifications can be made by one skilled in the art without departing from the spirit and scope of the invention, and the scope of the invention is defined by the appended claims.
Claims (8)
1. A method for removing impurities in varlitinib mesylate is characterized by comprising the following steps:
(1) Adding phenyl (4- ((6-carbamoyl-7-methoxyquinolin-4-yl) oxy) -2-chlorophenyl) carbamate, an intermediate for preparing lenvatinib mesylate, to a 10-volume amount of a first solvent, and stirring with heating;
(2) Raising the temperature of the solution to 55-65 ℃, and dropwise adding a second solvent with the volume of 10 times of that of the intermediate, wherein the temperature is controlled to be 55-65 ℃;
(3) Keeping the temperature and stirring for l-2h after the dropwise adding is finished;
(4) After the heat preservation is finished, reducing the temperature to 25-45 ℃, preserving the heat for l-3h, carrying out suction filtration, stirring a filter cake by using a second solvent, and then carrying out suction filtration and vacuum drying to obtain a white-like product;
(5) The obtained off-white product was used for the preparation of varlitinib mesylate.
2. The method of claim 1, wherein the first solvent comprises one or more of N, N-dimethylformamide, N-dimethylacetamide, and methylacetamide.
3. The method of claim 1, wherein the second solvent comprises one or more of acetonitrile and ethyl acetate.
4. The method of claim 1, wherein the first solvent is N, N-dimethylformamide and the second solvent is acetonitrile.
5. The method according to claim 1, wherein the temperature of heating, dropping and reacting in the step (2) is 65 ℃.
6. The method according to claim 1, wherein the cooling and crystallization stirring in the step (4) is 35 ℃ to 45 ℃.
7. The method as claimed in claim 6, wherein the cooling and crystallization stirring in the step (4) is 40 ℃.
8. The method according to claim 1, wherein the prepared varlitinib mesylate has an impurity C-1 content of 0.05% or less or is not detected, and the impurity C-1 has the following chemical structural formula:
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| CN202211023662.1A CN115572261A (en) | 2022-08-22 | 2022-08-22 | Method for removing impurities of varlitinib mesylate |
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| CN202211023662.1A CN115572261A (en) | 2022-08-22 | 2022-08-22 | Method for removing impurities of varlitinib mesylate |
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