CN112645934A - Ostinib intermediate and refining method thereof - Google Patents
Ostinib intermediate and refining method thereof Download PDFInfo
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract
The invention relates to an Ostinib intermediate and a refining method thereof. The purification method of the Ostinib intermediate comprises the following steps: mixing a refined solvent and an Ostinib intermediate crude product, heating until the Ostinib intermediate crude product is dissolved, then cooling to separate out crystals, and collecting the crystals; the refined solvent is selected from one or more of 2-butanone, methyl isobutyl ketone and methyl tert-butyl ether; the Ostinib intermediate has a structure as shown in formula (1). Different from the conventional purification method, the method provided by the invention has the advantages that the crude product of the Ostinib intermediate is recrystallized by using a specific refined solvent, so that the purity of the Ostinib intermediate is effectively improved, the residue of a reactant can be obviously reduced, and a process byproduct is obviously reduced. The purity of the Ostinib intermediate can reach more than 99.8% through HPLC detection, and the limit of impurities is less than 0.1%.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparation synthesis, in particular to an Ostinib intermediate and a refining method thereof.
Background
Austenitib (Osimertinib), also known as austenitib, original factory name: tagrisso, chinese commodity name: tagares, AZD9291 is its development code. The chemical name is N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide, the molecular weight is 499.61, the molecular formula is C28 hours 33N7O2, and the chemical structural formula is as follows:
ostinib is a lung cancer therapeutic drug, is mainly applied to the lung cancer type non-small cell lung cancer (NSCLC) which is the most difficult to effectively treat, and is an oral, irreversible, third-generation EGFR inhibitor (EGFR-TKI). Because most of patients taking gefitinib (Iressa) and home-made Kernel and erlotinib hydrochloride (Tarceva) have T790M mutation after drug resistance, particularly, patients taking Iressa and Kernel generally have drug resistance after about one year, and some patients can take 3-5 years to have drug resistance, but the patients are few, most of patients have drug resistance within 1-2 years, and although the improvement can be realized by properly increasing the dosage and replacing erlotinib hydrochloride (Tarceva), the traditional treatment method does not last for a long time. The drug resistance time of erlotinib hydrochloride (Tarceva) is far shorter than that of Irceva, the drug resistance generally begins to be generated more than half a year, most patients have drug resistance between half a year and one year, and the effect of more than one year of erlotinib hydrochloride (Tarceva) administration is still obvious. However, Ostinib has a very obvious treatment effect after the advanced lung cancer patients taking the domestic Kaimeina, gefitinib (Iressa) and erlotinib hydrochloride (Tarceva) have resistance to an epidermal growth factor receptor tyrosine kinase (EGFR) inhibitor and the drug resistance of the T790M mutation of the gatekeeper residue, and the patients with the Ostinib have hopes. Compared to first-generation EGFR inhibitors (e.g., erlotinib, gefitinib, and erlotinib) and second-generation EGFR inhibitors (e.g., lenatinib, afatinib, and dacatinib), ostinib has more favorable physical properties (e.g., higher aqueous solubility, higher permeability, and/or lower plasma protein binding) and/or favorable toxicity profiles and/or favorable metabolic profiles.
In the step of synthesizing austenitib, the following steps will generally be included:
therefore, the compound with the structure shown in the formula (1) is an important intermediate for synthesizing the Ostinib.
However, when the ostinib intermediate having the structure represented by formula (1) is synthesized through the above-mentioned route, the compound having the structure represented by formula (2) and the compound having the structure represented by formula (3) remain in the product, and even if the product is purified through a purification process which is continuously repeated, it is still found that the residual amount of the compound having the structure represented by formula (2) is about 0.7% and the residual amount of the compound having the structure represented by formula (3) is about 1%, that is, the conventional purification process cannot remove the residual reactant in the product to make it reach 0.5% or less even through the continuous repetition. Meanwhile, some byproducts are produced in the above synthetic route, which affects the overall reaction efficiency of synthesizing austenib.
Disclosure of Invention
Based on the method, the invention provides a method for refining an Ostinib intermediate. Different from the conventional purification method, the crude product of the Ostinib intermediate is recrystallized by a specific refined solvent, so that the purity of the Ostinib intermediate is effectively improved, the residues of the compound with the structure shown in the formula (2) and the compound with the structure shown in the formula (3) can be remarkably reduced, and the process by-products are remarkably reduced. The purity of the Ostinib intermediate can reach more than 99.8% by HPLC detection.
The purification method of the Ostinib intermediate comprises the following steps:
mixing a refined solvent and an Ostinib intermediate crude product, heating until the Ostinib intermediate crude product is dissolved, then cooling to separate out crystals, and collecting the crystals;
the refined solvent is selected from one or more of 2-butanone, methyl isobutyl ketone and methyl tert-butyl ether;
the Ostinib intermediate has a structure as described in formula (1):
in one preferred embodiment, the refining solvent is selected from 2-butanone, methyl isobutyl ketone, methyl tert-butyl ether, a mixed solvent of methyl isobutyl ketone and methyl tert-butyl ether, or a mixed solvent of methyl isobutyl ketone and 2-butanone.
In one preferred embodiment, the temperature after the temperature rise is 50-60 ℃.
In one preferred embodiment, the temperature after the temperature rise is 55-60 ℃.
In one preferred embodiment, the temperature after cooling is 0-10 ℃.
In one preferred embodiment, the temperature after cooling is 6-8 ℃.
In one preferred embodiment, the mass-to-volume ratio of the crude austenib intermediate to the refined solvent is (1-2) g: (2-4) mL.
In one preferred embodiment, the preparation method of the crude austenib intermediate comprises the following steps:
mixing a compound with a structure shown in a formula (2) and a compound with a structure shown in a formula (3) in a solvent, and reacting for 4-8 hours at 60-100 ℃;
in one preferred embodiment, the solvent is selected from toluene.
The invention also provides an Ostinib intermediate.
The Ostinib is prepared by the refining method and has high purity.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, the Ostinib intermediate with the structure shown in the formula (1) is dissolved in the refined solvent through heating, then the temperature is reduced to precipitate crystals, the crude product of the Ostinib intermediate is recrystallized through the specific refined solvent, the purity of the Ostinib intermediate is effectively improved, the residues of the compound with the structure shown in the formula (2) and the compound with the structure shown in the formula (3) can be remarkably reduced, the residual amount of the compounds is less than 0.2%, and meanwhile, the process by-products can be remarkably reduced. The purity of the Ostinib intermediate can reach more than 99.8% through HPLC detection, and the limit of impurities is less than 0.1%.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the step of synthesizing austenitib, the following steps will generally be included:
therefore, the compound with the structure shown in the formula (1) is an important intermediate for synthesizing the Ostinib.
However, when the ostinib intermediate having the structure represented by formula (1) is synthesized through the above-mentioned route, the compound having the structure represented by formula (2) and the compound having the structure represented by formula (3) remain in the product, and even if the product is purified through a purification process which is continuously repeated, it is still found that the residual amount of the compound having the structure represented by formula (2) is about 0.7% and the residual amount of the compound having the structure represented by formula (3) is about 1%, that is, the conventional purification process cannot remove the residual reactant in the product to make it reach 0.5% or less even through the continuous repetition. Meanwhile, some byproducts are produced in the above synthetic route, which affects the overall reaction efficiency of synthesizing austenib.
The invention provides a refining method of an Ostinib intermediate.
The specific technical scheme is as follows:
a refining method of an Ostinib intermediate comprises the following steps:
mixing a refined solvent and an Ostinib intermediate crude product, heating until the Ostinib intermediate crude product is dissolved, then cooling to separate out crystals, and collecting the crystals;
the refined solvent is selected from one or more of 2-butanone, methyl isobutyl ketone and methyl tert-butyl ether;
the Ostinib intermediate has a structure as described in formula (1):
the inventor of the application finds that when the refined solvent is one or more selected from 2-butanone, methyl isobutyl ketone and methyl tert-butyl ether, the Ostinib intermediate with the structure shown in formula (1) is dissolved in the refined solvent by heating, then the temperature is reduced to precipitate crystals, and the crude Ostinib intermediate is recrystallized by using the specific refined solvent, so that the purity of the Ostinib intermediate is effectively improved, the residues of the compound with the structure shown in formula (2) and the compound with the structure shown in formula (3) can be remarkably reduced, the residual amount is less than 0.2%, and meanwhile, the process by-products can be remarkably reduced. The purity of the Ostinib intermediate can reach more than 99.8% through HPLC detection, and the limit of impurities is less than 0.1%.
By further optimizing the purification solvent, higher purity of the ostinib intermediate is favorably obtained. It is to be understood that the refining solvent may be a mixed solvent of the above solvents. The solvent is refined after mixing, which is also beneficial to improving the intermediate purity of the Ostinib.
In one preferred embodiment, the refining solvent is selected from 2-butanone, methyl isobutyl ketone, methyl tert-butyl ether, a mixed solvent of methyl isobutyl ketone and methyl tert-butyl ether, or a mixed solvent of methyl isobutyl ketone and 2-butanone.
Preferably, in the mixed solvent composed of methyl isobutyl ketone and methyl tert-butyl ether, the volume ratio of methyl isobutyl ketone to methyl tert-butyl ether is 4: (0.8-1.2).
Preferably, in the mixed solvent composed of methyl isobutyl ketone and 2-butanone, the volume ratio of methyl isobutyl ketone to 2-butanone is 4: (0.8-1.2).
In one preferred embodiment, the mass-to-volume ratio of the crude austenib intermediate product to the refined solvent is (1-2) g: (2-4) mL. It is understood that the mass-to-volume ratio of the crude austenib intermediate to the refined solvent includes, but is not limited to: 1 g: 2mL, 1.5 g: 2mL, 2 g: 2mL, 1 g: 2.5mL, 1.5 g: 2.5mL, 2 g: 2.5mL, 1 g: 3mL, 1.5 g: 3mL, 2 g: 3mL, 1 g: 3.5mL, 1.5 g: 3.5mL, 2 g: 3.5mL, 1 g: 4mL, 1.5 g: 4mL, 2 g: 4 mL. Further preferably, the mass-to-volume ratio of the crude austenib intermediate product to the refined solvent is 1 g: (2-2.5) mL.
In one preferred embodiment, the temperature after the temperature rise is 50-60 ℃.
After the temperature is raised, the crude product of the Ostinib intermediate is dissolved in the specific refined solvent, and understandably, a stirring step can be added in the process to play a role in accelerating the dissolution.
Furthermore, it is understood that the temperature after the temperature rise is based on the fact that the ostinib intermediate can be completely dissolved. The elevated temperature includes, but is not limited to: the temperature of the heating element is 50 degrees centigrade, 51 degrees centigrade, 52 degrees centigrade, 53 degrees centigrade, 54 degrees centigrade, 55 degrees centigrade, 56 degrees centigrade, 57 degrees centigrade, 58 degrees centigrade, 59 degrees centigrade and 60 degrees centigrade, and further preferably, the temperature after heating is 55 degrees centigrade to 60 degrees centigrade.
And (3) after the temperature is raised to completely dissolve the Ostinib intermediate, cooling to separate out crystals, wherein the cooling process is based on whether the crystals can be separated out or not.
In one preferred embodiment, the temperature after cooling is 0-10 ℃. It is understood that the reduced temperature includes, but is not limited to: 0 degree centigrade, 1 degree centigrade, 2 degrees centigrade, 3 degrees centigrade, 4 degrees centigrade, 5 degrees centigrade, 6 degrees centigrade, 7 degrees centigrade, 8 degrees centigrade, 9 degrees centigrade, 10 degrees centigrade, further preferably, the temperature after cooling is 6 degrees centigrade to 8 degrees centigrade.
It is understood that the time for precipitating crystals includes, but is not limited to, 0.5 hour, 1 hour, 1.5 hours.
It is understood that after the crystals are collected, the steps of suction filtration, reduced pressure drying and the like can also be included.
Preferably, the temperature of the reduced pressure drying is 40-60 degrees celsius, including but not limited to 40, 45, 50, 55, 60 degrees celsius.
In one preferred embodiment, the preparation method of the crude austenib intermediate comprises the following steps:
mixing a compound with a structure shown in a formula (2) and a compound with a structure shown in a formula (3) in a solvent, and reacting for 4-8 hours at 60-100 ℃;
in one preferred embodiment, the solvent is selected from toluene.
It is understood that, when the compound having the structure shown in formula (2) and the compound having the structure shown in formula (3) are reacted, the reaction temperature includes, but is not limited to: 60 degrees centigrade, 65 degrees centigrade, 70 degrees centigrade, 75 degrees centigrade, 80 degrees centigrade, 85 degrees centigrade, 90 degrees centigrade, 95 degrees centigrade, 100 degrees centigrade.
It is understood that, when the compound having the structure shown in formula (2) and the compound having the structure shown in formula (3) are reacted, the reaction time includes, but is not limited to: 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours.
An Ostinib intermediate is prepared by the refining method.
The Ostinib intermediate has high purity.
The following examples and comparative examples are further described below, and the starting materials used in the following examples can be commercially available, unless otherwise specified, and the equipment used therein can be commercially available, unless otherwise specified.
Example 1
The embodiment provides an ostinib intermediate and a refining method thereof, which comprises the following steps:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into 400mL of methyl isobutyl ketone, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ for crystallization for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 187g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 93.5%, and the purity of the Ostinib intermediate refined product is 99.8% and the maximum single impurity content is 0.03% by HPLC detection.
Example 2
This example provides an ostinib intermediate and its refining method, which is substantially the same as the steps of example 1, with the main difference that: different refined solvents are adopted, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into a mixed solvent consisting of 400mL of methyl isobutyl ketone and 100mL of methyl tert-butyl ether, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ to crystallize for 1 hour, performing suction filtration, and performing reduced pressure drying at 50 ℃ to obtain 180g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 90%, the purity of the Ostinib intermediate refined product is 99.8% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity is 0.04%.
Example 3
This example provides an ostinib intermediate and its refining method, which is substantially the same as the steps of example 1, with the main difference that: different refined solvents are adopted, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into a mixed solvent consisting of 400mL of methyl isobutyl ketone and 100mL of 2-butanone, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ to crystallize for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 179g of a red crystal refined product, namely the Ostinib intermediate refined product, wherein the yield is 89.5%, the purity of the Ostinib intermediate refined product is 99.9% by HPLC detection, and the maximum single impurity is 0.04%.
Example 4
This example provides an ostinib intermediate and its refining method, which is substantially the same as the steps of example 1, with the main difference that: different refined solvents are adopted, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into 400mL of 2-butanone, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ to crystallize for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 186g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 93%, and the purity of the Ostinib intermediate refined product is 99.9% and the maximum single impurity content is 0.06% by HPLC detection.
Example 5
This example provides an ostinib intermediate and its refining method, which is substantially the same as the steps of example 1, with the main difference that: different refined solvents are adopted, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into 400mL of methyl tert-butyl ether, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ for crystallization for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 176g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 88%, and the purity of the Ostinib intermediate refined product is 99.8% and the maximum single impurity is 0.08% by HPLC detection.
Example 6
This example provides an ostinib intermediate and its refining method, which is substantially the same as the steps of example 1, with the main difference that: the dosage of the refined solvent is different, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into 800mL of methyl isobutyl ketone, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ for crystallization for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 160g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 80%, and the purity of the Ostinib intermediate refined product is 99.9% and the maximum single impurity content is 0.05% by HPLC detection.
Example 7
This example provides an ostinib intermediate and its refining method, which is substantially the same as the steps of example 1, with the main difference that: the temperature after cooling is different, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into 400mL of methyl isobutyl ketone, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 5 ℃ to crystallize for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 150g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 75%, and the purity of the Ostinib intermediate refined product is 99.8% and the maximum single impurity is 0.06% by HPLC detection.
Comparative example 1
The comparative example provides an Ostinib intermediate and a refining method thereof, which are basically the same as the steps of example 1, and mainly have the following differences: different refined solvents are adopted, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into 400mL of isopropyl ether, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ to crystallize for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 180g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 90%, and the purity of the Ostinib intermediate refined product is 97.5% and the maximum single impurity is 0.8% by HPLC detection.
Comparative example 2
The comparative example provides an Ostinib intermediate and a refining method thereof, which are basically the same as the steps of example 1, and mainly have the following differences: different refined solvents are adopted, and the specific steps are as follows:
step 1) synthesizing crude product of Ostinib intermediate
Adding 250g of the compound with the structure shown in the formula (2), 86.1g of the compound with the structure shown in the formula (3) and 2000mL of toluene into a three-necked flask, reacting for 6 hours at 80 ℃ to obtain crude product of the Ostinib intermediate, wherein the purity of the crude product of the Ostinib intermediate is 96.9% by HPLC detection, and the synthetic route is as follows:
step 2) crude product refining
Adding 200g of the crude Ostinib intermediate prepared in the step 1) into 400mL of ethyl acetate, heating to 59 ℃ to dissolve the crude Ostinib intermediate, cooling to 7 ℃ for crystallization for 1 hour, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 176g of red crystallized refined product, namely the Ostinib intermediate refined product, wherein the yield is 88%, and the purity of the Ostinib intermediate refined product is 97.8% and the maximum single impurity is 0.9% as detected by HPLC.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A refining method of an Ostinib intermediate is characterized by comprising the following steps:
mixing a refined solvent and an Ostinib intermediate crude product, heating until the Ostinib intermediate crude product is dissolved, then cooling to separate out crystals, and collecting the crystals;
the refined solvent is selected from one or more of 2-butanone, methyl isobutyl ketone and methyl tert-butyl ether;
the Ostinib intermediate has a structure as described in formula (1):
2. the process for refining an Ostinib intermediate according to claim 1, wherein the refining solvent is selected from the group consisting of 2-butanone, methyl isobutyl ketone, methyl tert-butyl ether, a mixed solvent of methyl isobutyl ketone and methyl tert-butyl ether, and a mixed solvent of methyl isobutyl ketone and 2-butanone.
3. The method for refining an Ostinib intermediate according to claim 1, wherein the temperature after the temperature rise is 50-60 ℃.
4. The method for refining an Ostinib intermediate according to claim 3, wherein the temperature after the temperature rise is 55-60 ℃.
5. The method for refining an Ostinib intermediate according to claim 1, wherein the temperature after cooling is 0-10 ℃.
6. The method for refining an Ostinib intermediate according to claim 5, wherein the temperature after cooling is 6-8 ℃.
7. The method for purifying an Ostinib intermediate according to claim 1, wherein the mass-to-volume ratio of the crude Ostinib intermediate to the purification solvent is (1-2) g: (2-4) mL.
8. The method for purifying an Ostinib intermediate according to any one of claims 1-7, wherein the method for preparing the crude Ostinib intermediate comprises the following steps:
mixing a compound with a structure shown in a formula (2) and a compound with a structure shown in a formula (3) in a solvent, and reacting for 4-8 hours at 60-100 ℃;
9. the process for refining an Ostinib intermediate according to claim 8, wherein the solvent is selected from toluene.
10. An ostinib intermediate, characterized by being prepared by the purification method of any one of claims 1-9.
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