CN115433135A - Gefitinib refining method - Google Patents
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- CN115433135A CN115433135A CN202211209202.8A CN202211209202A CN115433135A CN 115433135 A CN115433135 A CN 115433135A CN 202211209202 A CN202211209202 A CN 202211209202A CN 115433135 A CN115433135 A CN 115433135A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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Abstract
The invention belongs to the technical field of preparation of chemical raw material medicines, and particularly relates to a gefitinib refining method. The invention provides a gefitinib refining method which comprises the following steps: heating and mixing the gefitinib crude product, the low-carbon alcohol solvent, water and a decolorizing agent to obtain a mixed feed liquid; carrying out first solid-liquid separation on the mixed feed liquid to obtain a liquid phase component; cooling and crystallizing the liquid phase component, and performing second solid-liquid separation to obtain a gefitinib-alcohol compound; mixing and pulping the gefitinib-alcohol compound and an ester organic solvent to obtain a gefitinib solution; and (3) cooling and recrystallizing the gefitinib solution, and carrying out third solid-liquid separation to obtain the gefitinib fine product. The refining method provided by the invention is beneficial to reducing the organic solvent residue in the refined gefitinib and improving the purity and yield of the refined gefitinib. The refining method provided by the invention is simple to operate, reduces the using amount of non-alcohol organic solvents, is green and environment-friendly, reduces the environmental protection pressure and reduces the production cost.
Description
Technical Field
The invention belongs to the technical field of preparation of raw material medicaments, and particularly relates to a gefitinib refining method.
Background
The preparation process of the bulk drug, especially the process scheme of the last step of refining in the clean zone, is crucial to the control of the quality parameters of the bulk drug, such as: the yield and purity of the raw material medicine, the control of solvent residue and the like, and the parameters not only influence the stability of the raw material medicine, but also have key influence on indexes such as safety, bioavailability and the like.
Gefitinib (structural formula shown in formula 1) is used as an oral antitumor drug, and the quality of raw materials such as yield, purity, residual solvent and the like are key points of quality research, and directly influence the market application of gefitinib and the treatment effect on patients.
However, the existing gefitinib refining process generally comprises the steps of placing a gefitinib crude product in dimethyl sulfoxide and ethyl acetate to obtain a gefitinib solvate, and then removing the solvate, but the obtained gefitinib raw material has low purity, and cannot obtain a gefitinib raw material drug product with the purity of more than 99.9%.
Disclosure of Invention
The invention aims to provide a gefitinib refining method, which is high in purity and yield of the gefitinib fine product, simple to operate, green and environment-friendly.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides a gefitinib refining method, which comprises the following steps:
heating and mixing the gefitinib crude product, the low-carbon alcohol solvent, water and a decolorizing agent to obtain a mixed feed liquid;
carrying out first solid-liquid separation on the mixed feed liquid to obtain a liquid phase component;
cooling and crystallizing the liquid phase component, and performing second solid-liquid separation to obtain a gefitinib-alcohol compound;
mixing and pulping the gefitinib-alcohol compound and an ester organic solvent to obtain a gefitinib solution;
and (3) cooling and recrystallizing the gefitinib solution, and carrying out third solid-liquid separation to obtain the gefitinib fine product.
Preferably, the low-carbon alcohol solvent comprises one or more of methanol, ethanol and isopropanol;
the volume ratio of the low-carbon alcohol solvent to the water is (1-5) to 1.
Preferably, the mass ratio of the gefitinib crude product to the water is 1 (2-4).
Preferably, the decolorizing agent is activated carbon; the mass ratio of the decoloring agent to the gefitinib crude product is (0.005-0.1): 1.
Preferably, the temperature for heating and mixing is 60-80 ℃; the temperature of the mixed material liquid for the first solid-liquid separation is 60-80 ℃.
Preferably, the heat preservation temperature of the cooling crystallization is-20 to 50 ℃; the heat preservation time of the cooling crystallization is 1-2 h.
Preferably, the ester organic solvent comprises one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate and ethyl propionate;
the ratio of the volume of the ester organic solvent to the mass of the gefitinib crude product is (3-10) mL:1g.
Preferably, the temperature of the mixing and pulping is 20-85 ℃; the heat preservation time of the mixing and pulping is 1-2 h.
Preferably, the temperature of the temperature reduction recrystallization is-20 to 50 ℃; the temperature reduction recrystallization heat preservation time is 2-3 h.
Preferably, the step of obtaining a gefitinib wet refined product after the third solid-liquid separation further comprises drying the refined gefitinib crystal wet product to obtain the gefitinib refined product; the drying temperature is 60-80 ℃, and the drying heat preservation time is 4-8 h.
The invention provides a gefitinib refining method, which comprises the following steps: heating and mixing the gefitinib crude product, the low-carbon alcohol solvent, water and a decolorizing agent to obtain a mixed feed liquid; carrying out first solid-liquid separation on the mixed feed liquid to obtain a liquid phase component; cooling and crystallizing the liquid phase component, and performing second solid-liquid separation to obtain a gefitinib-alcohol compound; mixing and pulping the gefitinib-alcohol compound and an ester organic solvent to obtain a gefitinib solution; and (3) cooling and recrystallizing the gefitinib solution, and carrying out third solid-liquid separation to obtain the gefitinib fine product. The refining method provided by the invention comprises the steps of firstly, cooling and crystallizing gefitinib in a mixed solvent of low-carbon alcohol and water to obtain gefitinib-alcohol compound; then cooling and recrystallizing the gefitinib-alcohol compound in an ester organic solvent, and removing solvent to obtain a gefitinib fine product; compared with the gefitinib solvate obtained in dimethyl sulfoxide and ethyl acetate in the prior art, the gefitinib-alcohol intermediate product is generated by the refining method provided by the invention, so that the organic solvent residue in the refined gefitinib is reduced, and the purity and yield of the refined gefitinib are improved. The results of the embodiment show that the purity of the refined gefitinib obtained by the refining method provided by the invention is more than or equal to 99.95%, and the yield is more than 70%. The refining method provided by the invention is simple to operate, reduces the using amount of non-alcohol organic solvents, is green and environment-friendly, reduces the environmental protection pressure and reduces the production cost.
Drawings
FIG. 1 is an HPLC profile of crude gefitinib prepared in example 1;
FIG. 2 is an HPLC profile of a fine gefitinib product obtained in example 1;
FIG. 3 is an HPLC profile of a fine gefitinib product obtained in example 2;
FIG. 4 is an HPLC profile of a fine gefitinib product obtained in example 3;
FIG. 5 is an HPLC chromatogram of the refined gefitinib obtained in comparative example 1;
fig. 6 is an XRD pattern of the fine bulk drug of gefitinib obtained in example 1;
figure 7 is an XRD pattern of gefitinib medicinal crystal form reported in patent CN 100404032C.
Detailed Description
The invention provides a gefitinib refining method, which comprises the following steps:
heating and mixing a gefitinib crude product, a low-carbon alcohol solvent, water and a decolorizing agent to obtain a mixed feed liquid;
carrying out first solid-liquid separation on the mixed feed liquid to obtain a liquid phase component;
cooling and crystallizing the liquid phase component, and performing second solid-liquid separation to obtain a gefitinib-alcohol compound;
mixing and pulping the gefitinib-alcohol compound and an ester organic solvent to obtain a gefitinib solution;
and (3) cooling and recrystallizing the gefitinib solution, and carrying out third solid-liquid separation to obtain the gefitinib fine product.
In the present invention, all the preparation starting materials/components are commercially available products well known to those skilled in the art unless otherwise specified.
The method comprises the step of heating and mixing a gefitinib crude product, a low-carbon alcohol solvent, water and a decolorizing agent to obtain a mixed feed liquid.
The invention has no special requirement on the source of the crude gefitinib product.
In a specific embodiment of the present invention, the method for preparing the crude gefitinib preferably comprises the following steps:
mixing 7-methoxy-6- (3-morpholine-4-ylpropoxy) quinazoline-4 (3H) -ketone, oxalyl chloride and an organic solvent to perform chlorination reaction to obtain a chlorinated intermediate product;
mixing the alcoholic solution of the chlorinated intermediate product with the alcoholic solution of 3-chloro-4-fluoroaniline to carry out substitution reaction, and mixing the reaction solution obtained by the substitution reaction with hydrochloric acid to obtain gefitinib hydrochloride;
and dissolving the gefitinib hydrochloride in an alcohol-water mixed solvent, and carrying out crystallization reaction under an alkaline condition to obtain the gefitinib crude product.
The invention mixes 7-methoxy-6- (3-morpholine-4-yl propoxy) quinazoline-4 (3H) -ketone, oxalyl chloride and organic solvent to generate chlorination reaction, and obtains a chlorinated intermediate product.
In the present invention, the mass ratio of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazolin-4 (3H) -one to oxalyl chloride is preferably 0.7.
In the present invention, the organic solvent is preferably a mixed solvent of chloroform and N, N-Dimethylformamide (DMF), and the mass ratio of chloroform to DMF is preferably 74.
In the present invention, the mass ratio of DMF to oxalyl chloride is preferably 1:5.
In the invention, the temperature of the chlorination reaction is preferably-20-30 ℃; the incubation time for the chlorination reaction is preferably 5 hours.
In the invention, the chlorination reaction obtains a chlorination reaction liquid, and the chlorination reaction liquid is preferably subjected to post-treatment to obtain the chlorination intermediate product. In the present invention, the post-treatment preferably comprises: sequentially carrying out: washing and organic phase removal of the reaction solvent. In the present invention, the washing solvent is preferably an aqueous sodium bicarbonate solution. The embodiment for removing the reaction solvent is preferably concentration, and the present invention has no particular requirement for the specific implementation process of the concentration.
Obtaining a chlorinated intermediate product; mixing an alcoholic solution of the chlorinated intermediate product and an alcoholic solution of 3-chloro-4-fluoroaniline to perform substitution reaction, and mixing a reaction solution obtained by the substitution reaction with hydrochloric acid to obtain gefitinib hydrochloride;
in the present invention, the alcoholic solution of the chlorinated intermediate is particularly preferably an isopropanol solution of the chlorinated intermediate.
In the present invention, the alcohol solution of 3-chloro-4-fluoroaniline is particularly preferably an isopropanol-soluble solution of 3-chloro-4-fluoroaniline.
In the present invention, the mass ratio of the oxalyl chloride to the 3-chloro-4-fluoroaniline is preferably 10.
In the present invention, the temperature of the substitution reaction is 40 to 60 ℃, and the heat-preserving time of the substitution reaction is preferably 3 hours.
In the present invention, the mass concentration of the hydrochloric acid is preferably 36%.
The method has no special requirement on the dosage of the hydrochloric acid, and the product obtained by the substitution reaction is completely converted into the gefitinib hydrochloride.
In the present invention, after the reaction solution obtained by the substitution reaction is mixed with hydrochloric acid, the gefitinib hydrochloride is preferably obtained by solid-liquid separation and then drying. In the present invention, the solid-liquid separation is particularly preferably filtration or centrifugation.
After gefitinib hydrochloride is obtained, the gefitinib hydrochloride is dissolved in an alcohol-water mixed solvent, and crystallization reaction is carried out under an alkaline condition to obtain a gefitinib crude product.
In the invention, the alcohol-water mixed solvent is preferably a mixed solvent of ethanol and water, the mass ratio of the ethanol to the water is preferably 1:1,
in the invention, the alkaline condition is preferably that the pH value of a solution formed by dissolving the gefitinib hydrochloride in the alcohol-water mixed solvent is regulated to be more than or equal to 8 by using sodium hydroxide.
In the present invention, the temperature of the crystallization reaction is preferably-20 to 20 ℃, and the holding time of the crystallization reaction is preferably 2 hours.
In the invention, the crystallization reaction is carried out to obtain a crystallization reaction liquid, and the crystallization reaction liquid is preferably subjected to post-treatment to obtain the crude product of gefitinib. In the present invention, the post-treatment preferably comprises: solid-liquid separation and drying, wherein the solid-liquid separation is particularly preferably centrifugation, and the drying process is not particularly required.
In the present invention, the lower alcohol solvent preferably includes one or more of methanol, ethanol and isopropanol, more preferably methanol, ethanol or isopropanol.
In the present invention, the volume ratio of the lower alcohol to water is preferably (1 to 5): 1, more preferably (2.5 to 4.5): 1.
In the invention, the mass ratio of the gefitinib crude product to the water is preferably 1 (2-4), more preferably 1 (2.1-3.5).
In the present invention, the decoloring agent is specifically preferably activated carbon.
In the invention, the mass ratio of the decolorizing agent to the crude gefitinib is preferably (0.005-0.1): 1, more preferably (0.01-0.08): 1.
In the present invention, the temperature for the heating and mixing is 60 to 80 ℃, more preferably 70 to 78 ℃.
In the present invention, the heating and mixing preferably includes the steps of: mixing the gefitinib crude product, a low-carbon alcohol solvent and water to obtain a gefitinib crude product solution; and mixing the crude gefitinib solution with a decoloring agent. In the invention, after the gefitinib crude product solution and the decolorizing agent are mixed, the stirring, the heat preservation and the stirring are preferably continued for 0.5h.
After the mixed material liquid is obtained, the mixed material liquid is subjected to first solid-liquid separation to obtain a liquid phase component.
In the present invention, the temperature of the first solid-liquid separation of the mixed material liquid is preferably 60 to 80 ℃.
In the present invention, the first solid-liquid separation embodiment is preferably centrifugation or filtration.
After the liquid phase component is obtained, the temperature of the liquid phase component is reduced for crystallization, and the gefitinib-alcohol compound is obtained through second solid-liquid separation.
In the invention, the temperature of the cooling crystallization is preferably-20 to 50 ℃, and more preferably 0 to 10 ℃.
In the present invention, the temperature-decreasing crystallization is preferably maintained for 1 to 2 hours, and more preferably for 1 hour or 2 hours.
In the present invention, the second solid-liquid separation embodiment is preferably centrifugation or filtration.
After the gefitinib-alcohol compound is obtained, the gefitinib-alcohol compound and an ester organic solvent are mixed and pulped to obtain a gefitinib solution.
In the present invention, the ester-based organic solvent preferably includes one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate and ethyl propionate, and more preferably ethyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate or ethyl propionate.
In the invention, the ratio of the volume of the ester organic solvent to the mass of the gefitinib crude product is preferably (3-10) mL to 1g, and more preferably (3.2-9.5) mL to 1g.
In the invention, the mixing and beating temperature is preferably 20-85 ℃, and more preferably 40-80 ℃.
In the invention, the holding time of the mixing and beating is preferably 1-2 h, and more preferably 1h.
In the invention, the mixing and pulping are preferably carried out under the condition of stirring, and the invention has no special requirements on the specific implementation process of the stirring.
After the gefitinib solution is obtained, the gefitinib solution is cooled and recrystallized, and the gefitinib fine product is obtained after the third solid-liquid separation.
In the invention, the temperature of the temperature reduction recrystallization is preferably-20 to 50 ℃, and more preferably 10 to 30 ℃.
In the present invention, the temperature-reducing recrystallization is preferably carried out for 2 to 3 hours, more preferably for 2 hours.
In the invention, the temperature-reducing recrystallization is preferably carried out under the condition of stirring, and the invention has no special requirement on the specific implementation process of stirring.
In the invention, the third solid-liquid separation after the temperature reduction and recrystallization is carried out to obtain the gefitinib wet refined product, preferably, the invention also comprises the step of drying the gefitinib wet refined product to obtain the gefitinib refined product; the drying temperature is preferably 60-80 ℃, and the drying heat preservation time is preferably 4-8 h.
According to the refining method of the refined gefitinib, provided by the invention, the gefitinib crude product is decolored by active carbon, crystallized by cooling and centrifuged in a mixed solvent of low-carbon alcohol and water to obtain a corresponding gefitinib-alcohol compound, and the gefitinib-alcohol compound is directly desolvated by ethyl acetate without being dried, crystallized by cooling, centrifuged and dried to obtain a gefitinib refined product.
In order to further illustrate the present invention, the following detailed description of the technical solutions provided by the present invention is made with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of the present invention.
Example 1
100L of chloroform, 2kgN, N-Dimethylformamide (DMF) and 7kg of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazolin-4 (3H) -one (CAS: 199327-61-2) were placed in a 200L reactor, 10kg of oxalyl chloride was added, and the temperature was raised to 30 ℃ for reaction for 5 hours. After the reaction, adding 120kg of sodium bicarbonate water solution into the reaction solution at room temperature for washing, concentrating the organic phase to remove the organic solvent, adding 21kg of isopropanol, heating to 40 ℃, adding 3.42kg of isopropanol solution of 3-chloro-4-fluoroaniline, and keeping the temperature at 50 ℃ for reaction for 3 hours until the reaction is complete. After the reaction, 1.7kg of hydrochloric acid is added to obtain a gefitinib hydrochloride wet product, and the gefitinib hydrochloride is dried to obtain gefitinib hydrochloride.
Adding gefitinib hydrochloride into a mixed solvent of 40kg ethanol and 40kg water, heating to dissolve, adding sodium hydroxide aqueous solution, adjusting pH to be not less than 8, crystallizing at room temperature for 2h, centrifuging, taking a solid product and drying to obtain a white-like gefitinib crude product, wherein the yield is 80.5%, and the purity is 97.30%. The HPLC profile of the crude gefitinib prepared in this example is shown in fig. 1.
Adding 30kg of methanol and 10kg of purified water into a 200L reaction kettle, adding 5kg of gefitinib crude product, heating to 70-75 ℃, adding 250g of activated carbon after dissolution, continuously keeping the temperature and stirring for 0.5h, carrying out hot filtration, stirring and cooling filtrate to 0-10 ℃, keeping the temperature and stirring for crystallization for 2h, and centrifuging to obtain a gefitinib-methanol compound wet product;
and adding the obtained gefitinib-methanol compound wet product into 50L ethyl acetate, heating to 45 ℃, keeping the temperature and stirring for 2h, cooling to 20-30 ℃, keeping the temperature and crystallizing for 2h, centrifuging, and drying the solid product at 60 ℃ for 8h to obtain 4.22kg of gefitinib refined product with the purity of 99.97 percent and the yield of 84.4 percent. The HPLC pattern of the gefitinib fine product prepared in the embodiment is shown in figure 2, and the XRD pattern is shown in figure 6. Fig. 6 is an XRD pattern of the fine bulk drug of gefitinib obtained in example 1; FIG. 7 is XRD pattern of pharmaceutical crystal form of gefitinib reported in patent CN 100404032C; the consistency between the crystal form of the gefitinib fine product prepared by the embodiment of the present invention and the pharmaceutical crystal form reported in the original research can be obtained by comparing fig. 6 and fig. 7.
Example 2
Preparing a crude gefitinib product according to the method of example 1;
adding 400mL of ethanol and 100mL of purified water into a reaction bottle, adding 25g of gefitinib crude product, heating to 78 ℃ for dissolving, adding 2.5g of activated carbon, stirring at a constant temperature for 0.5h, carrying out hot filtration, stirring the filtrate, cooling to 0 ℃, stirring at a constant temperature for crystallization for 1h, and carrying out suction filtration to obtain a gefitinib-ethanol compound wet product;
adding the obtained gefitinib-ethanol compound wet product into 250mL ethyl acetate, heating to 60 ℃, stirring for 1h under heat preservation, cooling to 10 ℃, crystallizing for 2h under heat preservation, filtering, drying the solid product for 4h at 80 ℃ to obtain 18.80g gefitinib fine product, wherein the yield is 75.2%, and the purity is 99.95%. The HPLC profile of the gefitinib fine product prepared in this example is shown in fig. 3.
Example 3
Preparing a crude gefitinib product according to the method of example 1;
adding 300mL of isopropanol and 100mL of purified water into a reaction bottle, adding 25g of gefitinib crude product, heating to 78 ℃ for dissolving, adding 1.25g of activated carbon, stirring for 0.5 hour under heat preservation, carrying out hot filtration, cooling the filtrate to 0 ℃, stirring for crystallization for 1 hour under heat preservation, and carrying out suction filtration to obtain a gefitinib-isopropanol compound wet product;
and adding the obtained gefitinib-isopropanol compound wet product into 250mL of isopropyl acetate, heating to 80 ℃, keeping the temperature and stirring for 1h, cooling to 10 ℃, crystallizing for 2h, performing suction filtration, and drying a solid product for 4h at 80 ℃ to obtain 17.56g of gefitinib fine product, wherein the yield is 70.2%, and the purity is 99.95%. The HPLC profile of the gefitinib fine product prepared in this example is shown in fig. 4.
Comparative example 1
Refer to chinese patent CN102030722B, example 3 and example 4: adding 10g of crude gefitinib into 9mLDMSO and 60mL of ethyl acetate, adding 2g of diatomite, heating to 74 ℃ to prepare gefitinib-DMSO solvate, adding the gefitinib-DMSO solvate into 40mL of ethyl acetate, heating to remove the solvate, cooling to 0 ℃ for crystallization, performing suction filtration, and drying a filter cake to obtain refined gefitinib with the purity of 99.65% and the maximum unknown single impurity content of 0.16%. The HPLC profile of the fine gefitinib product prepared by the comparative example is shown in FIG. 5.
By analyzing HPLC profiles of the products prepared in examples 1 to 3 and comparative example 1, it can be concluded that: the refining method disclosed in chinese patent CN102030722B has low purity, and cannot obtain gefitinib-qualified raw material drug (API) product, and the product prepared in comparative example 1 needs to be further subjected to crystal transformation to continue to be made into a pharmaceutical crystal form, which increases production processes and potentially introduces operational risks, thereby causing lot-to-lot variation or unqualified products. The gefitinib raw material drug with correct crystal form and qualification can be obtained by the method provided by the embodiment of the application at one time.
Although the above embodiments have been described in detail, they are only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and all of the embodiments belong to the protection scope of the present invention.
Claims (10)
1. A gefitinib refining method is characterized by comprising the following steps:
heating and mixing a gefitinib crude product, a low-carbon alcohol solvent, water and a decolorizing agent to obtain a mixed feed liquid;
carrying out first solid-liquid separation on the mixed feed liquid to obtain a liquid phase component;
cooling and crystallizing the liquid phase component, and performing second solid-liquid separation to obtain a gefitinib-alcohol compound;
mixing and pulping the gefitinib-alcohol compound and an ester organic solvent to obtain a gefitinib solution;
and (3) cooling and recrystallizing the gefitinib solution, and carrying out third solid-liquid separation to obtain the gefitinib fine product.
2. The refining method of claim 1, wherein the low-carbon alcohol solvent comprises one or more of methanol, ethanol, and isopropanol;
the volume ratio of the low-carbon alcohol solvent to the water is (1-5) to 1.
3. The refining method according to claim 1 or 2, wherein the mass ratio of the gefitinib crude product to the water is 1 (2-4).
4. The refining method of claim 1 or 3, wherein the decolorizing agent is activated carbon; the mass ratio of the decoloring agent to the gefitinib crude product is (0.005-0.1): 1.
5. The refining method according to claim 1, wherein the temperature for heating and mixing is 60 to 80 ℃; the temperature of the mixed material liquid for the first solid-liquid separation is 60-80 ℃.
6. The refining method according to claim 1 or 5, wherein the temperature of the temperature-decreasing crystallization is-20 to 50 ℃; the heat preservation time of the cooling crystallization is 1-2 h.
7. The refining method according to claim 1, wherein the ester-based organic solvent includes one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, and ethyl propionate;
the ratio of the volume of the ester organic solvent to the mass of the gefitinib crude product is (3-10) mL:1g.
8. The refining method of claim 1, wherein the temperature of the mixing and beating is 20-85 ℃; the heat preservation time of the mixing and pulping is 1-2 h.
9. The refining method according to claim 1 or 8, wherein the temperature of the temperature-decreasing recrystallization is maintained at-20 to 50 ℃; the temperature reduction recrystallization heat preservation time is 2-3 h.
10. The refining method of claim 1, wherein the third solid-liquid separation is performed to obtain a gefitinib wet refined product, further comprising drying the refined gefitinib crystal wet product to obtain the gefitinib fine product; the drying temperature is 60-80 ℃, and the drying heat preservation time is 4-8 h.
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| CN104693127A (en) * | 2015-02-14 | 2015-06-10 | 齐鲁制药有限公司 | Gefitinib ethylene glycol solvate as well as preparation method and application thereof |
| CN105399688A (en) * | 2015-12-02 | 2016-03-16 | 西南科技大学 | Gefitinib preparation method |
| CN107098863A (en) * | 2017-05-26 | 2017-08-29 | 重庆莱美隆宇药业有限公司 | A kind of preparation method of Gefitinib |
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| CN111533703A (en) * | 2020-05-07 | 2020-08-14 | 山东安弘制药有限公司 | Gefitinib purification process |
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