CN111533703A - Gefitinib purification process - Google Patents
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- CN111533703A CN111533703A CN202010377190.4A CN202010377190A CN111533703A CN 111533703 A CN111533703 A CN 111533703A CN 202010377190 A CN202010377190 A CN 202010377190A CN 111533703 A CN111533703 A CN 111533703A
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- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 83
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 83
- 238000000746 purification Methods 0.000 title claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000012065 filter cake Substances 0.000 claims abstract description 31
- 238000001914 filtration Methods 0.000 claims abstract description 29
- 238000003756 stirring Methods 0.000 claims abstract description 28
- QSDWDQNREXOYPH-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroisoquinolin-4-yl)ethanol Chemical compound C1=CC=C2C(CCO)CNCC2=C1 QSDWDQNREXOYPH-UHFFFAOYSA-N 0.000 claims abstract description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 22
- 238000001816 cooling Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000002425 crystallisation Methods 0.000 claims abstract description 19
- 230000008025 crystallization Effects 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 18
- PIAZYBLGBSMNLX-UHFFFAOYSA-N 4-(3-chloropropyl)morpholine Chemical compound ClCCCN1CCOCC1 PIAZYBLGBSMNLX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 11
- 239000011780 sodium chloride Substances 0.000 claims abstract description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 12
- 238000005185 salting out Methods 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 239000003518 caustics Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 22
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003513 alkali Substances 0.000 abstract description 6
- 238000005406 washing Methods 0.000 abstract description 5
- 230000000052 comparative effect Effects 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- QUINXWLATMJDQF-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine;hydrochloride Chemical compound Cl.C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 QUINXWLATMJDQF-UHFFFAOYSA-N 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D239/94—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a gefitinib purification process, which comprises the following steps: adding potassium carbonate, potassium iodide and gefitinib intermediate 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol into N, N-dimethylformamide, stirring, heating to 70 ℃, adding N- (3-chloropropyl) morpholine, and reacting to obtain gefitinib reaction liquid; adding dilute hydrochloric acid into the gefitinib reaction liquid, cooling to room temperature, adding sodium chloride, stirring for crystallization, filtering to obtain a filter cake, adding the filter cake into a sodium bicarbonate solution, washing with alkali, and recrystallizing the obtained product in ethanol to obtain the high-purity gefitinib. The purification method provided by the invention is simple in process, and the obtained gefitinib product is high in purity.
Description
Technical Field
The invention relates to a gefitinib purification process, and belongs to the technical field of drug refinement.
Background
Gefitinib, a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor developed by astrazeneca, is suitable for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) which has been previously treated with chemotherapy or is not suitable for chemotherapy, and is the first small-molecule protein tyrosine kinase inhibitor targeted anticancer drug for treating solid tumors. The chemical name of the compound is N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline-4-amine, and the structure is shown as the formula I:
the gefitinib medicament for the first-line, second-line and third-line treatment of locally advanced or metastatic non-small cell lung cancer is large in dosage and relatively expensive, so that the safety and the refining process of the medicament are very important. In order to obtain a high-purity gefitinib product, the Chinese patent document CN103012290A adds a gefitinib crude product into ethanol, performs reflux dissolution, cools to-5 ℃, centrifuges, and dries to obtain a gefitinib pure product with the purity of more than 99.9 percent, but the method has larger ethanol consumption and more waste liquid; and the crystallization temperature is lower, and the energy consumption is higher. The chinese patent document CN102584720A is to add crude gefitinib into a formamide solvent mixture to be heated and dissolved, then cool and crystallize to prepare formamide solvate, and perform deamidation in ethyl acetate to prepare high-purity gefitinib, but the above method has the disadvantages of low process stability, incomplete crystallization, difficult solvent recovery, and the like, and is not suitable for large-scale production.
Therefore, there is an urgent need to develop a gefitinib purification process with simple and safe process and high product purity.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a gefitinib purification process, which comprises three procedures of salt-forming salting-out, alkali washing and ethanol recrystallization.
Description of terms:
room temperature: having a meaning well known in the art, typically 25. + -. 5 ℃.
Gefitinib: the chemical name of the compound is N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline-4-amine, and the structural formula is shown as a formula I.
Gefitinib intermediate: the chemical name is 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol, and the structural formula is shown as a formula II.
The structural formula of the N- (3-chloropropyl) morpholine is shown as a formula III.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a gefitinib purification process comprises the following steps:
(1) salt-forming salting-out of gefitinib
Adding potassium carbonate, potassium iodide and gefitinib intermediate into N, N-dimethylformamide, stirring and heating to 70 ℃, adding N- (3-chloropropyl) morpholine, and reacting to obtain gefitinib reaction liquid; adding dilute hydrochloric acid into the gefitinib reaction liquid, cooling to room temperature, adding sodium chloride, stirring for crystallization, and filtering to obtain a filter cake;
(2) gefitinib caustic wash
Adding the filter cake obtained in the step (1) into a sodium bicarbonate solution, stirring at room temperature, and filtering to obtain a filter cake;
(3) gefitinib ethanol recrystallization
And (3) adding the filter cake obtained in the step (2) into ethanol, heating to dissolve, decoloring and filtering, cooling the filtrate for crystallization, filtering, and drying to obtain the high-purity gefitinib.
According to the present invention, preferably, the molar ratio of gefitinib intermediate to potassium carbonate in step (1) is: 0.2-2:1.
According to the present invention, it is preferred that the molar ratio of gefitinib intermediate to potassium iodide in step (1) is 1-5: 1.
According to the invention, the molar ratio of the gefitinib intermediate and the N- (3-chloropropyl) morpholine in the step (1) is preferably 0.8-1.2: 1.
According to the invention, the ratio of the volume of DMF to the mass of gefitinib intermediate in the step (1) is preferably 2-5mL:1 g.
According to the present invention, it is preferred that the reaction time in step (1) is 5 to 7 hours.
According to the invention, preferably, the mass fraction of the dilute hydrochloric acid in the step (1) is 3-12%, and the mass ratio of the volume of the dilute hydrochloric acid to the gefitinib intermediate is 5-20mL:1 g.
According to the invention, the ratio of the mass of the sodium chloride to the volume of the diluted hydrochloric acid in the step (1) is preferably 0.2-0.4g:1 mL.
According to the present invention, it is preferable that the crystallization time in step (1) is 0.5 to 3 hours.
According to the invention, preferably, the mass fraction of the sodium bicarbonate solution in the step (2) is 2-6%, and the mass ratio of the volume of the sodium bicarbonate solution to the gefitinib intermediate is 3-10mL:1 g.
According to the present invention, it is preferred that the stirring time in step (2) is 5 to 10 hours.
According to the invention, the mass ratio of the volume of the ethanol to the filter cake in the step (3) is 10-15mL:1 g.
According to the present invention, it is preferable that the temperature rise in the step (3) is a temperature rise to 65 to 75 ℃.
According to the present invention, it is preferable that the decoloring step in the step (3) is: and heating to dissolve, adding activated carbon, stirring and decoloring for 30min, wherein the mass ratio of the activated carbon to the gefitinib intermediate is 0.02: 1.
According to the invention, preferably, the temperature reduction in the step (3) is to room temperature, the temperature reduction rate is 5-10 ℃/h, and the crystallization time is 1-5 h.
According to the present invention, it is preferred that the drying in step (3) is drying at 50-70 ℃ for 6-10 hours.
According to the present invention, the reaction scheme of gefitinib is as follows:
the invention has the following technical characteristics and beneficial effects:
1. in the purification process, dilute hydrochloric acid is added into the obtained reaction liquid, the temperature is reduced to room temperature, sodium chloride is added for crystallization, the salt concentration of the system is improved, and a salting-out effect is formed to separate out gefitinib hydrochloride in the system; washing the filter cake obtained by salting out with alkali, wherein the alkali washing is used for dissolving redundant sodium chloride and neutralizing gefitinib hydrochloride to form gefitinib; and the filter cake washed by the alkali is recrystallized by adopting ethanol, so that the purity of the gefitinib product is further improved.
2. The purification process comprises the steps of firstly forming a gefitinib crude product into hydrochloride, removing part of impurities by salting out crystallization by utilizing the solubility difference of the impurity hydrochloride and the product hydrochloride, and then washing with alkali to form gefitinib; and then, dissolving gefitinib in ethanol, adsorbing and filtering by using active carbon, slowly cooling and crystallizing to reduce impurity inclusion, and further improving the product purity.
3. The purification method of the invention has simple process and high purity of the obtained product.
Detailed Description
The present invention is further illustrated by, but not limited to, the following examples.
Raw materials used in the examples are all common commercial products unless otherwise specified; the methods used are all methods commonly used in the art unless otherwise specified.
Example 1
A gefitinib purification process comprises the following steps:
(1) salt-forming salting-out of gefitinib
Adding 10g of potassium carbonate, 2g of potassium iodide and 10g of gefitinib intermediate 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol into 30mL of N, N-dimethylformamide, stirring and heating to 70 ℃, adding 5.1g N- (3-chloropropyl) morpholine, and reacting for 6 hours to obtain gefitinib reaction liquid; adding 100mL of dilute hydrochloric acid with the mass fraction of 12% into the gefitinib reaction liquid, cooling to room temperature, adding 20g of sodium chloride, stirring for crystallization for 2h, and filtering to obtain a filter cake;
(2) gefitinib caustic wash
Adding the filter cake obtained in the step (1) into 100mL of sodium bicarbonate solution with the mass fraction of 2%, stirring for 5h at room temperature, and then filtering to obtain 15.5g of filter cake;
(3) gefitinib ethanol recrystallization
And (3) adding the filter cake obtained in the step (2) into 200mL of ethanol, heating to 70 ℃, dissolving, adding 0.2g of activated carbon, decoloring for 30min, filtering, cooling the filtrate to room temperature at a cooling rate of 8 ℃/h, crystallizing for 3h, filtering, and drying the obtained product at 60 ℃ for 6h to obtain the high-purity gefitinib.
The gefitinib product prepared by the embodiment has the purity of 99.97% and the yield of 86.9%.
Example 2
A gefitinib purification process comprises the following steps:
(1) salt-forming salting-out of gefitinib
Adding 15g of potassium carbonate, 5g of potassium iodide and 10g of gefitinib intermediate 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol into 30mL of N, N-dimethylformamide, stirring and heating to 70 ℃, adding 5.1g N- (3-chloropropyl) morpholine, and reacting for 6 hours to obtain gefitinib reaction liquid; adding 50mL of dilute hydrochloric acid with the mass fraction of 12% into the gefitinib reaction liquid, cooling to room temperature, adding 15g of sodium chloride, stirring for crystallization for 2h, and filtering to obtain a filter cake;
(2) gefitinib caustic wash
Adding the filter cake obtained in the step (1) into 100mL of sodium bicarbonate solution with the mass fraction of 2%, stirring for 5h at room temperature, and then filtering to obtain 16.1g of filter cake;
(3) gefitinib ethanol recrystallization
And (3) adding the filter cake obtained in the step (2) into 200mL of ethanol, heating to 70 ℃, dissolving, adding 0.2g of activated carbon, decoloring for 30min, filtering, cooling the filtrate to room temperature at a cooling rate of 8 ℃/h, crystallizing for 3h, filtering, and drying the obtained product at 60 ℃ for 6h to obtain the high-purity gefitinib.
The gefitinib product prepared by the embodiment has the purity of 99.95% and the yield of 86.5%.
Example 3
A gefitinib purification process comprises the following steps:
(1) salt-forming salting-out of gefitinib
Adding 10g of potassium carbonate, 2g of potassium iodide and 10g of gefitinib intermediate 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol into 30mL of N, N-dimethylformamide, stirring and heating to 70 ℃, adding 5.1g N- (3-chloropropyl) morpholine, and reacting for 6 hours to obtain gefitinib reaction liquid; adding 100mL of dilute hydrochloric acid with the mass fraction of 12% into the gefitinib reaction liquid, cooling to room temperature, adding 30g of sodium chloride, stirring for crystallization for 2h, and filtering to obtain a filter cake;
(2) gefitinib caustic wash
Adding the filter cake obtained in the step (1) into 100mL of sodium bicarbonate solution with the mass fraction of 4%, stirring for 5h at room temperature, and then filtering to obtain 16.8g of filter cake;
(3) gefitinib ethanol recrystallization
And (3) adding the filter cake obtained in the step (2) into 200mL of ethanol, heating to 70 ℃, dissolving, adding 0.2g of activated carbon, decoloring for 30min, filtering, cooling the filtrate to room temperature at a cooling rate of 7 ℃/h, crystallizing for 3h, filtering, and drying the obtained product at 60 ℃ for 6h to obtain the high-purity gefitinib.
The gefitinib product prepared by the embodiment has the purity of 99.97% and the yield of 88.3%.
Comparative example 1
Adding 10g of potassium carbonate, 2g of potassium iodide and 10g of gefitinib intermediate 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol into 30mL of N, N-dimethylformamide, stirring and heating to 70 ℃, adding 5.1g N- (3-chloropropyl) morpholine, and reacting for 6 hours to obtain gefitinib reaction liquid; cooling to room temperature, adding 200mL of purified water, stirring for crystallization for 2h, filtering, and drying the obtained product to obtain 11.5g of crude product.
And transferring all the crude products into a reaction bottle, adding 230mL of ethanol, heating to dissolve, cooling to room temperature, crystallizing for 3h, filtering, and drying the obtained product at 60 ℃ for 6h to obtain gefitinib.
The gefitinib product prepared by the comparative example has the purity of 99.82 percent and the yield of 75.6 percent, and the obtained product has lower yield and purity.
Comparative example 2
Adding 10g of potassium carbonate, 2g of potassium iodide and 10g of gefitinib intermediate 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol into 30mL of N, N-dimethylformamide, stirring and heating to 70 ℃, adding 5.1g N- (3-chloropropyl) morpholine, and reacting for 6 hours to obtain gefitinib reaction liquid; adding 100mL of dilute hydrochloric acid with the mass fraction of 12% into the gefitinib reaction liquid, cooling to room temperature, stirring for crystallization for 2 hours, filtering to obtain a filter cake with the wet weight of only 6.6g and the yield being too low.
Comparative example 3
(1) Salt-forming salting-out of gefitinib
Adding 10g of potassium carbonate, 2g of potassium iodide and 10g of gefitinib intermediate 4- (3-chloro-4-fluoroaniline) -7-methoxyquinazoline-6-alcohol into 30mL of N, N-dimethylformamide, stirring and heating to 70 ℃, adding 5.1g N- (3-chloropropyl) morpholine, and reacting for 6 hours to obtain gefitinib reaction liquid; adding 100mL of dilute hydrochloric acid with the mass fraction of 12% into the gefitinib reaction liquid, cooling to room temperature, adding 30g of sodium chloride, stirring for crystallization for 2h, and filtering to obtain a filter cake;
(2) gefitinib caustic wash
Adding the filter cake obtained in the step (1) into 100mL of sodium bicarbonate solution with the mass fraction of 4%, stirring for 5h at room temperature, and then filtering to obtain 15.8g of filter cake;
(3) gefitinib ethanol recrystallization
And (3) adding the filter cake obtained in the step (2) into 200mL of ethanol, heating to 70 ℃, dissolving, adding 0.2g of activated carbon, decoloring for 30min, filtering, quickly cooling the filtrate to room temperature at the cooling rate of 40 ℃/h, crystallizing for 3h, filtering, and drying the obtained product at 60 ℃ for 6h to obtain gefitinib.
The gefitinib product prepared by the comparative example has the purity of 99.71 percent and the yield of 81.5 percent.
Claims (10)
1. A gefitinib purification process comprises the following steps:
(1) salt-forming salting-out of gefitinib
Adding potassium carbonate, potassium iodide and gefitinib intermediate into N, N-dimethylformamide, stirring and heating to 70 ℃, adding N- (3-chloropropyl) morpholine, and reacting to obtain gefitinib reaction liquid; adding dilute hydrochloric acid into the gefitinib reaction liquid, cooling to room temperature, adding sodium chloride, stirring for crystallization, and filtering to obtain a filter cake;
(2) gefitinib caustic wash
Adding the filter cake obtained in the step (1) into a sodium bicarbonate solution, stirring at room temperature, and filtering to obtain a filter cake;
(3) gefitinib ethanol recrystallization
And (3) adding the filter cake obtained in the step (2) into ethanol, heating to dissolve, decoloring and filtering, cooling the filtrate for crystallization, filtering, and drying to obtain the high-purity gefitinib.
2. The process for purifying gefitinib as claimed in claim 1, wherein the molar ratio of gefitinib intermediate to potassium carbonate in step (1) is: 0.2-2: 1; the molar ratio of the gefitinib intermediate to potassium iodide is 1-5: 1; the molar ratio of the gefitinib intermediate to the N- (3-chloropropyl) morpholine is 0.8-1.2: 1; the mass ratio of the volume of the DMF to the gefitinib intermediate is 2-5mL:1 g; the reaction time is 5-7 hours.
3. The process for purifying gefitinib according to claim 1, wherein the mass fraction of the dilute hydrochloric acid in step (1) is 3-12%, and the volume of the dilute hydrochloric acid to the mass of gefitinib intermediate is 5-20mL:1 g.
4. The process for purifying gefitinib of claim 1, wherein the ratio of the mass of sodium chloride to the volume of diluted hydrochloric acid in step (1) is 0.2-0.4g:1 mL.
5. The process for purifying gefitinib of claim 1, wherein the crystallization time in step (1) is 0.5-3 h.
6. The process for purifying gefitinib according to claim 1, wherein the mass fraction of the sodium bicarbonate solution in step (2) is 2-6%, and the volume of the sodium bicarbonate solution to the mass of gefitinib intermediate is 3-10mL:1 g; the stirring time is 5-10 h.
7. The process for purifying gefitinib of claim 1, wherein the volume of ethanol to mass of filter cake in step (3) is 10-15mL:1 g.
8. The process for purifying gefitinib of claim 1, wherein the temperature in step (3) is raised to 65-75 ℃.
9. The process for purifying gefitinib as claimed in claim 1, wherein the decolorizing step in step (3) is: and heating to dissolve, adding activated carbon, stirring and decoloring for 30min, wherein the mass ratio of the activated carbon to the gefitinib intermediate is 0.02: 1.
10. The process for purifying gefitinib as claimed in claim 1, wherein in step (3), the temperature is reduced to room temperature, the temperature reduction rate is 5-10 ℃/min, and the crystallization time is 1-5 h; the drying is drying at 50-70 deg.C for 6-10 h.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115433135A (en) * | 2022-09-30 | 2022-12-06 | 山东鲁抗医药股份有限公司 | Gefitinib refining method |
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