CN105801567A - Purifying method of afatinib dimaleate - Google Patents
Purifying method of afatinib dimaleate Download PDFInfo
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- CN105801567A CN105801567A CN201410847035.9A CN201410847035A CN105801567A CN 105801567 A CN105801567 A CN 105801567A CN 201410847035 A CN201410847035 A CN 201410847035A CN 105801567 A CN105801567 A CN 105801567A
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- maleic acid
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Abstract
The invention discloses a purifying method of afatinib dimaleate. The method comprises the following steps: dissolving afatinib free base in a dichloromethane and methanol mixed solution, drying the obtained solution by using anhydrous sodium sulfate, carrying out reduced pressure concentration until a pale yellow sticky material, rapidly adding methyl tert-butyl ether, beating to obtain a white solid, filtering the white solid, drying the white solid to obtain white powder, carrying out alcohol re-crystallization on the white powder to obtain highly pure free base, and carrying out salt formation in ethanol. The purity of the afatinib dimaleate product obtained through the method is greater than 99.5%, and the content of every single impurity is smaller than 0.1%, so the afatinib dimaleate accords with needs of an afatinib dimaleate bulk drug for drug production.
Description
Technical field
The present invention relates to a kind of double; two maleic acid Afatinib purification technique to improve, belong to medicine, chemical technology field.
Background technology
Afatinib is by a kind of Mutiple Targets small-molecule drug of Boehringer Ingelheim company of Germany research and development, it belongs to EGF-R ELISA (EGFR) and the kinase whose irreversible inhibitor of people's epidermal receptor (HER2) TYR, is also first for the lung cancer therapy medicine after epidermal growth factor receptor inhibitor Endodontic failure.Clinically for treating advanced Non-small cell lung and the treatment of advanced breast cancer, intestinal cancer.This medicine was passed through by the quickly examination & approval of FDA (Food and Drug Adminstration) (FDA) on February 15th, 2008, commodity fame and position TOVOK.
Patent CN1867564B reports a kind of new route synthesizing Afatinib free alkali, and its synthetic route is:
And on synthesis basis, report recrystallization method namely use butyl acetate and hexahydrotoluene recrystallization, yield is 78%, and purity is 99.4%, and water content is 5.4%.
Above method does not provide and obtains purity higher than 99.5%, the single impurity purification process meeting pharmaceutical production standard less than 0.1%, we are through improving and purification on this basis, obtain purity higher than 99.5%, and single impurity is less than 0.1% pair of maleic acid Afatinib.
Summary of the invention
The Afatinib free alkali synthetic method of patent CN1867564B report is: joined in 4.4L water by the hydrochloric acid (53.17mol) of 5.6L30%.(dimethylamino)-acetaldehyde-diethyl acetal (26.59mol) of 95% that then 20 minutes are added dropwise over 4.28kg at 30 DEG C of temperature.Stirring 8 hours at 35 DEG C of temperature, be cooled to 5 DEG C and protect in argon, this solution is referred to as solution B.4.55kg (68.06mol) potassium hydroxide is dissolved in 23.5L water and is cooled to-5 DEG C.This solution is referred to as solution C.By 5.88kg (10.63mol) ((the chloro-4-fluoro-phenyl amino of 4-(3-)-7-(oxolane-3-base oxygen)-quinazoline-6-base carbamyl)-methyl)-diethyl phosphate and 0.45kg lithium chloride (10.63mol) put in 23.5L oxolane, and be cooled to-7 DEG C.Then cold solution C is added in 10 minutes at such a temperature.Then within 1 hour at-7 DEG C of temperature, solution B is added.After one hour of the stirring reactant liquor it is heated to 20 DEG C at-5 DEG C of temperature and mixes with 15L water, being cooled to 3 DEG C, sucking filtration float, use water washing precipitate and dry.Obtain thick product.
Purification process of the present invention is the purification carried out on above synthesis basis, concrete operation method is: dissolved by the thick product of above method gained in the dichloromethane mixed solution with methanol, anhydrous sodium sulfate dries, it is evaporated to faint yellow glutinous shape thing, it is rapidly added methyl tertiary butyl ether(MTBE) making beating and obtains white solid, filter, drying obtains white powder, white powder alcohol recrystallization obtains highly purified free alkali, then become salt in ethanol, purity can be obtained more than the 99.5% single impurity double; two maleic acid Afatinib crude drug meeting pharmaceutical production less than 0.1%.
In above-mentioned purification process, making beating solidifies the solvent used by free alkali is methyl tertiary butyl ether(MTBE).
In above-mentioned purification process, the alcohol used by recrystallization is ethanol or isopropanol.
The method of above-mentioned one-tenth salt is: respectively with ethanol free alkali and maleic acid is dissolved and is heated, in the alcoholic solution of the free alkali being then added drop-wise in stirring by the maleic acid solution of ethanol and continue to stir.
Adopt the method disclosed in the present, purity can be obtained more than 99.5%, the single impurity double; two maleic acid Afatinib crude drug meeting pharmaceutical production less than 0.1%.The highly purified product obtained meets the requirement of double; two maleic acid Afatinib crude drug in pharmaceutical production.
Detailed description of the invention
Embodiment:
The hydrochloric acid (5.317mol) of 560ml30% is joined in 440ml water.Then (dimethylamino)-acetaldehyde-diethyl acetal (2.659mol) of 428g within 20 minutes at 30 DEG C of temperature, it is added dropwise over.Stirring 8 hours at 35 DEG C of temperature, be cooled to 5 DEG C and protect in argon, this solution is referred to as solution B.455g (6.806mol) potassium hydroxide is dissolved in 2.35L water and is cooled to-5 DEG C.This solution is referred to as solution C.By 588g (1.063mol) ((the chloro-4-fluoro-phenyl amino of 4-(3-)-7-(oxolane-3-base oxygen)-quinazoline-6-base carbamyl)-methyl)-diethyl phosphate and 45g lithium chloride (1.063mol) put in 2.35L oxolane, and be cooled to-7 DEG C.Then cold solution C is added in 10 minutes at such a temperature.Then within 1 hour at-7 DEG C of temperature, solution B is added.After one hour of the stirring reactant liquor it is heated to 20 DEG C at-5 DEG C of temperature and mixes with 1.5L water, being cooled to 3 DEG C, sucking filtration float, use water washing precipitate and dry.Obtain thick product.
Obtain thick product obtained as above 50 grams, it is dissolved into 500 milliliters of dichloromethane and (volume ratio is 4:1) in the mixed solution of methanol, anhydrous sodium sulfate dries, filtration, concentrating under reduced pressure, obtain faint yellow glutinous shape thing, rapidly join 150 milliliters of methyl tertiary butyl ether(MTBE)s and stir, having white solid to precipitate out, filter, dry, being joined by gained solid in 120 milliliters of ethanol, be heated to 60 DEG C, solid all dissolves, stop heating, being naturally cooling to room temperature, have white solid to precipitate out, ice-water bath is cooled to 0 DEG C, filter, dry, obtain high-purity free alkali 44 grams.Gained free alkali is joined in 300ml ethanol and is heated to 60 DEG C, solid all dissolves, 23g maleic acid is joined and 140 milliliters of ethanol are heated to 60 DEG C make it all dissolve, the alcoholic solution of maleic acid is added drop-wise in the alcoholic solution of free alkali, and continuing stirring 1 hour, slow cooling, to 20 DEG C, has a large amount of faint yellow solid to precipitate out, filtering, dry obtain double; two maleic acid Afatinib 60.97g, purity is 99.82%.
Obtain thick product obtained as above 50 grams, it is dissolved into 500 milliliters of dichloromethane and (volume ratio is 4:1) in the mixed solution of methanol, anhydrous sodium sulfate dries, filtration, concentrating under reduced pressure, obtain faint yellow glutinous shape thing, rapidly join 150 milliliters of methyl tertiary butyl ether(MTBE)s and stir, having white solid to precipitate out, filter, dry, being joined by gained solid in 120 milliliters of isopropanols, be heated to 60 DEG C, solid all dissolves, stop heating, being naturally cooling to room temperature, have white solid to precipitate out, ice-water bath is cooled to 0 DEG C, filter, dry, obtain high-purity free alkali 41 grams.Gained free alkali is joined in 300ml ethanol and is heated to 60 DEG C, solid all dissolves, 21g maleic acid is joined and 110 milliliters of ethanol are heated to 60 DEG C make it all dissolve, the alcoholic solution of maleic acid is added drop-wise in the alcoholic solution of free alkali, and continuing stirring 1 hour, slow cooling, to 20 DEG C, has a large amount of faint yellow solid to precipitate out, filtering, dry obtain double; two maleic acid Afatinib 55.81g, purity is 99.79%.
Obtain thick product obtained as above 50 grams, it is dissolved into 500 milliliters of dichloromethane and (volume ratio is 4:1) in the mixed solution of methanol, anhydrous sodium sulfate dries, filtration, concentrating under reduced pressure, obtain faint yellow glutinous shape thing, rapidly join 150 milliliters of methyl tertiary butyl ether(MTBE)s and stir, having white solid to precipitate out, filter, dry, being joined by gained solid in 120 milliliters of isopropanols, be heated to 60 DEG C, solid all dissolves, stop heating, being naturally cooling to room temperature, have white solid to precipitate out, ice-water bath is cooled to 0 DEG C, filter, dry, gained free alkali 46 grams.Gained free alkali is joined in 300ml ethanol and is heated to 60 DEG C, solid all dissolves, 24g maleic acid is joined and 160 milliliters of ethanol are heated to 60 DEG C make it all dissolve, the alcoholic solution of maleic acid is added drop-wise in the alcoholic solution of free alkali, and continuing stirring 1 hour, slow cooling, to 20 DEG C, has a large amount of faint yellow solid to precipitate out, filtering, dry obtain double; two maleic acid Afatinib 61.28g, purity is 99.61%.
Obtain thick product obtained as above 50 grams, it is dissolved into 500 milliliters of dichloromethane and (volume ratio is 4:1) in the mixed solution of methanol, anhydrous sodium sulfate dries, filtration, concentrating under reduced pressure, obtain faint yellow glutinous shape thing, rapidly join 150 milliliters of methyl tertiary butyl ether(MTBE)s and stir, having white solid to precipitate out, filter, dry, being joined by gained solid in 120 milliliters of ethanol, be heated to 60 DEG C, solid all dissolves, stop heating, being naturally cooling to room temperature, have white solid to precipitate out, ice-water bath is cooled to 0 DEG C, filter, dry, gained free alkali 42 grams.Gained free alkali is joined in 300ml ethanol and is heated to 60 DEG C, solid all dissolves, 22g maleic acid is joined and 120 milliliters of ethanol are heated to 60 DEG C make it all dissolve, the alcoholic solution of maleic acid is added drop-wise in the alcoholic solution of free alkali, and continuing stirring 1 hour, slow cooling, to 20 DEG C, has a large amount of faint yellow solid to precipitate out, filtering, dry obtain double; two maleic acid Afatinib 56.32g, purity is 99.78%.
Obtain thick product obtained as above 50 grams, it is dissolved into 500 milliliters of dichloromethane and (volume ratio is 4:1) in the mixed solution of methanol, anhydrous sodium sulfate dries, filtration, concentrating under reduced pressure, obtain faint yellow glutinous shape thing, rapidly join 150 milliliters of methyl tertiary butyl ether(MTBE)s and stir, having white solid to precipitate out, filter, dry, being joined by gained solid in 120 milliliters of ethanol, be heated to 60 DEG C, solid all dissolves, stop heating, being naturally cooling to room temperature, have white solid to precipitate out, ice-water bath is cooled to 0 DEG C, filter, dry, gained free alkali 44 grams.Gained free alkali is joined in 300ml ethanol and is heated to 60 DEG C, solid all dissolves, 23g maleic acid is joined and 140 milliliters of ethanol are heated to 60 DEG C make it all dissolve, the alcoholic solution of maleic acid is added drop-wise in the alcoholic solution of free alkali, and continuing stirring 1 hour, slow cooling, to 20 DEG C, has a large amount of faint yellow solid to precipitate out, filtering, dry obtain double; two maleic acid Afatinib 60.11g, purity is 99.87%.
Claims (4)
1. the purification process of pair maleic acid Afatinib, it is characterized in that, described purification process is to be dissolved into by Afatinib crude free base in the mixed solution of dichloromethane and methanol, dried with anhydrous sodium sulfate, it is evaporated to faint yellow glutinous shape thing, is rapidly added methyl tertiary butyl ether(MTBE) making beating and obtains white solid, filter, drying obtains white powder, white powder alcohol recrystallization obtains highly purified free alkali, then becomes salt in ethanol, obtains double; two maleic acid Afatinib.
2. the purification process of double; two maleic acid Afatinib as claimed in claim 1, it is characterised in that: in above-mentioned purification process, making beating solidifies the solvent used by free alkali is methyl tertiary butyl ether(MTBE).
3. the purification process of double; two maleic acid Afatinib as claimed in claim 1, it is characterised in that: in above-mentioned purification process, the alcohol used by recrystallization is ethanol or isopropanol.
4. the purification process of double; two maleic acid Afatinib as claimed in claim 1, it is characterized in that: the method becoming salt is respectively with ethanol free alkali and maleic acid to be dissolved and heated, in the alcoholic solution of the free alkali then maleic acid solution of ethanol being added drop-wise in stirring and continue to stir.
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| CN201410847035.9A CN105801567A (en) | 2014-12-31 | 2014-12-31 | Purifying method of afatinib dimaleate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037824A2 (en) * | 2003-10-17 | 2005-04-28 | Boehringer Ingelheim International Gmbh | Method for the production of amino crotonyl compounds |
| CN103242303A (en) * | 2013-05-16 | 2013-08-14 | 苏州明锐医药科技有限公司 | Afatinib preparation method |
| CN103476770A (en) * | 2010-11-25 | 2013-12-25 | 拉蒂欧制药有限责任公司 | Novel salts and polymorphic forms of afatinib |
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- 2014-12-31 CN CN201410847035.9A patent/CN105801567A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037824A2 (en) * | 2003-10-17 | 2005-04-28 | Boehringer Ingelheim International Gmbh | Method for the production of amino crotonyl compounds |
| CN101402631A (en) * | 2003-10-17 | 2009-04-08 | 贝林格尔.英格海姆国际有限公司 | Amino quinazoline 2-maleate, production method and uses thereof |
| CN103476770A (en) * | 2010-11-25 | 2013-12-25 | 拉蒂欧制药有限责任公司 | Novel salts and polymorphic forms of afatinib |
| CN103242303A (en) * | 2013-05-16 | 2013-08-14 | 苏州明锐医药科技有限公司 | Afatinib preparation method |
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