CN104003946A - Preparation method for erlotinib hydrochloride impurity - Google Patents
Preparation method for erlotinib hydrochloride impurity Download PDFInfo
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- CN104003946A CN104003946A CN201410097800.XA CN201410097800A CN104003946A CN 104003946 A CN104003946 A CN 104003946A CN 201410097800 A CN201410097800 A CN 201410097800A CN 104003946 A CN104003946 A CN 104003946A
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- 0 COCCCOC(CC1*=C*=C(*c2cccc(C#C)c2)C1C1)=C1OCCCOC Chemical compound COCCCOC(CC1*=C*=C(*c2cccc(C#C)c2)C1C1)=C1OCCCOC 0.000 description 1
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- 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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Abstract
The present invention relates to a preparation method for an erlotinib hydrochloride impurity N-(3-vinyl-phenyl)--quinolineamine hydrochloride. Firstly, 6,7-bis-(2-methoxyethoxy)-4(3H)-quinazolinone reacts with an acylating reagent to obtain 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline, then the 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline reacts with m-aminostyrene to generate the target product N-(3-vinyl-phenyl)--quinolineamine hydrochloride. The present method has characteristics of a short synthetic route, simple operation and high product purity up to 99.77%, and provides conditions for the qualitative and quantitative analysis of impurity in the production of erlotinib hydrochloride, thereby further improving the quality standards of erlotinib hydrochloride and providing guidance for safe medication of people.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, the preparation method field of erlotinid hydrochloride impurity especially, specifically refers to the preparation method of a kind of N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride.
Background technology
Erlotinid hydrochloride is the oral antitumour drug of 4-aminophenyl quinazoline ditosylate salt of U.S. SOI Pharmaceuticals company exploitation, its English Erlotinib Hydrochloride by name, chemistry N-(3-acetylene phenyl)-[6 by name, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride, structural formula is as follows:
Erlotinid hydrochloride went on the market in the U.S. first in 2004, be used for the treatment of carcinoma of the pancreas and Metastatic Nsclc, be current unique targeting antitumor medicine that is proved to be able to significant prolongation patient life, the quality of making the life better in the world, and the mixture of Tarceva and gemcitabine is the medicine of first treatment advanced pancreatic cancer.At present, the clinical Antitumor Mechanism of erlotinid hydrochloride is not yet completely clear and definite, investigator finds that erlotinid hydrochloride can suppress the intracellular tyrosine kinase whose phosphorylation relevant to EGF-R ELISA (EGFR), whether but to other tyrosine kinase receptor, have specific inhibitory effect not yet completely clear and definite, a large amount of investigators are still devoted to the research to the erlotinid hydrochloride mechanism of action and chemical structure.
Erlotinid hydrochloride impurity can produce for erlotinid hydrochloride in the qualitative and quantitative analysis of impurity, thereby improve the quality standard of erlotinid hydrochloride, for people's safe medication provides important directive significance.The preparation method who the invention provides a kind of erlotinid hydrochloride impurity N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride, in prior art, has no this chemical substance preparation method's open report; The structural formula of N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride is as follows:
Summary of the invention
Technical problem to be solved by this invention is the present situation for prior art, a kind of erlotinid hydrochloride impurity N-(3-vinyl phenyl)-[6 is provided, 7-bis--(2-methoxyethoxy)] preparation method of-quinolyl amine hydrochloride, the method synthetic route is short, simple to operate and products obtained therefrom purity is higher.
The present invention solves the problems of the technologies described above adopted technical scheme: a kind of preparation method of erlotinid hydrochloride impurity, is characterized in that comprising the following steps:
(1) make the compound 6 of following formula (I), 7-bis--(2-methoxyethoxy)-4 (3H)-quinazolinones react compound 4-chloro-6 that obtain following formula (II) with acylating reagent, 7-bis--(2-methoxyethoxy)-quinazoline;
(2) make formula (II) compound 4-chloro-6 that obtain in step (1), 7-bis--(2-methoxyethoxy)-quinazoline and m-aminophenyl ethylene reaction generate compound N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride of following formula (III).
In order to obtain the target product that purity is higher, formula (III) compound N-(the 3-vinyl phenyl) obtaining in step (2)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride is carried out to recrystallization purifying.
As preferably, the acylating reagent described in step (1) is one or more in thionyl chloride, phosphorus oxychloride or oxalyl chloride.
As preferably, a kind of in methylene dichloride, tetrahydrofuran (THF), toluene of the reaction solvent using in step (1), temperature of reaction is 30 ℃～80 ℃.
Preferably, the described 4-that adds in step (2) is chloro-6, and the mol ratio of 7-bis--(2-methoxyethoxy)-quinazoline and m-aminophenyl ethene is 1:1～1:3.
Preferably, a kind of in methylene dichloride, ethyl acetate, acetonitrile, ethanol, Virahol, toluene of the reaction solvent using in step (2), temperature of reaction is 30 ℃～120 ℃.
Preferably, the reaction solvent using in step (3) is one or more in acetone, tetrahydrofuran (THF), acetonitrile, methyl alcohol, ethanol, Virahol, DMF, and temperature of reaction is 60 ℃～120 ℃.
Compared with prior art, the invention has the advantages that: a kind of erlotinid hydrochloride impurity N-(3-vinyl phenyl)-[6 is provided, 7-bis--(2-methoxyethoxy)] preparation method of-quinolyl amine hydrochloride, first make 6, 7-bis--(2-methoxyethoxy)-4 (3H)-quinazolinones react with acylating reagent and obtain 4-chloro-6, 7-bis--(2-methoxyethoxy)-quinazoline, then make 4-chloro-6, 7-bis--(2-methoxyethoxy)-quinazoline and m-aminophenyl ethylene reaction generate target product N-(3-vinyl phenyl)-[6, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride, the method synthetic route is short, simple to operate, the purity of products obtained therefrom reaches 99.77%, simultaneously the method for erlotinid hydrochloride produce in the qualitative and quantitative analysis of impurity condition is provided, to further improving the quality standard of erlotinid hydrochloride, for the people's safe medication provides guidance.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of the embodiment of the present invention 2 gained compounds (III);
Fig. 2 is the NMR collection of illustrative plates of the embodiment of the present invention 2 gained compounds (III);
Fig. 3 is the LC-MS collection of illustrative plates of the embodiment of the present invention 2 gained compounds (III).
Embodiment
Below in conjunction with accompanying drawing, embodiment is described in further detail the present invention.
Embodiment 1:
Step (1): in the reaction flask of a 5ml, add successively 100mg6, 7-bis--(2-methoxyethoxy)-4 (3H)-quinazolinones, 240mg thionyl chloride and 2ml toluene, under stirring action, be slowly warming up to 50 ℃, reaction continues to close heating after 3h under stirring action, and be cooled to room temperature under stirring action, then to adding the 1ml shrend reaction of going out in reactor, isolate organic layer and with saturated sodium-chloride water solution, it washed, by anhydrous sodium sulphate, be dried again, finally concentrate and obtain light yellow solid 102mg, through identifying, the main component of this light yellow solid is 4-chloro-6, 7-bis--(2-methoxyethoxy)-quinazoline, yield is 96%,
Step (2): in the reaction flask of a 5ml, add successively the 4-chloro-6 obtaining in 100mg step (1), 7-bis--(2-methoxyethoxy)-quinazoline, 76mg m-aminophenyl ethene and 3ml ethyl acetate, under stirring action, be slowly warming up to 70 ℃, reaction continues to close heating after 3h under stirring action, and be cooled to room temperature under stirring action, then reaction solution is filtered, gained filter cake is placed in vacuum-drying at 50 ℃ and obtains off-white color solid 130mg, through identifying, the main component of such white solid is N-(3-vinyl phenyl)-[6, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride, yield is 94%,
Step (3): the off-white color solid obtaining in step (2) is refined, in the reaction flask of a 5ml, add successively the off-white color solid and the 3ml tetrahydrofuran (THF) that in 100mg step (2), obtain, under stirring action, be slowly warming up to 65 ℃, under stirring action, reflux after 30min and close heating, and be cooled to room temperature under stirring action, then above-mentioned reaction flask is carried out to ice bath and be cooled to 0 ℃, 0 ℃ be incubated and stir 1h after reaction solution is filtered, gained filter cake is placed in the target product N-(3-vinyl phenyl)-[6 after 50 ℃ of vacuum-dryings are refined, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride 88mg, yield is 88%.
Embodiment 2:
Step (1): in the reaction flask of a 25ml, add successively 1.00g6, 7-bis--(2-methoxyethoxy)-4 (3H)-quinazolinones, 2.59g oxalyl chloride and 15ml tetrahydrofuran (THF), under stirring action, be slowly warming up to 65 ℃, reaction continues to close heating after 3h under stirring action, and be cooled to room temperature under stirring action, then to adding the 1ml shrend reaction of going out in reactor, isolate organic layer and with saturated sodium-chloride water solution, it washed, by anhydrous sodium sulphate, be dried again, finally concentrate and obtain light yellow solid 1.34g, through identifying, the main component of this light yellow solid is 4-chloro-6, 7-bis--(2-methoxy (ethoxy))-quinazoline, yield is 97%,
Step (2): in the reaction flask of a 25ml, add successively the 4-chloro-6 obtaining in 1.00g step (1), 7-bis--(2-methoxyethoxy)-quinazoline, 1.12g m-aminophenyl ethene and 20ml toluene, under stirring action, be slowly warming up to 120 ℃, reaction continues to close heating after 3h under stirring action, and be cooled to room temperature under stirring action, then reaction solution is filtered, gained filter cake is placed in vacuum-drying at 50 ℃ and obtains off-white color solid 1.31g, through identifying, the main component of such white solid is N-(3-vinyl phenyl)-[6, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride, yield is 95%,
Step (3): the off-white color solid obtaining in step (2) is refined, in the reaction flask of a 25ml, add successively the off-white color solid and the 15ml N that in 1.00g step (2), obtain, dinethylformamide, under stirring action, be slowly warming up to 120 ℃, under stirring action, reflux after 30min and close heating, and be cooled to room temperature under stirring action, then above-mentioned reaction flask is carried out to ice bath and be cooled to 1 ℃, 1 ℃ be incubated and stir 1h after reaction solution is filtered, gained filter cake is placed in the target product N-(3-vinyl phenyl)-[6 after 50 ℃ of vacuum-dryings are refined, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride 900mg, yield is 90%.
N-in Fig. 1 (3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)] the HPLC collection of illustrative plates of-quinolyl amine hydrochloride is known, the purity of N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride is 99.77%.
As the NMR collection of illustrative plates of Fig. 2, wherein, lay respectively at 5.31 (d, J=11.2Hz, 1H), 5.86 (d, J=17.6Hz, the double peak of 1H) locating is N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)] two H in the alkene-CH2 of functional group of-quinolyl amine hydrochloride, the multiplet that 6.71-6.78 (m, 1H) locates is the H in the alkene-CH-of functional group.
As the LC-MS collection of illustrative plates of Fig. 3, when retention time is T=25.488min, m/e=395 place is the M peak of N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride free alkali; M/e=394 place is the M-1 peak of N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride free alkali.
Embodiment 3:
Step (1): in the reaction flask of a 250ml, add successively 10g6, 7-bis--(2-methoxyethoxy)-4 (3H)-quinazolinones, 20.8g phosphorus oxychloride and 200ml toluene, under stirring action, be slowly warming up to 80 ℃, reaction continues to close heating after 3h under stirring action, and be cooled to room temperature under stirring action, then to adding the 50ml shrend reaction of going out in reactor, isolate organic layer and with saturated sodium-chloride water solution, it washed, by anhydrous sodium sulphate, be dried again, finally concentrate and obtain light yellow solid 10.2g, through identifying, the main component of this light yellow solid is 4-chloro-6, 7-bis--(2-methoxyethoxy)-quinazoline, yield is 96%,
Step (2): in the reaction flask of a 250ml, add successively the 4-chloro-6 obtaining in 10g step (1), 7-bis--(2-methoxyethoxy)-quinazoline, 7.49g m-aminophenyl ethene and 200ml ethanol, under stirring action, be slowly warming up to 60 ℃, reaction continues to close heating after 3h under stirring action, and be cooled to room temperature under stirring action, then reaction solution is filtered, gained filter cake is placed in vacuum-drying at 50 ℃ and obtains off-white color solid 13.0g, through identifying, the main component of such white solid is N-(3-vinyl phenyl)-[6, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride, yield is 94%,
Step (3): the off-white color solid obtaining in step (2) is refined, in the reaction flask of a 250ml, add successively the off-white color solid and the 200ml ethanol that in 10g step (2), obtain, under stirring action, be slowly warming up to 80 ℃, under stirring action, reflux after 30min and close heating, and be cooled to room temperature under stirring action, then above-mentioned reaction flask is carried out to ice bath and be cooled to 2 ℃, 2 ℃ be incubated and stir 1h after reaction solution is filtered, gained filter cake is placed in the target product N-(3-vinyl phenyl)-[6 after 50 ℃ of vacuum-dryings are refined, 7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride 9.00g, yield is 90%.
Claims (7)
1. a preparation method for erlotinid hydrochloride impurity, is characterized in that comprising the following steps:
(1) make the compound 6 of following formula (I), 7-bis--(2-methoxyethoxy)-4 (3H)-quinazolinones react compound 4-chloro-6 that obtain following formula (II) with acylating reagent, 7-bis--(2-methoxyethoxy)-quinazoline;
(2) make formula (II) compound 4-chloro-6 that obtain in step (1), 7-bis--(2-methoxyethoxy)-quinazoline and m-aminophenyl ethylene reaction generate compound N-(3-vinyl phenyl)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride of following formula (III).
2. the preparation method of erlotinid hydrochloride impurity according to claim 1, it is characterized in that: formula (III) compound N-(the 3-vinyl phenyl) obtaining in step (2)-[6,7-bis--(2-methoxyethoxy)]-quinolyl amine hydrochloride is carried out to recrystallization purifying.
3. the preparation method of erlotinid hydrochloride impurity according to claim 1 and 2, is characterized in that: the acylating reagent described in step (1) is one or more in thionyl chloride, phosphorus oxychloride or oxalyl chloride.
4. the preparation method of erlotinid hydrochloride impurity according to claim 1 and 2, is characterized in that: a kind of in methylene dichloride, tetrahydrofuran (THF), toluene of the reaction solvent using in step (1), temperature of reaction is 30 ℃～80 ℃.
5. the preparation method of erlotinid hydrochloride impurity according to claim 1 and 2, is characterized in that: the described 4-that adds in step (2) is chloro-6, and the mol ratio of 7-bis--(2-methoxyethoxy)-quinazoline and m-aminophenyl ethene is 1:1～1:3.
6. the preparation method of erlotinid hydrochloride impurity according to claim 1 and 2, it is characterized in that: a kind of in methylene dichloride, ethyl acetate, acetonitrile, ethanol, Virahol, toluene of the reaction solvent using in step (2), temperature of reaction is 30 ℃～120 ℃.
7. the preparation method of erlotinid hydrochloride impurity according to claim 1 and 2, it is characterized in that: the reaction solvent using in step (3) is acetone, tetrahydrofuran (THF), acetonitrile, methyl alcohol, ethanol, Virahol, N, one or more in dinethylformamide, temperature of reaction is 60 ℃～120 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910080A (en) * | 2015-05-26 | 2015-09-16 | 大连理工大学 | Novel erlotinib-related substance and preparation method thereof |
| CN109574940A (en) * | 2018-11-20 | 2019-04-05 | 成都新恒创药业有限公司 | A kind of degradation impurity and its preparation, detection method and application of erlotinib Hydrochloride |
| CN111548314A (en) * | 2020-05-22 | 2020-08-18 | 上海万巷制药有限公司 | Production method of N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine |
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| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| WO2010109443A1 (en) * | 2009-03-26 | 2010-09-30 | Ranbaxy Laboratories Limited | Process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof |
| CN102584719A (en) * | 2012-02-02 | 2012-07-18 | 瑞阳制药有限公司 | Preparing technology of erlotinib hydrochloride |
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Patent Citations (3)
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| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| WO2010109443A1 (en) * | 2009-03-26 | 2010-09-30 | Ranbaxy Laboratories Limited | Process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof |
| CN102584719A (en) * | 2012-02-02 | 2012-07-18 | 瑞阳制药有限公司 | Preparing technology of erlotinib hydrochloride |
Non-Patent Citations (1)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910080A (en) * | 2015-05-26 | 2015-09-16 | 大连理工大学 | Novel erlotinib-related substance and preparation method thereof |
| CN109574940A (en) * | 2018-11-20 | 2019-04-05 | 成都新恒创药业有限公司 | A kind of degradation impurity and its preparation, detection method and application of erlotinib Hydrochloride |
| CN111548314A (en) * | 2020-05-22 | 2020-08-18 | 上海万巷制药有限公司 | Production method of N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine |
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