CN103242303A - Afatinib preparation method - Google Patents
Afatinib preparation method Download PDFInfo
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- CN103242303A CN103242303A CN2013101827784A CN201310182778A CN103242303A CN 103242303 A CN103242303 A CN 103242303A CN 2013101827784 A CN2013101827784 A CN 2013101827784A CN 201310182778 A CN201310182778 A CN 201310182778A CN 103242303 A CN103242303 A CN 103242303A
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Abstract
The invention discloses an Afatinib (I) preparation method which comprises the following steps: performing etherification reaction on 4-chloro-6-amino-7-hydroxyquinazoline (II) and (S)-3-hydroxytetrahydrofuran to generate 4-chloro-6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (III); performing acylation reaction on the compound (III) and 4-(N,N-dimethylamino)-2-ene-butyryl chloride to generate 4-chloro-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (IV); and performing condensation reaction on the compound (IV) and 4-fluoro-3-chloroaniline to obtain Afatinib (I). The preparation method is simple, economic and environment-friendly in process, and meets the requirements for large-scale industrialization.
Description
But other two applications for a patent for invention that patent REFERENCE TO RELATED people of the present invention submits on the same day, its title are respectively " preparation method of 4-chloro-6-amino-7-hydroxyl quinazoline " and " preparation method of a kind of 4-chloro-6-amino-7-hydroxyl quinazoline ".
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly a kind of Ah method is for Buddhist nun's preparation method.
Background technology
Ah method is a kind of many target spots small-molecule drug by the research and development of the Boehringer Ingelheim company of Germany for the Buddhist nun, the irreversible inhibitor that belongs to EGF-R ELISA (EGFR) and people's epidermis acceptor (HER2) Tyrosylprotein kinase also is first for the lung cancer therapy medicine after the epidermal growth factor receptor inhibitor treatment failure.Can be used for nonsmall-cell lung cancer and the treatment of advanced breast cancer, intestinal cancer in late period clinically.This medicine on February 15th, 2008 by FDA (Food and Drug Adminstration) (FDA) examine passage fast, commodity are called Tovok.
Ah method is for Buddhist nun (Afatinib, I), chemistry 4-[(3-chloro-4-fluorophenyl by name) amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline.
The former world patent that grinds of Boehringer Ingelheim company has been reported the preparation method of Ah method for the Buddhist nun for WO0250043A1 number and WO03094921A2 number: with parent nucleus 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-fluquinconazole quinoline (V) is starting raw material, under potassium tert.-butoxide catalysis, with S-3-hydroxyl-tetrahydrofuran (THF) generation substitution reaction, generate 4-[(3-chloro-4-fluorophenyl) amino]-the oxygen base of 6-nitro-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (VI); This intermediate (VI) obtains corresponding aminocompound (VII) through the nitroreduction of 6-position; Compound (VII) obtains intermediate (VIII) with bromo Ba Dousuan acyl chlorides generation amidate action, and this intermediate (VIII) passes through the amination reaction with dimethylamine, and the Ah method that obtains is for Buddhist nun (I).
Find out thus, Ah method for the key of Buddhist nun's technology of preparing be the quinazoline parent nucleus structure design with become the ring selection on opportunity.Ah method is the modified with functional group that carries out 7-and 6-position by the quinazoline parent nucleus (V) of 4-position functionalization successively for Buddhist nun's preparation method at present.This method steps is more, and raw material be difficult for to obtain, and total recovery is lower, and most step need separate and purifying by column chromatography, thereby is not suitable for the requirement of industrialization.
Summary of the invention
The objective of the invention is to according to the synthetic theory of the Atom economy of Green Chemistry, provide a kind of new Ah method to replace Buddhist nun's preparation method, this preparation method's raw material is easy to get, technology is succinct, economic environmental protection is conducive to the suitability for industrialized production of this medicine, promotes the development of the economic technology of this bulk drug.
To achieve these goals, main technical schemes provided by the present invention is as follows: a kind of Ah method is for Buddhist nun's preparation method, described Ah method is for Buddhist nun's chemistry 4-[(3-chloro-4-fluorophenyl by name) amino]-6-{[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (I)
It is characterized in that described preparation method comprises the steps: that 4-chloro-6-amino-7-hydroxyl quinazoline (II) and (S)-3-hydroxyl tetrahydrofuran generation etherification reaction generates the oxygen base of 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III); the oxygen base of described 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III) and 4-(N; the N-dimethylamino)-2-alkene-butyryl chloride carries out acylation reaction and generates 4-chloro-6-{[4-(N; the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV); described 4-chloro-6-{[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV) makes described Ah method for Buddhist nun (I) with 4-fluoro-3-chloroaniline generation condensation reaction.
In addition, the present invention also provides following attached technical scheme:
The molar ratio of the raw material 4-chloro-6-amino-7-hydroxyl quinazoline (II) of described etherification reaction and (S)-3-hydroxyl tetrahydrofuran is 1: 1-3, preferred 1: 1.5-2.5.
The promotor of described etherification reaction can be diethylazodicarboxylate (DEAD), diisopropyl azo-2-carboxylic acid (DIAD), azo-2-carboxylic acid's dipropyl (DPAD), azodicarboxy dimethyl phthalate (DMAD), azo-2-carboxylic acid's two p-chlorobenzyls (DCAD), N, N, N ', N '-tetramethyl-azodicarboxy acid amides (TMAD), N, N, N ', N '-tetra isopropyl azodicarboxy acid amides (TIPA) or azo two formyls, two piperidines (ADDP), preferred diethylazodicarboxylate (DEAD) or diisopropyl azo-2-carboxylic acid (DIAD).
The promotor of described etherification reaction also can be triphenylphosphine (TPP), tributylphosphine (TBP), trimethyl-phosphine (TMA) or cyano group methylene tri butyl phosphorane (CMBP), triphenylphosphine (TPP) or tributylphosphine (TBP).
The solvent of described etherification reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, dioxane, methylene dichloride, chloroform, 1,2-ethylene dichloride, methyl-sulphoxide, acetonitrile, N, dinethylformamide, acetone or tetrahydrofuran (THF), preferred methylene dichloride or tetrahydrofuran (THF).
The oxygen base of the raw material 4-chloro-6-amino of described acylation reaction-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III) is 1 with the molar ratio of 4-(N, N-dimethylamino)-2-alkene-butyryl chloride: 1-2, preferred 1: 1.1-1.3.
The acid binding agent of described acylation reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate or salt of wormwood, preferred triethylamine or salt of wormwood.
The raw material 4-chloro-6-{[4-(N of described condensation reaction, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV) is 1 with the molar ratio of 4-fluoro-3-chloroaniline: 1-2, preferred 1: 1.1-1.3.
The acid binding agent of described condensation reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate or salt of wormwood, preferred triethylamine or pyridine.
The solvent of described condensation reaction is methyl alcohol, ethanol, Virahol, methylene dichloride, trichloromethane, 1,2,-ethylene dichloride, acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, toluene, dimethylbenzene, ether, isopropyl ether, dioxane, tetrahydrofuran (THF) or methyl tertiary butyl ether, preferred Virahol or toluene.
Than prior art; Ah method involved in the present invention is for Buddhist nun's preparation method; it is by the oxygen base of reaction raw materials 4-chloro-6-amino-7-hydroxyl quinazoline (II) and (S)-3-hydroxyl tetrahydrofuran generation etherification reaction generation 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III); compound (III) carries out acidylate and condensation reaction again and can make described Ah method for Buddhist nun (I) then; thereby this preparation method's advantage mainly is that raw material is easy to get; technology is succinct; economic environmental protection; the suitability for industrialized production that is conducive to this medicine promotes the development of the economic technology of this bulk drug.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive detailed description.Side chain (S)-3-hydroxyl tetrahydrofuran and 4-(N, N-dimethylamino)-2-alkene-butyryl chloride can be referring to world patent WO0250043A1 number and the WO03094921A2 number description to the similar compound preparation method.
Embodiment one:
Under the room temperature, (3mL, 15mmol) with tetrahydrofuran (THF) 5mL, (4.0g, tetrahydrofuran (THF) 25mL solution 15mmol) kept room temperature reaction 2 hours to drip triphenylphosphine under the room temperature to add the diisopropyl azo-2-carboxylic acid in the 100mL there-necked flask.Under nitrogen protection, with (S)-3-hydroxyl tetrahydrofuran (0.3g, tetrahydrofuran (THF) 5mL solution 3.4mmol) dropwise joins in the above-mentioned reaction system; drip complete after; (0.59g, 3.0mmol), stirring at room was reacted 4 hours to add 4-chloro-6-amino-7-hydroxyl quinazoline (II).(0.23g, tetrahydrofuran (THF) 5mL solution 2.6mmol) continued room temperature reaction 2 hours, and the TLC monitoring reaction finishes to drip (S)-3-hydroxyl tetrahydrofuran.Vacuum distillation recovered solvent, resistates is transferred pH=5-6 with dilute hydrochloric acid, uses ethyl acetate extraction, and organic phase is transferred pH=10-11 with saturated sodium carbonate.Tell water, vacuum freezedrying gets the oxygen base of off-white color solid 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III) 0.69g, yield is 86.8%.
Embodiment two:
In the 100mL there-necked flask, add the oxygen base of 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III) (0.66g, 2.5mmol), triethylamine (0.25g, 2.5mmol) and methylene dichloride 20mL, be warming up to 40-45 ℃, be stirred to system dissolving homogeneous.Be down to below 10 ℃, (0.42g, methylene dichloride 10mL solution 2.8mmol) drip off the back room temperature and continue reaction 6 hours, and the TLC detection reaction finishes slowly to drip 4-(N, N-dimethylamino)-2-alkene-butyryl chloride.Reaction solution is used 10% sodium hydrogen carbonate solution and water washing, anhydrous sodium sulfate drying respectively.Decompression and solvent recovery, the residuum re-crystallizing in ethyl acetate, obtain white solid 4-chloro-6-{[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV) 0.84g, yield 89.4%.
Embodiment three:
In the 100mL there-necked flask, add 4-chloro-6-{[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV) (1.13g, 3.0mmol), triethylamine (0.45g, 4.5mmol) and Virahol 30mL, be stirred to system dissolving homogeneous.(0.48g, Virahol 20mL solution 3.3mmol) drip off the back room temperature and continue reaction 12 hours, and the TLC detection reaction finishes slowly to drip 4-fluoro-3-chloroaniline.Reaction solution is poured in the 100mL frozen water, filters.Behind the filtration cakes torrefaction, use the dehydrated alcohol recrystallization, obtain white solid Ah method for Buddhist nun (I) 1.15g, yield 79.0%.
It is pointed out that above-described embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (8)
1. an Ah method is for Buddhist nun's preparation method, described Ah method is for Buddhist nun's chemistry 4-[(3-chloro-4-fluorophenyl by name) amino]-6-{[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (I)
It is characterized in that described preparation method comprises the steps: that 4-chloro-6-amino-7-hydroxyl quinazoline (II) and (S)-3-hydroxyl tetrahydrofuran generation etherification reaction generates the oxygen base of 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III); the oxygen base of described 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III) and 4-(N; the N-dimethylamino)-2-alkene-butyryl chloride carries out acylation reaction and generates 4-chloro-6-{[4-(N; the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV); described 4-chloro-6-{[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV) makes described Ah method for Buddhist nun (I) with 4-fluoro-3-chloroaniline generation condensation reaction.
2. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: the promotor of described etherification reaction is diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid, azo-2-carboxylic acid's dipropyl, azodicarboxy dimethyl phthalate, azo-2-carboxylic acid's two p-chlorobenzyls, N, N, N ', N '-tetramethyl-azodicarboxy acid amides, N, N, N ', N '-tetra isopropyl azodicarboxy acid amides or azo two formyls two piperidines.
3. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: the promotor of described etherification reaction is triphenylphosphine, tributylphosphine, trimethyl-phosphine or cyano group methylene tri butyl phosphorane.
4. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun; it is characterized in that: the raw material of described acylation reaction; the oxygen base of 4-chloro-6-amino-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (III) is 1 with the molar ratio of 4-(N, N-dimethylamino)-2-alkene-butyryl chloride: 1-2.
5. according to the preparation method of the described Ah method of claim 4 for the Buddhist nun, it is characterized in that: the acid binding agent of described acylation reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate or salt of wormwood.
6. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: raw material 4-chloro-6-{[4-(N, N-the dimethylamino)-1-oxo-2-butylene-1-yl of described condensation reaction] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline (IV) is 1 with the molar ratio of 4-fluoro-3-chloroaniline: 1-2.
7. according to the preparation method of the described Ah method of claim 6 for the Buddhist nun, it is characterized in that: the acid binding agent of described condensation reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate or salt of wormwood.
8. according to the preparation method of the described Ah method of claim 6 for the Buddhist nun, it is characterized in that: the solvent of described condensation reaction is methyl alcohol, ethanol, Virahol, methylene dichloride, trichloromethane, 1,2,-ethylene dichloride, acetonitrile, N, dinethylformamide, N,N-dimethylacetamide, toluene, dimethylbenzene, ether, isopropyl ether, dioxane, tetrahydrofuran (THF) or methyl tertiary butyl ether.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310182778.4A CN103242303B (en) | 2013-05-16 | 2013-05-16 | Afatinib preparation method |
| PCT/CN2014/076537 WO2014183560A1 (en) | 2013-05-16 | 2014-04-30 | Afatinib and preparation method of intermediate thereof |
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| CN201310182778.4A CN103242303B (en) | 2013-05-16 | 2013-05-16 | Afatinib preparation method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755688A (en) * | 2013-12-24 | 2014-04-30 | 江苏奥赛康药业股份有限公司 | Preparation method for afatinib compound |
| CN104710413A (en) * | 2013-12-16 | 2015-06-17 | 江苏豪森药业股份有限公司 | Preparation method of afatinib dimaleate |
| CN105801567A (en) * | 2014-12-31 | 2016-07-27 | 徐州万邦金桥制药有限公司 | Purifying method of afatinib dimaleate |
| CN106188018A (en) * | 2015-04-29 | 2016-12-07 | 上海法默生物科技有限公司 | Afatinib alcohol solvent compound and method for crystallising thereof |
| CN107488171A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of Afatinib preparation method |
| CN108864063A (en) * | 2018-08-01 | 2018-11-23 | 余锋 | A kind of drug solvent for the treatment of cancer closes object and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104710413A (en) * | 2013-12-16 | 2015-06-17 | 江苏豪森药业股份有限公司 | Preparation method of afatinib dimaleate |
| CN104710413B (en) * | 2013-12-16 | 2019-05-03 | 江苏豪森药业集团有限公司 | The preparation method of two maleic acid Afatinibs |
| CN103755688A (en) * | 2013-12-24 | 2014-04-30 | 江苏奥赛康药业股份有限公司 | Preparation method for afatinib compound |
| CN103755688B (en) * | 2013-12-24 | 2015-11-18 | 江苏奥赛康药业股份有限公司 | A kind of Ah method is for the preparation method of Buddhist nun's compound |
| CN105801567A (en) * | 2014-12-31 | 2016-07-27 | 徐州万邦金桥制药有限公司 | Purifying method of afatinib dimaleate |
| CN106188018A (en) * | 2015-04-29 | 2016-12-07 | 上海法默生物科技有限公司 | Afatinib alcohol solvent compound and method for crystallising thereof |
| CN107488171A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of Afatinib preparation method |
| CN108864063A (en) * | 2018-08-01 | 2018-11-23 | 余锋 | A kind of drug solvent for the treatment of cancer closes object and preparation method thereof |
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