CN103254182A - Method for preparing Afatinib - Google Patents
Method for preparing Afatinib Download PDFInfo
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- CN103254182A CN103254182A CN2013101734173A CN201310173417A CN103254182A CN 103254182 A CN103254182 A CN 103254182A CN 2013101734173 A CN2013101734173 A CN 2013101734173A CN 201310173417 A CN201310173417 A CN 201310173417A CN 103254182 A CN103254182 A CN 103254182A
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Abstract
The invention discloses a method for preparing Afatinib. The method comprises the following steps: 4-fluoro-3-chloroaniline and N,N-dimethylformamide dimethylacetal (DMF-DMA) are subjected to condensation reaction so as to produce a Schiff base (III), and the Schiff base (III), without to the need of separation, is subjected to cyclization reaction with 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline so as to prepare Afatinib. According to the method, the steps for preparing Afatinib are reduced obviously, and the cost is reduced greatly.
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 " Ah method is for Buddhist nun's intermediates preparation " and " Ah method is for Buddhist nun's preparation method ".
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 it 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 (IV) is starting raw material, under the catalysis of basic catalyst potassium tert.-butoxide, with the substitution reaction of S-3-hydroxyl-tetrahydrofuran (THF) generation halogens fluorine, generate 4-[(3-chloro-4-fluorophenyl) amino]-the oxygen base of 6-nitro-7-[(S)-(tetrahydrofuran (THF)-3-yl)] quinazoline (V); Intermediate (V) obtains corresponding aminocompound (VI) through the nitroreduction of 6-position; This compound (VI) obtains intermediate (VII) with bromo Ba Dousuan acyl chlorides generation amidate action, and this intermediate (VII) 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 (IV) of 4-position functionalization successively for Buddhist nun's preparation method at present.This method is to prepare the quinazoline parent nucleus earlier, carries out the side chain functionalities conversion again.This method is because step is more, and total recovery is also 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 seek new preparation approach, according to the synthetic theory of the Atom economy of Green Chemistry, provide a kind of improved Ah method preparation method for the Buddhist nun, this preparation method is succinct, economy and environmental protection, is fit to the requirement that industrialization is amplified.
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 (4-[(3-chloro-4-fluorophenyl) 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) preparation method
It is characterized in that: described preparation method comprises the steps: at first 4-fluoro-3-chloroaniline and N, dinethylformamide dimethylacetal (DMF-DMA) carries out condensation reaction and forms schiff bases (III), described schiff bases (III) directly and 2-itrile group-4-[4-(N then, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (II) carries out ring-closure reaction, makes described Ah method for Buddhist nun (I).
Raw material 4-fluoro-3-chloroaniline and the N of described condensation reaction, the molar ratio of dinethylformamide dimethylacetal (DMF-DMA) is: 1: 1-2, preferred 1: 1.4.
The catalyzer of described condensation reaction is formic acid, acetic acid, methylsulphonic acid, sulfuric acid or phosphoric acid, preferred acetic acid.
The temperature of described condensation reaction is 0-150 ℃, preferred 100-110 ℃.
The solvent of described condensation reaction is toluene, dimethylbenzene, dioxane, 1,2-ethylene dichloride, methyl-sulphoxide or tetrahydrofuran (THF), preferred toluene.
In the described ring-closure reaction, 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (II) is 1 with the molar ratio of 4-fluoro-3-chloroaniline: 1-2, preferred 1: 1.2-1.4.
The temperature of described ring-closure reaction is 0-150 ℃, preferred 120-130 ℃.
The solvent of described ring-closure reaction is the mixed solvent that formic acid, acetic acid or above-mentioned two kinds of acid form with toluene respectively, the mixed solvent of preferred acetic acid or acetic acid and toluene.
The related alkaline neutraliser of the aftertreatment of described ring-closure reaction is sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, sodium methylate, ammoniacal liquor or triethylamine, preferred ammoniacal liquor.
Than prior art, Ah method involved in the present invention is for Buddhist nun's preparation method, its advantage mainly is the raw material that is easy to get by economy, condensation and cyclisation are merged reaction, make that preparation process is easier, economy and 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.
Embodiment one:
(14.5g, 0.10mol), N, (17.8mL 0.14mol) and toluene 150mL, stirs and adds catalyzer anhydrous acetic acid 2.8mL down dinethylformamide dimethylacetal (DMF-DMA) to add 3-chloro-4-fluoroaniline in the 500mL there-necked flask.Be warming up to 105-110 ℃, and keep this thermotonus 3 hours (collecting methyl alcohol with water-and-oil separator), the TLC monitoring reaction finishes.Toluene is reclaimed in 50 ℃ of following underpressure distillation, obtains colorless oil 19.5g, and yield is 97.4%, and this colorless oil need not can be directly used in following reaction through separating.
Above-mentioned oily matter with the dissolving of 150mL anhydrous acetic acid, is transferred in the there-necked flask of 500mL.Add 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (II) (23.8g, 0.072mol).Stir, be warming up to 115-120 ℃ and also keep refluxing 4 hours, the TLC monitoring reaction finishes.Most of acetic acid is reclaimed in underpressure distillation, is cooled to room temperature, regulates pH to 8-9 with 5% ammoniacal liquor, has solid to separate out.Slowly be cooled to 5 ℃, stirred crystallization was filtered, and is used the ethyl acetate washing leaching cake after 1 hour.Use methyl alcohol, acetone and water recrystallization successively, 40-50 ℃ of vacuum-drying gets light yellow solid Ah method for Buddhist nun 24.5g, and yield is 70.2%.
Embodiment two:
(14.5g, 0.10mol), N, (17.8mL 0.14mol) and toluene 150mL, stirs and adds catalyzer anhydrous formic acid 2.5mL down dinethylformamide dimethylacetal (DMF-DMA) to add 3-chloro-4-fluoroaniline in the 500mL there-necked flask.Be warming up to 105-110 ℃, and keep this thermotonus 4 hours (collecting methyl alcohol with water-and-oil separator), the TLC monitoring reaction finishes.Toluene is reclaimed in 50 ℃ of following underpressure distillation, obtains colorless oil 19.2g, and yield is 96.2%, and this colorless oil need not can be directly used in following reaction through separating.
Above-mentioned oily matter with 25mL anhydrous acetic acid and the dissolving of 125mL toluene, is transferred in the there-necked flask of 500mL.Add 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (II) (22.5g, 0.068mol).Stir, be warming up to 120-130 ℃, and keep refluxing 4 hours, the TLC monitoring reaction finishes.Vacuum distillation recovered solvent is cooled to room temperature, regulates pH to 8-9 with 5% ammoniacal liquor, has solid to separate out.Slowly be cooled to 5 ℃, stirred crystallization was filtered, and is used the ethyl acetate washing leaching cake after 1 hour.Use methyl alcohol, acetone and water recrystallization successively, 40-50 ℃ of vacuum-drying gets off-white color solid Ah method for Buddhist nun 22.9g, and yield is 69.4%.
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 (9)
1. an Ah method is for Buddhist nun's (4-[(3-chloro-4-fluorophenyl) amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline, preparation method I),
It is characterized in that described preparation method comprises the steps: at first 4-fluoro-3-chloroaniline and N, the dinethylformamide dimethylacetal carries out condensation reaction and forms schiff bases (III), described schiff bases (III) directly and 2-itrile group-4-[4-(N then, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (II) carries out ring-closure reaction, and the Ah method that makes is for Buddhist nun (I).
2. 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-fluoro-3-chloroaniline and the N of described condensation reaction, the molar ratio of dinethylformamide dimethylacetal is: 1: 1-2.
3. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: the catalyzer of described condensation reaction is formic acid, acetic acid, methylsulphonic acid, sulfuric acid or phosphoric acid.
4. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: the temperature of described condensation reaction is 0-150 ℃.
5. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: the solvent of described condensation reaction is toluene, dimethylbenzene, dioxane, 1,2-ethylene dichloride, methyl-sulphoxide or tetrahydrofuran (THF).
6. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: in the described ring-closure reaction, 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (II) 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 1 for the Buddhist nun, it is characterized in that: the temperature of described ring-closure reaction is 0-150 ℃.
According to the described Ah method of claim 1 for Buddhist nun's preparation method, it is characterized in that: the solvent of described ring-closure reaction is the mixed solvent that formic acid, acetic acid or above-mentioned two kinds of acid form with toluene respectively.
9. according to the preparation method of the described Ah method of claim 1 for the Buddhist nun, it is characterized in that: the related alkaline neutraliser of the aftertreatment of described ring-closure reaction is sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, sodium methylate, ammoniacal liquor or triethylamine.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101734173A CN103254182A (en) | 2013-05-10 | 2013-05-10 | Method for preparing Afatinib |
| PCT/CN2014/076536 WO2014180271A1 (en) | 2013-05-10 | 2014-04-30 | Method for preparing afatinib and intermediate thereof |
| US14/957,607 US9845315B2 (en) | 2013-05-10 | 2015-12-03 | Method for preparing Afatinib and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101734173A CN103254182A (en) | 2013-05-10 | 2013-05-10 | Method for preparing Afatinib |
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|---|---|
| CN103254182A true CN103254182A (en) | 2013-08-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013101734173A Pending CN103254182A (en) | 2013-05-10 | 2013-05-10 | Method for preparing Afatinib |
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Cited By (4)
| 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 |
| WO2014180271A1 (en) * | 2013-05-10 | 2014-11-13 | 苏州明锐医药科技有限公司 | Method for preparing afatinib and intermediate thereof |
| CN104478863A (en) * | 2014-12-23 | 2015-04-01 | 康伯莱（天津）药物研发有限责任公司 | Preparation method of Afatinib |
| CN109776514A (en) * | 2019-03-22 | 2019-05-21 | 徐州工业职业技术学院 | A kind of Afatinib highly finished product synthetic method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002050043A1 (en) * | 2000-12-20 | 2002-06-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof |
| CN101402610A (en) * | 2008-11-13 | 2009-04-08 | 浙江精进药业有限公司 | Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline |
-
2013
- 2013-05-10 CN CN2013101734173A patent/CN103254182A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002050043A1 (en) * | 2000-12-20 | 2002-06-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof |
| CN101402610A (en) * | 2008-11-13 | 2009-04-08 | 浙江精进药业有限公司 | Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014180271A1 (en) * | 2013-05-10 | 2014-11-13 | 苏州明锐医药科技有限公司 | Method for preparing afatinib and intermediate thereof |
| 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 |
| CN104478863A (en) * | 2014-12-23 | 2015-04-01 | 康伯莱（天津）药物研发有限责任公司 | Preparation method of Afatinib |
| CN109776514A (en) * | 2019-03-22 | 2019-05-21 | 徐州工业职业技术学院 | A kind of Afatinib highly finished product synthetic method |
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Application publication date: 20130821 |