CN104926798A - High purity preparation method of Afatinib intermediate - Google Patents
High purity preparation method of Afatinib intermediate Download PDFInfo
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- CN104926798A CN104926798A CN201410106940.9A CN201410106940A CN104926798A CN 104926798 A CN104926798 A CN 104926798A CN 201410106940 A CN201410106940 A CN 201410106940A CN 104926798 A CN104926798 A CN 104926798A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to a high purity preparation method of Afatinib intermediate, and particularly relates to a high purity preparation method of an antineoplastic treatment medicine maleate Afatinib intermediate (II) compound, the method comprises the following steps: an objective product is obtained sequentially through substitution in two steps, reduction reaction and the like of 6-amino-7-fluoro-3,4-dihydro-quinazolin-4-one. The method is simple in process, economic and environmental-friendly, and suitable for industrial amplification requirements, and the manufactured finished product is high in purity.
Description
Technical field
The present invention relates to organic chemistry and medicinal chemistry art, particularly relate to (S)-N
4the preparation method of-(the chloro-4-fluorophenyl of 3-)-7-((tetrahydrofuran (THF)-3-base) oxygen base)-quinazoline-4,6-diamines.
Background technology
Toxilic acid Ah method is the oral small-molecule drug of a kind of Mutiple Targets researched and developed by the Bo Linge Yin Han nurse company of Germany for Buddhist nun, is the irreversible inhibitor of EGF-R ELISA (EGFR) and people's epidermal receptor 2 (HER2) Tyrosylprotein kinase.It is the tyrosine kinase inhibitor of s-generation efficient double non reversibility.This medicine was the examination & approval of July 12 by U.S. FDA in 2013.Commodity are called Gilotrif.
Toxilic acid Ah method is for Buddhist nun (I), chemistry 4-by name [(the chloro-4-fluorophenyl of 3-) is amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] is amino }-7-((S)-tetrahydrofuran (THF)-3-base oxygen base)-quinazoline 2-maleate.
Current toxilic acid Ah method is in numerous synthetic methods of Buddhist nun, main be all through type (II) compound through condensation, salt-forming steps or prepare through condensation, Witting-Horner, salt-forming steps, formula (II) compound is wherein requisite intermediate.The synthesis of formula (II) compound of patent and bibliographical information is before through type (VII) nitro-compound reduction gained, but the method reported is not aftertreatment trouble, is difficult to industrialization, is exactly can produce dehalogenate impurity in reaction process to be difficult to obtain high purity formula (II) compound.
Find out thus, the requirement preparation method finding new applicable industrialization is most important for the economic technology development of this medicine.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, the preparation method that one is simple, safe, highly purified toxilic acid Ah method replaces Buddhist nun's intermediate and formula (II) compound is provided.
The present invention is realized by following technical proposal:
The method of preparation formula (II) compound, with formula (III) compound for starting raw material, obtains target product after two steps replacements, reduction.
Preferably, described preparation method specifically comprises the steps:
(1) substitution reaction 1: formula (III) compound, chlorination reagent, formula (IV) compound, alkali A, organic solvent A are added in reaction flask and carries out substitution reaction and obtain formula V compound;
(2) substitution reaction 2: formula V compound, formula (VI) compound, alkali B, organic solvent B are added in reaction flask and carries out substitution reaction and obtain formula (VII) compound;
(3) reduction reaction: formula (VII) compound, catalyzer, hydrogen source, organic solvent C are added in reaction flask and carries out reduction reaction and obtain formula (II) compound.
Preferably, in described substitution reaction 1, chlorination reagent is selected from phosphorus oxychloride, thionyl chloride, more preferably phosphorus oxychloride.
Preferably, the alkali A in described substitution reaction 1 is selected from organic bases or mineral alkali, more preferably organic bases, most preferably dimethylamine, diethylamine, triethylamine, pyridine or n-Butyl Lithium, particularly preferably triethylamine.
Preferably, in described substitution reaction 1, chlorination reagent is selected from phosphorus oxychloride or thionyl chloride, more preferably phosphorus oxychloride.
Preferably, the alkali B in described substitution reaction 2 is selected from sodium hydride, potassium hydride KH, hydrolith or potassium tert.-butoxide, more preferably potassium tert.-butoxide;
Preferably, the catalyzer in described reduction reaction is selected from Fe
3o
4, Fe (OH)
3, FeO (OH), FeCl
3, Fe (OAc)
2, more preferably FeCl
3;
Preferably, the hydrogen source in described reduction reaction is selected from ammonium formiate, hydrazine hydrate, ammonium chloride; More preferably hydrazine hydrate.
Preferably, organic solvent A in described substitution reaction 1, substitution reaction 2 and reduction reaction, B and C are selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, ethers, amides, diol, derivatives class, esters solvent or phenol independently of one another, more preferably benzene, toluene, hexanaphthene, methyl alcohol, ethanol, the trimethyl carbinol, ether, acetone, trieline, ethyl acetate, DMF.
Particularly preferred, the organic solvent A in described substitution reaction 1 is selected from acetonitrile and Isosorbide-5-Nitrae-dioxane, and the organic solvent B in described substitution reaction 2 is selected from DMF, and the organic solvent C in described reduction reaction is tetrahydrofuran (THF).
Preferably, the catalyzer in described reduction reaction is selected from Fe
3o
4, Fe (OH)
3, FeO (OH), FeCl
3or Fe (OAc)
2, more preferably FeCl
3.
Preparation method's route of the present invention is short, easy to prepare, greatly can reduce production cost, do not relate to danger or have serious application of poisoning reagent, and final high yield has obtained target compound, be applicable to suitability for industrialized production application.
Accompanying drawing explanation
Fig. 1 is formula (II) compound
1h-nmr spectrum.
Embodiment
Should be appreciated that, those skilled in the art, based on content disclosed herein, can carry out variously not departing from various amendment in spirit and scope of the invention and improvement to the present invention.They should all drop in the scope of patent protection of claim definition of the application.In addition, should be appreciated that, embodiment provided herein only for illustration of object of the present invention, and should not be construed as restriction of the present invention.
Embodiment 1:
Formula (III) compound (50g) joins in acetonitrile (200ml), slowly add phosphorus oxychloride (41.25g), then triethylamine (27g) is instilled, be heated to backflow, and keep backflow 5h, dropping type (IV) compound (38.75g) is dissolved in the mixing solutions of Isosorbide-5-Nitrae-dioxane (250ml).Drip off rear continuation backflow 1h, be down to room temperature and add water (200ml), adjust pH to be 7 ~ 8 with the sodium hydroxide solution of 5N, stir 1h, filter, filter cake use water (200ml × 2) washs, drain, the dry 12h of the air dry oven that solid is 50 DEG C, obtains yellow formula V compound 72g.
Embodiment 2:
Formula (VI) compound (13.6g) adds DMF(385ml) in, put into ice bath stir and add potassium tert.-butoxide (48g) in batches, finish, insulation reaction 1h, add formula V compound 40g and room temperature reaction 2h in batches, slowly add in water (2L), adjust pH to be 7 ~ 8, stirring at room temperature 1h with 2N hydrochloric acid soln, filter, the dry 12h of the air dry oven that solid is 50 DEG C, obtains yellow formula (VII) compound 47g.
Embodiment 3:
By 1.5L THF, formula (VII) compound 100g, gac 10g, FeCl
31g, hydrazine hydrate 100g drop into reaction flask, back flow reaction 3h successively, filter, filtrate stirring at room temperature 4h, and filter, solid is 50 DEG C of air dry oven dryings.Obtain off-white color solid 88g, molar yield 95%, HPLC99.57%.Gained end product structural identification collection of illustrative plates as shown in Figure 1.
1H-NMR（DMSO-d6）δ:2.13(m,1H),2.33(m,1H),3.80(m,1H),3.96(m,3H),5.24(br,1H),5.38(s,2H),7.06(s,1H),7.39(s,1H),7.81(m,1H)，8.20(m,1H)，8.38(s,1H),9.39(s,1H).
Claims (9)
1. a method for preparation formula (II) compound, is characterized in that, described method for starting raw material, obtains target product through steps such as two step replacements, reduction with formula (III) compound,
2. the method for preparation formula according to claim 1 (II) compound, is characterized in that, specifically comprise the steps:
1) substitution reaction 1: formula (III) compound, chlorination reagent, formula (IV) compound, alkali A, organic solvent A are added in reaction flask and carries out substitution reaction and obtain formula V compound;
2) substitution reaction 2: formula V compound, formula (VI) compound, alkali B, organic solvent B are added in reaction flask and carries out substitution reaction and obtain formula (VII) compound;
3) reduction reaction: formula (VII) compound, catalyzer, hydrogen source, organic solvent C are added in reaction flask and carries out reduction reaction and obtain formula (II) compound.
3. the method for preparation formula according to claim 2 (II) compound, it is characterized in that, described organic solvent A, organic solvent B and organic solvent C are selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, ethers, amides, diol, derivatives class, esters solvent or phenol independently of one another; More preferably benzene, toluene, hexanaphthene, methyl alcohol, ethanol, the trimethyl carbinol, ether, acetone, trieline, ethyl acetate or DMF.
4. the method for preparation formula according to claim 2 (II) compound, is characterized in that, described organic solvent A is selected from acetonitrile and Isosorbide-5-Nitrae-dioxane, and described organic solvent B is selected from DMF, and described organic solvent C is selected from tetrahydrofuran (THF).
5. the method for preparation formula according to claim 2 (II) compound, is characterized in that, in described substitution reaction 1, chlorination reagent is selected from phosphorus oxychloride or thionyl chloride, preferred phosphorus oxychloride.
6. the method for preparation formula according to claim 2 (II) compound, is characterized in that, the alkali A in described substitution reaction 1 is selected from organic bases or mineral alkali, preferred organic bases, more preferably dimethylamine, diethylamine, triethylamine, pyridine or n-Butyl Lithium, most preferably triethylamine.
7. the method for preparation formula according to claim 2 (II) compound, is characterized in that, the alkali B in described substitution reaction 2 is selected from sodium hydride, potassium hydride KH, hydrolith or potassium tert.-butoxide, more preferably potassium tert.-butoxide.
8. the method for preparation formula according to claim 2 (II) compound, is characterized in that, the catalyzer in described reduction reaction is selected from Fe
3o
4, Fe (OH)
3, FeO (OH), FeCl
3or Fe (OAc)
2, preferred FeCl
3.
9. the method for preparation formula according to claim 2 (II) compound, is characterized in that, the hydrogen source in described reduction reaction is selected from ammonium formiate, hydrazine hydrate or ammonium chloride; Preferred hydrazine hydrate.
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| CN201410106940.9A CN104926798B (en) | 2014-03-21 | 2014-03-21 | The high-purity preparation method of afatinib intermediate |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175400A (en) * | 2015-09-29 | 2015-12-23 | 河北神威药业有限公司 | Preparation method of Afatinib intermediate |
| CN105712940A (en) * | 2016-02-26 | 2016-06-29 | 南京师范大学 | Preparation method for Afatinib intermediate 6-nitryl-7-chlorol-4-quinazolinone |
| CN107216317A (en) * | 2016-03-21 | 2017-09-29 | 上海医药工业研究院 | A kind of preparation method of afatinib intermediate |
| 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 |
| CN107488153A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of afatinib intermediate compound |
| CN111518088A (en) * | 2020-06-10 | 2020-08-11 | 山东创新药物研发有限公司 | Preparation method and application of aniline quinazoline intermediate |
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| CN1956966A (en) * | 2004-02-19 | 2007-05-02 | 雷克斯安公司 | Quinazoline derivatives and therapeutic use thereof |
| CN101723906A (en) * | 2008-10-10 | 2010-06-09 | 山西仁源堂药业有限公司 | Compound, medical composition containing same as well as preparation method and application |
| CN102686581A (en) * | 2009-12-21 | 2012-09-19 | 张强 | Novel quinazoline derivatives |
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2014
- 2014-03-21 CN CN201410106940.9A patent/CN104926798B/en active Active
Patent Citations (4)
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| CN1539805A (en) * | 2003-10-24 | 2004-10-27 | 中国科学院广州化学研究所 | Method for synthesizing pterostilbene |
| CN1956966A (en) * | 2004-02-19 | 2007-05-02 | 雷克斯安公司 | Quinazoline derivatives and therapeutic use thereof |
| CN101723906A (en) * | 2008-10-10 | 2010-06-09 | 山西仁源堂药业有限公司 | Compound, medical composition containing same as well as preparation method and application |
| CN102686581A (en) * | 2009-12-21 | 2012-09-19 | 张强 | Novel quinazoline derivatives |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175400A (en) * | 2015-09-29 | 2015-12-23 | 河北神威药业有限公司 | Preparation method of Afatinib intermediate |
| CN105175400B (en) * | 2015-09-29 | 2018-04-10 | 河北神威药业有限公司 | A kind of preparation method of afatinib intermediate |
| CN105712940A (en) * | 2016-02-26 | 2016-06-29 | 南京师范大学 | Preparation method for Afatinib intermediate 6-nitryl-7-chlorol-4-quinazolinone |
| CN107216317A (en) * | 2016-03-21 | 2017-09-29 | 上海医药工业研究院 | A kind of preparation method of afatinib intermediate |
| CN107216317B (en) * | 2016-03-21 | 2020-04-07 | 上海医药工业研究院 | Preparation method of afatinib intermediate |
| 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 |
| CN107488153A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of afatinib intermediate compound |
| CN107488153B (en) * | 2016-06-10 | 2020-06-23 | 山东新时代药业有限公司 | Afatinib intermediate compound |
| CN111518088A (en) * | 2020-06-10 | 2020-08-11 | 山东创新药物研发有限公司 | Preparation method and application of aniline quinazoline intermediate |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL Co.,Ltd. |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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