CN104744302A - Preparation method of 2-(4-aminophenyl)-2-methyl propionitrile compound - Google Patents
Preparation method of 2-(4-aminophenyl)-2-methyl propionitrile compound Download PDFInfo
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- CN104744302A CN104744302A CN201310750190.4A CN201310750190A CN104744302A CN 104744302 A CN104744302 A CN 104744302A CN 201310750190 A CN201310750190 A CN 201310750190A CN 104744302 A CN104744302 A CN 104744302A
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Abstract
The invention relates to a preparation method a 2-(4-aminophenyl)-2-methyl propionitrile compound. The preparation method comprises the following steps: by taking DMF as a solvent, carrying out methylation on nitrophenylacetonitrile and methyl iodide under the action of sodium hydride to obtain an intermediate product; and carrying out iron powder reduction to obtain 2-(4-aminophenyl)-2-methyl propionitrile, wherein the total recovery of the reaction is higher than 80%. The preparation method has the advantages of being easily available in raw materials, mild in reaction condition, simple in postprocessing process, high in yield and suitable for industrial production, and the like, has good application prospect and provides a novel way for the synthesis of propionitrile compounds.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, specifically the preparation method of 2-(4-aminophenyl)-2-methyl-prop nitrile compound.
Background technology
2-(4-aminophenyl)-2-methyl propionitrile is a kind of important medicine intermediate, is mainly used in synthetic proteins kinase inhibitor, angiogenesis inhibitor etc.2-(4-aminophenyl)-2-methyl propionitrile synthetic method is many, and committed step, in this step of nitroreduction, as US2009/137595A1, is mentioned in 2009 and used Pd/c to carry out reduction reaction as catalyzer; US2012/108583A1, mentions in 2012 and uses tin chloride to carry out reduction reaction as catalyzer.But above-mentioned catalyzer is expensive, aftertreatment is difficult, and easily causes very large pollution to environment.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of 2-(4-aminophenyl)-2-methyl-prop nitrile compound, the method adopts reductibility iron powder to be catalyzer, has reaction conditions gentleness, last handling process is simple, yield is high, free from environmental pollution, is applicable to the advantages such as suitability for industrialized production.
Method of the present invention can represent with following reaction formula:
Using DMF as solvent, para orientation nitration (compound 1) is under sodium hydride effect, with methyl iodide generation methylation reaction, intermediate product 2-(4-nitrophenyl)-2-methyl propionitrile (compound 2) obtained, again through iron powder reducing, obtain 2-(4-aminophenyl)-2-methyl propionitrile (compound 3).
Synthetic method of the present invention comprises the steps:
A：
The DMF (4-6v/v) of ice is added 60%NaH (2.4-2.6eq).Para orientation nitration (compound 1 is dripped at 0-5 DEG C, DMF (3-5v/v) solution 1.0-1.23mo1), and keep this temperature, dropwise, keep reaction 0.5-2 hour, slow dropping MeI (2.85-3eq), then be naturally raised to room temperature to react, TLC monitoring reaction is to reacting completely, by reaction controlling to 0-5 DEG C, drip the NaH that 10-15ml water destruct is unnecessary, then add water (21-23v/v), obtain suction filtration after abundant stirring, after oven dry, obtain 2-(4-nitrophenyl)-2-methyl propionitrile (compound 2).
B：
By 2-(4-nitrophenyl)-2-methyl propionitrile (1eq), reductibility iron powder (2-4eq), 10% ammonium chloride (0.1-0.3eq), 75% ethanol (7.8-10v/v), reflux, till TLC detection raw material reaction is complete, be down to room temperature, suction filtration, add ethyl acetate (2.5-3v/v) after filtrate is concentrated to dissolve, alkalize is washed with saturated sodium bicarbonate solution, wash with saturated common salt, anhydrous magnesium sulfate drying, crude product obtains high purity 2-(4-aminophenyl)-2-methyl propionitrile (compound 3) after ethanol (7.5-9v/v) recrystallization.
To contribute to understanding the present invention by following embodiment, but be not restricted to content of the present invention.
The synthetic method of embodiment 1 2-(4-nitrophenyl)-2-methyl propionitrile (compound 2)
The 1000ml DMF of ice is added 60%130gNaH, the DMF800ml solution of 200g para orientation nitration (compound 1) is dripped at 5 DEG C, and keep this temperature, dropwise, keep reaction 1 hour, slow dropping MeI526g, naturally be raised to room temperature to react, TLC monitoring reaction is to reacting completely, by reaction controlling to 5 DEG C, drip the NaH that 15ml water destruct is unnecessary, then add 4000ml water, obtain suction filtration after abundant stirring, after oven dry, obtain 230g2-(4-nitrophenyl)-2-methyl propionitrile (compound 2).
The synthetic method of embodiment 2 2-(4-aminophenyl)-2-methyl propionitrile (compound 3)
By 230g2-(4-nitrophenyl)-2-methyl propionitrile (compound 2), reductibility iron powder 196g (be namely 3:1 with the mol ratio of compound 2), 21g10% ammonium chloride, 2000m175% ethanol, reflux, till TLC detection raw material reaction is complete, be down to room temperature, suction filtration, 600ml acetic acid ethyl dissolution is added after filtrate is concentrated, alkalize is washed with saturated sodium bicarbonate solution, wash with saturated common salt, anhydrous magnesium sulfate drying, crude product obtains high purity 158g2-(4-aminophenyl)-2-methyl propionitrile (compound 3) after 1800ml ethyl alcohol recrystallization, yield is 89%.
Its physicochemical data is as follows:
1hNMR (CDCl
3): δ 1.67 (s, 6H), 3.48 (S, 2H) 6.68 (d, J=8.7Hz, 2H) 7.24 (d, J=8.7Hz, 2H) synthetic method of embodiment 3 2-(4-aminophenyl)-2-methyl propionitrile (compound 3)
By 230g2-(4-nitrophenyl)-2-methyl propionitrile (compound 2), reductibility iron powder 131g (be namely 2:1 with the mol ratio of compound 2), 21g10% ammonium chloride, 2000m175%7 alcohol, reflux, till TLC detection raw material reaction is complete, be down to room temperature, suction filtration, 600ml acetic acid ethyl dissolution is added after filtrate is concentrated, alkalize is washed with saturated sodium bicarbonate solution, wash with saturated common salt, anhydrous magnesium sulfate drying, crude product obtains high purity 150g2-(4-aminophenyl)-2-methyl propionitrile (compound 3) after 1800ml ethyl alcohol recrystallization, yield is 84%.
The synthetic method of embodiment 4 2-(4-aminophenyl)-2-methyl propionitrile (compound 3)
By 230g2-(4-nitrophenyl)-2-methyl propionitrile (compound 2), reductibility iron powder 262g (be namely 4:1 with the mol ratio of compound 2), 21g10% ammonium chloride, 2000m175% ethanol, reflux, till TLC detection raw material reaction is complete, be down to room temperature, suction filtration, 600ml acetic acid ethyl dissolution is added after filtrate is concentrated, alkalize is washed with saturated sodium bicarbonate solution, wash with saturated common salt, anhydrous magnesium sulfate drying, crude product obtains high purity 156g2-(4-aminophenyl)-2-methyl propionitrile (compound 3) after 1800ml ethyl alcohol recrystallization, yield is 88%.
Claims (3)
1. the preparation method of 2-(4-aminophenyl)-2-methyl-prop nitrile compound, it comprises using DMF as solvent, para orientation nitration (compound 1) is under sodium hydride effect, with methyl iodide generation methylation reaction, intermediate product 2-(4-nitrophenyl)-2-methyl propionitrile (compound 2) obtained, again through catalyst reduction, obtain 2-(4-aminophenyl)-2-methyl propionitrile (compound 3), it is characterized in that adopting reductibility iron powder as catalyzer.
2. the method for claim 1, is characterized in that the mol ratio that described reductibility iron powder and intermediate product 2-(4-nitrophenyl)-2-methyl propionitrile (compound 2) react is 4-2:1.
3. the method for claim 1, is characterized in that the mol ratio that described reductibility iron powder and intermediate product 2-(4-nitrophenyl)-2-methyl propionitrile (compound 2) react is 3:1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113999136A (en) * | 2021-12-07 | 2022-02-01 | 山东第一医科大学(山东省医学科学院) | Rheum officinale amide derivative, preparation method and application thereof, and liver cancer inhibitor specifically expressed by RECQL4 |
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| US20080161302A1 (en) * | 2005-05-18 | 2008-07-03 | F2G Ltd. | Antifungal Agents |
| CN101541801A (en) * | 2006-08-04 | 2009-09-23 | 武田药品工业株式会社 | Fused heterocyclic derivative and use thereof |
| CN102199152A (en) * | 2010-03-25 | 2011-09-28 | 高大新 | Heterocycle imidazoles phosphatide kinases inhibitor |
| US20130040973A1 (en) * | 2011-08-10 | 2013-02-14 | Incyte Corporation | JAK PI3K/mTOR COMBINATION THERAPY |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080161302A1 (en) * | 2005-05-18 | 2008-07-03 | F2G Ltd. | Antifungal Agents |
| CN101541801A (en) * | 2006-08-04 | 2009-09-23 | 武田药品工业株式会社 | Fused heterocyclic derivative and use thereof |
| CN102199152A (en) * | 2010-03-25 | 2011-09-28 | 高大新 | Heterocycle imidazoles phosphatide kinases inhibitor |
| US20130040973A1 (en) * | 2011-08-10 | 2013-02-14 | Incyte Corporation | JAK PI3K/mTOR COMBINATION THERAPY |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999136A (en) * | 2021-12-07 | 2022-02-01 | 山东第一医科大学(山东省医学科学院) | Rheum officinale amide derivative, preparation method and application thereof, and liver cancer inhibitor specifically expressed by RECQL4 |
| CN113999136B (en) * | 2021-12-07 | 2023-08-04 | 山东第一医科大学(山东省医学科学院) | Rhein derivative, preparation method and application thereof, and liver cancer inhibitor specifically expressed by RECQL4 |
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Application publication date: 20150701 |