CN103508945A - Preparation method of 2-chloro-4-methyl nicotinonitrile - Google Patents
Preparation method of 2-chloro-4-methyl nicotinonitrile Download PDFInfo
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- CN103508945A CN103508945A CN201210213277.3A CN201210213277A CN103508945A CN 103508945 A CN103508945 A CN 103508945A CN 201210213277 A CN201210213277 A CN 201210213277A CN 103508945 A CN103508945 A CN 103508945A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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Abstract
The invention discloses a preparation method of 2-chloro-4-methyl nicotinonitrile. The preparation method disclosed by the invention comprises the following steps: with (E)-4-(dimethylamine) yl-3-butene-2-ketone and malononitrile as raw materials, catalyzing and condensing; and finally, chlorinating closed-loops to obtain 2-chloro-4-methyl nicotinonitrile under the effect of phosphorus oxychloride and phosphorus pentachloride. The total yield of the two reactions can reach 55.7%. The preparation method is simple in process, convenient to operate, low in equipment demand and very applicable to industrial production.
Description
Technical field
The present invention relates to the preparation method of the chloro-4-methyl of a kind of 2-nicotinic acid nitrile.
Background technology
CN101157654 be take acetone, manthanoate and sodium methylate and through sodium salt, addition, is obtained 4 as raw material, 4-dimethoxy fourth-2-ketone, then react, be hydrolyzed closed loop, by phosphorus oxychloride chloro, obtain the chloro-4-methyl of 2-nicotinic acid nitrile, total recovery 43.8% (in propane dinitrile) through Knoevenagel with propane dinitrile.
US2002052507 reacts, is hydrolyzed closed loop, by phosphorus oxychloride chloro, obtains the chloro-4-methyl of 2-nicotinic acid nitrile, total recovery 75.6% (in propane dinitrile) through Knoevenagel with 4,4-dimethoxy fourth-2-ketone and propane dinitrile.
WO0043365 reacts through Knoevenagel with acetone and propane dinitrile, again with triethyl orthoformate acetic anhydride solution reaction, cyclization under anhydrous NH3/ ethanol, obtains the chloro-4-methyl of 2-nicotinic acid nitrile, total recovery 14.0% (in propane dinitrile) through Sang De mayer and chlorination reaction.
US5668287 with methyl aceto acetate and Malonamide nitrile under potassium hydroxide existence condition through condensation closed loop, then use phosphorus oxychloride chloro, through catalytic hydrogenation, obtaining 4-methyl nicotinic acid nitrile, yield 63.3%.After also need to carry out selective chlorination.
All there is variety of issue in above-mentioned synthetic method, the raw material 4 that wherein CN101157654 and US2002052507 use, and 4-dimethoxy fourth-2-ketone is not very stable, yield does not have document said so high by experiment.The product of the Knoeveangel of WO0043365 is not to be easy to carry out with reacting of triethyl orthoformate acetic anhydride solution, and this route is longer simultaneously, and yield is very low.This step of US5668287 catalytic hydrogenation is used expensive palladium carbon or Palladous chloride, and reaction be not to be easy to carry out, can produce a series of impurity, finally also need to carry out selective chlorination and obtain the chloro-4-methyl of 2-nicotinic acid nitrile.
Summary of the invention
The preparation method who the object of this invention is to provide the chloro-4-methyl of a kind of 2-nicotinic acid nitrile (formula I), is comprised of following two steps:
The first step, take (E)-4-(dimethylamine) base-3-alkene-2-butanone and propane dinitrile is raw material, catalyzer (piperidines, Beta-alanine and piperidines acetate, Beta-alanine acetate), solvent (methyl alcohol, toluene, methyl tertiary butyl ether), at 0～100 ℃, drip above-mentioned raw materials, then at 0～100 ℃ of reaction 1～24h, preparation 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-Pentadienamide;
Second step, with 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-Pentadienamide and phosphorus oxychloride, phosphorus pentachloride are raw material, at 0～150 ℃ of reaction 1～24h, the chloro-4-methyl of preparation 2-nicotinic acid nitrile;
The preparation method of the chloro-4-methyl of above-described 2-nicotinic acid nitrile, it is characterized in that preparing the chloro-4-methyl of 2-nicotinic acid nitrile raw material used for preparing and the more stable industrial chemicals of chemical property than being easier to, processing unit requires simply, reaction conditions is gentle, be applicable to suitability for industrialized production, thick product purity can reach more than 96%.
The preparation method of the chloro-4-methyl of above-described 2-nicotinic acid nitrile, is characterized in that catalyzer used in the first step is piperidines, Beta-alanine and piperidines acetate, Beta-alanine acetate, preferably Beta-alanine acetate.
The preparation method of the chloro-4-methyl of above-described 2-nicotinic acid nitrile, is characterized in that solvent used in the first step is methyl alcohol, toluene, methyl tertiary butyl ether, particular methanol.
The preparation method of the chloro-4-methyl of above-described 2-nicotinic acid nitrile, is characterized in that the Heating temperature described in the first step is 0～100 ℃, is preferably 20～30 ℃.
The preparation method of the chloro-4-methyl of above-described 2-nicotinic acid nitrile, is characterized in that chlorination reagent used in second step can be the mixture of phosphorus oxychloride, phosphorus oxychloride and phosphorus pentachloride, preferably phosphorus oxychloride.
The preparation method of the chloro-4-methyl of above-described 2-nicotinic acid nitrile, is characterized in that the Heating temperature described in second step is 0～150 ℃, is preferably 80～110 ℃.
Embodiment
Embodiment mono-,
(1) 2-cyano group-5-(dimethylamine) base-3-methyl-2, the preparation of 4-Pentadienamide
In the 250mL four-hole boiling flask with mechanical stirring, thermometer, add 100mL methyl alcohol, then add 3g (0.05mol) Glacial acetic acid, 0.2g Beta-alanine and 23.1g (0.204mol) (E)-4-(dimethylamine) base-3-alkene-2-butanone, stir and use water-bath cooling.Under room temperature, drip 13.2g (0.2mol) propane dinitrile, time for adding is 1～2h approximately.Stirring reaction 24h at room temperature after propane dinitrile finishes.Reaction finishes, and with ice-water bath, is cooled to 5～10 ℃.Suction filtration, 10mL ice methanol wash for filter cake, dries filter cake and obtains 47.5g orange solid, i.e. 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-limonene acid amides.Yield: 88.4%; Purity: 98%.
(2) preparation of the chloro-4-methyl of 2-nicotinic acid nitrile
In the 250mL four-hole boiling flask with mechanical stirring, thermometer and spherical condensating tube, add 17.9g (0.1mol) 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-limonene acid amides and 23g (0.15mol) phosphorus oxychloride, stirs.With oil bath, be slowly heated to reflux, (105～110 ℃) reaction 5h refluxes.With water-bath, be cooled to room temperature, then reaction solution slowly splashed in 100mL frozen water, have a large amount of heat and hydrogen chloride gas and generate, tail gas absorbs with sodium hydroxide solution.Use 100mL dichloromethane extraction, evaporate to dryness organic phase, obtains 9.6g brown solid again, yield 63%, purity 96%.
Embodiment bis-,
(1) 2-cyano group-5-(dimethylamine) base-3-methyl-2, the preparation of 4-Pentadienamide
As synthetic in the method for embodiment mono-(1) and condition, only catalyzer is changed to piperidines acetate, make 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-limonene acid amides, yield 75.5%, purity 98.3%.
(2) preparation of the chloro-4-methyl of 2-nicotinic acid nitrile
As synthetic in the method for embodiment mono-(2) and condition, only chlorination reagent phosphorus oxychloride is changed to the mixture of phosphorus oxychloride (1.5eq) and phosphorus pentachloride (0.5eq), make the chloro-4-methyl of 2-nicotinic acid nitrile, yield 62%, purity 93%.
Embodiment tri-,
(1) 2-cyano group-5-(dimethylamine) base-3-methyl-2, the preparation of 4-Pentadienamide
As synthetic in the method for embodiment mono-(1) and condition, only catalyzer is changed to piperidines, make 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-limonene acid amides, yield 63%, purity 93.2%.
(2) preparation of the chloro-4-methyl of 2-nicotinic acid nitrile
As synthetic in the method for embodiment mono-(2) and condition.
Embodiment tetra-,
(1) 2-cyano group-5-(dimethylamine) base-3-methyl-2, the preparation of 4-Pentadienamide
As synthetic in the method for embodiment mono-(1) and condition, only catalyzer is changed to Beta-alanine, make 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-limonene acid amides, yield 69.3%, purity 97.2%.
(2) preparation of the chloro-4-methyl of 2-nicotinic acid nitrile
As synthetic in the method for embodiment mono-(2) and condition, only temperature of reaction is changed to 80～85 ℃, make the chloro-4-methyl of 2-nicotinic acid nitrile, yield 37.6%, purity 87.7%.
Embodiment five,
(1) 2-cyano group-5-(dimethylamine) base-3-methyl-2, the preparation of 4-Pentadienamide
As synthetic in the method for embodiment mono-(1) and condition, only solvent is changed to toluene, make 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-limonene acid amides, yield 83.3%, purity 93.7%.
(2) preparation of the chloro-4-methyl of 2-nicotinic acid nitrile
As synthetic in the method for embodiment mono-(2) and condition.
Embodiment six,
(1) 2-cyano group-5-(dimethylamine) base-3-methyl-2, the preparation of 4-Pentadienamide
As synthetic in the method for embodiment mono-(1) and condition, only solvent is changed to methyl tertiary butyl ether, make 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-limonene acid amides, yield 78.5%, purity 92.3%.
(2) preparation of the chloro-4-methyl of 2-nicotinic acid nitrile
As synthetic in the method for embodiment mono-(2) and condition.
Claims (7)
1. a preparation method for the chloro-4-methyl of 2-nicotinic acid nitrile (formula I), is comprised of following two steps:
The first step, take (E)-4-(dimethylamine) base-3-alkene-2-butanone and propane dinitrile is raw material, catalyzer (piperidines, Beta-alanine and piperidines acetate, Beta-alanine acetate), at 0～100 ℃, drip above-mentioned raw materials, then at 0～100 ℃ of reaction 1～24h, preparation 2-cyano group-5-(dimethylin)-3-methyl-2,4-Pentadienamide;
Second step, with 2-cyano group-5-(dimethylamine) base-3-methyl-2,4-Pentadienamide and phosphorus oxychloride, phosphorus pentachloride are raw material, at 0～150 ℃ of reaction 1～24h, the chloro-4-methyl of preparation 2-nicotinic acid nitrile.
2. method according to claim 1, it is characterized in that preparing the chloro-4-methyl of 2-nicotinic acid nitrile raw material used for preparing and the more stable industrial chemicals of chemical property than being easier to, processing unit requires simply, reaction conditions is gentle, be applicable to suitability for industrialized production, thick product purity can reach more than 96%.
3. according to the method described in claim 1～2, it is characterized in that catalyzer used in the first step is piperidines, Beta-alanine and piperidines acetate, Beta-alanine acetate, preferably Beta-alanine acetate.
4. according to the method described in claim 1～2, it is characterized in that solvent used in the first step is methyl alcohol, toluene, methyl tertiary butyl ether, particular methanol.
5. according to the method described in claim 1～2, it is characterized in that the Heating temperature described in the first step is 0～100 ℃, be preferably 20～30 ℃.
6. according to the method described in claim 1～2, it is characterized in that chlorination reagent used in second step can be the mixture of phosphorus oxychloride, phosphorus oxychloride and phosphorus pentachloride, preferably phosphorus oxychloride.
7. according to the method described in claim 1～2, it is characterized in that the Heating temperature described in second step is 0～150 ℃, be preferably 80～110 ℃.
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| CN201210213277.3A CN103508945A (en) | 2012-06-26 | 2012-06-26 | Preparation method of 2-chloro-4-methyl nicotinonitrile |
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| CN201210213277.3A CN103508945A (en) | 2012-06-26 | 2012-06-26 | Preparation method of 2-chloro-4-methyl nicotinonitrile |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015031718A1 (en) * | 2013-08-29 | 2015-03-05 | Mcquade D Tyler | Methods of making 2-halonicotinonitriles |
| CN114181143A (en) * | 2021-12-03 | 2022-03-15 | 京博农化科技有限公司 | Preparation method of 3-cyano-2, 6-dichloro-4- (trifluoromethyl) pyridine |
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| US20020052507A1 (en) * | 2000-10-10 | 2002-05-02 | Gupton Bernard Franklin | Process for making 3-amino-2-chloro-4-methylpyridine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015031718A1 (en) * | 2013-08-29 | 2015-03-05 | Mcquade D Tyler | Methods of making 2-halonicotinonitriles |
| US9951020B2 (en) | 2013-08-29 | 2018-04-24 | Virginia Commonwealth University | Methods of making 2-halonicotinonitriles |
| CN114181143A (en) * | 2021-12-03 | 2022-03-15 | 京博农化科技有限公司 | Preparation method of 3-cyano-2, 6-dichloro-4- (trifluoromethyl) pyridine |
| CN114181143B (en) * | 2021-12-03 | 2023-06-30 | 山东京博农化科技股份有限公司 | Preparation method of 3-cyano-2, 6-dichloro-4- (trifluoromethyl) pyridine |
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