CN101891649B - Novel 3-cyano methyl benzoate preparing method - Google Patents
Novel 3-cyano methyl benzoate preparing method Download PDFInfo
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Abstract
The invention relates to a novel 3-cyano methyl benzoate preparing method. A reaction comprises the two steps that: 1, raw materials including 3-chloromethyl methyl benzoate, an N-containing compound and a phase transfer catalyst undergo a nucleophilic substitution reaction in alkaline solution to generate sievert salt, the sievert salt is hydrolyzed in heated acid to generate pure 3-aldehyde methyl benzoate products, and 3-aldehyde methyl benzoate is obtained by a subsequent treatment process; and 2, the 3-aldehyde methyl benzoate, hydroxylamine and industrial formic acid undergo a reflux reaction, water generated in a reaction process is separated by solid ion exchange technology, and crude products are crystallized and refined to give the pure 3-cyano methyl benzoate product. The novel 3-cyano methyl benzoate preparing method has the advantages of simple process, low production cost, mild reaction condition, high product yield, high product purity and environmental friendliness. When the method is used, the total yield can reach over 80 percent; the 3-cyano methyl benzoate content can reach 98 percent; the product quality is high; and thus, the method is suitable for industrial mass production.
Description
Technical field
The present invention relates to a kind of new production process of the 3-of preparation cyano-benzoic acid methyl ester.
Background technology
The 3-cyano-benzoic acid methyl ester is a kind of important organic synthesis intermediate.Being widely used in preparing cardiovascular drugs (XR-9051, Britain Xenova company), microbiotic, anodyne and neural system and regulating (CN1316416A) such as class medicines, is also the important source material of synthetic liquid crystal material.
The synthetic method of existing 3-cyano-benzoic acid methyl ester compound mainly contains following several:
Method one: utilize the 3-cyanobenzoic acid as raw material, methyl alcohol is as esterifying reagent, and by different approach, the 3-cyano-benzoic acid methyl ester is synthesized in reaction.
As: utilize oxalyl chloride with 3-cyanobenzoic acid acidylate, then obtain 3-cyano-benzoic acid methyl ester (WO2005020899, WO2005021500) with methanol esterification.Utilize sulfur oxychloride with 3-cyanobenzoic acid acidylate, then obtain 3-cyano-benzoic acid methyl ester (" bioorganic chemistry ", 11 (19), 4189-4206 with methanol esterification; 2003).Utilize the reaction of Anhydrous potassium carbonate and 3-cyanobenzoic acid to generate 3-cyanobenzoic acid potassium, then generate 3-cyano-benzoic acid methyl ester (WO2006044503) with iodomethane reaction.
The method has following defective: use oxalyl chloride, sulfur oxychloride, thereby the three wastes are many; Raw material methyl iodide in reaction is difficult to obtain, thereby cost is higher; Raw material 3-cyanobenzoic acid is difficult to separate with the 3-cyano-benzoic acid methyl ester, can affect the content of product 3-cyano-benzoic acid methyl ester, therefore the having little significance of suitability for industrialized production.
Method two: utilize 3-halogenated benzoic acid methyl esters as raw material, prussiate synthesizes the 3-cyano-benzoic acid methyl ester as replacing reagent by different approaches.
As: utilize 3-Chlorobenzoic Acid methyl esters and zinc cyanide at (Ph
2P)
2Under the condition of-ferrocene as catalyzer, synthetic 3-cyano-benzoic acid methyl ester (" tetrahedron communication ", 2005,46 (11): 1815-1818).Utilize 3-bromobenzoic acid methyl esters and cuprous cyanide under the condition of DMF as solvent, synthetic 3-cyano-benzoic acid methyl ester (" tetrahedron communication ", 2000,41 (18): 3271-3273).Utilize 3-bromobenzoic acid methyl esters and potassium cyanide at DMF as solvent, Pd (PPh
3)
4Do under the condition of catalyzer synthetic 3-cyano-benzoic acid methyl ester (" Czechoslovakia's chemical communication ", 1983,48 (6): 1765-73).Utilize 3-Chlorobenzoic Acid methyl esters and potassium cyanide at DMF as solvent, Pd (PPh
3)
4Do under the condition of catalyzer synthetic 3-cyano-benzoic acid methyl ester (" organic chemistry magazine ", 1979,44 (24): 4443-4).
The method is owing to having used hypertoxic prussiate (as potassium cyanide, zinc cyanide, cuprous cyanide) as cyanating reagent, and the three wastes are difficult to process, thereby industrialization is also more difficult.
Summary of the invention
The objective of the invention is for above-mentioned present situation, aim to provide and a kind ofly can satisfy industrialization production requirements, yield and the purity of product are high, the new production process of the preparation 3-cyano-benzoic acid methyl ester that environmental pollution is little, cost is low.
The implementation of the object of the invention is, a kind of new production process for preparing the 3-cyano-benzoic acid methyl ester, and reaction is carried out in two steps:
The first step, 3-chloromethyl benzoic acid methyl esters, contain N compound, phase-transfer catalyst in weakly alkaline solution, 100 ℃-110 ℃ backflow 1-18 hour, nucleophilic substitution reaction occurs generate not salt of west, then back hydrolysis 1-18h in the acid of 100-110 ℃, generate 3-aldehyde benzoic acid methyl esters, with water-fast polar organic solvent extracting and demixing, the organic phase of extraction washes with water successively until neutral, and after the organic phase drying, normal pressure steams solvent, then fraction is collected in underpressure distillation, obtain 3-aldehyde benzoic acid methyl esters sterling
Described phase-transfer catalyst refers to contain N salt, crown ether, PEG class, as cetyl trimethylammonium bromide, and PEG-400, hexaoxacyclooctadecane-6-6,4-(dimethylamino)-N-(2-ethyl) hexyl pyridine () salt,
The described N of containing compound refers to hexamethylenetetramine, ammoniacal liquor, urea or volatile salt class,
Described acid refers to contain technical hydrochloric acid, industrial sulphuric acid, industrial phosphoric acid or industrial nitric acid class,
Described water-fast polar organic solvent refers to 1,2-ethylene dichloride,
Second step, 3-aldehyde benzoic acid methyl esters and azanol, industrial formic acid are at 100 ℃ of-110 ℃ of back flow reaction 1-18h, by the Solid-state Ion-exchange device except the water in formic acid removal, with water-fast polar organic solvent extracting and demixing, the organic phase of extraction washes with water successively until neutral, and after the organic phase drying, normal pressure steams solvent, then fraction is collected in underpressure distillation, get 3-cyano-benzoic acid methyl ester sterling
Described water-fast polar organic solvent refers to 1,2-ethylene dichloride,
Concrete reaction formula is:
The present invention adopt contain 3-chloromethyl benzoic acid methyl esters first with contain N compound, phase-transfer catalyst and nucleophilic substitution reaction occurs in weakly alkaline solution generate not salt of west, then be hydrolyzed generation aldehyde benzoic acid methyl esters in the acid of being heated; The aldehyde benzoic acid methyl esters generates cyano-benzoic acid methyl ester with the dehydration of azanol class substance reaction again, and its technique is simple, production cost is low, and reaction conditions is gentle, and the three wastes are few, and environmental pollution is little, and yield and the purity of product are high.Adopt the present invention, total recovery can reach more than 80%, and the content of 3-cyano-benzoic acid methyl ester can reach 98%,, quality product is high, is suitable for industrialized mass.
Embodiment
Reaction of the present invention is carried out in two steps:
The first step, 3-chloromethyl benzoic acid methyl esters, contain N compound, phase-transfer catalyst in basic solution, at 100-110 ℃ of backflow 1-18 hour, nucleophilic substitution reaction occurs generate not salt of west, then back hydrolysis 1-18h in the acid of 100-110 ℃, generate 3-aldehyde benzoic acid methyl esters, with water-fast polar organic solvent extracting and demixing, the organic phase of extraction washes with water successively until neutral, after the organic phase drying, normal pressure steams solvent, fraction is collected in underpressure distillation again, gets 3-aldehyde benzoic acid methyl esters sterling.
Second step, 3-aldehyde benzoic acid methyl esters and azanol, industrial formic acid are at 100 ℃ of-110 ℃ of back flow reaction 1-18h, by the Solid-state Ion-exchange device except the water in formic acid removal, with water-fast polar organic solvent extracting and demixing, the organic phase of extraction washes with water successively until neutral, after the organic phase drying, normal pressure steams solvent, and crude product gets 3-cyano-benzoic acid methyl ester sterling through rectification under vacuum or recrystallization.
The below describes the present invention in detail with specific embodiment:
Embodiment 1, with the 3-chloromethyl benzoic acid methyl esters of 2.5Kmol, the hexamethylenetetramine of 5Kmol, the water of 1500Kg, the PEG-400 of 5Kg add in the enamel reaction still of 3000l, heat up to accelerate to stir, when material temperature reached 70-80 ℃, solid was entirely molten.Refluxed 10 hours when being warmed up to 100-110 ℃.When material temperature drops to 80 ℃, drip 50% nitric acid of 660 liters, refluxed 2 hours.Reaction is finished, and cools to room temperature.
In reactor, add 500kg water, add 100 liter 1, the 2-ethylene dichloride stirred standing demix 30 minutes.The organic phase of extraction is with 100 liter 1, and the 2-ethylene dichloride stirs extraction once, standing demix.Merge organic layer.Organic layer 150 premium on currency, standing, tell lower floor's organic layer, remove upper aqueous layer.Organic layer repeatedly washs to neutrality.
1,2-ethylene dichloride is reclaimed in the organic layer air distillation.Cooling, crystallization, suction filtration gets the crystallization of micro-yellow powder shape 3-aldehyde benzoic acid methyl esters, and content is more than 98%.
In 1000 liters of reactors of mechanical stirrer, thermometer, reflux exchanger and Solid-state Ion-exchange device are housed, add successively people 1Kmol 3-aldehyde benzoic acid methyl esters, 1.06Kmol oxammonium hydrochloride, 500 liters of industrial formic acid.Start stirring, heating, when reacting liquid temperature rose to approximately 95 ℃, reactant all dissolved, and backflows that come to life in the time of 110 ℃ removes moisture content in formic acid removal through the Solid-state Ion-exchange device.The analysis showed that through GC, after backflow 18h, 3-aldehyde benzoic acid methyl esters transforms substantially fully.Beginning to heat up steams solvent, to almost all steaming, finishes reaction.After remaining liquid cooling but, then add 300L water, 500 liter 1, the 2-ethylene dichloride divides to add the anhydrous sodium carbonate powder three times, and regulating the pH value is 9-10.Stir standing demix.Tell lower floor's organic layer, remove upper aqueous layer.Water layer is used 50 liter 1 again, and the 2-ethylene dichloride stirs extraction once, standing demix.Merge organic layer.Organic layer adds 150 premium on currency again, and extraction once, and is standing, tells organic layer, removes water layer.Organic layer repeatedly washs to neutrality.
1,2-ethylene dichloride is reclaimed in the first air distillation of organic layer.Cooling, crystallization, suction filtration gets the crystallization of little yellow sand shape 3-cyano-benzoic acid methyl ester.
Embodiment 2, with the 3-chloromethyl benzoic acid methyl esters of 1.5Kmol, the volatile salt of 3Kmol, the water of 2000Kg, the cetyl trimethylammonium bromide of 3Kg add in the enamel reaction still of 3000l, heat up to accelerate to stir, when material temperature reached 70-80 ℃, solid was entirely molten.Refluxed 16 hours when being warmed up to 100-110 ℃.When material temperature drops to 80 ℃, drip 30% concentrated hydrochloric acid of 500 liters, refluxed 1 hour.Reaction is finished, and cools to room temperature.
Add 300 liter 1 in reactor, the 2-ethylene dichloride stirred standing demix 30 minutes.Lower floor's (organic layer) contains product and continues to employ.Use 100 liter 1, the 2-ethylene dichloride stirs extraction once, standing demix again.Merge organic layer.Organic layer 150 premium on currency, standing, tell organic layer.Organic layer repeatedly washs to neutrality.
1,2-ethylene dichloride is reclaimed in the organic layer air distillation.Cooling, crystallization, suction filtration gets the crystallization of micro-yellow powder 3-aldehyde benzoic acid methyl esters, and content is more than 98%.
In 1500 liters of reactors of mechanical stirrer, thermometer, reflux exchanger and Solid-state Ion-exchange device are housed, add successively people 1Kmol 3-aldehyde benzoic acid methyl esters, 1.2Kmol oxammonium hydrochloride, 500 liters of industrial formic acid.Start stirring, heating, when reacting liquid temperature rose to approximately 95 ℃, reactant all dissolved, and backflows that come to life in the time of 110 ℃ removes moisture content in formic acid removal through the Solid-state Ion-exchange device.The analysis showed that through GC, after backflow 3h, 3-aldehyde benzoic acid methyl esters transforms substantially fully.Beginning to heat up steams solvent, to almost all steaming, finishes reaction.After remaining liquid cooling but, then add 300L water, 500 liter 1, the 2-ethylene dichloride, gradation adds the anhydrous sodium carbonate powder, and regulating the pH value is 9-10.Stir standing demix.Tell lower floor's organic layer, remove upper aqueous layer.Water layer is used 50 liter 1 again, and the 2-ethylene dichloride stirs extraction once, standing demix.Merge organic layer.Organic layer adds 150 premium on currency again, and extraction once, and is standing, tells organic layer, removes water layer.Organic layer repeatedly washs to neutrality.
1,2-ethylene dichloride is reclaimed in the first air distillation of organic layer.142-150 ℃/0.667kPa fraction is collected in rectification under vacuum, coolingly is white 3-cyano-benzoic acid methyl ester product.
Embodiment 3, with the 3-chloromethyl benzoic acid methyl esters of 0.5Kmol, the urea of 3Kmol, the water of 1500Kg, the hexaoxacyclooctadecane-6 of 0.5Kg-6 add in the enamel reaction still of 3000l, heat up to accelerate to stir, when material temperature reached 70-80 ℃, solid was entirely molten.Refluxed 12 hours when being warmed up to 100-110 ℃.When material temperature drops to 80 ℃, drip 98% vitriol oil of 330 liters, refluxed 1 hour.Reaction is finished, and cools to room temperature.
In the four-hole reaction flask of 3000 liters, then add 500kg water, after stirring, add 100 liter 1, the 2-ethylene dichloride stirred standing demix 30 minutes.Tell organic layer.Use 100 liter 1, the 2-ethylene dichloride stirs extraction once, standing demix again.Merge organic layer.Organic layer 150 premium on currency, standing, tell organic layer, remove water layer.Organic layer repeatedly washs to neutrality.
1,2-ethylene dichloride is reclaimed in the organic layer air distillation.Cooling, crystallization, suction filtration gets the crystallization of micro-yellow powder 3-aldehyde benzoic acid methyl esters, and content is more than 98%.
In 1000 liters of reactors of mechanical stirrer, thermometer and reflux exchanger are housed, add successively people 1Kmol3-aldehyde benzoic acid methyl esters, 1.1Kmol oxammonium hydrochloride, 500 liters of industrial formic acid.Start stirring, heating, when reacting liquid temperature rose to approximately 95 ℃, reactant all dissolved, and backflow comes to life in the time of 110 ℃.The analysis showed that through GC, after backflow 3h, 3-aldehyde benzoic acid methyl esters transforms substantially fully.Beginning to heat up steams solvent, to almost all steaming, finishes reaction.After remaining liquid cooling but, then add 300L water, 500 liter 1, the 2-ethylene dichloride, gradation adds the anhydrous sodium carbonate powder, and regulating the pH value is 9-10.Stir standing demix.Tell lower floor's organic layer, remove upper aqueous layer.Water layer is used 50 liter 1 again, and the 2-ethylene dichloride stirs extraction once, standing demix.Merge organic layer.Organic layer adds 150 premium on currency again, and extraction once, and is standing, tells organic layer, removes water layer.
1,2-ethylene dichloride is reclaimed in the first air distillation of organic layer.Cooling, crystallization, suction filtration gets the crystallization of little yellow sand shape 3-cyano-benzoic acid methyl ester.
Embodiment 4, with the 3-chloromethyl benzoic acid methyl esters of 1.5Kmol, the hexamethylenetetramine of 3Kmol, the water of 2000Kg, the 4-of 2Kg (dimethylamino)-N-(2-ethyl) hexyl pyridine () salt adds in the enamel reaction still of 3000l, heat up and accelerate to stir, when material temperature reached 70-80 ℃, solid was entirely molten.Refluxed 18 hours when being warmed up to 100-110 ℃.When material temperature drops to 80 ℃, drip 80% phosphoric acid of 100 liters, refluxed 1 hour.Reaction is finished, and cools to room temperature.
Add 300 liter 1 in reactor, the 2-ethylene dichloride stirred standing demix 30 minutes.Lower floor's (organic layer) contains product and continues to employ.Use 100 liter 1, the 2-ethylene dichloride stirs extraction once, standing demix again.Merge organic layer.Organic layer 150 premium on currency, standing, tell organic layer.Organic layer repeatedly washs to neutrality.
1,2-ethylene dichloride is reclaimed in the organic layer air distillation.Cooling, crystallization, suction filtration gets the crystallization of micro-yellow powder 3-aldehyde benzoic acid methyl esters.
In 1500 liters of reactors of mechanical stirrer, thermometer, reflux exchanger and Solid-state Ion-exchange device are housed, add successively people 1Kmol 3-aldehyde benzoic acid methyl esters, 1.5Kmol oxammonium hydrochloride, 500 liters of industrial formic acid.Start stirring, heating, when reacting liquid temperature rose to approximately 95 ℃, reactant all dissolved, and backflows that come to life in the time of 110 ℃ removes moisture content in formic acid removal through the Solid-state Ion-exchange device.The analysis showed that through GC, after backflow 3h, 3-aldehyde benzoic acid methyl esters transforms substantially fully.Beginning to heat up steams solvent, to almost all steaming, finishes reaction.After remaining liquid cooling but, then add 300L water, 500 liter 1, the 2-ethylene dichloride, gradation adds the anhydrous sodium carbonate powder, and regulating the pH value is 9-10.Stir standing demix.Lower floor's (organic layer) contains product and continues to employ, and upper strata (water layer) uses 50 liter 1 again, and the 2-ethylene dichloride stirs extraction once, standing demix.Merge organic layer.Organic layer adds 150 premium on currency again, and extraction once, and is standing, tells organic layer, removes water layer.
1,2-ethylene dichloride is reclaimed in the first air distillation of organic layer.112-120 ℃/0.99kPa fraction is collected in rectification under vacuum, coolingly is white 3-cyano-benzoic acid methyl ester product.
Claims (3)
1. production method for preparing the 3-cyano-benzoic acid methyl ester is characterized in that reaction in two steps:
The first step, 3-chloromethyl benzoic acid methyl esters, contain N compound, phase-transfer catalyst in weakly alkaline solution, at 100-110 ℃ of backflow 1-18 hour, nucleophilic substitution reaction occurs generate not salt of west, then in the acid of 100-110 ℃ back hydrolysis 1-18 hour, generate 3-aldehyde benzoic acid methyl esters, with water-fast polar organic solvent extracting and demixing, the organic phase of extraction washes with water successively until neutral, after the organic phase drying, normal pressure steams solvent, then underpressure distillation collection fraction, obtains 3-aldehyde benzoic acid methyl esters sterling;
Described phase-transfer catalyst refers to cetyl trimethylammonium bromide, PEG-400, and hexaoxacyclooctadecane-6-6 or 4-(dimethylamino)-N-(2-ethyl) hexyl pyridine () salt,
The described N of containing compound refers to hexamethylenetetramine, ammoniacal liquor, urea or volatile salt,
Described acid is industrial sulphuric acid,
Described water-fast polar organic solvent refers to 1,2-ethylene dichloride;
Second step, 3-aldehyde benzoic acid methyl esters and azanol, industrial formic acid are at 100 ℃ of-110 ℃ of back flow reaction 1-18h, by the Solid-state Ion-exchange device except the water in formic acid removal, with water-fast polar organic solvent extracting and demixing, the organic phase of extraction washes with water successively until neutral, after the organic phase drying, normal pressure steams solvent, then underpressure distillation collection fraction, gets 3-cyano-benzoic acid methyl ester sterling;
Described water-fast polar organic solvent refers to 1,2-ethylene dichloride,
Concrete reaction formula is:
2. a kind of production method for preparing the 3-cyano-benzoic acid methyl ester according to claim 1, is characterized in that 100-110 ℃ of backflow after 10 hours, when material temperature drops to 80 ℃, drips 98% sulfuric acid, refluxed 2 hours, reaction is finished, and cools to room temperature, then adds entry and/or 1, the 2-ethylene dichloride stirs, standing demix, and organic phase is with 1, the 2-ethylene dichloride stirs extraction, and standing demix merges organic layer, water stirs, and is standing, tell lower floor's organic layer, remove water layer, organic layer repeatedly washs to neutrality.
3. a kind of production method for preparing the 3-cyano-benzoic acid methyl ester according to claim 1, it is characterized in that through the Solid-state Ion-exchange device except the moisture content in formic acid removal, intensification steams solvent, after remaining liquid cooling but, then adds water, 1, the 2-ethylene dichloride, divide to add the anhydrous sodium carbonate powder three times, regulating the pH value is 9-10, stirs, standing demix is told lower floor's organic layer and upper aqueous layer; Water layer uses 1,2-ethylene dichloride to stir extraction again, and standing demix merges organic layer, and organic layer adds entry again, and organic layer is told in extraction, standing, removes water layer, through repeatedly washing to neutral.
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| CN106674042A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Method for preparing 3-cyan-4-hydroxy ethyl benzoate |
| CN106674055A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method of phenyl 3-cyano-4-hydroxybenzoate |
| CN106674053A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method of 3-cyano-4-isopropoxy methyl benzoate |
| CN106674044A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Method for preparing 3-cyano-4-isopropoxybenzoic acid |
| CN106674045A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method of 3-cyano-4-isopropoxybenzoic acid |
| CN106674047A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Method for preparing 3-cyano-4-isopropoxybenzoic acid |
| CN106674051A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method for 3-cyano-4-isopropoxy phenyl benzoate |
| CN106674046A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method of 3-cyano-4-isopropyloxybenzoic acid |
| CN106674052A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method of methyl 3-cyano-4-hydroxybenzoate |
| CN106674054A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Method for preparing 3-cyan-4-isopropoxy ethyl benzoate |
| CN116143656A (en) * | 2023-02-22 | 2023-05-23 | 湖北仙盛科技股份有限公司 | Preparation method of m-cyano methyl benzoate |
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