CN103553910B - A kind of method of Whitfield's ointment synthesis o-ethoxybenzoic acid - Google Patents
A kind of method of Whitfield's ointment synthesis o-ethoxybenzoic acid Download PDFInfo
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- CN103553910B CN103553910B CN201310548157.3A CN201310548157A CN103553910B CN 103553910 B CN103553910 B CN 103553910B CN 201310548157 A CN201310548157 A CN 201310548157A CN 103553910 B CN103553910 B CN 103553910B
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
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Abstract
The present invention relates to the method for a kind of Whitfield's ointment synthesis o-ethoxybenzoic acid, the method is by Whitfield's ointment, acetone, potassium hydroxide adds reaction flask, stirring at room temperature drips monobromethane, temperature rising reflux 9 ~ 15 hours, reclaim under reduced pressure acetone, add water and liquid caustic soda, temperature rising reflux 2 ~ 4 hours again, be cooled to room temperature, pH=3 ~ 4 are adjusted with ice acid acid, be cooled to 1 DEG C-15 DEG C again, suction filtration is separated, washing, vacuum-drying obtains o-ethoxybenzoic acid, wherein Whitfield's ointment: potassium hydroxide: monobromethane: these four kinds of material mol ratios of liquid caustic soda are 1: 2.0 ~ 2.5: 2.1 ~ 2.5: 1.5.The method technique is simple, and easy to operate, material cost is low, and yield is high, and quality is good, is convenient to suitability for industrialized production.
Description
Technical field
The present invention relates to medicine intermediate synthesis technical field, specifically, is a kind of method about Whitfield's ointment synthesis o-ethoxybenzoic acid.
Background technology
O-ethoxybenzoic acid is a kind of important intermediate of synthesis treatment ED medicine (viagra), it is more that this intermediate synthesizes domestic and international relevant report, typically have following two kinds, one uses 0-chloro-benzoic acid etherificate, and the method raw materials cost is high, and need High Temperature High Pressure operation easier large, be unfavorable for suitability for industrialized production, first by after Whitfield's ointment esterification, through etherificate, alkaline hydrolysis must this product more again for another kind of method, and the method synthesis cost is high, reaction conditions is wayward, is difficult to realize large-scale industrial production.
[summary of the invention]
The object of the invention is for deficiency of the prior art, provide a kind of Whitfield's ointment to synthesize the method for o-ethoxybenzoic acid.
For achieving the above object, the technical scheme that the present invention takes is: a kind of method of Whitfield's ointment synthesis o-ethoxybenzoic acid, by Whitfield's ointment, acetone, potassium hydroxide adds reaction flask, stirring at room temperature drips monobromethane, temperature rising reflux 9 ~ 15 hours, reclaim under reduced pressure acetone, add water and liquid caustic soda, temperature rising reflux 2 ~ 4 hours again, be cooled to room temperature, PH=3 ~ 4 are adjusted with ice acid acid, be cooled to 1 DEG C-15 DEG C again, suction filtration is separated, washing, vacuum-drying obtains o-ethoxybenzoic acid, wherein Whitfield's ointment: potassium hydroxide: monobromethane: these four kinds of material mol ratios of liquid caustic soda are 1:2.0 ~ 2.5:2.1 ~ 2.5:1.5.
Described, Whitfield's ointment: potassium hydroxide: monobromethane: these four kinds of material mol ratios of liquid caustic soda are 1:2.5:2.5:1.5.
Described Whitfield's ointment 0.72mol, acetone 900ml, potassium hydroxide 1.80mol adds in reaction flask.
Reaction equation of the present invention is as follows:
The invention has the advantages that: the present invention adopts Whitfield's ointment to be raw material, acetone as solvent, acid binding agent made by potassium hydroxide, monobromethane is made ethylating agent and is first generated o-ethoxybenzoic acid ethyl ester, then steam and desolventize, then add appropriate aqueous sodium hydroxide solution intensification hydrolysis, obtain o-ethoxybenzoic acid salt brine solution, be acidified to PH=3 ~ 4 with Glacial acetic acid, after separation, obtain o-ethoxybenzoic acid.The method technique is simple, and easy to operate, material cost is low, and yield is high, and quality is good, is convenient to suitability for industrialized production.
Embodiment
Below embodiment provided by the invention is elaborated.
Embodiment 1
By Whitfield's ointment 50g (0.36mol), acetone 500ml adds reaction flask, temperature control is less than the potassium hydroxide solid (90%) 42.6 gram (0.76mol) that 40 DEG C add porphyrize, add intensification and be incubated 3 hours at reflux, be cooled to 20 DEG C, slowly drip 86g(0.79mol) monobromethane, monobromethane dropwises, be warming up to backflow, reflux state is kept to be incubated 10 hours, insulation terminates reclaim under reduced pressure acetone, recover acetone terminates, add 300ml water, 50 gram of 30% liquid caustic soda (i.e. the sodium hydroxide of liquid state) (0.38mol) is warming up to 90 DEG C, and be incubated 2 hours at this temperature, insulation end is cooled to 30 ~ 35 DEG C, slowly drip Glacial acetic acid at this temperature, control reaction solution and drop to PH=3 ~ 4, a large amount of solid is now had to separate out, be further cooled to 14 DEG C, suction filtration, water washing final vacuum is dry, obtain o-ethoxybenzoic acid 53.3g(0.32mol), yield 89.10%, purity 99.33%(GC, Conditions Instrument: GC-9790 gas-chromatography, fid detector, chromatographic column model: DM-5,30m 0.25mmID 0.25um, GC testing conditions: detector: FID carrier gas: nitrogen, carrier gas flux: 0.10Mpa, column temperature: 230 DEG C, injector temperature: 260 DEG C, detected temperatures: 270 DEG C, sample concentration 1.0g/10ml acetone solution, sample size: 2ul).
Embodiment 2
By Whitfield's ointment 65g (0.47mol), acetone 400ml adds reaction flask, temperature control is less than the potassium hydroxide solid (90%) 67.3 gram (1.08mol) that 40 DEG C add porphyrize, add intensification and be incubated 3 hours at reflux, be cooled to 20 DEG C, slowly drip 117.8g(1.08mol) monobromethane, monobromethane dropwises, be warming up to backflow, reflux state is kept to be incubated 12 hours, insulation terminates reclaim under reduced pressure acetone, recover acetone terminates, add 500ml water, 62.7 gram of 30% liquid caustic soda (i.e. the sodium hydroxide of liquid state) (0.47mol) is warming up to 90 DEG C, and be incubated 3 hours at this temperature, insulation end is cooled to 30 ~ 35 DEG C, slowly drip Glacial acetic acid at this temperature, control reaction solution and drop to PH=3 ~ 4, a large amount of solid is now had to separate out, be further cooled to 10 DEG C, suction filtration, water washing final vacuum is dry, obtain o-ethoxybenzoic acid 71.3g(0.43), yield 91.24%, purity 99.41%(GC, Conditions Instrument: GC-9790 gas-chromatography, fid detector, chromatographic column model: DM-5,30m 0.25mmID 0.25um, GC testing conditions: detector: FID carrier gas: nitrogen, carrier gas flux: 0.10Mpa, column temperature: 230 DEG C, injector temperature: 260 DEG C, detected temperatures: 270 DEG C, sample concentration 1.0g/10ml acetone solution, sample size: 2ul).
Embodiment 3
By Whitfield's ointment 100g (0.72mol), acetone 900ml adds reaction flask, temperature control is less than the potassium hydroxide solid (90%) 112.2 gram (1.80mol) that 40 DEG C add porphyrize, add intensification and be incubated 3 hours at reflux, be cooled to 20 DEG C, slowly drip 196g(1.80mol) monobromethane, monobromethane dropwises, be warming up to backflow, reflux state is kept to be incubated 15 hours, insulation terminates reclaim under reduced pressure acetone, recover acetone terminates, add 600ml water, 96 gram of 30% liquid caustic soda (i.e. the sodium hydroxide of liquid state) (0.72mol) is warming up to 90 DEG C, and be incubated 4 hours at this temperature, insulation end is cooled to 30 ~ 35 DEG C, slowly drip Glacial acetic acid at this temperature, control reaction solution and drop to PH=3 ~ 4, a large amount of solid is now had to separate out, be further cooled to 1 DEG C, suction filtration, water washing final vacuum is dry, obtain o-ethoxybenzoic acid 103.3g (0.62mol), yield 86.32%, purity 99.51%(GC normalization method, Conditions Instrument: GC-9790 gas-chromatography, fid detector, chromatographic column model: DM-5,30m 0.25mmID 0.25um, GC testing conditions: detector: FID carrier gas: nitrogen, carrier gas flux: 0.10Mpa, column temperature: 230 DEG C, injector temperature: 260 DEG C, detected temperatures: 270 DEG C, sample concentration 1.0g/10ml acetone solution, sample size: 2ul).
Embodiment 4
By Whitfield's ointment 65g (0.47mol), acetone 500ml adds reaction flask, temperature control is less than the potassium hydroxide solid (90%) 52.7 gram (0.94mol) that 40 DEG C add porphyrize, add intensification and be incubated 3 hours at reflux, be cooled to 20 DEG C, slowly drip 107g(0.99mol) monobromethane, monobromethane dropwises, be warming up to backflow, reflux state is kept to be incubated 10 hours, insulation terminates reclaim under reduced pressure acetone, recover acetone terminates, add 300ml water, 62.7 gram of 30% liquid caustic soda (i.e. the sodium hydroxide of liquid state) (0.47mol) is warming up to 90 DEG C, and be incubated 2 hours at this temperature, insulation end is cooled to 30 ~ 35 DEG C, slowly drip Glacial acetic acid at this temperature, control reaction solution and drop to PH=3 ~ 4, a large amount of solid is now had to separate out, be further cooled to 14 DEG C, suction filtration, water washing final vacuum is dry, obtain o-ethoxybenzoic acid 53.3g(0.32mol), yield 89.10%, purity 99.33%(GC, Conditions Instrument: GC-9790 gas-chromatography, fid detector, chromatographic column model: DM-5,30m 0.25mmID 0.25um, GC testing conditions: detector: FID carrier gas: nitrogen, carrier gas flux: 0.10Mpa, column temperature: 230 DEG C, injector temperature: 260 DEG C, detected temperatures: 270 DEG C, sample concentration 1.0g/10ml acetone solution, sample size: 2ul).
Embodiment 5
By Whitfield's ointment 50g (0.36mol), acetone 400ml adds reaction flask, temperature control is less than the potassium hydroxide solid (90%) 50.5 gram (0.9mol) that 40 DEG C add porphyrize, add intensification and be incubated 3 hours at reflux, be cooled to 20 DEG C, slowly drip 98g(0.9mol) monobromethane, monobromethane dropwises, be warming up to backflow, reflux state is kept to be incubated 12 hours, insulation terminates reclaim under reduced pressure acetone, recover acetone terminates, add 500ml water, 71.8 gram of 30% liquid caustic soda (i.e. the sodium hydroxide of liquid state) (0.54mol) is warming up to 90 DEG C, and be incubated 3 hours at this temperature, insulation end is cooled to 30 ~ 35 DEG C, slowly drip Glacial acetic acid at this temperature, control reaction solution and drop to PH=3 ~ 4, a large amount of solid is now had to separate out, be further cooled to 10 DEG C, suction filtration, water washing final vacuum is dry, obtain o-ethoxybenzoic acid 71.3g(0.43), yield 91.24%, purity 99.41%(GC, Conditions Instrument: GC-9790 gas-chromatography, fid detector, chromatographic column model: DM-5,30m 0.25mmID 0.25um, GC testing conditions: detector: FID carrier gas: nitrogen, carrier gas flux: 0.10Mpa, column temperature: 230 DEG C, injector temperature: 260 DEG C, detected temperatures: 270 DEG C, sample concentration 1.0g/10ml acetone solution, sample size: 2ul).
Embodiment 6
By Whitfield's ointment 100g (0.72mol), acetone 900ml adds reaction flask, temperature control is less than the potassium hydroxide solid (90%) 95.4 gram (1.70mol) that 40 DEG C add porphyrize, add intensification and be incubated 3 hours at reflux, be cooled to 20 DEG C, slowly drip 185.1g(1.70mol) monobromethane, monobromethane dropwises, be warming up to backflow, reflux state is kept to be incubated 15 hours, insulation terminates reclaim under reduced pressure acetone, recover acetone terminates, add 600ml water, 141.5 gram of 30% liquid caustic soda (i.e. the sodium hydroxide of liquid state) (0.94mol) is warming up to 90 DEG C, and be incubated 4 hours at this temperature, insulation end is cooled to 30 ~ 35 DEG C, slowly drip Glacial acetic acid at this temperature, control reaction solution and drop to PH=3 ~ 4, a large amount of solid is now had to separate out, be further cooled to 1 DEG C, suction filtration, water washing final vacuum is dry, obtain o-ethoxybenzoic acid 103.3g (0.62mol), yield 86.32%, purity 99.51%(GC normalization method, Conditions Instrument: GC-9790 gas-chromatography, fid detector, chromatographic column model: DM-5,30m 0.25mmID 0.25um, GC testing conditions: detector: FID carrier gas: nitrogen, carrier gas flux: 0.10Mpa, column temperature: 230 DEG C, injector temperature: 260 DEG C, detected temperatures: 270 DEG C, sample concentration 1.0g/10ml acetone solution, sample size: 2ul).
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (1)
1. the method with Whitfield's ointment synthesis o-ethoxybenzoic acid, it is characterized in that, 0.36mol Whitfield's ointment, 400ml acetone, 0.9mol potassium hydroxide are added reaction flask, add intensification and be incubated 3 hours at reflux, be cooled to 20 DEG C, stirring at room temperature drips 0.9mol monobromethane, temperature rising reflux 12 hours, reclaim under reduced pressure acetone, add 500ml water and 0.54mol liquid caustic soda, be warming up to 90 DEG C of backflows 3 hours again, be cooled to room temperature, adjust PH=3 ~ 4 with Glacial acetic acid, be cooled to 10 DEG C again, suction filtration is separated, and washing, vacuum-drying obtains o-ethoxybenzoic acid.
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| Shu-Ting Huang, et al.Synthesis and anticancer evaluation of bis(benzimidazoles),bis(benzoxazoles),and benzothiazoles.《Bioorganic & * |
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