CN103553991B - A kind of method preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate - Google Patents
A kind of method preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate Download PDFInfo
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- CN103553991B CN103553991B CN201310548145.0A CN201310548145A CN103553991B CN 103553991 B CN103553991 B CN 103553991B CN 201310548145 A CN201310548145 A CN 201310548145A CN 103553991 B CN103553991 B CN 103553991B
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Abstract
The present invention relates to a kind of method preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate, the present invention is through halogen halogenation (chlorination, bromination, iodate) by 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester, then with sodium ethanesulfinate condensation target product, its advantage operational path is simple, product yield is high, and total recovery reaches 80%, good product quality, purity reaches 99.5%, and outward appearance is white.
Description
Technical field
The present invention relates to technical field of medical intermediate preparation, specifically, is about a kind of method preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate.
Background technology
Psychosis (psychosis) refers to serious psychological disorders, and lasting obvious exception all can appear in the psychological activity such as understanding, emotion, will, action behavior of patient; Can not learn normally, work, live; Action behavior is difficult to be understood by common people; Under the domination of morbid psychology, there is the action behavior of committing suiside or attacking, injuring other people.2-methoxyl group-4-amino-5-ethyl sulfone phenylformic acid is the important intermediate of antipsychotic drug amisulpride (amisulpride).The current relevant report of its synthetic route is a lot, the mainly following route that current suitability for industrialized production is used:
This route be with 2-methoxyl group-PABA methyl esters through deacetylation, thiocyanation, ethylization, be oxidized to obtain target product; through 5 step reactions; and each step yield is low; and second-rate, through the author's checking, total recovery about 50%; the by product produced in thiocyanation process takes in finished product always; be difficult to remove, and its outward appearance is light yellow, still cannot transfer white to through repeatedly purifying.Purity 98%(HPLC) left and right.
Summary of the invention
The object of the invention is for deficiency of the prior art, a kind of method preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate is provided.
For achieving the above object, the technical scheme that the present invention takes is:
A kind of method preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate, with (A) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester and halogen with mol ratio 1:1-1.2, take methylene dichloride as solvent, at 10-40 DEG C of reaction 2-8 hour, negative pressure concentrated (B) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro methyl benzoate or 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-methyl-bromobenzoate or 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-iodo-benzoic acid methyl esters, after drying, again by (B) and sodium ethanesulfinate with mol ratio 1:1.2-2.0, solvent is made with DMF, under catalyst, at 50-90 DEG C, reaction 5-10 hour, through being separated (C) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, again further with methanol as solvent, the vitriol oil makes catalyzer, back flow reaction, 5-10 hour, crystallisation by cooling obtains 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate, described catalyzer is cuprous chloride.
Described halogen is chlorine, bromine or iodine.
Described 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester and halogen are with mol ratio 1:1.1.
Described 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester and halogen are with mol ratio 1:1.04.
Described 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester and halogen are with mol ratio 1:1.15.
The present invention adopt 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester through halogen halogenation (chlorination, bromination, iodate) again with sodium ethanesulfinate through catalyzing and condensing (catalyzer for be oxidized sub-Red copper oxide, cuprous chloride, cuprous bromide, cuprous iodide), then obtain 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate through deacetylation.
Synthetic route of the present invention is as follows:
The present invention mainly solves that operational path in former technique is long, and yield is low, poor product quality, and the quantity of three wastes greatly and not easily shortcoming such as process, solvent for use of the present invention and the equal recoverable of by product, be more suitable for industrialization production requirements.The present invention is through halogen halogenation (chlorination, bromination, iodate) by 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester, then with sodium ethanesulfinate condensation target product, its advantage operational path is simple, product yield is high, total recovery reaches 80%, good product quality, purity reaches 99.5% and outward appearance is white.
Embodiment
Below embodiment provided by the invention is elaborated.
embodiment one
300g methylene dichloride will be added in the reaction flask that hydrogen chloride absorption device is housed, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 200g (0.89mol), be cooled to less than 10 DEG C, 10-15 DEG C is kept slowly to pass into chlorine under agitation condition, when air flow reaches 69.5g (0.98mol), stop logical chlorine, continue stirring reaction, after 1 hour, reaction solution is concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether through negative pressure, 400 grams of DMF are added in same reaction flask, sodium ethanesulfinate 155g (1.33mol), 6g (0.04mol) Red copper oxide, reinforced complete, slowly be warming up to 65-70 DEG C, and be incubated 8 hours at this temperature, insulation terminates, be cooled to less than 10 DEG C, filter (3) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, (3) are joined in the reaction flask with stirring and refluxing device, add in 300ml methyl alcohol and 5 grams of vitriol oils, temperature rising reflux is also under reflux conditions incubated 5 hours, insulation terminates, in reaction solution, add 2 grams of gacs take advantage of heat filtering, filtrate is cooled to less than 5 DEG C, filter, 60 DEG C of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 199.5g (0.73mol, the crystallization of yield 82.02% appearance white, content 99.51%(HPLC) (moving phase: 700 ml waters, methyl alcohol 200 milliliters.Determined wavelength: 240nm, flow velocity 1.0ml/min, 0.01 gram, sample, is diluted to 25 milliliters by moving phase, sample size 5 μ l).
embodiment two
225g methylene dichloride is added in the reaction flask that hydrogen bromide absorption unit is housed, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 150g (0.67mol), be cooled to less than 10 DEG C, 10-15 DEG C is kept slowly to drip bromine 112.4g(0.70mol under agitation condition), drip and terminate to keep 10-15 DEG C of insulation 4 hours, reaction solution is being concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-methyl-bromobenzoate through negative pressure, 300 grams of DMF are added in same reaction flask, 124.5g(1.07mol) sodium ethanesulfinate, 5g (0.05mol) cuprous chloride, reinforced complete, slowly be warming up to 75-80 DEG C, and be incubated 8 hours at this temperature, insulation terminates, be cooled to less than 10 DEG C, filter (3) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, (3) are joined in the reaction flask with stirring and refluxing device, add in 250ml methyl alcohol and 4 grams of vitriol oils, temperature rising reflux is also under reflux conditions incubated 5 hours, insulation terminates, in reaction solution, add 1.5 grams of gacs take advantage of heat filtering, filtrate is cooled to less than 5 DEG C, filter, 60 DEG C of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 155.6g (0.57mol) yield 85.07%, appearance white crystallization, content 99.70%(HPLC). (moving phase: 700 ml waters, methyl alcohol 200 milliliters.Determined wavelength: 240nm, flow velocity 1.0ml/min, 0.01 gram, sample, is diluted to 25 milliliters by moving phase, sample size 5 μ l).
embodiment three
600g methylene dichloride is added in 1000ml reaction flask, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 300g (1.34mol), 390g(1.54mol) iodine, reinforced complete, be warming up to 35-40 DEG C, and be incubated 10 hours at this temperature, insulation terminates reaction solution and is concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether through negative pressure, 600 grams of DMF are added in same reaction flask, 417g(2.68mol) sodium ethanesulfinate and 8g (0.04mol) cuprous iodide, reinforced complete, slowly be warming up to 65-70 DEG C, and be incubated 10 hours at this temperature, insulation terminates, be cooled to less than 10 DEG C, filter (3) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, (3) are joined in the reaction flask with stirring and refluxing device, add in 450ml methyl alcohol and 8 grams of vitriol oils, temperature rising reflux is also under reflux conditions incubated 5 hours, insulation terminates, in reaction solution, add 3 grams of gacs take advantage of heat filtering, filtrate is cooled to less than 5 DEG C, filter, 60 DEG C of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 311.6g (1.14mol), yield 85.07%, appearance white crystallization, content 99.73%(HPLC). (moving phase: 700 ml waters, methyl alcohol 200 milliliters.Determined wavelength: 240nm, flow velocity 1.0ml/min, 0.01 gram, sample, is diluted to 25 milliliters by moving phase, sample size 5 μ l).
embodiment four
225g methylene dichloride is added in the reaction flask that hydrogen bromide absorption unit is housed, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 150g (0.67mol), be cooled to less than 10 DEG C, 10-15 DEG C is kept slowly to drip bromine 112.4g(0.70mol under agitation condition), drip and terminate to keep 10-15 DEG C of insulation 4 hours, reaction solution is being concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-methyl-bromobenzoate through negative pressure, 300 grams of DMF are added in same reaction flask, 124.5g(1.07mol) sodium ethanesulfinate, 7.2g (0.05mol) cuprous bromide, reinforced complete, slowly be warming up to 75-80 DEG C, and be incubated 8 hours at this temperature, insulation terminates, be cooled to less than 10 DEG C, filter (3) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, (3) are joined in the reaction flask with stirring and refluxing device, add in 250ml methyl alcohol and 4 grams of vitriol oils, temperature rising reflux is also under reflux conditions incubated 5 hours, insulation terminates, in reaction solution, add 1.5 grams of gacs take advantage of heat filtering, filtrate is cooled to less than 5 DEG C, filter, 60 DEG C of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 155.6g (0.57mol) yield 85.07%, appearance white crystallization, content 99.70%(HPLC). (moving phase: 700 ml waters, methyl alcohol 200 milliliters.Determined wavelength: 240nm, flow velocity 1.0ml/min, 0.01 gram, sample, is diluted to 25 milliliters by moving phase, sample size 5 μ l).
embodiment five
300g methylene dichloride will be added in the reaction flask that hydrogen chloride absorption device is housed, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 200g (0.89mol), be cooled to less than 10 DEG C, 10-15 DEG C is kept slowly to pass into chlorine under agitation condition, when air flow reaches 69.5g (0.98mol), stop logical chlorine, continue stirring reaction, after 1 hour, reaction solution is concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether through negative pressure, 400 grams of DMF are added in same reaction flask, sodium ethanesulfinate 125g (1.07mol), 6g (0.04mol) Red copper oxide, reinforced complete, slowly be warming up to 65-70 DEG C, and be incubated 8 hours at this temperature, insulation terminates, be cooled to less than 10 DEG C, filter (3) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, (3) are joined in the reaction flask with stirring and refluxing device, add in 300ml methyl alcohol and 5 grams of vitriol oils, temperature rising reflux is also under reflux conditions incubated 5 hours, insulation terminates, in reaction solution, add 2 grams of gacs take advantage of heat filtering, filtrate is cooled to less than 5 DEG C, filter, 60 DEG C of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 199.5g (0.73mol, the crystallization of yield 82.02% appearance white, content 99.51%(HPLC) (moving phase: 700 ml waters, methyl alcohol 200 milliliters.Determined wavelength: 240nm, flow velocity 1.0ml/min, 0.01 gram, sample, is diluted to 25 milliliters by moving phase, sample size 5 μ l).
embodiment six
600g methylene dichloride is added in 1000ml reaction flask, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 300g (1.34mol), 339g(1.34mol) iodine, reinforced complete, be warming up to 35-40 DEG C, and be incubated 10 hours at this temperature, insulation terminates reaction solution and is concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether through negative pressure, 600 grams of DMF are added in same reaction flask, 417g(2.68mol) sodium ethanesulfinate and 8g (0.04mol) cuprous iodide, reinforced complete, slowly be warming up to 65-70 DEG C, and be incubated 10 hours at this temperature, insulation terminates, be cooled to less than 10 DEG C, filter (3) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, (3) are joined in the reaction flask with stirring and refluxing device, add in 450ml methyl alcohol and 8 grams of vitriol oils, temperature rising reflux is also under reflux conditions incubated 5 hours, insulation terminates, in reaction solution, add 3 grams of gacs take advantage of heat filtering, filtrate is cooled to less than 5 DEG C, filter, 60 DEG C of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 311.6g (1.14mol), yield 85.07%, appearance white crystallization, content 99.73%(HPLC). (moving phase: 700 ml waters, methyl alcohol 200 milliliters.Determined wavelength: 240nm, flow velocity 1.0ml/min, 0.01 gram, sample, is diluted to 25 milliliters by moving phase, sample size 5 μ l).
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. prepare the method for 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate for one kind, it is characterized in that, described method is: in the reaction flask that hydrogen bromide absorption unit is housed, add 225g methylene dichloride, 150g2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester, be cooled to less than 10 DEG C, 10-15 DEG C is kept slowly to drip bromine 112.4g under agitation condition, drip and terminate to keep 10-15 DEG C of insulation 4 hours, reaction solution is concentrated into dry solid 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-methyl-bromobenzoate through negative pressure, 300gDMF is added in same reaction flask, 124.5g sodium ethanesulfinate, 5g cuprous chloride, reinforced complete, slowly be warming up to 75-80 DEG C, and be incubated 8 hours at this temperature, insulation terminates, be cooled to less than 10 DEG C, filter to obtain 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate is joined in the reaction flask with stirring and refluxing device, add in 250ml methyl alcohol and the 4g vitriol oil, temperature rising reflux is also under reflux conditions incubated 5 hours, insulation terminates, 1.5g gac filtered while hot is added in reaction solution, filtrate is cooled to less than 5 DEG C, filter, 60 DEG C of vacuum-dryings obtain 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate 155.6g, yield 85.07%, appearance white crystallization, content 99.70%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1793836C1 (en) * | 1964-04-27 | 1980-02-07 | Ile De France | Process for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-bromobenzamide |
| CN101072773A (en) * | 2004-12-14 | 2007-11-14 | 诺瓦提斯公司 | Pyrrole derivatives having CRTH2 receptor antagonist activity |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1793836C1 (en) * | 1964-04-27 | 1980-02-07 | Ile De France | Process for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-bromobenzamide |
| CN101072773A (en) * | 2004-12-14 | 2007-11-14 | 诺瓦提斯公司 | Pyrrole derivatives having CRTH2 receptor antagonist activity |
Non-Patent Citations (1)
| Title |
|---|
| 氨磺必利的合成;程玉红等;《中国医药工业杂志》;20111231;第42卷(第11期);801-803 * |
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