CN103588686A - Method for preparing 2-methoxy-4-amino-5-ethysulfonyl benzoic acid methyl ester by halogen halogenation - Google Patents
Method for preparing 2-methoxy-4-amino-5-ethysulfonyl benzoic acid methyl ester by halogen halogenation Download PDFInfo
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Abstract
The invention relates to a method for preparing 2-methoxy-4-amino-5-ethysulfonyl benzoic acid methyl ester by halogen halogenation. According to the invention, 2-methoxy-4-acetyl methyl anthranilate is subjected to halogen halogenation (chlorination, bromination or iodization) and then is condensed with sodium ethanesulfinate to obtain a target product. The method has the advantages that the process route is simple, the product yield is high, the total yield reaches 80 percent, the product quality is high, the purity reaches 99.5 percent, and the appearance is white.
Description
Technical field
The present invention relates to medicine intermediate preparing technical field, specifically, is the method for preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate with halogen halogenation about a kind of.
Background technology
Psychosis (psychosis) refers to serious psychological disorders, and the psychological activities such as patient's understanding, emotion, will, action behavior all can occur lasting significantly abnormal; 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, and what suitability for industrialized production was used at present is mainly following route:
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 it is low respectively to walk yield; and second-rate, through the author's checking, total recovery 50% left and right; the by product producing in thiocyanation process takes in finished product always; be difficult to remove, and its outward appearance is light yellow, through purifying repeatedly, still cannot transfers white to.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 of preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate with halogen halogenation is provided.
For achieving the above object, the technical scheme that the present invention takes is:
A kind of method of preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate with halogen halogenation, 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 ℃ of reaction 2-8 hour, negative pressure concentrates to obtain (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, with DMF, make solvent, under catalyst, at 50-90 ℃, reaction 5-10 hour, through separation, obtain (C) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, further with methyl alcohol, make solvent again, the vitriol oil is made 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 bromide.
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 is oxidation sub-Red copper oxide, cuprous chloride, cuprous bromide, cuprous iodide), then through deacetylation, obtain 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate.
Synthetic route of the present invention is as follows:
The present invention mainly solves in former technique that operational path is long, and yield is low, poor product quality, and quantity of three wastes is large and be difficult for the shortcomings such as processing, and the equal recoverable of solvent for use of the present invention and by product, is 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 reach 99.5% and outward appearance for white.
Embodiment
Below embodiment provided by the invention is elaborated.
embodiment one
In the reaction flask that hydrogen chloride absorption device is housed, will add 300g methylene dichloride, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 200g (0.89mol), below being cooled to 10 ℃, under agitation condition, keep 10-15 ℃ slowly to pass into chlorine, 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, in same reaction flask, add 400 grams of DMF, sodium ethanesulfinate 155g (1.33mol), 6g (0.04mol) Red copper oxide, reinforced complete, slowly be warming up to 65-70 ℃, and be incubated 8 hours at this temperature, insulation finishes, be cooled to below 10 ℃, filter to obtain (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 finishes, in reaction solution, add 2 grams of gacs to take advantage of heat filtering, filtrate is cooled to below 5 ℃, filter, 60 ℃ of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 199.5g (0.73mol, yield 82.02% appearance white crystallization, content 99.51%(HPLC) (moving phase: 700 ml waters, 200 milliliters of methyl alcohol.Detect 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
In the reaction flask that hydrogen bromide absorption unit is housed, add 225g methylene dichloride, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 150g (0.67mol), below being cooled to 10 ℃, under agitation condition, keep 10-15 ℃ and slowly drip bromine 112.4g(0.70mol), drip and finish to keep 10-15 ℃ 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, in same reaction flask, add 300 grams of DMF, 124.5g(1.07mol) sodium ethanesulfinate, 5g (0.05mol) cuprous chloride, reinforced complete, slowly be warming up to 75-80 ℃, and be incubated 8 hours at this temperature, insulation finishes, be cooled to below 10 ℃, filter to obtain (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 finishes, in reaction solution, add 1.5 grams of gacs to take advantage of heat filtering, filtrate is cooled to below 5 ℃, filter, 60 ℃ 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, 200 milliliters of methyl alcohol.Detect 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
In 1000ml reaction flask, add 600g methylene dichloride, (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 ℃, and be incubated 10 hours at this temperature, insulation finishes reaction solution and is concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether through negative pressure, in same reaction flask, add 600 grams of DMF, 417g(2.68mol) sodium ethanesulfinate and 8g (0.04mol) cuprous iodide, reinforced complete, slowly be warming up to 65-70 ℃, and be incubated 10 hours at this temperature, insulation finishes, be cooled to below 10 ℃, filter to obtain (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 finishes, in reaction solution, add 3 grams of gacs to take advantage of heat filtering, filtrate is cooled to below 5 ℃, filter, 60 ℃ 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, 200 milliliters of methyl alcohol.Detect 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
In the reaction flask that hydrogen bromide absorption unit is housed, add 225g methylene dichloride, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 150g (0.67mol), below being cooled to 10 ℃, under agitation condition, keep 10-15 ℃ and slowly drip bromine 112.4g(0.70mol), drip and finish to keep 10-15 ℃ 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, in same reaction flask, add 300 grams of DMF, 124.5g(1.07mol) sodium ethanesulfinate, 7.2g (0.05mol) cuprous bromide, reinforced complete, slowly be warming up to 75-80 ℃, and be incubated 8 hours at this temperature, insulation finishes, be cooled to below 10 ℃, filter to obtain (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 finishes, in reaction solution, add 1.5 grams of gacs to take advantage of heat filtering, filtrate is cooled to below 5 ℃, filter, 60 ℃ 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, 200 milliliters of methyl alcohol.Detect 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
In the reaction flask that hydrogen chloride absorption device is housed, will add 300g methylene dichloride, (1) 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester 200g (0.89mol), below being cooled to 10 ℃, under agitation condition, keep 10-15 ℃ slowly to pass into chlorine, 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, in same reaction flask, add 400 grams of DMF, sodium ethanesulfinate 125g (1.07mol), 6g (0.04mol) Red copper oxide, reinforced complete, slowly be warming up to 65-70 ℃, and be incubated 8 hours at this temperature, insulation finishes, be cooled to below 10 ℃, filter to obtain (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 finishes, in reaction solution, add 2 grams of gacs to take advantage of heat filtering, filtrate is cooled to below 5 ℃, filter, 60 ℃ of vacuum-dryings obtain (3) 2-methoxyl group-4-amino-5-ethylsulfonyl methyl benzoate 199.5g (0.73mol, yield 82.02% appearance white crystallization, content 99.51%(HPLC) (moving phase: 700 ml waters, 200 milliliters of methyl alcohol.Detect 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
In 1000ml reaction flask, add 600g methylene dichloride, (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 ℃, and be incubated 10 hours at this temperature, insulation finishes reaction solution and is concentrated into dry solid (2) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether through negative pressure, in same reaction flask, add 600 grams of DMF, 417g(2.68mol) sodium ethanesulfinate and 8g (0.04mol) cuprous iodide, reinforced complete, slowly be warming up to 65-70 ℃, and be incubated 10 hours at this temperature, insulation finishes, be cooled to below 10 ℃, filter to obtain (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 finishes, in reaction solution, add 3 grams of gacs to take advantage of heat filtering, filtrate is cooled to below 5 ℃, filter, 60 ℃ 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, 200 milliliters of methyl alcohol.Detect 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, do not departing under the prerequisite of the inventive method; can also make some improvement and supplement, these improvement and supplement and also should be considered as protection scope of the present invention.
Claims (5)
1. a method of preparing 2-methoxyl group-4-amino-5-ethyl sulfone methyl benzoate with halogen halogenation, it is characterized in that, 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 ℃ of reaction 2-8 hour, negative pressure concentrates to obtain (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, with DMF, make solvent, under catalyst, at 50-90 ℃, reaction 5-10 hour, through separation, obtain (C) 2-methoxyl group-4-acetylaminohydroxyphenylarsonic acid 5-ethyl sulfone methyl benzoate, further with methyl alcohol, make solvent again, the vitriol oil is made 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 bromide.
2. method according to claim 1, is characterized in that, described halogen is chlorine, bromine or iodine.
3. method according to claim 1, is characterized in that, described 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester and halogen are with mol ratio 1:1.1.
4. method according to claim 1, is characterized in that, described 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester and halogen are with mol ratio 1:1.04.
5. method according to claim 1, is characterized in that, described 2-methoxyl group-4-acetyl-amino-benzoic acid methyl ester and halogen are with mol ratio 1:1.15.
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| CN105523952A (en) * | 2015-12-28 | 2016-04-27 | 济南诚汇双达化工有限公司 | Preparation method of methyl 4-acetamido-5-chloro-2-methoxybenzoate |
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| 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523952A (en) * | 2015-12-28 | 2016-04-27 | 济南诚汇双达化工有限公司 | Preparation method of methyl 4-acetamido-5-chloro-2-methoxybenzoate |
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