CN103553991A - Method for preparing methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate - Google Patents
Method for preparing methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate Download PDFInfo
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- CN103553991A CN103553991A CN201310548145.0A CN201310548145A CN103553991A CN 103553991 A CN103553991 A CN 103553991A CN 201310548145 A CN201310548145 A CN 201310548145A CN 103553991 A CN103553991 A CN 103553991A
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- methoxyl group
- amino
- benzoic acid
- halogen
- acetyl
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- 238000000034 method Methods 0.000 title claims abstract description 16
- BBWJVKZAKHIKRQ-UHFFFAOYSA-N methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate Chemical compound CCS(=O)(=O)C1=CC(C(=O)OC)=C(OC)C=C1N BBWJVKZAKHIKRQ-UHFFFAOYSA-N 0.000 title abstract 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 54
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 25
- UWIVVFQECQYHOB-UHFFFAOYSA-M sodium;ethanesulfinate Chemical compound [Na+].CCS([O-])=O UWIVVFQECQYHOB-UHFFFAOYSA-M 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 239000002253 acid Substances 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- ZXMISUUIYPFORW-UHFFFAOYSA-N 2-bromo-5-methylbenzoic acid Chemical compound CC1=CC=C(Br)C(C(O)=O)=C1 ZXMISUUIYPFORW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- NPXOIGSBRLCOSD-UHFFFAOYSA-N methyl 3-iodobenzoate Chemical class COC(=O)C1=CC=CC(I)=C1 NPXOIGSBRLCOSD-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000031709 bromination Effects 0.000 abstract description 3
- 238000005893 bromination reaction Methods 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract description 3
- 230000026030 halogenation Effects 0.000 abstract description 3
- 238000005658 halogenation reaction Methods 0.000 abstract description 3
- 238000010992 reflux Methods 0.000 description 18
- 238000009413 insulation Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000000630 rising effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- -1 5-chloro benzoic ether Chemical compound 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 description 2
- 229960003036 amisulpride Drugs 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 238000006365 thiocyanation reaction Methods 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate. The method comprises the steps of performing halogenation (chlorination, bromination and iodization) to 2-methoxy-4-acetylamine methyl benzoate, and then condensing together with ethane sulfinic acid sodium salt to obtain a target product. The method has the advantages that the technological route is simple, and the product is high in yield which achieves the total yield up to 80%, good in the quality with the purity up to 99.5%, and is white in appearance.
Description
Technical field
The present invention relates to medicine intermediate preparing technical field, specifically, is a kind of method about the 2-of preparation methoxyl group-4-amino-5-ethyl sulfone methyl benzoate.
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 the 2-of preparation 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 of 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 ℃ 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 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 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, 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 chloride.
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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| CN118388329A (en) * | 2024-05-16 | 2024-07-26 | 江苏海洋大学 | Preparation method of tapentadol intermediate |
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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 |
-
2013
- 2013-11-08 CN CN201310548145.0A patent/CN103553991B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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