CN101628886B - Synthesis method for 2- methoxyl-4-amino-5-ethylsulfonylbenzoic acid - Google Patents
Synthesis method for 2- methoxyl-4-amino-5-ethylsulfonylbenzoic acid Download PDFInfo
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- CN101628886B CN101628886B CN2009101693285A CN200910169328A CN101628886B CN 101628886 B CN101628886 B CN 101628886B CN 2009101693285 A CN2009101693285 A CN 2009101693285A CN 200910169328 A CN200910169328 A CN 200910169328A CN 101628886 B CN101628886 B CN 101628886B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a synthesis method for 2-methoxyl-4-amino-5-ethylsulfonylbenzoic acid which is an important immediate for antipsychotics Amisulpride. The method uses 2-methoxyl-4-methyl anthranilate as raw material, and carries out amino protection, sulphurization, deamination protection, chloridization, reduction, thylization, esterolysis and crystallization, and then the 2-methoxyl-4-amine-5-ethylsulfonylbenzoic acid is prepared. The method uses common reagents with easy obtainment as reaction mediums, the reaction condition is high, and the prepared product has the advantages of high purity and high yield, and is suitable for industrialization production.
Description
Technical field
The present invention relates to a kind of important intermediate 2-methoxyl group-4-amino-benzoic compound method of 5-ethyl sulfone of psychotroptic drug Majorem.Belong to medical technical field.
Background technology
2-methoxyl group-4-amino-5-ethyl sulfone phenylformic acid is the important intermediate of synthetic psychotroptic drug Majorem.Different with synthetic initial feed difference of being selected for use or response path, the compound method of having reported at present has:
Circuit 1
Circuit 2
Circuit 3
Relative merits are respectively arranged in the aforesaid method.In the circuit 1, this method is simple to operate, and two steps can obtain product, and reaction time is short, and mild condition is simple to operate.Its shortcoming is that reaction raw materials is too expensive, and the second step yield is low.Involved solvent chlorsulfonic acid and ethyl sulfate high volatility in the circuit 2 is very big to the hazardness of human body.Though circuit 3 only needed for three steps can obtain required midbody, the yield of its first step is very low, and per step all relate to issues of purification, it is more loaded down with trivial details to operate.
Summary of the invention
To above-mentioned situation, the present invention provides a kind of ability to be fit to suitability for industrialized production and has more the above-mentioned 2-methoxyl group of preparation-4-amino-benzoic new synthetic method of 5-ethyl sulfone that commercialization is worth.
Technical scheme of the present invention is that raw material and aceticanhydride amido protecting, concentrated acid sulfonation, phosphorus pentachloride chlorination, S-WAT reduction, monobromethane ethylize, the methyl esters hydrolysis with 2-methoxyl group-4-Methyl anthranilate, and recrystallization obtains product.Like circuit 4:
Circuit 4
Specific embodiments
Synthesizing of embodiment 1:2-methoxyl group-4-acetamido-5-sulfonyl methyl benzoate
In the there-necked flask of 250ml, add 2-methoxyl group-4-Methyl anthranilate 50g, aceticanhydride 72.5g, acetic acid 105g, controlled temperature 20-30 degree drips vitriol oil 24.5g fast, drips back temperature reaction 1h, and cooling is filtered and is obtained white product 60g.
Synthesizing of embodiment 2:2-methoxyl group-4-amido-5-sulfonyl methyl benzoate
In 500 there-necked flask, add products therefrom 60g among the embodiment 1, methyl alcohol 600g is in 20-25 degree reaction 12h, suction filtration exsiccant product 47g.
Synthesizing of embodiment 3:2-methoxyl group-4-amido-5-chlorosulfonyl oil of Niobe
In the there-necked flask of 500ml, add products therefrom 47g among the embodiment 2, phosphorus pentachloride 50g, acetonitrile 78g; Be warming up to 84 degree, refluxed 1 hour, reaction finishes; Reaction solution is poured in the mixing solutions of ETHYLE ACETATE and water; Static layering obtains the ethyl acetate solution of title product, and anhydrous magnesium sulfate drying filters.
Synthesizing of embodiment 4:2-methoxyl group-4-amido-5-sulfinyl oil of Niobe
In the there-necked flask of 500ml, add S-WAT 45g, sodium hydrogencarbonate 94g, water 188g stirs, and drips the ethyl acetate solution of embodiment 3, has great amount of bubbles to emerge.After adding, temperature reaction 2h.Reaction finishes, and static cooling layering obtains the aqueous solution of title product.
Synthesizing of embodiment 5:2-methoxyl group-4-amido-5-ethyl sulfone oil of Niobe
The aqueous solution that in the there-necked flask of 500ml, adds embodiment 4, ETHYLE ACETATE 150g, acetone 100g, Tetrabutyl amonium bromide 1g; Stir down and add Sulfothiorine 15g, monobromethane 50g, 50 degree reaction 3h; The reaction cooling layering that finishes, water layer is with ethyl acetate extraction 3 times, 50ml at every turn; Merge methacrylate layer, wash three times, saturated common salt is washed once.Obtain solid in 70 degree evaporated under reduced pressure ETHYLE ACETATE, solid joins 50ml absolute ethyl alcohol backflow 0.5h, and crystallisation by cooling gets title product 21g.
Embodiment 6:2-methoxyl group-4-amido-5-ethyl sulfone is benzoic synthetic
In the there-necked flask of 250ml, add embodiment 5 product 21g, water 105g, sodium hydroxide 12.6g.Reflux 2h.Be cooled to room temperature, transfer pH value to 2-3 with concentrated hydrochloric acid, stir and separate out white solid, filtered water is washed till neutrality, obtains title product 14g.
Embodiment 7: embodiment 6 title product recrystallizations
Title product 14 heating of embodiment 6 are dissolved in the methyl alcohol of 52ml, and stirring adds water 52ml, slowly separates out white solid, and filtration drying gets title product 10g.
Claims (7)
1. 2-methoxyl group-4-amino-benzoic compound method of 5-ethyl sulfone is characterized in that through following synthetic route and midbody to reach the synthetic of title product:
2. the 2-methoxyl group according to claim 1-4-amino-benzoic compound method of 5-ethyl sulfone; It is characterized in that midbody (I) synthetic be to be raw material with 2-methoxyl group-4-Methyl anthranilate; In acetic acid, add aceticanhydride; Drip the vitriol oil fast, controlled temperature is between 20～30 degree, and reaction 1.5h obtains.
3. the 2-methoxyl group according to claim 1-4-amino-benzoic compound method of 5-ethyl sulfone is characterized in that the synthetic of midbody (II) is to obtain with the protection of methyl alcohol hydrolysis midbody (I) deaminize.
4. the 2-methoxyl group according to claim 1-4-amino-benzoic compound method of 5-ethyl sulfone; It is characterized in that midbody (III) synthetic be that midbody (II) is chlorizating agent backflow 1h with the phosphorus pentachloride in acetonitrile, reaction finishes to be cooled to 0 degree disaggregating treatment in frozen water and obtains with ethyl acetate extraction.
5. the 2-methoxyl group according to claim 1-4-amino-benzoic compound method of 5-ethyl sulfone; It is characterized in that midbody (IV) synthetic be to be acid-acceptor with the sodium hydrogencarbonate, be that reductive agent drips midbody (III) in water ethyl acetate solution reduction obtains with the S-WAT.
6. the 2-methoxyl group according to claim 1-4-amino-benzoic compound method of 5-ethyl sulfone is characterized in that the synthetic of midbody (VI) is midbody (V) back hydrolysis in 12% sodium hydroxide, and concentrated hydrochloric acid adjust pH to 2～3 are separated out solid and obtained.
7. according to claim 1 or 6 described 2-methoxyl group-4-amino-benzoic compound methods of 5-ethyl sulfone, the solvent that crystallization is selected for use that it is characterized in that midbody (VI) is 50% methanol refining crystallization.
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| CN2009101693285A CN101628886B (en) | 2009-08-25 | 2009-08-25 | Synthesis method for 2- methoxyl-4-amino-5-ethylsulfonylbenzoic acid |
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| CN2009101693285A CN101628886B (en) | 2009-08-25 | 2009-08-25 | Synthesis method for 2- methoxyl-4-amino-5-ethylsulfonylbenzoic acid |
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| CN101628886B true CN101628886B (en) | 2012-12-12 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807516A (en) * | 2012-08-16 | 2012-12-05 | 四川省百草生物药业有限公司 | Intermediate in amisulpride and method for preparing amisulpride by using intermediate |
| CN103304453A (en) * | 2013-06-18 | 2013-09-18 | 苏州诚和医药化学有限公司 | Method for synthesizing 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid in two steps |
| CN103319384A (en) * | 2013-06-18 | 2013-09-25 | 苏州诚和医药化学有限公司 | Method for preparing 2-methoxyl-4-amino-5-ethylsulfonyl methyl benzoate |
| CN103319385B (en) * | 2013-06-18 | 2015-07-08 | 苏州诚和医药化学有限公司 | Method for synthesizing 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid |
| CN103553989B (en) * | 2013-11-08 | 2015-03-11 | 苏州诚和医药化学有限公司 | Synthetic method of 2-methoxyl-4-amino-5-ethyl sulfuryl methyl benzoate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4294828A (en) * | 1978-01-20 | 1981-10-13 | Societe D'etudes Scientifiques Et Industrielles De L'ile De-France | New derivatives of 4-amino-5-alkyl sulphonyl orthoanisamides, methods of preparing them and their application as psychotropic agents |
| GB2083033A (en) * | 1980-08-28 | 1982-03-17 | Ile De France | Novel benzamide as a medicament |
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2009
- 2009-08-25 CN CN2009101693285A patent/CN101628886B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4294828A (en) * | 1978-01-20 | 1981-10-13 | Societe D'etudes Scientifiques Et Industrielles De L'ile De-France | New derivatives of 4-amino-5-alkyl sulphonyl orthoanisamides, methods of preparing them and their application as psychotropic agents |
| GB2083458A (en) * | 1978-01-20 | 1982-03-24 | Ile De France | 5-substituted 2-methoxy-4-aminobenzoic acids and their preparation |
| GB2083033A (en) * | 1980-08-28 | 1982-03-17 | Ile De France | Novel benzamide as a medicament |
Non-Patent Citations (1)
| Title |
|---|
| 李付刚等.2-甲氧基-4-氨基-5-乙砜基苯甲酸的合成.《研发前沿》.2008,第16卷(第13期),16-17. * |
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Address after: 100176, 5 block, block A, 16 building, 8 hospital, two Shui Jie, Beijing economic and Technological Development Zone, Beijing. Patentee after: BEIJING WISTA PHARMA TECHNOLOGY CO.,LTD. Address before: 102209 No. 16, Bai Miao Industrial Park, Beiqijia Town, Changping District, Beijing Patentee before: BEIJING WISTA TONGDA SCIENCE & TECHNOLOGY CO.,LTD. |
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Effective date of registration: 20180605 Address after: 157009 332 Daqing street, Aimin District, Mudanjiang, Heilongjiang Patentee after: Mudanjiang Hengyuan pharmaceutical Limited by Share Ltd. Address before: 100176, 5 block, block A, 16 building, 8 hospital, two Shui Jie, Beijing economic and Technological Development Zone, Beijing. Patentee before: BEIJING WISTA PHARMA TECHNOLOGY CO.,LTD. |
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Effective date of registration: 20230426 Address after: 501, Building A, Building 6, Han's Enterprise Bay, No. 8 Liangshuihe Second Street, Beijing Economic and Technological Development Zone, Daxing District, Beijing, 100176 Patentee after: BEIJING WISTA PHARMA TECHNOLOGY CO.,LTD. Address before: 157009 332 Daqing street, Aimin District, Mudanjiang, Heilongjiang Patentee before: Mudanjiang Hengyuan pharmaceutical Limited by Share Ltd. |