CN102531940A - Preparation method for high purity etofenamate - Google Patents
Preparation method for high purity etofenamate Download PDFInfo
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- CN102531940A CN102531940A CN2011104374132A CN201110437413A CN102531940A CN 102531940 A CN102531940 A CN 102531940A CN 2011104374132 A CN2011104374132 A CN 2011104374132A CN 201110437413 A CN201110437413 A CN 201110437413A CN 102531940 A CN102531940 A CN 102531940A
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Abstract
The invention relates to a preparation method for high purity etofenamate. Flufenamic acid reacts with diethylene glycol in non-protic organic solvent in the presence of an organic carboxylic acid activating agent (R*-C1) such as chlorosilane and sulfonyl chloride, reactant is hydrolyzed under the acidic condition and then extracted and separated simply to obtain high purity etofenamate. Compared with the prior art, the preparation method for the high purity etofenamate has the advantages of being less in equipment investment and reaction steps, easy to operate, high in productivity and product purity and the like and has wide application prospects.
Description
Technical field
The present invention relates to a kind of preparation method of etofenamate compound, belong to technical field of medicine synthesis.
Background technology
Etofenamate, its English name are Etofenamate, and chemical name is 2-(2-hydroxyl-oxethyl)-ethyl-2-[3-(trifluoromethyl) anilino] benzoic ether, CAS number: [30544-47-9], molecular formula: C
18H
18F
3NO
4, molecular weight: 369.33.Structural formula:
Etofenamate is a kind of fenamic acids NSAIDs, by Beyer Co., Ltd research and development and in 1977 in Germany's listing, after go on the market in countries and regions such as Australia, Switzerland, Spain, Taiwan in succession.Beyer Co., Ltd released creme in 1999 in China, sold emulsifiable paste in 2002, sold sprays and bulk drug in 2005.Bayer (China) got permission to produce emulsifiable paste in 2002, registration goods " excellent stepping " by name (Traumon).This products material medicine is recorded by European Pharmacopoeia.
Etofenamate has analgesia, rheumatism, analgesic, antiinflammatory property.It has extremely strong close ester property and certain wetting ability, and this makes it that performance of good transdermal arranged.Can suppress the release and the effect of kallidin-9, cyclooxygenase, ester oxidase, I4EA, serotonin, mucinase and total complement; Stablize lysosome membrane; Minimizing is to the reaction of foreign matters such as prostaglandin(PG) and other inflammatory mediators, thus performance anti-inflammatory, analgesic activity.Etofenamate can be treated: the various soft tissue injuries in soft tissue rheumatism, joint etc.; The soft tissue rheumatism property disease of skeletal musculature is like muscle rheumatism, shoulder pain and stiff, muscle spasm (pain around the scapulohumeral periarthritis joint), pain in the back, sciatica, tenosynovitis, bursitis; Rachiopathy and joint disease due to the overworked or degeneration, wound are as dampening, sprain and strain etc.
The present disclosed preparation method of etofenamate mainly contains following several kinds:
(DE1939112 US3692818) discloses the preparation method of etofenamate to patent GB1285400 the earliest, uses Tecramine sylvite and 2-(2-chloroethoxy) ethanol reacting by heating in DMF, and separation obtaining etofenamate through silicagel column then.Because 2-(2-chloroethoxy) alcoholic acid hydroxyl is more active, make that this byproduct of reaction is many and concentration is big, be difficult to obtain pure article with general separation purification method, restricted the use of this method.
To the problems referred to above; Patent DE2735569 has announced that one is improved one's methods, and earlier a hydroxyl of glycol ether is used benzyl protection, reacts with sulfur oxychloride then; Generate chloro diglycol monotertiary benzyl oxide; And then with Tecramine sylvite reaction, obtain the etofenamate of benzyl protection, last hydrogenation and removing benzyl protection obtains finished product.This route needs through four-step reaction, complicated operation, and total recovery is low.
Patent ES471375 has announced an other route; Use an alkali metal salt of o-iodobenzoic acid; Earlier with 2-(2-chloroethoxy) ethanol synthesis, and then and a trifluoromethyl aniline carry out aminating reaction, generation etofenamate structure; Raw materials used expensive and product is formed very complicated, and it is very low to separate the yield that obtains pure article.
Patent DE2834169 utilizes Tecramine and PCl earlier
5Reaction obtains acyl chlorides, and then carries out esterification with glycol ether, generates the etofenamate title product, but reaction product is also very complicated, the separation and purification difficulty, and yield is lower than 50%.We attempt using sulfur oxychloride as acylating agent with reference to this method, obtain the chloride thing of Tecramine earlier, with the glycol ether reaction, have obtained and the similar result of patent then, and reaction product is very complicated, is difficult to purifying.
What patent DE2834268 and DE4436269 announced is ester exchange method; Use Tecramine and propyl carbinol to carry out esterification earlier; Obtain the positive butyl ester of Tecramine; Under sodium methylate catalysis, carry out transesterification reaction with glycol ether then, can obtain the etofenamate of 90% purity, again through the rectifying of high vacuum high temperature could separate refined product (170 ~ 175 ℃/0.001mmHg).High-vacuum apparatus investment when reaction is amplified is huge; And we find through the THERMAL STABILITY to the etofenamate product; It just obviously produces dimerization impurity 170 ℃ of placements after 1 hour; Be the impurity D (2,2 '-oxygen-two ethyls-two-[2-[[3-(trifluoromethyl) phenyl] amino] benzoic ether]) that European Pharmacopoeia EP6.0 describes, the limit of this impurity in pharmacopeia is for being not more than 0.5%.This means that also rectifying need use special devices could obtain effect of separating purification.ES512031 adopts similar method, carries out transesterify behind the formation methyl esters earlier, and the result roughly the same.
Also have patent report to use conventional Lewis acid catalysis, directly make Tecramine and glycol ether carry out the method for esterification, such as DE3811119 and ES2003782 report, yield is also on the low side, the purifying products difficulty.
Patent ES534122 has announced a relatively more atypical method; React earlier, generate the Er hydrogen benzoxazinone structure of 75% yield with formaldehyde and Tecramine, then in the presence of catalytic amount sodium hydroxide and glycol ether in 175 ℃ of reactions; Exchange also discharges the etofenamate product; The high energy of exchange step yield reaches 78%, but needs the high vacuum rectification purifying, and total recovery is also lower.Patent ES548225 has continued to use this thinking; Replace the condensation of formaldehyde elder generation with Vinyl chloroformate, exist refluxed to carry out cyclization at sulfur oxychloride etc. then, generate Er hydrogen benzoxazinone structure; React with glycol ether again; High energy separates the etofenamate that obtains 98.5% purity, but total recovery is lower, and the index of quality product and European Pharmacopoeia differs bigger.
Shortcoming such as high vacuum high temperature rectifying device, product appearance difference and the content of in the method for the synthetic etofenamate of above bibliographical information, have all that yield is on the low side, separation difficulty, needs are special is low.At present, domestic also do not have producer to produce this product in mass-producing ground, all is to rely on import to produce preparation.Therefore, novel method for synthesizing and the route of developing these article have very high social benefit and economic benefit.
Summary of the invention
The present invention aims to provide a kind of high purity etofenamate preparation method; Shortcomings such as high vacuum high temperature rectifying device, product appearance difference and the content of solve that the yield that exists in the prior art is on the low side, separation difficulty, needs are special is low; Produce the high purity product that meets European Pharmacopoeia, ensure clinical application and security requirement.
Technical scheme provided by the invention is following:
The new preparation process of a kind of high purity etofenamate (formula (I)),
Said method comprises reacts with glycol ether Tecramine in the presence of organic carboxyl acid acvators (R*-Cl) such as chlorosilane, SULPHURYL CHLORIDE in non-proton organic solvent; Pass through follow-up lock out operation behind the reactant acidic hydrolysis again, can obtain highly purified etofenamate.Reaction formula is following:
Wherein, formula (II) compound is a Tecramine, and formula (III) compound is a glycol ether, and the R*-Cl compound is organic carboxyl acid acvators such as chlorosilane or SULPHURYL CHLORIDE.
The preparation method of the etofenamate of said structure provided by the invention comprises the steps:
Tecramine is joined in the non-proton organic solvent, add organic carboxyl acid acvators (R*-Cl) such as chlorosilane, SULPHURYL CHLORIDE, stir, add glycol ether again and continue reaction.After reaction finishes, different according to the polarity of reaction solvent, can reaction solution directly be added hydrolysis in the weak acid water, perhaps concentrate the back and add hydrolysis in the weak acid water, promptly generate the etofenamate structure.Regulate pH then to alkalescence, standing demix perhaps extracts with water-insoluble organic solvent, and organic layer can obtain highly purified etofenamate again behind washing for several times, activated carbon decolorizing, filtration, concentrating under reduced pressure.
The organic carboxyl acid acvator (R*-Cl) that uses can be trimethylchlorosilane (TMSCl), TERT-BUTYL DIMETHYL CHLORO SILANE chlorosilanes such as (TBDMSCl), or Tosyl chloride (TsCl), Methanesulfonyl chloride (MsCl), trifluoromethyl SULPHURYL CHLORIDE, p-nitrophenyl SULPHURYL CHLORIDE (Nosyl Cl), ortho-nitrophenyl SULPHURYL CHLORIDE (Nps Cl), benzene sulfonyl chloride (C
6H
5SO
2Cl) etc. SULPHURYL CHLORIDE is preferably trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, Tosyl chloride or Methanesulfonyl chloride.
Used non-proton organic solvent can be nonpolar organic solvent; It also can be the polar organic solvent; Such as toluene, benzene, methylene dichloride, chloroform, 1; 2-ethylene dichloride, chlorobenzene, normal hexane, sherwood oil, isopropyl ether, MTBE (MTBE), MIBK (MIBK), THF, acetonitrile, DMF etc. one or several, be preferably toluene, methylene dichloride, acetonitrile or DMF.
In the above-mentioned compound method, the mol ratio of " Tecramine: R*-Cl: glycol ether " is " 1.0: 1.8 ~ 2.5: 2.0 ~ 30.0 ", and preferred mol ratio is " 1.0: 2.0 ~ 2.2: 10.0 ~ 20.0 ".
In the above-mentioned compound method, the temperature of Tecramine and organic carboxyl acid acvator (R*-Cl) reaction can be-20 ℃ ~ 80 ℃, and preferred range is 0 ℃ ~ 40 ℃.The temperature that adds glycol ether continuation reaction again can be 0 ℃ ~ 100 ℃, and preferred range is 20 ℃ ~ 60 ℃.
In the above-mentioned compound method; When the aprotic non-polar organic solvent is used in reaction; Like toluene, benzene, methylene dichloride, chloroform, 1, when 2-ethylene dichloride, chlorobenzene, normal hexane, sherwood oil, isopropyl ether, MTBE (MTBE), MIBK (MIBK) etc., the reaction product aftertreatment can directly be added to hydrolysis in the weak acid water; Re-adjustment pH is direct standing demix to the alkalescence back, does not need to extract with water-insoluble organic solvent again.When the aprotic polar organic solvent is used in reaction, during like THF, acetonitrile, DMF etc., the reaction product aftertreatment can concentrate earlier, adds hydrolysis in the weak acid water then, and re-adjustment pH extracts with water-insoluble organic solvent to the alkalescence back.Used water-insoluble organic solvent can be toluene, benzene, methylene dichloride, chloroform, 1; One or several mixing of 2-ethylene dichloride, chlorobenzene, normal hexane, sherwood oil, isopropyl ether, MTBE (MTBE), MIBK (MIBK) etc. are preferably toluene, methylene dichloride or MTBE.
Add the weak acid be used for hydrolysis in the above-mentioned compound method and can be one or several of Hydrogen chloride, dilute sulphuric acid, glacial acetic acid aqueous solution or saturated aqueous ammonium chloride etc.Regulating the used alkali of pH can be sodium hydroxide, Pottasium Hydroxide, calcium hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus etc., is preferably yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus.PH can be adjusted to 7 ~ 14, is preferably 8 ~ 10.
As a particularly preferred embodiment according to the invention, the preparation method of etofenamate provided by the invention comprises the steps:
Tecramine is joined in the non-proton organic solvent, be cooled to 5 ~ 10 ℃, add organic carboxyl acid acvators (R*-Cl) such as chlorosilane, SULPHURYL CHLORIDE, stirring reaction under this temperature adds glycol ether then, is warming up to 30 ~ 40 ℃ and continues reaction.If the solvent that reaction is used is toluene or methylene dichloride, reaction finishes the back and directly adds Hydrogen chloride in 30 ~ 40 ℃ of reactions that are hydrolyzed; If the solvent that reaction is used is acetonitrile or DMF, reaction finishes the back and concentrates earlier, adds Hydrogen chloride then in 30 ~ 40 ℃ of reactions that are hydrolyzed.After hydrolysis reaction finishes; Be cooled to about 10 ℃; Use then about the pH to 9 of yellow soda ash conditioned reaction system, standing demix perhaps extracts with water-insoluble organic solvent, and organic layer can obtain highly purified etofenamate again behind washing for several times, activated carbon decolorizing, filtration, concentrating under reduced pressure.HPLC condition according to European Pharmacopoeia (EP 6.0) correlative is measured is analyzed, and we all meet the requirements by the correlative impurity of product.
The preparation method of high purity etofenamate provided by the invention compares with prior art; Do not need column purification; Do not need special high vacuum high temperature rectifying device to come the separation and purification product yet; Have advantages such as reactions step is few, productive rate is high, separation and purification is simple, product purity is high, outward appearance is good, have broad application prospect.
Description of drawings
Fig. 1: the collection of illustrative plates of etofenamate reference substance under the EP6.0 correlative HPLC analysis condition.
Fig. 2: the etofenamate typical sample collection of illustrative plates for preparing according to this patent method under the EP6.0 correlative HPLC analysis condition.
Specific embodiment
Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
Embodiment 1: the preparation of etofenamate.
281.5 gram Tecramine are joined in the 1000 gram toluene, stir and be cooled to 10 ℃, add 217.5 gram trimethylchlorosilanes (R*=TMS), stirring reaction is 1 hour under this temperature.Add 1062 gram glycol ethers then, be warming up to 30 ℃ and continue reaction 5 hours.Reaction process is followed the tracks of with TLC or HPLC and is detected to Tecramine raw material and midbody disappearance, adds 10% Hydrogen chloride 800 again and restrains in 30 ~ 40 ℃ of stirring hydrolysis 1 hour, and HPLC follows the tracks of and detects to all being converted into etofenamate.Reaction solution is cooled to about 10 ℃, uses about the pH to 9 of yellow soda ash conditioned reaction system standing demix then.Organic layer divides five washings with pure water 1000 grams, adds the proper amount of active carbon decolouring then, crosses and filters colorless clear liquid.50 ℃ are evaporated to solvent-free steaming, and then strengthen vacuum tightness to less than-0.095MPa, are controlled at 70 ~ 80 ℃ and continue to take out 1 hour, all remove remaining solvent, obtain etofenamate finished product 329.5 and restrain, and purity is greater than 99%, yield 89.2%.ESI-MS m/z 370.1 [M+H]
+, the HPLC relative retention time is consistent with reference substance, and color is not deeper than GY1, and correlative impurity all meets the European Pharmacopoeia requirement.
Embodiment 2: the preparation of etofenamate.
Restrain Tecramine with 281.5 and join in the 1000 gram toluene, stir and be cooled to 10 ℃, add 331.6 gram TERT-BUTYL DIMETHYL CHLORO SILANEs (R*=TBDMS), and be controlled at 20 ℃ of continuation stirring reactions 1 hour.Add 1592 gram glycol ethers then, be warming up to 40 ℃ and continue reaction 5 hours.Reaction process is followed the tracks of with TLC or HPLC and is detected to Tecramine raw material and midbody disappearance, adds 10% Hydrogen chloride 900 then and restrains in 30 ~ 40 ℃ of stirring hydrolysis 1 hour, and HPLC follows the tracks of and detects to all being converted into etofenamate.Reaction solution is cooled to about 10 ℃, uses about the pH=9 of salt of wormwood conditioned reaction system standing demix then.Organic layer divides six washings with pure water 1200 grams again, adds the proper amount of active carbon decolouring then, crosses and filters colourless clear liquid.50 ℃ are evaporated to solvent-free steaming, and then strengthen vacuum tightness to less than-0.095MPa, are controlled at 70 ~ 80 ℃ and continue to take out 1 hour; All remove remaining solvent; Obtain etofenamate finished product 321.8 gram, purity is greater than 99%, yield 87.1%; Color is not deeper than GY1, and correlative impurity all meets the European Pharmacopoeia requirement.
Embodiment 3: the preparation of etofenamate.
281.5 gram Tecramine are joined stir among the DMF of 1200 grams and be cooled to 10 ℃, add 381.5 gram Tosyl chlorides (R*=Ts), and be controlled at 20 ℃ and continued stirring reactions 1 hour.Add 1062 gram glycol ethers then, be warming up to 40 ℃ and continue reaction 5 hours.Reaction is followed the tracks of with TLC or HPLC and is detected to Tecramine raw material and midbody disappearance; At 50 ~ 60 ℃ of concentrating under reduced pressure reaction solutions to about 1700ml; Add 10% Hydrogen chloride, 800 grams then, in 30 ~ 40 ℃ of stirring hydrolysis 2 hours, HPLC followed the tracks of and detects to all being converted into etofenamate.Reaction solution is cooled to about 10 ℃, uses then about the pH to 10 of yellow soda ash conditioned reaction system, and reaction solution extracts with toluene 1000 grams at twice.Merge organic layer, divide five washings, add the proper amount of active carbon decolouring then, cross and filter colorless clear liquid with pure water 1000 grams.50 ℃ are evaporated to solvent-free steaming, and then strengthen vacuum tightness to less than-0.095MPa, are controlled at 70 ~ 80 ℃ and continue distillation 1 hour; The solvent of remnants is all removed; Obtain etofenamate finished product 305.1 gram, purity is greater than 99%, yield 82.6%; Color is not deeper than GY1, and correlative impurity all meets the European Pharmacopoeia requirement.
Embodiment 4: the preparation of etofenamate.
281.5 gram Tecramine are joined in the 1000 gram acetonitriles, stir and be cooled to 5 ℃, add 252.1 gram Methanesulfonyl chlorides (R*=Ms), and be controlled at 5 ℃ of left and right sides stirring reactions 1 hour.Add 1592 gram glycol ethers then, be warming up to 30 ℃ and continue reaction 5 hours.Reaction is followed the tracks of with TLC or HPLC and is detected to Tecramine raw material and midbody disappearance; At 40 ℃ of concentrating under reduced pressure reaction solutions to about 2300ml; Add 10% Hydrogen chloride, 900 grams then, in 30 ~ 40 ℃ of stirring hydrolysis 2 hours, HPLC followed the tracks of and detects to all being converted into etofenamate.Reaction solution is cooled to about 10 ℃, uses then about the pH to 10 of yellow soda ash conditioned reaction system, and reaction solution divides three extractions with MTBE 1200 grams.Merge organic layer, divide six washings with pure water 1200 grams again, add the proper amount of active carbon decolouring then, cross and filter colorless clear liquid.40 ℃ are evaporated to solvent-free steaming, and then strengthen vacuum tightness to less than-0.095MPa, are controlled at 60 ~ 70 ℃ and continue distillation 1 hour; The solvent of remnants is all removed; Obtain etofenamate finished product 312.4 gram, purity is greater than 99%, yield 84.6%; Color is not deeper than GY1, and correlative impurity all meets the European Pharmacopoeia requirement.
Claims (13)
1. the new preparation process of a high purity etofenamate (formula (I)),
Said method comprises Tecramine in the presence of organic carboxyl acid acvators (R*-Cl) such as chlorosilane, SULPHURYL CHLORIDE; React in non-proton organic solvent with glycol ether; Reactant passes through follow-up lock out operation again after the hydrolysis under acidic conditions; Can obtain highly purified etofenamate, reaction formula is following:
Wherein, formula (II) compound is a Tecramine, and formula (III) compound is a glycol ether, and the R*-Cl compound is organic carboxyl acid acvators such as chlorosilane or SULPHURYL CHLORIDE.
2. preparation method according to claim 1, it comprises the steps:
Tecramine is joined in the non-proton organic solvent, add organic carboxyl acid acvators (R*-Cl) such as chlorosilane, SULPHURYL CHLORIDE, stir, add glycol ether again and continue reaction; After reaction finishes; Polarity according to reaction solvent is different, can reaction solution directly be added hydrolysis in the weak acid water, perhaps concentrates the back and adds hydrolysis in the weak acid water; Promptly generate the etofenamate structure; Regulate pH then to alkalescence, standing demix perhaps extracts with water-insoluble organic solvent, and organic layer can obtain highly purified etofenamate again behind washing for several times, activated carbon decolorizing, filtration, concentrating under reduced pressure.
3. preparation method according to claim 2; It is characterized in that organic carboxyl acid acvator (R*-Cl) can be trimethylchlorosilane (TMSCl), TERT-BUTYL DIMETHYL CHLORO SILANE chlorosilanes such as (TBDMSCl), or Tosyl chloride (TsCl), Methanesulfonyl chloride (MsCl), trifluoromethyl SULPHURYL CHLORIDE, p-nitrophenyl SULPHURYL CHLORIDE (Nosyl Cl), ortho-nitrophenyl SULPHURYL CHLORIDE (Nps Cl), benzene sulfonyl chloride (C
6H
5SO
2Cl) etc. SULPHURYL CHLORIDE is preferably trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, Tosyl chloride or Methanesulfonyl chloride.
4. preparation method according to claim 2; It is characterized in that used non-proton organic solvent can be nonpolar organic solvent; It also can be the polar organic solvent; Such as toluene, benzene, methylene dichloride, chloroform, 1, one or several mixing such as 2-ethylene dichloride, chlorobenzene, normal hexane, sherwood oil, isopropyl ether, MTBE (MTBE), MIBK (MIBK), THF, acetonitrile, DMF are preferably toluene, methylene dichloride, acetonitrile or DMF.
5. preparation method according to claim 2 is characterized in that the mol ratio of " Tecramine: R*-Cl: glycol ether " is " 1.0: 1.8 ~ 2.5: 2.0 ~ 30.0 ", and preferred mol ratio is " 1.0: 2.0 ~ 2.2: 10.0 ~ 20.0 ".
6. preparation method according to claim 2 is characterized in that the temperature of Tecramine and organic carboxyl acid acvator (R*-Cl) reaction can be-20 ℃ ~ 80 ℃, and preferred range is 0 ℃ ~ 40 ℃.
7. preparation method according to claim 2 is characterized in that the temperature that adds glycol ether continuation reaction again can be 0 ℃ ~ 100 ℃, and preferred range is 20 ℃ ~ 60 ℃.
8. preparation method according to claim 2; It is characterized in that using the aprotic non-polar organic solvent, like toluene, benzene, methylene dichloride, chloroform, 1, when 2-ethylene dichloride, chlorobenzene, normal hexane, sherwood oil, isopropyl ether, MTBE (MTBE), MIBK (MIBK) etc. when reaction; Post-reaction treatment can directly add hydrolysis in the weak acid water; Regulate pH to alkalescence, directly standing demix does not need to extract with water-insoluble organic solvent again.
9. preparation method according to claim 2; It is characterized in that using the aprotic polar organic solvent when reaction; During like THF, acetonitrile, DMF etc., post-reaction treatment can concentrate earlier, adds hydrolysis in the weak acid water then; Regulate pH to alkalescence, extract with water-insoluble organic solvent again.
10. preparation method according to claim 9; It is characterized in that the water-insoluble organic solvent that extracts usefulness can be toluene, benzene, methylene dichloride, chloroform, 1; One or several mixing of 2-ethylene dichloride, chlorobenzene, normal hexane, sherwood oil, isopropyl ether, MTBE (MTBE), MIBK (MIBK) etc. are preferably toluene, methylene dichloride or MTBE.
11. preparation method according to claim 2 is characterized in that the weak acid that adds can be one or several of Hydrogen chloride, dilute sulphuric acid, glacial acetic acid aqueous solution or saturated aqueous ammonium chloride etc.
12. compound method according to claim 2; After it is characterized in that the acidified generation etofenamate of reaction solution structure; Regulate pH to alkalescence; Used alkali can be sodium hydroxide, Pottasium Hydroxide, calcium hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus etc., is preferably yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus; PH can be adjusted to 7 ~ 14, is preferably 8 ~ 10.
13. compound method according to claim 2; It is characterized in that: Tecramine is joined in the non-proton organic solvent; Be cooled to 5 ~ 10 ℃, add organic carboxyl acid acvators (R*-Cl) such as chlorosilane, SULPHURYL CHLORIDE, stirring reaction under this temperature; Add glycol ether then, be warming up to 30 ~ 40 ℃ and continue reaction; Determine whether to concentrate according to claims 8 and 9 described solvent polarities; Add Hydrogen chloride again in 30 ~ 40 ℃ of reactions that are hydrolyzed; Be cooled to about 10 ℃; Using yellow soda ash conditioned reaction system then is about 9 to pH, and standing demix perhaps extracts with water-insoluble organic solvent, and organic layer can obtain highly purified etofenamate again behind washing, concentrating under reduced pressure.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3692818A (en) * | 1969-08-01 | 1972-09-19 | Troponwerke Dinklage & Co | New pharmacologically active esters of n-(3-trifluoromethylphenyl)-anthranilic acid |
| ES2003782A6 (en) * | 1987-02-06 | 1988-11-16 | Union Quimico Farma | Fluophenamic acid deriv. prepn. |
-
2011
- 2011-12-23 CN CN201110437413.2A patent/CN102531940B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3692818A (en) * | 1969-08-01 | 1972-09-19 | Troponwerke Dinklage & Co | New pharmacologically active esters of n-(3-trifluoromethylphenyl)-anthranilic acid |
| ES2003782A6 (en) * | 1987-02-06 | 1988-11-16 | Union Quimico Farma | Fluophenamic acid deriv. prepn. |
Non-Patent Citations (1)
| Title |
|---|
| JORDI ERAS ET AL: "Chlorotrimethylsilane: A Suitable Reagent for the Synthesis of Chlorohydrin Esters", 《J. ORG. CHEM.》 * |
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