CN101077872A - Method for preparing etodolac methyl ester - Google Patents
Method for preparing etodolac methyl ester Download PDFInfo
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- CN101077872A CN101077872A CN 200710015592 CN200710015592A CN101077872A CN 101077872 A CN101077872 A CN 101077872A CN 200710015592 CN200710015592 CN 200710015592 CN 200710015592 A CN200710015592 A CN 200710015592A CN 101077872 A CN101077872 A CN 101077872A
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- tryptosol
- ethyl
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Abstract
The present invention relates to new process of preparing methyl etodolate as the intermediate of non-steroid indole anti-inflammatory analgesic etodolic acid. The process includes the reaction between 7-ethyl tryptosol and 3-methyl oxy valerate inside mixed solvent of C1-C2 alcohol and benzene in the presence of acid catalyst, separating out acid layer after reaction, neutralizing the organic phase, concentrating, re-crystallizing. The process has high stability, high yield, high product quality, conversion rate near to 100 %, simple operation low cost, environment friendship and other advantages, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of new preparation process for preparing a kind of intermediate etodolac methyl ester of indoles non-steroidal anti-inflammatory analgesics R-ETODOLAC.
Background technology
R-ETODOLAC, its chemical name are 1,8-diethyl-1,3,4,9-tetrahydropyrans also [3,4-b] indoles-1-acetate (1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indol-1-aceticacid), being used for the treatment of rheumatic arthritis, rheumatoid arthritis, osteoarthritis and post-operative pain, analgesic activity is stronger.Etodolac methyl ester (1,8-diethyl-1,3,4, the 9-tetrahydropyrans is [3,4-b] indoles-1-methyl acetate also) be the important intermediate of synthetic R-ETODOLAC, it is as follows that it generally can make (seeing US6,006,741) its reaction by 7-ethyl tryptosol and 3-oxopentanoic acid methyl esters:
Former technology is to be dissolved with in the toluene of 7-ethyl tryptosol and 3-oxopentanoic acid methyl esters, drips 20% hydrogenchloride isobutanol solution.After reaction finishes, in the sodium bicarbonate aqueous solution of mixture impouring 10%, layering, water extracts with toluene, underpressure distillation, recrystallizing methanol, more after filtration, wash, be drying to obtain, product appearance is poor, and yield is up to 78%.This technology at first prepares the isobutanol solution of hydrogenchloride, complicated operation, because after the reaction end, in the direct impouring sodium bicarbonate aqueous solution of mixture, products obtained therefrom is of poor quality, yield is low, and the aftertreatment three wastes are many, and the production cost height does not meet suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of improved etodolac methyl ester, the yield height, and quality is good, and the three wastes are few, and production cost is low, is fit to suitability for industrialized production.
The preparation method of etodolac methyl ester of the present invention is made by 7-ethyl tryptosol and the reaction of 3-oxopentanoic acid methyl esters, and it is characterized in that: reaction solvent adopts C
1～C
2Lower alcohol and the mixed solvent formed of benzene-like compounds, reaction is to carry out under the katalysis of acid, after reaction finishes, acid layer is told, organic phase makes with buck neutralization, concentrated, recrystallization.
The present invention is by 7-ethyl tryptosol, and in the presence of mixed solvent, under the vitriol oil or the oleum catalysis, with the reaction of 3-oxopentanoic acid methyl esters, its reaction is as follows:
(in the formula: R, R
1=-H or-CH
3R
2=-CH
3Or-C
2H
5)
Wherein, the mol ratio during reaction is: 7-ethyl tryptosol: 3-oxopentanoic acid methyl esters: acid=1: (1～2): (2～5), and preferably: 1: (1.2～1.5): (3～4).
Acid is meant the vitriol oil or oleum, the first-selected vitriol oil.
Mixed solvent is by C
1～C
2Lower alcohol and benzene-like compounds form, lower alcohol is methyl alcohol or ethanol, benzene-like compounds is benzene, toluene or dimethylbenzene.The volume ratio of lower alcohol and benzene-like compounds is: 1: (1～10), and preferably: 1: (3～5).Best solvent is: the mixture of methyl alcohol and toluene.
Temperature of reaction is :-5～20 ℃, preferably :-5～0 ℃.
Advantage of the present invention is: this process stabilizing, and the reaction conditions gentleness is easy to control, products obtained therefrom purity height, the yield height can reach more than 98%, and transformation efficiency almost reaches 100%.Aftertreatment is easy, and the three wastes are few, and mother liquor can use continuously, and production cost is low, is fit to suitability for industrialized production.
Embodiment
Embodiment 1:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 360 milliliters of benzene and 45.8 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 86 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: reaction is finished, and static layering is told the acid layer, and acid with the toluene extraction once merges organic phase, neutralizes with aqueous sodium carbonate.The organic phase underpressure distillation is to doing.Get 88 gram (yield 99.55%) etodolac methyl esters with recrystallizing methanol.Mp＝129.5～131℃
Embodiment 2:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 480 milliliters of toluene and 45.8 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 86 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Embodiment 3:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 600 milliliters of dimethylbenzene and 45.8 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 86 gram vitriol oils, kept 0～10 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Embodiment 4:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 360 milliliters of toluene and 45.8 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 115 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B:, get 88.3 gram (yield 99.87%) etodolac methyl esters with embodiment 1 step B.Mp＝130～131℃
Embodiment 5:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 480 milliliters of toluene and 45.8 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 115 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Embodiment 6:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 600 milliliters of toluene and 45.8 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 115 gram vitriol oils, kept 10～20 ℃ of stirring reactions 1 hour.
Step B: with embodiment 1 step B.
Embodiment 7:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 360 milliliters of toluene and 57.2 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 86 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Embodiment 8:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 480 milliliters of toluene and 57.2 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 86 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Embodiment 9:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 600 milliliters of toluene and 57.2 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 86 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Embodiment 10:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 360 milliliters of toluene and 57.2 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 115 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B:, get 88.3 gram (yield 99.87%) etodolac methyl esters with embodiment 1 step B.Mp＝130～131℃
Embodiment 11:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 480 milliliters of toluene and 57.2 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 115 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Embodiment 12:
Steps A: in the 1000ml four-hole reaction flask of agitator, thermometer is housed, add 70.0 gram (content 79.3%W/W, 0.2935 7-ethyl tryptosol mole), 120 milliliters of anhydrous methanols, 600 milliliters of toluene and 57.2 gram 3-oxopentanoic acid methyl esters, be cooled to 0～-5 ℃ under stirring, drip the 115 gram vitriol oils, kept 0～-5 ℃ of stirring reaction 1 hour.
Step B: with embodiment 1 step B.
Claims (5)
1, a kind of preparation method of etodolac methyl ester is made by 7-ethyl tryptosol and the reaction of 3-oxopentanoic acid methyl esters, and it is characterized in that: reaction solvent adopts C
1～C
2Lower alcohol and the mixed solvent formed of benzene-like compounds, reaction is to carry out under the katalysis of acid, after reaction finishes, acid layer is told, organic phase makes with buck neutralization, concentrated, recrystallization.
2, method according to claim 1 is characterized in that described benzene-like compounds is benzene, toluene or dimethylbenzene.
3, method according to claim 1 is characterized in that described acid is the vitriol oil or oleum.
4, method according to claim 1 is characterized in that: the volume ratio of described lower alcohol and benzene-like compounds is: 1: 1～1: 10, the reaction mol ratio was: 7-ethyl tryptosol: 3-oxopentanoic acid methyl esters: acid=1: (1～2): (2～5).
5, method according to claim 1 is characterized in that described temperature of reaction is-5～20 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710015592 CN101077872B (en) | 2007-06-21 | 2007-06-21 | Method for preparing etodolac methyl ester |
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|---|---|---|---|
| CN 200710015592 CN101077872B (en) | 2007-06-21 | 2007-06-21 | Method for preparing etodolac methyl ester |
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|---|---|
| CN101077872A true CN101077872A (en) | 2007-11-28 |
| CN101077872B CN101077872B (en) | 2012-01-11 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106944133A (en) * | 2017-04-17 | 2017-07-14 | 浙江工业大学 | A kind of sulfonic acid carbon nano tube solid acid catalyst and its preparation method and application |
| CN107199050A (en) * | 2017-04-17 | 2017-09-26 | 浙江工业大学 | A kind of sulfonic acid carbon nano tube solid acid and its preparation method and application |
| CN111303172A (en) * | 2020-03-18 | 2020-06-19 | 浙江外国语学院 | Method for preparing etodolac methyl ester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6066741A (en) * | 1998-09-08 | 2000-05-23 | A.M.S.A. Anonima Materie Sintetiche & Affini S.P.A. | Process for the preparation of etodolac |
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2007
- 2007-06-21 CN CN 200710015592 patent/CN101077872B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106944133A (en) * | 2017-04-17 | 2017-07-14 | 浙江工业大学 | A kind of sulfonic acid carbon nano tube solid acid catalyst and its preparation method and application |
| CN107199050A (en) * | 2017-04-17 | 2017-09-26 | 浙江工业大学 | A kind of sulfonic acid carbon nano tube solid acid and its preparation method and application |
| CN107199050B (en) * | 2017-04-17 | 2019-11-19 | 浙江工业大学 | A kind of sulfonic acid carbon nano tube solid acid and its preparation method and application |
| CN111303172A (en) * | 2020-03-18 | 2020-06-19 | 浙江外国语学院 | Method for preparing etodolac methyl ester |
| CN111303172B (en) * | 2020-03-18 | 2021-04-02 | 浙江外国语学院 | Method for preparing etodolac methyl ester |
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| CN101077872B (en) | 2012-01-11 |
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