CN102827058A - Production method of N-t-butoxycarbonyl-L-pyroglutamate - Google Patents
Production method of N-t-butoxycarbonyl-L-pyroglutamate Download PDFInfo
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- CN102827058A CN102827058A CN2012103459087A CN201210345908A CN102827058A CN 102827058 A CN102827058 A CN 102827058A CN 2012103459087 A CN2012103459087 A CN 2012103459087A CN 201210345908 A CN201210345908 A CN 201210345908A CN 102827058 A CN102827058 A CN 102827058A
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- tertbutyloxycarbonyl
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- acid ester
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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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a production method of N-t-butyloxycarboryl-L- pyroglutamate. The production method is characterized by comprising the following steps of: adding L-pyroglutamic acid, absolute alcohol and catalyst into a high-pressure kettle, and closing the high-pressure reaction kettle; performing a heating reaction, cooling after the reaction is completed, and recovering excessive ethanol; dissolving the residues with solvents for cleaning, and then directly adding the catalyst DMAP (4-dimethylaminopyridine) to react with di-tert-butyl carbonate to obtain a product; and performing post-treatment to obtain a pure target product. The production method has a simple process and is easy in operation, and a target product with higher purity can be obtained.
Description
Technical field
The present invention relates to the working method of a kind of N-tertbutyloxycarbonyl-L-pyroglutamic acid ester.
Background technology
The working method of existing a kind of N-tertbutyloxycarbonyl-L-pyroglutamic acid ester; Be with L-L-glutamic acid and absolute alcohol esterification under the condition that sulfur oxychloride exists; The cyclization aftertreatment obtains the midbody II under alkaline condition again; After purifying, react with the dimethyl dicarbonate butyl ester again, obtain target product.This technology is used sulfur oxychloride, has a large amount of waste gas to emit in the reaction process, must absorb with a large amount of liquid caustic soda, produces great amount of wastewater, and midbody must be purified, and yield is low.In order to seek an operational path that is fit to industrialization more, and can obtain more highly purified target product, we change and explore technology.Confirmed sharp catalysis highly compressed method synthetic intermediate body, after treatment, need not to purify, directly synthetic target product.
Summary of the invention
Goal of the invention: the object of the present invention is to provide a kind of technology simple, can access highly purified target product, and the three wastes are few.Be convenient to the synthesis route of industrialization.
Technical solution of the present invention is: the working method of a kind of N-tertbutyloxycarbonyl-L-pyroglutamic acid ester may further comprise the steps:
(1) L-Pyrrolidonecarboxylic acid and alcohol are under the catalysis of catalyzer, in 60-200 ℃, 0-5MPa pressure pressurization back flow reaction 2-48 hour down; Reaction finishes postcooling; Reclaim excess ethanol, residuum is dissolved in YLENE, is the L-pyroglutamic acid ester through washing, filtrating dry, that filtration obtains;
(2) add catalyzer 4-Dimethylamino pyridine (DMAP) in the above-mentioned L-Pyrrolidonecarboxylic acid ethyl ester; Add the dimethyl dicarbonate butyl ester down at 15-20 ℃, be warming up to 25-30 ℃ then, reacted 1-2 hour; After reacting completely; Be cooled to below 20 ℃, solvent extraction is used in the washing back, again through the refining target product that obtains of aftertreatment.
Reaction formula is:
As optimization, in the above-mentioned steps (1), L-Pyrrolidonecarboxylic acid: alcohol: catalyst molar ratio is 1:1-20:0.2-10, and said catalyzer is meant anhydrous hydrogen chloride, p-methyl benzenesulfonic acid; ROH is meant C
1-C
5Alcohol.
As optimization, in the above-mentioned steps (1), the temperature of pressurization back flow reaction is 80-140 ℃, and the reaction times is 4-24 hour.
As optimization, in the above-mentioned steps (2), solvent for use is toluene or YLENE.
As optimization, in the above-mentioned steps (2), said L-Pyrrolidonecarboxylic acid ethyl ester need not through the directly synthetic target product of purifying.
Beneficial effect: technology of the present invention is simple, and is easy to operate, and the three wastes are few, pollutes little.
Embodiment
Below in conjunction with embodiment the present invention is described further:
Synthesizing of embodiment 1:N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, absolute ethyl alcohol is closed the logical people's nitrogen replacement air of autoclave three times for 600 milliliters, directly adds 36.5 gram anhydrous hydrogen chlorides after the emptying; Begin to stir intensification degree to 125 degree after closing, and be incubated 12 hours, reaction finishes postcooling; Reaction solution is transferred to distillation recovery excess ethyl alcohol in the other reactor drum, and residuum is dissolved in 800 milliliters of YLENE, through after the carrying out washing treatment; Use anhydrous sodium sulfate drying, filter, add 3.1 gram 4-Dimethylamino pyridines in the filtrating; Under the 15-20 degree, drip 218 gram dimethyl dicarbonate butyl esters, after dropwising, be warming up to 25～30 ℃ of reactions 1～2 hour.After reacting completely, be cooled to below 20 ℃ water and saturated common salt water washing.Merge lower floor's washing water of telling, extract with YLENE.Merge all upper strata organic layers, concentrating under reduced pressure.Be cooled to about 30 ℃, the adding sherwood oil is cooled to about 20 ℃ and stirred 1 hour, is cooled to 0～5 ℃ of stirred crystallization again 4 hours, filters, with refining white solid 215.8 grams that obtain of petroleum ether.
Synthesizing of embodiment 2:N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid methyl esters
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, 460 milliliters of anhydrous methanols and tosic acid 58 grams.Close the logical people's nitrogen replacement air of autoclave three times, begin to stir intensification degree to 125 degree, and be incubated 12 hours, reaction finishes postcooling; Reaction solution is transferred to distillation recovery excessive methanol in the other reactor drum, and residuum is dissolved in 800 milliliters of toluene, through after the carrying out washing treatment; Use anhydrous sodium sulfate drying, filter, add 3.1 gram 4-Dimethylamino pyridines in the filtrating; Under the 15-20 degree, drip 218 gram dimethyl dicarbonate butyl esters, after dropwising, be warming up to 25～30 ℃ of reactions 1～2 hour.After reacting completely, be cooled to below 20 ℃ water and saturated common salt water washing.Merge lower floor's washing water of telling, use methylbenzene extraction.Merge all upper strata organic layers, concentrating under reduced pressure.Be cooled to about 30 ℃, the adding sherwood oil is cooled to about 20 ℃ and stirred 1 hour, is cooled to 0～5 ℃ of stirred crystallization again 4 hours, filters, with refining white solid 186.3 grams that obtain of petroleum ether.
Synthesizing of embodiment 3:N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, 600 milliliters of absolute ethyl alcohols and tosic acid 58 grams.Close the logical people's nitrogen replacement air of autoclave three times, begin to stir intensification degree to 125 degree, and be incubated 12 hours, reaction finishes postcooling; Reaction solution is transferred to distillation recovery excess ethyl alcohol in the other reactor drum, and residuum is dissolved in 800 milliliters of toluene, through after the carrying out washing treatment; Use anhydrous sodium sulfate drying, filter, add 3.1 gram 4-Dimethylamino pyridines in the filtrating; Under the 15-20 degree, drip 218 gram dimethyl dicarbonate butyl esters, after dropwising, be warming up to 25～30 ℃ of reactions 1～2 hour.After reacting completely, be cooled to below 20 ℃ water and saturated common salt water washing.Merge lower floor's washing water of telling, use methylbenzene extraction.Merge all upper strata organic layers, concentrating under reduced pressure.Be cooled to about 30 ℃, the adding sherwood oil is cooled to about 20 ℃ and stirred 1 hour, is cooled to 0～5 ℃ of stirred crystallization again 4 hours, filters, with refining white solid 225.4 grams that obtain of petroleum ether.
Synthesizing of embodiment 4:N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, absolute ethyl alcohol is closed the logical people's nitrogen replacement air of autoclave three times for 160 milliliters, directly adds 25.4 gram anhydrous hydrogen chlorides after the emptying; Begin to stir intensification degree to 60 degree after closing, and be incubated 48 hours, reaction finishes postcooling; Reaction solution is transferred to distillation recovery excess ethyl alcohol in the other reactor drum, and residuum is dissolved in 800 milliliters of YLENE, through after the carrying out washing treatment; Use anhydrous sodium sulfate drying, filter, add 3.1 gram 4-Dimethylamino pyridines in the filtrating; Under the 15-20 degree, drip 218 gram dimethyl dicarbonate butyl esters, after dropwising, be warming up to 25～30 ℃ of reactions 1～2 hour.After reacting completely, be cooled to below 20 ℃ water and saturated common salt water washing.Merge lower floor's washing water of telling, extract with YLENE.Merge all upper strata organic layers, concentrating under reduced pressure.Be cooled to about 30 ℃, the adding sherwood oil is cooled to about 20 ℃ and stirred 1 hour, is cooled to 0～5 ℃ of stirred crystallization again 4 hours, filters, with refining white solid 215.2 grams that obtain of petroleum ether.
Synthesizing of embodiment 5:N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, absolute ethyl alcohol is closed the logical people's nitrogen replacement air of autoclave three times for 600 milliliters, directly adds 36.5 gram anhydrous hydrogen chlorides after the emptying; Begin to stir intensification degree to 200 degree after closing, and be incubated 2 hours, reaction finishes postcooling; Reaction solution is transferred to distillation recovery excess ethyl alcohol in the other reactor drum, and residuum is dissolved in 800 milliliters of YLENE, through after the carrying out washing treatment; Use anhydrous sodium sulfate drying, filter, add 3.1 gram 4-Dimethylamino pyridines in the filtrating; Under the 15-20 degree, drip 218 gram dimethyl dicarbonate butyl esters, after dropwising, be warming up to 25～30 ℃ of reactions 1～2 hour.After reacting completely, be cooled to below 20 ℃ water and saturated common salt water washing.Merge lower floor's washing water of telling, extract with YLENE.Merge all upper strata organic layers, concentrating under reduced pressure.Be cooled to about 30 ℃, the adding sherwood oil is cooled to about 20 ℃ and stirred 1 hour, is cooled to 0～5 ℃ of stirred crystallization again 4 hours, filters, with refining white solid 215.6 grams that obtain of petroleum ether.
Synthesizing of embodiment 6:N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, 600 milliliters of absolute ethyl alcohols and tosic acid 58 grams.Close the logical people's nitrogen replacement air of autoclave three times, begin to stir intensification degree to 80 degree, and be incubated 24 hours, reaction finishes postcooling; Reaction solution is transferred to distillation recovery excess ethyl alcohol in the other reactor drum, and residuum is dissolved in 800 milliliters of toluene, through after the carrying out washing treatment; Use anhydrous sodium sulfate drying, filter, add 3.1 gram 4-Dimethylamino pyridines in the filtrating; Under the 15-20 degree, drip 218 gram dimethyl dicarbonate butyl esters, after dropwising, be warming up to 25～30 ℃ of reactions 1～2 hour.After reacting completely, be cooled to below 20 ℃ water and saturated common salt water washing.Merge lower floor's washing water of telling, use methylbenzene extraction.Merge all upper strata organic layers, concentrating under reduced pressure.Be cooled to about 30 ℃, the adding sherwood oil is cooled to about 20 ℃ and stirred 1 hour, is cooled to 0～5 ℃ of stirred crystallization again 4 hours, filters, with refining white solid 225.2 grams that obtain of petroleum ether.
Synthesizing of embodiment 7:N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, 600 milliliters of absolute ethyl alcohols and tosic acid 58 grams.Close the logical people's nitrogen replacement air of autoclave three times, begin to stir intensification degree to 140 degree, and be incubated 4 hours, reaction finishes postcooling; Reaction solution is transferred to distillation recovery excess ethyl alcohol in the other reactor drum, and residuum is dissolved in 800 milliliters of toluene, through after the carrying out washing treatment; Use anhydrous sodium sulfate drying, filter, add 3.1 gram 4-Dimethylamino pyridines in the filtrating; Under the 15-20 degree, drip 218 gram dimethyl dicarbonate butyl esters, after dropwising, be warming up to 25～30 ℃ of reactions 1～2 hour.After reacting completely, be cooled to below 20 ℃ water and saturated common salt water washing.Merge lower floor's washing water of telling, use methylbenzene extraction.Merge all upper strata organic layers, concentrating under reduced pressure.Be cooled to about 30 ℃, the adding sherwood oil is cooled to about 20 ℃ and stirred 1 hour, is cooled to 0～5 ℃ of stirred crystallization again 4 hours, filters, with refining white solid 225.5 grams that obtain of petroleum ether.
Claims (5)
1. the working method of N-tertbutyloxycarbonyl-L-pyroglutamic acid ester is characterized in that: may further comprise the steps:
(1) L-Pyrrolidonecarboxylic acid and alcohol are under the catalysis of catalyzer, in 60-200 ℃, 0-5MPa pressure pressurization back flow reaction 2-48 hour down; Reaction finishes postcooling; Reclaim excess ethanol, residuum is dissolved in YLENE, is the L-pyroglutamic acid ester through washing, filtrating dry, that filtration obtains;
(2) add catalyzer 4-Dimethylamino pyridine (DMAP) in the above-mentioned L-Pyrrolidonecarboxylic acid ethyl ester; Add the dimethyl dicarbonate butyl ester down at 15-20 ℃, be warming up to 25-30 ℃ then, reacted 1-2 hour; After reacting completely; Be cooled to below 20 ℃, solvent extraction is used in the washing back, again through the refining target product that obtains of aftertreatment.
2. the working method of a kind of N-tertbutyloxycarbonyl according to claim 1-L-pyroglutamic acid ester; It is characterized in that: in the above-mentioned steps (1); L-Pyrrolidonecarboxylic acid: alcohol: catalyst molar ratio is 1:1-20:0.2-10, and said catalyzer is meant anhydrous hydrogen chloride, p-methyl benzenesulfonic acid; ROH is meant C
1-C
5Alcohol.
3. the working method of a kind of N-tertbutyloxycarbonyl according to claim 1 and 2-L-pyroglutamic acid ester is characterized in that: in the above-mentioned steps (1), the temperature of pressurization back flow reaction is 80-140 ℃, and the reaction times is 4-24 hour.
4. the working method of a kind of N-tertbutyloxycarbonyl according to claim 1-L-pyroglutamic acid ester is characterized in that: in the above-mentioned steps (2), solvent for use is toluene or YLENE.
5. the working method of a kind of N-tertbutyloxycarbonyl according to claim 1-L-pyroglutamic acid ester is characterized in that: in the above-mentioned steps (2), said L-Pyrrolidonecarboxylic acid ethyl ester need not through the directly synthetic target product of purifying.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106336371A (en) * | 2016-08-16 | 2017-01-18 | 成都百事兴科技实业有限公司 | Synthetic method of Boc-L-Pyroglutamic acid methyl ester |
| WO2019062027A1 (en) * | 2017-09-29 | 2019-04-04 | 新发药业有限公司 | Green preparation method for n-substituted-l-pyroglutamic acid ester |
| CN109721522A (en) * | 2018-12-29 | 2019-05-07 | 常州吉恩药业有限公司 | A kind of high-quality N- tertbutyloxycarbonyl-L-Glutimic acid benzyl ester industrialized preparing process |
Citations (1)
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|---|---|---|---|---|
| WO2010038081A2 (en) * | 2008-10-03 | 2010-04-08 | Astrazeneca Ab | Heterocyclic derivatives and methods of use thereof |
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- 2012-09-18 CN CN2012103459087A patent/CN102827058A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010038081A2 (en) * | 2008-10-03 | 2010-04-08 | Astrazeneca Ab | Heterocyclic derivatives and methods of use thereof |
Non-Patent Citations (2)
| Title |
|---|
| 任君等: "L-焦谷氨酸酯的合成方法", 《湖北大学学报（自然科学版）》 * |
| 邢其毅等: "第13章 羧酸", 《基础有机化学（第三版）上册》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106336371A (en) * | 2016-08-16 | 2017-01-18 | 成都百事兴科技实业有限公司 | Synthetic method of Boc-L-Pyroglutamic acid methyl ester |
| WO2019062027A1 (en) * | 2017-09-29 | 2019-04-04 | 新发药业有限公司 | Green preparation method for n-substituted-l-pyroglutamic acid ester |
| CN109721522A (en) * | 2018-12-29 | 2019-05-07 | 常州吉恩药业有限公司 | A kind of high-quality N- tertbutyloxycarbonyl-L-Glutimic acid benzyl ester industrialized preparing process |
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Application publication date: 20121219 |