CN102827059A - Production method for N-tert-butoxycarbonylation-L-ethyl-pyroglutamic acid - Google Patents
Production method for N-tert-butoxycarbonylation-L-ethyl-pyroglutamic acid Download PDFInfo
- Publication number
- CN102827059A CN102827059A CN2012103459091A CN201210345909A CN102827059A CN 102827059 A CN102827059 A CN 102827059A CN 2012103459091 A CN2012103459091 A CN 2012103459091A CN 201210345909 A CN201210345909 A CN 201210345909A CN 102827059 A CN102827059 A CN 102827059A
- Authority
- CN
- China
- Prior art keywords
- pyrrolidonecarboxylic acid
- ethyl ester
- acid ethyl
- tertbutyloxycarbonyl
- working method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a production method for N-tert-butoxycarbonylation-L-ethyl-pyroglutamic acid. The method is characterized by comprising the following steps of adding L-pyroglutamic acid, absolute ethyl alcohol and catalyst in a high pressure kettle, and closing the high pressure reaction kettle; heating the high pressure reaction kettle to enable the mixture to react; cooling the kettle after the reaction is finished; and recovering excessive ethanol, dissolving, washing and processing the residues with solvent, and directly adding catalyst DMAP (dimethylamino-pyridine) and di-tert-butyl carbonate to react with the residues, obtaining the product, and obtaining pure target product by aftertreatment. According to the method provided by the invention, the process is simple, the operation is easy, and the target product with high purity can be obtained.
Description
Technical field
The present invention relates to the working method of a kind of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester.
Background technology
The working method of existing a kind of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester; Be with L-L-glutamic acid and absolute ethyl 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.
Summary of the invention
Goal of the invention: the object of the present invention is to provide a kind of catalysis highly compressed method of utilizing to synthesize L-Pyrrolidonecarboxylic acid ethyl ester intermediate, after treatment, need not to purify, directly synthetic target product.
Technical solution of the present invention is: the working method of a kind of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester may further comprise the steps:
(1) L-Pyrrolidonecarboxylic acid and absolute ethyl alcohol; Catalysis through catalyzer; In 60-200 ℃, 0-5MPa pressure pressurization back flow reaction 2-48 hour down, reaction finishes postcooling, reclaims excess ethanol; Residuum is dissolved in toluene, is L-Pyrrolidonecarboxylic acid ethyl ester through washing, filtrating dry, that filtration obtains;
(2) add catalyzer DMAP in the above-mentioned L-Pyrrolidonecarboxylic acid ethyl ester, add the dimethyl dicarbonate butyl ester down, be warming up to 25-30 ℃ then at 15-20 ℃; Reacted 1-2 hour, and 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:
As optimization, in above-mentioned steps (1), said L-Pyrrolidonecarboxylic acid: absolute ethyl alcohol: catalyst molar ratio is 1:1-20:0.2-10, and said catalyzer is anhydrous hydrogen chloride or p-methyl benzenesulfonic acid.
As optimization, pressurization back flow reaction temperature is 80-140 ℃ in the step (1), and the time 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, can access highly purified target product, and the three wastes are few, it is little to pollute.Be convenient to the synthesis route of industrialization.
Embodiment
Below in conjunction with embodiment the present invention is described further:
Embodiment 1
Synthesizing of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester:
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, absolute ethyl alcohol is closed autoclave for 600 milliliters and is fed the nitrogen replacement air three times, directly adds 36.5 gram anhydrous hydrogen chlorides after the emptying; Begin to stir intensification degree to 125 degree after closing autoclave, 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 the refining white solid that obtains of petroleum ether.
Embodiment 2
Synthesizing of 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 autoclave and feed the nitrogen replacement air 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 the refining white solid that obtains of petroleum ether.
Embodiment 3
Synthesizing of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester:
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, absolute ethyl alcohol is closed autoclave for 160 milliliters and is fed the nitrogen replacement air three times, directly adds 25.4 gram anhydrous hydrogen chlorides after the emptying; Begin to stir intensification degree to 60 degree after closing autoclave, 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 the refining white solid that obtains of petroleum ether.
Embodiment 4
Synthesizing of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester:
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, absolute ethyl alcohol is closed autoclave for 3218 milliliters and is fed the nitrogen replacement air three times, directly adds 1270 gram anhydrous hydrogen chlorides after the emptying; Begin to stir intensification degree to 200 degree after closing autoclave, 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 the refining white solid that obtains of petroleum ether.
Embodiment 5
Synthesizing of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester:
In 1 liter the autoclave, add L-Pyrrolidonecarboxylic acid 127 grams, absolute ethyl alcohol is closed autoclave for 600 milliliters and is fed the nitrogen replacement air three times, directly adds 36.5 gram anhydrous hydrogen chlorides after the emptying; Begin to stir intensification degree to 80 degree after closing autoclave, 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 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 the refining white solid that obtains of petroleum ether.
Embodiment 6
Synthesizing of 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 autoclave and feed the nitrogen replacement air 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 the refining white solid that obtains of petroleum ether.
Claims (5)
1. the working method of N-tertbutyloxycarbonyl-L-Pyrrolidonecarboxylic acid ethyl ester is characterized in that: may further comprise the steps:
(1) L-Pyrrolidonecarboxylic acid and absolute ethyl alcohol; Catalysis through catalyzer; In 60-200 ℃, 0-5MPa pressure pressurization back flow reaction 2-48 hour down, reaction finishes postcooling, reclaims excess ethanol; Residuum is dissolved in toluene, is L-Pyrrolidonecarboxylic acid ethyl 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-Pyrrolidonecarboxylic acid ethyl ester; It is characterized in that: in above-mentioned steps (1); Said L-Pyrrolidonecarboxylic acid: absolute ethyl alcohol: catalyst molar ratio is 1:1-20:0.2-10, and said catalyzer is anhydrous hydrogen chloride or p-methyl benzenesulfonic acid.
3. the working method of a kind of N-tertbutyloxycarbonyl according to claim 1 and 2-L-Pyrrolidonecarboxylic acid ethyl ester is characterized in that: pressurization back flow reaction temperature is 80-140 ℃ in the step (1), and the time is 4-24 hour.
4. the working method of a kind of N-tertbutyloxycarbonyl according to claim 1-L-Pyrrolidonecarboxylic acid ethyl 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-Pyrrolidonecarboxylic acid ethyl 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103459091A CN102827059A (en) | 2012-09-18 | 2012-09-18 | Production method for N-tert-butoxycarbonylation-L-ethyl-pyroglutamic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103459091A CN102827059A (en) | 2012-09-18 | 2012-09-18 | Production method for N-tert-butoxycarbonylation-L-ethyl-pyroglutamic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102827059A true CN102827059A (en) | 2012-12-19 |
Family
ID=47330402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103459091A Pending CN102827059A (en) | 2012-09-18 | 2012-09-18 | Production method for N-tert-butoxycarbonylation-L-ethyl-pyroglutamic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102827059A (en) |
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 |
-
2012
- 2012-09-18 CN CN2012103459091A patent/CN102827059A/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研究", 《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》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101121688A (en) | Improved method for synthesizing oxiracetam | |
| CN101284772B (en) | Synthetic method of D-(+)-2-chloro-propanoyl chloride | |
| CN110615753A (en) | Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid | |
| CN102367260A (en) | Synthesis method of 2-aminopyrimidine-5-boric acid | |
| CN102827058A (en) | Production method of N-t-butoxycarbonyl-L-pyroglutamate | |
| CN103204801A (en) | Synthesis method for N-Boc-3-piperidone | |
| CN103864615A (en) | Method for preparing ethyl trifluoroacetate through continuous non-catalytic method | |
| CN104860872A (en) | Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method | |
| CN102838437A (en) | Production method of amino-acid ester | |
| CN101486687B (en) | Preparation technique of setastine hydrochloride | |
| CN110981779B (en) | Synthesis method of R-2- (2, 5-difluorophenyl) pyrrolidine | |
| CN102701991A (en) | Method for preparing nonane diamine | |
| CN105111155B (en) | A kind of synthetic method of 4,7- diaza spiro [2.5] octane -7- t-butyl formate | |
| CN104974057B (en) | The preparation method and important intermediate of a kind of bromfenac sodium | |
| CN103709039B (en) | Method for synthesizing methyl (ethyl) gallate through catalysis of Cu-mordenite | |
| CN102827059A (en) | Production method for N-tert-butoxycarbonylation-L-ethyl-pyroglutamic acid | |
| CN111393402B (en) | N & lt/EN & gt acid/quaternary ammonium salt composite catalytic CO 2 Method for preparing cyclic carbonate by cycloaddition with epoxide | |
| CN101348475A (en) | Novel method for synthesizing orlistat, intermediate compound and preparation thereof | |
| CN104370953B (en) | (R)-tert-butyl dimethyl siloxy-glutaric acid monoester preparation method | |
| CN103483308A (en) | Method for preparing 4,5-dimethyl-1,3-dioxole-2-ketone by using carbon dioxide | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN106946724A (en) | The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2 | |
| CN106810485A (en) | A kind of Preparation Method And Their Intermediate of chiral boxidine alkanone | |
| CN114989060A (en) | Preparation method of brivaracetam | |
| CN101088999A (en) | Process of synthesizing 3-amino quinine dihydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20121219 |