CN105732454A - Production technology of L-pyroglutamic acid benzyl ester - Google Patents
Production technology of L-pyroglutamic acid benzyl ester Download PDFInfo
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- CN105732454A CN105732454A CN201610094371.XA CN201610094371A CN105732454A CN 105732454 A CN105732454 A CN 105732454A CN 201610094371 A CN201610094371 A CN 201610094371A CN 105732454 A CN105732454 A CN 105732454A
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- Prior art keywords
- benzyl ester
- glutimic acid
- production technology
- acid benzyl
- reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
Abstract
The invention belongs to the technical field of medicine chemical engineering, and particularly relates to a production technology of L-pyroglutamic acid benzyl ester. The technology comprises the following steps that an organic solvent, L-pyroglutamic acid and an acid binding agent are mixed and stirred to be uniform, the temperature of reaction liquid is controlled below 20 DEG C, benzyl chloride is dropwise added, after benzyl chloride is completely added, the temperature rises to 50-80 DEG C, a reaction is conducted for 6-20 h, raw materials are detected to react completely through TLC, aftertreatment is conducted after cooling is conducted, an organic layer is dried and filtered, concentration is conducted, and L-pyroglutamic acid benzyl ester is obtained. According to the production technology of L-pyroglutamic acid benzyl ester, 1,2-dichloroethane serves as a solvent for the reaction, after the reaction is conducted, water is added for liquid separation, the obtained organic solvent 1,2-dichloroethane solution is dried and can be distilled for recycling, environmental friendliness is achieved, and the production cost is greatly reduced. By means of the selected reaction condition, the reaction time is obviously shortened, and human and material resources are saved.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to the production technology of a kind of L-Glutimic acid benzyl ester.
Background technology
L-Glutimic acid benzyl ester chemical molecular formula C12H13NO3, molecular weight 219.24；Its structural formula is:。
L-Glutimic acid benzyl ester is a kind of important medicine and chemical intermediate, is subject in industries such as medicine, chemical industry and coating
To extensive concern.In field of medicaments, L-Glutimic acid benzyl ester be novel ss-lactam enzyme inhibitor A Wei Batan important in
Mesosome.
The L-Glutimic acid benzyl ester preparation technology of document report, typically reacts with benzylalcohol for raw material, and the response time is relatively
Length and yield are on the low side；Also react with bromobenzyl for raw material, as patent CN105130870A discloses a kind of L-Glutimic acid benzyl
The preparation method of ester, particularly as follows: add 800ml acetone in the there-necked flask of 2000ml, adds 100g pyroglutamic acid afterwards, stirs
Mix, be cooled to less than 5 DEG C, be added dropwise to 198.8g cylite, add 294.5ml triethylamine, react 30 hours at 25 DEG C, it
Rear addition 400ml water, 600ml petroleum ether washes impurity, and with 1.5L ethyl acetate extraction product, product is washed with water saturated salt mutually
Washing, process TLC(chloroform: methanol: acetic acid volume ratio=85:10:5), it is concentrated to dryness crystallisation by cooling afterwards and adds petroleum ether and grind
Broken, gained solid dry product 110g, it is L-Glutimic acid benzyl ester, HPLC is the highest by 96.81%.This reaction yield and product purity are relatively
Height, but, owing to water and the solvent acetone added is dissolved each other, make solvent be difficult to reclaim, be unfavorable for industrialized great production.
Also document is had to react with benzyl chloride for raw material: document J. Chem. Soc., Perkin Trans. 1 1996,
Reporting in 507 514 with acetone as solvent, L-Glutimic acid and benzyl chloride back flow reaction obtain the L-Jiao Gu of molar yield 85% for 7 days
Propylhomoserin benzyl ester, ethyl acetate extraction during post processing, saturated sodium bicarbonate solution washing, dilute hydrochloric acid acid adjustment, this technological reaction time
Oversize, and post-processing operation is loaded down with trivial details.Tetrahedron 54(1998) 1753 report with oxolane as solvent, L-Glutimic acid
With the L-Glutimic acid benzyl ester that benzyl chloride back flow reaction obtains molar yield 97% for 5 days.The document above report response time is longer, work
Though skill condition makes reaction yield be significantly improved, but solvent acetone and oxolane can not recovery, and tetrahydrochysene furan
Muttering expensive, cost of material is high is unfavorable for industrialized production；And post-reaction treatment step is more makes the production cycle relatively
Long.
Accordingly, it would be desirable to it is short, simple to operate to continually look for the response time, the production of environment amenable L-Glutimic acid benzyl ester
Technique.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides the production technology of a kind of L-Glutimic acid benzyl ester.This work
Skill is with 1, and 2-dichloroethanes is that solvent reacts, and post-reaction treatment adds water separatory, and gained organic solvent 1,2-dichloroethanes is molten
The most retortable being circulated of liquid is applied mechanically, environmentally friendly and greatly reduce production cost；The reaction condition chosen is obvious
Shorten the response time, save manpower and materials.
The present invention is to be realized by following technical scheme:
The production technology of a kind of L-Glutimic acid benzyl ester, comprises the following steps:
By organic solvent, L-Glutimic acid and acid binding agent mixing and stirring, reactant liquor temperature control less than 20 DEG C drips benzyl chloride, drips and finishes
After be warming up to 50-80 DEG C, reaction 6-20h, TLC detection raw material reaction is complete, and cooling carries out post processing, and organic layer is dried, filters,
Concentrate and i.e. obtain L-Glutimic acid benzyl ester.Using this technique to prepare L-Glutimic acid benzyl ester, molar yield can reach more than 99.5%,
Liquid phase purity more than 97.1%.
Described TLC thin-layer developing agent is petroleum ether: ethyl acetate=1:1.
In the production technology of above-mentioned L-Glutimic acid benzyl ester, described organic solvent is petroleum ether, t-butyl methyl ether, acetic acid
One or more in ethyl ester, hexamethylene, toluene, dichloromethane, chloroform, 1,2-dichloroethanes.
Preferably, in the production technology of above-mentioned L-Glutimic acid benzyl ester, described organic solvent is 1,2-dichloroethanes.
In the production technology of above-mentioned L-Glutimic acid benzyl ester, described acid binding agent is triethylamine, diethylamine, diisopropyl second
One or both in base amine, natrium carbonicum calcinatum, Anhydrous potassium carbonate, potassium hydroxide and sodium hydroxide.
Preferably, in the production technology of above-mentioned L-Glutimic acid benzyl ester, described acid binding agent is triethylamine.
In the production technology of above-mentioned L-Glutimic acid benzyl ester, described L-Glutimic acid is 1 with the weight ratio of organic solvent:
3-8；Described L-Glutimic acid is 1:1-3 with the mol ratio of benzyl chloride；Described L-Glutimic acid is 1:1-with the mol ratio of acid binding agent
3。
Preferably, in the production technology of above-mentioned L-Glutimic acid benzyl ester, described L-Glutimic acid and the weight of organic solvent
Amount ratio is 1:4；Described L-Glutimic acid is 1:1.2 with the mol ratio of benzyl chloride；Described L-Glutimic acid and the mol ratio of acid binding agent
For 1:1.25.
Preferably, in the production technology of above-mentioned L-Glutimic acid benzyl ester, described reaction temperature is 70 DEG C, during described reaction
Between be 12h.
In the production technology of above-mentioned a kind of L-Glutimic acid benzyl ester, post-processing operation is as follows: raw material reaction is complete, reaction
Liquid is cooled to 20 ~ 30 DEG C, adds water and washed once, separatory；Organic layer adds saturated aqueous common salt and washed once, separatory；Organic
Layer is dried, filters, and concentrates and i.e. obtains L-Glutimic acid benzyl ester, and the consumption of described water is the 40-80% of consumption of organic solvent, described full
The 40-80% that consumption is consumption of organic solvent with saline solution.
The production technology of above-mentioned a kind of L-Glutimic acid benzyl ester, detailed step is as follows:
By solvent 1,2-dichloroethanes 200kg, L-Glutimic acid 64.55kg and triethylamine 63.25kg, put into 500L reaction successively
In still, reactant liquor stirring cooling, temperature control less than 20 DEG C dropping benzyl chloride 75.95kg, drip finish be warming up to 50 ~ 80 DEG C, reaction 6 ~ 20h,
TLC detection raw material reaction is complete.Reactant liquor is cooled to 20 ~ 30 DEG C, adds 100kg and washes once, and separatory, organic layer adds full
Washed once with saline solution 100kg, organic layer is dried, filters, and concentrates and i.e. obtains L-Glutimic acid benzyl ester.
The production technology of the preferred L-Glutimic acid benzyl ester of the present invention, its reaction equation is as follows:
。
The production technology of the L-Glutimic acid benzyl ester of the present invention, is suitable for pilot scale and large-scale industrial production Jiao's L-paddy ammonia
Acid benzyl ester.
The invention have the benefit that
Existing technique has been done improvement and has carried out producing amplification by this patent, and with 1,2-dichloroethanes is solvent, with triethylamine is
Acid binding agent；Response time relatively document report substantially shortens, and avoids the use of the higher bromobenzyl of price；Solvent and acid binding agent
Cost of material the most inexpensively, simultaneously 1,2-dichloroethanes is recyclable as solvent and recycling, post-reaction treatment simplify into
One step alleviates environmental protection pressure.Technique has saved cost of material, simple to operate, is suitable for industrialized production.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further described, in order to those skilled in the art knows more about
The present invention, but and it is not so limited the present invention.
Embodiment 1
By 1,2-dichloroethanes 200kg, L-Glutimic acid 64.55kg and triethylamine 63.25kg, put into 500L reactor successively
In, reactant liquor stirring cooling, temperature control less than 20 DEG C dropping benzyl chloride 75.95kg.Drip to finish and be warming up to 50 DEG C, react 18h, TLC(oil
Ether: ethyl acetate=1:1, lower same.) detection raw material reaction complete.Reactant liquor is cooled to 20 ~ 30 DEG C, adds 100kg and washes once,
Separatory, organic layer adds saturated aqueous common salt 100kg and washed once, organic layer 1,2-dichloroethane solution Matrii Sulfas Exsiccatus is dried,
Filtering, filtrate concentrates and i.e. obtains brown color L-Glutimic acid benzyl ester 21.81kg；Molar yield 99.5%, liquid phase purity 97.24%.
Embodiment 2
By 1,2-dichloroethanes 200kg, L-Glutimic acid 64.55kg and triethylamine 63.25kg, put into 500L reactor successively
In, reactant liquor stirring cooling, temperature control less than 20 DEG C dropping benzyl chloride 75.95kg.Drip to finish and be warming up to 60 DEG C, reaction 15h, TLC detection
Raw material reaction is complete.Reactant liquor is cooled to 20 ~ 30 DEG C, adds 100kg and washes once, and separatory, organic layer adds saturated common salt
Water 100kg washed once, organic layer 1, and 2-dichloroethane solution Matrii Sulfas Exsiccatus is dried, filters, and filtrate concentrates and i.e. obtains brown color L-
Pyroglutamic acid benzyl ester 21.92kg；Molar yield 100%, liquid phase purity 97.10%.
Embodiment 3
By 1,2-dichloroethanes 200kg, L-Glutimic acid 64.55kg and triethylamine 63.25kg, put into 500L reactor successively
In, reactant liquor stirring cooling, temperature control less than 20 DEG C dropping benzyl chloride 75.95kg.Drip to finish and be warming up to 70 DEG C, reaction 12h, TLC detection
Raw material reaction is complete.Reactant liquor is cooled to 20 ~ 30 DEG C, adds 100kg and washes once, and separatory, organic layer adds saturated common salt
Water 100kg washed once, organic layer 1, and 2-dichloroethane solution Matrii Sulfas Exsiccatus is dried, filters, and filtrate concentrates and i.e. obtains brown color L-
Pyroglutamic acid benzyl ester 21.90kg；Molar yield 99.9%, liquid phase purity 97.40%.
Embodiment 4
By 1,2-dichloroethanes 200kg, L-Glutimic acid 64.55kg and triethylamine 63.25kg, put into 500L reactor successively
In, reactant liquor stirring cooling, temperature control less than 20 DEG C dropping benzyl chloride 75.95kg.Drip to finish and be warming up to 80 DEG C, reaction 10h, TLC detection
Raw material reaction is complete.Reactant liquor is cooled to 20 ~ 30 DEG C, adds 100kg and washes once, and separatory, organic layer adds saturated common salt
Water 100kg washed once, separatory；Organic layer 1,2-dichloroethane solution Matrii Sulfas Exsiccatus is dried, filters, filtrate concentrate i.e. obtain pale brown
Color L-Glutimic acid benzyl ester 21.86kg；Molar yield 99.7%, liquid phase purity 97.18%.
Claims (10)
1. the production technology of a L-Glutimic acid benzyl ester, it is characterised in that comprise the following steps:
By organic solvent, L-Glutimic acid and acid binding agent mixing and stirring, reactant liquor temperature control less than 20 DEG C drips benzyl chloride, drips and finishes
After be warming up to 50-80 DEG C, reaction 6-20h, TLC detection raw material reaction is complete, and cooling carries out post processing, and organic layer is dried, filters,
Concentrate and i.e. obtain L-Glutimic acid benzyl ester.
The production technology of L-Glutimic acid benzyl ester the most according to claim 1, it is characterised in that described organic solvent is stone
One or several in oil ether, t-butyl methyl ether, ethyl acetate, hexamethylene, toluene, dichloromethane, chloroform, 1,2-dichloroethanes
Kind.
The production technology of L-Glutimic acid benzyl ester the most according to claim 2, it is characterised in that described organic solvent is 1,
2-dichloroethanes.
The production technology of L-Glutimic acid benzyl ester the most according to claim 1, it is characterised in that described acid binding agent is three second
One in amine, diethylamine, diisopropyl ethyl amine, natrium carbonicum calcinatum, Anhydrous potassium carbonate, potassium hydroxide and sodium hydroxide or two
Kind.
The production technology of L-Glutimic acid benzyl ester the most according to claim 4, it is characterised in that described acid binding agent is three second
Amine.
The production technology of L-Glutimic acid benzyl ester the most according to claim 1, it is characterised in that described L-Glutimic acid with
The weight ratio of organic solvent is 1:3-8；Described L-Glutimic acid is 1:1-3 with the mol ratio of benzyl chloride；Described L-Glutimic acid with
The mol ratio of acid binding agent is 1:1-3.
The production technology of L-Glutimic acid benzyl ester the most according to claim 6, it is characterised in that described L-Glutimic acid with
The weight ratio of organic solvent is 1:4；Described L-Glutimic acid is 1:1.2 with the mol ratio of benzyl chloride；Described L-Glutimic acid with tie up
The mol ratio of acid agent is 1:1.25.
The production technology of L-Glutimic acid benzyl ester the most according to claim 1, it is characterised in that described reaction temperature is 70
DEG C, the described response time is 12h.
The production technology of a kind of L-Glutimic acid benzyl ester the most according to claim 1, it is characterised in that described post processing walks
Suddenly it is: raw material reaction is complete that reactant liquor is cooled to 20 ~ 30 DEG C, adds water and washed once, separatory；Organic layer adds saturated food
Saline washed once, separatory；Organic layer is dried, filters, and concentrates and i.e. obtains L-Glutimic acid benzyl ester, and the consumption of described water is organic molten
The 40-80% of agent consumption, the consumption of described saturated aqueous common salt is the 40-80% of consumption of organic solvent.
The production technology of a kind of L-Glutimic acid benzyl ester the most according to claim 1, detailed step is as follows:
By solvent 1,2-dichloroethanes 200kg, L-Glutimic acid 64.55kg and triethylamine 63.25kg, put into 500L reaction successively
In still, reactant liquor stirring cooling, temperature control less than 20 DEG C dropping benzyl chloride 75.95kg, drip finish be warming up to 50 ~ 80 DEG C, reaction 6 ~ 20h,
TLC detection raw material reaction is complete, and reactant liquor is cooled to 20 ~ 30 DEG C, adds 100kg water and washed once, separatory；Organic layer adds
100kg saturated aqueous common salt washed once, separatory；Organic layer is dried, filters, and concentrates and i.e. obtains L-Glutimic acid benzyl ester.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602436A (en) * | 2017-09-29 | 2018-01-19 | 新发药业有限公司 | A kind of environment-friendly preparation method thereof of N substitutions L pyroglutamic acid esters |
| 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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| JPH02157262A (en) * | 1988-12-10 | 1990-06-18 | Meiji Seika Kaisha Ltd | New pyrrolidine derivative having physiological activity |
| WO2014137930A1 (en) * | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
| CN105130870A (en) * | 2015-09-11 | 2015-12-09 | 南京肽业生物科技有限公司 | Preparation method of L-pyroglutamic acid benzyl ester |
-
2016
- 2016-02-22 CN CN201610094371.XA patent/CN105732454A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02157262A (en) * | 1988-12-10 | 1990-06-18 | Meiji Seika Kaisha Ltd | New pyrrolidine derivative having physiological activity |
| WO2014137930A1 (en) * | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
| CN105130870A (en) * | 2015-09-11 | 2015-12-09 | 南京肽业生物科技有限公司 | Preparation method of L-pyroglutamic acid benzyl ester |
Non-Patent Citations (4)
| Title |
|---|
| FERNANDO BERNARDI,等: "Pseudopeptide Foldamers: The Homo-Oligomers of Pyroglutamic Acid", 《CHEMISTRY-A EUROPEAN JOURNAL》 * |
| JAMES E. TARVER,等: "Hetero-Diels-Alder and pyroglutamate approaches to (2S,4R)-2-methylamino-5-hydroxy-4-methylpentanoic acid", 《TETRAHEDRON》 * |
| RYAN A. AUGUST,等: "Stereospecific synthesis of (2S,4R)-[5,5,5-2H3]leucine", 《JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1》 * |
| 潘仙华: "1.Kaitocephalin及Halipeptin A的合成研究 2.CuI/氨基酸催化下烯基碘与酰胺的偶联反应", 《复旦大学博士学位论文》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602436A (en) * | 2017-09-29 | 2018-01-19 | 新发药业有限公司 | A kind of environment-friendly preparation method thereof of N substitutions L pyroglutamic acid esters |
| 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: 20160706 |