CN103420888A - Preparation method of L-pyroglutamic acid menthyl acetate - Google Patents
Preparation method of L-pyroglutamic acid menthyl acetate Download PDFInfo
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- CN103420888A CN103420888A CN2013103498599A CN201310349859A CN103420888A CN 103420888 A CN103420888 A CN 103420888A CN 2013103498599 A CN2013103498599 A CN 2013103498599A CN 201310349859 A CN201310349859 A CN 201310349859A CN 103420888 A CN103420888 A CN 103420888A
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Abstract
The invention relates to a preparation method of L-pyroglutamic acid menthyl acetate. The preparation method includes the steps of firstly, under ice-bath, adding methylene chloride, L-pyroglutamic acid and sulfoxide chloride into a reaction kettle, stirring for an hour, and rotating to remove organic solvent; secondly, adding methylene chloride and menthyl acetate to the rotation dried product, allowing for reaction for 1-2 hours, dropwise adding triethylamine under ice-bath, and stirring for 1-2 hours; thirdly, adding water for washing, drying with anhydrous sodium sulfate, filtering, decompressing filtrate to remove solvent, and allowing for cryogenic crystallization to obtain solid L-pyroglutamic acid menthyl acetate. The preparation method is mild in reaction condition, low in cost, simple in process and easy to industrialize.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of preparation method of L-Glutimic acid menthyl ester.
Background technology
L-Glutimic acid menthyl ester (PCA menthyl ester) is the light thick liquid of clarification, facile hydrolysis under strong acid, highly basic.As amendment, wetting Agent for Printing Inks etc., be widely used in the personal-care supplies field, as paste shampoo, cleansing milk, facial mask, shower product, prickly-heat powder, moisturizing breast, cigarette etc.The PCA menthyl ester due to the enzyme of skin slowly hydrolysis discharge menthol and pyrrolidone carboxylic acid, thereby obtain lasting refrigerant sense, can burn hardly, skin irritation, and there is the anti-inflammatory effect, its refrigerant effect is better than p-Menthyl lactate.The L-Glutimic acid menthyl ester also has the mosquito-repelling effect, effective, and hypotoxicity has no side effect to human body.The L-Glutimic acid menthyl ester also can be used as emulsion stabilizer, dispersion agent.L-Glutimic acid menthyl ester Application Areas is extensive, and its demand constantly increases.
The preparation method of L-Glutimic acid menthyl ester in the past (PCA menthyl ester), the suitability for industrialized production degree is low, long reaction time, yield is low, cost is high, unstable product quality, environmental pollution is more serious.
The people such as the Zhao Xuefei of Dakang Ind Co., Ltd., Jiangsu are for above-mentioned defect, proposing new method is first by menthol, L-Glutimic acid, N, N-diformazan-4-amino based pyridine, methylene dichloride join in reactor, stir into homogeneous phase, make reactor temperature drop to 2～8 ℃, again by N, N '-dicyclohexylcarbodiimide adds into mixing solutions with after the methylene dichloride mixed dissolution, and return stirring is to the menthol complete reaction, and vacuum distilling makes the L-Glutimic acid menthyl ester.The method reaction conditions gentleness, product is more stable, but the method reaction is not exclusively, and aftertreatment is cumbersome, and yield is not high, and the time is also long.
" the Journal of Synthetic Communications such as Panday, 2011,41 (24): 3654-3661 " the employing method is under ice bath, thionyl chloride is added drop-wise in the anhydrous tetrahydrofuran solution of L-Glutimic acid to stirring at room, the thionyl chloride vacuum is revolved, after adding anhydrous tetrahydro furan to dissolve, be added drop-wise to triethylamine under ice bath, menthol, in the anhydrous tetrahydro furan system, room temperature reaction.The method generation impurity is many, and reaction system is unstable, but raw material reaction is complete, and aftertreatment is more convenient, needs to be improved.
Summary of the invention
The object of the invention is to propose a kind of method of synthetic L-Glutimic acid menthyl ester, incomplete with the method reaction that solves now synthetic L-Glutimic acid menthyl ester, product is unstable, and impurity is many, and the not high technical problem of purity L-Glutimic acid menthyl ester.
The present invention solves the problems of the technologies described above by the following technical solutions, reaches purpose of the present invention:
A kind of method of synthetic L-Glutimic acid menthyl ester comprises the following steps:
1) under ice bath, in reactor, add organic solvent, reactant L-Glutimic acid, chlorizating agent, stir 1 hour, revolve organic solvent;
2) add organic solvent, menthol to above-mentioned being spin-dried in thing, react 1～2 hour, add weakly alkaline solvent in a small amount under ice bath, stir 1～2 hour;
3) add water washing, drying, filter, be spin-dried for, cryogenic crystallization, drying obtain L-Glutimic acid menthyl ester product.
Described step 1), in, described organic solvent is tetracol phenixin, methylene dichloride, chloroform, is preferable over methylene dichloride.
Described step 1), in, described chlorizating agent is sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride, chlorine, is preferable over sulfur oxychloride.
Described step 1), in, the mol ratio of reactant L-Glutimic acid and chlorizating agent is 1: 1.1～2, be preferably 1: 1.1～and 1.5.Lower than this scope reaction not exclusively, low conversion rate.Higher than this scope impurity, generate many.
Described step 1), in, the temperature of reaction system is controlled between-10～10 ℃.
Described step 2), in, the mol ratio of reactant menthol and L-Glutimic acid is 1: 1.1～1.5.
Described step 2) in, described weak base solvent borne is one or more the mixing in diisopropyl ethyl amine, triethylamine, quadrol, butanediamine, pyridine, and the mol ratio of weakly alkaline solvent and L-Glutimic acid is 1: 2～5.
Described step 2) organic solvent in is tetracol phenixin, methylene dichloride, chloroform.
Described step 2) in, reaction minute two stages carry out: the first stage temperature of reaction is 10～30 ℃, and the reaction times is 1～2 hour; The subordinate phase temperature of reaction is-10～10 ℃, and the reaction times is 1～2 hour.
Described step 3), in, deep cooling crystallization solvent used is ether.
The present invention adopts safety, economic solvent and catalyzer to synthesize the L-Glutimic acid menthyl ester, and the L-Glutimic acid menthyl ester synthetic method craft provided is simple, safe ready, mild condition, yield reaches more than 85%, and reaction solvent used can be recycled, and easily realizes suitability for industrialized production.
Embodiment
Below embodiments of the invention are elaborated: the present embodiment is implemented take technical solution of the present invention under prerequisite, provided at length embodiment and process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
Under ice bath, get L-Glutimic acid 26g, methylene dichloride 300ml, phosphorus pentachloride 20ml is added in there-necked flask, controlling temperature is-10～10 ℃, stir after 1 hour, revolve organic solvent, add methylene dichloride 200ml, menthol 31g, controlling temperature is 10～30 ℃, stir 1～2 hour, drip triethylamine 10ml under ice bath, stir 1～2 hour, add water 200ml, all washings at twice, the anhydrous sodium sulfate drying organic phase, filter, precipitation, add the 50ml ether, subzero 30 ℃ of stirring and crystallizing, obtain the L-Glutimic acid menthyl ester 43g that purity is greater than 98%, yield is 81.1%.
Embodiment 2
Under ice bath, get L-Glutimic acid 26g, methylene dichloride 300ml, sulfur oxychloride 32ml is added in there-necked flask, controlling temperature is-10～10 ℃, stir after 1 hour, revolve organic solvent, add methylene dichloride 200ml, menthol 31g, controlling temperature is 10～30 ℃, stir 1～2 hour, drip triethylamine 10ml under ice bath, stir 1～2 hour, add water 200ml, all washings at twice, the anhydrous sodium sulfate drying organic phase, filter, precipitation, add the 50ml ether, subzero 30 degree stirring and crystallizing, obtain the L-Glutimic acid menthyl ester 46g that purity is greater than 98%, yield is 86.8%.
Embodiment 3
Under ice bath, get L-Glutimic acid 26g, methylene dichloride 300ml, sulfur oxychloride 32ml is added in there-necked flask, controlling temperature is-10～10 ℃, stir after 1 hour, revolve organic solvent, add methylene dichloride 200ml, menthol 31g, controlling temperature is 10～30 ℃, stir 1～2 hour, drip pyridine 10ml under ice bath, stir 1～2 hour, add water 200ml, all washings at twice, the anhydrous sodium sulfate drying organic phase, filter, precipitation, add the 50ml ether, subzero 30 degree stirring and crystallizing, obtain the L-Glutimic acid menthyl ester 44.5g that purity is greater than 98%, yield is 84%.
Claims (8)
1. the present invention is specifically related to a kind of preparation method of L-Glutimic acid menthyl ester, it is characterized in that take that L-Glutimic acid, as starting raw material and chlorination reaction generation acyl chlorides, generates the L-Glutimic acid menthyl ester with menthol reaction under the effect of weakly alkaline solvent.
2. according to the method for producing the L-Glutimic acid peppermint described in claim 1, it is characterized in that in chlorination reaction, chlorizating agent used is sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride, chlorine, the mol ratio of reactant L-Glutimic acid and chlorizating agent is 1: 1.1～1.5.
3. according to the method for producing the L-Glutimic acid peppermint described in claim 1, it is characterized in that in chlorination reaction, organic solvent used is tetracol phenixin, methylene dichloride, chloroform, 10～12.5 times of amount volumes.
4. according to the method for producing the L-Glutimic acid peppermint described in claim 1, it is characterized in that with menthol reaction first stage temperature of reaction be 10～30 ℃, the reaction times is 1～2 hour; The subordinate phase temperature of reaction is-10～10 ℃, and the reaction times is 1～2 hour.
5. according to the method for producing the L-Glutimic acid peppermint described in claim 1, the mol ratio that it is characterized in that reactant menthol and L-Glutimic acid is 1: 1.1～1.5.
6. according to the method for producing the L-Glutimic acid peppermint described in claim 1, it is characterized in that into weak base solvent borne described in ester reaction and be one or more the mixing in diisopropyl ethyl amine, triethylamine, quadrol, butanediamine, pyridine, the mol ratio of weakly alkaline solvent and L-Glutimic acid is 1: 2～5.。
7. according to the method for producing the L-Glutimic acid peppermint described in claim 1, it is characterized in that deep cooling crystallization solvent used is ether.
8. according to the method for producing the L-Glutimic acid peppermint described in claim 1, it is characterized in that the first activated carboxylic of technique of the present invention, the resterification reaction, and then improve reaction yield.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829514A (en) * | 2015-05-12 | 2015-08-12 | 江苏福瑞生物医药有限公司 | Synthesis method for medical intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1792630A1 (en) * | 2005-12-02 | 2007-06-06 | The Procter & Gamble Company | Conjugates of amino acids and vitamin B3 for percutaneous delivery of vitamin B3 |
| CN101475522A (en) * | 2009-01-16 | 2009-07-08 | 江苏大康实业有限公司 | Preparation of menthyl pyroglutamate |
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- 2013-08-13 CN CN2013103498599A patent/CN103420888A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1792630A1 (en) * | 2005-12-02 | 2007-06-06 | The Procter & Gamble Company | Conjugates of amino acids and vitamin B3 for percutaneous delivery of vitamin B3 |
| CN101475522A (en) * | 2009-01-16 | 2009-07-08 | 江苏大康实业有限公司 | Preparation of menthyl pyroglutamate |
Non-Patent Citations (2)
| Title |
|---|
| SHARAD KUMAR PANDAY等: "STRAIGHTFORWARD AND FACILE APPROACH TOWARD THE N-DERIVATIZATION OF PYROGLUTAMATES THROUGH MITSUNOBU REACTION: SYNTHESIS OF N-ALKYL/N-ACYL PYROGLUTAMATES", 《SYNTHETIC COMMUNICATIONS》 * |
| 胡昆等: "匹多莫德的合成", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829514A (en) * | 2015-05-12 | 2015-08-12 | 江苏福瑞生物医药有限公司 | Synthesis method for medical intermediate |
| CN104829514B (en) * | 2015-05-12 | 2017-10-03 | 江苏福瑞生物医药有限公司 | A kind of synthetic method of pharmaceutical intermediate |
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Application publication date: 20131204 |