CN1264892C - Process for synthesizing L-glutamic acid with high molecular weight - Google Patents
Process for synthesizing L-glutamic acid with high molecular weight Download PDFInfo
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Abstract
The present invention relates to a method for synthesizing biodegradable high-molecular poly L-glutamic acid. The method of the present invention comprises the steps: synthesizing gamma-phenyl-L-glutamic acid-N-carboxylic anhydride, synthesizing poly-L-benzyl-gamma-glutamate, and synthesizing poly-L-glutamic acid, wherein firstly, L-glutamic acid and benzoic alcohol are used as raw materials to prepare L-glutamic acid-gamma-benzyl ester; secondly, the L-glutamic acid-gamma-benzyl ester reacts with triphosgene to obtain white needle crystals of gamma-phenyl-L-glutamic acid-N-carboxylic anhydride; thirdly, poly-L-benzyl-gamma-glutamate is prepared by using the gamma-phenyl-L-glutamic acid-N-carboxylic anhydride as monomers and using triethylamine as an initiator; finally, phenyl of the poly-L-benzyl-gamma-glutamate is eluted with an HBr acetic acid solution to obtain products of poly-L-glutamic acid. The method of the present invention uses an HBr solution to elute phenyl under ordinary pressure and obtains a favorable effect; high-molecular poly-L-glutamic acid can be obtained; the present invention has the advantages of high safety in the reaction process, little toxicity and strong operability.
Description
Technical field:
The present invention relates to a kind of synthetic method of polyamino acid.Particularly a kind of synthetic method of biodegradable L-glutamic acid with high molecular weight.
Background technology:
Polyglutamic acid is the pharmaceutical macromolecular material of a kind of good biodegradable.Owing to have a large amount of free carboxies on its molecular chain, be easy to modify, easily combine with medicine.Because of it has some special nature, secondary structure as chirality, polypeptide chain uniqueness, energy and cell, tissue and other biotic component demonstrate excellent biological compatibility, and degraded, metabolism voluntarily, absorbed by body and drain, be difficult for putting aside and produce toxic side effect in vivo, underwent operative is removed again, thereby has advantages such as slowly-releasing, safe ready, few side effects, saving medicine.The carrier and the organizational project aspect of slowly-releasing, controlled release and targeted drug have been widely used in.
The preparation of polyglutamic acid at present mainly contains chemical synthesis, extraction method, biopolymerization method, and the extraction process of extraction method is very complicated, and production cost is very high; Culture medium preparation equally also is subjected to influence of various factors in the biopolymerization method, thereby production technique is also more loaded down with trivial details, and the molecular weight of resulting polymers is difficult for quantified controlling; And chemical synthesis is a peptide class synthetic important method, and the molecular weight of polymkeric substance can be regulated.
For the chemosynthesis of L-glutamic acid (PLGA), worked mainly concentrates on synthesizing of poly-L-glutamic acid acid benzyl ester (PBLG) in the past, and removing also of high molecular PBLG benzyl is not well solved.
Summary of the invention:
The object of the present invention is to provide a kind of synthetic method of L-glutamic acid with high molecular weight, can under condition of normal pressure, from the poly-L-glutamic acid acid benzyl ester, slough benzyl smoothly, the preparation L-glutamic acid with high molecular weight.
For achieving the above object, the reaction mechanism of institute of the present invention foundation is as follows:
[notes] R:
According to above-mentioned reaction mechanism, the present invention adopts following technical scheme:
A kind of synthetic method of L-glutamic acid with high molecular weight comprises synthetic three parts of synthetic, poly--L-L-glutamic acid of synthetic, poly--L-L-glutamic acid-γ-benzyl ester of γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride it is characterized in that the concrete steps of this method are as follows:
A. γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride is synthetic:
The synthetic method of the ester of (1) employing routine is a raw material with L-L-glutamic acid and phenylcarbinol, makes catalyzer with the vitriol oil, preparation L-L-glutamic acid-γ-benzyl ester in 60-80 ℃ water-bath;
(2) in the exsiccant reaction flask, add L-L-glutamic acid-γ-benzyl ester, with the tetrahydrofuran (THF) is solvent, form suspension, reaction flask is placed 45-55 ℃ of water-bath, stir, lead to nitrogen, after treating homo(io)thermism, the triphosgene of adding, the mass ratio of control L-L-glutamic acid-γ-benzyl ester and triphosgene is 2: 1-1.1; React to reaction solution and become clarification, stop to stir and removing water-bath, continued logical nitrogen 20-40 minute, under violent stirring, precipitate in the sherwood oil that reaction solution is poured into, filter to such an extent that white crystal is head product; After this head product is dissolved in ethyl acetate, transfer in the separating funnel, clean with saturated sodium bicarbonate frozen water solution earlier, clean with frozen water solution again, collect the supernatant liquid body, and add anhydrous magnesium sulfate, insert in the refrigerator then and spend the night; After taking out filtration, filtrate is transferred in the exsiccant confined reaction bottle, and vacuum nitrogen filling gas, carry out recrystallization with sherwood oil again, after filtering, the filter cake acetic acid ethyl dissolution is used the sherwood oil recrystallization again, three times so repeatedly; After filtering at last, with filter cake vacuum-drying at room temperature, obtain white needle-like crystals and be γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride;
B. poly--L-L-glutamic acid-γ-benzyl ester is synthetic: in the exsiccant reaction flask, add γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride, and vacuum nitrogen filling gas, three times repeatedly, the solvent dioxane reinjects; Treat that fully initiator triethylamine is injected in the dissolving back, the mol ratio of monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and initiator triethylamine, be that A/I is 1-200: 1, the back room temperature that stirs leaves standstill to reaction solution and becomes viscous fluid, under the violent stirring reaction solution is slowly poured in the dehydrated alcohol and precipitates, and this moment, the adularescent fibrous polymer was separated out, after filtration, vacuum-drying gets the white fiber shaped polymer, is poly--L-L-glutamic acid-γ-benzyl ester;
C. poly--L-L-glutamic acid is synthetic: in 45-55 ℃ of water bath with thermostatic control, to gather-L-L-glutamic acid-γ-the benzyl ester is dissolved in the dichloro acetic acid, adding concentration in 1 ratio that restrains the HBr acetum of poly--L-L-glutamic acid-γ-benzyl ester adding 4-6 milliliter again is the HBr acetum of 25-33%, reaction is 1.5-2.5 hour under stirring, 45-55 ℃ temperature, left standstill 5-15 hour, the reaction solution ether sedimentation, after filtration, vacuum-drying, get final product product poly--L-L-glutamic acid.
The used monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and the mol ratio of initiator triethylamine among the above-mentioned step b, promptly A/I is 1-50: 1
The used monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and the mol ratio of initiator triethylamine among the above-mentioned step b, promptly A/I is 50-200: 1
In the aforesaid method, the mol ratio of control monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and initiator triethylamine, institute's synthetic gathers-and the molecular weight of L-L-glutamic acid is at 7-35 ten thousand.
Compare with prior art, the present invention has following conspicuous outstanding preferential and distinguishing feature: in the building-up process of the γ-benzyl of the inventive method-L-L-glutamic acid-N-carboxylic acid anhydride, use triphosgene to replace conventional phosgene to have safety, little, the workable characteristics of toxicity; Use triethylamine to make initiator, dioxane is that solvent can prepare high-molecular weight PBLG, and can be by regulating A/I ratio control molecular weight between 7-35 ten thousand, and when A/I ratio greater than 50 the time, resulting polymers molecular weight and A/I ratio have nothing to do.The inventive method is a raw material with L-L-glutamic acid, has synthesized γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride (BLG-NCA), and is monomer with it, simultaneously solvent and initiator has been carried out optimized choice, has synthesized high molecular PBLG.Under normal pressure, slough benzyl at last and obtained effect preferably, obtained high-molecular weight PLGA with HBr solution.
Resulting polymers characterizes with means such as GPC, IR, H-NMR, viscosimetries, and the dependency structure of product and molecular weight have all obtained confirmation.
Embodiment:
Embodiment one:
1. γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride is synthetic:
Synthesizing of a.L-L-glutamic acid-γ-benzyl ester (BLG): in there-necked flask, add 120g L-L-glutamic acid and 100ml phenylcarbinol, there-necked flask is inserted violent stirring in 70 ℃ of water-baths, when homo(io)thermism, slowly drip 60% vitriol oil 96ml, after the clarification of question response liquid, stop to stir and heating, naturally cool to room temperature, slowly pour reaction solution into 800ml and be dissolved with 130gNaHCO
3Supersaturation frozen water solution in, put into the refrigerator freeze overnight after stirring.Filter 2000ml80 ℃ dissolved in distilled water of back filter cake, slowly cool to room temperature then, freezing again about 3 hours, filter, filter cake cleans respectively three times with ethanol, ether, and room temperature vacuum-drying 24 hours obtains white flakey material and is BLG.
B. adding freshly prepd BLG of 10g and 100ml newly steam tetrahydrofuran (THF) (THF) in the exsiccant there-necked flask, stir and form suspension, reaction flask inserted in 50 ℃ the water bath with thermostatic control, in reaction solution, lead to nitrogen simultaneously, when homo(io)thermism, add 5g triphosgene (using chloroform recrystallization three times), become to reaction solution and clarify, stop to stir and removing water-bath, continue logical nitrogen half an hour; Under violent stirring, reaction solution is poured in the sherwood oil of 500ml and is precipitated, filter, white crystal be the BLG-NCA head product; This head product is dissolved in the 100ml ethyl acetate, transfers to then in the separating funnel, clean with 50ml frozen water solution again after cleaning with 50ml saturated sodium bicarbonate frozen water solution; Collect the supernatant liquid body, add to insert in the refrigerator behind an amount of anhydrous magnesium sulfate and spend the night; Take out and filter, transfer in the exsiccant confined reaction bottle, vacuum nitrogen filling gas (triplicate) is concentrated into filtrate about 40ml, injects the new sherwood oil (boiling range is 60-90 ℃) that steams about 40ml, carries out recrystallization; Filter, filter cake with the 20ml acetic acid ethyl dissolution after adding 20ml left and right sides sherwood oil (boiling range is 60-90 ℃) carry out recrystallization; Behind the recrystallization three times, after filtration,, obtain white needle-like crystals and be γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride monomer that purity reaches polymerization-grade, productive rate about 65% so repeatedly filter cake vacuum-drying at room temperature 12 hours.
2. poly--L-L-glutamic acid-γ-benzyl ester is synthetic:
In the reaction flask of oven dry, put into the γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride monomer of 1 gram, vacuum nitrogen filling gas (guaranteeing the anhydrous and oxygen-free condition), inject 20ml and newly steam dioxane, monomer dissolving back inject metering (with monomeric mol ratio be 1: 1) new steaming triethylamine, mix the back room temperature and left standstill 3 days, the reaction solution very thickness that becomes is under violent stirring, in the excessive dehydrated alcohol that this reaction solution is poured into, have a large amount of white fiber shape materials to separate out this moment; Vacuum-drying after filtering 24 hours, resulting polymers is poly--L-L-glutamic acid-γ-benzyl ester.
3. poly--L-L-glutamic acid is synthetic:
Get freshly prepd poly--L-L-glutamic acid-γ-benzyl ester 0.66 gram, 50 ℃ are dissolved in the 6.6ml dichloro acetic acid, add 3ml concentration again and be 33% HBr acetum, keep 50 ℃ 2 hours, the room temperature standing over night.Reaction solution slowly poured in the intensively stirred 200ml ether precipitate, filtered final vacuum dry 24 hours.Get final product to such an extent that molecular weight is 7.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment two: present embodiment and embodiment one are basic identical, and the mol ratio of different is monomer and triethylamine is 5: 1, and in step 3, the concentration of used HBr acetum is 25%, and add-on is 4 milliliters.Finally can get molecular weight is 14.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment three: present embodiment and embodiment one are basic identical, and the mol ratio of different is monomer and triethylamine is 10: 1.Finally can get molecular weight is 15.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment four: present embodiment and embodiment one are basic identical, and the mol ratio of different is monomer and triethylamine is 15: 1.Finally can get molecular weight is 16.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment five: present embodiment and embodiment one are basic identical, and the mol ratio of different is monomer and triethylamine is 20: 1.Finally can get molecular weight is 28.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment six: present embodiment and embodiment two are basic identical, and the mol ratio of different is monomer and triethylamine is 30: 1.Finally can get molecular weight is 30.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment seven: present embodiment and embodiment two are basic identical, and the mol ratio of different is monomer and triethylamine is 50: 1.Finally can get molecular weight is 35.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment eight: present embodiment and embodiment two are basic identical, and the mol ratio of different is monomer and triethylamine is 100: 1.Finally can get molecular weight is 35.2 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment nine: present embodiment and embodiment two are basic identical, and the mol ratio of different is monomer and triethylamine is 150: 1.Finally can get molecular weight is 35.0 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Embodiment ten: present embodiment and embodiment two are basic identical, and the mol ratio of different is monomer and triethylamine is 200: 1.Finally can get molecular weight is 35.3 * 10
4About poly--L-L-glutamic acid, transformation efficiency is about 70%.
Claims (4)
1. the synthetic method of a L-glutamic acid with high molecular weight comprises synthetic four parts of synthetic, poly--L-L-glutamic acid of synthetic, poly--L-L-glutamic acid-γ-benzyl ester of γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride it is characterized in that the concrete steps of this method are as follows:
A. γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride is synthetic:
The synthetic method of the ester of (1) employing routine is a raw material with L-L-glutamic acid and phenylcarbinol, makes catalyzer with the vitriol oil, preparation L-L-glutamic acid-γ-benzyl ester in 60-80 ℃ water-bath;
(2) in the exsiccant reaction flask, add L-L-glutamic acid-γ-benzyl ester, with the tetrahydrofuran (THF) is solvent, form suspension, reaction flask is placed 45-55 ℃ of water-bath, stir, lead to nitrogen, after treating homo(io)thermism, the triphosgene of adding, the mass ratio of control L-L-glutamic acid-γ-benzyl ester and triphosgene is 2: 1-1.1; React to reaction solution and become clarification, stop to stir and removing water-bath, continued logical nitrogen 20-40 minute, under violent stirring, precipitate in the sherwood oil that reaction solution is poured into, filter to such an extent that white crystal is head product; After this head product is dissolved in ethyl acetate, transfer in the separating funnel, clean with saturated sodium bicarbonate frozen water solution earlier, clean with frozen water solution again, collect the supernatant liquid body, and add anhydrous magnesium sulfate, insert in the refrigerator then and spend the night; After taking out filtration, filtrate is transferred in the exsiccant confined reaction bottle, and vacuum nitrogen filling gas, carry out recrystallization with sherwood oil again, after filtering, the filter cake acetic acid ethyl dissolution is used the sherwood oil recrystallization again, three times so repeatedly; After filtering at last, with filter cake vacuum-drying at room temperature, obtain white needle-like crystals and be γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride;
B. synthetic gathering-L-L-glutamic acid-γ-benzyl ester: in the exsiccant reaction flask, add γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride, vacuum nitrogen filling gas, three times repeatedly, the solvent dioxane reinjects; Treat that fully initiator triethylamine is injected in the dissolving back, the mol ratio of monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and initiator triethylamine, be that A/I is 1-200: 1, the back room temperature that stirs leaves standstill to reaction solution and becomes viscous fluid, under the violent stirring reaction solution is slowly poured in the dehydrated alcohol and precipitates, and this moment, the adularescent fibrous polymer was separated out, after filtration, vacuum-drying gets the white fiber shaped polymer, is poly--L-L-glutamic acid-γ-benzyl ester;
C. poly--L-L-glutamic acid is synthetic: in 45-55 ℃ of water bath with thermostatic control, to gather-L-L-glutamic acid-γ-the benzyl ester is dissolved in the dichloro acetic acid, adding concentration in 1 ratio that restrains the HBr acetum of poly--L-L-glutamic acid-γ-benzyl ester adding 4-6 milliliter again is the HBr acetum of 25-33%, reaction is 1.5-2.5 hour under stirring, 45-55 ℃ temperature, left standstill 5-15 hour, the reaction solution ether sedimentation, after filtration, drying, get final product product poly--L-L-glutamic acid.
2. the synthetic method of L-glutamic acid with high molecular weight according to claim 1 is characterized in that, the used monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and the mol ratio of initiator triethylamine in step b, and promptly A/I is 1-50: 1.
3. the synthetic method of L-glutamic acid with high molecular weight according to claim 1 is characterized in that, the used monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and the mol ratio of initiator triethylamine in step b, and promptly A/I is 50-200: 1.
4. according to the synthetic method of claim 1,2 or 3 described L-glutamic acid with high molecular weight, it is characterized in that, the mol ratio of control monomer γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride and initiator triethylamine, institute's synthetic gather-and the molecular weight of L-L-glutamic acid is at 7-35 ten thousand.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2019133B1 (en) * | 2006-05-23 | 2013-05-22 | Toyobo Co., Ltd. | MICROORGANISM CAPABLE OF PRODUCING gamma-L-PGA, METHOD FOR PRODUCTION OF gamma-L-PGA USING THE MICROORGANISM, CROSSLINKED PRODUCT, AND AGENT FOR EXTERNAL APPLICATION TO THE SKIN |
| CN101280047B (en) * | 2008-05-06 | 2010-06-23 | 华南理工大学 | Poly benzyl glutamate-containing degradable composite material and preparation thereof |
| CN102617851B (en) * | 2012-03-31 | 2014-06-11 | 上海大学 | Method for preparing poly (L-glutamic acid) with controllable molecular weight |
| CN103289078B (en) * | 2013-05-17 | 2015-10-07 | 中山大学 | A kind of method and application preparing polyamino acid and derivative thereof fast |
| CN105949458A (en) * | 2016-06-08 | 2016-09-21 | 长春理工大学 | Poly(L-glutamate)-grafted cinnamyl alcohol, preparation method and drug-loaded nano-material |
| CN108186672A (en) * | 2018-01-29 | 2018-06-22 | 中国药科大学 | The preparation and application of α-polyglutamic acid-CDDP complex |
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