CN1631875A - Synthesis method of L-aspartic acid-beta-benzylester - Google Patents
Synthesis method of L-aspartic acid-beta-benzylester Download PDFInfo
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- CN1631875A CN1631875A CN 200310122694 CN200310122694A CN1631875A CN 1631875 A CN1631875 A CN 1631875A CN 200310122694 CN200310122694 CN 200310122694 CN 200310122694 A CN200310122694 A CN 200310122694A CN 1631875 A CN1631875 A CN 1631875A
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Abstract
The invention relates to a method for synthesizing L-organic acid selenium beta-benzyl ester, which includes the following steps1) add benzyl alcohol, L-organic acid selenium, catalyzer-hydrate of paratoluenesulfonic acid into reaction vessel, agtate them for 1-3 hours in the temperature of 25-100deg.C; (2) after the reaction add into alcohol, then use saturated sodium carbonate solution to adjust PH value to seven, acquire the primary product, the sendiment is filtered and washed, then recrystallization to be L-organic acid selenium beta-benzyl ester; the mol ratio of L-organic acid selenium, benzyl alcohol and catalyzer-hydrate of paratoluenesulfonic acid is 1.0:1.3-13.0:0.07-7.0. The invention has fewer side-reaction, simple technique, convenient operation and lower toxicity of solvent, suitable for industrialized production, the product is the important raw material for synthesizing polypeptide medicine.
Description
Technical field
The present invention relates to the synthetic method of L-aspartic acid-beta-benzene methyl.
Background technology
When synthesizing polypeptide, for fear of the generation of side reaction, some amino acid whose side chain functionalities need adopt suitable protecting group to be protected.The side chain carboxyl group of L-aspartic acid is active functional group, and generally speaking, its side chain carboxyl group often adopts the benzene methyl protection.L-aspartic acid and phenylcarbinol are the important source material of synthetic L-aspartic acid-beta-benzene methyl, and L-aspartic acid-beta-benzene methyl is the important source material of synthetic polypeptide medicaments.Therefore the study on the synthesis exploitation to L-aspartic acid-beta-benzene methyl seems particularly important.
The clear 37-13976 of prior art (1) Japanese Patent (1962) discloses a kind of synthetic method of L-aspartic acid-beta-benzene methyl, L-aspartic acid, the vitriol oil, water and phenylcarbinol is mixed, 70 ℃ of reactions 30 minutes.Vacuum concentration then.Add sodium hydrogen carbonate solution in the concentrated solution, solid is separated out, and the water recrystallization gets L-aspartic acid-beta-benzene methyl.
In this synthetic method, used strong acid catalyst---the vitriol oil.Though that the vitriol oil has is acid strong, excellent catalytic effect, stable in properties, water-absorbent reach advantages such as inexpensive by force.But, therefore can cause side reactions such as sulfonation, carbonization or polymerization because it has oxidisability.Because raw material L-aspartic acid and phenylcarbinol, carbochain is long, molecular weight is big and temperature of reaction is higher, esterification thereby should not use the vitriol oil as catalyzer.In addition, use the vitriol oil cumbersome when operation.
The clear 57-26658 of prior art (2) Japanese Patent (nineteen eighty-two), clear 57-26659 (nineteen eighty-two) and clear 57-28090 (nineteen eighty-two) disclose the synthetic method of L-aspartic acid-beta-benzene methyl, to add 80% sulfuric acid and 250 gram phenylcarbinols in the 100 gram L-aspartic acids successively, reaction is 2 hours 30 minutes under 70 ℃ of reduced pressure.Add saturated sodium carbonate solution (140 gram anhydrous sodium carbonates are dissolved in 500 ml waters) and 300 milliliters of ether in the reaction solution.Stir, solid is separated out, filter, and washing, recrystallization gets L-aspartic acid-beta-benzene methyl in water, yield 52%, 222 ℃ of fusing points.
In this synthetic method, an compares with prior art (1), has used strong acid catalyst equally, i.e. the vitriol oil.Though it has plurality of advantages, it has oxidisability thereby causes many side reactions.Because the carbochain of raw material is long, molecular weight is big and temperature of reaction is higher, thereby esterification should not use the vitriol oil as catalyzer usually.In addition, use the vitriol oil cumbersome when operation.The used recrystallisation solvent of the 2nd, is an ether.Ether toxicity is big, volatile, dangerous big, and operation has been brought inconvenience.
Therefore, from economic considerations, its industrial prospect is unsatisfactory, thereby causes the present invention in order to overcome above defective.
Summary of the invention
The purpose of this invention is to provide a kind of can be in industrial mass production, economical rationality, side reaction synthetic method less, L-aspartic acid-beta-benzene methyl that solvent toxicity is less, processing ease.
It is as follows that the present invention gets chemical equation:
The present invention is achieved in that the synthetic method of this L-aspartic acid-beta-benzene methyl may further comprise the steps:
(1) phenylcarbinol, L-aspartic acid and catalyzer tosic acid hydrate are added in the reactor, 25～100 ℃ of stirring reactions 1～3 hour.
(2) after the reaction end, add dehydrated alcohol in the reaction solution, regulate pH with saturated sodium carbonate solution then and equal 7, get thick product precipitation, precipitation is washed after filtration, and recrystallization gets L-aspartic acid-beta-benzene methyl product in water.
Among the present invention, the mol ratio of L-aspartic acid and phenylcarbinol is 1.0: 1.3～13.0, and the mol ratio of L-aspartic acid and tosic acid hydrate is 1.0: 0.07～7.0, and the mol ratio of L-aspartic acid and dehydrated alcohol is 1.0: 2.3～23.0.
Among the present invention, L-aspartic acid and phenylcarbinol the mole be preferably 1.0: 5.5～6.5, L-aspartic acid and tosic acid hydrate the mole be preferably 1.0: 1.4～1.5.
Strong acid type catalyzer used in the present invention is the aromatic sulphonic acid series compound, serves as better with the tosic acid hydrate wherein.
Crystallizing agent used herein is the lower alcohols compound, wherein with dehydrated alcohol the best.
Neutralizing agent used herein is the saturated sodium carbonate solution that anhydrous sodium carbonate is made into.
The present invention has following advantage compared with the prior art:
One. the present invention is the strong acid type catalyzer with the tosic acid hydrate, and it has advantages such as acid strong, excellent catalytic effect, stable in properties, and the anaerobic voltinism, carboniogenesis a little less than, technology is simple.Overcome in the prior art and caused side reactions such as sulfonation, carbonization or polymerization as catalyzer, made the cumbersome defective of post-processing operation with the vitriol oil.Two. the present invention is owing to being recrystallisation solvent with the dehydrated alcohol, and therefore easy to operate, toxicity is little, and is cheap, reclaims easily, and recycles.Having overcome in the prior art with the ether is recrystallisation solvent, and toxicity is big, volatile, dangerous big, and operation has been brought inconvenient defective.Three. technology of the present invention is simple, and is easy to operate, and unit consumption is low, and quality product and yield and prior art are suitable, are suitable for suitability for industrialized production.
Embodiment
In order to implement synthetic method of the present invention better, be described further especially exemplified by following embodiment, but the present invention is not limited to embodiment.
Embodiment 1:
35.5 add 3.6 gram (0.018 mole) tosic acid hydrates and 35 gram (0.26 mole) L-aspartic acids in milliliter (0.34 mole) phenylcarbinol successively.25～100 ℃ of stirring reactions 1～3 hour.After reaction finishes, add 35～350 milliliters of (0.59～5.94 mole) dehydrated alcohols in the reaction solution, regulate pH with saturated sodium carbonate solution and equal 7, get thick product precipitation, precipitation is washed after filtration, recrystallization gets product L-aspartic acid-beta-benzene methyl 23 grams in water, yield 39.63%, fusing point: 224 ℃ (decomposition), specific rotatory power [α]
D 20=+27.7 ° (C=1.2 is in 1N hydrochloric acid).
Embodiment 2:
Except the L-aspartic acid is that 35 grams (0.26 mole), phenylcarbinol are that 150 milliliters (1.42 moles) and tosic acid hydrate are 70 grams (0.36 mole), all the other processing steps and reaction parameter are all with embodiment 1, the result obtains L-aspartic acid-beta-benzene methyl 25 grams, yield 43.24%, fusing point: 224 ℃ (decomposition), specific rotatory power [α]
D 20=+28.11 ° (C=1.2 is in 1N hydrochloric acid).
Embodiment 3:
Except the L-aspartic acid is that 700 grams (5.18 moles), phenylcarbinol are that 3500 milliliters of (33.15 moles), tosic acid hydrates are that 1520 grams (7.75 moles) and dehydrated alcohol are 700～7000 milliliters (11.88～118.83 moles), all the other processing steps and reaction parameter are all with embodiment 1, the result obtains L-aspartic acid-beta-benzene methyl 550 grams, yield 47.56%, fusing point: 224 ℃ (decomposition), specific rotatory power [α]
D 20=+27.19 ° (C=1.2 is in 1N hydrochloric acid).
Embodiment 4:
Except the L-aspartic acid is that 35 grams (0.26 mole), phenylcarbinol are that 355 milliliters (3.39 moles) and tosic acid hydrate are 360 grams (1.84 moles), all the other processing steps and reaction parameter are all with embodiment 1, the result obtains L-aspartic acid-beta-benzene methyl 24 grams, yield 41.51%, fusing point: 224 ℃ (decomposition), specific rotatory power [α]
D 20=+26.95 ° (C=1.2 is in 1N hydrochloric acid).
Claims (3)
1. the synthetic method of a L-aspartic acid-beta-benzene methyl is a raw material with L-aspartic acid and phenylcarbinol, it is characterized in that this method may further comprise the steps:
(1) phenylcarbinol, L-aspartic acid and catalyzer tosic acid hydrate are added in the reactor, 25～100 ℃ of stirring reactions 1～3 hour.
(2) after the reaction end, add dehydrated alcohol in the reaction solution, regulate pH with saturated sodium carbonate solution then and equal 7, get thick product precipitation, precipitation is washed after filtration, and recrystallization gets L-aspartic acid-beta-benzene methyl product in water.
2. method according to claim 1, it is characterized in that: the mol ratio of L-aspartic acid and phenylcarbinol is 1.0: 1.3～13.0, the mol ratio of L-aspartic acid and tosic acid hydrate is 1.0: 0.07～7.0, and the mol ratio of L-aspartic acid and dehydrated alcohol is 1.0: 2.3～23.0.
3. method according to claim 1 is characterized in that: L-aspartic acid and phenylcarbinol the mole be preferably 1.0: 5.5～6.5, L-aspartic acid and tosic acid hydrate the mole be preferably 1.0: 1.4～1.5.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101226948A CN1303057C (en) | 2003-12-24 | 2003-12-24 | Synthesis method of L-aspartic acid-beta-benzylester |
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| CNB2003101226948A CN1303057C (en) | 2003-12-24 | 2003-12-24 | Synthesis method of L-aspartic acid-beta-benzylester |
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| Publication Number | Publication Date |
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| CN1631875A true CN1631875A (en) | 2005-06-29 |
| CN1303057C CN1303057C (en) | 2007-03-07 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102381999A (en) * | 2011-09-14 | 2012-03-21 | 杭州澳赛诺化工有限公司 | Synthetic method of L-aspartate-4-methyl ester-1-benzyl ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3710192A1 (en) * | 1987-03-27 | 1988-10-13 | Diamalt Ag | METHOD FOR PRODUCING ASPARAGIC ACID 4- (PHENYLMETHYL) ESTER |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102381999A (en) * | 2011-09-14 | 2012-03-21 | 杭州澳赛诺化工有限公司 | Synthetic method of L-aspartate-4-methyl ester-1-benzyl ester |
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| CN1303057C (en) | 2007-03-07 |
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Granted publication date: 20070307 Termination date: 20100125 |