CN103724217A - Asymmetric syntheses method for D-tyrosine - Google Patents
Asymmetric syntheses method for D-tyrosine Download PDFInfo
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- CN103724217A CN103724217A CN201210384766.5A CN201210384766A CN103724217A CN 103724217 A CN103724217 A CN 103724217A CN 201210384766 A CN201210384766 A CN 201210384766A CN 103724217 A CN103724217 A CN 103724217A
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- 0 C*(*)c1ccc(C=C(*)NC(C)=O)cc1 Chemical compound C*(*)c1ccc(C=C(*)NC(C)=O)cc1 0.000 description 2
- MVXVHKALKUDTHC-MRVPVSSYSA-N N[C@H](Cc(cc1)ccc1O)Cl Chemical compound N[C@H](Cc(cc1)ccc1O)Cl MVXVHKALKUDTHC-MRVPVSSYSA-N 0.000 description 1
Abstract
A provided asymmetric syntheses method for D-tyrosine comprises the following steps: performing a condensation reaction on p-hydroxybenzaldehyde and acetylglycine, then performing hydrolysis or alcoholysis to obtain a dehyddroamino acid or ester; and then utilizing rhodium to perform catalytic asymmetric hydrogenation, and performing hydrolysis to obtain a key intermediate D-tyrosine. According to the method, the whole process has no complex separation steps, the preparation technology is simple, a chromatography column is not needed, the reaction steps can be further reduced by utilizing rhodium catalysis asymmetric hydrogenation technology, the production cost is reduced, and the method is extremely suitable for industrialized batch production.
Description
Technical field
What the present invention relates to is a kind of D-Tyrosine synthetic method, specifically a kind of synthetic method of utilizing rhodium catalysis asymmetric hydrogenation technology to prepare D-Tyrosine.
Background technology
Salvianic acidA ((R)-β-(3,4-dihydroxy phenyl) Sodium.alpha.-hydroxypropionate) is one of main water-soluble chemical component in the herbal medicine red sage root (being separated for 1980), is the effective constituent of Radix Salviae Miltiorrhizae drop pill, Radix Salviae Miltiorrhizae Tabellae, Radix Salviae Miltiorrhizae Injection etc.Research shows, Salvianic acidA has vasodilation, increases coronary flow, anti-myocardial ischemina, antithrombotic form and improve the effects such as microcirculation, aspect treatment coronary heart disease and stenocardia, has unique curative effect.At the aspect such as antitumor, also produce effect in addition.The traditional preparation method of this compound is by extracting from the root of red cinnabar Salvia japonica Thunb. and Salvianic acidA, but this extraction process is comparatively complicated, and chemical purity is not high.Although the process of its chemosynthesis is also known, the product of most of report is all racemic mixture, only have method few in number synthetic be optical purity product.Wherein, with respect to the method that is raw material with 3,4-Dihydroxy benzaldehyde, take the metastable p-Hydroxybenzaldehyde that is cheaply easy to get, via the method for key intermediate D-Tyrosine, have more cost advantage as raw material.As: 1997, D.E.Bogucki and J.L.Charlton have reported a kind of by synthetic (S)-(+)-β-(3 of natural TYR, 4 – dihydroxy phenyls) method of lactic acid, but final synthetic product is not Salvianic acidA (the Canada Journal of Chemistry of needed (S) configuration, 1997,75,1783.).2011, the people such as Yu Pei utilize similar method from synthetic (R)-(+)-β-(3 of non-natural D-Tyrosine, 4-dihydroxy phenyl) lactic acid is Salvianic acidA, see " a kind of synthetic method of Salvianic acidA " (Chinese Patent Application No.: CN20111005899.0) and " a kind of new Salvianic acidA preparation method " (Chinese medicinal materials, 2011,34,472.).But the method need to be passed through complicated post technique excessively, and the raw material non-natural D-Tyrosine price of using is still too expensive, is unsuitable for industrial mass production.
D-Tyrosine is alpha-non-natural amino acid, except above-mentioned, can be used for Salvianic acidA synthetic, and recent bibliographical information shows take it as starting raw material or building block can be prepared many medicines, has huge potential market demand.Now industrial what often use is method for splitting, and process complexity, efficiency are low, and cost high, be unsuitable for suitability for industrialized production.2012, the human hairs such as Zhang Wanbin understand a kind ofly divides through being hydrolyzed to obtain the method for D-Tyrosine through Dynamic Kinetic watchman's clapper from TYR ester again, can obtain good productive rate and enantioselectivity, can effectively lower the production cost (Chinese Patent Application No.: CN201210045393.9) of D-Tyrosine, but the use of chiral selectors greatly reduces the efficiency of this reaction.So the research and development of the D-Tyrosine method of asymmetric synthesis of high efficiency, low cost are that the crucial of association area Product industrialization is also current bottleneck place simultaneously.
On the other hand, asymmetric catalytic hydrogenation technology is since nineteen sixty-eight occurs, experienced the development of more than 30 year, because the advantage of its economy and environmental protection becomes at present in the most ripe aspect an asymmetric synthesis and most active field, have to exceed 20 industrialization projects and adopted this technology, at present more in the project of grinding.
Asymmetric catalytic hydrogenation technology also has relevant report aspect optical activity tyrosine derivative synthetic, but does not up to the present realize satisfactory results.As: 1989, Achiwa report utilize the complex-catalyzed hydrogenation synthesis of optically active of BPPM-Rh tyrosine derivative, only obtain 91% enantioselectivity (Chem.Lett.1989,305.); 2002, Chan reported and has utilized the two complex-catalyzed hydrogenation synthesis of optically active of phosphine-Rh tyrosine derivatives, obtained 98% enantioselectivity (Tetrahedron Lett.2002,43,6803.) under TON=500 condition; 2003, Chan reported monodentate phosphine ligand-Rh catalytic hydrogenation synthesis of optically active tyrosine derivative, has obtained the enantioselectivity up to 99%, but TON is only 100(J.Org.Chem.2003,68,4539.).
The present invention is just based on above-mentioned research background, and the complex-catalyzed asymmetric hydrogenation method of novel biphosphine ligand and Rh a kind of of having researched and developed is for the synthesis of D-Tyrosine, enantioselectivity up to 99%, TON up to 10000.The method is more efficient, more economical, and more environmental protection, is more suitable in suitability for industrialized production.
Summary of the invention
The object of the invention is Sodium Danshensu and aftertreatment too expensive, that can only obtain racemization for above-mentioned existing D-Tyrosine raw material and need the defects such as column chromatography, research and develop a kind of method of asymmetric synthesis and technique of D-Tyrosine of new more economical more environmental protection, and obtain optically pure Sodium Danshensu as intermediate, reduce the synthetic cost of Sodium Danshensu, thereby realize the industrialization of Sodium Danshensu.
For achieving the above object, the technical solution used in the present invention is:
A method of asymmetric synthesis for Sodium Danshensu key intermediate D-Tyrosine, comprises following steps:
(1) by p-Hydroxybenzaldehyde, be the synthetic 2-methyl-4-(4-acetoxyl group benzal base of raw material) oxazolone, via an one-step hydrolysis or alcoholysis, obtain dehydroamino acid or ester IIa-IIf.
(2) under biphosphine ligand-Rhodium Complexes Catalyzed, be there is to asymmetric hydrogenation in dehydroamino acid or ester IIa-IIf, then through simple hydrolysis, obtain D-Tyrosine.
Wherein, R
1for hydrogen or ethanoyl, R
2for hydrogen, methyl or ethyl.
The net reaction of above-mentioned steps is as follows:
Wherein, R1 is hydrogen or ethanoyl, and R2 is hydrogen, methyl or ethyl.
Preferably, described step (1), be specially: after p-Hydroxybenzaldehyde, acetyl glycine, anhydrous sodium acetate and diacetyl oxide are mixed under 80 ° of C stirring reaction 4 hours, then cooling, filter 2-methyl-4-(4-acetoxyl group benzal base of obtaining) the direct one-step hydrolysis of oxazolone I or alcoholysis obtain dehydroamino acid or ester IIa-IIf through simple aftertreatment recrystallization.
Preferably, the described dehydroamino acid of step (1) or ester IIa-IIf are by 2-methyl-4-(4-acetoxyl group benzal base) oxazolone is in a direct step alcoholysis and process is filtered and recrystallization obtains.
Preferably, the reagent that the described alcoholysis of step (1) is used is methyl alcohol or ethanol, and temperature of reaction is 20 ° of C～reflux temperatures, and the reaction times is 1～24 hour.
Preferably, there is asymmetric hydrogenation by dehydroamino acid or ester IIa-IIf in what step (2) was described under biphosphine ligand-Rhodium Complexes Catalyzed, be in solvent, under hydrogen condition, the lower asymmetric hydrogenation condition that occurs of room temperature (20 ° of C ± 5 ° C).
Preferably, the described solvent of step (2) is toluene, methylene dichloride, trichloromethane, tetrahydrofuran (THF), acetone, ethyl acetate and water, and hydrogen condition is 3atm～20atm pressure, and the reaction times is 0.3～48 hour.
Preferably, the amount ranges of the biphosphine ligand-rhodium complex catalyst described in step (2) is 1/200～1/10000 of dehydroamino acid or ester IIa-IIf mole dosage.
Preferably, the biphosphine ligand-rhodium complex structure described in step (2) is as follows:
The present invention is first synthetic 2-methyl-4-(4-acetoxyl group benzal base of raw material by p-Hydroxybenzaldehyde) oxazolone, via an one-step hydrolysis or alcoholysis, obtain dehydroamino acid ester.Then utilize the complex-catalyzed asymmetric hydrogenation of biphosphine ligand-Rh to obtain D-Tyrosine.Take the synthetic D-Tyrosine of the present invention as raw material, in conjunction with prior art (technology of recording as Chinese patent CN201210045393.9) via acidylate, diazotization hydroxyl replace, carboxylic acid salify can finally synthesize Sodium Danshensu with lower cost and environmental cost after oxidation phenolic hydroxyl group.
Compared with prior art, the present invention has following beneficial effect:
Whole process of the present invention is without complex separations step, and technique is simple, without crossing chromatography column, and utilizes rhodium catalysis asymmetric hydrogenation technology further to reduce reactions steps, reduces production costs, and is applicable to very much industrialized mass production.The D-Tyrosine purity >99% that adopts aforesaid method to make, enantioselectivity >98%.The method and salify method for splitting, Enzymatic Resolution method and higher, the more economical also more environmental protection of D-Tyrosine synthetic method phase specific efficiency of report before this, be therefore more suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
Embodiment 1 dehydroamino acid methyl esters IIc's is synthetic
In dry 500ml single port bottle, add 2-methyl-4-(4-acetoxyl group benzal base) oxazolone 25.0g(0.1mol, 1.0eq), 0.4g sodium acetate (4.8mmol, 0.05eq), add 250ml methanol solvate, stirring and dissolving, reflux 1 hour, stops heating.Be spin-dried for system solvent, ethyl acetate/normal hexane (1/1) recrystallization obtains 11.1g dehydroamino acid ester IIc(white crystal), productive rate is 40%.
1H?NMR(400MHz,CD
3OD):δ7.66(d,J=8.6Hz,2H),7.28-7.22(m,3H),3.70(s,3H),2.27(s,3H),2.01(s,3H).
Embodiment 2 dehydroamino acid methyl esters IIc's is synthetic
In dry 500ml single port bottle, add 2-methyl-4-(4-acetoxyl group benzal base) oxazolone 25.0g(0.1mol, 1.0eq), 0.4g sodium acetate (4.8mmol, 0.05eq), add 250ml methanol solvate, stirring and dissolving, reflux.TLC plate monitoring reaction, after 6 hours, raw material point disappears, and stops heating.Be spin-dried for system solvent, ethyl acetate/normal hexane (1/1) recrystallization obtains 21.7g dehydroamino acid ester IIc(white crystal), yield is 78%.
Embodiment 3 dehydroamino acid methyl esters IIc's is synthetic
In dry 500ml single port bottle, add 2-methyl-4-(4-acetoxyl group benzal base) oxazolone 25.0g(0.1mol, 1.0eq), 0.4g sodium acetate (4.8mmol, 0.05eq), add 250ml methanol solvate, 20 ° of C stir 24 hours.Be spin-dried for system solvent, ethyl acetate/normal hexane (1/1) recrystallization obtains 8.3g dehydroamino acid ester IIc(white crystal), yield is 30%.
Embodiment 4 dehydroamino acid ethyl ester IIe's is synthetic
In dry 500ml single port bottle, add 2-methyl-4-(4-acetoxyl group benzal base) oxazolone 25.0g(0.1mol, 1.0eq), 0.4g sodium acetate (4.8mmol, 0.05eq), add 250ml alcohol solvent, stirring and dissolving, reflux.TLC plate monitoring reaction, after 6 hours, raw material point disappears, and stops heating.Be spin-dried for system solvent, ethyl acetate/normal hexane (1/1) recrystallization obtains 23.2g dehydroamino acid ester IIe(white crystal), yield is 80%.
The asymmetric catalytic hydrogenation result of the different dehydroamino acids of embodiment 5 (ester)
Exemplary steps: add dehydroamino acid (ester) (0.4mmol) in 10mL reaction tube, catalyzer [Rh ((R, R)-QuinoxP*) (cod)] SbF
6(1.6mg, 2 μ mol, TON=200), vacuumize and change hydrogen 3 times, then under hydrogen shield, add the MeOH(2mL after degassed), finally hydrogen pressure is transferred to vigorous stirring 22h after 5atm.Reaction is got 0.2mL after finishing, and removes under reduced pressure after MeOH and measures transformation efficiency with NMR.And then get 0.4mL, prepare the rear HPLC of plate purifying (EtOAc is as eluent) and measure enantioselectivity.Before carboxylic acid substrate purifying, first add THF, (CH3)
3siCHN
2(2.0M in Hexane, 0.1mL) esterification.Concrete reaction formula and response data are as follows:
The asymmetric catalytic hydrogenation result of embodiment 6 different catalysts
Exemplary steps: add dehydroamino acid (ester) IIa(88.9mg, 0.4mmol in 10mL reaction tube), catalyzer [Rh ((R, R)-L*) is (cod)] SbF
6(2 μ mol, TON=200), vacuumizes and changes hydrogen 3 times, then under hydrogen shield, adds the MeOH(2mL after degassed), finally hydrogen pressure is transferred to vigorous stirring 22h after 5atm.Reaction is got 0.2mL after finishing, and removes under reduced pressure after MeOH and measures transformation efficiency with NMR.And then get 0.4mL, add THF after first removing MeOH under reduced pressure, (CH3)
3siCHN
2(2.0M in Hexane, 0.1mL) esterification.Then after preparing plate purifying (EtOAc is as eluent), HPLC measures enantioselectivity.Concrete reaction formula and response data are as follows:
Asymmetric catalytic hydrogenation result-1 of embodiment 7 different hydrogen pressure and TON
Exemplary steps: add dehydroamino acid IIa in 10mL reaction tube, catalyzer [Rh ((R, R)-QuinoxP*) (cod)] SbF
6, vacuumize and change hydrogen 3 times, then under hydrogen shield, add the MeOH(2mL after degassed), finally hydrogen pressure is transferred to vigorous stirring after 3～20atm.Reaction is got 0.2mL after finishing, and removes under reduced pressure after MeOH and measures transformation efficiency with NMR.And then get 0.4mL, add THF after first removing MeOH under reduced pressure, (CH3)
3siCHN
2(2.0M in Hexane, 0.1mL) esterification.Then after preparing plate purifying (EtOAc is as eluent), HPLC measures enantioselectivity.Concrete reaction formula and response data are as follows:
Asymmetric catalytic hydrogenation result-2 of embodiment 8 different hydrogen pressure and TON
Exemplary steps: add dehydroamino acid ester IIc in 10mL reaction tube, catalyzer [Rh ((R, R)-QuinoxP*) (cod)] SbF
6, vacuumize and change hydrogen 3 times, then under hydrogen shield, add the MeOH(2mL after degassed), finally hydrogen pressure is transferred to vigorous stirring after 3～20atm.Reaction is got 0.2mL after finishing, and removes under reduced pressure after MeOH and measures transformation efficiency with NMR.And then get 0.4mL, first remove under reduced pressure prepare plate purifying (EtOAc is as eluent) after MeOH after HPLC measure enantioselectivity.Concrete reaction formula and response data are as follows:
Asymmetric catalytic hydrogenation result-3 of embodiment 9 different hydrogen pressure and TON
Exemplary steps: add dehydroamino acid ester IIe in 10mL reaction tube, catalyzer [Rh ((R, R)-QuinoxP*) (cod)] SbF
6, vacuumize and change hydrogen 3 times, then under hydrogen shield, add the MeOH(2mL after degassed), finally hydrogen pressure is transferred to vigorous stirring after 3～20atm.Reaction is got 0.2mL after finishing, and removes under reduced pressure after MeOH and measures transformation efficiency with NMR.And then get 0.4mL, first remove under reduced pressure prepare plate purifying (EtOAc is as eluent) after MeOH after HPLC measure enantioselectivity.Concrete reaction formula and response data are as follows:
Embodiment 10 hydrolysis D-Tyrosines
Exemplary steps: in 500ml single port bottle, add II, hydrochloric acid, stirring and dissolving, reflux.TLC plate monitoring reaction, after 3 hours, raw material point disappears, and stops heating.Add ammoniacal liquor to adjust pH to 3.5 hydrolyzed solution, add 1% gac, stir and boil 10min, in 90 ℃ of stirring in water bath insulation 30min, filtered while hot, active carbon layer distilled water wash 3 times, filtrate and washing lotion merge.Be placed in 10 ℃ of following quiet 24h of putting, i.e. crystallization D-Tyrosines.
Embodiment 11D-tyrosine synthesizes Sodium Danshensu
Taking 14.5g(0.08mol) D-Tyrosine is dissolved in 350mL oil of mirbane, add 42.4g aluminum trichloride (anhydrous), at 25 ° of C, be stirred to homogeneous phase, then add 7.2mL(0.1mol) Acetyl Chloride 98Min., at 100 ° of C reaction 6h, reaction solution is poured in 500g ice and 80mL concentrated hydrochloric acid, separatory, and water is extracted with ethyl acetate three times.Then vacuum rotary steam, to 250mL, is put into refrigerator crystallization, filters to obtain 15.5g(R)-β-(3-ethanoyl-4-hydroxyl) phenyl-α-amido propionic salt hydrochlorate.
Taking 7g(0.03mol) β-(3-ethanoyl-4-hydroxyl) phenyl-α-amido propionic salt hydrochlorate is dissolved in 140mL water, under cryosel bath condition, adds Sodium Nitrite.Room temperature reaction 24h; reaction solution is extracted with ethyl acetate; vacuum rotary steam obtains crude product; by normal hexane and re-crystallizing in ethyl acetate (volume ratio 1:5); then add methylene dichloride to stir; separate out and obtain jonquilleous pulverous solid 4.5g, be i.e. (R)-β-(3-ethanoyl-4-hydroxyl) phenyl-alpha-hydroxypropionic acid.
Taking 4g(0.018mol) (R)-β-(3-ethanoyl-4-hydroxyl) phenyl-alpha-hydroxypropionic acid is dissolved in 5mol/LNaOH solution, in cryosel is bathed, adds 30%H
2o
2, be warming up to 40 ° of C, reaction half hour.Acidifying, ethyl acetate extraction, vacuum rotary steam obtains crude product, and hexanaphthene and propyl acetate (volume ratio 1:8) recrystallization obtains Salvianic acidA 2.0g.
Above-mentioned Salvianic acidA is dissolved in 5mL methyl alcohol, adds the methanol solution of 2mol/LNaOH, pH=6.7, cryopreservation crystallization.Filter to obtain white crystalline solid Sodium Danshensu 2.2g.
1HNMR(400MHz,CD
3OD):δ6.74(d,J=1.6Hz,1H),6.67-6.57(m,2H),4.04(dd,J=8.4,3.6Hz,3H),3.00-2.93(m,1H),2.67-2.58(s,1H).
Above specific embodiments of the invention are described.It will be appreciated that, the present invention is not limited to above-mentioned specific implementations, and those skilled in the art can make various distortion or modification within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (9)
1. a method of asymmetric synthesis for D-Tyrosine, is characterized in that step is:
(1) by p-Hydroxybenzaldehyde, be the synthetic 2-methyl-4-(4-acetoxyl group benzal base of raw material) oxazolone I, via an one-step hydrolysis or alcoholysis, obtain dehydroamino acid or ester IIa-IIf; Reaction formula is as follows:
(2) under biphosphine ligand-Rhodium Complexes Catalyzed, be there is to asymmetric hydrogenation in dehydroamino acid or ester IIa-IIf, then through simple hydrolysis, obtain D-Tyrosine; Reaction formula is as follows:
Wherein, R
1for hydrogen or ethanoyl, R
2for hydrogen, methyl or ethyl.
2. the method for asymmetric synthesis of D-Tyrosine according to claim 1, it is characterized in that, described step (1), be specially: after p-Hydroxybenzaldehyde, acetyl glycine, anhydrous sodium acetate and diacetyl oxide are mixed under 80 ° of C stirring reaction 4 hours, then cooling, filter 2-methyl-4-(4-acetoxyl group benzal base of obtaining) the direct one-step hydrolysis of oxazolone I or alcoholysis through filtering and recrystallization obtains dehydroamino acid or ester IIa-IIf.
3. the synthetic method of D-Tyrosine according to claim 1 and 2, it is characterized in that, the reagent that the alcoholysis of step (1) described dehydroamino acid ester IIc and IIe is used is methyl alcohol or ethanol, and temperature of reaction is 20 ° of C～reflux temperatures, and the reaction times is 1～24 hour.
4. the synthetic method of D-Tyrosine according to claim 1, it is characterized in that, there is asymmetric hydrogenation by dehydroamino acid or ester IIa-IIf in what step (2) was described, be in solvent, under hydrogen condition, under room temperature, asymmetric hydrogenation occur under biphosphine ligand-Rhodium Complexes Catalyzed.
5. according to the synthetic method of the D-Tyrosine described in claim 1 or 4, it is characterized in that, the described solvent of step (2) is toluene, methylene dichloride, trichloromethane, tetrahydrofuran (THF), acetone, ethyl acetate and water.
6. according to the synthetic method of the D-Tyrosine described in claim 1 or 4, it is characterized in that, the described hydrogen condition of step (2) is 3atm～20atm pressure.
7. according to the synthetic method of the D-Tyrosine described in claim 1 or 4, it is characterized in that, the described reaction times of step (2) is 0.3～48 hour.
8. according to the synthetic method of the D-Tyrosine described in claim 1 or 4, it is characterized in that, the amount ranges of the described biphosphine ligand-rhodium complex catalyst of step (2) is 1/200～1/10000 of dehydroamino acid or ester IIa-IIf mole dosage.
9. according to the synthetic method of the D-Tyrosine described in claim 1 or 4, it is characterized in that, the described biphosphine ligand-rhodium complex structure of step (2) is as follows:
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| CN104016872A (en) * | 2014-05-28 | 2014-09-03 | 浙江工业大学 | Synthetic method for chiral alpha-unnatural amino acid |
| CN104892447A (en) * | 2015-06-26 | 2015-09-09 | 周治国 | Method for preparing high-purity alpha-dehydroamino acid compounds |
| CN105085264A (en) * | 2014-05-05 | 2015-11-25 | 上海交通大学 | Asymmetric synthesis method for tanshinol ester derivative |
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| CN102352392A (en) * | 2011-09-29 | 2012-02-15 | 重庆邮电大学 | Chemical-enzyme method for preparing D-tyrosine |
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| CN102352392A (en) * | 2011-09-29 | 2012-02-15 | 重庆邮电大学 | Chemical-enzyme method for preparing D-tyrosine |
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| RONGWEI GUO等: "Rhodium-catalyzed asymmetric hydrogenation with aminophosphine ligands derived from 1,1 -binaphthyl-2,2’-diamine", 《TETRAHEDRON LETTERS》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085264A (en) * | 2014-05-05 | 2015-11-25 | 上海交通大学 | Asymmetric synthesis method for tanshinol ester derivative |
| CN104016872A (en) * | 2014-05-28 | 2014-09-03 | 浙江工业大学 | Synthetic method for chiral alpha-unnatural amino acid |
| CN104016872B (en) * | 2014-05-28 | 2016-07-06 | 浙江工业大学 | A kind of synthetic method of chiral alpha-non-natural amino acid |
| CN104892447A (en) * | 2015-06-26 | 2015-09-09 | 周治国 | Method for preparing high-purity alpha-dehydroamino acid compounds |
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