CN1876628B - Method for preparing levocysteine and dextral cysteine using chemical resolution method - Google Patents
Method for preparing levocysteine and dextral cysteine using chemical resolution method Download PDFInfo
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- CN1876628B CN1876628B CN2006100820186A CN200610082018A CN1876628B CN 1876628 B CN1876628 B CN 1876628B CN 2006100820186 A CN2006100820186 A CN 2006100820186A CN 200610082018 A CN200610082018 A CN 200610082018A CN 1876628 B CN1876628 B CN 1876628B
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Abstract
The invention relates the method of preparing L-Cys and D-Cys with chemical resolution method, comprising the following steps: using DL-Cys as raw material, using inorganic acid as dissolvent, using D-DBTA and L-DBTA as resolution agent, dissolving the DL-Cys and resolution agent at the rate of 1:0.5-1.2 in the dilute inorganic acid solution, stirring for 0.5-2.0 hours at the temperature 60-100Deg.C, cooling, filtering, neutralizing crystallization salt and mother liquid with alkali, and separately getting L-Cys and D-Cys. The invention has the advantages of simple technology. The resolution agent can be recovered.
Description
Technical field
The present invention is a kind of technology of preparing of chiral organic compound, the preparation method of especially a kind of left-handed halfcystine and D-Cysteine.
Background technology
Halfcystine has another name called 2-amino-3 thiohydracrylic acid.Halfcystine is a kind of neutral amino acids that contains sulfydryl, and promptly it is amino identical with carboxyl quantity.Have 1 chiral carbon atom in its molecular structure, i.e. 1 chiral centre, thereby have the existence of a pair of enantiomorph, promptly left-handed halfcystine (L-Cys) and D-Cysteine (D-Cys), its structure as shown in the formula:
Left-handed halfcystine (L-Cys) D-Cysteine (D-Cys)
Left-handed halfcystine and D-Cysteine all are important compounds, can be widely used in industries such as medicine, food, makeup, feed.Left-handed halfcystine mainly extracts from the hydrolysate of nature material, extracts in the hair like people's hair and animal, at present should technology be widely used in the production of left-handed halfcystine.
D-Cysteine is a kind of alpha-non-natural amino acid, and in recent years along with the reach of science, its effect in medicine is synthetic is more and more outstanding, especially receives much attention as antibiotics synthetic midbody.D-Cysteine can not extract from occurring in nature as a kind of alpha-non-natural amino acid, can only obtain through synthetic perhaps fractionation of chirality.Chirality is synthetic to be one of method for preparing chipal compounds, has only the minority chipal compounds can adopt chirality synthetic method to produce at present, and the method for preparing the employing fractionation of most of chipal compounds.In D-Cysteine synthetic, have only through the synthetic racemize halfcystine of the left-handed halfcystine of racemization, perhaps obtain the racemize halfcystine, and then get D-Cysteine through splitting enantiomorph through chemical synthesis process.
At present, the method for splitting of racemize halfcystine comprises that induced crystallization method, enzyme split and chemical resolution method.
The method (Japanese Patent, the patent No. 4613688/1986) that people such as Chozo Inoue have invented a kind of induced crystallization method resolution of racemic halfcystine.At first the racemize halfcystine is changed into its hydrochloride; And be mixed with the saturated or supersaturated aqueous solution of its hydrochloride; With left-handed or D-Cysteine hydrochloride as crystal seed; Then the temperature of saturated solution slowly is reduced to 29-31 ℃ from 35-40 ℃, can the optical activity enantiomorph of correspondence be crystallized out from the saturated solution of mixture.The product that this method obtains is left-handed or the D-Cysteine hydrochloride monohydrate, and optical siomerism body disposable resolution yield is about 10%, and the optical purity of target product is at 75%-90%.This method product yield is low, and purity is not high, can not satisfy the requirement of pharmaceutical industry, therefore in the production of left-handed and D-Cysteine, does not have actual application value.
Method as for the enzyme fractionation; Japanese Patent (patent No. 29293/1976) has been introduced racemize halfcystine acidylate has been prepared into N-acylations racemize halfcystine; Utilize the acyl group saccharase to act on the racemize halfcystine of N-acylations again, thereby obtain optically active left-handed or D-Cysteine.This method not only need be used the enzyme of biological tissue, and requires selected enzyme to have very high specificity, stability and biological activity; Also need carry out polystep reactions such as acylations and deacylated tRNA base in the building-up process.This shows that this method reactions step is more, comprehensive yield is not high, in the production of left-handed and D-Cysteine, does not have too big commercial value yet.
Chemical resolution method is to utilize chemical resolution reagent and racemic halfcystine with chirality directly to act on, and utilizes the dissolubility difference of diastereomer in selected solvent that is generated to carry out isolating method.It is resolving agent that people such as Hiroyuki Nohira (patent No. 4621151/1986) in the patent of invention in 1986 propose with optically active racemic melic acid, the racemize halfcystine is split obtain optically active left-handed halfcystine.The halfcystine raw material that this invention is adopted can be racemic halfcystine, also can be the salt of racemic halfcystine, example hydrochloric acid salt or vitriol.Thereby the yield that this invention employing L-racemic melic acid resolution of racemic halfcystine obtains left-handed halfcystine is about 20%, and product yield is lower, and does not relate to the synthetic of D-Cysteine.
Summary of the invention
The purpose of this invention is to provide a kind of chemical new method for splitting for preparing left-handed halfcystine and D-Cysteine, it is high to use this method to split DL-cysteine products obtained therefrom yield, and optical purity is high.
Chemical resolution method of the present invention prepares the method for left-handed halfcystine and D-Cysteine, and (DL-Cys) is raw material with the racemize halfcystine, is solvent with the mineral acid; With dextrorotation dibenzoyl tartaric acid (D-DBTA) and levorotation benzhydryl formyl tartrate (L-DBTA) is resolving agent; With racemize halfcystine and resolving agent in 1: the ratio of 0.5-1.2 is dissolved in rare inorganic acid solution, stirs 0.5-2.0 hour down at 60-100 ℃, is cooled to room temperature more gradually; Leach crystal salt; Crystal salt and mother liquor neutralize with alkali in water, alcohol equal solvent respectively, promptly obtain left-handed halfcystine (L-Cys) and D-Cysteine (D-Cys) respectively, and operational path is:
H wherein
+Be hydrogen ion.
The mineral acid solvent is Hydrogen chloride or dilute sulfuric acid aqueous solution, the amount of solvent be 5-20 doubly to halfcystine, the concentration of acid is 0.1-1.0mol/L.
Temperature of reaction is 60-100 ℃, and the reaction times is 0.5-2.0 hour.
In the ammonification with needed alkali be ammonia, ammoniacal liquor, triethammonia and other low-grade aliphatic amine, volatile salt, yellow soda ash, salt of wormwood, sodium hydroxide etc.
Be lower aliphatic alcohols and acetone such as water and methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol with used solvent in the ammonification.
Because halfcystine is the neutral amino acids that contains sulfydryl; Be that raw material has synthesized acid stronger have certain inflexible resolving agent D-DBTA and L-DBTA with tartrate; They form diastereoisomeric salt with DL-Cys respectively; Because the difference in solubility of diastereoisomeric salt in acidic aqueous solution is bigger, so can successfully DL-Cys be split into D-Cys and L-Cys.
When splitting agent with D-DBTA, the solubleness of salt D-CysD-DBTA in solution is less, after the cooling, from solution, separates out, and its diastereoisomeric salt is then stayed in the solution.The D-Cys.D-DBTA that filtration obtains can obtain D-Cys. with the alkali neutralization and split the concentrated back of mother liquor with adjusting PH with base value to 5.5, and the yield that promptly gets L-Cys.D-Cys and L-Cys is all more than 75%, and optical purity is greater than 99%.
With the L-DBTA agent that splits similar situation is arranged, the salt of different is when splitting L-Cys and L-DBTA formation precipitates from solution separates out, and the salt of D-Cys is then stayed in the mother liquor; With the corresponding salt of alkaline purification; Also can obtain title product, yield is greater than more than 75%, and optical purity is greater than 99%.
Racemize halfcystine and chiral organic acid effect generate diastereoisomeric salt, and the different solubility of diastereoisomeric salt in solution can separate them by the difference of solubleness.Among the present invention, after in DL-Cys solution, adding D-DBTA, the salt that D-Cys and D-DBTA generated solubleness in diluted acid is less, from solution, separates out, and the salt solubility that L-Cys generated is more then stayed in the solution.Balance can be separated them through filtering after for some time.Equally, after in DL-Cys solution, adding L-DBTA, the salt that L-Cys and L-DBTA generated solubleness in diluted acid is less, from solution, separates out, and the salt solubility that D-Cys generated is more then stayed in the solution.
Prepare D-Cys or L-Cys is based on simple acid-base neutralisation reaction principle by the diastereoisomeric salt ammonification.
In the present invention, stronger alkali ammoniacal liquor or triethammonia and stronger sour D-CysD-DBTA effect generate more weak sour tartrate ammonium salt and more weak alkali D-Cys.
D-CysD-DBTA+NH
3------→ D-Cys+D-DBTA ammonium salt
The synthesis material of the used resolving agent of the present invention is easy to get, synthesis technique is simple; Splitting the back resolving agent can recycling; Splitting solvent for use is dilute acid solution, and production cost is low, and environmental pollution is little, and the ammonium salt of mineral acid by-product can be used for agriculture prodn; The use of mineral acid is this invention and traditional resolution process different features, and mineral acid had both helped the dissolving of DL-Cys, also reduced the consumption of resolving agent.Under top condition, D-Cys (D-Cysteine) or L-Cys (left-handed halfcystine) resolution yield reaches 90%, and optical purity reaches 100%.
In sum, the invention solves by DL-Cys and prepare in D-Cys and the L-Cys technology problems such as yield is low, cost height.Therefore, above-mentionedly split with DBTA that agent prepares D-Cys by DL-Cys and the L-Cys resolution process can be used for suitability for industrialized production.
Embodiment
1, being raw material with DL-Cys (racemize halfcystine), is solvent with Hydrogen chloride or dilute sulphuric acid, prepares L-Cys (left-handed halfcystine) and D-Cys (D-Cysteine) through chemical method for splitting.
2, resolving agent is dibenzoyl tartaric acid D-DBTA and L-DBTA.
3, resolution solvent is Hydrogen chloride, dilute sulphuric acid or other rare inorganic acid aqueous solution.The amount of solvent be 5-20 doubly to halfcystine, optimum dose be halfcystine 8-16 doubly.The concentration 0.1-1.0mol/L of acid, optimal concentration is 0.2-0.8mol/L.
4, the temperature of resolution reaction is 70-100 ℃, and optimal temperature is 75-95 ℃.
5, diastereoisomeric salt washing solvent for use is ether, acetone, ethanol, water etc.
6, in the ammonification and needed alkali be ammonia, ammoniacal liquor, triethammonia and other low-grade aliphatic amine, amine carbonate, yellow soda ash, salt of wormwood, sodium hydroxide etc.
7, in the ammonification and used solvent be lower aliphatic alcohols and acetone such as water and methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol.
Operational path:
Embodiment 1:
DL-Cys2.43g (0.02mol) is dissolved in the 20ml Hydrogen chloride, under agitation is heated to 80-100 ℃, adds L-DBTA3.58g (0.01mol), under this temperature, reacts half a hour; Kept 1 hour at 60 ℃ then, have deposition to generate gradually, be cooled to about 15 ℃ suction filtration again; Filter cake is dissolved in the triethylamine of 30ml ethanol and 2 times of amounts, stirred 1 hour, and suction filtration, and use washing with alcohol; Dry 1.06g L-Cys, resolution yield 87.5%, [α] of getting
D 20=+8.7 ° (C=8,1N HCl), L-Cys optical purity of products 99.3%.Splitting and using alkali adjusting adjust pH after mother liquor concentrates is 5.5, stirs, and the adularescent solid is separated out, and suction filtration is also used washing with alcohol, dry 0.96gD-Cys, yield 79.2%, [α] of getting
D 22=-8.6 ° (C=8,1N HCl), D-Cys optical purity of products 99.2%.
Embodiment 2:
DL-Cys2.43g (0.02mol) is dissolved in the 20ml Hydrogen chloride, stirs, and is heated to 90-100 ℃, adds 3.58g D-DBTA; Reaction is 50 minutes under this temperature, and 60 ℃ kept 1 hour then, has deposition to generate gradually, is cooled to about 15 ℃ again; Suction filtration also uses water washing, filter cake to be dissolved in the triethylamine of 30ml ethanol and 2 times of amounts, stirs suction filtration 1 hour; And use washing with alcohol, dry 1.06g D-Cys, resolution yield 87.5%, [α]
D 22=-8.8 ° (C=8,1N HCl), D-Cys optical purity of products 99.5%.。Splitting and using alkali adjusting pH value after mother liquor concentrates is 5.5, stirs, and the adularescent solid is separated out, and suction filtration is also used washing with alcohol, dry 0.94gL-Cys, yield 77.4%, [α] of getting
D 22=+8.7 ° (C=8,1N HCl), D-Cys optical purity of products 99.3%.
Embodiment 3:
DL-Cys2.43g (0.02mol) is dissolved in the 20ml Hydrogen chloride, under agitation is heated to 80-100 ℃, adds L-DBTA7.16g (0.02mol), under this temperature, reacts half a hour; Kept 1 hour at 60 ℃ then, have deposition to generate gradually, be cooled to about 15 ℃ suction filtration again; Filter cake is dissolved in the triethylamine of 30ml ethanol and 2 times of amounts, stirred 1 hour, and suction filtration, and use washing with alcohol; Dry 1.08g L-Cys, resolution yield 88.9%, [α] of getting
D 20=+8.8 ° (C=8,1N HCl), L-Cys optical purity of products 99.5%.Splitting and using alkali adjusting adjust pH after mother liquor concentrates is 5.5, stirs, and the adularescent solid is separated out, and suction filtration is also used washing with alcohol, dry 0.90gD-Cys, yield 74.1%, [α] of getting
D 22-8.6 ° (C=8,1N HCl), D-Cys optical purity of products 99.2%.
Embodiment 4:
DL-Cys2.43g (0.02mol) is dissolved in the 20ml Hydrogen chloride, under agitation is heated to 80-100 ℃, adds L-DBTA8.59g (0.024mol), under this temperature, reacts half a hour; Kept 1 hour at 60 ℃ then, have deposition to generate gradually, be cooled to about 15 ℃ suction filtration again; Filter cake is dissolved in the triethylamine of 30ml ethanol and 2 times of amounts, stirred 1 hour, and suction filtration, and use washing with alcohol; Dry 0.98g L-Cys, resolution yield 80.7%, [α] of getting
D 20=+8.0 ° (C=8,1N HCl), L-Cys optical purity of products 98.5%.Splitting and using alkali adjusting adjust pH after mother liquor concentrates is 5.5, stirs, and the adularescent solid is separated out, and suction filtration is also used washing with alcohol, dry 0.94gD-Cys, yield 77.4%, [α] of getting
D 22=-7.6 ° (C=8,1N HCl), D-Cys optical purity of products 98.0%.
Claims (4)
1. a chemical resolution method prepares the method for left-handed halfcystine and D-Cysteine; It is characterized in that: (DL-Cys) is raw material with DL-cysteine, is solvent with the mineral acid, is resolving agent with dextrorotation dibenzoyl tartaric acid (D-DBTA) or levorotation benzhydryl formyl tartrate (L-DBTA); With DL-cysteine (DL-Cys) and resolving agent by 1: the molar ratio of 0.5-1.2 is dissolved in the inorganic acid solution that concentration is 0.1-1.0mol/L; Stirred 0.5-2.0 hour down at 60-100 ℃, be cooled to room temperature more gradually, leach crystal salt; Crystal salt is made solvent with alcohol; Mother liquor uses water as solvent, respectively with the alkali neutralization, promptly obtains left-handed halfcystine (L-Cys) and D-Cysteine (D-Cys) respectively again.
2. chemical resolution method according to claim 1 prepares the method for left-handed halfcystine and D-Cysteine; It is characterized in that: the mineral acid solvent is Hydrogen chloride or dilute sulfuric acid aqueous solution; The amount of solvent be 5-20 doubly to halfcystine, the concentration of acid is 0.2-0.8mol/L.
3. chemical resolution method according to claim 1 prepares the method for left-handed halfcystine and D-Cysteine, it is characterized in that: the temperature of reaction of described halfcystine and dibenzoyl tartaric acid is 75-95 ℃.
4. chemical resolution method according to claim 1 prepares the method for left-handed halfcystine and D-Cysteine, it is characterized in that: in the alkali with needed alkali be ammonia, ammoniacal liquor, triethylamine, volatile salt, yellow soda ash, salt of wormwood, sodium hydroxide.
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| WO2013057736A2 (en) * | 2011-06-07 | 2013-04-25 | Emcure Pharmaceuticals Limited | Preparation of eptifibatide peptide |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0065867A1 (en) * | 1981-05-21 | 1982-12-01 | Hiroyuki Nohira | Optical resolution of DL-cysteine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0065867A1 (en) * | 1981-05-21 | 1982-12-01 | Hiroyuki Nohira | Optical resolution of DL-cysteine |
Non-Patent Citations (2)
| Title |
|---|
| 张涛等.D-(-)-扁桃酸拆分DL-半胱氨酸盐酸盐的研究.精细与专用化学品14 6.2006,14(6),26-28. |
| 张涛等.D-(-)-扁桃酸拆分DL-半胱氨酸盐酸盐的研究.精细与专用化学品14 6.2006,14(6),26-28. * |
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