CN105085246A - Method for preparing R-chloromandelic acid - Google Patents
Method for preparing R-chloromandelic acid Download PDFInfo
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- CN105085246A CN105085246A CN201510554274.XA CN201510554274A CN105085246A CN 105085246 A CN105085246 A CN 105085246A CN 201510554274 A CN201510554274 A CN 201510554274A CN 105085246 A CN105085246 A CN 105085246A
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- chloromelic acid
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- naphthalene ethylamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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Abstract
The invention discloses a method for preparing R-chloromandelic acid through resolution with R-(+)-1-(1-naphthyl)ethylamine used as a chiral resolution agent. Chloromandelic acid reacts with the resolution agent R-(+)-1-(1-naphthyl)ethylamine in a corresponding solvent to produce R-(+)-1-(1-naphthyl)ethylamine salt of the chloromandelic acid, the R-(+)-1-(1-naphthyl)ethylamine salt of the R-chloromandelic acid can be obtained through crystal separation, and the R-chloromandelic acid can be obtained through acidizing; the resolution agent R-(+)-1-(1-naphthyl)ethylamine can be recovered through reaction residual solution alkali treatment. The method has the characteristics that conditions are mild, the operation is simple, the product yield is high, and the optical purity is high, besides, the resolution agent can be recycled and is extremely suitable for industrial production of the R-chloromandelic acid.
Description
Technical field
The present invention relates to a kind of chemical method to split and prepare the method for chipal compounds, particularly relate to a kind of with R-1-naphthalene ethylamine for resolving agent splits the method preparing R-o-Chloromelic acid.
Background technology
O-Chloromelic acid, has R type and S type two kinds of enantiomorph configurations, is all widely used in multiple fields such as medicine production, asymmetric synthesis, optical resolution.Wherein R type o-Chloromelic acid is conjunction is new type of safe anti-important intermediate of assembling medicine clopidogrel for platelet efficiently.Clopidogrel is widely used in the cardiovascular and cerebrovascular diseases such as prevention myocardial infarction, apoplexy, arteriosclerosis clinically.Compared with other several Application comparison widely platelet suppressant drug acetylsalicylic acid, ticlopidine etc., its effect is stronger, tolerance is higher, side effect is less.It is the antithrombotic reagent that occupation rate is the highest in the market.
As the intermediate that clopidogrel is important, the preparation method of R-o-Chloromelic acid mainly contains two large classes: (1) asymmetric method synthesis R-o-Chloromelic acid.And asymmetric method synthesis R-o-Chloromelic acid can be subdivided into chiral alcohol cyanogen enzyme-chemically method (AppliedMicrobiologyandBiotechnology, 2007,76,309-320; JournalofBiotechnology, 2007,129,30-38), nitrilase method (JP2009232693), method of asymmetrically reducing (EP1382674), chemical synthesis (OrganicLetters, 2011,13,1254-1257) etc.But all there is certain defect in the method for this several asymmetric synthesis R-o-Chloromelic acid of report.Chiral alcohol cyanogen enzyme-chemically method realize process in use a large amount of deadly poisonous compound prussic acid, produce security and concerning in the pollution of environment, there is certain defect.Utilize nitrilase method to produce the nitrilase limited source that will use in R-o-Chloromelic acid process, thus limit its industrial applications.The NADH utilizing alpha-ketoacid reductase enzyme will use in asymmetric reduction 2-chloro-acetophenone acid preparation R-o-Chloromelic acid process under NADH coenzyme exists is expensive, significantly increases production cost.The catalyzer used in chemical method synthesis R-o-Chloromelic acid process, there is expensive problem equally, simultaneous reactions condition is also very harsh, does not therefore also have industrialized meaning.(2) R-o-Chloromelic acid is prepared by splitting racemization o-Chloromelic acid.The method for splitting of the o-Chloromelic acid of current report has many kinds, wherein electrochemical process, Extraction resolution method, Chromatographic resolution method, electrophoresis Split Method, and enzyme Split Method, owing to splitting scale and splitting the reasons such as efficiency, is difficult to realize suitability for industrialized production.Therefore, produce R-o-Chloromelic acid at present and still rely on chemical resolution method, chemical resolution method is technical maturity comparatively speaking, is easy to realize industrialization.How better to realize splitting effect, the selection of resolving agent is crucial.
Summary of the invention
The present invention adopts R-1-naphthalene ethylamine to be resolving agent, can successfully realize splitting preparation R-o-Chloromelic acid.Invention operation is as follows:
The present invention take o-Chloromelic acid as raw material, R-1-naphthalene ethylamine is resolving agent, reacts in corresponding solvent, obtains the R-1-naphthalene ethylamine salt of o-Chloromelic acid, can be obtained the R-1-naphthalene ethylamine salt of R-o-Chloromelic acid by Crystallization Separation, salt dissociates through acid can obtain R-o-Chloromelic acid; Reaction mother liquor, through concentration and recovery, adds alkali and dissociates, recyclable resolving agent R-1-naphthalene ethylamine.
Be R-1-naphthalene ethylamine according to resolving agent used in described the present invention, in system, added in molar amounts is 1.0 ~ 2.0 times of o-Chloromelic acid.
Realize particular by following operation according to the fractionation preparation of described R-o-Chloromelic acid: take o-Chloromelic acid as raw material, R-1-naphthalene ethylamine is resolving agent, react in the solvent that methyl alcohol or ethanol and water are prepared with 1:1 ~ 3 volume ratio, obtain the R-1-naphthalene ethylamine salt of o-Chloromelic acid, the total mass number of the required solvent of reaction is 10-30 times of R-o-Chloromelic acid, through cooling after reaction terminates, crystallization, be separated the R-1-naphthalene ethylamine salt obtaining R-o-Chloromelic acid, gained salt utilizes hydrochloric acid or sulfuric acid to dissociate, again through the extraction of organic solvent dichloromethane or ethyl acetate, dry, concentrate to obtain R-o-Chloromelic acid.
Can be reclaimed by following operation according to described resolving agent R-1-naphthalene ethylamine: after the methyl alcohol in reaction mother liquor or ethanol are steamed, mother liquor after concentrated adds a certain amount of alkali, regulate pH value to 11 ~ 13, then through the extraction of organic solvent dichloromethane or ethyl acetate, drying, concentratedly to obtain R-1-naphthalene ethylamine.
Use the present invention to prepare R-o-Chloromelic acid, R-o-Chloromelic acid can reach more than 40% relative to the yield of racemization o-Chloromelic acid, and the ee value that can realize product is greater than 99%.
Meanwhile, the present invention also possesses simple to operate, technical maturity, mild condition, and split efficiency high, good product purity, resolving agent is easy to the features such as recovery.Be suitable for very much suitability for industrialized production R-o-Chloromelic acid.
Specific implementation method:
Embodiment 1
(1) fractionation of o-Chloromelic acid
In 50L reactor, add 15L methyl alcohol and 15L water, be mixed with the required solvent of reaction.In still, add 1.87KG racemization o-Chloromelic acid again, open stirring, heat up.Under reflux conditions, in system, drip R-1-naphthalene ethylamine 1.80KG.Dropwise, reflux conditions is down to room temperature after reacting 1.0 hours, will separate out white solid and filter, and obtain the R-1-naphthalene ethylamine salt 1.61KG of crude product R-o-Chloromelic acid.The R-1-naphthalene ethylamine salt of gained 1.61KGR-o-Chloromelic acid is joined in the methanol solution with 15L, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, after being down to room temperature, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 1.42KG of the R-o-Chloromelic acid after must refining.
(2) acidolysis salt obtains R-o-Chloromelic acid
The R-1-naphthalene ethylamine salt 1.42KG of upper step gained R-o-Chloromelic acid is dissolved in 5KG water, drip hydrochloric acid and reconcile pH value to 4,2.0L methylene dichloride is added in system, extract, after separatory, upper aqueous layer uses 1.0L washed with dichloromethane twice again, carries out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrates to obtain R-o-Chloromelic acid 0.79KG, yield is 42.2%, and the ee value detecting R-o-Chloromelic acid is 99.6%.
(3) R-1-naphthalene ethylamine is reclaimed
The mother liquor splitting o-Chloromelic acid is concentrated, steams except methyl alcohol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain R-o-Chloromelic acid is concentrated in together, use 40%NaOH solution adjustment pH value to 12.After regulating pH value, in system, add 3.0L methylene dichloride, extract, after separatory, upper aqueous layer uses 1.0L washed with dichloromethane twice again, and carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain R-1-naphthalene ethylamine 1.65KG, the rate of recovery is 91.7%.
Embodiment 2
(1) fractionation of o-Chloromelic acid
In 50L reactor, add 10L ethanol and 20L water, be mixed with the required solvent of reaction.In still, add 1.87KG racemization o-Chloromelic acid again, open stirring, heat up.Under reflux conditions, in system, drip R-1-naphthalene ethylamine 1.80KG.Dropwise, reflux conditions is down to room temperature after reacting 1 hour, will separate out white solid and filter, and obtain the R-1-naphthalene ethylamine salt 1.56KG of crude product R-o-Chloromelic acid.The R-1-naphthalene ethylamine salt of gained 1.56KGR-o-Chloromelic acid is joined in the ethanolic soln with 15L, heats up and dissolve, after waiting solid to dissolve completely, lower the temperature, after being down to room temperature, crystalline solid is filtered, the R-1-naphthalene ethylamine salt 1.40KG of the R-o-Chloromelic acid after must refining.
(2) acidolysis salt obtains R-o-Chloromelic acid
The R-1-naphthalene ethylamine salt 1.40KG of upper step gained R-o-Chloromelic acid is dissolved in 5KG water, drip hydrochloric acid and reconcile pH value to 4,2.0L ethyl acetate is added in system, extract, after separatory, lower aqueous layer washes twice by 1.0L ethyl acetate again, carries out drying by extracting the ethyl acetate anhydrous sodium sulphate obtained several times, concentrates to obtain R-o-Chloromelic acid 0.75KG, yield is 40.1%, and the ee value detecting R-o-Chloromelic acid is 99.7%.
(3) R-1-naphthalene ethylamine is reclaimed
The mother liquor splitting o-Chloromelic acid is concentrated, steams except ethanol.After cooling, the water layer that the mother liquor after concentrated and acidolysis obtain R-o-Chloromelic acid is concentrated in together, use 40%NaOH solution adjustment pH value to 12.After regulating pH value, in system, add 3.0L methylene dichloride, extract, after separatory, upper aqueous layer uses 1.0L washed with dichloromethane twice again, and carry out drying by extracting the methylene dichloride anhydrous sodium sulphate obtained several times, concentrate to obtain R-1-naphthalene ethylamine 1.70KG, the rate of recovery is 94.4%.
Claims (6)
1. the preparation method of a R-o-Chloromelic acid is characterized in that: the present invention take o-Chloromelic acid as raw material, R-1-naphthalene ethylamine is resolving agent, react in corresponding solvent, obtain the R-1-naphthalene ethylamine salt of o-Chloromelic acid, utilize two kinds of configurations different solubility in a solvent, cooling, crystallization, suction filtration obtain the R-1-naphthalene ethylamine salt of R-o-Chloromelic acid, and salt in alcoholic solvent after recrystallization, acidifying, extraction, drying, concentratedly to obtain R-o-Chloromelic acid; Reaction and recrystallization mother liquor carry out dealcoholation treatment, then merge with acidifying remaining aqueous layer, add that alkali is free, extraction, drying, concentration and recovery resolving agent R-1-naphthalene ethylamine.
2. the preparation method of a kind of R-o-Chloromelic acid according to claim 1, it is characterized in that: resolving agent used in the present invention is R-1-naphthalene ethylamine, in system, added in molar amounts is 1.0 ~ 2.0 times of o-Chloromelic acid.
3. the preparation method of a kind of R-o-Chloromelic acid according to claim 1, is characterized in that: split and recrystallization reaction solvent for use is methyl alcohol or ethanol.
4. the preparation method of a kind of R-o-Chloromelic acid according to claim 1, is characterized in that: acidified process acid used is hydrochloric acid or sulfuric acid.
5. the preparation method of a kind of R-o-Chloromelic acid according to claim 1, is characterized in that: it is methylene dichloride or ethyl acetate that step 2 and step 3 extract organic solvent used.
6. the preparation method of a kind of R-o-Chloromelic acid according to claim 1, is characterized in that: the alkali that alkalization reclaims R-1-naphthalene ethylamine used is sodium hydroxide solution or ammonia soln.
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| CN201510554274.XA CN105085246A (en) | 2015-09-02 | 2015-09-02 | Method for preparing R-chloromandelic acid |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61227549A (en) * | 1985-04-01 | 1986-10-09 | Hiroyuki Nohira | Optical resolution of (+-)-2-chlorobutanoic acid |
| CN102336653A (en) * | 2011-11-08 | 2012-02-01 | 广州辉宏生物医药科技有限公司 | Preparation method of optically pure chiral 2-chloromandelic acid |
| CN102548965A (en) * | 2009-09-25 | 2012-07-04 | 安斯泰来制药株式会社 | Substituted amide compound |
| CN103804179A (en) * | 2014-02-27 | 2014-05-21 | 西南化工研究设计院有限公司 | Preparation method of novel chiral resolving agent and (R)-chloromandelic acid |
-
2015
- 2015-09-02 CN CN201510554274.XA patent/CN105085246A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61227549A (en) * | 1985-04-01 | 1986-10-09 | Hiroyuki Nohira | Optical resolution of (+-)-2-chlorobutanoic acid |
| CN102548965A (en) * | 2009-09-25 | 2012-07-04 | 安斯泰来制药株式会社 | Substituted amide compound |
| CN102336653A (en) * | 2011-11-08 | 2012-02-01 | 广州辉宏生物医药科技有限公司 | Preparation method of optically pure chiral 2-chloromandelic acid |
| CN103804179A (en) * | 2014-02-27 | 2014-05-21 | 西南化工研究设计院有限公司 | Preparation method of novel chiral resolving agent and (R)-chloromandelic acid |
Non-Patent Citations (1)
| Title |
|---|
| 胡昱等: "邻氯扁桃酸的绿色手性拆分研究", 《化学世界》 * |
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Application publication date: 20151125 |