CN103804179A - Preparation method of novel chiral resolving agent and (R)-chloromandelic acid - Google Patents
Preparation method of novel chiral resolving agent and (R)-chloromandelic acid Download PDFInfo
- Publication number
- CN103804179A CN103804179A CN201410068327.2A CN201410068327A CN103804179A CN 103804179 A CN103804179 A CN 103804179A CN 201410068327 A CN201410068327 A CN 201410068327A CN 103804179 A CN103804179 A CN 103804179A
- Authority
- CN
- China
- Prior art keywords
- acid
- resolving agent
- chloromandelic acid
- chloromandelic
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a novel chiral resolving agent S-(1) which is used for chemically resolving (RS)-chloromandelic acid to prepare the (R)-chloromandelic acid. The invention further discloses a preparation method of the (R)-chloromandelic acid. The preparation method comprises the following steps: making the resolving agent S-(1) react with the (RS)-chloromandelic acid to obtain a (R)-chloromandelic acid and resolving agent diastereomer salt, decomposing the (R)-chloromandelic acid and resolving agent diastereomer salt to obtain the (R)-chloromandelic acid, and optionally recovering the S-(1). The preparation method has the beneficial effects that (1), the chiral resolving agent (S)-1 is high in resolving efficiency, stable in chemical property, and easy to separate and recycle, and the recycling purity is more than 99 percent; (2), an industrial line of the preparation method is developed, the process condition is mild, and industrialized production is facilitated; (3), the content of the prepared (R)-chloromandelic acid is more than 99 percent, and the ee value is more than 99 percent; (4), the used organic solvent can be recycled, and no special and toxic reagents are used.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of new chiral resolving agent and use this chiral resolving agent to carry out a kind of preparation method of medicine intermediate, especially a kind of chiral resolving agent of aminoalcohol derivative and this chiral resolving agent of use are prepared the method for clopidogrel intermediate (R)-2-chloromandelic acid.
Background technology
Clopidogrel is a kind of anticoagulant, is widely used in clinically preventing the cardiovascular and cerebrovascular diseases such as myocardial infarction, apoplexy, arteriosclerosis, compared with other platelet suppressant drug, has that effect is strong, better tolerance and an advantage such as side effect is little.Within 1998, in the U.S. and Britain's listing, in Discussion on Chinese Listed, be the antithrombotic reagent that share of market is the highest at present August calendar year 2001.
Research shows, it is active that the platelet aggregation that (S)-clopidogrel demonstrates suppresses, much larger than (R)-clopidogrel, so the effective constituent of clopidogrel is (S)-clopidogrel, only have the clopidogrel of synthetic single (S) configuration to sell as medicine.Adopting chirality (R)-2-chloromandelic acid is the (S)-clopidogrel that production that raw material carries out clopidogrel can obtain single configuration, without clopidogrel being split again.Therefore,, along with the expansion in clopidogrel market, the market requirement of (R)-2-chloromandelic acid also can expanding day.
(R)-2-chloromandelic acid belongs to optical active substance, and at present, its synthetic method mainly contains two large classes:
(1), the direct optically pure isomer of asymmetric synthesis.Dissymmetric synthesis is without a kind of method that splits direct synthesis of chiral product, mainly comprises: chiral alcohol cyanogen enzyme-chemically method, nitrilase method, method of asymmetrically reducing, chemical synthesis etc.(the Applied Microbiology and Biotechnology such as Purkarthofer, 2007,76,309-320) and (the Journal of Biotechnology such as Gaisberger, 2007,129,30-38) utilize chiral alcohol cyanogen enzyme-chemically method to successfully synthesize (R)-2-chloromandelic acid, but this method need to be used the prussic acid of a large amount of severe toxicity, at the aspect such as security and the pollution concerning environment producing, also there is certain defect.Japanese Patent JP 2009232693 utilizes nitrilase to carry out asymmetric hydrolysis to racemization o-Chloromelic acid can make (R)-2-chloromandelic acid, but the source of nitrilase is limited, is unfavorable for the actual industrialization application of the method.European patent EP 1382674 utilizes alpha-ketoacid reductase enzyme can the acid of asymmetric reduction 2-chloro-acetophenone obtain (R)-2-chloromandelic acid under NADH coenzyme exists, but NADH coenzyme is expensive, has greatly increased production cost.(the Organic Letters such as Ohkuma, 2011,13,1254-1257) take prussic acid and o-chlorobenzaldehyde as raw material, utilize chirality ruthenium ligand catalysis preparation (R)-adjacent chlorocyanohydrin intermediate, then obtain (R)-2-chloromandelic acid by hydrolysis (R)-adjacent chlorocyanohydrin, productive rate reaches 98%, and chirality ee value reaches 91%, but the catalyzer that the method is used is expensive, severe reaction conditions, does not therefore have industrialized meaning.
(2), first prepare (RS)-o-Chloromelic acid, then the raceme of preparation is carried out to optical isomer fractionation.The method of synthesising racemation (RS)-o-Chloromelic acid mainly contains at present: the adjacent chlorobenzene acetonitrile hydrolysis method of beta-hydroxy, β, β-dichloro o-chloroacetophenone hydrolysis method and o-chlorobenzaldehyde phase transfer catalysis process.(RS) method for splitting of-o-Chloromelic acid has many kinds, wherein electrochemical process, and extraction Split Method, chromatogram Split Method, electrophoresis Split Method, enzyme Split Method, due to fractionation scale, splits the reasons such as efficiency and is difficult to realize suitability for industrialized production.At present, the acquisition of industrial (R)-2-chloromandelic acid still mainly relies on chemical resolution method, and chemical resolving racemic is a kind of traditional method, and its operational path maturation, is easy to industrialization.Chemical resolution method is the method by chemical reaction, two enantiomorphs in raceme mixture are transformed into diastereomer with chiral reagent, and then separated by physics, the chemical qualitative difference of diastereomer, the diastereomer again separation being obtained decomposes, slough resolving agent, just can obtain a kind of pure enantiomer.At present, the chiral selectors of amygdalic acid compounds mainly contains alkaloid (ephedrine and derivative thereof), amine and derivative thereof, amino acid and derivative thereof etc., the resolution reagents such as its Ephedrine, 2-amino-n-butyl alcohol are applied to fractionation amygdalic acid and have good fractionation effect, and the yield of amygdalic acid can reach more than 80%.Utilizing chemical resolution method to prepare (R)-2-chloromandelic acid is the methods that can realize suitability for industrialized production few in number.
Summary of the invention
The object of this invention is to provide a kind of new chiral resolving agent S-(1), S-(1) chemical structure be general formula I:
General formula I
Wherein, R
1and R
2be respectively the H of ortho position, a position or para-orientation, CH
3, OH, OCH
3, F, Cl, Br, I, or NO
2in one, R
1and R
2for substituted radical independently, can be identical or not identical.
This chiral resolving agent S-(1) preparation conventionally can (comprise R by amino alcohol
1group part) (comprise R with corresponding aromatic aldehyde
2group part) dehydration formation Schiff base intermediate, Schiff base intermediate can be reduced easily and obtain corresponding chiral resolving agent S-(1).
Above-mentioned resolving agent is for the preparation of (R)-2-chloromandelic acid, and specifically, above-mentioned resolving agent splits by (RS)-o-Chloromelic acid (raceme) being carried out to chemistry the preparation that realizes (R)-2-chloromandelic acid.
A kind of preferred S-(1) scheme, the R of general formula I
1and R
2be all H, the reaction scheme that this preferred resolving agent (S)-1 is prepared for (R)-2-chloromandelic acid is:
Another object of the present invention is to utilize resolving agent S-(1) provide a kind of simple to operate, to split efficiency high, chiral resolving agent and solvent can carry out recovery, are applicable to the method for preparation of industrialization (R)-2-chloromandelic acid.
The preparation method of (R)-2-chloromandelic acid is by comprising resolving agent S-(1) in solvent, react and obtain (R)-2-chloromandelic acid resolving agent diastereo-isomerism salt with (RS)-o-Chloromelic acid, this diastereo-isomerism salinity solution is obtained to (R)-2-chloromandelic acid, simultaneously the optional resolving agent S-(1 that reclaims).
Above-mentioned (RS)-o-Chloromelic acid has the chemical structure of general formula I I:
General formula I I
Particularly, the preparation method of (R)-2-chloromandelic acid comprises:
(1) under atmosphere of inert gases, by (the RS)-o-Chloromelic acid of racemization and chiral resolving agent S-(1) add in solvent and dissolve, heating makes it reaction, stirs cooling, separate out solid suction filtration, dry afterwards, collect solid ((R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt);
(2) solid of collecting in step (1) is added to the water, acid adding or acid-salt decompose, and add and the immiscible organic solvent of water extraction, reclaim under reduced pressure organic solvent or add the insoluble solvent of (R)-2-chloromandelic acid with crystallize out, obtains (R)-2-chloromandelic acid.
Also comprise alternatively:
(3) pH of regulating step (2) residue water, to alkalescence, adds organic solvent extraction, reclaims solvent, the chiral resolving agent being recycled.
Particularly, one is utilized resolving agent S-(1) prepare the method for (R)-2-chloromandelic acid, comprising:
(1) under rare gas element, add (the RS)-o-Chloromelic acid of racemization and use dissolution with solvents, add again chiral resolving agent (S)-1, heat temperature raising, insulation reaction, cooling, add (R)-2-chloromandelic acid resolving agent diastereo-isomerism salt as crystal seed, stir cool overnight, the solid of separating out carries out suction filtration, washing, dry remove residual solvent and obtains (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt;
(2) recrystallization (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, add deionized water, stir lower dropping acid or acid-salt, after dissolution of solid, add and the immiscible organic solvent of water, extraction, extraction times is advisable with three times, and organic phase is fully washed with saturated aqueous common salt and deionized water, until washing water is neutral, reclaim under reduced pressure organic solvent or add the insoluble solvent of (R)-2-chloromandelic acid with crystallize out, obtains (R)-2-chloromandelic acid solid;
Also comprise alternatively:
(3) by adding alkali under the residue water stirring of step (2), regulate water pH to be greater than 10, add organic solvent extraction, extraction times is advisable with three times, merges organic phase, and decompression is removed organic solvent recovery and obtained chiral resolving agent (S)-1.
The resolving agent using in above-mentioned preparation method is preferably R
1=H and R
2the S-(1 of=H); (S)-1 can adopt independent one, also can use multiple mixing to use.
In above-mentioned preparation method's step (1), rare gas element is preferably nitrogen or argon gas; (RS)-o-Chloromelic acid: resolving agent (S)-1: the mol ratio of solvent is preferably 1:0.3 ~ 1.0:5 ~ 15, (RS)-o-Chloromelic acid: more preferably 1:0.4 ~ 0.6 of mol ratio of resolving agent (S)-1; The temperature of reaction of above-mentioned steps (1) is preferably 70 ~ 120 ℃, more preferably 70 ~ 80 ℃; Reaction times is preferably 0.5 ~ 3 hour, more preferably 0.5 ~ 1 hour; Solvent in step (1) is preferably the straight or branched alcohol of carbon two ~ carbon four, more preferably carbon triol.
In above-mentioned preparation method's step (2), preferably drip after acid or acid-salt and regulate pH to acid, further preferably regulating pH is 1 ~ 3; Acid in above-mentioned steps (2) can be selected from sulfuric acid, hydrochloric acid, nitric acid, methylsulphonic acid etc., and acid-salt can be selected from iron(ic) chloride etc., and acid is strong acid, more preferably hydrochloric acid preferably; In step (2), be preferably ether, ethyl acetate, methylene dichloride, isopropyl ether, chloroform or methyl tertiary butyl ether with the immiscible organic solvent of water.
In above-mentioned preparation method's step (3), alkali is preferably sodium hydroxide or the potassium hydroxide aqueous solution of 10 ~ 20% mass percent concentrations; Be preferably ethyl acetate, methylene dichloride or chloroform for the organic solvent extracting; Regulate water pH to be preferably 10 ~ 14, more preferably 12 ~ 14.
In above-mentioned preparation method, in order further to improve the rate of recovery, after diastereo-isomerism salt being separated in step (1), in remaining mother liquor, in fact also there is photoactive (S)-2-chloromandelic acid, after photoactive (S)-2-chloromandelic acid is reclaimed, can again be split for the preparation of (R)-2-chloromandelic acid by chiral resolving agent through racemization.The conventional method that adds alkali post-heating can easily realize racemization.
In the decomposition course of diastereomeric salt, use strong acid to decompose this salt and can obtain better effect, because alkaline condition carries out salt, decomposition must cause racemization, affect the optical purity of final (R)-2-chloromandelic acid, therefore in the preparation method of the present patent application, carry out salt decomposition with acid.
For resolving agent (S)-1, be insoluble in organic solvent because the salt of its generation is water-soluble, thereby in extraction process, be easy to enter water respectively with the (R)-2-chloromandelic acid that of dissociating and organic phase is separated.Resolving agent (S)-1 is all very stable under acidity or alkaline condition, therefore in residue water by add highly basic can make it free out, recyclable after extraction, remove extraction solvent after rectifying can obtain (S)-1 that percentage composition is greater than 99%, can directly reuse economic environmental protection.
Above-mentioned preparation method, the yield of (R)-2-chloromandelic acid is more than 80%, and the product content obtaining is greater than 99%, ee value (percent enantiomeric excess) and is greater than 99%.
Beneficial effect of the present invention is:
(1) it is high that the chiral resolving agent (S)-1 adopting splits efficiency, stable chemical nature, and be easy to Separation and Recovery, (S)-1 purity of recovery is greater than 99%, can be recycled, and can effectively reduce costs.
(2) adopt chemical resolution method, industrial route maturation, processing condition gentleness, intermediate product easily separates, simple to operate, is easy to suitability for industrialized production.
(3) in the product that preparation method of the present invention obtains, (R)-2-chloromandelic acid percentage composition is greater than 99%, ee value and is greater than 99%.
(4) the equal recoverable of organic solvent used in the present invention, uses without special, toxic reagent, is conducive to environmental protection and safety in production.
Embodiment
By concrete embodiment, the present invention is further described below, but should not be understood as limitation of the invention.Others skilled in the art, according to technique scheme, can also make modification, replacement and the change of various ways, and all modifications of doing based on above-mentioned technological thought, replacement and change all belong to scope of the present invention.
In embodiment, various chemical used and reagent are commercially available purchase if no special instructions.
embodiment 1
The chiral resolving agent S-(1 of the present embodiment) be R in general formula I
1=Cl, the position of substitution is ortho position, R
2=H, (S)-1 concrete structure of the present embodiment is as follows:
A preparation method for (R)-2-chloromandelic acid, concrete steps are as follows:
In reaction vessel, being filled with in advance nitrogen replaces, take 18.6g(0.1mol) (the RS)-o-Chloromelic acid of racemization is dissolved in 69g(1.5mol completely) in dehydrated alcohol, stirring is cooled to 15 ℃, (S)-1 of amount of substance such as slowly add, after adding, in solution, there are a large amount of white precipitates to produce, be heated to 80 ℃, insulation continues stirring reaction 0.5 hour, keep naturally cooling under whipped state to reduce temperature to 20 ℃, place after 10 hours and filter, filter the absolute ethanol washing that is cooled in advance 0 ℃ for white needles solid, in vacuum drying oven, 60 ℃ of vacuum-dryings are to constant weight, the white needles solid of gained is (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, by 2 (80 ℃ of heating for dissolving temperature of dehydrated alcohol recrystallization for above-mentioned diastereo-isomerism salt, 20 ℃ of Tcs), add in 90g deionized water, under ice bath, drip concentrated nitric acid dissolved solids, in the time of pH=1, stop adding nitric acid, being stirred well to solid dissolves completely, add and the isopyknic dichloromethane extraction of water three times, merge the methylene dichloride of three extractions, with saturated aqueous common salt and the deionization washing of 1/3 volume of water, air distillation recovery methylene dichloride obtains white plates solid and is (R)-2-chloromandelic acid, under normal temperature, residual solvent is removed in vacuum-drying, weigh and obtain (R)-2-chloromandelic acid 6.3g, the (R)-2-chloromandelic acid chemical purity obtaining is 98%, optical purity is 95.7%, under stirring, to the above-mentioned sour water aqueous sodium hydroxide solution that middle dropping mass percent is 10% mutually, while regulating pH=10, add 50mL ethyl acetate extraction three times, merge the ethyl acetate of three extractions, remove ethyl acetate under reduced pressure, recovery obtains (S)-1.
embodiment 2
The chiral resolving agent S-(1 of the present embodiment) be R in general formula I
1=Cl, the position of substitution is contraposition, R
2=NO
2, the position of substitution is contraposition, (S)-1 concrete structure is as follows:
A preparation method for (R)-2-chloromandelic acid, concrete steps are as follows:
In reaction vessel, being filled with in advance nitrogen replaces, take 558g(3mol) racemic (RS)-o-Chloromelic acid is dissolved in 1334g(18mol completely) in the trimethyl carbinol, stirring is cooled to 15 ℃, slowly add 644g(2.1mol) (S)-1, from adding (S)-1 to start to produce with regard to adularescent precipitation in solution, be heated to 120 ℃, insulation continues stirring reaction 2 hours, while reducing temperature to 80 ℃, add a small amount of (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt as crystal seed, keep naturally cooling under whipped state to reduce temperature to 18 ℃, place after 5 hours and filter, filtrate for later use, filter the trimethyl carbinol washing that is cooled in advance 0 ℃ for white powder solid, in vacuum drying oven, 80 ℃ of vacuum-dryings are to constant weight, the white needles solid of gained is (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, by 2 (80 ℃ of heating for dissolving temperature of dehydrated alcohol recrystallization for above-mentioned diastereo-isomerism salt, 20 ℃ of Tcs), add in 540g deionized water, under ice bath, drip concentrated hydrochloric acid dissolved solids, in the time of pH=3, stop adding hydrochloric acid, being stirred well to solid dissolves completely, add and the extracted with diethyl ether of 1/3 volume of water three times, merge the ether of three extractions, with saturated aqueous common salt and the deionization washing of 1/2 volume of water, air distillation recovery ether obtains white plates solid and is (R)-2-chloromandelic acid, under normal temperature, residual solvent is removed in vacuum-drying, weigh and obtain (R)-2-chloromandelic acid 218g, the chemical purity of the (R)-2-chloromandelic acid obtaining is 98.2%, optical purity is 96.3%, under stirring, to the above-mentioned sour water aqueous sodium hydroxide solution that middle dropping massfraction is 20% mutually, while regulating pH=11, add 1000mL chloroform extraction three times, merge the chloroform of three extractions, remove chloroform under reduced pressure, reclaim and obtain (S)-1.
Above-mentioned filtration is obtained to filtrate (having pointed out filtrate for later use in the above-mentioned steps) evaporated under reduced pressure of this step of (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, solid residue after evaporate to dryness adds in the deionized water of treble amount, Xiang Shuizhong adds concentrated hydrochloric acid to regulate pH=3, being stirred well to solid dissolves completely, add the extracted with diethyl ether three times of 1/3 volume of water, merge the ether of three extractions, with saturated aqueous common salt and the deionization washing of 1/2 volume of water, air distillation recovery ether obtains white plates solid and is (S)-2-chloromandelic acid, vacuum-drying, the chemical purity of the (S)-2-chloromandelic acid obtaining is 95.2%, optical purity is 66.3%, the (S)-2-chloromandelic acid obtaining is dissolved in 30% potassium hydroxide aqueous solution, heating reflux reaction, the constantly specific rotation of sampling detection reaction liquid, in the time that becoming 0, reaction solution specific rotation stops heating, under ice bath, slowly drip hydrochloric acid and regulate pH=3, being stirred well to solid dissolves completely, add the extracted with diethyl ether three times of 1/3 volume of water, merge the ether of three extractions, with saturated aqueous common salt and the deionization washing of 1/2 volume, air distillation recovery ether obtains white powder solid and is (RS)-o-Chloromelic acid.
embodiment 3
The chiral resolving agent S-(1 of the present embodiment) be R in general formula I
1=H, R
2=NO
2, the position of substitution is contraposition, (S)-1 concrete structure is as follows:
A preparation method for (R)-2-chloromandelic acid, concrete steps are as follows:
In reaction vessel, being filled with in advance argon gas replaces, take 186g(1mol) racemic (RS)-o-Chloromelic acid is dissolved in 300g(5mol completely) in Virahol, stirring is cooled to 15 ℃, slowly add 109g(0.4mol) (S)-1, in adition process, in solution, there are a large amount of white precipitates to produce, be heated to 70 ℃, insulation continues stirring reaction 1 hour, keep naturally cooling under whipped state to reduce temperature to 10 ℃, place after 12 hours and filter, filter the washed with isopropyl alcohol that is cooled in advance 0 ℃ for white needles solid, in vacuum drying oven, vacuum-drying is to constant weight, the white needles solid of gained is (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, by 2 (heating for dissolving temperature 70 Cs of Virahol recrystallization for above-mentioned diastereo-isomerism salt, 10 ℃ of Tcs), add in 144g deionized water, under ice bath, drip concentrated sulfuric acid dissolution solid, in the time of pH=2, stop adding sulfuric acid, being stirred well to solid dissolves completely, add and the isopyknic ethyl acetate extraction of water three times, merge the ethyl acetate of three extractions, with saturated aqueous common salt and the deionization washing of 1/3 volume of water, to the normal hexane that the volume of water such as adds in ethyl acetate, adularescent solid is separated out, filter, obtain white filter cake and be (R)-2-chloromandelic acid, under normal temperature, residual solvent is removed in vacuum-drying, weigh and obtain (R)-2-chloromandelic acid 57g, the chemical purity of the (R)-2-chloromandelic acid obtaining is 98.7%, optical purity is greater than 99%, under stirring, to the above-mentioned sour water potassium hydroxide aqueous solution that middle dropping mass percent concentration is 20% mutually, while regulating pH=14, add 200mL chloroform extraction three times, merge the chloroform of three extractions, remove chloroform under reduced pressure, reclaim and obtain (S)-1, its content is greater than 99%.
embodiment 4
Chiral resolving agent in the present embodiment comprises two kinds, is respectively component one and component two, and component one is general formula I, wherein R
1=R
2=H; Component two is general formula I, wherein R
1=Cl, the position of substitution is ortho position, R
2=H, the component one of chiral resolving agent and the concrete structure of component two are as follows:
A preparation method for (R)-2-chloromandelic acid, concrete steps are as follows:
In reaction vessel, being filled with in advance argon gas replaces, take 93g(0.5mol) racemic (RS)-o-Chloromelic acid is dissolved in 370g(5mol completely) in propyl carbinol, stirring is cooled to 10 ℃, slowly add 0.25mol(S) two kinds of structural constituent mol ratios of-1(are 1:1), in adition process, in solution, there are a large amount of white precipitates to produce, be heated to 110 ℃, insulation continues stirring reaction 3 hours, keep naturally cooling under whipped state to reduce temperature to 13 ℃, place after 20 hours and filter, filter the propyl carbinol washing that is cooled in advance 0 ℃ for white needles solid, in vacuum drying oven, vacuum-drying is to constant weight, the white needles solid of gained is (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, by 2 (heating for dissolving temperature 70 Cs of Virahol recrystallization for above-mentioned diastereo-isomerism salt, 10 ℃ of Tcs), add in 63g deionized water, under ice bath, drip concentrated sulfuric acid dissolution solid, in the time of pH=2, stop adding sulfuric acid, being stirred well to solid dissolves completely, add the isopropyl ether of 1/2 volume of water to extract three times, merge the isopropyl ether of three extractions, with saturated aqueous common salt and the deionization washing of 1/2 volume of water, removing isopropyl ether under reduced pressure obtains white needles solid and is (R)-2-chloromandelic acid, under normal temperature, residual solvent is removed in vacuum-drying, weigh and obtain (R)-2-chloromandelic acid 32g, the chemical purity of the (R)-2-chloromandelic acid obtaining is greater than 99%, optical purity is greater than 99%, under stirring, to the above-mentioned sour water potassium hydroxide aqueous solution that middle dropping mass percentage concentration is 20% mutually, while regulating pH=12, add 200mL dichloromethane extraction three times, merge the methylene dichloride of three extractions, normal pressure steams except methylene dichloride, reclaims and obtains (S)-1, and its content is 98%.
embodiment 5
The chiral resolving agent S-(1 of the present embodiment) R in general formula I
1=Cl, the position of substitution is ortho position, R
2=H, (S)-1 concrete structure of the present embodiment is as follows:
A preparation method for (R)-2-chloromandelic acid, concrete steps are as follows:
In reaction vessel, being filled with in advance argon gas replaces, take 18.6kg(100mol) racemic (RS)-o-Chloromelic acid is dissolved in 48kg(1600mol completely) in n-propyl alcohol, stirring is cooled to 0 ℃, slowly add (S)-1 of 15.7kg, in adition process, in solution, there are a large amount of white precipitates to produce, be heated to 90 ℃, insulation continues stirring reaction 1.5 hours, keep naturally cooling under whipped state to reduce temperature to 5 ℃, place after 2 hours and filter, filter the n-propyl alcohol washing that is cooled in advance 0 ℃ for white needles solid, be dried to constant weight, the white needles solid of gained is (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, by 2 (90 ℃ of heating for dissolving temperature of n-propyl alcohol recrystallization for above-mentioned diastereo-isomerism salt, 5 ℃ of Tcs), add in 12.6kg deionized water, under ice bath, drip methylsulphonic acid dissolved solids, while controlling pH=2, stop, being stirred well to solid dissolves completely, add and the isopyknic chloroform extraction of water three times, merge the chloroform of three extractions, with saturated aqueous common salt and the deionization washing of 1/2 volume of water, removing chloroform under reduced pressure obtains white needles solid and is (R)-2-chloromandelic acid, under normal temperature, residual solvent is removed in vacuum-drying, weigh and obtain (R)-2-chloromandelic acid 7.7kg, the chemical purity of the (R)-2-chloromandelic acid obtaining is 98.9%, optical purity is greater than 99%, under stirring, to the above-mentioned sour water potassium hydroxide aqueous solution that middle dropping mass percentage concentration is 10% mutually, while regulating pH=13, add 2000mL dichloromethane extraction three times, merge the methylene dichloride of three extractions, normal pressure steams and removes methylene dichloride, and recovery obtains (S)-1.
embodiment 6
The chiral resolving agent of the present embodiment is to adopt (S)-1 of reclaiming in embodiment 5 as resolving agent, a kind of preparation method of (R)-2-chloromandelic acid, and concrete steps are as follows:
In reaction vessel, being filled with in advance argon gas replaces, take 930g(5mol) racemic (RS)-o-Chloromelic acid is dissolved in 3700g(50mol completely) in isopropylcarbinol, stirring is cooled to 20 ℃, slowly add (S)-1 of 1047g, in adition process, in solution, there are a large amount of white precipitates to produce, be heated to 105 ℃, insulation continues stirring reaction 2.5 hours, keep naturally cooling under whipped state to reduce temperature to 20 ℃, place after 5 hours and filter, filter the isopropylcarbinol washing that is cooled in advance 0 ℃ for white needles solid, be dried to constant weight, the white needles solid of gained is (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, by 2 (105 ℃ of heating for dissolving temperature of isopropylcarbinol recrystallization for above-mentioned diastereo-isomerism salt, 20 ℃ of Tcs), add in 630g deionized water, under ice bath, drip iron(ic) chloride dissolved solids, while controlling pH=3, stop, being stirred well to solid dissolves completely, add and the isopyknic methyl tertiary butyl ether extraction of water three times, merge the methyl tertiary butyl ether of three extractions, with saturated aqueous common salt and the deionization washing of 1/4 volume of water, removing methyl tertiary butyl ether under reduced pressure obtains white needles solid and is (R)-2-chloromandelic acid, under normal temperature, residual solvent is removed in vacuum-drying, weigh and obtain (R)-2-chloromandelic acid 377g, the chemical purity of the (R)-2-chloromandelic acid obtaining is 98.5%, optical purity is greater than 97.2%, under stirring, to the above-mentioned sour water potassium hydroxide aqueous solution that middle dropping mass percentage concentration is 20% mutually, while regulating pH=12, add 30L dichloromethane extraction three times, merge the methylene dichloride of three extractions, normal pressure steams and removes methylene dichloride, and recovery obtains (S)-1.
embodiment 7
The chiral resolving agent S-(1 of the present embodiment) be R in general formula I
1=H, R
2=H, the concrete structure of the chiral resolving agent (S)-1 of the present embodiment is as follows:
A preparation method for (R)-2-chloromandelic acid, concrete steps are as follows:
In reaction vessel, being filled with in advance argon gas replaces, take 18.6g(0.1mol) racemic (RS)-o-Chloromelic acid is dissolved in 40.1g(0.8mol completely) in n-propyl alcohol, stirring is cooled to 0 ℃, slowly add (S)-1 of 18.2g, in adition process, in solution, there are a large amount of white precipitates to produce, be heated to 95 ℃, insulation continues stirring reaction 2 hours, keep naturally cooling under whipped state to reduce temperature to 5 ℃, place after 2 hours and filter, filter the n-propyl alcohol washing that is cooled in advance 0 ℃ for white needles solid, be dried to constant weight, the white needles solid of gained is (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, by 2 (95 ℃ of heating for dissolving temperature of n-propyl alcohol recrystallization for above-mentioned diastereo-isomerism salt, 5 ℃ of Tcs), add in 12.6g deionized water, under ice bath, drip sulfuric acid dissolution solid, while controlling pH=2, stop, being stirred well to solid dissolves completely, add and the isopyknic methyl tertiary butyl ether extraction of water three times, merge the methyl tertiary butyl ether of three extractions, with saturated aqueous common salt and the deionization washing of 1/2 volume of water, removing methyl tertiary butyl ether under reduced pressure obtains white needles solid and is (R)-2-chloromandelic acid, under normal temperature, residual solvent is removed in vacuum-drying, weigh and obtain (R)-2-chloromandelic acid 7.72g, the chemical purity of the (R)-2-chloromandelic acid obtaining is 99.5%, optical purity is greater than 99%, under stirring, to the above-mentioned sour water potassium hydroxide aqueous solution that middle dropping mass percentage concentration is 20% mutually, while regulating pH=14, add 200mL dichloromethane extraction three times, merge the methylene dichloride of three extractions, normal pressure steams and removes methylene dichloride, and recovery obtains (S)-1.
embodiment 8
The chiral resolving agent of four kinds of different substituents groups is for the preparation of the effect comparison of (R)-2-chloromandelic acid.
Adopt four kinds of different chiral resolving agents (substituted radical difference), four kinds of different substituted radicals are as shown in table 1, the Cl in table 1 and NO
2the position of substitution be ortho position, adopt them to carry out respectively the preparation of (R)-2-chloromandelic acid, preparation method is identical with the preparation method described in embodiment 7, finally the yield to the (R)-2-chloromandelic acid obtaining, chemical purity and optical purity detect.Detected result is as shown in table 1.
Table 1
| Numbering | R 1 | R 2 | Yield | Chemical purity | Optical purity |
| 1 | H | H | 84% | 99.5% | >99% |
| 2 | Cl | H | 76% | 99% | 98.3% |
| 3 | Cl | NO 2 | 71% | 98.4% | 97.8% |
| 4 | H | NO 2 | 69% | 98.9% | 99.1% |
The present invention is not limited to aforesaid embodiment.The present invention expands to any new feature or any new combination disclosing in this manual, and the arbitrary new method disclosing or step or any new combination of process.
Claims (10)
1. a novel chiral resolving agent, is characterized in that, described resolving agent is S-(1), there is the chemical structure of general formula I:
General formula I
Wherein, R
1and R
2be respectively the H of ortho position, a position or para-orientation, CH
3, OH, OCH
3, F, Cl, Br, I, or NO
2in one.
2. a kind of novel chiral resolving agent as claimed in claim 1, is characterized in that described R
1=H and R
2=H.
3. a kind of novel chiral resolving agent as claimed in claim 1 or 2, is characterized in that, described resolving agent is for the preparation of (R)-2-chloromandelic acid.
4. the preparation method of a (R)-2-chloromandelic acid, it is characterized in that, comprise resolving agent S-(1 claimed in claim 1) in solvent, react and obtain (R)-2-chloromandelic acid resolving agent diastereo-isomerism salt with (RS)-o-Chloromelic acid, described diastereo-isomerism salinity solution is obtained to (R)-2-chloromandelic acid, and reclaim alternatively resolving agent S-(1).
5. the preparation method of a kind of (R)-2-chloromandelic acid as claimed in claim 4, is characterized in that, comprises the following steps:
(1) under atmosphere of inert gases, by (RS)-o-Chloromelic acid and chiral resolving agent S-(1) add in solvent and dissolve, heating, stirs coolingly, separates out suction filtration after solid, dry, collects solid;
(2) solid of collecting in step (1) is added to the water, acid adding or acid-salt decompose, and add and the immiscible organic solvent of water extraction, reclaim under reduced pressure organic solvent or add the insoluble solvent of (R)-2-chloromandelic acid with crystallize out, obtains (R)-2-chloromandelic acid;
Also comprise alternatively:
(3) pH of regulating step (2) residue water, to alkalescence, adds organic solvent extraction, reclaims solvent, the chiral resolving agent being recycled.
6. the preparation method of a kind of (R)-2-chloromandelic acid as claimed in claim 5, is characterized in that, comprises the following steps:
(1) under atmosphere of inert gases, add (the RS)-o-Chloromelic acid of racemization and use dissolution with solvents, add again chiral resolving agent (S)-1, heat temperature raising, insulation reaction, cooling, add (R)-2-chloromandelic acid resolving agent diastereo-isomerism salt as crystal seed, stir cool overnight, the solid of separating out carries out suction filtration, washing, dry remove residual solvent and obtains (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt;
(2) recrystallization (R)-2-chloromandelic acid (S)-1 diastereo-isomerism salt, add deionized water, stir lower drip acid or acid-salt, after dissolution of solid, add and the immiscible organic solvent of water extraction, organic phase is fully washed with saturated aqueous common salt and deionized water, until washing water be neutrality, reclaim under reduced pressure organic solvent or add the insoluble solvent of (R)-2-chloromandelic acid with crystallize out, obtains (R)-2-chloromandelic acid solid;
Also comprise alternatively:
(3) the residue water of step (2) is under agitation dripped to sodium hydroxide or the potassium hydroxide aqueous solution of 10 ~ 20% massfraction concentration, regulate the pH of water to be greater than 10, add organic solvent extraction, decompression is removed organic solvent recovery and is obtained chiral resolving agent (S)-1.
7. the preparation method of a kind of (R)-2-chloromandelic acid as claimed in claim 6, it is characterized in that, (RS)-o-Chloromelic acid in described step (1): resolving agent (S)-1: the mol ratio of solvent is 1:0.3 ~ 1.0:5 ~ 15, temperature of reaction is 70 ~ 120 ℃, and the reaction times is 0.5 ~ 3 hour.
8. the preparation method of a kind of (R)-2-chloromandelic acid as claimed in claim 6, is characterized in that, the solvent in described step (1) is straight chain alcohol or the branched-chain alcoho of carbon two ~ carbon four.
9. the preparation method of a kind of (R)-2-chloromandelic acid as claimed in claim 6, is characterized in that, described acid is selected from sulfuric acid, hydrochloric acid, nitric acid, methylsulphonic acid, and described acid-salt is selected from iron(ic) chloride, and it is 1 ~ 3 that dropping acid or acid-salt regulate pH.
10. the preparation method of a kind of (R)-2-chloromandelic acid as claimed in claim 6, is characterized in that, in described step (3), regulating pH is 12 ~ 14.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410068327.2A CN103804179B (en) | 2014-02-27 | 2014-02-27 | The preparation method of chiral resolving agent and (R)-2-chloromandelic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410068327.2A CN103804179B (en) | 2014-02-27 | 2014-02-27 | The preparation method of chiral resolving agent and (R)-2-chloromandelic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103804179A true CN103804179A (en) | 2014-05-21 |
| CN103804179B CN103804179B (en) | 2016-03-02 |
Family
ID=50701620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410068327.2A Active CN103804179B (en) | 2014-02-27 | 2014-02-27 | The preparation method of chiral resolving agent and (R)-2-chloromandelic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103804179B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085246A (en) * | 2015-09-02 | 2015-11-25 | 彭静 | Method for preparing R-chloromandelic acid |
| CN108069855A (en) * | 2016-11-18 | 2018-05-25 | 鲁南制药集团股份有限公司 | A kind of recoverying and utilizing method of S- o-chloromandelic acids |
| CN113355299A (en) * | 2018-03-22 | 2021-09-07 | 浙江工业大学 | Ketoacid reductase, gene, engineering bacterium and application in synthesis of chiral aromatic 2-hydroxy acid |
| WO2023229293A1 (en) * | 2022-05-23 | 2023-11-30 | 재단법인 대구경북첨단의료산업진흥재단 | Pharmaceutical composition comprising bicycle derivative as active ingredient for prevention or treatment of cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001072644A (en) * | 1999-09-06 | 2001-03-21 | Yamakawa Yakuhin Kogyo Kk | Production of optically active 2-chloromandelic acid and production intermediate |
| CN102603518A (en) * | 2012-01-30 | 2012-07-25 | 郑州大学 | Resolution method for 2-chloromandelic acid by crystalizing diastereomeric salts |
-
2014
- 2014-02-27 CN CN201410068327.2A patent/CN103804179B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001072644A (en) * | 1999-09-06 | 2001-03-21 | Yamakawa Yakuhin Kogyo Kk | Production of optically active 2-chloromandelic acid and production intermediate |
| CN102603518A (en) * | 2012-01-30 | 2012-07-25 | 郑州大学 | Resolution method for 2-chloromandelic acid by crystalizing diastereomeric salts |
Non-Patent Citations (1)
| Title |
|---|
| JIA DENG ET AL.,: "Sulfonic acid supported on hydroxyapatite-encapsulated-γ-Fe2O3 nanocrystallites as a magnetically separable catalyst for one-pot reductive amination of carbonyl compounds", 《GREEN CHEM.》, vol. 13, 31 December 2011 (2011-12-31) * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085246A (en) * | 2015-09-02 | 2015-11-25 | 彭静 | Method for preparing R-chloromandelic acid |
| CN108069855A (en) * | 2016-11-18 | 2018-05-25 | 鲁南制药集团股份有限公司 | A kind of recoverying and utilizing method of S- o-chloromandelic acids |
| CN108069855B (en) * | 2016-11-18 | 2021-02-02 | 鲁南制药集团股份有限公司 | Method for recycling S-o-chloromandelic acid |
| CN113355299A (en) * | 2018-03-22 | 2021-09-07 | 浙江工业大学 | Ketoacid reductase, gene, engineering bacterium and application in synthesis of chiral aromatic 2-hydroxy acid |
| WO2023229293A1 (en) * | 2022-05-23 | 2023-11-30 | 재단법인 대구경북첨단의료산업진흥재단 | Pharmaceutical composition comprising bicycle derivative as active ingredient for prevention or treatment of cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103804179B (en) | 2016-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103804179B (en) | The preparation method of chiral resolving agent and (R)-2-chloromandelic acid | |
| JP2004161749A (en) | Method for producing optically active, nitrogen-containing compound | |
| CN104140420A (en) | Synthesis process of thiothiamine | |
| CN102241555A (en) | Method for preparing photoactived amino acid through resolution | |
| CN101429180A (en) | Process for producing S-tetrahydrochysene furoic acid | |
| CN101580472B (en) | Resolving agent for 1, 1'-bi-2-naphthol and resolving method thereof | |
| CN104086439A (en) | Method for recovering pregabalin intermediate resolving agent (R)-(+)-alpha-phenylethylamine | |
| CN113354581B (en) | Preparation method and application of chiral chloroquine and phosphate thereof | |
| CN109879780B (en) | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate | |
| JP5092289B2 (en) | Process for producing optically active N-tert-butylcarbamoyl-L-tert-leucine | |
| CN103102280B (en) | The preparation method of optical voidness 1-(alpha-amido benzyl)-beta naphthal | |
| CN102516034A (en) | Chiral resolution method of racemic 1,1'-bi-2-naphthol | |
| CN113087630A (en) | Method for recycling and applying perindopril intermediate resolving agent (R) - (+) -alpha-phenylethylamine | |
| CN103497145B (en) | A kind of preparation technology of optical purity E2020 | |
| CN104844524A (en) | Synthetic method of ambrisentan | |
| CN106831540B (en) | A kind of preparation method of (S)-nipecotic acid | |
| CN100497335C (en) | Optical resolution method substituting oxyphosphonate acetate | |
| JPH07330732A (en) | Optically active 3-amino-1-benzylpiperidine derivative | |
| US4621151A (en) | Optical resolution of DL-cysteine | |
| EP3725766A1 (en) | Method for producing 2-octylglycine ester having optical activity | |
| JP4104319B2 (en) | Process for producing optically active 2-hydroxy-3-nitropropionic acid | |
| KR102537780B1 (en) | AMINO ACID EXTRACTION PROCESS USING t-BUTYL KETONE BINAPHTHOL DERIVATIVES OR t-BUTYL KETONE DERIVATIVES, AND A CONTINUOUS REACTOR PERFORMING THE SAME | |
| CN109516899B (en) | Preparation method of high-purity resveratrol | |
| CN102659634B (en) | Synthetic method for 2-(N-4-fluorobenzyl) methoxy-acetyl-amino methyl isobutyrate | |
| CN105085243A (en) | Preparing method of (S)-(-)-4-bromine mandelic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |