CN102093284B - Method for enriching piperidine-2-formanilide optically active compound - Google Patents
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Abstract
The invention relates to a method for enriching a piperidine-2-formanilide optically active compound. The method comprises the following steps of: mixing R type ropivacaine and bupivacaine or an intermediate thereof with an inert solvent, an initiating agent and mercaptan and carrying out a racemization reaction to obtain a reaction solution containing RS configuration ropivacaine, bupivacaine or the intermediate thereof; adding acid to the reaction solution to carrying out salifying reaction, bleaching and extracting through an organic solvent, drying and dewatering an organic phase, and carrying out spinning evaporating to obtain racemized ropivacaine, bupivacaine or the intermediate solid thereof; adding the obtained solid salt to acetone to separate out DBTA (Dibenzoyl Tartaric Acid) salt which is an S type enantiomer, wherein at the moment, a large quantity of white precipitates are generated in the solution, and bleaching to obtain white solid; and dissolving the solid into alkali, and then bleaching to obtain an enriched piperidine-2-formanilide optically active compound. The method provided by the invention shortens the time and reduces the temperature of the racemization reaction, reduces pollution to environment, caused by wastes and improves the production efficiency.
Description
Technical field
The present invention relates to the method for a kind of enrichment piperidines-2-carboxanilide optically-active compound.
Background technology
The compound of structural formula 1
R wherein
2Be 2,6-3,5-dimethylphenyl, and R
1For methyl (mepivacaine), n-propyl (ropivacaine), normal-butyl (Levobupivacaine) are widely used in clinical toponarcosis.Work as R
1During for H, corresponding compound is the important intermediate of synthetic these local anesthetics.
Biological study shows: (the S)-enantiomorph of this class N-alkyl-piperidines-2-formylaniline has lower cardiac toxic than its corresponding racemoid when the identical anesthesia effect, so the clinical application potentiality of their (S)-enantiomorph are larger.So the effective ways of the single enantiomer of preparation formula 1 compound need to be arranged.Yet, the yield that obtains in theory single enantiomer with the corresponding raceme of traditional method fractionation only has at most 50%, and in actual production for to obtain meeting the optics sterling yield of quality standard especially less than 30%, this not only causes the huge waste of raw material, and after splitting, the processing of another enantiomorph has also brought immense pressure to environment.For the utilization ratio, the raising production capacity that improve raw material, second half enantiomeric compounds after need to splitting by handle is carried out racemization and is again again split.Therefore, huge to exploration, research and the using value of the chiral separation that is fit to large formula 1 compound of producing and racemization processing method.
The Study on Racemization about formula 1 compound single enantiomer of report all concentrates on two following aspects at present.
A kind of method is, under acidic conditions (the pH value of controlling the racemization system is 1~6), normally (in the medium of C1~C4), high temperature (100 ℃~150 ℃) carries out racemization reaction at carboxylic acid.Shiraiwa discloses under the existence of chiral resolving agent and acetaldehyde in Bull.Chem.Soc.Jpn.64:3251-3255 (1991), the asymmetric conversion of heating 2 piperidine carboxylic acid in the alkanoic acid solvent.Relevant patent has therewith, and Chiroscience Ltd is at the CN1159184A of China's application.But the shortcoming of this method is, under hot conditions, the N base on the carboxylic acid in the racemization system and formula 1 intermediate piperidine ring easily occur acylation reaction [Marianne Langston, Ulrich C.Dyer,
Graham A.C.Frampton, Racemisation of R-Bupivacaine:A Key Factor in the Integrated and EconomicProcess for the Production of Levobupivacaine.Organic Process Research ﹠amp; Development 2000,4,530-533], the by product of generation has had a strong impact on follow-up purifying and overall productive rate.Operation simultaneously is also inconvenient, also need add the protection of nitrogen as narrated racemization reaction in the CN1159184A patent.
Another kind method is, the high temperature long-time heating is carried out racemization reaction in water and ethanol (or polyvalent alcohol, V: V is 10%) double solvents.Fyhr etc., Acta.Pharm.Suec. (1988) 25:121-132, the dilute aqueous soln of having reported optically active ropivacaine hydrochloride is racemization slowly under 1~6 and 80~130 ℃ in the pH value.As patent CN1168134A, the shortcoming of this method is, energy consumption is high, one requires temperature more than 130 ℃, does not meet the proposal of national energy-saving consumption reduction, and long reaction time, same high temperature reacts for a long time, and the amido linkage in formula 1 faces the possibility of hydrolysis, has increased the generation of by product.
Announced a kind of intermediate pipecoloxylidide and chiral resolving agent crystallization in patent CN1189822A and formed stable water-containing crystal system and split, the method complex operation, and crystallisation process is consuming time.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of raising and splits efficient, and waste can be regenerated and recycle, the method for the enrichment piperidines that the optics sterling yield that finally obtains is high-2-carboxanilide optically-active compound.
Purpose of the present invention can realize as follows:
(1) R type ropivacaine, bupivacaine or its intermediate are mixed with inert solvent, initiator, mercaptan, stirring is warming up to 70~110 ℃ and carries out racemization, obtain containing the reaction solution of RS configuration ropivacaine, bupivacaine or its intermediate (product after racemization), the racemization time is 2~10 hours;
(2) reaction solution with step (1) gained adds acid to carry out salt-forming reaction, make its water layer pH to 1~6, add the organic solvent B extracting to separate organic phase, it is 8~13 that aqueous phase adds adjusting PH with base, add the organic solvent B extraction at aqueous phase, the organic phase drying dewaters to revolve and steams ropivacaine, bupivacaine or its intermediate solid that obtains racemization;
(3) ropivacaine, bupivacaine or its intermediate and chiral resolving agent L-(-)-dibenzoyl tartaric acid (DBTA) are prior to salify in alcoholic solution, again to becoming in salt system to add ketone solution, the DBTA of the enantiomorph of S type salts out, a large amount of white precipitates appear in solution, suction filtration gets white solid, and filtrate is reclaimed;
(4) step (3) gained solid, with alcohol-ketone mixed solution dissolving, the crystallization suction filtration can get S type enantiomorph-DBTA salt refining product, and filtrate is reclaimed;
(5) to be dissolved in bases and to make its system pH be 10~12 to step (4) gained solid, the organic solvent extracting, and drying is revolved the single enantiomer that steams the ropivacaine that obtains the S type, bupivacaine and synthetic intermediate pipecoloxylidide thereof.
(6) with step (3), (4) gained filtrate decompression evaporate to dryness, the solid that obtains repeats above step (1)-(5) through alkalization.
In step (1), initiator divides three times and adds, the timed interval that gradation adds be 0.5~4 hour once, the amount that at every turn adds is 1/3rd of the total add-on of initiator.
With molar ratio computing, R type ropivacaine, bupivacaine or its intermediate: initiator: mercaptan=1: 0.2~1.6: 0.2~2.0.
Initiator in step (1) is selected from 2,2'-Azobis(2,4-dimethylvaleronitrile), Diisopropyl azodicarboxylate, peroxidation two acyls, benzoyl peroxide or dilauroyl peroxide.
The described inert solvent of step (1) is selected from toluene, p-Xylol, acetonitrile, methylene dichloride, ethyl acetate or o-Xylol.
Mercaptan selected from mercapto methyl propionate described in step (1), Methyl Thioglycolate, positive eight mercaptan, sulfydryl methyl-butyrate, ethyl thioglycolate or mercaptopropionic acid ethyl ester.
Control water layer pH to 4~5 when adding acid to carry out salt-forming reaction the reaction solution of step (1) gained in step (2), add the organic solvent B extracting to separate organic phase, it is 11~12 that aqueous phase adds alkali to transfer pH.
Hydrochloric acid, sulfuric acid, nitric acid, Hydrogen bromide or phosphoric acid are selected in the acid of the salify in step (2); In and the alkali used of water select lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, magnesium hydroxide or ammoniacal liquor.
Organic solvent B formic acid propyl ester, propyl acetate, ethyl acetate, toluene, p-Xylol, acetonitrile, methylene dichloride, o-Xylol, ether or methyl tertiary butyl ether in step (2).
Alcoholic solution in step (3) selects a kind of to the lower aliphatic alcohols below C5, is preferably methyl alcohol, ethanol, propyl alcohol, propyl carbinol, and ketone solution selects a kind of to acetone, butanone, pentanone or the isobutyl ketone, and alcohol is 1: 1~10: 1 with the ratio of ketone..
Alcohol in step (4)-ketone mixing solutions, alcohol select a kind of to the lower aliphatic alcohols below C5, are preferably a kind of in methyl alcohol, ethanol, propyl alcohol, propyl carbinol; Ketone selects a kind of to acetone, butanone, pentanone or the isobutyl ketone; Alcohol is 1: 1~10: 1 with the ratio of ketone..
Organic solvent in step (5) can be selected propyl formate, propyl acetate, ethyl acetate, toluene, p-Xylol, acetonitrile, methylene dichloride, o-Xylol.
The method of enrichment piperidines provided by the invention-2-carboxanilide optically-active compound, improved the fractionation efficient of ropivacaine, bupivacaine and synthetic intermediate thereof, can obtain S type enantiomorph highly finished product through step (4) in the present invention, repeat this step twice, can make S type enantiomorph ee%100.The filtrate that reclaim step (3), (4), be rich in a large amount of R type enantiomorphs-DBTA salt and small part R type enantiomorph-DBTA salt, this mixture is through alkalization, repeating step (1)-(5), optics sterling yield is criticized in racemization-fractionation again, the list that finally obtains can reach 40%~50%, applies mechanically industrial filtrate, can greatly improve yield, reduce costs.The method makes castoff regenerative and recycle, and yield is compared other racemization methods and is significantly improved, and has reduced simultaneously the pollution of waste to environment; Racemization method of the present invention makes temperature of reaction be reduced to 70~110 ℃ from the past 130 ℃, and the time also shortens to 2-10 hour, reduce the generation of racemization byproduct in process thing, reduced simultaneously energy consumption, reduced cost, present method is simple to operate, is fit to suitability for industrialized production.
Description of drawings
Fig. 1 is R type intermediate color atlas.
Fig. 2 is racemization intermediate color atlas.
Fig. 3 is S type intermediate color atlas.
Fig. 4 is the color atlas of mother liquor recovery (R, S type) after intermediate splits.
Fig. 5 is the color atlas of ropivacaine (S type).
Fig. 6 is the color atlas of ropivacaine racemization.
Fig. 7 is the color atlas of ropivacaine (S type).
Fig. 8 is ropivacaine (racemic modification) color atlas.
Fig. 9 is Levobupivacaine (S type) color atlas.
Figure 10 is Levobupivacaine (racemic modification) color atlas.
Figure 11 is Levobupivacaine (S type) color atlas.
Figure 12 is Levobupivacaine (racemic modification) color atlas.
Embodiment
Principle of work of the present invention and step are as follows:
(1) R type ropivacaine, bupivacaine or its intermediate are mixed with inert solvent, initiator, mercaptan, stirring is warming up to 70~110 ℃ and carries out racemization, obtains containing the reaction solution of RS configuration ropivacaine, bupivacaine or its intermediate (product after racemization).According to different raw materials, one racemization time is 2~10 hours, preferred 8 hours.
The described inert solvent of this step is selected from toluene, p-Xylol, acetonitrile, methylene dichloride, ethyl acetate or o-Xylol.
The described initiator of this step is selected from 2,2'-Azobis(2,4-dimethylvaleronitrile), Diisopropyl azodicarboxylate, peroxidation two acyls, benzoyl peroxide or dilauroyl peroxide.
The described mercaptan selected from mercapto of this step methyl propionate, Methyl Thioglycolate, positive eight mercaptan, sulfydryl methyl-butyrate, ethyl thioglycolate or mercaptopropionic acid ethyl ester.
With molar ratio computing, R type ropivacaine, bupivacaine or its intermediate: initiator: mercaptan=1: 0.2~1.6: 0.2~2.0.
In this step, in order at utmost to bring into play the activity of initiator, take gradation to add, optimum is 3 times, the timed interval that gradation adds be 0.5~4 hour once, the amount that at every turn adds for its total add-on 1/3rd.Preferred 70~110 ℃ of the temperature of described racemization.Described mercaptan is equivalent to the effect of stablizer.After question response finished, the intermediate after racemization was water-soluble after with sour salify, and organic layer still contains a large amount of mercaptan, but direct repeat use after drying dewaters.
(2) aftertreatment adds acid to carry out salt-forming reaction the reaction solution of step (1) gained, make its water layer pH to 1~6 (preferred 4~5), add the organic solvent B extracting to separate organic phase, it is 8~13 (preferred 11~12) that aqueous phase adds alkali to transfer pH, add the organic solvent B extraction at aqueous phase, the organic phase drying dewaters to revolve and steams ropivacaine, bupivacaine or its intermediate solid that obtains racemization.
The acid of the described salify of this step can be selected from hydrochloric acid, sulfuric acid, nitric acid, Hydrogen bromide or phosphoric acid, preferred hydrochloric acid.In and the alkali used of water can be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, magnesium hydroxide or ammoniacal liquor, preferred sodium hydroxide, potassium hydroxide.
The described organic solvent B of this step is selected from propyl formate, propyl acetate, ethyl acetate, toluene, p-Xylol, acetonitrile, methylene dichloride, o-Xylol, ether, methyl tertiary butyl ether.
(3) ropivacaine, bupivacaine and synthetic intermediate thereof and chiral resolving agent L-(-)-dibenzoyl tartaric acid (DBTA) are prior to salify in alcoholic solution, again to becoming in salt system to add ketone solution, the DBTA of the enantiomorph of S type salts out, a large amount of white precipitates appear in solution, suction filtration gets white solid, and filtrate is reclaimed.
The described alcoholic solution of this step selects a kind of to the lower aliphatic alcohols below C5, is preferably methyl alcohol, ethanol, propyl alcohol, propyl carbinol; Ketone solution selects a kind of to acetone, butanone, pentanone or the isobutyl ketone.
(4) step (3) gained solid, with alcohol-ketone mixed solution dissolving, the crystallization suction filtration can get S type enantiomorph-DBTA salt refining product, and filtrate is reclaimed;
The described alcoholic solution of this step selects a kind of to the lower aliphatic alcohols below C5, is preferably methyl alcohol, ethanol, propyl alcohol, propyl carbinol; Ketone solution selects a kind of to acetone, butanone, pentanone or the isobutyl ketone.
(5) to be dissolved in bases and to make its system pH be 10~12 to step (4) gained solid, the organic solvent extracting, and drying is revolved the single enantiomer that steams the ropivacaine, bupivacaine or its intermediate that obtain the S type.
The described organic solvent of this step can be selected propyl formate, propyl acetate, ethyl acetate, toluene, p-Xylol, acetonitrile, methylene dichloride, o-Xylol.
(6) with step (3), (4) gained filtrate decompression evaporate to dryness, the solid that obtains repeats above step (1)-(5) through alkalization.
Fractionation of the present invention, racemization formula are as follows:
Wherein, R
1Be the substituting group of H or maximum 20 C atoms, R
2For reaching most alkyl or the aryl of 20 C atoms.As R
2=2,6-3,5-dimethylphenyl, and R
1=methyl is mepivacaine, R
1=n-propyl is ropivacaine, R
1=normal-butyl is Levobupivacaine, R
1During=H, corresponding compound is intermediate N (2,6-3,5-dimethylphenyl)-2-piperidyl urea.
Racemization and the fractionation of embodiment 1 intermediate
Add 17gR type intermediate (ee%=100, Fig. 1) in 150ml toluene, the 5ml ethyl thioglycolate, the 5g Diisopropyl azodicarboxylate adds the racemization system, 70 ℃ of back flow reaction three times every 2 little time-division.
React after 8 hours, add purified water in reaction solution, regulating water layer pH value with hydrochloric acid is 4, toluene extracting, separating machine phase.It is 10~11 that water is regulated the pH value with potassium hydroxide, the toluene extracting, and the organic layer anhydrous sodium sulfate drying, concentrated, obtain racemization product 15g (R=50.2%, S=49.8%, Fig. 2).
With the racemic intermediate pipecoloxylidide of 15g, be dissolved in the ethanol of 100ml with 11g L-(-)-dibenzoyl tartaric acid (DBTA) resolving agent and stir, add again 35ml acetone, the white solid suction filtration of separating out, get the DBTA salt 16g of the S single enantiomer of intermediate, filtrate is reclaimed.
The DBTA salt of 16g S single enantiomer is made with extra care twice repetition twice with 135ml ethanol-acetone (volume ratio 3: 1) mixing solutions, gets the DBTA salt 9g of the S single enantiomer of intermediate, and filtrate is reclaimed.
The DBTA salt of 9g S intermediate is transferred pH=11 with sodium hydroxide solution, with toluene extracting and separating organic phase, the organic phase anhydrous sodium sulfate drying, vacuum is revolved to steam and is obtained the 5.2g solid, is the S type single enantiomer (ee%=100, Fig. 3) of intermediate pipecoloxylidide.
Reclaim the DBTA salt 15g that the filtrate decompression evaporate to dryness must contain a large amount of R type intermediate pipecoloxylidide, through a large amount of R type intermediates and the small portion S type intermediate of alkalizing to get.(R=74.8%, S=25.2%, Fig. 4).This mixed type intermediate can continue to repeat above racemization-split process, continues to obtain ee% and be 100 S type enantiomer.
Racemization and the fractionation of embodiment 2 ropivacaines
Add 10g ropivacaine (ee%=100, Fig. 5) in 200ml toluene, the 3.1ml ethyl thioglycolate, the 3.1g Diisopropyl azodicarboxylate adds the racemization system, 75~85 ℃ of back flow reaction three times every 2 little time-division.
Reacted 2 hours, and added purified water in reaction solution, regulating water layer pH value with hydrochloric acid is 3~5, and organic phase is abandoned in the p-Xylol extracting.It is 9~11 that water is regulated the pH value with sodium hydroxide, the p-Xylol extracting, and the organic layer anhydrous sodium sulfate drying, concentrated, obtain racemization product 8.7g (ee%=0, Fig. 6).
8.7g racemic ropivacaine is dissolved in the propyl carbinol of 45ml with 6.5g L-(-)-dibenzoyl tartaric acid (DBTA) resolving agent and stirs salify.Add 19ml acetone, the white solid suction filtration of separating out gets the DBTA salt 9.28g of the S single enantiomer of ropivacaine, and filtrate is reclaimed.
9.28g the DBTA salt of S single enantiomer makes with extra care twice with 135ml methyl alcohol-butanone (volume ratio 1: 1) mixing solutions, gets the DBTA salt 5.22g of the S single enantiomer of intermediate, filtrate is reclaimed.
The potassium hydroxide solution of dilution and the DBTA salt of 5.22g S ropivacaine are mixed, transfer pH=11, with ethyl acetate 116ml extracting and separating organic phase, the organic phase anhydrous sodium sulfate drying, vacuum is revolved to steam and is obtained the 3.01g solid, be the S type single enantiomer (ee%=100, Fig. 7) of ropivacaine.
Filtrate recovery and evaporated under reduced pressure must contain the DBTA salt 8.8g of a large amount of R type ropivacaines, and solids can obtain 4.8g RS mixed type ropivacaine (R=80.6%, S=19.4%, Fig. 8) through alkalization.This mixed type ropivacaine can repeat above step, is used for continuing to split after racemization.
The racemization of embodiment 3 Levobupivacaines
Add 15g Levobupivacaine (ee%=100, Fig. 9) in 300ml toluene, with the 4.6ml ethyl thioglycolate, the 4.6g Diisopropyl azodicarboxylate divides three times every 2h and adds in reaction system, 85~95 ℃ of lower back flow reaction.
Reacted 10 hours, and added purified water in reaction solution, regulating water layer pH with hydrochloric acid is 4~5, and o-Xylol extracts, and abandons organic phase.It is 10~11 that water is regulated the pH value with sodium hydroxide, and o-Xylol extracts, and the organic layer anhydrous sodium sulfate drying is concentrated, obtains racemization product 12.3g (ee%=0, Figure 10)
12.3g the Levobupivacaine of racemization is dissolved in the methyl alcohol of 35ml with 9.18g L-(-)-dibenzoyl tartaric acid (DBTA) resolving agent and stirs salify.Add 15ml acetone, the white solid suction filtration of separating out, suction filtration get the DBTA salt 13.12g of the S single enantiomer of Levobupivacaine, and filtrate is reclaimed.
13.12g the DBTA salt of S single enantiomer with 120ml propyl carbinol-acetone (volume ratio 10: 1), gets the DBTA salt 7.38g of the S single enantiomer of bupivacaine, filtrate is reclaimed.
DBTA salt with sodium hydroxide solution and 7.38g S bupivacaine mixes, and transfers pH=11, with toluene 150ml extracting and separating organic phase, the organic phase anhydrous sodium sulfate drying, vacuum is revolved to steam and is obtained the 4.25g solid, is the S type single enantiomer (ee%=100, Figure 11) of bupivacaine.
Reclaim the DBTA salt 9.8g that filtrate and evaporated under reduced pressure must contain a large amount of R type bupivacaines, this solids can obtain 4.8g RS mixed type Levobupivacaine (R=52.1%, S=37.9%, Figure 12) through alkalization.This mixed type Levobupivacaine can continue with splitting after the above-mentioned steps racemization.
Claims (17)
1. the method for enrichment piperidines-2-carboxanilide optically-active compound, is characterized in that: comprise the steps:
(1) R type ropivacaine, bupivacaine or its intermediate are mixed with inert solvent, initiator, mercaptan, stirring is warming up to 70~110 ℃ and carries out racemization, obtain containing RS configuration ropivacaine, bupivacaine or its common intermediate N (2, the reaction solution of the product after the 6-3,5-dimethylphenyl)-2-piperidyl urea racemization, the racemization time is 2~10 hours, N-(2,6-3,5-dimethylphenyl)-the 2-piperidyl urea is pipecoloxylidide, hereinafter to be referred as: intermediate;
(2) reaction solution with step (1) gained adds acid to carry out salt-forming reaction, make its water layer pH to 1~6, add the organic solvent B extracting to separate organic phase, it is 8~13 that aqueous phase adds adjusting PH with base, add the organic solvent B extraction at aqueous phase, the organic phase drying dewaters to revolve and steams ropivacaine, bupivacaine or its intermediate solid that obtains racemization;
(3) ropivacaine, bupivacaine or its intermediate and chiral resolving agent L-(-)-dibenzoyl tartaric acid are prior to salify in alcoholic solution, again to becoming in salt system to add ketone solution, the L-(-) of the enantiomorph of S type-dibenzoyl tartaric acid salts out, a large amount of white precipitates appear in solution, suction filtration gets white solid, and filtrate is reclaimed;
(4) step (3) gained solid, with alcohol-ketone mixed solution dissolving, the crystallization suction filtration can get S type enantiomorph-L-(-)-dibenzoyl tartaric acid salt refining product, and filtrate is reclaimed;
(5) to be dissolved in bases and to make its system pH be 10 ~ 12 to step (4) gained solid, the organic solvent extracting, and drying is revolved the single enantiomer that steams the ropivacaine, bupivacaine or its intermediate that obtain the S type;
(6) with step (3), (4) gained filtrate decompression evaporate to dryness, the solid that obtains repeats above step (1)-(5) through alkalization;
Organic solvent B formic acid propyl ester, propyl acetate, ethyl acetate, toluene, p-Xylol, acetonitrile, methylene dichloride, o-Xylol, ether or methyl tertiary butyl ether in step (2).
2. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that:
In step (1), initiator divides three times and adds, the timed interval that gradation adds be 0.5~4 hour once, the amount that at every turn adds is 1/3rd of the total add-on of initiator.
3. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that: with molar ratio computing, and R type ropivacaine, bupivacaine or its intermediate: initiator: mercaptan=1: 0.2~1.6: 0.2~2.0.
4. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound, it is characterized in that: the initiator in step (1) is selected from 2,2'-Azobis(2,4-dimethylvaleronitrile), Diisopropyl azodicarboxylate, peroxidation two acyls or benzoyl peroxide.
5. the method for enrichment piperidines according to claim 4-2-carboxanilide optically-active compound, it is characterized in that: described peroxidation two acyls are dilauroyl peroxides.
6. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound, it is characterized in that: the described inert solvent of step (1) is selected from toluene, p-Xylol, acetonitrile, methylene dichloride, ethyl acetate or o-Xylol.
7. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound, is characterized in that: the mercaptan selected from mercapto methyl propionate described in step (1), Methyl Thioglycolate, positive eight mercaptan, sulfydryl methyl-butyrate, ethyl thioglycolate or mercaptopropionic acid ethyl ester.
8. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound, it is characterized in that: control water layer pH to 4~5 when adding acid to carry out salt-forming reaction the reaction solution of step (1) gained in step (2), add the organic solvent B extracting to separate organic phase, it is 11~12 that aqueous phase adds alkali to transfer pH.
9. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that:
Hydrochloric acid, sulfuric acid, nitric acid, Hydrogen bromide or phosphoric acid are selected in the acid of the salify in step (2); In and the alkali used of water select lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, magnesium hydroxide or ammoniacal liquor.
10. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that: add alcoholic solution to be selected from a kind of in the following lower aliphatic alcohols of C5 in step (3).
11. the method for enrichment piperidines according to claim 10-2-carboxanilide optically-active compound is characterized in that: described lower aliphatic alcohols is methyl alcohol, ethanol, propyl alcohol or propyl carbinol.
12. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that: add ketone solution to be selected from a kind of in acetone, butanone or pentanone in step (3).
13. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that: add alcohol and ketone liquor capacity ratio to be 1:1~10:1 in step (3).
14. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound, it is characterized in that: add alcohol-ketone mixing solutions in step (4), alcohol is selected from a kind of in methyl alcohol, ethanol, propyl alcohol, propyl carbinol, and ketone is selected from a kind of in acetone, pentanone or butanone.
15. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that: add alcohol-ketone mixing solutions in step (4), alcohol is 1:1~10:1 with the volume ratio of ketone.
16. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound is characterized in that: be used for organic solvent formic acid propyl ester, propyl acetate, ethyl acetate, toluene, p-Xylol, acetonitrile, methylene dichloride, the o-Xylol of extracting in step (5).
17. the method for enrichment piperidines according to claim 1-2-carboxanilide optically-active compound, step (4) repeat twice, then passing through step (5), to make S type enantiomorph ee% be 100.
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