CN101209990A - Resolution method for 3-piperidine formic acid ester - Google Patents
Resolution method for 3-piperidine formic acid ester Download PDFInfo
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Abstract
The invention relates to a method used for resolving 3-piperidine formate, which takes methanol or isopropanol or mixture of the methanol and the isopropanol as solvent. 3- piperidine formate that is a mixture of (R)-3-piperidine formate and (S)-3-piperidine formate is put into react with optically pure tartaric acid to generate a mixture of (R)-3-piperidine formate tartrate and (S)-3- piperidine formate tartrate, then the mixture is cooled to separate out a 3- piperidine formate tartrate crystal, the solubility of which is relatively low, the crystal is added with inorganic alkaline solution to make reaction, and finally an enantiomer of the 3- piperidine formate is prepared. The purity of finished product can be up to 90 percent after once crystallization is carried out by using the method of the invention and the product with relatively high purity (ee value of which is up to 99 percent) can be prepared after twice crystallization, thereby the operation is simple and consumption of organic solvent is saved, besides, the cost is low while the yield is high.
Description
Technical field
The invention belongs to the separation technology field of organic steric isomer, be specifically related to a kind of method that the nipecotic acid ester is split.
Background technology
Identical and the chemical structure difference of molecular formula in the organism, thereby the phenomenon that shows different physico-chemical properties is called isomery, abbreviates isomery as.These organic compound are called isomers each other, are called for short isomer.Isometry can be divided into structure isomery and stereoisomerism two big classes.The structure isomery is different with order by the mode that interconnects of atom in the molecule, caused isomery; Stereoisomerism is meant that the interconnected mode of the atom in the molecule is identical with order, but in spatial arrangement mode difference, and the isomery that causes.Stereoisomerism can be divided into cis-trans isomerism, conformational isomerism and enantiomerism again.Cis-trans isomerism is meant in the molecule can determine two keys of a planar or ring if contain, in this pair key or the member ring systems carbon atom and different substituting group in conjunction with the time, different substituting groups can form different distributions in the planar both sides, the result produces the isomery of different configurations.Conformational isomerism is meant the isomery that produces because of the intramolecularly rotation, and the rotation of this intramolecularly does not produce the fracture of key and formation again; And in the molecule if contain can determine a planar pair keys cis-trans isomerism when formation, if rotation phenomenon is arranged, then this turning effort will be accompanied by the fracture of key and the appearance of forming process again.Enantiomerism is meant the in kind each other and mirror image of two isomerss, enantiomorphous isomery each other, and they can not overlap.The difference of this structure is reflected on the physical properties, is exactly the opticity difference, and general a pair of enantiomer (being called for short a pair of enantiomorph) can be divided into levo form and dextrorotatory form according to the difference of its opticity; And in laboratory or factory, under general condition synthetic has the compound of opticity, and the levo form and the dextrorotatory form of its equivalent mix, and what this mixture externally demonstrated is no opticity, therefore again this mixture is called racemic modification.Very little for a pair of enantiomorph because of their structural difference, though the physical properties except that opticity is identical as molten boiling point, solubleness etc., chemical property is also basic identical, but their biological activity is often different, in industries such as pharmacy, how easy, fast obtain needed levo form or dextrorotatory form, just racemic modification being taken apart is exactly a very important problem, often needs just can carry out taking apart of racemic modification with special physics and chemofacies bonded method or biochemical method.
The nipecotic acid ester generally all is the mixture of enantiomer (R)-nipecotic acid ester and (S)-nipecotic acid ester, (mixture must become the racemic modification of levo form and dextrorotatory form equivalent through the racemization rear, is not directly to be exactly the two equivalent for the levo form of equivalent and dextrorotatory form blended racemic modification after racemization; Racemic modification does not externally have opticity).It is synthetic that optically pure (R)-nipecotic acid ester and (S)-nipecotic acid ester can be used for the plurality of raw materials medicine, wherein optically pure (R)-nipecotic acid ester can be used for the synthetic of Sai Jiabin, so be necessary (R)-nipecotic acid ester to be taken apart with (S)-nipecotic acid ester mixture and separated (also claiming the nipecotic acid ester is split) optically pure (R)-nipecotic acid ester to obtain and/or (S)-nipecotic acid ester.Physics that the enantiomer of nipecotic acid ester is taken apart and chemofacies bonded separation method are generally racemic nipecotic acid ester and L-tartrate or D-tartrate are reacted in solvent, form the mixture of (R)-nipecotic acid ester-L-tartrate and (S)-nipecotic acid ester-two kinds of salt of L-tartrate, or (R)-mixture of nipecotic acid ester-D-tartrate and (S)-nipecotic acid ester-two kinds of salt of D-tartrate, utilize the different solubility of salt under same temperature of resulting two kinds of diastereomers, use suitable solvent that two kinds of salt are all dissolved, cooling crystallizes out a kind of salt wherein earlier again, thereby obtain optically pure (R)-nipecotic acid ester-L-tartrate, perhaps obtain optically pure (S)-nipecotic acid ester-D-tartrate, then this salt and the inorganic alkaline aqueous solution are reacted, obtain optically pure (R)-nipecotic acid ester at last, perhaps optically pure (S)-nipecotic acid ester.
Magazine " chirality " (Chirality.1995 in the 7th phase of nineteen ninety-five; 7 (2): disclose document " synthesizing of antithrombotic piperidine carboxylic acid ester steric isomer " (Synthesis of Stereoisomers of AntithromboticNipecotamides) 90-5), periodical " American Chemical Society " (J.Am.Chem.Soc.2000 2000 the 122nd phases, 122, disclose document 3995-4004) and " comprised the stereochemistry control that the hair clip formula of the β-peptide of nipecotic acid counter-rotating section constitutes " (Stereochemical Control of Hairpin Formation in β-Peptides Containing Dinipecotic AcidReverse Turn Segments), these two pieces of documents adopt above-mentioned separation method that the nipecotic acid ester is split exactly, wherein the solvent that is adopted is a dehydrated alcohol, racemic nipecotic acid ester and L-tartrate are reacted generation (R)-nipecotic acid ester-L-tartrate and (S)-nipecotic acid ester-L-tartrate in dehydrated alcohol, cooling is separated out the lower salt crystallization of solubleness then, add basic metal or the oxyhydroxide of alkaline-earth metal or the reactant aqueous solution of carbonated, obtain corresponding a kind of enantiomer of optically pure nipecotic acid ester at last, the shortcoming of the method for these two pieces of documents is that the crystalline number of times is too many, generally want crystallization about 5 times, operate more loaded down with trivial details, need to consume a large amount of organic solvents simultaneously, and yield is not high yet, generally about 10%～23%.
Publication number is that the Japanese documentation of JP2001354652 discloses a kind of " separation method of piperidine carboxylic acid derivative " (METHOD FOR OPTICAL RESOLUTION OF PIPERIDINECARBOXYLIC ACIDDERIVATIVE), adopt amygdalic acid to come to react in the document with the racemic modification of nipecotic acid ester as separating agent, generate nipecotic acid ester-mandelate, cooling is separated out the lower salt crystallization of solubleness then, add basic metal or the oxyhydroxide of alkaline-earth metal or the reactant aqueous solution of carbonated, obtain a kind of enantiomer of optically pure nipecotic acid ester at last, but the price of amygdalic acid is higher, the source is subjected to certain restriction, therefore use amygdalic acid to separate the nipecotic acid ester and can improve production cost, and isolating yield is not high yet.
Summary of the invention
The purpose of this invention is to provide a kind of simple to operate, yield is higher, the lower-cost method that the nipecotic acid ester is split simultaneously.
The technical scheme that realizes the object of the invention is: the method with the nipecotic acid ester splits may further comprise the steps: 1. add organic solvent in reaction vessel, this organic solvent is the mixture of methyl alcohol, Virahol or methyl alcohol and Virahol; Add then is (R)-nipecotic acid ester and (S)-nipecotic acid ester and the L-tartrate or the D-tartrate of the mixture of nipecotic acid ester, heating under agitation make L-tartrate or D-tartrate and the reaction of nipecotic acid ester generate (R)-nipecotic acid ester tartrate with (S)-mixture of nipecotic acid ester tartrate; Wherein, when tartrate is L-tartrate, generate the mixture of (R)-nipecotic acid ester-L-tartrate and (S)-nipecotic acid ester-L-tartrate, when tartrate is D-tartrate, generate the mixture of (R)-nipecotic acid ester-D-tartrate and (S)-nipecotic acid ester-D-tartrate; 2. 1. step being reacted the resulting mixture in back lowers the temperature, when this mixture is the mixture of (R)-nipecotic acid ester-L-tartrate and (S)-nipecotic acid ester-L-tartrate, then (R)-nipecotic acid ester-L-tartrate is separated out from crystallization wherein by cooling, then material is filtered, obtain (R)-nipecotic acid ester-L-tartrate salt crystals; When this mixture is the mixture of (R)-nipecotic acid ester-D-tartrate and (S)-nipecotic acid ester-D-tartrate, then (S)-nipecotic acid ester-D-tartrate is separated out from crystallization wherein by cooling, then material is filtered, obtain (S)-nipecotic acid ester-D-tartrate salt crystals; 3. in other reaction vessel, drop into organic solvent, make the cooling of this organic solvent, add (R)-nipecotic acid ester-L-tartrate salt crystals that 2. step make or (S)-nipecotic acid ester-D-tartrate salt crystals then; When the crystal that is added is (R)-nipecotic acid ester-L-tartrate salt crystals, under agitation in mixture, add inorganic alkaline solution, this inorganic alkaline solution with (R)-reaction of nipecotic acid ester-L-tartrate generates (R)-nipecotic acid ester, continue to stir to make to react completely after adding inorganic alkaline solution, separatory obtains the organic phase material then, in the organic phase material, add the dry moisture content of siccative, filter then, the organic phase material normal pressure or the underpressure distillation that obtain after filtering are made the organic solvent volatilization, thereby obtain (R)-nipecotic acid ester of colorless liquid; When the crystal that is added is (S)-nipecotic acid ester-D-tartrate salt crystals, under agitation in mixture, add inorganic alkaline solution, this inorganic alkaline solution with (S)-reaction of nipecotic acid ester-D-tartrate generates (S)-nipecotic acid ester, continue to stir to make to react completely after adding inorganic alkaline solution, separatory obtains the organic phase material then, in the organic phase material, add the dry moisture content of siccative, filter then, the organic phase material normal pressure or the underpressure distillation that obtain after filtering are made the organic solvent volatilization, thereby obtain (S)-nipecotic acid ester of colorless liquid.
2. aforesaid method also has step ' treating process, treating process step 2. and step 3. between; Treating process is carried out following operation: add organic solvent in other reactor, this organic solvent is the mixture of methyl alcohol, Virahol or methyl alcohol and Virahol; Add the crystal that 2. step makes then, when the 2. prepared crystal of step is (R)-nipecotic acid ester-L-tartrate salt crystals, under agitation the heated mixt material dissolves crystal fully, (R)-nipecotic acid ester-L-tartrate crystallization is wherein separated out the mixture cooling again, then with material filtering and dry purity higher (R)-nipecotic acid-L-ester tartrate salt crystals that obtains; When the 2. prepared crystal of step is (S)-nipecotic acid ester-D-tartrate salt crystals, under agitation the heated mixt material dissolves crystal fully, (S)-nipecotic acid ester-D-tartrate crystallization is wherein separated out the mixture cooling again, then with material filtering and dry higher (the S)-nipecotic acid ester-D-tartrate salt crystals of purity that obtains.
Above-mentioned steps is 2. ' in the mol ratio of the step that added crystal that 2. makes and the organic solvent that is added be (1: 0.2)～(1: 25); It is 66 ℃～68 ℃ that the heated mixt material makes the temperature of dissolution of crystals; The temperature that crystal is separated out the mixture cooling is 18 ℃～20 ℃.
Above-mentioned steps is carried out in 3. after separatory handles, with the organic phase material that obtains as first group of organic phase material; Inorganic phase materials for separatory obtains under agitation mixes with organic solvent, separatory then, with the organic phase material that obtains as second group of organic phase material; Then with first group of organic phase material with after second group of organic materials mixes, add siccative again.
The nipecotic acid ester of above-mentioned steps in 1. is nipecotic acid methyl esters, nipecotic acid ethyl ester, nipecotic acid propyl ester or nipecotic acid butyl ester; Step 3. in used organic solvent be methyl tertiary butyl ether, methyl ether, ether or ethyl acetate; The inorganic alkaline solution of step in 3. is the aqueous solution, the aqueous solution of alkali metal carbonate compound or the aqueous solution of alkaline-earth metal carbonated of the oxyhydroxide of metal on the aqueous solution, alkali of alkali-metal oxyhydroxide, the aqueous solution, the aqueous solution of potassium hydroxide, the aqueous solution of yellow soda ash or the aqueous solution of salt of wormwood of preferred sodium hydroxide; Step 3. in used siccative be anhydrous magnesium sulfate or anhydrous sodium sulphate.
Above-mentioned steps in 1. (the R)-nipecotic acid ester in the used nipecotic acid ester with (S)-mol ratio of nipecotic acid ester is (1: 9)～(9: 1), step in 1. used nipecotic acid ester and the mol ratio of organic solvent be (1: 0.5)～(1: 50), used tartrate is optical purity tartrate, the mol ratio of this tartrate and organic solvent is (1: 0.5)～(1: 50), and the mol ratio of this tartrate and nipecotic acid ester is (1: 0.5)～(1: 5); Above-mentioned steps in 3. the used 2. resulting crystal of step and basic solution and with the mol ratio of organic solvent be 1: (1～10): (1～30).
When above-mentioned steps heated mixture in 1., making its temperature was 45 ℃～50 ℃.When above-mentioned steps was lowered the temperature to mixture in 2., making its temperature was 18 ℃～20 ℃.When above-mentioned steps was lowered the temperature to organic solvent in 3., making its temperature was 0 ℃～5 ℃, and remained to reacting completely of generation (R)-nipecotic acid ester or (S)-nipecotic acid ester always; When step added basic solution in 3., its adding mode was for dripping; The step 3. pressure of middle underpressure distillation is 4 * 10
3Pa～8 * 10
3Pa.
The present invention has positive effect: (1) the inventive method adopts the mixture of methyl alcohol or Virahol or methyl alcohol and Virahol as solvent, corresponding tartrate with nipecotic acid ester and tartaric a kind of enantiomerism precursor reactant generation nipecotic acid ester, at this moment product is a diastereomer, thereby can utilize the deliquescent difference between the diastereomer, a kind of nipecotic acid ester tartrate crystallization that solubleness is lower under the certain temperature is separated out, add basic solution and its reaction then, obtain a kind of enantiomer of nipecotic acid ester at last.Adopt method of the present invention, operate fairly simple, the consumption of having saved organic solvent simultaneously.(2) the present invention can be only step 2. in the employing primary crystallization, the purity of this method end product can reach 90%, yield is 33%～40%; If increase step 2. ', then whole invention also only need be carried out twice crystallization operation, and not only operation is still fairly simple, and can obtain purity high product (the ee value can reach 99%), and the yield after the crystallization is compared higher generally more than 28% with the yield 10%～23% of prior art.(3) the inventive method does not adopt the amygdalic acid that the source is restricted and price is also higher, but has adopted tartrate cheap and easy to get as separating agent and the reaction of nipecotic acid ester, makes production cost lower yet.
Embodiment
(embodiment 1)
Present embodiment is for splitting the method that obtains (R)-nipecotic acid methyl esters with the racemic modification of nipecotic acid methyl esters ((R)-nipecotic acid methyl esters with (S)-nipecotic acid methyl esters mol ratio is 1: 1).Wherein solvent for use is methyl alcohol and Virahol and its mixture, and described inorganic alkaline solution is salt of wormwood, and used organic solvent is a methyl tertiary butyl ether, and used siccative is an anhydrous magnesium sulfate.The nipecotic acid methyl esters can oneself prepare, and is also commercially available, and present embodiment is self-control, and the remaining reaction thing is commercial.Wherein the preparation method of nipecotic acid methyl esters is as follows:
Add methyl alcohol 500ml to reactor, and it is cooled to 0 ℃～5 ℃, past then wherein dripping thionyl chloride 180g, rate of addition is as the criterion at 0 ℃～5 ℃ to control temperature, drip under agitation to divide behind the sulfur oxychloride and add nipecotic acid 129g several times, adding the back continues to stir 0.5 hour, being heated to the mixture temperature then is to stir under 20 ℃～25 ℃ conditions to make the mixture reaction generate the nipecotic acid methyl esters in 10 hours, reheat to mixture temperature is to stir under 50 ℃～55 ℃ conditions 1 hour, is heated to back flow reaction then and makes in 4 hours and react completely.
Is 6 * 10 with above-mentioned reaction product at pressure
3Pa, temperature are that methyl alcohol is removed in underpressure distillation under 105 ℃～165 ℃ the condition, under agitation add methyl tertiary butyl ether 300ml then, adding the back is cooled to mixture below 10 ℃ with ice bath, be 30% sodium hydroxide solution toward wherein dripping mass percent then, making itself and nipecotic acid reaction generate nipecotic acid receives, and control makes the temperature of mixture be no more than 10 ℃, checks PH with test paper, is to stop the hydro-oxidation sodium solution at 9～9.5 o'clock.Separatory obtains organic materials then, in organic materials, add 10g anhydrous magnesium sulfate and 2g gac, controlled temperature stirs under 0 ℃～5 ℃ conditions and filtered then in 2～3 hours, is that methyl tertiary butyl ether is reclaimed in air distillation under 50 ℃～65 ℃ conditions with the organic materials that obtains in temperature, is 6 * 10 at pressure again
3Pa, temperature are that underpressure distillation under 105 ℃～165 ℃ conditions, racemize obtain colorless liquid product nipecotic acid methyl esters 80g (wherein the mol ratio of (R)-nipecotic acid methyl esters and (S)-nipecotic acid methyl esters is 1: 1), yield 56.0%.
The racemic modification of above-mentioned nipecotic acid methyl esters split and obtain the method (being called for short L-tartrate scheme) of (R)-nipecotic acid methyl esters, may further comprise the steps:
1. the L-tartrate for preparing the nipecotic acid methyl esters.In empty reaction flask, drop into methyl alcohol 12.4mol (500ml), add L-tartrate 0.6mol (90g) then, heating makes the mixture temperature to be 20 ℃～55 ℃ and to stir L-tartrate is dissolved fully, add above-mentioned homemade nipecotic acid methyl esters racemic modification 0.56mol (80g) then and (can add L-tartrate earlier, also the nipecotic acid methyl esters can be added earlier or the two adds together, present embodiment is for adding L-tartrate earlier), it is 45 ℃～50 ℃ that heating under agitation makes the temperature of mixture temperature, continue to stir then 5～10 minutes, make the reaction of nipecotic acid methyl esters and L-tartrate generate (R)-nipecotic acid methyl esters-L-tartrate with (S)-mixture of nipecotic acid methyl esters-L-tartrate.
2. crystallization goes out (R)-nipecotic acid methyl esters-L-tartrate.Under agitation in step post reaction mixture material 1., add Virahol 6.5mol (500ml), add the back and continue to stir after 30 minutes that (the solvent Virahol of Jia Ruing also can add with methyl alcohol in 1. in step herein, as adding in 1. in step, the step that then adds Virahol herein can be omitted), cooling mixing material to its temperature is 36 ℃～38 ℃, (R)-nipecotic acid methyl esters-L-tartrate salt crystals 1 gram that adds the amount of inducing is as the crystal seed induced crystallization, in 5 hours, mixture is cooled to 18 ℃～20 ℃, (R)-nipecotic acid methyl esters-L-tartrate crystallization is separated out, then material is filtered, obtain the wet product 0.192mol (56.4g) of (R)-nipecotic acid methyl esters-L-tartrate crude product, sampling uses chiral chromatographic column to detect, and the ee value is more than 90%.
2. ' treating process, treating process step 2. and step 3. between; Treating process is carried out following operation: add methyl alcohol 6.2mol (250ml) and Virahol 3.3mol (250ml) in other reactor, add (R)-nipecotic acid methyl esters-L-tartrate crude product that 2. above-mentioned steps makes then, under agitation to make its temperature be 66 ℃～68 ℃ to the heated mixt material, after treating that solid dissolves fully, mixture is cooled to 59 ℃～60 ℃, (R)-nipecotic acid methyl esters-L-tartrate salt crystals 0.5 gram that adds the amount of inducing then is as the crystal seed induced crystallization, in 5 hours mixture being cooled to 18 ℃～20 ℃ separates out (R)-nipecotic acid methyl esters-L-tartrate crystallization wherein, then with material filtering and dry, obtain the wet product of (R)-nipecotic acid methyl esters-L-tartrate 0.16mol (47g) elaboration, productive rate is 28.6%, sampling uses chiral chromatographic column to detect, and the ee value is more than 99%.
3. by (R)-nipecotic acid methyl esters-L-tartrate preparation (R)-nipecotic acid methyl esters.In other reactor, add methyl tertiary butyl ether 4.6mol (550ml), and it is cooled to 0 ℃～5 ℃, then toward wherein adding step 2. ' (R)-nipecotic acid methyl esters-L-tartrate 47g (0.16mol) of making, the Carbon Dioxide aqueous solutions of potassium of Dropwise 5 .4mol/L (wherein containing Anhydrous potassium carbonate 0.40mol) in mixture under agitation, make its with (R)-reaction of nipecotic acid methyl esters-L-tartrate (0.16mol) generates (R)-nipecotic acid methyl esters, rate of addition is as the criterion to control temperature, continue after dripping to stir to make in 2 hours to react completely, separatory obtains the organic phase material then, with the organic phase material that obtains as first group of organic phase material; The inorganic phase materials that obtains for separatory, under agitation mix with methyl tertiary butyl ether, separatory then, with the organic phase material that obtains as second group of organic phase material, then with first group of organic phase material and second group of organic phase mixing of materials, adding anhydrous magnesium sulfate in the mixed organic phase material and carry out dry moisture content, filter then, is 6 * 10 with the filtrate organic phase material that obtains after filtering at pressure
3Pa, temperature are that underpressure distillation makes the methyl tertiary butyl ether volatilization under 105 ℃～165 ℃ conditions, obtain (R)-nipecotic acid methyl esters 0.119mol (17g) of colorless liquid.
(embodiment 2 to embodiment 10)
Embodiment 2 to embodiment 10 still splits the method (L-tartrate scheme) that obtains (R)-nipecotic acid methyl esters for the racemic modification with the nipecotic acid methyl esters, the rest part of these embodiment is substantially the same manner as Example 1, its difference is: the nipecotic acid methyl esters is commercial, each reactant composition and mol ratio thereof see Table 1 to table 2 ((R)-nipecotic acid methyl esters that 2. step makes in the table-L-tartrate crude product abbreviation crude product, step is 2. ' (R)-nipecotic acid methyl esters of making for the treatment of process-L-tartrate elaboration is called for short elaboration, "/" expression does not have).
(embodiment 11 to embodiment 20)
The method that embodiment 11 to embodiment 20 obtains (R)-nipecotic acid ethyl ester for the racemic modification with the nipecotic acid ethyl ester splits (L-tartrate scheme), the rest part of these embodiment is substantially the same manner as Example 1, its difference is: the main raw material of step in 1. is the nipecotic acid ethyl ester, the nipecotic acid ethyl ester is commercial, the organic solvent of step in 3. is methyl ether, the inorganic alkaline solution of step in 3. is aqueous sodium carbonate, the reactant composition of relevant step and mol ratio thereof see Table 3 to table 4 ((R)-nipecotic acid ethyl ester that 2. step makes in the table-L-tartrate crude product abbreviation crude product, step is 2. ' (R)-nipecotic acid ethyl ester of making for the treatment of process-L-tartrate elaboration is called for short elaboration, "/" expression does not have).
(embodiment 21 to embodiment 30)
The method that embodiment 21 to embodiment 30 obtains (S)-nipecotic acid propyl ester for the racemic modification with the nipecotic acid propyl ester splits (being called for short D-tartrate scheme), the rest part of these embodiment is substantially the same manner as Example 1, and its difference is:
The main raw material nipecotic acid propyl ester of step in 1., the nipecotic acid propyl ester is commercial, and the organic solvent of step in 3. is ether, and the inorganic alkaline solution of step in 3. is aqueous sodium hydroxide solution;
The tartrate that step adds in 1. is D-tartrate, D-tartrate and the reaction of nipecotic acid propyl ester generate (R)-nipecotic acid propyl ester-D-tartrate with (S)-mixture of nipecotic acid propyl ester-D-tartrate;
The crystal seed that step is used for induced crystallization in 2. is (S)-nipecotic acid propyl ester-D-tartrate salt crystals, and what crystallization was separated out is (S)-nipecotic acid propyl ester-D-tartrate, and filtering the crystal that obtains is (S)-nipecotic acid propyl ester-D-tartrate salt crystals;
Step is 2. ' crystal that 2. makes of the step that adds in the organic solvent in the treating process is (S)-nipecotic acid propyl ester-D-tartrate salt crystals, treat that the crystal seed that is used for induced crystallization that adds after solid dissolves fully is (S)-nipecotic acid propyl ester-D-tartrate salt crystals, (S)-nipecotic acid propyl ester-D-tartrate that the cooling post crystallization is separated out, what the filtration after drying obtained is (S)-nipecotic acid propyl ester-D-tartrate salt crystals;
The step that step adds in the organic solvent ether in 3. is 2. ' crystal that makes is (S)-nipecotic acid propyl ester-D-tartrate salt crystals, inorganic alkaline solution be aqueous sodium hydroxide solution with (S)-nipecotic acid propyl ester-D-tartrate reaction generates (S)-nipecotic acid propyl ester, the used siccative of separatory after drying is an anhydrous sodium sulphate, and what underpressure distillation obtained is (S)-nipecotic acid propyl ester.
The reactant composition of relevant step and mol ratio thereof see Table 5 to table 6 ((S)-nipecotic acid propyl ester that 2. step makes in the table-D-tartrate crude product abbreviation crude product, step is 2. ' (S)-nipecotic acid propyl ester of making for the treatment of process-D-tartrate elaboration is called for short elaboration, "/" expression does not have).
(embodiment 31 to embodiment 40)
The method that embodiment 31 to embodiment 40 obtains (S)-nipecotic acid butyl ester for the racemic modification with the nipecotic acid butyl ester splits (D-tartrate scheme), the rest part of these embodiment and embodiment 21 to embodiment 30 are basic identical, its difference is: the main raw material of step in 1. is the nipecotic acid butyl ester, the organic solvent of step in 3. is ethyl acetate, the inorganic alkaline solution of step in 3. is potassium hydroxide aqueous solution, the reactant composition of relevant step and mol ratio thereof see Table 7 to table 8 ((S)-nipecotic acid butyl ester that 2. step makes in the table-D-tartrate crude product abbreviation crude product, step is 2. ' (S)-nipecotic acid butyl ester of making for the treatment of process-D-tartrate elaboration is called for short elaboration, "/" expression does not have).
In the foregoing description 1 to embodiment 10, step 2. in the resulting filtrate, (R)-nipecotic acid methyl esters-L-tartrate with (S)-nipecotic acid methyl esters-L-tartrate mol ratio is about 3: 7 (about 1: 2.3), to this filtrate cooling make wherein (R)-nipecotic acid methyl esters-L-tartrate and (S)-nipecotic acid methyl esters-whole crystallizations of L-tartrate separate out, carry out the similar step operation 3. among the embodiment then, thereby obtain mol ratio be about (R)-nipecotic acid methyl esters of 3: 7 with (S)-mixture of nipecotic acid methyl esters, this mixture be can be used as raw material carries out follow-up fractionation.The tartaric scheme of L-can be still adopted in this follow-up fractionation.In the follow-up fractured operation, the nipecotic acid methyl esters is not a racemic modification, but the quantity of (S)-nipecotic acid methyl esters of enantiomer is more than the quantity of (R)-nipecotic acid methyl esters, and in the 2. resulting filtrate of the step of follow-up fractionation each time, because being arranged, (the R)-nipecotic acid methyl esters-L-tartrate crystallization about half tells, so (R)-nipecotic acid methyl esters-L-tartrate with (S)-numeric ratio last time of nipecotic acid methyl esters-L-tartrate mol ratio reduces, be reduced to 1: 9 until this ratio, thus when being used for splitting next time by this filtrate is resulting as (R)-nipecotic acid methyl esters of the nipecotic acid methyl esters of raw material with (S)-mol ratio of nipecotic acid methyl esters is exactly 1: 9.
Otherwise, if with step in the foregoing description 1 to embodiment 10 2. in resulting filtrate cooling make wherein mol ratio be about (R)-nipecotic acid methyl esters-L-tartrate of 3: 7 and (S)-nipecotic acid methyl esters-whole crystallizations of L-tartrate to separate out, carry out the similar step operation 3. among the embodiment then, thus obtain mol ratio be about (R)-nipecotic acid methyl esters of 3: 7 with (S)-mixture of nipecotic acid methyl esters.This mixture is carried out follow-up fractionation with the tartaric scheme of D-, so, in the 2. resulting filtrate of the step of follow-up fractionation each time, because being arranged, (the S)-nipecotic acid methyl esters-D-tartrate crystallization about half tells, so (R)-nipecotic acid methyl esters-D-tartrate with (S)-numeric ratio of nipecotic acid methyl esters-D-tartrate mol ratio is last to be increased, increase to 9: 1 until this ratio, thus when being used for splitting next time by this filtrate is resulting as (R)-nipecotic acid methyl esters of the nipecotic acid methyl esters of raw material with (S)-mol ratio of nipecotic acid methyl esters is exactly 9: 1.
Similar therewith, 2. the step of the foregoing description 11 to embodiment 20 passes through in the filtering filtrate, (R)-nipecotic acid ethyl ester-L-tartrate with (S)-nipecotic acid ethyl ester-L-tartrate mol ratio is inequality, through different follow-up fractionation, the mol ratio of (R)-nipecotic acid ethyl ester and (S) in the used main raw material-nipecotic acid ethyl ester can be selected between (9: 1)～(1: 9).
Similar therewith, 2. the step of the foregoing description 21 to embodiment 30 passes through in the filtering filtrate, (R)-nipecotic acid propyl ester-D-tartrate with (S)-nipecotic acid propyl ester-D-tartrate mol ratio is inequality, through different follow-up fractionation, the mol ratio of (R)-nipecotic acid propyl ester and (S) in the used main raw material-nipecotic acid propyl ester can be selected between (9: 1)～(1: 9).
Similar therewith, 2. the step of the foregoing description 31 to embodiment 40 passes through in the filtering filtrate, (R)-nipecotic acid butyl ester-D-tartrate with (S)-nipecotic acid butyl ester-D-tartrate mol ratio is inequality, through different follow-up fractionation, the mol ratio of (R)-nipecotic acid butyl ester and (S) in the used main raw material-nipecotic acid butyl ester can be selected between (9: 1)～(1: 9).
Table 1
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
Table 8
Claims (10)
1. method that the nipecotic acid ester is split, may further comprise the steps: 1. add organic solvent in reaction vessel, this organic solvent is the mixture of methyl alcohol, Virahol or methyl alcohol and Virahol; Add then is (R)-nipecotic acid ester and (S)-nipecotic acid ester and the L-tartrate or the D-tartrate of the mixture of nipecotic acid ester, heating under agitation make L-tartrate or D-tartrate and the reaction of nipecotic acid ester generate (R)-nipecotic acid ester tartrate with (S)-mixture of nipecotic acid ester tartrate; Wherein, when tartrate is L-tartrate, generate the mixture of (R)-nipecotic acid ester-L-tartrate and (S)-nipecotic acid ester-L-tartrate, when tartrate is D-tartrate, generate the mixture of (R)-nipecotic acid ester-D-tartrate and (S)-nipecotic acid ester-D-tartrate; 2. 1. step being reacted the resulting mixture in back lowers the temperature, when this mixture is the mixture of (R)-nipecotic acid ester-L-tartrate and (S)-nipecotic acid ester-L-tartrate, then (R)-nipecotic acid ester-L-tartrate is separated out from crystallization wherein by cooling, then material is filtered, obtain (R)-nipecotic acid ester-L-tartrate salt crystals; When this mixture is the mixture of (R)-nipecotic acid ester-D-tartrate and (S)-nipecotic acid ester-D-tartrate, then (S)-nipecotic acid ester-D-tartrate is separated out from crystallization wherein by cooling, then material is filtered, obtain (S)-nipecotic acid ester-D-tartrate salt crystals; 3. in other reaction vessel, drop into organic solvent, make the cooling of this organic solvent, add (R)-nipecotic acid ester-L-tartrate salt crystals that 2. step make or (S)-nipecotic acid ester-D-tartrate salt crystals then; When the crystal that is added is (R)-nipecotic acid ester-L-tartrate salt crystals, under agitation in mixture, add inorganic alkaline solution, this inorganic alkaline solution with (R)-reaction of nipecotic acid ester-L-tartrate generates (R)-nipecotic acid ester, continue to stir to make to react completely after adding inorganic alkaline solution, separatory obtains the organic phase material then, in the organic phase material, add the dry moisture content of siccative, filter then, the organic phase material normal pressure or the underpressure distillation that obtain after filtering are made the organic solvent volatilization, thereby obtain (R)-nipecotic acid ester of colorless liquid; When the crystal that is added is (S)-nipecotic acid ester-D-tartrate salt crystals, under agitation in mixture, add inorganic alkaline solution, this inorganic alkaline solution with (S)-reaction of nipecotic acid ester-D-tartrate generates (S)-nipecotic acid ester, continue to stir to make to react completely after adding inorganic alkaline solution, separatory obtains the organic phase material then, in the organic phase material, add the dry moisture content of siccative, filter then, the organic phase material normal pressure or the underpressure distillation that obtain after filtering are made the organic solvent volatilization, thereby obtain (S)-nipecotic acid ester of colorless liquid.
2. method according to claim 1 is characterized in that: also have step 2. ' treating process, treating process step 2. and step 3. between; Treating process is carried out following operation: add organic solvent in other reactor, this organic solvent is the mixture of methyl alcohol, Virahol or methyl alcohol and Virahol; Add the crystal that 2. step makes then, when the 2. prepared crystal of step is (R)-nipecotic acid ester-L-tartrate salt crystals, under agitation the heated mixt material dissolves crystal fully, (R)-nipecotic acid ester-L-tartrate crystallization is wherein separated out the mixture cooling again, then with material filtering and dry purity higher (R)-nipecotic acid-L-ester tartrate salt crystals that obtains; When the 2. prepared crystal of step is (S)-nipecotic acid ester-D-tartrate salt crystals, under agitation the heated mixt material dissolves crystal fully, (S)-nipecotic acid ester-D-tartrate crystallization is wherein separated out the mixture cooling again, then with material filtering and dry higher (the S)-nipecotic acid ester-D-tartrate salt crystals of purity that obtains.
3. method according to claim 2 is characterized in that: step is 2. ' in the mol ratio of the step that added crystal that 2. makes and the organic solvent that is added be (1: 0.2)～(1: 25); It is 66 ℃～68 ℃ that the heated mixt material makes the temperature of dissolution of crystals; The temperature that crystal is separated out the mixture cooling is 18 ℃～20 ℃.
4. method according to claim 2 is characterized in that: step is carried out in 3. after separatory handles, with the organic phase material that obtains as first group of organic phase material; Inorganic phase materials for separatory obtains under agitation mixes with organic solvent, separatory then, with the organic phase material that obtains as second group of organic phase material; Then with first group of organic phase material with after second group of organic materials mixes, add siccative again.
5. according to the described method of one of claim 1 to 4, it is characterized in that: the nipecotic acid ester of step in 1. is nipecotic acid methyl esters, nipecotic acid ethyl ester, nipecotic acid propyl ester or nipecotic acid butyl ester; Step 3. in used organic solvent be methyl tertiary butyl ether, methyl ether, ether or ethyl acetate; The inorganic alkaline solution of step in 3. is the aqueous solution, the aqueous solution of alkali metal carbonate compound or the aqueous solution of alkaline-earth metal carbonated of oxyhydroxide of the aqueous solution, the alkaline-earth metal of alkali-metal oxyhydroxide; Step 3. in used siccative be anhydrous magnesium sulfate or anhydrous sodium sulphate.
6. method according to claim 5 is characterized in that: the inorganic alkaline solution of step in 3. is the aqueous solution of sodium hydroxide, the aqueous solution of potassium hydroxide, the aqueous solution of yellow soda ash or the aqueous solution of salt of wormwood.
7. according to the described method of one of claim 1 to 4, it is characterized in that: step in 1. (the R)-nipecotic acid ester in the used nipecotic acid ester with (S)-mol ratio of nipecotic acid ester is (9: 1)～(1: 9), step used (R)-nipecotic acid ester and (S) in the 1.-mixture of nipecotic acid ester and the mol ratio of organic solvent are (1: 0.5)～(1: 50), used tartrate is optical purity tartrate, the mol ratio of this tartrate and organic solvent is (1: 0.5)～(1: 50), and the mol ratio of this tartrate and nipecotic acid ester is (1: 0.5)～(1: 5); Above-mentioned steps in 3. the used 2. resulting crystal of step and basic solution and with the mol ratio of organic solvent be 1: (1～10): (1～30).
8. according to the described method of one of claim 1 to 4, it is characterized in that: when step heated mixture in 1., making its temperature was 45 ℃～50 ℃.
9. according to the described method of one of claim 1 to 5, it is characterized in that: when step was lowered the temperature to mixture in 2., making its temperature was 18 ℃～20 ℃.
10. according to the described method of one of claim 1 to 4, it is characterized in that: when step was lowered the temperature to organic solvent in 3., making its temperature was 0 ℃～5 ℃, and remained to reacting completely of generation (R)-nipecotic acid ester or (S)-nipecotic acid ester always; When step added basic solution in 3., its adding mode was for dripping; The step 3. pressure of middle underpressure distillation is 4 * 10
3Pa～8 * 10
3Pa.
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| CN102952065A (en) * | 2011-08-24 | 2013-03-06 | 重庆华邦胜凯制药有限公司 | Resolution method for cis-2,3-pyridine diformate |
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| CN102952065A (en) * | 2011-08-24 | 2013-03-06 | 重庆华邦胜凯制药有限公司 | Resolution method for cis-2,3-pyridine diformate |
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| CN104356051A (en) * | 2014-11-24 | 2015-02-18 | 苏州乔纳森新材料科技有限公司 | Analgesic intermediate and synthesis method thereof |
| CN104557677A (en) * | 2014-12-31 | 2015-04-29 | 大连联化化学有限公司 | Chemical resolution preparation method for optical pure 2-pipecolic acid |
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