CN111153819A - Method for splitting 3-chloro-phenylglycine enantiomer by liquid-liquid extraction - Google Patents
Method for splitting 3-chloro-phenylglycine enantiomer by liquid-liquid extraction Download PDFInfo
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- CN111153819A CN111153819A CN202010040754.5A CN202010040754A CN111153819A CN 111153819 A CN111153819 A CN 111153819A CN 202010040754 A CN202010040754 A CN 202010040754A CN 111153819 A CN111153819 A CN 111153819A
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
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Abstract
The invention relates to the technical field of medicinal chemistry, in particular to a method for separating 3-chloro-phenylglycine enantiomer by liquid-liquid extraction. The method comprises the steps of dissolving chiral ferrocene diphosphine ligand and palladium ions in an organic solvent to obtain an organic phase containing a chiral extracting agent; dissolving the 3-chloro-phenylglycine enantiomer in a buffer aqueous solution with the pH value of 7-9 to obtain a water phase containing the 3-chloro-phenylglycine enantiomer; mixing and oscillating an organic phase containing a chiral extraction agent and a water phase containing a 3-chloro-phenylglycine enantiomer, standing until the organic phase and the water phase are separated, and enriching the two enantiomers of the 3-chloro-phenylglycine in the organic phase and the water phase respectively to realize separation. Compared with the prior art, the method has the advantages of high extraction efficiency, simple process, lower cost and easy industrialization.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a method for separating 3-chloro-phenylglycine enantiomer by liquid-liquid extraction.
Background
3-chloro-phenylglycine is α -amino acid, is an important intermediate of pyrrole and imidazole pesticides, and can be used for synthesizing penicillin derivatives and cephalosporin derivatives in addition, 3-chloro-phenylglycine is a chiral molecule, and in the prior art, the preparation method of a single enantiomer mainly comprises an asymmetric synthesis method and a racemate crystallization resolution method.
For example, the document (Yangguang. asymmetric phase transfer catalysis synthesis photoactivity α -amino acid [ J ]. chemical reagent, 2002,24(2):136-138.) utilizes two different chiral phase transfer catalysts (N-benzyl cinchonidine chloride and N-benzyl cinchonine chloride) to synthesize corresponding R-type and S-type α -chloro phenylglycine, the two chiral phase transfer catalysts both show good catalytic activity and obtain more than 50% of yield, but the problems of preparation, price and recovery of the chiral phase transfer catalysts are not easy to solve and influence the application of the method, D-camphorsulfonic acid is adopted as a resolving agent to resolve 3-chloro-phenylglycine raceme, and D-camphorsulfonic acid can form crystalline salt with D-type 3-chloro-phenylglycine, so that the resolution of a single enantiomer is realized, but the resolving method still has the defects of difficult recovery of sulfonic acid, high price and the like.
In the prior art, the cost for obtaining α -amino acid single enantiomer can be effectively reduced by adopting a liquid-liquid extraction method, for example, the invention patent of China (application number: 201910144949.1) provides a method for splitting 3-chloro-phenylglycine enantiomer, the 3-chloro-phenylglycine enantiomer is extracted and separated by taking an (S, S) -DIOP-metal palladium complex as a chiral extraction agent, the L-3-chloro-phenylglycine is preferentially identified by the extraction agent, and the separation factor can reach more than 1.8.
Therefore, in order to solve the problems in the prior art, it is important to provide a technology for resolving 3-chloro-phenylglycine enantiomer, which has high distribution coefficient, simple and convenient operation, low cost and easy industrialization.
Disclosure of Invention
The invention aims to provide a resolution method for 3-chloro-phenylglycine enantiomer, which has the advantages of high distribution coefficient, simple and convenient operation, lower cost and easy industrialization.
In order to achieve the purpose, the technical scheme of the invention comprises the following steps:
the method comprises the following steps: dissolving chiral ferrocene diphosphine ligand (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and palladium ions in an organic solvent, and stirring for 0.5-24 hours to obtain an organic phase containing a chiral extractant; step two: dissolving the 3-chloro-phenylglycine enantiomer in a buffer aqueous solution with the pH value of 7-9 to obtain a water phase containing the 3-chloro-phenylglycine enantiomer;
step three: mixing and oscillating the organic phase containing the chiral extraction agent and the water phase containing the 3-chloro-phenylglycine enantiomer for 1-48 hours, standing for 1-48 hours until the organic phase and the water phase are separated, and enriching the two enantiomers of the 3-chloro-phenylglycine into the organic phase and the water phase respectively to realize separation.
(S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene has the following chemical structure:
therefore, the complex of (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and palladium is used as a chiral extraction agent, the liquid-liquid extraction separation of the 3-chloro-phenylglycine enantiomer can be realized, the D-3-chloro-phenylglycine is preferentially identified by the extraction agent, the separation factor can reach more than 1.8, and the extraction process has a higher distribution coefficient (k) than that of the existing method and higher extraction efficiency. The method also has the characteristics of no gas or solid in the separation process, simple and convenient operation, lower cost and easy industrialization.
Preferably, the palladium ion is provided by palladium acetate, bis (acetonitrile) dichloropalladium or palladium trifluoroacetate.
Preferably, the organic solvent is dichloromethane, trichloromethane or 1, 2-dichloroethane.
Preferably, in the first step, stirring is carried out for 12-24 hours, and the (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and palladium ions are complexed to form a metal complex. Among them, 24 hours is preferable.
Preferably, the buffer salt of the aqueous buffer solution is acetic acid/sodium acetate or sodium dihydrogen phosphate/disodium hydrogen phosphate.
Preferably, the method for resolving 3-chloro-phenylglycine enantiomers according to the present invention has a higher separation factor when the pH of the aqueous buffer solution is 7.
Preferably, the oscillation time in the third step is 12-24 hours.
Preferably, the shaking temperature in the third step is 5 ℃.
The invention has the beneficial effects that:
the invention relates to a method for separating 3-chloro-phenylglycine enantiomer by liquid-liquid extraction. Dissolving (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and palladium ions in an organic solvent to obtain an organic phase containing a chiral extracting agent; dissolving the 3-chloro-phenylglycine enantiomer in a buffer aqueous solution with the pH value of 7-9 to obtain a water phase containing the 3-chloro-phenylglycine enantiomer; mixing and oscillating an organic phase containing a chiral extraction agent and a water phase containing a 3-chloro-phenylglycine enantiomer, standing until the organic phase and the water phase are separated, and enriching the two enantiomers of the 3-chloro-phenylglycine in the organic phase and the water phase respectively to realize separation. Therefore, the method takes (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene as a ligand for the first time, the ligand is complexed with metal palladium to form a chiral extraction agent, the 3-chloro-phenylglycine enantiomer is extracted and separated, the extraction agent preferentially identifies D-3-chloro-phenylglycine, the separation factor can reach more than 1.8, and the extraction efficiency is higher than that of the existing method. The method also has the advantages of high separation factor, no gas or solid in the separation process, simple and convenient operation, low cost and easy industrialization.
Detailed Description
The specific embodiments of the present invention will be further described with reference to the following examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and are not intended to limit the scope of the present invention as claimed.
Example 1:
(1) dissolving 0.1mmol of (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and 0.1mmol of bis (acetonitrile) dichloropalladium in 100mL of 1, 2-dichloroethane, and stirring for 16 hours to complex to form a chiral extractant with the concentration of 1.0 mmol/L;
(2) dissolving 0.2mmol of 3-chloro-phenylglycine enantiomer in 100mL of sodium dihydrogen phosphate/disodium hydrogen phosphate buffer aqueous solution with the pH value of 7.0 to obtain a 2.0 mmol/L3-chloro-phenylglycine enantiomer aqueous phase;
(3) mixing the organic phase and the water phase in the step (1) and the step (2) by 10mL respectively, shaking in a water bath constant temperature oscillator at 5 ℃ for 24 hours, standing for 48 hours to separate the two phases, and respectively measuring the distribution coefficients k of D-3-chloro-phenylglycine, L-3-chloro-phenylglycine and 3-chloro-phenylglycine in the organic phase and the water phase by using a high performance liquid chromatographyDAnd kL1.035 and 0.555, respectively, and a separation factor (α) of 1.86.
Example 2:
(1) dissolving 0.3mmol of (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and 0.3mmol of bis (acetonitrile) dichloropalladium in 100mL of dichloromethane, and stirring for 16 hours to complex to form a chiral extracting agent with the concentration of 3.0 mmol/L;
(2) dissolving 0.2mmol of 3-chloro-phenylglycine enantiomer in 100mL of sodium dihydrogen phosphate/disodium hydrogen phosphate buffer aqueous solution with the pH value of 7.0 to obtain a 2.0 mmol/L3-chloro-phenylglycine enantiomer aqueous phase;
(3) mixing the organic phase and the water phase in the step (1) and the step (2) by 10mL respectively, shaking in a water bath constant temperature oscillator at 5 ℃ for 24 hours, standing for 48 hours to separate the two phases, and respectively measuring the distribution coefficients k of D-3-chloro-phenylglycine, L-3-chloro-phenylglycine and 3-chloro-phenylglycine in the organic phase and the water phase by using a high performance liquid chromatographyDAnd kL5.503 and 2.869, respectively, the separation factor (α) was 1.92.
Example 3:
(1) dissolving 0.1mmol of (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and 0.1mmol of palladium acetate in 100mL of dichloromethane, and stirring for 17 hours to complex to form a chiral extractant with the concentration of 1.0 mmol/L;
(2) dissolving 0.2mmol of 3-chloro-phenylglycine enantiomer in 100mL of sodium dihydrogen phosphate/disodium hydrogen phosphate buffer aqueous solution with the pH value of 7.0 to obtain a 2.0 mmol/L3-chloro-phenylglycine enantiomer aqueous phase;
(3) mixing the organic phase and the water phase in the step (1) and the step (2) by 10mL respectively, shaking in a water bath constant temperature oscillator at 10 ℃ for 24 hours, standing for 48 hours to separate the two phases, and respectively measuring the distribution coefficients k of D-3-chloro-phenylglycine, L-3-chloro-phenylglycine and 3-chloro-phenylglycine in the organic phase and the water phase by using a high performance liquid chromatographyDAnd kL0.995 and 0.545, respectively, and a separation factor (α) of 1.83.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. A method for separating 3-chloro-phenylglycine enantiomer by liquid-liquid extraction comprises the following steps:
the method comprises the following steps: dissolving chiral ferrocene diphosphine ligand (S, S) - (-) -2,2 '-bis [ (R) - (N, N-dimethylamino) (phenyl) methyl ] -1,1' -bis (diphenylphosphino) ferrocene and palladium ions in an organic solvent, and stirring for 0.5-24 hours to obtain an organic phase containing a chiral extractant;
step two: dissolving the 3-chloro-phenylglycine enantiomer in a buffer aqueous solution with the pH value of 7-9 to obtain a water phase containing the 3-chloro-phenylglycine enantiomer;
step three: mixing and oscillating the organic phase containing the chiral extraction agent and the water phase containing the 3-chloro-phenylglycine enantiomer for 1-48 hours, standing for 1-48 hours until the organic phase and the water phase are separated, and enriching the two enantiomers of the 3-chloro-phenylglycine into the organic phase and the water phase respectively to realize separation.
2. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: the palladium ion is provided by palladium acetate, bis (acetonitrile) dichloropalladium or palladium trifluoroacetate.
3. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: the organic solvent is dichloromethane, trichloromethane or 1, 2-dichloroethane.
4. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: in the first step, the stirring time is 12-24 hours.
5. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: the buffer salt of the buffer aqueous solution is acetic acid/sodium acetate.
6. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: the buffer salt of the buffer aqueous solution is sodium dihydrogen phosphate/disodium hydrogen phosphate.
7. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: the pH value of the buffer aqueous solution is 7.
8. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: and step three, the oscillation time is 12-24 hours.
9. The method for resolving 3-chloro-phenylglycine enantiomer of claim 1, wherein the method comprises the following steps: and step three, setting the oscillation temperature of oscillation to be 5 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1995248A1 (en) * | 2007-05-23 | 2008-11-26 | Evonik Degussa GmbH | Process for the production of amino alcohols by asymmetric hydrogenation |
| CN106317094A (en) * | 2015-07-01 | 2017-01-11 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral boron compound containing trifluoromethyl and compound |
| CN108659041A (en) * | 2017-12-13 | 2018-10-16 | 浙江大学 | Phosphine ligands compound and its intermediate and preparation method based on tetramethyl spiro indan skeleton and purposes |
| CN109810010A (en) * | 2019-02-27 | 2019-05-28 | 湖南科技大学 | A method of splitting the chloro- phenylglycine enantiomer of 3- |
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- 2020-01-15 CN CN202010040754.5A patent/CN111153819B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1995248A1 (en) * | 2007-05-23 | 2008-11-26 | Evonik Degussa GmbH | Process for the production of amino alcohols by asymmetric hydrogenation |
| CN106317094A (en) * | 2015-07-01 | 2017-01-11 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral boron compound containing trifluoromethyl and compound |
| CN108659041A (en) * | 2017-12-13 | 2018-10-16 | 浙江大学 | Phosphine ligands compound and its intermediate and preparation method based on tetramethyl spiro indan skeleton and purposes |
| CN109810010A (en) * | 2019-02-27 | 2019-05-28 | 湖南科技大学 | A method of splitting the chloro- phenylglycine enantiomer of 3- |
Non-Patent Citations (1)
| Title |
|---|
| 黄钰清等: "手性萃取剂与液-液萃取拆分对映体技术研究进展", 《化工进展》 * |
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