A CHIRAL RESOLUTION METHOD MIMICKING MAGNETIC BENEFICIATION AND THE MAGNETIC NANO-INHIBITORS FOR SELECTIVE ENRICHMENT

Abstract

A core-shell nanocomposite is formed by co-assembly of an amphiphilic polymer and hydrophobically modified magnetic nanoparticles, with its core being a hydrophobically modified magnetic nanomaterial and its shell being the amphiphilic polymer, wherein hydrophilic segments in the amphiphilic polymer are located at an outermost layer of the shell. The above composite can be used as additives in the crystallization of conglomerates and obtain optically pure crystals of both enantiomers in a single process. The key thereof is that the composite is used to enrich molecules with the same configuration while inhibit the crystallization of the other enantiomer in a supersaturated solution of conglomerates, such that a non-magnetic crystal and a magnetic crystal (which are enantiomers of each other) are generated in a unit operation. Optically pure crystals of both enantiomers with over 90 ee % can be obtained by one-time crystallization, and the total yield can be as high as 40%.

Claims

1. A core-shell nanocomposite, which is formed by co-assembly of an amphiphilic polymer and hydrophobically modified magnetic nanoparticles, with a hydrophobically modified magnetic nanomaterial as its core and the amphiphilic polymer as its shell, wherein hydrophilic segments in the amphiphilic polymer are located at an outermost layer of the shell.

2. The core-shell nanocomposite according to claim 1, wherein a crosslinking reaction is carried out between the hydrophilic segments to form a cross-linked shell.

3. The core-shell nanocomposite according to claim 1, wherein: the hydrophilic segments in the amphiphilic polymer are at least one selected from the group consisting of the following structural formulas: ##STR00003## wherein R.sub.2 in formulas a-c is a group having the following function: capable of being adsorbed on a crystal surface of a crystal to be resolved through non-covalent bond interaction, thus inhibiting crystallization and the following enrichment to promote nucleation; wherein R.sub.1 in formula a is at least one selected from the group consisting of methyl and hydrogen atoms; and the hydrophobic segments in the amphiphilic polymer are at least one selected from the group consisting of the following polymers or at least one selected from the group consisting of block copolymers, random copolymers, graft copolymers, and hyperbranched polymers based on the repeating units of the following polymers: polystyrene, polyethylene, polypropylene, polybutadiene, polyisoprene, polydimethylsiloxane, polymethylhydrosiloxane, polymethacrylate, polymethacrylamide, polyamide, polyimide, polyformaldehyde, polycarbonate, cellulose, and derivatives thereof; wherein in formulas a-c, m represents the polymerization degree of the hydrophilic segments and ranges from 10 to 60.

4. The core-shell nanocomposite according to claim 3, wherein: R.sub.2 in formulas a-c is at least one selected from the group consisting of the following groups: ##STR00004## wherein in the above groups, * represents a bonding position.

5. The core-shell nanocomposite according to claim 1, wherein the magnetic nanomaterial is selected from magnetic nanoparticles formed by the following materials: Fe, Co, Ni, FePt, CoPt, FeAu, FePd, SmCo.sub.5, Fe.sub.3O.sub.4, γ-Fe.sub.2O.sub.3, M.sub.1Fe.sub.2O.sub.4, MO.6Fe.sub.2O.sub.3, and M.sub.2Fe.sub.12O.sub.19, wherein M.sub.1 in M.sub.1Fe.sub.2O.sub.4 represents Zn, Mn, Ni, or Co, and M.sub.2 in M.sub.2Fe.sub.12O.sub.19 represents Ba or Sr; wherein the magnetic nanoparticles have a diameter in the range from 3 nm to 500 nm; and wherein hydrophobic molecules used in the hydrophobically modified magnetic nanomaterial are at least one selected from the group consisting of oleic acid, oleamine, pyrrolidone, 11,11-dihydroxymethyl undecane, poly(tetravinylpyridine), and block copolymers of poly(tetravinylpyridine) and polyethylene.

6. A method for preparing the core-shell nanocomposite according to claim 1 comprising the steps of: 1) dissolving the amphiphilic polymer in a cosolvent to obtain an amphiphilic polymer solution; dispersing the hydrophobically modified magnetic nanoparticles in a cosolvent to obtain a dispersion of the hydrophobically modified magnetic nanoparticles; and 2) mixing the amphiphilic polymer solution with the dispersion of the hydrophobically modified magnetic nanoparticles in proportion to form a mixed solution, and then adding deionized water to the mixed solution until a stable assembly is formed.

7. The method according to claim 6, wherein in step 1), the cosolvent is at least one selected from the group consisting of DMSO, N,N-dimethylformamide, tetrahydrofuran, dioxane, CH.sub.3CN, acetone, methanol, ethanol, and isopropanol; wherein in step 2), the mass ratio of the amphiphilic polymer to the hydrophobically modified magnetic nanoparticles in the mixed solution is in the range from 1:0.1 to 1; and wherein in step 2), the deionized water is dropwise added into the mixed solution, and the volume ratio of the mixed solution to the deionized water is in the range from 1:2 to 8.

8. The method according to claim 6, wherein the method further comprises the step of adding a crosslinking agent into a reaction system in which the stable assembly is formed to perform a shell crosslinking reaction, followed by dialysis in pure water to remove an organic solvent and unreacted small molecules, centrifugal separation, and freeze drying, wherein the crosslinking agent is at least one selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and glycol bis 2-aminoethyl ether.

9. (canceled)

10. A chiral resolution method mimicking magnetic beneficiation, comprising the steps of: (1) formulating a racemic substrate to be resolved into a supersaturated solution, followed by hot filtration; (2) adding the core-shell nanocomposite of claim 1 to the supersaturated solution, followed successively by ultrasonic dispersion, cooling to a crystallization temperature, addition of an optical pure seed of the racemic substrate to be resolved, and standing still, wherein if the core-shell nanocomposite has S-hydrophilic segments, R-optically pure seeds are added, or otherwise, S-seeds are added; (3) obtaining mixed crystals of colored crystals and colorless crystals at the end of crystallization; and (4) approaching the mixed crystals with a magnet, wherein the colored crystals of one enantiomer can be attracted by the magnet, while the colorless crystals of the other enantiomer cannot to be attracted by the magnet, i.e., resolution of two enantiomers is effectuated.

11. The method according to claim 10, wherein the method further comprising: dissolving the colored crystal in water, and recycling the core-shell nanocomposite by magnetic attraction, wherein the recycled core-shell nanocomposite can be reused after being washed.

12. The method according to claim 10 wherein in step (1), the racemic substrate is asparagine monohydrate with a concentration in the range from 50 mg.Math.mL.sup.−1 to 150 mg.Math.mL.sup.−1.

13. The method according to claim 10, wherein the substrate to be resolved is asparagine monohydrate or threonine, and the hydrophilic segments of the amphiphilic polymer in the core-shell nanocomposite are poly(N.sup.6-methacryloyl-S-lysine hydrochloride); or the substrate to be resolved is p-hydroxyphenylglycine p-methylbenzene sulfonate, and the hydrophilic segments of the amphiphilic polymer in the core-shell nanocomposite are poly(p-methacryloyl-S-phenylalanine hydrochloride).

14. The method according to claim 10, wherein in step (2), the magnetic nano-inhibitor accounts for 0.1-2.0 wt % of the racemic substrate to be resolved; an adding amount of the optically pure seeds of the racemic substrate accounts for 0.1-0.5 wt % of the racemic substrate to be resolved; and the ultrasonic dispersion is performed in water at a temperature in the range from 40° C. to 60° C., at a power in the range from 40 KHz to 80 KHz, and for a period in the range from 15 min to 60 min; and wherein the standing is performed at a temperature in the range from 0° C. to 40° C. for a period in the range from 6 h to 144 h.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0040] FIG. 1 is a reaction flow chart for preparing a magnetic nano-inhibitor of the present invention.

[0041] FIG. 2 is a reaction flow chart for preparing a magnetic nano-inhibitor in Example 1.

[0042] FIG. 3 is a reaction flow chart for preparing a magnetic nano-inhibitor in Example 2.

[0043] FIG. 4 shows magnetic hysteresis loops of oleic acid coated Fe.sub.3O.sub.4 nanoparticles and the magnetic nano-inhibitor prepared in Example 1, as well as pictures thereof dispersed in water and attracted by a magnet.

[0044] FIG. 5 shows morphologies of polymeric assemblies by using different polymers with various block compositions.

[0045] FIG. 6a shows crystal mixture of R-asparagine monohydrate and S-asparagine monohydrate obtained in Example 3, and 6b is a picture of the mixed crystals after being attracted by a magnet, wherein the S-crystals can be attracted and the R-crystals cannot be attracted; and

[0046] FIG. 7 shows a typical result of crystal ee % value tested by chiral HPLC in Example 3.

[0047] FIG. 8 shows the structure diagram of the magnetic nano-inhibitor, [0048] wherein represents the hydrophobically modified magnetic nanomaterial; represents a hydrophobic segment; and represents a hydrophilic segment.

DETAILED DESCRIPTION OF EMBODIMENTS

[0049] The present invention will be described in the following through specific examples. However, the present invention is not limited thereto. Any amendment, equivalent replacement, improvement, and the like made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

[0050] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0051] The materials, reagents, and the like used in the following examples can all be obtained commercially without special instructions.

Example 1 Preparation of a Magnetic Enrichment Nano Inhibitor

[0052] The preparation was performed according to the flow chart shown in FIG. 2.

[0053] (1) (S)-PMAL-b-Ps was obtained by reversible addition and fragmentation chain transfer (RAFT) polymerization. The polymerization degree of inhibitor segments was controlled at 25, and the polymerization degree of PS chain segments was controlled at 125.

[0054] (2) Oleic acid coated Fe.sub.3O.sub.4 nanoparticles (Fe.sub.3O.sub.4@oleic acid) were prepared with reference to the document (Shouheng Sun, Hao Zeng, David B. Robinson, Simone Raoux, Philip M. Rice, J. Am. Chem. Soc. 2004, 126, 273-279). The diameter of the nanoparticles was controlled at about 6 nm.

[0055] (3) Solution A (50 mg of polymer (S)-PMAL-b-Ps dissolved in 5 mL of DMSO) and solution B (100 mg of Fe.sub.3O.sub.4@oleic acid dissolved in 100 mL of THF) were prepared. 5 mL of solution A was taken and added into 45 mL of DMSO for dilution, followed by dropwise addition of 50 mL of solution B and homogeneous mixing. 320 mL of deionized water was dropwise added under stirring within two hours.

[0056] (4) An aqueous solution (10 mg/mL) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and an aqueous solution (10 mg/mL) of glycol bis 2-aminoethyl ether were prepared. 1.15 mL of the EDC solution and 0.56 mL of the diamine solution were added into the above solution, followed by stirring at room temperature overnight.

[0057] (5) The above solution was placed into pure water for dialysis over 48 hours, with the water being changed every three hours. After centrifugation at 15000 rpm, the supernatant was poured, and final product was obtained by freeze drying under vacuum.

[0058] FIG. 4 shows hysteresis loops of oleic acid coated Fe.sub.3O.sub.4 nanoparticles and the magnetic nano-inhibitor prepared in Example 1, and pictures of dispersed nano-inhibitors in water and attracted by a magnet. As can be seen from FIG. 4, both the Fe.sub.3O.sub.4 nanoparticles and the magnetic nano-inhibitor as prepared had superparamagnetic properties, i.e., they had high magnetism under an external magnetic field, and the magnetism disappeared immediately once the magnetic field was removed.

[0059] FIG. 5 shows the morphologies of the magnetic nano-inhibitor. As can be seen from the figure, different morphologies could be obtained when polymers with different block ratios were used. Taking (S)-PMAL(25)-b-Ps (125) as an example, wormlike micelles were obtained.

Example 2 Preparation of a Magnetic Enrichment Nano Inhibitor

[0060] The preparation was performed according to the flow chart shown in FIG. 3.

[0061] (1) (S)-PMPA-b-Ps was obtained by reversible addition and fragmentation chain transfer (RAFT) polymerization. The polymerization degree of inhibitor segments was controlled at 45, and that of PS segments was controlled at 115.

[0062] (2) Oleic acid coated Fe.sub.3O.sub.4 nanoparticles (Fe.sub.3O.sub.4@oleic acid) were prepared with reference to the aforementioned document, the diameter thereof being controlled at about 6 nm.

[0063] (3) Solution A (50 mg of polymer (S)-PMPA-b-Ps dissolved in 5 mL of DMSO), and solution B (100 mg of Fe.sub.3O.sub.4@oleic acid dissolved in 100 mL of THF) were prepared. 5 mL of solution A was taken and added into 45 mL of DMSO for dilution, followed by dropwise addition of 50 mL of solution B, and homogeneous mixing. 320 mL of deionized water was dropwise added under stirring in two hours.

[0064] (4) An aqueous solution (10 mg/mL) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and an aqueous solution (10 mg/mL) of glycol bis 2-aminoethyl ether were prepared. 1.15 mL of the EDC solution and 0.56 mL of the diamine solution were added into the above solution, followed by stirring at room temperature overnight.

[0065] (5) The above solution was placed into pure water for dialysis over 48 h, with water being changed every three hours. After centrifugation at 15000 rpm, the supernatant was poured, and final product was obtained by freeze drying under vacuum.

Example 3 Resolution of Racemic Asparagine Monohydrate

[0066] In this example, Fe.sub.3O.sub.4-(S)PMAL(25)-PS(81) was selected as a crystallization additive, and its preparation method was the same as that of Fe.sub.3O.sub.4-(S)PMAL(25)-PS(125) in Example 1, except that the polymerization degree of PS polymerization chains was 81.

[0067] Specific operation steps were as follows.

[0068] (1) 9 mL water was added into 1 g racemic asparagine monohydrate, followed by heating to 60° C. and dissolving under sufficient stirring. A clear and transparent supersaturated solution at a concentration of 111 mg/mL was obtained after hot filtering.

[0069] (2) 5 g solution obtained in step (1) was taken and added with 10.4 g of nano-inhibitor Fe.sub.3O.sub.4-(S)PMAL(25)-PS(81) (the content of the inhibitor segments was 0.25 wt % to the racemic substrate), followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slowly cooling to room temperature, 0.5 mg seeds of R-asparagine monohydrate were added in.

[0070] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0071] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0072] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the crystal mixture. The colored crystals were attracted by the magnet, while the colorless ones cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated. See FIGS. 6a and 6b.

[0073] The crystal yields and enantiomeric excess values (Table 1) were calculated in this example, and the enantiomeric excess values were characterized by chiral HPLC (see FIG. 7).

Example 4 Resolution of Racemic Asparagine Monohydrate

[0074] In this example, Fe.sub.3O.sub.4-(S)PMAL(25)-PS(125) in Example 1 was selected as a crystallization additive, and specific operation steps were as follows.

[0075] (1) 9 mL water was added into 1 g racemic asparagine monohydrate, followed by heating to 60° C. and dissolving under sufficient stirring. A clear and transparent supersaturated solution at a concentration of 111 mg/mL was obtained after hot filtering.

[0076] (2) 5 g solution obtained in step (1) was taken and added with 11.4 g of nano-inhibitor Fe.sub.3O.sub.4-(S)PMAL(25)-PS(125) ((the content of the inhibitor segments was 0.25 wt %), followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slowly cooling to room temperature, 0.5 mg seeds of R-asparagine monohydrate were added in.

[0077] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0078] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0079] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the mixed crystals. The colored crystals were attracted by the magnet, while the colorless crystals cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated.

[0080] The crystal yields and enantiomeric excess values (Table 1) were calculated in this example, and the enantiomeric excess values were characterized by chiral HPLC.

Example 5 Resolution of Racemic Asparagine Monohydrate

[0081] In this example, Fe.sub.3O.sub.4-(S)PMAL(25)-PS(174) was selected as a crystallization additive, and its preparation method was the same as that of Fe.sub.3O.sub.4-(S)PMAL(25)-PS(125) in Example 1, except that the polymerization degree of PS polymerization chains was 174.

[0082] Specific operation steps were as follows.

[0083] (1) 9 mL water was added into 1 g racemic asparagine monohydrate, followed by heating to 60° C. and dissolving under sufficient stirring. A clear and transparent supersaturated solution at a concentration of 111 mg/mL was obtained after hot filtering.

[0084] (2) 5 g solution obtained in step (1) was taken and added with 12.2 g of nano-inhibitor Fe.sub.3O.sub.4-(S)PMAL(25)-PS(174) (the content of the inhibitor segments was 0.25 wt % to the racemic substrate), followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slowly cooling to room temperature, 0.5 mg seeds of R-asparagine monohydrate were added in.

[0085] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0086] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0087] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the crystal mixture. The colored crystals were attracted by the magnet, while the colorless ones cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated. See FIGS. 6a and 6b.

[0088] The crystal yields and enantiomeric excess values (Table 1) were calculated in this example, and the enantiomeric excess values were characterized by chiral HPLC.

Example 6 Resolution of Racemic Asparagine Monohydrate

[0089] In this example, Fe.sub.3O.sub.4-(S)PMAL(25)-PS(225) was selected as a crystallization additive, and its preparation method was the same as that of Fe.sub.3O.sub.4-(S)PMAL(25)-PS(125) in Example 1, except that the polymerization degree of PS polymerization chains was 225.

[0090] Specific operation steps were as follows.

[0091] (1) 9 mL water was added into 1 g racemic asparagine monohydrate, followed by heating to 60° C. and dissolving under sufficient stirring. A clear and transparent supersaturated solution at a concentration of 111 mg/mL was obtained after hot filtering.

[0092] (2) 5 g solution obtained in step (1) was taken and added with 8.7 g of nano-inhibitor Fe.sub.3O.sub.4-(S)PMAL(25)-PS(225) (the content of the inhibitor segments was 0.25 wt % to the racemic substrate), followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slowly cooling to room temperature, 0.5 mg seeds of R-asparagine monohydrate were added in.

[0093] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0094] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0095] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the crystal mixture. The colored crystals were attracted by the magnet, while the colorless ones cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated. See FIGS. 6a and 6b.

[0096] The crystal yields and enantiomeric excess values (Table 1) were calculated in this example, and the enantiomeric excess values were characterized by chiral HPLC.

Example 7 Resolution of Racemic Asparagine Monohydrate

[0097] In this example, Fe.sub.3O.sub.4-(S)PMAL(12)-PS(122) was selected as a crystallization additive, and its preparation method was the same as that of Fe.sub.3O.sub.4-(S)PMAL(25)-PS(125) in Example 1, except that the polymerization degree of PS polymerization chains was 122.

[0098] Specific operation steps were as follows.

[0099] (1) 9 mL water was added into 1 g racemic asparagine monohydrate, followed by heating to 60° C. and dissolving under sufficient stirring. A clear and transparent supersaturated solution at a concentration of 111 mg/mL was obtained after hot filtering.

[0100] (2) 5 g solution obtained in step (1) was taken and added with 10.2 g of nano-inhibitor Fe.sub.3O.sub.4-(S)PMAL(12)-PS(122) (the content of the inhibitor segments was 0.25 wt % to the racemic substrate), followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slowly cooling to room temperature, 0.5 mg seeds of R-asparagine monohydrate were added in.

[0101] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0102] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0103] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the crystal mixture. The colored crystals were attracted by the magnet, while the colorless ones cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated. See FIGS. 6a and 6b.

[0104] The crystal yields and enantiomeric excess values (Table 1) were calculated in this example, and the enantiomeric excess values were characterized by chiral HPLC.

Example 8 Resolution of Racemic Asparagine Monohydrate

[0105] In this example, Fe.sub.3O.sub.4-(S)PMAL(40)-PS(122) was selected as a crystallization additive, and its preparation method was the same as that of Fe.sub.3O.sub.4—(S)PMAL(25)-PS(125) in Example 1, except that the polymerization degree of PMAL segments was 40.

[0106] Specific operation steps were as follows.

[0107] (1) 9 mL water was added into 1 g racemic asparagine monohydrate, followed by heating to 60° C. and dissolving under sufficient stirring. A clear and transparent supersaturated solution at a concentration of 111 mg/mL was obtained after hot filtering.

[0108] (2) 5 g solution obtained in step (1) was taken and added with 8.3 g of nano-inhibitor Fe.sub.3O.sub.4—(S)PMAL(40)-PS(122) (the content of the inhibitor segments was 0.25 wt % to the racemic substrate), followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slowly cooling to room temperature, 0.5 mg seeds of R-asparagine monohydrate were added in.

[0109] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0110] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0111] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the crystal mixture. The colored crystals were attracted by the magnet, while the colorless ones cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated. See FIGS. 6a and 6b.

[0112] The crystal yields and enantiomeric excess values (Table 1) were calculated in this example, and the enantiomeric excess values were characterized by chiral HPLC.

Example 9 Resolution of Racemic Asparagine Monohydrate

[0113] In this example, Fe.sub.3O.sub.4—(S)PMAL(59)-PS(129) was selected as a crystallization additive, and its preparation method was the same as that of Fe.sub.3O.sub.4—(S)PMAL(25)-PS(125) in Example 1, except that the polymerization degree of PMAL segments was 59.

[0114] Specific operation steps were as follows.

[0115] (1) 9 mL water was added into 1 g racemic asparagine monohydrate, followed by heating to 60° C. and dissolving under sufficient stirring. A clear and transparent supersaturated solution at a concentration of 111 mg/mL was obtained after hot filtering.

[0116] (2) 5 g solution obtained in step (1) was taken and added with 7.6 g of nano-inhibitor Fe.sub.3O.sub.4—(S)PMAL(59)-PS(129) (the content of the inhibitor segments was 0.25 wt % to the racemic substrate), followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slowly cooling to room temperature, 0.5 mg seeds of R-asparagine monohydrate were added in.

[0117] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0118] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0119] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the crystal mixture. The colored crystals were attracted by the magnet, while the colorless ones cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated. See FIGS. 6a and 6b.

[0120] The crystal yields and enantiomeric excess values (Table 1) were calculated in this example, and the enantiomeric excess values were characterized by chiral HPLC.

Example 10 Resolution of Racemic p-Hydroxyphenylglycine p-Toluenesulfonate

[0121] In this example, Fe.sub.3O.sub.4—(S)PMPA(45)-PS(115) prepared in Example 2 was selected as a crystallization additive.

[0122] Specific operation steps were as follows.

[0123] (1) 951 mg p-toluenesulfonic acid monohydrate was added into 10 mL deionized water. 500 mg racemic p-hydroxyphenylglycine p-toluenesulphonate was taken and dissolved in 2 mL of the above solution. The temperature was elevated to 60° C., and the racemic p-hydroxyphenylglycine p-toluenesulphonate was dissolved under sufficient stirring. A clear and transparent supersaturated solution was obtained after hot filtering.

[0124] (2) 7.3 g of nano-inhibitor Fe.sub.3O.sub.4—(S)PMPA(45)-PS(115) (the content of the inhibitor was 0.25 wt %) was added into the above solution, followed by ultrasonic dispersion in 60° C. hot water for 15 min. After slow cooling to room temperature, 0.5 mg seeds of R-p-hydroxyphenylglycine p-toluenesulphonate were added in.

[0125] (3) The solution obtained in step (2) was stood at 25° C. for 72 h.

[0126] (4) After crystallization, crystals precipitated at the bottom and an upper liquid was poured out. The remained crystals were dried under vacuum.

[0127] (5) The vessel containing the crystals was taken out, and a magnet (with a surface magnetic field strength >0.3 T) was used to approach the mixed crystals. The colored crystals were attracted by the magnet, while the colorless ones cannot be attracted by the magnet, i.e., resolution of the two enantiomers was effectuated.

TABLE-US-00001 TABLE 1 Resolution results with different additives Ex- Polymer e.e Total am- Standing content/ Yield/ value/ yield/ ple time/D % Crystal % % % 3 3 0.25 R (nonmagnetic) 14.6 99.9 38.3 S (magnetic) 24.7 78.1 4 3 0.25 R (nonmagnetic) 17.0 98.3 39.8 S (magnetic) 23.8 91.5 5 3 0.25 R (nonmagnetic) 16.9 99.9 39.1 S (magnetic) 22.2 88.9 6 3 0.25 R (nonmagnetic) 16.9 99.7 40.7 S (magnetic) 23.8 89.5 7 3 0.25 R (nonmagnetic) 19.5 98.3 41.0 S (magnetic) 21.5 60.5 8 3 0.25 R (nonmagnetic) 20.4 88.1 42.2 S (magnetic) 21.8 88.1 9 3 0.25 R (nonmagnetic) 20.6 76.7 41.1 S (magnetic) 20.5 88.1

INDUSTRIAL APPLICATION

[0128] 1. The present invention uses a kind of magnetic nano-inhibitors for the first time as an additive to introduce the microscopic properties of nanoparticles into the enantiomeric crystals, such that a macroscopic magnetic difference is generated between two enantiomeric crystals. A new chiral separation method mimicking magnetic beneficiation has been effectuated.

[0129] 2. The magnetic nano-inhibitor is obtained by co-assembly, the synthesis being simple. The polymer portion can be readily replaced to achieve the resolution of different conglomerates.

[0130] 3. Shell crosslinking can provide a stable assembly structure, which is suitable for use in different crystallization systems and concentrations, and can be recycled efficiently.

[0131] 4. The present invention requires simple operations. Only magnetic field is necessary in the resolution process. Simple devices are used, and automatic resolution can be achieved. This is beneficial for industrial, large-scale production.