CN115611811A - Chiral ionic liquid and application thereof - Google Patents
Chiral ionic liquid and application thereof Download PDFInfo
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- CN115611811A CN115611811A CN202211252398.9A CN202211252398A CN115611811A CN 115611811 A CN115611811 A CN 115611811A CN 202211252398 A CN202211252398 A CN 202211252398A CN 115611811 A CN115611811 A CN 115611811A
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- ionic liquid
- chiral
- threonine
- acid
- chiral ionic
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- 239000002608 ionic liquid Substances 0.000 title claims abstract description 89
- 239000004473 Threonine Substances 0.000 claims abstract description 74
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000000203 mixture Substances 0.000 claims abstract description 31
- 238000001914 filtration Methods 0.000 claims abstract description 25
- 239000000243 solution Substances 0.000 claims abstract description 22
- 239000000706 filtrate Substances 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 17
- 239000006184 cosolvent Substances 0.000 claims abstract description 14
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 13
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000011090 malic acid Nutrition 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 10
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims abstract description 9
- QWCKQJZIFLGMSD-GSVOUGTGSA-N D-alpha-aminobutyric acid Chemical compound CC[C@@H](N)C(O)=O QWCKQJZIFLGMSD-GSVOUGTGSA-N 0.000 claims abstract description 9
- 150000001450 anions Chemical class 0.000 claims abstract description 9
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 238000001704 evaporation Methods 0.000 claims abstract description 9
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 claims abstract description 8
- 239000011347 resin Substances 0.000 claims abstract description 8
- 229920005989 resin Polymers 0.000 claims abstract description 8
- 238000005342 ion exchange Methods 0.000 claims abstract description 6
- 229940116298 l- malic acid Drugs 0.000 claims abstract description 6
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 99
- 229960002898 threonine Drugs 0.000 claims description 72
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 22
- 239000012047 saturated solution Substances 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 16
- 239000012452 mother liquor Substances 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- HXFCKUQYAULHNH-UHFFFAOYSA-N [Br].C(CCCCC)N1CN(C=C1)C Chemical compound [Br].C(CCCCC)N1CN(C=C1)C HXFCKUQYAULHNH-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 38
- BGSUDDILQRFOKZ-UHFFFAOYSA-M 1-hexyl-3-methylimidazol-3-ium;bromide Chemical compound [Br-].CCCCCCN1C=C[N+](C)=C1 BGSUDDILQRFOKZ-UHFFFAOYSA-M 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 2
- 238000012546 transfer Methods 0.000 abstract description 2
- RVEJOWGVUQQIIZ-UHFFFAOYSA-N 1-hexyl-3-methylimidazolium Chemical compound CCCCCCN1C=C[N+](C)=C1 RVEJOWGVUQQIIZ-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- AYFVYJQAPQTCCC-STHAYSLISA-N D-threonine Chemical compound C[C@H](O)[C@@H](N)C(O)=O AYFVYJQAPQTCCC-STHAYSLISA-N 0.000 description 16
- 238000005070 sampling Methods 0.000 description 15
- 230000014759 maintenance of location Effects 0.000 description 14
- 238000002390 rotary evaporation Methods 0.000 description 13
- 239000012265 solid product Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 238000000926 separation method Methods 0.000 description 6
- WGVGZVWOOMIJRK-UHFFFAOYSA-N 1-hexyl-3-methyl-2h-imidazole Chemical compound CCCCCCN1CN(C)C=C1 WGVGZVWOOMIJRK-UHFFFAOYSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 description 4
- 229930182822 D-threonine Natural products 0.000 description 4
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 4
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N tryptophan Chemical compound C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- 229910021642 ultra pure water Inorganic materials 0.000 description 4
- 239000012498 ultrapure water Substances 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 150000003588 threonines Chemical class 0.000 description 3
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 3
- -1 1-hexyl-3-methylimidazole L-malate Chemical compound 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000000622 liquid--liquid extraction Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical group OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- OOPFQTZOUGTFQN-UHFFFAOYSA-N 1-hexyl-3-methyl-1,2-dihydroimidazol-1-ium;bromide Chemical compound [Br-].CCCCCC[NH+]1CN(C)C=C1 OOPFQTZOUGTFQN-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229920002160 Celluloid Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 208000015606 cardiovascular system disease Diseases 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005557 chiral recognition Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000019621 digestibility Nutrition 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 230000001766 physiological effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000009834 selective interaction Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Analytical Chemistry (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of chemical products, and particularly relates to a chiral ionic liquid and application thereof. The preparation method of the chiral ionic liquid comprises the following steps: ion exchange is carried out on 1-hexyl-3-methylimidazolium bromide and 717 anion resin to obtain [ C 6 mim]An aqueous OH solution; will be provided with[C 6 mim]Performing neutralization reaction on the OH aqueous solution and chiral acid to obtain a mixture, wherein the chiral acid is selected from L-2-aminobutyric acid, D-2-aminobutyric acid, L-malic acid or D-malic acid; removing water from the mixture, adding an organic solvent to separate out the chiral acid, and filtering to remove solids to obtain a filtrate; evaporating the filtrate, and drying to obtain chiral ionic liquid. By the cosolvent formed by the chiral ionic liquid and water, the mass transfer influence caused by high viscosity of the ionic liquid is solved, the solubility of the racemic threonine is improved, and the efficient resolution of the racemic threonine is completed.
Description
Technical Field
The invention belongs to the technical field of chemical products, and particularly relates to chiral ionic liquid and application thereof.
Background
Chirality is a fundamental property of organisms in nature, and enantiomers that are mirror images of each other often exhibit certain different characteristics, such as reaction speed or physiological effects, in a chiral environment. Particularly, for the pharmaceutical industry, different configurations of active pharmaceutical ingredients with chiral centers sometimes lead to different clinical reactions, pharmacological activities and toxicology. Threonine (Threonine), also known as beta-hydroxy-alpha-aminobutyric acid, has two single enantiomers, L-type and D-type, wherein L-Threonine (L-Thr) is an essential amino acid and is mainly used in the aspects of medicines, feed additives and the like; for animals, L-threonine can improve the nutritional value of feed raw materials with low amino acid digestibility and improve the production performance of low-energy feed; for human, it is used for adjuvant treatment of peptic ulcer, and can also be used for treating anemia and cardiovascular system diseases such as angina pectoris, aortic inflammation and cardiac insufficiency, while D-threonine has no biological activity, and the presence of D-threonine or its racemate will greatly limit the therapeutic effect of related drugs. Therefore, it is very important to develop a resolution technology of racemic threonine with high product purity, simple operation, environmental protection and high efficiency.
Chinese patent with application number CN200710185671.X discloses a new method for preparing L-and D-threonine by direct biocatalytic hydrolysis and resolution of DL-N-acetyl threonine ester. But the method firstly has severer conditions for the screening, the processing technique, the preservation and the like of the strains; secondly, in the process of utilizing the enzyme to split threonine, the conditions of controlling the temperature, controlling the pH value of the solution, adding metal ions, adding a cosolvent and the like are excessive; the finally obtained product-containing aqueous solution still needs to be treated by ion exchange resin to obtain the product, and the post-treatment requirement is higher. In a word, the method has the disadvantages of complicated process, time-consuming process and higher cost.
Chinese patent No. CN201710542082.6 discloses a method for fractional crystallization and resolution by adding a polymer compounded with dye molecules and seed crystals to a saturated racemic threonine solution and separating out threonine enantiomer crystals with different colors after cooling. However, the method firstly selects the complex polymer synthesis steps, and has high technical requirements and high cost; secondly, the polymer is used as an inhibitor while a seed crystal still needs to be added; the ee value of the final product purity is less than 99 percent, and the purity is not high. In a word, the method has high technical requirement and low purity, and is not beneficial to industrialization.
Chinese patent with application number CN201410152313.9 discloses preparation and immobilization of novel tropine alcohol amino acid anionic chiral ionic liquid and a method for resolving DL-phenylalanine and DL-tryptophan by using the same. In this patent, tropine is reacted with CH 3 (CH 2 ) n Br (n = 1-7) is heated to react to obtain tropine bromide, the tropine bromide is processed by strong-base anion resin, the obtained solution is concentrated and added with L-proline to finally obtain a yellow viscous liquid product, and then the ionic liquid and a salt solution form a double aqueous phase liquid-liquid extraction separation of DL-tryptophan and phenylalanine. In the patent, the chiral ionic liquid is applied to liquid-liquid extraction resolution, but the resolution product has low purity.
In conclusion, the enzymatic resolution of racemic threonine and the fractional crystallization resolution method of adding seed crystal and polymer in the above patent have the defects of complicated process and low purity. Therefore, a method for resolving a racemate with a simple process and high purity is required.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a chiral ionic liquid, which can be used for resolving racemic threonine to obtain L-threonine, and the L-threonine resolved by the method has the advantages of high ee value, high purity and simple process.
In order to achieve the purpose, the invention can adopt the following technical scheme:
the invention provides a chiral ionic liquid, and a preparation method thereof comprises the following steps: (1) Ion exchange is carried out on 1-hexyl-3-methylimidazolium bromide and 717 anion resin to obtain [ C 6 mim]An aqueous OH solution; (2) Will [ C ] 6 mim]Performing neutralization reaction on the OH aqueous solution and excessive chiral acid to obtain a mixture, wherein the chiral acid is selected from L-2-aminobutyric acid, D-2-aminobutyric acid, L-malic acid or D-malic acid; (3) After the mixture is dewatered, adding an organic solvent to separate out chiral acid, and filtering to remove solids to obtain filtrate 1; and (4) evaporating the filtrate 1 and drying to obtain the chiral ionic liquid.
In another aspect, the present invention provides a method for resolving racemic threonine, which comprises: (1) Mixing the chiral ionic liquid with water to obtain a latent solvent; (2) Mixing excessive racemic threonine in a cosolvent until solid-liquid balance is achieved to obtain a saturated solution; (3) And cooling and crystallizing the saturated solution, and filtering to obtain the L-threonine.
The beneficial effects of the invention include:
(1) The chiral ionic liquid provided by the invention has the advantages of simple synthesis steps, excellent chiral recognition effect and recyclability; the problem of mass transfer influence caused by high viscosity of the ionic liquid is solved and the solubility of racemic threonine is improved through a latent solvent formed by the chiral ionic liquid and water;
(2) In the process of using the chiral ionic liquid as a chiral solvent to crystallize and split racemic threonine, stronger acting force exists between the heterochiral ionic liquid and a threonine enantiomer, so that the chiral ionic liquid inhibits nucleation of the heterochiral enantiomer thereof, and the homochiral enantiomer thereof is preferentially nucleated and separated out. In the operation process, the separation can be completed only through chiral ionic liquid, no additional crystal seed is needed to be added, the ee value of the high-purity threonine enantiomer is more than 99 percent by performing 1-2 times of cyclic crystallization separation processes, the operation is simple, the separation effect is obvious, the process is cyclic, the cost is low, and the problems of complex process, low purity and the like (enzyme separation and fractional crystallization separation by adding crystal seed and polymer) in the prior art are solved.
Drawings
FIG. 1 is a nuclear magnetic map of chiral ionic liquid [ Hmim ] [ L-2-AbA ] of example 1;
FIG. 2 is a thermogravimetric analysis diagram of the chiral ionic liquid [ Hmim ] [ L-2-AbA ] of example 1;
FIG. 3 shows chiral ionic liquid [ Hmim ] of example 2] 2 [L-MA]Nuclear magnetic maps of (a);
FIG. 4 shows chiral ionic liquid [ Hmim ] of example 2] 2 [L-MA]Thermogravimetric analysis of (a);
FIG. 5 is a graph showing the solubility of racemic threonine in various concentrations of cosolvent of [ Hmim ] [ L-2-AbA ] prepared in example 1;
FIG. 6 is [ Hmim ] prepared in example 2] 2 [L-MA]Solubility profile of racemic threonine in different concentrations of cosolvent;
FIG. 7 is an HPLC chromatogram of standard racemic threonine;
FIG. 8 is an HPLC chromatogram of the product of example 5;
FIG. 9 is an HPLC chromatogram of the product of example 6;
FIG. 10 is an HPLC chromatogram of the product of example 7;
FIG. 11 is an HPLC chromatogram of the product of example 8;
FIG. 12 is an HPLC chromatogram of the product of example 9;
FIG. 13 is an HPLC chromatogram of the product of example 10.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. Unless the context has a significantly different meaning, the singular forms of expressions include the plural forms of expressions. As used herein, it is understood that terms such as "comprising," "having," "including," and the like are intended to refer to the presence of features, numbers, operations, components, parts, elements, materials, or combinations thereof. The terminology of the present invention is disclosed in the specification and is not intended to exclude the possibility that one or more other features, numbers, operations, components, parts, elements, materials or combinations thereof may be present or may be added. As used herein, "/" can be interpreted as "and" or "depending on the situation.
One embodiment of the present invention provides a chiral ionic liquid, and a preparation method thereof includes: (1) Ion exchange is carried out on 1-hexyl-3-methylimidazolium bromide and 717 anion resin to obtain [ C 6 mim]An aqueous OH solution; (2) Will [ C ] 6 mim]Performing neutralization reaction on the OH aqueous solution and excessive chiral acid to obtain a mixture, wherein the chiral acid is selected from L-2-aminobutyric acid, D-2-aminobutyric acid, L-malic acid or D-malic acid; (3) Removing water from the mixture, adding an organic solvent to separate out the chiral acid, and filtering to remove solids to obtain a filtrate 1; and (4) evaporating the filtrate 1 and drying to obtain the chiral ionic liquid.
In step (4), the chiral ionic liquid prepared is 1-hexyl-3-methylimidazole L-2-aminobutyrate ([ Hmim ]][L-2-AbA]) 1-hexyl-3-methylimidazole D-2-aminobutyrate ([ Hmim ]][D-2-AbA]) 1-hexyl-3-methylimidazole L-malate ([ Hmim) ]] 2 [L-MA]) And 1-hexyl-3-methylimidazole D-malate ([ Hmim)] 2 [D-MA])。
Ionic Liquids (ILs) are salts composed of an organic cation and an inorganic or organic anion, which are liquid at or near room temperature. Chiral Ionic Liquids (CILs) are one type of functionalized ionic liquids, and have the dual characteristics of chiral materials and liquid materials. Compared with the traditional chiral solvent, the chiral ionic liquid has the supercooling tendency, so that the chiral ionic liquid has a relatively wide liquid-phase operating temperature range, and the problem caused by overhigh melting point of the chiral solvent is avoided.
In addition, in the preparation of the chiral ionic liquid, cations are provided by imidazole bromide salt 1-hexyl-3-methylimidazole bromide salt, anions are provided by monoacid L-2-aminobutyric acid, D-2-aminobutyric acid, diacid L-malic acid and D-malic acid, and the chiral ionic liquid is obtained by performing acid-base neutralization reaction on hydroxide of the 1-hexyl-3-methylimidazole bromide salt after the hydroxide passes through the strong basic anion resin and chiral acid.
In some embodiments, in the above method for preparing chiral ionic liquid, in step (2), the neutralization reaction is performed in an ice bath.
In some embodiments, in the above method for preparing a chiral ionic liquid, in the step (3), the method for removing water from the mixture includes: the mixture is rotary evaporated at 323.15K-333.15K for 1.8h-2.2h, such as at 333.15K for 2h.
In some embodiments, in the preparation method of the chiral ionic liquid, in the step (3), after the mixture is subjected to water removal, an organic solvent is added to the mixture at 273.15K to 276.15K to precipitate the chiral acid; wherein the organic solvent is selected from mixed solvent of acetonitrile and methanol or mixed solvent of acetonitrile and diethyl ether. In the mixing, the organic solvent may be added and dissolved while vigorously stirring.
In some embodiments, in the above preparation method of chiral ionic liquid, in step (3), the volume ratio of acetonitrile to methanol in the mixed solvent of acetonitrile and methanol is 8-10, preferably 9; in the mixed solvent of acetonitrile and diethyl ether, the volume ratio of acetonitrile to diethyl ether is 8-10, preferably 9. It is to be noted that the mixed solvent of acetonitrile and methanol correspondingly removes chiral acids L-and D-2-aminobutyric acid; the mixed solvent of acetonitrile and diethyl ether correspondingly removes the chiral acid L-and D-malic acid.
In some embodiments, in the above preparation method of chiral ionic liquid, in step (4), the evaporation may be rotary evaporation, and the drying may be vacuum drying.
Another embodiment of the present invention provides a method for resolving racemic threonine, comprising: (1) Mixing the chiral ionic liquid with water to obtain a latent solvent; (2) Mixing excessive racemic threonine in a cosolvent until solid-liquid balance is achieved to obtain a saturated solution; (3) And cooling and crystallizing the saturated solution, and filtering to obtain the L-threonine.
It should be noted that, in the process of resolving racemic threonine, the chiral solvent provides a chiral environment for the whole solution system, and selective interaction is generated between the chiral solvent and the chiral solute, which helps to distinguish two single enantiomers, so that the racemate can be successfully resolved.
In some embodiments, in the above method for resolving racemic threonine, the concentration of the chiral ionic liquid in the cosolvent in step (1) is 10wt% to 70wt%.
In some embodiments, in the method for resolving racemic threonine, the time for mixing until solid-liquid equilibrium is reached in step (2) is 12-36 h.
It should be noted that, the time for reaching the solid-liquid equilibrium is determined by the concentration of the chiral ionic liquid aqueous solution, and when the concentration is less than 30wt%, the stirring time and the standing time are respectively 12 hours; when the content is more than or equal to 30wt% and less than 60wt%, stirring and standing time are respectively 24 hours; when it is 60wt% or more, the stirring and standing time is 36 hours, respectively. And the temperature during stirring and standing was 313.15K.
In some embodiments, in the method for resolving racemic threonine, in the step (3), during cooling crystallization, the stirring speed is 340rpm to 360rpm, and the cooling rate is 0.05K/min to 0.15K/min; for example, the stirring speed may be 350rpm, and the cooling rate may be 0.1K/min.
In some embodiments, in the above method for resolving racemic threonine, the ee value is detected in the step (3) when the saturated solution is crystallized by cooling, and the filtration is performed when the ee value is highest.
In some embodiments, in the above method for resolving racemic threonine, in step (3), the mother liquor is obtained by filtration; evaporating the mother liquor to remove water, dissolving with an organic solvent, and filtering to remove threonine to obtain a filtrate 2; and (4) evaporating the filtrate 2 to remove the organic solvent, and drying to obtain the chiral ionic liquid. In some embodiments, the chiral ionic liquid in the mother liquor is recovered by: after removal of water by rotary evaporation of the mother liquor, the resulting mixture was dissolved and vigorously stirred with acetonitrile and methanol in a volume ratio of 9. The filtrate was collected and the organic solvent removed by rotary evaporation and dried in a 333.15K vacuum oven for 48 hours to give the chiral ionic liquid which was reused.
In the above method for resolving racemic threonine, the ratio is 30wt% [ Hmim ]] 2 [L-MA]And [ Hmim ]][L-2-AbA]In latent solvent with water, the times of obtaining high-purity product by crystallization resolution circulation1 and 2 times respectively.
In some embodiments, the above method of resolving racemic threonine can comprise the steps of:
(1) Preparing latent solvents of the chiral ionic liquid and water with different concentrations as a chiral solvent system for crystal resolution; dissolving excessive racemic threonine in a chiral ionic liquid aqueous solution, stirring for 12-36 hours at 313.15K, and standing for 12-36 hours to ensure that the solution reaches solid-liquid balance.
(2) Taking out the saturated solution under 313.15K, putting the saturated solution into a 313.15K crystallizer connected with a program temperature control device, starting to cool at the stirring speed of 350rpm and the cooling rate of 0.2K/min, and starting to sample after a product is separated out. Sampling once every 5min, sampling 10 times in total, and filtering to obtain a solid product; detecting the optical purity of the sample for 15 times by using a high performance liquid chromatography, and determining the time point with the highest ee value of the product;
(3) Repeating the steps (1) and (2), and sampling and filtering to obtain the product only at the time point with the highest ee value of the product when performing the step (2).
(4) After the mother liquor was subjected to rotary evaporation to remove water, the resulting mixture was dissolved in an organic solvent, and threonine was removed by filtration. Collecting the filtrate, performing rotary evaporation and vacuum drying to obtain chiral ionic liquid which can be recycled;
(5) Repeating the steps (1), (2) and (3) on the solid product in the step (3); the high-purity product can be obtained by circulating for 1-2 times.
For a better understanding of the present invention, the following examples are provided to further illustrate the present invention, but the present invention is not limited to the following examples.
EXAMPLE 1 preparation of chiral Ionic liquids [ Hmim ] [ L-2-AbA ] and [ Hmim ] [ D-2-AbA ]
2.47g (0.01 mol) of 1-hexyl-3-methylimidazolium bromide ([ C ] is weighed out 6 mim]Br) and dissolved with 10mL of ultrapure water; it is subjected to ion exchange by a pretreated 717 strongly basic anion resin to obtain [ C 6 mim]An aqueous OH solution; secondly, under the condition of ice bath, the [ C ] is reacted 6 mim]The aqueous OH solution is slowly added dropwise via a constant pressure dropping funnel, containing 1.03g (0.01 mol) L2-aminobutyric acid or D-2-aminobutyric acid and 20mL of ultrapure water, stirring for reaction for 12 hours, and performing rotary evaporation on the solution after the reaction is finished to remove water; dissolving the obtained mixture by using acetonitrile and methanol in a volume ratio of 9 to the mixture under ice bath conditions, stirring vigorously, filtering to remove excessive L-2-aminobutyric acid or D-2-aminobutyric acid, and performing rotary evaporation on the filtrate to remove the solvent; and finally, putting the obtained liquid into a 353.15K vacuum oven to be dried for 48h to obtain the chiral ionic liquid.
The prepared [ Hmim ] [ L-2-AbA ] chiral ionic liquid was subjected to nuclear magnetic resonance analysis, and the results are shown in fig. 1, 1HNMR (400mhz, dmso-d 6) δ 9.44 (d, J =1.7hz, 1h), 7.81 (t, J =1.8hz, 1h), 7.74 (t, J =1.8hz, 1h), 4.17 (t, J =7.2hz, 2h), 3.87 (s, 3H), 1.78 (p, J =7.4hz, 2h), 1.54 (dtd, J =14.9,7.4,4.8hz, 2h), 1.36-1.15 (m, 8H), 0.90-0.83 (m, 3H), 0.79 (t, J =7.4hz, 3h), which demonstrated successful synthesis of the chiral ionic liquid [ Hmim ] [ L-2-AbA ];
thermogravimetric analysis is carried out on the prepared [ Hmim ] [ L-2-AbA ] chiral ionic liquid, and the result is shown in figure 2, the decomposition temperature of the chiral ionic liquid [ Hmim ] [ L-2-AbA ] is 476.26K, and the chiral ionic liquid serving as a solvent has good thermal stability;
in addition, the L-type ionic liquid and the corresponding D-type ionic liquid only have optical rotation difference, and the two are consistent in physical characteristics, so that the chiral ionic liquids [ Hmim ] [ L-2-AbA ] and [ Hmim ] [ D-2-AbA ] are successfully synthesized, and have good thermal stability.
Example 2 preparation of chiral ionic liquid 1-hexyl-3-methylimidazole L-malate ([ Hmim ]] 2 [L-MA]) And 1-hexyl-3-methylimidazole D-malate ([ Hmim)] 2 [D-MA])
2.47g (0.01 mol) of 1-hexyl-3-methylimidazolium bromide ([ C ] was weighed out 6 mim]Br) and dissolved with 10mL of ultrapure water; subjecting it to ion exchange with pretreated 717 strongly basic anion resin to obtain [ C ] 6 mim]An aqueous OH solution; secondly, under the condition of ice bath, the [ C ] is reacted 6 mim]Slowly adding the OH aqueous solution into a flask filled with 0.67g (0.005 mol) of L-malic acid or D-malic acid and 20mL of ultrapure water dropwise through a constant-pressure dropping funnel, stirring for reacting for 12 hours, and performing rotary evaporation on the solution after the reaction is finished to remove water;the mixture obtained is then dissolved with acetonitrile and diethyl ether in a volume ratio of 9. Finally, putting the obtained liquid into a 353.15K vacuum oven for drying for 48h to obtain chiral ionic liquid;
the prepared chiral ionic liquid [ Hmim)] 2 [L-MA]Nuclear magnetic resonance analysis was performed, and the results are shown in FIG. 3, 1HNMR (400MHz, DMSO-d 6) delta 9.27 (d, J =1.7Hz, 2H), 7.81 (t, J =1.8Hz, 2H), 7.74 (t, J =1.8Hz, 2H), 4.17 (t, J =7.2Hz, 4H), 4.02 (dd, J =8.3,5.3Hz, 1H), 3.86 (s, 6H), 2.58-2.52 (m, 1H), 2.43-2.33 (m, 1H), 1.78 (p, J =7.4Hz, 4H), 1.33-1.18 (m, 12H), 0.91-0.81 (m, 6H), and demonstrate that a chiral ionic liquid [ Hmim ] is] 2 [L-MA]Successfully synthesizing;
the prepared chiral ionic liquid [ Hmim] 2 [L-MA]Thermogravimetric analysis is carried out, and the result is shown in figure 4, chiral ionic liquid [ Hmim] 2 [L-MA]Has a decomposition temperature of 495.17K and has good thermal stability as a solvent.
In addition, the L-type ionic liquid and the corresponding D-type ionic liquid only have optical rotation difference, and the two are consistent in physical characteristics, so that the chiral ionic liquid [ Hmim ]] 2 [L-MA]And [ Hmim ]] 2 [D-MA]Are synthesized successfully and have good thermal stability.
EXAMPLE 3 solubility of latent solvents at different concentrations
[ Hmim ] prepared in example 1][L-2-AbA]The solubilities in different concentrations of the cosolvent (10 wt%, 30wt%, 50wt%, and 70 wt%) as compared to water are plotted in FIG. 5; [ Hmim ] prepared in example 2] 2 [L-MA]The solubilities of the different concentrations of cosolvent (10 wt%, 30wt%, 50wt%, and 70 wt%) in water are plotted in FIG. 5; as can be seen from FIGS. 5 and 6, the solubility of the latent solvent formed by chiral ionic liquid and water at a ratio of 30wt% is the greatest and exceeds that in pure water, compared to the solubility of racemic threonine in pure water, and it can be seen that racemic threonine is 30wt% [ Hmim ]] 2 [L-MA]Has a solubility slightly higher thanAt 30wt% [ Hmim ]][L-2-AbA]。
Example 4 racemic threonine HPLC chromatogram
In the embodiment of the invention, the standard racemic threonine is detected by High Performance Liquid Chromatography (HPLC), and the HPLC detection method comprises the following steps: xylonite CROWNPAKCR (+) chiral column, mobile phase is perchloric acid solution with pH =1.5, elution rate is 0.2mL/min, elution time is 20min, column incubator temperature is 278.15K, detector wavelength is 200nm. The detection result is shown in FIG. 7, in which the retention time of L-threonine is 10.70min and the retention time of D-threonine is 8.15min.
Example 5 resolution of racemic threonine Using the chiral Ionic liquid prepared in example 1
(1) And (3) configuring a latent solvent of 10wt% of [ Hmim ] [ L-2-AbA ] and water to realize a chiral solvent system with low viscosity. Dissolving excessive racemic threonine in 10wt% of water solution of [ Hmim ] [ L-2-AbA ], stirring at 313.15K for 12 hours, and standing for 12 hours to reach solid-liquid balance;
(2) Taking out the saturated solution under 313.15K, putting the saturated solution into a 313.15K crystallizer connected with a program temperature control device, starting to cool at the stirring speed of 350rpm and the cooling rate of 0.1K/min, starting to sample after the product is separated out, sampling once every 5min, sampling 15 times in total, and filtering to obtain a solid product. Detecting the optical purity of the sample for 15 times by using a high performance liquid chromatography (the method is the same as the example 4), and determining the time point with the highest ee value of the product;
(3) Repeating the steps (1) and (2), and sampling and filtering only at the time point with the highest ee value of the product to obtain the product in the step (2); the HPLC chromatogram when the ee value is highest is shown in FIG. 8, L-Thr exists at the retention time of 9.86min, and the peak area percentage of L-Thr is 66.45; D-Thr was present at a retention time of 7.21min, and the peak area percentage of D-Thr was 33.54, whereby L-Thr was obtained as an enantiomeric excess, and ee value was 32.92%;
(4) The mother liquor was rotary evaporated to remove water, the resulting mixture was dissolved and vigorously stirred with acetonitrile and methanol in a volume ratio of 9. The filtrate was collected and the organic solvent removed by rotary evaporation and dried in a 333.15K vacuum oven for 48 hours to obtain chiral ionic liquid which was reused.
Example 6 resolution of racemic threonine Using the chiral ionic liquid prepared in example 1
(1) Preparing a cosolvent of 30wt% of [ Hmim ] [ L-2-AbA ] and water to realize a chiral solvent system with low viscosity, dissolving excessive racemic threonine in an aqueous solution of 30wt% of [ Hmim ] [ L-2-AbA ], stirring the solution for 24 hours at 313.15K, and standing the solution for 24 hours to ensure that the solution reaches solid-liquid balance;
(2) Taking out the saturated solution under 313.15K, putting the saturated solution into a 313.15K crystallizer connected with a program temperature control device, starting to cool at the stirring speed of 350rpm and the cooling rate of 0.1K/min, starting to sample after the product is separated out, sampling once every 5min, sampling 15 times in total, and filtering to obtain a solid product. Detecting the optical purity of the sample for 15 times by using a high performance liquid chromatography (the method is the same as the example 4), and determining the time point with the highest ee value of the product;
(3) Repeating the steps (1) and (2), and sampling and filtering only at the time point with the highest ee value of the product to obtain the product in the step (2); an HPLC chromatogram when the ee value is the highest is shown in FIG. 9, L-Thr exists at the retention time of 9.47min, and the peak area percentage of L-Thr is 79.87; D-Thr was present at a retention time of 7.13min, and the peak area percentage of D-Thr was 20.13, whereby L-Thr was obtained as an enantiomeric excess, ee value was 59.74%;
(4) The mother liquor was rotary evaporated to remove water, the resulting mixture was dissolved with acetonitrile and methanol in a volume ratio of 9. The filtrate was collected and the organic solvent removed by rotary evaporation and dried in a 333.15K vacuum oven for 48 hours to obtain chiral ionic liquid which was reused.
Example 7 resolution of racemic threonine Using the chiral ionic liquid prepared in example 1
(1) The solid product in step (3) of example 6 was dissolved in excess in 30wt% [ Hmim ] [ L-2-AbA ] and water as a cosolvent, stirred at 313.15K for 24 hours, and then allowed to stand for 24 hours to reach solid-liquid equilibrium;
(2) Repeating the steps (1), (2) and (3) in the example 6, and circulating the operation for 2 times to obtain a high-purity product, wherein the chromatogram of HPLC chromatographic detection (the method is the same as the example 4) of the product is shown in figure 10, L-Thr exists at the retention time of 10.04min, and the peak area percentage of the L-Thr is 99.54; D-Thr was present at a retention time of 7.00min, and the percentage of the peak area of D-Thr was 0.46, from which it was obtained: the enantiomeric excess of L-Thr is 99.08% ee.
Example 8 resolution of racemic threonine Using the chiral ionic liquid prepared in example 2
(1) Configuration 10wt% [ Hmim ]] 2 [L-MA]A latent solvent with water to achieve a chiral solvent system of low viscosity. The excess racemic threonine was dissolved in 10wt% [ Hmim ]] 2 [L-MA]Stirring the mixture for 12 hours at 313.15K, and standing the mixture for 12 hours to ensure that the solid-liquid balance is achieved;
(2) Taking out the saturated solution under 313.15K, putting the saturated solution into a 313.15K crystallizer connected with a program temperature control device, starting to cool at the stirring speed of 350rpm and the cooling rate of 0.1K/min, starting to sample after the product is separated out, sampling once every 5min, sampling 15 times in total, and filtering to obtain a solid product. Detecting the optical purity of 15 samples by using high performance liquid chromatography (the method is the same as the example 4), and determining the time point with the highest ee value of the product;
(3) Repeating the steps (1) and (2), and sampling and filtering only at the time point with the highest ee value of the product to obtain the product in the step (2); the HPLC chromatogram when the ee value was the highest was shown in FIG. 11, L-Thr was present at a retention time of 9.34min, and the peak area percentage of L-Thr was 83.71; D-Thr was present at a retention time of 7.10min, and the percentage of the peak area of D-Thr was 16.29, from which it was obtained: the enantiomeric excess of L-thr is 67.42 percent;
(4) Removing water from the mother liquor by rotary evaporation, dissolving the obtained mixture by using acetonitrile and methanol in a volume ratio of 9; the filtrate was collected and the organic solvent was removed by rotary evaporation and placed in a 353.15K vacuum oven for drying for 48 hours to obtain chiral ionic liquid which was reused.
Example 9 resolution of racemic threonine Using the chiral ionic liquid prepared in example 2
(1) The preparation of [ Hmim ] is 300wt%] 2 [L-MA]A latent solvent with water to achieve a chiral solvent system of low viscosity. The excess of racemic threonine was dissolved in 30wt% [ Hmim ]] 2 [L-MA]Stirring the mixture for 24 hours at 313.15K, and standing the mixture for 24 hours to ensure that the solid-liquid balance is achieved;
(2) Taking out the saturated solution under 313.15K, putting the saturated solution into a 313.15K crystallizer connected with a program temperature control device, starting to cool at the stirring speed of 350rpm and the cooling rate of 0.1K/min, starting to sample after the product is separated out, sampling once every 5min, sampling 15 times in total, and filtering to obtain a solid product. Detecting the optical purity of the sample for 15 times by using a high performance liquid chromatography (the method is the same as the example 4), and determining the time point with the highest ee value of the product;
(3) Repeating the steps (1) and (2), sampling and filtering only at the time point with the highest ee value of the product when the step (2) is carried out to obtain the product, wherein an HPLC chromatogram with the highest ee value is shown in FIG. 12, L-Thr exists at the retention time of 9.34min, and the peak area percentage of the L-Thr is 89.10; D-Thr was present at a retention time of 7.11min, and the percentage of the peak area of D-Thr was 10.90, whereby it was obtained: the enantiomeric excess of L-thr is 78.2 percent;
(4) The mother liquor was rotary evaporated to remove water, the resulting mixture was dissolved with acetonitrile and methanol in a volume ratio of 9. The filtrate was collected and the organic solvent was removed by rotary evaporation and placed in a 353.15K vacuum oven for drying for 48 hours to obtain chiral ionic liquid which was reused.
Example 10 resolution of racemic threonine Using the chiral ionic liquid prepared in example 2
(1) The solid product in step (3) of example 9 was dissolved in excess in 30wt% [ Hmim ]] 2 [L-MA]Stirring the mixture and a latent solvent of water for 24 hours at 313.15K, and standing for 24 hours to ensure that the mixture reaches solid-liquid balance;
(2) Repeating the steps (1), (2) and (3) in the example 9, and repeating the operation for 1 time to obtain a product with a high ee value, wherein a chromatogram map of HPLC chromatographic detection (the method is the same as the example 4) of the product is shown in FIG. 13, L-Thr exists at the retention time of 9.27min, and the peak area percentage of the L-Thr is 99.61; D-Thr was present at a retention time of 7.09min, and the percentage of the peak area of D-Thr was 0.39, whereby it was found that: the enantiomeric excess of L-thr is 99.22%.
Finally, the above embodiments are only intended to illustrate the technical solution of the present invention and not to limit the same, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention, which shall be covered by the claims of the present invention.
Claims (10)
1. A chiral ionic liquid is characterized in that the preparation method comprises the following steps:
(1) Ion exchange is carried out on 1-hexyl-3-methylimidazole bromine salt and 717 anion resin to obtain [ C 6 mim]An aqueous OH solution;
(2) Will [ C ] 6 mim]Performing neutralization reaction on the OH aqueous solution and excessive chiral acid to obtain a mixture, wherein the chiral acid is selected from L-2-aminobutyric acid, D-2-aminobutyric acid, L-malic acid or D-malic acid;
(3) After the mixture is dewatered, adding an organic solvent to separate out chiral acid, and filtering to remove solids to obtain filtrate 1;
(4) Evaporating the filtrate 1 and drying to obtain the chiral ionic liquid.
2. The chiral ionic liquid of claim 1, wherein in step (3), the water removal method of the mixture comprises: the mixture was rotary evaporated at 323.15K-333.15K for 1.8h-2.2h.
3. The chiral ionic liquid of claim 1 or 2, wherein in step (3), after the mixture is dewatered, an organic solvent is added to the mixture at 273.15K to 276.15K to precipitate the chiral acid; wherein the organic solvent is selected from mixed solvent of acetonitrile and methanol or mixed solvent of acetonitrile and diethyl ether.
4. The chiral ionic liquid according to claim 3, wherein in the mixed solvent of acetonitrile and methanol in the step (3), the volume ratio of acetonitrile to methanol is 8-10; in the mixed solvent of acetonitrile and diethyl ether, the volume ratio of acetonitrile to diethyl ether is 8-10.
5. A method for resolving racemic threonine comprising: (1) Mixing the chiral ionic liquid of any one of claims 1 to 4 with water to obtain a cosolvent; (2) Mixing excessive racemic threonine in a cosolvent until solid-liquid balance is achieved to obtain a saturated solution; (3) And cooling and crystallizing the saturated solution, and filtering to obtain the L-threonine.
6. The process for resolving racemic threonine as set forth in claim 5, wherein the concentration of the chiral ionic liquid in the cosolvent in step (1) is in the range of 10wt% to 70wt%.
7. The method for resolving racemic threonine as claimed in claim 5 or 6, wherein the time for mixing until solid-liquid equilibrium is reached in step (2) is 12 to 36 hours.
8. The method for resolving racemic threonine as claimed in claim 5 or 6, wherein in the step (3), the stirring speed is 340rpm to 360rpm and the cooling rate is 0.05K/min to 0.15K/min during cooling crystallization.
9. The process according to claim 5 or 6, wherein in step (3), the ee value is detected when the saturated solution is crystallized by cooling, and the filtration is performed when the ee value is the highest.
10. The process for resolving racemic threonine according to claim 5 or 6, wherein in the step (3), the mother liquor is obtained by filtration; evaporating the mother liquor to remove water, dissolving with an organic solvent, and filtering to remove threonine to obtain a filtrate 2; and (4) evaporating the filtrate 2 to remove the organic solvent, and drying to obtain the chiral ionic liquid.
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