CN1301967C - Method of chiral separation for D,L-phenylalanine ester or its salt - Google Patents
Method of chiral separation for D,L-phenylalanine ester or its salt Download PDFInfo
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- CN1301967C CN1301967C CNB2004100660455A CN200410066045A CN1301967C CN 1301967 C CN1301967 C CN 1301967C CN B2004100660455 A CNB2004100660455 A CN B2004100660455A CN 200410066045 A CN200410066045 A CN 200410066045A CN 1301967 C CN1301967 C CN 1301967C
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- Prior art keywords
- salt
- phenylalanine
- ester
- phenylalanine ester
- optical purity
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 69
- -1 D,L-phenylalanine ester Chemical class 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000000926 separation method Methods 0.000 title claims abstract description 23
- 229960005190 phenylalanine Drugs 0.000 claims abstract description 43
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 30
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims abstract description 28
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 238000009835 boiling Methods 0.000 claims abstract description 5
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 4
- 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 claims abstract description 3
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 3
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 3
- 238000000638 solvent extraction Methods 0.000 claims abstract description 3
- 230000003287 optical effect Effects 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 claims description 14
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 claims description 14
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 claims description 14
- 229930182832 D-phenylalanine Natural products 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000006340 racemization Effects 0.000 claims description 4
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 3
- 238000004458 analytical method Methods 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 5
- 239000003053 toxin Substances 0.000 abstract 1
- 231100000765 toxin Toxicity 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000463 material Substances 0.000 description 13
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 229960002510 mandelic acid Drugs 0.000 description 10
- 239000013078 crystal Substances 0.000 description 9
- VSDUZFOSJDMAFZ-SECBINFHSA-N methyl (2r)-2-amino-3-phenylpropanoate Chemical compound COC(=O)[C@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-SECBINFHSA-N 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 238000005352 clarification Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- SWVMLNPDTIFDDY-SBSPUUFOSA-N methyl (2r)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-SBSPUUFOSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- CJGXMNONHNZEQQ-UHFFFAOYSA-N ethyl 2-amino-3-phenylpropanoate Chemical compound CCOC(=O)C(N)CC1=CC=CC=C1 CJGXMNONHNZEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- VSDUZFOSJDMAFZ-UHFFFAOYSA-N methyl 2-amino-3-phenylpropanoate Chemical compound COC(=O)C(N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-UHFFFAOYSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- QOISWWBTZMFUEL-LLVKDONJSA-N tert-butyl (2r)-2-amino-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)[C@H](N)CC1=CC=CC=C1 QOISWWBTZMFUEL-LLVKDONJSA-N 0.000 description 2
- QOISWWBTZMFUEL-NSHDSACASA-N tert-butyl (2s)-2-amino-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 QOISWWBTZMFUEL-NSHDSACASA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HOBFSNNENNQQIU-SNVBAGLBSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-2-phenylacetic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 HOBFSNNENNQQIU-SNVBAGLBSA-N 0.000 description 1
- JKMPXGJJRMOELF-UHFFFAOYSA-N 1,3-thiazole-2,4,5-tricarboxylic acid Chemical compound OC(=O)C1=NC(C(O)=O)=C(C(O)=O)S1 JKMPXGJJRMOELF-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- CRNDLOROBWPGMJ-FUHGYEQSSA-N COC([C@@H](N)CC1=CC=CC=C1)=O.C(C)(C)(C)OC(=O)N[C@H](C1=CC=CC=C1)C(=O)O Chemical compound COC([C@@H](N)CC1=CC=CC=C1)=O.C(C)(C)(C)OC(=O)N[C@H](C1=CC=CC=C1)C(=O)O CRNDLOROBWPGMJ-FUHGYEQSSA-N 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- CBQJSKKFNMDLON-SNVBAGLBSA-N N-acetyl-D-phenylalanine Chemical compound CC(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-SNVBAGLBSA-N 0.000 description 1
- 101710150975 N-acyl-L-amino acid amidohydrolase Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- RKRPVYQEZHEXEN-FVGYRXGTSA-N [N+](=O)(O)[O-].COC([C@@H](N)CC1=CC=CC=C1)=O Chemical compound [N+](=O)(O)[O-].COC([C@@H](N)CC1=CC=CC=C1)=O RKRPVYQEZHEXEN-FVGYRXGTSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- FPFQPLFYTKMCHN-PPHPATTJSA-N ethyl (2s)-2-amino-3-phenylpropanoate;hydron;chloride Chemical compound Cl.CCOC(=O)[C@@H](N)CC1=CC=CC=C1 FPFQPLFYTKMCHN-PPHPATTJSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
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- 235000019634 flavors Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- SWVMLNPDTIFDDY-UHFFFAOYSA-N hydron;methyl 2-amino-3-phenylpropanoate;chloride Chemical compound Cl.COC(=O)C(N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-UHFFFAOYSA-N 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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- 238000005809 transesterification reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a chiral resolution method for D, L-phenyl alanine ester and a salt thereof. In the method, an optically-pure aromatic acetic acid derivative is used as a resolving agent. The method comprises the following steps: (1) the D, L-phenyl alanine ester or a salt thereof is proportionally mixed with the aromatic acetic acid derivative are, and the mixture is dissolved in solvent; after the mixture is heated and cooled, aromatic organic acid and a double salt crude product of phenylalanine ester are obtained, and then are recrystallized; (2) the refined salt of the double salt is taken, the double salt is decomposed with an acidolysis method or an alkaline hydrolysis method at 0 DEG C to the boiling temperature of the solvent within a controlled pH value range; the resolving agent and the optically-pure phenylalanine ester are separated with a conventional organic solvent extraction method or an ion-exchange resin separation method. Thus, the optically-pure phenylalanine ester or the phenylalanine which has high yield and high quality is obtained. The method has the advantages of low cost and low consumption of the used resolving agent, and no toxin and low cost of the used solvent, and the method is suitable for large-scale industrialized production.
Description
One, technical field
The invention belongs to chipal compounds chemical separation technology field.Specifically relate to a kind of preparation method of chiral organic compound, especially prepare the method for D type or L type phenylalanine ester, also applicable to the preparation of other chiral amino acid esters compound.
Two, technical background
Having optically active phenylalanine ester class is important medicine and edible chemical intermediate.In recent years, the Application and Development of amino acids cancer therapy drug, dietary supplements has promoted the production development of optical purity phenylalanine Ester.
The optical purity phenylalanine ester is widely used in fields such as medicine, food and agricultural chemicals.In polypeptide was synthetic, the esterification of phenylalanine was the important step of protection and activated amino acid, can improve the activity and the selectivity of ester group greatly, and is synthetic significant to polypeptide.
Optical purity phenylalanine ester derivative at present and the development in future target be as medicine or medicine intermediate.Utilize special perviousness and the enzyme catalysis specificity of amino acid, strengthened medicine dissolving and absorption in vivo as carrier, significantly reduce the toxic side effect of medicine with amino acid to organism.Have very strong oxidation-resistance as the optical purity phenylalanine ester, body is delayed senility, D-phenylalanine ester derivative has anti-tumor activity.Therefore, the optical purity phenylalanine ester is used for new drug development as medicine intermediate wide application prospect.
The L-phenylalanine ester can replace phenylalanine to use in foodstuff additive, can change the mouthfeel and the local flavor of food, increases the freshness date of food.As the L-phenylalanine methyl ester is the main raw material of synthetic sweetener aspartame, this novel sweetener has obtained Huaihe River and has used more than 100 countries and regions, be applied in the products such as more than 6000 kind of beverage, food and medicine, it is efficient, safe nutritional type sweeting agent, the international market demand amount is higher than the rate of growth of other artificial sweetening agent average annual 5% far away with the speed increment of average annual 15%-20%.
Since the seventies in 20th century, Japan has successfully synthesized multiple optical purity aminoacid alkyl ester hydrochloride and vitriol.Studies show that wherein to optical purity phenylalanine ester character, this compounds not only has good surfactivity effect, but also the mattress deinsectization effect of killing with characteristics, particularly this compounds such as skin care, antirust, sterilization and disinfestation, anti-oxidant and softening fibre elements more and more causes people's attention.In recent years, these compounds are widely used in the agricultural chemicals, with this compounds is that major ingredient can be made various sterilization deinsectization mixture, they are very easy by daylight or by natural microbiological deterioration, do not stay residual hazard in soil, plant materials and in the fruit, its degradation material also can be used as the nutritive substance of farm crop, improves quality and the output of farm crop.
At present, the method for resolution of racemic phenylalanine ester class mainly contains methods such as chiral separation method, enzyme Split Method, membrane separation process and chromatography.
Adopting chiral separation method resolution of racemic chiral isomer, is the main method of current separating chiral enantiomorph material.
(1) use N-carbobenzoxy-(Cbz)-L-phenylalanine successfully to split D, the L-phenylalanine tert-butyl ester [Teresa Sokolowska, et al.Roczniki.Chem., 1966 as resolving agent; 40 (11/12): 1895].Its resolving agent is too expensive, and will use the bigger phosgene of toxicity in preparation process, is unsuitable for large-scale production and environmental protection requirement.
(2) use N-acetyl-D-phenylalanine to be chiral separation agent [Paul B.Sollman.US3941831,1976; Paul B.Sollman.GB1458740,1976; Paul B.Sollman.CA1062726,1979; James M.Schlatter.US3983162,1976; James M.Schlatter.GB1533850,1978; ], successfully split D, the L-phenylalanine methyl ester.Its resolving agent costs an arm and a leg, and is not suitable for large-scale commercial production.
(3) with chiral separation agent R (-) thiazolidinethion-2-4-carboxylic acid (R (-) TTCA) to D; the L-phenylalanine ester carries out chiral separation [Li Yezhi; Guo Chunxiao etc. SCI; 1998; 19 (6): 885-889]; obtain R (-) thiazolidinethion-2-4-carboxylic acid D-phenylalanine ester and optical activity L-phenylalanine ester respectively, R (-) thiazolidinethion-2-4-carboxylic acid D-phenylalanine ester is decomposed under alkaline condition can obtain the D-phenylalanine ester again.In addition, the pure Pyrrolidonecarboxylic acid of applied optics is that resolving agent also can split D, L-phenylalanine ester [JP7229341].
(4) utilize porcine pancreatic lipase catalysis D in single-phase organic solvent, and the transesterification reaction of L-phenylalanine methyl ester and n-Octanol [Xie Zhidong, Liu Li equality. Science Bulletin, 1994; 39 (21): 1965-1967], realized D, the fractionation of L-phenylalanine methyl ester.Used organic solvent has increased production cost in the fractionation, and the stability of biological enzyme is lower, is unfavorable for reusing.Also utilize the porous silica gel immobilizing chymotrypsin to split D, the L-phenylalanine methyl ester obtains L-phenylalanine [Liu Lijian, poplar equality, Chinese Journal of Pharmaceuticals, 1997; 28 (8): 333-343].The source approach of this enzyme is less, and the preparation cost height of immobilized enzyme, and pollution control is strict in the production process.
(5) utilize membrane separating method with N-acetyl-D, the n-Octanol of L-phenylalanine ethyl ester racemic mixture or nonylcarbinol solution are substrate, with the L-Aminoacylase is catalyzer, hydrolysis L-ester and generate the L-phenylalanine optionally, then utilize extraction agent and stock liquid counter-current extraction, finally obtain high-optical-purity the L-phenylalanine [Jiang Zhongyi, Qiu Liqin etc. chemical industry journal, 1999; 50 (4): 530-534].Because mould material and zymin are comparatively expensive, be not suitable in large-scale production, using.
(6) utilize chirality Chiralcel OD post performance liquid chromatographic column to a series of phenylalanine ester derivative enantiomers carried out splitting [Fu Fangmin, building Rong Liang etc. analytical chemistry, 1998; 26 (2): 200-202], obtain separating resulting preferably.But this method only is suitable for analyzing and laboratory scale preparation.
Up to the present, adopting optical purity phenyl ring family acetogenin is resolving agent, and chiral separation prepares the method for optical purity phenylalanine ester and do not see bibliographical information.
Three, summary of the invention
1. goal of the invention
The purpose of this invention is to provide that a kind of production cost is lower, aftertreatment is easy, facility investment is few, be fit to the racemic phenylalanine ester of suitability for industrialized production or the method for splitting of its salt.
2. technical scheme
A kind of D, L-phenylalanine ester or its salt chiral separation method is characterized in that it is a resolving agent with optical purity aromatic series acetogenin, this resolving agent is that its structural formula of aromatic series acetogenin is:
C wherein
1Be chiral carbon atom, R
2Be alkyl, aryl, N-alkyloyl, N-aroyl, N-carbalkoxy, N-aryloxy carbonyl, hydroxyl or alkoxyl group; R
3Be substituting groups such as halogen, hydroxyl or alkoxyl group;
Chiral separation D, L-phenylalanine ester or its salt, its method for splitting step is as follows:
(1) with D, L-phenylalanine ester or its salt are with after optical purity aromatic series acetogenin mixes, be dissolved in the solvent to solvent boiling point at 0 ℃, after the insulation cooling, separable optical purity aromatic series acetogenin and a kind of double salt crude product of optical purity phenylalanine ester wherein of obtaining, gained double salt crude product is recrystallization again, can obtain this double salt refined salt;
(2) getting above-mentioned double salt refined salt can analyse or the alkaline hydrolysis analysis method decomposes this double salt with acidolysis, and then the organic solvent extraction separation method by routine can make optical purity L-phenylalanine ester or its salt, or optical purity D-phenylalanine ester or its salt; Or can make optical purity L-phenylalanine, or optical purity D-phenylalanine with the separation method of conventional ion exchange resin.
The described D of above-mentioned steps (1), L-phenylalanine ester or its salt are the outer fully D that revolves of imitating that revolve or partly outer of imitating, L-phenylalanine ester or its salt, and D, its structural formula of L-phenylalanine ester is:
R wherein
1Be that carbonatoms is the low alkyl group of 1-6, or aryl; Described D, L-phenylalanine ester salt is hydrochloride, vitriol, nitrate or phosphoric acid salt;
The described D of above-mentioned steps (1), L-phenylalanine ester or its salt are 1 with resolving agent optical purity aromatic series acetogenin with mol ratio: 5-5: 1 mixes.
The described solvent of above-mentioned steps (1) comprises: any mixed solvent of water, hydrophilic solvent or these solvents, wherein hydrophilic solvent comprises lower alcohols, rudimentary ketone etc.
The described D of above-mentioned steps (1) after L-phenylalanine ester or its salt and optical purity aromatic series acetogenin are mixed in the solvent, needs insulation 0-6 hour.
The described parsing acid of above-mentioned steps (2) can be that mineral acid comprises hydrochloric acid, sulfuric acid, and phosphoric acid or nitric acid etc. and solution thereof, or mix mineral acid and solution thereof; Also can be that organic acid comprises formic acid, acetate, propionic acid etc. and solution and derivative.
The described parsing alkali of above-mentioned steps (2) can be that mineral alkali comprises sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood, saleratus, calcium hydroxide, hydrated barta, ammoniacal liquor etc. and solution or ammonia, or mixes mineral alkali and solution thereof; Also can be that organic bases comprises ethamine, diethylamine, triethylamine etc. and solution thereof.
The described double salt acidolysis of above-mentioned steps (2) can 0 ℃ to solvent boiling point, pH value is controlled at and adds mineral acid or organic acid in the 1-7 scope and carry out double salt and decompose; The double salt alkaline hydrolysis can 0 ℃ to solvent boiling point, pH value is controlled at and adds mineral alkali or organic bases in the 7-12 scope and carry out double salt and decompose.
3. technique effect
The present invention is a kind of not only economically feasible but also the method with suitable suitability for industrialized production of efficient fractionation efficient.From present studies show that, be economically viable with optical purity aromatic series acetogenin as the resolving agent of phenylalanine ester, be suitable for large-scale industrial production.The invention solves the following problem in the fractionation of racemization phenylalanine ester:
(1), use solvent toxicological harmless, cheap, and be easy to reclaim.
A. the present invention has reduced the use of valuable organic solvent, and employed solvent is nontoxic hydrophilic solvent system, and cheap, and convenient the acquisition is easy to reclaim.
B. by splitting recycling of mother liquor, reduce the usage quantity of solvent, reduced production cost.
(2), double salt is refining easily purifies.
Utilize optical purity aromatic series acetogenin and D, the formed two kinds of diastereomeric salts of L-phenylalanine ester have significantly different solubility property in specific solvent, obtained the crystallization of wherein a kind of diastereomeric salt refined salt easily, this double salt is decomposed, obtain highly purified optical purity phenylalanine ester.
(3), the resolving agent price is low, consumption is few, recyclable the applying mechanically of holding concurrently.
What the present invention at first used is lower-cost a kind of or several in present numerous organic acid resolving agents, then successfully utilizes employed resolving agent characteristic, has solved the too much problem of resolving agent consumption in the split process, and has carried out recovery set usefulness well.
Four, embodiment
Further understand essence of the present invention by following examples:
Embodiment 1
D-Alpha-Methyl 4-Chlorophenylacetic acid 18.5 gram (0.1mol) and D, L-phenylalanine methyl ester 17.9 grams (0.1mol) dissolve in the water content of 200ml is water-ethanolic soln of 80%, be warming up to 75 ℃, make solution clarification, then slowly be cooled to 4 ℃, allow its sufficient crystallising 8h.Filter resulting white crystals, this material is a D-Alpha-Methyl 4-Chlorophenylacetic acid L-phenylalanine methyl ester crude product, washs with 50% ethanolic soln.Is recrystallization in 80% water-ethanolic soln with this material in water content, obtains D-Alpha-Methyl 4-Chlorophenylacetic acid L-phenylalanine methyl ester refined salt 16.5 grams.
Getting D-Alpha-Methyl 4-Chlorophenylacetic acid L-phenylalanine methyl ester refined salt 15 gram, to be dissolved in the 100ml water content be in water-ethanolic soln of 80%, with 3N hydrochloric acid soln adjust pH to 2.Steam ethanol, and be cooled to 4 ℃, can obtain resolving agent D-Alpha-Methyl 4-Chlorophenylacetic acid white crystals 7.14 grams.Mother liquor then adds 5N sodium hydrogen carbonate solution adjust pH to 8.There is this moment oily liquids to occur on the solution upper strata, extracts this solution twice, then collect extraction liquid, dried overnight with the toluene solvant of 30ml.The steaming of solvent in the extraction liquid is removed, and the hydrochloric acid soln of the methyl alcohol of adding 20ml and the 6N of 5ml can obtain white L-phenylalanine methyl ester hydrochloride crude product, this crude product is used in recrystallizing methanol can obtains L-phenylalanine methyl ester hydrochloride 7.08 grams, [α]
D 20=+33.2 ° of (c=2, C
2H
5OH).
Embodiment 2
The D of L-Alpha-Methyl 4-Chlorophenylacetic acid 18.5 grams (0.1mol) and partial racemization, L-phenylalanine methyl ester 17.9 grams (0.1mol), its optical purity (%o.p.) counts 65% with the D-phenylalanine methyl ester, in the methanol solution of 150ml, dissolve, be warming up to 70 ℃, make solution clarification, then slowly be cooled to 4 ℃, allow its sufficient crystallising 8h.Filter resulting white crystals, this material is a L-Alpha-Methyl 4-Chlorophenylacetic acid D-phenylalanine methyl ester crude product, washs with 50% methanol solution.Is recrystallization in water-methanol solution of 80% with this material in water content, obtains L-Alpha-Methyl 4-Chlorophenylacetic acid D-phenylalanine methyl ester refined salt 26.3 grams.
Get L-Alpha-Methyl 4-Chlorophenylacetic acid D-phenylalanine methyl ester refined salt 15 grams and be dissolved in the methanol solution of 80ml, then add the sulphuric acid soln of the 3N of 15ml.And be cooled to 4 ℃, can obtain crystallization 7.05 grams of resolving agent L-Alpha-Methyl 4-Chlorophenylacetic acid white.Mother liquor then adds the chloroform of 50ml, then under agitation feeds ammonia.Collect solution lower floor separately oily liquids is arranged, then concentrating under reduced pressure steams and removes chloroform, can obtain white crystals or thick white solid matter D-phenylalanine methyl ester, the 6N hydrochloric acid mixed solution recrystallization of this material 30ml methyl alcohol and 10ml can be obtained D-phenylalanine methyl ester hydrochloride 7.14 grams, [α]
D 20=-33.1 ° of (c=2, C
2H
5OH).
Embodiment 3
According to the method for embodiment 1, D, L-phenylalanine ethyl ester can become salt formation white D-Alpha-Methyl 4-Chlorophenylacetic acid L-phenylalanine ethyl ester double salt with D-Alpha-Methyl 4-Chlorophenylacetic acid.Then the method for handling double salt by embodiment 1 can obtain L-phenylalanine ethyl ester hydrochloride.
Embodiment 4
The D of L-Alpha-Methyl 4-Chlorophenylacetic acid 18.5 grams (0.1mol) and partial racemization, L-phenylalanine methyl ester 17.9 grams (0.1mol), its optical purity (%o.p.) counts 10% with the D-phenylalanine methyl ester, according to the method for embodiment 2, obtain L-Alpha-Methyl 4-Chlorophenylacetic acid D-phenylalanine methyl ester refined salt 21.6 grams.
Get L-Alpha-Methyl 4-Chlorophenylacetic acid D-phenylalanine methyl ester refined salt 15 grams and be dissolved in the aqueous solution of 100ml, then add the 1N potassium hydroxide solution and transfer pH value to 8.5.Be cooled to 25 ℃, have this moment oily liquids to occur on the solution upper strata.Extract this upper strata oily liquids at twice with the 50ml ethyl acetate, then collect extraction liquid, dried overnight.The steaming of solvent in the extraction liquid is removed, and the hydrochloric acid soln of the methyl alcohol of adding 20ml and the 6N of 5ml can obtain white D-phenylalanine methyl ester hydrochloride crude product, this crude product is used in recrystallizing methanol can obtains D-phenylalanine methyl ester hydrochloride 7.12 grams, [α]
D 20=-33.3 ° of (c=2, C
2H
5OH).The contained resolving agent of mother liquor is then recyclable to be applied mechanically.
Embodiment 5
R-(-)-amygdalic acid 15.2 gram (0.1mol) and D, L-phenylalanine methyl ester hydrochloride 43.1 grams (0.2mol) dissolve in the water of 200ml, are warming up to 80 ℃, make the solution clarification, then slowly are cooled to 4 ℃, allow its sufficient crystallising 10h.Filtration obtains white crystals, and this material is R-(-)-amygdalic acid L-phenylalanine methyl ester crude product, with 0 ℃ of frozen water washing.With this material recrystallization in water, obtain R-(-)-amygdalic acid L-phenylalanine methyl ester refined salt 33.2 grams.
Get R-(-)-amygdalic acid L-phenylalanine methyl ester refined salt 30 grams and be dissolved in 50 ℃ of water of 100ml, then use 8N hydrochloric acid soln adjust pH to 1.Be cooled to 4 ℃, can obtain resolving agent R-(-)-amygdalic acid white crystals 8.96 grams.Mother liquor adds 5N sodium hydrogen carbonate solution adjust pH to 5, and dilutes this solution to 200ml.Separate this mother liquor with 732 resin cation (R.C.)s, can obtain L-phenylalanine 15.06 grams, [α]
D 20=-33.2 ° (c=2, water).
Embodiment 6
Fetch resolving agent R-(-)-amygdalic acid 4.56 gram (0.03mol) and the D of receipts, L-phenylalanine methyl ester nitrate 24.2 grams (0.1mol) are carried out to reactant salt in 100ml 30% water-acetone soln, be warming up to 70 ℃, make the solution clarification, then slowly be cooled to 4 ℃, allow its sufficient crystallising 10h.Filter resulting white crystals, this material is R-(-)-amygdalic acid L-phenylalanine methyl ester crude product, uses solution washing.With this material recrystallization in water, obtain R-(-)-amygdalic acid L-phenylalanine methyl ester refined salt 8.18 grams.
Get R-(-)-amygdalic acid L-phenylalanine methyl ester refined salt 8 grams and be dissolved in the 100ml aqueous solution, be warmed up to 80 ℃ with formic acid adjust pH to 2.Be cooled to 4 ℃, can obtain resolving agent R-(-)-amygdalic acid white crystals 3.51 grams.Mother liquor then adds diethylamine adjust pH to 8.The back is according to the method for embodiment 1.Can obtain L-phenylalanine methyl ester hydrochloride 4.16 grams, [α]
D 20=+32.6 ° of (c=2, C
2H
5OH).
Embodiment 7
N-acetyl-L D-pHPG 20.9 gram (0.1mol) and D, the L-phenylalanine tert-butyl ester 22.1 grams (0.1mol) are carried out to reactant salt according to the method for embodiment 5 and can obtain the N-acetyl-L-D-pHPG D-phenylalanine tert-butyl ester 20.5 grams.Then get the N-acetyl-L-D-pHPG D-phenylalanine tert-butyl ester 20 grams, can obtain D-phenylalanine 7.41 grams, [α] according to the separation method among the embodiment 5
D 20=+34.7 ° (c=2, water).
Embodiment 8
N-tertbutyloxycarbonyl-D-phenylglycine 20.1 gram (0.08mol) and D, L-phenylalanine methyl ester 19.5 grams (0.1mol), method according to embodiment 6 is carried out to reactant salt, can obtain N-tertbutyloxycarbonyl-D-phenylglycine L-phenylalanine methyl ester complex salt crystal 21 grams of white.
Get these double salt 20 grams and be dissolved in the aqueous solution of 100ml, then add triethylamine solution and transfer pH value to 8.Be cooled to 25 ℃, have this moment oily liquids to occur on the solution upper strata.Then the separation method according to embodiment 4 can obtain L-phenylalanine methyl ester hydrochloride 7.21 grams, [α]
D 20=+33.4 ° of (c=2, C
2H
5OH).The contained resolving agent of mother liquor is then recyclable to be applied mechanically.
Claims (3)
1, a kind of D, L-phenylalanine ester or its salt chiral separation method is characterized in that it is a resolving agent with optical purity aromatic series acetogenin, this its structural formula of resolving agent aromatic series acetogenin is:
C wherein
1Be chiral carbon atom, R
2Be alkyl, aryl, N-alkyloyl, N-aroyl, N-carbalkoxy, N-aryloxy carbonyl, hydroxyl or alkoxyl group; R
3Be halogen, hydroxyl or alkoxyl group;
Chiral separation D, L-phenylalanine ester or its salt, its method for splitting step is as follows:
(1) with D, L-phenylalanine ester or its salt are with after optical purity aromatic series acetogenin mixes, be dissolved in the solvent to solvent boiling point at 0 ℃, after the insulation cooling, separable optical purity aromatic series acetogenin and a kind of double salt crude product of optical purity phenylalanine ester wherein of obtaining, gained double salt crude product is recrystallization again, obtains this double salt refined salt;
(2) get that above-mentioned double salt refined salt is analysed with acidolysis or the alkaline hydrolysis analysis method decomposes this double salt, then the organic solvent extraction separation method by routine can make optical purity L-phenylalanine ester or its salt, or optical purity D-phenylalanine ester or its salt; Or can make optical purity L-phenylalanine, or optical purity D-phenylalanine with the separation method of conventional ion exchange resin.
2, D according to claim 1, L-phenylalanine ester or its salt chiral separation method is characterized in that the described D of step (1), L-phenylalanine ester or its salt are the complete racemic or D of partial racemization, L-phenylalanine ester or its salt, D, its structural formula of L-phenylalanine ester is:
R wherein
1Be that carbonatoms is the low alkyl group of 1-6, or aryl; Described D, L-phenylalanine ester salt is hydrochloride, vitriol, nitrate or phosphoric acid salt.
3, D according to claim 1, L-phenylalanine ester or its salt chiral separation method is characterized in that the described D of step (1), L-phenylalanine ester or its salt are 1 with resolving agent optical purity aromatic series acetogenin with mol ratio: 5-5: 1 mixes.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59181244A (en) * | 1983-03-29 | 1984-10-15 | Yamakawa Yakuhin Kogyo Kk | Optical resolution of dl-phenylalanine |
| US4542236A (en) * | 1983-08-02 | 1985-09-17 | Nippon Kayaku Kabushiki Kaisha | Process for preparing optically active phenylalanine |
| US4582928A (en) * | 1984-04-06 | 1986-04-15 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active phenylalanine |
| CN1123562C (en) * | 2000-07-05 | 2003-10-08 | 北京清华紫光英力化工技术有限责任公司 | Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59181244A (en) * | 1983-03-29 | 1984-10-15 | Yamakawa Yakuhin Kogyo Kk | Optical resolution of dl-phenylalanine |
| US4542236A (en) * | 1983-08-02 | 1985-09-17 | Nippon Kayaku Kabushiki Kaisha | Process for preparing optically active phenylalanine |
| US4582928A (en) * | 1984-04-06 | 1986-04-15 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active phenylalanine |
| CN1123562C (en) * | 2000-07-05 | 2003-10-08 | 北京清华紫光英力化工技术有限责任公司 | Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester |
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