CN113636950A - 一种手性4-芳基-β-氨基酸衍生物的制备方法 - Google Patents
一种手性4-芳基-β-氨基酸衍生物的制备方法 Download PDFInfo
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- CN113636950A CN113636950A CN202010394976.7A CN202010394976A CN113636950A CN 113636950 A CN113636950 A CN 113636950A CN 202010394976 A CN202010394976 A CN 202010394976A CN 113636950 A CN113636950 A CN 113636950A
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- trifluorophenyl
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- beta
- amino acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- -1 enamine compounds Chemical class 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 7
- 150000003624 transition metals Chemical class 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 239000010948 rhodium Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000005984 hydrogenation reaction Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 150000001576 beta-amino acids Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical group [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006546 (C4-C10) cycloalkyl group Chemical group 0.000 claims description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000520 N-substituted aminocarbonyl group Chemical group [*]NC(=O)* 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical group [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910052707 ruthenium Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 239000011982 enantioselective catalyst Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- BBGGHUOAAZMMET-SECBINFHSA-N methyl (3r)-3-acetamido-4-(2,4,5-trifluorophenyl)butanoate Chemical compound COC(=O)C[C@H](NC(C)=O)CC1=CC(F)=C(F)C=C1F BBGGHUOAAZMMET-SECBINFHSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- IZFJPBWBAPIUAN-UITAMQMPSA-N methyl (z)-3-acetamido-4-(2,4,5-trifluorophenyl)but-2-enoate Chemical compound COC(=O)\C=C(NC(C)=O)\CC1=CC(F)=C(F)C=C1F IZFJPBWBAPIUAN-UITAMQMPSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 5
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 5
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 150000002081 enamines Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- RHCVXZBZEKGRQP-GFCCVEGCSA-N tert-butyl n-[(2r)-4-oxo-4-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-1-(2,4,5-trifluorophenyl)butan-2-yl]carbamate Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)NC(=O)OC(C)(C)C)C1=CC(F)=C(F)C=C1F RHCVXZBZEKGRQP-GFCCVEGCSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 2
- XKJLQAJESSUVAA-DAXSKMNVSA-N methyl (z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate Chemical compound COC(=O)\C=C(/N)CC1=CC(F)=C(F)C=C1F XKJLQAJESSUVAA-DAXSKMNVSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 2
- 229960004034 sitagliptin Drugs 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- OSQPRQRJSJMQRJ-UHFFFAOYSA-N 2-(2,3,4-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C(F)=C1F OSQPRQRJSJMQRJ-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- AQCSCRYRCRORET-UHFFFAOYSA-N 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;hydrochloride Chemical compound Cl.C1NCCN2C(C(F)(F)F)=NN=C21 AQCSCRYRCRORET-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- YVPFEPDAUAITIE-UHFFFAOYSA-N OC=CC1=C(F)C=C(F)C(F)=C1 Chemical group OC=CC1=C(F)C=C(F)C(F)=C1 YVPFEPDAUAITIE-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- NDNHENJSVVVLFB-SNVBAGLBSA-N ethyl (3R)-3-acetamido-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(C[C@@H](CC(C=C(C(F)=C1)F)=C1F)NC(C)=O)=O NDNHENJSVVVLFB-SNVBAGLBSA-N 0.000 description 1
- BUTHYEJVFPPHDD-POHAHGRESA-N ethyl (Z)-3-acetamido-4-(2,4,5-trifluorophenyl)but-2-enoate Chemical compound CCOC(/C=C(/CC(C=C(C(F)=C1)F)=C1F)\NC(C)=O)=O BUTHYEJVFPPHDD-POHAHGRESA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- INQCBWDBMIXHDN-SNVBAGLBSA-N methyl (3r)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CC(C)(C)OC(=O)N[C@@H](CC(=O)OC)CC1=CC(F)=C(F)C=C1F INQCBWDBMIXHDN-SNVBAGLBSA-N 0.000 description 1
- XAKRGTQXCNOINF-YFHOEESVSA-N methyl (z)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(2,4,5-trifluorophenyl)but-2-enoate Chemical compound CC(C)(C)OC(=O)NC(=C/C(=O)OC)\CC1=CC(F)=C(F)C=C1F XAKRGTQXCNOINF-YFHOEESVSA-N 0.000 description 1
- IZFJPBWBAPIUAN-UHFFFAOYSA-N methyl 3-acetamido-4-(2,4,5-trifluorophenyl)but-2-enoate Chemical compound COC(=O)C=C(NC(C)=O)CC1=CC(F)=C(F)C=C1F IZFJPBWBAPIUAN-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
- B01J31/2471—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom
- B01J31/2476—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
-
- 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
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/821—Ruthenium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- C07C2531/24—Phosphines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种手性4‑芳基‑β‑氨基酸衍生物的制备方法,所述制备方法包括在有机溶剂中,在包含过渡金属和BIBOPs的催化剂的存在下,氢化具有如式Ⅲ所示结构的烯胺化合物。本发明的制备方法具有选用的不对称催化剂用量少、操作简单、反应条件温和、收率高,立体选择性高,具有较好的工业应用和经济价值。
Description
技术领域
本发明涉及制备对映体富集的β-氨基酸衍生物的方法,其是药学中重要的中间体,具体地说,涉及制备对映体富集的β-氨基酸衍生物的新方法,用于合成治疗糖尿病药物西格列汀。
背景技术
如J.Med.Chem.2005,48(1):141所公开,通式结构Ⅱ是二肽基肽酶- Ⅳ(DPP-Ⅳ)抑制剂,用来治疗Ⅱ型糖尿病的商购药物(Sitagliptin, Januvia)。
如WO2004085378,WO2005097733,WO2006065826所公开,在铑催化剂和Joshiphos配体存在下不对称催化烯胺,然而需要使用特殊溶剂,催化剂用量相对较多,所得手性产物的ee值相对较低,使得该法不经济。
如WO2009064476所公开,中间体手性β-氨基酸衍生物由 BINAP-RuCl2作催化剂不对称氢化烯胺所制备。所得手性产物的ee值和收率相对较低。
如US8278486/CN102271504所公开,中间体手性β-氨基酸衍生物由TangPhosRh(COD)BF4作催化剂不对称氢化烯胺所制备,所得手性产物的ee值和收率相对较高,但该催化剂配体成本较高,商业来源不稳定,工业应用存在风险。
发明内容
本发明提供以有效的对映选择性方式,提供了一种手性4-芳基-β- 氨基酸衍生物的制备方法,所述手性4-芳基-β-氨基酸衍生物为具有如式Ι所示结构的β-氨基酸衍生物,
其中:立体中心用*标记的R-构型或S-构型;
所述制备方法包括在有机溶剂中,在包含铑和BIBOPs的过渡金属催化剂的存在下,氢化具有如式Ⅲ所示结构的烯胺化合物;
其中:Ar为苯基,其用一至五个或一至五个混合独立选自卤素、三氟甲基、烷氧基的取代基取代;PG是氢、醛基、乙酰基、苄基、Boc、 Cbz、PMB、Fmoc、COOR1、CONR2;Z是OR1、SR1和NR3R4;其中: R1=H、C1-6烷基;R2=H、C1-6烷基或含有氮、氧、硫的三至六元杂环; R3和R4是各自独立H、C1-6烷基、C4-10环烷基、芳基或R3和R4与它们连接至氮原子形成的任选含有选自O、S、N-C1-5烷基的额外杂原子的C4-7元杂环。
在本发明的制备方法的优选技术方案中,优选地,所述手性配体为BIBOPs(其制备方法可参考US8552212,Org.Lett.,2010,12(1):176),其具有式Ⅳ结构:所述配体BIBOPs具有如式Ⅳ所示的结构:
其中,R’是氢、烷基、卤素、羟基、烷氧基、芳基。优选的构型为式Ⅳa,R为甲氧基。
在本发明的制备方法的优选技术方案中,优选地,如式Ⅳ所示的结构构型为式(S,S,S’,S’)-Ⅳa和式(R,R,R’,R’)-Ⅳb,
在本发明的制备方法的优选技术方案中,优选地,所述过渡金属包含[M(NBD)2]X、[M(COD)2]X,其中:X选自四氟硼酸根、六氟锑酸根、三氟甲磺酸根的非配位阴离子;M是铑、铱、钌。其中:COD为 1,5-环辛二烯,和NBD为降冰片二烯。优选的过渡金属为 [Rh(NBD)2]BF4、[Rh(COD)2]BF4。
在本发明的制备方法的优选技术方案中,优选地,所述有机溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸甲酯、乙酸丁酯、四氢呋喃、甲基叔丁基醚、异丙醚、甲苯、丙酮、乙腈、二氯甲烷、正庚烷中的一种或两种以上。优选的有机溶剂为甲醇、乙醇。
在本发明的制备方法的优选技术方案中,优选地,手性配体和过渡金属的用量为0.001~1mol%。
在本发明的制备方法的优选技术方案中,优选地,氢气的压力为 0.1~10MPa。优选地0.1~2.5MPa。
在本发明的制备方法的优选技术方案中,优选地,所述氢化的反应温度为室温至100℃。优选地,室温至80℃。
在本发明的制备方法的优选技术方案中,优选地,所述氢化的反应时间2~36h。优选地6~24h。
本发明提供的手性β-氨基酸衍生物(式Ι)的制备方法,具有以下有益效果:选用的不对称催化剂用量少、操作简单、反应条件温和、收率高,纯度高达99.9%,立体选择性高,具有较好的工业应用和经济价值。
具体实施方式
为了更好地理解本发明的技术方案,下面结合具体实施例作进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1:5-[1-羟基-2-(2,4,5-三氟苯基)-亚乙基]-2,2-二甲基-1,3-二氧六环-4,6-二酮
250mL反应釜中加入四氢呋喃(40.0g)、三氟苯乙酸(10.0g),控温在0~5℃,分批加入N,N-羰基二咪唑(CDI,9.4g),加毕后室温反应3h,加入米氏酸(8.4g),室温搅拌16h。减压蒸除溶剂,加入水(20.0g)、用1N盐酸调pH至2左右,二氯甲烷萃取、洗涤、干燥得到类白色固体[5-[1-羟基-2-(2,4,5-三氟苯基)-亚乙基]-2,2-二甲基-1,3-二氧六环-4,6- 二酮]14.6g,收率88%。HRMS[M+H]+:317.0628;1H-NMR(400MHz, CDCl3):15.50(s,1H),7.13-7.19(m,1H),6.93-6.99(m,1H), 4.54(s,2H),1.77(s,6H)。
实施例2:(Z)-3-氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯
250mL反应釜中加入甲醇(48.0g)、实施例1的产品5-[1-羟基 -2-(2,4,5-三氟苯基)-亚乙基]-2,2-二甲基-1,3-二氧六环-4,6-二酮(14.0g), 60℃反应4h,加入乙酸铵(5.0g),60℃反应10h小时,减压浓缩,加入二氯甲烷、水,萃取、洗涤、干燥,减压回收溶剂至干,得到淡黄色固体[(Z)-3-氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯]10.0g,收率92%。HRMS[M+H]+:246.0735;1H-NMR(400MHz,CDCl3):7.05-7.12(m,1H),6.92-6.98(m,1H),4.57(s,1H),3.65(s,3H),3.41(s, 2H)。
实施例3:(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯
100mL反应瓶中加入四氢呋喃(40.0g),实施例2的产品(Z)-3-氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(10.0g)、醋酐(8.0g)、吡啶(9.0g),回流反应20h,用盐酸调pH至3左右。减压蒸除溶剂至近干,硅胶纯化得到9.3g白色固体[(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯] (79%,HPLC纯度99.8%)。HRMS[M+H]+:288.0838;1H-NMR(400MHz,CDCl3):11.14(s,1H),7.03-7.09(m,1H),6.89-6.96(m,1H), 4.82(s,1H),4.15(s,2H),3.71(s,3H),2.15(s,3H)。
实施例4:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
氢化釜中加入甲醇(16.0g)、实施例3的产品(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(4.0g)、MeO-BIBOP/[Rh(NBD)2]BF4 (2.0mg),先后用氮气、氢气置换,氢气压力至1.0Mpa,室温反应36h,减压蒸除溶剂至干,得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.8%ee,纯度99.4%。HRMS[M+H]+:290.0998;1H-NMR(400MHz,CDCl3):7.02-7.09(m,1H),6.87-6.93(m,1H),6.31-6.33 (m,1H),4.44-4.45(m,1H),3.71(s,3H),2.87-2.89(m,2H), 2.49-2.61(m,2H)1.93(s,3H)。
实施例5:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
氢化釜中加入乙醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基 -4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD)2]BF4 (1.0mg),先后用氮气、氢气置换,氢气压力至1.0Mpa,60℃反应18h,减压蒸除溶剂至干,得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.5%ee,纯度99.4%。
实施例6:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
氢化釜中加入四氢呋喃(10.0g)、实施例3的产品(Z)-3-乙酰氨基 -4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD)2]BF4 (1.0mg),先后用氮气、氢气置换,氢气压力至1.5Mpa,50℃反应10h,减压蒸除溶剂至干,得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.8%ee,纯度高达99.7%。
实施例7:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
氢化釜中加入甲醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基 -4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD)2]BF4 (1.0mg),先后用氮气、氢气置换,氢气压力至2.5Mpa,60℃反应6h,减压蒸除溶剂至干,得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.2%ee,纯度99.8%。
实施例8:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
氢化釜中加入甲醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基 -4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(COD)2]BF4 (1.5mg),先后用氮气、氢气置换,氢气压力至1.0Mpa,40℃反应24h,减压蒸除溶剂至干,得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.5%ee,纯度高达99.5%。
实施例9:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸乙酯
氢化釜中加入甲醇(16.0g)、(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2- 丁烯酸乙酯(4.0g)、MeO-BIBOP/[Rh(NBD)2]BF4(2.0mg),先后用氮气、氢气置换,氢气压力至1.0Mpa,50℃反应14h,减压蒸除溶剂至干,得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸乙酯定量收率 98.7%ee,纯度99.8%。HRMS[M+H]+:304.1150;1H-NMR(400MHz, CDCl3):7.04-7.10(m,1H),6.88-6.93(m,1H),6.30-6.33(m,1H), 4.42-4.45(m,1H),4.10(q,J=7.2Hz,2H)3.72(s,3H),2.87-2.90 (m,2H),2.49-2.61(m,2H)1.26(t,J=6.8Hz,3H)。
实施例10:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
氢化釜中加入甲醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基 -4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD)]SbF6 (1.5mg),先后用氮气、氢气置换,氢气压力至1.0Mpa,50℃反应24h,减压蒸除溶剂至干,得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.0%ee,纯度高达99.0%。
实施例11:(3R)-N-叔丁氧羰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
50mL反应瓶中加入(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯(3.0g),盐酸(9.0g),回流过夜,减压浓缩,加入2mol/L NaOH 溶液调pH>13.5,滴加Boc酸酐(2.7g),室温反应5h。加入乙酸乙酯 (9.0g),用2N盐酸调节pH至2.5~3.5,分层、萃取、洗涤,减压至干,得到类白色固体(3R)-N-叔丁氧羰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯3.1g,收率90%,纯度99.7%。HRMS[M+H]+:334.1276;1H-NMR (400MHz,DMSO-d6):12.19(s,1H)7.41-7.48(m,1H),7.24-7.31 (m,1H),6.77-6.79(d,1H,J=8.8Hz),4.00-4.02(m,1H),2.57 (dd,1H,J=3.2,13.2Hz),2.83(dd,1H,J=4.4,15.2Hz),2.40(d, 2H,J=6.4Hz)1.27(s,9H)。
实施例12:N-Boc西格列汀
250mL反应瓶加入二氯甲烷(30.0g)、(3R)-N-叔丁氧羰基-3-氨基 -4-(2,4,5-三氟苯基)丁酸甲酯(3.0g)、3-(三氟甲基)-5,6,7,8-四氢-[1,2,4] 三唑并[4,3-a]吡嗪盐酸盐(2.4g),加入HOBT(1.4g)、EDC·HCl(1.9g),温度控制在0.0~10.0℃,缓慢加入DIPEA(3.5g),室温反应12h,加入水(70.0g),减压蒸除溶剂,加入无水乙醇(24.0g)升温至溶解后过滤,冷却结晶,干燥得到白色固体3.75g(收率82%)。HRMS[M+H]+: 508.1666;1H-NMR(400MHz,DMSO-d6):7.40-7.47(m,1H),7.29-7.36 (m,1H),6.74-6.77(m,1H),4.88-5.04(m,2H),4.22-4.32(m, 1H),3.96-4.10(m,2H),2.61-2.89(m,4H)1.24(s,9H)。
实施例13:西格列汀
100mL反应瓶依次投入甲醇(10.0g)、N-Boc西格列汀(2.0g),缓慢加入盐酸(4.5g),室温反应14h,减压浓缩后,加入水(2.5g)搅拌,氢氧化钠溶液调节pH值8.0~9.0,加入乙酸乙酯萃取,减压浓缩,异丙醇(10.0g)重结晶,得到白色固体1.3g(收率80%,≥99.9%ee)。 HRMS[M+H]+:408.1260;1H-NMR(400MHz,D2O):7.17-7.24(m, 1H),7.01-7.11(m,1H),4.82-5.00(m,2H),4.14-4.27(m,2H), 3.93-4.01(m,1H),2.91-3.09(m,2H),2.79-2.97(m,2H)。
实施例14:N-Boc西格列汀
氢化釜中加入甲醇(10.0g)、(Z)-叔丁氧羰基-4-氧代-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]-1-(2,4,5-三氟苯基)-丁 -2-烯-2-基氨基甲酸酯(2.0g)、MeO-BIBOP/[Rh(NBD)2]BF4(2.0mg),先后用氮气、氢气置换,氢气压力至1.5Mpa,50℃反应16h,减压蒸除溶剂至干,得到定量收率90.0%ee。
实施例15:(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
氢化釜中加入甲醇(10.0g)、(Z)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD)2]BF4(1.0mg),先后用氮气、氢气置换,氢气压力至1.0Mpa,50℃反应14h,过滤、减压蒸除溶剂至干,得到定量收率99.3%ee,纯度99.9%。HRMS[M+H]+: 348.1421;1H-NMR(400MHz,CDCl3):7.04-7.12(m,1H),6.84-6.93 (m,1H),5.09-5.12(m,1H),4.10-4.22(m,1H),3.70(s,3H), 2.85-2.90(m,1H),2.50-2.61(m,1H),1.40(s,9H)。
本发明不受上述实施例的限制,上述实施例和说明书中描述的只是为了说明原理,在阅读了本发明的上述内容后,本领域技术人员可以对本发明做各种修改而不背离本发明的精神和范围,这些等同形式的修改同样落在本发明的保护范围之内。
Claims (10)
1.一种手性4-芳基-β-氨基酸衍生物的制备方法,所述手性4-芳基-β-氨基酸衍生物为具有如式Ι所示结构的β-氨基酸衍生物,
其中:立体中心用*标记的R-构型或S-构型;
所述制备方法包括在有机溶剂中,在包含过渡金属和BIBOPs的催化剂的存在下,氢化具有如式Ⅲ所示结构的烯胺化合物;
其中:Ar为苯基,其用一至五个或一至五个混合独立选自卤素、三氟甲基、烷氧基的取代基取代;PG是氢、醛基、乙酰基、苄基、Boc、Cbz、PMB、Fmoc、COOR1、CONR2;Z是OR1、SR1和NR3R4;其中:
R1=H、C1-6烷基;
R2=H、C1-6烷基或含有氮、氧、硫的三至六元杂环;
R3和R4是各自独立H、C1-6烷基、C4-10环烷基、芳基或R3和R4与它们连接至氮原子形成的任选含有选自O、S、N-C1-5烷基的额外杂原子的C4-7元杂环。
2.根据权利要求1的制备方法,其中,所述过渡金属包含[M(NBD)2]X、[M(COD)2]X,其中:X选自四氟硼酸根、六氟锑酸根、三氟甲磺酸根的非配位阴离子;M是铑、铱、钌。
5.根据权利要求1的制备方法,其中,所述有机溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸甲酯、乙酸丁酯、四氢呋喃、甲基叔丁基醚、异丙醚、甲苯、丙酮、乙腈、二氯甲烷、正庚烷中的一种或两种以上。
6.根据权利要求1的制备方法,其中,式Ⅲ中Ar是2,4,5-三氟苯基,PG是乙酰基,Z是OCH3。
8.根据权利要求1所述的制备方法,其中,氢气的压力为0.1~10MPa。
9.根据权利要求1所述的制备方法,其中,所述氢化的反应温度为室温至100℃。
10.根据权利要求1所述的制备方法,其中,所述氢化的反应时间为2~36h。
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WO2022188501A1 (zh) * | 2021-03-09 | 2022-09-15 | 台州市生物医化产业研究院有限公司 | 一种乙酰麦氏酸衍生物降解废弃物的回收利用方法 |
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