CN113480506A - Preparation method of corey lactone diol - Google Patents
Preparation method of corey lactone diol Download PDFInfo
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- CN113480506A CN113480506A CN202110698822.1A CN202110698822A CN113480506A CN 113480506 A CN113480506 A CN 113480506A CN 202110698822 A CN202110698822 A CN 202110698822A CN 113480506 A CN113480506 A CN 113480506A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- VYTZWRCSPHQSFX-GBNDHIKLSA-N (-)-corey lactone Chemical compound O1C(=O)C[C@@H]2[C@@H](CO)[C@H](O)C[C@@H]21 VYTZWRCSPHQSFX-GBNDHIKLSA-N 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 73
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- 150000007513 acids Chemical class 0.000 claims description 26
- 150000007514 bases Chemical class 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 230000035484 reaction time Effects 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 10
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 150000001299 aldehydes Chemical class 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004327 boric acid Substances 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 4
- 150000002596 lactones Chemical group 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 claims description 3
- 238000007273 lactonization reaction Methods 0.000 claims description 3
- 238000007142 ring opening reaction Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000007106 1,2-cycloaddition reaction Methods 0.000 claims description 2
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
- BVXMSQWCZAGNTO-UHFFFAOYSA-N 3,5-dinitrobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 BVXMSQWCZAGNTO-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 2
- 238000010478 Prins reaction Methods 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 2
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 claims 1
- 229940005991 chloric acid Drugs 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- ZAMHYUCJYGXBHR-UHFFFAOYSA-N phenoxy nitrate Chemical compound [O-][N+](=O)OOC1=CC=CC=C1 ZAMHYUCJYGXBHR-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- -1 lactone diol Chemical class 0.000 description 3
- 239000004367 Lipase Substances 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000007036 catalytic synthesis reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 1
- VYTZWRCSPHQSFX-UCROKIRRSA-N (3ar,4r,5r,6as)-5-hydroxy-4-(hydroxymethyl)-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-one Chemical compound O1C(=O)C[C@@H]2[C@H](CO)[C@H](O)C[C@@H]21 VYTZWRCSPHQSFX-UCROKIRRSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical group C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000002330 Congenital Heart Defects Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 208000028831 congenital heart disease Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000000382 dechlorinating effect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种corey内酯二醇的制备方法，该方法具有原料易得、反应条件温和、操作简便、合成路线简捷、化学收率高、成本低等特点，适合工业化生产。The invention provides a preparation method of corey lactone diol. The method has the characteristics of readily available raw materials, mild reaction conditions, simple operation, simple synthesis route, high chemical yield and low cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of corey lactone diol.
Background
Chiral Cory lactone diol (I) with the chemical name of (1S,5R,6R,7R) -6-hydroxymethyl-7-hydroxy-2-oxabicyclo [3.3.0] octan-3-one is a general key intermediate for prostaglandin drug synthesis. The prostaglandin chiral medicine can be used for clinically treating various diseases, such as congenital heart disease, pulmonary hypertension, peptic ulcer, glaucoma, blood coagulation disorder, asthma and the like, and plays an important role. More than 20 prostaglandins are sold on the market globally by 2020, with a total sale of over $ 41 billion, and thus still have great market and development potential. However, the synthesis process of the chiral Corey lactone diol (I) in the domestic market is still immature, mainly depends on import and is expensive. Therefore, a simple, economic and efficient synthesis process of the general intermediate (I) is developed, so that the synthesis technology of the prostaglandin medicament with high barrier is broken, the production cost is reduced, and the domestic market demand is further met.
At present, the synthesis method of chiral Cory lactone diol (I) and derivatives thereof mainly comprises a racemate resolution method and an asymmetric catalytic synthesis method. Although a variety of efficient asymmetric catalytic synthesis strategies have emerged over the last decade, such as: the 2012 Aggarwal group reported that bimolecular succinaldehyde was used as a starting material, and a Corey-like lactone strategy was constructed by a tandem intermolecular Adol-intramolecular Adol reaction catalyzed by organic small-molecule proline (Nature,2012,489,278.); 2019, a high-efficiency chiral spiro-phosphate organic small molecule catalyzed enantioselective Baeyer-Villiger oxidation reaction is developed by a Chen Feng team to construct Corey lactone diol (I) (Angew. chem. int.Ed.2019,58,9923.); in addition, the 2020 Hayashi group reported an asymmetric [3+2] cycloaddition reaction strategy centered on the tandem Michael/Michael reaction to efficiently and rapidly construct Corey lactone diol (I) (chem. sci.,2020,11, 1205). Although the asymmetric catalysis of the small organic molecules can realize the precise construction of chiral compounds, the realization of industrial large-scale production by expensive chiral catalysts needs further exploration.
And the racemate resolution method is more economical and convenient, and is more suitable for industrial production. In the racemate resolution method, 1) cyclopentadiene is firstly proposed by E.J.Corey as an initial raw material, and (+) -ephedrine is used as a chiral resolving agent to prepare the derivative of chiral Cory lactone diol (I) through 9 steps of reaction (J.Am.chem.Soc.1970,92,397.). The synthesis route is complicated, the reaction conditions are harsh, the resolving agent is not easy to obtain, and the method is not suitable for industrial production.
2) In 1991, two enzymes, namely Lipase AK and Lipase PS, separated from Pseudomonas were used by Sugahara et al to carry out biological enzyme resolution on racemic (+/-) -I and (+/-) -16 to obtain Corey lactone diol derivatives of (-) -8 and (-) -10 with optical purities of more than 99% ee, but the consumption of biological enzyme in the method is 50-100% wt of the substrate, and the separated products need column purification (chem. pharm. Bull.,1991,39, 2758.). Therefore, industrialization is still difficult to realize.
3) It was proposed from e.j.corey in 1973 that intermediate 12 could be resolved from (+) -phenethylamine (j.am.chem.soc.1973,95,6832.), and further could be used for the synthesis of chiral Corey lactone diol (I), and recently patent reports were made to apply the resolution method of (+) -phenethylamine (CN 107573309 a, CN 107573310 a, CN 108546258 a). Although the synthetic route is simple, the thermal stability of the organic salt formed by (+) -phenethylamine and a resolution substrate is poor, and a product with ee of more than 99 percent needs to be obtained by two recrystallization operations in the crystallization resolution process, so the resolution process is unstable and efficient.
In the above synthesis method, on one hand, the synthesis steps are too many and the operation is more complicated, and on the other hand, the defects of difficulty in obtaining the resolving agent, poor thermal stability of the resolving agent and the like, and the defects of repeated recrystallization operations and the like exist in the chiral resolution process. The synthesis of chiral Corey lactone diol (I) is therefore limited.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of Corey lactone diol (I). The method is simple, convenient and efficient, has low cost, and has the total yield of the route being more than 12 percent.
In order to realize the purpose, the technical scheme is as follows: a method for preparing corey lactone diol, comprising the steps of:
(1) in the presence of a first alkaline compound, carrying out a [2+2] cycloaddition reaction on cyclopentadiene shown in a formula (II) and dichloroacetyl chloride shown in a formula (III) in a first solvent to obtain a compound shown in a formula (IV); the reaction formula is as follows:
(2) under the action of a peroxidating agent, carrying out Baeyer-Villiger oxidation reaction on the compound shown in the formula (IV) in a second solvent to obtain a compound shown in the formula (V); the reaction formula is as follows:
(3) dechlorinating the compound shown in the formula (V) in a third solvent in the presence of the first acidic compound and under the action of a reducing agent to obtain a compound shown in the formula (VI); the reaction formula is as follows:
(4) subjecting a compound represented by formula (VI) to a lactone ring-opening reaction in a fourth solvent in the presence of a second basic compound;
(5) reacting the product obtained in the step (4) with a resolving agent in a fifth solvent to form diastereoisomer salt, and recrystallizing the obtained diastereoisomer salt in a sixth solvent to obtain single diastereoisomer salt;
(6) carrying out lactonization reaction on the single diastereomer salt obtained in the step (5) in a seventh solvent in the presence of a third basic compound to obtain a compound shown as a formula (VII);
(7) prins reaction of a compound represented by formula (VII) with an aldehyde in an eighth solvent in the presence of a second acidic compound;
(8) in the presence of a third acidic compound, carrying out hydrolysis reaction on the product obtained in the step (7) in a ninth solvent to obtain the corey lactone diol shown in the formula (I);
the synthesis route of the corey lactone diol provided by the invention is as follows:
preferably, the first basic compound in the step (1) includes sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine (Et)3At least one of N), N-Diisopropylethylamine (DIPEA), Pyridine (Pyridine), and 4-N, N-Dimethylpyridine (DMAP); the first solvent includes at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, and n-hexane. The first basic compound described above can each catalyze the reaction well. More preferably, the first basic compound in step (1) is triethylamine, which has the best reaction promoting effect; the first solvent is n-hexane.
Preferably, the mol ratio of the cyclopentadiene represented by the formula (II), the dichloroacetyl chloride represented by the formula (III) and the first basic compound in the step (1) is 1.0-5.0: 1: 0.2-2.0. More preferably, the molar ratio of the cyclopentadiene represented by the formula (II), the dichloroacetyl chloride represented by the formula (III) and the first basic compound in the step (1) is 3:1: 1.
Preferably, the molar ratio of the compound shown in the formula (IV) in the step (2) to the hyperoxidant is 1: 1.0-1: 5.0. More preferably, the molar ratio of the compound represented by the formula (IV) in the step (2) to the hyperoxidant is 1: 4.9.
Preferably, the molar ratio of the compound represented by the formula (V) in the step (3), the reducing agent and the first acidic compound is 1: 1-7: 0-7. More preferably, the molar ratio of the compound represented by formula (V) in step (3), the reducing agent and the first acidic compound is 1:6.6: 6.6.
Preferably, the reaction temperature in the step (1) is-5-25 ℃, and the reaction time is 6-24 hours. More preferably, in the step (1), the materials are added at the temperature of-5 ℃, and then the reaction is carried out for 12-18 hours after the temperature is naturally raised to 20-25 ℃.
Preferably, the reaction temperature in the step (2) is-5-10 ℃, and the reaction time is 2-18 h. More preferably, the reaction temperature in the step (2) is-5 ℃, and the reaction time is 5-7 h.
Preferably, the reaction temperature in the step (3) is 0-100 ℃, and the reaction time is 2-24 h. More preferably, the step (3) is carried out by adding at 0 ℃, and then reacting for 3 hours after slowly raising the temperature to 70 ℃.
Preferably, the reaction temperature in the step (4) is-20 to 100 ℃, and the reaction time is 1 to 50 hours; in the step (5), the reaction temperature is-20-40 ℃, and the reaction time is 1-50 h; the temperature used for recrystallization in the step (5) is-30-80 ℃, and the time for recrystallization is 1-50 h; in the step (6), the reaction temperature is 0-40 ℃, and the reaction time is 1-50 h. More preferably, in the step (4), feeding is carried out at a temperature of-5 ℃, and the reaction is carried out for 2-3 hours after the temperature is naturally raised to 20-25 ℃; in the step (5), the reaction temperature is 0-4 ℃, and the reaction time is 12 hours; the step (5) of recrystallization comprises the steps of uniformly dispersing diastereomer salt in a sixth solvent at the temperature of 20-25 ℃, then transferring to a constant-speed temperature-control constant-temperature bath, and crystallizing under program cooling and stirring; in the step (6), the reaction temperature is 20-25 ℃, and the reaction time is 1 h.
Preferably, the reaction temperature in the step (7) is 25-100 ℃, and the reaction time is 3-30 h. More preferably, the reaction temperature in the step (7) is 80 ℃ and the reaction time is 24 h.
Preferably, the reaction temperature in the step (8) is 25-100 ℃, and the reaction time is 3-30 h. More preferably, the reaction temperature in the step (8) is 65 ℃ and the reaction time is 3-5 h.
Preferably, the peroxidating agent in the step (2) comprises at least one of trifluoro peroxyacetic acid, 3, 5-dinitroperoxybenzoic acid, paranitroperoxybenzoic acid, m-chloroperoxybenzoic acid, peroxyformic acid, peroxybenzoic acid, peroxyacetic acid, hydrogen peroxide and tert-butyl hydroperoxide; the second solvent is a mixture of an organic solvent and water or an organic solvent, and the organic solvent comprises at least one of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol and trifluoroethanol. More preferably, the peroxide in the step (2) comprises 30% of hydrogen peroxide; the second solvent is trifluoroethanol.
Preferably, the reducing agent in the step (3) comprises at least one of zinc and a compound thereof, platinum and a compound thereof, palladium and a compound thereof, and supported palladium; the first acidic compound includes at least one of sulfuric acid, hydrochloric acid, nitric acid, boric acid, perchloric acid, formic acid, acetic acid, oxalic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, copper sulfate, ferric chloride, ammonium chloride, aluminum chloride, and ferric sulfate; the third solvent includes at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile. The first acidic compound described above can each catalyze the reaction well. More preferably, the reducing agent in the step (3) is zinc powder; the first acidic compound is ammonium chloride; the third solvent is methanol. The supported palladium is a hydroxyapatite-supported nano palladium catalytic system Pd-HAP or polyurea-supported nano palladium catalyst Pd-PU.
Preferably, the second basic compound in the step (4) includes at least one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide, and the fourth solvent includes at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, acetone and n-hexane; in the step (5), the fifth solvent comprises at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, acetone and n-hexane, the sixth solvent comprises at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, acetone and n-hexane, and the resolving agent is R- (+) -naphthylethylamine; the third basic compound in the step (6) includes at least one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide, and the seventh solvent includes at least one of water, tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, acetone and n-hexane. The second basic compounds all have good catalytic effects. The third basic compound has good catalytic effect. More preferably, the second basic compound in step (4) is sodium hydroxide, and the fourth solvent is a mixture of tetrahydrofuran and water; in the step (5), the fifth solvent is acetone, the sixth solvent is acetone, and the resolving agent is R- (+) -naphthylethylamine; in the step (6), the third alkaline compound is sodium hydroxide, and the seventh solvent is water. Most preferably, the fourth solvent is a mixture of tetrahydrofuran and water, and the volume ratio of tetrahydrofuran to water is 3: 2. r- (+) -naphthylethylamine with better thermal stability is used as a resolving agent, so that the number of crystallization times can be reduced, the resolving efficiency is more efficient, and meanwhile, the recovery efficiency of the resolving agent is high, and the recovery cost is further reduced, so that the resolving agent is suitable for large-scale popularization and use.
Preferably, the molar ratio of the compound shown in the formula (VI) in the step (4) to the second basic compound is 1: 1.2-1: 5. More preferably, the molar ratio of the compound represented by formula (VI) in step (4) to the second basic compound is 1: 1.5.
Preferably, the molar ratio of the product to the resolving agent in the step (5) is 1: 1.0-1: 5. More preferably, the molar ratio of the product to the resolving agent in step (5) is 1: 1.1.
Preferably, the molar ratio of the single diastereomer salt to the third basic compound in step (6) is 1:1.2 to 1:5. More preferably, the molar ratio of the single diastereoisomeric salt to the third basic compound in step (6) is 1: 1.2.
Preferably, the aldehyde in the step (7) comprises at least one of trioxymethylene and paraformaldehyde, the second acidic compound comprises at least one of sulfuric acid, hydrochloric acid, nitric acid, boric acid, phosphoric acid, perchloric acid, hypochlorous acid, p-toluenesulfonic acid, boron trifluoride, aluminum trichloride, zinc dichloride and titanium tetrachloride, and the eighth solvent comprises at least one of formic acid, tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, acetone and n-hexane; the third acidic compound in the step (8) includes at least one of sulfuric acid, hydrochloric acid, nitric acid, boric acid, phosphoric acid, perchloric acid, hypochlorous acid, and p-toluenesulfonic acid, and the ninth solvent includes at least one of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, acetone, and n-hexane. The second acidic compound described above can catalyze the reaction to occur well. More preferably, in the step (7), the aldehyde is paraformaldehyde, the second acidic compound is concentrated sulfuric acid, and the eighth solvent is anhydrous formic acid; in the step (8), the third acidic compound is hydrochloric acid, and the ninth solvent is methanol. The second acidic compound described above can catalyze the reaction to occur well.
Preferably, the molar ratio of the compound represented by the formula (VII) in the step (7), the aldehyde and the second acidic compound is 1: 1.0-5: 0.1-5. More preferably, the molar ratio of the compound represented by formula (VII) in step (7), the aldehyde, and the second acidic compound is 1:1.2: 0.7.
Preferably, the molar ratio of the product to the third acidic compound in the step (8) is 1: 0.1-1: 5.
Has the advantages that:
the preparation method provided by the invention has the characteristics of easily available raw materials, mild reaction conditions, simple and convenient operation, simple and quick synthetic route, high chemical yield, low cost and the like, and is suitable for industrial production.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
EXAMPLE 1 preparation of Compound (IV)
Under the protection of argon, uniformly dispersing cyclopentadiene monomer (II) (106g,1.60mol) in a 0 ℃ low-temperature bath tank by using 800mL of n-hexane (4A MS for drying), slowly dripping dichloroacetyl chloride (III) (79g,0.54mol) into the solution, controlling the dripping for 30-40 min, and then continuously stirring for 50-60 min at-5 ℃. And then, slowly dripping a solution of triethylamine (56g,0.55mol) in n-hexane (200mL) into the system, and controlling the dripping time to be 50-60 min, wherein the reaction solution is changed into white or light skin color pasty turbid solution from colorless clarification. After the dripping is finished, naturally heating the reaction solution from-5 to 5 ℃ to 20 to 25 ℃ overnight (12 to 18 hours). And (3) carrying out suction filtration on the reaction liquid to remove light skin color insoluble substances, washing a filter cake by using 125mL of n-hexane for 4 times each time until no product exists, collecting filtrate, and carrying out spin drying to obtain a brown oily crude product. And carrying out reduced pressure distillation on the crude product, and collecting 1.5 mmHg/58-62 ℃ fractions to obtain 85g of compound (IV) colorless liquid with the yield of 91%. Compound (IV):
1H NMR(400MHz,Chloroform-d)δ6.06–6.02(m,1H),5.82–5.87(m,1H),4.29–4.23(m,1H),4.10–4.44(m,1H),2.86–2.76(m,1H),2.62–2.52(m,1H)。
13C NMR(100MHz,Chloroform-d)δ197.96,136.98,128.59,88.19,59.69,58.70,35.34。
EXAMPLE 2 preparation of Compound (V)
In a 0 ℃ low-temperature bath tank, uniformly dispersing a compound (IV) (70g,0.39mol) by 200mL of trifluoroethanol, slowly dropping 30% hydrogen peroxide (195mL,1.9mol) into the mixture for controlling the solution to be dropped for 30-40 min, changing the reaction solution from colorless clarification to white turbidity, continuing to react at-5 ℃ for 5-7 h, and gradually changing the reaction solution from white turbidity to near colorless clarification. And (3) TLC detection reaction, adjusting the pH of the reaction solution to 9 by using saturated sodium bicarbonate aqueous solution under ice bath, extracting by using ethyl acetate for 3 times, using 500-600 mL of ethyl acetate each time, combining organic phases, washing by using 200-150 mL of saturated saline solution once, drying by using anhydrous sodium sulfate, and then removing the solvent by rotation to obtain a crude compound (V), wherein 52g of a light yellow oily substance is obtained, and the next reaction is carried out without purification.
Compound (V):
1H NMR(400MHz,Chloroform-d)δ6.01-5.95(m,1H),5.77–5.70(m,1H),5.27-5.21(m,1H),4.09-4.03(m,1H),2.83–2.77(m,2H)。
13C NMR(100MHz,Chloroform-d)δ167.60,133.41,126.84,81.14,79.87,63.47,39.32。
EXAMPLE 3 preparation of Compound (VI)
Activated zinc powder (115g,1.78mol) and ammonium chloride (95g,1.78mol) were dispersed uniformly in 400mL of methanol (4A MS dried) in a 0 ℃ low temperature bath under argon. Then, a solution of the crude compound (V) (52g,0.27mol) in methanol (100mL) was gradually added dropwise to the above reaction system. After the dripping is finished, the reaction solution is moved to room temperature and stirred, and is slowly heated to 70 ℃ for reflux reaction for 3 hours. TLC detection reaction, suction filtration reaction liquid to remove insoluble substances, 100mL methanol washing 5 times, filter cake no product, after collecting filtrate and removing solvent, the residue obtained water and ethyl acetate (300mL EtOAc +300mL water) re-dissolved, and using ethyl acetate extraction water layer 4 times (each time 150mL), the combined organic phase through 200mL saturated salt water washing once, anhydrous sodium sulfate drying, removal of solvent to obtain compound (VI) crude product, yellow brown oil. And carrying out reduced pressure distillation on the crude product, and collecting 1.0 mmHg/70-72 ℃ fractions to obtain 18g of compound (VI) colorless liquid, wherein the yield is 40%, and the purity is more than 98% (GC-MS). Compound (VI):
1H NMR(400MHz,Chloroform-d)δ5.83-5.75(m,1H),5.61-5.55(m,1H),5.16-5.10(m,1H),3.55-3.47(m,1H),2.82–2.73(m,1H),2.72-2.68(m,2H),2.48-2.40(m,1H)。
13C NMR(100MHz,Chloroform-d)δ176.87,131.39,129.89,83.17,45.70,39.66,33.41。
EXAMPLE 4 preparation of Compound (VII)
1. Lactone ring opening
In an ice bath, uniformly dispersing the compound (VI) (15g,120.8mmol) in 90mL of tetrahydrofuran and 60mL of water, precooling for 10min, slowly dripping a 2M sodium hydroxide aqueous solution (90.6mL,181.2mmol) into the mixture, changing the reaction solution from light yellow to dark yellow to brown to clear along with the dripping, naturally heating to room temperature at 0 ℃ after the dripping is finished, and stirring for 2 h. The reaction was checked by TLC. The workup was transferred to an ice bath, the reaction was adjusted to pH 3 with saturated oxalic acid solution, the organic phases were combined by extraction with EtOA: THF 10:1 (150 mL. times.10), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure of 0 deg.C (vacuum: less than 40mmHg) to give crude yellow oil.
2. Preparation of diastereomeric salts
The crude yellow oil was dispersed uniformly in 120mL of acetone (1mL/mol) in an ice bath, and then R- (+) -naphthylethylamine (22.6g, 132.2mmol) was added dropwise slowly to the mixture, which gradually turned into a creamy yellow thick syrup, which was then transferred to a refrigerator at 4 ℃ and stirred overnight (12 h). Then, a milky white to cream yellow solid filter cake and apricot yellow clear filtrate are obtained by suction filtration, and the filter cake is washed for 2 times by 10mL of cold acetone. The filter cake was transferred to room temperature and dried under vacuum to give 32.8g of diastereoisomeric salt (milky white to cream yellow solid powder) in 93% yield. Diastereoisomeric salt:
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝8.4Hz,1H),7.93(dd,J＝8.0,2.0Hz,1H),7.81(d,J＝8.4Hz,1H),7.73(d,J＝7.2Hz,1H),7.60–7.46(m,3H),5.68–5.62(m,1H),5.59–5.53(m,1H),4.91(q,J＝6.4Hz,1H),4.29(td,J＝6.4,3.6Hz,1H),2.88–2.77(m,1H),2.49–2.44(m,1H),2.44–2.35(m,1H),2.19–2.09(m,2H),1.42(d,J＝6.4Hz,3H)。
13C NMR(100MHz,DMSO-d6)δ174.92,142.60,133.35,133.03,130.20,128.69,128.30,126.95,126.00,125.59,125.48,123.10,122.10,70.64,45.99,45.96,41.16,33.88,24.69。
3. preparation of salts of single isomers
At room temperature, diastereoisomer salt (10g,31.9mmol) was uniformly dispersed with 243mL acetone (7.6mL/mol), transferred to a constant temperature controlled constant temperature bath, and crystallized with programmed cooling (see Table 1 below) under stirring. After the temperature program is finished, carrying out suction filtration, washing the filter cake for 2 times by using 20mL of glacial acetone, transferring to room temperature, and carrying out vacuum drying to obtain 4.09g of single isomer salt (white solid powder), wherein the yield is 40.9%, [ alpha ]]20 D-16.07(c ═ 1.05, MeOH), optical purity 95.6% ee, theoretical value about-16.80. The obtained single isomer salt can be recrystallized again from acetone to obtain 3.50g with optical purity>99% ee single isomer salt, recrystallization yield 85%.
Single isomer salts:
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝8.4Hz,1H),7.94(d,J＝8.0Hz,1H),7.84(d,J＝8.4Hz,1H),7.75(d,J＝7.2Hz,1H),7.66–7.45(m,3H),6.39–6.08(m,4H),5.66–5.59(m,1H),5.58–5.52(m,1H),5.01(q,J＝6.4Hz,1H),4.31(td,J＝6.4,3.6Hz,1H),2.83(q,J＝7.2Hz,1H),2.47–2.33(m,2H),2.20–2.08(m,2H),1.48(d,J＝6.4Hz,3H)。
13C NMR(100MHz,DMSO-d6)δ176.04,140.67,133.33(2C),130.05,128.73,128.00,127.36,126.21,125.63,125.54,122.97,122.36,70.81,46.46,45.74,41.10,34.99,23.62。
filtering to obtain filtrate for recycling R- (+) -naphthylethylamine.
The temperature program is as follows in table 1:
TABLE 1 temperature program
| Temperature program segment | Temperature interval | Maintenance time | Linear rate of temperature control | Operation/phenomenon |
| 1 | 25–65℃ | 40min | +1℃/min | — |
| 2 | 65℃ | 2min | — | Placing the reaction vessel in the reaction vessel, and refluxing to clear |
| 3 | 65–35℃ | 30min | -1℃/min | Forming a saturated solution and clarifying |
| 4 | 35℃ | 2min | — | Forming a saturated solution and clarifying |
| 5 | 35–5℃ | 600min | -0.05℃/min | Gradually precipitate white solid, become white and turbid |
| 6 | 5℃ | 500min | — | Aging and white turbidity |
Recovering R- (+) -naphthylethylamine: and removing the solvent from the clear filtrate under reduced pressure to obtain 8.4g of a yellow solid crude product, uniformly dispersing the crude product in 40mL of water, slowly dripping 1M sodium hydroxide aqueous solution (40mL, with the pH value greater than 10) into the water, and stirring the solution at room temperature for 30-60 min after dripping is finished to obtain a brown yellow emulsion of the reaction solution. At this time, the organic phases were combined with EtOAc extraction (50mL × 4), dried over anhydrous sodium sulfate and spin-dried to give a yellow oil, and R- (+) -naphthylethylamine 5.33g was recovered with an optical purity of > 99% ee.
4. Lactonization reaction
At room temperature, the mono-isomer salt (4.0g,12.5mmol) is dispersed evenly in 80mL of water, then 1M sodium hydroxide aqueous solution (15.0mL,15.1mmol) is slowly dropped into the water, and after dropping, the reaction solution is stirred at room temperature for 30-60 min, and the reaction solution turns from white turbid into semitransparent emulsion. At this time, the EtOAc extraction reaction (30mL × 4) combined the organic phases, dried over anhydrous sodium sulfate and spin dried to give a colorless oil, recovered R- (+) -naphthylethylamine 2.17g, with an optical purity > 99% ee. And (3) placing the water phase in an ice bath, adjusting the pH value to 1-2 by using 2M hydrochloric acid, naturally raising the temperature to room temperature, and stirring for 2 hours. The reaction was checked by TLC, and the EtOAc extraction reaction (30 mL. times.4) combined the organic phases, dried over anhydrous sodium sulfate and spin-dried to give compound (VII) as a white oil (or as a white solid crystallized at room temperature), 1.5g, 96% yield, 99% optical purity ee. Compound (VII):
1H NMR(400MHz,Chloroform-d)δ5.84-5.74(m,1H),5.63–5.54(m,1H),5.17–5.09(m,1H),3.54-3.45(m,1H),2.82-2.73(m,1H),2.73-2.69(m,2H),2.45(dd,J＝18.0,1.6Hz,1H)。
13C NMR(100MHz,Chloroform-d)δ176.95,131.39,129.94,83.22,45.73,39.69,33.44。
EXAMPLE 5 preparation of corey lactone diol (I)
In ice bath, compound (VII) (0.5g, 4.0mmol) and paraformaldehyde (0.4g, 13.3mmol) (analytically pure, content > 95%, Shanghai span cloud chemical Co., Ltd.) were uniformly dispersed with 4mL of anhydrous formic acid, and concentrated sulfuric acid (125. mu.L, 2.3mmol) was slowly added thereto, and then placed in a pressurized reaction flask, slowly heated to 80 ℃, and stirred for 20-24 h. And (3) adjusting the pH value to 8-9 by using saturated sodium bicarbonate, combining organic phases of the EtOAc extraction reaction liquid (30mL multiplied by 3), drying the combined organic phases by using anhydrous sodium sulfate, then carrying out spin drying, dispersing the obtained yellow oily matter into a methanol solution (6mL) of hydrochloric acid with the mass concentration of 6%, slowly heating to 65 ℃, and stirring for 3-4 h. After the solvent was spin-dried, it was recrystallized from chloroform to obtain Corey lactone diol (I) as a white solid, 0.53g, in 85% yield, and in 99% optical purity ee. Corey lactone diol (I):
1H NMR(400MHz,Chloroform-d)δ4.93(td,J＝6.8,2.8Hz,1H),4.19(q,J＝6.4Hz,1H),3.75(dd,J＝10.8,5.6Hz,1H),3.63(dd,J＝10.8,7.2Hz,1H),2.81(dd,J＝18.0,9.9Hz,1H),2.68–2.56(m,1H),2.53(dd,J＝18.0,2.4Hz,1H),2.43(dt,J＝14.8,6.4Hz,1H),2.10–1.94(m,2H)。
13C NMR(100MHz,DMSO-d6)δ177.36,83.85,72.81,61.19,56.10,40.26,39.37,35.47。
finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
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