NZ753171B2 - 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative and method for synthesizing optical isomer thereof - Google Patents
3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative and method for synthesizing optical isomer thereof Download PDFInfo
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- NZ753171B2 NZ753171B2 NZ753171A NZ75317117A NZ753171B2 NZ 753171 B2 NZ753171 B2 NZ 753171B2 NZ 753171 A NZ753171 A NZ 753171A NZ 75317117 A NZ75317117 A NZ 75317117A NZ 753171 B2 NZ753171 B2 NZ 753171B2
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- 230000002194 synthesizing Effects 0.000 title claims abstract description 41
- 230000003287 optical Effects 0.000 title claims abstract description 40
- OTTAJAMCDCCHPI-UHFFFAOYSA-N C1(=CC=CC=C1)C1CC=2C(=C3CCCOC3=CC=2)OC1 Chemical class C1(=CC=CC=C1)C1CC=2C(=C3CCCOC3=CC=2)OC1 OTTAJAMCDCCHPI-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 401
- 239000000126 substance Substances 0.000 claims abstract description 154
- 125000000217 alkyl group Chemical group 0.000 claims description 118
- -1 methylphenylsilyl group Chemical group 0.000 claims description 102
- 125000003545 alkoxy group Chemical group 0.000 claims description 99
- 125000005843 halogen group Chemical group 0.000 claims description 89
- 125000004001 thioalkyl group Chemical group 0.000 claims description 89
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 230000027455 binding Effects 0.000 claims description 11
- 230000001808 coupling Effects 0.000 claims description 11
- 238000010168 coupling process Methods 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 11
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 10
- 125000005336 allyloxy group Chemical group 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 8
- OYQSQQMXRUOJGB-XCHXSORBSA-N (1Z,5Z)-cycloocta-1,5-diene;iridium;[2-[(4R,5R)-5-methyl-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]-1,3-diphenylpropan-2-yl]oxy-diphenylphosphane;tetrakis[3,5-bis(trifluoromethyl)phenyl]boranuide Chemical compound [Ir].C\1C\C=C/CC\C=C/1.C=1C=CC=CC=1CC(OP(C=1C=CC=CC=1)C=1C=CC=CC=1)([C@@H]1N=C(O[C@@H]1C)C=1C=CC=CC=1)CC1=CC=CC=C1.FC(F)(F)C1=CC(C(F)(F)F)=CC([B-](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)(C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 OYQSQQMXRUOJGB-XCHXSORBSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000001184 potassium carbonate Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 239000003638 reducing agent Substances 0.000 claims description 5
- 150000007514 bases Chemical class 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- 239000001187 sodium carbonate Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical compound C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 2
- 229910052700 potassium Inorganic materials 0.000 claims 2
- 239000011591 potassium Substances 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 2
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 35
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- UOEWNDLAIQCQRZ-UHFFFAOYSA-N C1(=CC=CC=C1)C1=CC=2C(=C3C=CCOC3=CC=2)OC1 Chemical class C1(=CC=CC=C1)C1=CC=2C(=C3C=CCOC3=CC=2)OC1 UOEWNDLAIQCQRZ-UHFFFAOYSA-N 0.000 description 8
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 206010022489 Insulin resistance Diseases 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
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- LADOFGASZSKWMF-XCHXSORBSA-N (1Z,5Z)-cycloocta-1,5-diene;dicyclohexyl-[2-[(4R,5R)-5-methyl-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]-1,3-diphenylpropan-2-yl]oxyphosphane;iridium;tetrakis[3,5-bis(trifluoromethyl)phenyl]boranuide Chemical compound [Ir].C\1C\C=C/CC\C=C/1.C=1C=CC=CC=1CC(OP(C1CCCCC1)C1CCCCC1)([C@@H]1N=C(O[C@@H]1C)C=1C=CC=CC=1)CC1=CC=CC=C1.FC(F)(F)C1=CC(C(F)(F)F)=CC([B-](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)(C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 LADOFGASZSKWMF-XCHXSORBSA-N 0.000 description 4
- RWFJSKPPTKHQFL-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=C(C=CC(=C1)OC)C1=CC=2C(=C3C=CC(OC3=CC=2)(C)C)OC1 Chemical compound C(C1=CC=CC=C1)OC1=C(C=CC(=C1)OC)C1=CC=2C(=C3C=CC(OC3=CC=2)(C)C)OC1 RWFJSKPPTKHQFL-UHFFFAOYSA-N 0.000 description 4
- GELWGNVYODNEOJ-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=C(C=CC(=C1)OCC)C1=CC=2C(=C3C=CC(OC3=CC=2)(C)C)OC1 Chemical compound C(C1=CC=CC=C1)OC1=C(C=CC(=C1)OCC)C1=CC=2C(=C3C=CC(OC3=CC=2)(C)C)OC1 GELWGNVYODNEOJ-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- WULIZEOAYMSIHS-UHFFFAOYSA-N 4-chloro-5-methylpyrrolo[3,2-d]pyrimidine-6-carbaldehyde Chemical compound C1=NC(Cl)=C2N(C)C(C=O)=CC2=N1 WULIZEOAYMSIHS-UHFFFAOYSA-N 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 3
- 206010012601 Diabetes mellitus Diseases 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
- 210000001789 adipocyte Anatomy 0.000 description 3
- KYNSBQPICQTCGU-UHFFFAOYSA-N benzopyran Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004027 cells Anatomy 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-Cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- QWUWMCYKGHVNAV-UHFFFAOYSA-N Bibenzyl Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 2
- 208000008787 Cardiovascular Disease Diseases 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- 230000002503 metabolic Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- JNFDRDAXBUYMLD-UHFFFAOYSA-N tetrakis[3,5-bis(trifluoromethyl)phenyl]boranuide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC([B-](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)(C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 JNFDRDAXBUYMLD-UHFFFAOYSA-N 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- AUCYLOFJAOZPBM-UHFFFAOYSA-N 2-(8,8-dimethyl-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]chromen-3-yl)-5-methoxyphenol Chemical compound OC1=CC(OC)=CC=C1C1CC(C=CC2=C3CCC(C)(C)O2)=C3OC1 AUCYLOFJAOZPBM-UHFFFAOYSA-N 0.000 description 1
- DJPNFFJPIXWYAZ-UHFFFAOYSA-N 2H-chromene-2-carbaldehyde Chemical compound C1=CC=C2C=CC(C=O)OC2=C1 DJPNFFJPIXWYAZ-UHFFFAOYSA-N 0.000 description 1
- CBVUHJOBRNRUAE-UHFFFAOYSA-N C1(=CC=CC=C1)C1CC=2C(=C3CCC(OC3=CC=2)(C)C)OC1 Chemical class C1(=CC=CC=C1)C1CC=2C(=C3CCC(OC3=CC=2)(C)C)OC1 CBVUHJOBRNRUAE-UHFFFAOYSA-N 0.000 description 1
- 206010062060 Hyperlipidaemia Diseases 0.000 description 1
- 208000006575 Hypertriglyceridemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910015044 LiB Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 230000003178 anti-diabetic Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N ethanone Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The present invention relates to a method for synthesizing a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative and an optical isomer thereof, and an intermediate Compound (Chemical Formula 3 or 4) which may be used for the synthesis method, and when the method and the intermediate Compound are used, the 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative and the optical isomer thereof may be effectively synthesized. ound are used, the 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative and the optical isomer thereof may be effectively synthesized.
Description
[DESCRIPTION]
[Invention Title]
3-PHENYL-2,3,4,8,9,10-HEXAHYDROPYRANO[2,3-f]CHROMENE
DERIVATIVE AND METHOD FOR SYNTHESIZING OPTICAL ISOMER
THEREOF
[Technical Field]
The present specification claims priority to and the
benefit of Korean Patent Application No. 100127805
filed in the Korean Intellectual Property Office on October
4, 2016, the entire contents of which are incorporated
herein by reference.
The present invention relates to a method for
synthesizing a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromene derivative and an optical isomer thereof, and an
intermediate Compound which may be used for the method.
[Background Art]
About 20 billion or more adipocytes are present in
the human body, and when much more energy is supplied to
the human body than the need for energy, energy is stored
as triglyceride in adipocytes in the human body, and when
energy is used up, the triglyceride is decomposed into free
fatty acid and glucose and thus is used as an energy source.
Obesity, which about 30 to 40% of modern people suffer from,
occurs when excessive energy is accumulated due to the
imbalance of the procedure, and is shown as a phenomenon in
which the size of adipocytes is increased or the number
thereof is increased.
The metabolic syndrome conceptualizes a clustering
phenomenon of risk factors of various cardiovascular
diseases and type 2 diabetes as one disease group. The
metabolic syndrome is a concept which may comprehensively
explain various metabolic abnormalities and clinical
aspects, and refers to a syndrome in which risk factors
such as obesity, diabetes, fatty liver, and
hypertriglyceridemia are together increased. Accordingly,
in the case of a metabolic syndrome, the risk of incidence
of a cardiovascular disease or type 2 diabetes is increased.
Insulin resistance refers to a phenomenon in which,
even though insulin is normally secreted in the body, a
supply of glucose into cells, which is performed by insulin,
does not work properly. Since glucose in the blood cannot
enter cells, hyperglycemia is exhibited, and cells cannot
perform normal functions thereof due to a shortage of
glucose, and as a result, metabolic syndrome symptoms are
manifested.
The diabetic symptom thus manifested is called type 2
diabetes (non-insulin-dependent diabetes mellitus: NIDDM)
which is differentiated from type 1 diabetes (insulin-
dependent diabetes mellitus) resulting from a shortage of
insulin. For this reason, the most preferable method of
treating type 2 diabetes is to induce insulin to be capable
of performing normal functions thereof by alleviating
insulin resistance. Nevertheless, a therapeutic agent of
alleviating insulin resistance has hardly been developed up
until now.
Most of the type 2 diabetes therapeutic agents
currently used or developed aim to increase the amount of
insulin secreted in order to supplement the functions of
insulin lost by insulin resistance. However, when the
amount of insulin secreted is increased from our bodies,
not only obesity and inflammation are caused, but also
various side effects such as an increase in cancer
incidence rate are accompanied, so that unless the insulin
resistance problem is alleviated, it is possible to expect
that blood sugar is temporarily normalized, but the health
is negatively influenced even more. For this reason, there
is a more desperate social need for a type 2 diabetes
therapeutic agent capable of normalizing blood sugar by
alleviating insulin resistance.
Meanwhile, Patent Document 1 discloses that a
pyranochromenyl phenol derivative is effective for
preventing and treating a metabolic syndrome including
hyperlipidemia, fatty liver, sugar metabolic abnormality,
diabetes, and obesity, and have effects such as anti-
inflammatory action.
Therefore, even though a method for efficiently and
economically synthesizing the pyranochromenyl phenol
derivative is very useful, a method for synthesizing the
pyranochromenyl phenol derivative has been little known up
until now, except for a method established based on a
method for synthesizing (±)-glabridin (Non-Patent Document
1) developed by the present inventor.
[References of the Related Art]
[Patent Documents]
1. Korean Patent Application Laid-Open No. 10
0075030
[Non-Patent Documents]
1. Sang-Ku Yoo, Keepyung Nahm; Bull. Korean Chem. Soc.
2007(28) 481~484
[Detailed Description of the Invention]
[Technical Problem]
An object of the present invention is to provide a
method for synthesizing a 3-phenyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene derivative and an optical
isomer thereof, and a 3-phenyl-2,8-dihydropyrano[2,3-
f]chromene derivative which may be used for the method.
[Technical Solution]
In order to accomplish the object, an aspect of the
present invention provides a method for synthesizing a 3-
phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
derivative of Chemical Formula (I), the method including:
a) coupling a Compound represented by Chemical
Formula 1 with a Compound represented by Chemical Formula 2
to form a Compound of Chemical Formula 3;
b) reducing the Compound of Chemical Formula 3 to
form a Compound of Chemical Formula 4; and
c) cyclizing the Compound of Chemical Formula 4 to
form a Compound of Chemical Formula 5:
[Reaction Formula 1]
wherein,
R and R are each independently hydrogen atom;
hydroxy group; straight or branched C to C alkyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; halogen atom; straight or branched C to C alkoxy
group unsubstituted or substituted with halogen atom,
straight or branched C to C alkyl group, straight or
branched C to C alkoxy group, or straight or branched C
1 5 1
to C thioalkyl group; straight or branched C to C
3 1 4
thioalkyl group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group; allyloxy group unsubstituted or
substituted with halogen atom, straight or branched C to
C alkyl group, straight or branched C to C alkoxy group,
1 5
or straight or branched C to C thioalkyl group; or
aryloxy group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group;
R is hydrogen atom or C to C alkyl group or C to C
3 1 2 1 2
alkoxy group;
R and R are each independently hydrogen atom or C
4 5 1
to C alkyl group;
P is a protecting group selected from straight or
branched C to C alkyl group unsubstituted or substituted
with halogen atom, straight or branched C to C alkyl
group, straight or branched C to C alkoxy group, or
straight or branched C to C thioalkyl group; benzyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; allyl group unsubstituted or substituted with
halogen atom, straight or branched C to C alkyl group,
straight or branched C to C alkoxy group, or straight or
branched C to C thioalkyl group; tert-butyldimethylsilyl
group; tert-butyldiphenylsilyl group; methylphenylsilyl
group; trimethylphenylsilyl group; MeSO and p-TsSO ;
n is 1 to 3; and
two or more OPs are the same or different from each
other.
Another aspect of the present invention provides a
Compound represented by the following Chemical Formula 3 or
a solvate thereof:
[Chemical Formula 3]
wherein,
R and R are each independently hydrogen atom;
hydroxy group; straight or branched C to C alkyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; halogen atom; straight or branched C to C alkoxy
group unsubstituted or substituted with halogen atom,
straight or branched C to C alkyl group, straight or
branched C to C alkoxy group, or straight or branched C
1 5 1
to C thioalkyl group; straight or branched C to C
3 1 4
thioalkyl group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group; allyloxy group unsubstituted or
substituted with halogen atom, straight or branched C to
C alkyl group, straight or branched C to C alkoxy group,
1 5
or straight or branched C to C thioalkyl group; or
aryloxy group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group;
R is hydrogen atom or C to C alkyl group or C to C
3 1 2 1 2
alkoxy group;
R and R are each independently hydrogen atom or C
4 5 1
to C alkyl group;
P is a protecting group selected from straight or
branched C to C alkyl group unsubstituted or substituted
with halogen atom, straight or branched C to C alkyl
group, straight or branched C to C alkoxy group, or
straight or branched C to C thioalkyl group; benzyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; allyl group unsubstituted or substituted with
halogen atom, straight or branched C to C alkyl group,
straight or branched C to C alkoxy group, or straight or
branched C to C thioalkyl group; tert-butyldimethylsilyl
group; tert-butyldiphenylsilyl group; methylphenylsilyl
group; trimethylphenylsilyl group; MeSO and p-TsSO ;
n is 1 to 3; and
two or more OPs are the same or different from each
other.
Further, still another aspect of the present
invention provides a Compound represented by the following
Chemical Formula 4 or a solvate thereof:
[Chemical Formula 4]
R to R , P, and n in Chemical Formula 4 are the same
as those defined in Chemical Formula 3.
Further, yet another aspect of the present invention
provides a 3-phenyl-2,8-dihydropyrano[2,3-f]chromene
Compound represented by the following Chemical Formula 5 or
a solvate thereof:
[Chemical Formula 5]
R to R , P, and n in Chemical Formula 5 are the same
as those defined in Chemical Formula 3.
In addition, still yet another aspect of the present
invention provides a method for synthesizing an optical
isomer of a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromene derivative of Chemical Formula (I), the method
including:
A) coupling a Compound represented by Chemical
Formula 1 with a Compound represented by Chemical Formula 2
to form a Compound of Chemical Formula 3;
B) reducing the Compound of Chemical Formula 3 to
form a Compound of Chemical Formula 4;
C) cyclizing the Compound of Chemical Formula 4 to
form a Compound of Chemical Formula 5; and
D) subjecting the Compound represented by Chemical
Formula 5 to an asymmetric hydrogenation reaction to form
an optical isomer Compound of Chemical Formula 6a (R-form)
or 6b (S-form):
[Reaction Formula 2]
R to R , P, and n in the chemical formulae are the
same as those defined in Reaction Formula 1.
Furthermore, a further aspect of the present
invention provides an optical isomer Compound represented
by the following Chemical Formula 6a (R-form) or 6b (S-
form) or a solvate thereof:
[Chemical Formula 6a]
[Chemical Formula 6b]
R to R , P, and n in Chemical Formula 6a or 6b are
the same as those defined in Chemical Formula 3.
[Advantageous Effects]
According to a synthesizing method of the present
invention, it is possible to effectively synthesize a 3-
phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
derivative and an optical isomer thereof by using the 3-
phenyl-2,8-dihydropyrano[2,3-f]chromene derivative.
[Mode for Invention]
Hereinafter, the present invention will be described
in more detail.
All the technical terms used in the present invention
are used in the same sense as those generally understood by
the person skilled in the related art of the present
invention, unless otherwise defined. Further, in the
present specification, a preferred method or sample is
described, but those similar or equivalent thereto also
fall within the scope of the present invention. The
contents of all the publications described as a reference
document in the present specification are incorporated into
the present specification by reference.
An aspect of the present invention provides a method
for synthesizing a 3-phenyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene derivative of Chemical
Formula (I), the method including:
a) coupling a Compound represented by Chemical
Formula 1 with a Compound represented by Chemical Formula 2
to form a Compound of Chemical Formula 3;
b) reducing the Compound of Chemical Formula 3 to
form a Compound of Chemical Formula 4; and
c) cyclizing the Compound of Chemical Formula 4 to
form a Compound of Chemical Formula 5:
[Reaction Formula 1]
wherein,
R and R are each independently hydrogen atom;
hydroxy group; straight or branched C to C alkyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; halogen atom; straight or branched C to C alkoxy
group unsubstituted or substituted with halogen atom,
straight or branched C to C alkyl group, straight or
branched C to C alkoxy group, or straight or branched C
1 5 1
to C thioalkyl group; straight or branched C to C
3 1 4
thioalkyl group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group; allyloxy group unsubstituted or
substituted with halogen atom, straight or branched C to
C alkyl group, straight or branched C to C alkoxy group,
1 5
or straight or branched C to C thioalkyl group; or
aryloxy group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group;
R is hydrogen atom or C to C alkyl group or C to C
3 1 2 1 2
alkoxy group;
R and R are each independently hydrogen atom or C
4 5 1
to C alkyl group;
P is a protecting group selected from straight or
branched C to C alkyl group unsubstituted or substituted
with halogen atom, straight or branched C to C alkyl
group, straight or branched C to C alkoxy group, or
straight or branched C to C thioalkyl group; benzyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; allyl group unsubstituted or substituted with
halogen atom, straight or branched C to C alkyl group,
straight or branched C to C alkoxy group, or straight or
branched C to C thioalkyl group; tert-butyldimethylsilyl
group; tert-butyldiphenylsilyl group; methylphenylsilyl
group; trimethylphenylsilyl group; MeSO and p-TsSO ;
n is 1 to 3; and
two or more OPs are the same or different from each
other.
According to an exemplary embodiment of the present
invention, the method for synthesizing a 3-phneyl-
2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative of
Chemical Formula (I) may further include a process of
reducing the Compound of Chemical Formula 5. Specifically,
through two hydrogen addition reactions and one de-
protecting group process, it is possible to effectively
synthesize a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromene derivative of Chemical Formula (I), which is a
pyranochromenyl phenol derivative having excellent anti-
obese, anti-diabetic, and anti-inflammatory efficacies.
Examples of the 3-phenyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene derivative of Chemical
Formula (I) include the following Compounds:
<Compound Ⅰ-1> <Compound Ⅰ-2>
<Compound Ⅰ-3> <Compound Ⅰ-4>
<Compound Ⅰ-5> <Compound Ⅰ-6>
<Compound Ⅰ-7> <Compound Ⅰ-8>
<Compound Ⅰ-9> <Compound Ⅰ-10>
<Compound Ⅰ-11> <Compound Ⅰ-12>
<Compound Ⅰ-13> <Compound Ⅰ-14>
<Compound Ⅰ-15> <Compound Ⅰ-16>
<Compound Ⅰ-17> <Compound Ⅰ-18>
<Compound Ⅰ-19> <Compound Ⅰ-20>
<Compound Ⅰ-21> <Compound Ⅰ-22>
<Compound Ⅰ-23> <Compound Ⅰ-24>
<Compound Ⅰ-25> <Compound Ⅰ-26>
<Compound Ⅰ-27> <Compound Ⅰ-28>
<Compound Ⅰ-29> <Compound Ⅰ-30>
<Compound Ⅰ-31> <Compound Ⅰ-32>
<Compound Ⅰ-33> <Compound Ⅰ-34>
<Compound Ⅰ-35> <Compound Ⅰ-36>
<Compound Ⅰ-37> <Compound Ⅰ-38>
<Compound Ⅰ-39> <Compound Ⅰ-40>
<Compound Ⅰ-41> <Compound Ⅰ-42>
<Compound Ⅰ-43> <Compound Ⅰ-44>
<Compound Ⅰ-45> <Compound Ⅰ-46>
<Compound Ⅰ-47> <Compound Ⅰ-48>
<Compound Ⅰ-49>
According to an exemplary embodiment, it is preferred
that the coupling of the Compound of Chemical Formula 1
with the Compound of Chemical Formula 2 in step a) is
performed under basic conditions, and it is further
preferred that the coupling of the Compound of Chemical
Formula 1 with the Compound of Chemical Formula 2 is
performed by using a weak basic Compound as a catalyst. In
this case, a synthesis of an undesired Compound by
intramolecular aldol condensation reaction may be prevented.
Further, according to an exemplary embodiment, the
weak basic Compound may be one or more selected from a
group consisting of sodium carbonate (Na CO ), lithium
carbonate (Li CO ), potassium carbonate (K CO ), sodium
2 3 2 3
hydrogen carbonate (NaHCO ), potassium hydrogen carbonate
(KHCO ), triethylamine, and pyridine, and is preferably
potassium carbonate or sodium carbonate.
According to an exemplary embodiment, the reducing of
the Compound of Chemical Formula 3 in step b) is a step of
preparing the Compound of Chemical Formula 4 by selectively
reducing only a formyl group (-COH) in a state where a
carbonyl group (-CO-) of ketone is safely maintained. The
selective reduction may be carried out by adding any one or
more reducing agents selected from a group consisting of L-
selectride {Li[CH(CH )CH CH ] BH}, N-selectride
3 2 3 3
{NaB[CH(CH )C H ] H}, K-selectride {K[CH(CH )CH CH ] BH}, and
3 2 5 3 3 2 3 3
LS-selectride {LiB[CH(CH )CH(CH ) ] H}. The reducing is
3 3 2 3
carried out preferably at -10°C or less, more preferably at
-60°C or less, and most preferably at -78°C or less.
According to an exemplary embodiment, the cyclizing
in step c) is an intramolecular cyclization reaction, may
be started with a step of dissolving the Compound of
Chemical Formula 4 in acetonitrile (CH CN) and adding
triphenylphosphonium bromide (Ph P•HBr), and may be
composed of a step of concentrating the resulting product
and a step of dissolving the concentrate obtained and
adding sodium ethoxide (NaOEt).
[Reaction Formula 3]
According to an exemplary embodiment, it is preferred
that the concentrating of the resulting product or the
dissolving of the concentrate obtained uses ethanol.
According to an exemplary embodiment, when a benzyl
group or an analogue thereof is used as a protecting group
(P) of the Compound of Chemical Formula 5 in Reaction
Formula 1 or 3, a Compound of Chemical Formula (I) may be
obtained by simultaneously carrying out a reduction process
of a double bond through a hydrogen addition reaction,
which uses Pd/C (palladium on carbon) as a catalyst, and a
de-protecting group process. If necessary, a
pyranochromenyl phenol derivative in a state of having a
protecting group may be synthesized, and the protecting
group may be removed at an arbitrary time.
Further, another aspect of the present invention
provides a Compound represented by the following Chemical
Formula 3 or a solvate thereof:
[Chemical Formula 3]
wherein,
R and R are each independently hydrogen atom;
hydroxy group; straight or branched C to C alkyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; halogen atom; straight or branched C to C alkoxy
group unsubstituted or substituted with halogen atom,
straight or branched C to C alkyl group, straight or
branched C to C alkoxy group, or straight or branched C
1 5 1
to C thioalkyl group; straight or branched C to C
3 1 4
thioalkyl group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group; allyloxy group unsubstituted or
substituted with halogen atom, straight or branched C to
C alkyl group, straight or branched C to C alkoxy group,
1 5
or straight or branched C to C thioalkyl group; or
aryloxy group unsubstituted or substituted with halogen
atom, straight or branched C to C alkyl group, straight
or branched C to C alkoxy group, or straight or branched
C to C thioalkyl group;
R is hydrogen atom or C to C alkyl group or C to C
3 1 2 1 2
alkoxy group;
R and R are each independently hydrogen atom or C
4 5 1
to C alkyl group;
P is a protecting group selected from straight or
branched C to C alkyl group unsubstituted or substituted
with halogen atom, straight or branched C to C alkyl
group, straight or branched C to C alkoxy group, or
straight or branched C to C thioalkyl group; benzyl group
unsubstituted or substituted with halogen atom, straight or
branched C to C alkyl group, straight or branched C to C
1 5 1 5
alkoxy group, or straight or branched C to C thioalkyl
group; allyl group unsubstituted or substituted with
halogen atom, straight or branched C to C alkyl group,
straight or branched C to C alkoxy group, or straight or
branched C to C thioalkyl group; tert-butyldimethylsilyl
group; tert-butyldiphenylsilyl group; methylphenylsilyl
group; trimethylphenylsilyl group; MeSO and p-TsSO ;
n is 1 to 3; and
two or more OPs are the same or different from each
other.
According to an exemplary embodiment of the present
invention, a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromene derivative of Chemical Formula (I) may be
prepared by using the Compound of Chemical Formula 3.
Specifically, the Compound of Chemical Formula (I) may be
synthesized by a method including a step of synthesizing
the Compound of Chemical Formula 4 by reducing the Compound
of Chemical Formula 3 of the present invention and a step
of cyclizing the Compound of Chemical Formula 4. In this
case, the Compound of Chemical Formula 3 may use a Compound
synthesized by coupling the Compound of Chemical Formula 1
with the Compound of Chemical Formula 2, or a Compound
prepared by another method.
In addition, still another aspect of the present
invention provides a Compound represented by the following
Chemical Formula 4 or a solvate thereof:
[Chemical Formula 4]
R to R , P, and n in Chemical Formula 4 are the same
as those defined in Chemical Formula 3.
According to an exemplary embodiment of the present
invention, a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromene derivative of Chemical Formula (I) may be
prepared by using the Compound of Chemical Formula 4.
Specifically, the Compound of Chemical Formula (I) may be
synthesized by a method including cyclizing the Compound of
Chemical Formula 4. In this case, the Compound of Chemical
Formula 4 may use a Compound synthesized by reducing the
Compound of Chemical Formula 3 or a Compound prepared by
another method.
The Compound of Chemical Formula 3 or 4 according to
the present invention may include all the solvates
including all the salts and hydrates, which may be prepared
by typical methods.
Further, yet another aspect of the present invention
provides a 3-phenyl-2,8-dihydropyrano[2,3-f]chromene
Compound represented by the following Chemical Formula 5 or
a solvate thereof:
[Chemical Formula 5]
R to R , P, and n in Chemical Formula 5 are the same
as those defined in Chemical Formula 3.
According to an exemplary embodiment, the 3-phenyl-
2,8-dihydropyrano[2,3-f]chromene Compound of Chemical
Formula 5 may be one or more of the following Compounds:
<Compound 5-1> <Compound 5-2>
<Compound 5-3> <Compound 5-4>
<Compound 5-5> <Compound 5-6>
<Compound 5-7> <Compound 5-8>
<Compound 5-9> <Compound 5-10>
<Compound 5-11> <Compound 5-12>
<Compound 5-13> <Compound 5-14>
<Compound 5-15> <Compound 5-16>
<Compound 5-17> <Compound 5-18>
<Compound 5-19> <Compound 5-20>
<Compound 5-21> <Compound 5-22>
<Compound 5-23> <Compound 5-24>
<Compound 5-25> <Compound 5-26>
<Compound 5-27> <Compound 5-28>
<Compound 5-29> <Compound 5-30>
<Compound 5-31> <Compound 5-32>
<Compound 5-33> <Compound 5-34>
<Compound 5-35> <Compound 5-36>
<Compound 5-37> <Compound 5-38>
<Compound 5-39> <Compound 5-40>
<Compound 5-41> <Compound 5-42>
<Compound 5-43> <Compound 5-44>
<Compound 5-45> <Compound 5-46>
<Compound 5-47> <Compound 5-48>
<Compound 5-49> <Compound 5-50>
<Compound 5-51> <Compound 5-52>
<Compound 5-53> <Compound 5-54>
<Compound 5-55> <Compound 5-56>
<Compound 5-57> <Compound 5-58>
<Compound 5-59> <Compound 5-60>
<Compound 5-61> <Compound 5-62>
According to an exemplary embodiment of the present
invention, a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromene derivative of Chemical Formula (I) may be
prepared by using the Compound of Chemical Formula 5.
Specifically, the Compound of Chemical Formula (I) may be
synthesized by reducing the double bond and removing the
protecting group in the Compound of Chemical Formula 5. In
this case, the Compound of Chemical Formula 5 may use a
Compound synthesized by the method of Reaction Formula 1 or
a Compound prepared by another method.
The 3-phenyl-2,8-dihydropyrano[2,3-f]chromene
Compound of Chemical Formula 5 according to the present
invention may include all the solvates including all the
salts and hydrates, which may be prepared by typical
methods.
In addition, still yet another aspect of the present
invention provides a method for synthesizing an optical
isomer of a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromene derivative of Chemical Formula (I), the method
including:
A) coupling a Compound represented by Chemical
Formula 1 with a Compound represented by Chemical Formula 2
to form a Compound of Chemical Formula 3;
B) reducing the Compound of Chemical Formula 3 to
form a Compound of Chemical Formula 4;
C) cyclizing the Compound of Chemical Formula 4 to
form a Compound of Chemical Formula 5; and
D) subjecting the Compound represented by Chemical
Formula 5 to an asymmetric hydrogenation reaction to form
an optical isomer Compound of Chemical Formula 6a (R-form)
or 6b (S-form):
[Reaction Formula 2]
R to R , P, and n in the chemical formulae are the
same as those defined in Reaction Formula 1.
According to an exemplary embodiment of the present
invention, the method for synthesizing the optical isomer
of the 3-phneyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
derivative of Chemical Formula (I) may further include a
process of removing a protecting group from the Compound of
Chemical Formula 6a or 6b. Specifically, through one de-
protecting group process, the optical isomer of the 3-
phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
derivative of Chemical Formula (I) may be effectively
synthesized from the optical isomer Compound of Chemical
Formula 6a or 6b.
Examples of the optical isomer of the 3-phenyl-
2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative of
Chemical Formula (I) include the following Compounds:
<Compound Ⅰ-2a> <Compound Ⅰ-2b>
<Compound Ⅰ-3a> <Compound Ⅰ-3b>
<Compound Ⅰ-5a> <Compound Ⅰ-5b>
<Compound Ⅰ-7a> <Compound Ⅰ-7b>
<Compound Ⅰ-9a> <Compound Ⅰ-9b>
<Compound Ⅰ-13a> <Compound Ⅰ-13b>
<Compound Ⅰ-14a> <Compound Ⅰ-14b>
According to an exemplary embodiment of the present
invention, the reactions in Steps A) to C) are the same as
Steps a) to c) in Reaction Formula 1, that is, in the
process of synthesizing the 3-phenyl-2,3,4,8,9,10—
hexahydropyrano[2,3-f]chromene derivative of Chemical
Formula (I).
According to an exemplary embodiment of the present
invention, the asymmetric hydrogenation reaction in Step D)
uses a chiral ligand which serves as a catalyst, and the
asymmetric hydrogenation reaction may be carried out
because the reaction position is specified due to a
stereoscopic factor or an electronic factor between the
chiral ligand and the Compound of Chemical Formula 5.
The chiral ligand is preferably selected from a group
consisting of a phospholane ligand, a SimplePHOX ligand, a
PHOX ligand, and UbaPHOX, and is most preferably UbaPHOX.
It is preferred that the UbaPHOX uses [((4S,5S)-Cy2-
UbaPHOX)Ir(COD)]BARF, that is, 1,5-
cyclooctadiene{[dibenzyl((4S,5S)methylphenyl-4,5-
dihydrooxazolyl)methyl]dicyclohexylphosphinite
κN:κP}iridium(I) tetrakis(3,5-
bis(trifluoromethyl)phenyl)borate when an R isomer of the
Compound of Chemical Formula (I) is synthesized. Further,
it is preferred that the UbaPHOX uses [((4R,5R)-Cy2-
UbaPHOX)Ir(COD)]BARF, that is, 1,5-
cyclooctadiene{[dibenzyl((4R,5R)methylphenyl-4,5-
dihydrooxazolyl)methyl]dicyclohexylphosphinite
κN:κP}iridium(I) tetrakis(3,5-
bis(trifluoromethyl)phenyl)borate when an S isomer of the
Compound of Chemical Formula (I) is synthesized.
According to an exemplary embodiment, when a benzyl
group or an analogue thereof is used as a protecting group
(P) of the optical isomer Compound of Chemical Formula 6a
or 6b in Reaction Formula 2, the protecting group may be
removed by using Pd/C (palladium on carbon) as a catalyst.
Furthermore, a further aspect of the present
invention provides an optical isomer Compound represented
by the following Chemical Formula 6a or 6b, or a solvate
thereof:
[Chemical Formula 6a]
[Chemical Formula 6b]
R to R , P, and n in Chemical Formula 6a or 6b are
the same as those defined in Chemical Formula 3.
According to an exemplary embodiment of the present
invention, the optical isomer Compound of Chemical Formula
6a or 6b may be one or more from the following Compounds:
<Compound 6-2a> <Compound 6-2b>
<Compound 6-3a> <Compound 6-3b>
<Compound 6-5a> <Compound 6-5b>
<Compound 6-7a> <Compound 6-7b>
<Compound 6-9a> <Compound 6-9b>
<Compound 6-13a> <Compound 6-13b>
<Compound 6-14a> <Compound 6-14b>
According to an exemplary embodiment of the present
invention, an optical isomer of a 3-phenyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene derivative of Chemical
Formula (I) may be prepared by using the Compound of
Chemical Formula 6a or 6b. Specifically, the optical
isomer Compound of Chemical Formula (I) may be synthesized
by removing the protecting group from the Compound of
Chemical Formula 6a or 6b. In this case, the Compound of
Chemical Formula 6a or 6b may use a Compound synthesized by
the method of Reaction Formula 2 or a Compound prepared by
another method.
The optical isomer Compound of Chemical Formula 6a or
6b according to the present invention may include all the
solvates including all the salts and hydrates, which may be
prepared by typical methods.
Hereinafter, one or more specific examples will be
described in more detail through Preparation Examples and
Examples. However, these Preparation Examples and Examples
are provided only for exemplarily explaining one or more
specific examples, and the scope of the present invention
is not limited by these Preparation Examples and Examples.
As the reagents used in the following Preparation
Examples and Examples, those purchased from Sigma-Aldrich,
Inc. (USA) were used unless otherwise specifically
indicated.
Preparation Example 1: Synthesis of 3-(2-(benzyloxy)-
4-methoxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-
f]chromene (Compound 5-1)
1-1: Preparation of 5-(2-(2-benzyloxy
methoxyphenyl)oxoethoxy)-2,2-dimethyl-2H-chromene
carbaldehyde
4.08 g (20.0 mmol) of 5-hydroxy-2,2-dimethyl-2H-
chromenecarbaldehyde and 6.70 g (20.0 mmol) of 1-(2-
(benzyloxy)methoxyphenyl)bromoethanone were dissolved
in 20 ml of acetone (CH COCH ), 2.76 g (20.0 mmol) of
potassium carbonate (K CO ) was added to the solution, and
then the resulting mixture was vigorously stirred at room
temperature for 12 hours. Solid components were removed by
filtering the reaction mixture, the resulting mixture was
concentrated, the concentrate obtained was dissolved again
in 20 ml of ethyl acetate (CH COOC H ), the resulting
3 2 5
solution was washed with saturated brine, and the organic
solution layer was separated, and then dried over magnesium
sulfate (MgSO ). Thereafter, magnesium sulfate was removed
by filtering the organic solution layer, and then the
solution was concentrated and recrystallized with isopropyl
alcohol (IPA), thereby obtaining 7.46 g (16.3 mmol) of 5-
(2-(2-benzyloxymethoxyphenyl)oxoethoxy)-2,2-dimethyl-
1 13
2H-chromenecarbaldehyde (Yield: 81.4%). H-NMR and C-
NMR results for the obtained Compound are as follows.
H-NMR (CDCl3): 10.152(s, 1H), 8.066(d, 1H, J=8.8Hz),
7.618(d, 1H, J=8.4Hz), 7.280(m, 5H), 6.629(d, 1H, J=8.8Hz),
6.582(dd, 1H, J=8.8, 2.4Hz), 6.562(d, 1H, J=10.0Hz),
6.500(d, 1H, J=2.4Hz), 5.567(d, 1H, J=10.0Hz), 5.084(s, 2H),
.070(s, 2H), 3.846(s, 3H), 1.406(s, 6H).
C-NMR (CDCl3): 192.083, 188.584, 165,281, 160.344,
159.600, 158.640, 135.146, 133.140, 130.319, 129.751,
128.704, 128.574, 127.759, 122.578, 117.958, 116.116,
114.234, 113.234, 106.271, 99.133, 82.035, 77.319, 71.020,
55.632, 28.108.
1-2: Preparation of 1-(2-(benzyloxy)
methoxyphenyl)((6-hydroxymethyl-2,2-dimethyl-2H-chromen-
-yl)oxy)ethanone
4.61 g (10.0 mmol) of 5-(2-(2-benzyloxy
methoxyphenyl)oxoethoxy)-2,2-dimethyl-2H-chromene
carbaldehyde obtained in Preparation Example 1-1 was
dissolved in 50 ml of tetrahydrofuran (THF) under a
nitrogen atmosphere, and then the solution was cooled to -
78°C. The cooled reaction solution was vigorously stirred,
and 10 ml of a 1.0 M solution of L-Selectride -THF was
slowly added thereto for 30 minutes in a state where the
reaction temperature was maintained at -78°C. The reaction
solution was additionally stirred at -78°C for 30 minutes,
and then additionally vigorously stirred for 30 minutes in
a state where the reaction solution was slowly heated to
room temperature. Thereafter, the reaction was terminated
by slowly adding 20 ml of concentrated brine in a state
where the reaction solution was cooled to 0°C, the organic
solution layer was separated, and then the aqueous layer
was extracted once more by using 20 ml of ethyl acetate,
and mixed with the organic solution layer. The organic
solution layer was concentrated by removing moisture over
magnesium sulfate, and then performing distillation under
reduced pressure. The concentrate obtained was cleanly
separated by silica gel, thereby obtaining 3.43 g (7.45
mmol) of 1-(2-benzyloxymethoxyphenyl)-2—((6-
hydroxymethyl-2,2-dimethyl-2H-chromeneyl)oxy)ethanone
1 13
(Yield: 74.5%). H-NMR and C-NMR results for the obtained
Compound are as follows.
H-NMR (CDCl3): 8.074(d, 1H, J=8.8Hz), 7.32~7.39(b,
5H), 7.010(d, 1H, J=8.0Hz), 6.599(d, 1H, J=8.8, 2.0Hz),
6.533(d, 1H, J=8.0Hz), 6.506(d, 1H, J=2.0Hz), 6.384(d, 1H,
J=10.0Hz) 5.467(d, 1H, J=10.0Hz), 5.132(s, 2H), 5.097(s,
2H), 4.523(d, 2H, J=6.4Hz), 3.844(s, 3H), 3.520(t, 1H,
J=6.4Hz), 1.368(s, 6H).
C-NMR (CDCl3): 194.139, 165.340, 160,469, 154.230,
153.719, 135.322, 133.295, 130.284, 129.700, 128.760,
128.571, 127.896, 126.099, 117.908, 117.245, 114.330,
112.064, 106.223, 99.169, 80.718, 75.488, 70.941, 61.432,
55.627, 27.528.
1-3: Preparation of {3-(2-(benzyloxy)
methoxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-
f]chromene
3.43 g (7.45 mmol) of 1-(2-benzyloxy
methoxyphenyl)-2—((6-hydroxymethyl-2,2-dimethyl-2H-
chromeneyl)oxy)ethanone obtained in Preparation Example
1-2 was dissolved in 25 ml of acetonitrile (CH CN), and
2.81 g (8.20 mmol) of triphenylphosphonium bromide
(Ph P•HBr) was gradually added thereto while vigorously
stirring the resulting solution at room temperature. The
prepared reaction solution was vigorously stirred at room
temperature for 10 hours, and then concentrated by
performing distillation under reduced pressure, and the
concentrate obtained was dissolved by adding 20 ml of
ethanol to the concentrate. Thereafter, the solution was
concentrated again by performing distillation under reduced
pressure, and the concentrate obtained was dissolved by
adding 20 ml of ethanol to the concentrate.
Next, 0.24 g (35 mmol) of sodium ethoxide (NaOEt) was
added thereto at room temperature while vigorously stirring
the reaction solution, and then a solid was precipitated by
stirring the resulting solution overnight in a state where
the solution was heated to 35°C. The precipitated solid
was filtered, and then 20 ml of ethanol was added again
thereto, and the resulting mixture was refluxed for 1 hour
while being vigorously stirred, and additionally stirred
for 1 hour in a state where the mixture was cooled to room
temperature. The produced solid was filtered, and the
filtered solid was washed with iced ethanol at 0°C.
The solid was thoroughly dried in vacuum, thereby
obtaining 2.34 g (5.47 mmol) of 3-(2-benzyloxy
methoxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-
1 13
f]chromene (Yield: 73.5%). H-NMR and C-NMR results for
the obtained Compound are as follows.
H-NMR (CDCl3): 7.25~7.43(m, 5H), 7.248(d, 2H,
J=8.8Hz), 6.807(d, 1H, J=8.0Hz), 6.625(d, 1H, J=10.0Hz),
6.521(s, 1H), 6.520(d, 1H, J=2.4Hz), 6.512(dd, 1H, J=8.8,
2.4Hz), 6.364(d, 1H, J=8.0Hz), 5.573(d, 1H, J=10.0Hz),
.043(s, 2H), 4.991(s, 2H), 3.789(s, 3H), 1.415(s, 6H).
C-NMR (CDCl3): 160.484, 157.297, 153.356, 149.196,
136.496, 129.335, 129.254, 128.603, 128.559, 127.994,
127.410, 126.520, 121.591, 121.314, 116.947, 116.641,
109.521, 109.211, 105.064, 99.963, 76.038, 70.414, 68.490,
55.402, 27.826.
Preparation Example 2: Synthesis of 3-(2-(benzyloxy)-
4-ethoxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-
f]chromene (Compound 5-2)
2-1: Preparation of 5-(2-(2-(benzyloxy)
ethoxyphenyl)oxoethoxy)-2,2-dimethyl-2H-chromene
carbaldehyde
-hydroxy-2,2-dimethyl-2Hcarbaldehyde and 1-(2-
(benzyloxy)ethoxyphenyl)bromoethanone were reacted by
using the same method as in Preparation Example 1-1,
thereby obtaining 5-(2-(2-(benzyloxy)ethoxyphenyl)
oxoethoxy)-2,2-dimethyl-2H-chromenecarbaldehyde. H-NMR
and C-NMR results for the obtained Compound are as
follows.
H-NMR (CDCl3): 10.151(s, 1H), 8.053(d, 1H, J=8.8Hz),
7.617(d, 1H, J=8.8Hz), 7.30(m, 5H), 6.627(d, 1H, J=8.8Hz),
6.585(dd, 1H, J=8.8, 2.4Hz), 6.562(d, 1H, J=10.0Hz),
6.495(d, 1H, J=2.4Hz), 6.556(d, 1H, J=10.0Hz), 5.566(d, 1H,
J=10.0Hz), 5.082(s, 2H), 5.062(s, 2H), 4.077(q, 2H,
J=7.2Hz), 1.421(t, 3H, J=7.2Hz), 1.404(s, 6H).
C-NMR (CDCl3): 192.036, 188.581, 164,708, 160.366,
159.592, 158.671, 135.191, 133.108, 130.304, 129.706,
128.690, 128.550, 127.742, 122.585, 117.759, 116.122,
114.235, 113.226, 106.728, 99.482, 82.060, 77.320, 70.986,
63.973, 28.105, 14.578.
2-2: Preparation of 1-(2-(benzyloxy)ethoxyphenyl)-
2-((6-hydroxymethyl-2,2-dimethyl-2H-chromen
yl)oxy)ethanone
-(2-(2-(benzyloxy)ethoxyphenyl)oxoethoxy)-2,2-
dimethyl-2H-chromenecarbaldehyde obtained in Preparation
Example 2-1 was reacted by using the same method as in
Preparation Example 1-2, thereby obtaining 1-(2-benzyloxy-
4-ethoxyphenyl)-2((6-hydroxymethyl-2,2-dimethyl-2H-
1 13
chromeneyl)oxy)ethanone. H-NMR and C-NMR results for
the obtained Compound are as follows.
H-NMR (CDCl3): 8.063(d, 1H, J=8.8Hz), 7.28~7.42(b,
5H), 7.008(d, 1H, J=8.0Hz), 6.586(d, 1H, J=8.8, 2.0Hz),
6.532(d, 1H, J=8.0Hz), 6.503(d, 1H, J=2.0Hz), 6.383(d, 1H,
J=10.0Hz) 5.464(d, 1H, J=10.0Hz), 5.130(s, 2H), 5.092(s,
2H), 4.522(s, 2H), 4.078(q, 2H, J=6.8Hz), 3.502(b, 1H),
1.424(t, 3H, J=6.8Hz), 1.367(s, 6H).
C-NMR (CDCl3): 194.136, 164.785, 160,506, 154.276,
153.734, 135.384, 133.298, 130.280, 129.713, 128.772,
128.570, 127.905, 126.120, 117.735, 117.273, 114.343,
112.067, 106.684, 99.536, 80.734, 75.497, 70.927, 63.988,
61.479, 27.543, 14.594.
2-3: Preparation of 3-(2-(benzyloxy)ethoxyphenyl)-
8,8-dimethyl-2,8-dihydropyrano[2,3-f]chromene
1-(2-benzyloxyethoxyphenyl)-2((6-hydroxymethyl-
2,2-dimethyl-2H-chromeneyl)oxy)ethanone obtained in
Preparation Example 2-2 was reacted by using the same
method as in Preparation Example 1-3, thereby obtaining 3-
(2-benzyloxyethoxyphenyl)-8,8-dimethyl-2,8-
1 13
dihydropyrano[2,3-f]chromene. H-NMR and C-NMR results
for the obtained Compound are as follows.
H-NMR (CDCl3): 7.25~7.43(m, 5H), 7.236(d, 1H,
J=8.8Hz), 6.807(d, 1H, J=8.0Hz), 6.625(d, 1H, J=10.0Hz),
6.48~6.55(m, 3H), 6.363(d, 1H, J=8.0Hz), 5.575(d, 1H,
J=10.0Hz), 5.045(s, 2H), 4.990(s, 2H), 4.023(q, 2H,
J=6.8Hz), 1.417(s, 6H), 1.408(t, 3H, J=6.8Hz).
C-NMR (CDCl3): 159.850, 157.304, 153.334, 149.196,
136.543, 129.306, 129.250, 128.615, 128.602, 127.980,
127.406, 126.503, 121.516, 121.140, 116.980, 116.655,
109.523, 109.199, 105.670, 100.370, 76.037, 70.391, 68.508,
63.596, 27.829, 14.790.
Hereinafter, various 3-phenyl-2,8-dihydropyrano[2,3-
f]chromene derivatives as in the following Table 1 were
synthesized by using the same method as in Preparation
Example 1.
[Table 1]
Number of Chemical
1 13
H-NMR, C-NMR (CDCl , δ)
Preparation structure
Example
7.25~7.43(m, 5H), 7.248(d, 1H,
J=8.8Hz), 6.807(d, 1H, J=8.0Hz),
6.625(d, 1H, J=10.0Hz), 6.521(s,
1H), 6.520(d, 1H, J=2.4Hz),
6.512(dd, 1H, J=8.8, 2.4Hz),
6.364(d, 1H, J=8.0Hz), 5.573(d,
1H, J=10.0Hz), 5.043(s, 2H),
4.991(s, 2H), 3.789(s, 3H),
1.415(s, 6H).
160.484, 157.297, 153.356,
149.196, 136.496, 129.335,
(Compound 5-1)
129.254, 128.603, 128.559,
127.994, 127.410, 126.520,
121.591, 121.314, 116.947,
116.641, 109.521, 109.211,
105.064, 99.963, 76.038, 70.414,
68.490, 55.402, 27.826.
7.25~7.43(m, 5H), 7.236(d, 1H,
J=8.8Hz), 6.807(d, 1H, J=8.0Hz),
6.625(d, 1H, J=10.0Hz),
6.48~6.55(m, 3H), 6.363(d, 1H,
J=8.0Hz), 5.575(d, 1H, J=10.0Hz),
.045(s, 2H), 4.990(s, 2H),
(Compound 5-2)
4.023(q, 2H, J=6.8Hz), 1.417(s,
6H), 1.408(t, 3H, J=6.8Hz).
159.850, 157.304, 153.334,
149.196, 136.543, 129.306,
129.250, 128.615, 128.602,
127.980, 127.406, 126.503,
121.516, 121.140, 116.980,
116.655, 109.523, 109.199,
105.670, 100.370, 76.037, 70.391,
68.508, 63.596, 27.829, 14.790.
7.25~7.43(m, 5H), 7.233(d, 1H,
J=8.8Hz), 6.805(d, 1H, J=8.0Hz),
6.624(d, 1H, J=10.0Hz), 6.523(d,
1H, J=2.4Hz), 6.516(s, 1H),
6.505(dd, 1H, J=8.0, 2.4Hz),
6.362(d, 1H, J=8.0Hz), 5.573(d,
1H, J=10.0Hz), 5.043(s, 2H),
(Compound 5-3)
4.987(s, 2H), 3.908(t, 2H,
J=6.4Hz), 1.798(m, 2H), 1.415(s,
6H), 1.032(t, 3H, J=7.2Hz).
160.064, 157.309, 153.326,
149.193, 136.551, 129.292,
129.241, 128.629, 128.593,
127.975, 127.427, 126.500,
121.489, 121.085, 116.984,
116.658, 109.518, 109.194,
105.749, 100.360, 76.032, 70.407,
69.656, 68.517, 27.829, 22.535,
.512.
7.216(d, 1H, J=8.0Hz), 6.825(d,
1H, J=8.0Hz), 6.653(d, 1H,
J=10.0Hz), 6.498(s, 1H),
6.486(dd, 1H, J=8.0, 2.4Hz),
6.453(d, 1H, J=2.4Hz), 6.372(d,
1H, J=8.0Hz), 6.026(m, 1H),
.589(d, 1H, J=10.0Hz), 5.395(m,
1H, J=17.2Hz, 1.6Hz), 5.272(m,
1H, J=14.8, 1.6Hz), 5.028(s, 2H),
4.523(m, 2H, J=5.2, 1.6Hz),
(Compound 5-4)
3.918(t, 2H, J=6.4Hz), 1.810(m,
2H), 1.425(s, 6H), 1.040(t, 3H,
J=7.2Hz).
160.051, 157.161, 153.327,
149.178, 132.919, 129.275,
128.859, 126.494, 121.412,
120.975, 117.754, 116.993,
116.680, 109.562, 109.212,
105.663, 100.250, 76.029, 69.644,
69.184, 68.492, 27.813, 22.557,
.514.
7.25~7.43(m, 5H), 7.227(d, 1H,
J=8.8Hz), 6.805(d, 1H, J=8.0Hz),
6.626(d, 1H, J=10.0Hz), 6.519(d,
1H, J=2.4Hz), 6.509(s, 1H),
6.500(dd, 1H, J=8.8, 2.4Hz),
6.362(d, 1H, J=8.0Hz), 5.573(d,
1H, J=10.0Hz), 5.035(s, 2H),
4.991(s, 2H), 4.526(m, 1H,
J=6.0Hz), 1.415(s, 6H), 1.327(d,
6H, J=6.0Hz).
158.785, 157.373, 153.323,
(Compound 5-5)
149.193, 136.580, 129.256,
129.229, 128.632, 128.585,
127.957, 127.399, 126.492,
121.475, 120.365, 116.986,
116.661, 109.513, 109.184,
106.974, 101.569, 76.025, 70.400,
69.997, 27.826, 22.021.
7.25~7.43(m, 5H), 7.231(d, 1H,
J=8.8Hz), 6.803(d, 1H, J=8.0Hz),
6.627(d, 1H, J=10.0Hz), 6.520(d,
1H, J=2.4Hz), 6.514(s, 1H),
6.510(dd, 1H, J=8.8, 2.4Hz),
6.361(d, 1H, J=8.0Hz), 5.570(d,
1H, J=10.0Hz), 5.040(s, 2H),
4.985(s, 2H), 3.947(t, 2H,
J=8.4Hz), 1.744(m, 2H), 1.483(m,
2H), 1.435(s, 6H), 0.973(t, 3H,
J=7.4Hz).
(Compound 5-6)
160.078, 157.305, 153.323,
149.192, 136.552, 129.290,
129.245, 128.638, 128.596,
127.977, 127.429, 126.499,
121.486, 121.074, 116.988,
116.659, 109.520, 109.197,
105.728, 100.344, 76.036, 70.401,
68.518, 67.837, 31.261, 27.830,
19.224, 13.841.
7.25~7.43(m, 5H), 7.246(d, 1H,
J=8.8Hz), 6.819(d, 1H, J=8.0Hz),
6.638(d, 1H, J=10.0Hz), 6.535(d,
(Compound 5-7)
1H, J=2.4Hz), 6.529(s, 1H),
6.518(dd, 1H, J=8.8, 2.4Hz),
6.377(d, 1H, J=8.0Hz), 5.586(d,
1H, J=10.0Hz), 5.058(s, 2H),
.002(s, 2H), 3.955(t, 2H,
J=8.4Hz), 1.790(m, 2H),
1.37~1.44(m, 4H), 1.430(s, 6H),
0.949(t, 3H, J=7.4Hz).
160.062, 157.296, 153.316,
149.183, 136.544, 129.276,
129.225, 128.616, 128.578,
127.961, 127.412, 126.491,
121.472, 121.052, 116.976,
116.651, 109.505, 109.184,
105.732, 100.346, 76.018, 70.393,
68.506, 68.133, 28.906, 28.156,
27.819, 22.430, 14.008.
7.25~7.43(m, 5H), 7.231(d, 1H,
J=8.8Hz), 6.803(d, 1H, J=8.0Hz),
6.623(d, 1H, J=10.0Hz), 6.520(d,
1H, J=2.4Hz), 6.514(s, 1H),
6.503(dd, 1H, J=8.8, 2.4Hz),
(Compound 5-8)
6.361(d, 1H, J=8.0Hz), 5.561(d,
1H, J=10.0Hz), 5.041(s, 2H),
4.986(s, 2H), 3.939(t, 2H,
J=8.4Hz), 1.766(m, 2H),
1.37~1.50(m, 2H), 1.415(s, 6H),
1.30~1.40(m, 4H), 0.910(t, 3H,
J=7.4Hz).
160.062, 157.296, 153.316,
149.183, 136.544, 129.276,
129.225, 128.616, 128.578,
127.961, 127.412, 126.491,
121.472, 121.052, 116.976,
116.651, 109.505, 109.184,
105.732, 100.346, 76.018, 70.393,
68.506, 68.133, 28.906, 28.156,
27.819, 22.430, 14.008.
7.25~7.43(m, 5H), 7.231(d, 1H,
J=8.4Hz), 6.802(d, 1H, J=8.0Hz),
6.623(d, 1H, J=10.0Hz),
6.45~6.53(m, 3H), 6.361(d, 1H,
J=8.0Hz), 5.578(d, 1H, J=10.0Hz),
.040(s, 2H), 4.987(s, 2H),
3.971(t, 2H, J=6.4Hz), 1.828(m,
(Compound 5-9)
1H), 1.663(m, 2H), 1.414(s, 6H),
0.959(d, 6H, J=6.8Hz).
160.067, 157.311, 153.338,
149.202, 136.560, 129.287,
129.224, 128.620, 128.589,
127.972, 127.427, 126.504,
121.497, 121.088, 116.982,
116.666, 109.517, 109.195,
105.751, 100.389, 76.024, 70.416,
68.518, 66.509, 37.928, 27.834,
.010, 22.565.
7.25~7.43(m, 5H), 7.235(d, 1H,
J=8.4Hz), 6.806(d, 1H, J=8.0Hz),
6.627(d, 1H, J=10.0Hz), 6.587(d,
1H, J=2.4Hz), 6.520(s, 1H),
6.517(dd, 1H, J=8.4, 2.4Hz),
6.362(d, 1H, J=8.0Hz), 5.578(d,
1H, J=10.0Hz), 5.036(s, 2H),
4.986(s, 2H), 4.108(t, 2H,
J=4.4Hz), 3.740(t, 2H, J=4.4Hz),
3.447(s, 3H), 1.416(s, 6H).
(Compound 5-10)
159.651, 157.280, 153.364,
149.209, 136.493, 129.249,
128.595, 128.520, 127.982,
127.387, 126.524, 121.640,
121.522, 116.945, 116.640,
109.516, 109.205, 105.609,
100.711, 76.041, 70.941, 70.405,
68.477, 67.356, 59.200, 27.830.
7.28~7.43(m, 10H), 7.241(d, 1H,
J=8.0Hz), 6.805(d, 1H, J=8.0Hz),
6.628(d, 1H, J=10.0Hz), 6.600(d,
1H, J=2.0Hz), 6.585(dd, 1H,
J=8.0, 2.0Hz), 6.518(s, 1H),
6.364(d, 1H, J=8.0Hz), 5.573(d,
1H, J=10.0Hz), 5.046(s, 2H),
.027(s, 2H), 4.988(s, 2H),
1.416(s, 6H).
159.666, 157.308, 153.382,
149.212, 136.727, 136.473,
(Compound 5-11)
129.318, 129.262, 128.625,
128.615, 128.518, 128.071,
128.000, 127.519, 127.409,
126.537, 121.678, 121.555,
116.941, 116.647, 109.531,
109.221, 106.077, 100.760,
76.051, 70.421, 70.203, 68.481,
27.836.
7.30~7.45(m, 5H), 7.205(d, 2H,
J=8.4Hz), 6.817(d, 1H, J=8.4Hz),
6.649(d, 1H, J=10.0Hz), 6.551(dd,
1H, J=8.4, 2.4Hz), 6.542(d, 1H,
J=2.4Hz), 6.485(s, 1H), 6.370(d,
(Compound 5-12)
1H, J=8.4Hz), 5.587(d, 1H,
J=10.0Hz), 5.065(s, 3H), 5.004(s,
3H), 3.781(s, 3H), 1.420(s, 6H).
159.793, 158.233, 153.368,
149.135, 136.749, 129.302,
129.223, 128.786, 128.618,
128.064, 127.530, 126.532,
121.573, 121.047, 116.894,
116.659, 109.584, 109.236,
105.488, 99.537, 76.032, 70.185,
68.353, 55.374, 27.786.
7.30~7.45(m, 5H), 7.215(d, 2H,
J=8.4Hz), 6.822(d, 1H, J=8.4Hz),
6.652(d, 1H, J=10.0Hz), 6.547(dd,
1H, J=8.4, 2.4Hz), 6.512(d, 1H,
J=2.4Hz), 6.490(s, 1H), 6.373(d,
1H, J=8.4Hz), 5.587(d, 1H,
J=10.0Hz), 5.053(s, 3H), 5.029(s,
3H), 3.987(q, 2H, J=6.8Hz),
(Compound 5-13)
1.423(s, 6H), 1.391(t, 3H,
J=6.8Hz).
159.723, 157.565, 153.336,
149.196, 136.787, 129.292,
129.108, 128.970, 128.606,
128.039, 127.517, 126.519,
121.350, 121.326, 116.998,
116.667, 109.553, 109.223,
105.537, 100.155, 76.031, 70.158,
68.443, 63.757, 27.809, 14.730.
7.30~7.45(m, 5H), 7.222(d, 2H,
J=8.4Hz), 6.823(d, 1H, J=8.4Hz),
6.659(d, 1H, J=10.0Hz), 6.546(dd,
1H, J=8.4, 2.4Hz), 6.522(d, 1H,
J=2.4Hz), 6.498(s, 1H), 6.375(d,
1H, J=8.4Hz), 5.589(d, 1H,
J=10.0Hz), 5.058(s, 3H), 5.026(s,
3H), 3.885(t, 2H, J=6.4Hz),
1.794(m, 2H), 1.425(s, 6H),
1.024(t, 3H, J=7.2Hz).
(Compound 5-14) 159.732, 157.763, 153.337,
149.218, 136.812, 129.281,
129.105, 128.897, 128.612,
128.043, 127.521, 126.521,
121.357, 121.261, 117.026,
116.683, 109.553, 109.219,
105.449, 100.108, 76.044, 70.167,
69.824, 68.513, 27.832, 22.517,
.802.
7.30~7.45(m, 5H), 7.219(d, 2H,
J=8.4Hz), 6.824(d, 1H, J=8.4Hz),
6.657(d, 1H, J=10.0Hz), 6.547(dd,
1H, J=8.4, 2.4Hz), 6.511(d, 1H,
J=2.4Hz), 6.467(s, 1H), 6.374(d,
1H, J=8.4Hz), 5.588(d, 1H,
J=10.0Hz), 5.053(s, 3H), 5.013(s,
3H), 4.501(m, 1H, J=6.0Hz),
1.423(s, 6H), 1.307(d, 6H,
J=6.0Hz).
159.646, 156.361, 153.301,
(Compound 5-15)
149.208, 136.818, 129.350,
129.296, 129.262, 128.618,
128.042, 127.522, 126.478,
122.274, 121.161, 117.059,
116.673, 109.558, 109.213,
105.618, 101.356, 76.025, 70.234,
70.192, 68.537, 27.815, 21.983.
7.30~7.45(m, 5H), 7.219(d, 2H,
J=8.4Hz), 6.823(d, 1H, J=8.4Hz),
6.664(d, 1H, J=10.0Hz), 6.540(dd,
1H, J=8.4, 2.4Hz), 6.527(d, 1H,
(Compound 5-16)
J=2.4Hz), 6.496(s, 1H), 6.375(d,
1H, J=8.4Hz), 5.589(d, 1H,
J=10.0Hz), 5.056(s, 3H), 5.016(s,
3H), 3.921(t, 2H, J=6.4Hz),
1.751(m, 2H), 1.467(m, 2H),
1.426(s, 6H), 9.55(t, 3H,
J=7.2Hz).
159.721, 157.763, 153.329,
149.217, 136.806, 129.263,
129.088, 128.853, 128.598,
128.029, 127.512, 126.517,
121.339, 121.254, 117.018,
116.678, 109.536, 109.211,
105.409, 100.094, 76.034, 70.158,
68.488, 67.934, 31.204, 27.830,
19.359, 13.808.
7.30~7.45(m, 5H), 7.222(d, 2H,
J=8.4Hz), 6.820(d, 1H, J=8.4Hz),
6.662(d, 1H, J=10.0Hz), 6.571(dd,
1H, J=8.4, 2.4Hz), 6.534(d, 1H,
J=2.4Hz), 6.516(s, 1H), 6.372(d,
1H, J=8.4Hz), 5.588(d, 1H,
(Compound 5-17)
J=10.0Hz), 5.057(s, 3H), 5.030(s,
3H), 4.075(t, 2H, J=4.8Hz),
3.716(t, 2H, J=4.8Hz), 3.417(s,
6H), 1.426(s, 6H).
159.631, 157.399, 153.348,
149.248, 136.737, 129.240,
129.175, 128.634, 128.613,
128.053, 127.506, 126.530,
121.569 121.476, 117.000,
116.693, 109.534, 109.191,
106.098, 100.507, 76.037, 70.856,
70.180, 68.405, 67.595, 59.105,
27.827.
7.30~7.45(m, 5H), 7.269(d, 2H,
J=7.2Hz), 6.848(d, 1H, J=7.2Hz),
6.831(d, 1H, J=8.0Hz), 6.821(s,
1H), 6.647(d, 1H, J=10.0Hz),
6.582(s, 1H), 6.385(d, 1H,
J=8.0Hz), 5.591(d, 1H, J=10.0Hz),
.091(s, 2H), 5.029(s, 2H),
2.661(q, 2H, J=7.6Hz), 1.437(s,
6H), 1.258(t, 3H, J=7.6Hz).
(Compound 5-18)
156.345, 153.498, 149.352,
145.527, 136.824, 129.242,
128.850, 128.721, 128.572,
127.924, 127.459, 126.647,
125.831, 122.230, 120.671,
116.927, 116.664, 112.085,
109.547, 109.230, 76.069, 70.449,
68.484, 28.892, 27.856, 15.468.
8.241(d, 2H, J=8.8Hz), 7.794(d,
2H, J=8.8Hz), 7.268(d, 1H,
J=8.0Hz), 6.882(d, 1H, J=8.0Hz),
6.837(d, 1H, J=8.0Hz), 6.763(s,
1H), 6.635(d, 1H, J=10.0Hz),
6.571(s, 1H), 6.395(d, 1H,
J=8.0Hz), 5.605(d, 1H, J=10.0Hz),
.190(s, 2H), 5.010(s, 2H),
2.650(q, 2H, J=7.6Hz), 1.436(s,
6H), 1.243(t, 3H, J=7.6Hz).
(Compound 5-19)
155.619, 153.656, 149.223,
147.562, 145.681, 144.206,
129.448, 129.089, 128.357,
127.662, 126.670, 125.875,
123.867, 122.720, 121.343,
116.696, 116.482, 112.132,
109.596, 109.411, 76.156, 69.267,
68.325, 28.849, 27.860, 15.464.
7.203(d, 1H, J=7.6Hz), 6.827(d,
1H, J=8.4Hz), 6.784(dd, 1H,
J=7.6, 1.2Hz), 6.703(d, 1H,
J=1.2Hz), 6.653(d, 1H, J=10.0Hz),
(Compound 5-20)
6.528(s, 1H), 6.372(d, 1H,
J=8.4Hz), 5.588(d, 1H, J=10.0Hz),
.027(s, 2H), 3.815(s, 3H),
2.588(t, 2H, J=7.6Hz), 1.660(m,
2H, J=7.6Hz), 1.422(s, 6H),
0.965(t, 3H, J=7.6Hz).
157.051, 153.435, 149.241,
144.030, 129.276, 129.163,
128.480, 126.617, 125.217,
122.038, 120.889, 116.882,
116.666, 111.117, 109.585,
109.230, 76.031, 68.337, 55.302,
38.117, 27.784, 24.503, 13.887.
7.30~7.45(m, 5H), 7.252(d, 1H,
J=7.2Hz), 6.825(d, 1H, J=7.2Hz),
6.820(d, 1H, J=8.0Hz), 6.793(s,
1H), 6.642(d, 1H, J=10.0Hz),
6.580(s, 1H), 6.370(d, 1H,
J=8.0Hz), 5.587(d, 1H, J=10.0Hz),
.082(s, 2H), 5.025(s, 2H),
(Compound 5-21)
2.589(t, 2H, J=7.6Hz), 1.655(m,
2H, J=7.6Hz), 1.433(s, 6H),
0.958(t, 3H, J=7.6Hz).
156.249, 153.492, 149.357,
143.970, 136.831, 129.235,
128.862, 128.593, 128.565,
127.914, 127.456, 126.642,
125.820, 122.222, 121.337,
116.936, 116.668, 112.668,
109.542, 109.224, 76.066, 70.449,
68.486, 38.060, 27.859, 24.436,
13.828.
7.343(s, 4H), 7.239(d, 1H,
J=8.0Hz), 6.819(d, 2H, J=8.0Hz),
6.745(s, 1H), 6.629(d, 1H,
J=10.0Hz), 6.550(s, 1H), 6.374(d,
1H, J=8.0Hz), 5.587(d, 1H,
J=10.0Hz), 5.031(s, 2H), 4.981(s,
(Compound 5-22)
2H), 2.574(t, 2H, J=7.2Hz),
1.639(m, 2H), 1.425(s, 6H),
0.945(t, 3H, J=7.2Hz).
7.472(d, 1H, J=8.0Hz), 7.421(d,
1H, J=2.0Hz), 7.250(dd, 1H,
J=8.0, 2.0Hz), 7.238(d, 1H,
J=8.0Hz), 6.834(d, 1H, J=8.0Hz),
(Compound 5-23)
6.828(d, 1H, J=8.0Hz), 6.744(s,
1H), 6.636(d, 1H, J=10.0Hz),
6.557(s, 1H), 6.381(d, 1H,
J=8.0Hz), 5.595(d, 1H, J=10.0Hz),
.123(s, 2H), 5.000(s, 2H),
2.582(t, 2H, J=7.2Hz), 1.643(m,
2H), 1.429(s, 6H), 0.948(t, 3H,
J=7.2Hz).
7.289(d, 2H, J=8.0Hz), 7.234(d,
1H, J=8.4Hz), 7.170(d, 2H,
J=8.0Hz), 6.809(d, 1H, J=8.4Hz),
6.793(dd, 1H, J=8.4, 2.0Hz),
6.778(d, 1H, J=2.0Hz), 6.625(d,
1H, J=10.0Hz), 6.548(s, 1H),
6.362(d, 1H, J=8.4Hz), 5.571(d,
1H, J=10.0Hz), 5.012(s, 2H),
4.993(s, 2H), 2.572(t, 2H,
J=7.6Hz), 2.349(s, 3H), 1.642(m,
2H, J=7.6Hz), 1.415(s, 6H),
(Compound 5-24)
0.946(t, 3H, J=7.2Hz).
156.286, 153.417, 149.335,
143.948, 137.651, 133.719,
129.221, 128.974, 128.524,
127.591, 126.612, 125.784,
122.081, 121.208, 116.958,
116.667, 112.522, 109.514,
109.186, 76.040, 70.301, 68.478,
38.060, 27.829, 24.468, 13.854.
8.231(d, 2H, J=8.8Hz), 7.587(d,
2H, J=8.8Hz), 7.250(d, 1H,
J=8.0Hz), 6.847(d, 1H, J=8.0Hz),
6.820(d, 1H, J=8.0Hz), 6.728(s,
1H), 6.629(d, 1H, J=10.0Hz),
6.566(s, 1H), 6.387(d, 1H,
J=8.0Hz), 5.597(d, 1H, J=10.0Hz),
.176(s, 2H), 5.003(s, 2H),
2.572(t, 2H, J=7.2Hz), 1.630(m,
2H), 1.428(s, 6H), 0.938(t, 3H,
J=7.6Hz).
(Compound 5-25)
155.522, 153.649, 149.224,
147.548, 144.214, 144.120,
129.433, 128.954, 128.364,
127.656, 126.663, 125.854,
123.850, 122.705, 121.992,
116.702, 116.485, 112.695,
109.588, 109.399, 76.144, 69.253,
68.321, 37.985, 27.860, 24.427,
13.791.
8.172(d, 1H, J=8.0Hz), 7.895(d,
1H, J=8.0Hz), 7.658(t, 1H,
J=8.0Hz), 7.478(t, 1H, J=8.0Hz),
(Compound 5-26)
7.243(d, 1H, J=8.0Hz), 6.848(d,
2H, J=8.0Hz), 6.752(s, 1H),
6.648(d, 1H, J=10.0Hz), 6.586(s,
1H), 6.392(d, 1H, J=8.0Hz),
.599(d, 1H, J=10.0Hz), 5.510(s,
2H), 5.042(s, 2H), 2.569(t, 2H,
J=7.2Hz), 1.625(m, 2H), 1.433(s,
6H), 0.936(t, 3H, J=7.6Hz).
155.504, 153.590, 149.288,
146.781, 144.288, 134.182,
133.766, 129.380, 128.983,
128.630, 128.479, 128.311,
126.677, 125.737, 124.973,
122.756, 121.887, 116.793,
116.543, 112.905, 109.587,
109.346, 76.121, 68.356, 67.312,
37.992, 27.872, 24.480, 13.801.
7.30~7.45(m, 5H), 7.281(d, 1H,
J=7.2Hz), 6.877(d, 1H, J=7.2Hz),
6.843(s, 1H), 6.833(d, 1H,
J=8.0Hz), 6.646(d, 1H, J=10.0Hz),
6.582(s, 1H), 6.385(d, 1H,
(Compound 5-27)
J=8.0Hz), 5.593(d, 1H, J=10.0Hz),
.096(s, 2H), 5.031(s, 2H),
2.910(m, 1H, J=7.0Hz), 1.436(s,
6H), 1.267(d, 6H, J=7.0Hz).
156.295, 153.471, 150.198,
149.340, 136.814, 129.240,
128.873, 128.691, 128.564,
127.924, 127.501, 126.636,
125.938, 122.224, 119.160,
116.925, 116.659, 110.754,
109.543, 109.216, 76.062, 70.446,
68.453, 34.166, 27.840, 23.914.
7.30~7.45(m, 5H), 7.264(d, 1H,
J=7.2Hz), 6.840(d, 1H, J=7.2Hz),
6.832(d, 1H, J=8.0Hz), 6.804(s,
1H), 6.654(d, 1H, J=10.0Hz),
6.590(s, 1H), 6.394(d, 1H,
J=8.0Hz), 5.598(d, 1H, J=10.0Hz),
.091(s, 2H), 5.036(s, 2H),
2.622(t, 2H, J=7.6Hz), 1.623(m,
(Compound 5-28)
2H), 1.444(s, 6H), 1.375(m, 2H),
0.954(t, 3H, J=7.6Hz).
156.212, 153.455, 149.331,
144.180, 136.791, 129.229,
128.867 128.588, 128.553,
127.902, 127.449, 126.626,
125.728, 122.179, 121.252,
116.929, 116.652, 112.540,
109.529, 109.213, 76.054, 70.380,
68.463, 35.669, 33.512, 27.837,
22.345, 13.954.
7.30~7.45(m, 5H), 7.250(d, 1H,
J=7.2Hz), 6.825(d, 1H, J=7.2Hz),
6.816(d, 1H, J=8.0Hz), 6.787(s,
1H), 6.635(d, 1H, J=10.0Hz),
6.574(s, 1H), 6.375(d, 1H,
J=8.0Hz), 5.585(d, 1H, J=10.0Hz),
.080(s, 2H), 5.018(s, 2H),
2.598(t, 2H, J=7.6Hz), 1.618(m,
2H), 1.428(s, 6H), 1.325(m, 4H),
0.906(t, 3H, J=6.8Hz).
156.212, 153.449, 149.330,
(Compound 5-29)
144.237, 136.793, 129.239,
128.881, 128.595, 128.561,
127.912, 127.452, 126.627,
125.728, 122.179, 121.238,
116.934, 116.651, 112.504,
109.533, 109.215, 76.059, 70.372,
68.464, 35.956, 31.479, 31.068,
27.837, 22.538, 14.036.
7.30~7.45(m, 5H), 7.271(d, 1H,
J=7.2Hz), 6.860(d, 1H, J=7.2Hz),
6.851(s, 1H), 6.833(d, 1H,
J=8.0Hz), 6.638(d, 1H, J=10.0Hz),
6.577(s, 1H), 6.383(d, 1H,
J=8.0Hz), 5.592(d, 1H, J=10.0Hz),
.085(s, 2H), 5.016(s, 2H),
3.616(t, 2H, J=6.8Hz), 3.368(s,
3H), 2.887(t, 2H, J=6.8Hz),
1.433(s, 6H).
156.258, 153.509, 149.343,
(Compound 5-30)
140.209, 136.709, 129.253,
128.726, 128.566, 127.931,
127.447, 126.663, 126.362,
122.375, 121.594, 116.867,
116.621, 112.952, 109.534,
109.237, 76.068, 73.341, 70.385,
68.401, 58.694, 36.173, 27.835.
7.30~7.45(m, 5H), 7.100(d, 1H,
J=8.0Hz), 6.981(d, 1H, J=8.0Hz),
6.851(d, 1H, J=8.0Hz), 6.672(d,
1H, J=10.0Hz), 6.643(s, 1H),
(Compound 5-31)
6.409(d, 1H, J=8.0Hz), 5.613(d,
1H, J=10.0Hz), 5.078(s, 2H),
4.770(s, 2H), 2.306(s, 3H),
2.230(s, 3H), 1.455(s, 6H).
154.695, 153.636, 149.312,
138.313, 137.128, 129.312,
128.827, 128,679, 128.498,
128.425, 128.176, 127.986,
126.703, 126.018, 125.858,
122.605, 116.661, 116.609,
109.601, 109.266, 76.131, 74.894,
68.268, 27.878, 20.124, 12.428.
7.30~7.45(m, 5H), 7.125(s, 1H),
6.838(d, 1H, J=8.0Hz), 6.780(s,
1H), 6.652(d, 1H, J=10.0Hz),
6.581(s, 1H), 6.390(d, 1H,
J=8.0Hz), 5.597(d, 1H, J=10.0Hz),
.061(s, 2H), 5.033(s, 2H),
2.275(s, 3H), 2.237(s, 3H),
1.438(s, 6H).
154.361, 153.428, 149.310,
(Compound 5-32)
137.257, 136.995, 129.915,
129.224, 129.077, 128.861,
128.541, 127.843, 127.370,
126.605, 125.653, 122.002,
116.932, 116.666, 114.121,
109.528, 109.200, 76.049, 70.647,
68.528, 27.838, 19.986, 18.803.
7.598(d, 2H, J=7.2Hz),
7.30~7.50(m, 9H), 7.246(d, 1H,
J=7.2Hz), 7.202(s, 1H), 6.875(d,
1H, J=7.2Hz), 6.688(s, 1H),
6.676(d, 1H, J=10.0Hz), 6.422(d,
1H, J=8.0Hz), 5.818(d, 1H,
J=10.0Hz), 5.176(s, 2H), 5.091(s,
2H), 1.461(s, 6H).
156.596, 153.662, 149.427,
141.997, 140.685, 136.574,
(Compound 5-33)
129.294, 129.086, 128.793,
128.627, 128.339, 128.034,
127.496, 127.344, 127.004,
126.802, 122.871, 120.081,
116.828, 116.601, 111.175,
109.560, 109.334, 76.121, 70.551,
68.363, 27.860.
7.30~7.45(m, 5H), 7.273(d, 1H,
J=7.2Hz), 7.140(t, 1H, J=7.2Hz),
7.030(d, 2H, J=7.2Hz), 6.835(d,
1H, J=8.0Hz), 6.659(d, 1H,
J=2.4Hz), 6.641(d, 1H, J=10.0Hz),
(Compound 5-34)
6.587(dd, 1H, J=8.0, 2.4Hz),
6.562(s, 1H), 6.386(d, 1H,
J=8.0Hz), 5.595(d, 1H, J=10.0Hz),
.021(s, 2H), 5.018(s, 2H),
1.433(s, 6H).
158.032, 157.286, 156.689,
153.527, 149.284, 136.226,
129.791, 129.487, 129.306,
128.620, 128.283, 128.044,
127.691, 127.471, 126.652,
123.538, 123.433, 122.286,
119.085, 116.823, 116.603,
110.737, 109.552, 109.291,
76.098, 70.450, 68.380, 27.846.
7.30~7.45(m, 10H), 7.133(d, 2H,
J=8.4Hz), 6.840(d, 1H, J=8.0Hz),
6.750(d, 1H, J=8.4Hz), 6.669(d,
1H, 10.0Hz), 6.605(s, 1H),
6.405(d, 1H, J=8.0Hz), 5.613(d,
1H, J=10.0Hz), 5.115(s, 2H),
(Compound 5-35)
.062(s, 2H), 4.796(s, 2H),
2.247(s, 3H), 1.426(s, 6H).
157.621, 155.594, 153.525,
149.214, 137.161, 137.008,
129.322, 128.594, 128.539,
128.435, 128.255, 128.040,
127.844, 127.101, 126.590,
126.327, 125.439, 122.095,
120.918, 116.754, 116.618,
109.597, 109.244, 107.807,
76.116, 74.951, 70.207, 68.309,
27.873, 9.441.
7.30~7.42(m, 5H), 7.267(dd, 1H,
J=8.8, 6.8Hz), 6.821(d, 1H,
J=8.4Hz), 6.65~6.71(m, 2H),
6.619(d, 1H, J=10.0Hz), 6.524(s,
1H), 6.375(d, 1H, J=8.4Hz),
.581(d, 1H, J=10.0Hz), 5.041(s,
2H), 4.972(s, 2H), 1.419(s, 6H).
36 163.801, 162.400, 157.261,
153.659, 149.306, 135.951,
(Compound 5-36)
129.599, 129.346, 128.695,
128.191, 127.898, 127.405,
126.733, 124.477, 122.747,
116.650, 116.545, 109.455,
107.590, 100.416, 76.129, 70.638,
68.260, 27.729.
7.30~7.42(m, 5H), 7.244(d, 1H,
J=8.0Hz), 6.961(dd, 1H, J=8.0,
2.0Hz), 6.943(d, 1H, J=2.0Hz),
6.822(d, 1H, J=8.4Hz), 6.611(d,
1H, J=10.0Hz), 6.564(s, 1H),
6.372(d, 1H, J=8.4Hz), 5.581(d,
1H, J=10.0Hz), 5.050(s, 2H),
4.962(s, 2H), 1.419(s, 6H).
156.753, 153.804, 149.400,
135.940, 134.044, 129.483,
(Compound 5-37)
129.371, 128.700, 128.225,
127.620, 127.483, 127.015,
126.856, 123.236, 121.313,
116.580, 116.509, 112.791,
109.567, 109.421, 76.177, 70.718,
68.140, 27.871.
7.556(d, 2H, J=8.0Hz), 7.068(d,
1H, J=8.0Hz), 7.029(d, 2H,
J=8.0Hz), 6.943(d, 1H, J=2.8Hz),
6.805(dd, 1H, J=8.0, 2.8Hz),
6.632(d, 1H, J=8.0Hz), 6.602(d,
1H, J=10.0Hz), 6.353(d, 1H,
(Compound 5-38)
J=8.0Hz), 5.954(s, 1H), 5.612(d,
1H, J=10.0Hz), 4.716(s, 2H),
3.822(s, 3H), 2.277(s, 3H),
1.450(s, 6H).
159.744, 153.799, 148.644,
147.537, 145.335, 132.181,
129.582, 129.482, 129.462,
128.463, 126.541, 125.429,
124.620, 123.330, 116.449,
116.134, 113.703, 109.478,
109.368, 109.202, 76.191, 67.578,
55.652, 27.851, 21.610.
7.544(d, 2H, J=8.0Hz), 7.202(s,
1H), 7.079(s, 2H), 7.026(d, 2H,
J=8.0Hz), 6.644(d, 1H, J=8.0Hz),
6.603(d, 1H, J=10.0Hz), 6.356(d,
1H, J=8.0Hz), 6.015(s, 1H),
.618(d, 1H, J=10.0Hz), 4.743(s,
2H), 2.669(q, 2H, J=7.6Hz),
2.277(s, 3H), 1.451(s, 6H),
1.240(t, 3H, J=7.6Hz).
(Compound 5-39)
153.897, 148.748, 146.776,
145.591, 145.213, 132.320,
129.511, 129.444, 128.889,
128.441, 126.962, 126.666,
125.673, 123.839, 123.339,
116.440, 116.090, 109.485,
109.223, 76.209, 67.526, 28.311,
27.853, 21.604, 15.134.
7.535(d, 2H, J=8.0Hz), 7.188(s,
1H), 7.061(s, 2H), 7.023(d, 2H,
J=8.0Hz), 6.644(d, 1H, J=8.0Hz),
6.606(d, 1H, J=10.0Hz), 6.357(d,
1H, J=8.0Hz), 6.012(s, 1H),
.618(d, 1H, J=10.0Hz), 4.746(s,
2H), 2.601(t, 2H, J=7.6Hz),
2.277(s, 3H), 1.643(m, 2H,
J=7.6Hz), 1.451(s, 6H), 0.948(t,
3H, J=7.6Hz).
153.900, 148.761, 146.696,
(Compound 5-40)
145.202, 144.065, 132.281,
129.525, 129.439, 128.779,
128.446, 127.572, 126.667,
125.683, 123.889, 123.846,
116.445, 116.103, 109.489,
109.227, 76.217, 67.528, 37.349,
27.857, 24.165, 21.605, 13.654.
7.546(d, 2H, J=8.0Hz), 7.042(d,
1H, J=8.0Hz), 7.020(d, 2H,
J=8.0Hz), 6.943(d, 1H, J=2.4Hz),
6.787(dd, 1H, J=8.0, 2.4Hz),
(Compound 5-41)
6.625(d, 1H, J=8.0Hz), 6.602(d,
1H, J=10.0Hz), 6.351(d, 1H,
J=8.0Hz), 5.937(s, 1H), 5.617(d,
1H, J=10.0Hz), 4.707(s, 2H),
4.042(q, 2H, J=6.8Hz), 2.273(s,
3H), 1.450(s, 6H), 1.429(t, 3H,
J=6.8Hz).
159.115, 153.775, 148.633,
147.492, 145.304, 132.172,
129.524, 129.465, 128.455,
126.521, 125.478, 124.390,
123.236, 116.461, 116.161,
114.219, 109.834, 109.475,
109.187, 76.185, 67.579, 63.966,
27.849, 21.607, 14.617.
7.551(d, 2H, J=8.0Hz), 7.042(d,
1H, J=8.0Hz), 7.022(d, 2H,
J=8.0Hz), 6.936(d, 1H, J=2.4Hz),
6.794(dd, 1H, J=8.0, 2.4Hz),
6.625(d, 1H, J=8.0Hz), 6.602(d,
1H, J=10.0Hz), 6.350(d, 1H,
(Compound 5-42)
J=8.0Hz), 5.941(s, 1H), 5.616(d,
1H, J=10.0Hz), 4.708(s, 2H),
3.920(t, 2H, J=6.4Hz), 2.272(s,
3H), 1.819(m, 2H), 1.449(s, 6H),
1.046(t, 3H, J=7.6Hz).
159.301, 153.744, 148.610,
147.462, 145.303, 132.136,
129.498, 129.456, 128.454,
126.507, 125.487, 124.322,
123.190, 116.452, 116.161,
114.236, 109.818, 109.464,
109.175, 76.176, 69.927, 67.570,
27.834, 22.387, 21.602, 10.442.
7.119(d, 1H, J=8.0Hz), 6.787(m,
1H), 6.785(s, 2H), 6.63~6.68(m,
2H), 6.587(d, 1H, J=10.0Hz),
6.332(d, 1H, J=8.0Hz), 6.180(s,
1H), 5.602(d, 1H, J=10.0Hz),
4.765(s, 2H), 3.817(t, 2H,
J=6.4Hz), 2.447(s, 6H), 2.180(s,
3H), 1.758(m, 2H), 1.442(s, 6H),
(Compound 5-43)
1.006(t, 3H, J=7.2Hz).
159.117, 153.685, 148.693,
147.612, 143.784, 140.248,
131.765, 131.454, 129.671,
129.324, 126.718, 125.536,
124.557, 123.119, 116.515,
115.959, 114.058, 109.507,
109.369, 109.032, 76.093, 69.855,
67.793, 27.823, 23.048, 22.325,
21.013, 10.367.
7.162(d, 1H, J=8.0Hz), 6.989(s,
2H), 6.818(d, 1H, J=8.0Hz),
6.626(d, 1H, J=10.0Hz), 6.528(d,
1H, J=2.0Hz), 6.511(s, 1H),
6.501(dd, 1H, J=8.0, 2.0Hz),
6.371(d, 1H, J=8.0Hz), 5.934(m,
1H), 5.588(d, 1H, J=10.0Hz),
.327(m, 1H, J=17.2Hz, 1.6Hz),
.253(m, 1H, J=14.8, 1.6Hz),
4.969(s, 2H), 4.381(m, 2H, J=5.2,
1.6Hz), 2.580(s, 6H), 2.329(s,
(Compound 5-44)
3H), 1.420(s, 6H).
156.543, 153.818, 149.550,
149.364, 143.871, 140.470,
132.189, 131.753, 130.643,
129.398, 129.020, 127.631,
127.065, 126.838, 123.321,
118.251, 116.521, 116.479,
114.280, 109.575, 109.422,
106.804, 76.165, 69.363, 68.043,
27.844, 22.755, 21.072.
7.543(d, 2H, J=8.0Hz), 7.052(d,
1H, J=8.0Hz), 7.025(d, 2H,
J=8.0Hz), 6.963(d, 1H, J=2.4Hz),
6.818(dd, 1H, J=8.0, 2.4Hz),
6.630(d, 1H, J=8.0Hz), 6.601(d,
1H, J=10.0Hz), 6.353(d, 1H,
J=8.0Hz), 6.045(m, 1H), 5.946(s,
1H), 5.617(d, 1H, J=10.0Hz),
.434(m, 1H, J=17.2Hz, 1.6Hz),
.376(m, 1H, J=14.8, 1.6Hz),
4.713(s, 2H), 4.544(m, 2H, J=5.2,
1.6Hz), 2.276(s, 3H), 1.449(s,
6H).
(Compound 5-45)
158.672, 153.796, 148.639,
147.442, 145.329, 132.481,
132.124, 129.546, 129.474,
129.458, 128.454, 126.539,
125.393, 124.751, 123.351,
118.220, 116.441, 116.126,
114.418, 110.139, 109.475,
109.200, 76.191, 69.158, 67.551,
27.844, 21.609.
7.128(d, 1H, J=8.4Hz), 6.812(dd,
1H, J=8.4, 2.4Hz), 6.791(s, 2H),
6.681(d, 1H, J=2.4Hz), 6.662(d,
1H, J=8.4Hz), 6.588(d, 1H,
J=10.0Hz), 6.333(d, 1H, J=8.4Hz),
6.186(s, 1H), 5.985(m, 1H),
.601(s, 1H, J=10.0Hz), 5.368(m,
1H, J=17.2Hz, 1.6Hz), 5.287(m,
1H, J=14.8, 1.6Hz), 4.771(s, 2H),
4.448(m, 1H, J=2H, J=5.2, 1.6Hz),
2.444(s, 6H), 2.185(s, 3H),
1.442(s, 6H).
(Compound 5-46)
158.518, 153.742, 148.727,
147.604, 143.833, 140.268,
132.498, 131.794, 131.426,
129.731, 129.348, 126.758,
125.455, 125.018, 123.273,
118.102, 116.513, 115.943,
114.200, 109.880, 109.392,
109.065, 76.122, 69.078, 67.777,
27.832, 23.048, 21.023.
7.552(d, 2H, J=8.0Hz), 7.042(d,
1H, J=8.0Hz), 7.022(d, 2H,
J=8.0Hz), 6.931(d, 1H, J=2.4Hz),
6.789(dd, 1H, J=8.0, 2.4Hz),
(Compound 5-47)
6.625(d, 1H, J=8.0Hz), 6.601(d,
1H, J=10.0Hz), 6.349(d, 1H,
J=8.0Hz), 5.945(s, 1H), 5.614(d,
1H, J=10.0Hz), 4.709(s, 2H),
3.959(t, 2H, J=6.4Hz), 2.273(s,
3H), 1.774(m, 2H), 1.499(m, 2H),
1.448(s, 6H), 0.989(t, 3H,
J=7.2Hz).
159.334, 153.764, 148.632,
147.487, 145.299, 132.196,
129.504, 129.464, 128.470,
126.522, 125.508, 124.334,
123.219, 116.464, 116.170,
114.247, 109.824, 109.477,
109.185, 76.186, 68.179, 67.595,
31.094, 27.848, 21.603, 19.162,
13.817.
7.29~7.45(m, 5H), 7.251(d, 1H,
J=8.4Hz), 6.687(d, 1H, J=8.0Hz),
6.598(d, 1H, J=10.0Hz), 6.542(d,
1H, J=2.0Hz), 6.509(dd, 1H,
J=8.4, 2.0Hz), 6.244(s, 1H),
(Compound 5-48)
.510(d, 1H, J=10.0Hz), 5.035(s,
2H), 4.926(s, 2H), 4.025(q, 2H,
J=6.8Hz), 2.206(s, 3H), 1.408(t,
3H, J=6.8Hz), 1.402(s, 6H).
159.787, 157.312, 152.757,
149.379, 136.481, 134.884,
129.198, 128.588, 128.214,
128.026, 128.003, 127.527,
121.428, 118.980, 116.758,
115.624, 110.796, 107.503,
105.609, 100.286, 76.000, 70.387,
68.069, 63.599, 27.859, 18.734,
14.787.
7.29~7.45(m, 5H), 7.253(d, 1H,
J=8.4Hz), 6.685(d, 1H, J=8.0Hz),
6.597(d, 1H, J=10.0Hz), 6.540(d,
1H, J=2.0Hz), 6.506(dd, 1H,
J=8.4, 2.0Hz), 6.245(s, 1H),
.511(d, 1H, J=10.0Hz), 5.038(s,
2H), 4.923(s, 2H), 3.918(t, 2H,
J=6.8Hz), 2.207(s, 3H), 1.804(m,
(Compound 5-49)
2H, J=6.8Hz), 1.402(s, 6H),
1.037(t, 3H, J=7.2Hz).
160.015, 157.339, 152.768,
149.394, 136.516, 134.887,
129.196, 128.588, 128.212,
128.049, 128.005, 127.553,
121.404, 118.975, 116.775,
115.638, 110.803, 107.510,
105.733, 100.320, 76.005, 70.432,
68.093, 64.405, 27.873, 22.546,
18.726, 10.509.
7.29~7.48(m, 5H), 7.269(d, 1H,
J=8.4Hz), 6.824(s, 1H), 6.553(d,
1H, J=10.0Hz), 6.513(d, 1H,
J=2.0Hz), 6.489(dd, 1H, J=8.4,
2.0Hz), 6.011(s, 1H), 5.431(d,
1H, J=10.0Hz), 5.028(s, 2H),
4.941(s, 2H), 4.015(q, 2H,
J=6.8Hz), 3.776(s, 3H), 1.415(s,
6H), 1.401(t, 3H, J=6.8Hz).
159.676, 157.284, 155.986,
(Compound 5-50)
154.098, 150.056, 136.637,
129.408, 128.549, 127.899,
127.423, 126.678, 126.154,
121.687, 116.663, 116.373,
106.515, 105.675, 103.168,
100.316, 92.899, 76.547, 70.380,
68.433, 63.576, 55.556, 27.880,
14.798.
7.29~7.48(m, 5H), 7.266(d, 1H,
J=8.4Hz), 6.825(s, 1H), 6.553(d,
1H, J=10.0Hz), 6.522(d, 1H,
J=2.4Hz), 6.496(dd, 1H, J=8.4,
2.4Hz), 6.010(s, 1H), 5.427(d,
1H, J=10.0Hz), 5.025(s, 2H),
4.940(s, 2H), 3.900(t, 2H,
J=6.8Hz), 3.772(s, 3H), 1.791(m,
2H, J=6.8Hz), 1.413(s, 6H),
1.046(t, 3H, J=6.8Hz).
159.876, 157.271, 155.967,
(Compound 5-51)
154.077, 150.038, 136.626,
129.378, 128.527, 127.883,
127.430, 126.679, 126.134,
121.603, 116.654, 116.325,
106.506, 105.717, 103.151,
100.276, 92.880, 76.526, 70.367,
69.626, 68.428, 55.534, 27.863,
22.541, 10.502.
7.29~7.45(m, 5H), 7.270(d, 1H,
J=8.0Hz), 6.838(d, 1H, J=8.0Hz),
6.814(s, 1H), 6.734(s, 1H),
6.599(d, 1H, J=10.0Hz), 6.247(s,
1H), 5.509(d, 1H, J=10.0Hz),
(Compound 5-52)
.063(s, 2H), 4.943(s, 2H),
2.630(q, 2H, J=7.6Hz), 2.207(s,
3H), 1.402(s, 6H), 1.244(t, 3H,
J=7.6Hz).
154.431, 153.000, 149.650,
145.470, 137.004, 135.040,
128.637, 128.579, 128.313,
128.239, 127.965, 127.583,
126.092, 120.617, 119.729,
116.775, 115.607, 111.892,
110.873, 107.544, 76.049, 70.396,
68.051, 28.925, 27.886, 18.744,
.559.
7.294(d, 2H, J=8.0Hz), 7.252(d,
1H, J=9.2Hz), 7.169(d, 2H,
J=8.0Hz), 6.801(d, 1H, J=9.2Hz),
6.794(s, 1H), 6.599(d, 1H,
J=10.0Hz), 6.243(s, 1H), 5.512(d,
1H, J=10.0Hz), 5.011(s, 2H),
4.928(s, 2H), 2.584(t, 2H,
(Compound 5-53)
J=7.6Hz), 2.349(s, 3H), 2.208(s,
3H), 1.660(m, 2H, J=7.6Hz),
1.403(s, 6H), 0.954(t, 3H,
J=7.6Hz).
156.315, 152.861, 149.545,
143.872, 137.691, 135.012,
133.692, 129.223, 128.443,
128.414, 128.191, 127.707,
126.075, 121.169, 119.601,
116.785, 115.630, 112.406,
110.794, 107.510, 76.021, 70.292,
68.053, 38.082, 27.886, 24.504,
21.181, 18.726, 13.852.
7.231(d, 1H, J=8.0Hz), 6.832(d,
1H, J=8.0Hz), 6.811(d, 1H,
J=8.0Hz), 6.718(s, 1H), 6.656(d,
1H, J=10.0Hz), 6.542(s, 1H),
6.375(d, 1H, J=8.0Hz), 6.037(m,
1H), 5.588(d, 1H, J=10.0Hz),
.395(m, 1H, J=17.6Hz, 1.6Hz),
.266(m, 1H, J=9.2, 1.4Hz),
.050(s, 2H), 4.552(m, 2H),
(Compound 5-54)
2.639(q, 2H, J=7.6Hz), 1.425(s,
6H), 1.244(t, 3H, J=7.6Hz).
156.148, 153.464, 149.310,
145.475, 133.165, 129.285,
129.091, 128.681, 126.627,
125.671, 122.101, 120.537,
117.621, 116.929, 116.669,
111.934, 109.581, 109.241,
76.060, 69.182, 68.441, 28.887,
27.822, 15.484.
7.219(d, 1H, J=8.0Hz), 6.830(d,
1H, J=8.0Hz), 6.786(d, 1H, J=8.0,
1.2Hz), 6.693(d, 1H, J=1.2Hz),
6.655(d, 1H, J=10.0Hz), 6.544(s,
1H), 6.373(d, 1H, J=8.0Hz),
6.038(m, 1H), 5.588(d, 1H,
J=10.0Hz), 5.391(m, 1H, J=17.6Hz,
1.6Hz), 5.261(m, 1H, J=9.2,
1.4Hz), 5.049(s, 2H), 4.545(m,
2H), 2.570(t, 2H, J=7.6Hz),
1.645(m,2H), 1.424(s, 6H),
(Compound 5-55)
0.955(t, 3H, J=7.6Hz).
156.052, 153.450, 149.311,
143.924, 133.160, 129.277,
129.102, 128.548, 126.622,
125.646, 122.087, 121.192,
117.609, 116.940, 116.671,
112.491, 109.576, 109.233,
76.053, 69.170, 68.440, 38.062,
27.820, 24.473, 13.859.
7.212(d, 1H, J=8.0Hz), 6.823(d,
1H, J=8.0Hz), 6.782(d, 1H, J=8.0,
1.2Hz), 6.691(d, 1H, J=1.2Hz),
6.654(d, 1H, J=10.0Hz), 6.540(s,
1H), 6.371(d, 1H, J=8.0Hz),
6.032(m, 1H), 5.581(d, 1H,
J=10.0Hz), 5.387(m, 1H, J=17.6Hz,
1.6Hz), 5.255(m, 1H, J=9.2,
1.4Hz), 5.047(s, 2H), 4.533(m,
2H), 2.588(t, 2H, J=7.6Hz),
1.598(m,2H), 1.419(s, 6H),
1.372(m, 2H), 0.932(t, 3H,
(Compound 5-56)
J=7.6Hz).
155.791, 153.435, 149.293,
144.111, 133.149, 129.238,
129.072, 128.529, 126.603,
125.586, 122.055, 121.128,
117.564, 116.922, 116.658,
112.450, 109.551, 109.213,
76.031, 69.156, 68.421, 35.653,
33.457, 27.799, 22.348, 13.836.
Example 1: Preparation of 3-(2-hydroxy
methoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-1)
6.98 g (16.4 mmol) of 3-(2-benzyloxy
methoxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-
f]chromene (Compound 5-1) obtained in Preparation Example 1
was dissolved in 20 ml of THF, a high-pressure reactor was
filled with the resulting solution, and 500 mg of 10% Pd/C
(palladium on carbon) was added thereto. 5 atm of hydrogen
was added thereto in a state where the temperature of the
reactor was maintained at 50°C, and then the resulting
mixture was vigorously stirred for 48 hours. Thereafter,
hydrogen was removed from the high-pressure reactor, the
reactor was replaced with a nitrogen atmosphere, and then
the Pd/C catalyst was removed by filtering the reaction
solution with a celite pad. The filtered solution was
thoroughly concentrated by performing distillation under
reduced pressure, and then recrystallized with IPA, thereby
obtaining 5.27 g (15.5 mol) of a white powder 3-(2-hydroxy-
4-methoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Yield: 94.5%).
H-NMR (CDCl3): 7.022(d, 1H, J=8.8Hz), 6.838(d, 1H,
J=8.4Hz), 6.488(dd, 1H, J=8.4, 2.4Hz), 6.388(d, 1H,
J=8.8Hz), 6.364(d, 1H, J=2.4Hz), 5.059(s, 1H), 4.392(m, 1H,
J=10.4, 2.4, 0.8Hz), 4.024(t, 1H, J=10.4Hz), 3.768(s, 1H),
3.488(m, 1H), 3.017(dd, 1H, J=15.6, 10.4Hz), 2.875(ddd, 1H,
J=15.6, 5.2, 2.4Hz), 2.646(m, 2H), 1.778(t, 2H, J=5.8Hz),
1.335(s, 3H), 1.321(s, 3H).
C-NMR (CDCl3): 159.257, 154.516, 152.772, 152.160,
128.184, 127.546, 120.182, 112.994, 109.394, 109.340,
105.957, 102.118, 73.917, 70.069, 55.340, 32.391, 31.811,
.671, 26.833, 26.459, 17.187.
Example 2: Preparation of 3-(2-hydroxy
ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-2)
3-(2-benzyloxyethoxyphenyl)-8,8-dimethyl-2,8-
dihydropyrano[2,3-f]chromene (Compound 5-2) obtained in
Preparation Example 2 was used by the same method as in
Example 1, thereby obtaining 3-(2-hydroxyethoxyphenyl)-
8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene.
H-NMR (CDCl3): 7.029(d, 1H, J=8.0Hz), 6.834(d, 1H,
J=8.0Hz), 6.766(dd, 1H, J=8.0, 1.2Hz), 6.596(d, 1H,
J=1.2Hz), 6.389(d, 1H, J=8.0Hz), 4.909(s, 1H), 4.415(m, 1H,
J=10.4, 3.2, 2.0Hz), 4.041(t, 1H, J=10.4Hz), 3.542(m, 1H),
3.034(dd, 1H, J=15.6, 10.4Hz), 2.875(ddd, 1H, J=15.6, 5.2,
2.0Hz), 2.647(m, 2H), 2.574(q, 2H, J=7.6Hz), 1.774(t, 2H,
J=6.8Hz), 1.332(s, 3H), 1.318(s, 3H), 1.208(t, 3H, J=7.6Hz).
C-NMR (CDCl3): 153.373, 152.716, 152.102, 144.205,
127.472, 127.415, 124.773, 120.499, 114.963, 112.898,
109.310, 109.248, 73.795, 69.897, 32.308, 32.054, 30.532,
28.276, 26.784, 26.374, 17.120, 15.308.
3-phenyl-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene derivatives shown in the
following Table 2 were synthesized by using 3-phenyl-2,8-
dihydropyrano[2,3-f]chromene derivatives in Table 1 in
accordance with the method in Example 1:
[Table 2]
Number of Chemical
H-NMR (CDCl3, δ)
Example structure
(Number of
Preparation
Example
correspondi
ng to the
reactant
used)
7.022(d, 1H, J=8.8Hz), 6.838(d,
1H, J=8.4Hz), 6.488(dd, 1H,
(Preparation
J=8.4, 2.4Hz), 6.388(d, 1H,
J=8.8Hz), 6.364(d, 1H, J=2.4Hz),
Example 1) (Compound I-1)
.059(s, 1H), 4.392(m, 1H,
J=10.4, 2.4, 0.8Hz), 4.024(t,
1H, J=10.4Hz), 3.768(s, 1H),
3.488(m, 1H), 3.017(dd, 1H,
J=15.6, 10.4Hz), 2.875(ddd, 1H,
J=15.6, 5.2, 2.4Hz), 2.646(m,
2H), 1.778(t, 2H, J=5.8Hz),
1.335(s, 3H), 1.321(s, 3H).
6.989(d, 1H, J=8.4Hz), 6.825(d,
1H, J=8.0Hz), 6.458(dd, 1H,
J=8.0, 2.4Hz), 6.387(d, 1H,
J=8.4Hz), 6.324(d, 1H, J=2.4Hz),
.355(s, 1H), 4.386(m, 1H,
J=10.4, 3.2, 2.0Hz), 4.007(t,
1H, J=10.4Hz), 3.954(q, 2H,
(Preparation
J=7.2Hz), 3.484(m, 1H),
3.006(dd, 1H, J=15.6, 11.2Hz),
Example 2) (Compound I-2)
2.852(m, 1H, J=15.6, 4.8,
1.6Hz), 2.641(m, 2H), 1.770(t,
2H, J=6.8Hz), 1.378(t, 2H,
J=6.8Hz), 1.331(s, 3H), 1.316(s,
3H).
6.976(d, 1H, J=8.4Hz), 6.817(d,
1H, J=8.4Hz), 6.452(dd, 1H,
J=8.4, 2.0Hz), 6.391(d, 1H,
J=8.4Hz), 6.316(d, 1H, J=2.0Hz),
.600(s, 1H), 4.385(d, 1H,
J=10.0Hz), 4.000(t, 1H,
J=10.0Hz), 3.812(t, 2H,
(Preparation
J=6.4Hz), 3.488(m, 1H),
(Compound I-3)
2.997(dd, 1H, J=15.6, 11.2Hz),
Example 3)
2.837(dd, 1H, J=15.6, 4.4Hz),
2.640(m, 2H), 1.782(t, 2H,
J=6.8Hz), 1.765(m, 2H), 1.329(s,
3H), 1.314(s, 3H), 0.994(t, 3H,
J=7.2Hz).
7.000(d, 1H, J=8.4Hz), 6.845(d,
1H, J=8.0Hz), 6.472(dd, 1H,
J=8.0, 2.4Hz), 6.404(d, 1H,
J=8.4Hz), 6.344(d, 1H, J=2.4Hz),
.333(s, 1H), 4.450(m, 1H,
(Preparation
J=6.0Hz), 4.409(m, 1H, J=10.4,
3.2, 2.0Hz), 4.026(t, 1H,
Example 5) (Compound I-4)
J=10.4Hz), 3.498(m, 1H),
3.026(dd, 1H, J=15.2, 11.2Hz),
2.871(m, 1H, J=15.2, 4.8,
1.6Hz), 2.669(m, 2H), 1.789(t,
2H, J=6.8Hz), 1.378(t, 2H,
J=6.8Hz), 1.349(s, 3H), 1.331(s,
3H), 1.324(d, 6H, J=6.0Hz).
6.995(d, 1H, J=8.0Hz), 6.831(d,
1H, J=8.0Hz), 6.469(dd, 1H,
J=8.0, 2.4Hz), 6.384(d, 1H,
J=8.0Hz), 6.342(d, 1H, J=2.4Hz),
.029(s, 1H), 4.387(m, 1H,
J=10.4Hz), 4.011(t, 1H,
J=10.4Hz), 3.901(t, 2H,
(Preparation
J=6.4Hz), 3.478(m, 1H),
(Compound I-5)
3.012(dd, 1H, J=15.6, 11.2Hz),
Example 6)
2.879(m, 1H, J=15.6, 4.4Hz),
2.642(m, 2H), 1.68~1.81(m, 4H),
1.468(m, 2H), 1.331(s, 3H),
1.316(s, 3H), 0.962(t, 3H,
J=7.2Hz).
7.008(d, 1H, J=8.0Hz), 6.846(d,
1H, J=8.0Hz), 6.482(dd, 1H,
J=8.0, 2.4Hz), 6.408(d, 1H,
(Preparation
J=8.0Hz), 6.355(d, 1H, J=2.4Hz),
(Compound I-6)
.313(s, 1H), 4.406(m, 1H,
Example 7)
J=10.4Hz), 4.027(t, 1H,
J=10.4Hz), 3.906(t, 2H,
J=6.4Hz), 3.503(m, 1H),
3.027(dd, 1H, J=15.6, 11.2Hz),
2.874(m, 1H, J=15.6, 4.4Hz),
2.662(m, 2H), 1.71~1.81(m, 4H),
1.40~1.87(m, 4H), 1.353(s, 3H),
1.338(s, 3H), 0.941(t, 3H,
J=7.2Hz).
6.991(d, 1H, J=8.4Hz), 6.827(d,
1H, J=8.4Hz), 6.468(dd, 1H,
J=8.4, 2.4Hz), 6.385(d, 1H,
J=8.4Hz), 6.335(d, 1H, J=2.4Hz),
.083(s, 1H), 4.387(m, 1H,
J=10.4, 3.2, 2.0Hz), 4.011(t,
1H, J=10.4Hz), 3.918(t, 2H,
J=6.4Hz), 3.484(m, 1H),
(Preparation
3.008(dd, 1H, J=15.6, 11.2Hz),
(Compound I-7)
Example 9)
2.857(m, 1H, J=15.6, 3.6,
1.6Hz), 2.642(m, 2H), 1.806(m,
1H), 1.772(t, 2H, J=6.4Hz),
1.643(q, 2H, J=6.4Hz), 1.331(s,
3H), 1.316(s, 3H), 0.949(d, 6H,
J=6.4Hz).
6.976(d, 1H, J=8.4Hz), 6.833(d,
1H, J=8.4Hz), 6.489(d, 1H,
J=2.4Hz), 6.433(dd, 1H, J=8.4,
2.4Hz), 6.386(d, 1H, J=8.4Hz),
6.170(s, 1H), 4.388(m, 1H,
J=10.4, 2.4Hz), 4.083(t, 2H,
J=4.4Hz), 3.997(t, 1H,
(Preparation
J=10.4Hz), 3.784(t, 2H,
(Compound I-8)
J=4.4Hz), 3.500(m, 1H), 3.475(s,
Example 10)
3H), 3.006(dd, 1H, J=15.6,
11.2Hz), 2.853(m, 1H, J=15.6,
3.6Hz), 2.650(t, 2H), 1.777(t,
2H, J=6.8Hz), 1.336(s, 3H),
1.322(s, 3H).
6.909(d, 1H, J=8.0Hz), 6.829(d,
1H, J=8.4Hz), 6.395(dd, 1H,
J=8.4, 2.4Hz), 6.287(d, 1H,
J=2.4Hz), 5.597(b, 2H), 4.355(m,
1H), 4.034(t, 1H, J=10.0Hz),
(Preparation
3.478(m, 1H), 2.983(dd, 1H,
J=15.6, 10.4Hz), 2.878(ddd, 1H,
Example 11) (Compound I-9)
J=15.6, 4.8, 1.6Hz), 2.634(t,
2H, J=6.8Hz), 1.763(t, 2H,
J=6.8Hz), 1.323(s, 3H), 1.314(s,
3H).
6.939(d, 1H, J=8.4Hz), 6.824(d,
1H, J=8.4Hz), 6.421(d, 1H,
2.4Hz), 6.36~6.40(m, 2H),
.269(s, 1H), 4.343(m, 1H,
J=10.0, 2.0, 0.8Hz), 3.968(t,
1H, J=10.0Hz), 3.762(s, 3H),
(Preparation
3.536(m, 1H), 2.965(dd, 1H,
Example 12) (Compound I-10)
J=15.2, 11.6Hz), 2.821(dd, 1H,
J=15.2, 3.2Hz), 2.645(t, 2H,
J=6.4Hz), 1.774(t, 2H, J=6.4Hz),
1.334(s, 3H), 1.319(s, 3H).
6.934(d, 1H, J=8.4Hz), 6.829(d,
1H, J=8.4Hz), 6.412(d, 1H,
2.4Hz), 6.35~6.40(m, 2H),
.143(s, 1H), 4.341(m, 1H,
J=10.0, 2.0, 0.8Hz), 4.012(t,
1H, J=10.0Hz), 3.989(q, 2H,
(Preparation
J=6.4Hz), 3.562(m, 1H),
2.961(dd, 1H, J=15.2, 11.6Hz),
Example 13) (Compound I-11)
2.851(dd, 1H, J=15.2, 3.2Hz),
2.648(t, 2H, J=6.4Hz), 1.776(t,
2H, J=6.4Hz), 1.392(t, 2H,
J=6.4Hz), 1.334(s, 3H), 1.323(s,
3H).
6.937(d, 1H, J=8.4Hz), 6.829(d,
1H, J=8.4Hz), 6.409(d, 1H,
2.4Hz), 6.35~6.40(m, 2H),
4.446(m, 1H, J=10.0, 2.0,
0.8Hz), 3999(t, 1H, J=10.0Hz),
3.889(q, 2H, J=6.4Hz), 3.572(m,
(Preparation
1H), 2.965(dd, 1H, J=15.2,
11.6Hz), 2.846(dd, 1H, J=15.2,
Example 14) (Compound I-12)
3.2Hz), 2.646(t, 2H, J=6.4Hz),
1.75~1.87(m, 4H), 1.332(s, 3H),
1.324(s, 3H), 1.023(t, 3H,
J=6.4Hz).
7.029(d, 1H, J=8.0Hz), 6.834(d,
1H, J=8.0Hz), 6.766(dd, 1H,
J=8.0, 1.2Hz), 6.596(d, 1H,
J=1.2Hz), 6.389(d, 1H, J=8.0Hz),
4.909(s, 1H), 4.415(m, 1H,
J=10.4, 3.2, 2.0Hz), 4.041(t,
(Preparation
1H, J=10.4Hz), 3.542(m, 1H),
Example 18) (Compound I-13)
3.034(dd, 1H, J=15.6, 10.4Hz),
2.875(ddd, 1H, J=15.6, 5.2,
2.0Hz), 2.647(m, 2H), 2.574(q,
2H, J=7.6Hz), 1.774(t, 2H,
J=6.8Hz), 1.332(s, 3H), 1.318(s,
3H), 1.208(t, 3H, J=7.6Hz).
7.029(d, 1H, J=8.0Hz), 6.842(d,
1H, J=8.0Hz), 6.755(d, 1H,
J=8.0Hz), 6.597(s, 1H), 6.390(d,
1H, J=8.4Hz), 4.804(s, 1H),
4.423(m, 1H, J=10.4, 2.4Hz),
4.046(t, 1H, J=10.4Hz), 3.537(m,
1H), 3.042(dd, 1H, J=15.6,
(Preparation
11.2Hz), 2.886(m, 1H), 2.652(m,
Example 21) (Compound I-14)
2H), 2.518(t, 2H, J=7.6Hz),
1.781(t, 2H, J=6.8Hz), 1.612(m,
2H, J=7.2Hz), 1.338(s, 3H),
1.323(s, 3H), 0.947(t, 3H,
J=7.2Hz).
7.058(d, 1H, J=8.0Hz), 6.853(d,
1H, J=8.0Hz), 6.812(dd, 1H,
J=8.0, 1.2Hz), 6.641(d, 1H,
J=1.2Hz), 6.408(d, 1H, J=8.0Hz),
4.973(s, 1H), 4.444(m, 1H,
(Preparation
J=10.4, 3.2, 2.0Hz), 4.060(t,
Example 27) (Compound I-15)
1H, J=10.4Hz), 3.552(m, 1H),
3.056(dd, 1H, J=15.6, 11.2Hz),
2.892(m, 1H, J=15.6, 5.2,
1.6Hz), 2.859(m, 1H, J=6.8Hz),
2.668(m, 2H), 1.794(t, 2H,
J=6.8Hz), 1.352(s, 3H), 1.337(s,
3H), 1.235(d, 6H, J=6.8Hz).
7.034(d, 1H, J=8.0Hz), 6.851(d,
1H, J=8.0Hz), 6.756(dd, 1H,
J=8.0, 1.2Hz), 6.595(d, 1H,
J=1.2Hz), 6.406(d, 1H, J=8.0Hz),
4.904(s, 1H), 4.426(m, 1H,
J=10.4, 3.2, 2.0Hz), 4.056(t,
1H, J=10.4Hz), 3.549(m, 1H),
(Preparation
3.050(dd, 1H, J=15.6, 11.2Hz),
(Compound I-16)
2.892(m, 1H, J=15.6, 5.2,
Example 28)
1.6Hz), 2.667(m, 2H), 2.546(t,
2H, J=4.4H), 1.792(t, 2H,
J=6.8Hz), 1.584(m, 2H), 1.375(m,
2H), 1.351(s, 3H), 1.336(s, 3H),
0.939(t, 2H, J=7.4Hz).
7.033(d, 1H, J=8.0Hz), 6.849(d,
1H, J=8.0Hz), 6.756(dd, 1H,
J=8.0, 1.2Hz), 6.598(d, 1H,
(Preparation
J=1.2Hz), 6.403(d, 1H, J=8.0Hz),
(Compound I-17)
4.898(s, 1H), 4.437(m, 1H,
Example 29)
J=10.4, 3.2, 2.0Hz), 4.054(t,
1H, J=10.4Hz), 3.548(m, 1H),
3.048(dd, 1H, J=15.6, 11.2Hz),
2.895(m, 1H, J=15.6, 5.2,
1.6Hz), 2.667(m, 2H), 2.536(t,
2H, J=4.4H), 1.790(t, 2H,
J=6.8Hz), 1.599(m, 2H), 1.36(m,
4H), 1.348(s, 3H), 1.333(s, 3H),
0.908(t, 2H, J=7.4Hz).
6.901(d, 1H, J=8.0Hz), 6.857(d,
1H, J=8.4Hz), 6.790(d, 1H,
J=8.0Hz), 6.411(d, 1H, J=8.4Hz),
4.834(s, 1H), 4.430(m, 1H,
J=10.0, 3.2, 2.0Hz), 4.051(t,
1H, J=10.0Hz), 3.543(m, 1H),
(Preparation
3.036(dd, 1H, J=15.6, 11.2Hz),
2.896(m, 1H, J=15.6, 5.2,
Example 31) (Compound I-18)
2.0Hz), 2.672(m, 2H), 2.297(s,
3H), 2.199(s, 3H), 1.798(t, 2H,
J=6.8Hz), 1.357(s, 3H), 1.344(s,
3H).
6.886(s, 1H), 6.857(d, 1H,
J=4.8Hz), 6.579(s, 1H), 6.418(d,
(Preparation
1H, J=4.8Hz), 4.965(s, 1H),
4.433(dd, 1H, J=6.0Hz), 4.053(t,
Example 32) (Compound I-19)
1H, J=6.0Hz), 3.534(m, 1H),
3.067(dd, 1H, J=8.8, 6.8Hz),
2.873(ddd, 1H, J=8.8, 2.4,
0.8Hz), 2.680(m, 2H), 2.203(s,
6H), 1.803(t, 2H, J=4.0Hz),
1.364(s, 3H), 1.348(s, 3H).
6.839(d, 1H, J=8.0Hz), 6.819(d,
1H, J=8.0Hz), 6.395(d, 1H,
J=8.0Hz), 6.385(d, 1H, J=8.0Hz),
4.927(s, 1H), 4.891(s, 1H),
4.388(m, 1H, J=10.4, 3.2,
2.0Hz), 4.011(t, 1H, J=10.4Hz),
(Preparation
3.469(m, 1H), 2.997(dd, 1H,
J=15.6, 11.2Hz), 2.869(ddd, 1H,
Example 35) (Compound I-20)
J=15.6, 5.2, 1.6Hz), 2.653(m,
2H), 2.167(s, 3H), 1.783(t, 2H,
J=6.8Hz), 1.341(s, 3H), 1.328(s,
3H).
7.044(dd, 1H, J=8.4, 6.4Hz),
6.834(dd, 1H, J=8.4, 2.0Hz),
6.620(dt, 1H, J=8.4, 2.4Hz),
(Preparation
6.501(dd, 1H, J=9.6, 2.4Hz),
6.396(d, 1H, J=8.4Hz), 5.400(s,
Example 36) (Compound I-21)
1H), 4.379(m, 1H, J=10.0, 3.6,
2.0Hz), 4.039(t, 1H, J=10.0Hz),
3.523(m, 1H), 2.997(dd, 1H,
J=15.6, 10.4Hz), 2.892(ddd, 1H,
J=15.6, 5.2, 2.0Hz), 2.642(m,
2H), 1.777(t, 2H, J=6.8Hz),
1.335(s, 3H), 1.321(s, 3H).
7.025(d, 1H, J=8.4Hz), 6.888(dd,
1H, J=8.4, 2.0Hz), 6.832(d, 1H,
J=8.4Hz), 6.759(d, 1H, J=2.0Hz),
6.397(d, 1H, J=8.4Hz), 5.256(s,
1H), 4.375(m, 1H, J=10.0, 3.6,
2.0Hz), 4.047(t, 1H, J=10.0Hz),
(Preparation
3.532(m, 1H), 2.989(dd, 1H,
Example 37) (Compound I-22)
J=15.6, 10.4Hz), 2.896(ddd, 1H,
J=15.6, 5.2, 1.6Hz), 2.637(m,
2H), 1.775(t, 2H, J=6.8Hz),
1.333(s, 3H), 1.320(s, 3H).
7.010(d, 1H, J=8.4Hz), 6.475(dd,
1H, J=8.4, 2.4Hz), 6.341(d, 1H,
J=2.4Hz), 6.311(s, 1H), 5.189(s,
1H), 4.352(m, 1H, J=10.4, 3.2,
(Preparation
2.0Hz), 4.007(t, 1H, J=10.4Hz),
Example 48) (Compound I-23)
3.966(q, 2H, J=7.2Hz), 3.484(m,
1H), 3.006(dd, 1H, J=15.6,
11.2Hz), 2.816(m, 1H), 2.756(m,
1H), 2.621 (m, 2H), 2.138(s,
3H), 1.742(t, 2H, J=6.8Hz),
1.385(t, 2H, J=6.8Hz), 1.325(s,
3H), 1.309(s, 3H).
7.008(d, 1H, J=8.4Hz), 6.476(dd,
1H, J=8.4, 2.4Hz), 6.347(d, 1H,
J=2.4Hz), 6.312(s, 1H), 5.263(s,
1H), 4.352(m, 1H, J=10.4, 3.2,
2.0Hz), 4.006(t, 1H, J=10.4Hz),
3.850(t, 2H, J=7.2Hz), 3.593(m,
(Preparation
1H), 2.826(dd, 1H, J=15.6,
(Compound I-24)
11.2Hz), 2.756(dd, 1H, J=15.6,
Example 49)
.0Hz)), 2.621 (m, 2H),
2.137(s, 3H), 1.73~1.82(m, 4H),
1.325(s, 3H), 1.309(s, 3H),
1.011(t, 2H, J=6.8Hz).
7.007(d, 1H, J=8.4Hz), 6.441(dd,
1H, J=8.4, 2.4Hz), 6.310(d, 1H,
J=2.4Hz), 6.009(s, 1H), 5.439(s,
1H), 4.358(m, 1H, J=10.4, 3.2,
(Preparation
2.0Hz), 3.978(t, 1H, J=10.4Hz),
Example 50) (Compound I-25)
3.933(q, 2H, J=7.2Hz), 3.735(s,
3H), 3.424(m, 1H), 2.922(dd, 1H,
J=15.6, 11.2Hz), 2.722(dd, 1H,
J=15.6, 10.8), 2.582(m, 2H),
2.621 (m, 2H), 1.756(t, 2H,
J=6.8Hz), 1.367(t, 2H, J=6.8Hz),
1.334(s, 3H), 1.321(s, 3H).
7.022(d, 1H, J=8.4Hz), 6.462(dd,
1H, J=8.4, 2.4Hz), 6.344(d, 1H,
J=2.4Hz), 6.004(s, 1H), 5.024(s,
1H), 4.360(m, 1H, J=10.4, 3.2,
2.0Hz), 3.978(t, 1H, J=10.4Hz),
3.858(t, 2H, J=6.8Hz), 3.744(s,
(Preparation
3H), 3.412(m, 1H), 2.929(dd, 1H,
J=15.6, 11.2Hz), 2.721(dd, 1H,
Example 51) (Compound I-26)
J=15.6, 10.8), 2.583(m, 2H),
1.73~1.80 (m, 4H), 1.336(s, 3H),
1.323(s, 3H). 1.014(t, 2H,
J=7.2Hz).
Synthesis Example 1: Preparation of (R)(2-hydroxy-
4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-2a) and (S)
(2-hydroxyethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-2b)
1-1: Preparation of (R)(2-benzyloxy
ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound 6-2a) and (S)
(2-benzyloxyethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound 6-2b)
.0 g (43.8 mmol) of 3-(2-benzyloxyethoxyphenyl)-
8,8-dimethyl-2,8-dihydropyrano[2,3-f]chromene (Compound 5-
2) obtained in Preparation Example 2 was dissolved in 50 ml
of methylene chloride (CH Cl ), and 400 mg of UbaPHOX
[((4S,5S)-Cy2-UbaPHOX)Ir(COD)]BARF was added thereto. Next,
7 atm of hydrogen was added thereto, and then the resulting
mixture was stirred for 12 hours in a state where the
temperature of the reactor was maintained at 35°C. The
reaction was terminated, and then the solvent was
concentrated, thereby obtaining 19.68 g (yield 98%) of (R)-
3-(2-benzyloxyethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound 6-2a).
UbaPHOX [((4R,5R)-Cy2-UbaPHOX)Ir(COD)]BARF was used
by the same method, thereby obtaining (S)(2-benzyloxy
ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound 6-2b). H-NMR
results for the obtained Compound are as follows.
H-NMR (CDCl3): 7.30~7.45(m, 5H), 7.026(d, 1H,
J=8.4Hz), 6.824(d, 1H, J=8.4Hz), 6.545(d, 1H, J=2.0Hz),
6.466(dd, 1H, J=8.4, 2.0Hz), 6.373(d, 1H, J=8.4Hz), 5.075(s,
2H), 4.371(m, 1H, J=10.4, 3.6, 2.0Hz), 4.002(t, 1H,
J=10.4Hz), 3.991 (q, 2H, J=7.0Hz), 3.652(m, 1H), 2.983(dd,
1H, J=15.6, 10.8Hz), 2.866(m, 1H, J=15.6, 5.2, 1.6Hz),
2.628(t, 2H, J=6.8Hz), 1.762(t, 2H, J=6.8Hz), 1.388(t, 2H,
J=7.0Hz), 1.322(s, 3H), 1.313(s, 3H).
1-2: Preparation of (R)(2-hydroxyethoxyphenyl)-
8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
(Compound I-2a) and (S)(2-hydroxyethoxyphenyl)-8,8-
dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
(Compound I-2b)
After 19.68 g (42.9 mmol) of (R)(2-benzyloxy
ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound 6-2a) obtained in
Synthesis Example 1-1 was dissolved in 50 ml of THF, a
high-pressure reactor was filled with the resulting
solution, and 400 mg of 10% Pd/C was added thereto. 5 atm
of hydrogen was added thereto in a state where the
temperature of the reactor was maintained at 50°C, and then
the resulting mixture was vigorously stirred for 15 hours.
Thereafter, hydrogen was removed from the high-pressure
reactor, the reactor was replaced with a nitrogen
atmosphere, and then the Pd/C catalyst was removed by
filtering the reaction solution with a celite pad. The
filtered solution was thoroughly concentrated by performing
distillation under reduced pressure, and then
recrystallized with IPA, thereby obtaining 14.96 g (40.6
mmol) of a white powder (R)(2-hydroxyethoxyphenyl)-
8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
(Compound I-2a) (Yield: 94.5%).
(S)(2-hydroxyethoxyphenyl)-8,8-dimethyl-
2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene (Compound I-2b)
was obtained from (S)(2-benzyloxyethoxyphenyl)-8,8-
dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene
1 13
(Compound 6-2b) by using the same method. H-NMR, C-NMR,
optical rotation, and M.P. results for the obtained
Compound are as follows.
H-NMR (CDCl3): 6.989(d, 1H, J=8.4Hz), 6.825(d, 1H,
J=8.0Hz), 6.458(dd, 1H, J=8.0, 2.4Hz), 6.387(d, 1H,
J=8.4Hz), 6.324(d, 1H, J=2.4Hz), 5.355(s, 1H), 4.386(m, 1H,
J=10.4, 3.2, 2.0Hz), 4.007(t, 1H, J=10.4Hz), 3.954(q, 2H,
J=7.2Hz), 3.484(m, 1H), 3.006(dd, 1H, J=15.6, 11.2Hz),
2.852(m, 1H, J=15.6, 4.8, 1.6Hz), 2.641(m, 2H), 1.770(t, 2H,
J=6.8Hz), 1.378(t, 2H, J=6.8Hz), 1.331(s, 3H), 1.316(s, 3H).
C-NMR (CDCl3): 158.552, 154.340, 152.719, 152.091,
128.075, 127.465, 119.882, 112.909, 109.305, 109.248,
106.572, 102.504, 73.798, 70.018, 63.450, 32.311, 31.749,
.614, 26.776, 26.390, 17.116, 14.781.
Optical Rotation data
R-enantiomer- : -6.2° (c=0.025, ethanol); and
S-enantiomer- : +6.0° (c=0.025, ethanol).
M. P.
R-enantiomer: 132.5°C; and
S-enantiomer: 132.0°C.
Synthesis Example 2: Preparation of (R)(2-hydroxy-
4-propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-3a) and (S)
(2-hydroxypropoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-3b)
19.68 g (yield 98%) of (R)(2-benzyloxy
propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound 6-3a) was obtained
from 20.0 g of 3-(2-benzyloxyporopoxyphenyl)-8,8-
dimethyl-2,8-dihydropyrano[2,3-f]chromene (Compound 5-3)
obtained in Preparation Example 3 by using the same method
as in Synthesis Example 1. Further, (S)(2-benzyloxy
propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound 6-3b) was obtained
by using the same method as in Synthesis Example 1-1, and
1 13
H-NMR and C-NMR results for the obtained Compound are as
follows.
H-NMR (CDCl3): 7.30~7.45(m, 5H), 7.031(d, 1H,
J=8.4Hz), 6.828(d, 1H, J=8.4Hz), 6.558(d, 1H, J=2.4Hz),
6.476(dd, 1H, J=8.4, 2.4Hz), 6.373(d, 1H, J=8.4Hz), 5.082(s,
2H), 4.371(m, 1H, J=10.4, 3.6, 2.0Hz), 4.002(t, 1H,
J=10.4Hz), 3.886 (q, 2H, J=7.0Hz), 3.647(m, 1H), 2.949(dd,
1H, J=15.6, 10.8Hz), 2.868(m, 1H, J=15.6, 5.2, 1.6Hz),
2.628(t, 2H, J=6.8Hz), 1.796(t, 2H, J=6.8Hz), 1.764(m, 2H),
1.325(s, 3H), 1.316(s, 3H), 1.024(t, 2H, J=7.6Hz).
C-NMR (CDCl3): 158.989, 157.253, 152.783, 152.207,
136.917, 128.581, 127.827, 127.600, 127.430, 127.132,
122.230, 112.913, 109.236, 109.120, 105.244, 100.336,
73.614, 70.224, 70.004, 69.541, 32.315, 31.317, 30.807,
26.790, 26.482, 22.553, 17.127, 10.536.
In addition, (R)- and (S)(2-hydroxy
propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromenes were obtained from (R)- and
(S)(2-benzyloxypropoxyphenyl)-8,8-dimethyl-
2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes (Compounds 6-
3a and 6-3b), respectively, by using the same method as in
1 13
Synthesis Example 1-2. H-NMR, C-NMR, optical rotation,
and M.P. results for the obtained Compounds are as follows.
H-NMR (CDCl3): 6.976(d, 1H, J=8.4Hz), 6.817(d, 1H,
J=8.4Hz), 6.452(dd, 1H, J=8.4, 2.0Hz), 6.391(d, 1H,
J=8.4Hz), 6.316(d, 1H, J=2.0Hz), 5.600(s, 1H), 4.385(d, 1H,
J=10.0Hz), 4.000(t, 1H, J=10.0Hz), 3.812(t, 2H, J=6.4Hz),
3.488(m, 1H), 2.997(dd, 1H, J=15.6, 11.2Hz), 2.837(dd, 1H,
J=15.6, 4.4Hz), 2.640(m, 2H), 1.782(t, 2H, J=6.8Hz),
1.765(m, 2H), 1.329(s, 3H), 1.314(s, 3H), 0.994(t, 3H,
J=7.2Hz).
C-NMR (CDCl3): 158.678, 154.412, 152.596, 152.054,
128.015, 127.483, 119.827, 113.016, 109.299, 109.226,
106.588, 102.460, 73.888, 70.014, 69.537, 32.287, 31.702,
.552, 26.728, 26.349, 22.453, 17.096, 10.458.
Optical Rotation data
R-enantiomer- : -5.3° (c=0.025, ethanol); and
S-enantiomer- : +5.8° (c=0.025, ethanol).
M. P.
R-enantiomer: 153.6°C; and
S-enantiomer: 153.4°C.
Synthesis Example 3: Preparation of (R)(2-hydroxy-
4-butoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-5a) and (S)
(2-hydroxybutoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-5b)
(R)- and (S)(2-hydroxybutoxyphenyl)-8,8-
dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes with
> 96 %ee were synthesized by using 3-(2-benzyloxy
butoxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-f]chromene
(Compound 5-6) synthesized in Preparation Example 6 and the
method in Synthesis Example 1, respectively, and H-NMR,
C-NMR, optical rotation, and M.P. results for the
obtained Compounds are as follows.
H-NMR (CDCl3): 6.995(d, 1H, J=8.0Hz), 6.831(d, 1H,
J=8.0Hz), 6.469(dd, 1H, J=8.0, 2.4Hz), 6.384(d, 1H,
J=8.0Hz), 6.342(d, 1H, J=2.4Hz), 5.029(s, 1H), 4.387(m, 1H,
J=10.4Hz), 4.011(t, 1H, J=10.4Hz), 3.901(t, 2H, J=6.4Hz),
3.478(m, 1H), 3.012(dd, 1H, J=15.6, 11.2Hz), 2.879(m, 1H,
J=15.6, 4.4Hz), 2.642(m, 2H), 1.68~1.81(m, 4H), 1.468(m,
2H), 1.331(s, 3H), 1.316(s, 3H), 0.962(t, 3H, J=7.2Hz).
C-NMR (CDCl3): 158.793, 154.331, 152.721, 152.092,
128.047, 127.461, 119.777, 112.909, 109.299, 109.248,
106.628, 102.511, 73.786, 70.023, 67.738, 32.317, 31.756,
31.227, 30.626, 26.777, 26.390, 19.193, 17.117, 13.807.
Optical Rotation data
R-enantiomer- : -5.3° (c=0.025, ethanol); and
S-enantiomer- : +5.1° (c=0.025, ethanol).
M. P.
R-enantiomer: 115.9°C; and
S-enantiomer: 114.6°C.
Synthesis Example 4: Preparation of (R)(2-hydroxy-
4-isopentyloxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-7a) and (S)
(2-hydroxyisopentyloxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-7b)
(R)- and (S)(2-hydroxyisopentyloxyphenyl)-8,8-
dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes with
> 96 %ee were synthesized by using 3-(2-benzyloxy
isopentyloxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-
f]chromene (Compound 5-9) synthesized in Preparation
Example 9 and the method in Synthesis Example 1,
1 13
respectively, and H-NMR, C-NMR, optical rotation, and M.P.
results for the obtained Compounds are as follows.
H-NMR (CDCl3): 6.991(d, 1H, J=8.4Hz), 6.827(d, 1H,
J=8.4Hz), 6.468(dd, 1H, J=8.4, 2.4Hz), 6.385(d, 1H,
J=8.4Hz), 6.335(d, 1H, J=2.4Hz), 5.083(s, 1H), 4.387(m, 1H,
J=10.4, 3.2, 2.0Hz), 4.011(t, 1H, J=10.4Hz), 3.918(t, 2H,
J=6.4Hz), 3.484(m, 1H), 3.008(dd, 1H, J=15.6, 11.2Hz),
2.857(m, 1H, J=15.6, 3.6, 1.6Hz), 2.642(m, 2H), 1.806(m,
1H), 1.772(t, 2H, J=6.4Hz), 1.643(q, 2H, J=6.4Hz), 1.331(s,
3H), 1.316(s, 3H), 0.949(d, 6H, J=6.4Hz).
C-NMR (CDCl3): 158.881, 154.197, 152.861, 152.137,
128.120, 127.459, 119.736, 112.789, 109.288, 109.284,
106.724, 102.561, 73.700, 70.031, 66.431, 37.940, 32.345,
31.805, 30.710, 26.836, 26.434, 25.031, 22.573, 17.150.
Optical Rotation data
R-enantiomer- : -1.7° (c=0.001, methylene
chloride); and
S-enantiomer- : +1.5° (c=0.001, methylene
chloride).
M. P.
R-enantiomer: 164.7°C; and
S-enantiomer: 164.1°C.
Synthesis Example 5: Preparation of (R)(2,4-
dihyroxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-9a) and (S)
(2,4-dihyroxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-9b)
(R)- and (S)(2,4-dihydroxyphenyl)-8,8-dimethyl-
2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes with > 96 %ee
were synthesized by using 3-(2-benzyloxy
dihydroxyphenyl)-8,8-dimethyl-2,8-dihydropyrano[2,3-
f]chromene (Compound 5-11) synthesized in Preparation
Example 11 and the same method as in Synthesis Example 1,
1 13
respectively, and H-NMR, C-NMR, and optical rotation
results for the obtained Compounds are as follows.
H-NMR (DMSO-d6): 9.372(b, 1H), 9.117(b, 1H), 6.854(d,
1H, J=8.4Hz), 6.774(d, 1H, J=8.4Hz), 6.321(d, 1H, J=2.4Hz),
6.233(d, 1H, J=8.4Hz), 6.183(dd, 1H, J=8.4, 2.4Hz), 4.226(m,
1H, J=10.4, 2.8, 20Hz), 3.894(t, 1H, J=10.4Hz), 3.288(m,
1H), 2.897(dd, 1H, J=15.6, 11.6Hz), 2.673(ddd, 1H,
J=15.6Hz), 2.520(t, 2H, J=6.8Hz), 1.698(t, 2H, J=6.8Hz),
1.233(s, 6H).
C-NMR (DMSO-d6): 156.832, 155.862, 152.311, 151.702,
127.543, 127.368, 117.543, 112.893, 108.621, 108.464,
106.286, 102.499, 73.216, 69.717, 31.705, 30.978, 30.132,
26.442, 26.249, 16.839.
13C-NMR (CDCl3): 155.094, 154.575, 152.696, 152.038,
128.285, 127.498, 120.023, 112.956, 109.343, 107.765,
103.055, 73.881, 70.000, 32.285, 31.619, 30.477, 26.783,
26.403, 17.103.
Optical Rotation data
R-enantiomer- : -7.0° (c=0.025, ethanol); and
S-enantiomer- : +7.9° (c=0.025, ethanol).
Synthesis Example 6: Preparation of (R)(2-hydroxy-
4-ethylphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-13a) and (S)
(2-hydroxyethylphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-13b)
(R)- and (S)(2-benzyloxyethylphenyl)-8,8-
dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes
(Compounds 6-13a and 6-13b) were obtained by using 3-(2-
benzyloxyethylphenyl)-8,8-dimethyl-2,8-
dihydropyrano[2,3-f]chromene (Compound 5-18) synthesized in
Preparation Example 18 and the method in Synthesis Example
1 13
1-1, respectively. H-NMR and C-NMR results for the
obtained Compounds are as follows.
In addition, (R)- and (S)(2-hydroxy
ethylphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-
f]chromenes with > 96 %ee were synthesized from (R)- and
(S)(2-benzyloxyethylphenyl)-8,8-dimethyl-
2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes (Compounds 6-
13a and 6-13b), respectively, by using the same method as
1 13
in Synthesis Example 1-2, and H-NMR, C-NMR, and optical
rotation results for the obtained Compounds are as follows.
H-NMR (CDCl3): 7.28~7.45(m, 5H), 7.063(d, 1H,
J=8.0Hz), 6.827(d, 1H, J=8.0Hz), 6.817(s, 1H), 6.906(d, 1H,
J=8.0Hz), 6.376(d, 1H, J=8.0Hz), 5.104(s, 2H), 4.395(m, 1H,
J=10.4, 3.6, 2.0Hz), 4.024(t, 1H, J=10.4Hz), 3.710(m, 1H),
3.004(dd, 1H, J=15.6, 11.2Hz), 2.876(m, 1H, J=15.6, 5.2,
1.6Hz), 2.650(t, 2H, J=7.2Hz), 2.632(t, 2H, J=7.2Hz),
1.763(t, 2H, J=7.2Hz), 1.323(s, 3H), 1.313(s, 3H), 1.226(t,
2H, J=7.6Hz).
C-NMR (CDCl3): 156.350, 152.801, 152.217, 144.082,
137.160, 128.558, 127.778, 127.436, 127.331, 127.159,
127.107, 120.322, 112.897, 111.702, 109.250, 109.147,
73.611, 70.132, 70.015, 32.328, 31.619, 30.780, 28.802,
26.793, 26.488, 17.133, 15.483..
Synthesis Example 7: Preparation of (R)(2-hydroxy-
4-propylphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-14a) and (S)
(2-hydroxypropylphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (Compound I-14b)
(R)- and (S)(2-benzyloxypropylphenyl)-8,8-
dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes
(Compounds 6-14a and 6-14b) were synthesized by using 3-(2-
benzyloxypropylphenyl)-8,8-dimethyl-2,8-
dihydropyrano[2,3-f]chromene (Compound 5-21) synthesized in
Preparation Example 21 and the same method as in Synthesis
1 13
Example 1-1, respectively. H-NMR and C-NMR results for
the obtained Compounds are as follows.
H-NMR(CDCl3): 7.28~7.45(m, 5H), 7.052(d, 1H,
J=8.0Hz), 6.828(d, 1H, J=8.0Hz), 6.791(s, 1H), 6.784(d, 1H,
J=8.0Hz), 6.375(d, 1H, J=8.0Hz), 5.102(s, 2H), 4.395(m, 1H,
J=10.4, 3.6, 2.0Hz), 4.023(t, 1H, J=10.4Hz), 3.713(m, 1H),
3.003(dd, 1H, J=15.6, 11.2Hz), 2.876(m, 1H, J=15.6, 5.2,
1.6Hz), 2.632(t, 2H, J=6.8Hz), 2.554(t, 2H, J=7.6Hz),
1.766(t, 2H, J=6.8Hz), 1.626(m, 2H, J=7.6Hz), 1.325(s, 3H),
1.315(s, 3H), 0.937(t, 2H, J=7.6Hz).
C-NMR(CDCl3): 156.242, 152.786, 152.210, 142.542,
137.154, 128.549, 127.766, 127.435, 127.295, 127.154,
126.979, 120.981, 112.917, 112.244, 109.247, 109.128,
73.617, 70.139, 69.992, 38.015, 32.319, 31.605, 30.779,
26.793, 26.481, 24.489, 17.132, 13.892.
In addition, 10 g of (R)(2-hydroxy
propylphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene and 10 g of (S)(2-
hydroxypropylphenyl)-8,8-dimethyl-2,3,4,8,9,10-
hexahydropyrano[2,3-f]chromene (> 96 %ee) were synthesized
from (R)- and (S)(2-benzyloxypropylphenyl)-8,8-
dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromenes
(Compounds 6-14a and 6-14b), respectively, by using the
1 13
same method as in Synthesis Example 1-2, and H-NMR, C-NMR,
and optical rotation results for the obtained Compounds are
as follows.
H-NMR(CDCl3): 7.029(d, 1H, J=8.0Hz), 6.842(d, 1H,
J=8.0Hz), 6.755(d, 1H, J=8.0Hz), 6.597(s, 1H), 6.390(d, 1H,
J=8.4Hz), 4.804(s, 1H), 4.423(m, 1H, J=10.4, 2.4Hz),
4.046(t, 1H, J=10.4Hz), 3.537(m, 1H), 3.042(dd, 1H, J=15.6,
11.2Hz), 2.886(m, 1H), 2.652(m, 2H), 2.518(t, 2H, J=7.6Hz),
1.781(t, 2H, J=6.8Hz), 1.612(m, 2H, J=7.2Hz), 1.338(s, 3H),
1.323(s, 3H), 0.947(t, 3H, J=7.2Hz).
C-NMR(CDCl3): 153.296, 152.802, 152.143, 142.679,
127.463, 127.331, 124.838, 121.188, 115.572, 112.888,
109.322, 109.286, 73.749, 69.933, 37.502, 32.366, 32.149,
.605, 26.809, 26.411, 24.276, 17.141, 13.846.
Optical Rotation data
R-enantiomer- : -3.9° (c=0.025, ethanol); and
S-enantiomer- : +2.4° (c=0.025, ethanol).
When the methods disclosed in the Preparation
Examples, the Examples, and the Synthesis Examples are used,
it is possible to simply prepare a 3-phenyl-2,3,4,8,9,10—
hexahydropyrano[2,3-f]chromene derivative, or an optical
isomer thereof from a 3-phenyl-2,8-dihydropyrano[2,3-
f]chromene derivative through the hydrogen addition
reaction and the de-protecting process.
From the foregoing, the present invention has been reviewed
mainly based on the preferred examples thereof. A person
with ordinary skill in the art to which the present
invention pertains will be able to understand that the
present invention may be implemented in a modified form
without departing from the essential characteristics of the
present invention. Therefore, the disclosed examples
should be considered not from a restrictive viewpoint, but
from an explanatory viewpoint. The scope of the present
invention is defined not in the above-described explanation,
but in the claims, and it should be interpreted that all
the differences within a range equivalent thereto are
included in the present invention.
[
Claims (19)
- [Claim 1] A method for synthesizing a 3-phenyl-2,3,4,8,9,10- hexahydropyrano[2,3-f]chromene derivative of Chemical Formula (I), the method comprising: a) coupling a Compound represented by Chemical Formula 1 with a Compound represented by Chemical Formula 2 to form a Compound of Chemical Formula 3; b) reducing the Compound of Chemical Formula 3 to form a Compound of Chemical Formula 4; and c) cyclizing the Compound of Chemical Formula 4 to form a Compound of Chemical Formula 5: [Reaction Formula 1] wherein, R and R are each independently hydrogen atom; hydroxy group; straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; halogen atom; straight or branched C to C alkoxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C 1 5 1 to C thioalkyl group; straight or branched C to C 3 1 4 thioalkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; allyloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, 5 1 5 or straight or branched C to C thioalkyl group; or aryloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, straight or branched C 1 5 1 to C thioalkyl group;or phenyl group; R is hydrogen atom or C to C alkyl group or C to C 3 1 2 1 2 alkoxy group; R and R are each independently hydrogen atom or C 4 5 1 to C alkyl group; P is a protecting group selected from straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; benzyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, straight or branched C to C thioalkyl group, or nitro; allyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; tert-butyldimethylsilyl group; tert-butyldiphenylsilyl group; methylphenylsilyl group; trimethylphenylsilyl group; MeSO p-toluenesulfonyl and 2,4,6-trimethylbenzenesulfonyl; n is 1 to 3; and two or more OPs are the same or different from each other.
- [Claim 2] The method of claim 1, further comprising: reducing the Compound of Chemical Formula 5.
- [Claim 3] The method of claim 1, wherein the coupling in Step a) is performed under basic conditions.
- [Claim 4] The method of claim 3, wherein the basic conditions are created by adding one or more weak basic Compounds selected from a group consisting of sodium carbonate (Na CO ), lithium carbonate (Li CO ), potassium carbonate 2 3 2 3 (K CO ), sodium hydrogen carbonate (NaHCO ), potassium 2 3 3 hydrogen carbonate (KHCO ), triethylamine, and pyridine.
- [Claim 5] The method of claim 1, wherein the reducing in Step b) is carried out by adding any one or more reducing agents selected from a group consisting of L-Selectride, N- Selectride, K-Selectride, and LS-Selectride.
- [Claim 6] The method of claim 5, wherein the reducing agent is added at -10°C or less.
- [Claim 7] The method of claim 1, wherein the cyclizing in Step c) includes the following steps: i) dissolving the Compound of Chemical Formula 4 in acetonitrile and adding triphenylphosphonium bromide (Ph P•HBr) thereinto; ii) concentrating the resulting product in Step i); iii) dissolving the concentrate obtained in Step ii) and adding sodium ethoxide (NaOEt) thereinto.
- [Claim 8] A Compound represented by the following Chemical Formula 3, or a solvate thereof: [Chemical Formula 3] wherein, R and R are each independently hydrogen atom; hydroxy group; straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; halogen atom; straight or branched C to C alkoxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C 1 5 1 to C thioalkyl group; straight or branched C to C 3 1 4 thioalkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; allyloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, 5 1 5 or straight or branched C to C thioalkyl group; or aryloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, straight or branched C 1 5 1 to C thioalkyl group;or phenyl group; R is hydrogen atom or C to C alkyl group or C to C 3 1 2 1 2 alkoxy group; R and R are each independently hydrogen atom or C 4 5 1 to C alkyl group; P is a protecting group selected from straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; benzyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, straight or branched C to C thioalkyl group, or nitro; allyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; tert-butyldimethylsilyl group; tert-butyldiphenylsilyl group; methylphenylsilyl group; trimethylphenylsilyl group; MeSO p-toluenesulfonyl and 2,4,6-trimethylbenzenesulfonyl; n is 1 to 3; and two or more OPs are the same or different from each other.
- [Claim 9] A Compound represented by the following Chemical Formula 4, or a solvate thereof: [Chemical Formula 4] wherein, R and R are each independently hydrogen atom; hydroxy group; straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; halogen atom; straight or branched C to C alkoxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C 1 5 1 to C thioalkyl group; straight or branched C to C 3 1 4 thioalkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; allyloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, 5 1 5 or straight or branched C to C thioalkyl group; or aryloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; or phenyl group; R is hydrogen atom or C to C alkyl group or C to C 3 1 2 1 2 alkoxy group; R and R are each independently hydrogen atom or C 4 5 1 to C alkyl group; P is a protecting group selected from straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; benzyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, straight or branched C to C thioalkyl group, or nitro; allyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; tert-butyldimethylsilyl group; tert-butyldiphenylsilyl group; methylphenylsilyl group; trimethylphenylsilyl group; MeSO p-toluenesulfonyl and 2,4,6-trimethylbenzenesulfonyl ; n is 1 to 3; and two or more OPs are the same or different from each other.
- [Claim 10] A 3-phenyl-2,8-dihydropyrano[2,3-f]chromene Compound represented by the following Chemical Formula 5-1, or a solvate thereof: [Chemical Formula 5-1] wherein, R and R are each independently hydrogen atom; hydroxy group; straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; halogen atom; straight or branched C to C alkoxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C 1 5 1 to C thioalkyl group; straight or branched C to C 3 1 4 thioalkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; allyloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, 5 1 5 or straight or branched C to C thioalkyl group; or aryloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, straight or branched C 1 5 1 to C thioalkyl group; or phenyl group; R is hydrogen atom or C to C alkyl group or C to C 3 1 2 1 2 alkoxy group; R and R are each independently hydrogen atom or C 4 5 1 to C alkyl group; P is a protecting group selected from benzyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, straight or branched C to C thioalkyl group, or nitro; allyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; tert-butyldimethylsilyl group; tert-butyldiphenylsilyl group; methylphenylsilyl group; trimethylphenylsilyl group and 2,4,6- trimethylbenzenesulfonyl.
- [Claim 11] A method for synthesizing an optical isomer of a 3- phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative of Chemical Formula (I), the method comprising: A) coupling a Compound represented by Chemical Formula 1 with a Compound represented by Chemical Formula 2 to form a Compound of Chemical Formula 3; B) reducing the Compound of Chemical Formula 3 to form a Compound of Chemical Formula 4; C) cyclizing the Compound of Chemical Formula 4 to form a Compound of Chemical Formula 5; and D) subjecting the Compound represented by Chemical Formula 5 to an asymmetric hydrogenation reaction to form an optical isomer Compound of Chemical Formula 6a (R-form) or 6b (S-form): [Reaction Formula 2] wherein, R and R are each independently hydrogen atom; hydroxy group; straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; halogen atom; straight or branched C to C alkoxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C 1 5 1 to C thioalkyl group; straight or branched C to C 3 1 4 thioalkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; allyloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, 5 1 5 or straight or branched C to C thioalkyl group; or aryloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, straight or branched C 1 5 1 to C thioalkyl group; or phenyl group; R is hydrogen atom or C to C alkyl group or C to C 3 1 2 1 2 alkoxy group; R and R are each independently hydrogen atom or C 4 5 1 to C alkyl group; P is a protecting group selected from straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; benzyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, straight or branched C to C thioalkyl group, or nitro; allyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; tert-butyldimethylsilyl group; tert-butyldiphenylsilyl group; methylphenylsilyl group; trimethylphenylsilyl group; MeSO p-toluenesulfonyl and 2,4,6-trimethylbenzenesulfonyl;; n is 1 to 3; and two or more OPs are the same or different from each other.
- [Claim 12] The method of claim 11, wherein the coupling in Step A) is performed under basic conditions.
- [Claim 13] The method of claim 12, wherein the basic conditions are created by adding one or more weak basic Compounds selected from a group consisting of sodium carbonate (Na CO ), lithium carbonate (Li CO ), potassium carbonate 2 3 2 3 (K CO ), sodium hydrogen carbonate (NaHCO ), potassium 2 3 3 hydrogen carbonate (KHCO ), triethylamine, and pyridine.
- [Claim 14] The method of claim 11, wherein the reducing in Step B) is carried out by adding any one or more reducing agents selected from a group consisting of L-Selectride, N- Selectride, K-Selectride, and LS-Selectride.
- [Claim 15] The method of claim 14, wherein the reducing agent is added at -10°C or less.
- [Claim 16] The method of claim 11, wherein the cyclization reaction in Step C) includes the following steps: i) dissolving the Compound of Chemical Formula 4 in acetonitrile and adding triphenylphosphonium bromide (Ph P•HBr) thereinto; ii) concentrating the resulting product in Step i); iii) dissolving the concentrate obtained in Step ii) and adding sodium ethoxide (NaOEt) thereinto.
- [Claim 17] The method of claim 11, wherein the asymmetric hydrogenation reaction in Step D) is a reaction caused by adding a chiral ligand.
- [Claim 18] The method of claim 17, wherein the chiral ligand is any one selected from the group consisting of a phospholane ligand, a SimplePHOX ligand, a PHOX ligand, and UbaPHOX.
- [Claim 19] An optical isomer Compound represented by the following Chemical Formula 6a-1 (R-form) or 6b-1 (S-form), or a solvate thereof: [Chemical Formula 6a-1] [Chemical Formula 6b-1] wherein, R and R are each independently hydrogen atom; straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, 5 1 5 or straight or branched C to C thioalkyl group; halogen atom; straight or branched C to C alkoxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; straight or branched C to C thioalkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; allyloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; or aryloxy group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, or straight or branched C to C thioalkyl group; or phenyl group; R is hydrogen atom or C to C alkyl group or C to C 3 1 2 1 2 alkoxy group; R and R are each independently hydrogen atom or C 4 5 1 to C alkyl group; P is a protecting group selected from straight or branched C to C alkyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; benzyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C 1 5 1 5 alkoxy group, straight or branched C to C thioalkyl group, or nitro; allyl group unsubstituted or substituted with halogen atom, straight or branched C to C alkyl group, straight or branched C to C alkoxy group, or straight or branched C to C thioalkyl group; tert-butyldimethylsilyl group; tert-butyldiphenylsilyl group; methylphenylsilyl group; trimethylphenylsilyl group; MeSO , p-toluenesulfonyl and 2,4,6-trimethylbenzenesulfonyl.
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PCT/KR2017/010679 WO2018066872A1 (en) | 2016-10-04 | 2017-09-27 | 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative and method for synthesizing optical isomer thereof |
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