CN112010882A - 立体选择性制备1,3-双取代环己烷类化合物的方法及应用 - Google Patents
立体选择性制备1,3-双取代环己烷类化合物的方法及应用 Download PDFInfo
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- CN112010882A CN112010882A CN201910470693.3A CN201910470693A CN112010882A CN 112010882 A CN112010882 A CN 112010882A CN 201910470693 A CN201910470693 A CN 201910470693A CN 112010882 A CN112010882 A CN 112010882A
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- disubstituted
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- -1 1, 3-disubstituted cyclohexane compounds Chemical class 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- UVJHQYIOXKWHFD-UHFFFAOYSA-N cyclohexa-1,4-diene Chemical compound C1C=CCC=C1 UVJHQYIOXKWHFD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 229910052751 metal Inorganic materials 0.000 claims abstract description 14
- 239000002184 metal Substances 0.000 claims abstract description 14
- 239000000654 additive Substances 0.000 claims abstract description 13
- 230000000996 additive effect Effects 0.000 claims abstract description 13
- 238000004440 column chromatography Methods 0.000 claims abstract description 13
- 150000001502 aryl halides Chemical class 0.000 claims abstract description 12
- 230000000707 stereoselective effect Effects 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 7
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000009466 transformation Effects 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 3
- 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract 2
- 125000000217 alkyl group Chemical class 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 19
- 239000011541 reaction mixture Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 13
- 125000002252 acyl group Chemical class 0.000 claims description 11
- 229910000077 silane Inorganic materials 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000011261 inert gas Substances 0.000 claims description 8
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 8
- 150000004756 silanes Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000002813 thiocarbonyl group Chemical class *C(*)=S 0.000 claims description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims description 2
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000003003 phosphines Chemical class 0.000 claims description 2
- 150000008039 phosphoramides Chemical class 0.000 claims description 2
- 150000008300 phosphoramidites Chemical class 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000007970 thio esters Chemical group 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000003368 amide group Chemical class 0.000 claims 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 1
- 125000005587 carbonate group Chemical group 0.000 claims 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims 1
- 125000001240 enamine group Chemical group 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 150000002611 lead compounds Chemical class 0.000 abstract description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 9
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 8
- 239000001632 sodium acetate Substances 0.000 description 7
- 235000017281 sodium acetate Nutrition 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 4
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 3
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 2
- 150000001934 cyclohexanes Chemical class 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 1
- JZJWCDQGIPQBAO-UHFFFAOYSA-N 1-(4-iodophenyl)ethanone Chemical compound CC(=O)C1=CC=C(I)C=C1 JZJWCDQGIPQBAO-UHFFFAOYSA-N 0.000 description 1
- NXYICUMSYKIABQ-UHFFFAOYSA-N 1-iodo-4-phenylbenzene Chemical group C1=CC(I)=CC=C1C1=CC=CC=C1 NXYICUMSYKIABQ-UHFFFAOYSA-N 0.000 description 1
- ONZHMGRKWJMTDE-UHFFFAOYSA-N 3-chloro-4-iodoaniline Chemical compound NC1=CC=C(I)C(Cl)=C1 ONZHMGRKWJMTDE-UHFFFAOYSA-N 0.000 description 1
- GHICCUXQJBDNRN-UHFFFAOYSA-M 4-iodobenzoate Chemical compound [O-]C(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-M 0.000 description 1
- XOKDXPVXJWTSRM-UHFFFAOYSA-N 4-iodobenzonitrile Chemical compound IC1=CC=C(C#N)C=C1 XOKDXPVXJWTSRM-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- GYZOIIIWBFUCDF-UHFFFAOYSA-N B(O)O.OC(C)(C)C(C)(C)O.B(O)O Chemical compound B(O)O.OC(C)(C)C(C)(C)O.B(O)O GYZOIIIWBFUCDF-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- INBXHFRQITUXGJ-UHFFFAOYSA-N diazidoazaniumylideneazanide Chemical group [N-]=[N+]=N[N+](=[N-])N=[N+]=[N-] INBXHFRQITUXGJ-UHFFFAOYSA-N 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 150000002081 enamines Chemical group 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical group O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
- C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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Abstract
本发明公开了一种立体选择性制备1,3‑双取代环己烷类化合物的方法及应用。所述1,3‑双取代环己烷类化合物的结构式为
所述方法包括：在金属钯类催化剂PdA、碱和添加剂作用下，将1,4‑环己二烯、芳基卤代物R1‑X与联硼酸频哪醇酯溶于有机溶剂中并进行反应，经柱层析分离纯化得到上述结构的1,3‑双取代环己烷类化合物。本发明方法可高效合成上述结构的1,3‑双取代环己烷类化合物，具有优秀的区域选择性和立体选择性，且产物中含有硼基团，可应用于进一步进行立体专一性转化，从而产生各种高度官能团化的环己烷类化合物，为合成复杂药物分子及药物先导化合物提供了新方法。
Description
技术领域
本发明属于有机合成领域，具体涉及一种立体选择性制备1,3-双取代环己烷 类化合物的方法及应用。
背景技术
1,3-双取代的环己烷类有机化合物广泛存在于天然产物及药物分子中[a)L.S.Melvin,M.R.Johnson,C.A.Harbert,G.M.Milne,A.Weissman,J.Med.Chem. 1984,27,67-71；b)R.M.Soll,L.G.Humber,D.Deininger,A.A.Asselin,T.T.Chau, B.M.Weichman,J.Med.Chem.1986,29,1457-1460；c)S.Tsuchiya,N.Yasuda,T. Matsumoto,K.Hiratsuka,H.Iizuka,A.Hukuzaki,K.Matsunaga,WO 97/15549 A1, 1997；d)J.L.Wiley,I.D.Beletskaya,E.W.Ng,Z.M.Dai,P.J.Crocker,A. Mahadevan,R.K.Razdan,B.R.Martin,J.Pharmacol.Exp.Ther.2002,301, 679-689；e)J.W.Huffman,A.L.Thompson,J.L.Wiley,B.R.Martin,Bioorg.Med. Chem.2008,16,322-335；f)P.Kare,J.Bhat,M.E.Sobhia,MolDivers 2013,17, 111-122；g)P.T.W.Cheng,D.S.Yoon,WO 2016/040225 A1,2016]。
目前，合成1,3-双取代的环己烷类有机化合物的通用方法：芳基试剂先对环 己烯酮进行1,4-加成反应，其次对羰基进行还原得到目标化合物[a)J.W.Huffman,A.L.Thompson,J.L.Wiley,B.R.Martin,Bioorg.Med.Chem.2008,16,322-335；b)H.Tajuddin,L.Shukla,A.C.Maxwell,T.B.Marder,P.G.Steel,Org.Lett.2010,12, 5700-5703；c)S.Llona-Minguez,S.P.Mackay,Beilstein J.Org.Chem.2014,10, 1333-1338；d)L.M.Martinez-Prieto,A.Ferry,L.Rakers,C.Richter,P.Lecante,K. Philippot,B.Chaudret,F.Glorius,Chem.Commun.2016,52,4768-4771]。尽管芳基 试剂可以对环己烯酮高选择性的进行1,4-加成反应，但随后环己酮的还原反应， 目前还无法控制其非对映体选择性，导致合成的环己烷类化合物存在顺反两种构 型，不易分离，而且得到的1,3-双取代环己烷化合物结构单一，不符合化学合成 的多样性，无法满足现代高通量药物筛选的需求。
因此，一种更为可行的思路是通过研究寻找一种具有高区域选择性和非对映 选择性并且能高效合成1,3-双取代的环己烷类有机化合物方法。
发明内容
本发明的目的之一在于提供一种立体选择性制备1,3-双取代环己烷类化合物 的方法，该方法操作简便，原料廉价易得，底物官能团兼容性好，具有优秀的区 域选择性和非对映体选择性。
本发明的目的之二在于提供上述立体选择性制备1,3-双取代环己烷类化合物 的方法的应用，应用于进行立体专一性转化，产生各种高度官能团化的环己烷类 化合物，为合成复杂药物分子及药物先导化合物提供了新方法。
本发明实现上述目的之一采用以下技术方案：
一种立体选择性制备1,3-双取代环己烷类化合物的方法，所述1,3-双取代环 己烷类化合物的结构式如下：
所述立体选择性制备上述结构式的1,3-双取代环己烷类化合物的方法包括 以下步骤：在金属钯类催化剂PdA、碱和添加剂作用下，将1,4-环己二烯、芳基 卤代物R1-X与联硼酸频哪醇酯溶于有机溶剂中并进行反应，经柱层析分离纯化 得到上述结构的1,3-双取代环己烷类化合物；
所述方法合成路线如下：
所述R1为取代或未取代芳环化合物及杂芳环化合物，所述的取代芳环化合 物及杂芳环化合物的取代基为任意以下结构的一种或几种：卤素、羟基、巯基、 烷氧基、酚氧基、烷硫基、酚硫基、烷基取代的酰基、芳基取代的酰基、烷氧基 取代的酰基、酚氧基取代的酰基、烷基取代的硫代羰基、芳基取代的硫代羰基、 烷氧基取代的硫代羰基、酚氧基取代的硫代羰基、烷基或者芳基取代的酰胺基、 烷基或者芳基取代的酯基、烷基或者芳基取代的硫酯基、烷基或者芳基取代的碳 酸酯基、烷基或者芳基取代的硫代碳酸酯基、氰基、异氰基、硝基、亚硝基、烷 基或者芳基取代的偶氮、重氮、叠氮、烷基或者芳基取代的胺、烷基或者芳基取 代的亚胺、烷基或者芳基取代的烯胺、烷基或者芳基取代的膦、烷基或者芳基取 代的亚磷酸酯、烷基或者芳基取代的亚磷酰胺、烷基或者芳基取代的磷酸酯、烷 基或者芳基取代的磷酰胺、硼烷、烷基或者芳基取代的硼烷、硼酸、硼酸酯、硼 酸盐、硅烷、烷基取代的硅烷、烷氧基取代的硅烷、酚氧基取代的硅烷、卤素取 代的硅烷，或者是取代的链状或者环状的烷烃、含氟烷烃、烯烃、芳烃、芳杂环 结构单元，或者是含氧、氮、硫、膦的C3-C12的杂环；所述X为原子溴或者碘。
所述上述结构式的1,3-双取代环己烷类化合物的制备方法具体步骤如下：
在惰性气体中，将金属钯类催化剂PdA、碱、添加剂和联硼酸频哪醇酯溶于 干燥的有机溶剂中，然后加入1,4-环己二烯和芳基卤代物R1-X，得到反应混合 物，随后将上述反应混合物密封并从惰性气体中取出，反应完全后，减压浓缩除 去有机溶剂，再经柱层析分离纯化得到目标产物1,3-双取代环己烷类化合物
其中，金属钯类催化剂PdA：碱：添加剂：1,4-环己二烯：芳基卤代物R1-X： 联硼酸频哪醇酯：有机溶剂的用量比为摩尔：摩尔：摩尔：摩尔：摩尔：摩尔： 体积mL＝0.05：2：1：3：1：1：2。
所述的金属钯类催化剂PdA中，A为Cl–、[CH3COO]–、[CF3COO]–、[acac]–、 PPh3、二亚苄基丙酮中的任一种。
所述的碱，其阳离子为Li+、Na+、K+和Cs+中的任一种，阴离子为F–、CO3 2–、 HCO3 –、PO4 3–、HPO4 2–、H2PO4 –、OH–、[CH3COO]–、[CF3COO]–、[OMe]–和[OtBu]– 中的任一种。
所述的添加剂，其阳离子为Li+、Na+、K+、Cs+、Mg2+、Ca2+、Cu+、Cu2+、 Zn2+，Ag+、[(CnH2n+1)4N]+中的任一种，阴离子为F–、Cl–、Br–、I–、BF4 –、 NO2 –、NO3 –、SO3 2–、SO4 2–中的任一种；其中，所述n为1到8之间的任意整数。
所述的有机溶剂为甲醇、乙醇、异丙醇、四氢呋喃、2-甲基四氢呋喃、1,4- 二氧六环、乙醚、甲基叔丁基醚、乙二醇二甲醚、N-甲基吡咯烷酮、N,N-二甲基 甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、二氯甲烷、1,2-二氯乙烷、氯仿、四 氯化碳、苯、甲苯、二甲苯、三甲苯、氯苯、1,2-二氯苯、丙酮、乙腈、C3-C12的饱和烷基腈中的一种或几种。
本发明实现目的之二采用以下技术方案：
一种所述立体选择性制备1,3-双取代环己烷类化合物的方法的应用，其特征 在于：应用于进行立体专一性转化，产生高度官能团化的环己烷类化合物，所述 应用包括以下步骤：
将所述1,3-双取代环己烷类化合物
在NaOH和H2O2作用 下，在四氢呋喃溶剂中继续进行反应，制得高度官能团化的1,3-双取代环己烷 类化合物
所述应用的路线如下：
所述应用具体步骤如下：
1)在惰性气体中，将金属钯类催化剂PdA、碱、添加剂和联硼酸频哪醇酯 溶于干燥的有机溶剂中，然后加入1,4-环己二烯和芳基卤代物R1-X，得到反应 混合物，随后将上述反应混合物密封并从惰性气体中取出，反应完全后得到反应 液Ⅰ；
2)将所述反应液Ⅰ用硅藻土过滤，然后用乙酸乙酯洗涤并浓缩，将得到的 浓缩混合物溶于四氢呋喃中，得到反应液Ⅱ，然后在0℃下，向反应液Ⅱ中加入 一定量的2M NaOH水溶液和30％H2O2溶液，然后将反应温度升至室温，并搅 拌均一，待反应结束后，用饱和Na2S2O3淬灭，再用乙酸乙酯萃取，然后合并有 机层并减压浓缩除去溶剂，再经柱层析分离纯化得到目标产物
其中，金属钯类催化剂PdA：碱：添加剂：1,4-环己二烯：芳基卤代物R1-X： 联硼酸频哪醇酯：有机溶剂：四氢呋喃：2M NaOH水溶液：30％H2O2溶液的用 量比为摩尔：摩尔：摩尔：摩尔：摩尔：摩尔：体积mL：体积mL：体积mL： 体积mL＝0.05：2：1：3：1：1：2：10：6：3。
与现有技术相比，本发明具有以下有益效果：
本发明公开的立体选择性制备1,3-双取代环己烷类化合物的方法，使用1,4- 环己二烯，芳基卤代物和联硼酸频哪醇酯，在金属钯催化剂作用下，一锅法反应 制备顺式环己烷1,3-芳硼化的有机化合物，该反应方法不但可以高效的合成目标 化合物，而且底物适用性强，具有优秀的区域选择性和立体选择性，此方法所使 用的原料廉价易得，操作简便，底物官能团兼容性好，可以高效的合成环己烷-1， 3-芳硼化产物。
同时，本发明所述方法的应用，上述立体选择性制备1,3-双取代环己烷类化 合物的方法合成的产物中含有硼基团，其可以进一步进行立体专一性转化，目标 化合物进行进一步立体选择性转化，简单高效的合成其它官能团化的1,3-双取代 的环己烷类有机化合物，为合成复杂药物分子及药物先导化合物提供了新方法。
具体实施方式
通过以下详细说明可以进一步理解本发明的特点和优点。所提供的实施例仅 是对本发明方法的说明，而不以任何方式限制本发明揭示的其余内容。
下述实施例中，具体操作未涉及温度的，均是指室温下进行。
RT是指室温。B2pin2是指联硼酸频哪醇酯，结构式为
Pd(acac)2是指二(乙酰丙酮)钯。NaOAc是指乙酸钠，Me4NCl是指四甲基氯化铵。 CHCl3是指氯仿。THF是指四氢呋喃。
【实施例1】
在充满氩气的手套箱中，将二(乙酰丙酮)钯(7.6mg，0.025mmol)、乙酸钠(82.0mg，1.0mmol)、四甲基氯化铵(54.8mg，0.5mmol)、联硼酸频哪醇酯 (127mg，0.5mmol)和4-氰基碘苯(114.5mg，0.5mmol)溶于1mL干燥的 氯仿溶剂中，然后加入1,4-环己二烯(142μL，1.5mmol)，将反应管密封并从手 套箱中取出，在60℃下反应24小时。反应结束后，减压浓缩除去反应溶剂， 柱层析分离纯化得到cis-3'-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1'，2'， 3'，6'-四氢-[1,1'-联苯]-4-甲腈(无色油，产率50％)。1H NMR(400MHz, Chloroform-d)δ7.57(d,J＝7.9Hz,2H),7.32(d,J＝7.9Hz,2H),5.81-5.74(m,2H),2.91-2.73(m,1H),2.29-2.09(m,2H),2.07-1.92(m,2H),1.75-1.65(m,1H), 1.23(s,12H)ppm；13C NMR(101MHz,Chloroform-d)δ153.1,132.3,127.9,127.4, 125.4,119.3,109.8,83.5,41.2,32.8,31.3,24.9ppm；HRMS(ESI)calculated for C19H24BNNaO2[M+Na]+:332.1792,found 332.1820.
【实施例2】
在充满氩气的手套箱中，将二(乙酰丙酮)钯(7.6mg，0.025mmol)、乙酸钠(82.0mg，1.0mmol)、四甲基氯化铵(54.8mg，0.5mmol)、联硼酸频哪醇酯 (127mg，0.5mmol)和3-氯-4-碘苯胺(126.7mg，0.5mmol)溶于1mL干燥 的氯仿溶剂中，然后加入1,4-环己二烯(142μL，1.5mmol)，将反应管密封并从 手套箱中取出，在60℃下反应24小时。反应结束后，减压浓缩除去反应溶剂， 柱层析分离纯化得到cis-2-氯-3'-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1'， 2'，3'，6'-四氢-[1,1'-联苯基]-4-胺(白色固体，产率84％)。1HNMR(400MHz, Chloroform-d)δ7.02(d,J＝8.3Hz,1H),6.68(d,J＝2.4Hz,1H),6.54(dd,J＝8.3, 2.4Hz,1H),5.82-5.72(m,2H),3.62(s,2H),3.22-3.08(m,1H),2.30-2.18(m,1H),2.10-2.00(m,2H),1.98-1.91(m,1H),1.64(q,J＝12.0Hz,1H),1.24(s,12H)ppm； 13C NMR(101MHz,Chloroform-d)δ145.2,134.1,134.0,127.9,127.1,126.3,115.7, 114.1,83.3,36.0,31.9,30.8,24.8,24.8ppm；HRMS(ESI)calculated for C18H26BClNO2[M+H]+:334.1740,found 334.1765.
【实施例3】
在充满氩气的手套箱中，将二(乙酰丙酮)钯(7.6mg，0.025mmol)、乙酸钠(82.0mg，1.0mmol)、四甲基氯化铵(54.8mg，0.5mmol)、联硼酸频哪醇酯 (127mg，0.5mmol)和4-碘联苯(140mg，0.5mmol)溶于1mL干燥的氯仿 溶剂中，然后加入1,4-环己二烯(142μL，1.5mmol)，将反应管密封并从手套箱 中取出，在60℃下反应24小时。反应结束后，减压浓缩除去反应溶剂，柱层 析分离纯化得到4,4,5,5-四甲基-2-(cis-1,2,3,6-四氢-[1,1'：4'，1”-三联苯]-3-基) -1,3,2-二氧杂硼烷(白色固体，产率62％)。1H NMR(400MHz,Chloroform-d)δ 7.60(d,J＝7.6Hz,2H),7.55(d,J＝8.0Hz,2H),7.45(t,J＝7.5Hz,2H),7.34(t,J＝ 7.4Hz,3H),5.87-5.81(m,2H),2.88-2.82(m,1H),2.37-2.22(m,2H),2.09(d,J＝ 8.2Hz,2H),1.78(q,J＝13.2Hz,1H),1.27(s,12H)ppm；13C NMR(101MHz, Chloroform-d)δ146.7,141.3,139.0,128.8,127.5,127.3,127.2,127.1,127.1,126.2, 83.4,40.6,33.1,31.9,24.9,24.9ppm；HRMS(ESI)calculated for C24H29BNaO2[M +Na]+:383.2153,found383.2161.
【实施例4】
在充满氩气的手套箱中，将二(乙酰丙酮)钯(7.6mg，0.025mmol)、乙酸钠(82.0mg，1.0mmol)、四甲基氯化铵(54.8mg，0.5mmol)、联硼酸频哪醇酯 (127mg，0.5mmol)和4-碘苯甲醚(117.0mg，0.5mmol)溶于1mL干燥的氯 仿溶剂中，然后加入1,4-环己二烯(142μL，1.5mmol)，将反应管密封并从手套 箱中取出，在60℃下反应24小时。反应结束后，减压浓缩除去反应溶剂，柱 层析分离纯化得到cis-4'-甲氧基-1,2,3,6-四氢-[1,1'-联苯]-3-基)-4,4,5,5-四甲基 -1,3,2-二氧杂硼杂环戊烷(白色固体，产率67％)。1H NMR(400MHz, Chloroform-d)δ7.23–7.17(m,2H),6.92–6.86(m,2H),5.88–5.79(m,2H),3.82(s,3H),2.85–2.70(m,1H),2.33–2.15(m,2H),2.14–2.01(m,2H),1.80–1.67(m, 1H),1.29(s,12H)ppm；13C NMR(101MHz,Chloroform-d)δ157.8,139.6,127.8, 127.1,126.2,113.7,83.2,55.2,40.0,33.3,32.0,24.8,24.8ppm.HRMS(ESI) calculated for C19H27BNaO3[M+Na]+:337.1945,found 337.1951.
【实施例5】
在充满氩气的手套箱中，将二(乙酰丙酮)钯(7.6mg，0.025mmol)、乙酸钠(82.0mg，1.0mmol)、四甲基氯化铵(54.8mg，0.5mmol)、联硼酸频哪醇酯 (127mg，0.5mmol)和对碘苯甲酸甲酯(140mg，0.5mmol)溶于1mL干燥 的氯仿溶剂中，然后加入1,4-环己二烯(142μL，1.5mmol)，将反应管密封并从 手套箱中取出，在60℃下反应24小时。反应结束后，将反应液用硅藻土过滤， 用乙酸乙酯洗涤并浓缩，将得到的混合物溶于5mL四氢呋喃中，然后在0℃下， 向反应液中加入3.0mL 2M的NaOH水溶液和1.5mL 30％H2O2溶液，将反应温 度升至室温，搅拌2-3小时，待反应结束后，用饱和Na2S2O3淬灭，用30mL乙 酸乙酯分三次萃取，合并有机层并减压浓缩，柱层析分离纯化得到cis-3'-羟基-1'， 2'，3'，6'-四氢-[1,1'-联苯]-4-羧酸甲酯(白色固体，产率82％)。1H NMR(400MHz, Chloroform-d)δ8.00(d,J＝8.4Hz,2H),7.30(d,J＝8.2Hz,2H),5.88-5.82(m, 1H),5.82-5.76(m,1H),4.50(s,1H),3.92(s,3H),3.08-2.90(m,1H),2.37-2.23 (m,2H),2.23-2.04(m,2H),1.85-1.69(m,1H)ppm；13C NMR(101MHz, Chloroform-d)δ167.2,151.0,131.3,130.0,128.3,128.2,126.9,68.3,52.2,39.4, 39.1,33.5ppm；HRMS(ESI)calculated for C14H16NaO3[M+Na]+:255.0992,found. 255.0993.
【实施例6】
在充满氩气的手套箱中，将二(乙酰丙酮)钯(7.6mg，0.025mmol)、乙酸钠(82.0mg，1.0mmol)、四甲基氯化铵(54.8mg，0.5mmol)、联硼酸频哪醇酯 (127mg，0.5mmol)和4-碘苯乙酮(123.0mg，0.5mmol)溶于1mL干燥的 氯仿溶剂中，然后加入1,4-环己二烯(142μL，1.5mmol)，将反应管密封并从手 套箱中取出，在60℃下反应24小时。反应结束后，将反应液用硅藻土过滤， 用乙酸乙酯洗涤并浓缩，将得到的混合物溶于5mL四氢呋喃中，然后在0℃下， 向反应液中加入3.0mL 2M的NaOH水溶液和1.5mL 30％H2O2溶液，将反应温 度升至室温，搅拌2-3小时，待反应结束后，用饱和Na2S2O3淬灭，用30mL乙 酸乙酯分三次萃取，合并有机层并减压浓缩，柱层析分离纯化得到1-(cis-3'-羟 基-1'，2'，3'，6'-四氢-[1,1'-联苯]-4-基)乙-1-酮(白色固体，产率82％)。1H NMR (400MHz,Chloroform-d)δ7.91(d,J＝8.4Hz,2H),7.31(d,J＝8.2Hz,2H),5.89- 5.81(m,1H),5.81-5.74(m,1H),4.58-4.42(m,1H),3.07-2.90(m,1H),2.59(s, 3H),2.37-2.22(m,2H),2.22-2.04(m,1H),1.85(d,J＝6.4Hz,1H),1.80-1.71(m, 1H)ppm；13C NMR(101MHz,Chloroform-d)δ198.0,151.3,135.6,131.3,128.9, 128.3,127.1,68.3,39.4,39.1,33.5,26.7ppm；HRMS(ESI)calculated forC14H16NaO2[M+Na]+:239.1043,found 239.1043.
以下【实施例7】-【实施例27】均以上述【实施例1】-【实施例6】的方 法步骤进行，合成得到的化合物结构和名称、NMR与HRMS数据及产率如下表 所示：
Claims (9)
1.一种立体选择性制备1,3-双取代环己烷类化合物的方法，其特征在于：
所述1,3-双取代环己烷类化合物的结构式如下：
所述立体选择性制备上述结构式的1,3-双取代环己烷类化合物的方法包括以下步骤：在金属钯类催化剂PdA、碱和添加剂作用下，将1,4-环己二烯、芳基卤代物R1-X与联硼酸频哪醇酯溶于有机溶剂中并进行反应，经柱层析分离纯化得到上述结构的1,3-双取代环己烷类化合物；
所述方法合成路线如下：
2.如权利要求1所述的立体选择性制备1,3-双取代环己烷类化合物的方法，其特征在于：所述R1为取代或未取代芳环化合物及杂芳环化合物，所述的取代芳环化合物及杂芳环化合物的取代基为任意以下结构的一种或几种：卤素、羟基、巯基、烷氧基、酚氧基、烷硫基、酚硫基、烷基取代的酰基、芳基取代的酰基、烷氧基取代的酰基、酚氧基取代的酰基、烷基取代的硫代羰基、芳基取代的硫代羰基、烷氧基取代的硫代羰基、酚氧基取代的硫代羰基、烷基或者芳基取代的酰胺基、烷基或者芳基取代的酯基、烷基或者芳基取代的硫酯基、烷基或者芳基取代的碳酸酯基、烷基或者芳基取代的硫代碳酸酯基、氰基、异氰基、硝基、亚硝基、烷基或者芳基取代的偶氮、重氮、叠氮、烷基或者芳基取代的胺、烷基或者芳基取代的亚胺、烷基或者芳基取代的烯胺、烷基或者芳基取代的膦、烷基或者芳基取代的亚磷酸酯、烷基或者芳基取代的亚磷酰胺、烷基或者芳基取代的磷酸酯、烷基或者芳基取代的磷酰胺、硼烷、烷基或者芳基取代的硼烷、硼酸、硼酸酯、硼酸盐、硅烷、烷基取代的硅烷、烷氧基取代的硅烷、酚氧基取代的硅烷、卤素取代的硅烷，或者是取代的链状或者环状的烷烃、含氟烷烃、烯烃、芳烃、芳杂环结构单元，或者是含氧、氮、硫、膦的C3-C12的杂环；所述X为原子溴或者碘。
3.如权利要求1或2所述的立体选择性制备1,3-双取代环己烷类化合物的方法，其特征在于：所述上述结构式的1,3-双取代环己烷类化合物的制备方法具体步骤如下：
在惰性气体中，将金属钯类催化剂PdA、碱、添加剂和联硼酸频哪醇酯溶于干燥的有机溶剂中，然后加入1,4-环己二烯和芳基卤代物R1-X，得到反应混合物，随后将上述反应混合物密封并从惰性气体中取出，反应完全后，减压浓缩除去有机溶剂，再经柱层析分离纯化得到目标产物1,3-双取代环己烷类化合物
其中，金属钯类催化剂PdA：碱：添加剂：1,4-环己二烯：芳基卤代物R1-X：联硼酸频哪醇酯：有机溶剂的用量比为摩尔：摩尔：摩尔：摩尔：摩尔：摩尔：体积mL＝0.05：2：1：3：1：1：2。
4.如权利要求1所述的立体选择性制备1,3-双取代环己烷类化合物的方法，其特征在于：所述的金属钯类催化剂PdA中，A为Cl–、[CH3COO]–、[CF3COO]–、[acac]–、PPh3、二亚苄基丙酮中的任一种。
5.如权利要求1所述的立体选择性制备1,3-双取代环己烷类化合物的方法，其特征在于：所述的碱，其阳离子为Li+、Na+、K+和Cs+中的任一种，阴离子为F–、CO3 2–、HCO3 –、PO4 3–、HPO4 2–、H2PO4 –、OH–、[CH3COO]–、[CF3COO]–、[OMe]–和[OtBu]–中的任一种。
6.如权利要求1所述的立体选择性制备1,3-双取代环己烷类化合物的方法，其特征在于：所述的添加剂，其阳离子为Li+、Na+、K+、Cs+、Mg2+、Ca2+、Cu+、Cu2+、Zn2+，Ag+、[(CnH2n+1)4N]+中的任一种，阴离子为F–、Cl–、Br–、I–、BF4 –、NO2 –、NO3 –、SO3 2–、SO4 2–中的任一种；其中，所述n为1到8之间的任意整数。
7.如权利要求1所述的立体选择性制备1,3-双取代环己烷类化合物的方法，其特征在于：所述的有机溶剂为甲醇、乙醇、异丙醇、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙醚、甲基叔丁基醚、乙二醇二甲醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、苯、甲苯、二甲苯、三甲苯、氯苯、1,2-二氯苯、丙酮、乙腈、C3-C12的饱和烷基腈中的一种或几种。
8.一种如权利要求1～7任一项所述立体选择性制备1,3-双取代环己烷类化合物的方法的应用，其特征在于：应用于进行立体专一性转化，产生高度官能团化的环己烷类化合物，所述应用包括以下步骤：
将所述1,3-双取代环己烷类化合物
在NaOH和H2O2作用下，在四氢呋喃溶剂中继续进行反应，制得高度官能团化的1,3-双取代环己烷类化合物
所述应用的路线如下：
9.如权利要求8所述立体选择性制备1,3-双取代环己烷类化合物的方法的应用，其特征在于：具体步骤如下：
1)在惰性气体中，将金属钯类催化剂PdA、碱、添加剂和联硼酸频哪醇酯溶于干燥的有机溶剂中，然后加入1,4-环己二烯和芳基卤代物R1-X，得到反应混合物，随后将上述反应混合物密封并从惰性气体中取出，反应完全后得到反应液Ⅰ；
2)将所述反应液Ⅰ用硅藻土过滤，然后用乙酸乙酯洗涤并浓缩，将得到的浓缩混合物溶于四氢呋喃中，得到反应液Ⅱ，然后在0℃下，向反应液Ⅱ中加入一定量的2M NaOH水溶液和30％H2O2溶液，然后将反应温度升至室温，并搅拌均一，待反应结束后，用饱和Na2S2O3淬灭，再用乙酸乙酯萃取，然后合并有机层并减压浓缩除去溶剂，再经柱层析分离纯化得到目标产物
其中，金属钯类催化剂PdA：碱：添加剂：1,4-环己二烯：芳基卤代物R1-X：联硼酸频哪醇酯：有机溶剂：四氢呋喃：2M NaOH水溶液：30％H2O2溶液的用量比为摩尔：摩尔：摩尔：摩尔：摩尔：摩尔：体积mL：体积mL：体积mL：体积mL＝0.05：2：1：3：1：1：2：10：6：3。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6090817A (en) * | 1996-03-08 | 2000-07-18 | Novartis Ag | Phenylpyridine derivatives useful as phosphodiesterase inhibitors |
| CN105612163A (zh) * | 2013-10-01 | 2016-05-25 | 科勒研究有限公司 | 用于内炔类的反式-选择性硼氢化的方法 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6090817A (en) * | 1996-03-08 | 2000-07-18 | Novartis Ag | Phenylpyridine derivatives useful as phosphodiesterase inhibitors |
| CN105612163A (zh) * | 2013-10-01 | 2016-05-25 | 科勒研究有限公司 | 用于内炔类的反式-选择性硼氢化的方法 |
Non-Patent Citations (4)
| Title |
|---|
| DONG WANG ET AL.: "Copper-Catalyzed, Stereoselective Cross-Coupling of Cyclic Allyl Boronic Acids with α ‑Diazoketones", 《ORGANIC LETTERS》 * |
| GIANFRANCO FONTANA ET AL.: "Investigation of the aqueous transmetalation of p-allylpalladium with indium salt: the use of the Pd(OAc)2-TPPTS catalyst", 《ORGANIC BIOMOLECULAR & CHEMISTRY》 * |
| HONG-PING DENG ET AL.: "Direct Allylation of Quinones with Allylboronates", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| JOHANNA M. LARSSON ET AL.: "Mechanistic Investigation of the Palladium-Catalyzed Synthesis ofAllylic Silanes and Boronates from Allylic Alcohols", 《JOURNAL OF THE AMERICANC CHEIMSTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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