CN106187702A - A kind of Preparation Method And Their Intermediate of 2 [1 cycloalkyl vinyl base] phenol - Google Patents
A kind of Preparation Method And Their Intermediate of 2 [1 cycloalkyl vinyl base] phenol Download PDFInfo
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- CN106187702A CN106187702A CN201610371421.4A CN201610371421A CN106187702A CN 106187702 A CN106187702 A CN 106187702A CN 201610371421 A CN201610371421 A CN 201610371421A CN 106187702 A CN106187702 A CN 106187702A
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- Prior art keywords
- compound
- reaction
- formula
- preparation
- methyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- 229920002554 vinyl polymer Polymers 0.000 title abstract description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- 238000000034 method Methods 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- -1 methoxyl group Chemical group 0.000 claims description 49
- 239000000460 chlorine Substances 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 34
- 229910052801 chlorine Inorganic materials 0.000 claims description 33
- 229910052794 bromium Inorganic materials 0.000 claims description 32
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 31
- 125000005842 heteroatom Chemical group 0.000 claims description 31
- 239000003054 catalyst Substances 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 239000000539 dimer Substances 0.000 claims description 26
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 24
- 239000004327 boric acid Substances 0.000 claims description 24
- 229910052751 metal Inorganic materials 0.000 claims description 24
- 239000002184 metal Substances 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 239000013638 trimer Substances 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 18
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 235000011056 potassium acetate Nutrition 0.000 claims description 16
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 15
- 239000001632 sodium acetate Substances 0.000 claims description 15
- 235000017281 sodium acetate Nutrition 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 14
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 229910052741 iridium Inorganic materials 0.000 claims description 13
- 229910052744 lithium Inorganic materials 0.000 claims description 13
- 229910052707 ruthenium Inorganic materials 0.000 claims description 13
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- 150000002118 epoxides Chemical class 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 150000004696 coordination complex Chemical class 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 239000000377 silicon dioxide Substances 0.000 claims description 11
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052759 nickel Inorganic materials 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 235000011181 potassium carbonates Nutrition 0.000 claims description 10
- 229910052703 rhodium Inorganic materials 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- ZYGAMJLTPLERBC-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid propan-2-ol Chemical compound B(O)(O)OC(C)(C)C(C)(C)O.C(C)(C)O ZYGAMJLTPLERBC-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 229910000085 borane Inorganic materials 0.000 claims description 9
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 9
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 9
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 239000011698 potassium fluoride Substances 0.000 claims description 8
- 235000003270 potassium fluoride Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 239000001488 sodium phosphate Substances 0.000 claims description 8
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 8
- 235000011008 sodium phosphates Nutrition 0.000 claims description 8
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 8
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 8
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 4
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052756 noble gas Inorganic materials 0.000 claims description 4
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 claims description 3
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- 230000000630 rising effect Effects 0.000 claims 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 1
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 150000002989 phenols Chemical class 0.000 abstract description 4
- WLMSWDHYJKAXGN-UHFFFAOYSA-N 2-(1-cyclopropylethyl)phenol Chemical class C=1C=CC=C(O)C=1C(C)C1CC1 WLMSWDHYJKAXGN-UHFFFAOYSA-N 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 13
- 208000035126 Facies Diseases 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- BMBBENHDFOWXPL-UHFFFAOYSA-N 2-(1-cyclopropylethenyl)-6-propan-2-ylphenol Chemical compound C1(CC1)C(=C)C1=C(C(=CC=C1)C(C)C)O BMBBENHDFOWXPL-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 230000001681 protective effect Effects 0.000 description 1
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- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical compound [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 description 1
- 229910001630 radium chloride Inorganic materials 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- CMLWFCUAXGSMBB-UHFFFAOYSA-N tris(2,6-dimethoxyphenyl)phosphane Chemical compound COC1=CC=CC(OC)=C1P(C=1C(=CC=CC=1OC)OC)C1=C(OC)C=CC=C1OC CMLWFCUAXGSMBB-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- 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
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation method of a kind of 2 [1 cycloalkyl vinyl base] phenol derivatives, i.e. lead to the Preparation Method And Their Intermediate of the compound shown in formula (I) and isomer thereof, the method has that reaction scheme is short, raw material is cheap and easy to get, productivity advantages of higher, can be as the intermediate of 2 (1 cyclopropylethyl) phenol derivatives synthesis.Logical formula (I) compound structure is as follows, R, R1Definition with n is consistent with description definition.
Description
Technical field
The present invention relates to the preparation method of a kind of 2-[1-cycloalkyl vinyl base] phenol derivatives, i.e. lead to shown in formula (I)
Compound and the Preparation Method And Their Intermediate of isomer thereof, the method has that reaction scheme is short, raw material is cheap and easy to get, productivity is high
Etc. advantage, can be as the intermediate of 2-(1-cyclopropylethyl) phenol derivatives synthesis.
Background technology
GABAAReceptor is inhibitory neurotransmitter main in central nervous system.GABAAReceptor is by transmembrane polypeptide
The pentamer of subunit is constituted, and 19 kinds of different subunits constitute multiple different GABAAReceptor subtype.GABAAReceptor relates to fiber crops
The pathogenesis of the multiple diseases such as liquor-saturated, depressed, anxiety, epilepsy, dysmnesia, drug dependence and diagnoses and treatment.
WO2014180305 describes class phenol derivatives and preparation method thereof and the purposes in nervus centralis field, and
There is good GABAAReceptor agonist activity, some compound has the GABA more higher than commercially available propofolAAgonist activity, especially
It is some 2-(1-cyclopropylethyl) phenol derivatives (such as 2-(1-cyclopropylethyl)-6-isopropyl-phenol) and isomer exists
The free dense of aqueous phase in bigger therapeutic index, higher safety index, broader treatment window or corresponding preparation is shown in zoopery
Spending low, measurable have the effect avoiding injection pain, has good potential applicability in clinical practice, and its formula is as follows:
Also disclose that the preparation method of 2-[1-cycloalkylethyl] phenol derivatives simultaneously, specific as follows:
The method route is long, reaction harshness, is unfavorable for commercial production.
It is an object of the invention to solve its weak point, the invention provides a kind of new intermediate, it is provided that Yi Zhongxin
Route short, the preparation method that is more easy to of reaction.
Summary of the invention
The present invention relates to the compound shown in a kind of formula (I) and the preparation method of stereoisomer thereof, be wherein by logical
One in formula (II-1) compound or its dimer or trimer, formula (II-2) compound and their stereoisomer or
The mixture of multiple compounds, is prepared by coupling reaction with logical formula (III) compound,
Formula (II-1), (II-2) compound are respectively
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；N is selected from 1,2 or 3；
R2、R3、R4It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled former
Son forms 4 to 15 rings together, and described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S, described
Ring can optionally by 0 to 4 selected from H, C1-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide.
Preferred version of the present invention, the compound shown in a kind of formula (I) and the preparation method of stereoisomer thereof, wherein:
Formula (II-1) compound is selected from one of following structure
Formula (II-2) compound is selected from
The dimer of formula (II-1) compound is selected from
R is H or hydroxyl protecting group；Preferably H；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide；Preferably Br or trifluoro-methanesulfonyl oxy；
N is selected from 1,2 or 3；Preferably 1.
Preferred version of the present invention, the compound shown in a kind of formula (I) and the preparation method of stereoisomer thereof, wherein:
Catalyst used in reaction is selected from load type metal catalyst or metal complex, and described metal is selected from
Pd, Ru, Ir, Rh or Ni；
Solvent used in reaction is selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N, N-dimethyl methyl
Any one in amide, water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；
Alkali used in reaction is selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, carbonic acid
Hydrogen potassium, potassium acetate, potassium phosphate, triethylamine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine.
Preferred version of the present invention, the compound shown in a kind of formula (I) and the preparation method of stereoisomer thereof, wherein:
Formula (II-1) compound is selected from one of following structure
Formula (II-2) compound is selected from
The dimer of formula (II-1) compound is selected from
R is H or hydroxyl protecting group；Preferably H；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide；Preferably Br or trifluoro-methanesulfonyl oxy；
N is selected from 1,2 or 3；Preferably 1
Catalyst used in reaction is selected from load type metal catalyst or metal complex, and described metal is selected from
Pd, Ru, Ir, Rh or Ni；
Solvent used in reaction is selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N, N-dimethyl methyl
Any one in amide, water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；
Alkali used in reaction is selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, carbonic acid
Hydrogen potassium, potassium acetate, potassium phosphate, triethylamine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine.
Preferred version of the present invention, the compound shown in a kind of formula (I) and the preparation method of stereoisomer thereof, wherein
Catalyst used in reaction is selected from Pd (OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、
(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、
Pd(dppf)Cl2、Pd(PPh3)4、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P、Pd(PPh3)2Cl2Or Pd2(dba)3/t-
Bu3P。
Preferred version of the present invention, the compound shown in a kind of formula (I) and the preparation method of stereoisomer thereof, wherein
Formula (II-1) compound is selected from one of following structure
Formula (II-2) compound is selected from
The dimer of formula (II-1) compound is selected from
R is H or hydroxyl protecting group；Preferably H；
N is selected from 1,2 or 3；Preferably 1；
Catalyst used in reaction is selected from load type metal catalyst or metal complex, and described metal is selected from
Pd, Ru, Ir, Rh or Ni；
Solvent used in reaction is selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N, N-dimethyl methyl
Any one in amide, water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；
Alkali used in reaction is selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, carbonic acid
Hydrogen potassium, potassium acetate, potassium phosphate, triethylamine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine；
Catalyst used in reaction is selected from Pd (OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、
(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、
Pd(dppf)Cl2、Pd(PPh3)4、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P、Pd(PPh3)2Cl2Or Pd2(dba)3/t-
Bu3P。
The present invention relates to a kind of formula (II-1) compound or its dimer or trimer preparation method, wherein pass through
Logical formula (IV) compound reacts with boric acid or borate and prepares,
Described logical formula (IV) compound is selected from
Described boric acid or borate are selected from
X is selected from H, F, Cl, Br or I；R2、R3、R7It is independently selected from H, OH, F, Cl, Br or C1-6Alkoxyl, or
R2And R3Atom that can be coupled forms 4-15 ring together, and described ring is in addition to containing hetero atom B, possibly together with 0 to 4 choosing
From the hetero atom of O, N or S, described ring is selected from H, (=O), C by 0 to 4 the most further1-6Alkyl or C1-6Taking of alkoxyl
Replaced for base；
R6Selected from hydroxyl protecting group.
Preferred version of the present invention, a kind of formula (II-1) compound or its dimer or trimer, formula (II-2) chemical combination
The preparation method of thing, wherein:
R2And R3It is independently selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy, or R2And R3Can be coupled
Atom forms 5 to 15 rings together, and described ring is selected from
R6Selected from THP trtrahydropyranyl, methyl, benzyl, methoxy, 1-ethoxyethyl group or pi-allyl；
R7Selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy.
Preferred version of the present invention, a kind of formula (II-1) compound or its dimer or trimer, formula (II-2) chemical combination
The preparation method of thing, wherein:
Described boric acid or borate are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid frequency
That alcohol boron ester, isopropanol pinacol borate or
Preferred version of the present invention, a kind of formula (II-1) compound or its dimer or trimer, formula (II-2) chemical combination
The preparation method of thing, wherein:
R2And R3It is independently selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy, or R2And R3Can be coupled
Atom form 5 to 15 rings together, described ring is selected from
R6Selected from THP trtrahydropyranyl, methyl, benzyl, methoxy, 1-ethoxyethyl group or pi-allyl；
R7Selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy；
Described boric acid or borate are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid frequency
That alcohol boron ester, isopropanol pinacol borate or
Preferred version of the present invention, a kind of formula (II-1) compound or its dimer or trimer, formula (II-2) chemical combination
The preparation method of thing, wherein:
Used in reaction, solvent is selected from water, glycol dimethyl ether, isopropanol, n-butyl alcohol, propanol, methanol, ethanol, dioxy
In six rings, hexane, ethyl acetate, oxolane, ether, dichloromethane, toluene, N,N-dimethylformamide or dimethyl sulfoxide
Any one or appoint several arbitrary proportions mixture；
Any one in butyl lithium, potassium acetate, sodium acetate, sodium tert-butoxide or potassium tert-butoxide of alkali used in reaction
Or appoint the mixture of several arbitrary proportions.
Preferred version of the present invention, a kind of formula (II-1) compound or its dimer or trimer, formula (II-2) chemical combination
The preparation method of thing, wherein:
R2And R3It is independently selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy, or R2And R3Can be coupled
Atom form 5 to 15 rings together, described ring is selected from
R6Selected from THP trtrahydropyranyl, methyl, benzyl, methoxy, 1-ethoxyethyl group or pi-allyl；
R7Selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy；
Described boric acid or borate are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid frequency
That alcohol boron ester, isopropanol pinacol borate or
Used in reaction, solvent is selected from water, glycol dimethyl ether, isopropanol, n-butyl alcohol, propanol, methanol, ethanol, dioxy
In six rings, hexane, ethyl acetate, oxolane, ether, dichloromethane, toluene, N,N-dimethylformamide or dimethyl sulfoxide
Any one or appoint several arbitrary proportions mixture；
Any one in butyl lithium, potassium acetate, sodium acetate, sodium tert-butoxide or potassium tert-butoxide of alkali used in reaction
Or appoint the mixture of several arbitrary proportions.
The present invention provides the preparation method of compound shown in a kind of logical formula (III), and its spy is that by logical formula V and acid
Reaction obtains,
Described acid is selected from trifluoromethanesulfonic acid or p-methyl benzenesulfonic acid；
R5Selected from trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide.
Preferred version of the present invention, the preparation method of compound shown in a kind of logical formula (III), the wherein temperature used in reaction
Degree is selected from-80 DEG C to-40 DEG C.
The present invention provides the compound shown in a kind of logical formula (I) and the preparation method of stereoisomer thereof, wherein
A) logical formula (IV) compound or its stereoisomer react with boric acid or borate and prepare formula (II-1) change
One or more compounds in compound or its dimer or trimer, formula (II-2) compound and their stereoisomer
Mixture；Described boric acid or borate are selected fromFormula (II-1), (II-2) compound are respectively
B) formula (II-1) compound or its dimer or trimer, formula (II-2) compound and their stereoisomerism
The mixture of one or more compounds in body, prepares logical formula (I) with logical formula (III) compound by coupling reaction
Compound；
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；N is selected from 1,2 or 3；
R2、R3、R4、R7It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled
Atom form 4-15 ring together, described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S,
Described ring optionally can be selected from H, C by 0 to 41-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide；
R6Selected from hydroxyl protecting group.
Preferred version of the present invention, the compound shown in a kind of logical formula (I) and the preparation method of stereoisomer thereof, wherein
A) boric acid or borate described in are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid
Pinacol boron ester, isopropanol pinacol borate or
B) catalyst used in reaction is selected from load type metal catalyst or metal complex, and described metal is selected from
Pd, Ru, Ir, Rh or Ni.
Preferred version of the present invention, the compound shown in a kind of logical formula (I) and the preparation method of stereoisomer thereof, wherein
A) logical formula (IV) compound or its stereoisomer react with boric acid or borate and prepare formula (II-1) change
One or more compounds in compound or its dimer or trimer, formula (II-2) compound and their stereoisomer
Mixture；Described boric acid or borate are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid
Pinacol boron ester, isopropanol pinacol borate orFormula (II-1), (II-2) compound are respectively
B) formula (II-1) compound or its dimer or trimer, formula (II-2) compound and their stereoisomerism
The mixture of one or more compounds in body, prepares logical formula (I) with logical formula (III) compound by coupling reaction
Compound；Catalyst used in reaction be selected from load type metal catalyst or metal complex, described metal selected from Pd,
Ru, Ir, Rh or Ni.
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；N is selected from 1,2 or 3；
R2、R3、R4、R7It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled
Atom form 4-15 ring together, described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S,
Described ring optionally can be selected from H, C by 0 to 41-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide；
R6Selected from hydroxyl protecting group.
Preferred version of the present invention, the compound shown in a kind of logical formula (I) and the preparation method of stereoisomer thereof, wherein
A) reaction used in solvent selected from methanol, ethanol, dioxane, hexane, ethyl acetate, oxolane, ether,
Any one in dichloromethane, toluene, N,N-dimethylformamide or dimethyl sulfoxide or the mixture of several arbitrary proportions；
Alkali used in reaction is selected from any one in butyl lithium, potassium acetate, sodium acetate, sodium tert-butoxide or potassium tert-butoxide or appoints several
The mixture of arbitrary proportion.
B) solvent used in reaction is selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N, N-dimethyl
Any one in Methanamide, water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；Reaction is made
Alkali selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, potassium bicarbonate, potassium acetate, potassium phosphate,
Triethylamine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine.
Preferred version of the present invention, the compound shown in a kind of logical formula (I) and the preparation method of stereoisomer thereof, wherein
A) logical formula (IV) compound and stereoisomer thereof react with boric acid or borate and prepare formula (II-1) change
One or more compounds in compound or its dimer or trimer, formula (II-2) compound and their stereoisomer
Mixture；Described boric acid or borate are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid
Pinacol boron ester, isopropanol pinacol borate orFormula (II-1), (II-2) compound are respectivelySolvent selected from methanol used in reaction, ethanol, dioxane, hexane, ethyl acetate,
In oxolane, ether, dichloromethane, toluene, N,N-dimethylformamide or dimethyl sulfoxide any one or appoint several
The mixture of meaning ratio；Alkali used in reaction is in butyl lithium, potassium acetate, sodium acetate, sodium tert-butoxide or potassium tert-butoxide
Any one or appoint several arbitrary proportions mixture；
B) formula (II-1) compound or its dimer or trimer, formula (II-2) compound and their stereoisomerism
The mixture of one or more compounds in body, prepares logical formula (I) with logical formula (III) compound by coupling reaction
Compound；Catalyst used in reaction be selected from load type metal catalyst or metal complex, described metal selected from Pd,
Ru, Ir, Rh or Ni；Solvent used in reaction is selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N, N-diformazan
Any one in base Methanamide, water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；Institute in reaction
The alkali used is selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, potassium bicarbonate, potassium acetate, phosphoric acid
Potassium, triethylamine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine.
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；N is selected from 1,2 or 3；
R2、R3、R4、R7It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled
Atom form 4-15 ring together, described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S,
Described ring optionally can be selected from H, C by 0 to 41-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide；
R6Selected from hydroxyl protecting group.
Preferred version of the present invention, the compound shown in a kind of logical formula (I) and the preparation method of stereoisomer thereof, b) reaction
Used in catalyst selected from Pd (OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、(PhCN)2PdCl2、Ni
(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd
(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P or Pd2(dba)3/t-Bu3P。
Preferred version of the present invention, the compound shown in a kind of logical formula (I) and the preparation method of stereoisomer thereof, wherein
A) logical formula (IV) compound and stereoisomer thereof react with boric acid or borate and prepare formula (II-1) change
One or more compounds in compound or its dimer or trimer, formula (II-2) compound and their stereoisomer
Mixture；Described boric acid or borate are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid
Pinacol boron ester, isopropanol pinacol borate orFormula (II-1), (II-2) compound are respectivelySolvent selected from methanol used in reaction, ethanol, dioxane, hexane, ethyl acetate,
In oxolane, ether, dichloromethane, toluene, N,N-dimethylformamide or dimethyl sulfoxide any one or appoint several
The mixture of meaning ratio；Alkali used in reaction is in butyl lithium, potassium acetate, sodium acetate, sodium tert-butoxide or potassium tert-butoxide
Any one or appoint several arbitrary proportions mixture.
B) formula (II-1) compound or its dimer or trimer, formula (II-2) compound and their stereoisomerism
The mixture of one or more compounds in body, prepares logical formula (I) with logical formula (III) compound by coupling reaction
Compound；Catalyst used in reaction is selected from selected from Pd (OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、
(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、
Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P or Pd2(dba)3/t-
Bu3P；Solvent used in reaction is selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N, N-dimethyl formyl
Any one in amine, water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；Used in reaction
Alkali is selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, potassium bicarbonate, potassium acetate, potassium phosphate, three second
Amine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine.
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；N is selected from 1,2 or 3；
R2、R3、R4、R7It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled
Atom form 4-15 ring together, described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S,
Described ring optionally can be selected from H, C by 0 to 41-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide；
R6Selected from hydroxyl protecting group.
The present invention relates to the compound shown in a kind of formula (II-1) and stereoisomer thereof, wherein
R is H or hydroxyl protecting group；
R1Selected from methyl, ethyl or cyclopropyl；
R2Or R3It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled former
Son forms 4-15 ring together, and described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S, described
Ring can optionally by 0 to 4 selected from H, C1-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
Condition is, when R is H, R1During for methyl, R2And R3It is asynchronously hydrogen.
Preferred version of the present invention, the compound shown in a kind of formula (II-1) and stereoisomer, wherein this compound
It is selected from
R is H, methyl, benzyl or methoxy；
R1Selected from methyl, ethyl or cyclopropyl.
The present invention relates to the compound shown in a kind of formula (II-2) and stereoisomer thereof, wherein
R is H or hydroxyl protecting group；Preferably H, methyl, benzyl or methoxy；
M is selected from Na, K or Li；Preferably K；
R1Selected from methyl, ethyl or cyclopropyl；
R2、R3、R4It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled former
Son forms 4-15 ring together, and described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S, described
Ring can optionally by 0 to 4 selected from H, C1-6Alkyl or C1-6The substituent group of alkoxyl is replaced；Preferably R2、R3、R4The most solely
Vertical selected from F.
The present invention relates to the compound shown in a kind of formula (II-d) and stereoisomer thereof, wherein
R is H or hydroxyl protecting group；Preferably H, methyl, benzyl or methoxy；
R1Selected from methyl, ethyl or cyclopropyl.
The present invention relates to compound and the preparation method of stereoisomer thereof shown in a kind of logical formula (I), be wherein by logical
Formula (VI) compound prepares with logical formula (VII) compound and stereoisomerism precursor reactant thereof:
Wherein, R is selected from H or hydroxyl protecting group；X is selected from H, Cl, Br or I；
R1Selected from methyl, ethyl or cyclopropyl；
R8Selected from H ,-SiR8aR8bR8c；Preferably H, trimethyl are silica-based, triethyl group is silica-based, t-Butyldimethylsilyl or three second
Epoxide is silica-based；
R8a、R8bAnd R8cIt is independently selected from H, phenyl, C1-6Alkyl or C1-6Alkoxyl；Preferably H, phenyl, methyl, second
Base, propyl group, isopropyl, methoxyl group, ethyoxyl, third support base or different oxygen propyl group；
N is selected from 1,2 or 3；Preferably 1.
Preferred version of the present invention, compound and the preparation method of stereoisomer thereof shown in a kind of logical formula (I), wherein:
The reagent used in reaction is selected from magnesium metal, lithium metal, phenyl lithium, n-BuLi, s-butyl lithium or tert-butyl lithium；
Reaction makes blanketing with inert gas；Described noble gas is selected from nitrogen or argon.
Preferred version of the present invention, compound and the preparation method of stereoisomer thereof shown in a kind of logical formula (I), wherein:
The reagent used in reaction is selected from magnesium metal, lithium metal, phenyl lithium, n-BuLi, s-butyl lithium or tert-butyl lithium；
Reaction makes blanketing with inert gas；Described noble gas is selected from nitrogen or argon；
The solvent used in reaction is selected from petroleum ether, ether, 5 to 6 rings or C containing 1 to 12 carbon atom1-6In alkane
Any one or appoint several arbitrary proportions mixture；Described ring contains 0 to 4 hetero atom selected from N, O, S, described
Ether, ring or alkane are selected from H, F, Cl, Br, I, (=O), methyl, ethyl, isopropyl or trifluoromethyl by 0 to 6 the most further
Substituent group replaced；In reaction use the preferred petroleum ether of solvent, methyl ether, ether, butyl ether, amyl ether, hexane, hexamethylene, four
One or more in hydrogen furan, methyltetrahydrofuran, benzene,toluene,xylene and trimethylbenzene.
Preferred version of the present invention, compound and the preparation method of stereoisomer thereof shown in a kind of logical formula (I), wherein:
Adding additive in reaction further, described additive is selected from N, N, N, N '-tetramethylethylenediamine (TMEDA),
HMPA (HMPA), N, N-dimethyl propylene thiazolinyl urea (DMPU), CeCl3Or ZnCl2。
Preferred version of the present invention, compound and the preparation method of stereoisomer thereof shown in a kind of logical formula (I), wherein:
The reagent used in reaction is selected from magnesium metal, lithium metal, phenyl lithium, n-BuLi, s-butyl lithium or tert-butyl lithium；
Reaction makes blanketing with inert gas；Described noble gas is selected from nitrogen or argon；
The solvent used in reaction is selected from petroleum ether, ether, 5 to 6 rings or C containing 1 to 12 carbon atom1-6In alkane
Any one or appoint several arbitrary proportions mixture；Described ring contains 0 to 4 hetero atom selected from N, O, S, described
Ether, ring or alkane are selected from H, F, Cl, Br, I, (=O), methyl, ethyl, isopropyl or trifluoromethyl by 0 to 6 the most further
Substituent group replaced；In reaction use the preferred petroleum ether of solvent, methyl ether, ether, butyl ether, amyl ether, hexane, hexamethylene, four
One or more in hydrogen furan, methyltetrahydrofuran, benzene,toluene,xylene and trimethylbenzene；
Adding additive in reaction further, described additive is selected from N, N, N, N '-tetramethylethylenediamine (TMEDA),
HMPA (HMPA), N, N-dimethyl propylene thiazolinyl urea (DMPU), CeCl3Or ZnCl2。
The present invention relates to the synthetic method of compound described in a kind of logical formula (VIII), be wherein by logical formula (X) compound
React with logical formula (IX) compound and prepare:
X is selected from Cl, Br or I；
R8a、R8bAnd R8cIt is independently selected from H, phenyl, C1-6Alkyl or C1-6Alkoxyl；Preferably H, phenyl, methyl, second
Base, propyl group, isopropyl, methoxyl group, ethyoxyl, third support base or different oxygen propyl group；
N is selected from 1,2 or 3；Preferably 1.
Preferred version of the present invention, the synthetic method of compound described in a kind of logical formula (VIII), wherein reaction adds further
Enter CuI.
Halogenated cyclopropyl alkene is referred to CN102381925A preparation or buys.
Compound (II-2) is referred to Chemical Biology&Drug Design, 79 (1), 9-21；2012 preparations
Or buy.
Unless there are contrary statement, the term used in the specification and in the claims has following implication.
When the general formula compound that the present invention relates to exists chiral centre, in addition to clearly indicating, general formula compound can be to disappear
Rotation body, it is also possible to be optical isomer.
When the present invention relates to be replaced by multiple substituent groups, each substituent group can be identical or differ.
When the present invention relates to containing multiple hetero atom, each hetero atom can be identical or differ.
Elemental carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in group of the present invention and compound all include theirs
Elemental carbon, hydrogen, oxygen, sulfur or nitrogen involved in isotope situation, and group of the present invention and compound is optionally further by 1
Isotope to 5 they correspondences is substituted, and wherein the isotope of carbon includes12C、13C and14C, the isotope of hydrogen include protium (H),
Deuterium (D is again heavy hydrogen), tritium (T is again superheavy hydrogen), the isotope of oxygen includes16O、17O and18O, the isotope of sulfur includes32S、33S、34S and36S, the isotope of nitrogen includes14N and15N, the isotope of fluorine19F, the isotope of chlorine includes35Cl and37Cl, bromine same
Position element includes79Br and81Br。
Hydroxyl protecting group is selected from alkyl ether protection group, esters protection group or silicon ethers protection group, and hydroxyl protecting group includes
But be not limited to methyl, benzyl, methoxy, to methoxy-benzyl, trityl, the tert-butyl group, methoxymethyl ether, methoxy (ethoxy)
Ylmethyl, tetrahydrofuran base, tert-butyl carbonyl, benzoyl, acetyl group, chloromethyl carbonyl, tert-butoxycarbonyl, benzyloxy carbonyl
Base, trimethyl are silica-based, triethyl group is silica-based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, di-t-butyl hydroxyl is silica-based or
R-(1-phenyl) ethyl aminocarbonyl；
Alkyl ether protection group can remove under basic or acidic conditions, and described alkali or acid include but not limited to hydrogenation
Sodium, Feldalat NM, potassium carbonate, potassium hydroxide, sodium hydroxide, pyridine, trifluoroacetic acid, hydrochloric acid, formic acid or acetic acid；
Esters protection group can remove in the basic conditions, and described alkali includes but not limited to Feldalat NM, potassium carbonate, hydroxide
Potassium, sodium hydroxide, lithium aluminium hydride reduction, pyridine or ammonia；
Silicon ethers protection group can remove under the conditions of fluohydric acid gas, tetrabutyl ammonium fluoride etc..
" coordination compound " is also referred to as complex, refers to the compound containing list of coordination units.Joined with several by central atom or ion
Complicated molecule that body molecule or ion are formed so that coordinate bond combines or ion, commonly referred to list of coordination units.
" metal complex " refers to that list of coordination units is to be made up of metal and part, when metal is combined with multiple parts, joins
Body can be identical, it is also possible to differs.Described metal be selected from transition metal, limiting examples include Co, Ni, Ru, Pd, Ir or
Rh；The limiting examples of described part includes Cl-、OAc-、CN-、COD、PPh3、P(i-Pr)3, P (cyclohexyl)3、P(o-
MeOPh)3、P(p-MeOPh)3、Ph2P(CH2)3PPh2、Ph2P(CH2)2PPh2、Ph2P(CH2)4PPh2、Ph2P(CH2)2PPh2
(dppe)、Ph2P(CH2)3PPh2(dppp), dppp, dppb, dppe, dba, BINAP, TDMPP, TMPP, TMSPP, P (O-neighbour's first
Phenyl)3, P (O-p-methoxyphenyl)3, pyridine, Bu3P、n-Bu3P、(MeO)3P、AsPh3\P(OEt)3.Except list of coordination units
Outer metal complex can contain simple ion, it is also possible to default, and described simple ion is selected from Cl-、BF4 -、PF6 -、CF3SO3 -、
B(C6F5)4 -、B(C6H5)4 -、Al(OC(CF3)3)4 -Or [B [3,5-(CF3)2C6H3]4]-.The limiting examples of metal complex
Including Pd (OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd(dba)2、(dppp)NiCl2、Ru(OAc)2BINAP、(Ph3P)3·RuClH、[(Ph)3P]3RuCl2、[(Ph)3P]3Ru(CO)H2、Ph3P)3·IrH、Ir(dppe)2、
Ph3P)3·RhCl、[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、[Ru(BIPHEP)(C6H6)Cl]Cl、Ir(Tol-SDP)(COD)
Cl, Ir (MeO-BIPHEP) (COD) Cl or by Pd (OAc)2、PdCl2With AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2
(dppe)、Ph2P(CH2)3PPh2(dppp) catalyst system and catalyzing formed.
" loaded catalyst " is supported on carrier surface by catalytic active component and forms, and conventional carrier has oxidation
Alumina supporter, silica-gel carrier, absorbent charcoal carrier and some natural product such as Pumex, kieselguhr etc..
" load type metal catalyst " refers to the loaded catalyst that catalytic active component is metal, and described metal was selected from
Crossing metal, limiting examples includes but not limited to Co, Ni, Ru, Pd, Ir or Rh；The non-limiting reality of load type metal catalyst
Example includes but not limited to palladium carbon, Raney's nickel etc..
Detailed description of the invention
Implementation process and the beneficial effect of generation of the present invention is described in detail, it is intended to help to read below by way of specific embodiment
Reader is more fully understood that essence and the feature of the present invention, not as can the restriction of practical range to this case.
The structure of compound by nuclear magnetic resonance, NMR (NMR) or (with) mass spectrum (MS) determines.NMR displacement (δ) is with 10-6
(ppm) unit is given.The mensuration of NMR is with (Bruker Avance III 400 and Bruker Avance 300) nuclear-magnetism
Instrument, measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), deuterated acetonitrile
(CD3CN), tetramethylsilane (TMS) inside it is designated as.
The mensuration of MS uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
The mensuration of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6mm).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin layer chromatography (TLC) makes
Silica gel plate use specification be 0.15mm～0.20mm, the isolated and purified product of thin layer chromatography use specification be 0.4mm～
0.5mm。
It is carrier that column chromatography generally uses Yantai Huanghai Sea silica gel 200～300 mesh silica gel.
The initiation material that oneself of the present invention knows can use or synthesize according to methods known in the art, or commercially available in
The companies such as safe smooth science and technology, resistance to Jilin Chemical of pacifying, Shanghai moral are silent, Chengdu section dragon chemical industry, splendid remote chemistry science and technology, lark prestige science and technology.
(Ph3P)3RhCl: three (triphenylphosphine) radium chloride
(Ph3P)3RuClH: three (triphenylphosphine) chlorine hydrogenation ruthenium
(Ph3P)3Iridium is closed in IrH: three (triphenylphosphine) hydrogenation
(R)-Ru(OAc)2BINAP: diethyl acid group [(R)-(+)-2,2'-two (diphenylphosphino)-1,1'-binaphthyl] ruthenium
[(Ph)3P]3RuCl2: three (triphenylphosphine) ruthenous chloride
[(Ph)3P]3Ru(CO)H2: three (triphenylphosphine) carbonyl dihydro ruthenium
PdCl2: palladium chloride
Pd(OAc)2: Palladium Diacetate
PdCl2(PPh3)2: three (triphenylphosphine) palladium chloride
Pd(PPh3)4: tetrakis triphenylphosphine palladium
PdCl2(dppf): [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride
Pd(dba)2: three (dibenzalacetone) two palladium
(dppp)NiCl2: double (diphenylphosphine) the propane Nickel dichloride. of 1,3-
Intermediate 1
1-cyclopropyl-2-(trimethyl silicane methyl) ketone (intermediate 1)
1-cyclopropyl-2-(trimethylsilyl)ethanone
Hydro-Giene (Water Science). (12.57g, 66mmol) is placed in there-necked flask, N2Replace 3 times, at N2Under protection, add tetrahydrochysene
Furan (30mL), is down to-10 DEG C, is slowly added dropwise (trimethyl is silica-based) methyl-magnesium-chloride (TMSCH2MgCl) solution (66mL,
66mmol), add continuation stirring 10 minutes, drip oxolane (30mL) solution of ring the third formyl chloride (6.27g, 60mmol),
React 30 minutes after adding, rise to 0 DEG C and react 2 hours.Add water (30mL) cancellation reaction, add ethyl acetate (60mL) dilution
Reactant liquor, filters through kieselguhr, filters off insoluble matter, collects filtrate, separates organic facies, and aqueous phase ethyl acetate (30mL × 2) extracts
Taking, merge organic facies, organic facies anhydrous sodium sulfate is dried, and filters, residue removal of solvent under reduced pressure, obtains light yellow transparent liquid
1-cyclopropyl-2-(trimethyl silicane methyl) ketone (intermediate 1) (8.1g, 86%).
1H NMR(400MHz,CDCl3)δ2.33(s,2H),1.77(m,1H),0.97(m,2H),0.79(m,2H),0.11
(s,9H).
Embodiment 1
2-(1-cyclopropylethenyl)-6-isopropyl-phenol (compound 1)
2-(1-cyclopropylvinyl)-6-isopropylphenol
The first step: 2-hydroxyl-3-isopropyl benzene boronic acid (1B)
(2-hydroxy-3-isopropylphenyl)boronic acid
At N2Under protection, 1-THP trtrahydropyranyl-2 cumene (1A) (11.08g, 50.0mmol) is dissolved in anhydrous tetrahydrochysene furan
Mutter in (90mL), be down to 0 DEG C, be slowly added dropwise the hexane solution (26mL, 65mmol) of butyl lithium, add reaction 15 minutes, rise
Reaction 30 minutes is continued to room temperature；It is down to 0 DEG C, adds triisopropyl borate ester (12.2g, 65mmol), add reaction 15 minutes, rise
To room temperature reaction 3 hours.In reactant liquor, add saturated ammonium chloride solution (20mL), pH about=8, stir 20 minutes, filter, filter
Removing insoluble matter, separatory, aqueous phase is extracted with ethyl acetate (50mL × 2), merging organic facies, organic phase washed with water (50mL × 2),
Anhydrous sodium sulfate is dried, and is concentrated to give faint yellow solid, adds 3mL petroleum ether, filters, and filters by (2mL × 2) petroleum ether
Cake, drains to obtain faint yellow solid.It is dissolved in methanol (25mL), adds methanol hydrochloride solution (2mL, 1mol/L), stirring half
Hour, decompression remove major part methanol, filter, with petroleum ether (1mL × 2) wash filter cake, drain white solid 2-hydroxyl-
The mixture (1B:1B`=1:1,4.6g, productivity 50%) of 3-isopropyl benzene boronic acid 1B and dimer 1B ' thereof.
1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.81(d,1H),7.63(d,1H),7.49(d,1H),7.40
(d, 1H), 7.18 (t, 1H), 6.96 (t, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 1.34 (d, 6H), 1.27 (d, 6H).
Second step: 1-cyclopropylethenyl triflate (1D)
1-cyclopropylvinyl trifluoromethanesulfonate
N2Under protection, ring the third acetylene (1C) (4.36g, 66mmol) is dissolved in chloroform (66mL), is down to-78 DEG C, slowly
Dropping trifluoromethanesulfonic acid (1b) (9.0g, 60mmol), added after 10 minutes, continued reaction 5 minutes, adds toluene (10mL), subtracts
Pressure removes ring third acetylene of chloroform and excess and obtains 1-cyclopropylethenyl triflate (1D), and freezen protective is standby.
1H NMR(400MHz,CDCl3)δ5.03(d,1H),4.90(dd,1H),1.61(m,1H),0.89(m,2H),0.75
(m,2H)。
3rd step: 2-(1-cyclopropylethenyl)-6-isopropyl-phenol (compound 1)
2-(1-cyclopropylvinyl)-6-isopropylphenol
The mixture (5.4g, 30mmol) of 2-hydroxyl-3-isopropyl benzene boronic acid 1B and dimer 1B` thereof is dissolved in toluene
(240mL), in, the wet chemical (50mL) of 4N, N are added2Displaced air, while stirring displaced air about 30 minutes, add
Catalyst Pd (dppf) Cl2(1.22g, 1.5mmol), continues N2After displaced air 3 times, add the 1-cyclopropylethenyl of existing system
Toluene (10mL) solution of triflate (1D), adds and is placed in 65 DEG C of oil baths reaction 3 hours.Reactant liquor is cooled to naturally
Room temperature, separates organic facies, and aqueous phase is extracted with ethyl acetate (60mL × 2), merging organic facies, organic phase washed with water (50mL ×
2), anhydrous sodium sulfate is dried, and is concentrated to give dark viscous liquid, residue silica gel column chromatography separating-purifying (petroleum ether: acetic acid second
Ester (v/v)=1:0～30:1) obtain title compound 2-(1-cyclopropylethenyl)-6-isopropyl-phenol (compound 1), nothing
Color liquid (2.95g, productivity 48.7%).
1H NMR(400MHz,CDCl3)δ7.10(dd,1H),6.95(dd,1H),6.84(t,1H),5.67(s,1H),
5.30 (s, 1H), 5.04 (s, 1), 3.31 (m, 1H), 1.64 (m, 1H), 1.24 (d, 6H), 0.77 (m, 2H), 0.52 (m, 2H).
Embodiment 2:
The preparation method two of compound 1B
The first step: 2-hydroxyl-3-isopropyl benzene boronic acid pinacol ester (2B)
2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
By bromo-for 2-3-isopropyl-phenol 2A (10.76g, 50mmol) and (BPin)2(25.40g, 100mmol) is dissolved in
In 170mL Isosorbide-5-Nitrae-dioxane, add potassium acetate (14.72g, 150mmol), N2Displaced air, displaced air is about while stirring
30min.Add catalyst PdCl2(dppf) (1.22g, 1.5mmol), continues N2After displaced air 3 times, it is placed in 65 DEG C of oil baths
React 5 hours.Reactant liquor is cooled to naturally room temperature, adds 40mL shrend and go out reaction, add 80mL diluted ethyl acetate and react
Liquid, separates organic facies, and aqueous phase is extracted with ethyl acetate (60mL × 2), merging organic facies, organic phase washed with water (50mL × 2),
Anhydrous sodium sulfate is dried, filter, concentrating under reduced pressure obtains dark viscous liquid, residue with silica gel column chromatography separating-purifying (petroleum ether:
Ethyl acetate (v/v)=1:0～40:1) obtain title compound 2-hydroxyl-3-isopropyl benzene boronic acid pinacol ester (2B), colourless
Liquid (3.0g, productivity 22.9%).
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.45(dd,1H),7.31(dd,1H),6.86(d,1H),
3.33 (m, 1H), 3.40 (m, 1H), 1.36 (s, 12H), 1.24 (d, 6H).
Second step: 2-hydroxyl-3-isopropyl benzene boronic acid (1B)
(2-hydroxy-3-isopropylphenyl)boronic acid
Compound 2-hydroxyl-3-isopropyl benzene boronic acid pinacol ester (2B) (2.66g, 10mmol) of upper step gained is dissolved in
In the 15mL mixed solvent of acetone/water (1:1), be sequentially added into ammonium acetate (2.31g, 30mmol), sodium metaperiodate (6.42g,
30mmol), add be stirred at room temperature reaction 12 hours.Filtering off solid insoluble, filtrate removes acetone through decompression, and residue adds
40mL ethyl acetate, separates organic facies, and aqueous phase is extracted with ethyl acetate (20mL × 2), merges organic facies, and anhydrous sodium sulfate is done
Dry, filter, concentrating under reduced pressure obtains dark viscous liquid, residue silica gel column chromatography separating-purifying (petroleum ether: ethyl acetate (v/
V)=20:1～10:1) obtain title compound 2-hydroxyl-3-isopropyl benzene boronic acid 1B and anhydride dimer 1B ' (1:1,1.1g,
Productivity 60%).
1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.81(d,1H),7.63(d,1H),7.49(d,1H),7.40
(d, 1H), 7.18 (t, 1H), 6.96 (t, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 1.34 (d, 6H), 1.27 (d, 6H)..
Embodiment 3
2-(1-cyclopropylethenyl)-6-isopropyl-phenol (compound 1)
2-(1-cyclopropylvinyl)-6-isopropylphenol
Bromo isopropyl-phenol (2A) (1.076g, 5mmol) is dissolved in anhydrous tetrahydro furan (15mL), is down to 0 DEG C, N2
Displaced air 3 times, N2Under protection, it is slowly added dropwise the hexane solution (4.3mL, 10.75mmol) of butyl lithium, adds reaction 15 points
Zhong Hou, rise to 18 DEG C react 30 minutes, be slowly added dropwise 1-cyclopropyl-2-(trimethyl silicane methyl) ketone (intermediate 1) (0.39g,
Oxolane (5mL) solution 2.5mmol), adds and rises to 30 DEG C of reactions 2 hours, then rise to 45 DEG C of reactions 2 hours.To reaction
Adding water (5mL) cancellation reaction in liquid, add hydrochloric acid (10mL, 3mol/L) aqueous solution, adjust pH=3,30 DEG C are stirred reaction 30 points
Clock, separates organic facies, and aqueous phase ethyl acetate (15mL × 2) extracts, and merges organic facies, and anhydrous sodium sulfate is dried, and filters, residual
Thing removal of solvent under reduced pressure, crude product send HPLC to separate to obtain 2-(1-cyclopropylethenyl)-6-isopropyl-phenol (compound 1)
(0.4g, productivity 40.2%).
1H NMR(400MHz,CDCl3)δ7.10(dd,1H),6.95(dd,1H),6.84(t,1H),5.67(s,1H),
5.30(s,1H),5.04(s,1H),3.31(m,1H),1.64(m,1H),1.24(d,6H),0.77(m,2H),0.52(m,2H)。
Claims (29)
1. the compound shown in a formula (I) and the preparation method of stereoisomer thereof, it is characterised in that be by formula (II-
1) one or more in compound or its dimer or trimer, formula (II-2) compound and their stereoisomer are changed
The mixture of compound, is prepared by coupling reaction with logical formula (III) compound,
Formula (II-1), (II-2) compound are respectively
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；N is selected from 1,2 or 3；
R2、R3、R4It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Atom one that can be coupled
Rising and form 4 to 15 rings, described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S, described ring
Optionally can be selected from H, C by 0 to 41-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide.
Preparation method the most according to claim 1, it is characterised in that:
Formula (II-1) compound is selected from one of following structure
Formula (II-2) compound is selected from
The dimer of formula (II-1) compound is selected from
R5Selected from Br or trifluoro-methanesulfonyl oxy.
Preparation method the most according to claim 2, it is characterised in that:
R is H；R1Selected from methyl, ethyl or cyclopropyl；N is 1.
4. according to the preparation method described in claims 1 to 3 any one, it is characterised in that:
Catalyst used in reaction be selected from load type metal catalyst or metal complex, described metal selected from Pd, Ru,
Ir, Rh or Ni；
Solvent used in reaction selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N,N-dimethylformamide,
Any one in water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；
Alkali used in reaction selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, potassium bicarbonate,
Potassium acetate, potassium phosphate, triethylamine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine.
Preparation method the most according to claim 4, it is characterised in that
Catalyst used in reaction is selected from Pd (OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd
(dppf)Cl2、Pd(PPh3)4、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P、Pd(PPh3)2Cl2Or Pd2(dba)3/t-
Bu3P。
6. formula (II-1) compound or its dimer or trimer preparation method, it is characterised in that be logical formula (IV)
Compound reacts with boric acid or borate and prepares,
Described logical formula (IV) compound is selected from
Described boric acid or borate are selected from
X is selected from H, F, Cl, Br or I；
R2、R3、R7It is independently selected from H, OH, F, Cl, Br or C1-6Alkoxyl, or R2And R3Atom that can be coupled
Forming 4-15 ring together, described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S, described
Ring is selected from H, (=O), C by 0 to 4 the most further1-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R6Selected from hydroxyl protecting group.
Preparation method the most according to claim 6, it is characterised in that:
R2And R3It is independently selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy, or R2And R3Can be coupled
Atom forms 5 to 15 rings together, and described ring is selected from
R6Selected from THP trtrahydropyranyl, methyl, benzyl, methoxy, 1-ethoxyethyl group or pi-allyl；
R7Selected from H, OH, F, methoxyl group, ethyoxyl or isopropoxy.
Preparation method the most according to claim 7, it is characterised in that:
Described boric acid or borate are selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid pinacol
Boron ester, isopropanol pinacol borate or
Preparation method the most according to claim 8, it is characterised in that:
Used in reaction, solvent is selected from water, glycol dimethyl ether, isopropanol, n-butyl alcohol, propanol, methanol, ethanol, dioxy six
In ring, hexane, ethyl acetate, oxolane, ether, dichloromethane, toluene, N,N-dimethylformamide or dimethyl sulfoxide
Any one or appoint several arbitrary proportions mixture；
Alkali used in reaction is selected from any one in butyl lithium, potassium acetate, sodium acetate, sodium tert-butoxide or potassium tert-butoxide or appoints
The mixture of several arbitrary proportions.
10. a preparation method for compound shown in logical formula (III), its spy is that and is obtained with acid reaction by logical formula V,
Described acid is selected from trifluoromethanesulfonic acid or p-methyl benzenesulfonic acid；
R5Selected from trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide.
11. preparation methoies according to claim 10, it is characterised in that the temperature used in reaction selected from-80 DEG C to-
40℃。
Compound shown in 12. 1 kinds of logical formula (I) and the preparation method of stereoisomer thereof, it is characterised in that:
A) logical formula (IV) compound or its stereoisomer react with boric acid or borate and prepare formula (II-1) compound
Or one or more compounds in its dimer or trimer, formula (II-2) compound and their stereoisomer is mixed
Compound；Described boric acid or borate are selected fromFormula (II-1), (II-2) compound are respectively
B) in formula (II-1) compound or its dimer or trimer, formula (II-2) compound and their stereoisomer
The mixture of one or more compounds, prepare logical formula (I) chemical combination with logical formula (III) compound by coupling reaction
Thing；
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；N is selected from 1,2 or 3；
R2、R3、R4、R7It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Can be coupled former
Son forms 4-15 ring together, and described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S, described
Ring can optionally by 0 to 4 selected from H, C1-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
R5Selected from Cl, Br, I, trifluoro-methanesulfonyl oxy or tolysulfonyl epoxide；
R6Selected from hydroxyl protecting group.
13. preparation methoies according to claim 12, it is characterised in that:
A) boric acid described in or borate selected from triisopropyl borate, trimethyl borate, pinacol borine, connection boric acid frequency that
Alcohol boron ester, isopropanol pinacol borate or
B) catalyst used in reaction is selected from load type metal catalyst or metal complex, described metal selected from Pd,
Ru, Ir, Rh or Ni.
14. preparation methoies according to claim 13, it is characterised in that:
A) solvent selected from methanol, ethanol, dioxane, hexane, ethyl acetate, oxolane, ether, dichloro used in reaction
Any one in methane, toluene, N,N-dimethylformamide or dimethyl sulfoxide or the mixture of several arbitrary proportions；Reaction
Used in alkali in butyl lithium, potassium acetate, sodium acetate, sodium tert-butoxide or potassium tert-butoxide any one or appoint several arbitrarily
The mixture of ratio；
B) solvent used in reaction is selected from toluene, dioxane, oxolane, dimethyl sulfoxide, N, N-dimethyl formyl
Any one in amine, water, glycol dimethyl ether or dichloroethanes or the mixture of several arbitrary proportions；Used in reaction
Alkali is selected from sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, potassium bicarbonate, potassium acetate, potassium phosphate, three second
Amine, potassium fluoride, tert-butylamine, N, N-diisopropylethylamine, tri-n-butylamine or pyridine.
15. preparation methoies according to claim 14, it is characterised in that:
B) catalyst used in reaction is selected from Pd (OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd
(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P or Pd2(dba)3/t-
Bu3P。
Compound shown in 16. 1 kinds of formulas (II-1) and stereoisomer thereof, wherein,
R is H or hydroxyl protecting group；
R1Selected from methyl, ethyl or cyclopropyl；
R2Or R3It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Atom that can be coupled is together
Forming 4-15 ring, described ring is in addition to containing hetero atom B, and possibly together with 0 to 4 hetero atom selected from O, N or S, described ring can
To be optionally selected from H, C by 0 to 41-6Alkyl or C1-6The substituent group of alkoxyl is replaced；
Condition is, when R is H, R1During for methyl, it is hydrogen when R2 with R3 is different.
17. according to the compound shown in claim 16 and stereoisomer thereof, and wherein this compound is selected from:
R is H, methyl, benzyl or methoxy.
Compound shown in 18. 1 kinds of formulas (II-2) and stereoisomer thereof, wherein
R is H or hydroxyl protecting group；
M is selected from Na, K or Li；
R1Selected from methyl, ethyl or cyclopropyl；
R2、R3、R4It is independently selected from H, OH, F, Cl, Br, C1-6Alkoxyl, or R2And R3Atom one that can be coupled
Rising and form 4-15 ring, described ring is in addition to containing hetero atom B, possibly together with 0 to 4 hetero atom selected from O, N or S, described ring
Optionally can be selected from H, C by 0 to 41-6Alkyl or C1-6The substituent group of alkoxyl is replaced.
19. according to the compound shown in claim 18 and stereoisomer thereof, wherein
R is H, methyl, benzyl or methoxy；
M is K；
R2、R3、R4It is independently selected from F.
Compound shown in 20. 1 kinds of formulas (II-d) and stereoisomer thereof, wherein
R is H or hydroxyl protecting group；
R1Selected from methyl, ethyl or cyclopropyl.
21. according to the compound shown in claim 20 and stereoisomer thereof, wherein
R is H, methyl, benzyl or methoxy.
Compound and the preparation method of stereoisomer thereof shown in 22. 1 kinds of logical formula (I), it is characterised in that be by logical formula (VI)
Compound prepares with logical formula (VII) compound and stereoisomerism precursor reactant thereof:
Wherein, R is selected from H or hydroxyl protecting group；X is selected from H, Cl, Br or I；
R1Selected from methyl, ethyl or cyclopropyl；
R8Selected from H ,-SiR8aR8bR8c；
R8a、R8bAnd R8cIt is independently selected from H, phenyl, C1-6Alkyl or C1-6Alkoxyl；
N is selected from 1,2 or 3.
23. preparation methoies according to claim 22, wherein:
N is 1；R8Selected from H, trimethyl is silica-based, triethyl group is silica-based, t-Butyldimethylsilyl or triethoxy silica-based.
24. preparation methoies according to claim 23, it is characterised in that:
The reagent used in reaction is selected from magnesium metal, lithium metal, phenyl lithium, n-BuLi, s-butyl lithium or tert-butyl lithium；
Reaction makes blanketing with inert gas；Described noble gas is selected from nitrogen or argon.
25. preparation methoies according to claim 24, it is characterised in that:
The solvent used in reaction is selected from petroleum ether, ether, 5 to 6 rings or C containing 1 to 12 carbon atom1-6Appointing in alkane
A kind of or appoint several arbitrary proportions mixture；Described ring contains 0 to 4 hetero atom selected from N, O, S, described ether, ring
Or alkane is the most further by 0 to 6 taking selected from H, F, Cl, Br, I, (=O), methyl, ethyl, isopropyl or trifluoromethyl
Replaced for base.
26. preparation methoies according to claim 25, it is characterised in that:
The solvent used in reaction is selected from petroleum ether, methyl ether, ether, butyl ether, amyl ether, hexane, hexamethylene, oxolane, methyl
One or more in oxolane, benzene,toluene,xylene and trimethylbenzene.
27. preparation methoies according to claim 26, it is characterised in that:
Reaction adds additive further, described additive be selected from N, N, N, N '-tetramethylethylenediamine, hexamethyl phosphinylidyne three
Amine, N, N-dimethyl propylene thiazolinyl urea, CeCl3Or ZnCl2。
The synthetic method of compound described in 28. 1 kinds of logical formula (VIII), it is characterised in that be by logical formula (X) compound and formula
(IX) compound reaction prepares:
X is selected from Cl, Br or I；
R8a、R8bAnd R8cIt is independently selected from H, phenyl, C1-6Alkyl or C1-6Alkoxyl；
N is selected from 1,2 or 3.
29. methods according to claim 28, it is characterised in that add CuI in reaction further.
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| WO2023143158A1 (en) * | 2022-01-26 | 2023-08-03 | 天地恒一制药股份有限公司 | Phenol derivative, crystal form thereof, and preparation method therefor |
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