CN110078652B - 手性四芳基取代甲烷及其制备方法 - Google Patents
手性四芳基取代甲烷及其制备方法 Download PDFInfo
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 84
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 30
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 28
- 239000003054 catalyst Substances 0.000 claims description 28
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- TVCXVUHHCUYLGX-UHFFFAOYSA-N 2-Methylpyrrole Chemical compound CC1=CC=CN1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 17
- -1 2-hydroxyphenyl Chemical group 0.000 claims description 14
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 14
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 5
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- IRTLROCMFSDSNF-UHFFFAOYSA-N 2-phenyl-1h-pyrrole Chemical compound C1=CNC(C=2C=CC=CC=2)=C1 IRTLROCMFSDSNF-UHFFFAOYSA-N 0.000 claims description 2
- KQBVVLOYXDVATK-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indole Chemical compound C1CCCC2=C1C=CN2 KQBVVLOYXDVATK-UHFFFAOYSA-N 0.000 claims description 2
- 229950005499 carbon tetrachloride Drugs 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 26
- 125000003118 aryl group Chemical group 0.000 abstract description 15
- 229910052799 carbon Inorganic materials 0.000 abstract description 11
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000009509 drug development Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000002547 new drug Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 32
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 26
- 230000003287 optical effect Effects 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 238000003556 assay Methods 0.000 description 15
- 230000014759 maintenance of location Effects 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000010409 thin film Substances 0.000 description 15
- 239000002994 raw material Substances 0.000 description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 150000003233 pyrroles Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000005561 phenanthryl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- DPGHISRNNOYQGP-UHFFFAOYSA-N 1-(1,2,3,4,4a,5,6,7-octahydronaphthalen-1-yl)naphthalene Chemical group C1=CC=C2C(C3CCCC4C3=CCCC4)=CC=CC2=C1 DPGHISRNNOYQGP-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 description 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000004062 acenaphthenyl group Chemical group C1(CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000002431 aminoalkoxy group 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
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000003914 fluoranthenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC=C4C1=C23)* 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000007398 protein translocation Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于合成化学技术领域,具体涉及一种手性四芳基取代甲烷及其制备方法。所述手性四芳基取代甲烷的结构通式为说明书中式I:在式I所示的结构通式中,Ar1、Ar2、Ar3和Ar4分别独立选自芳基、杂芳基、取代的芳基和取代的杂芳基中的任意一种,且Ar1、Ar2、Ar3和Ar4互不相同。该手性四芳基取代甲烷具有特殊的分子形状和立体构型,使得其具有特殊的药学性质并在新药物开发方面具有极大的前景,而该制备方法克服了化学和药物合成领域中无法直接催化构建手性四芳基季碳中心即合成手性四芳基甲烷结构的难题,同时该制备方法操作简单实用,产率好,制备过程具有绿色经济性,对环境友好,易于工业化的特点。
Description
技术领域
本发明属于合成化学技术领域,具体涉及一种手性四芳基取代甲烷及其制备方法。
背景技术
由于芳基取代的甲烷在光学器件、功能材料框架、药物释放和蛋白质易位检测等方面的应用,使其在有机材料、生命科学以及超分子化学等领域引起了广泛的关注。然而,目前芳基甲烷的合成方法有限,这也使得其在合成和药物开发领域的应用发展受到极大的限制。
发明内容
本发明的目的在于提供一种手性四芳基取代甲烷及其制备方法,旨在解决现有芳基甲烷的种类和合成有限的技术问题。
为实现上述发明目的,本发明采用的技术方案如下:
本发明一方面提供一种手性四芳基取代甲烷,所述手性四芳基取代甲烷的结构通式为下述式I:
在式I所示的结构通式中,Ar1、Ar2、Ar3和Ar4分别独立选自芳基、杂芳基、取代的芳基和取代的杂芳基中的任意一种,且Ar1、Ar2、Ar3和Ar4互不相同。
本发明另一方面提供一种手性四芳基取代甲烷的制备方法,包括如下步骤:
将式II所示的化合物和式III所示的化合物溶解在溶剂中,在手性磷酸催化剂的条件下进行合成反应,得到式Ⅰ所示的化合物;
其中,上述化合物中,Ar1、Ar2、Ar3和Ar4分别独立选自芳基、杂芳基、取代的芳基和取代的杂芳基中的任意一种,且Ar1、Ar2、Ar3和Ar4互不相同。
本发明提供了一种手性四芳基甲烷结构即具有手性季碳中心的有机化合物,以及一种催化构建手性四芳基甲烷的催化合成方法;该手性四芳基取代甲烷具有特殊的分子形状和立体构型,使得其具有特殊的药学性质并在新药物开发方面具有极大的前景,而该制备方法克服了化学和药物合成领域中无法直接催化构建手性四芳基季碳中心即合成手性四芳基甲烷结构的难题,同时本发明提供的制备方法操作简单实用,产率好,制备过程具有绿色经济性,对环境友好,易于工业化的特点,而且该制备方法可扩升级到克以上级别后产物的产率和立体选择性仍然保持,因此在合成和药物开发领域具有很好的应用前景。
具体实施方式
为了使本发明要解决的技术问题、技术方案及有益效果更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
“芳基”是指一种环状的芳香基团,包括但不限于如苯基、萘基、蒽基、菲基以及其它类似基团。
“杂芳基”是指单环或多环或稠环的杂环芳香基团,其中的一个或多个碳原子已被如氮、氧或硫等杂原子取代。
“取代”指一基团内的一个或多个氢原子可独立地替换为相同或不同的取代基。
一方面,本发明实施例提供了一种手性四芳基取代甲烷,所述手性四芳基取代甲烷的结构通式为下述式I:
在式I所示的结构通式中,Ar1、Ar2、Ar3和Ar4分别独立选自芳基、杂芳基、取代的芳基和取代的杂芳基中的任意一种,且Ar1、Ar2、Ar3和Ar4互不相同。
在一些实施例中,在上述Ar1、Ar2、Ar3和Ar4分别独立选自芳基、杂芳基、取代的芳基和取代的杂芳基中,所述芳基可以为单环芳基或多环芳基(如稠环芳烃基),具体地,所述芳基选自苯基、萘基、菲基、蒽基、苊烯基、苊基、芴基、芘基和荧蒽基中的至少一种。所述杂芳基可以为五元杂环基、六元杂环基、苯稠杂环基(苯环与杂环稠合)、稠杂环基(几个杂环稠合),具体地,所述杂芳基选自吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噻唑基、恶唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲哚基、苯并噻吩基、苯并呋喃基、苯并吡唑基、苯并咪唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基和嘌呤基中的至少一种。所述取代的芳基和取代的杂芳基中的取代基分别独立选自氟、氯、溴、碘、氰基、羟基、氨基、羧基、烷基、卤代烷基、烷氧基、烷硫基、烯基、炔基、硝基、巯基、羟基烷基、羟基烷氧基、氨基烷氧基、烷基酯基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、环烷基、芳氧基、杂芳氧基、卤代烷基氧基和环烷基烷基中的至少一种,即上述取代基单取代或相同或不同的多取代芳基或杂芳基。其中,上述取代基中,烷基可以为C1-C20烷基或C1-C10烷基;烯基可以为C2-C20烯基或C2-C10烯基;炔基可以为C2-C20炔基或C2-C10炔基;烷氧基可以为C1-C20烷氧基或C1-C10烷氧基;烷硫基可以为C1-C20烷硫基或C1-C10烷硫基;杂环基可以为C3-C10杂环烷基、C3-C10杂环烯基或C3-C10杂环炔基;环烷基可以为C3-C20环烷基或C3-C10环烷基。
在一些实施例中,上述Ar1、Ar2和Ar4分别独立选自芳基、杂芳基、取代的芳基和取代的杂芳基,而Ar3选自芳基或取代的芳基中的任意一种。例如,Ar3为苯基,如实施例中的Ia、Ib、Ic、Id、Ie、If、Ik、Il、Im、In、Io所示的手性四芳基取代甲烷;或者Ar3为取代苯基如4-氟苯基或4-甲氧基苯基,如实施例中的Ig、Ih所示的手性四芳基取代甲烷;或者Ar3为2-萘基,如实施例中的Ii所示的手性四芳基取代甲烷。当然Ar3可以为杂芳基,如3-噻吩基,如实施例中的Ii所示的手性四芳基取代甲烷。
在一些实施例中,Ar4选自杂芳基或取代的杂芳基中的任意一种。
另一方面,本发明实施例还提供了一种手性四芳基取代甲烷的制备方法,包括如下步骤:
将式II所示的化合物和式III所示的化合物溶解在溶剂中,在手性磷酸催化剂的条件下进行合成反应,得到式Ⅰ所示的化合物;
其中,上述化合物中,Ar1、Ar2、Ar3和Ar4分别独立选自芳基、杂芳基、取代的芳基和取代的杂芳基中的任意一种,且Ar1、Ar2、Ar3和Ar4互不相同。
本发明实施例提供的上述制备方法中,利用式II所示的化合物即三芳基取代甲醇和式III所示的化合物即芳基亲核试剂,在手性磷酸催化剂的条件下反应,一步直接催化得到高光学纯的手性四芳基甲烷。
对于制备方法中的原料,其中Ar1、Ar2、Ar3和Ar4具体选择上文已经详细阐述。而优选地,所述式III的化合物为杂芳基化合物或取代的杂芳基化合物,即Ar4选自杂芳基或取代的杂芳基中的任意一种。
在一实施例中,所述合成反应的温度为-20℃至40℃;所述合成反应的时间为24h至72h。所述溶剂选自1,2-二氯乙烷(DCE)、二氯甲烷(DCM)、三氯甲烷(CHCl3)、四氯甲烷(CCl4)、氯苯(PhCl)、氟苯(PhF)、甲苯(PhMe)和三氟甲苯(PhCF3)中的至少一种。
在一实施例中,所述手性磷酸催化剂选自基于联萘的手性磷酸催化剂(如下IV结构式)、基于八氢联萘的手性磷酸催化剂(如下V结构式)和基于螺环骨架的手性磷酸催化剂(如下VI结构式)中的至少一种。
上述基于轴手性骨架的手性磷酸的催化剂,可以使用(S)-型手性磷酸催化所得产物具有与同类骨架(R)-型手性磷酸催化所的产物相反的立体构型。其中,上述手性催化剂的使用量为5-15mol%。
优选地,所述手性磷酸催化剂为(R)-BINOL-2,4,6-Cy3C6H2-OH,具体的化学结构如下所示:
在一实施例中,手性四芳基甲烷的制备方法为:取0.2mmol三芳基取代甲醇II和0.4mmol芳基亲核试剂III,溶解在3.6mL的溶剂DCE中,并置于0℃环境温度下。将0.4mL含有0.015mmol手性磷酸催化剂(结构式如下)(R)-BINOL-2,4,6-Cy3C6H2-OH的溶液,缓慢滴加入反应混合物溶液中。然后保持0℃下搅拌48小时,通过TLC确定反应情况,反应完毕后通过柱色谱分离得到高产率,高光学纯的手性四芳基甲烷I。具体反应式如下:
本发明先后进行过多次试验,现举一部分试验结果作为参考对发明进行进一步详细描述,下面结合具体实施例进行详细说明。
实施例1
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(61.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃搅拌48小时。其反应方程式如下:
将反应液直接用于硅胶柱层析得到目标产物Ia浅黄色发泡状固体71.7mg,计算产率为97%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+6.9(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:9.7min(major),11.1min(minor)。计算结果为96%ee。
3、核磁共振分析的氢谱、碳谱、红外和高分辨质谱。
1H NMR(400MHz,acetone-d6)δ8.78(s,1H),8.22(s,1H),7.29–7.25(m,1H),7.22–7.12(m,5H),7.00–6.85(m,5H),6.71(d,J=8.7Hz,2H),5.70–5.63(m,1H),5.58–5.60(m,1H),3.17(s,3H),2.13(s,3H).
13C NMR(100MHz,acetone-d6)δ158.8,156.0,146.9,137.6,136.6,136.5,132.1,130.8,130.5,129.1,127.8,127.5,126.2,121.0,114.4,114.0,110.4,105.3,59.1,55.5,13.1.
IR(thin film)3446,3384,3056,2983,2839,1588,1247,1039,733,700cm-1.
HRMS(CI+)Calcd for C25H23NO2(M+):369.1729,Found:369.1725.
实施例2
采用Ar1为4-羟基苯基,Ar2为2-苯并[1,3]-间二氧环戊基,Ar3为苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(64.0mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ib浅黄色发泡状固体72.1mg,计算产率为94%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+4.5(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelAD-H柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:38.9min(major),40.8min(minor)。计算结果为78%ee。
3、核磁共振分析的氢谱、碳谱、红外和高分辨质谱。
1H NMR(400MHz,acetone-d6)δ9.08(s,1H),8.30(s,1H),7.26–7.13(m,5H),6.94(d,J=8.4Hz,2H),6.81(d,J=8.4Hz,1H),6.77–6.71(m,3H),6.55(d,J=8.0,1H),5.72–5.59(m,4H),2.16(s,3H).
13C NMR(100MHz,acetone-d6)δ156.5,148.6,146.3,146.1,136.3,135.0,131.9,131.2,130.7,128.1,128.0,126.9,123.5,121.8,114.8,110.7,108.3,105.45,100.8,58.2,13.1.
IR(thin film)3440,3416,3052,2975,2885,1589,1440,1259,733cm-1.
HRMS(LD+)Calcd for C25H21NO3(M+):383.1521,Found:383.1519.
实施例3
采用Ar1为4-羟基苯基,Ar2为2-羟基苯基,Ar3为苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(58.4mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至-20℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于-20℃搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ic浅黄色发泡状固体66.6mg,计算产率为94%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+4.3(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;5%i-PrOH的hexanes;1.0mL/min;保留时间:7.5min(major),9.6min(minor)。计算结果为88%ee。
3、核磁共振分析的氢谱、碳谱、红外和高分辨质谱。
1H NMR(400MHz,acetone-d6)δ9.39(s,1H),8.34(br,1H),7.27–7.12(m,6H),6.94(d,J=8.4Hz,2H),6.86(d,J=7.7Hz,1H),6.79–6.73(m,4H),6.39(br,1H),5.87–5.80(m,1H),5.77–5.71(m,1H),2.17(s,3H).
13C NMR(100MHz,acetone-d6)δ156.7,156.6,146.4,136.5,134.3,133.3,132.2,131.1,130.9,130.0,129.4,128.1,127.0,120.1,117.8,115.0,110.7,105.8,58.4,13.1.
IR(thin film)3427,3387,3054,2981,2862,1603,1261,1210,1179,737,700cm-1.
HRMS(CI+)Calcd for C24H21NO2(M+):355.1572,Found:355.1581.
实施例4
采用Ar1为4-羟基苯基,Ar2为2-(1-萘磺酰胺基)苯基,Ar3为苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(96.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于二氯甲烷(3.6mL)中,并将混合物冷却至-20℃,缓慢滴加手性磷酸(29.8mg,0.030mmol)的二氯甲烷(0.4mL)溶液。之后,置于40℃搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Id浅黄色发泡状固体92.9mg,计算产率为85%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+4.5(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;30%i-PrOH的hexanes;1.0mL/min;保留时间:12.4min(major),15.1min(minor)。计算结果为95%ee。
3、核磁共振分析的氢谱、碳谱、红外和高分辨质谱。
1H NMR(400MHz,acetone-d6)δ9.42(s,1H),8.50(s,1H),8.24(d,J=7.3Hz,1H),8.19(d,J=8.2Hz,1H),8.07–7.98(m,2H),7.67–7.61(m,3H,),7.46(s,1H),7.30–7.24(m,3H),7.15–7.09(m,4H),6.93–6.88(m,4H),6.74(d,J=8.5Hz,2H),6.19-6.11(m,1H),6.00-5.94(m,1H),2.13(s,3H).
13C NMR(100MHz,acetone-d6)δ156.9,145.9,138.9,138.2,136.2,135.2,135.1,134.5,133.3,132.2,131.7,131.2,130.9,129.7,129.3,129.1,128.7,128.6,128.4,127.7,127.4,125.3,125.2,123.2,118.9,115.3,111.0,106.4,59.0,13.2.
IR(thin film)3435,3376,3057,2925,2851,1589,1264,743,700cm-1.
HRMS(LD+)Calcd for C34H28N2O3S(M+):544.1821,Found:544.1840.
实施例5
采用Ar1为4-羟基苯基,Ar2为2-丁硫基苯基,Ar3为苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(72.8mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,室温下,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于室温下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ie浅黄色发泡状固体76.5mg,计算产率为90%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+7.1(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:8.3min(major),9.7min(minor)。计算结果为81%ee。
3、核磁共振分析的氢谱、碳谱、红外和高分辨质谱。.
1H NMR(400MHz,acetone-d6)δ8.74(s,1H),8.28(s,1H),7.46(d,J=7.5Hz,1H),7.26–7.16(m,6H),7.11(t,J=7.8Hz,1H),6.99–6.94(m,3H),6.71(d,J=8.6Hz,2H),5.68–5.64(m,1H),5.61–5.56(m,1H),2.37(t,J=6.9Hz,2H),2.13(s,3H),1.22–1.10(m,4H),0.76(t,J=6.9Hz,3H).
13C NMR(100MHz,acetone-d6)δ156.3,148.5,146.2,140.7,136.5,136.2,132.9,132.6,131.4,131.2,128.2,128.0,127.7,126.5,126.1,114.6,111.1,105.6,61.0,35.6,31.5,22.7,13.9,13.1.
IR(thin film)3444,3386,3052,2957,2927,2865,1587,1262,1175,735,700cm-1.
HRMS(LD+)Calcd for C28H29NOS(M+):427.1970,Found:427.1982.
实施例6
采用Ar1为4-羟基苯基,Ar2为2-氟-4-甲氧基苯基,Ar3为苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(64.8mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,室温下,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于室温下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物If浅黄色发泡状固体80.6mg,计算产率为93%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+1.5(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelOD-H柱;5%i-PrOH的hexanes;1.0mL/min;保留时间:19.1min(major),24.2min(minor)。计算结果为91%ee。
3、核磁共振分析的氢谱、碳谱、氟谱、红外和高分辨质谱。
1H NMR(400MHz,acetone-d6)δ8.97(s,1H),8.31(s,1H),7.27–7.16(m,5H),6.96–6.91(m,3H),6.74(d,J=8.8Hz,2H),6.67(dd,J1=12.9,J2=2.6Hz,1H),6.61(dd,J1=12.9,J2=2.7Hz,1H),5.68–5.65(m,2H),3.79(s,3H),2.15(m,3H).
13C NMR(100MHz,acetone-d6)δ163.3(d,J=247.6Hz),162.1(d,J=11.0Hz),156.5,146.5,136.5,135.3,131.8(d,J=5.7Hz),131.7,130.3,128.3,128.0,127.9(d,J=11.3Hz),126.8,114.9,110.3,109.4(d,J=2.6Hz),105.5,103.0(d,J=26.5Hz),57.8,55.8,13.1.
19F NMR(376MHz,acetone-d6)δ-97.8.
IR(thin film)3446,3054,2932,1616,1261,824,733cm-1.
HRMS(CI+)Calcd for C25H22FNO2(M+):387.1635,Found:387.1624.
实施例7
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为4-氟苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(62.8mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ig浅黄色发泡状固体72.1mg,计算产率为93%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+6.9(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:8.7min(major),9.8min(minor)。计算结果为92%ee。
3、核磁共振分析的氢谱、碳谱、氟谱、红外和高分辨质谱。
1H NMR(400MHz,acetone-d6)δ8.84(s,1H),8.27(s,1H),7.30–7.25(m,1H),7.18–7.14(m,2H),7.00–6.90(m,6H),6.88(td,J1=7.6,J2=1.0Hz,1H),6.72(d,J=8.8Hz,2H),5.66(t,J=2.4Hz,1H),5.58(t,J=3.0Hz,1H),3.21(s,3H),2.13(s,3H).
13C NMR(100MHz,acetone-d6)δ161.6(d,J=240.1Hz),158.7,156.1,142.8(d,J=3.3Hz),137.4,136.4,132.2(d,J=6.7Hz),131.9,130.7,129.3,128.0,121.0,114.5,114.0(d,J=21.0Hz),113.8,110.4,105.4,58.5,55.4,13.1.
19F NMR(376MHz,acetone-d6)δ-118.1.
IR(thin film)3447,3053,2980,2936,1593,1476,1261,1020,733cm-1.
HRMS(CI+)Calcd for C25H22NFO2(M+):387.1635,Found:387.1638.
实施例8
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为4-甲氧基苯基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(67.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ih浅黄色发泡状固体74.7mg,计算产率为94%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+1.7(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;5%i-PrOH的hexanes;1.0mL/min;保留时间:8.7min(major),10.1min(minor)。计算结果为83%ee。
3、核磁共振分析的氢谱、碳谱、红外和高分辨质谱。
1H NMR(400MHz,acetone-d6)δ8.76(s,1H),8.19(s,1H),7.26(t,J=7.9Hz,1H),7.04(d,J=8.4Hz,2H),6.92–6.92(m,4H),6.86(t,J=7.4Hz,1H),6.77(d,J=8.7Hz,2H),6.69(d,J=8.2Hz,2H),5.68–5.61(m,1H),5.68–5.54(m,1H),3.75(s,3H),3.20(s,3H),2.13(s,3H).
13C NMR(100MHz,acetone-d6)δ158.9,158.4,155.9,138.7,137.9,137.3,136.9,131.8,131.7,130.7,129.1,127.6,121.0,114.4,114.0,112.8,110.2,105.3,58.4,55.6,55.3,13.1.
IR(thin film)3445,3389,3050,2838,1590,1249,1176,1031,821,735cm-1.
HRMS(LD+)Calcd for C26H25NO3(M+):399.1834,Found:399.1827.
实施例9
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为2-萘基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(71.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ii浅黄色发泡状固体88.7mg,计算产率为92%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+11.8(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:11.7min(major),13.3min(minor)。计算结果为93%ee。
1H NMR(400MHz,acetone-d6)δ8.90(s,1H),8.25(s,1H),7.83(d,J=7.3Hz,1H),7.72–7.64(m,3H),7.45–7.28(m,4H),7.09–7.03(m,3H),6.96–6.89(m,2H),6.74(d,J=8.6Hz,2H),5.73–5.65(m,2H),3.16(s,3H),2.13(s,3H).
13C NMR(100MHz,acetone-d6)δ159.0,156.1,144.0,137.4,136.9,136.3,133.9,132.8,132.0,130.9,130.4,129.3,128.9,128.4,128.0,128.0,126.4,126.31,126.22,121.1,114.5,114.0,110.5,105.5,59.2,55.5,13.1.
IR(thin film)3441,3380,3052,2836,1588,1243,734,698cm-1.
HRMS(LD+)Calcd for C29H25NO2(M+):419.1885,Found:419.1883.
实施例10
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为3-噻吩基的三芳基甲醇和2-甲基吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(62.4mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ij浅黄色发泡状固体65.5mg,计算产率为87%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+11.8(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelAD-H柱;5%i-PrOH的hexanes;1.0mL/min;保留时间:12.9min(major),14.8min(minor)。计算结果为87%ee。
1H NMR(400MHz,acetone-d6)δ8.87(s,1H),8.20(s,1H),7.29–7.24(m,2H),6.97–6.92(m,3H),6.86–6.81(m,3H),6.78(d,J=5.0Hz,1H),6.69(d,J=8.6Hz,2H),5.66–5.61(m,1H),5.55(t,J=2.9Hz,1H),3.27(s,3H),2.14(s,3H).
13C NMR(100MHz,acetone-d6)δ159.0,156.1,148.2,137.6,137.6,135.9,131.3,131.0,130.4,129.2,127.5,123.8,123.3,121.0,114.6,114.1,109.7,105.5,56.1,55.7,13.1.
IR(thin film)3443,3393,3049,2837,1587,1251,1175,733,703cm-1.
HRMS(LD+)Calcd for C23H21NO2S(M+):375.1298,Found:375.1311.
实施例11
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为苯基的三芳基甲醇和取代吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(61.2mg,0.2mmol)和4,5,6,7-四氢吲哚(48.4mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Ik浅黄色发泡状固体75.0mg,计算产率为92%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+0.8(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:8.3min(major),9.3min(minor)。计算结果为83%ee。
1H NMR(400MHz,acetone-d6)δ8.47(s,1H),8.23(s,1H),7.28–7.21(m,6H),7.03–6.85(m,5H),6.70(d,J=8.2Hz,2H),5.46(s,1H),3.16(s,3H),2.45(t,J=5.9Hz,2H),2.40(t,J=5.7Hz,2H),1.72–1.69(m,4H).
13C NMR(100MHz,acetone-d6)δ158.9,156.0,146.9,137.9,136.6,136.1,132.1,130.8,130.5,129.1,127.5,127.0,126.1,121.0,115.5,114.4,114.0,109.7,59.1,55.5,24.8,24.3,23.7,23.4.
IR(thin film)3447,3402,3054,2844,1598,1241,1174,733,700cm-1.
HRMS(LD+)Calcd for C28H27NO2(M+):409.2042,Found:409.2054.
实施例12
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为苯基的三芳基甲醇和取代吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(61.2mg,0.2mmol)和2-苯基吡咯(57.2mg,0.4mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Il浅黄色发泡状固体84.9mg,计算产率为98%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+8.8(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelOD-H柱;5%i-PrOH的hexanes;1.0mL/min;保留时间:11.2min(major),12.2min(minor)。计算结果为81%ee。
1H NMR(400MHz,acetone-d6)δ9.50(s,1H),8.32(s,1H),7.49(d,J=7.8Hz,2H),7.32–7.19(m,8H),7.13–7.07(m,2H),7.02–7.00(m,3H),6.90(t,J=7.6Hz,1H),6.77(d,J=8.6Hz,2H),6.46(t,J=2.9Hz,1H),5.86(t,J=2.8Hz,1H),3.25(s,3H).
13C NMR(100MHz,acetone-d6)δ158.8,156.2,146.7,139.8,136.9,136.4,134.1,132.3,132.1,131.0,130.5,129.4,129.3,127.7,126.5,126.1,124.2,121.2,114.6,114.3,112.6,105.8,59.3,55.7.
IR(thin film)3449,3366,3054,2836,1600,1254,732,697cm-1.
HRMS(LD+)Calcd for C30H25NO2(M+):431.1885,Found:431.1876.
实施例13
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为苯基的三芳基甲醇和吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(61.2mg,0.2mmol)和吡咯(67.0mg,1.0mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物Im浅黄色发泡状固体66.8mg,计算产率为94%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+3.6(c=1.0,CHCl3)。
1H NMR(400MHz,acetone-d6)δ9.06(s,1H),8.26(s,1H),7.30–7.13(m,6H),6.96–6.85(m,5H),6.72–6.68(m,3H),6.03–5.93(m,1H),5.82–5.71(m,1H),3.19(s,3H).
13C NMR(100MHz,acetone-d6)δ158.9,156.1,146.9,137.9,137.4,136.7,132.0,130.7,130.5,129.3,127.6,126.3,121.0,118.1,114.5,114.0,110.2,107.3,59.1,55.5.
IR(thin film)3447,3055,2835,1598,1241,1176,731cm-1.
HRMS(LD+)Calcd for C24H21NO2(M+):355.1572,Found:355.1556.
实施例14
采用Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为苯基的三芳基甲醇和取代吡咯作为反应原料,用手性磷酸催化剂进行反应。具体实施过程如下:
将三芳基甲醇(61.2mg,0.2mmol)和4,7-二氢吲哚(47.6mg,0.2mmol)溶解于1,2-二氯乙烷(3.6mL)中,并将混合物冷却至0℃,缓慢滴加手性磷酸(14.9mg,0.015mmol)的1,2-二氯乙烷(0.4mL)溶液。之后,置于0℃下搅拌48小时。
将反应液直接用于硅胶柱层析得到目标产物In浅黄色发泡状固体70.4mg,计算产率为86%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:+2.2(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelIC柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:9.0min(minor),10.7min(major)。计算结果为86%ee。
1H NMR(400MHz,acetone-d6)δ8.66(s,1H),8.21(s,1H),7.29–7.14(m,6H),7.02–6.86(m,5H),6.72–6.69(m,2H),5.85-5.82(m,1H),5.79-5.76(m,1H),5.53–5.52(m,1H),3.15–3.10(m,4H),3.17(s,3H).
13C NMR(100MHz,acetone-d6)δ158.9,156.1,146.9,137.7,137.0,136.6,132.1,130.8,130.5,129.2,127.6,126.5,126.2,124.32,124.27,121.0,114.4,114.0,112.7,108.9,59.2,55.5,25.6,24.7.
IR(thin film)3447,3405,2831,1696,1599,1255,1175,1108,820,731cm-1.
HRMS(CI+)Calcd for C28H25NO2(M+):407.1885,Found:407.1888.
实施例15:
手性四芳基甲烷的氧化衍生化反应。
室温下,向手性四芳基甲烷In(61.1mg,0.15mmol)的丙酮溶液(4mL)中陆续加入碘甲烷(64.4mg,0.45mmol)和碳酸钾(104mg,0.75mmol,5.0equiv.),反应混合液在室温下搅拌24小时。其后,将反应混合物用简易短硅胶柱过滤,乙醚冲洗,减压下浓缩滤液后得到粗产物。将粗物溶解在无水二氯甲烷(8mL),加入氧化剂DDQ(38mg,0.175mmol),反应混合物保持在室温下搅拌3小时。其后,加入二氯甲烷(15mL)稀释后用NaOH溶液(15mL,10%wt.)和水(2×15mL)洗涤,用无水Na2SO4干燥洗涤后的有机相。将有机相浓缩后直接用于硅胶柱层析得到目标产物Io浅黄色发泡状固体51.2mg,计算产率为81%。
在该步骤制备完成之后,为了进一步验证所纯化得到的化合物确实为本实施例中所要制备的目的产物,对所得到产物进行分析,分析的手段采用测定比旋光度、高效液相色谱分析测定ee值、核磁共振。其中,测试的分析如下:
1、26℃下D线测定的比旋光度[α]D 26:-1.5(c=1.0,CHCl3)。
2、高效液相色谱分析测定ee值:手性柱DaicelOD-H柱;3%i-PrOH的hexanes;1.0mL/min;保留时间:10.3min(minor),11.1min(major)。计算结果为86%ee。
1H NMR(400MHz,acetone-d6)δ9.46(s,1H),7.46(d,J=7.7Hz,1H),7.28–7.18(m,6H),7.09(d,J=8.9Hz,2H),7.03–6.88(m,5H),6.82(d,J=8.9Hz,2H),6.34(s,1H),3.77(s,3H),3.20(s,3H).
13C NMR(100MHz,acetone-d6)δ159.0,158.8,146.0,145.5,137.7,137.2,136.1,132.2,130.81,130.75,129.7,128.7,127.9,126.7,121.7,121.2,120.7,119.8,114.0,113.2,111.8,104.3,59.6,55.5,55.4.
IR(thin film)3448,3053,2836,1592,1290,1105,799,731cm-1.
HRMS(CI+)Calcd for C29H25NO2(M)+:419.1885Found:419.1886.
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (3)
1.一种手性四芳基取代甲烷的制备方法,其特征在于,包括如下步骤:
将式II所示的化合物和式III所示的化合物溶解在溶剂中,在手性磷酸催化剂的条件下进行合成反应,得到式Ⅰ所示的化合物;
其中,上述化合物中,
所述式II中的Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为苯基;或者,Ar1为4-羟基苯基,Ar2为2-苯并[1,3]-间二氧环戊基,Ar3为苯基;或者,Ar1为4-羟基苯基,Ar2为2-羟基苯基,Ar3为苯基;或者,Ar1为4-羟基苯基,Ar2为2-(1-萘磺酰胺基)苯基,Ar3为苯基;或者,Ar1为4-羟基苯基,Ar2为2-丁硫基苯基,Ar3为苯基;或者,Ar1为4-羟基苯基,Ar2为2-氟-4-甲氧基苯基,Ar3为苯基;或者,Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为4-氟苯基;或者,Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为4-甲氧基苯基;或者,Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为2-萘基;或者,Ar1为4-羟基苯基,Ar2为2-甲氧基苯基,Ar3为3-噻吩基;
所述式III为吡咯、2-苯基吡咯、2-甲基吡咯、4,7-二氢吲哚和4,5,6,7-四氢吲哚中的至少一种;
所述手性磷酸催化剂的化学结构如下所示:
2.如权利要求1所述的制备方法,其特征在于,所述手性催化剂的使用量为5-15mol%;和/或,
所述合成反应的温度为-20℃至40℃;和/或,
所述合成反应的时间为24h至72h。
3.如权利要求1所述制备方法,其特征在于,所述溶剂选自1,2-二氯乙烷、二氯甲烷、三氯甲烷、四氯甲烷、氯苯、氟苯、甲苯和三氟甲苯中的至少一种。
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