CN103408492A - Preparation method of 6-substitute-5,6-dihydro phenanthridine derivative - Google Patents
Preparation method of 6-substitute-5,6-dihydro phenanthridine derivative Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 phenylboronic acid ester Chemical class 0.000 claims abstract description 6
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 7
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [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 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 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 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- SKJCWIFHLDWPEO-UHFFFAOYSA-N 3-benzyl-4-phenylbutan-2-one Chemical compound C=1C=CC=CC=1CC(C(=O)C)CC1=CC=CC=C1 SKJCWIFHLDWPEO-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229940093916 potassium phosphate Drugs 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 20
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical class NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 4
- 238000006845 Michael addition reaction Methods 0.000 abstract description 2
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 150000005053 phenanthridines Chemical class 0.000 description 30
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 239000012265 solid product Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 0 CC(CC(*)=O)c1c(B2OC(C)(C)C(C)(C)O2)cccc1 Chemical compound CC(CC(*)=O)c1c(B2OC(C)(C)C(C)(C)O2)cccc1 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HERGPIKZUJHAPU-UHFFFAOYSA-N 2-bromo-n-fluoroaniline Chemical compound FNC1=CC=CC=C1Br HERGPIKZUJHAPU-UHFFFAOYSA-N 0.000 description 2
- YQQRKUQVFWYEPV-UHFFFAOYSA-N 5,6-dihydrophenanthridine Chemical class C1=CC=C2CNC3=CC=CC=C3C2=C1 YQQRKUQVFWYEPV-UHFFFAOYSA-N 0.000 description 2
- MKLHYMKPRPGNQN-UHFFFAOYSA-N CC1=C2C3=CC=CC=C3C(NC2=CC=C1)C(=O)OC Chemical class CC1=C2C3=CC=CC=C3C(NC2=CC=C1)C(=O)OC MKLHYMKPRPGNQN-UHFFFAOYSA-N 0.000 description 2
- UVRRJILIXQAAFK-UHFFFAOYSA-N 2-bromo-4-methylaniline Chemical compound CC1=CC=C(N)C(Br)=C1 UVRRJILIXQAAFK-UHFFFAOYSA-N 0.000 description 1
- 102000017916 BDKRB1 Human genes 0.000 description 1
- 108010044231 Bradykinin B1 Receptor Proteins 0.000 description 1
- UESVBHOUEQVVQZ-UHFFFAOYSA-N Cc(cc1)ccc1S(N1c(ccc(F)c2)c2-c2ccccc2C1CC(CI)=O)(=O)=O Chemical compound Cc(cc1)ccc1S(N1c(ccc(F)c2)c2-c2ccccc2C1CC(CI)=O)(=O)=O UESVBHOUEQVVQZ-UHFFFAOYSA-N 0.000 description 1
- MQOOLCIUPIHNIK-UHFFFAOYSA-N Cc(cc1)ccc1S(N1c(ccc(F)c2)c2-c2ccccc2C1CC(c1ccccc1)=O)(=O)=O Chemical compound Cc(cc1)ccc1S(N1c(ccc(F)c2)c2-c2ccccc2C1CC(c1ccccc1)=O)(=O)=O MQOOLCIUPIHNIK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UGVHBURDLZFBOE-UHFFFAOYSA-N n-(2-bromo-4-methylphenyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(C)C=C1Br UGVHBURDLZFBOE-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
Abstract
The invention relates to the field of organic synthesis, and particularly relates to a preparation method of a 6-substitute-5,6-dihydro phenanthridine derivative. The preparation method disclosed by the invention comprises the following steps of: carrying out Suzuki-Miyaura reaction and Michael addition reaction on phenylboronic acid ester II and an o-bromoaniline derivative III which used as raw materials in the presence of a palladium catalyst in a one-pot manner. The method has the advantages of easily available raw material, wide substrate application range, high yield, and the like.
Description
Technical field
The present invention relates to the organic synthesis field.Be specifically related to the preparation method of 6-replacement-5,6-dihydro phenanthridine derivatives.
Background technology
5,6-dihydro phenanthridine derivatives is the mother nucleus structure of multiple natural product, and its derivative has multiple biological activity.Document (Bioorg Med Chem Lett, 2012,22,3095 – 3099) has reported that a class contains the derivative of 5,6-dihydro phenanthridines structure, and finds that they have the bradykinin b 1 receptor antagonistic activity.
Document (J Org Chem, 1998,63,5211-5215) 5 of report, the synthetic route of 6-dihydro phenanthridine derivatives is as follows:
There is following shortcoming in aforesaid method: the source difficulty of (1) biphenyl derivatives 1; (2) use two kinds of noble metal catalysts.
Summary of the invention
The objective of the invention is to find a kind of with low cost, raw material conveniently is easy to get, eco-friendly preparation 6-replaces-5,6-dihydro phenanthridine derivatives method.
The invention discloses the preparation method that a kind of 6-replaces-5,6-dihydro phenanthridine derivatives (I), comprising:
Wherein: R
1Alkyl, phenyl, methoxy or ethoxy for C1～C6; R
2For hydrogen, chlorine, fluorine or methyl; R
3For hydrogen or p-toluenesulfonyl;
Catalyzer is tetrakis triphenylphosphine palladium, [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound, two (bis-Ya Benzyl benzylacetone) palladium or [two (triphenyl phosphorus)] palladium chloride.
The inventive method be take borate ester (II) and o-bromoaniline derivative (III) and is raw material, and Suzuki-Miyaura reaction and Michael addition reaction are carried out to " treating different things alike ", reacts under the existence of catalyzer and alkali.Filter after completion of the reaction, filtrate decompression concentration and recovery organic solvent, (ethyl acetate: sherwood oil=0-10:1) separate obtains I to the residue column chromatography.
The preferred tetrakis triphenylphosphine palladium of catalyzer wherein.
Alkali is preferably from aqueous sodium carbonate, wet chemical, aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, cesium fluoride, potassiumphosphate, DIPEA, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene or triethylamine.Alkali is aqueous sodium carbonate or wet chemical more preferably.The concentration of the aqueous solution of above-mentioned alkali is preferably 0.1mol/L～5mol/L; More preferably 1mol/L～3mol/L.
Reaction solvent is glycol dimethyl ether, ethylene glycol diethyl ether, Isosorbide-5-Nitrae-dioxane or DMF.More preferably glycol dimethyl ether.
Preferably 50 ℃～120 ℃ of wherein said temperature of reaction; More preferably 80 ℃～110 ℃.
In present method, the molar ratio of each component is preferred: substrate II: substrate III: catalyzer: alkali=1:0.5～2:0.01～0.2:1～10; More preferably 1:0.9～1.1:0.05～0.1:4～8.
Preparation method of the present invention and document (J Org Chem, 1998,63,5211-5215) compare, have that raw material is easy to get, the substrate wide accommodation, only need a kind of catalyzer, productive rate advantages of higher.
Embodiment
Embodiment 1
6-(3-oxopropyl)-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-1) synthetic:
In the 500ml three-necked bottle, by (E)-2-(3-oxo-1-butylene base) phenylo boric acid pinacol ester (II-1:R=CH
3) (2.72g, 0.01mol), N-(4-tosyl group)-2-bromaniline (3.24g; 0.01mol), tetrakis triphenylphosphine palladium (1.16g, 0.001mol) and 2mol/L aqueous sodium carbonate (6.36g; 0.06mol) all be dissolved in the 300mL glycol dimethyl ether, pass into nitrogen protection, be heated to the 6h that refluxes; after the TLC monitoring reaction completes, be cooled to room temperature, filter; filtrate decompression is concentrated, and the residue column chromatography for separation, obtain yellow oil product I-1; heavy 2.76g, productive rate 84.9%.
1H-NMR(300MHz,CDCl3)δ7.74(dd,J=7.6,1.4Hz,1H),7.57(dd,J=7.4,1.7Hz,1H),7.43–7.29(m,2H),7.23–7.13(m,2H),7.13–7.02(m,2H),6.88(d,J=8.2Hz,2H),6.65(d?J=8.1Hz,2H),5.82(t,J=7.2Hz,1H),2.67(dd,J=16.1,7.4Hz,1H),2.47(dd,J=16.1,7.1Hz,1H),2.10(s,3H),2.09(s,3H).
13C-NMR(75MHz,CDCl3)δ204.61,142.61,133.82,133.34,132.50,129.51,129.07,128.88,128.82,28.73,128.16,127.88,127.49,127.26,127.21,126.51,126.37,123.13,122.93,54.19,48.37,29.88,20.77.
Embodiment 2
2-methyl-6-(3-oxopropyl)-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-2) synthetic:
With (E)-2-(3-oxo-1-butylene base) phenylo boric acid pinacol ester (II-1:R=CH
3) and 4-methyl-N-(4-tosyl group)-2-bromaniline be raw material, the operation with embodiment 1, obtain yellow oil product I-2, productive rate 92%.
1H-NMR(300MHz,CDCl3)δ7.66(d,J=8.2Hz,1H),7.40(s,1H),7.26–7.17(m,3H),7.16–7.20(m,2H),6.94(d,J=8.3Hz,2H),6.70(d,J=8.0Hz,2H),5.81(t,J=7.2Hz,1H),2.71(dd,J=16.2,7.4Hz,1H),2.50(dd,J=16.1,7.2Hz,1H),2.44(s,3H),2.16(s,3H),2.14(s,3H).
13C-NMR(75MHz,CDCl
3)δ204.61,142.32,137.00,133.89,133.52,130.03,129.37,129.16,129.02,128.75,127.81,127.26,127.04,126.78,126.60,126.45,123.61,122.62,122.02,54.95,48.37,29.88,20.91,20.72.
Embodiment 3
The fluoro-6-of 2-(3-oxopropyl)-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-3) synthetic:
With (E)-2-(3-oxo-1-butylene base) phenylo boric acid pinacol ester (II-1:R=CH
3) and the fluoro-N-of 4-(4-tosyl group)-2-bromaniline be raw material, the operation with embodiment 1, obtain yellow solid product I-3, productive rate 83%, 123～125 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.75(dd,J=8.9,5.3Hz,1H),7.26(dd,J=9.33,3.0Hz,1H),7.21(s,1H),7.19–7.06(m,4H),6.91(d,J=8.3Hz,2H),6.69(d,J=8.0Hz,2H),5.84(t,J=7.2Hz,1H),2.68(dd,J=16.2,7.3Hz,1H),2.50(dd,J=16.2,7.3Hz,1H),2.14(s,3H),2.12(s,3H).
13C-NMR(75MHz,CDCl
3)δ204.10,163.02,159.84,142.70,133.94,133.12,131.42,131.31,130.90,130.77,128.15,127.95,127.28,126.59,122.88,115.28,115.01,109.82,109.51,54.70,48.37,29.31,20.82.
Embodiment 4
6-benzoyl methyl-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-4) synthetic:
Take (E)-2-(3-oxo-3-phenyl propenyl) phenylo boric acid pinacol ester (II-2:R=Ph) and N-(4-tosyl group)-2-bromaniline is raw material; operation is with embodiment 1; obtain white solid product I-4, productive rate 87%, 144～147 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.76(d,J=1.3Hz,1H),7.73(d,J=1.3Hz,1H),7.65–7.59(m,1H),7.54-7.43(m,2H),7.41–7.33(m,2H),7.30–7.20(m,2H),7.30–7.21(m,2H),7.15–7.04(m,2H),6.95(d,J=8.3Hz,2H),6.69(d,J=8.1Hz,2H),6.08(dd,J=7.9,5.9Hz,1H),3.34(dd,J=16.4,8.1Hz,1H),3.01(dd,J=16.4,8.1Hz,1H),2.14(s,3H).
13C-NMR(75MHz,CDCl
3)δ195.75,142.60,142.37,136.20,134.08,133.73,132.95,132.72,132.12,129.55,128.95,128.91,128.04,128.01,127.93,127.83,127.62,127.35,127.11,127.06,126.88,126.56,126.49,123.07,122.68,54.70,43.30,20.51.
Embodiment 5
2-methyl-6-benzoyl methyl-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-5) synthetic:
Take (E)-2-(3-oxo-3-phenyl propenyl) phenylo boric acid pinacol ester (II-2:R=Ph) and 4-methyl-N-p-toluenesulfonyl-2-bromaniline is raw material; operation is with embodiment 1; obtain faint yellow solid product I-5, productive rate 88%, 131～135 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.81(d,J=7.7Hz,1H),7.75(d,J=7.8Hz,1H),7.61(d,J=7.9Hz,1H),7.53-7.46(m,2H),7.42–7.35(m,3H),7.24–7.19(m,2H),7.07(m,2H),6.95(d,J=8.0Hz,2H),6.69(d,J=7.9Hz,2H),6.04(t,J=6.9Hz,1H),3.34(dd,J=16.4,5.7Hz,1H),3.00(dd,J=16.3,7.8Hz,1H),2.41(s,3H),2.14(s,3H).
13C-NMR(75MHz,CDCl3)δ195.75,142.23,138.23,136.81,134.10,133.77,132.65,130.38,129.21,129.05,128.91,128.72,128.61,128.00,127.93,127.81,127.65,127.18,127.02,126.97,126.85,126.60,126.50,123.54,122.60,54.63,43.60,20.91,20.71.
Embodiment 6
The fluoro-6-benzoyl of 2-methyl-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-6) synthetic:
Take (E)-2-(3-oxo-3-phenyl propenyl) phenylo boric acid pinacol ester (II-2:R=Ph) and the fluoro-N-of 4-(4-tosyl group)-2-bromaniline is raw material, and operation, with embodiment 1, obtains white solid product I-6,104～107 ℃ of productive rates.
1H-NMR(300MHz,CDCl
3)δ7.81(d,J=7.3Hz,1H),7.75(d,J=7.5,1H),7.72–7.66(m,1H),7.55–7.45(m,2H),7.40–7.35(m,2H),7.32–7.26(m,2H),7.14–7.08(m,2H),6.94(d,J=8.1Hz,2H),6.70(d,J=8.0Hz,2H),6.08(t,J=6.9Hz,1H),3.33(dd,J=16.4,5.9Hz,1H),3.00(dd,J=16.5,7.9Hz,1H),2.15(s,3H).
13C-NMR(75MHz,CDCl
3)δ195.49,142.58,140.75,134.15,132.90,132.16,130.91,130.79,129.53,129.20,128.08,127.94,127.60,127.25,126.97,126.85,126.58,126.50,123.33,122.90,115.19,114.88,109.88,109.51,54.95,43.91,20.77.
Embodiment 7
6-ethoxycarbonylmethyl group-5-p-toluenesulfonyl-5,6-dihydro phenanthridines (I-7) synthetic:
With (E)-2-(3-oxyethyl group-3-oxo-1-propenyl) phenylo boric acid pinacol ester (II-3:R=OCH
2CH
3) and N-(4-tosyl group)-2-bromaniline be raw material, the operation with embodiment 1, obtain white solid product I-7, productive rate 90%, 103～104 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.77(dd,J=7.8,1.2Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.42–7.29(m,2H),7.25–7.20(m,1H),7.16–7.04(m,3H),6.90(d,J=8.2Hz,2H),6.66(d,J=8.1Hz,2H),5.79(t,J=7.6Hz,1H),4.16(q,J=7.0Hz,2H),2.54(dd,J=15.0,8.3Hz,1H),2.40(dd,J=15.0,7.1Hz,1H),2.12(s,3H),1.27(t,J=7.1Hz,3H).
13C-NMR(75MHz,CDCl
3)δ169.16,142.43,133.58,133.53,133.23,132.46,129.26,129.02,129.00,128.13,127.82,127.39,127.30,127.10,126.53,126.18,126.16,123.02,122.77,60.27,55.39,39.94,20.90,13.76.
Embodiment 8
2-methyl-6-ethoxycarbonylmethyl group-5-p-toluenesulfonyl-5,6-dihydro phenanthridines (I-8) synthetic:
With (E)-2-(3-oxyethyl group-3-oxo-1-propenyl) phenylo boric acid pinacol ester (II-3:R=OCH
2CH
3) and 4-methyl-N-(4-tosyl group)-2-bromaniline be raw material, the operation with embodiment 1, obtain faint yellow oily product I-8, productive rate 82%.
1H-NMR(300MHz,CDCl
3)δ7.64(d,J=8.2Hz,1H),7.37(s,1H),7.25–7.15(m,2H),7.16–7.09(m,3H),6.92(d,J=8.0Hz,2H),6.67(d,J=8.0Hz,2H),5.76(t,J=7.6Hz,1H),4.16(q,J=7.1Hz,2H),2.53(dd,J=14.9,8.3Hz,1H),2.46–2.33(m,4H),2.13(s,3H),1.27(t,J=7.0Hz,3H).
13C-NMR(75MHz,CDCl
3)δ169.34,142.33,136.88,133.65,133.35,132.32,129.87,129.19,129.09,129.05,128.93,128.78,127.81,127.20,126.85,126.54,126.18,123.55,122.67,60.36,55.33,39.81,20.88,20.73,13.80.
Embodiment 9
6-ethoxycarbonylmethyl group-5,6-dihydro phenanthridines (I-9) synthetic:
With (E)-2-(3-oxyethyl group-3-oxo-1-propenyl) phenylo boric acid pinacol ester (II-3:R=OCH
2CH
3) and the 2-bromaniline be raw material, the operation with embodiment 1, obtain white solid product I-9, productive rate 85%, 102～103 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.76(d,J=8.0Hz,1H),7.27(dd,J=7.9,1.26Hz,1H),7.36(td,J=7.6,1.4Hz,1H),7.26(td,J=7.4,1.2Hz,1H),7.19–7.11(m,2H),6.87(td,J=7.7,1.1Hz,1H),6.72(dd,J=7.9,0.9Hz,1H),4.86(dd,J=10.3,3.1Hz,1H),4.19(q,J=7.1Hz,2H),2.88(dd,J=16.5,10.4Hz,1H),2.45(dd,J=16.5,3.2Hz,1H),1.27(t,J=7.1Hz,3H).
13C-NMR(75MHz,CDCl
3)δ171.69,142.57,134.21,130.66,128.71,127.52,126.86,125.56,122.89,122.20,120.30,119.02,115.73,60.52,51.66,39.50,13.93.
Embodiment 10
2-methyl-6-ethoxycarbonylmethyl group-5,6-dihydro phenanthridines (I-10) synthetic:
With (E)-2-(3-oxyethyl group-3-oxo-1-propenyl) phenylo boric acid pinacol ester (II-3:R=OCH
2CH
3) and 4-methyl-2-bromaniline be raw material, the operation with embodiment 1, obtain white solid product I-10, productive rate 85%, 140～143 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.73(d,J=7.7Hz,1H),7.51(s,1H),7.33(td,J=7.6,1.4Hz,1H),7.23(td,J=7.3,1.1Hz,1H),7.13(d,J=6.8Hz,1H),6.95(d,J=7.4Hz,1H),6.62(d,J=8.0Hz,1H),4.79(dd,J=10.3,3.1Hz,1H),4.16(q,J=7.1Hz,2H),2.86(dd,J=10.3,1.47Hz,1H),2.41(td,J=3.2,16.4Hz,1H),2.32(s,3H),1.25(t,J=7.2Hz,3H).
13C?NMR(75MHz,CDCl
3)δ171.94,139.82,134.13,130.79,129.34,127.69,127.42,126.74,125.50,123.20,122.11,120.33,115.49,60.01,51.91,39.32,20.35,13.80.
Embodiment 11
The fluoro-6-ethoxycarbonylmethyl group-5 of 2-, 6-dihydro phenanthridines (I-11) synthetic:
With (E)-2-(3-oxyethyl group-3-oxo-1-propenyl) phenylo boric acid pinacol ester (II-3:R=OCH
2CH
3) and the fluoro-2-bromaniline of 4-be raw material, the operation with embodiment 1, obtain white solid product I-11, productive rate 75%, 136～138 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.65(d,J=7.7Hz,1H),7.39(dd,J=9.9,2.8Hz,1H),7.33(dd,J=7.6,1.3Hz,1H),7.30–7.23(m,1H),7.14(dd,J=7.4,0.8Hz,1H),6.85(td,J=8.5,2.8Hz,1H),6.63(dd,J=8.7,4.8Hz,1H),4.80(dd,J=10.4,3.0Hz,1H),4.17(q,J=7.1Hz,2H),2.83(dd,J=16.5,10.4Hz,1H),2.41(dd,J=16.5,3.1Hz,1H),1.26(t,J=7.1Hz,3H).
13C-NMR(75MHz,CDCl
3)δ171.84,158.03,134.09,127.57,127.46,125.52,122.30,116.19,116.05,115.39,115.03,109.32,109.05,60.32,51.91,39.41,13.94.
Embodiment 12
6-methoxycarbonyl methyl-5,6-dihydro phenanthridines (I-12) synthetic:
With (E)-2-(3-methoxyl group-3-oxo-1-propenyl) phenylo boric acid pinacol ester (II-4:R=OCH
3) and the 2-bromaniline be raw material, the operation with embodiment 1, must look for oily product I-12, productive rate 72%.
1H-NMR(300MHz,CDCl
3)δ7.73(d,J=7.7Hz,1H),7.69(dd,J=7.8,1.1Hz,1H),7.33(td,J=7.6,1.3Hz,1H),7.26–7.20(m,2H),7.15–7.09(m,2H),6.84(td,J=7.5,0.8Hz,1H),6.69(d,J=7.9Hz,1H),4.82(dd,J=10.4,3.0Hz,1H),3.69(s,3H),2.87(dd,J=16.6,10.4Hz,1H),2.43(dd,J=16.7,3.1Hz,1H).
13C-NMR(75MHz,CDCl
3)δ172.19,142.33,133.84,130.80,128.71,127.56,126.72,125.56,122.94,122.21,120.43,118.65,115.61,51.67,51.15,39.50.
Embodiment 13
The fluoro-6-methoxycarbonyl of 2-methyl-5,6-dihydro phenanthridines (I-13) synthetic:
With (E)-2-(3-methoxyl group-3-oxo-1-propenyl) phenylo boric acid pinacol ester (II-4:R=OCH
3) and the fluoro-2-bromaniline of 4-be raw material, the operation with embodiment 1, obtain white solid product I-13, productive rate 67%, 101～103 ℃ of melting ranges.
1H-NMR(300MHz,CDCl
3)δ7.64(d,J=7.9Hz,1H),7.38(dd,J=9.9,2.7Hz,1H),7.33(dd,J=7.7,1.4Hz,1H),7.26(td,J=7.4,1.3Hz,1H),7.13(d,J=7.4Hz,1H),6.84(td,J=8.5,2.8Hz,1H),6.62(dd,J=8.7,4.8Hz,1H),4.80(dd,J=10.4,3.1Hz,1H),3.70(s,3H),2.84(dd,J=16.6,10.4Hz,1H),2.42(dd,J=16.6,3.1Hz,1H).
13C-NMR(75MHz,CDCl
3)δ171.92,158.06,138.21,127.61,127.49,125.51,122.37,116.21,116.16,115.39,115.09,109.36,109.05,51.75,51.19,38.97.
Embodiment 14
6-(3-oxopropyl)-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-1) synthetic:
In the 500ml three-necked bottle, by (E)-2-(3-oxo-1-butylene base) phenylo boric acid pinacol ester (II-1:R=CH
3) (2.72g, 0.01mol), N-(4-tosyl group)-2-bromaniline (3.24g; 0.01mol), [two (triphenyl phosphorus)] palladium chloride (0.70g, 0.001mol) and 2mol/L aqueous sodium carbonate (6.36g; 0.06mol) all be dissolved in the 300mL glycol dimethyl ether, pass into nitrogen protection, be heated to the 6h that refluxes; after TLC monitoring raw material disappears, be cooled to room temperature, filter; filtrate decompression is concentrated; the residue column chromatography for separation, obtain yellow oil product I-1, productive rate 62%.
Embodiment 15
6-(3-oxopropyl)-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-1) synthetic:
In the 500ml three-necked bottle, by (E)-2-(3-oxo-1-butylene base) phenylo boric acid pinacol ester (II-1:R=CH
3) (2.72g, 0.01mol), N-(4-tosyl group)-2-bromaniline (3.24g; 0.01mol), tetrakis triphenylphosphine palladium (1.16g, 0.001mol) and 2mol/L wet chemical (8.29g; 0.06mol) all be dissolved in the 300mL glycol dimethyl ether, pass into nitrogen protection, be heated to the 6h that refluxes; after TLC monitoring raw material disappears, be cooled to room temperature, filter; filtrate decompression is concentrated; the residue column chromatography for separation, obtain yellow oil product I-1, productive rate 79%.
Embodiment 16
6-(3-oxopropyl)-5-(4-tosyl group)-5,6-dihydro phenanthridines (I-1) synthetic:
In the 500ml three-necked bottle, by (E)-2-(3-oxo-1-butylene base) phenylo boric acid pinacol ester (II-1:R=CH
3) (2.72g, 0.01mol), N-(4-tosyl group)-2-bromaniline (3.24g; 0.01mol), tetrakis triphenylphosphine palladium (1.16g, 0.001mol) and 2mol/L aqueous sodium carbonate (6.36g; 0.06mol) all be dissolved in Isosorbide-5-Nitrae-dioxane of 300mL, pass into nitrogen protection; be heated to the 8h that refluxes, after TLC monitoring raw material disappears, be cooled to room temperature; filter, filtrate decompression is concentrated, the residue column chromatography for separation; obtain yellow oil product I-1, productive rate 41%.
Claims (10)
1. a 6-replaces the preparation method of-5,6-dihydro phenanthridine derivatives (I), comprising:
Wherein: R
1Alkyl, phenyl, methoxy or ethoxy for C1～C6; R
2For hydrogen, chlorine, fluorine or methyl; R
3For hydrogen or p-toluenesulfonyl;
Catalyzer is tetrakis triphenylphosphine palladium, [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound, two (bis-Ya Benzyl benzylacetone) palladium or [two (triphenyl phosphorus)] palladium chloride.
2. the preparation method of claim 1, wherein catalyzer is tetrakis triphenylphosphine palladium.
3. the preparation method of claim 1, wherein alkali is aqueous sodium carbonate, wet chemical, aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, cesium fluoride, potassiumphosphate, N, N
-Diisopropylethylamine, 1,8
-Diazabicyclo [5.4.0] 11 carbon-7-alkene or triethylamine.
4. the preparation method of claim 3, wherein alkali is aqueous sodium carbonate or wet chemical.
5. the preparation method of claim 1, wherein reaction solvent is glycol dimethyl ether, ethylene glycol diethyl ether, Isosorbide-5-Nitrae-dioxane or DMF.
6. the preparation method of claim 5, wherein reaction solvent is glycol dimethyl ether.
7. the preparation method of claim 1, wherein the molar ratio of II, III, catalyzer, alkali is 1:0.5～2:0.01～0.2:1～10.
8. the preparation method of claim 7, wherein the molar ratio of II, III, catalyzer, alkali is 1:0.9～1.1:0.05～0.1:4～8.
9. the preparation method of claim 1, wherein temperature of reaction is 50 ℃～120 ℃.
10. the preparation method of claim 9, wherein temperature of reaction is 80 ℃～110 ℃.
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| CN107778241A (en) * | 2016-08-29 | 2018-03-09 | 中山大学 | A kind of new synthetic method of the dihydrophenanthridine class compound of 6 aryl 5,6 |
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Cited By (7)
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| CN107935925A (en) * | 2017-11-22 | 2018-04-20 | 浙江大学 | A kind of preparation method of polysubstituted triphenylene acridine compound |
| CN107935925B (en) * | 2017-11-22 | 2020-06-19 | 浙江大学 | Preparation method of polysubstituted phenanthridine compound |
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Address after: Tong Xiang, Gulou District of Nanjing city of Jiangsu Province, No. 24 210009 Patentee after: CHINA PHARMACEUTICAL University Address before: 211200 Kechuang Center, 688 Tianshengqiao Avenue, Yongyang Town, Lishui County, Nanjing City, Jiangsu Province Patentee before: CHINA PHARMACEUTICAL University |