CN104628643A - Preparation method of isoquinolone and derivatives thereof - Google Patents

Preparation method of isoquinolone and derivatives thereof Download PDF

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Publication number
CN104628643A
CN104628643A CN201510084724.3A CN201510084724A CN104628643A CN 104628643 A CN104628643 A CN 104628643A CN 201510084724 A CN201510084724 A CN 201510084724A CN 104628643 A CN104628643 A CN 104628643A
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preparation
compounds
reaction
cyanobenzene
butoxide
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CN104628643B (en
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包明
于晓强
冯秀娟
默罕默德谢里夫马佑
王娇
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Dalian University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical and chemical intermediates and related chemicals and relates to a preparation method of isoquinolone and derivatives thereof. The isoquinolone and derivatives thereof are important biologically active molecules, skeletal structures frequently appear in natural molecules and drug molecules, and have better therapeutic effect on hypertension, cancer and anxiety disorders and important applications in the fields of organic synthesis and pharmaceutical chemistry. The method is short in synthesis route, mild in conditions and simple in operation and is expected to achieve industrial production and has the advantages of short synthetic route, mild conditions, simple operation and high yield and the like. The isoquinolone and derivatives thereof have greater application value and social and economic benefits.

Description

The preparation method of a kind of isoquinolines and derivative thereof
Technical field
The invention belongs to pharmaceutical-chemical intermediate and related chemistry technical field, relate to a kind of isoquinolines and derivative preparation method thereof.
Background technology
Isoquinolines and derivative thereof be a class important there is bioactive molecules, its skeleton structure frequently comes across in natural molecule and drug molecule, there is good result for the treatment of to hypertension, lung cancer and anxiety disorder, have important application in the field such as organic synthesis and pharmaceutical chemistry.
About the synthesis of compound of isobioquin group, usually adopt the following two kinds method:
(1) transition metal-catalyzed arylamide and the annulation of alkynes
The reaction conditions of the method is very harsh, usually needs pyroreaction condition; Use the noble metal catalyst such as rhodium, palladium, be not suitable for suitability for industrialized production [see (a) Hyster, T.K.; Rovis, T.J.Am.Chem.Soc.2010,132,10565-10569; (b) Mochida, S.; Umeda, N.; Miura, M.et al.Chem.Lett.2010,39,744-746; (c) Song, G.Y.; Chen, D.; Li, X.W.et al.J.Org.Chem.2010,75,7487-7490.]
(2) annulation of arylamide bimetal
The reaction conditions of the method is very harsh, needs cold operation, polystep reaction yield is low, is also not suitable for suitability for industrialized production [see (a) Davis, S.E.; Cameron Church, A.; Mazat Griffith, C.L.; Beam, C.F.Synth.Commun.1997,27,2961. (b) Fisher, L.E.; Muchowski, J.M.; Clark, R.D.J.Org.Chem.1992,57,2700. (c) Poindexter, G.S.J.Org.Chem.1982,47,3787.]
Summary of the invention
The invention provides the preparation method of a kind of isoquinolines and derivative thereof, with 2-halogeno-benzene formonitrile HCN and ketone compounds for raw material, using mantoquita as catalyzer, under inorganic alkaline Conditioning, there is ring-closure reaction synthesize a series of isoquinolines and derivative thereof.
The present invention is that mantoquita, as catalyzer, ring-closure reaction occurs under inorganic alkaline Conditioning and synthesizes a series of isoquinolines and derivative thereof with 2-halogeno-benzene formonitrile HCN and ketone compounds for raw material.Synthetic route is as follows:
In the reaction of above-mentioned synthetic method, on 2-halogeno-benzene formonitrile HCN aromatic ring, X is selected from chlorine, bromine, iodine; R on the aromatic ring of 2-halogeno-benzene formonitrile HCN compounds 1be selected from hydrogen, halogen, alkyl; Ketone compounds R 2be selected from hydrogen, alkyl, alkoxyl group, trifluoromethyl.
In the reaction of above-mentioned synthetic method, copper salt catalyst used is that Red copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, trifluoromethane sulfonic acid are cuprous, one or more mixing in cupric oxide, cupric bromide, cupric chloride, copper triflate, neutralized verdigris; The add-on of copper salt catalyst is the 1-50mol% of cyanobenzene analog derivative.
In the reaction of above-mentioned synthetic method, mineral alkali is one or more mixing in potassium tert.-butoxide, cesium carbonate, sodium hydroxide, sodium tert-butoxide, potassium hydroxide, sodium carbonate, salt of wormwood.The add-on of mineral alkali is the 100-300mol% of cyanobenzene analog derivative.
In the reaction of above-mentioned synthetic method, organic solvent used is benzene, toluene, 1, one or more mixing in 4-dioxane, dimethyl sulfoxide (DMSO), DMF, methyl alcohol, ethanol, Virahol, propyl carbinol, methylene dichloride, trichloromethane, n-butyl ether, tetracol phenixin, ethyl acetate, sherwood oil, methyl tertiary butyl ether, tetrahydrofuran (THF), acetone, acetonitrile; The add-on of organic solvent is 2-100 times of cyanobenzene analog derivative weight.
In the reaction of above-mentioned synthetic method, temperature of reaction is at 30 ~ 120 DEG C.
Method synthetic route of the present invention is short, mild condition, simple to operate and yield is higher, has a extensive future.Compound of isobioquin group is widely used in the many aspects of chemical field, has wide market outlook.Such as isoquinolines and derivative thereof be a class important there is bioactive molecules, its skeleton structure frequently comes across in natural molecule and drug molecule, there is good result for the treatment of to hypertension, lung cancer and anxiety disorder, have important application in the field such as organic synthesis and pharmaceutical chemistry.
Accompanying drawing explanation
Fig. 1 is compound 3a in embodiment 1 1h nuclear magnetic spectrogram.
Fig. 2 is compound 3b in embodiment 2 1h nuclear magnetic spectrogram.
Fig. 3 is compound 3c in embodiment 3 1h nuclear magnetic spectrogram.
Fig. 4 is compound 3d in embodiment 4 1h nuclear magnetic spectrogram.
Fig. 5 is compound 3e in embodiment 5 1h nuclear magnetic spectrogram.
Fig. 6 is compound 3f in embodiment 6 1h nuclear magnetic spectrogram.
Fig. 7 is compound 3g in embodiment 7 1h nuclear magnetic spectrogram.
Fig. 8 is compound 3h in embodiment 8 1h nuclear magnetic spectrogram.
Fig. 9 is compound 3i in embodiment 9 1h nuclear magnetic spectrogram.
Figure 10 is compound 3n in embodiment 10 1h nuclear magnetic spectrogram.
Figure 11 is compound 3o in embodiment 11 1h nuclear magnetic spectrogram.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.These embodiments are only not used in for illustration of the present invention and limit the scope of the invention.The simple replacement done the present invention those skilled in the art or improve all belongs within the technical scheme that the present invention protects.
The synthesis of embodiment 1:3-phenyl isoquinolin quinoline ketone (3a)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), neutralized verdigris (1.0mg, 0.01mmol), potassium tert.-butoxide (56.0mg, 0.5mmol), acetophenone (60.0mg, 0.5mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add toluene 0.2mL, 30 DEG C are reacted 4 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain faint yellow solid product 0.091g, yield is 82%.Mp 204–205℃. 1H NMR(400MHz,CDCl 3)δ6.79(s,1H),7.45–7.55(m,4H),7.60(d,J＝7.6Hz,1H),7.65–7.69(m,1H),7.75–7.78(m,2H),8.41(d,J＝8.0Hz,1H),10.44(s,1H).
The synthesis of embodiment 2:3-p-methylphenyl isoquinolines (3b)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), neutralized verdigris (9.1mg, 0.1mmol), potassium tert.-butoxide (56.0mg, 0.5mmol), corresponding phenyl ketone (134.0mg, 1.0mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add methyl alcohol 1.0mL, 50 DEG C are reacted 5 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.099g, yield is 85%.Mp 224–226℃. 1H NMR(400MHz,CDCl 3)δ2.43(s,3H),6.76(s,1H),7.32(d,J＝8.0Hz,2H),7.46–7.50(m,1H),7.59(d,J＝7.7Hz,1H),7.64–7.67(m,3H),8.41(d,J＝8.0Hz, 1H),10.23(s,1H).
The synthesis of embodiment 3:3-(4-p-methoxy-phenyl) isoquinolines (3c)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), neutralized verdigris (18.2mg, 0.2mmol), potassium tert.-butoxide (84.0mg, 1.0mmol), corresponding phenyl ketone (90.0mg, 0.75mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add glycol dimethyl ether 0.5mL, 60 DEG C are reacted 6 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.111g, yield is 88%; Mp 237 – 239 DEG C. 1h NMR (400MHz, DMSO-d 6) δ 4.07 (s, 3H), 7.10 (s, 1H), 7.30 (d, J=8.6Hz, 2H), 7.68 – 7.72 (m, 1H), 7.92 – 8.02 (m, 4H), 8.44 (d, J=8.0Hz, 1H), 11.71 (s, 1H).
The synthesis of embodiment 4:3-(2-aminomethyl phenyl) isoquinolines (3d)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), neutralized verdigris (1.0mg, 0.005mmol), salt of wormwood (69.0mg, 0.5mmol), corresponding phenyl ketone (127.0mg, 1.0mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add ethanol 2.0mL, 90 DEG C are reacted 9 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.076g, yield is 65%; Mp 182 – 184 DEG C. 1h NMR (400MHz, DMSO-d 6) δ 2.31 (s, 3H), 6.48 (s, 1H), 7.26 – 7.38 (m, 4H), 7.48 (dd, J=7.8,6.8Hz, 1H), 7.65 – 7.72 (m, 2H), 8.21 (d, J=8.0Hz, 1H), 11.44 (s, 1H).
The synthesis of embodiment 5:3-(2-fluorophenyl) isoquinolines (3e)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), cupric bromide (2.2mg, 0.01mmol), potassium tert.-butoxide (78.5mg, 1.0mmol), corresponding phenyl ketone (138.0mg, 1.0mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add acetonitrile 3.0mL, 50 DEG C are reacted 10 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain faint yellow solid product 0.039g, yield is 32%; Mp 243 – 245 DEG C. 1h NMR (400MHz, DMSO-d 6) δ 6.72 (s, 1H), 7.30 – 7.37 (m, 2H), 7.49 – 7.54 (m, 2H), 7.60 – 7.64 (m, 1H), 7.69 – 7.74 (m, 2H), 8.21 (d, J=8.9Hz, 1H), 11.53 (s, 1H);
The synthesis of embodiment 6:3-(4-fluorophenyl) isoquinolines (3f)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), cupric oxide (8.0mg, 0.1mmol), potassium tert.-butoxide (78.5mg, 1.0mmol), corresponding phenyl ketone (69.0mg, 0.5mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add glycol dimethyl ether 3.0mL, 50 DEG C are reacted 12 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.078g, yield is 65%; Mp 222 – 223 DEG C. 1h NMR (400MHz, DMSO-d 6) δ 6.89 (s, 1H), 7.33 (dd, J=8.4,8.4Hz, 2H), 7.48 – 7.50 (m, 1H), 7.68 – 7.73 (m, 2H), 7.82 – 7.85 (m, 2H), 8.19 (d, J=7.9Hz, 1H), 11.55 (s, 1H).
The synthesis of embodiment 7:3-(4-fluoroform phenyl) isoquinolines (3g)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), cuprous (the 0.8mg of trifluoromethane sulfonic acid, 0.005mmol), sodium carbonate (106.0mg, 1.0mmol), corresponding phenyl ketone (188.0mg, 1.0mmol) join successively in Schlenk reaction flask, vacuum, after nitrogen replacement 3 times, in nitrogen atmosphere, add tetrahydrofuran (THF) 1.0mL, 50 DEG C are reacted 12 hours, after reaction terminates, removal of solvent under reduced pressure, (eluent is sherwood oil to column chromatography for separation: ethyl acetate=20:1, V:V), obtain white solid product 0.109g, yield is 75%, Mp 270 – 272 DEG C. 1h NMR (400MHz, DMSO-d 6) δ 7.05 (s, 1H), 7.52 – 7.56 (m, 1H), 7.76 (d, J=3.7Hz, 2H), 7.86 (d, J=8.4Hz, 2H), 8.02 (d, J=8.2Hz, 2H), 8.24 (d, J=8.0Hz, 1H), 11.70 (s, 1H).
The synthesis of embodiment 8:3-(4-iodophenyl) isoquinolines (3h)
By 2-bromobenzylcyanide (90.48mg, 0.5mmol), cuprous chloride (2.0mg, 0.02mmol), potassium hydroxide (112.0mg, 1.0mmol), corresponding phenyl ketone (246.0mg, 1.0mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add acetonitrile 4.0mL, 30 DEG C are reacted 12 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.087g, yield is 50%; Mp 261 – 263 DEG C. 1h NMR (400MHz, DMSO-d 6) δ 6.94 (s, 1H), 7.48 – 7.52 (m, 1H), 7.59 (d, J=8.6Hz, 2H), 7.71 – 7.73 (m, 2H), 7.86 (d, J=8.6Hz, 2H), 8.20 (d, J=7.7Hz, 1H), 11.56 (s, 1H).
The synthesis of embodiment 9:4-methyl-3-phenyl isoquinolin quinoline ketone (3i)
By 2-bromobenzylcyanide (90.5mg, 0.5mmol), cuprous bromide (1.4mg, 0.01mmol), sodium tert-butoxide (96.1mg, 1.0mmol), corresponding phenyl ketone (134.0mg, 1.0mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add normal hexane 4.0mL, 50 DEG C are reacted 12 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.080g, yield is 68%; Mp 186 – 188 DEG C. 1h NMR (400MHz, CDCl 3) δ 2.27 (s, 3H), 7.45 – 7.55 (m, 6H), 7.76 (dd, J=1.1,4.2Hz, 2H), 8.46 (d, J=8.0Hz, 1H), 8.83 (s, 1H).
The synthesis of embodiment 10:6-methyl-3-phenyl isoquinolin quinoline ketone (3n)
By 4-methyl 2-bromobenzylcyanide (97.5mg, 0.5mmol), cuprous iodide (18.9mg, 0.1mmol), salt of wormwood (60.0mg, 1.5mmol), acetophenone (90.0mg, 0.75mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add toluene 4.0mL, 120 DEG C are reacted 12 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.116g, yield is 98%; Mp 211 – 213 DEG C. 1h NMR (400MHz, CDCl 3) δ 2.50 (s, 3H), 6.72 (s, 1H), 7.30 (dd, J=1.1,8.2Hz, 1H), 7.38 (s, 1H), 7.44 – 7.48 (m, 1H), 7.50 – 7.54 (m, 2H), 7.75 (dd, J=1.5,7.0Hz, 2H), 8.29 (d, J=8.2Hz, 1H), 10.28 (s, 1H).
The synthesis of embodiment 11:7-chloro-3-phenyl isoquinolin quinoline ketone (3o)
By chloro-for 5-2-bromobenzylcyanide (107.5mg, 0.5mmol), Red copper oxide (36.0mg, 0.25mmol), cesium carbonate (489.3mg, 1.5mmol), acetophenone (60.0mg, 0.5mmol) join successively in Schlenk reaction flask, after vacuum, nitrogen replacement 3 times, in nitrogen atmosphere, add ethanol 10.0mL, 60 DEG C are reacted 12 hours, after reaction terminates, removal of solvent under reduced pressure, column chromatography for separation (eluent is sherwood oil: ethyl acetate=20:1, V:V), obtain white solid product 0.127g, yield is 99%; Mp 258 – 260 DEG C. 1h NMR (400MHz, DMSO-d 6) δ 6.10 (s, 1H), 6.61 – 6.67 (m, 3H), 6.90 – 6.94 (m, 4H), 7.28 (dd, J=0.8,1.0Hz, 1H), 10.86 (s, 1H).

Claims (8)

1. the preparation method of an isoquinolines and derivative thereof, it is characterized in that, with 2-halogeno-benzene formonitrile HCN compounds and ketone compounds for raw material, as catalyzer, there is ring-closure reaction and synthesize a series of isoquinolines and derivative thereof in mantoquita under inorganic alkaline Conditioning; Synthetic route is as follows:
In above-mentioned synthetic method, on 2-halogeno-benzene formonitrile HCN aromatic ring, X is selected from chlorine, bromine, iodine; R on the aromatic ring of cyanobenzene compounds 1be selected from hydrogen, halogen, alkyl; Ketone compounds R 2be selected from hydrogen, alkyl, alkoxyl group, trifluoromethyl;
The mol ratio of ketone compounds and cyanobenzene compounds is 1 ~ 2:1;
The mol ratio of mineral alkali and cyanobenzene compounds is 1 ~ 3:1;
The add-on of copper salt catalyst is 1 ~ 50mol% of cyanobenzene analog derivative;
The add-on of organic solvent is 2 ~ 100 times of cyanobenzene analog derivative weight.
2. preparation method according to claim 1, in, described copper salt catalyst, its feature is also that Red copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, trifluoromethane sulfonic acid are cuprous, one or more mixing in cupric oxide, cupric bromide, cupric chloride, copper triflate, neutralized verdigris.
3. preparation method according to claim 1 and 2, it is characterized in that, described organic solvent is tetrahydrofuran (THF), 1, one or more mixing in 4-dioxane, glycol dimethyl ether, dimethyl sulfoxide (DMSO), toluene, DMF, acetonitrile, ethanol, hexanaphthene, normal hexane.
4. preparation method according to claim 1 and 2, is characterized in that, described mineral alkali is one or more mixing in potassium tert.-butoxide, cesium carbonate, sodium hydroxide, sodium tert-butoxide, potassium hydroxide, sodium carbonate, salt of wormwood.
5. preparation method according to claim 3, is characterized in that, described mineral alkali is one or more mixing in potassium tert.-butoxide, cesium carbonate, sodium hydroxide, sodium tert-butoxide, potassium hydroxide, sodium carbonate, salt of wormwood.
6. the preparation method according to claim 1,2 or 5, is characterized in that described temperature of reaction is 30-120 DEG C.
7. preparation method according to claim 3, is characterized in that described temperature of reaction is 30-120 DEG C.
8. preparation method according to claim 4, is characterized in that described temperature of reaction is 30-120 DEG C.
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Cited By (5)

* Cited by examiner, † Cited by third party
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CN106632039A (en) * 2016-12-15 2017-05-10 温州医科大学附属第二医院 Synthetic method of antitumor nitrogen-containing heterocyclic drug intermediates
CN108794395A (en) * 2018-07-06 2018-11-13 大连理工大学 A kind of preparation method of 2- quinolinones compounds
CN109912492A (en) * 2019-03-29 2019-06-21 大连理工大学 A kind of synthetic method of 3- benzal 1-isoindolinone derivative
CN112645887A (en) * 2020-12-21 2021-04-13 淮阴工学院 Preparation method of quinazolinone derivative
CN115286572A (en) * 2022-07-15 2022-11-04 绍兴文理学院 4-acyl-isoquinoline derivative and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632039A (en) * 2016-12-15 2017-05-10 温州医科大学附属第二医院 Synthetic method of antitumor nitrogen-containing heterocyclic drug intermediates
CN108794395A (en) * 2018-07-06 2018-11-13 大连理工大学 A kind of preparation method of 2- quinolinones compounds
CN109912492A (en) * 2019-03-29 2019-06-21 大连理工大学 A kind of synthetic method of 3- benzal 1-isoindolinone derivative
CN109912492B (en) * 2019-03-29 2022-06-14 大连理工大学 Synthetic method of 3-benzylidene isoindoline-1-one derivative
CN112645887A (en) * 2020-12-21 2021-04-13 淮阴工学院 Preparation method of quinazolinone derivative
CN115286572A (en) * 2022-07-15 2022-11-04 绍兴文理学院 4-acyl-isoquinoline derivative and preparation method and application thereof
CN115286572B (en) * 2022-07-15 2023-10-13 绍兴文理学院 4-acyl-isoquinoline derivative and preparation method and application thereof

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