CN109678798A - A kind of synthetic method of isoquinoline compound - Google Patents

A kind of synthetic method of isoquinoline compound Download PDF

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CN109678798A
CN109678798A CN201910050644.4A CN201910050644A CN109678798A CN 109678798 A CN109678798 A CN 109678798A CN 201910050644 A CN201910050644 A CN 201910050644A CN 109678798 A CN109678798 A CN 109678798A
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arh
compound
synthetic method
alkoxy
amino
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CN109678798B (en
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赵云辉
唐子龙
谢文林
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Hunan University of Science and 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
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

The invention discloses a kind of synthetic methods of isoquinoline compound.The isoquinoline compound is shown in formula I, wherein R1For hydrogen, halogen atom, alkyl, alkoxy or amino, R2For hydrogen, halogen atom, alkyl, alkoxy or amino.The present invention is using adjacent alkynyl aldehyde and gumbix as raw material, tandem reaction, which is eliminated, through imidization, cyclisation, oxidation synthesizes target product, synthetic method is succinct, quick, and target compound yield is higher, provides necessary basis for further research compound of formula I or related compound.

Description

A kind of synthetic method of isoquinoline compound
Technical field
The present invention relates to organic chemical synthesis fields, and in particular to a kind of synthetic method of isoquinoline compound.
Background technique
Alkaloid containing isoquinolin skeleton structure is a kind of important alkaloid, this Alkaloid has extremely strong life Reason activity is always that domestic and international chemist and drug scholar research and develop the hot spot utilized.Either extracted from natural products Or fully synthetic or molecular structure alteration, and the research of structure-activity relationship, isoquinoline class derivate are always to find to have exploitation The lead compound of application prospect and the source of bioactive ingredients.Its main pharmacological includes anti-inflammatory, antibacterial, the mistake of the anti-rhythm of the heart Often, analgesia antibechic, protection cardiovascular and cerebrovascular, anti-AIDS, conciliation immunization and anticancer etc..So important physiological activity, adds The characteristics of upper Small side effects, makes this substance have very high value of exploiting and utilizing and more wide application prospect.Thus open Send out simple and direct, the method that efficiently synthesizes isoquinoline compound is particularly important.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic methods of isoquinoline compound, shown in formula I:
I
Wherein, R1For hydrogen, halogen atom, alkyl, alkoxy or amino, R2For hydrogen, halogen atom, alkyl, alkoxy or amino.
The synthetic method of above-mentioned isoquinoline compound, includes the following steps:
The preparation of target compound I
Compound 1, benzylamine and metallic catalyst are dissolved in solvent, the substance of the compound 1, benzylamine and metallic catalyst The ratio between amount is 1:1-5:0.1-3, is stirred under 60-100 degree, and TLC monitors reaction process, to fully reacting, stops reaction, will react Object is cooled to room temperature, and vacuum rotary steam removes solvent, and residue carries out column chromatography, obtains target product shown in Formulas I；
Above each compound is distinguish with serial number below compound each in reaction equation, wherein R1For hydrogen, halogen atom, alkane Base, alkoxy or amino, R2For hydrogen, halogen atom, alkyl, alkoxy or amino.
Further, R1Preferably H, Cl or Me.
Further, R2Preferably H, OMe, F, Cl,n- Bu or Me.
Further, in synthesis step, the preferred gumbix of the benzylamine.
Further, in synthesis step, the solvent preferred alcohol.
Further, in synthesis step, the preferred silver nitrate of the metallic catalyst.
Reactant in the present invention only has adjacent alkynyl aldehyde 1 and gumbix, but experienced imidization/cyclisation/oxidation The tandem reaction course of elimination, gumbix play the role of providing ammonia source in this reaction, and reaction condition is mild, yield phase Than previously it has been reported that method improve a lot.
Specific embodiment
The present invention is done below by way of specific embodiment and is further described in detail, but this should not be interpreted as in the present invention The range for stating theme is only limitted to embodiment below.All technologies realized based on above content of the present invention belong to of the invention Range.
Instrument and reagent of the present invention:
Nuclear Magnetic Resonance: Bruker AV-II 500 MHz NMR, TMS are internal standard, CDCl3For solvent;Infrared spectrometer: TFS- 40 types, KBr tabletting.
Agents useful for same is that commercially available chemistry is pure or analysis is pure.
Embodiment 1
The synthesis of the compounds of this invention
The compounds of this invention preparation approach is as follows:
The synthesis of target compound 2a-2l:
The silver nitrate of the compound 1 of 1 mmol, the gumbix of 1.5 mmol and 0.3 mmol is taken to be dissolved in ethyl alcohol, under 80 degree It is stirred to react, TLC monitors reaction process, to fully reacting, stops reaction, reactant is cooled to room temperature, vacuum rotary steam removes Solvent, residue carry out column chromatography, obtain target product shown in Formulas I.
, 3-phenyl isoquinolin quinolines, white solid, yield 63%,1H NMR (500 MHz, CDCl3) δ 9.37 (s, 1H, ArH), 8.16 (d, J = 7.5 Hz, 2H, ArH), 8.10 (s, 1H, ArH), 8.02 (d, J = 8.0 Hz, 1H, ArH), 7.91 – 7.89 (d, J = 8.0 Hz, 1H, ArH), 7.75 – 7.70 (m, 1H, ArH), 7.63 – 7.60 (m, 1H, ArH), 7.56 – 7.53 (m, 2H, ArH), 7.47 – 7.44 (m, 1H, ArH).
2b, 7- methyl-3-phenyl isoquinolin quinoline, light yellow solid, yield 78%,1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1H, ArH), 8.11 (d, J = 7.5 Hz, 2H, ArH), 8.01 (s, 1H, ArH), 7.77 – 7.71 (m, 2H, ArH), 7.5 – 7.48 (m, 3H, ArH), 7.42 – 7.38 (m, 1H, ArH), 2.54 (s, 3H, Ar-CH3).
Chloro- 3-phenyl isoquinolin the quinoline of 2c, 7-, light green solid, yield 72%,1H NMR (500 MHz, CDCl3) δ 9.25 (s, 1H, ArH), 8.12 – 8.08 (m, 2H, ArH), 8.02 (s, 1H, ArH), 7.95 (d, J = 1.5 Hz, 1H, ArH), 7.79 (d, J = 9.0 Hz, 1H, ArH), 7.61 (dd, J = 9.0, 2.0 Hz, 1H, ArH), 7.52 – 7.49 (m, 2H, ArH), 7.44 – 7.43 (m, 1H, ArH).
2d, 7- methyl-3-(4- aminomethyl phenyl) isoquinolin, pale red solid, yield 83%, 148~149 DEG C of fusing point,1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H, ArH), 8.00 (d, J = 8.0 Hz, 2H, ArH), 7.97 (s, 1H, ArH), 7.74 – 7.70 (m, 2H, ArH), 7.49 (dd, J = 8.5, 1.0 Hz, 1H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 2.53 (s, 3H, Ar-CH3), 2.41 (s, 3H, Ar-CH3).
2e, 7- methyl-3-(4- chlorphenyl) isoquinolin, yellow solid, yield 66%, 149~150 DEG C of fusing point,1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H, ArH), 8.04 (d, J = 8.5 Hz, 2H, ArH), 7.98 (s, 1H, ArH), 7.75 (d, J = 9.0 Hz, 2H, ArH), 7.54 – 7.52(m, 1H, ArH), 7.45 (d, J = 8.5 Hz, 2H, ArH), 2.55 (s, 3H, Ar-CH3).
2f, 7- chloro- 3-(4- aminomethyl phenyl) isoquinolin, green solid, yield 83%, 159~160 DEG C of fusing point,1H NMR (500 MHz, CDCl3) δ 9.23 (s, 1H, ArH), 8.01 (s, 1H, ArH), 7.99 (d, J = 3.5 Hz, 2H, ArH), 7.94 (d, J = 1.5 Hz, 1H, ArH), 7.78 (d, J = 9.0 Hz, 1H, ArH), 7.59 (dd, J = 9.0, 2.0 Hz, 1H, ArH), 7.31 (d, J = 8.0 Hz, 2H, ArH), 2.42 (s, 3H, Ar-CH3).
2g, 7- chloro- 3-(4- chlorphenyl) isoquinolin, light green solid, yield 72%, 157~158 DEG C of fusing point,1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H, ArH), 8.05-8.02 (m, 2H, ArH), 7.98 (s, 1H, ArH), 7.94 (d, J = 1.5 Hz, 1H, ArH), 7.78 (d, J = 9.0 Hz, 1H, ArH), 7.62 (dd,J = 8.5, 2.0 Hz, 1H, ArH), 7.49 – 7.43 (m, 2H, ArH).
2h, 3-(4- aminomethyl phenyl) isoquinolin, light yellow solid, yield 81%,1H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.04 – 8.00 (m, 3H, ArH), 7.95 (d, J = 7.5 Hz, 1H, ArH), 7.83 – 7.81(m, 1H, ArH), 7.68 – 7.62 (m, 1H, ArH), 7.55 – 7.51(m, 1H, ArH), 7.30 (d,J = 8.0 Hz, 2H, ArH), 2.41 (s, 3H, Ar-CH3).
2i, 3-(4- n-butylphenyl) isoquinolin, light yellow solid, yield 78%, 54~55 DEG C of fusing point,1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H, ArH), 8.07 – 8.01(m, 3H, ArH), 7.97 (d, J = 8.0 Hz, 1H, ArH), 7.85 (d, J = 8.0 Hz, 1H, ArH), 7.70 – 7.63 (m, 1H, ArH), 7.58 – 7.53 (m, 1H, ArH), 7.32 (d, J = 8.0 Hz, 2H, ArH), 2.68 (t, J=7.5 Hz, 2H, Ar- CH2-), 1.69 – 1.62 (m, 2H, -CH2-Et), 1.43 – 1.36 (m, 2H, -CH2-Me), 0.95 (t, J = 7.5 Hz, 3H, -CH3).
2j, 3-(4- methoxyphenyl) isoquinolin, light yellow solid, yield 82%,1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H, ArH), 8.09 – 8.06 (m, 2H, ArH), 7.97 (s, 1H, ArH), 7.94 (d, J = 8.0 Hz, 1H, ArH), 7.81 (d, J = 8.0 Hz, 1H, ArH), 7.67 – 7.62 (m, 1H, ArH), 7.55 – 7.50 (m, 1H, ArH), 7.05 – 7.01 (m, 2H, ArH), 3.86 (s, 3H, -OCH3).
2k, 3-(4- fluorophenyl) isoquinolin, light yellow solid, yield 76%,1H NMR (500 MHz, CDCl3)δ 9.31 (s, 1H, ArH), 8.12 – 8.07 (m, 2H, ArH), 7.99 (s, 1H, ArH), 7.97 (d, J = 8.5 Hz, 1H, ArH), 7.84 (d, J = 8.0 Hz, 1H, ArH), 7.71 – 7.66 (m, 1H, ArH), 7.60 – 7.55 (m, 1H, ArH), 7.21 – 7.16 (m, 2H, ArH).
2l, 3-(4- chlorphenyl) isoquinolin, yellow solid, yield 72%,1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H, ArH), 8.08 – 8.03 (m, 2H, ArH), 8.00 (s, 1H, ArH), 7.96 (d, J = 8.0 Hz, 1H, ArH), 7.83 (d, J = 8.0 Hz, 1H, ArH), 7.70 – 7.66 (m, 1H, ArH), 7.60 – 7.55 (m, 1H, ArH), 7.48 – 7.43 (m, 2H, ArH).
Embodiment 2
The silver nitrate of the compound 1a of 1 mmol, the gumbix of 1.5 mmol and 0.3 mmol is taken to be dissolved in ethyl alcohol, 100 degree Under be stirred to react, TLC monitors reaction process, to fully reacting, stops reaction, reactant is cooled to room temperature, vacuum rotary steam removes Solvent is removed, residue carries out column chromatography, obtains target product 2a, yield 71%.
Embodiment 3
The silver nitrate of the compound 1a of 1 mmol, the gumbix of 1.5 mmol and 0.5 mmol is taken to be dissolved in ethyl alcohol, 80 degree Under be stirred to react, TLC monitors reaction process, to fully reacting, stops reaction, reactant is cooled to room temperature, vacuum rotary steam removes Solvent is removed, residue carries out column chromatography, obtains target product 2a, yield 45%.
Embodiment 4
The silver nitrate of the compound 1a of 1 mmol, the gumbix of 1.5 mmol and 1.0 mmol is taken to be dissolved in ethyl alcohol, 80 degree Under be stirred to react, TLC monitors reaction process, to fully reacting, stops reaction, reactant is cooled to room temperature, vacuum rotary steam removes Solvent is removed, residue carries out column chromatography, obtains target product 2a, yield 78%.

Claims (5)

1. a kind of synthetic method of isoquinoline compound, the isoquinoline compound is shown in formula I,
I
Wherein, R1For hydrogen, halogen atom, alkyl, alkoxy or amino, R2For hydrogen, halogen atom, alkyl, alkoxy or amino； It is characterized in that, it includes the following steps:
The preparation of target compound I
Compound 1, benzylamine and metallic catalyst are dissolved in solvent, the substance of the compound 1, benzylamine and metallic catalyst The ratio between amount is 1:1-5:0.1-3, is stirred under 60-100 degree, and TLC monitors reaction process, to fully reacting, stops reaction, will react Object is cooled to room temperature, and vacuum rotary steam removes solvent, and residue carries out column chromatography, obtains target product shown in Formulas I；
Above each compound is distinguish with serial number below compound each in reaction equation, wherein R1For hydrogen, halogen atom, alkane Base, alkoxy or amino, R2For hydrogen, halogen atom, alkyl, alkoxy or amino.
2. the synthetic method of isoquinoline compound according to claim 1, it is characterised in that: R1For H, Cl or Me；R2For H 、OMe、F、Cl、n- Bu or Me.
3. the synthetic method of isoquinoline compound according to claim 1, it is characterised in that: in synthesis step, used Benzylamine be gumbix.
4. the synthetic method of isoquinoline compound according to claim 1, it is characterised in that: described in synthesis step Solvent is ethyl alcohol or methanol.
5. the synthetic method of isoquinoline compound according to claim 1, it is characterised in that: in synthesis step, metal is urged Agent is silver nitrate.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK196885A (en) * 1984-05-03 1985-11-04 Glaxo Group Ltd PHARMACEUTICAL PREPARATIONS CONTAINING ISOQUINOLIN DERIVATIVES AND ISOQUINOLIN DERIVATIVES CONTAINING SUCH DERIVATIVES
CN105503722A (en) * 2016-01-26 2016-04-20 湖南科技大学 Method for synthesizing isoquinoline compound
CN105541713A (en) * 2016-01-26 2016-05-04 湖南科技大学 Isoquinoline compound and synthetic method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK196885A (en) * 1984-05-03 1985-11-04 Glaxo Group Ltd PHARMACEUTICAL PREPARATIONS CONTAINING ISOQUINOLIN DERIVATIVES AND ISOQUINOLIN DERIVATIVES CONTAINING SUCH DERIVATIVES
CN105503722A (en) * 2016-01-26 2016-04-20 湖南科技大学 Method for synthesizing isoquinoline compound
CN105541713A (en) * 2016-01-26 2016-05-04 湖南科技大学 Isoquinoline compound and synthetic method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
VIRSINHA REDDY等: "A room-temperature protocol to access isoquinolines through Ag(i) catalysed annulation of o-(1-alkynyl)arylaldehydes and ketones with NH4OAc: elaboration to berberine and palmatine", 《ORG. BIOMOL. CHEM.》 *
YONGXING TANG等: "An efficient approach to isoquinoline via AgNO3-promoted 6-endo-dig cyclization followed by oxidative elimination of o-alkynylarylaldimines and its application in fluoride recognition", 《TETRAHEDRON LETTERS》 *

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