CN105130894B - Isoquinoline compound and its synthetic method - Google Patents

Isoquinoline compound and its synthetic method Download PDF

Info

Publication number
CN105130894B
CN105130894B CN201510589678.2A CN201510589678A CN105130894B CN 105130894 B CN105130894 B CN 105130894B CN 201510589678 A CN201510589678 A CN 201510589678A CN 105130894 B CN105130894 B CN 105130894B
Authority
CN
China
Prior art keywords
phenyl
reaction
compound
methyl
grams
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201510589678.2A
Other languages
Chinese (zh)
Other versions
CN105130894A (en
Inventor
许斌
于洋
毛宏
刘秉新
谭启涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Shanghai for Science and Technology
Original Assignee
University of Shanghai for Science and Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Shanghai for Science and Technology filed Critical University of Shanghai for Science and Technology
Priority to CN201510589678.2A priority Critical patent/CN105130894B/en
Publication of CN105130894A publication Critical patent/CN105130894A/en
Application granted granted Critical
Publication of CN105130894B publication Critical patent/CN105130894B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/08—Aza-anthracenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a kind of isoquinoline compound and its synthetic method, the structural formula of such compound is： R1For：Phenyl, 4 aminomethyl phenyls or 2 methoxyl group naphthyls；R2For：Hydrogen, methyl, phenyl, 4 aminomethyl phenyls or benzyl；R3 For：Methyl formate, Ethyl formate or formamide；R4For：Phenyl, 4 chlorphenyls, alkyl or methyl formate.The substituted isoquinoline compound of the present invention is a kind of highly useful organic synthesis building block, and such compound also has higher bioactivity and potential physiological and pharmacological activity.The raw material of the present invention is easy to get, and reaction selectivity is high, and using cheap four gentle hydration manganese acetates as catalyst, relatively inexpensive novelty.And using conventional reaction dissolvent, simple to operate, mild condition, reaction environmental protection, when outstanding in yield, there is good development prospect in the industrial production.

Description

Isoquinoline compound and its synthetic method
Technical field
The present invention relates to a kind of isoquinoline compound and its synthetic method.
Background technology
Nitrogen heterocyclic ring is a kind of very common pharmacophoric group in drug research field, is current small-molecule drug research and development One of important goal.Before global sales in 2014 in the brand medicine of 25, all with nitrogen heterocyclic ring skeleton.Various substitutions Isoquinoline compound be a kind of important nitrogen heterocyclic ring, they are widely used in field of medicaments.This kind of compound by The features such as antibiotic property in its wide spectrum, stronger antibacterial action, preferable drug tolerance, as important synthetic antibacterial drug It is widely applied clinically.For example, jamaicin is to hemolytic streptococcus, staphylococcus aureus, gonococcus and Freund, will Hayes shigella dysenteriae has antibacterial action, and has enhancing white blood cell phagocytosis.The hydrochloride of jamaicin, it is commonly called as the hydrochloric acid coptis Element, treatment gastroenteritis, bacillary dysentery etc. are widely used in, to pulmonary tuberculosis, scarlet fever, acute tonsillitis and respiratory tract infection Also there is certain curative effect.Therefore development one kind can efficiently synthesize isoquinoline compound, particularly prepare all kinds of substituted isoquinolin The new method of class compound, has great importance.It can not only provide important synthetic intermediate for iloquinoline derivative medicine （See reference document：IJzerman, A. P. et al.J. Med. Chem. 2000, 43, 2227）.Simultaneously synthesizing is each The isoquinoline compound of kind substitution also is available for physiologically active screening in itself（See reference document：Koskinen, A. M. P. et al. Bioorg.Med. Chem.2009, 17, 4441）.
The method for the synthesis isoquinoline compound reported in document mainly has following several：
（One）2007, Porco groups realized the series connection of intramolecular under the silver catalysis of three fluosulfonic acid by designing substrate Cycloisomerisation, Dipolar Cycloaddition then is carried out with alkynes to build isoquinoline compound molecular skeleton.Study mechanism is sent out Existing, the cycloisomerisation generation N- methylene imine ylides of silver catalysis are the key intermediates to form pyrroles's isoquinolin skeleton.But The Material synthesis of this method is complex（See reference document：Su, S.; Porco, J. A.J. Am. Chem. Soc.2007, 129, 7744）.
（Two）Ellman seminars under Rh catalysis, are then entered under palladium carbon catalysis again using N- benzyls imines and alkynes Row hydrogenation synthesizes isoquinoline class derivate.But this method equally exists the shortcomings of Material synthesis complexity（See reference document： Ellman, J. A. J. Am. Chem. Soc.2008, 130, 3645）.
（Three）2012, Liu Guosheng seminars utilized the imines substrate of ortho position alkynes substitution, by the use of silver nitrate as urging Agent, for NFSI as Fluorine source and oxidant, one-step method obtains the isoquinoline compound of 4- fluorine substitution.But this method is to substrate Scope have larger limitation, and used excess raw material cause to waste（See reference document：Xu, T.; Liu, G.Org. Lett.2012, 14, 5416）.
(4) 2014 years, yellow Chinese seminar passed through the C-H/N-N keys of order by the use of Rh (III) as catalyst Priming reaction, ketone azo-compound is reacted with alkynes, efficiently obtain polysubstituted isoquinoline compound.This reaction Atom economy it is high, completed using only air as oxidant can under conditions of room temperature（See reference document：Huang, H. Org. Lett.2014, 16, 3532）.
In summary, the synthetic method of isoquinoline compound has that the above is several, but substrates of these reactions are all relative It is more complicated, often to react to obtain by several steps.Also, these reactions generally require to use transition metal conduct costly Catalyst.
The content of the invention
An object of the present invention is to provide a kind of isoquinoline compound.
The second object of the present invention is the preparation method for providing such compound.
To reach above-mentioned purpose, the reaction mechanism that the inventive method uses for：
R1For：Phenyl, 4- aminomethyl phenyls, 2- methoxyl group naphthyls；
R2For：Methyl, phenyl, 4- aminomethyl phenyls, benzyl；
R3For：Methyl formate, Ethyl formate, formamide；
R4For：Phenyl, 4- chlorphenyls, the tert-butyl group, methyl formate.
According to above-mentioned reaction mechanism, present invention employs following technical scheme：
A kind of polysubstituted isoquinoline compound, it is characterised in that the structural formula of such compound is：
R1For：Phenyl, 4- aminomethyl phenyls or 2- methoxyl group naphthyls；R2For：Hydrogen, methyl, phenyl, 4- aminomethyl phenyls or benzyl；R3For：Methyl formate, Ethyl formate or formamide；R4For：Phenyl, 4- chlorphenyls, alkyl or formic acid Methyl esters.
A kind of synthetic method for preparing polysubstituted isoquinoline compound according to claim 1, its feature exist There are following steps in this method：Under an inert atmosphere, by alkenyl isonitrile, hydrazine, manganese acetate, peroxidized t-butyl perbenzoate（Business Product reagent）By 1：（2.0~8.0）：（0.2~1.0）：（2.0~10.0）Mol ratio be added in acetonitrile solvent, in 60~ 80 oStirring reaction to reaction raw materials disappear under C；After reaction terminates, washed respectively with water and saturated sodium bicarbonate solution, use second Acetoacetic ester extracts product, and organic phase obtains crude product after removing solvent；The crude product obtains iloquinoline derivative chemical combination through separating-purifying Thing；The structural formula of described alkenyl isonitrile is：；The structural formula of described hydrazine is：。
The substituted isoquinoline compound of the present invention is a kind of important organic reaction intermediate, by different types of Organic chemical reactionses, such as annulation, addition reaction, reduction reaction, it can quickly and easily synthesize and a series of contain isoquinoline The alkaloid of quinoline skeleton.Isoquinoline compound is not only important pharmaceutical intermediate, and is the important knot of natural products Structure.
Isoquinoline compound can as the intermediate of organic synthesis, come synthesize the reactive compound of some iloquinoline derivatives or Medicine.It is exemplified below：
（One）German Eberhard groups are reacted from isoquinoline compound tetrahydrobiopterin synthesis isoquinoline using Bruylants Quinoline compound, product structure witho- methyl armepavine is more similar, has certain pharmaceutical activity（See reference document： Eberhard, R.; Christian, E. Mon. Fur. Chem. 2004, 135, 1289-1295）.
（Two）Berberine is Isoquinolinium hydrochloride, has more patent report to synthesize 1,2 by isoquinoline compound, 3,4- four hydrogen isoquinoline hydrochloric acid salt medicines.Such as following reaction synthesizes 4- methyl isophthalic acids from 4- methylisoquinoliniums, 2,3,4- tetrahydrochysenes are different Quinoline hydrochloride（See reference document：Gottschling, D.; Dahmann, G.; Doods, H. Patent: US 195954A1, 2011,104-105）.
（Three）Jamaicin can be synthesized by isoquinoline compound as initiation material, and its synthetic route is in related text Middle report is offered, its synthetic reaction is as follows（See reference document：Zinovia, K.; Fichtner, R. H.; Poplawski, J.; Nalliah, B. C.; MacLean, D. B.Can. J. Chem. 1980 , 58, 2770-2779）.
As can be seen here, development one kind can efficiently synthesize isoquinoline compound, particularly prepare all kinds of substituted isoquinolin The new method of class compound, has great importance.It can not only provide important synthetic intermediate for iloquinoline derivative medicine, Simultaneously synthesizing various substituted isoquinoline compounds also are available for physiologically active screening in itself.
The inventive method raw material is simple and easy to get, and avoids the harshnesses such as strong acid as catalyst using cheap manganese acetate Condition use.Reaction has used the reaction dissolvent of routine, and simple to operate, mild condition, reaction is environmentally friendly, when excellent in yield Show, there is good development prospect in the industrial production.
Embodiment
Embodiment one：The carboxylate methyl ester isoquinolin of 1,4 diphenyl 3
The carboxylate methyl ester isoquinolin of 1,4 diphenyl 3 uses following step：1. add 13.1 in 1000 milliliters of reaction bulbs Gram diphenylacrylate methyl esters of 2 isonitrile base 3,3,26.2 grams of phenylhydrazines, 2 grams of manganese acetates, 51.0 grams of tertiary fourths of perbenzoic acid Ester, 650 milliliters of acetonitriles, is heated to 70 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；2. reaction terminates Afterwards, into system plus water quenching is gone out reaction, it is extracted with ethyl acetate product, organic phase is through saturated common salt water washing, with revolving after drying Turn evaporimeter and remove solvent, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=20: 1）Purifying, is obtained To 11.89 grams of carboxylate methyl ester isoquinolin of Isosorbide-5-Nitrae diphenyl 3, yield 83%.
IR (KBr, cm–1):1723.8, 1545.8, 1336.8, 1225.8, 1178.3, 996.3, 761.9, 698.7, 665.7.
1H NMR (CDCl3, 500 MHz):δ 8.18 (d, J = 8.0 Hz, 1H), 7.77 (td, J = 7.5, 1.5 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (td, J = 7.5, 1.5 Hz, 1H), 7.61 (td, J = 7.5, 1.5 Hz, 1H), 7.57-7.49 (m, 6H), 7.41 (dd, J = 8.0, 1.5 Hz, 2H), 3.70 (s, 3H).
13C NMR (CDCl3, 125 MHz):δ 167.69, 160.35, 141.40, 138.88, 136.67, 136.15, 132.92, 130.75, 130.36, 129.97, 129.10, 128.58. 128.45, 128.42, 128.17, 127.91, 127.32, 126.87, 52.55.
EI-MS m/z (%): 339 (44) [M+], 281 (35), 280 (100), 279 (24), 278 (47).
Embodiment two：The phenyl isoquinolin quinoline of 1 (4 chlorphenyl) 3 carboxylate methyl ester 4
The phenyl isoquinolin quinoline of 1 (4 chlorphenyl) 3 carboxylate methyl ester 4 uses following step：1. in 1000 milliliters of reaction bulbs Add 17.4 gram of 2 diphenylacrylate methyl esters of isonitrile base 3,3,28.9 gram of 4 chlorophenyl hydrazine, 3 grams of manganese acetates, 48.0 grams of peroxidating T-butyl perbenzoate, 500 milliliters of acetonitriles, is heated to 60 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；② After reaction terminates, into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, and organic phase is dry through saturated common salt water washing Remove solvent with Rotary Evaporators after dry, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=20: 1） Purifying, obtains 22.00 gram of 1 phenyl isoquinolin quinoline of (4 chlorphenyl) 3 carboxylate methyl ester 4, yield 81%.
IR (KBr, cm–1): 1715.6, 1597.4, 1491.0, 1437.7, 1326.2, 1225.7, 1170.7, 1086.1, 1003.5, 970.2, 841.7, 767.3, 694.9.
1H NMR (CDCl3, 500 MHz):δ 8.13 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 3H), 7.67 (td, J = 6.5, 1.0 Hz, 1H), 7.62 (td, J = 7.5, 1.5 Hz, 1H), 7.54-7.49 (m, 5H), 7.40 (dd, J = 8.0, 1.5 Hz, 2H), 3.70 (s, 3H).
13C NMR (CDCl3, 125 MHz):δ 167.55, 158.92, 141.41, 137.30, 136.58, 135.91, 135.19, 133.06, 131.60, 130.72, 129.80, 128.73, 128.55, 128.33, 128.12, 127.30, 127.04, 126.90, 52.46.
EI-MS m/z (%): 375 (20) [M+ (37Cl)], 373 (42) [M+ (35Cl)], 316 (39), 315 (51), 314 (100).
Embodiment three：The phenyl isoquinolin quinoline of 1 tert-butyl group, 3 carboxylate methyl ester 4
The phenyl isoquinolin quinoline of 1 tert-butyl group, 3 carboxylate methyl ester 4 uses following step：1. added in 1000 milliliters of reaction bulbs 21.7 gram of 2 diphenylacrylate methyl esters of isonitrile base 3,3,346.8 grams of Tertiary butyl hydrazine hydrochlorides, 289.2 grams of sodium acid carbonates, 4.3 Gram manganese acetate, 75.0 grams of peroxidized t-butyl perbenzoates, 750 milliliters of acetonitriles, is heated to 60 DEG C.Tracked with thin-layer chromatography method Reaction, disappeared to reaction raw materials；After 2. reaction terminates, into system plus water quenching is gone out reaction, and product is extracted with ethyl acetate, organic Mutually through saturated common salt water washing, remove solvent with Rotary Evaporators after drying, obtain crude product；3. crude product column chromatography（Oil Ether:Ethyl acetate=10: 1）Purifying, obtains 33.65 gram of 1 phenyl isoquinolin quinoline of 3 carboxylate methyl ester of the tert-butyl group 4, yield is 80%。
IR (KBr, cm–1): 1729.9, 1441.6, 1361.5, 1235.6, 1160.4, 987.4, 771.6, 697.3, 556.9.
1H NMR (CDCl3, 500 MHz):δ 8.63 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 8.0, 1.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.59-7.55 (m, 1H), 7.50-7.44 (m, 3H), 7.35- 7.33 (m, 2H), 3.67 (s, 3H), 1.73 (s, 9H).
13C NMR (CDCl3, 125 MHz):δ 168.28, 166.75, 139.95, 136.90, 136.50, 131.87, 129.89, 129.25, 128.17, 127.81, 127.78, 127.12, 126.80, 126.57, 52.12, 40.11, 31.19.
EI-MS m/z (%): 319 (100) [M+], 318 (44), 304 (52), 277 (82), 258 (84).
HRMS (ESI) m/z: calcd for C21H22NO2: 320.1651; found: 320.1645.
Example IV：The phenyl isoquinolin quinoline of 1,3 dicarboxylic acid methylester 4
The phenyl isoquinolin quinoline of 1,3 dicarboxylic acid methylester 4 uses following step：1. add 44.3 in 1000 milliliters of reaction bulbs Gram diphenylacrylate methyl esters of 2 isonitrile base 3,3,28.9 grams of methyl hydrazinocarboxylates, 20 grams of manganese acetates, 50.0 grams of benzoyl peroxides T-butyl formate, 500 milliliters of acetonitriles, is heated to 80 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；It is 2. anti- After should terminating, into system plus water quenching is gone out reaction, product is extracted with ethyl acetate, organic phase is through saturated common salt water washing, drying Remove solvent with Rotary Evaporators afterwards, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=10: 1）It is pure Change, obtain 48.50 gram 1, the phenyl isoquinolin quinoline of 3 dicarboxylic acid methylester 4, yield 45%.
IR (KBr, cm–1): 1731.4, 1434.8, 1368.8, 1236.5, 1198.0, 1154.5, 988.5, 762.7, 698.7.
1H NMR (CDCl3, 500 MHz): δ 8.84 (d, J = 8.5 Hz, 1H), 7.78-7.75 (m, 1H), 7.70-7.69 (m, 2H), 7.51-7.50 (m, 3H), 7.33 (dd, J = 7.5, 2.0 Hz, 2H), 4.12 (s, 3H), 3.71 (s, 3H).
13C NMR (CDCl3, 125 MHz):δ 166.56, 165.86, 148.17, 140.48, 137.37, 136.80, 135.48, 131.21, 129.87, 129.45, 128.36, 128.32, 127.01, 126.95, 126.42, 53.25, 52.62.
EI-MS m/z (%): 321 (298) [M+], 231 (826), 203 (815), 202 (552).
HRMS (ESI) m/z: calcd for C19H16NO4: 322.1079; found: 322.1074.
Embodiment five：1 phenyl 3 carboxylate methyl ester 4 (4 aminomethyl phenyl) 7 methylisoquinoliniums
1 phenyl 3 carboxylate methyl ester 4 (4 aminomethyl phenyl) 7 methylisoquinoliniums use following step：1. in 1000 millis Rise and 15.3 gram of 2 isonitrile base 3,3 two (4 aminomethyl phenyl) methyl acrylate, 85.3 grams of phenylhydrazines, 7.5 grams of vinegar are added in reaction bulb Sour manganese, 25.0 grams of peroxidized t-butyl perbenzoates, 500 milliliters of acetonitriles, it is heated to 70 DEG C.Tracked and reacted with thin-layer chromatography method, Disappeared to reaction raw materials；2. after reaction terminates, into system plus water quenching is gone out reaction, product is extracted with ethyl acetate, organic phase passes through Saturated common salt water washing, remove solvent with Rotary Evaporators after drying, obtain crude product；3. crude product column chromatography（Petroleum ether: Ethyl acetate=20: 1）Purifying, obtains 20.40 gram of 1 methyl isoquinoline of 3 carboxylate methyl ester 4 (4 aminomethyl phenyl) of phenyl 7 Quinoline, yield 70%.Fusing point：143-144 ℃.
IR (KBr, cm–1): 1724.9, 1313.7, 1224.7, 1164.0, 1012.2, 770.8, 700.8, 523.8.
1H NMR (CDCl3, 500 MHz):δ 7.90 (s, 1H), 7.76-7.74 (m, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.57-7.47 (m, 4H), 7.33-7.27 (m, 4H), 3.72 (s, 3H), 2.48 (d, J = 6.0 Hz, 6H).
13C NMR (CDCl3, 125 MHz):δ 167.57, 159.24, 140.28, 138.78, 138.69, 137.68, 134.98, 133.11, 133.06, 132.84, 130.21, 129.67, 129.03, 128.89, 128.45, 127.44, 126.73, 126.57, 52.47, 21.95, 21.43.
EI-MS m/z (%): 367 (52) [M+], 322 (14), 309 (30), 308 (100), 294 (69).
Embodiment six：The benzylisoquinoline of 1 phenyl, 3 carboxylate methyl ester 4
The benzylisoquinoline of 1 phenyl, 3 carboxylate methyl ester 4 uses following step：1. added in 1000 milliliters of reaction bulbs 9.9 grams (Z) 23,4 diphenyl of isonitrile base, 2 M Cr, 36.8 grams of phenylhydrazines, 14.0 grams of manganese acetates, 125.0 grams of peroxides Change t-butyl perbenzoate, 600 milliliters of acetonitriles, be heated to 70 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials； 2. after reaction terminates, into system plus water quenching is gone out reaction, be extracted with ethyl acetate product, organic phase through saturated common salt water washing, Remove solvent with Rotary Evaporators after drying, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=30: 1）Purifying, obtains 16.30 gram of 1 benzylisoquinoline of 3 carboxylate methyl ester of phenyl 4, yield 60%.
IR (KBr, cm–1): 1722.7, 1441.5, 1380.9, 1248.0, 1213.6, 1070.9, 990.9, 771.4, 703.0.
1H NMR (CDCl3, 500 MHz):δ 8.12 (t, J = 8.5 Hz, 2H), 7.73 (d, J = 7.0 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.58-7.50 (m, 4H), 7.28-7.21 (m, 4H), 7.19-7.16 (m, 1H), 4.76 (s, 2H), 3.96 (s, 3H);
13C NMR (CDCl3, 125 MHz):δ 168.16, 159.87, 142.44, 140.02, 139.05, 136.61, 130.78, 130.34, 129.73, 128.98, 128.67, 128.54, 128.47, 128.26, 127.71, 126.29, 125.33, 52.93, 33.99.
EI-MS m/z (%): 353 (67) [M+], 321 (100), 320 (57), 293 (24), 292 (72).
Embodiment seven：1 phenyl, 3 carboxylate methyl ester, 4 methyl 8 methoxyl group benzo [h] isoquinolin
1 phenyl, 3 carboxylate methyl ester, 4 methyl 8 methoxyl group benzo [h] isoquinolin uses following step：1. 1000 Milliliter reaction bulb in add 15.3 grams (Z) -2- isonitrile bases -3- (6- methoxyl group -2- naphthyls) 2- M Crs, 25.3 grams of benzene Hydrazine, 7.5 grams of manganese acetates, 25.0 grams of peroxidized t-butyl perbenzoates, 650 milliliters of acetonitriles, it is heated to 80 DEG C.With thin-layer chromatography side Method tracking reaction, disappears to reaction raw materials；After 2. reaction terminates, into system plus water quenching is gone out reaction, and production is extracted with ethyl acetate Thing, organic phase remove solvent with Rotary Evaporators after drying, obtain crude product through saturated common salt water washing；3. crude product post layer Analysis（Petroleum ether:Ethyl acetate=5: 1）Purifying, obtains 26.00 gram of 1 methoxyl group of 3 carboxylate methyl ester of phenyl, 4 methyl 8 Benzo [h] isoquinolin, yield 60%.Fusing point：181-182 ℃.
IR (KBr, cm–1): 1708.6, 1609.2, 1504.4, 1448.2, 1346.8, 1219.9, 1206.8, 1137.4, 1021.5, 847.6, 708.5, 623.9.
1H NMR (CDCl3, 500 MHz):δ 8.02 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.56-7.55 (m, 2H), 7.46-7.45 (m, 3H), 7.22-7.21 (m, 1H), 6.82 (dd, J = 9.5, 2.5 Hz, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 2.90 (s, 3H);
13C NMR (CDCl3, 125 MHz):δ 168.00, 158.51, 155.83, 143.60, 141.49, 136.66, 135.13, 131.72, 130.08, 129.21, 129.13, 128.45, 127.65, 125.01, 123.71, 122.02, 116.50, 108.35, 55.36, 52.65, 14.78.
EI-MS m/z (%): 357 (90) [M+], 299 (100), 297 (73), 254 (36).
Embodiment eight：The carboxylic acid, ethyl ester isoquinolin of 1,4 diphenyl 3
The carboxylic acid, ethyl ester isoquinolin of 1,4 diphenyl 3 uses following step：1. add 15.3 in 1000 milliliters of reaction bulbs Gram diphenyl-ethyl acrylate of 2 isonitrile 3,3,44.4 grams of phenylhydrazines, 29.0 grams of manganese acetates, 52.0 grams of tertiary fourths of perbenzoic acid Ester, 500 milliliters of acetonitriles, is heated to 70 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；2. reaction terminates Afterwards, into system plus water quenching is gone out reaction, it is extracted with ethyl acetate product, organic phase is through saturated common salt water washing, with revolving after drying Turn evaporimeter and remove solvent, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=10: 1）Purifying, is obtained To 24.20 grams of carboxylic acid, ethyl ester isoquinolin of Isosorbide-5-Nitrae diphenyl 3, yield 67%.Fusing point：131-132 ℃.
IR (KBr, cm–1): 1729.6, 1391.4, 1223.5, 1178.2, 1107.0, 1008.6, 770.1, 701.0.
1H NMR (CDCl3, 500 MHz): δ 8.18 (d, J = 8.0 Hz, 1H), 7.78-7.76 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (td, J = 7.0, 1.5 Hz, 1H), 7.60 (td, J = 6.5, 1.0 Hz, 1H), 7.57-7.48 (m, 6H), 7.44-7.42 (m, 2H), 4.12 (q, J = 7.0 Hz, 2H), 0.98 (t, J = 7.0 Hz, 3H).
13C NMR (CDCl3, 125 MHz):δ 167.48, 160.27, 142.14, 138.78, 136.42, 136.09, 132.00, 130.60, 130.27, 130.05, 128.95, 128.41, 128.28, 128.18, 128.04, 127.80, 127.07, 126.58, 61.32, 13.70. EI-MS m/z (%): 353 (21) [M+], 281 (33), 280 (100), 279 (15), 277 (18).
HRMS (ESI) m/z: calcd for C24H20NO2: 354.1494; found: 354.1488.
Embodiment nine：The acylpiperidine isoquinolin of 1,4 diphenyl 3
The acylpiperidine isoquinolin of 1,4 diphenyl 3 uses following step：1. add 15.3 in 1000 milliliters of reaction bulbs Gram 2- isonitrile -3,3- diphenyl -1- (1- piperidines) allydione, 44.4 grams of phenylhydrazines, 29.0 grams of manganese acetates, 52.0 grams of benzoyl peroxide first Tert-butyl acrylate, 500 milliliters of acetonitriles, is heated to 70 DEG C.Tracked and reacted with thin-layer chromatography method, disappeared to reaction raw materials；2. react After end, into system plus water quenching is gone out reaction, is extracted with ethyl acetate product, and organic phase is through saturated common salt water washing, after drying Remove solvent with Rotary Evaporators, obtain crude product；3. crude product column chromatography（Petroleum ether:Ethyl acetate=10: 1）It is pure Change, obtain 24.20 grams of acylpiperidine isoquinolin of Isosorbide-5-Nitrae diphenyl 3, yield 80%.Fusing point：214-215 ℃.
IR (KBr, cm–1): 1744.3, 1631.3, 1433.1, 1377.8, 1245.2, 1024.1, 985.9, 758.2, 698.0.
1H NMR (CDCl3, 500 MHz):δ 8.14 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 7.0 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.57-7.47 (m, 9H), 3.51 (s, 2H), 3.11 (t, J = 5.0 Hz, 2H), 1.45-1.44 (m, 2H), 1.35 (s, 2H), 1.15 (s, 2H);
13C NMR (CDCl3, 125 MHz):δ 167.35, 160.38, 146.11, 138.88, 136.11, 134.87, 130.77, 130.52, 130.24, 128.81, 128.50, 128.36, 128.24, 127.79, 127.37, 126.40, 125.93, 47.54, 42.10, 25.81, 25.13, 24.32.
EI-MS m/z (%): 392 (9) [M+], 281 (51), 280 (100), 208 (53), 256 (40) 。

Claims (1)

1. a kind of preparation method of polysubstituted isoquinoline compound, the structural formula of such compound are：
R1For：Phenyl, 4- aminomethyl phenyls or 2- methoxyl group naphthyls；R2For：Hydrogen, methyl, phenyl, 4- methyl Phenyl or benzyl；R3For：Methyl formate base, group-4 ethyl formate or formamido；R4For：Phenyl, 4- chlorphenyls, alkyl or formic acid Carbomethoxy；It is characterized in that this method has following steps：Under an inert atmosphere, by alkenyl isonitrile, hydrazine, manganese acetate, peroxidating T-butyl perbenzoate presses 1：(2.0~8.0)：(0.2~1.0)：The mol ratio of (2.0~10.0) is added in acetonitrile solvent, in Stirring reaction to reaction raw materials disappear at 60~80 DEG C；After reaction terminates, washed, used respectively with water and saturated sodium bicarbonate solution Ethyl acetate extracts product, and organic phase obtains crude product after removing solvent；The crude product obtains iloquinoline derivative through separating-purifying Compound；The structural formula of described alkenyl isonitrile is：The structural formula of described hydrazine is：R4-NHNH2。
CN201510589678.2A 2015-09-17 2015-09-17 Isoquinoline compound and its synthetic method Expired - Fee Related CN105130894B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510589678.2A CN105130894B (en) 2015-09-17 2015-09-17 Isoquinoline compound and its synthetic method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510589678.2A CN105130894B (en) 2015-09-17 2015-09-17 Isoquinoline compound and its synthetic method

Publications (2)

Publication Number Publication Date
CN105130894A CN105130894A (en) 2015-12-09
CN105130894B true CN105130894B (en) 2018-03-06

Family

ID=54716529

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510589678.2A Expired - Fee Related CN105130894B (en) 2015-09-17 2015-09-17 Isoquinoline compound and its synthetic method

Country Status (1)

Country Link
CN (1) CN105130894B (en)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Mn-Catalyzed Oxidative Annulation of Vinyl Isocyanides with Hydrazines: Synthesis of Multi-substituted Isoquinolines;毛宏, 洪小虎, 许斌;《中国化学会全国第十一届有机合成化学学术研讨会论文集》;20141031;第255页 *
异腈参与的惰性键活化反应研究进展;王浩，许斌;《有机化学》;20150107;第588-602页 *

Also Published As

Publication number Publication date
CN105130894A (en) 2015-12-09

Similar Documents

Publication Publication Date Title
CN107674083B (en) A kind of preparation method and applications of the L-Leu ring substituent norcantharidin derivative of the structure containing pyridazinone
CN108033922B (en) Preparation method of 3-acyl quinoxalinone derivative
CN105801575A (en) Synthetic method of imidazo[1,2-a]pyridine
CN105732619B (en) A kind of synthetic method of 5,6,7,8 tetrahydropyridines simultaneously [2,3 d] pyrimidines
Dunwell et al. Synthesis and antiinflammatory activity of some 2-heteroaryl-. alpha.-methyl-5-benzoxazoleacetic acids
CN103232462B (en) The synthetic method of coumarin-pyrrole compound
CN105481752B (en) A kind of preparation method of the trifluoromethyl oxidized indole compounds of 3 fluorine alkenyl Oxoindole spiral shell 3,3 '
CN107082771A (en) Double α cyano group imines substituted isochroman class compounds and its synthetic method
CN112812084B (en) Synthetic method of benzofuran compound
Yan et al. Copper acetate aerobic oxidative synthesis of pyrido [1, 2-a] benzimidazoles from aminopyridines and phenylboronic acids
CN105130894B (en) Isoquinoline compound and its synthetic method
CN105237491B (en) Isoxazole compounds and its synthetic method
CN104311553B (en) Ortho position monochloro substituted compound and the synthetic method thereof of N-aryl azaindole
CN108164483B (en) Novel five-membered aromatic heterocycle and aromatic ring and five-membered aromatic heterocycle arylation synthesis method
CN113636968B (en) Synthetic method of 3-acyl pyrrole compound
CN113968819B (en) Synthesis method of polysubstituted pyrazole compound
CN108440384A (en) The preparation method of the trifluoromethyl hydroxylation derivative of isoindolone
CN105001163B (en) A kind of synthetic method of four substituted imidazoles
CN102718694B (en) 3-cyan substituted indole compound and synthetic method thereof
Giuglio-Tonolo et al. A convenient synthesis of quinolin-2 (1H)-one ring system as precursor of active drugs
CN101691355B (en) Substituted 4-quinolinone compounds and preparation method thereof
CN106083649B (en) A kind of synthetic method of the Cyclohexadiene derivatives of 3,5 diaryl, 2,6,6 tricyano, 1 imino group 2,4
CN110885323A (en) Triazole alcohol derivative, and preparation method and application thereof
CN108299303A (en) A kind of new synthetic method of four arylpyrazoles compound
CN102702069A (en) 2-cyano-substituted indole compound and synthetic method thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20180306

Termination date: 20200917

CF01 Termination of patent right due to non-payment of annual fee