CN104529896B - Synthetic method of diaryl substituted isoquinoline compound - Google Patents

Synthetic method of diaryl substituted isoquinoline compound Download PDF

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CN104529896B
CN104529896B CN201410757773.4A CN201410757773A CN104529896B CN 104529896 B CN104529896 B CN 104529896B CN 201410757773 A CN201410757773 A CN 201410757773A CN 104529896 B CN104529896 B CN 104529896B
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synthetic method
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palladium
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CN104529896A (en
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陈久喜
吴华悦
刘妙昌
丁金昌
高文霞
黄小波
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Wenzhou University
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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
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

The invention relates to a synthetic method of a diaryl substituted isoquinoline compound. The synthetic method comprises a step of enabling a diaryl carbonyl compound to react with aryl trifluoro-borate in a solvent in the presence of a palladium catalyst, a nitrogen-containing ligand and an accelerant so as to prepare the diaryl substituted isoquinoline compound through one step. The synthetic method is simple in reaction, convenient to operate and high in yield, is a brand-new synthetic method for the diaryl substituted isoquinoline compound, provides a new synthetic route for preparing the compound, and has a good scientific research value and an industrial potential.

Description

A kind of synthetic method of diaryl substituted isoquinoline compound
Technical field
The present invention relates to a kind of synthetic method of nitrogenous fused heterocyclic compound, particularly a kind of diaryl replaces isoquinoline The synthetic method of quinoline compound, belongs to organic chemical synthesis field.
Background technology
In vitochemical multiple concrete application fields are related to, especially in medicinal chemistry art, nitrogen-containing hetero cyclisation Compound is a kind of widely used medicine intermediate, or final active pharmaceutical compounds also Jing often contains nitrogen heterocyclic ring, just It is because that nitrogen-containing heterocycle compound has potential biologically active and medical value and widely paid close attention to.
In miscellaneous nitrogen-containing heterocycle compound, isoquinolin skeleton has important effect and status, is that synthesis is more Important as precursors, fragment and/or the intermediate of medicine are planted, for example it is the important component part of antibacterials, it is different by introducing Chinoline backbone, many advantages, such as gained medicine generally has antibacterial, antiviral, antitumor, antidepression.
For isoquinoline compound and its synthesis, researcher synthesized various new isoquinoline compound and Such as its preparation method, so as to provide base stock for the synthesis of final medical compounds, there is following different in prior art Quinolines and/or its synthetic method：
A kind of synthetic method of 7- bromo-isoquinolines is disclosed in CN102875465A, bromine method is become by diazotising, non- 7- bromo-isoquinolines are obtained through multistep reaction in aqueous solvent, concrete course of reaction is as follows：
CN102627604A discloses two class isoquinilone derivatives and its application as cancer therapy drug, finds through research It has significant suppression and killing activity to human cancer cell, and the two classes isoquinoline compound structural formula is as follows：
WO2012086727A discloses a kind of isoquinolin -6- sulfamide derivatives, and the derivative can be used to treat green light Eye, Bulbi hypertonia and circulation system disease, the derivant structure is as follows：
The derivative can be obtained by a plurality of synthetic route through up at least 4 steps reaction.
WO2012026529A discloses a kind of novel synthesis of isoquinilone derivatives, is included in nitrile solvents, acid amides molten In the presence of at least one and alkali in agent, sulfoxide type solvents and ureas solvent, formula III compound is obtained with the reaction of Formula II compound Compound of formula I：
WO2011162274A discloses a kind of isoquinilone derivatives, and it can be used as CRTH2 inhibitor, and structural formula is as follows：
The compound is reacted by least 5 steps and is obtained, and course of reaction is loaded down with trivial details and expensive reagents.
WO2010027889A discloses a kind of method of substituted isoquinoline compound of formula I, and methods described includes：
In the presence of methyl alcohol and high price iodine oxidation agent, with anhydrous acid processing formula A compound, then by products therefrom chlorination Agent is processed, and so as to obtain compound of formula I, wherein Formulas I and A structural formula of compound is as follows：
CN101544636A discloses a kind of polyhalogenated isoquinoline Formulas I derivative with pharmaceutically active and its synthesis side Method, the derivative grinds heating response by II and III under condition of no solvent, is subsequently adding catalyst and continues to react and obtain Arrive：
As mentioned above, although disclose the various methods for preparing isoquinoline compound in prior art, but these methods or Person's reactions steps are various, or product yield is relatively low, or used expensive reagent, still cannot meet at present for isoquinolin The extensive and easy requirement of compound preparation method.Therefore the exploration of the preparation method for isoquinoline compound, it is still mesh An important development direction and focus in the front field.
The content of the invention
In view of this, in order to solve present in above-mentioned prior art, such as yield is too low, process is loaded down with trivial details, expensive reagents are rare Etc. many defects, the present inventor has made intensive studies for the chemical synthesis process of isoquinoline compound, is paying a large amount of wounds After the property made work, so as to complete the present invention.
Here, applicant is intended to explanation, the technical scheme is that in state natural sciences fund (numbering： 21472140) it is accomplished under subsidy, here is expressed thanks.
The present invention relates to a kind of synthetic method of diaryl substituted isoquinoline compound, methods described is included in a solvent, In the presence of palladium catalyst, containing n-donor ligand and accelerator, diaryl carbonyls is set to react with aryl trifluoroborate And a step has been obtained isoquinoline compound.
Specifically, the invention provides the synthetic method of diaryl substituted isoquinoline compound shown in a kind of formula (I),
Methods described includes：
In the presence of palladium catalyst, containing n-donor ligand and accelerator, formula (II) compound is reacting molten with formula (III) compound React in agent, generate the diaryl substituted isoquinoline compound of formula (I),
Wherein：R1Selected from H, halogen, nitro, C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkyl, halo C1-C6Alcoxyl Base or phenyl；
R2Selected from H, halogen or C1-C6Alkyl；
M is alkali metal；
Ar1、Ar2It is each independently phenyl, the phenyl with 1-5 substituent, naphthyl or with 1-5 substituent Naphthyl；
The substituent is halogen, C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl or benzene Base.
In the synthetic method of the present invention, the palladium catalyst is organic palladium or inorganic palladium compound.For example can be Palladium acetylacetonate (Pd (acac)2), acid chloride, palladium trifluoroacetate, palladium bichloride, Na2PdCl4、Pd(NH3)4Cl2、Pd(PPh3)4、 PdCl2(dppf)、dppePdCl2、Na2PdCl2、PdCl2(CH3CN)2、PdCl2(PPh3)2、Pd(NH3)4Cl2、PdCl2(cod) in Any or any various mixture.
Preferably, the palladium catalyst is selected from palladium acetylacetonate (Pd (acac)2), acid chloride, palladium trifluoroacetate, palladium bichloride Any one of or various mixtures, most preferably palladium acetylacetonate (Pd (acac)2)。
In the synthetic method of the present invention, the containing n-donor ligand is L1 or L2：
Wherein, X1-X8It is each independently selected from H or C1-C6Alkyl, Y1-Y4It is each independently selected from H, C1-C6Alkyl or benzene Base.
The containing n-donor ligand is preferably any one in following formula L-1 to L-4：
The containing n-donor ligand is most preferably L-1, i.e., 2, and 2 '-bipyridyl (is sometimes referred to as below " bpy ").
In the methods described of the present invention, C1-C6The implication of alkyl refers to the straight or branched alkane with 1-6 carbon atom Base, in non-limiting manner for example can for methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, positive penta Base, isopentyl or n-hexyl etc..
In the methods described of the present invention, C1-C6Alkoxyl refers to " C defined above1-C6After alkyl " is connected with O atom Group.
In the methods described of the present invention, unless otherwise prescribed, the halogen in halogen or halo for example can for F, Cl, Br or I。
In the synthetic method of the present invention, M is alkali metal, for example, can be Li, Na or K.
In the methods described of the present invention, Ar1Or Ar2It is each independently phenyl, the phenyl with 1-5 substituent, naphthalene Base or the naphthyl with 1-5 substituent, phenyl or naphthyl therein can be replaced by 1-5 above-mentioned substituent, for example, can be 1 Individual, 2,3,4 or 5 substituents replacements.
In the synthetic method of the present invention, the accelerator is trifluoroacetic acid (TFA), lower formula (IV) compound or formula (IV) monohydrate of compound：
Wherein R is H, nitro or C1-C6Alkyl.
The accelerator is preferably the monohydrate of formula (IV) compound or formula (IV) compound, more preferably formula (IV) monohydrate of compound, is still more preferably p-methyl benzenesulfonic acid or p-methyl benzenesulfonic acid monohydrate, most preferably right Toluenesulfonic acid monohydrate.
In the synthetic method of the present invention, the reaction dissolvent is water, benzene,toluene,xylene, chlorobenzene, Isosorbide-5-Nitrae-two The ring of oxygen six, 1,6- dioxane, tetrahydrofuran (THF), 2- methyltetrahydrofurans, N,N-dimethylformamide (DMF), dimethyl Sulfoxide (DMSO), dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, n-hexane, ether, methyl alcohol, ethanol, normal propyl alcohol, One or more in isopropanol, butanol, amylalcohol, hexanol etc., most preferably water.The not special limit of the consumption of reaction dissolvent It is fixed, can be selected according to the common knowledge of organic synthesis field, such as selection causes to react can steadily be carried out, easily controllable Amount, or the amount for being easy to post-process etc..
In the synthetic method of the present invention, formula (II) compound is 1 with the mol ratio of (III) compound:1- 3, the scope includes any subinterval scope therein, also includes any concrete point value therein, exemplarily for example may be used For 1:1、1:1.2、1:1.4、1:1.6、1:1.8、1:2、1:2.2、1:2.4、1:2.6、1:2.8 or 1:3.
In the synthetic method of the present invention, the mole dosage of the palladium catalyst is formula (II) compound mole dosage 2-10%, for example can be 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
In the synthetic method of the present invention, the palladium catalyst is 1 with the mol ratio of the containing n-donor ligand:2-3, example Such as can be 1:1.2、1:1.5、1:1.7、1:1.9、1:2、1:2.2、1:2.4、1:2.6、1:2.8 or 1:3.
In the synthetic method of the present invention, the formula (II) is 1 with the mol ratio of the accelerator:5-15, for example Can be 1:5、1:7、1:9、1:10、1:12、1:14 or 1:15.
The present invention the synthetic method in, reaction temperature be 60-140 DEG C, in non-limiting manner for example can for 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C or 140 DEG C.
In the synthetic method of the present invention, the reaction time, there is no particular limitation, for example, can be examined by liquid chromatogram Survey the residual percentage of purpose product or raw material and determine the suitable reaction time, it typically is 15-30 hours, in non-limiting manner For example, 15 hours, 17 hours, 19 hours, 21 hours, 23 hours, 25 hours, 27 hours, 29 hours or 30 hours.
In the synthetic method of the present invention, the post processing after reaction terminates can be following method：After reaction terminates, will Mixture is poured in ethyl acetate, sequentially uses saturation NaHCO3The aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, Merge organic layer (merging the organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4It is dried, negative pressure evaporation is removed Solvent is removed, (n-hexane/ethyl acetate, both volume ratios are 1 to residue by flash column chromatography:1-3) purify, obtain target product Thing.
In the synthetic method of the present invention, enumerate as one kind, Ar1For phenyl, 3- aminomethyl phenyls or 4- chlorphenyls.
In the synthetic method of the present invention, enumerate as one kind, Ar2For phenyl, 3- aminomethyl phenyls, 4- chlorphenyls or Naphthalene -2- bases.
In the synthetic method of the present invention, enumerate as one kind, R1For H or Br.
In the synthetic method of the present invention, enumerate as one kind, R2For H.
Compared with prior art, the present invention is used as reaction substrate by selecting formula (II) and (III) compound, with palladium chemical combination Used as catalyst, by the synergy of specific containing n-donor ligand accelerator, one-step synthesis obtains diaryl substituted isoquinoline to thing Compound.Methods described reacts simple, easy to operate, high income, is a kind of brand-new synthesis of diaryl substituted isoquinoline compound Method, the preparation for diaryl substituted isoquinoline compound provides new synthetic route.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action Protection scope of the present invention is confined to this.
Wherein following group refers to following implication：
Me：Methyl
Ph：Phenyl.
3-MePh：3- tolyls.
4-ClPh：4- chlorphenyls.
Embodiment 1：The synthesis of bis- tolyl isoquinolin of 1,3-
In reaction vessel add 100ml water, 20mmol formulas (II) compound, 20mmol formulas (III) compound, 0.4mmol palladium acetylacetonates, 0.8mmol containing n-donor ligand L-1 and 100mmol p-methyl benzenesulfonic acid monohydrates, under 60 DEG C of stirrings Reaction 30 hours.After reaction terminates, mixture is poured in ethyl acetate, sequentially uses saturation NaHCO3The aqueous solution and salt are washed Wash, after aqueous layer with ethyl acetate extraction, merge organic layer (merging the organic layer after washing and the organic layer being obtained by extraction), Use anhydrous Na2SO4It is dried, negative pressure evaporation removes solvent, residue passes through flash column chromatography (n-hexane/ethyl acetate, Liang Zheti Product is than being 1:1) purify, obtain the target product for liquid.Yield is 83.6%, and purity is 99.2% (HPLC).
Nuclear magnetic resonance：1HNMR(500MHz,CDCl3) δ 8.11 (d, J=10Hz, 1H), 8.05 (d, J=10Hz, 2H), 7.98 (d, J=10Hz, 1H), 7.93 (d, J=5Hz, 1H), 7.68 (dd, J=10Hz, 1H), 7.62 (s, 1H), 7.58 (d, J =10Hz, 1H), 7.43-7.52 (m, 2H) 7.39 (dd, J=5Hz, 1H), 7.33 (d, J=10Hz, 1H), 7.22 (d, J= 10Hz,1H),2.49(s,3H),2.46(s,3H)。
Embodiment 2：The synthesis of the rubigan isoquinolin of 1,3- bis-
100ml water, 20mmol formulas (II) compound, 40mmol formulas (III) compound, 1mmol are added in reaction vessel Palladium acetylacetonate, 3mmol containing n-donor ligand L-1 and 200mmol p-methyl benzenesulfonic acid monohydrates are little in the lower reaction 20 of 80 DEG C of stirrings When.After reaction terminates, mixture is poured in ethyl acetate, sequentially uses saturation NaHCO3The aqueous solution and salt water washing, in water layer After being extracted with ethyl acetate, merge organic layer (merging organic layer and the organic layer that is obtained by extraction after washing), with anhydrous Na2SO4It is dried, negative pressure evaporation removes solvent, and by flash column chromatography, (n-hexane/ethyl acetate, both are at volume ratio residue 1:2) purify, obtain the target product for solid.Yield is 93.8%, and purity is 98.5% (HPLC).
Fusing point：150-151℃；
Nuclear magnetic resonance：1HNMR(500MHz,CDCl3) δ 8.06-8.15 (m, 4H), 7.94 (d, J=10Hz, 1H), 7.69- 7.75 (m, 3H), 7.53-7.56 (m, 3H), 7.46 (d, J=10Hz, 2H).
Embodiment 3：The synthesis of 1,3- dibiphenylyl -4- base isoquinolin
100ml water, 20mmol formulas (II) compound, 60mmol formulas (III) compound, 2mmol are added in reaction vessel Palladium acetylacetonate, 5mmol containing n-donor ligand L-1 and 300mmol p-methyl benzenesulfonic acid monohydrates are little in the lower reaction 15 of 140 DEG C of stirrings When.After reaction terminates, mixture is poured in ethyl acetate, sequentially uses saturation NaHCO3The aqueous solution and salt water washing, in water layer After being extracted with ethyl acetate, merge organic layer (merging organic layer and the organic layer that is obtained by extraction after washing), with anhydrous Na2SO4It is dried, negative pressure evaporation removes solvent, and by flash column chromatography, (n-hexane/ethyl acetate, both are at volume ratio residue 1:3) purify, obtain target product.Yield is 68.8%, and purity is 98.9% (HPLC).
Fusing point：114.7-116.5℃；
Nuclear magnetic resonance：1H NMR(500MHz,CDCl3)δ8.21-8.20(m,2H),8.08-8.07(m,2H),7.94- 7.93(m,1H),7.77-7.76(m,2H),7.70-7.67(m,1H),7.55-7.49(m,5H),7.43-7.40(m,1H)。
Embodiment 4：The synthesis of 1,3- dinaphthyl -2- base isoquinolin
In reaction vessel add 100ml water, 20mmol formulas (II) compound, 50mmol formulas (III) compound, 0.8mmol palladium acetylacetonates, 2mmol containing n-donor ligand L-1 and 150mmol p-methyl benzenesulfonic acid monohydrates, it is lower anti-in 100 DEG C of stirrings Answer 20 hours.After reaction terminates, mixture is poured in ethyl acetate, sequentially uses saturation NaHCO3The aqueous solution and salt water washing, After aqueous layer with ethyl acetate extraction, merge organic layer (merging the organic layer after washing and the organic layer being obtained by extraction), use Anhydrous Na2SO4It is dried, negative pressure evaporation removes solvent, residue passes through flash column chromatography (n-hexane/ethyl acetate, both volumes Than for 1:1) purify, obtain the target product for solid.Yield is 87.5%, and purity is 98.7% (HPLC).
Fusing point：116.5-118.4℃；
Nuclear magnetic resonance：1H NMR(500MHz,CDCl3)δ8.29-8.27(m,3H),8.21-8.19(m,1H),8,12(s, 1H),8.06-8.04(m,1H),7,99-7.96(m,4H),7.71-7.68(m,1H),7.60-7.51(m,5H),7.45-7.42 (m,1H)。
Embodiment 5：The synthesis of the bromo- 1,3- diphenyl isoquinolin of 7-
In reaction vessel add 100ml water, 20mmol formulas (II) compound, 30mmol formulas (III) compound, 1.5mmol palladium acetylacetonates, 3.5mmol containing n-donor ligand L-1 and 250mmol p-methyl benzenesulfonic acid monohydrates, under 80 DEG C of stirrings Reaction 16 hours.After reaction terminates, mixture is poured in ethyl acetate, sequentially uses saturation NaHCO3The aqueous solution and salt are washed Wash, after aqueous layer with ethyl acetate extraction, merge organic layer (merging the organic layer after washing and the organic layer being obtained by extraction), Use anhydrous Na2SO4It is dried, negative pressure evaporation removes solvent, residue passes through flash column chromatography (n-hexane/ethyl acetate, Liang Zheti Product is than being 1:2) purify, obtain the target product for solid.Yield is 63.1%, and purity is 98.8% (HPLC).
Fusing point：136-137℃；
Nuclear magnetic resonance：1HNMR(500MHz,CDCl3)δ8.18-8.26(m,3H),8.01(s,1H),7.71-7.79(m, 4H),7.47-7.58(m,5H),7.39-7.42(m,1H)。
Can be seen that by above-described embodiment 1-5, when using by reaction substrate of the present invention, catalyst, part and accelerator institute structure During the compound system built, can be with higher yields and high-purity by various types of diaryl carbonyls and phenylboric acid Salt and obtain corresponding diaryl substituted isoquinoline compound.
Embodiment 6-11
In addition to catalyst acetyl acetone palladium therein is replaced with into following palladium compound, with embodiment 1-5 identical Mode and implement embodiment 6-11 respectively, the yield of embodiment corresponding relation and corresponding diaryl substituted isoquinoline compound It is as shown in the table.
As seen from the above table, when using acid chloride, palladium trifluoroacetate and palladium bichloride, the yield of corresponding product has aobvious The reduction of work, this demonstrate that palladium acetylacetonate has the catalysis selectivity of best catalytic performance and uniqueness.
Embodiment 12-21
In addition to catalyst acetyl acetone palladium therein is replaced with into following palladium compound, with embodiment 1-5 identical Mode and implement embodiment 12-21 respectively, the yield of embodiment corresponding relation and corresponding diaryl isoquinoline compound is such as Shown in following table.
Note：" -- " represents unreacted.
As seen from the above table, when using other palladium compounds, hardly react.
Embodiment 22-33
During except aqueous solvent therein is replaced with such as solvent in following table, to divide with embodiment 1-5 identical mode The yield for not implementing embodiment 22-33, embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
As seen from the above table, when using other organic solvents, reaction also can be carried out, but yield is significantly reduced, from And demonstrate in the organic reaction, it is that the water of non-organic solvent has on the contrary best solvent for organic solvent Effect.
Embodiment 34-44
It is following with external except ligand L -1 therein is replaced with, with embodiment 1-5 identical mode and implement respectively The yield of embodiment 34-45, embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
During except part being changed to into following part, respectively implementing enforcement respectively with embodiment 1-5 identical mode Example 40-44：
It was found that the yield of corresponding diaryl isoquinoline compound is 16.9-33.4%.
As can be seen here, part of the invention being smoothed out with the acquisition of the high yield of product with significant shadow for reaction Effect is rung, wherein 2,2 '-bipyridyl has best synergy, even has 4, the 4 '-two of identical precursor structure with it Methyl bipyridyl or 5,5 '-dimethylbipyridine can not all obtain such identical reaction effect.
Embodiment 45-49
In addition to p-methyl benzenesulfonic acid monohydrate therein is replaced with into following accelerator, with embodiment 1-6 identical side Formula and implement embodiment 45-49 respectively, the yield of embodiment corresponding relation and corresponding diaryl substituted isoquinoline compound It is as shown in the table.
Embodiment 50-54
In addition to accelerator is not used, to implement embodiment 53-58 respectively with embodiment 1-5 identical mode, in fact The yield for applying a corresponding relation and corresponding diaryl substituted isoquinoline compound is as shown in the table.
Note：" -- " represents and does not contain.
From embodiment 45-54, accelerator significantly affects for the yield of product has, wherein the water of p-methyl benzenesulfonic acid one Compound has best promotion system effect, and even using p-methyl benzenesulfonic acid, its yield is also significantly lower than p-methyl benzenesulfonic acid one Hydrate.And when accelerator is not used, then products collection efficiency is greatly lowered, or even without the necessity studied and lose industrialization Potentiality
In sum, can clearly be found out by above-mentioned all embodiments, when using using the method for the present invention palladium is selected from Palladium catalyst (especially palladium acetylacetonate), selected from the containing n-donor ligand (especially L-1) of L-1 to L-4, and suitable solvent is (outstanding It is water) and Suitable accelerators (especially p-methyl benzenesulfonic acid monohydrate) constituted recombination reaction system when, can be with height Yield and high-purity obtain diaryl substituted isoquinoline compound, are a kind of brand-new synthesis sides for having very much a prospects for commercial application Method, the efficient quick synthesis for diaryl substituted isoquinoline compound provides brand-new synthetic route.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the protection model of the present invention Enclose.Additionally, it will also be appreciated that after the technology contents for having read the present invention, those skilled in the art can make each to the present invention Plant and change, change and/or modification, all these equivalent form of value equally falls within the guarantor that the application appended claims are limited Within the scope of shield.

Claims (7)

1. the synthetic method of diaryl substituted isoquinoline compound shown in a kind of formula (I),
Methods described includes：
In the presence of palladium catalyst, containing n-donor ligand and accelerator, formula (II) compound is with formula (III) compound in reaction dissolvent React, generate the diaryl substituted isoquinoline compound of formula (I),
Wherein：R1Selected from H, halogen, nitro, C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl or Phenyl；
R2Selected from H, halogen or C1-C6Alkyl；
M is alkali metal；
Ar1、Ar2It is each independently phenyl, the phenyl with 1-5 substituent, naphthyl or the naphthyl with 1-5 substituent；
The substituent is halogen, C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl or phenyl；
The palladium catalyst is palladium acetylacetonate；
The containing n-donor ligand is L-1：
The accelerator is p-methyl benzenesulfonic acid or p-methyl benzenesulfonic acid monohydrate；
The reaction dissolvent is water.
2. synthetic method as claimed in claim 1, it is characterised in that：The accelerator is p-methyl benzenesulfonic acid monohydrate.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (II) compound rubs with (III) compound You are than being 1:1-3.
4. synthetic method as claimed in claim 1, it is characterised in that：The mole dosage of the palladium catalyst is formula (II) chemical combination The 2-10% of thing mole dosage.
5. synthetic method as claimed in claim 1, it is characterised in that：The mol ratio of the palladium catalyst and the containing n-donor ligand For 1:2-3.
6. the synthetic method as described in any one of claim 1-5, it is characterised in that：The formula (II) is rubbed with the accelerator You are than being 1:5-15.
7. synthetic method as claimed in claim 6, it is characterised in that：Reaction temperature is 60-140 DEG C；Reaction time is 15-30 Hour.
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