CN103980280A - Method for synthesizing quinazolino indazole derivatives under acidic condition - Google Patents
Method for synthesizing quinazolino indazole derivatives under acidic condition Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract
The invention relates to a method for synthesizing quinazolino indazole derivatives under acidic condition, which comprises the following steps: under existence of a catalyst and an oxidizing agent, an intramolecular dehydrogenation coupling reaction of 2-aryl-3-aryl amino quinazolinone derivatives is produced in an acidic organic solvent so as to obtain the quinazolino indazole derivatives with diversified structures. The method is characterized in that under the synergistic effect of the catalyst, the oxidizing agent and the acidic organic solvent, a reaction for efficiently synthesizing the quinazolino indazole derivatives by a one-pot method is achieved, and the method has the advantages of high efficiency, environmental friendliness, high yield and purity and the like, and has good research value and application prospect.
Description
Technical field
The invention provides the synthetic method of a kind of quinazolinone indazole derivatives, more specifically, provide a kind of method of synthesizing quinazolinone indazole derivatives under acidic conditions, belong to organic chemical synthesis field.
Background technology
Quinazolinone is as the novel many rings nitrogen-containing heterocycle compound of a class, can be used as the structure construction fragment of active medicine, agricultural chemical compound etc., in organic chemistry filed, there is important effect, thereby have a wide range of applications such as medicine, agricultural, chemical industry etc. of a plurality of concrete Application Areass.Such as multi-medicament, all belong to quinazolinones medicine as antihypertensive drug Prazosin, hydragog(ue) methaqualone etc.And in Agricultural methods, it can be used as sterilant, weedicide etc.For example, at present existing efficient miticide Fenazaquin is pushed to the market as disinfectant use in agriculture, and will quinazolinone heterocycle skeleton can be used for making weedicide after transformation, if outstanding commercialization weedicide bentazone is that carbon by the 2-position skeleton of sulfur quinazolinone heterocycle skeleton is synthetic and make.
Except above-mentioned application, quinazolinone analog derivative also can be used as organic fluorescence agent, as additive, can make the antiwear and friction reduction property of whiteruss increase substantially, and its application in industries such as plating, METAL EXTRACTION and smeltings is also very extensive in addition.
As can be seen here, Quinazol derivative has more wide application prospect.Just because of their excellent properties and great potential, scientists is synthesized and has been carried out a large amount of research it, has developed multiple synthetic method and route in recent years.
The people (" A new cascade reaction:concurrent construction of six and five membered rings leading to novel fused quinazolinones " such as K.Siva Kumar, Organic & Biomolecular Chemistry, 2012,10, isatoic anhydride compounds and R-NH-NH are disclosed in 3098-3103)
2react and make quinazolinone benzindole compounds, wherein using Pd (PPh
3) be catalyzer, BINAP is part.
The people such as Dong-Sheng Chen (" Copper (I)-catalyzed synthesis of5-aryli – dazolo[3; 2-b] quinazolin-7 (5H)-one via Ullman-type reaction ", The Journal Organic Chemistry, 2013,78,5700-5704) disclose with 2-amino-N '-aryl benzhydrazide and o-halogenated benzaldehyde and reacted under CuBr and cesium carbonate existence, obtain also [3,2-b] quinazoline-7-(5H)-one of 5-arylindazoles.
Weiguang, the people such as Yang (" Copper-catalyzed intramolecular C-N bond formation reaction of3-amino-2-(2-bromophenyl) dihydroquinazolinon – es:synthesis of indazolo[3; 2-b] quinazolinones ", Tetrahedron, 2013,69,9852-9856) disclose 3-amino-2-(2-bromophenyl) dihydroquinazoline ketone and take copper compound/L-PROLINE as catalyzer, under cesium carbonate exists, in nitrogen atmosphere, react, and obtain quinazolinone indazole compound.
But these methods are all used halogen compound for substrate carries out linked reaction, use Cu compound or metal complex as catalyzer simultaneously.And well-known, halid use environmental pollution has caused great destruction.
The applicant's CN201310717678.7 discloses the synthetic method of not using halid quinazolinone indazole derivatives, and described method is to using palladium compound as catalyzer,
Under alkali and molecular sieve existence, in oxygen atmosphere, dehydrogenation linked reaction in formula (II) compound generation molecule, thereby the formula of obtaining (I) derivative:
The method can a step obtain object product, but in reaction system, component is more: need catalyzer, alkali and molecular sieve, and under oxygen atmosphere.
Many disadvantages based on existing in above-mentioned prior art, develop a kind of simple, efficient, the more friendly synthetic quinazolinone of environment the method for indazole derivatives are still necessary, this basis and power place that also the present invention is accomplished just.
Summary of the invention
In order to overcome above-mentioned pointed many defects, seek the brand-new and simple method of synthetic quinazolinone indazole derivatives, the inventor conducts in-depth research, and after having paid a large amount of creative works, thereby has completed the present invention.
Particularly, technical scheme of the present invention and content relate to the quinazolinone shown in following formula (I) the synthetic method of indazole derivatives, described method is: using palladium compound as catalyzer, under oxygenant exists, in acid organic solvent, dehydrogenation linked reaction in formula (II) compound generation molecule, thereby the formula of obtaining (I) derivative:
Wherein:
Ar is following group:
R
1, R
2, R
3be selected from independently of one another H, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, and it has comprised C
1alkyl, C
2alkyl, C
3alkyl, C
4alkyl, C
5alkyl or C
6alkyl, indefiniteness ground is such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, C
2-C
6the implication of thiazolinyl refers to the straight or branched thiazolinyl with 2-6 carbon atom, such as vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1-pentenyl, 1-hexenyl etc.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " group after being connected with O atom.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, the implication of halogen refers to haloid element, non-exclusively for example can be F, Cl, Br or I.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, halo C
1-C
6the implication of alkyl refers to the " C defined above being replaced by halogen
1-C
6alkyl ", indefiniteness ground is such as being trifluoromethyl, pentafluoroethyl group, difluoromethyl, chloromethyl etc.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, halo C
1-C
6the implication of alkoxyl group refers to the " C defined above being replaced by halogen
1-C
6alkoxyl group ", indefiniteness ground is such as being trifluoromethoxy, five fluorine oxyethyl groups, difluoro-methoxy, chlorine methoxyl group etc.
In described synthetic method of the present invention, " * " in Ar group represents to be connected with N.
In described synthetic method of the present invention, as a kind of, exemplify R
1can be H, methyl.
In described synthetic method of the present invention, as a kind of, exemplify R
2can be H, methyl, F, Cl or Br.
In described synthetic method of the present invention, as a kind of, exemplify R
3can be H, methyl or trifluoromethyl.
In described synthetic method of the present invention, as the described palladium compound of catalyzer, be inorganic palladium compound, organic palladium compound or both mixtures.
Wherein, described inorganic palladium compound can be PdCl
2, Na
2pdCl
4, Pd (NH
3)
4cl
2in any or any multiple mixture.
Wherein, described organic palladium compound can be Pd (OAc)
2, Pd (PPh
3)
4, PdCl
2(dppf), Pd (acac)
2, dppePdCl
2, Na
2pdCl
2, PdCl
2(CH
3cN)
2, PdCl
2(PPh
3)
2, Pd (NH
3)
4cl
2, PdCl
2(cod) any or any multiple mixture in.
Described palladium compound as catalyzer most preferably is Pd (OAc)
2.
In described synthetic method of the present invention, described oxygenant is silver compound, copper compound, benzoquinone compound, oxygen, ozone, TBHP (tertbutyl peroxide), Potassium Persulphate, PhI (OAc)
2, any or any multiple mixture in Silver Nitrate etc.
Wherein, described silver compound can be AgOAc (silver acetate), Ag
2o, Sulfuric acid disilver salt, trifluoroacetic acid silver or silver triflate;
Described copper compound can be venus crystals or Red copper oxide;
Described benzoquinone compound can be DDQ (2,3-bis-chloro-5,6-dicyano benzoquinone) or BQ (benzoquinones).
Described oxygenant is preferably silver compound, more preferably silver acetate, Ag
2o, Sulfuric acid disilver salt or trifluoroacetic acid silver, most preferably be silver acetate.
In described synthetic method of the present invention, the mol ratio of formula (II) compound and catalyzer (being palladium compound) is 1:0.05-0.15, for example can be to indefiniteness 1:0.05,1:0.07,1:0.09,1:0.1,1:0.12,1:0.14 or 1:0.15.
In described synthetic method of the present invention, the mol ratio of formula (II) compound and oxygenant is 1:3-6, for example can be to indefiniteness 1:3,1:3.5,1:4,1:4.5,1:5,1:5.5 or 1:6.
In described synthetic method of the present invention, described acid organic solvent can be acetic acid, propionic acid, formic acid, dimethyl sulfoxide (DMSO) (DMSO), N, any in dinethylformamide (DMF), dimethylbenzene, dioxane, or for acetic acid be selected from DMSO, DMF, dimethylbenzene, dioxane any mixture.When being mixture, in acetic acid and DMSO, DMF, dimethylbenzene, dioxane, any volume ratio is 1:0.1-10, for example can be 1:0.1,1:0.5,1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9 or 1:10, be preferably 1:0.1-3.
Wherein, described acid organic solvent is preferably the mixture of mixture, acetic acid and dioxane of mixture, acetic acid and dimethylbenzene of mixture, acetic acid and the DMF of acetic acid, propionic acid, acetic acid and DMSO, the more preferably mixture of the mixture of the mixture of the mixture of acetic acid, propionic acid, acetic acid and DMSO, acetic acid and DMF, acetic acid and dimethylbenzene, acetic acid and dioxane.
In described synthetic method of the present invention, temperature of reaction is 80-150 ℃, for example can be to indefiniteness 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃ or 150 ℃.
In described synthetic method of the present invention, reaction times there is no special restriction, for example can how much determine the suitable reaction times by the residual quantity of liquid chromatography or TLC detection raw material, it typically is 20-50 hour, is indefiniteness for example 20 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours or 50 hours.
In described synthetic method of the present invention, the aftertreatment of reaction after finishing can be any processing means in crystallization, recrystallization, column chromatography purification, extraction etc. or the combination of multiple processing means.As a kind of exemplary aftertreatment means, for example can be: after reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, add again aqueous sodium hydroxide solution, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:5-15 of ethyl acetate and sherwood oil wherein, thus obtain target product formula (I) compound.
In sum, the present invention use palladium compound as catalyzer, use silver compound as oxygenant, can be by formula (II) compound reaction in acid organic solvent and a step obtains quinazolinone the indazole derivatives of formula (I), there is the plurality of advantages such as products collection efficiency is high, purity is high, there is good scientific research value and application prospect, for the preparation of this compounds provides brand-new route, can in the fields such as pharmaceutical intermediate, pesticide intermediate, play a significant role.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not real protection scope of the present invention is formed to any type of any restriction, more non-protection scope of the present invention is confined to this.
Embodiment 1:5-phenyl indazole [3,2-b] quinazoline-7 (5H)-one
50ml solvent acetic acid is joined in reaction vessel, then add 10mmol (II) compound, 0.5mmol Pd (OAc)
2, 30mmol silver acetate, under the stirring of stirrer, be warming up to 80 ℃ of lower seals reaction 48 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:5 of ethyl acetate and sherwood oil wherein, obtain target product formula (I) the compound 5-phenyl indazole [3 for faint yellow solid, 2-b] quinazoline-7 (5H)-one.Productive rate is 91.2%, and purity is 99.1% (HPLC).
Fusing point: 230-231 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, CDCl
3) δ 8.34-8.32 (m, 1H), 8.29 (d, J=8.0Hz, 1H), 7.91 (d, J=8.5Hz, 1H), 7.83-7.80 (m, 1H), 7.63-7.60 (m, 1H), 7.50-7.35 (m, 7H), 7.21 (d, J=8.5Hz, 1H).
13CNMR(125Mz,CDCl
3)δ156.5,149.2,148.8,148.3,141.9,134.1,133.5,129.6(2C),128.7,127.1,126.8,125.5,124.7(2C),124.4,123.4,119.9,118.9,112.5。
Embodiment 2:5-p-methylphenyl indazole [3,2-b] quinazoline-7 (5H)-one
50ml solvent acetic acid is joined in reaction vessel, then add 10mmol (II) compound, 1mmol Pd (OAc)
2, 40mmol silver acetate, under the stirring of stirrer, be warming up to 90 ℃ of lower seals reaction 40 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:10 of ethyl acetate and sherwood oil wherein, obtain target product formula (I) the compound 5-p-methylphenyl indazole [3 for faint yellow solid, 2-b] quinazoline-7 (5H)-one.Productive rate is 92.7%, and purity is 98.6% (HPLC)
Fusing point: 184-185 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, CDCl
3) δ 8.34-8.32 (m, 1H), 8.28 (d, J=7.5Hz, 1H), 7.91 (d, J=8.0Hz, 1H), 7.83-7.79 (m, 1H), 7.63-7.59 (m, 1H), 7.47-7.39 (m, 2H), 7.28-7.24 (m, 4H), 7.18 (d, J=8.0Hz, 1H), 2.40 (s, 3H).
13CNMR(125Mz,CDCl
3)δ156.5,149.4,148.7,148.3,139.3,138.8,134.1,135.5,130.3(2C),127.0,126.8,125.4,124.7(2C),124.3,123.3,119.9,118.8,112.5,21.4。
Embodiment 3:5-is to fluoroform phenyl indazole [3,2-b] quinazoline-7 (5H)-one
50ml solvent acetic acid is joined in reaction vessel, then add 10mmol (II) compound, 1.5mmol Pd (OAc)
2, 50mmol silver acetate, under the stirring of stirrer, be warming up to 100 ℃ of lower seals reaction 30 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:15 of ethyl acetate and sherwood oil wherein, obtain target product formula (I) compound 5-for faint yellow solid to trifluorophenyl indazole [3, 2-b] quinazoline-7 (5H)-one.Productive rate is 84.7%, and purity is 98.9% (HPLC)
Fusing point: 214-215 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, DMSO-d
6) δ 8.27 (d, J=8.0Hz, 1H), 8.19 (d, J=8.0Hz, 1H), 7.94-7.90 (m, 2H), 7.86 (d, J=8.5Hz, 2H), 7.79-7.74 (m, 3H), 7.57-7.52 (m, 2H), 7.49 (d, J=8.0Hz, 1H).
13CNMR(125Mz,DMSO-d
6)δ155.3,148.2,147.7,147.4,144.9,134.2,133.9,128.0,126.9(2C),126.4,126.3,126.0,125.5,125.1,124.3(2C),123.1,119.4,118.6,112.2。
Embodiment 4:5-is to fluorophenyl indazole [3,2-b] quinazoline-7 (5H)-one
50ml solvent acetic acid is joined in reaction vessel, then add 10mmol (II) compound, 0.7mmol Pd (OAc)
2, 60mmol silver acetate, under the stirring of stirrer, be warming up to 110 ℃ of lower seals reaction 25 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:7 of ethyl acetate and sherwood oil wherein, thereby obtain target product formula (I) compound 5-into faint yellow solid to fluorophenyl indazole [3, 2-b] quinazoline-7 (5H)-one.Productive rate is 92.1%, and purity is 99.2% (HPLC)
Fusing point: 197-198 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, DMSO-d
6) δ 8.25 (d, J=7.5Hz, 1H), 8.17 (d, J=8.0Hz, 1H), 7.92-7.88 (m, 2H), 7.77-7.74 (m, 1H), 7.57-7.49 (m, 4H), 7.33-7.30 (m, 3H).
13CNMR(125Mz,DMSO-d
6)δ162.2,160.2,155.3,148.8,147.6,137.9,134.0,133.8,126.9,125.9,125.3,124.6,122.9(2C),119.4,118.3,116.1,115.9,112.3(2C)。
Embodiment 5:9-methyl-5-phenyl indazole [3,2-b] quinazoline-7 (5H)-one
50ml solvent acetic acid is joined in reaction vessel, then add 10mmol (II) compound, 0.9mmol Pd (OAc)
2, 35mmol silver acetate, under the stirring of stirrer, be warming up to 130 ℃ of lower seals reaction 20 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:10 of ethyl acetate and sherwood oil wherein, thereby obtain target product formula (I) the compound 9-methyl-5-phenyl indazole [3 into faint yellow solid, 2-b] quinazoline-7 (5H)-one.Productive rate is 79.7%, and purity is 98.0% (HPLC)
Fusing point: 241-242 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, CDCl
3) δ 8.27 (d, J=7.5Hz, 1H), 8.11 (s, 1H), 7.82 (d, J=8.5Hz, 1H), 7.65-7.59 (m, 2H), 7.49-7.34 (m, 6H), 7.22-7.20 (m, 1H), 2.50 (s, 3H).
13CNMR(125Mz,CDCl
3)δ156.4,149.2,147.8,146.8,142.1,135.8,135.7,133.3(2C),129.6,128.6,126.9,126.1,124.5(2C),124.4,123.2,119.7,119.1,112.5,21.5。
The fluoro-5-phenyl of embodiment 6:3-indazole [3,2-b] quinazoline-7 (5H)-one
50ml solvent acetic acid is joined in reaction vessel, then add 10mmol (II) compound, 1.2mmol Pd (OAc)
2, 45mmol silver acetate, under the stirring of stirrer, be warming up to 140 ℃ of lower seals reaction 40 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:12 of ethyl acetate and sherwood oil wherein, thereby obtain the fluoro-5-phenyl of target product formula (I) the compound 3-indazole [3 into faint yellow solid, 2-b] quinazoline-7 (5H)-one.Productive rate is 88.9%, and purity is 98.3% (HPLC)
Fusing point: 216-217 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, CDCl
3) δ 8.32-8.25 (m, 2H), 7.89 (d, J=8.0Hz, 1H), 7.84-7.80 (m, 1H), 7.52-7.43 (m, 4H), 7.37-7.35 (m, 2H), 7.16-7.11 (m, 1H), 6.88-6.86 (m, 1H).
13CNMR(125Mz,CDCl
3)δ167.3,165.2,156.2,150.3,148.6,147.4,141.2,134.2,129.7(2C),128.9,126.8,126.7,125.5,124.6(2C),119.5,114.9,113.0,99.5。
Embodiment 7:3-methyl-5-phenyl indazole [3,2-b] quinazoline-7 (5H)-one
50 ml solvent acetic acid are joined in reaction vessel, then add 10 mmol (II) compound, 1.5 mmol Pd (OAc)
2, 30 mmol silver acetates, under the stirring of stirrer, be warming up to 150 ℃ of lower seals reaction 25 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:15 of ethyl acetate and sherwood oil wherein, thereby obtain target product formula (I) the compound 3-methyl-5-phenyl indazole [3 into faint yellow solid, 2-b] quinazoline-7 (5H)-one.Productive rate is 78.5%, and purity is 97.5% (HPLC)
Fusing point: 254-255 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, CDCl
3) δ 8.32 (d, J=8.0Hz, 1H), 8.16 (d, J=8.0Hz, 1H), 7.89 (d, J=8.5Hz, 1H), 7.82-7.79 (m, 1H), 7.50-7.42 (m, 4H), 7.35 (d, J=7.5Hz, 2H), 7., 24 (d, J=8.0Hz, 1H), 6.99 (s, 1H), 2.46 (s, 3H).
13CNMR(125Mz,CDCl
3)δ156.6,149.7,148.9,148.4,145.0,142.1,134.1,129.6(2C),128.6,127.0,126.8,126.2,125.3,124.7(2C),123.0,119.8,116.5,112.4,22.6。
The chloro-5-phenyl of embodiment 8:3-indazole [3,2-b] quinazoline-7 (5H)-one
50ml solvent acetic acid is joined in reaction vessel, then add 10mmol (II) compound, 0.8mmol Pd (OAc)
2, 55mmol silver acetate, under the stirring of stirrer, be warming up to 105 ℃ of lower seals reaction 45 hours.
After reaction finishes, reaction mixture is cooled to room temperature, transfer in separating funnel, be incorporated as volume of mixture 3-5 ethyl acetate doubly, adding mass concentration is 20% aqueous sodium hydroxide solution again, system pH is adjusted to alkalescence, separatory, saturated common salt water washing 1-3 time for organic layer, then rotary evaporation, residue is crossed 300-400 order silicagel column, take ethyl acetate/petroleum ether as eluent, the volume ratio 1:6 of ethyl acetate and sherwood oil wherein, thereby obtain target product formula (I) compound 3-chlorin-5-phenyl indazole [3 into faint yellow solid, 2-b] quinazoline-7 (5H)-one.Productive rate is 83.7%, and purity is 98.6% (HPLC)
Fusing point: 212-213 ℃;
Nucleus magnetic resonance:
1hNMR (500Mz, CDCl
3) δ 8.33-8.31 (m, 1H), 8.21 (d, J=8.5Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.84-7.83 (m, 1H), 7.52-7.45 (m, 4H), 7.40-7.35 (m, 3H), 7.18 (s, 1H).
13CNMR(125Mz,CDCl
3)δ156.3,149.6,148.6,147.4,141.2,139.9,134.3,129.8(2C),129.1,127.1,126.8,125.7,125.3,124.7(2C),124.4,119.8,117.4,112.6。
By above-described embodiment 1-8, can be found out, when adopting described method of the present invention, can be by dehydrogenation coupling in formula (II) compound generation molecule under acidic conditions, and obtain corresponding quinazolinone indazole derivatives, and there is good yield and high purity.
Embodiment 9-16
Remove Pd wherein (OAc)
2replace with outside following palladium compound, in the mode identical with embodiment 1-8, implemented respectively embodiment 9-16, the yield of the palladium compound that uses, embodiment corresponding relation and corresponding product is as shown in the table.
As seen from the above table, when using other palladium compound, can access corresponding product equally, but its productive rate will be significantly lower than Pd (OAc)
2, this has proved the Pd (OAc) of the method for the invention
2catalyzer has good catalytic performance to this substrate.
Embodiment 17-28
Except oxygenant silver acetate is wherein replaced with following oxygenant, in the mode identical with embodiment 1-8, implemented respectively embodiment 17-28, the yield of the oxygenant that uses, embodiment corresponding relation and corresponding product is as shown in the table.
Nd: do not detect.
As seen from the above table, when using other oxygenant as Ag
2when O, Sulfuric acid disilver salt, trifluoromethyl silver acetate, venus crystals, DDQ, also can obtain object product, but productive rate significantly reduces; And when using other oxygenant, even if the very strong ozone of oxidation capacity, TBHP etc., but still can not obtain object product.
Embodiment 29-39
Except acid organic solvent acetic acid wherein being replaced with to (being the volume ratio of mixed solvent in bracket) isopyknic following organic solvent, in the mode identical with embodiment 1-8, implemented respectively embodiment 29-39, the yield of acid organic solvent compound, embodiment corresponding relation and corresponding product that uses as shown in the table.
As seen from the above table, acetic acid has specific effect for this reaction, even if use with acetic acid very similarly when formic acid or propionic acid, productive rate is very low or do not react.And while using separately DMSO, DMF, dimethylbenzene or dioxane, do not react completely, but when use with acetic acid mixture time, react.Proved thus essential for the inventive method of acetic acid solvent.
In sum, by above-mentioned all embodiment, can clearly be found out, when adopting method of the present invention, can be smoothly by formula (II) compound with high yield and high purity and obtain object product quinazolinone indazole derivatives, be a kind of brand-new synthetic method that has very much prospects for commercial application, brand-new synthetic route is provided for the efficient quick of quinazolinone indazole derivatives is synthetic.
The purposes that should be appreciated that these embodiment only limits the scope of the invention for the present invention being described but not being intended to.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various changes, modification and/or modification to the present invention, within these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. the quinazolinone shown in a formula (I) the synthetic method of indazole derivatives, described method is: using palladium compound as catalyzer, under oxygenant exists, in acid organic solvent, dehydrogenation linked reaction in formula (II) compound generation molecule, thereby the formula of obtaining (I) derivative:
Wherein:
Ar is following group:
R
1, R
2, R
3be selected from independently of one another H, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group.
2. synthetic method as claimed in claim 1, is characterized in that: described palladium compound is inorganic palladium compound, organic palladium compound or both mixtures.
3. synthetic method as claimed in claim 2, is characterized in that: wherein, described inorganic palladium compound is PdCl
2, Na
2pdCl
4, Pd (NH
3)
4cl
2in any or any multiple mixture;
Described organic palladium compound is Pd (OAc)
2, Pd (PPh
3)
4, PdCl
2(dppf), Pd (acac)
2, dppePdCl
2, Na
2pdCl
2, PdCl
2(CH
3cN)
2, PdCl
2(PPh
3)
2, Pd (NH
3)
4cl
2, PdCl
2(cod) any or any multiple mixture in;
Described palladium compound most preferably is Pd (OAc)
2.
4. the synthetic method as described in claim 1-3 any one, is characterized in that: described oxygenant is silver compound, copper compound, benzoquinone compound, oxygen, ozone, TBHP (tertbutyl peroxide), Potassium Persulphate, PhI (OAc)
2, any or any multiple mixture in Silver Nitrate, most preferably be silver acetate.
5. the synthetic method as described in claim 1-4 any one, is characterized in that: the mol ratio of formula (II) compound and catalyzer is 1:0.05-0.15.
6. the synthetic method as described in claim 1-5 any one, is characterized in that: the mol ratio of formula (II) compound and oxygenant is 1:3-6.
7. the synthetic method as described in claim 1-6 any one, it is characterized in that: described acid organic solvent is any in acetic acid, propionic acid, formic acid, dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), dimethylbenzene, dioxane.
8. the synthetic method as described in claim 1-6 any one, it is characterized in that: described acid organic solvent is acetic acid and be selected from DMSO, DMF, dimethylbenzene, dioxane any mixture, and in acetic acid and DMSO, DMF, dimethylbenzene, dioxane, any volume ratio is 1:0.1-10.
9. the synthetic method as described in claim 1-8 any one, is characterized in that: temperature of reaction is 80-150 ℃.
10. the synthetic method as described in claim 1-8 any one, is characterized in that: the reaction times is 20-50 hour.
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| CN104557942A (en) * | 2014-12-22 | 2015-04-29 | 温州大学 | Synthetic method of nitrogen-containing fused ring compound |
| CN104725385A (en) * | 2015-04-10 | 2015-06-24 | 温州大学 | Quinazolinone and pyrazole compound and synthesis method for same |
| CN104744479A (en) * | 2015-04-10 | 2015-07-01 | 温州大学 | Quinazolinonedihydropyrazol compound and preparation method thereof |
| CN106377530A (en) * | 2016-08-29 | 2017-02-08 | 温州医科大学附属第二医院 | Pharmaceutical composition for treating cancer, especially liver cancer |
| CN106389436A (en) * | 2016-08-29 | 2017-02-15 | 温州大学 | Pharmaceutical composition containing quinazolino indazole derivatives |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557942A (en) * | 2014-12-22 | 2015-04-29 | 温州大学 | Synthetic method of nitrogen-containing fused ring compound |
| CN104725385A (en) * | 2015-04-10 | 2015-06-24 | 温州大学 | Quinazolinone and pyrazole compound and synthesis method for same |
| CN104744479A (en) * | 2015-04-10 | 2015-07-01 | 温州大学 | Quinazolinonedihydropyrazol compound and preparation method thereof |
| CN104725385B (en) * | 2015-04-10 | 2017-04-12 | 温州大学 | Quinazolinone and pyrazole compound and synthesis method for same |
| CN106377530A (en) * | 2016-08-29 | 2017-02-08 | 温州医科大学附属第二医院 | Pharmaceutical composition for treating cancer, especially liver cancer |
| CN106389436A (en) * | 2016-08-29 | 2017-02-15 | 温州大学 | Pharmaceutical composition containing quinazolino indazole derivatives |
| CN106377530B (en) * | 2016-08-29 | 2019-05-24 | 温州医科大学附属第二医院 | A kind of pharmaceutical composition for the treatment of cancer especially liver cancer |
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