CN102675234A - Synthetic method of sym-triazine derivative - Google Patents
Synthetic method of sym-triazine derivative Download PDFInfo
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- CN102675234A CN102675234A CN2012101391287A CN201210139128A CN102675234A CN 102675234 A CN102675234 A CN 102675234A CN 2012101391287 A CN2012101391287 A CN 2012101391287A CN 201210139128 A CN201210139128 A CN 201210139128A CN 102675234 A CN102675234 A CN 102675234A
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Abstract
The invention relates to a synthetic method of a sym-triazine derivative. The method comprises the following step of: performing a coupling reaction on chlorinated sym-triazine and Negishi of an organic zinc reagent by taking a chlorinated sym-triazine solution and the organic zinc reagent as substrates and taking a palladium salt catalyst, a palladium composition catalyst and a palladium-phosphine ligand mixed catalyst with high catalyzing activities as catalysts to synthesize a polysubstitution sym-triazine derivative. In a reaction process, the using amounts of the catalysts are small, and the reaction yield is high; a zinc alkyl reagent, a zinc aryl reagent and a zinc heteroaryl reagent with appropriate reaction activities used in the reaction process have high functional group compatibility and wide substrate application ranges, and have high reaction selectivity in synthesis of an asymmetric sym-triazine derivative; and moreover, cheap and readily-available chlorinated sym-triazine is taken as an active ingredient in the reaction, so that the method has general applicability to synthesis of sym-triazine derivatives, and is relatively low in cost.
Description
Technical field
The invention belongs to the chemosynthesis technical field of cyanidin(e), specifically is a kind of compound method of utilizing palladium salt, palladium complex and palladium salt, palladium complex and phosphine ligand mixture as the cyanidin(e) of catalyzer.
Background technology
At present, mainly be polyreaction for the traditional compound method of pyrrolotriazine derivatives through the cyanic acid compounds, but this method long reaction time; The substrate functional group poor compatibility; The productive rate of resultant is low, and the kind of the pyrrolotriazine derivatives that can prepare is less, and difficulty is relatively large; Particularly, use this kind method almost to be difficult to realize for asymmetric pyrrolotriazine derivatives.
In addition, also there is the people to prepare pyrrolotriazine derivatives, but the minority report is only arranged through linked reaction.People such as Menicagli have attempted having prepared three grades of big sterically hindered pyrrolotriazine derivatives of alkyl through Grignard reagent and chloro triazine through coupling.In addition; People such as Knochel are converted into the higher iodo triazine of reactive behavior with the chloro triazine; Through obtaining the triazine Grignard reagent with the exchange of alkyl Grignard reagent; Triazine Grignard reagent and zinc chloride generation metal exchange obtain the triazine zincon, and the triazine zincon prepares the aryl-triazine verivate with the aryl bromide linked reaction again.
The contriver finds that in test and research process all there is following problem in above-mentioned method:
1, reaction substrate functional group poor compatibility, the scope of application is less, and the selectivity of reaction product is relatively poor;
2, loaded down with trivial details, the long reaction time of process step, catalyst levels is big, reaction yield is relatively low.
Seeing that the existence of above-mentioned defective makes that synthesizing in industrial applications of existing pyrrolotriazine derivatives limited to a certain extent, therefore need further study this aspect.
Summary of the invention
Prepare in order to solve polysubstituted cyanidin(e) of the prior art that catalyst levels is big in the process, reaction yield is low, the substrate scope of application is little, the problem of reaction preference difference, the invention provides a kind of compound method of cyanidin(e) of efficient, high regioselectivity.
The technical scheme of technical solution problem is: the compound method of cyanidin(e) may further comprise the steps:
1)-30 ℃～75 ℃, dry reactor is passed through N
2Add chloro s-triazine, organic zinc reagent and catalyzer after the displacement successively, the mol ratio of chloro s-triazine and organic zinc reagent, catalyzer is 1:1.00～2.50:0.0025～0.20, reacts 1.5～4.5 hours;
2) in reacted solution, adding concentration is that hydrochloric acid soln to the cancellation of 1mol/L reacts completely, and the water of generation merges organic layer with extraction 3 times, and drying concentrates, the bullion cyanidin(e);
3) the bullion cyanidin(e) gets cyanidin(e) through silica gel chromatography;
Above-mentioned catalyzer is any one in the mixed catalyst of mixed catalyst, palladium complex and phosphine part of palladium salt catalyst, palladium complex catalyst, palladium salt and phosphine part; The mol ratio of palladium salt and phosphine part is 1:0.05～8 in the mixed catalyst of palladium salt and phosphine part, and the mixed catalyst mol ratio of palladium complex and phosphine part is 1:0.05～8;
Above-mentioned organic zinc reagent is a kind of in alkyl zinc reagent, aryl zincon, the heteroaryl zincon.
Further, in step 1) and step 2) between comprise that also step a) adds organic zinc reagent again in the step 1) reacted solution, the chloro s-triazine is 1:1～2.5 with the mol ratio of the organic zinc reagent that adds once more, reacts 1.5～4.5 hours.
The mol ratio of the above-mentioned chloro s-triazine and first organic zinc reagent, catalyzer is preferable in 1:1.50～2.00:0.03～0.15 scope.
Above-mentioned chloro s-triazine is a 2-chloro-4,6-dimethoxy-1,3,5-triazines or 2,4-two chloro-6-methoxyl group-1,3,5-triazines.
The mol ratio of palladium salt and phosphine part is to be good in 1:1～4 scopes in the mixed catalyst of above-mentioned palladium salt and phosphine part, and the mixed catalyst mol ratio of palladium complex and phosphine part is that 1:1～4 scopes are good.
Above-mentioned palladium salt is palladium or palladium chloride or its combination.
Above-mentioned palladium complex is the arbitrary combination of any one or at least two kinds in four (triphenyl phosphorus) palladium, two (triphenyl phosphorus) palladium chloride, three (dibenzalacetones), two palladiums, two (methyl ethyl diketone) palladium.
Above-mentioned phosphine part is triphenylphosphine or 1, two (diphenylphosphine) ethane of 2-.
The abovementioned alkyl zincon is sec.-propyl chlorination zinc or normal-butyl chlorination zinc or benzyl zinc chloride;
Above-mentioned aryl zincon is any one in phenyl zinc chloride, 4-aminomethyl phenyl zinc chloride, 4-p-methoxy-phenyl zinc chloride, 4-bromophenyl zinc chloride, the 4-cyano-phenyl zinc chloride;
Above-mentioned heteroaryl zincon is 2-thienyl zinc chloride or 2-pyridine chlorination zinc.
The present invention is a substrate with chloro s-triazine solution and organic zinc reagent; The palladium salt catalyst of high catalytic activity, palladium complex catalyst, palladium-phosphine part mixed catalyst are catalyzer; Negishi linked reaction through chloro s-triazine and organic zinc reagent has been synthesized polysubstituted cyanidin(e); The catalyzer usage quantity is few in the reaction process, reaction yield is high, and moderate alkyl zinc reagent and aryl zincon and the heteroaryl zincon of the reactive behavior of using in the reaction process, and it is good to have functional group's compatibility; Wide application range of substrates has high reaction preference in synthetic asymmetric pyrrolotriazine derivatives; The chloro triazine that react the use cheapness in addition, is easy to get makes this method in synthetic cyanidin(e), have general applicability as effective constituent, and cost is relatively low.
Embodiment
To further explain of the present invention, but the invention is not restricted to these embodiment below in conjunction with embodiment.
Embodiment 1
The compound method of the cyanidin(e) of present embodiment, realized by following steps:
Step 1: under 0 ℃; With the effective nitrogen replacement of the dry reaction of the 50mL that stirrer and rubber plug are housed three times; In reaction tubes, adding 1.25mL concentration is the phenyl-magnesium-bromide of 1.20mol/L and the zinc chloride tetrahydrofuran solution that 1.50mL concentration is 1.0 mol/L; Stirred 15 minutes, rising to room temperature preparation, to become 1.25ml concentration be the phenyl zinc chloride of 1.2mol/L; The 2-chloro-4 that in the phenyl zinc chloride for preparing, adds 175.6mg again, 6-dimethoxy-1,3; Two (triphenylphosphine) palladium chlorides of 5-triazine and 35.1mg and 26.2mg triphenylphosphine mix the catalyzer of forming, 2-chloro-4,6-dimethoxy-1; 3; The mol ratio of 5-triazine and phenyl zinc chloride and mixed catalyst is: 1:1.5:0.15, and two (triphenylphosphine) palladium chlorides in the catalyzer and the mol ratio of triphenylphosphine are 1:2, reaction is 3 hours under the room temperature;
Step 2: step 1 is accomplished the back, and in reaction tubes, to add concentration be that hydrochloric acid soln to the cancellation of 1mol/L reacts completely, and the water of generation merges organic layer with 5ml extracted with diethyl ether 3 times, and adding 0.5g anhydrous sodium sulfate drying is concentrated, obtains the bullion cyanidin(e);
Step 3: get 2 of 215.1mg through silica gel chromatography, 4-dimethoxy-6-phenyl-1,3,5-triazines, productive rate are 99%.
Above-mentioned product is passed through NMR (300 mepses; Deuterochloroform is made solvent; Mark in the tetramethyl-chlorosilane is done) nucleus magnetic hydrogen spectrum and the nuclear-magnetism carbon of having measured this compound are composed; Measured the content of the carbon in the compound, hydrogen, nitrogen element through elemental analyser, measured the fusing point of compound through micro-fusing point appearance, concrete outcome is following:
Nucleus magnetic hydrogen spectrum (δ refers to chemical shift, unit be 1,000,000/): δ 8.50 (d, J=7.5 Hz, 2H), 7.65-7.36 (m, 3H), 4.13 (s, 6H).
Nuclear-magnetism carbon spectrum (δ refers to chemical shift, unit be 1,000,000/): δ 174.92,172.90, and 135.03,132.82,129.01,128.48,55.20.
(the compound molecule formula is C in ultimate analysis
11H
11N
3O
2): theoretical value C 60.82, and H 5.10, and N 19.34; Measured value C 60.88, H 5.13, and N 19.29.
Fusing point: measured value 88-89 ℃, literature value 89-90 ℃.
Can be known that by above-mentioned experimental data 8.50 and 7.65-7.36 places are five hydrogenation displacement studies on the phenyl ring in the nucleus magnetic hydrogen spectrum, 4.13 places are the chemical shift of six hydrogen of methoxyl group on the triazine ring; 174.92 and 172.90 are respectively on the triazine ring chemical shift that is connected carbon atom with methoxyl group with chlorine in the nuclear-magnetism carbon spectrum; 135.03,132.82; 129.01,128.48 for the carbon potential on the phenyl ring that links to each other with triazine ring moves, 55.20 is to be connected the chemical shift of carbon atom in the methoxyl group on the triazine ring.Show through above-mentioned determination of elemental analysis result: the measured value of carbon, hydrogen, nitrogen element percentage composition is consistent with theoretical value in this compound.The fusing point of reporting in the actual measurement fusing point of this compound and the document is consistent.Can draw this compound thus is exactly target compound 2,4-dimethoxy-6-phenyl-1,3,5-triazines.
Embodiment 2
The compound method of the cyanidin(e) of present embodiment, realized by following steps:
Step 1: under-10 ℃, to the 2-chloro-4 of dry reactor adding 175.6mg, 6-dimethoxy-1; 3,5-triazine, 1.67ml concentration are the phenyl zinc chloride of 1.2mol/L and the mixed catalyst of being made up of two (triphenylphosphine) palladium chlorides and the 3.9mg triphenylphosphine of 10.5mg, 2-chloro-4; 6-dimethoxy-1; 3, the mol ratio of 5-triazine and phenyl zinc chloride, mixed catalyst is 1:2:0.03, and the mol ratio of two (triphenylphosphine) palladium chlorides and triphenylphosphine is 1:1 in the mixed catalyst; Reacted 4 hours, other steps are identical with embodiment 1 in this step.
Other step is identical with embodiment 1, obtains 212.9mg 2, and 4-dimethoxy-6-phenyl-1,3,5-triazines, productive rate are 98%.
Embodiment 3
The compound method of the cyanidin(e) of present embodiment, realized by following steps:
Step 1: under 45 ℃, to the 2-chloro-4 of dry reactor adding 175.6mg, 6-dimethoxy-1; 3,5-triazine, 1.46ml concentration are the phenyl zinc chloride of 1.2mol/L and the mixed catalyst of being made up of two (triphenylphosphine) palladium chlorides and the 18.9mg triphenylphosphine of 12.6mg, 2-chloro-4; 6-dimethoxy-1; 3, the mol ratio of 5-triazine and phenyl zinc chloride, mixed catalyst is 1:1.75:0.09, and the mol ratio of two (triphenylphosphine) palladium chlorides and triphenylphosphine is 1:4 in the mixed catalyst; Reacted 2 hours, other steps are identical with embodiment 1 in this step.
Other step is identical with embodiment 1, obtains 206.4mg 2, and 4-dimethoxy-6-phenyl-1,3,5-triazines, productive rate are 95%.
Embodiment 4
The compound method of the cyanidin(e) of present embodiment, realized by following steps:
Step 1: under-30 ℃, to the 2-chloro-4 of dry reactor adding 175.6mg, 6-dimethoxy-1; 3,5-triazine, 0.84ml concentration are the phenyl zinc chloride of 1.2mol/L and the mixed catalyst of being made up of two (triphenylphosphine) palladium chlorides and the 0.1mg triphenylphosphine of 1.7mg, 2-chloro-4; 6-dimethoxy-1; 3, the mol ratio of 5-triazine and phenyl zinc chloride, mixed catalyst is 1:1:0.0025, and the mol ratio of two (triphenylphosphine) palladium chlorides and triphenylphosphine is 1:0.05 in the mixed catalyst; Reacted 4.5 hours, other steps are identical with embodiment 1 in this step.
Other step is identical with embodiment 1, obtains 197.7mg 2, and 4-dimethoxy-6-phenyl-1,3,5-triazines, productive rate are 91%.
Embodiment 5
The compound method of the cyanidin(e) of present embodiment, realized by following steps:
Step 1: under 75 ℃, in reaction tubes, add the 2-chloro-4 of 175.6mg, 6-dimethoxy-1; 3,5-triazine, 2.08ml concentration are the phenyl zinc chloride of 1.2mol/L and the mixed catalyst of being made up of two (triphenylphosphine) palladium chlorides of 19.5mg and 46.6mg triphenylphosphine, 2-chloro-4; 6-dimethoxy-1; 3, the mol ratio of 5-triazine and phenyl zinc chloride, mixed catalyst is 1:2.5:0.2, and the mol ratio of two (triphenylphosphine) palladium chlorides and triphenylphosphine is 1:8 in the catalyzer; Reacted 1.5 hours, other steps are identical with embodiment 1 in this step.
Other step is identical with embodiment 1, obtains 212.9mg 2, and 4-dimethoxy-6-phenyl-1,3,5-triazines, productive rate are 98%.
Embodiment 6
In the step 1 of the foregoing description 1 ~ 5, effective constituent 2-chloro-4,6-dimethoxy-1,3,5-triazines are with 2 of equimolar amount, and 4-two chloro-6-methoxyl groups-1,3,5-triazines is replaced, and other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 7
In the step 1 of the foregoing description 1 ~ 6; Two (triphenyl phosphorus) palladium chlorides in the mixed catalyst are with any one replacement in four (triphenyl phosphorus) palladium of equimolar amount, three (dibenzalacetones), two palladiums, two (methyl ethyl diketone) palladium, and other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 8
In the step 1 of the foregoing description 1 ~ 6, two (triphenyl phosphorus) palladium chlorides in the mixed catalyst are with palladium or the palladium chloride or the replacement of this compsn of two kinds of equimolar amount, and other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 9
In the step 1 of the foregoing description 1 ~ 8, the triphenylphosphine in the mixed catalyst is with 1 of equimolar amount, and two (diphenylphosphine) ethane of 2-are replaced, and other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 10
In the step 1 of the foregoing description 1 ~ 9, mixed catalyst is with the palladium catalyzer or the replacement of palladium chloride catalyzer of equimolar amount, and other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 11
In the step 1 of the foregoing description 1 ~ 9, mixed catalyst is with the equimolar mixed catalyst replacement of being made up of palladium and palladium chloride, and other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 12
In the step 1 of the foregoing description 1 ~ 9; Mixed catalyst is with any one replacement in four (triphenyl phosphorus) palladium catalyst of equimolar amount, two (triphenyl phosphorus) palladium chloride catalyzer, three (dibenzalacetones), two palladium catalysts, two (methyl ethyl diketone) palladium catalyst, and other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 13
In the step 1 of the foregoing description 1 ~ 9; The mixture replacement that mixed catalyst mixes with the arbitrary proportion of any two kinds or three kinds in four (triphenyl phosphorus) palladium catalyst of equimolar amount, two (triphenyl phosphorus) palladium chloride catalyzer, three (dibenzalacetones), two palladium catalysts, two (methyl ethyl diketone) palladium catalyst, other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 14
In the step 1 of the foregoing description 1 ~ 13; With any one replacement in the 4-aminomethyl phenyl zinc chloride of equimolar amount, 4-p-methoxy-phenyl zinc chloride, 4-bromophenyl zinc chloride, the 4-cyano-phenyl zinc chloride, other steps are identical with corresponding embodiment in this step as the phenyl zinc chloride of organic zinc reagent.
Other step is identical with corresponding embodiment.
Embodiment 15
In the step 1 of the foregoing description 1 ~ 13, with any one replacement in the sec.-propyl chlorination zinc of equimolar amount, normal-butyl chlorination zinc, the benzyl zinc chloride, other steps are identical with corresponding embodiment in this step as the phenyl zinc chloride of organic zinc reagent.
Other step is identical with corresponding embodiment.
Embodiment 16
In the step 1 of the foregoing description 1 ~ 13, replace with the 2-thienyl zinc chloride or the 2-pyridine chlorination zinc of equimolar amount as the phenyl zinc chloride of organic zinc reagent, other steps are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment.
Embodiment 17
After the step 1 of the foregoing description 1 ~ 13, carry out step a, specifically:
Any one of sec.-propyl chlorination zinc, normal-butyl chlorination zinc, benzyl zinc chloride, 4-aminomethyl phenyl zinc chloride, 4-p-methoxy-phenyl zinc chloride, 4-bromophenyl zinc chloride, 4-cyano-phenyl zinc chloride, 2-thienyl zinc chloride, 2-pyridine chlorination zinc that in the reaction solution of step 1), adds concentration again and be 1.1mol/l is as the organic zinc reagent that adds for the second time; 2; 4-two chloro-6-methoxyl groups-1; 3; The 5-triazine is 1:1.5 with the mol ratio of the organic zinc reagent that adds for the second time, reacts 3 hours, carry out step 2 after reacting completely.
Other step is identical with embodiment 1 ~ 13.
Embodiment 18
After the step 1 of the foregoing description 1 ~ 13, carry out step a, specifically:
In the reaction solution of step 1), add concentration again and be in the sec.-propyl chlorination zinc, normal-butyl chlorination zinc, benzyl zinc chloride, 4-aminomethyl phenyl zinc chloride, 4-p-methoxy-phenyl zinc chloride, 4-bromophenyl zinc chloride, 4-cyano-phenyl zinc chloride, 2-thienyl zinc chloride, 2-pyridine chlorination zinc of 1.1mol/l any one as the organic zinc reagent that adds for the second time; 2; 4-two chloro-6-methoxyl groups-1; 3; The 5-triazine is 1:1 with the mol ratio of the organic zinc reagent that adds for the second time, reacts 1.5 hours, carry out step 2 after reacting completely.
Other step is identical with embodiment 1 ~ 13.
Embodiment 19
After the step 1 of the foregoing description 1 ~ 13, carry out step a, specifically:
In the reaction solution of step 1), add concentration again and be in the sec.-propyl chlorination zinc, normal-butyl chlorination zinc, benzyl zinc chloride, 4-aminomethyl phenyl zinc chloride, 4-p-methoxy-phenyl zinc chloride, 4-bromophenyl zinc chloride, 4-cyano-phenyl zinc chloride, 2-thienyl zinc chloride, 2-pyridine chlorination zinc of 1.1mol/l any one as the organic zinc reagent that adds for the second time; 2; 4-two chloro-6-methoxyl groups-1; 3; The 5-triazine is 1:2.5 with the mol ratio of the organic zinc reagent that adds for the second time, reacts 4.5 hours, carry out step 2 after reacting completely.
Other step is identical with embodiment 1 ~ 13.
Existing preparation method with people such as Menicagli group and Knochel is the compound method of example 1 and Comparative Examples 2 and the cyanidin(e) of above-mentioned embodiments of the invention 1 and embodiment 6 contrast that makes an experiment as a comparison respectively.
Wherein Comparative Examples 1 is that Menicagli group passes through 2-chloro-4, and cyanidin(e) is synthesized in 6-dimethoxy-1,3,5-triazines and aryl zincon or the coupling of benzyl zincon, and compound method is following:
Step 1: at room temperature; Adding 1.2g (19mmol) zinc powder, 4.74g (6ml in reaction tubes successively; 115.5mmol, concentration 19.2mol/L) acetonitrile, chlorallylene and 21.7mg (0.19mmol) trifluoroacetic acid of 172.2mg (2.25mmol), slowly be warming up to 80 ℃; The bromobenzene that in reaction solution, adds 392.6mg (2.5mmol) again stirred 30 minutes.The 2-chloro-4 that in the above-mentioned phenyl zinc bromide for preparing, adds 543.1mg (2.5mmol), 6-dimethoxy-1,3; The cobaltous bromide of 5-triazine and 165mg (0.75mmol); 2-chloro-4,6-dimethoxy-1,3; The mol ratio of 5-triazine and phenyl zinc bromide and catalyzer is: 1:1:0.3, and 25 ℃ were reacted 12 hours down; Step 2: it is that ammonium chloride solution to the cancellation of 1.5mol/L reacts completely that step 1 is accomplished back adding concentration in reaction tubes; The water that generates merges organic layer, adding 1g anhydrous magnesium sulfate drying with 5mL dichloromethane extraction 3 times; Concentrate, obtain the bullion cyanidin(e); Step 3: get 2 of 65.2mg through silica gel chromatography, 4-dimethoxy-6-phenyl-1,3,5-triazines, productive rate are 30%.
This method has that catalyst levels reaches 30%, the reaction times reaches 12 hours, the productive rate of product and has only 30%, the substrate of reaction is applicable to aryl zincon or benzyl zincon.
Comparative Examples 2 is that Knochel seminar passes through 2, and cyanidin(e) is synthesized in the coupling of 4-two chloro-6-methoxyl group-1,3,5-triazines and alkyl Grignard reagent, and compound method is following:
Step 1: under-10 ℃,, add 2 of 180.0mg (1.0mmol) in the reaction tubes of nitrogen replacement successively to drying; The cuprous iodide catalyst of 4-two chloro-6-methoxyl group-1,3,5-triazines and 38.1mg (0.2mmol); Stir after 30 minutes, in above-mentioned reaction solution, adding 3.5mL concentration slowly is the tetrahydrofuran solution of the tertiary butyl chlorination magnesium of 1.0mol/L, 2; 4-two chloro-6-methoxyl groups-1; 3, the mol ratio of 5-triazine and tertiary butyl chlorination magnesium and catalyzer is: 1:3.5:0.2, and 0 ℃ was reacted 12 hours down; Step 2: it is that ammonium chloride solution to the cancellation of 1.5mol/L reacts completely that step 1 is accomplished back adding concentration in reaction tubes; The water that generates merges organic layer, adding 1.5g anhydrous magnesium sulfate drying with 5mL ethyl acetate extraction 3 times; Concentrate, obtain the bullion cyanidin(e); Step 3: 2-chloro-4-methoxyl group-6-phenyl-1,3,5-triazines that gets 66.5mg through silica gel chromatography and, the 2-chloro-4 of 52.7mg, 6-phenylbenzene-1,3,5-triazines with, wherein single the replacement with disubstituted mol ratio is: 60:40, overall yield is 50%.
Catalyst consumption reaches 20% in this method, and the reaction times reaches 12 hours, and productive rate also has only 50%, and the Grignard reagent that reaction is used is confined to the alkyl Grignard reagent, and single replacement and disubstituted mol ratio are in the reaction product: 1.5:1, poor selectivity.
Experimental result is following:
The compound method contrast of table 1 prior art and cyanidin(e) of the present invention
2-chloro-4 in the last table, the product that the 6-dimethoxy-the 1,3,5-triazines reaction generates is 2,4-dimethoxy-6-phenyl-1,3,5-triazines; 2, single substitution product that 4-two chloro-6-methoxyl groups-the 1,3,5-triazines reaction generates is 2-chloro-4-methoxyl group-6-phenyl-1,3,5-triazines, and two substitution products are 2-methoxyl groups-4,6-phenylbenzene-1,3,5-triazines.
Result by last table can know that the amount of catalyzer used herein is few, and the reaction times is short, and is high than the productive rate of Comparative Examples 1 and 2, and single substitution product of the present invention: two substitution product values are 100:0, and compared with prior art its selectivity is better.
Claims (9)
1. the compound method of a cyanidin(e) is characterized in that: may further comprise the steps:
1)-30 ℃～75 ℃, dry reactor is passed through N
2Add chloro s-triazine, organic zinc reagent and catalyzer after the displacement successively, the mol ratio of chloro s-triazine and organic zinc reagent, catalyzer is 1:1.00～2.50:0.0025～0.20, reacts 1.5～4.5 hours;
2) in reacted solution, adding concentration is that hydrochloric acid soln to the cancellation of 1mol/L reacts completely, and the water of generation merges organic layer with extraction 3 times, and drying concentrates, the bullion cyanidin(e);
3) the bullion cyanidin(e) gets cyanidin(e) through silica gel chromatography;
Above-mentioned catalyzer is any one in the mixed catalyst of mixed catalyst, palladium complex and phosphine part of palladium salt catalyst, palladium complex catalyst, palladium salt and phosphine part; The mol ratio of palladium salt and phosphine part is 1:0.05～8 in the mixed catalyst of palladium salt and phosphine part, and the mixed catalyst mol ratio of palladium complex and phosphine part is 1:0.05～8;
Above-mentioned organic zinc reagent is a kind of in alkyl zinc reagent, aryl zincon, the heteroaryl zincon.
2. the compound method of cyanidin(e) according to claim 1; It is characterized in that: step 1) and step 2) between comprise that also step a) adds organic zinc reagent again in the step 1) reacted solution; The chloro s-triazine is 1:1～2.5 with the mol ratio of the organic zinc reagent that adds once more, reacts 1.5～4.5 hours.
3. the compound method of cyanidin(e) according to claim 1, it is characterized in that: the mol ratio of the said chloro s-triazine and first organic zinc reagent, catalyzer is 1:1.50～2.00:0.03～0.15.
4. according to the compound method of each described cyanidin(e) in the claim 1 to 3, it is characterized in that: said chloro s-triazine is a 2-chloro-4,6-dimethoxy-1,3,5-triazines or 2,4-two chloro-6-methoxyl group-1,3,5-triazines.
5. the compound method of cyanidin(e) according to claim 1; It is characterized in that: the mol ratio of palladium salt and phosphine part is 1:1～4 in the mixed catalyst of said palladium salt and phosphine part, and the mixed catalyst mol ratio of palladium complex and phosphine part is 1:1～4.
6. according to the compound method of claim 1 or 5 described cyanidin(e)s, it is characterized in that: said palladium salt is palladium or palladium chloride or its combination.
7. according to the compound method of claim 1 or 5 described cyanidin(e)s, it is characterized in that: said palladium complex is the arbitrary combination of any one or at least two kinds in four (triphenyl phosphorus) palladium, two (triphenyl phosphorus) palladium chloride, three (dibenzalacetones), two palladiums, two (methyl ethyl diketone) palladium.
8. according to the compound method of claim 1 or 5 described cyanidin(e)s, it is characterized in that: said phosphine part is triphenylphosphine or 1, two (diphenylphosphine) ethane of 2-.
9. the compound method of cyanidin(e) according to claim 1 is characterized in that:
Said alkyl zinc reagent is sec.-propyl chlorination zinc or normal-butyl chlorination zinc or benzyl zinc chloride;
Said aryl zincon is any one in phenyl zinc chloride, 4-aminomethyl phenyl zinc chloride, 4-p-methoxy-phenyl zinc chloride, 4-bromophenyl zinc chloride, the 4-cyano-phenyl zinc chloride;
Said heteroaryl zincon is 2-thienyl zinc chloride or 2-pyridine chlorination zinc.
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| CN106784887A (en) * | 2016-12-08 | 2017-05-31 | 湘潭大学 | Catalyst as prepared by the cyclopolymer of s-triazine containing aryl as presoma and its preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1970552A (en) * | 2005-11-25 | 2007-05-30 | 中国科学院上海药物研究所 | Substituted[1,3,5] triazine compound, its preparing process and its application |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1970552A (en) * | 2005-11-25 | 2007-05-30 | 中国科学院上海药物研究所 | Substituted[1,3,5] triazine compound, its preparing process and its application |
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| BEGOUIN J. M. ET AL.: "Cobalt-Catalyzed Arylation or Benzylation of 2-Chloro-4,6-dimethoxy-1,3,5-triazine", 《SYNLETT》 * |
| SAMARITANI S. ET AL.: "Organometallic alkylation of 2-chloro-4,6-dimethoxy-1,3,5-triazine: a study", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106784887A (en) * | 2016-12-08 | 2017-05-31 | 湘潭大学 | Catalyst as prepared by the cyclopolymer of s-triazine containing aryl as presoma and its preparation method and application |
| CN106784887B (en) * | 2016-12-08 | 2019-11-05 | 湘潭大学 | As the cyclopolymer of s-triazine containing aryl as catalyst prepared by presoma and its preparation method and application |
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| CN102675234B (en) | 2015-01-07 |
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