CN104387301B - The synthetic method of the fluoro-4-Methyl benzenesulfonyl of a kind of 2-methyl isonitrile - Google Patents
The synthetic method of the fluoro-4-Methyl benzenesulfonyl of a kind of 2-methyl isonitrile Download PDFInfo
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- CN104387301B CN104387301B CN201410629190.3A CN201410629190A CN104387301B CN 104387301 B CN104387301 B CN 104387301B CN 201410629190 A CN201410629190 A CN 201410629190A CN 104387301 B CN104387301 B CN 104387301B
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Abstract
The invention discloses the synthetic method of the fluoro-4-Methyl benzenesulfonyl of a kind of 2-methyl isonitrile: it is raw material that the present invention adopts SPTS, make tosyl methyl isonitrile through similar Mannich condensation and dehydration of amide reaction, and add wherein hydrofluoric acid aqueous solution and Ni-CO catalyst, under nitrogen protection, it is fully reacted, through suction filtration, washing, dry to obtain the fluoro-4-Methyl benzenesulfonyl of light yellow crystal 2-methyl isonitrile, productive rate reaches more than 92%, purity is 99.8%, this technique has reaction raw materials and is easy to get, mild condition, product yield is high, be applicable to the advantages such as suitability for industrialized production.
Description
Technical field
The present invention is a kind of synthetic method of compound, the fluoro-4-Methyl benzenesulfonyl of a kind of 2-methyl isonitrile syntheticMethod.
Background technology
Methyl benzenesulfonyl methyl isonitrile has a wide range of applications in organic synthesis, is synthetic with five yuan of nitrogen-containing heterosLopps compound is as important intermediate such as imidazoles, thiazole, oxazole, triazoles, and this is because Methyl benzenesulfonyl methylIsonitrile, except having the electrophilic center and nucleophilic center of isonitrile group, also has one and well dredges core leaving groupGroup-Tos, can be for the synthesis of multi-products. For example, aspect medicine, agricultural chemicals and other Minute Organic SynthesisThere is purposes widely.
With the synthetic fluoro-4-Methyl benzenesulfonyl of the 2-methyl isonitrile of method of Leusen, be with ethers traditionally, mainIf 1,2-dimethoxy-ethane is solvent, but this solvent price of existing market is more expensive, and does not reclaim after reaction.In the time using THF or dioxane, its productive rate does not all reduce, but they exist same problem, because of itself and waterMix, generally do not reclaim, while preparation in a large number, increase cost and contaminated environment, according to the feature of this reaction, considerWith cheap or easily recovered solvent replacement, for this reason, the present invention utilizes chloro alkanes for solvent, and the ring of optimizingUnder border, obtain good yield.
Summary of the invention
The invention provides the fluoro-4-of 2-that a kind of reaction condition is simple, productive rate is high, cost is low and contaminated environment is lessThe synthetic method of Methyl benzenesulfonyl methyl isonitrile.
For achieving the above object, the synthetic route of the fluoro-4-Methyl benzenesulfonyl of 2-of the present invention methyl isonitrile is:
The building-up process of the fluoro-4-Methyl benzenesulfonyl of the 2-methyl isonitrile the present invention relates to comprises the following steps:
1, tolysulfonyl NMF is synthetic
(1) in the 500mL four-hole bottle with mechanical agitation, reflux condensing tube and thermometer, throw in successively 92.1gMass fraction is 97% SPTS, 75.2g paraformaldehyde, 113.1g formamide, stirs lowerAdd 157.2g mass fraction and be 88% formic acid;
(2), after dropwising, be warming up to 90 DEG C, insulation reaction 2h, below then cooling reactant liquor to 50 DEG C,Add cold water 100mL, stir, cryosel is bathed and is cooled to below 0 DEG C;
(3) filter, 20mL cold water drip washing for filter cake, vacuum drying obtains white crystal.
2, synthesizing sulfonyloxy methyl methyl isonitrile
(1) throw in successively 42.8g tolysulfonyl NMF, 300mL carrene, 71.2g triethylamineIn 1000mL there-necked flask, stirring and dissolving, bathes and is cooled to-4--2 DEG C with cryosel;
(2) to the mixed solution that drips 21mL POCl3 and 21mL carrene in dropping funel, dropping processIn control all the time temperature between-4-0 DEG C, about 2-3h drips off;
(3) react 1h after dripping off again, slowly add 50mL water, continue to stir 30min, stratification, addsThe sodium hydroxide solution of 300mL7% stirs and is adjusted to pH=14, leaves standstill and separates triethylamine layer, after being dried, returnsReceive triethylamine and can be directly used in reaction;
(4) separatory, organic layer is washed 1 time with the sodium carbonate of 60mL10%, separates organic layer anhydrous sodium sulfate dryDry, first normal pressure in water-bath, then decompression distillation recovery carrene, till there is crystallization to edge, then slowSlowly add the benzinum of 2.5 times of content volumes, more than standing 30min, suction filtration, dry, 40.6g weighs to obtainFallow crystal.
3, the synthetic method of the fluoro-4-Methyl benzenesulfonyl of 2-methyl isonitrile
(1) under the protection of nitrogen, by the hydrofluoric acid aqueous solution to sulfonyloxy methyl methyl isonitrile, 30mL of 35.2gPut in reactor with 0.23gNi-Co, after stirring and dissolving 2-3h, bathe and be cooled to below 5 DEG C with cryosel;(2) separatory, 100mL water washing 1 time for organic layer, with anhydrous sodium sulfate drying, suction filtration, weighs, andCalculate productive rate and detect its purity.
Specific embodiments
The building-up process of the fluoro-4-Methyl benzenesulfonyl of a kind of 2-methyl isonitrile the present invention relates to comprises the following steps:
In the 500mL four-hole bottle with mechanical agitation, reflux condensing tube and thermometer, throwing in successively 92.1g quality dividesNumber is 97% SPTS, 75.2g paraformaldehyde, 113.1g formamide, stirs the lower 157.2g of droppingMass fraction is 88% formic acid; After dropwising, be warming up to 90 DEG C, insulation reaction 2h is then cooling anti-Answer below liquid to 50 DEG C, add cold water 100mL, stir, cryosel is bathed and is cooled to below 0 DEG C; Filter filter cakeWith the drip washing of 20mL cold water, vacuum drying obtains white crystal. With mechanical agitation, reflux condensing tube and temperatureIn the 500mL four-hole bottle of meter, throw in successively 42.8g tolysulfonyl NMF, 300mL carrene,71.2g triethylamine is put into 1000mL there-necked flask successively, and stirring and dissolving is bathed and is cooled to-4--2 DEG C with cryosel;To the mixed solution that drips 21mL POCl3 and 21mL carrene in dropping funel, in dropping process all the timeControl temperature between-4-0 DEG C, about 2-3h drips off; After dripping off, react again 1h, slowly add 50mL water,Continue to stir 30min, stratification, adds the sodium hydroxide solution stirring of 300mL7% to be adjusted to pH=14, quietPut and separate triethylamine layer, after being dried, reclaiming triethylamine and can be directly used in reaction; Separatory, organic layer is usedThe sodium carbonate washing of 60mL10% 1 time, separates organic layer anhydrous sodium sulfate drying, first normal pressure in water-bath,Carrene is reclaimed in decompression distillation again, till there is crystallization, then slowly adds content volume 2.5 to edgeBenzinum doubly, more than standing 30min, suction filtration, dry, the fallow crystal of 40.6g of weighing to obtain. ?Under the protection of nitrogen, by the hydrofluoric acid aqueous solution to sulfonyloxy methyl methyl isonitrile, 30mL of 35.2g and0.23gNi-Co puts in reactor, after stirring and dissolving 2-3h, bathes and is cooled to below 5 DEG C with cryosel;Separatory, 100mL water washing 1 time for organic layer, with anhydrous sodium sulfate drying, suction filtration, weighs, and calculates its productRate and purity.
Example 1
In the 500mL four-hole bottle with mechanical agitation, reflux condensing tube and thermometer, throwing in successively 92.1g quality dividesNumber is 97% SPTS, 75.2g paraformaldehyde, 113.1g formamide, stirs the lower 157.2g of droppingMass fraction is 88% formic acid; After dropwising, be warming up to 90 DEG C, insulation reaction 2h is then cooling anti-Answer below liquid to 50 DEG C, add cold water 100mL, stir, cryosel is bathed and is cooled to below 0 DEG C; Filter filter cakeWith the drip washing of 20mL cold water, vacuum drying obtains white crystal. With mechanical agitation, reflux condensing tube and temperatureIn the 500mL four-hole bottle of meter, throw in successively 42.8g tolysulfonyl NMF, 300mL carrene,71.2g triethylamine is put into 1000mL there-necked flask successively, and stirring and dissolving is bathed and is cooled to-4 DEG C with cryosel; ToIn dropping funel, drip the mixed solution of 21mL POCl3 and 21mL carrene, control all the time in dropping processTemperature processed is between-4 DEG C, and about 2h drips off; After dripping off, react again 1h, slowly add 50mL water, continue to stirMix 30min, stratification, adds the sodium hydroxide solution stirring of 300mL7% to be adjusted to pH=14, leaves standstill and separatesTriethylamine layer, after being dried, reclaiming triethylamine and can be directly used in reaction; Separatory, organic layer 60mL10%Sodium carbonate washing 1 time, separate organic layer anhydrous sodium sulfate drying, first normal pressure in water-bath, then decompression steamingHeat up in a steamer recovery carrene, till there is crystallization to edge, then slowly add the oil of 2.5 times of content volumesEther, more than standing 30min, suction filtration, dry, the fallow crystal of 40.6g of weighing to obtain. The guarantor of nitrogenProtect down, hydrofluoric acid aqueous solution and the 0.23gNi-Co to sulfonyloxy methyl methyl isonitrile, 30mL of 35.2g are putEnter in reactor, after stirring and dissolving 2-3h, bathe and be cooled to below 5 DEG C with cryosel; Separatory, organic layerWith 100mL water washing 1 time, with anhydrous sodium sulfate drying, suction filtration, weighs, and productive rate reaches more than 92%, purityBe 99.8%.
Example 2
In the 500mL four-hole bottle with mechanical agitation, reflux condensing tube and thermometer, throwing in successively 92.1g quality dividesNumber is 97% SPTS, 75.2g paraformaldehyde, 113.1g formamide, stirs the lower 157.2g of droppingMass fraction is 88% formic acid; After dropwising, be warming up to 90 DEG C, insulation reaction 2h is then cooling anti-Answer below liquid to 50 DEG C, add cold water 100mL, stir, cryosel is bathed and is cooled to below 0 DEG C; Filter filter cakeWith the drip washing of 20mL cold water, vacuum drying obtains white crystal. With mechanical agitation, reflux condensing tube and temperatureIn the 500mL four-hole bottle of meter, throw in successively 42.8g tolysulfonyl NMF, 300mL carrene,71.2g triethylamine is put into 1000mL there-necked flask successively, and stirring and dissolving is bathed and is cooled to-3 DEG C with cryosel; ToIn dropping funel, drip the mixed solution of 21mL POCl3 and 21mL carrene, control all the time in dropping processTemperature processed is between-2 DEG C, and about 2.5h drips off; After dripping off, react again 1h, slowly add 50mL water, continueStir 30min, stratification, adds the sodium hydroxide solution stirring of 300mL7% to be adjusted to pH=14, leaves standstill and dividesGo out triethylamine layer, after being dried, reclaiming triethylamine and can be directly used in reaction; Separatory, organic layer 60mL10%Sodium carbonate washing 1 time, separate organic layer anhydrous sodium sulfate drying, first normal pressure in water-bath, then decompression steamingHeat up in a steamer recovery carrene, till there is crystallization to edge, then slowly add the oil of 2.5 times of content volumesEther, more than standing 30min, suction filtration, dry, the fallow crystal of 40.6g of weighing to obtain. The guarantor of nitrogenProtect down, hydrofluoric acid aqueous solution and the 0.23gNi-Co to sulfonyloxy methyl methyl isonitrile, 30mL of 35.2g are putEnter in reactor, after stirring and dissolving 2.5h, bathe and be cooled to below 5 DEG C with cryosel; Separatory, organic layerWith 100mL water washing 1 time, with anhydrous sodium sulfate drying, suction filtration, weighs, and productive rate reaches more than 92%, purityBe 99.8%.
Example 3
In the 500mL four-hole bottle with mechanical agitation, reflux condensing tube and thermometer, throwing in successively 92.1g quality dividesNumber is 97% SPTS, 75.2g paraformaldehyde, 113.1g formamide, stirs the lower 157.2g of droppingMass fraction is 88% formic acid; After dropwising, be warming up to 90 DEG C, insulation reaction 2h is then cooling anti-Answer below liquid to 50 DEG C, add cold water 100mL, stir, cryosel is bathed and is cooled to below 0 DEG C; Filter filter cakeWith the drip washing of 20mL cold water, vacuum drying obtains white crystal. With mechanical agitation, reflux condensing tube and temperatureIn the 500mL four-hole bottle of meter, throw in successively 42.8g tolysulfonyl NMF, 300mL carrene,71.2g triethylamine is put into 1000mL there-necked flask successively, and stirring and dissolving is bathed and is cooled to-2 DEG C with cryosel; ToIn dropping funel, drip the mixed solution of 21mL POCl3 and 21mL carrene, control all the time in dropping processTemperature processed is between 0 DEG C, and a month 3h drips off; After dripping off, react again 1h, slowly add 50mL water, continue to stir30min, stratification, adds the sodium hydroxide solution stirring of 300mL7% to be adjusted to pH=14, leaves standstill and separates three secondAmine layer, after being dried, reclaiming triethylamine and can be directly used in reaction; Separatory, the carbon of 60mL10% for organic layerAcid sodium washing 1 time, separates organic layer anhydrous sodium sulfate drying, first normal pressure in water-bath, then decompression distillation is returnedReceive carrene, till there is crystallization to edge, then slowly add the benzinum of 2.5 times of content volumes,More than standing 30min, suction filtration, dry, the fallow crystal of 40.6g of weighing to obtain. Under the protection of nitrogen,Hydrofluoric acid aqueous solution and the 0.23gNi-Co to sulfonyloxy methyl methyl isonitrile, 30mL of 35.2g are put into insteadAnswer in still, after stirring and dissolving 3h, bathe and be cooled to below 5 DEG C with cryosel; Separatory, organic layer 100mLWater washing 1 time, with anhydrous sodium sulfate drying, suction filtration, weighs, and productive rate reaches more than 92%, and purity is 99.8%.
Claims (1)
1. a synthetic method for the fluoro-4-Methyl benzenesulfonyl of 2-methyl isonitrile, is characterized in that concrete synthesis step is:
(1) in the 500mL four-hole bottle with mechanical agitation, reflux condensing tube and thermometer, throw in successively 92.1gMass fraction is 97% SPTS, 75.2g paraformaldehyde, 113.1g formamide, stirs lowerAdd 157.2g mass fraction and be 88% formic acid;
(2), after dropwising, be warming up to 90 DEG C, insulation reaction 2h, below then cooling reactant liquor to 50 DEG C,Add cold water 100mL, stir, cryosel is bathed and is cooled to below 0 DEG C;
(3) filter, 20mL cold water drip washing for filter cake, vacuum drying obtains white crystal;
(4) take white crystal, 300mL carrene, the 71.2g triethylamine that the above-mentioned vacuum drying of 42.8g obtainsPut into successively 1000mL there-necked flask, stirring and dissolving, bathes and is cooled to-4--2 DEG C with cryosel;
(5) to the mixed solution that drips 21mL POCl3 and 21mL carrene in dropping funel, dropping processIn control all the time temperature between-4-0 DEG C, about 2-3h drips off;
(6) react 1h after dripping off again, slowly add 50mL water, continue to stir 30min, stratification, addsThe sodium hydroxide solution of 300mL7% stirs and is adjusted to pH=14, leaves standstill and separates triethylamine layer, after being dried, returnsReceive triethylamine and can be directly used in reaction;
(7) separatory, organic layer is washed 1 time with the sodium carbonate of 60mL10%, separates organic layer anhydrous sodium sulfate dryDry, first normal pressure in water-bath, then decompression distillation recovery carrene, till there is crystallization to edge, then slowSlowly add the benzinum of 2.5 times of content volumes, more than standing 30min, suction filtration, dry, 40.6g weighs to obtainFallow crystal;
(8) under the protection of nitrogen, by water-soluble the hydrofluoric acid of fallow crystal obtained above 35.2g, 30mLLiquid and 0.23gNi-Co put in reactor, after stirring and dissolving 2-3h, with cryosel bathe be cooled to 5 DEG C withUnder;
(9) separatory, 100mL water washing 1 time for organic layer, with anhydrous sodium sulfate drying, suction filtration, weighs, andCalculate productive rate and detect its purity.
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