CN1863765A - Process for production of 1-aryl-5-(trifluoromethyl)-1h- tetrazoles - Google Patents
Process for production of 1-aryl-5-(trifluoromethyl)-1h- tetrazoles Download PDFInfo
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Abstract
A process for the production of N-aryl-2,2,2-trifluoro- acetimidoyl chloride represented by the general formula (2) by reacting a 2,2,2-trifluoro-N-arylacetamide represented by the general formula (1) with both at least one member selected from the group consisting of phosphorus oxychloride and diphenyl- phosphoric acid chloride and a tertiary amine in an organic solvent; and a process for the production of 1-aryl-5 -(trifluoromethyl)-1H-tetrazoles represented by the general formula (4) by reacting an N-aryl-2,2,2-trifluoroacetimidoyl chloride represented by the general formula (2) with an azide in an aromatic hydrocarbon solvent in the presence of an amine salt.
Description
Technical field
The present invention relates to 1-aryl-5-(trifluoromethyl)-1H-tetrazolium and producing intermediate is N-aryl-2,2, the preparation method of 2-trifluoroacetimidoyl chloride.1-aryl-5-(trifluoromethyl)-1H-tetrazolium is the important intermediate of multiple medicine.
Background technology
The known method of preparation tetrazole compound is under 200 ℃ or higher temperature, azoimide gas is blown in imido acyl chloride (imidoyl chloride) compound (J.Am.Chem.Soc., vol.80,1958, P.4647).Other known methods comprise: utilize sodiumazide in aqueous solvent, react (J.Org.Chem., vol.23,1958, p.1909); Utilize aprotic polar solvent such as DMF, acetonitrile etc. react (Synth.Commun., vol.1,1971, p.1; J.Org.Chem., vol.19,1979, p.3281; J.Fluorine Chem., vol.99,1999, p.83); And similar approach.
But the method that is blown into azoimide gas under 200 ℃ or higher temperature can make the deleterious azoimide reaction system of can overflowing, and brings major safety risks therefore for plant-scale production.In the reaction of adopting such as DMF, acetonitrile or similar solvent, when needs heat, sodiumazide meeting and solvent reaction.And because these solvents can be miscible with water, therefore in last handling process, a large amount of reaction product are dissolved in aqueous phase.In addition, when using DMF or similar high boiling solvent, if reaction product is liquid, solvent will be difficult to remove.Therefore, these prior preparation method are not industrial favourable.
The conventional preparation method's of imido acyl chloride compound example is with phosphoryl chloride, phosphorus pentachloride, thionyl chloride or similar chlorizating agent, and amide compound is converted into the imido acyl chloride compound.But when adopting in the method when having strong electron-withdrawing group group as the amide compound of trifluoromethyl, this reaction is carried out very slowly, thereby has hindered the High-efficient Production of imido acyl chloride compound.
J.Org.Chem., vol.58,1993, p.32 instructed a kind of High-efficient Production to contain the method for the imido acyl chloride compound of strong electrophilic trifluoromethyl, this method adopts excessive greatly tetracol phenixin as chlorizating agent.But this method can be brought environmental problem, because tetracol phenixin toxicity is very high, and because it may consume ozone, thereby be controlled substance.
The known preparation method who does not adopt tetracol phenixin adopts ethyl trichloroacetate.This method is produced for example N-(4-methoxyphenyl)-2,2, and 2-trifluoroacetimidoyl chloride, its productive rate are 76% (the open 2003-321431 of Japanese unexamined patent).But this method produces twice or more is multiple times than the solid oxidation triphenyl phosphine of target product weight, and is difficult to remove.And, because productive rate has only 76%, thus this method industrial be not favourable.
Summary of the invention
An object of the present invention is to provide that to be used for safety and to prepare 1-aryl-5-(trifluoromethyl)-1H-tetrazolium efficiently and produce intermediate be N-aryl-2,2, the method for 2-trifluoroacetimidoyl chloride.
The other objects and features of the invention will become obvious by disclosed content hereinafter.
In order to achieve the above object, the inventor has carried out big quantity research, find the preparation safely and efficiently by the following method of 1-aryl-5-(trifluoromethyl)-1H-tetrazolium, described method is under the condition that amine salt exists, in aromatic hydrocarbon solvent, make N-aryl-2,2,2-trifluoroacetimidoyl chloride and trinitride react, and therefore the inventor has partly finished the present invention.In addition, the inventor finds, N-aryl-2,2, the preparation safely and efficiently by the following method of 2-trifluoroacetimidoyl chloride, described method is with 2,2,2-trifluoro-N-arylacetamide, tertiary amine and at least a material that is selected from phosphoryl chloride and diphenyl phosphate chloride react in organic solvent, and the inventor has finished the present invention thus.
Particularly, the invention provides that to be used for safety and to prepare 1-aryl-5-(trifluoromethyl)-1H-tetrazolium efficiently and produce intermediate be N-aryl-2,2, the method for 2-trifluoroacetimidoyl chloride, as described below.
1. one kind prepares the N-aryl of being represented by general formula (2)-2,2, the method for 2-trifluoroacetimidoyl chloride,
In the formula, R is an aryl, randomly contains a substituting group;
Described method is included in makes tertiary amine in the organic solvent, by 2,2 of general formula (1) expression, the step that 2-trifluoro-N-arylacetamide and at least a material that is selected from phosphoryl chloride and diphenyl phosphate chloride react,
In the formula, the definition of R is the same.
2. according to the 1st method, wherein R is phenyl, aminomethyl phenyl, methoxyphenyl, fluoro phenyl, chlorophenyl, bromo phenyl, iodine substituted phenyl or naphthyl.
3. according to the 1st or 2 method, wherein tertiary amine is a triethylamine.
4. method for preparing by 1-aryl-5-(the trifluoromethyl)-1H-tetrazolium of general formula (4) expression,
In the formula, R is an aryl, randomly contains a substituting group, and described method is included in the N-aryl-2,2 that makes general formula (2) expression in the aromatic hydrocarbon solvent in the presence of amine salt, the step that the trinitride of 2-trifluoroacetimidoyl chloride and general formula (3) expression reacts;
The definition of R as mentioned above in the formula;
M (N
3)
n(3) in the formula, M is basic metal or alkaline-earth metal, and n is 1 or 2.
5. according to the 4th method, wherein R is phenyl, aminomethyl phenyl, methoxyphenyl, fluoro phenyl, chlorophenyl, bromo phenyl, iodine substituted phenyl or naphthyl.
6. according to the 4th or 5 method, wherein trinitride is a sodiumazide.
7. according to each method in the 4-6 item, wherein amine salt is a Triethylammonium chloride.
8. according to each method in the 4-7 item, wherein aromatic hydrocarbon solvent is be selected from toluene and dimethylbenzene at least a.
N-aryl-2,2, the preparation method of the preparation method of 2-trifluoroacetimidoyl chloride and 1-aryl-5-(trifluoromethyl)-1H-tetrazolium is described in detail below.
[N-aryl-2,2, the preparation of 2-trifluoroacetimidoyl chloride]
N-aryl-2 by general formula (2) expression, 2, the 2-trifluoroacetimidoyl chloride can be by making 2,2 of general formula (1) expression in organic solvent, 2-trifluoro-N-arylacetamide, tertiary amine and be selected from phosphoryl chloride and at least a reaction of diphenyl phosphate chloride prepares.
" R " in general formula (1) and (2) randomly contains a substituent aryl, is preferably randomly to contain a substituent phenyl or naphthyl.Naphthyl can be 1-naphthyl or 2-naphthyl.Substituent position is not limit.Substituent example is alkyl, alkoxyl group and halogen atom.
That described alkyl can be line style or contain side chain.When its when containing side chain, the quantity and the position of side chain are not limit.For reacting balance is carried out, described alkyl preferably contains 1-10 carbon atom, more preferably contains 1-4 carbon atom.Be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl and similar group preferably with concrete example.
That the moieties of described alkoxyl group can be line style or contain side chain.When its when containing side chain, the quantity and the position of side chain are not limit.For reacting balance is carried out, described moieties preferably contains 1-10 carbon atom, more preferably contains 1-4 carbon atom.Preferred and the object lesson of described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, fourth-2-oxygen base, 2-methyl-prop-1-oxygen base, 2-methyl-prop-2-oxygen base and similar group.
Described halogen atom can be fluorine, chlorine, bromine or iodine.
The special preferred embodiment of R is phenyl, aminomethyl phenyl, methoxyphenyl, fluoro phenyl, chlorophenyl, bromo phenyl, iodine substituted phenyl and naphthyl in general formula (1) and (2).
In the present invention, 2,2, the 2-trifluoro-N-arylacetamide can be according to any method preparation.Be 2 preferably with concrete example, 2,2-three fluoro-phenyl acetanilide,Phenacetylanilines, 2,2,2-three fluoro-N-(2-aminomethyl phenyl) ethanamide, 2,2,2-three fluoro-N-(3-aminomethyl phenyl) ethanamide, 2,2,2-three fluoro-N-(4-aminomethyl phenyl) ethanamide, 2,2,2-three fluoro-N-(2-methoxyphenyl) ethanamide, 2,2,2-three fluoro-N-(3-methoxyphenyl) ethanamide, 2,2,2-three fluoro-N-(4-methoxyphenyl) ethanamide, 2,2,2-three fluoro-N-(2-fluoro phenyl) ethanamide, 2,2,2-three fluoro-N-(3-fluoro phenyl) ethanamide, 2,2,2-three fluoro-N-(4-fluoro phenyl) ethanamide, 2,2,2-three fluoro-N-(2-chlorophenyl) ethanamide, 2,2,2-three fluoro-N-(3-chlorophenyl) ethanamide, 2,2,2-three fluoro-N-(4-chlorophenyl) ethanamide, 2,2,2-three fluoro-N-(2-bromo phenyl) ethanamide, 2,2,2-three fluoro-N-(3-bromo phenyl) ethanamide, 2,2,2-three fluoro-N-(4-bromo phenyl) ethanamide, 2,2,2-three fluoro-N-(2-iodine substituted phenyl) ethanamide, 2,2,2-three fluoro-N-(3-iodine substituted phenyl) ethanamide, 2,2,2-three fluoro-N-(4-iodine substituted phenyl) ethanamide, 2,2,2-three fluoro-N-(naphthalene-1-yl) ethanamide and 2,2,2-three fluoro-N-(naphthalene-2-yl) ethanamide.
The consumption of phosphoryl chloride is with respect to 1mol 2,2 among the present invention, and the 2-trifluoro-N-arylacetamide is preferably 0.6-3.0mol, more preferably 0.7-2.0mol.The consumption of diphenyl phosphate chloride is with respect to 1mol 2,2, and the 2-trifluoro-N-arylacetamide is preferably 1.0-3.0mol, more preferably 1.5-2.5mol.Phosphoryl chloride and chlorine phosphorus two benzoic ethers can be used singly or in combination.
Can be used for tertiary amine kind of the present invention does not limit.Be Trimethylamine 99 preferably with concrete example, triethylamine, tripropyl amine, diisopropylethylamine, Tributylamine, triamylamine (tripentylamine), triamylamine (triamylamine), trihexylamine, trioctylamine, triallylamine, pyridine, the 2-picoline, the 3-picoline, the 4-picoline, N-methylmorpholine, N, the N-dimethylcyclohexylamine, N, accelerine, N, N, N ', N '-Tetramethyl Ethylene Diamine, 4-dimethylaminopyridine, the N-Methylimidazole, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene etc.In above-mentioned example, preferred especially triethylamine.The consumption of tertiary amine is with respect to 1mol 2,2, and the 2-trifluoro-N-arylacetamide is preferably 1.0-3.0mol, more preferably 1.1-2.0mol.
Reaction solvent is not limit, as long as it does not react with reacted constituent.Concrete example is pentane, hexane, hexanaphthene, methylcyclohexane, heptane, octane and similar varsol; Benzene,toluene,xylene, 1, ethylbenzene, chlorobenzene, oil of mirbane, isopropyl benzene, toluene(mono)chloride, methyl-phenoxide and similar aromatic solvent; Diethyl ether, diisopropyl ether, dibutyl ether, t-butyl methyl ether, cyclopentyl-methyl ether, glycol dimethyl ether, tetrahydrofuran (THF) and similar ether solvent; Methylene dichloride, chloroform, ethylene dichloride, propylene dichloride and similar halogenated solvent; Methyl acetate, ethyl acetate, propyl acetate, butylacetate and similar ester group solvent; And acetonitrile and similar polar solvent.In these solvents, preferred polar solvent, preferred especially acetonitrile.The consumption of reaction solvent is with respect to 2,2 of every gram general formula (1) expression, and the 2-trifluoro-N-arylacetamide is preferably 1-15ml, more preferably 3-10ml.
Reactions steps of the present invention is as follows: with 2,2 of general formula (1) expression, and 2-trifluoro-N-arylacetamide, tertiary amine and be selected from phosphoryl chloride and at least a of diphenyl phosphate chloride joins in the organic solvent, heating then.Reaction temperature is spent low meeting and is reduced speed of reaction; Temperature of reaction is too high can to produce a large amount of by products.Therefore, temperature of reaction is preferably 0-150 ℃, more preferably 20-85 ℃.Reaction times is preferably 1-100 hour, more preferably 5-50 hour.
After the reaction, solvent evaporated obtains crude product.Carry out purifying by crystallization, recrystallization, distillation, column chromatography etc. subsequently, obtain the N-aryl-2,2 of general formula (2) expression, the 2-trifluoroacetimidoyl chloride.
According to the present invention, can prepare N-aryl-2,2 safely and efficiently, the 2-trifluoroacetimidoyl chloride.
[preparation of 1-aryl-5-(trifluoromethyl)-1H-tetrazolium]
1-aryl-5-(the trifluoromethyl)-1H-tetrazolium of general formula (4) expression can be by making the N-aryl-2 of general formula (2) expression under the condition that exists at amine salt, 2, the trinitride of 2-trifluoroacetimidoyl chloride and general formula (3) expression reacts in aromatic hydrocarbon solvent and obtains.
" R " in general formula (2) and (4) optional contains a substituent aryl, is preferably the optional substituent phenyl or naphthyl that contains.Naphthyl can be 1-naphthyl or 2-naphthyl.Substituent position is not limit.Substituent example is alkyl, alkoxyl group and halogen atom.
That described alkyl can be line style or contain side chain.When its when containing side chain, the quantity and the position of side chain are not limit.For reacting balance is carried out, described alkyl preferably contains 1-10 carbon atom, more preferably contains 1-4 carbon atom.Be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl and similar group preferably with concrete example.
That the moieties of described alkoxyl group can be line style or contain side chain.When its when containing side chain, the quantity and the position of side chain are not limit.For reacting balance is carried out, described moieties preferably contains 1-10 carbon atom, more preferably contains 1-4 carbon atom.Preferred and the concrete example of described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, fourth-2-oxygen base, 2-methyl-prop-1-oxygen base, 2-methyl-prop-2-oxygen base and similar group.
Described halogen atom can be fluorine, chlorine, bromine or iodine.
The special preferred embodiment of R is phenyl, aminomethyl phenyl, methoxyphenyl, fluoro phenyl, chlorophenyl, bromo phenyl, iodine substituted phenyl and naphthyl in general formula (2) and (4).
N-aryl-2,2, preferred and the concrete example of 2-trifluoroacetimidoyl chloride is a N-phenyl-2,2, the 2-trifluoroacetimidoyl chloride, N-(2-aminomethyl phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(3-aminomethyl phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(4-aminomethyl phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(2-methoxyphenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(3-methoxyphenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(4-methoxyphenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(2-fluoro phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(3-fluoro phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(4-fluoro phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(2-chlorophenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(3-chlorophenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(4-chlorophenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(2-bromo phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(3-bromo phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(4-bromo phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(2-iodine substituted phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(3-iodine substituted phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(4-iodine substituted phenyl)-2,2, the 2-trifluoroacetimidoyl chloride, N-(naphthalene-1-yl)-2,2,2-trifluoroacetimidoyl chloride and N-(naphthalene-2-yl)-2,2, the 2-trifluoroacetimidoyl chloride.
The example of the trinitride of general formula (3) expression is sodiumazide, potassium azide, Lithium Azide and similar alkali-metal trinitride; And the trinitride of azide calcium, azide magnesium and similar alkaline-earth metal.Be preferably an alkali metal azide, preferred especially sodiumazide.The consumption of trinitride is with respect to the N-aryl-2,2 of 1mol general formula (2) expression, and the 2-trifluoroacetimidoyl chloride is preferably 1.0-3.0mol, more preferably 1.1-2.0mol.
Can be used for amine salt of the present invention is formed by amine and acid.Described amine comprises primary, the second month in a season and tertiary amine, special preferred fat amine.The object lesson of amine salt is but is not limited to be methylamine salt, ethylamine salt, propylamine salt, butylamine salt, amylamine salt, hexylamine salt, cyclohexylamine salt, heptyl amice salt, octylamine salt, allyl amine salt, benzylamine salt, α-Ben Yian salt, β-phenylethylamine salt and similar primary amine salt; Dimethylamine salt, diethyl amine salt, dipropyl amine salt, dibutylamine salt, diamyl amine salt, dihexylamine salt, dicyclohexyl amine salt, diallyl amine salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, hexamethylene imine salt and similar secondary amine salt; Front three amine salt, triethylamine salt, tripropyl amine salt, Tributylamine salt, triamylamine salt, trihexylamine salt, triallyl amine salt, pyridinium salt, triethanolamine salt, N-methylmorpholine salt, N, N-dimethylcyclohexylamine salt, N, accelerine salt, N, N, N ', N '-Tetramethyl Ethylene Diamine salt, 4-dimethylaminopyridine salt and similar tertiary ammonium salt; Or the like.
Described amine salt can two or more be used in combination.Can be used for herein the salifiable acid of shape for normally with salifiable those acid of amine shape.Object lesson is but is not limited to be hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, boric acid, azoimide, chloric acid, carbonic acid, hydrogen sulfide and similar mineral acid; And formic acid, acetate, trifluoroacetic acid, propionic acid, oxalic acid, methylsulfonic acid, Phenylsulfonic acid, toluenesulphonic acids and similar organic acid.Preferred acid is hydrochloric acid, hydrogen bromide, sulfuric acid, azoimide, acetate and trifluoroacetic acid.In the above-mentioned amine salt that forms by amine and acid, preferred especially Triethylammonium chloride.The consumption of described amine salt is with respect to the N-aryl-2,2 of 1mol general formula (2) expression, and the 2-trifluoroacetimidoyl chloride is preferably 0.1-1.5mol, more preferably 0.3-1.0mol.
Preferred and the concrete example that can be used for aromatic hydrocarbon solvent of the present invention is benzene,toluene,xylene, 1, ethylbenzene, chlorobenzene, oil of mirbane, isopropyl benzene, toluene(mono)chloride etc., preferred especially toluene and dimethylbenzene.Described aromatic hydrocarbon solvent can two or more be used in combination.The consumption of described solvent is with respect to the N-aryl-2,2 of every gram general formula (2) expression, and the 2-trifluoroacetimidoyl chloride is 1-15ml, more preferably 3-10ml.
Reactions steps of the present invention is as follows: with the N-aryl-2,2 of general formula (2) expression, the trinitride and the amine salt of 2-trifluoroacetimidoyl chloride, general formula (3) expression join in the aromatic hydrocarbon solvent, heating then.Reaction temperature is spent low, can reduce speed of reaction; Temperature of reaction is too high, can produce a large amount of by products.Therefore, temperature of reaction is preferably 0-150 ℃, more preferably 50-100 ℃.Reaction times is preferably 5-50 hour, more preferably 12-30 hour.
After the reaction,, wash with water subsequently the reaction soln cool to room temperature.With the organic phase drying, solvent evaporated obtains crude product then.Carry out purifying by crystallization, recrystallization, column chromatography etc. subsequently, obtain 1-aryl-5-(the trifluoromethyl)-1H-tetrazolium of general formula (4) expression.
According to the present invention, can prepare 1-aryl-5-(trifluoromethyl)-1H-tetrazolium safely and efficiently.
Embodiment
The present invention will be described in more detail for following examples, but scope of the present invention is not limited to these embodiment.
Embodiment 1
N-phenyl-2,2, the 2-trifluoroacetimidoyl chloride
With 7g (37.0mmol) 2,2,2-three fluoro-phenyl acetanilide,Phenacetylanilines, 19.84g (74.0mmol) diphenyl phosphate chloride, 7.44g (74.0mmol) triethylamine and 28ml acetonitrile join in the flask of 100ml reaction refluxed simultaneously in 15 hours (82 ℃).After the reaction,,, subsequently throw out is removed by filter to wherein adding the 28ml ethyl acetate with the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 6.24g N-phenyl-2,2, the yellow liquid of 2-trifluoroacetimidoyl chloride (productive rate: 81.2%) to the crude product that obtains with column chromatography with the filtrate evaporation.
IR (pure, cm
-1): 1697,1489,1286,1223,1196,1161,947,766,725,691
1H-NMR(CDCl
3)：δ7.41-7.24(m，3H)，7.08-7.05(m，2H)
13C-NMR(CDCl
3)：δ143.47，131.94(q，J＝42.8Hz)，129.12，127.40，120.63，116.86(q，J＝275.8Hz)
Embodiment 2
1-phenyl-5-(trifluoromethyl)-1H-tetrazolium
With the N-phenyl-2 that obtains among 5g (24.1mmol) embodiment 1,2,2-trifluoroacetimidoyl chloride, 2.83g (43.4mmol) sodiumazide, 1.66g (12.1mmol) Triethylammonium chloride and 40ml toluene join in the flask of 100ml, react 16.5 hours down at 80 ℃.After the reaction, with the reaction soln cool to room temperature, water (30ml * 3) washing.Organic phase is used anhydrous magnesium sulfate drying 1 hour, filter, evaporation removes and desolvates then.(silica gel, ethyl acetate: purifying hexane=3: 7) obtains the light yellow oil (productive rate: 93.2%) of 4.81g 1-phenyl-5-(trifluoromethyl)-1H-tetrazolium with column chromatography for the crude product that obtains.
IR (pure, cm
-1): 3071,1531,1499,1312,1207,1167,1013,766,691
1H-NMR(CDCl
3)：δ7.60-7.54(m，3H)，7.38(d，J＝8.7Hz，2H)，7.06(d，J＝8.7Hz，2H)，3.89(s，3H)
13C-NMR(CDCl
3)：δ145.90(q，J＝42.0Hz)，132.41，131.59，131.58，129.79，129.76，125.05，117.73(q，J＝270.0Hz)
Ultimate analysis:
C
8H
5F
3N
4Calculated value: C, 44.87%; H, 2.35%; N, 26.16%
Measured value: C, 44.27%; H, 2.24%; N, 25.95%
Decomposition temperature (DSC): 290 ℃ (1.17kJ/g), 367 ℃ (1.55kJ/g)
Embodiment 3
N-(4-aminomethyl phenyl)-2,2, the 2-trifluoroacetimidoyl chloride
With 7g (34.5mmol) 2,2,2-three fluoro-N-(4-aminomethyl phenyl) ethanamide, 18.49g (68.9mmol) diphenyl phosphate chloride, 6.97g (68.9mmol) triethylamine and 35ml acetonitrile join in the flask of 100ml reaction refluxed simultaneously in 18 hours (82 ℃).After the reaction,, add the 25ml ethyl acetate, then throw out is removed by filter the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 6.77g N-(4-aminomethyl phenyl)-2,2, the yellow liquid of 2-trifluoroacetimidoyl chloride (productive rate: 88.6%) to the crude product that obtains with column chromatography with the filtrate evaporation.
IR (pure, cm
-1): 1684,1506,1286,1223,1196,1159,949,934,820
1H-NMR(CDCl
3)：δ7.26-7.22(m，2H)，7.10-7.04(m，2H)，2.39(s，3H)
13C-NMR(CDCl
3)：δ140.61，137.85，130.55(q，J＝42.8Hz)，129.69，121.23，116.92(q，J＝275.0Hz)，21.02
Embodiment 4
1-(4-aminomethyl phenyl)-5-Trifluoromethyl-1 H-tetrazolium
With the N-(4-aminomethyl phenyl)-2 that obtains among 5g (22.6mmol) embodiment 3,2,2-trifluoroacetimidoyl chloride, 2.68g (40.7mmol) sodiumazide, 1.57g (11.3mmol) Triethylammonium chloride and 40ml toluene join in the flask of 100ml, react 23 hours down at 80 ℃.After the reaction, with the reaction soln cool to room temperature, water (30ml * 3) washing.Organic phase is used anhydrous magnesium sulfate drying 1 hour, filter, evaporation removes and desolvates then.(silica gel, ethyl acetate: purifying hexane=3: 7) obtains the light yellow oil (productive rate: 97.3%) of 5.01g 1-(4-aminomethyl phenyl)-5-(trifluoromethyl)-1H-tetrazolium with column chromatography for the crude product that obtains.
IR (pure, cm
-1): 3045,2930,1531,1514,1312,1205,1167,1034,1011,822,756
1H-NMR(CDCl
3)：δ7.37-7.31(m，4H)，2.42(s，3H)
13C-NMR(CDCl
3)：δ145.96(q，J＝41.2Hz)，142.28，130.33，129.95，124.83，117.81(q，J＝270.9Hz)，21.10
Ultimate analysis:
C
9H
7F
3N
4Calculated value: C, 47.37%; H, 3.09%; N, 24.98%
Measured value: C, 46.89%; H, 2.63%; N, 24.64%
Decomposition temperature (DSC): 290 ℃ (1.09kJ/g), 360 ℃ (1.29kJ/g)
Embodiment 5
N-(4-methoxyphenyl)-2,2, the 2-trifluoroacetimidoyl chloride
With 5g (22.8mmol) 2,2,2-three fluoro-N-(4-methoxyphenyl) ethanamide, 12.26g (45.6mmol) diphenyl phosphate chloride, 4.62g (45.6mmol) triethylamine and 25ml acetonitrile join in the flask of 100ml reaction refluxed simultaneously in 22 hours (82 ℃).After the reaction,,, then throw out is removed by filter to wherein adding the 20ml ethyl acetate with the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 4.53g N-(4-methoxyphenyl)-2,2, the yellow liquid of 2-trifluoroacetimidoyl chloride (productive rate: 83.6%) to the crude product that obtains with column chromatography with the filtrate evaporation.
IR (pure, cm
-1): 1676,1599,1506,1285,1252,1194,1159,1032,943,924,833,766
1H-NMR(CDCl
3)：δ7.26-7.21(m，2H)，7.00-6.91(m，2H)，3.81(s，3H)
13C-NMR(CDCl
3)：δ159.37，135.25，127.93(q，J＝42.4Hz)，124.20，116.90(q，J＝274.0Hz)，114.12，55.45
Embodiment 6
N-(4-methoxyphenyl)-2,2, the 2-trifluoroacetimidoyl chloride
With 5g (22.8mmol) 2,2,2-three fluoro-N-(4-methoxyphenyl) ethanamide, 7.02g (45.6mmol) phosphoryl chloride, 4.62g (45.6mmol) triethylamine and 25ml acetonitrile join in the flask of 100ml reaction refluxed simultaneously in 22 hours (82 ℃).After the reaction,,, throw out is removed by filter to wherein adding the 20ml ethyl acetate with the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 4.52g N-(4-methoxyphenyl)-2,2, the yellow liquid of 2-trifluoroacetimidoyl chloride (productive rate: 83.4%) to the crude product that obtains with column chromatography with the filtrate evaporation.
1H-NMR(CDCl
3)：δ7.26-7.21(m，2H)，7.00-6.91(m，2H)，3.81(s，3H)
13C-NMR(CDCl
3)：δ159.37，135.25，127.93(q，J＝42.4Hz)，124.20，116.90(q，J＝274.0Hz)，114.12，55.45
Embodiment 7
N-(4-methoxyphenyl)-2,2, the 2-trifluoroacetimidoyl chloride
With 10g (45.6mmol) 2,2,2-three fluoro-N-(4-methoxyphenyl) ethanamide, 4.92g (32.0mmol) phosphoryl chloride, 9.23g (91.2mmol) triethylamine and 50ml acetonitrile join in the flask of 200ml reaction refluxed simultaneously in 19 hours (82 ℃).After the reaction,,, throw out is removed by filter to wherein adding the 30ml ethyl acetate with the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 8.94g N-(4-methoxyphenyl)-2,2, the yellow liquid of 2-trifluoroacetimidoyl chloride (productive rate: 82.5%) to the crude product that obtains with column chromatography with the filtrate evaporation.
1H-NMR(CDCl
3)：δ7.26-7.21(m，2H)，7.00-6.91(m，2H)，3.81(s，3H)
13C-NMR(CDCl
3)：δ159.37，135.25，127.93(q，J＝42.4Hz)，124.20，116.90(q，J＝274.0Hz)，114.12，55.45
Embodiment 8
1-(4-methoxyphenyl)-5-Trifluoromethyl-1 H-tetrazolium
With the N-(4-methoxyphenyl)-2 that obtains among 5g (21.0mmol) embodiment 7,2,2-trifluoroacetimidoyl chloride, 2.46g (37.8mmol) sodiumazide, 1.45g (10.5mmol) Triethylammonium chloride and 40ml toluene join in the flask of 100ml, react 15 hours down at 80 ℃.After the reaction, with the reaction soln cool to room temperature, water (30ml * 2) washing.Organic phase is used anhydrous magnesium sulfate drying 1 hour, filter, evaporation subsequently removes desolvates.(silica gel, ethyl acetate: purifying hexane=3: 7) obtains the light yellow oil (productive rate: 98.3%) of 5.05g 1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazolium with column chromatography for the crude product that obtains.
IR (pure, cm
-1): 1609,1533,1514,1466,1319,1310,1259,1205,1167,1111,1026,837,756,542
1H-NMR(CDCl
3)：δ7.38(d，J＝8.7Hz，2H)，7.06(d，J＝8.7Hz，2H)，3.89(s，3H)
13C-NMR(CDCl
3)：δ161.72，146.03(q，J＝42.1Hz)，126.51，124.95，117.81(q，J＝270.6Hz)，114.87，55.72
Ultimate analysis:
C
9H
7F
3N
4The calculated value of O: C, 44.27%; H, 2.89%; N, 22.95%
Measured value: C, 43.81%; H, 2.81%; N, 22.15%
Decomposition temperature (DSC): 286 ℃ (1.58kJ/g), 342 ℃ (0.64kJ/g)
Embodiment 9
N-(2-methoxyphenyl)-2,2, the 2-trifluoroacetimidoyl chloride
With 5g (22.8mmol) 2,2,2-three fluoro-N-(2-methoxyphenyl) ethanamide, 12.24g (45.6mmol) diphenyl phosphate chloride, 4.64g (45.6mmol) triethylamine and 25ml acetonitrile join in the flask of 100ml reaction refluxed simultaneously in 22.5 hours (82 ℃).After the reaction,,, then throw out is removed by filter to wherein adding the 20ml ethyl acetate with the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 4.55g N-(2-methoxyphenyl)-2,2, the yellow liquid of 2-trifluoroacetimidoyl chloride (productive rate: 84.3%) to the crude product that obtains with column chromatography with the filtrate evaporation.
IR (pure, cm
-1): 1699,1595,1495,1292,1252,1196,1161,949,750
1H-NMR(CDCl
3)：δ7.26-7.22(m，1H)，7.02-6.91(m，3H)，3.85(s，3H)
13C-NMR(CDCl
3)：δ149.18，133.95(q，J＝42.8Hz)，133.09，127.94，120.54，120.23，116.81(q，J＝275.0Hz)，111.78，55.58
Embodiment 10
1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazolium
With the N-(2-methoxyphenyl)-2 that obtains among 4g (16.8mmol) embodiment 9,2,2-trifluoroacetimidoyl chloride, 1.98g (30.2mmol) sodiumazide, 1.16g (8.42mmol) Triethylammonium chloride and 40ml toluene join in the flask of 100ml, react 14 hours down at 80 ℃.After the reaction, with the reaction soln cool to room temperature, water (30ml * 2) washing.Organic phase is used anhydrous magnesium sulfate drying 1 hour, filter, evaporation subsequently removes desolvates.(silica gel, ethyl acetate: purifying hexane=3: 7) obtains the light yellow oil (productive rate: 97.6%) of 4.01g 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazolium with column chromatography for the crude product that obtains.
IR (pure, cm
-1): 1601,1563,1506,1470,1441,1315,1288,1258,1169,1124,1107,1013,760,683
1H-NMR(CDCl
3)：δ7.59(ddd，J＝7.8，7.5，1.7Hz，1H)，7.36(dd，J＝7.8，1.7Hz，1H)，7.14-7.08(m，2H)，3.79(s，3H)
13C-NMR(CDCl
3)：δ153.55，147.00(q，J＝41.5Hz)，133.19，127.22，121.00，120.59，117.60(q，J＝270.4Hz)，112.07，55.76
Ultimate analysis:
C
9H
7F
3N
4The calculated value of O: C, 44.27%; H, 2.89%; N, 22.95%
Measured value: C, 44.35%; H, 3.18%; N, 23.05%
Decomposition temperature (DSC): 283 ℃ (1.08kJ/g), 353 ℃ (0.60kJ/g)
Embodiment 11
N-(4-chlorophenyl)-2,2, the 2-trifluoroacetimidoyl chloride
With 4g (17.9mmol) 2,2,2-three fluoro-N-(4-chlorophenyl) ethanamide, 9.61g (35.8mmol) diphenyl phosphate chloride, 3.62g (35.8mmol) triethylamine and 20ml acetonitrile join in the flask of 50ml reaction refluxed simultaneously in 16 hours (82 ℃).After the reaction,,, subsequently throw out is removed by filter to wherein adding the 16ml ethyl acetate with the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 3.40g N-(4-chlorophenyl)-2,2, the yellow liquid of 2-trifluoroacetimidoyl chloride (productive rate: 78.6%) to the crude product that obtains with column chromatography with the filtrate evaporation.
IR (pure, cm
-1): 1701,1487,1286,1225,1196,1163,1097,1015,951,833,735
1H-NMR(CDCl
3)：δ7.42-7.38(m，2H)，7.07-6.94(m，2H)
13C-NMR(CDCl
3)：δ141.66，133.28，132.52(q，J＝42.8Hz)，129.30，122.26，116.75(q，J＝275.0Hz)
Embodiment 12
1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-tetrazolium
With the N-(4-chlorophenyl)-2 that obtains among 3g (12.4mmol) embodiment 11,2,2-trifluoroacetimidoyl chloride, 1.46g (22.3mmol) sodiumazide, 0.85g (6.20mmol) Triethylammonium chloride and 30ml toluene join in the flask of 100ml, react 24.5 hours down at 80 ℃.After the reaction, with the reaction soln cool to room temperature, water (20ml * 2) washing.Organic phase is used anhydrous magnesium sulfate drying 1 hour, filter, evaporation subsequently removes desolvates.(silica gel, ethyl acetate: purifying hexane=3: 7) obtains the light yellow oil (productive rate: 92.2%) of 2.84g 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-tetrazolium with column chromatography for the crude product that obtains.
IR (pure, cm
-1): 3101,1531,1497,1313,1207,1167,1096,1009,835
1H-NMR(CDCl
3)：δ7.60-7.56(m，2H)，7.47-7.43(m，2H)
13C-NMR(CDCl
3)：δ146.02(q，J＝42.0Hz)，138.13，130.94，130.25，126.48，117.75(q，J＝270.9Hz)
Ultimate analysis:
C
8H
4ClF
3N
4Calculated value: C, 38.65%; H, 1.62%; N, 22.93%
Measured value: C, 38.51%; H, 1.74%; N, 22.40%
Decomposition temperature (DSC): 280 ℃ (0.97kJ/g), 368 ℃ (0.42kJ/g)
Embodiment 13
N-(naphthalene-1-yl)-2,2, the 2-trifluoroacetimidoyl chloride
With 5g (20.9mmol) 2,2,2-three fluoro-N-(naphthalene-1-yl) ethanamide, 11.23g (41.8mmol) diphenyl phosphate chloride, 4.22g (41.8mmol) triethylamine and 20ml acetonitrile join in the flask of 50ml reaction refluxed simultaneously in 15 hours (82 ℃).After the reaction,,, subsequently throw out is removed by filter to wherein adding the 15ml ethyl acetate with the reaction soln cool to room temperature.Except that desolvating, (silica gel, ethyl acetate: purifying hexane=3: 7) obtains 4.65g N-(naphthalene-1-yl)-2,2, the yellow oil of 2-trifluoroacetimidoyl chloride (productive rate: 86.2%) to the crude product that obtains with column chromatography with the filtrate evaporation.
IR (pure, cm
-1): 1686,1593,1393,1286,1211,1161,943,799,772,754,702
1H-NMR(CDCl
3)：δ7.89-7.86(m，1H)，7.82-7.79(m，2H)，7.56-7.48(m，3H)，7.18(d，J＝7.4Hz，1H)
13C-NMR(CDCl
3)：δ139.67，133.94，132.90(q，J＝42.8Hz)，128.07，127.65，126.85，126.73，126.23，125.11，122.69，116.9(q，J＝275.0Hz)，115.07
Embodiment 14
1-(naphthalene-1-yl)-5-(trifluoromethyl)-1H-tetrazolium
With the N-(naphthalene-1-yl)-2 that obtains among 4g (15.5mmol) embodiment 13,2,2-trifluoroacetimidoyl chloride, 1.84g (27.9mmol) sodiumazide, 1.08g (7.76mmol) Triethylammonium chloride and 40ml toluene join in the flask of 100ml, react 14 hours down at 80 ℃.After the reaction, with the reaction soln cool to room temperature, water (30ml * 2) washing.Organic phase is used anhydrous magnesium sulfate drying 1 hour, filter, evaporation subsequently removes desolvates.Simultaneously with the ice bath refrigerative, the crude product that obtains is precipitated 1 hour in the 18ml normal hexane, subsequent filtration is also dry, obtains the white powder (productive rate: 94.1%) of 3.86g 1-(naphthalene-1-yl)-5-(trifluoromethyl)-1H-tetrazolium thus.
Fusing point: 107.7-108.4 ℃
IR(KBr，cm
-1)：3067，1599，1531，1510，1470，1448，1393，1306，1215，1204，1167，1153，1117，1040，802，770，754，743，665
1H-NMR(CDCl
3)：δ8.11(d，J＝8.3Hz，1H)7.96(d，J＝8.3Hz，1H)，7.62-7.50(m，4H)，7.02(d，J＝8.3Hz，1H)
13C-NMR(CDCl
3)：δ147.68(q，J＝42.0Hz)，133.91，132.55，128.81，128.73，128.46，128.40，127.64，125.10，124.63，120.74，117.74(q，J＝270.9Hz)
Ultimate analysis:
C
12H
7F
3N
4Calculated value: C, 54.55%; H, 2.67%; N, 21.21%
Measured value: C, 54.27%; H, 2.66%; N, 21.21%
Decomposition temperature (DSC): 272 ℃ (0.67kJ/g), 311 ℃ (0.20kJ/g)
Claims (8)
1. one kind prepares the N-aryl-2,2 that general formula (2) is represented, the method for 2-trifluoroacetimidoyl chloride,
In the formula, R randomly contains a substituent aryl,
Described method is included in and makes 2,2 of tertiary amine, general formula (1) expression in the organic solvent, 2-trifluoro-N-arylacetamide and at least a step of reacting that is selected from phosphoryl chloride and diphenyl phosphate chloride:
In the formula, the definition of R as mentioned above.
2. method according to claim 1, wherein R is phenyl, aminomethyl phenyl, methoxyphenyl, fluoro phenyl, chlorophenyl, bromo phenyl, iodine substituted phenyl or naphthyl.
3. method according to claim 1, wherein tertiary amine is a triethylamine.
4. method for preparing 1-aryl-5-(the trifluoromethyl)-1H-tetrazolium of general formula (4) expression,
In the formula, R randomly contains a substituent aryl,
Described method is included in the N-aryl-2,2 that makes general formula (2) expression in the aromatic hydrocarbon solvent in the presence of amine salt, the step that the trinitride of 2-trifluoroacetimidoyl chloride and general formula (3) expression reacts:
In the formula, the definition of R as mentioned above;
M(N
3)
n (3)
In the formula, M is basic metal or alkaline-earth metal, and n is 1 or 2.
5. method according to claim 4, wherein R is phenyl, aminomethyl phenyl, methoxyphenyl, fluoro phenyl, chlorophenyl, bromo phenyl, iodine substituted phenyl or naphthyl.
6. method according to claim 4, wherein trinitride is a sodiumazide.
7. method according to claim 4, wherein amine salt is a Triethylammonium chloride.
8. method according to claim 4, wherein aromatic hydrocarbon solvent is be selected from toluene and dimethylbenzene at least a.
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| CN112047896B (en) * | 2020-10-12 | 2022-06-17 | 上海麦克林生化科技有限公司 | Method for synthesizing aromatic ring group or aromatic heterocyclic group tetrazole |
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