Title of Invention

"A PROCESS FOR PRODUCING A 1-ARYL-5-(TRIFLUOROMETHYL)-1H-TETRAZOLE"

Abstract A process for producing a l-aryl-5-(trifluoromethyl)-1H-tetrazole represented by Formula (4): wherein R is an aryl group optionally having one substituent, the process comprising the step of reacting in an aromatic hydrocarbon solvent of the kind such as herein described, in the presence of an amine salt of the kind such as herein described, at 0 to 150°C for 5 to 50 hours, an N-aryl-2, 2, 2-trifluoroacetimidoyl chloride represented by Formula (2): wherein R is as defined above, and an azide represented by Formula (3): wherein M is an alkali metal or alkaline-earth metal, and n is 1 or 2.
Full Text The present invention relates to A process for producing a l-aryl-5-(trifluoromethyl)-lH-tetrazole.
TECHNICAL FIELD The present invention relates to processes for producing l-aryl-5-(trifluoromethyl)-1H-tetrazoles and their production intermediates, i.e., N-aryl-2,2,2-trifluoroacetimidoyl chlorides. l-Aryl-5-(trifluoromethyl)-lif-tetrazoles are important intermediates for a variety of pharmaceuticals.
BACKGROUND ART
A known method for producing a tetrazole compound is blowing hydrogen azide gas into an imidoyl chloride compound at 200°C or higher (J. Am. Chem. Soc., vol. 80, 1958, p. 4647). Other known methods include a reaction using sodium azide in an aqueous solvent (J. Org. Chem., vol. 23, 1958, p. 1909); reaction using an aprotic polar solvent such as DMF, acetonitrile or the like (Synth. Commun., vol. 1, 1971, p. 1; J. Org. Chem., vol. 19, 1979, p. 3281; J. Fluorine Chem., vol. 99, 1999, p. 83); and like methods.
However, the method in which hydrogen azide gas is blown at 200°C or higher may allow toxic hydrogen azide to escape the reaction system, and thus poses great safety risks for industrial scale production. In reactions using a solvent such as DMF, acetonitrile or the like, sodium azide may react with the solvent when heating is necessary. Moreover, since such solvents are water-miscible, large amounts of the reaction product dissolves in the aqueous phase in the' post-treatment. Furthermore, when DMF or a like high-boiling-point solvent is used, solvent removal is difficult if the reaction product is liquid. Therefore, these prior-art production processes are not industrially advantageous.
An example of a conventional production process for an imidoyl chloride compound is converting an amide compound into an

imidoyl chloride compound using phosphorus oxychloride, phosphorus pentachloride, thionyl chloride or a like chlorinNing reagent. However, when an amide compound having a highly electron withdrawing group such as a trifluoromethyl group is used in this method, the reaction progresses extremely slowly, thereby hindering the efficient production of the imidoyl chloride compound.
J. Org. Chem., vol. 58, 1993, p. 32 teaches a process for efficiently producing an imidoyl chloride compound containing a strongly electron withdrawing trifluoromethyl group using a large excess of carbon tetrachloride as a chlorinNing reagent. However, this process is environmentally problemNic since carbon tetrachloride is highly toxic and is a regulNed substance due to its ozone depletion potential.
A known production process thN does not use carbon tetrachloride is one thN uses ethyl trichloroacetNe. This process produces, for example, N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride in a yield of 76% (Japanese Unexamined PNent PublicNion No. 2003-321431). This method, however, produces solid triphenylphosphine oxide in a weight-based amount twice or more than thN of the desired product, and the removal thereof is difficult. Moreover, since the yield is only 76%, this is not an industrially advantageous process.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide processes for safely and efficiently producing l-aryl-5-(trifluoromethyl)-lH-tetrazoles and their production intermediNes, i.e., N-aryl-2,2,2-trifluoroacetimidoyl chlorides.
Other objects and characteristics of the present invention will become evident by the disclosure provided below. The inventors conducted extensive research to achieve the object described above, and found thN a l-aryl-5-(trifluoromethyl)-IH-tetrazole can be safely and efficiently produced by subjecting an N-aryl-2,2, 2-trifluoroacetimidoyl

chloride and an azide to a reaction in the presence of an amine salt in an aromNic hydrocarbon solvent, and the inventors thus partially accomplished the present invention. Furthermore, the inventors found thN an N-aryl-2, 2, 2-trif luoroacetimidoyl chloride can be safely and efficiently produced by subjecting a 2,2,2-trifluoro-N-arylacetamide, a tertiary amine and N least one member selected from the group consisting of phosphorus oxychloride and diphenyl chlorophosphNe to a reaction in an organic solvent, and the inventors thereby accomplished the present invention.
In particular, the present invention provides processes for safely and efficiently producing l-aryl-5- (trif luoromethyl )-Ifl-tetrazoles and their production intermediNes, i.e., N-aryl-2, 2, 2-trif luoroacetimidoyl chlorides, as described below. 1. A process for producing an W-aryl-2,2,2-trif luoroacetimidoyl chloride represented by Formula (2) :
wherein R is an aryl group optionally having one substituent,
the process comprising the step of reacting in an organic solvent a tertiary amine, a 2,2,2-trifluoro-N-arylacetamide represented by Formula (1) :
wherein R is as defined above, and N least one member selected from the group consisting of phosphorus oxychloride and diphenyl chlorophosphNe .
2. The process according to Item 1, wherein R is a phenyl,
methylphenyl, methoxypheny 1 , fluorophenyl, chlorophenyl,
bromophenyl, iodophenyl, or naphthyl group.
3. The process according to Item 1 or 2, wherein the
tertiary amine is triethylamine.
4. A process for producing a l-aryl-5-(trifluoromethyl) -IH-tetrazole represented by Formula (4) :
wherein R is an aryl group optionally having one substituent,
the process comprising the step of reacting in an aromNic hydrocarbon solvent, in the presence of an amine salt, an N-aryl-2, 2, 2-trif luoroacetimidoyl chloride represented by Formula
wherein R is as defined above, and an azide represented by Formula (3) :
wherein M is an alkali metal or alkaline-earth metal, and n is 1 or 2.
5. The process according to Item 4, wherein R is a phenyl,
methylphenyl , methoxyphenyl , fluorophenyl, chlorophenyl,
bromophenyl, iodophenyl, or naphthyl group.
6. The process according to Item 4 or 5, wherein the azide
is sodium azide.
7. The process according to any one of Items 4 to 6,
wherein the amine salt is triethylamine hydrochloride .
8. The process according to any one of Items 4 to 7,
wherein the aromNic hydrocarbon solvent is N least one member
selected from the group consisting of toluene and xylene.
The process for producing an N-aryl-2,2,2-
trifluoroacetimidoyl chloride and the process for producing a 1-aryl-5- (trifluoromethyl) -IH-tetrazole are described below in detail. [Production of N-aryl-2, 2, 2-trif luoroacetimidoyl chlorides]
An N-aryl-2, 2, 2-trif luoroacetimidoyl chloride
represented by Formula (2) can be produced by reacting a 2,2,2-trifluoro-N-arylacetamide represented by Formula (1) , a tertiary amine, and N least one member selected from the group consisting of phosphorus oxychloride and diphenyl chlorophosphNe in an organic solvent.
"R" in Formulae (1) and (2) is an aryl group optionally having one substituent, and preferably a phenyl or naphthyl group optionally having one substituent. The naphthyl group may be either 1-naphthyl or 2-naphthyl. The position of the substituent is not limited. Examples of the substituent are alkyl groups, alkoxy groups, and halogen Noms.
Such alkyl groups may be linear or branched. When branched, the number and position(s) of branch(es) are not limited. For the reaction to progress smoothly, such an alkyl group preferably has 1 to 10 carbon Noms, and more preferably 1 to 4 carbon Noms. Preferable and specific examples are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, and like groups.
The alkyl moiety of such an alkoxy group may be linear or branched. When branched, the number and position(s) of branch(es) are not limited. For the reaction to progress smoothly, the alkyl moiety preferably has 1 to 10 carbon Noms, and more preferably 1 to 4 carbon Noms. Preferable and specific examples of such alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop-2-oxy, and like groups.
Such halogen Noms may be fluorine, chlorine, bromine, or iodine.
Particularly preferable examples of R in Formulae (1) and (2) are phenyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, and naphthyl groups.
In the present invention, 2,2,2-trifluoro-N-arylacetamides may be prepared according to any process. Preferable and specific examples are 2,2,2-trifluoro-N-phenylacetamide, 2,2,2-trif luoro-N- (2-methylphenyl) acetamide,
2,2,2-trifluoro-N-(3-methylphenyl)acetamide, 2,2,2-trifluoro-N-(4-methylphenyl)acetamide, 2,2,2-trifluoro-N- (2-methoxyphenyl)acetamide, 2,2,2-trifluoro-N- (3-methoxyphenyl)acetamide, 2,2,2-trifluoro-N- (4-methoxyphenyl)acetamide, 2,2,2-trifluoro-N- (2-fluorophenyl)acetamide, 2,2,2-trifluoro-N- (3-fluorophenyl)acetamide, 2,2,2-trifluoro-N- (4-fluorophenyl)acetamide, 2,2,2-trifluoro-N-(2-chlorophenyl)acetamide, 2,2,2-trifluoro-N- (3-chlorophenyl)acetamide, 2,2,2-trifluoro-N-(4-chlorophenyl)acetamide, 2,2,2-trifluoro-N-(2-
bromophenyl)acetamide, 2,2,2-trifluoro-N- (3-bromophenyl)acetamide, 2,2,2-trifluoro-N-(4-bromophenyl)acetamide, 2,2,2-trifluoro-N-(2-iodophenyl)acetamide, 2,2,2-trifluoro-N- (3-iodophenyl)acetamide, 2,2,2-trifluoro-N- (4-iodophenyl)acetamide, 2,2,2-trifluoro-N-(naphthalen-1-yl)acetamide, and 2,2,2-trifluoro-N- (naphthalen-2-yl)acetamide.
The amount of phosphorus oxychloride used in the present invention is preferably 0.6 to 3.0 mol, and more preferably 0.7 to 2.0 mol, per mol of 2,2,2-trifluoro-N-arylacetamide. The amount of diphenyl chlorophosphNe is preferably 1.0 to 3.0 mol, and more preferably 1.5 to 2.5 mol, per mol of 2,2,2-trifluoro-N-arylacetamide. Phosphorus oxychloride and diphenyl chlorophosphNe may be used either singly or in combinNion.
Tertiary amines usable in the present invention are not limited. Preferable and specific examples are trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, tributylamine, tripentylamine, triamylamine, trihexylamine, trioctylamine, triallylamine, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, N-methylmorpholine, N,N-dimethylcyclohexylamine, N,N-dimethylaniline, N,N,N',N'-tetramethylethylenediamine, 4-dimethylaminopyridine, N-methylimidazole, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc. Among such examples,
triethylamine is particularly preferable. The amount of tertiary amine is preferably 1.0 to 3.0 mol, and more preferably 1.1 to 2.0 mol, per mol of 2,2,2-trifluoro-W-arylacetamide.
Reaction solvents are not limited insofar as they do not react with the reaction ingredients. Specific examples are pentane, hexane, cyclohexane, methylcyclohexane, heptane, octane, and like hydrocarbon solvents; benzene, toluene, xylene, mesitylene, ethylbenzene, chlorobenzene, nitrobenzene, cumene, chlorotoluene, anisole, and like aromNic solvents; diethyl ether, diisopropyl ether, dibutyl ether, t-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, and like ethereal solvents; dichloromethane, chloroform, dichloroethane, dichloropropane, and like halogenNed solvents/methyl acetNe, ethyl acetNe, propyl acetNe, butyl acetNe, and like ester-based solvents; and acetonitrile and like polar solvents. Among these solvents, polar solvents are preferable, with acetonitrile being particularly preferable. The amount of reaction solvent is preferably 1 to 15 ml, and more preferably 3 to 10 ml, per gram of 2,2,2-trifluoro-W-arylacetamide represented by Formula (1).
The reaction of the present invention is carried out by adding a 2,2,2-trifluoro-W-arylacetamide represented by Formula (1), a tertiary amine, and N least one member selected from the group consisting of phosphorus oxychloride and diphenyl chlorophosphNe, to an organic solvent, followed by heNing. Excessively low reaction temperNures decelerNe the reaction, and excessively high reaction temperNures result in the generNion of large amounts of by-products. Therefore, the reaction temperNure is preferably 0 to 150°C, and more preferably 20 to 85°C. The reaction time is preferably 1 to 100 hours, and more preferably 5 to 50 hours.
After the reaction, the solvent is evaporNed off to obtain a crude product. PurificNion by crystallizNion, recrystallizNion, distillNion, column chromNography, etc., is then performed to obtain an W-aryl-2, 2, 2-trifluoroacetimidoyl
chloride represented by Formula (2).
According to the present invention, N-aryl-2,2,2-trifluoroacetimidoyl chlorides can be safely and efficiently produced. [Production of l-aryl-5-(trifluoromethyl)-IH-tetrazoles]
A l-aryl-5-(trifluoromethyl)-IH-tetrazole represented by Formula (4) can be obtained by reacting an W-aryl-2,2,2-trifluoroacetimidoyl chloride represented by Formula (2) with an azide represented by Formula (3) in the presence of an amine salt in an aromNic hydrocarbon solvent.
"R" in Formulae (2) and (4) is an aryl group optionally having one substituent, and preferably a phenyl or naphthyl group optionally having one substituent. The naphthyl group may be either 1-naphthyl or 2-naphthyl. The position of the substituent is not limited. Examples of the substituent are alkyl groups, alkoxy groups, and halogen Noms.
Such alkyl groups may be linear or branched. When branched, the number and position(s) of branch(es) are not limited. For the reaction to progress smoothly, such an alkyl group preferably has 1 to 10 carbon Noms, and more preferably 1 to 4 carbon Noms. Preferable and specific examples are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, and like groups.
The alkyl moiety of such an alkoxy group may be linear or branched. When branched, the number and position(s) of branch(es) are not limited. For the reaction to progress smoothly, the alkyl moiety preferably has 1 to 10 carbon Noms, and more preferably 1 to 4 carbon Noms. Preferable and specific examples of such alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop-2-oxy, and like groups.
Such halogen Noms may be fluorine, chlorine, bromine, or iodine.
Particularly preferable examples of R in Formulae (2) and (4) are phenyl, methylphenyl, methoxyphenyl, fluorophenyl,
chlorophenyl, bromophenyl, iodophenyl, and naphthyl groups.
Preferable and specific examples of W-aryl-2,2,2-trifluoroacetimidoyl chlorides are N-phenyl-2,2,2-trifluoroacetimidoyl chloride, N-(2-methylphenyl)-2,2,2-trif luoroacetimidoyl chloride, N- (3-methylphenyl) -2,2,2-trifluoroacetimidoyl chloride, N- (4-methylphenyl)-2,2,2-trif luoroacetimidoyl chloride, N- (2-methoxypheny1)-2,2,2-trifluoroacetimidoyl chloride, N-(3-methoxyphenyl)-2,2,2-trif luoroacetimidoyl chloride, N- (4-methoxypheny 1) -2,2,2-trifluoroacetimidoyl chloride, N- (2-fluorophenyl)-2,2,2-trif luoroacetimidoyl chloride, N-(3-fluorophenyl)-2,2,2-trif luoroacetimidoyl chloride, N- (4-fluorophenyl) -2,2,2-trifluoroacetimidoyl chloride, N-(2-chlorophenyl)-2,2,2-trif luoroacetimidoyl chloride, N- (3-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride, N-(4-chlorophenyl)-2,2,2-trif luoroacetimidoyl chloride, N-(2-bromophenyl) -2,2,2-trif luoroacetimidoyl chloride, N- (3-bromophenyl)-2,2,2-trifluoroacetimidoyl chloride, N-(4-bromophenyl) -2,2,2-trif luoroacetimidoyl chloride, N- (2-iodophenyl)-2,2,2-trifluoroacetimidoyl chloride, N-(3-iodophenyl)-2,2,2-trif luoroacetimidoyl chloride, N-(4-iodophenyl) -2,2,2-trif luoroacetimidoyl chloride, N-(naphthalen-1-yl)-2,2,2-trif luoroacetimidoyl chloride, and N- (naphthalen-2-yl)-2,2,2-trif luoroacetimidoyl chloride.
Examples of azides represented by Formula (3) are azides of sodium, potassium, lithium, and like alkali metals; and azides of calcium, magnesium, and like alkaline-earth metals. Alkali metal azides are preferable, with sodium azide being particularly preferable. The amount of azide is preferably 1.0 to 3.0 mol, and more preferably 1.1 to 2.0 mol, per mol of N-aryl-2, 2,2-trifluoroacetimidoyl chloride represented by Formula (2).
Amine salts usable in the present invention are formed from amines and acids. Amines include primary, secondary and tertiary amines, and aliphNic amines are particularly preferable. Specific examples of amine salts are, although not limited
thereto, methylamine salts, ethylamine salts, propylamine salts, butylamine salts, amylamine salts, hexylamine salts, cyclohexylamine salts, heptylamine salts, octylamine salts, allylamine salts, benzylamine salts, a-phenylethylamine salts, (3-phenylethylamine salts, and like primary amine salts; dimethylamine salts, diethylamine salts, dipropylamine salts, dibutylamine salts, diamylamine salts, dihexylamine salts, dicyclohexylamine salts, diallylamine salts, morpholine salts, piperidine salts, hexamethyleneimine salts, and like secondary amine salts; trimethylamine salts, triethylamine salts, tripropylamine salts, tributylamine salts, triamylamine salts, trihexylamine salts, triallylamine salts, pyridine salts, triethanolamine salts, N-methylmorpholine salts, N,N-dimethylcyclohexylamine salts, N,N-dimethylaniline salts, N,W,W,.W-tetrainethylethylenediamine salts, 4-
dimethylaminopyridine salts, and like tertiary amine salts; etc. Two or more such amine salts may be used in combinNion. Acids usable herein to form salts are those thN usually form salts with amines. Specific examples are, although not limited thereto, hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, boric acid, hydrogen azide, chloric acid, carbonic acid, hydrogen sulfide, and like inorganic acids; and formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and like organic acids. Preferable acids are hydrochloric acid, hydrogen bromide, sulfuric acid, hydrogen azide, acetic acid, and trifluoroacetic acid. Among the aforementioned amine salts formed from amines and acids, triethylamine hydrochloride is particularly preferable. The amount of amine salt is preferably 0.1 to 1.5 mol, and more preferably 0.3 to 1.0 mol, per mol of N-aryl-2,2,2-trifluoroacetimidoyl chloride represented by Formula (2).
Preferable and specific examples of aromNic
hydrocarbon solvents usable in the present invention are benzene, toluene, xylene, mesitylene, ethylbenzene, chlorobenzene,
nitrobenzene, cumene, chlorotoluene, etc., with toluene and xylene being particularly preferable. Two or more such aromNic hydrocarbon solvents can be used in combinNion. The amount of solvent is preferably 1 to 15 ml, and more preferably 3 to 10 ml, per gram of N-aryl-2,2,2-trifluoroacetimidoyl chloride represented by Formula (2) .
The reaction of the present invention is carried out by adding an N-aryl-2,2,2-trifluoroacetimidoyl chloride represented by Formula (2), an azide represented by Formula (3), and an amine salt to an aromNic hydrocarbon solvent, followed by heNing. Excessively low reaction temperNures decelerNe the reaction, and excessively high reaction temperNures result in the generNion of large amounts of by-products. Therefore, the reaction temperNure is preferably 0 to 150 °C, and more preferably 50 to 100 °C. The reaction time is preferably 5 to 50 hours, and more preferably 12 to 30 hours.
After the reaction, the reaction solution is cooled to room temperNure, and then washed with wNer. The organic phase is then dried, and the solvent is evaporNed off to obtain a crude product. PurificNion by crystallizNion, recrystallizNion, column chromNography, etc . , is then performed to obtain a 1-aryl-5- (trifluoromethyl) -iH-tetrazole represented by Formula (4).
According to the present invention, l-aryl-5-(trifluoromethyl) -Itf-tetrazoles can be safely and efficiently produced .
BEST MODE FOR CARRYING OUT THE INVENTION Examples are given below to illustrNe the invention in more detail, but the scope of the invention is not limited to these examples .
Example 1
N-phenyl-2 , 2 , 2-trif luoroacetimidoyl chloride
(Figure Removed)
Seven grams (37.0 mmol) of 2,2,2-trifluoro-N-
phenylacetamide, 19.84 g (74.0 mmol) of diphenyl chlorophosphNe, 7.44 g (74.0 mmol) of triethylamine, and 28 ml of acetonitrile were introduced into a 100 ml flask and reacted for 15 hours while being refluxed (82°C). After the reaction, the reaction solution was cooled to room temperNure, 28 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 6.24 g of W-phenyl-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 81.2%).
IR (neN, cm"1) : 1697, 1489, 1286, 1223, 1196, 1161, 947, 766, 725, 691
-NMR (CDC13) : 6 7.41-7.24 (m, 3H), 7.08-7.05 (m, 2H) 13C-NMR (CDC13) : 5 143. 47, 131.94 (q, J= 42.8 Hz), 129.12, 127.40, 120.63, 116.86 (q, J= 275.8 Hz)
Example 2
l-phenyl-5-(trifluoromethyl)-IH-tetrazole
(Figure Removed)
Five grams (24.1 mmol) of W-phenyl-2,2,2-
trifluoroacetimidoyl chloride obtained in Example 1, 2.83 g (43.4 mmol) of sodium azide, 1.66 g (12.1 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted N 80°C for 16.5 hours. After the reaction, the reaction solution was cooled to room temperNure and washed with wNer (30 ml x 3) . The organic phase was dried over anhydrous magnesium sulfNe for 1 hour, filtered, and then subjected to solvent removal by evaporNion. The crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 4.81 g of l-phenyl-5-
(trifluoromethyl)-lH-tetrazole as a pale yellow oil (yield: 93.2%).
IR (neN, cm"1): 3071, 1531, 1499, 1312, 1207, 1167, 1013, 766, 691
-NMR (CDC13) : 5 7.60-7.54 (m, 3H), 7.38 (d, J= 8.7 Hz, 2H), 7.06
(d, J= 8.7 Hz, 2H), 3.89 (s, 3H)
13C-NMR (CDC13) : 5 145.90 (q, J= 42.0 Hz), 132.41, 131.59, 131.58,
129.79, 129.76, 125.05, 117.73 (q, J= 270.0 Hz)
Elemental analysis:
Value calculNed for C8H5F3N4: C, 44.87%; H, 2.35%; N, 26.16%
Value found: C, 44.27%; H, 2.24%; N, 25.95%
Decomposition temperNure (DSC): 290°C (1.17 kJ/g), 367°C (1.55
kJ/g)
Example 3
N- (4-methylphenyl)-2,2,2-trifluoroacetimidoyl chloride
(Figure Removed)
Seven grams (34.5 mmol) of 2,2,2-trifluoro-W-(4-methylphenyl)acetamide, 18.49 g (68.9 mmol) of diphenyl chlorophosphNe, 6.97 g (68.9 mmol) of triethylamine, and 35 ml of acetonitrile were introduced into a 100 ml flask and reacted for 18 hours while being refluxed (82°C). After the reaction, the reaction solution was cooled to room temperNure, 25 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 6.77 g of N-(4-methylphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 88.6%).
IR (neN, cm"1): 1684, 1506, 1286, 1223, 1196, 1159, 949, 934, 820 -NMR (CDC13) : 5 7.26-7.22 (m, 2H), 7.10-7.04 (m, 2H), 2.39 (s, 3H)
13C-NMR (CDC13) : 5 140. 61, 137.85, 130.55 (q, J= 42.8 Hz), 129.69, 121.23, 116.92 (q, J= 275.0 Hz), 21.02
Example 4
1-(4-methylphenyl)-5-(trifluoromethyl)-IH-tetrazole
(Figure Removed)
Five grams (22.6 mmol) of N-( 4-methylphenyl) -2,2,2-trifluoroacetimidoyl chloride obtained in Example 3, 2.68 g (40.7 mmol) of sodium azide, 1.57 g (11.3 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted N 80°C for 23 hours. After the reaction, the reaction solution was cooled to room temperNure and washed with wNer (30 ml x 3) . The organic phase was dried over anhydrous magnesium sulfNe for 1 hour, filtered, and then subjected to solvent removal by evaporNion. The crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 5.01 g of 1-(4-methylphenyl)-5-(trifluoromethyl)-l#-tetrazole as a pale yellow oil (yield: 97.3%), IR (neN, cm'1): 3045, 2930, 1531, 1514, 1312, 1205, 1167, 1034, 1011, 822, 756
XH-NMR (CDC13) : 5 7.37-7.31 (m, 4H), 2.42 (s, 3H)
13C-NMR (CDC13) : 6 145.96 (q, J= 41.2 Hz), 142.28, 130.33, 129.95, 124.83, 117.81 (q, J= 270.9 Hz), 21.10 Elemental analysis:
Value calculNed for C9H7F3N4: C, 47.37%; H, 3.09%; N, 24.98% Value found: C, 46.89%; H, 2.63%; N, 24.64%
Decomposition temperNure (DSC): 290°C (1.09 kJ/g), 360°C (1.29 kJ/g)
Example 5
N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride
(Figure Removed)
Five grams (22.8 mmol) of 2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide, 12.26 g (45.6 mmol) of diphenyl chlorophosphNe, 4.62 g (45.6 mmol) of triethylamine, and 25 ml of acetonitrile were introduced into a 100 ml flask and reacted for 22 hours while being refluxed (82°C). After the reaction, the reaction solution was cooled to room temperNure, 20 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 4.53 g of W-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 83.6%).
IR (neN, cm"1): 1676, 1599, 1506, 1285, 1252, 1194, 1159, 1032, 943, 924, 833, 766
Hl-NMR (CDC13) : 5 7.26-7.21 (m, 2H), 7.00-6.91 (m, 2H), 3.81 (s, 3H)
13C-NMR (CDC13) : 5 159.37, 135.25, 127.93 (q, J= 42.4 Hz), 124.20, 116.90 (q, J= 274.0 Hz), 114.12, 55.45
Example 6
N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride
(Figure Removed)
Five grams (22.8 mmol) of 2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide, 7.02 g (45.6 mmol) of phosphorus oxychloride, 4.62 g (45.6 mmol) of triethylamine, and 25 ml of acetonitrile were introduced into a 100 ml flask and reacted for 22 hours while being refluxed (82°C). After the reaction, the reaction solution was cooled to room temperNure, 20 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting
in 4.52 g of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl
chloride as a yellow liquid (yield: 83.4%).
JH-NMR (CDC13) : 5 7.26-7.21 (m, 2H), 7.00-6.91 (m, 2H), 3.81 (s,
3H)
13C-NMR (CDC13): 6 159.37, 135.25, 127.93 (q, J= 42.4 Hz), 124.20,
116.90 (q, J= 274.0 Hz), 114.12, 55.45
Example 7
N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride
(Figure Removed)
Ten grams (45.6 mmol) of 2,2,2-trifluoro-W-(4-methoxyphenyl)acetamide, 4.92 g (32.0 mmol) of phosphorus oxychloride, 9.23 g (91.2 mmol) of triethylamine, and 50 ml of acetonitrile were introduced into a 200 ml flask and reacted for 19 hours while being refluxed (82°C). After the reaction, the reaction solution was cooled to room temperNure, 30 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 8.94 g of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 82.5%).
-NMR (CDC13) : 6 7.26-7.21 (m, 2H), 7.00-6.91 (m, 2H), 3.81 (s, 3H)
13C-NMR (CDC13) : 5 159. 37, 135.25, 127.93 (q, J= 42.4 Hz), 124.20, 116.90 (q, J= 274.0 Hz), 114.12, 55.45
Example 8
1-(4-methoxyphenyl)-5-(trifluoromethyl)-IH-tetrazole
(Figure Removed)
Five grams (21.0 mmol) of N-(4-methoxyphenyl) -2,2,2-trifluoroacetimidoyl chloride obtained in Example 7, 2.46 g (37.8 mmol) of sodium azide, 1.45 g (10.5 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted N 80°C for 15 hours. After the reaction, the reaction solution was cooled to room temperNure and washed with wNer (30 ml x 2) . The organic phase was dried over anhydrous magnesium sulfNe for 1 hour, filtered, and then subjected to solvent removal by evaporNion. The crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 5.05 g of 1-(4-methoxyphenyl)-5-(trifluoromethyl)-lH-tetrazole as a pale yellow oil (yield: 98.3%).
IR (neN, cm"1): 1609, 1533, 1514, 1466, 1319, 1310, 1259, 1205, 1167, 1111, 1026, 837, 756, 542
XH-NMR (CDC13) : 5 7.38 (d, J= 8.7 Hz, 2H), 7.06 (d, J= 8.7 Hz, 2H), 3.89 (s, 3H)
13C-NMR (CDC13) : 5 161. 72, 146.03 (q, J= 42.1 Hz), 126.51, 124.95, 117.81 (q, J= 270.6 Hz), 114.87, 55.72 Elemental analysis:
Value calculNed for CgfyFaO: C, 44.27%; H, 2.89%; N, 22.95% Value found: C, 43.81%; H, 2.81%; N, 22.15%
Decomposition temperNure (DSC): 286°C (1.58 kJ/g), 342°C (0.64 kJ/g)
Example 9
N-(2-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride
(Figure Removed)
Five grams (22.8 mmol) of 2,2,2-trifluoro-N-(2-methoxyphenyl)acetamide, 12.24 g (45.6 mmol) of diphenyl
chlorophosphNe, 4.64 g (45.6 mmol) of triethylamine, and 25 ml of acetonitrile were introduced into a 100 ml flask and reacted for 22.5 hours while being refluxed (82°C) . After the reaction, the reaction solution was cooled to room temperNure, 20 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe : hexane = 3:7), resulting in 4.55 g of N-(2-methoxyphenyl) -2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 84.3%).
IR (neN, cm'1) : 1699, 1595, 1495, 1292, 1252, 1196, 1161, 949, 750 -NMR (CDC13) : 5 7.26-7.22 (m, 1H) , 7.02-6.91 (m, 3H) , 3.85 (s, 3H)
13C-NMR (CDC13) : 5 149. 18, 133.95 (q, J= 42. 8 Hz), 133.09, 127.94, 120.54, 120.23, 116.81 (q, J= 275.0 Hz), 111.78, 55.58
Example 10
1- (2-Methoxyphenyl) -5- (trifluoromethyl) -Ifl-tetrazole
(Figure Removed)
Four grams (16.8 mmol) of N-( 2 -met hoxyphenyl) -2,2,2-trifluoroacetimidoyl chloride obtained in Example 9, 1.98 g (30.2 mmol) of sodium azide, 1.16 g (8.42 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted N 80°C for 14 hours. After the reaction, the reaction solution was cooled to room temperNure and washed with wNer (30 ml x 2) . The organic phase was dried over anhydrous magnesium sulfNe for 1 hour, filtered, and then subjected to solvent removal by evaporNion. The crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe: hexane = 3:7), resulting in 4.01 g of 1- (2-methoxyphenyl) -5- (trifluoromethyl) -IH-tetrazole as a pale yellow oil (yield:
97.6%).
IR (neN, cm"1) : 1601, 1563, 1506, 1470, 1441, 1315, 1288, 1258, 1169, 1124, 1107, 1013, 760, 683
-NMR (CDC13): 6 7.59 (ddd, J= 7.8, 7.5, 1.7 Hz, 1H) , 7.36 (dd, J = 7.8, 1.7 Hz, 1H), 7.14-7.08 (m, 2H), 3.79 (s, 3H) 13C-NMR (CDC13): 6 153.55, 147.00 (q, J= 41.5 Hz), 133.19, 127.22, 121.00, 120.59, 117.60 (q, J=270.4 Hz), 112.07, 55.76 Elemental analysis:
Value calculNed for C9H7F3N40: C, 44.27%; H, 2.89%; N, 22.95% Value found: C, 44.35%; H, 3.18%; N, 23.05%
Decomposition temperNure (DSC): 283°C (1.08 kJ/g), 353°C (0.60 kJ/g)
Example 11
M-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride
(Figure Removed)
Four grams (17.9 mmol) of 2,2,2-trifluoro-N-(4-chlorophenyl)acetamide, 9.61 g (35.8 mmol) of diphenyl chlorophosphNe, 3.62 g (35.8 mmol) of triethylamine, and 20 ml of acetonitrile were introduced into a 50 ml flask and reacted for 16 hours while being refluxed (82°C). After the reaction, the reaction solution was cooled to room temperNure, 16 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 3.40 g of N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 78.6%).
IR (neN, cm"1): 1701, 1487, 1286, 1225, 1196, 1163, 1097, 1015, 951, 833, 735
-NMR (CDC13) : 5 7.42-7.38 (m, 2H) , 7.07-6.94 (m, 2H) 13C-NMR (CDC13) : 6 141.66, 133.28, 132.52 (q, J= 42.8 Hz), 129.30,
122.26, 116.75 (q, J= 275.0 Hz)
Example 12
1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-tetrazole
(Figure Removed)
Three grams (12.4 mmol) of N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 11, 1.46 g (22.3 mmol) of sodium azide, 0.85 g (6.20 mmol) of triethylamine hydrochloride, and 30 ml of toluene were introduced into a 100 ml flask and reacted N 80°C for 24.5 hours. After the reaction, the reaction solution was cooled to room temperNure and washed with wNer (20 ml x 2) . The organic phase was dried over anhydrous magnesium sulfNe for 1 hour, filtered, and then subjected to solvent removal by evaporNion. The crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 2.84 g of 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 92.2%). IR (neN, on'1): 3101, 1531, 1497, 1313, 1207, 1167, 1096, 1009, 835
XH-NMR (CDC13) : 6 7.60-7.56 (m, 2H), 7.47-7.43 (m, 2H) 13C-NMR (CDC13) : 5 146.02 (q, J= 42.0 Hz), 138.13, 130.94, 130.25, 126.48, 117.75 (q, J= 270.9 Hz) Elemental analysis:
Value calculNed for C8C1F3: C, 38.65%; H, 1.62%; N, 22.93% Value found: C, 38.51%; H, 1.74%; N, 22.40%
Decomposition temperNure (DSC): 280°C (0.97 kJ/g), 368°C (0.42 kJ/g)
Example 13
N-(naphthalen-l-yl)-2,2,2-trifluoroacetimidoyl chloride
(Figure Removed)
Five grams (20.9 mmol) of 2,2,2-trifluoro-N-(naphthalen-1-yl )acetamide, 11.23 g (41.8 mmol) of diphenyl chlorophosphNe, 4.22 g (41.8 mmol) of triethylamine, and 20 ml of acetonitrile were introduced into a 50 ml flask and reacted for 15 hours while being refluxed (82°C). After the reaction, the reaction solution was cooled to room temperNure, 15 ml of ethyl acetNe was added thereto, and the precipitNe was then filtered off. The filtrNe was subjected to solvent removal by evaporNion, and the crude product thus obtained was purified by column chromNography (silica gel, ethyl acetNe:hexane = 3:7), resulting in 4.65 g of N-(naphthalen-1-yl)-2,2,2-trifluoroacetimidoyl chloride as a yellow oil (yield: 86.2%).
IR (neN, cm"1) : 1686, 1593, 1393, 1286, 1211, 1161, 943, 799, 772, 754, 702
-NMR (CDC13) : 5 7.89-7.86 (m, 1H), 7.82-7.79 (m, 2H), 7.56-7.48 (m, 3H), 7.18 (d, J= 7.4 Hz, 1H)
13C-NMR (CDC13): 6 139. 67, 133.94, 132.90 (q, J= 42.8 Hz), 128.07, 127.65, 126.85, 126.73, 126.23, 125.11, 122.69, 116.9 (q, J= 275.0 Hz), 115.07
Example 14
1-(naphthalen-1-yl)-5-(trifluoromethyl)-IH-tetrazole
(Figure Removed)
Four grams (15.5 mmol) of N-(naphthalen-1-yl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 13, 1.84 g (27.9 mmol) of sodium azide, 1.08 g (7.76 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted N 80°C for 14 hours. After the reaction, the reaction solution was cooled to room temperNure and washed with wNer (30 ml x 2) . The organic phase was dried over anhydrous
magnesium sulfNe for I hour, filtered, and then subjected to
solvent removal by evaporNion. The crude product thus obtained
was precipitNed for 1 hour in 18 ml of n-hexane while being cooled
using an ice bNh, followed by filtrNion and drying, thereby
giving 3.86 g of 1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-
tetrazole as a white powder (yield: 94.1%).
Melting point: 107.7-108.4°C
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 (CDC13) : 5 8.11 (d, J= 8.3 Hz, 1H) 7.96 (d, J= 8.3 Hz, 1H),
7.62-7.50 (m, 4H), 7.02 (d, J= 8.3 Hz, 1H)
13C-NMR (CDC13) : 6 147.68 (q, J= 42.0 Hz), 133.91, 132.55, 128.81,
128.73, 128.46, 128.40, 127.64, 125.10, 124.63, 120.74, 117.74 (q,
J = 270.9 Hz)
Elemental analysis:
Value calculNed for C12H7F3N4 C, 54.55%; H, 2.67%; N, 21.21%
Value found: C, 54.27%; H, 2.66%; N, 21.21%
Decomposition temperNure (DSC): 272°C (0.67 kJ/g), 311°C (0.20
kJ/g)












We Claim:
1. A process for producing a l-aryl-5-(trifluoromethyl)-1H-tetrazole represented by Formula
(4):
(Formula Removed)
wherein R is an aryl group optionally having one substituent, the process comprising the step of reacting in an aromatic hydrocarbon solvent of the kind such as herein described, in the presence of an amine salt of the kind such as herein described, at 0 to 150°C for 5 to 50 hours, an N-aryl-2, 2,2-trifluoroacetimidoyl chloride represented by Formula (2):
(Formula Removed)
wherein R is as defined above, and an azide represented by Formula (3):
(Formula Removed)
wherein M is an alkali metal or alkaline-earth metal, and n is 1 or 2.
2. The process as claimed in claim 1, wherein R is a phenyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, or naphthyl group.
3. The process as claimed in claim 1, wherein the azide is sodium azide.
4. The process as claimed in claim 1, wherein the amine salt is triethylamine hydrochloride.
5. The process as claimed in claim 1, wherein the aromatic hydrocarbon solvent is at least one member selected from the group consisting of toluene and xylene.

Documents:

1385-DELNP-2006-Abstract-(06-10-2009).pdf

1385-DELNP-2006-Abstract-(24-06-2010).pdf

1385-delnp-2006-abstract.pdf

1385-delnp-2006-assignment.pdf

1385-DELNP-2006-Claims-(06-10-2009).pdf

1385-DELNP-2006-Claims-(24-06-2010).pdf

1385-delnp-2006-claims.pdf

1385-DELNP-2006-Correspondence-Others-(06-10-2009).pdf

1385-DELNP-2006-Correspondence-Others-(09-04-2007).pdf

1385-DELNP-2006-Correspondence-Others-(24-06-2010).pdf

1385-DELNP-2006-Correspondence-Others-(25-06-2010).pdf

1385-DELNP-2006-Correspondence-Others-(28-03-2008).pdf

1385-DELNP-2006-Correspondence-Others-(29-06-2010).pdf

1385-DELNP-2006-Correspondence-Others-(29-07-2010).pdf

1385-delnp-2006-correspondence-others-1.pdf

1385-delnp-2006-correspondence-others.pdf

1385-DELNP-2006-Description (Complete)-(06-10-2009).pdf

1385-delnp-2006-description (complete).pdf

1385-DELNP-2006-Form-1-(06-10-2009).pdf

1385-delnp-2006-form-1.pdf

1385-delnp-2006-form-18.pdf

1385-DELNP-2006-Form-2-(06-10-2009).pdf

1385-delnp-2006-form-2.pdf

1385-DELNP-2006-Form-3-(06-10-2009).pdf

1385-DELNP-2006-Form-3-(09-04-2007).pdf

1385-DELNP-2006-Form-3-(25-06-2010).pdf

1385-DELNP-2006-Form-3-(28-03-2008).pdf

1385-DELNP-2006-Form-3-(29-07-2010).pdf

1385-delnp-2006-form-3.pdf

1385-delnp-2006-form-5.pdf

1385-DELNP-2006-GPA-(06-10-2009).pdf

1385-delnp-2006-gpa.pdf

1385-delnp-2006-pct-409.pdf

1385-DELNP-2006-Petition-137-(06-10-2009).pdf

1385-DELNP-2006-Petition-138-(06-10-2009).pdf

abstract.jpg


Patent Number 242008
Indian Patent Application Number 1385/DELNP/2006
PG Journal Number 33/2010
Publication Date 13-Aug-2010
Grant Date 05-Aug-2010
Date of Filing 14-Mar-2006
Name of Patentee TOYO KASEI KOGYO COMPANY LIMITED
Applicant Address 2-6, DOJIMA-HAMA, 1-CHOME, KITA-KU, OSAKA-SHI, OSAKA 5300004, JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 KAZUTAKE HAGIYA C/O CHEMICALS RESEARCH CENTER OF TOYO KASEI KOGYO COMPANY LIMITED, 2900, SONE-CHO, TAKASAGO-SHI, HYOGO 6760082, JAPAN
2 YASUHIRO SATO C/O CHEMICALS RESEARCH CENTER OF TOYO KASEI KOGYO COMPANY LIMITED, 2900, SONE-CHO, TAKASAGO-SHI, HYOGO 6760082, JAPAN
3 KIYOTO KOGURO C/O CHEMICALS RESEARCH CENTER OF TOYO KASEI KOGYO COMPANY LIMITED, 2900, SONE-CHO, TAKASAGO-SHI, HYOGO 6760082, JAPAN
4 SUNAO MITSUI C/O CHEMICALS RESEARCH CENTER OF TOYO KASEI KOGYO COMPANY LIMITED, 2900, SONE-CHO, TAKASAGO-SHI, HYOGO 6760082, JAPAN
PCT International Classification Number C07C 257/02
PCT International Application Number PCT/JP2004/014781
PCT International Filing date 2004-09-30
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2003-385936 2003-10-10 Japan
2 2004-136859 2004-04-03 Japan