Process for producing N-alkylpyrazoles

Abstract: A process for producing an N-alkylpyrazole of formula (1): wherein each R¹ is, independently, a hydrogen atom or a C₁-C₄ alkyl group, R² is a C₁-C₄ alkyl group and n is an integer of from 1 to 3, which comprises reacting an alkali metal salt of a pyrazole with an alkylating agent, said alkali metal salt having been obtained by previously reacting an alkali metal or an alkali metal-containing base with an N-unsubstituted pyrazole of formula (2): wherein R¹ and n are as defined above.

Description: The present invention relates to a process for producing N-alkyl pyrazoles, which are useful intermediates for medicines and agricultural chemicals, in particular herbicides. Known methods for carrying out N-alkylation of pyrazoles are: (1) Reacting 4-methylpyrazole and dimethyl sulfate in an aqueous 2N solution of sodium hydroxide (Justus Liebigs Annalen der Chemie, 625. 55 (1959)). However, the yield of 1,4-dimethylpyrazole in this method is as low as 56%. (2) Reacting 3(5)-methylpyrazole and methyl iodide in the presence of sodium methoxide in a methanol solution to obtain 1,3-dimethylpyrazole and 1,5-dimethylpyrazole (Chemisch Berichte, 59. 1282 (1926)). However, no satisfactory results are obtainable by this method (refer to Comparative Examples 1 and 2 described later). A process for producing N-alkylpyrazoles in a high yield is greatly desired. The present invention provides a process for producing an N-alkylpyrazole of formula (1): wherein each R 1 is, independently, a C 1 -C 4 alkyl group, R 2 is a C 1 -C 4 alkyl group and n is an integer of from 1 to 3, which comprises reacting an alkali metal salt of a pyrazole with an alkylating agent, said alkali metal salt having been obtained by previously reacting an alkali metal or an alkali metal-containing base with an N-unsubstituted pyrazole of formula (2): wherein R 1 and n are as defined above. As the alkali metal or the alkali metal-containing base, there can be used an inorganic base such as sodium hydride, potassium hydride, lithium hydride, metal sodium, metal potassium, metal lithium, lithium aluminum hydride, sodium borohydride, lithium borohydride, butyl lithium, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate, or an organic base such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, trimethylamine, triethylamine or pyridine. The amount of the alkali metal or alkali metal-containing base used is preferably from 0.7 to 5.0 mol, more preferably 1.0 to 2.0 mol, based on one mol of the N-unsubstituted pyrazole. The reaction temperature is preferably from -10 to 200°C and the reaction time is preferably from 0.5 to 30 hours. As the alkylating agent, there can be mentioned alkyl halides such as methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, isopropyl chloride, isopropyl bromide, isopropyl iodide or butyl bromide, and dimethyl sulfate and diethyl sulfate. The amount of the alkylating agent used is usually from 0.4 to 10.0 mol, preferably 0.5 to 5.0 mol, based on one mol of the N-unsubstituted pyrazole. The reaction temperature is usually from -10 to 200°C and the reaction time is preferably from 0.5 to 30 hours. The reaction of the present invention can be conducted without a solvent but a solvent may be used. As the solvent, there can be mentioned aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as methylene-chloride and 1,1,1-trichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; halogen-substituted aromatic hydrocarbons such as chlorobenzene, dichlorobenzene and 3,4-dichlorotoluene; alkoxy-substituted aromatic hydrocarbons such as anisole and 1,2-dimethoxybenzene; ethers such as diethyl ether, dipropyl ether, methyl tertiary butyl ether, ethylene glycol dibutyl ether, diethylene glycol dibutyl ether, tetrahydrofuran and dioxane; and aprotic polar solvents such as N,N'-dimethylformamide and acetonitrile. In addition, for forming the alkali metal salt of the pyrazole, alcohols such as methanol, ethanol, butanol and amylalcohol can also be used. Two or more of the above-mentioned solvents can also be used as a mixture or dispersion. The reaction of the present invention can be carried out either at atmospheric pressure or under pressure. The alkali metal salt of an N-unsubstituted pyrazole can be produced industrially in a good yield by the following methods. The first method is reacting an N-unsubstituted pyrazole with, for example, metal sodium or metal potassium. The reaction may proceed without a solvent but an inert solvent as described above may also be used. The metal sodium or metal potassium, for example, may be used as such in a solid state, but it is preferred to react them in a molten state. The second method, having a good efficiency, is reacting an N-unsubstituted pyrazole with, for example, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide or lithium hydroxide, while distilling off alcohol or water. Generally, a strongly acidic N-unsubstituted pyrazole having a strong electron attracting group such as a carboxylic acid ester group or a nitro group as a substituent can easily form a salt with a base, but weakly acidic N- unsubstituted pyrazoles such as an N-unsubstituted alkyl pyrazole used in the present invention hardly form salts. For instance, reaction of an alkoxide such as sodium methoxide with an N-unsubstituted pyrazole in an alcohol solvent followed by treatment with the alkylating agent described above cannot provide a satisfactory result (refer to Comparative Examples 1 and 2). This is considered to be attributable to the fact that a sodium salt of a pyrazole cannot be formed efficiently due to the following equilibrium reaction: (wherein R 1 represents a C 1 - C 4 alkyl group and Q represents a hydrogen atom or a methyl group). In view of the above, an alkali metal salt of a methyl pyrazole can be formed in good efficiency by distilling off alcohol or water from the reaction system, thereby shifting the above-mentioned equilibrium reaction rightward. The reaction can also be conducted in an inert solvent. A first embodiment of the present invention is a process for obtaining an N-alkylpyrazole of formula (1) by reacting an N-unsubstituted pyrazole with an alkali metal at 60 to 190°C for 0.5 to 5.0 hours, thereby obtaining an alkali metal salt of the pyrazole and, subsequently, reacting the obtaining alkali metal salt of the pyrazole with an alkylating agent at 20 to 150°C for 1.0 to 20 hours. A second embodiment is a process for obtaining an N-alkylpyrazole of formula (1) by reacting an N-unsubstituted pyrazole with an alkoxide or alkali hydroxide while distilling off alcohol or water to form an alkali metal salt of the pyrazole and, subsequently, reacting the obtained alkali metal salt of the pyrazole with an alkylating agent at 20 to 150°C for 1.0 to 20 hours. After finishing the reaction, inorganic materials in the reaction product are removed by filtration or by adding water to the reaction mixture and extracting the reaction product with an organic solvent. Subsequently N-alkylpyrazoles of formula (1) can be obtained by, for example, distillation. In accordance with the present invention, N-alkylation of N-unsubstituted pyrazoles can be conducted in an industrial scale and N-alkylpyrazoles of formula (1) can be obtained in a high yield. In particular, the present invention provides an effective process for producing 1,4-dimethylpyrazole. 1,4-dimethylpyrazole is useful as an intermediate for herbicides (JP-A-60-208977, corresponding to US-A-4,668,277 and US-A-4,689,417) used in corn farms (JP-A-2-191259). As shown in Comparative Examples 1 and 2 described later, the conversion ratio is low and the yield of N-alkylpyrazoles is less than 50% in the conventional method, whereas in the present invention the conversion ratio is high, for example, not less than 80%, and the yield of N-alkylpyrazoles is not less than 80%. Depending on the reaction conditions, the product can be obtained in a high yield of not less than 95%. The present invention is now be further explained in the following Examples. Example 1 In 5 g of dry toluene, 0.25 g (0.0109 mol) of metal sodium was melted at a temperature of 100 to 105°C, and 1.0 g (87.8% purity, 0.0107 mol) of 4-methylpyrazole was added under stirring for 10 min. After the dropping was over, the mixture was stirred for a further 45 min at 100 to 105°C and then allowed to cool to room temperature. After adding 6 ml of tetrahydrofuran, 1.60 g (0.0113 mol) of methyl iodide was dropped for 5 min and, after stirring for 3 hours, inorganic matter was separated by filtration. When the liquid filtrate was analyzed by liquid chromatography, 0.89 g of 1,4-dimethylpyrazole was found to be contained therein. The conversion ratio was 88% and the yield was 87% based on 4-methylpyrazole. Example 2 0.25 g (0.0109 mol) of metal sodium was melted in a reflux of 5 g of dry dioxane, to which 1.0 g (87.8% purity, 0.0107 mol) of 4-methylpyrazole was dropped for 10 min under stirring. After the dropping was over, the mixture was further stirred for 5 hours in a refluxing state and then allowed to cool to room temperature. After dropping 1.60 g (0.0113 mol) of methyl iodide for 5 min and stirring for 2 hours, inorganic matter was separated by filtration. When the liquid filtrate was analyzed by liquid chromatography, 0.91 g of 1,4-dimethylpyrazole was found to be contained therein. The conversion ratio was 91% and the yield was 88% based on 4-methylpyrazole. Example 3 0.27 g (0.0117 mol) of metal sodium was added to 1.7 g of dry methanol at a room temperature and dissolved with stirring to prepare sodium methoxide. After adding 5 g of heptane, 1.0-g-(87.8% purity, 0.0107 mol) of 4-aethylpyrazole was dropped for 5 min under stirring. After stirring at room temperature for 30 min, the temperature was elevated to 80°C, methanol was distilled off for one hour and, furthermore methanol was distilled off at 90°C for one hour. After the mixture was allowed to cool to room temperature, 5g of tetrahydrofuran was added and 1.67 g (0.0118 mol) of methyl iodide was dropped for 5 min. After stirring for 4 hours, inorganic matter was separated by filtration. When the liquid filtrate was analyzed by liquid chromatography, 0.96 g of 1,4-dimethylpyrazole was found to be contained therein. The yield was 94% based on 4-methylpyrazole. Example 4 0.27 g (0.0117 mol) of metal sodium was melted in a reflux of 5 g of dry dioxane, to which 1.0 g (87.8% purity, 0.0107 mol) of 4-methylpyrazole was dropped for 2 min under stirring. After the dropping was over, the mixture was further stirred for 4 hours and 20 min in a refluxing state, and then allowed to cool to 40°C. 6.48 g (0.1284 mol) of methyl chloride was blown in at 40°C for 2.5 hours and at 50°C for 2 hours, and thereafter inorganic matter was separated by filtration. When the liquid filtrate was analyzed by liquid chromatography, 1.02 g of 1,4-dimethylpyrazole was found to be contained therein. The yield was 99% based on 4-methylpyrazole. Example 5 0.51 g (0.0119 mol) of 93% sodium hydroxide was added to 2.1 g of dry methanol and dissolved at 50°C. After adding 5 g of heptane, 1.0 g (87.8% purity, 0.0107 mol) of 4-methylpyrazole was dropped under stirring for 5 min. After stirring for 30 min, the temperature was elevated and methanol was distilled off at 75 to 90°C for 2.0 hours. Subsequently, the mixture was allowed to cool to room temperature, 5 g of tetrahydrofuran was added and 1.67 g (0.0118 mol) of methyl iodide was dropped for 5 min. After stirring for 5 hours, inorganic matter was separated by filtration. When the liquid filtrate was analyzed by liquid chromatography, 1.0 g of 1,4-dimethylpyrazole was found to be contained therein. The conversion ratio was 98% and the yield was 97% based on 4-methylpyrazole. Example 6 0.51 g (0.0119 mol) of 93% sodium hydroxide was added to 2.1 g of dry methanol and dissolved at 50°C. After adding 5 g of heptane, 1.0 g (87.8% purity, 0.0107 mol) of 4-methylpyrazole was dropped under stirring for 5 min. After stirring for 30 min, the temperature was elevated and methanol was distilled off at 75 to 95°C for 2.5 hours. Subsequently, the mixture was allowed to cool to a room temperature, 5 g of tetrahydrofuran was added and 1.87 g (0.0168 mol) of 98% ethyl bromide was dropped for 5 min. After stirring for 2 hours, the temperature was elevated to 40°C and the stirring was continued for 14.5 hours. After separating inorganic matter by filtration, when the liquid filtrate was analyzed by liquid chromatography, 1.04 g of 1-ethyl-4-methylpyrazole was found to be contained therein. The conversion ratio was 94% and the yield was 89% based on 4-methylpyrazole. Example 7 0.57 g (0.0133 mol) of 93% sodium hydroxide was added to 2.3 g of dry methanol and dissolved at 50°C. After adding 5 g of heptane, 1.0 g (99% purity, 0.0121 mol) of 4-methylpyrazole was dropped under stirring for 10 min. After stirring for 30 min, the temperature was elevated and methanol was distilled off at 70 to 90°C for one hour. Then, the temperature was lowered to 40°C, 5 g of tetrahydrofuran was added and 2.26 g (0.0133 mol) of isopropyl iodide was dropped for 7 min. and stirred for 4 hours. The temperature was further elevated and stirring was continued for 33 hours while refluxing under heating. After separating inorganic matter by filtration, when the liquid filtrate was analyzed by liquid chromatography, 1.13 g of 1-isopropyl-4-methylpyrazole was found to be contained therein. The conversion ratio was 86% and the yield was 83% based on 4-nethylpyrazole. The boiling point was 61 - 65°C/18 mm Hg. Example 8 After adding a solution of 1.08 g (0.0251 mol) of 93% sodium hydroxide dissolved in 6 g of methanol to a liquid mixture containing 2.0 g (93.5% purity, 0.0228 mol) of 4-methylpyrazole and 10 g of chlorobenzene, the temperature was elevated and methanol was distilled off at 100°C in an outer bath. Then, the temperature was lowered and methyl chloride was blown in at 50 - 55°C at a rate of 10 ml per one min for 9 hours. After separating inorganic matter by filtration, when the filtrate was analyzed by liquid chromatography, 2.15 g of 1,4-dimethylpyrazole was found to be contained therein. The yield was 98% based on 4-methylpyrazole. Example 9 After adding a solution of 1.08 g (0.0251 mol) of 93% sodium hydroxide dissolved in 6 g of methanol to a liquid mixture containing 2.0 g (93.5% purity, 0.0228 mol) of 4-methylpyrazole and 45 g of methyl tertiary butyl ether, the temperature was elevated and methanol was distilled off at 51 - 53°C by azeotropic boiling with methyl tertiary butyl ether. Then, methyl chloride was blown in at 50 - 55°C at a rate of 10 ml per one min for 18 hours. After separating inorganic matter by filtration, when the filtrate was analyzed by liquid chromatography, 2.02 g of 1,4-dimethylpyrazole was found to be contained therein. The conversion ratio was 93% and the yield was 92% based on 4-methylpyrazole. Example 10 After adding a solution of 1.08 g (0.0251 mol) of 93% sodium hydroxide dissolved in 5 g of methanol to a liquid mixture containing 2.0 g (93.5% purity, 0.0228 mol) of 4-methylpyrazole and 10 g of 1,2-dimethoxybenzene, the temperature was elevated and methanol was distilled off at 100°C in an outer bath. Then, the temperature was lowered and methyl chloride was blown in at 50 - 55°C at a rate of 10 ml per one min for 3.5 hours. After separating inorganic matter by filtration, when the filtrate was analyzed by liquid chromatography, 2.17 g of 1,4-dimethylpyrazole was found to be contained therein. The yield was 99% based on 4-methylpyrazole. Example 11 1.10 g (0.0478 mol) of metal sodium was added to 10 g of dry methanol to prepare sodium methoxide. After adding 20 g of heptane, 4.0 g (0.0488 mol) of 3-methylpyrazole was dropped under stirring for 5 min. After stirring for 30 min, the temperature was elevated and methanol was distilled off at 75 - 90°C for 2.0 hours. Then, the mixture was allowed to cool to room temperature, 20 g of tetrahydrofuran was added and 9.26 g (0.0652 mol) of methyl iodide was dropped for 5 min. After stirring for 2 hours, inorganic matter was separated by filtration. When the liquid filtrate was analyzed by gas chrowatography, 4.3 g of a mixture containing 1,3-dimethylpyrazole and 1,5-dimethylpyrazole at a 1:1.7 ratio was found to be contained therein. The conversion ratio was 93% and the yield was 92% based on 3-methylpyrazole. Comparative Example 1 0.50 g (0.0218 mol) of metal sodium was added at room temperature to 20 g of dry methanol to prepare sodium methoxide. 2.0 g (84.9% purity, 0.0207 mol) of 4-methylpyrazole was dropped for 5.0 min and stirring was further applied at room temperature for 30 min. 3.09 g (0.0218 mol) of methyl iodide was dropped for 6 min and, after completion of the dropping, the resultant mixture was stirred for 5.5 hours at room temperature and for 3 hours at the methyl iodide refluxing temperature. Since the conversion ratio was low, 3.09 g (0.0218 mol) of methyl iodide was further added and the mixture was stirred for 7 hours at the refluxing temperature. When the reaction solution was analyzed by liquid chromatography, 0.73 g of 4-methylpyrazole and 1.00 g of 1,4-dimethylpyrazole were found to be contained therein. The conversion ratio was 63.5% and the yield was 50% based on the 4-methylpyrazole. Comparative Example 2 0.55 g (0.0239 mol) of metal sodium was added at room temperature to 10 g of dry methanol to prepare sodium methoxide. 2.0 g (0.0244 mol) of 3-methylpyrazole was dropped for 5.0 min and the stirring was further continued at room temperature for 30 min. 4.63 g (0.0326 mol) of methyl iodide was dropped for 20 min and, after completion of the dropping, the resultant mixture was stirred for 5.0 hours at room temperature. After distilling off methanol, 20 g of water was added to dissolve inorganic matter and the organic matter was extracted with 20 g of diethyl ether. The aqueous layer was extracted three times with 6 g of diethyl ether, and the obtained extract added to the above-mentioned organic layer. When the obtained organic layer was analyzed by gas chromatography and liquid chromatography, 1.30 g of 3-methylpyrazole and 0.77 g of a mixture containing 1,3-dimethylpyrazole and 1. 5-dimethylpyrazole at a 1:1.1 ratio were found to be contained therein. The conversion ratio was 35% and the yield was 33% based on 3-methylpyrazole.

Claims: A process for producing an N-alkylpyrazole of formula (1): wherein each R 1 is, independently, a C 1 -C 4 alkyl group, R 2 is a C 1 -C 4 alkyl group and n is an integer of from 1 to 3, which comprises reacting an alkali metal salt of a pyrazole with an alkylating agent, said alkali metal salt having been obtained by previously reacting an alkali metal or an alkali metal-containing base with an N-unsubstituted pyrazole of formula (2): wherein R 1 and n are as defined above. A process according to claim 1, wherein the N-alkylpyrazole of formula (1) has the formula (1a): wherein R 1 and R 2 are as defined in claim 1, and the N-unsubstituted pyrazole of formula (2) has the formula (2a): wherein R 1 is as defined above. A process according to claim 1 or 2, wherein R 2 is a methyl group. A process according to any one of the preceding claims, wherein R 1 is a methyl group. A process according to any one of the preceding claims, wherein the alkali metal or the alkali metal-containing base is at least one of sodium hydride, potassium hydride, lithium hydride, metallic sodium, metallic potassium, metallic lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, butyl lithium and lithium diisopropylamide. A process according to claim 5, wherein the alkali metal is metallic sodium or metallic potassium in a molten state. A process according to claim 5, wherein at least one of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide and lithium hydroxide is reacted with the N-unsubstituted pyrazole of formula (2) while distilling off an alcohol or water. A process according to any one of the preceding claims, wherein the alkylating agent is at least one of methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, isopropyl chloride, isopropyl bromide, isopropyl iodide, dimethyl sulfate and diethyl sulfate. A process according to any one of the preceding claims, wherein the reaction temperature in either or both steps is from -10 to 200°C. A process according to any one of the preceding claims, wherein a solvent is used in the reaction system in either or both steps. A process according to claim 10, wherein the solvent is at least one of hexane, heptane, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, N,N-dimethylformamide, acetonitrile, methanol, ethanol, butanol, amyl alcohol, di-n-propyl ether, methyl tertiary butyl ether, 1,2-dimethoxybenzene, ethylene glycol dibutyl ether, diethylene glycol dibutyl ether, 3,4-dichlorotoluene and 1,1,1-trichloroethane.

Inventors: HASHIBA ISAO, IWASAWA YOSHIHIRO, MURAKAMI HIROSHI, SUZUKI FUMIO, YAMAMOTO SUSUMU, HASHIBA, ISAO, IWASAWA, YOSHIHIRO, MURAKAMI, HIROSHI, SUZUKI, FUMIO, YAMAMOTO, SUSUMU
Applicants: NISSAN CHEMICAL IND LTD, NISSAN CHEMICAL INDUSTRIES LTD.
Application year: 1991
Main classification: C07D231
IPC codes: C07D231, C07D521