JPH09235268A - Production of trimethylsulfoxonium bromide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To shorten reaction time and safely obtain a compound useful as an intermediate for disinfectant azole derivatives in high purity and yield by reaction under atmospheric pressure. SOLUTION: Methyl bromide is added little by little to dimethyl sulfoxide heated to 50-75 deg.C under atmospheric pressure while keeping the temperature range and finally, methyl bromide in an amount of 0.40-0.70mol based on 1mol dimethyl sulfoxide is reacted with dimethyl sulfoxide to provide the objective trimethylsulfoxonium bromide. Further, at least one kind of compound selected from trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tetramethyl orthocarbonate, tetraethyl orthocarbonate, tetraisopropyl orthocarbonate and tetrapropyl orthocarbonate in an amount of 0.002-0.05mol based on 1mol dimethyl sulfoxide is preferably added to dimethyl sulfoxide.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing trimethylsulfoxonium bromide which is useful as an intermediate for bactericidal azole derivatives.

[0002]

BACKGROUND OF THE INVENTION Trimethylsulfoxonium bromide which can be produced by the present invention is a compound obtained by the reaction of dimethylsulfoxide and methyl bromide and is useful as an intermediate for bactericidal azole derivatives (JP-A-1-
No. 301664). Tetrahedron Lett., 1968 , 250
1-2502. Describes that dimethyl sulfoxide and methyl bromide can be synthesized by heating in a sealed tube at 80 to 90 ° C. for 48 hours. Catal. Org. Synth., 7 , 301-309 (1980). And Japanese Patent Application Laid-Open No. 54-48713 propose a manufacturing method improving aid such as trimethyl orthoformate by Skaros et al. . The reaction for synthesizing an onium bromide such as trimethylsulfoxonium bromide from methyl bromide and a heteroatom compound is usually preferably carried out in a sealed tube by first charging the raw material compound. For example, methyltriphenylphosphonium bromide can be stored in a sealed tube at room temperature,
It has been reported that an isolation yield of 95% is obtained in the reaction for 2 days (J. Am. Chem. Soc., 103 , 439 (1981)).
Trimethylsulfonium bromide, in a sealed tube, 80
It has been reported that an isolation yield of 80% can be obtained by the reaction at 5 ° C for 5 hours (J. Org. Chem., 29 , 3279 (1964)).

[0003]

[Problems to be Solved by the Invention] Even if the reaction temperature is high or low and the reaction time is long or short, in order to synthesize methyltriphenylphosphonium bromide, trimethylsulfonium bromide and trimethylsulfoxonium bromide in good yield, a sealed tube is used. And pressure resistant reactors are preferred. By the way, Skaros et al. Pointed out that hydrogen bromide produced as a by-product in the reaction between dimethyl sulfoxide and methyl bromide triggered the chain decomposition of dimethyl sulfoxide, and described the following matters. . (A) Pressure vessel (closed vessel, pressure bottl)
e), dimethyl sulfoxide (water content 100 pp
m) When 0.5 mol of methyl bromide is reacted at a reaction temperature of 60 ° C. per mol, the internal pressure of about 3 atm is reduced to about 1.3 atm 90 hours after the start of the reaction. If heating is continued, the reaction vessel will be damaged due to chain decomposition 212 hours after the start of the reaction. (B) This chain decomposition is affected by the water content in dimethylsulfoxide, and in the case of dimethylsulfoxide having a water content of 900 ppm, the container breaks due to chain decomposition 98 hours after the start of the reaction. (C) The method for improving the production method of methyl orthoformate or the like suppresses chain decomposition by capturing by-produced hydrogen bromide and water. (D) In a pressure resistant reactor, a mixture containing 0.025 mol of trimethyl orthoformate and 0.5 mol of methyl bromide was reacted at 60 ° C. for 50 hours per 1 mol of dimethyl sulfoxide, and the isolated yield was 80%. To obtain trimethylsulfoxonium bromide. (E) Atmospheric pressure, per mol of dimethyl sulfoxide,
A mixture containing 0.019 mol of trimethyl orthoformate and 0.39 mol of methyl bromide was reacted at room temperature for 5 weeks to obtain trimethylsulfoxonium with an isolated yield of 50%.
Obtaining bromide.

(D) by Skaros et al. Uses a pressure resistant reaction vessel even at a low high pressure, so that
There is a desire to manufacture under atmospheric pressure. Also,
(E) has room for improvement in terms of reaction time and yield. Therefore, the present inventor has made it a subject to shorten the reaction time, improve the yield, and establish the safety of the manufacturing operation by the reaction under atmospheric pressure.

[0005]

Means for Solving the Problems The present inventors have conducted extensive studies in order to achieve the above object, and as a result, added methyl bromide to heated dimethyl sulfoxide even in the reaction under atmospheric pressure. It has been found that the method can shorten the reaction time, improve the yield, and establish the safety of the manufacturing operation, and completed the present invention.

[0006]

That is, the present invention has the following structural features. Methyl bromide was added little by little to dimethylsulfoxide heated to 50 to 75 ° C. under atmospheric pressure while maintaining this temperature range (the method of adding little by little may be continuous or intermittent). , Or these may be combined), and finally 0.40 to 0.70 mol is reacted with 1 mol of dimethyl sulfoxide, and the present invention relates to a method for producing trimethylsulfoxonium bromide. Furthermore, at least one compound selected from the group consisting of trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tetramethyl orthocarbonate, tetraethyl orthocarbonate, tetraisopropyl orthocarbonate, and tetrapropyl orthocarbonate is used in an amount of 0. Dimethyl sulfoxide to which 002 to 0.05 mol was added was heated to 50 to 50 at atmospheric pressure.
It is heated to 75 ° C., and methyl bromide is added thereto at a rate such that it is gently refluxed in a condenser, and finally 0.40 to 0.70 mol is reacted with 1 mol of dimethyl sulfoxide. The present invention relates to a method for producing trimethylsulfoxonium bromide which is a feature.

Hereinafter, the present invention will be described in detail. The raw material compound, dimethyl sulfoxide, methyl bromide, and trimethyl orthoformate used in the present invention has a water content of 400 pp.
m or less, preferably 200 ppm or less, more preferably 100 ppm or less. Examples of the method for drying the raw material compound include the following methods. A method of drying a raw material compound using a molecular sieve as a desiccant. A method in which trimethyl orthoformate is added to dimethyl sulfoxide, and after heating, a low-boiling compound containing trimethyl orthoformate is distilled off as much as possible and dried.

The amount of methyl bromide used per 1 mol of dimethyl sulfoxide is 0.40 to 0.70 mol, preferably 0.45 to 0.55 mol, and more preferably
It is 0.48 to 0.53 mol. When the amount of methyl bromide used is less than 0.40 mol, the amount of the product dissolved in the filtrate becomes relatively large when the product is isolated by filtration, which is disadvantageous to the isolation yield. When methyl bromide is used in an amount of more than 0.70 mol, it takes a long time to complete the reaction, and therefore none of the problems of the present invention can be met.
The use of trimethyl orthoformate makes the effect of the present invention aiming at shortening the reaction time, improving the yield, and establishing the safety of the manufacturing operation, to further ensure the effect. The amount of trimethyl orthoformate used is preferably 0.002 to 0.05 mol, and more preferably 0.004 to 0.02 mol, per 1 mol of dimethyl sulfoxide. In addition to trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tetramethyl orthocarbonate, tetraethyl orthocarbonate, tetraisopropyl orthocarbonate, tetrapropyl orthocarbonate and the like can be used as similar auxiliary agents.

The outline of the reaction operation of the present invention is as follows. Glass-lined reaction vessels are preferably used. Attach a condenser to the reaction vessel. Further, preferably, a T-shaped tube is attached to the upper end of the cooling tube, and a rubber tube or a silicon tube is connected to one side of the cooling tube, and nitrogen,
An inert gas such as argon is allowed to flow, and a glass tube is attached to the tip of a rubber tube or a silicon tube connected to the other side, and the tip is immersed in silicon oil to prevent backflow of the atmosphere. Alternatively, a small amount of an inert gas may be continuously bubbled into a mixture of the raw material compounds described below to create an inert gas atmosphere. Charge a predetermined amount of dimethyl sulfoxide and trimethyl orthoformate into a reaction vessel,
Heat to 50-75 ° C. with stirring. A predetermined amount of gaseous or liquid methyl bromide in this mixture,
Cooling pipe (usually a coolant of -10 to -50 ° C passed)
Add at a rate such that it gently refluxes. Since the reaction mixture takes the form of a slurry during the addition of methyl bromide, stirring is performed during the reaction so that the slurry is sufficiently mixed. After adding a predetermined amount of methyl bromide, the mixture is further stirred for 3 to 18 hours at the same temperature as during addition. Then, the reaction mixture is cooled to room temperature, the insoluble matter is filtered off, washed with an organic solvent such as benzene, toluene, xylene and the like, and the washing solution is removed by filtration to obtain a white filter cake. The filter cake is dried under reduced pressure at 30 to 60 ° C. to isolate the target product having a purity of about 99% and a yield of about 90.
It can be obtained in%. The total time of the addition of methyl bromide and the reaction time after the addition requires 50 hours or more, and usually 100 to 160 hours. Therefore, although it is longer than 50 hours of low-pressure reaction by Skaros et al. The reaction time under atmospheric pressure is much shorter than that at room temperature for 5 weeks. Reaction under atmospheric pressure, product purity,
From the viewpoint of isolation yield and safety of manufacturing operation, it can be said to be an industrially useful manufacturing method. The advantages of the present invention performed under atmospheric pressure include the following in addition to reducing the consideration of pressure resistance of the reaction vessel. Boiling point of methyl bromide 4 ℃,
Boiling point of hydrogen bromide-67 ° C, boiling point of formaldehyde-2
Since it is 1 ° C, by-products can be removed from the reaction mixture by adjusting the temperature of the cooling pipe refrigerant. In particular, since hydrogen bromide is a compound which is pointed out to trigger the chain decomposition of dimethylsulfoxide, its rapid removal from the reaction mixture not only improves the isolation yield but also the product purity and In terms of safety of manufacturing operation, it also brings desirable results.

[0010]

The present invention will now be described by way of examples, which should not be construed as limiting the scope of the invention. Production Example 1 Production of trimethylsulfoxonium bromide A cooling pipe (the upper part communicating with the reaction vessel was filled with a nitrogen stream and a refrigerant of −30 ° C. was used) was attached 10
A 0 L glass-lined reaction vessel was charged with 47 kg of dimethyl sulfoxide (water content, 100 ppm) and 500 ml of trimethyl orthoformate and heated to 60 to 65 ° C. While maintaining the temperature of the heated mixture during the reaction at about 60 to 65 ° C, through a tube inserted into the heated mixture,
30 kg of methyl bromide was added from a cylinder at a rate such that it was gently refluxed with a cooling tube. The addition took 130 hours. During the addition, the reaction mixture takes the form of a slurry, so the slurry was stirred so that it was well mixed. After the total amount of methyl bromide was added, the mixture was further stirred at the same temperature for 10 hours. The yellow reaction mixture was cooled to room temperature and the insoluble matter was filtered off. The filter cake was washed with 74.4 L of toluene, the washing liquid was removed by vacuum filtration, and after washing, the filter cake was dried under reduced pressure at 50 ° C. Yield 49.6 kg Yield 90.5% Purity 99% or more (by ion pair chromatography)

Reference Production Example 1 5- (4-chlorobenzyl) -2,2-dimethyl-1
Synthesis of-(1H-1,2,4-triazol-1-ylmethyl) cyclopentanol [Using the trimethylsulfoxonium bromide produced in Production Example 1 above, the method described in JP-A-1-301664 was used. According to the above method, the title compound was synthesized] Into a 2-liter 4-neck flask, while flowing nitrogen, 200 ml of N-
Methyl-2-pyrrolidinone and 72 g of 60% oily sodium hydride were added, and the mixture was stirred while keeping the temperature below 80 ° C,
A mixed solution of 103.6 g of 1,2,4-triazole and 250 ml of N-methyl-2-pyrrolidinone was added dropwise. After completion of dropping, further stirring for 30 minutes, while maintaining below 80 ℃,
44.5 g of t-butanol was added dropwise. After completion of dropping, the mixture was stirred for 30 minutes and then heated to 115 ° C. to obtain 5- (4-
246.3 g of (chlorobenzyl) -2,2-dimethyl-1-cyclopentanone was added. Trimethylsulfoxonium bromide (208 g) and sodium t-butoxide (28.8 g) were each divided and added over 5 hours, and after the addition was completed, the reaction was continued for another 3 hours. Then, the reaction mixture was cooled, 700 ml of water was added, and the mixture was stirred well and then extracted twice with 700 ml of toluene. After washing the toluene layer 3 times with 1400 ml of water, 175 g of cis isomer
It was possible to obtain 1441 g of a toluene solution containing 4 g of trans isomer.

5- (4-chlorobenzyl) -2,2-
Dimethyl-1- (1H-1,2,4-triazole-1
Separation of cis-form of -ylmethyl) cyclopentanol 5- (4-chlorobenzyl) -2,2-dimethyl-1- (1H-1,2,4 obtained in Reference Production Example 1 above
-Triazol-1-ylmethyl) cyclopentanol in a toluene extract containing 100 g of cis and trans isomers,
95% sulfuric acid 1.39 g (molar ratio of sulfuric acid to the total of cis and trans isomers in 100 g of toluene extract = 0.3)
Was added, and azeotropic dehydration with toluene was performed while heating under reflux. After 5 hours the ratio of cis to trans was 98:
When it reached 2, it was cooled, 50 g of a 3% aqueous sodium hydroxide solution was added, and the mixture was stirred well. Then, the toluene layer was washed three times with water and dried over anhydrous sodium sulfate, and toluene was distilled off under reduced pressure to obtain 23.27 g of a residue.
As a result of analysis by HPLC, this concentrate was found to have a cis content of 51.4 wt.
%, The trans form was 1.1 wt%. From this value, the yield of cis form from the toluene extract was 98.5%, and the decomposition rate of trans form was 91.8%. To the obtained residue, 80 ml of methylcyclohexane was added and dissolved at 75 ° C, then 10 ° C /
It was cooled to 0 ° C at a rate of 60 minutes. The precipitated crystals were filtered, the filtered crystals were washed with 35 ml of methylcyclohexane and then dried at 65 ° C to obtain 11.64 g of crystals. Cis purity 97% Total cis yield from toluene extract 93.0% Trans content 0.9%

[0013]

EFFECTS OF THE INVENTION In the reaction under atmospheric pressure, methyl bromide was added little by little to dimethyl sulfoxide heated to 50 to 75 ° C., and finally 0.40 to 0.70 mol per 1 mol of dimethyl sulfoxide. By reacting with, the highly purified trimethylsulfoxonium bromide can be obtained in good isolated yield with a shortened reaction time and a safe production operation.

Claims (2)

[Claims] 1. Methyl bromide is added little by little to dimethyl sulfoxide heated to 50 to 75 ° C. under atmospheric pressure, and finally, per mol of dimethyl sulfoxide,
A method for producing trimethylsulfoxonium bromide, which comprises reacting 0.40 to 0.70 mol. 2. At least one compound selected from the group consisting of trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tetramethyl orthocarbonate, tetraethyl orthocarbonate, tetraisopropyl orthocarbonate, and tetrapropyl orthocarbonate is added to dimethyl sulfoxide 1 The production method according to claim 1, wherein methyl bromide is added to dimethylsulfoxide added in an amount of 0.002 to 0.05 mol per mol at a ratio such that methyl bromide is gently refluxed in a cooler.