WO2002088058A1 - Process for the preparation of benzyl alcohols - Google Patents

Abstract

A process for the preparation of benzyl alcohols represented by the general formula (I): (I) (wherein R1 is fluorinated and/or chlorinated alkyl), characterized by reacting an aryl chloride represented by the general formula (II): (II) with magnesium in the presence of a lower haloalkane to prepare a Grignard reagent represented by the general formula (III): (III) and then reacting this Grignard reagent with formaldehyde and/or a polymer thereof.

Description

 Manufacturing method of specifications

"Technical field"

 The present invention relates to a method for producing benzyl alcohols. Benzyl alcohols in which a haloalkyl group is substituted on the benzene ring are useful compounds as intermediates for agricultural chemicals or pharmaceuticals.

"Background technology"

 Various methods are known as methods for producing benzyl alcohols. For example

US Pat. No. 4,118,561 discloses a process for producing the corresponding benzyl alcohol by reacting 4- (trifluoromethyl) benzoic acid with lithium aluminum hydride as a reducing agent. However, there is a safety problem in using industrially hazardous chemicals such as lithium aluminum hydride on an industrial scale. Japanese Patent Application Laid-Open No. 2001-26001 discloses that, by reacting carbon bromide with a haloalkyl-substituted aryl bromide in the presence of a palladium catalyst and sodium formate, the equivalent is obtained. A method for producing benzyl alcohol is described, but this method is industrially problematic in that it uses expensive aryl bromide and requires the recovery of a palladium catalyst. JP-A-11-19855 describes a method for producing alcohols by reacting a Grignard reagent with paraformaldehyde in the presence of an alkali. Halogen is described as a method for producing a Grignard reagent. A method for reacting bromostyrene with metallic magnesium is described, but the use of expensive parabromostyrene poses an industrial problem.

"Disclosure of the invention"

The problem to be solved by the present invention is to produce benzyl alcohols, which are difficult to produce on an industrial scale by conventional methods or have to use expensive raw materials. The present invention provides safe and efficient production using inexpensive raw materials _(the present invention relates to formula (I);

(Wherein R ¹ is alkyl substituted with a fluorine atom and Z or a chlorine atom), which is a method for producing a benzyl alcohol represented by the formula (II):

(Wherein R ¹ is as defined above), and a formula (III) produced by reacting magnesium chloride and magnesium in the presence of a lower haloalkane;

(Wherein R ¹ is as defined above), and a reaction of the Grignard reagent with formaldehyde and / or a polymer thereof.

Examples of the alkyl substituted with a fluorine atom and Z or a chlorine atom contained in R ¹ include those having 1 to 6 carbon atoms.Specifically, _CF ₃ , -CF ₂ H, -CF ₂ CHF _{2 , -C1CF 2, - CF 2 CF} 2 CF 3, and the like _CH (CH ₃₎ CF _3. Of these, alkyl substituted with a fluorine atom is desirable, and alkyl having 1 to 3 carbon atoms substituted with a fluorine atom is more desirable.

The reaction of reacting alkaryl chloride of the formula (II) with magnesium in the presence of a lower halic acid to form a Grignard reagent of the formula (III) is based on the reaction of a Grignard from a less reactive halide such as aryl chloride. When a reagent is generated, a lower haloalkane is reacted with magnesium to enhance the reactivity of magnesium, thereby generating a desired Grignard reagent. Regarding the addition order of aryl chloride, magnesium and lower haloalkane in this reaction, even in the case of batch addition, any addition order, for example, reacting magnesium and a part of lower haloalkane in advance, and then adding the remaining A method of adding the lower haloalkane (same or different from the previously added one) and aryl chloride simultaneously or separately; For example, a lower haloalkane may be gradually dropped into a mixed solution of toluene and magnesium. The reaction for producing the Grignard reagent may be performed in an atmosphere of an inert gas such as nitrogen, helium, or argon, if necessary.

 In the above reaction, in order to further improve the reactivity of magnesium, magnesium may be subjected to a certain treatment as necessary. Specifically, in an atmosphere of an inert gas such as nitrogen, helium, or argon, a treatment can be performed to increase the surface area by pulverizing while removing moisture while heating magnesium. By improving the reactivity of magnesium, the yield of the benzyl alcohol of the formula (I) can be improved.

 Examples of the lower haloalkane used in the above reaction include an alkylene having 1 to 6 carbon atoms substituted by a chlorine atom, a bromine atom or an iodine atom. Specifically, bromoethane, 1,2-dibromoethane, eodoethane, 1-chloropropane, 2-chloropropane, 1-bromopropane, 2-bromopropane, 1,2-dichloropropane, 1,2-dib □ And mopropane. Above all, an Al channel having 1 to 6 carbon atoms substituted by a chlorine atom or a bromine atom is desirable, and an alkane having 1 to 3 carbon atoms substituted by a chlorine atom or a bromine atom is more desirable. The lower haloalkanes may be used alone or in combination of two or more. When two or more are used in combination, there is a tendency that the lower haloalkane tends to be desirable in terms of cost and yield. For example, a combination of an alkyne substituted with a chlorine atom and an alkyne substituted with a bromine atom, or a combination of an alkane substituted with a chlorine atom and an alkane substituted with an iodine atom is exemplified. However, it is preferable to use an alkane substituted with a chlorine atom and an alkane substituted with a bromine atom.

By reacting the Grignard reagent of formula (III) obtained by the above reaction with formaldehyde and / or a polymer thereof, benzyl alcohols of formula (I) can be produced. Here, the formaldehyde and / or its polymer refers to a polymer itself as paraformaldehyde, a monomer obtained by thermally decomposing paraformaldehyde at around 200 ° C., and a combination thereof. In this reaction, paraformaldehyde is dried in advance to remove water. It is desirable to increase the yield of the benzyl alcohol of the formula (I). This reaction may be performed in an atmosphere of an inert gas such as nitrogen, helium, or argon, if necessary.

 In the reaction of the Grignard reagent of the formula (III) with formaldehyde and Z or a polymer thereof, an alkali may be present if necessary. Examples of the alkali include tertiary amines such as trimethylamine, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] -17-decene, sodium methylate, sodium ethylate, and the like. Alkali metal alcoholates such as potassium tertiary butylate may be used. In this reaction, the presence of an alkali is effective for improving the yield of the benzyl alcohol of the formula (I). The reaction procedure is via the Grignard reagent of (III). The procedure is as follows: Aryl chloride represented by the formula (II) is reacted with magnesium in the presence of a lower haloalkane, and then the resulting reaction mixture is added to formaldehyde. And Z or a polymer thereof, if necessary, by adding an alkali. The reaction may be carried out in an inert gas atmosphere as described above, if necessary.

In the present invention, the amount of each of aryl chloride, magnesium, lower haloalkane, formaldehyde, a polymer thereof and an alkali used as required in the formula (Π) varies depending on the type of the compound, the reaction conditions, and the like. Although not specified, the following ratio is usually based on 1 mol of aryl chloride of the formula (II). Magnesium and formaldehyde (in terms of formaldehyde in the case of polymer) are 1.0 to 5.0 moles, respectively, preferably 1.5 to 3.0 moles, more preferably 1.6 to 2.4 moles, and particularly preferably. Is a ratio of 1.8 to 2.2 moles, and the lower haloalkane is 0.5 to 4.0 moles, preferably 0.8 to 2.0 moles, more preferably 0.8 to 1.2 moles, particularly Desirably, the amount is 0.9 to 1.1 mol, and the amount of alkali used is 0.001 to 1.0 mol, preferably 0.005 to 0.5 mol. In the present invention, the reaction is generally carried out in the presence of a solvent, and any solvent may be used as long as it does not adversely affect the reaction. Examples thereof include ethyl ether, tetrahydrofuran, n-propyl ether, and n-propyl ether. Examples thereof include ethers such as butyl ether, and among them, tetrahydrofuran is preferable.

 In the present invention, the reaction temperature and reaction time are as follows: aryl chloride, magnesium, lower haloalkane, formaldehyde or a polymer thereof of the formula (II), the alkali used as required, the type of each solvent, the use form, the addition order, The reaction temperature in the first half of the reaction to produce the Grignard reagent is usually 0 to 150 ° C, preferably 0 to 100 ° C (: more preferably 2 0 to 70 ° C., and the reaction time is 1 to 12 hours, desirably 1.5 to 8 hours, and more desirably 2 to 6 hours. The reaction temperature is usually from 0 to 150 ° C, preferably from 0 to 100 ° C, more preferably from 20 to 70 ° C, and the reaction time is from 0.5 to 24 hours, preferably from 0 to 24 hours. 5 to 12 hours, more preferably 1 to 6 It is.

 Various constituent elements in the present invention can be appropriately selected from the above-described plurality of examples and conditions, and can be combined with each other. That is, the aryl chloride, magnesium, lower haloalkane, formaldehyde or its polymer of the formula (II), the alkali used as required, the type of each solvent, the form of use, the order of addition and the amount used; the reaction temperature; The above-described examples and conditions in the normal range and the examples and conditions in the desirable range can be appropriately selected and combined with each other.

 After completion of the reaction, the desired compound of formula (I) can be obtained by subjecting the reaction product to hydrolysis, and then, if necessary, purification methods such as distillation and column chromatography can be performed. .

The benzyl alcohols obtained according to the present invention are useful as intermediates for agricultural chemicals or pharmaceuticals. For example, they are used for the final production of hydrazone-based compounds described in JP-A-5-279312. Can be used as a raw material compound when producing benzyl cyanide. Specifically, benzyl alcohols are reacted with an ordinary halogenating agent to produce benzyl halide, and then reacted with cyanide. By this, the benzyl cyanide can be produced.

Example 1

 In a 1-liter four-necked flask, 22.3 g (0.92 mol) of magnesium was heated to 100 ° C under a nitrogen gas atmosphere and finely ground with a stirrer for 1 hour. Thereto were added 300 ml of tetrahydrofuran and bromobenzene (0.041 mol) at once, and the mixture was refluxed for 1 hour and 30 minutes. Thereafter, 83.68 g (0.46 mol) of benzotrifluoride was added dropwise, and a solution of 49 g (0.45 mol) of bromazine dissolved in 50 ml of tetrahydrofuran was refluxed for 1 hour and 30 minutes. It dripped over. After the addition, reflux was continued for 30 minutes, and the reaction solution was cooled to 30 ° C. To this solution, 27.56 g (0.92 mol) of pre-dried paraformaldehyde was gradually added so that the reaction temperature did not rise above 30 ° C, followed by stirring at 40 ° C for 1 hour and refluxing for another 1 hour. I let it. The obtained solution was cooled, poured into ice water, and concentrated hydrochloric acid was added to adjust the pH to 2, followed by ether extraction. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was distilled under reduced pressure to obtain 43 • 7 g of 4-trifluoromethylbenzyl alcohol having a boiling point of 95 to 100 ° C / l lmniHg.

Example 2

In a 1-liter four-necked flask, 22.3 g (0.92 mol) of magnesium was heated to 100 ° C under a nitrogen gas atmosphere and finely ground with a stirrer for 1 hour. Thereto were added 300 ml of tetrahydrofuran and bromoene lg (0.041niol) at a time, and the mixture was refluxed for 30 minutes. Thereafter, 83.68 g (0.46 mol) of benzotrifluoride was added dropwise, and a solution of 49 g (0.45 mol) of bromoethane dissolved in 50 ml of tetrahydrofuran was added dropwise over 1 hour and 30 minutes under reflux. did. After the addition, reflux was continued for 30 minutes, and the reaction solution was cooled to 30 ° C. To this solution, formaldehyde gas produced by thermally decomposing 30.31 g (1.0 mol) of paraformaldehyde dried in advance at 200 ° C was applied for 1 hour so that the reaction temperature did not rise above 30 ° C. After stirring, the mixture was stirred at room temperature for 1 hour. The resulting solution was poured into ice water, and concentrated hydrochloric acid was added to adjust the pH to 2, followed by ether extraction. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was distilled under reduced pressure to obtain a boiling point of 95-100 ° C / l lmmHg. 20.lg of fluoromethylbenzyl alcohol was obtained.

Example 3

 In a 1-liter four-necked flask, 300 ml of tetrahydrofuran and 13.46 g (0.55 mol) of magnesium were heated to 40 ° C under a nitrogen gas atmosphere, and 1 g (0.0081 mol) of 2-bromopropane was heated. ) And stirred for 15 minutes, and then 50 g (0.28 mol) of benzotrifluoride 4-chloride was added at once. A solution of 34.06 g (0.28 mol) of 2-bromopropane in 50 ml of tetrahydrofuran was added dropwise thereto under reflux over 2 hours and 30 minutes. After the addition, the reflux was continued for further 15 minutes, and then the reaction solution was cooled to 50 ° C. 0.28 g (0.20028 mol) of triethylamine was added to this solution at once, and 16.63 g (0.55 mol) of paraformaldehyde was added over 1 hour, followed by refluxing for 30 minutes. The obtained solution was cooled, a solution of concentrated hydrochloric acid (60 ml) dissolved in cold water (300 ml) was added, and stirring was continued. Thereafter, the organic layer was separated and the solvent was distilled off. 500 ml of water and 2 ml of a 10% aqueous sulfuric acid solution were added to the residue, azeotropic distillation was performed, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 30.4 g of crude 4-trifluoromethylbenzyl alcohol. Example 4

 In a 1-liter four-necked flask, 300 ml of tetrahydrofuran and 13.46 g (0.55 mol) of magnesium were heated to 40 ° C under a nitrogen gas atmosphere, and 1 g (0.0081 mol) of 2-bromopropane was heated. ) And stirred for 15 minutes, and then 50 g (0.28 mol) of benzotrifluoride 4-chloride was added at once. A solution of 21.75 (0.28 mol) of 2-chloropropane in 50 ml of tetrahydrofuran was added dropwise thereto over 2 hours under reflux. After the addition was completed, reflux was continued for 15 minutes, and then the reaction solution was cooled to 50 ° C. To this solution, 0.28 g (0.20028niol) of triethylamine was added all at once, and 16.63 g (0.55 mol) of paraformaldehyde was added over 1 hour, and the mixture was refluxed for 30 minutes. The resulting solution was cooled, a solution of concentrated hydrochloric acid (60 ml) dissolved in cold water (300 ml) was added, and stirring was continued. Thereafter, the organic layer was separated and the solvent was distilled off. 500 ml of water and 2 ml of a 10% aqueous sulfuric acid solution were added to the residue, azeotropic distillation was performed, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 37.04 g of crude 4-trifluoromethylbenzyl alcohol.

Example 5 In a 1-liter four-necked flask, 200 ml of tetrahydrofuran, 14.58 g (0.60 mol) of magnesium, 0.74 g (0.0060 mol) of 2-bromopropane and benzotrifluoride 4-clo mouth 54. 17 g (0.30 mol) was added, and the mixture was refluxed for 15 minutes under a nitrogen gas atmosphere.After that, a solution of 30-63 g (0.39 mol) of 2-chloropropane in 70 m of tetrahydrofuran; Was added dropwise over 1 hour under reflux. After the addition, reflux was continued for 30 minutes, and then the reaction solution was cooled to 60 ° C. To this solution, 16.63 g (0.55 mol) of paraformaldehyde was added over 30 minutes, and the mixture was refluxed for 30 minutes. The resulting solution was cooled, a solution of concentrated sulfuric acid (32.37 g) dissolved in cold water (400 ml) was added, and stirring was continued. Thereafter, the organic layer was separated and the solvent was distilled off. 600 ml of water and 2 ml of 10% sulfuric acid aqueous solution were added to the residue, azeotropic distillation was performed, extracted with getyl ether, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude 4-trifluoromethylbenzyl alcohol 41. 78 g were obtained.

Claims

The scope of the claims 1. Formula (I)

(Wherein Ri is alkyl substituted with a fluorine atom and Z or a chlorine atom), wherein the benzyl alcohol is represented by the formula (II):

(Wherein R ¹ is as defined above), and a formula (II I) produced by reacting aryl and magnesium in the presence of a lower haloalkane;

(Wherein, R ¹ is as defined above). A method characterized by reacting with a formaldehyde and Z or a polymer thereof. 2. The method of R ¹ are described in claim 1 is a fluorine atom and Z or alkyl of one to 6 carbon substituted with a chlorine atom. 3. The method according to claim 1 R ¹ is an alkyl having a carbon number of 1 to 6 substituted with a fluorine atom.  4. The method according to claim 1, wherein as the lower haloalkane, one or two or more of alkenes having 1 to 6 carbon atoms substituted with a chlorine atom, a bromine atom or an iodine atom are used.  5. The method according to claim 1, wherein as the lower haloalkane, one or two or more alkenes having 1 to 6 carbon atoms substituted with a chlorine atom or a bromine atom are used.  6. The method according to claim 1, wherein an alkane having 1 to 6 carbon atoms substituted with a chlorine atom and an alkane having 1 to 6 carbon atoms substituted with a bromine atom are used as the lower haloalkane. 7. Magnesium is used in an amount of 1.0 to 5.0 moles per mole of aryl chloride of formula (Π). 2. The method according to claim 1, wherein 0.5 to 4.0 mol of lower haloalkane and 1.0 to 5.0 mol of formaldehyde (in the case of a polymer, in terms of formaldehyde) are used.  8. The method according to claim 1, wherein the Grignard reagent of the formula (II) is reacted with formaldehyde and Z or a polymer thereof in the presence of alcohol.  9. The process according to claim 8, wherein the alkali is used in an amount of 0.01 to 1.0 mol per mol of aryl chloride of the formula (II).  10. The method according to claim 1, which is performed in an atmosphere of an inert gas.  11. The method according to claim 1, wherein the method is performed in the presence of a solvent.  12. The method according to claim 1, wherein after completion of the reaction, the reaction product is hydrolyzed. 1 3 Formula (I)

(Wherein R ¹ is alkyl substituted with a fluorine atom and Z or a chlorine atom), a method for producing benzyl alcohols represented by the formula (II):

(Wherein R ¹ is as defined above) and magnesium are reacted in the presence of a lower haloalkane, and then the resulting reaction mixture is reacted by adding formaldehyde and / or a polymer thereof. A method comprising: