JPS644500B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 3,4,5-trialkoxybenzyl halides.

3,4,5-Trialkoxybenzyl halide is a compound useful as a raw material for synthesizing pharmaceuticals such as teliperim. Conventional 3, 4,
As a method for producing 5-trialkoxybenzyl halide, for example, 3,4,5
- A method is known in which trialkoxytoluene is irradiated with ultraviolet rays to cause halogen to undergo a heating reaction. However, this method requires expensive radical catalysts, ultraviolet irradiation equipment, etc., undesirable side reactions also occur, and the yield is low at about 40-50%, making it an industrially disadvantageous method. .

The present invention provides an industrially advantageous method for producing 3,4,5-trialkoxybenzyl halide, which has the general formula [In the formula, R ₁ and R ₂ are the same or different and represent a lower alkyl group] A cyclohexadiene derivative represented by the following is reacted with hydrogen halide or hydrohalic acid in a solvent to obtain the general formula [In the formula, X represents a halogen atom. R ₁ is the same as above. ] A 3,4,5-trialkoxybenzyl halide represented by
Relates to a method for producing trialkoxybenzyl halide.

The method of the present invention is extremely advantageous for the industrial production of 3,4,5-trialkoxybenzyl halide. That is, according to the present invention, the target compound can be obtained by simple operations under mild conditions and without using special reagents. Furthermore, the yield of the target compound is as high as about 90% or more, and the target compound can be isolated and purified from the reaction mixture to a high degree of purity by simple operations.

The cyclohexadiene derivative represented by the general formula () used as a starting material in the present invention is a new compound, for example [In the formula, R ₁ is the same as above. ] 3, 4,
It can be produced with a high yield of 90% or more by electrolyzing 5-trialkoxytoluene in a solvent in the presence of a neutral to alkaline supporting electrolyte.

3,4,5-trialkoxytoluene represented by the general formula () is a known compound that is easily available, such as 3,4,5-trimethoxytoluene,
Examples include 3,4,5-triethoxytoluene. Examples of the organic solvent used in the above electrolytic reaction include lower alcohols such as methanol and ethanol, but the amount used is preferably in the range of 500 ml to 15 ml per 1 mole of compound (), and approximately 5 to 10 ml is used per mole of compound (). Particular preference is given to using amounts. Compounds used as supporting electrolytes include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkali metals such as sodium and potassium; and tetraalkylammonium hydroxides such as tetramethylammonium hydroxide and tetraethyl. Alkali metal salts of aliphatic carboxylic acids such as ammonium hydroxide, tetrapropylammonium hydroxide, and tetrabutylammonium hydroxide include sodium formate,
Examples of alkali metal fluorides such as sodium acetate include sodium fluoride and potassium fluoride. The amount used is preferably in the range of about 0.01 to 1 mol, particularly preferably in the range of 0.1 to 0.5 mol, per 1 mol of compound (). Electrode materials include titanium, platinum, carbon, lead dioxide, nickel, iron, stainless steel, etc. for the anode, and platinum, carbon, titanium, nickel, etc. for the cathode.
It is preferable to use iron, stainless steel, etc. Also, the current density, which is most important for electrolysis, is approximately 1 to 200 m
It is carried out in the range of A/ ^cm2 , preferably about 5 to
It is in the range of 100mA/ ^cm2 . Further, the applied voltage is greatly influenced by the amount of supporting electrolyte added, but in the electrolytic reaction, it may be in the range of about 1.5 to 15V, and more preferably in the range of about 2 to 5V.
The electrolysis temperature should be in the range of about -10 to 50℃, but it should be about 10 to 50℃.
Preferably it is carried out at 30°C.

A wide variety of known hydrogen halides or hydrohalic acids can be used in the present invention. Examples of hydrogen halides include hydrogen chloride, hydrogen bromide, and hydrogen iodide, and examples of hydrohalic acids include hydrochloric acid, hydrobromic acid,
Examples include hydriodic acid. These hydrogen halides or hydrohalic acids are raw materials for producing the compound of the -acid formula (), and also act as catalysts themselves. Therefore, hydrogen halide or hydrohalic acid is preferably used in at least an equimolar amount, preferably an equimolar to 2 times the molar amount of the compound of general formula ().

The solvent used in the present invention is not particularly limited as long as it is inert to the starting materials and target compound, but examples include ethers such as ethyl ether, tetrahydrofuran, and dioxane;
Examples include halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, alcohols such as methanol and ethanol, and aromatic hydrocarbons such as benzene and toluene. Especially cyclic ethers such as tetrahydrofuran and dioxane,
Preferred are halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride.

In the present invention, the form of the reaction may be either a homogeneous reaction system or a heterogeneous reaction system. Reaction temperature is usually 0-100
It is about ℃.

The compound of general formula () thus obtained can be purified by commonly known methods such as concentration, extraction, distillation, recrystallization, column chromatography, etc.

The present invention will be explained below with reference to reference examples and examples.

Reference example Anode: platinum, cathode: platinum electrodes with an electrode area of 3 cm ² were immersed in a solution of 182 mg of 3,4,5-trimethoxytoluene and 20 mg of sodium hydroxide dissolved in 10 ml of methanol, and the electrodes were immersed with stirring at room temperature. 30mA
Electrolysis is carried out at a constant current of up to 3F/mole. The terminal voltage at this time is 3.5 to 3.7V. After electricity is applied, the reaction solution is concentrated under reduced pressure. The residue was extracted with dichloromethane, and the extract was concentrated under reduced pressure to recover 255 mg of a crude product. By purifying this crude product with an alumina column (benzene: ethyl acetate = 10:1), 224 mg of 1,3,5,6,6-pentamethoxy-3-methyl-1,4-cyclohexadiene was obtained as white crystals. obtained as. This amount was 92% of the theoretical yield. This compound was confirmed by NMR.

NMR (CDCl ₃ ) δ1.44 (s, 3H, CH ₃ C) 3.13 (s, 3H, CH ₃ O) 3.18 (s, 3H, CH ₃ O) 3.30 (s, 3H, CH ₃ O) 3.68 (s , 6H, CH ₃ O-C=) 4.98 (s, 2H, HC=) Example 1 244 mg of 1,3,5,6,6-pentamethoxy-3-methyl-1,4-cyclohexadiene and 2 ml of chloroform Add 200mg of concentrated hydrochloric acid to the mixed solution,
Stir for 1 hour at room temperature. After the reaction, the organic layer is separated, washed with an aqueous sodium bicarbonate solution, and concentrated under reduced pressure. 210 mg of oily crude product is recovered. This crude product was purified with a silica gel column (benzene:hexane:ethyl acetate=10:10:1) to obtain 203.5 mg of 3,4,5-trimethoxybenzyl chloride. This amount corresponds to 94% of the theoretical yield. This compound was confirmed by NMR.

NMR (CDCl ₃ ) δ3.83 (s, 3H, OCH ₃ ) 3.86 (s, 6H, OCH ₃ ) 4.51 (s, 2H, -CH ₂ -) 6.56 (s, 2H, H-Ar) Example 2 Implementation 3,4,5-
235 mg of trimethoxybenzyl bromide was obtained. This amount corresponds to 90% of the theoretical yield. This compound was confirmed by NMR.

NMR (CDCl ₃ ) δ3.84 (s, 3H, OCH ₃ ) 3.86 (s, 6H, OCH ₃ ) 4.36 (s, 2H, -CH ₂ -) 6.60 (s, 2H, H-Ar) Example 3 1 , 200 mg of concentrated hydrochloric acid was added to a mixed solution of 314 mg of 3,5,6,6-pentaethoxy-3-methyl-1,4-cyclohexadiene and 2 ml of chloroform.
In the same manner as in Example 1, 240 mg of 3,4,5-triethoxybenzyl chloride was obtained. This amount corresponds to 93% of the theoretical yield. This compound is NMR
Confirmation was carried out by

NMR (CDCl ₃ ) δ1.32 (t, 9H, CH ₃ ) 4.00 (q, 2H, −CH ₂ O−) 4.03 (q, 4H, −CH ² O−) 4.50 (s, 2H, −CH ₂ Cl ) 6.55 (s, 2H, H-Ar) Example 4 In Example 3, 47% hydrobromic acid was used instead of concentrated hydrochloric acid, and the same treatment was performed except for 3, 4, 5.
-276 mg of triethoxybenzyl bromide was obtained.
This amount corresponds to 91.5% of the theoretical yield. This compound was confirmed by NMR.

NMR (CDCl ₃ ) δ1.30 (t, 9H, CH ₃ ) 3.99 (q, 2H, −CH ₂ O−) 4.01 (q, 4H, −CH ₂ O−) 4.34 (s, 2H, −CH ₂ Br ) 6.58 (s, 2H, H-Ar)

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ and R ₂ are the same or different and represent a lower alkyl group. ] A cyclohexadiene derivative represented by the general formula [In the formula, X represents a halogen atom. R ₁ is the same as above. ] A 3,4,5-trialkoxybenzyl halide represented by
Method for producing trialkoxybenzyl halide. 2. The method according to claim 1, wherein the solvent is a cyclic ether such as tetrahydrofuran or dioxane, or a halogenated hydrocarbon such as methylene chloride, chloroform, or carbon tetrachloride. 3. The method according to claim 1 or 2, wherein the hydrogen halide is hydrogen chloride or hydrogen bromide. 4. The method according to claim 1 or 2, wherein the hydrohalic acid is hydrochloric acid or hydrobromic acid. 5. The method according to any one of claims 1 to 4, wherein the reaction is carried out at 0 to 100°C.