JPS6019740A - Production of 2,3,4,5-tetramethoxytoluene - Google Patents

Abstract

PURPOSE:To produce the titled substance which is a raw material of coenzyme Q10 useful as pharmaceuticals, from 2-bromo-3,4,5-trimethoxytoluene and sodium methylate, in improved quality and yield, without producing by-product, by using a specific mixed solvent. CONSTITUTION:The objective compound is produced by the thermal reaction of 1mol of 2-bromo-3,4,5-trimethoxytoluene with preferably 2-4mol of sodium methylate at 100-145 deg.C in the presence of copper or its compound as a catalyst, in a mixture of methanol and dimethylformamide. The amount of methanol in the mixed solvent is 50-14pts. per 1pt. of dimethylformamide, and the ratio of the mixed solvent to 2-bromo-3,4,5-trimethoxytoluene is preferably 3.0-6.0 to 1.

Description

[Detailed Description of the Invention] This invention relates to organic chemicals,
．． 4.5-Tetramethquine)v-ene is obtained industrially advantageously.

Since 2,3.4.5-tetramethoxytoluene is an important raw material for pharmaceutical coenzyme QIO, it is a challenge for those skilled in the art to obtain it by an industrially advantageous method.

Japanese Patent Publication No. 50-8067 is a representative example of a well-known general method for producing 2,3.4.5-tethomethoxytoluene. This method has drawbacks. Specifically, when an attempt is made to increase the yield rate of the obtained product, the amount of by-product impurities increases, and when an attempt is made to increase the quality of the obtained product, the yield rate decreases.

The present invention is free from these drawbacks and is described in detail below.

The starting materials are 2-bromo-3,4,,5-1-rimethoxytoluene and sodium methylate, which belong to halogenated aromatic compounds. The latter is blended at a ratio of 2 to 4 moles per 1 mole of the former. A specific solvent is added to these starting materials as follows. Specifically, 1 part of 2-bromo-8,4,5-) dimethomocitol (weight,
The same applies hereafter) to 3.0 to 6. os amount of methanol-
Add dimethylformamide mixed solvent to dissolve the starting material.

sol.Xllt,,methanol-dimethylfo! Remami)
-T, and the mixing proportion is 1 part of the latter (
It is necessary that the former be in an amount of 50 to 14 parts by weight (the same applies hereinafter). However, when methanol alone or dimethylformamide is used alone, the desired reaction does not occur. This is a feature of this invention.

A reaction catalyst is interposed in this thread and heated. As the catalyst, copper or its compounds in general are employed. Examples of such materials include copper sulfate, copper powder, copper iodide, copper chloride, and others. The amount used is 1 to 5% by weight of 2-bromo-8,4,5-trimethoxytoluene.

The above mixed yarn is made homogeneous by stirring or using other methods. This homogeneous system is heated to a temperature of 100-145°C. At this time, it is natural that the thread should be a closed system to prevent escape of the solvent. Maintaining this system at a temperature in this range for 4-6 hours provides the desired product. That is, by closed heating, methoxym of Na1-'Jummethyl-1.
-7-rhome-3,4゜5-trimethoxytoluene 1
The target object is generated by exchanging it with 0m.

Here, the purpose of this invention can be achieved.

Some of the functions and effects of snake light will be explained below.

(1) High yield of the target product.

(2) The target product is of high quality with few accompanying by-products of impurities.

(3) The presence of methanol and specified temperature conditions play a decisive role in the reaction.

What is correct about this is described below. This is proven by comparative experimental examples.

Dissolve 25.01 i' of 2-bromophenol in 69 g of dimethylformamide, and dissolve 0.8 i' of cuprous chloride. Then, 19.5% sodium methylate 88P' was added, and the mixture was heated and stirred. Methanol distills out when the temperature of the reaction solution reaches 75°C, and after 1 hour, the temperature of the reaction solution reaches 1.1°C.
Distillation of methanol stops at 5°C. Distillate is 685
? Met.

The dimethylamide was recovered by distillation under reduced pressure, the residue was discharged into water, neutralized with concentrated hydrochloric acid, extracted with 100 m4 of benzene, the extract was dehydrated with anhydrous sodium sulfate, and the benzene was distilled off under reduced pressure.
．． Of P-methoxyphenol was obtained.

8- Content 99.0% Phenol 0.9% Comparative Experimental Example (2) 2-bromo-3,4,5-1-rimethoxytoluene 20
, 91i', dimethylformamide 7.21 cuprous chloride i 0.8 ? 28% sodium methylate in a mixture of 448? When the reaction system is heated and stirred in the open, methanol will reflux when the temperature of the reaction solution reaches 80°C. 80
After reacting at ~81°C for 12 hours, it was cooled to 25°C and the cuprous chloride sodium bromide was filtered off. The filtrate was sized under reduced pressure at 50°C or higher and drained into 50 liters of water.

Extract with 100ml of toluene and analyze the extract using Ganuchromatography. Amount of methanol in the reactants - 82,21 Product composition 2 - Bromo-8,4,5-trimethoxytoluene 3,4
,5-F Lime(-xytoluene 3.3%2, 8,
4. 5-Tetramethoxytoluene 79.3% Comparative Experimental Example (3) Under open conditions, 2-bromo-3,4,5-)rimethoxytoluene 20. 9? , dimethylformamide 7,2
1, 4 - Add 44.81 i' of 28% sodium methylate into a mixture of 0.81 cuprous chloride and stir with heating. After 30 minutes of heating, the temperature of the reaction mixture reaches 80 °C and methanol distills. Start serving. If the mixture is heated and stirred while distilling off methanol, the temperature of the reaction solution will reach 95°C in 10 minutes. 15.0 during this time? of methanol was distilled out. 3 hours, 9
After heating and stirring at 5±1°C, the product was analyzed using Ganuchromatography in the same manner as in Comparative Example (1).

Product composition 2-bromo-8.4.5-)rimethoxytoluene 1.
7% B, 4.5-trimethoxytoluene 8.8%2,
8, 4. 5-tetramethoxytoluene 88.9
% Reactant amount of methanol Reaction liquid temperature 25-80°C 82.2f180-95
°C 82.2F-17.21? 〃95°C 17.2
? Composition when the reaction solution temperature reached 95°C 2, 3, 4. , 5-tetramethoxytoluene 1
4.9% Comparative Experimental Example (4) Comparative Example (21 (Same as 3J), add 19 months and heat and stir.

If heated in an open environment while distilling methanol, the reaction will occur 40 minutes after heating (the temperature will change from 95°C to 110°C
It foams when it reaches the point. One hour and 30 minutes after the temperature reached 95°C, the temperature reached 120°C, and the distillation of methanol stopped. The amount of methanol distilled out was 322 grams. 1 at 130″C
After heating and stirring for an hour, the mixture was cooled to 25°C, dissolved in 100 tnf of water, and extracted with 100 ml of toluene.

Product composition 2-bromo-8,4,5 to trimethoxytoluene 3,4
,5-1-liftoxytoluene 12.3%2, 3,
4, 5-Tetramethoxytoluene 86.9% Composition when the reaction solution temperature reaches 120°C 2-bromo-3.4.5-trimethoxytoluene 3,4
．． 5-1- Lime 1 xytoluene 1
2.3%2, 3, 4. , 5-Tetramethoxytoluene 86.8% Comparative Experimental Example (5) Performed in the same manner as Comparative Example (4) and heated from 95°C to 120° in the open air.
Heating time with reeds to reach C was 2 hours and 20 minutes. The subsequent operations are also performed in the same manner as in Comparative Example (3).

Composition when the reaction solution temperature reaches 120'C 2-brome-3.4.5-1-liftoxytoluene 0%3, 4.5-1-liftoxytoluene 10.
4% 2,8,4.5-tetramethoxytoluene 89.
0% Experimental Example (6) 2-bromo-3.4.5-trimethoxytoluene 8,7
? , dissolve in 19 g of dinotylformamide, add 05 g of cuprous chloride, and finally add 3 drops of powdered sodium methiate, heat, and stir. At 93°C for 10 minutes after heating,
At this temperature, the reaction took place at 10:00, but 2, 3, 4, 5
The absence of -tetramethoxytoluene was confirmed by thin layer chromatography.

Comparative Experiment Example (7) Dissolve 8.72 of 2-brome 8,4,5-1-rif I xytoluene in dimethylformamide 197, add cuprous chloride 052, and finally add powdered sodium 31 and heat and stir. . It reached 130'C in 10 minutes after heating,
React at the same temperature for 1 hour. After cooling, the same procedure as in Comparative Example (4) is carried out, followed by gas chromatographic analysis.

Composition of reactants 2-bromo-3,4.5-trimethoxytoluene 0.
1%B, 4.5-1-rif-1-xytoluene 65
8% 2, 3, 4. 5-tetramethoxytoluene 3
48% Softness Experimental Example (8) lll autoclaved benzene aOO is 112-brom-3, 4. , 5-trimethoxytoluene 54.41
ill.

Dimethylformamide 20 ii', cuprous chloride 1
ft” (r) Add powdered sodium tifut in sequence, and finally
Add 1.61 and seal. Heat to 130'C, stir, and pressurize to 6"j/ct112K. 1 3
After reacting at 0'C for 5 hours, benzene was recovered by vacuum distillation, the residue was poured into 300 tons of water, and 300 tons of toluene was added.
The extract was extracted using a gas chromad.

2-)omu-3,4,5-)liftoxytoluene2.

3, 4, 5-tetramethoxytoluene was not observed.

There was only 4,5-trimethyl-1-xytoluene.

Summary of experimental examples The results of 1 comparative example (21 to (5)) are summarized in Table (1).
Note on 1) Comparative experiment example (4) (5) is 1 8 0'
2-Brom-3,
Since 4,5-)liftoxyto)vene was no longer present, the temperature of the reaction solution was set at 95 to 120°C.

In Comparative Experimental Example (3), the reaction had progressed by the time the reaction solution temperature reached 95°C, but it was relatively small, so it was not considered.

The difference in product composition between Comparative Experimental Examples (4) and (5) is thought to be due to the difference in the time that methanol was present in the reaction yarn.

In Comparative Experiment Examples 2 to 5, the reaction was not carried out in a closed chamber, so the temperature of the reaction solution was determined by the methanol thread present in the chamber, and the result was It shows that things will change.

When methanol is not used, that is, when methanol is not present in the reaction system, there is no reaction at temperatures below 95°C as in Comparative Experimental Example (6), and at 130°C the reaction rate is 3.4 as in Comparative Experimental Example ('7). .5-1-liftoxytoluene is 65.8%
is also generated.

Furthermore, the use of dimethylformamide was reduced and benzene was used instead of methanol (11 JL), and the reaction was carried out at 130°C in an autoclave.

In the specific softness experiment example (8), the target product was not produced and 2-brome-3
Only 8,4,5-trimethoxytoluene, which is produced by deprotation of ,4,5-trimethoxytoluene, was produced.

Example 1 11 Add 300 tnl of methanol to an autoclave and add 54 tnl of 2-bromo, 3,4,5-1-lyftoxy]ruene. 4ii', dimethylforl, amiF' 2 (
l S' JjA copper chloride 1? are added sequentially, and finally 28
%Nat IJum methylate methanol solution 77.2 ?
'zAdd. After sealing, the heating and stirring level reached 12 hours after 1 hour.
5"C and shows a pressure Ir! 6. Okti /-. After reaction at 125-130 °C for 6 hours, cuprous chloride,
Metallic copper and thorium oxide are filtered out, and the filtrate is concentrated under reduced pressure.

Add the residue to 300 tyl of water to dissolve precipitated thorium bromide, and extract once with 800 ml of toluene.

The extract was condensed under reduced pressure to obtain 44.25' of 2.3.4.5-tetramexitoluene as a brown oil.

5 mm of this oil, T1. 2.3.4.5-Tetramethoxytoluene was distilled out at 113°C under reduced pressure to give 42.0 g of 2.8.
4.5-Tetramethoxytoluene is obtained. Purity 97
．． It contains 0.4% of 2-bromo-3,4,5-trimethoxytoluene and 1.8% of 3,4,5-trimethoxytoluene as impurities. The yield was 92.5%.

Claims (1)

[Claims] 2-bromo-3,4,5-trimethoxytoluene, sodium methylate, methanol and dimethylformamide 1
100 in the presence of copper or a copper compound in a mixed solvent of
2, characterized in that it is reacted at a temperature of ~145°C.
, 3.4.5-Tetramethoxy1-)vene production method.