JPS6041074B2 - Method for producing 3-methyl-3-(O-methoxyphenoxy)-benzo-2,4-dioxacyclohexanone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 3-methyl-3-(0-methoxyphenoxy)-benzo-2,4-dioxacyclohexanone represented by formula (1):

The compound represented by formula (1) has a cough effect, an antipyretic effect,
It has anti-inflammatory effects and is a pharmacologically important substance.

The method for producing compound (1) disclosed in Belgian Patent No. 890,731 consists of keeping acetylsalicyloyl chloride at a low temperature (0 to 4°C) in the presence of pyridine to produce a product and 2. - This is a method in which methoxyphenol (common name guaiacol) is reacted.

However, with this manufacturing method, many powders and compounds (
Instead of 1), only 2-methoxyphenyl acetylsalicylate can be obtained. It is believed that while acetylsalicyloyl chloride is kept at a low temperature, acetylsalicyloyl chloride changes into an isomer and reacts with 2-methoxyphenol to produce compound (1). However, the conversion conditions are not deterministic and cannot be reproduced by conventional methods. This drawback at the laboratory stage becomes unacceptable for industrial scale production. Further testing of the production method revealed that Compound (1) could only be obtained in an amount on the order of a few percent, and the yield at that time was extremely low (as described in Examples in Belgian Patent No. 890,731). (says the yield is 31%). As a result of extensive research, the present inventors have discovered a method for producing the compound (1) in a high yield and with high purity.

That is, the production method of the present invention is directed to acetylsalic acid.

chloride with 2-methoxyphenol in a 5 to 3 weight percent excess of the theoretical amount in an inert solvent at a temperature of 40 to 150 °C.
It is characterized in that the reaction is carried out for 12 to 48 hours within a range of 0. Hereinafter, this manufacturing method will be referred to as the first manufacturing method. Next, preferred embodiments of the first manufacturing method of the present invention will be shown.

{a} To a solution of acetylsalicyloyl chloride dissolved in an inert solvent, in the absence of pyridine or other tertiary base, an excess amount (5-30%) of 2-methoxyphenol is added.

'b} The reaction solution is heated within a temperature range of 40 to 150 qo for 12 to 4 hours until the reaction is complete.

The obtained solution is washed with aqueous ammonia and then with water, and the organic layer is evaporated to obtain compound (1) in high yield and purity.

The organic solvent used in this production method may be any inert solvent, and may include aromatic hydrocarbons and aliphatic chlorinated hydrocarbons, such as benzene, toluene, xylene, and chlorine.

Roform, dichloromethane and tetrachloroethane are preferred. Particularly preferred is dichloromethane. The compound (1) further comprises acetylsalicylic acid with the general formula (
0): (wherein R,, R2 and R3 are the same or different and represent a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 carbon atoms) and an anhydride represented by the formula: in an aprotic solvent at a temperature of The reaction is carried out at about 20 to 70 qo, the resulting clear solution is allowed to stand at room temperature for 1 minute to 1 hour, after which a substantial theoretical amount of 2-methoxyphenol is added and the reaction is carried out at a temperature of 1 to 4,000 qo. It can also be obtained in high yield and purity by reacting for 4 hours.

Hereinafter, this manufacturing method will be referred to as a second manufacturing method.Next, preferred embodiments of the second manufacturing method will be described.

(2) Acetylsalicylic acid is reacted with a theoretical amount of an anhydride represented by the above formula (n) in an aprotic solvent, preferably a mutually insoluble solvent with water at a temperature of about 20 to 70 qo.

'b) Leave the resulting clear solution at room temperature for a period of time to 12 hours.

{c- Add a substantially stoichiometric amount of 2-methoxyphenol and let the resulting mixture stand at 10-4000 for 1-4 hours.

The solution thus obtained is dissolved in water, preferably Wash with NaHC03 aqueous solution.

Compound (1) is easily extracted from the organic layer. Anhydrous (
Examples of 0) include acetic anhydride, propionic anhydride,
Butyric anhydride, isobutyric anhydride, dichloroacetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride or anhydride Q,Q-
One or more selected from the group consisting of dichloropropionic acids can be used, with trichloroacetic anhydride or trifluoroacetic anhydride being particularly preferred.

Moreover, benzene, toluene, and xylene are preferable as the solvent. All of the production methods of the present invention are reproducible and can produce compound (1) in extremely high yield and purity.

Examples are shown below, but the present invention is not limited only to these examples.

Example 1 Acetyl salicyloyl chloride 6 was added to the reactor of the customer.
．． 5.66 kg (45.6 mol) of 2-methoxyphenol dissolved in 8 kg (34.2 mol) and 22 mol of dichloromethane.
mole) was added.

This solution was heated at reflux temperature for 4 hours. Thereafter, the heating was stopped and the reaction mixture was allowed to cool to room temperature, and 10 ml of 10% ammonium hydroxide was added thereto and completely stirred. The organic layer was separated, washed with water, washed, and the organic layer was separated again. The organic layer was evaporated under reduced pressure to leave an oily residue.
．． I earned 74k9. The oily residue solidified upon addition of chilled ethanol. The obtained Zanko 6.80k9 was recrystallized from ethanol to obtain 5.70 kg (yield 58%) of Compound (1) as a purified product. The melting point of this thing is 73
~7400. This purified product had identical spectroscopic and qualitative analytical data to the commercial sample. Example 2 Tetrac in place of dichloromethane.

An experiment was conducted in the same manner as in Example 1 except that Roetan 20 was used. After heating at a temperature of 100 oo for 48 hours, the compound was obtained in a yield of 60% by recrystallization from isopropanol. The melting point of this product was 72 to 74 oo, and when analyzed by TLC (thin layer chromatography), the same analysis results as the commercial product were obtained. Example
3 An experiment was conducted in the same manner as in Example 1, except that toluene 22 was used instead of dichloromethane.

Heated at reflux temperature for 3 hours to obtain compound (1) in 57% yield.
It came out. The melting point of this product was 72-7400. T
It was analyzed by LC and confirmed to be compound (1). Example 4 60 kg of benzene, 9 k9 of acetylsalicylic acid, and 15.54 kg of trichloroacetic anhydride were added.

The temperature was gradually increased to 45 qo and maintained at this temperature for 15 minutes, resulting in a clear solution.Heating was stopped and after 2 hours of standing, 6.2k9 of 2-methoxyphenol was added. After leaving it for one hour at room temperature, 50k9 ice chips and 200ml of 5% NaHC03 aqueous solution were added while stirring vigorously. The organic layer was separated and the organic layer consisting of a benzene solution was evaporated under reduced pressure to obtain an oily clayey product. Add 40 liters of high temperature isopropanol to this clayey rice, and add about 100
I left it at 0. Compound (1) 8.5k9 (yield 55%) was obtained from this isopanol by recrystallization. The melting point of this product is 72 to 74°C, and it was analyzed by TLQ,
It was confirmed that it was the same as a commercially available sample. Example
5 An experiment was conducted in the same manner as in Example 4, except that substantially the same equivalent amount (5.6k9) of acetic anhydride was used in place of trichloroacetic anhydride.

Compound (1) 6.32k9 (yield 41.1%) was obtained by recrystallizing the residue from isopropanol.
It was analyzed by TLC and confirmed to be compound (1). Example 6 An experiment was conducted in the same manner as in Example 4 except that toluene was used instead of benzene.

After adding 2-methoxyphenol, the reaction solution was left to stand for 24 hours, yielding 9.44 kg of compound (1) (yield 61.3%).
) got it.

This product had the same TLC data as the commercially available sample. Example 7 Anhydrous Trichlor.

An experiment was carried out in the same manner as in Example 4, except that trifluoroacetic anhydride 10.5k9 was used instead of acetic acid, and the compound (
1) was obtained in 8.61k9 (yield 56%). This product had the same TLC data as the commercially available sample. Example 8 Example 4 except that toluene was used instead of benzene and propionic anhydride was used instead of trichloroacetic anhydride.
An experiment was carried out in the same manner as above, and compound (1) was
g (yield 38.6%).

Claims (1)

[Claims] 1. Acetylsalicyloyl chloride in a theoretical amount of 5 to 3
Formula (I) characterized by reacting with 0% by weight excess of 2-methoxyphenol in an inert solvent at a temperature of 40 to 150°C for 12 to 48 hours: ▲ Numerical formula, chemical formula,
There are tables etc. 3-methyl-3-(O-
Method for producing (methoxyphenoxy)-benzo-2,4-dioxacyclohexanone. 2. The production method according to claim 1, wherein the inert solvent is an aromatic hydrocarbon or an alicyclic chlorine hydrocarbon. 3. The manufacturing method according to claim 1, wherein the inert solvent is dichloroethane. 4. The production method according to claim 1, wherein the reaction is carried out at the reflux temperature of the reaction solution. 5 Acetylsalicylic acid is expressed by the general formula (II): ▲ Numerical formulas, chemical formulas, tables, etc. ) in an aprotic solvent at a temperature of about 20 to 70°C, and the resulting clear solution is left at room temperature for 10 minutes to 12 hours, after which substantially no 2-methoxyphenol is removed. Formula (I) is characterized by adding a theoretical amount and reacting at a temperature of 10 to 40°C for 1 to 48 hours. 3-Methyl-3-( A method for producing O-methoxyphenoxy)-benzo-2,4-dioxacyclohexanone. 6. The production method according to claim 5, wherein the anhydride represented by the general formula (II) is acetic anhydride, trichloroacetic anhydride, or trifluoroacetic anhydride.