KR850001225B1 - Process for preparing 3-methyl-3-(o-methoxyphenoxy)-benzo-2,4-dioxacyclohexanone - Google Patents

Abstract

Prepn. of 3-methyl-3-(o-methoxyphenoxy) benzo-2,4- dioxacylchlohexanone of formula (I) is claimed. One process comprises reacting acetylsalicycloyl chloride (II) with a 5-30 wt.% stoichiometric excess of 2-methoxyphenol (III) in an inert solvent at 40-150≰C for 12-48hrs. Another process comprises (a) reacting acetylsalicyclic acid with an anhydride (IV) of formula (R1R2R3C-CO)2O (where R1-R3 are H, halogen or C1-3 alkyl) in an aprotic solvent at 20-70≰C until a clear soln. is obtained; (b) allowing the mixt. to stand at room temp. for 7-720 min.; and (c) reacting the mixt. with a storichiometric amt. of (III) for 10-40 min.

Description

Method for preparing 3-methyl-3- (0-methoxyphenoxy) -benzo-2, 4-dioxacyclohexanone

The present invention provides a novel method for the preparation of 3-methyl-3- (0-methoxyphenoxy) -benzo-2, 4-dioxa cyclohexanone of the following structural formula (I) showing antitussive action, antipyretic action and anti-inflammatory action. It is about.

The compound was conventionally prepared by reacting 2-methoxyphenol (guaiacol) with acetylsalicyloyl chloride in the presence of pyridine and keeping the product obtained at low temperature (0-4 ° C.). (Belgium Patent 890,731)

In most cases, however, it has been found that when carried out as described in the above mentioned Belgian patent, 2-methoxyphenyl acetylsalicylate is obtained instead of the compound of formula (I). While apparently at low temperatures, acetylsalicyloyl chloride is sometimes converted to isomers to form compounds of formula (I) with 2-methoxyphenol. This conversion, however, depends on indeterminate conditions and does not exhibit leading edge reproducibility in conventional manner. This is a drawback of the laboratory method and cannot be solved even if the compound of formula (I) is prepared on an industrial scale. In fact, the compounds of formula (I) are obtained only in some cases, and even in very low yields. (According to the method described in the examples of the Belgian patent mentioned above, the yield here is 31%).

It has now been found that the present invention can produce the compound of formula (I) in high yield by the following simple method, and this method also shows complete reproducibility.

a) an excess (5-30%) of 2-methoxyphenol is added to a solution of acetylsalicylosyloyl chloride in an inert organic solvent in the absence of pyridine or other tertiary base,

b) The reaction mixture is heated to a temperature of 40 ° to 150 ° C. for 12 to 48 hours to complete the reaction.

The reaction solution is washed with aqueous ammonia, followed by water and the organic layer is evaporated to yield the desired product in a yield and high purity significantly higher than the yields according to the prior art. Suitable organic solvents for this process include in principle all solvents which are inert under the reaction conditions. Among them, arene and aliphatic chlorohydrocarbons such as benzene, toluene, xylene, chloroform, dichloromethane and tetrachloroethane are advantageous. Dichloromethane is particularly preferred.

Structural formula (I) compounds can also be prepared and obtained in high yield and high purity as follows.

a) acetylsalicylic acid is reacted in an almost stoichiometric amount with the anhydride of the following formula (II) in an aprotic solvent, preferably in a water immiscible solvent at 20 ° to 70 ° C. to produce a clear solution,

(Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen, halogen or an alkyl group of 1 to 3 carbon atoms)

b) let this solution stand at room temperature for 10 minutes to 12 hours,

c) To this is added an almost stoichiometric amount of 2-methoxyphenol and the mixture is left at about 10-40 ° C. for 1 hour to 48 hours.

This solution is washed with water (or aqueous NaHCO ₃ solution is preferred) to recover compound (I) from the organic phase without difficulty.

Examples of anhydrides (II) that can be used are acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, dichloroacetic anhydride, trichloroacetic anhydride, α, α-dichloropropionic anhydride and corresponding mixed anhydrides. Among them, trichloroacetic anhydride and trifluoroacetic anhydride are preferable. As the solvent, benzene, toluene and xylene are preferable.

The advantage of the method according to the invention is that it exhibits complete reproducibility and a markedly improved yield. The following examples are intended to further illustrate the invention and do not limit it.

Example 1

6.8 kg (34.2 moles) of acetylsalicyl chloride and 5.66 kg (45.6 moles) of 2-methoxyphenol in 22 l of methylene chloride are placed in a 50 l reactor. The solution is heated to reflux for 48 hours. The heating is stopped, the reaction mixture is cooled to room temperature and 10 l of 10% ammonium hydroxide is added with vigorous stirring. The phases are separated, the organic phase is washed with water and stirred before the phases are separated again. The organic phase is evaporated under reduced pressure to yield 9.74 kg of oily residue. Cold ethanol is added to initiate solidification of the product. This yields 6.80 kg of crude product which is recrystallized from ethanol to give 5.70 kg (58%) of very pure product having a melting point of 73 to 74 ° C. Examination of this by spectroscopic and elemental analysis confirms that it is a single substance and identical to a commercially available sample.

Example 2

It is carried out in almost the same manner as in Example 1 except using 20 l of tetrachloroethanol reaction solvent. After 48 h heating at 100 ° C., recrystallization from isopropanol affords the product (I) in 60% yield. Melting point 72-74 ° C. TLC analysis showed that the sample was a single substance.

Example 3

The same process as in Example 1 was carried out except that toluene (22l) was used as the reaction solvent. Heat to reflux for 36 hours and complete in conventional manner to afford product (I) with a melting point of 72 to 74 ° C. in 57% yield.

According to TLC analysis, the sample is a single substance.

Example 4

To 60 l of benzene is added 9 kg of acetylsalicylic acid and 15.54 kg of trichloroacetic anhydride. Gradually raising the temperature to 45 ° C. yields a clear solution after about 15 minutes at this temperature. The heating is stopped, the reaction mixture is left for about 2 hours and 6.2 kg of 2-methoxyphenol is added. After 10 hours at room temperature, 50 kg of ice cubes and 200 l of 5% aqueous NaHCO ₃ solution are added with vigorous stirring. After phase separation, the benzene solution is finally evaporated under reduced pressure to give a viscous oil. The residue is dissolved in 40 l of thermal isopropanol and left to stand at about + 10 ° C. Crystallization yields 8.5 kg (55%) of product (I), which according to TLC is a single material, identical to commercial samples. Melting Point 72 ~ 74 ℃

Example 5

Performed in the same manner as in Example 1 except using almost equivalents (5.6 kg) of acetic anhydride in place of trichloroacetic anhydride. The residue is recrystallized from isopropanol to give 6.32 kg (41.1%) of compound (I) which is homogeneous by TLC.

Example 6

Performed in the same manner as in Example 1, except that benzene is used instead of toluene. After addition of 2-methoxyphenol, the reaction mixture is allowed to stand for 24 hours. 9.44 kg (61.3%) of Compound (I) are obtained.

Example 7

In the same manner as in Example 1, using trifluoroacetic anhydride (10.5 kg) instead of trichloro acetic anhydride yields 8.61 kg (56%) of the desired compound.

Example 8

5.95 kg (38.6%) of Compound (I) is obtained using toluene instead of benzene and propionic anhydride instead of trichloroacetic anhydride in the same manner as in Example 1.

Claims (6)

The acetylsalicyloyl chloride was reacted with an excess of 5 to 30 percent (by weight) of theory with 2-methoxyphenol at 40 to 150 ° C. for 12 to 48 hours in an inert solvent. 3-Methyl-3- (0-methoxyphenoxy) -benzo-2, 4-dioxane cyclohexanone.

The method of claim 1, wherein an aromatic hydrocarbon or an aliphatic chlorinated hydrocarbon is used as a solvent. The method of claim 1 which is used as a dichloromethanol solvent. The process of claim 1 wherein the reaction is carried out at the reflux temperature of the mixture. Acetylsalicylic acid is then reacted with anhydride of formula (II) in an aprotic solvent at about 20 to 70 ° C. to produce a clear solution which is left at room temperature for 10 minutes to 12 hours and finally the mixture is about 10 ° 3-Methyl-3- (0-methoxyphenoxy) -benzo-2, 4 of Structural Formula (I), including reaction with an almost stoichiometric amount of 2-methoxyphenol at about 40 ° C. for 1 to 48 hours. A process for producing dioxa cyclohexanone.

(In the general formula, R ¹ , R ² and R ³ are the same as or different from each other, and represent hydrogen, halogen or alkyl group having 1 to 3 carbon atoms.) The process according to claim 5, wherein acetic anhydride, trichloroacetic anhydride and trifluoroacetic anhydride are used as the anhydride.