NL8202354A - PROCESS FOR PREPARING 3-MEHTYL-3- (O-METHOXYPHENOXY) -BENZO-2,4-DIOXACYCLOHEXANONE. - Google Patents

Description

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Process for the preparation of 3-methyl-3- (o-methoxyphenoxy) -benzo-2, if-dioxa-cyclobexanone.

The. The invention relates to a new improvement process for the preparation of 3-nonhyl-3-Co-methoxyphenoxy-benzo-2, U-dioxacyclohexanone according to formula 1 of the formula sheet.

This compound is of significant pharmaceutical origin. is long because of its anti-cough, anti-pyretic and anti-inflammatory properties. (according to Belgian Pat. No. 890,731) by reacting 2-methoxyphenol (guaiacol) with acetylsalcyloyl chloride in the presence of pyridine, the product obtained being kept at low temperature (0 - U ° C).

10 More has been observed. that if, in accordance with the prescription of. The above-mentioned Belgian patent specification proceeds in most cases 2-methoxy-phenylacetylsalicylate is obtained in plants of the compound of formula T.

Apparently it is. during the residence time at low temperatures, the acetylsalicyloyl chloride is sometimes converted into an isomer, which gives the compound of formula .1 with 2-metboxyphenol; however, this conversion has been found to depend on undetermined conditions and is thus not reproducible in a regular manner.

This is already a drawback on laboratory scales, but when the preparation according to formula 1 is carried out on an industrial scale, this cannot of course be tolerated.

Furthermore, experience has shown that compound (1) is only obtained in a limited number of reactions carried out, while in such cases the yield is also very low (as shown in the example of the aforementioned Belgian patent specification which yields a yield of $ 31.00k). ).

It has now been found that a compound of formula 1 can be prepared in higher yields in a fully reproducible manner and by a simple operation when one proceeds as follows: a) a solution of acetylsalicyloyl chloride in an inert organic solvent is used. an excess (5-30 $) of 2-metboxyphenol added in the absence of pyridine or other tertiary base; 8202354 Λ -4 · "" "1 '" "~ Γ ~"' "........

'; ! 2 b) the reaction mixture is heated to a temperature of 12 hours for a period of 12-8 hours. kQ - 150 ° C, until the reaction is completed. /

The reaction solution is washed with aqueous Annno-5 Niak, then with water; the organic layer is evaporated, whereby bet; the desired product is obtained in a yield which is considerably higher than the known yields and also in a very good purity.

The organic solvents used for this process are in principle all solvents which are inert under the reaction conditions.

Aromatics. and aliphatic chlorinated hydrocarbons, such as benzene, toluene ,. xylene, chloroform, dichloromethane and tetrachloroetane are favorable. Dichloromethane is particularly preferred.

Optionally. the compound of formula 1 can be obtained in good yield and purity by feeding the preparation as follows: a) acetylsalicylic acid is used with a substantially stoichiometric amount of an anhydride according to formula 2 of the formula-12 sheet ( wherein R, R and S ', which may be the same or different, represent hydrogen or halogen or alkyl groups having 1 to 3 carbon atoms), in an aprotic solvent - preferably immiscible with water - at a temperature of about 20 - 10 ° C reacted until a clear solution is obtained .; b) this solution is left at room temperature for a period of time ranging between 10 minutes and 12 hours; c) a substantially stoichiometric amount of 2-methoxy-phenol is added, then the mixture is allowed to stand at a temperature ranging from about 10 to 10 ° C for a time period ranging from 1 to 8 hours.

The solution was then washed with water (or preferably with an aqueous HaHCO2 solution) and the compound of formula 1 is taken from the organic phase without any effort.

Useful anhydrides of formula 2 are e.g. anhydrides derived from: acetic acid, propionic acid, butyric acid, isobutyric acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, α, α-dichloro-propionic acid; as well as the oven-derived mixed anhydride thereof. Tri- 8202354 ~ “i -. i; :; w5 * ** "I 3!; chloroacetic anhydride and trifluoroacetic acid tiaranhydride are preferred.

i. Preferred solvents are henzene, toluene and xylene.

The method of the invention has. the advantage: dab on. a fully reproducible manner a. considerably. better yield is obtained. The following non-limiting examples are provided for further explanation. the invention.

. Example I

6.8 kg (34.2 mol) of Acetylsalicyl chloride and 5.66 kg (45.6 mol) of 2-methoxyphenol in 22.1 methylene chloride were charged in a reactor; 10 with a volume of 5 (L.liter.

The thus obtained. solution was heated to reflux temperature for 8 hours. Then the heating was stopped, the reaction mixture cooled to room temperature and 10 l of 10% fs ammonium hydroxide added thereto under thorough stirring. The. phases were separated, the organic phase was washed with water and the. phases were separated again after stirring. The organic phase was then evaporated under reduced pressure to give 9.74 kg. an oily residue was obtained. Addition of cold ethanol caused the product to solidify. Thus, 6.80 kg of crude product was obtained, which was obtained. ethanol was recrystallized after which. 5.70 kg (5 &%) of a very seed product was obtained. Melting point 73 - 74 ° C. The product is spectroscopic and analytical single and identical to a commercial sample.

Example II

The reaction was carried out in the same manner as in Example I, but using 20 L of tetrachloroethane as the reaction solvent. Ha. heat on a. temperature of 100 ° C, the product of formula 1 was obtained with a yield of 60%. by recrystallization from isopropanol. Melting point 72-74 ° C; sample in TLC single ..

Example III

The reaction was run as in Example J, but the reaction solvent was toluene (22 L). It was heated to the reflux temperature for 36 hours. The usual work-up gave the product of the formula 1 in a yield of 5Ί%. Melting point J2 - 74 ° C. Sample 35 in TLC. single.

8202 3 54 fc * _ _} j -. - ''. -; t ·; ! «L! ! i - * i; k 'Example IV · ______! 6 liters of benzene were then mixed with 9 kg of acetylsalic cyclic acid and 15 5 kg of trichloroacetic anhydride. The temperature was slowly increased to C5 ° C; after about 15 minutes at this temperature a more bubble solution is obtained. The bitterness was stopped, the reaction mixture was left to stand for 2 hours, after which 6.2 kg of 2-metboxyphenol was added. - - i; I.

| ; After standing for 1.0 hours. evaporated at room temperature. 50 kg fine. - '| ! . : Make ice and add 200 l of a 5% aqueous solution of NaHCO4 with vigorous stirring. After phase separation, the benzene-containing solution is evaporated under reduced pressure until an oily residue is obtained. This was incorporated in Uo 1 bete isopropanol, after which it was bet. mixture at about + -10 ° C. standing. 8.5 kg (55%) of the product of formula 1 were obtained by crystallization melting point

72-7C ° C; single in TLC. and identical to a commercial sample. Example V

The reaction. carried out. according to example 17 sail - with the: replace tricloroacetic acid anhydride with a substantially equivalence quantity (5 * 6 kg) acetic anhydride. By recrystallization of the residue. 6.32 kg (C1, 1.1) of a compound of formula 1, obtained singly in TLC, were obtained from isopropanol.

Image VI

The reaction was carried out according to example ΓΥ using toluene instead of benzene.

25 Ha of addition of 2-metboxyphenol was allowed to proceed to the reaction mixture. stand for 2k hours. 9SWkg (61.3%) of the compound of formula 1 was obtained.

Example VII

The reaction was carried out according to example IV,

Replace the trifluoroacetic acid aydride (10.5 kg) in the case of tricloroacetic anhydride. 8.61 kg (56%) of the first compound was obtained. Example VIII

The reaction is carried out according to example IV, using toluene instead of benzene. and propionic anhydride in place of tricloroacetic anhydride. 5.95 kg (36.6%) of the compound of formula 1 were obtained.

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Claims (3)

2. Method of working according to claim 1, characterized in that / -; the solvent is an arcmatic hydrocarbon or an aliphatic chlorinated hydrocarbon :. The method of claim 1. with the attribute ,. that the solvent is dichloromethane. b. Method according to claim 1, characterized in. that the reaction is carried out at the reflux temperature of the mixture. 5 *. Method for the preparation of var.: 3-methyl-3- (o-methoxyphenoxy) -benzo-2 + dioxacyclohexanone according to formula 1. characterized in that acetylsalicylic acid is reacted in an aprotic solvent at an temperature of 20 DEG-10 DEG C. with an anhydride of formula 2, wherein R, R and R, which may be the same or different, are hydrogen or halogen or alkyl groups of 1 to 3 carbon atoms until a clear solution is obtained; The mixture thus obtained is allowed to stand at room temperature for 10 minutes to 12 hours and the said mixture is finally reacted at a temperature of about 10 to about 0 ° C for a time period ranging from 1 hour to hours. substantially stoichiometric amount of 2-25 methoxyphenol. 6. Process according to claim 5, characterized in that acetic anhydride, trichloroacetic anhydride and trifluoroacetic anhydride are used as the anhydride. —8202 3 54 --------