Synthesis of (phenylalkyloxy)phenyl-oxobutanoic acids
View Patent ↗A method for synthesizing (phenylalkyloxy)phenyl-oxobutanoic acid compounds is described. The corresponding (phenylalkyloxy)acylphenyl compound is halogenated, giving the alpha haloketone. The halide is displaced by the anion of a di-alkyl malonate to give a substituted malonic ester. Hydrolysis of the ester and decarboxylation of the diacid gives the desired product.
1. A method for producing a compound of Formula I
wherein
n is 1, 2 or 3;
R 1 and R 2 are each independently selected from the group consisting of halo, alkyl having one or two carbon atoms, perfluoromethyl, alkoxy having one or two carbon atoms, perfluoromethoxy, and hydroxy;
comprising:
(a) reacting the corresponding compound of Formula II with a halogenating agent in an ethereal solvent to yield crude compound of Formula III, wherein X is fluoro, chloro, bromo or iodo;
(b) reacting the compound of Formula III from the previous step with a malonate ester represented by the formula R 3 OC(O)CH 2 C(O)OR 3 and a base in a solvent, wherein the solvent comprises an alcohol represented by the formula R 3 OH, wherein R 3 is lower alkyl, to yield a crude preparation of the compound of Formula IV;
(c) hydrolyzing the compound of Formula IV from step (b) to yield the compound of Formula V; and
(d) decarboxylating the compound of Formula V from the previous step to yield the compound of Formula I.
2. The method of claim 1 , wherein the compound of Formula I is 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid.
3. A method for producing 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid, comprising:
(a) reacting 3-(2,6-dimethylbenzyloxy)acetophenone with bromine in dioxane/di-n-butyl ether at about 0° C. to yield 2-bromo-1-(3-(2,6-dimethylbenzyloxy)phenyl)ethanone;
(b) reacting the 2-bromo-1-(3-(2,6-dimethylbenzyloxy)phenyl)ethanone from the previous step with diethyl malonate and a base in THF/ethanol to yield a crude preparation of diethyl 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonate;
(c) treating the diethyl 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonate from step (b) with sodium hydroxide in water/ethanol at about +50° C. to yield a solution comprising 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid;
(d) extracting the 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid from the solution produced in step (c);
(e) heating the 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid from step (d) in toluene at reflux to yield a solution comprising 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid;
(f) extracting the 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid from the solution to yield isolated 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid.
4. The method of claim 3 , further comprising triturating the crude 2-bromo-1-(3-(2,6-dimethylbenzyloxy)phenyl)ethanone from step (a) in methanol to yield solid 2-bromo-1-(3-(2,6-dimethylbenzyloxy)phenyl)ethanone.
5. The method of claim 3 , where in step (b) the base is sodium ethoxide.
6. A method for producing diethyl 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonate, comprising reacting 2-bromo-1-(3-(2,6-dimethylbenzyloxy)phenyl)ethanone with diethyl malonate and a base in a solvent, wherein the solvent comprises ethanol, to yield a crude preparation of diethyl 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonate.
7. The method of claim 6 , wherein the base is sodium ethoxide.
8. The method of claim 6 , wherein the reaction is performed in THF/ethanol as solvent.
9. A method for producing 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid, comprising hydrolyzing diethyl 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonate to yield a solution comprising 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid.
10. The method of claim 9 , wherein the hydrolysis is performed by treating the diethyl 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonate with sodium hydroxide in water/ethanol and at a temperature of from +30° C. to +80° C.
11. The method of claim 10 , wherein the hydrolysis is performed at a temperature of about +50° C.
12. The method of claim 9 , further comprising extracting the 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid from the solution.
13. A method for producing 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid, comprising:
(a) decarboxylating 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid to yield a solution comprising 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid; and
(b) crystallizing or extracting the 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid from the solution to yield isolated 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid.
14. The method of claim 13 , wherein the decarboxylation of step (a) is performed by heating the 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid in toluene at reflux.