The present invention relates to a method for producing o-alkoxybenzoic acid. More specifically, the present invention relates to a method for producing o-monoalkoxybenzoic acid or o-dialkoxybenzoic acid, being useful as intermediates for pharmaceutical agents, agricultural chemicals, dyes, fragrances and the like and useful as functional pharmaceutical agents such as a second pharmaceutical solution for dental cement, components of adhesive agents and the like.
The following methods have conventionally been known as techniques for producing o-monoalkoxybenzoic acid as an o-alkoxybenzoic acid;
1. A method represented by a reaction formula (1) ##STR1## (wherein R represents a methyl-, ethyl-, propyl-, butyl-, n-pentyl-, n-hexyl- or n-octyl group; and X represents bromine, chlorine or iodine), comprising adding alkyl halide to an aqueous potassium hydroxide solution of o-hydroxybenzoic acid with 18-crown-6 added as a catalyst, and reacting them together [Zh. Org. Khim. 23(3), 667-668 (1987)];
2. A method represented by a reaction formula (2) ##STR2## comprising adding alkyl bromide to a potassium carbonate solution of methyl o-hydroxybenzoate and reacting them together under reflux [Azerb. Khim. Zh., (2) 46-49 (1987)];
The following two methods are known as techniques for producing 2,6-dialkoxybenzoic acid;
3. A method represented by a reaction formula (3) ##STR3## comprising effecting a Kolbe Schmitt reaction using resorcin as a starting material, methylating the reaction product with dimethyl sulfate, and further processing the product in an aqueous dilute sodium hydroxide solution at a higher temperature (Specifications of Hungarian Patent Nos. 162,756 and 162,757).
4. A method represented by a reaction formula (4) ##STR4## comprising metallation with metal potassium using 1,3-dimethoxybenzene as a starting material, and subsequently making the resulting product coexist with a base such as TMEDA (N,N,N,N-tetramethyl-1,2-ethylene diamine) (Specifications of U.S. Pat. Nos. 4,845,276 and 4,845,277; Japanese Patent Laid-open Nos. 2-108650 and 2-108651).
However, the method described in (1) is industrially disadvantageous in that a mixed product of o-alkoxybenzoic acid alkyl ester and o-alkoxybenzoic acid is obtained at a ratio of 3:2, and additionally in that the 18-crown-6 to be used as a catalyst is extremely expensive. The method described in (2) is not suitable industrially, because costly alkyl bromide must be used for the reaction and o-alkoxybenzoic acid methyl ester must be subjected to another step for hydrolysis.
The method described in (3) cannot be considered advantageous for industrial practice. The method employs potassium salt and carbon dioxide gas and involves a Kolbe Schmitt reaction under high temperature and high pressure conditions. In addition, a side reaction of the positional isomer via resorcin occurs, resulting in an extremely low yield of objective product, 2,6-dimethoxybenzoic acid, so that improvement of increase in yield is difficult. According to the reaction described in (4), a problem concerning selectivity can be avoided and the yield of the objective product gets higher. An Italian publication [Gazzetta Chimica Italiano, 111, 123 (1981)] describes that, if the starting material is a 1,3-dialkylbenzene other than 1,3-dimethoxybenzene, such as 1,3-diisopropylbenzene or 1-propoxy-3-methoxybenzene, the yield and selectivity are both poor because of the positional isomer of byproducts, so it is not preferable method for an industrial reaction.