Method for producing ortho-alkylated benzoic acid derivatives

Details Method for producing ortho-alkylated benzoic acid derivatives Method for producing ortho-alkylated benzoic acid derivatives

2001-04-05

2002-02-26

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S405000

Reexamination Certificate

active

06350904

ABSTRACT:

The invention relates to a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I
in which
A is an alkyl radical having from 1 to 4 carbon atoms, characterized in that an aryl bromide of the formula II
in which A is as defined in formula I, is reacted with a secondary or tertiary organolithium compound and CO
2
.
Ortho-alkylated benzoic acid derivatives of the formula I are important intermediates in industrial organic synthesis, e.g. in the preparation of fine chemicals, dyes and crop-protection compositions. They are also important intermediates in the preparation of medicaments, in particular in the preparation of inhibitors of the cellular Na
+
/H
+
antiporter, which are known from EP 0 699 666 A1 or EP 0 758 644. In particular, 4-chloro-2-methylbenzoic acid is an intermediate in the synthesis of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonyl)benzamide, known from EP 0 699 666 A1 or N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, known from EP 0 758 644.
From classical organic synthesis (see on this subject standard works on organic synthesis, such as Houben-Weyl, Methoden der organischen Chemie [Methods in Organic Chemistry], Georg-Thieme-Verlag, Stuttgart, or Beyer, Walter, Lehrbuch der organischen Synthese [Handbook of Organic Synthesis], S. Hirzel Verlag, Stuttgart), the preparation of ortho-alkylated benzoic acid derivatives from aniline derivatives by diazotization, Sandmeyer reaction and subsequent nitrile hydrolysis, or by ortho-metalation and subsequent alkylation of benzoic acid derivatives, is known. For economic and ecological reasons, these multistage synthesis sequences are unpracticable for industrial application.
H. Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f. describes the synthesis of benzoic acid derivatives by lithiation of the corresponding aryl bromides and subsequent carboxylation. The preparation of 2-methylbenzoic acid by reaction of o-bromotoluene with n-butyllithium and subsequent carboxylation with solid CO
2
achieves a yield of 83.8%. The reaction of 4-chlorobromobenzene with n-butyllithium and CO
2
gives 4-chlorobenzoic acid with a 90% yield.
Preparation of the ortho-alkylated compounds of the formula I, in particular of 4-chloro-2-methylbenzoic acid, is impossible using the synthesis described above. Under the reaction conditions described in H. Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f., and using the customary lithiation reagents n-butyllithium, n-hexyllithium, phenyllithium or methyllithium, the desired reaction does not take place at all or only with a very low yield.
These findings are further supported by the synthesis of 4-chloro-2-methylbenzoic acid which is described in U.S. Pat. No. 3,910,947. Firstly, 2-methyl-4-chloroaniline is diazotized and the diazonium salt is scavenged with KI to synthesize the very reactive 2-iodo-4-chlorotoluene, which is immediately converted into 4-chloro-2-methylbenzoic acid by reaction with n-butyllithium and CO
2
. The choice of the very reactive aryl iodide over the less expensive and more readily available bromine derivative confirms that it was hitherto impossible to convert the aryl bromides into the desired benzoic acid derivatives of the formula I in a satisfactory yield.
The object of the invention was therefore to develop a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I which permits the use of aryl bromides.
Surprisingly, it has been found that the reaction of the aryl bromides of the formula II with a secondary or tertiary organolithium compound as metalation agent takes place with a yield which is improved compared with the prior art or is very good.
As a result, we have provided a way of preparing the ortho-alkylated benzoic acid derivatives of the formula I by a reaction, which is easy to handle even on an industrial scale, as a one-pot synthesis under mild conditions and using bromine derivatives of the formula II, which are less expensive than the aryl iodides.
The invention therefore provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I
characterized in that an aryl bromide of the formula II
is reacted with a secondary or tertiary organolithium compound and CO
2
.
The invention further provides a process for the preparation of ortho-alkylated benzoic acids of the formula I, characterized in that a secondary organolithium compound chosen from the group consisting of sec-butyllithium, isopropyllithium, sec-amyllithium, 4-heptyllithium, cyclopropyllithium or cyclohexyllithium or a tertiary organolithium compound chosen from the group consisting of tert-butyllithium, tert-amyllithium, triethylmethyllithium, 1-methylcyclopentyllithium or adamantyllithium is used.
The invention further provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I, characterized in that the reaction is carried out at temperatures between −100° and +50° C., and the reaction product is precipitated by adding an acid.
The invention further provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I, characterized in that the reaction is carried out in an inert solvent chosen from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, hexane, petroleum ether or mixtures thereof.
The invention further provides a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I, characterized in that the aryl bromide of the formula II is introduced into an inert solvent, the secondary or tertiary organolithium compound is added, this reaction mixture is added dropwise to a CO
2
-saturated solvent, and the mixture is again saturated with CO
2
.
The invention preferably provides a process for the preparation of 4-chloro-2-methylbenzoic acid, characterized in that 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound and CO
2
.
The invention particularly preferably provides a process for the preparation of 4-chloro-2-methylbenzoic acid, characterized in that
a) 2-bromo-5-chlorotoluene is reacted with sec-butyllithium and CO
2
,
b) the reaction is carried out at temperatures between −100° and +50° C., and 4-chloro-2-methylbenzoic acid is precipitated by adding an acid,
c) the reaction is carried out in an inert solvent chosen from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, hexane, petroleum ether or mixtures thereof, and
d) the 2-bromo-5-chlorotoluene is introduced into an inert solvent, the sec-butyllithium is added, this reaction mixture is added dropwise to a CO
2
-saturated solvent, and the mixture is again saturated with CO
2
.
The invention further provides for the use of 4-chloro-2-methylbenzoic acid prepared from the process described above as intermediate in the synthesis of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide.
The invention also provides a process for the preparation of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide characterized in that
in stage a) 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO
2
to give 4-chloro-2-methylbenzoic acid,
in stage b) 4-chloro-2-methylbenzoic acid is reacted with chlorosulfonic acid, sodium sulfite and methyl iodide to give 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,
in stage c) 2-methyl-4-chloro-5-methylsulfonylbenzoic acid is reacted with benzylamine to give 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
in stage d) 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid is esterified with an alcohol to give the corresponding ester of 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
in stage e) the ester from stage d) is reduced to give the corresponding 4-amino-5-methylsulfonyl-2-methylbenzoic ester,
in stage f) 4-amino-5-methylsulfonyl-2-methylbenzoic ester is reacted with dimet

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