Process for preparing 2-(2-methylphenyl)-3-methoxyacrylic acid m

Details Process for preparing 2-(2-methylphenyl)-3-methoxyacrylic acid m Process for preparing 2-(2-methylphenyl)-3-methoxyacrylic acid m

1998-08-04

2000-12-19

Tsang, Cecilia

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

Organic compounds

Carboxylic acid esters

C07C 69612

Patent

active

061629456

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for preparing methyl 2-(2-methylphenyl)-3-methoxyacrylate (I) ##STR3## by formylation of methyl 2-methylphenylacetate (II) ##STR4## in an inert solvent in the presence of a base, and subsequent methylation of the enolate III formed ##STR5## where M.sup.+ is an alkali metal cation.
The preparation of methyl 2-(2-methylphenyl)-3-methoxyacrylate is described in many places in the literature (cf. EP-A 178 826, EP-A 203 606, EP-A 226 917, EP-A 473 980 and WO-A 94/05,622).
EP-A 178 826 describes the use of dimethylformamide as inert solvent and sodium hydride as base for the formulation. The formylation takes place at 0-5.degree. C. The subsequent methylation is carried out in dimethylformamide using dimethyl sulfate in the presence of potassium carbonate. Similar reactions are disclosed in EP-A 243 012, EP-A 273 572, EP-A 329 011 and EP-A 480 795.
EP-A 203 606 and EP-A 226 917 disclose formylation in ether in the presence of sodium hydride at the boiling point of the mixture. The subsequent methylation is carried out in acetone using dimethyl sulfate in the presence of potassium carbonate.
In another variant, 3-alkoxy-2-heteroazolylaminoacrylic esters are obtained by formylation in dimethylformamide in the presence of alkali metal alcoholates at 0-5.degree. C. and subsequent methylation using dimethyl sulfate (EP-A 473 980).
In addition, WO-A 94/05,622 describes the preparation of methyl 2-(2-methylphenyl)-3-methoxyacrylate (I) by formylation in hydrocarbons in the presence of a phase-transfer catalyst.
These known processes have the disadvantage that reaction on the industrial scale is possible only with provisos,
With a view to the use of methyl 2-(2-methylphenyl)-3-methoxyacrylate (I) as starting material for the active substances disclosed in the literature cited at the outset, it is desirable to have a process which can be used industrially and which, additionally, results substantially in the E isomer with good overall yields.
A process has accordingly been found for preparing methyl 2-(2-methylphenyl)-3-methoxyacrylate (I) by formylation of methyl 2-methylphenylacetate (II) in an inert solvent in the presence of a base, and subsequent methylation of the enolate III formed, where M.sup.+ is an alkali metal cation, wherein an organic aprotic dipolar solvent is used as inert solvent and an alkali metal alcoholate is used as base. ##STR6##
R.sup.a (ester of formic acid) and R.sup.b (alcoholate residue) are, independently of one another, alkyl groups, especially C.sub.1 -C.sub.4 -alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyl, in particular methyl.
X in the methylating reagent is a halogen atom (in particular chlorine, bromine and iodine) or an equivalent of a sulfate group.
The procedure for the process according to the invention is generally such that methyl 2-methylphenylacetate (II) and the alkyl formate are introduced into the inert aprotic polar solvent, and a solution of the alcoholate in the corresponding alcohol is added to this mixture at from -10.degree. C. to 50.degree. C., preferably 10.degree. C. to 30.degree. C., in particular 15.degree. C. to 25.degree. C.
The inert solvent used in the process according to the invention is generally an organic aprotic polar solvent, the nature of the solvent used normally having no effect on the course of the reaction. With a view to the workup of the reaction mixture, it has proven advantageous to use dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide or N-methylformanilide, especially N-methylpyrrolidone, because these solvents can easily be removed from the product by distillation.
The amount of solvent used is likewise of only minor importance for success of the process. The amount should in any event be sufficient to ensure uniform distribution of the reactants. Larger amounts of solvent are not in general an impediment but are undesirable from the economic viewpoint. About 1000 ml to 3000 ml of solvent are normally used per mole of (II), p

REFERENCES:
patent: 5438059 (1995-08-01), Clough et al.

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