Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1995-02-09
1999-04-27
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C07C 6976
Patent
active
058980814
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a chemical process and more particularly to an improved process for the preparation of methyl 2-(2-methylphenyl)-3-methoxypropenoate from methyl 2-methylphenylacetate.
A process for preparing methyl 2-(2-methylphenyl)-3-methoxypropenoate by the formylation of methyl 2-methylphenylacetate and methylation of the methyl 2-formyl-(2-methylphenyl)acetate so formed, is described in EP-A-0203606. The formylation is carried out in absolute ether in the presence of sodium hydride. The formylated material is isolated and methylated with dimethylsulphate in acetone in the presence of potassium carbonate.
Similar methods for preparing other compounds containing the 2-linked methyl 3-methoxypropenoate group are widely reported in recent patent literature beginning with EP-A-0178826. Mostly, the formylation and methylation steps are carried out separately, often in N,N-dimethylformamide (DMF) solvent. Methods of carrying out the two steps in a "one-pot" process are, however, also described in, for example, EP-A-0243012, EP-A-0480795, EP-A-0329011 and EP-A-0473980. In these methods DMF is again used as the solvent and sodium hydride or sodium methoxide as the base. In EP-A-0273572 a formylation method is described in which toluene is used as the solvent but the sodium salt of the formylated material is isolated before methylation in DMF.
According to the present invention there is provided an improved process for the preparation of methyl 2-(2-methylphenyl)-3-methoxypropenoate which comprises contacting methyl 2-methylphenylacetate with methyl formate in an aromatic hydrocarbon solvent in the presence of an alkali metal base and a phase transfer catalyst, and thereafter methylating, without isolation, the product so formed in the presence of water.
The aromatic hydrocarbon solvent used in the process of the invention is suitably an alkylbenzene, typically a methylbenzene, solvent, for example xylene or toluene.
The alkali metal base is suitably an alkali metal alkoxide, typically a sodium or potassium C.sub.1-4 alkoxide, for example sodium methoxide, sodium ethoxide or sodium t-butoxide.
By the term "phase transfer catalyst" is meant a substance which, being at least partly present in or wetted by a first (usually organic) phase promotes reaction between a reactant in the first phase and a reactant which it transfers from a second (usually aqueous but sometimes solid) phase to the first phase. After reaction, the phase transfer catalyst is released for transferring further reactant. Phase transfer catalysts are reviewed by E. V. Dehmlow in Angewante Chemie (International Edition) Vol. 13, No.3, 1974, page 170. Other reviews are by Jozef Dockx in Synthesis 1973 at pages 441-456 and by C. M. Starks in the Journal of the American Chemical Society (93) 1, Jan. 13 1971, pages 195-199.
Suitably the phase transfer catalyst is a quaternary ammonium or phosphonium salt preferably containing bulky organic groups, usually alkyl or aralkyl groups, to make it soluble in the organic phase. The molecular geometry of the quaternary ammonium or phosphonium cation is thought not to be of prime importance, but to confer preferential solubility in the first organic phase rather than the second phase. It is preferred that the phase catalyst is a tetraalkyl or aralkyl(eg benzyl)trialkyl ammonium or phosphonium salt in which the total number of carbon atoms attached to each nitrogen or phosphorus atom is greater than 10. There is little advantage in the number being above 70. It is especially preferred that the number should be in the range of from 16 to 40.
Examples of quaternary ammonium salts are: cetyltrimethylammonium bromide, dicetyldimethylammonium chloride, octyltributylammonium bromide, trioctylmethylammonium chloride, benzyldimethyllaurylammonium chloride, benzyltributylammonium chloride, dilauryldimethylammonium chloride, tetrabutylammonium sulphate and dieicosyldimethylammonium chloride. Tetrabutylammonium bromide is particularly suitable. Examples of quaternary phosphonium salts are cetyltripropylphosphon
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Dehmlow, E. V., "Phase-Transfer Catalyzed Two-Phase Reactions in Preparative Organic Chemistry", Angew. Chem. (Int. Edtn.), vol. 13, No. 3,
Dockx, Jozef, "Quaternary Ammonium Compounds in Organic Synthesis", Synthesis, 1973, pp. 441-456.
Starks, Charles, M., "Phase-Transfer Catalysis. I. Heterogeneous Reactions Involving Anion Transfer by Quaternary Ammonium and Phosphonium Salts", Journal of Americal Chemical Society, 93:1, Jan. 13, 1971, pp. 195-199.
Foster Nicholas Russell
Williams Alfred Glyn
Killos Paul J.
Thomson Marian T.
Zeneca Limited
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