Microwave irradiation process for preparing methyl esters

Details Microwave irradiation process for preparing methyl esters Microwave irradiation process for preparing methyl esters

2002-08-08

2003-11-25

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S009000, C560S081000, C560S105000, C560S147000, C560S155000, C560S179000, C560S205000

Reexamination Certificate

active

06653503

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides an accelerated process for preparing a methyl ester by reacting a carboxylic acid or salt thereof with dimethyl carbonate in the presence of a catalyst selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 4-dimethylaminopyridine (DMAP), wherein said reaction is conducted under microwave irradiation at a temperature of from about 120° C. to 300° C. for a period of time from about 1 second to about 300 minutes.
BACKGROUND OF THE INVENTION
Methylation of alcohols, amines, carboxylic acids, and activated methylenes is an important process in chemistry. However, due to the environmental and human impact of using toxic and unsafe methylating reagents such as methyl iodide or dimethyl sulfate, the investigation of safer, generally applicable alternatives continues. As an alternative to these toxic methylating agents, dimethyl carbonate has attracted considerable attention for the methylation of phenols, anilines, and activated methylenes. Dimethyl carbonate is non-toxic and generates CO
2
and methanol as by-products during methylations. Dimethyl carbonate is also a volatile liquid with a boiling point of 90° C. Hence, the unreacted dimethyl carbonate can be easily recovered by distillation from the reaction mixture and reused.
Microwave irradiation has been used for moisture analysis, organic synthesis, acid decomposition of botanical or biological samples, and rapid hydrolysis of peptides and proteins. Microwave irradiation has also been applied to several organic reactions. Krstenansky et al.,
Curr. Opin. Drug Discovery Dev
., Vol. 3, p. 454 (2000), describes converting alkyl and aryl amides to their corresponding nitrites under microwave irradiation. Wang et al.,
Synthetic Communications
, Vol. 26, No. 2, pp. 301-305 (1996), describes using microwave irradiation to synthesize aromatic ethers from phenols and halide in the absence of organic solvent and inorganic carrier. Bogdal et al.,
Synthetic Communications
, Vol. 28, No. 16, pp. 3029-3039 (1998), describes reacting phenols with primary alkyl halides under microwave irradiation to synthesize aromatic ethers.
Elder et al.,
Journal of Chemical Education
, Vol. 73, No. 5, pp. 104-105 (1996), describes using microwave irradiation to synthesize the following compounds: anthracene, octyl acetate, 2-naphthyl acetate, 2-methoxynaphthalene, and n-phenyl-2,4-dinitroaniline. Kabza et al.,
Journal of Organic Chemistry
, Vol. 65, No. 4, pp. 1210-1214 (2000), describes using microwave irradiation in the acid-catalyzed Fisher-type esterification of isopentyl alcohol and acetic acid. Kabza concluded that the esterification reaction behaved comparably under both microwave and thermal conditions. Caddick,
Tetrahedron
, Vol. 51, No. 38, pp. 10403-10432 (1995), describes microwave assisted organic reactions. Such organic reactions described are: pericyclic, cyclization, aromatic substitution, oxidation, catalytic transfer hydrogenation, alkene functionalization, alkylation, decarboxylation, carbohydrates, radical reactions, protecting groups, condensation, peptide synthesis, silicon, and rearrangement. Perreux et al.,
Tetrahedron
, Vol. 57, pp. 9199-9223 (2001), describes microwave effects in organic synthesis. Such organic syntheses include bimolecular reactions between neutral reactants, bimolecular reactions with one charged reactant, unimolecular reactions.
U.S. Pat. No. 4,513,146 describes a method for producing esters from highly hindered carboxylic acids and carbonates. The method involves reacting the highly hindered carboxylic acid with a carbonate with or without a catalyst at a temperature of 175° C. According to the only example, the reaction took 4 hours and 50 minutes. U.S. Pat. No. 4,513,146 states that exemplary bases are nitrogen-containing heterocyclic catalysts such as pyridine, 4-(dimethylamino)pyridine, imidazole, 2,6-lutidine, and 2,4,6-collidine.
U.S. Pat. No. 5,278,333 describes a process for preparing &agr;-phenylmethylpropionate by reacting a mixture of phenylacetic acid, dimethyl carbonate, and potassium carbonate in a molar ratio of 1:20:2, respectively, in an autoclave at a temperature of 225° C. for 15 hours.
It would be advantageous from a production standpoint to develop an accelerated process for preparing methyl esters which utilizes dimethyl carbonate as a reactant. In addition, the process should minimize degradation and/or racemization of optically pure compounds, and minimize the formation of by-products.
SUMMARY OF THE INVENTION
The invention provides an accelerated process for preparing a methyl ester having formula (III)
said process comprising reacting a carboxylic acid or salt thereof having formula (I)
with dimethyl carbonate having formula (II)
in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,4-diazabicyclo[2.2.2]octane; 4-dimethylaminopyridine; and combinations thereof, wherein R
1
is selected from the group consisting of an alkyl, aryl, alkoxy, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl, aralkyl, heterocyclic, heteroaralkyl, alkoxyalkyl, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, and haloalkyl; and M is selected from the group consisting of hydrogen, a monovalent metal, and a monovalent fractional part of a polyvalent metal, wherein said process is conducted under microwave irradiation at a frequency from 300 MHz to 30 GHz, and at a temperature of from about 120° C. to 300° C. for a period of microwave irradiation time from about 1 second to about 300 minutes.
According to another aspect, the invention provides a compound having formula (III)
wherein said compound is prepared by an accelerated process comprising reacting a carboxylic acid or salt thereof having formula (I)
with dimethyl carbonate having formula (II)
in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,4-diazabicyclo[2.2.2]octane; 4-dimethylaminopyridine; and combinations thereof, wherein R
1
is selected from the group consisting of an alkyl, aryl, alkoxy, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl, aralkyl, heterocyclic, heteroaralkyl, alkoxyalkyl, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, and haloalkyl; and M is selected from the group consisting of hydrogen, a monovalent metal, and a monovalent fractional part of a polyvalent metal, wherein said process is conducted under microwave irradiation at a frequency from 300 MHz to 30 GHz, and at a temperature of from about 120° C. to 300° C. for a period of microwave irradiation time from about 1 second to about 300 minutes.
The process of the invention is especially advantageous for preparing methyl esters since the process: (1) utilizes an environmentally friendly methylating reagent, dimethylcarbonate; (2) produces a high yield of the methyl ester, generally 95-99% conversion in less than 30 minutes of microwave irradiation; (3) minimizes degradation and/or racemization of optically pure compounds; and (4) minimizes the formation of by-products.
DESCRIPTION OF THE INVENTION
The accelerated process of the invention for preparing a methyl ester utilizes microwave irradiation. The microwave region of the electromagnetic spectrum corresponds to wavelengths from 1 cm to 1 m and frequencies from 300 MHz to 30 GHz. By International Convention, however, domestic and industrial microwave ovens generally operate at greater than 900 MHz, preferably about 2450 MHz to about 2455 MHz, in order to prevent interference with RADAR transmissions and telecommunications. Thus, the entire microwave region is not readily available for heating applications. Sources of microwave irradiation include multimode ovens and monomode ovens which may be batch or continuous devices. A preferred monomode oven is a continuous-flow reactor, such as a Milestone ETHOS-CFR continuous-flow reactor.
The methyl ester has formula (III)
in formula (III), R
1
is selected from the

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