Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-07-02
2003-04-22
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S226000, C549S295000, C549S326000, C564S134000, C564S142000, C564S190000, C564S448000
Reexamination Certificate
active
06552217
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to a process for the preparation of alkyl esters of 1-methylcyclopropanecarboxylic acid. More specifically, this invention pertains to a process for the synthesis of alkyl 1-methylcyclopropanecarboxylates by a novel combination of steps starting with &ggr;-butyrolactone.
BACKGROUND OF THE INVENTION
The present invention is directed to an improved process for the production of alkyl esters of 1-methylcyclopropanecarboxylic acid. This method includes the preparation of a solution of an alkyl 4-halo-2-methyl butyrate in a solvent such as xylene with the purification and continuous removal of the alkyl ester of 1-methylcyllopropanecarboxylate as it is formed. The most common method used to form alkyl esters of 1-methylcyclopropane carboxylic acid involves carbene insertion into esters of &agr;-methylacrylic acid. For example, Siegel et. al. (
J. Am. Chem. Soc
, 1950, 72, pages 3815-3817) disclose the reaction of diazomethane with methyl methacrylate to produce methyl 1-methylcyclopropane carboxylate in a 63% yield. The tendency for diazomethane to explode limits its use on an industrial scale.
Cannon and coworkers (
J. Am. Chem. Soc.
, 1959, 81, pages 1660-1666) disclose the reaction of &agr;-methyl-&ggr;-chlorobutyric acid ethyl ester with sodamide under strictly anhydrous conditions in benzene to provide 1-methylcyclopropane carboxylic acid ethyl ester in a yield of 47.6%. Schwarze and coworkers, U.S. Pat. No. 4,520,209, disclose the reaction of methyl 4-chloro-2-methylbutyrate in methanol with an excess of sodium methylate at a reaction temperature of 90° C. or higher. Although, an 87% yield was claimed by Schwarze et al., wiped film distillation or extraction was required to the separate methyl 1-methylcyclopropanecarboxylate from the sodium chloride by-product. Schwarze and coworkers disclose a boiling point for methyl 1-methylcyclopropanecarboxylate of 136° C. German Patent Publication DE 3026094 discloses the conversion of 4-chloro-2-methylbutyrate to 1-methylcyclopropaneamide via sodium methoxide/ammonia in an autoclave at 145° C.
There still exists a need for improved methods for the manufacture of alkyl esters of 1-methylcyclopropanecarboxylic acid. These esters are valuable intermediate products for the production of agrochemicals and pharmaceuticals. In particular alkyl esters of 1-methylcyclopropane carboxylic acid are useful intermediates for the manufacture of 1-methylcyclopropanecarboxamide and 1-methylcyclopropylamine.
BRIEF SUMMARY OF THE INVENTION
The process provided by the present invention for the preparation of alkyl 1-methylcyclopropanecarboxylate comprises the steps of:
(1) contacting &ggr;-butyrolactone with dimethylcarbonate in the presence of a basic catalyst to produce &agr;-methyl-&ggr;-butyrolactone;
(2) contacting the &agr;-methyl-&ggr;-butyrolactone from step (1) with a hydrogen halide in the presence of an alkanol to produce a reaction mixture containing an alkyl 4-halo-2-methylbutyrate;
(3) contacting the reaction mixture of step (2) with xylene to produce a xylene solution of an alkyl 4-halo-2-methylbutyrate;
(4) contacting the xylene solution of an alkyl 4-halo-2-methylbutyrate from step (3) with an alkali metal alkoxide under conditions of temperature and pressure which causes vaporization of (i) an alkanol as it is formed and (ii) an alkyl 1-methylcyclopropanecarboxylate as it is formed from the alkyl 4-halo-2-methylbutyrate.
The alkyl 1-methylcyclopropanecarboxylates obtained from our novel process may be converted to 1-methylcyclopropylamine by the steps of:
(5) contacting the alkyl 1-methylcyclopropanecarboxylate with an alkali metal hydroxide, carbonate or bicarbonate in the presence of water and a lower alkanol, e.g., an alkanol containing up to about 4 carbon atoms to produce an alkali metal 1-methyl cyclopropanecarboxylate;
(6) contacting the alkali metal 1-methylcyclopropanecarboxylate produced in step (5) with an acid to convert the alkali metal 1-methylcyclopropanecarboxylate to 1-methylcyclopropanecarboxylic acid;
(7) contacting the 1-methylcyclopropanecarboxylic acid produced in step (6) with thionyl chloride to convert the 1-methylcyclopropanecarboxylic acid to 1-methylcyclopropanecarbonyl chloride;
(8) contacting the 1-methyl cyclopropanecarbonyl chloride from step (7) with ammonia to convert the 1-methyl cyclopropanecarbonyl chloride to 1-methyl cyclopropanecarboxamide; and
(9) contacting the 1-methyl cyclopropanecarboxamide from step (8) with an alkali metal hydroxide and an alkali metal hypochlorite in the presence of water to convert the 1-methyl cyclopropanecarboxamide to 1-methyl cyclopropylamine.
A single-step embodiment of the present invention comprises the process of step (4) wherein an alkyl 1-methylcyclopropanecarboxylate is prepared and recovered by contacting a xylene solution of an alkyl 4-halo-2-methylbutyrate with an alkali metal alkoxide under conditions of temperature and pressure which causes vaporization of (i) an alkanol as it is formed and (ii) an alkyl 1-methylcyclopropanecarboxylate as it is formed from the alkyl 4-halo-2-methylbutyrate. 1-Methylcyclopropylamine is useful in the synthesis of antibacterial compounds described in U.S. Pat. No. 4,705,788.
DETAILED DESCRIPTION
The first step of the process is carried out by contacting &ggr;-butyrolactone with dimethylcarbonate in the presence of a basic catalyst to produce &agr;-methyl-&ggr;-butyrolactone. This reaction is described by M. Selva et al.,
J. Chem. Soc. Perkin Trans.
1; 1994, 1323, although methods for isolation of the product are not disclosed. In this step the dimethylcarbonate functions as both a solvent and reactant (methylating agent). Typically, the amounts of dimethylcarbonate and &ggr;-butyrolactone employed give a dimethylcarbonate:&ggr;-butyrolactone mole ratio in the range of about 1:1 to 20:1, preferably about 5:1 to 20:1. The first step may be carried out at a temperature in the range of about 160 to 250° C., preferably about 200 to 240° C. Especially preferred are reaction temperatures of about 210 to 240° C. and reaction times of about 1 to 14 hours. Longer reaction times and higher temperatures permit the complete conversion of &ggr;-butyrolactone which facilitates distillative purification of the produced &agr;-methyl-&ggr;-butyrolactone. The reaction of &ggr;-butyrolactone with dimethylcarbonate normally is carried out under super-atmospheric pressure, e.g., pressures in the range of about 27 to 90 bars absolute (bara—about 400 to 1300 pounds per square inch—psi). The basic catalyst employed in the first step may be selected from the alkali metal hydroxides, carbonate and bicarbonates, preferably the hydroxides and carbonates of sodium and potassium. Because of its solubility in the reaction mixture, potassium carbonate is the most preferred basic catalyst. The amount of basic catalyst used may be in the range of about 0.1 to 2 mole equivalents, preferably 0.5 to 2 mole equivalents, per mole of &ggr;-butyrolactone reactant. Careful distillation will provide a product stream of &agr;-methyl-&ggr;-butyrolactone in purities ranging between 90 and 100%. A high purity of &agr;-methyl-&ggr;-butyrolactone minimizes problems with impurities in later steps.
In the second step of the process of the present invention, a solution of a hydrogen halide in an alkanol is added to the &agr;-methyl-&ggr;-butyrolactone formed in step (1) to produce a reaction mixture containing an alkyl 4-halo-2-methylbutyrate. The preparation of methyl 4-chlorobutyrate and methyl cyclopropanecarboxylate from &ggr;-butyrolactone is disclosed in U.S. Pat. No. 3,711,549 and references cited therein. The reaction of &agr;-methyl-&ggr;-butyrolactone with HCl-saturated methanol for 24 hours followed by extraction into diethylether is disclosed by Ishikawa and coworkers,
Chem. Pharm. Bull.
1995, 43, 2014. Because of its low boiling point and flammability, diethylether is not easily used on an industrial scale.
The hydrogen halide utilized in our novel process preferably is hydrogen bromide or, most preferably, hydroge
Attride David Carl
Boaz Neil Warren
Ciula James Charles
Hubbs John Clark
Maddox John Thorton
Blake Michael J.
Eastman Chemical Company
Graves, Jr. Bernard J.
Killos Paul J.
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