Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1997-03-28
1998-02-17
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562438, C07C20500
Patent
active
057193177
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of nitrobenzene derivatives of formula: ##STR2## in which R.sub.1 and R.sub.2, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain or an alkoxy radical containing 1 to 6 carbon atoms in a straight or branched chain, or alternatively R.sub.1 and R.sub.2, together with the carbon atom to which they are attached, form a cycloalkyl radical containing 3 to 6 carbon atoms, these derivatives being useful in particular as intermediates for the preparation of pharmaceutical products (Patent WO 91/12,264) or as antidotes for certain insecticides (U.S. Pat. No. 4,859,232).
It is known to prepare these compounds by acid hydrolysis of the corresponding nitriles, which are themselves obtained from the corresponding halo derivatives and an alkali metal cyanide (E. Felder, J. Med. Chem., 13, 559 (1970) and U.S. Pat. No. 4,859,232). The use of alkali metal cyanide may pose pollution problems at the industrial level.
Moreover, it is known to dehalogenate halonitrobenzenes using triethylammonium formate, in the presence of palladium-on-charcoal, in a closed medium, without solvent and at a temperature of 100.degree. C. (N. A. Cortese et al., J. Org. Chem., 42, 22, 3491-3494 (1977)). Since this process is performed in a closed median and at 100.degree. C., it is difficult to industrialize. Furthermore, when applied to the preparation of compounds of formula (I), this process leads to a mixture of 3 products (expected product of formula (I), starting material and a dehalogenated product but in which the nitro is reduced to amino) which are difficult to separate, and the yield of expected product is low.
A non-polluting industrial process has now been found, which allows the pure compounds of formula (I) to be obtained in good yields.
This process consists in dehalogenating a derivative of formula: ##STR3## in which R.sub.1 and R.sub.2 have the same meanings as in formula (I) and Hal represents a chlorine or bromine atom, under atmospheric pressure, using 1 to 2 mol of triethylammonium formate, in the presence of 0.002 to 0.1 mol of palladium-on-charcoal per mole of compound of formula (II), in acetonitrile or tetrahydrofuran, at a temperature between 50.degree. C. and the boiling point of the reaction medium.
This reaction is preferably carried out under inert atmosphere (for example nitrogen).
It is particularly advantageous to use 1.5 mol of triethylammonium formate per 1 mol of derivative of formula (II).
The triethylammonium formate may be formed in situ from 2 molar equivalents of triethylamine and 1.5 molar equivalents of formic acid.
5% palladium-on-charcoal is preferably used and, in particular, 0.01 mol of 5% palladium-on-charcoal per mole of compound (II).
The preferred amount of acetonitrile or tetrahydrofuran is between 5 and 15 weight equivalents relative to the compound of formula (II), and in particular 10 equivalents.
The reaction temperature is preferably in the region of 80.degree. C.
The derivatives of formula (II) may be obtained by application or adaptation of the process described in Patent DE 22100418 or by nitration of the corresponding halo derivatives as described in the examples.
The examples which follow illustrate the invention.
EXAMPLE 1
16.5 ml of formic acid are added over 5 minutes to a round-bottomed flask, under inert atmosphere, containing 67.7 g of (RS)-2-(4-chloro-3-nitrophenyl) propionic acid, 87 ml of triethylamine and 6.1 g of 5% palladium-on-charcoal in 680 ml of acetonitrile. The reaction medium is heated at reflux for 18 hours and, after cooling to a temperature in the region of 20.degree. C., is then filtered through Celite. The filtrate is evaporated to dryness under reduced pressure and taken up in 500 ml of water and 400 ml of ethyl acetate. The organic phase is separated out after settling has taken place and the aqueous phase is extracted with twice 200 ml of ethyl acetate. The combined organic phases are dried over magn
REFERENCES:
patent: 4659862 (1987-04-01), Rajanbabu
patent: 4859232 (1989-08-01), Singh
Cortese et al., "Palladium-Catalyzed Reductions of Halo-and Nitroaromatic Compounds with Triethylammonium Formate", Journal of Organic Chemistry, 42(22):3491-3494 (1977).
Killos Paul J.
Rhone-Poulenc Rorer S.A.
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