Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-09-24
2001-08-28
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06281383
ABSTRACT:
This application claims the benefit of priority to German patent application serial no. 19844225.4, filed on Sep. 26, 1998, which priority document is incorporated by reference herein.
A process for preparation of &agr;,&agr;-dimethylphenylacetic acid from &agr;,&agr;-dimethylbenzyl cyanide is known. That preparation is described for instance in T
HE
J
OURNAL OF
M
EDICAL
C
HEMISTRY,
1977, volume 20, No. 8, page 1063. In this process, 2-phenyl-2-methylpropionic acid nitrile (&agr;,&agr;-dimethylbenzyl cyanide) is stirred in a solution of KOH (fivefold molar excess) and methanol in an autoclave at 140 to 150° C. under pressure for 20 hours, and the reaction mixture is then concentrated under reduced pressure, diluted with water, and acidified. The &agr;,&agr;-dimethylphenylacetic acid obtained as white crystals is then purified by an expensive purification process: filtration and recrystallization from ethanol. An &agr;,&agr;-dimethylphenylacetic acid with a melting point of 80° C. is obtained by this process, with a theoretical yield of 90%.
Our own experiments in which 2-phenyl-2-methylpropionic acid nitrile (&agr;,&agr;-dimethylbenzyl cyanide) was reacted in mixtures of n-butanol, water and KOH (threefold molar excess) at about 125° C. for 22 hours also did not lead to a complete hydrolysis of the nitrile employed. The corresponding amide intermediate was, furthermore, also found in amounts of 2%. Depletion of this intermediate would necessitate an additional purification step in order to obtain the desired &agr;,&agr;-dimethylphenylacetic acid of high purity.
Our own experiments in mixtures of n-butanol, water, and lithium hydroxide indicated only the formation of about 1% of the amide intermediate after a hydrolysis time of 4 hours at about 100° C. (under reflux). No hydrolysis up to the formation of the carboxylic acid was detected.
Further experiments of our own in 50% strength aqueous potassium or sodium hydroxide solution (threefold molar excess) at 125° C. with vigorous stirring showed the following analytical results after a reaction time of 20 hours:
Potassium
nitrile 0.4%
Amide 51%
carboxylic acid 47%
hydroxide
solution:
Sodium
nitrile 62%
Amide 34%
carboxylic acid 2.7%
hydroxide
solution:
The hydrolysis reaction with the stronger base, potassium hydroxide, proceeded much more rapidly than that with the weaker base, sodium hydroxide. Hence, our experiments indicated the following rates of hydrolysis therefore resulted: LiOH<NaOH<KOH.
It has now been found that the nitrile can be hydrolyzed to the carboxylic acid in a very short time under normal pressure in a mixture of a C
4
- or C
5
-alcohol, water and NaOH. Accordingly, the object of the invention is therefore to provide in high yields, by modification of the process conditions, an &agr;,&agr;-dimethylphenylacetic acid which is substantially free from 2-phenyl-2-methylpropionic acid nitrile (&agr;,&agr;-dimethylbenzyl cyanide) and 2-phenyl-2-methylpropionic acid amide.
The object is achieved by carrying out the reaction of &agr;,&agr;-dimethylbenzyl cyanide in the presence of sodium hydroxide, water, and a C
4
-or C
5
-alcohol at temperatures above 100° C. and then obtaining the &agr;,&agr;-dimethylphenylacetic acid by acidification. Additional purification steps are no longer necessary.
The invention therefore relates to a process for obtaining the compound of the formula I:
which comprises reacting a compound of the formula II:
in the presence of water, sodium hydroxide, and a C
4
-alcohol or C
5
-alcohol at temperatures of more than about 100° C. to give the corresponding carboxylic acid salt, and then obtaining the compound of the formula I by addition of an acid.
In the preparation of the compound of the formula I, a procedure is followed in which the C
4
- or C
5
-alcohol, water, the sodium hydroxide, and the compound of the formula II (&agr;,&agr;-dimethylbenzyl cyanide) are first mixed. The mixture is heated to more than about 100°, while stirring. A mixture of C
4
- and C
5
-alcohol can also be employed.
After an appropriate reaction time, the reaction mixture is cooled and &agr;,&agr;-dimethylphenylacetic acid is precipitated out with an acid. The &agr;,&agr;-dimethylphenylacetic acid is isolated, for example, by crystallization or extraction. The crystallization is promoted by cooling of the suspension and/or further evaporation of the solvent. The extraction takes place by addition of organic solvents to the &agr;,&agr;-dimethylphenylacetic acid, for example, toluene.
The term C
4
- and C
5
-alcohol is understood to include, for example, n-butanol, 2-methyl-1-propanol, n-pentanol, 2-pentanol, 3-pentanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2-methyl-3-butanol, 3-methyl-1-butanol or 2-methyl-1-butanol.
The term sodium hydroxide is understood to include caustic soda in solid form or in the form of alkaline solutions of various concentrations. The water present in the alkaline solution is then included in the calculation when preparing the hydrolysis mixture.
Suitable acids are, for example, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid, or mixtures of the acids.
About 120 mol to about 250 mol of water, for example, and about 150 mol to about 300 mol of sodium hydroxide, for example, may be used per 100 mol of the compound of the formula II for the hydrolysis reaction. The amount of C
4
- or C
5
-alcohol used is in general about 0.5 kg to about 1.5 kg per kg of the compound of the formula II, for example about 0.6 kg to about 1.0 kg.
The reaction time is in general from about 2 to about 6 hours, depending on the composition of the mixture and the temperature range chosen. The reaction temperature may be up to about 140° C., for example about 110° C. to about 130° C., depending on the C
4
- or C
5
-alcohol used. It will be appreciated that temperatures set forth herein are approximate because the most desirable in any given situation may depend upon the reactants used and the economically acceptable process times and yields. It is within the skill of one in the art to vary these conditions in light of the economically acceptable realities of manufacture.
The by-product 2-phenyl-2-methylpropionamide has been found to be present in the isolated &agr;,&agr;-dimethylphenylacetic acid in an amount of less than 0.1%, based on the compound of the formula I. The residual content of the starting substrate of the compound of the formula II (&agr;,&agr;-dimethylbenzyl cyanide) has not been detectable in the isolated &agr;,&agr;-dimethylphenylacetic acid.
The starting substances for the hydrolysis reaction according to the invention can be prepared by processes known from the literature. The process product is suitable for the preparation of a large number of secondary products, for example, for the preparation of medicaments having an antiallergic action, such as 4-[4-[4-(hydroxydiphenyl)-1-piperidinyl]-1-hydroxybutyl]-&agr;,&agr;-dimethylphenyl acetic acid as described in U.S. Pat. No.4,254,129.
The very short reaction times, the omission of additional purification steps, the high yields, and the high purity of the product prepared are advantageous. The substantially complete conversion into the compound of the formula I and a total content of by-products cf less than 0.1% are an advantage of the process according to the invention.
REFERENCES:
patent: 132658 (1978-10-01), None
patent: 31 17 510 A1 (1982-02-01), None
Buckle, D.R. et al., “Synthesis and Antiallergic Activity of 2-Hydroxy-3-nitro-1,4-naphthoquinones”, Journal of Medicinal Chemistry, vol. 20, No. 8, p. 1059-1064, (1977).
Fujio, M. et al., “Substituent Effect on the Acetolysis of Neophyl p-Bromobenzenesufonates”, Memoirs of the Faculty of Science, Kyushu University, Ser. C, vol. 14(2), p. 319-332, (1984).
Chemical Abstracts, vol. 64, No. 12, Makosza et al., “Reactions of Organic Anions. III. Synthesis of Phenyl-dialkylacetonitriles,” XP002128783 (Jun. 6, 1966).
Flemming Hans-Wolfram
Korb Gerhard
Lehnert Rudolf
Rybczynski Wolfgang
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Killos Paul J.
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