Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-08-07
2003-10-28
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S129000, C560S226000, C568S324000
Reexamination Certificate
active
06639100
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to processes for producing 4,4,4-trifluoro-3-hydroxybutyric acid derivatives. The present invention relates particularly to a process for producing optically active 4,4,4-trifluoro-3-hydroxybutyric acid ester derivatives, which are important intermediates for medicines, agricultural chemicals and functional materials such as ferroelectric liquid crystal. The present invention further relates particularly to a process for producing optically active 4,4,4-trifluoro-1,3-butanediol, which is also an important intermediate for medicines and agricultural chemicals.
There are several conventional processes for producing 4,4,4-trifluoro-3-hydroxybutyric acid ester derivatives. Each of Japanese Patent Laid-open Publication JP-A-64-3154 and EP-A-0424244 discloses an optical resolution of a diastereoisomer salt of optically active &agr;-phenyl ethyl amine and 4,4,4-trifluoro-3-hydroxybutyric acid through recrystallization. JP-A-8-289799, corresponding to U.S. Pat. No. 5,716,841 and EP-0736606-A1, discloses an optical resolution of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester through an asymmetric hydrolysis of lipase. There is a recent demand for a process for easily and efficiently producing optically active 4,4,4-trifluoro-3-hydroxybutyric acid ester derivatives.
Baeyer-Villiger oxidation is generally known as a common process for producing esters. In this oxidation, corresponding ketones are reacted with an oxidizing agent, thereby introducing oxygen atom to the ketone's one side having more substituents than those of the other side. Examples of such oxidizing agent are m-CPBA (Tetrahedron Lett., 25, 5043 (1984)), benzeneperoxyseleninic acid (J. Chem. Soc., Chem. Commun., 870 (1977)) and trifluoroperacetic acid (J. Am. Chem. Soc., 83, 2759 (1961)). It is important to select an optimum oxidizing agent in Baeyer-Villiger oxidation. The selection of an optimum oxidizing agent depends on distortion of the ketones and substituent transfer capability. Furthermore, it is necessary to consider the effect on other functional groups in the same molecule and decomposition such as tar formation by an excessive oxidation. In particular, if an optically active ketone is used as a raw material, it is important that the stereochemistry is maintained before and after the reaction.
JP-A-3-151348 discloses a process for producing an optically active fluorine-containing 3-hydroxybutyric acid ester by an ester exchange reaction between an alcohol and an optically active fluorine-containing 3-hydroxybutyric acid ethyl ester in the presence of an ammonium salt of sulfonic acid.
Helvetica Chimica Acta, 67, 1843, 1984 discloses a process for improving optical purity of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester. In this process, optical purity of the mother liquor is improved by the selective precipitation of racemic crystals in recrystallization. The precipitated racemic crystal has a melting point of 16° C. and is in the form of oil at room temperature. Therefore, it is necessary to conduct sequential operations, such as recrystallization and filtration, under a low temperature. The publication further discloses another process, in which 3,5-dinitrobenzoate form of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester is recrystallized, thereby improving the optical purity. In this process, it is necessary to induce ester from alcohol and to conduct hydrolysis after the purification.
J. Org. Chem., 52, 3211, 1987 discloses a process for asymmetrically hydrolyzing (±)-4,4,4-trifluoro-3-acetoxybutyric acid ethyl ester by lipase. This process requires a large amount of a high-price enzyme.
The above-mentioned process, which is disclosed in U.S. Pat. No. 5,716,841, also requires a large amount of a high-price enzyme. This publication further discloses a reduction of the unreacted (R)-4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester by sodium borohydride, thereby producing an optically active diol.
The above-mentioned resolution, which is disclosed in EP-A-0424244, requires the use of a high-price resolution agent. Furthermore, it is necessary to conduct several operations, such as neutralization and extraction, in order to regenerate optically active 4,4,4-trifluoro-3-hydroxybutyric acid.
Recently, there have been active researches for providing medicines, agricultural chemicals and various functional materials, such as ferroelectric liquid crystal, with unique physiological activity and physical characteristics by introducing perfluoroalkyl group into a particular site. Perfluoroalkylaldehyde can be used as a synthon for constructing a perfluoroalkylcarbinol derivative. In particular, an asymmetric reaction using a perfluoroalkylaldehyde can be used for easily and efficiently synthesizing an optically active perfluoroalkylcarbinol derivative. For example, it becomes possible to obtain an optically active trifluoromethylcarbinol derivative by (a) reacting &agr;-methoxystyrene derivative with fluoral in the presence of an optically active binaphthol-titanium complex, thereby obtaining a product corresponding to that of Friedel-Crafts reaction, and then by (b) hydrolyzing the product under an acid condition. Perfluoroalkylaldehyde is, however, low in boiling point and highly reactive. Therefore, it easily polymerizes by itself and thereby its handling is difficult. Thus, it is usual to stabilize perfluoroalkylaldehyde in the form of hemiacetal or hydrate. Upon heating, the stabilized perfluoroalkylaldehyde is dropped to concentrated sulfuric acid or phosphorus pentoxide, and the resulting gas is used in the above reaction. However, the generated perfluoroalkylaldehyde tends to polymerize partially or remain in the acid. Therefore, it is necessary to use an excessive amount of hemiacetal or hydrate. Furthermore, post-treatment of the acid used in an excessive amount may become a problem. Thus, the use of perfluoroalkylaldehyde for producing an optically active perfluoroalkylcarbinol derivative may be impractical in an industrial production.
There are several processes for synthesizing perfluoroalkylcarbinol derivatives by directly reacting perfluoroalkylaldehyde hemiacetal or its hydrate with nucleophiles. In fact, Tetrahedron Lett., 33, 1351 (1992) discloses a synthesis of fluoral ethylhemiacetal and trimethylsilylnitrile in dioxane in the presence of zinc iodide. Chem. Commun., 1996, 1929 discloses a synthesis of fluoral ethylhemiacetal and allylbromide in water in the presence of indium. Chem. Commun., 1998, 2051 and Synlett, 1999, 1477 disclose that a condensation of fluoral ethylhemiacetal or hydrate and enamine or imine proceeds easily in the absence of catalyst, thereby synthesizing 4,4,4-trifluoro-3-hydroxy-1-aryl-1-butanone derivative.
As mentioned above, optically active 4,4,4-trifluoro-1,3-butanediol is an important intermediate for medicines and agricultural chemicals. In particular, its R-form is a partial structure of BEFLOXATONE which is an antidepressant of Synthelabo Co. (EP-0736606-A1).
WO 9942590 discloses a process for producing (R)-4,4,4-trifluoro-3-hydroxybutyric acid ester, which is a precursor of (R)-4,4,4-trifluoro-1,3-butanediol, by an asymmetric reduction of a trifluoroacetoacetate using an enzyme prepared by a recombinant DNA technique. This process requires the use of NADP
+
, which is very high in price.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process for producing an optically active perfluoroalkylcarbinol derivative, which is a precursor of an optically active 3-perfluoroalkyl-3-hydroxypropionic acid derivative.
It is another object of the present invention to provide a process for increasing optical purity of an optically active 4,4,4-trifluoro-3-hydroxy-1-aryl-1-butanone derivative, which is a precursor of an optically active 4,4,4-trifluoro-3-hydroxybutyric acid derivative.
It is still another object of the present invention to provide a process for producing a 4,4,4-trifluoro-3-hydroxybutyric acid aryl ester derivative.
It is a further object of the present
Funabiki Kazumasa
Hayami Takashi
Ishii Akihiro
Kanai Masatomi
Kuriyama Yokusu
Central Glass Company Limited
Crowell & Moring LLP
Reyes Hector M
Rotman Alan L.
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