1. Field of the Invention
This invention relates to a process for producing an optically active 2-norbornanone useful as a starting material for synthesizing various physiologically active substances.
2. Description of the Related Art
A thromboxane A2 receptor antagonist useful as a blood coagulator can be synthesized from an optically active 3-ally1-2-norbornanone, as reported in Narisadaet al., J. Med. Chem., 31, 1847 (1988).
This optically active 3-allyl-2-norbornanone is usually produced by allylating the .alpha.-position of a carbony1 group of optically active 2-norbornanone. Hence, in the production of the thromboxane A2 receptor antagonist, it is necessary to obtain optically active 2-norbornanone.
The following three,processes have been hitherto proposed as processes for producing the optically active 2-norbornanone.
A first process comprises reacting a racemic modification of endo- or exo-2-norbornanol with phthalic anhydride to form a half ester of phthalic acid, subjecting it to optical resolution by a diastereomer method, and hydrolyzing the resolution product, further followed by oxidation to obtain optically active 2-norbornanone [Winstein et al., J. Am. Chem. Soc., 74, 1147, (1952)].
A second process comprises subjecting a racemic modification of exo-2-norbornanol or 2-norbornanone to asymmetric oxidation or asymmetric reduction, respectively, using horse liver alcohol dehydrogenase to obtain optically active 2-norbornanone [Irwin et al., J. Am. Chem. Soc., 98, 8476, (1976)].
A third process comprises subjecting an optically active acrylic ester and cyclopentadiene to Diels-Alder reaction to obtain an optically active norbornene-2-carboxylic acid ester, hydrolyzing the resulting ester, and subjecting the resulting optically active norbornene-2-carboxylic acid to catalytic hydrogenation to obtain optically active norbornane-2-carboxylic acid, further followed by oxidation to convert it into optically active 2-hydroxynorbornane-2-carboxylic acid, which is finally subjected to oxidative decarboxylation to obtain optically active 2-norbornanone (Japanese Patent Application Laid-open No. 5-51345).
However, in the case of the first process, the optically active 2-norbornanone obtained can not have a sufficient optical purity. In order to improve its optical purity, complicated operations for purification such as recrystallization must be repeated, resulting in a decrease in yield of the optically active 2-norbornanone and inversely an increase in production cost. Thus, there is a problem in the industrial application of the process.
In the case of the second process, the horse liver alcohol dehydrogenase used is very expensive and also can not promise a satisfactory asymmetric yield. Thus, there is also a problem in the industrial application of the process.
In the case of the third process, optically active norbornane-2-carboxylic acid is oxidized to obtain optically active 2-hydroxynorbornane-2-carboxylic acid, where a heavy metal salt potassium permanganate is used in the oxidation and there is a possibility of adversely affecting the environment.
Moreover, this third process employs sodium bismuthate-phosphoric acid (NaBiO.sub.3 --H.sub.3 PO.sub.4) as an oxidizing agent when the optically active 2-hydroxynorbornane-2-carboxylic acid is subjected to oxidative decarboxylation. Hence, it comes into environmental question how the heavy metal bismuth should be handled. In addition, the process can give a yield of as low as about 55%, and is not suited as an industrial means.
In this connection, regardless of an optical activity, it is proposed to carry out oxidative decarboxylation by reacting 2-hydroxynorbornane-2-carboxylic acid with an oxidizing agent, 2-chlorobenzoxazolium salt [T. Mukaiyama et al., J. Med. them. Soc., 31, 1847 (1988)] or sodium periodate [G. Helmchen et el., Tetrahadron Asymmetry, 1, 351 (1990)]. However, in order to carry out this reaction in an industrial scale, there is a problem of an excessively high material cost for the oxidizing agents. Accordingly, it is difficult to achieve industrial application of these oxidizing agents to the above third process.
Meanwhile, it is proposed to synthesize the 2-hydroxynorbornane-2-carboxylic acid through a spironorbornanone derivative obtained by subjecting a 5-methylene-1,3-dioxolan-4-one derivative and cyclopentadiene to Diels-Alder reaction [J. Matray et al., Chem. Bar., 122, 327 (1989)].
Accordingly, it is considered possible to produce optically active 2-norbornanone through the optically active 2-hydroxynorbornane-2-carboxylic acid if the optically active 5-methylene-1,3-dioxolan-4-one derivative can be simply produced.
Incidentally, regardless of an optical activity, it is proposed to produce a 5-methylene-1,3-dioxolan-4-one derivative by reacting a 5-bromo-5-methyl-1,3-dioxolan-4-one derivative with a dehydrohalogenating agent such as triethylamine [J. Matray et al., Chem. Bar., 122, 327 (1989)] or 1,8-diazabicyclo[5,4,0]-undeca-7-ene (DBU) [D. Seebach et al., Helv. Chim. Acta., 79, 1104 (1987)]. It is also proposed to produce it by reacting a 5-phenylsulfonylmethyl-1,3-dioxolan-4-one derivative with DBU [W. R. Rouch et al., J. Org. Chem., 57, 3380 (1992)].
However, there are the problems that the yield is as low as about 60% when triethylamine is used and in the meantime the DBU is expensive. There is another problem that the 5-phenylsulfonylmethyl derivative itself requires a high production cost. Thus, it is difficult from an industrial viewpoint to apply the production of 5-methylene-1,3-dioxolan-4-one derivative by the use of triethylamine or DBU as a dehydrohalogenating agent to the production of optically active 2-norbornanone.