Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1992-12-24
1994-07-12
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
562507, C07C20500
Patent
active
053290429
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a method of producing a (3S, 4R)-4-substituted-3-carboxycyclopentanone derivative represented by the following formula [A] and used as a starting material for a TRH derivative useful in a remedy for treating a prolonged clouding of consciousness and spinal cerebellar denaturation disease, ##STR3## (where R.sup.1 is a hydrogen atom, a lower alkyl group, or substituted or unsubstituted aryl group, and R.sup.2 is a hydrogen atom or a lower alkyl group. The wedge shape full lines indicate bonds facing in an upward direction from the page, and the dotted lines indicate bonds facing in a downward direction into the page),
and a method of producing a cyclohexene derivative, which can be an important intermediate in preparing a compound represented by the formula [A], for example, those represented by the following formulas [I], [VII], and [X], ##STR4## (where R.sup.1 and R.sup.2 represent the same as those of the above, and X is a halogen atom).
Prior Art
TRH (thyrotropin releasing hormone) is a tripeptide of L-pyroglutamyl-L-histidyl-L-proline amide (pGlu-His-Pro-NH.sub.2), and synthesized in the hypothalamus in the brain. TRH acts on the anterior lobe of the hypophysis to induce secretion of thyroid-stimulating hormone (TSH), which stimulate secretion of thyroid hormone, and secretion of luteinizing hormone. It is also known that in addition to the TSH secretion activating function, TRH is a useful remedy for prolonged clouding of consciousness and spinal cerebellar denaturation disease, caused by brain function disorder. Prior to the present invention, we proposed a novel TRH derivative represented by the following general formula [B] (See Published Unexamined Japanese Patent Application (PUJPA) No. 3-236397), ##STR5## (where each of R.sup.3 and R.sup.4 represents a hydrogen atom, a lower alkyl group, or phenyl group, and they may differ from each other, or be the same except that R.sup.3 and R.sup.4 must not be hydrogen atoms at the same time).
A TRH derivative represented by formula [B] can be obtained from an ordinary peptide forming reaction between a cyclopentanone derivative or a reactive derivative thereof, represented by the following general formula [A'], and a dipeptide compound or a salt thereof, represented by the following general formula [C], ##STR6## (where R.sup.3 and R.sup.4 represent the same as those of the above) ##STR7## (where A represents an imino group, and may be protected or not protected).
Of all the possible cyclopentanone derivatives represented by formula [A'], some types of stereoisomers and optical isomers can be prepared, for example, by a method including the following reactions (See Chem. Pharm. Bull., 33(7)2750-2761(1985)), ##STR8##
(R.sup.5 is a methyl group, and R.sup.6 is a benzyl group).
Based on the known technique described above, we also prepared a cyclopentanone derivative [A'] in the process of completion of our prior invention (PUJPA No. 3-236397), as a starting material of the invention.
However, as is obvious from its chemical structural formula, there are stereoisomers including cis-types and trans-types at positions 3 and 4 in a cyclopentanone derivative [A'], and in addition to these, there are optical isomers for each of the cis-, and trans-types in positions 3 and 4.
Therefore, it is difficult to selectively synthesize an optically active compound having a specific configuration (substituting groups of cyclopentanone at positions 3 and 4 have a cis-configuration), and a (3S, 4R) configuration at the same time. Thus, not only is the yield of the target compound low, but the handling of the products, for example physical and chemical separation of isomers, is complex.
DISCLOSURE OF THE INVENTION
The present inventors made intensive studies to solve the drawback of the conventional technique such as described above, and focused on a (1R, 2S)-2-methoxycarbonylhex-4-ene-l-carboxylic acid represented by formula [XII']. ##STR9##
Specifically, a method of preparing a compound [XII'] by an enzymatic process has
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Hara Katsuyoshi
Haruta Jun-ichi
Sakuma Kazuhiko
Uchida Itsuo
Yasuda Akihiro
Japan Tobacco Inc.
Killos Paul J.
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