Process for producing cyclohexylamino acids

Details Process for producing cyclohexylamino acids Process for producing cyclohexylamino acids

1997-08-07

2001-11-13

Keys, Rosalynd (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C562S507000

Reexamination Certificate

active

06316660

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for producing optically active amino acid derivatives having a cyclohexyl group. The products of the present process are important intermediates in the preparation of pharmaceuticals, such as renin inhibitors.
2. Discussion of the Background Art
A cyclohexyl group-containing amino acid is a residue of a renin inhibitor as described in WO 91/07430, EP 438311, EP 427939 and Japanese Laid-Open (Kokai) No. 9,162/1993. Since this compound is a synthetic derivative, it has aroused much interest with respect to its pharmacological activity.
A method of synthesizing a cyclohexyl group-containing amino acid is known per se. This known method produces a racemic compound. Although this method uses an optically active starting material, the optical purity of the resulting amino acid is unclear. Therefore, this method fails to produce an optically active amino acid product. This method also suffers from a low reaction yield and uses a solvent that is difficult to manipulate on an industrial scale.
Specific examples of the production of an amino acid which is optically active and contains a cyclohexyl group include the production of cyclohexylalanine by reducing L-phenylalanine in an aqueous acetic acid solution using a platinum oxide catalyst (J. Org. Chem., 1988, 53, 873 and Tetrahedron, 1992, 48, 307), and the production of cyclohexylglycine by reducing (R)-phenylglycine in a carbon-containing aqueous solution using a palladium hydroxide catalyst (Synth. Commun., 1978, 8, 345). However, in the former case, the optical purity of the product is unclear. In the latter case, the yield is as low as between 24 and 66%, and cyclohexyl acetate is formed as a by-product at a ratio of from 27 to 68%. Further, the optical purity of the resulting cyclohexylglycine is between 66 and 84% ee, which is not satisfactory. Accordingly, these methods are not useful on an industrial scale.
Incidentally, in the reduction of an aromatic hydrocarbon compound, the reaction is generally conducted at a hydrogen pressure in the presence of a catalyst such as rhodium, ruthenium, platinum or the like using an alcohol or the like as a solvent. With an unsubstituted aromatic hydrocarbon compound, the reaction proceeds relatively easily using a rhodium catalyst. However, with a hydrocarbon compound having a substituted aromatic ring, the reaction hardly proceeds owing to the influence of the resonance of the ring, or a side effect such as hydrogenolysis of a substituent or the like occurs. Thus, detailed studies on the reaction conditions are required in many cases (see, for example, J. Org. Chem., 1958, 23, 276 and Org. Syn., 1947, 27, 21).
With respect to reduction of an aromatic ring of an aromatic compound having a substituent with an asymmetric carbon atom, it is reported that optically active mandelic acid is reduced in the presence of a rhodium catalyst (J. Org. Chem., 1962, 27, 2288). This document describes that the racemization is suppressed almost completely. However, product crystals having an optical purity of 92% ee are obtained from a starting material having an optical purity of 95% ee. Thus, a loss of optical purity of several percent by racemization appears unavoidable with this process. Regarding the racemization of mandelic acid, it is considered that the substituent in the benzyl position participates in the reaction as in the reduction (R)-phenylglycine, described above, to form a conjugated system relative to the benzyl position, with the result that the side reaction occurs with racemization. Consequently, reducing the aromatic ring of optically active phenylglycine while maintaining the optical purity thereof is especially difficult.
It has been reported that a ketone group in L-cyclohexylalanine derivatives is reduced in an alcohol solvent in the presence of a Raney nickel catalyst (J. Org. Chem., 1988, 53, 873). However, in spite of mild conditions, racemization occurred at a ratio of 15% simultaneously with the reduction of the ketone moiety. It appears extremely difficult to avoid racemization during hydrogenation of amino acids containing aromatic rings.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an industrial process for producing optically active amino acid derivatives having a cyclohexyl group by reduction of the corresponding aromatic group containing amino acids, preferably in high yield and without substantial racemization.
The present inventors have conducted investigations to solve the above-mentioned problems, and have consequently invented a process for producing amino acids having a cyclohexyl group in high yields without substantial racemization by catalytically reducing aromatic amino acids using a ruthenium catalyst.
The present invention provides a process for producing an amino acid derivative represented by formula (I):
where
R
1
is an unsubstituted or substituted cyclohexyl group having from 6 to 15 carbon atoms or an unsubstituted or substituted cyclohexylalkyl group having from 7 to 15 carbon atoms;
P
1
and P
2
are each, independently, a hydrogen atom or an amino-protecting group, or
P
1
and P
2
together form a difunctional amino-protecting group;
P
3
is a hydrogen atom or a carboxyl-protecting group; and
* is an asymmetric carbon atom, by hydrogenating an aromatic amino acid represented by formula (II) in the presence of a ruthenium catalyst:
 where
R
2
is an unsubstituted or substituted aryl group having from 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group having from 7 to 15 carbon atoms;
P
1′
and P
2′
are each, independently, a hydrogen atom or an amino-protecting group, or P
1′
and P
2′
, together, form a difunctional amino-protecting group;
P
3′
is a hydrogen atom or a carboxyl-protecting group; and
* is as defined above.


REFERENCES:
patent: 4048222 (1977-09-01), Saito et al.
patent: 5107053 (1992-04-01), Wu
patent: 5334758 (1994-08-01), Saburi et al.
patent: 1 290 923 (1972-09-01), None
Derwent Abstracts, AN 77-41256Y, SU 526 616, Dec. 7, 1976.
Paul Francis Schuda, et al., Journal of Organic Chemistry, American Chemical Society, vol. 53, No. 4, pp. 873-875, “A Short and Efficient Synthesis Of (3S, 4S)-4-[(Tert-Butyloxycarbonyl)Amino]-5-Cyclohexyl-3-Hydroxypentanoic Acid Ethyl Ester”, Feb. 19, 1988.
M. Tamura, et al., Synthetic Communications, vol. 8, No. 5, pp. 345-351, “A Synthesis Of Optically Active &agr;-cyclohexylglycine”, 1978.

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