Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Patent
1998-05-11
1999-05-04
Lambkin, Deborah
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C07C25500
Patent
active
059005033
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for producing an optically active cyanohydrin, more specifically an optically active N-(protected)-3-amino-2-hydroxy-4-phenylbutyronitrile (hereinafter referred to as "optically active AHPBN" in some cases), efficiently in high yield.
The optically active AHPBN according to the present invention is an important compound as an intermediate of bestatin (an anticancer drug), a renin inhibitor (a hypotensive drug), a HIV-treating drug, etc.
BACKGROUND ART
As a process for synthesizing an optically active AHPBN selectively, there is the process described in Tetrahedron Letters, Vol. 29, p. 3295, 1988.
This process, however, is disadvantageous in that the selective synthesis of the optically active AHPBN requires expensive reagents and a reaction condition of a very low temperature of -20.degree. C. or lower. Therefore, this process is not industrially suitable. On the other hand, a process comprising reacting an N-protected-L-phenylalaninal with sodium hydrogensulfite and potassium cyanide (EP-A-211580) can be practiced at ordinary temperature. This process, however, is poor in selectivity for an optically active reaction product, and no method for industrially easy separation of only the optically active reaction product has been known. Therefore, it can give the optically active reaction product only in low yield, and it is unavoidably expensive as a process for obtaining the optically active reaction product.
DISCLOSURE OF THE INVENTION
We earnestly investigated these problems and consequently found the following facts. By treating diastereomers of AHPBN in the presence of an amine and an organic solvent, the configuration relating to the carbon atom at the 2-position can be changed to cause isomerization, and the isomerization can be continued by taking out an optically active substance with a lower solubility, so that the optically active substance with a lower solubility can be obtained in high yield. When an optically active substance such as a (2R, 3S) form of AHPBN is precipitated from one of the following solvents (a) and (b) comprising diastereomers of AHPBN, the desired (2R, 3S) form can be precipitated selectively in high yield: (a) a single ether solvent or a mixed solvent of an ether solvent and aliphatic hydrocarbon solvent, and (b) a mixed solvent of an aromatic hydrocarbon solvent and an aliphatic hydrocarbon solvent. In addition, an optically active AHPBN can be obtained in higher yield by combining the above two methods than by practicing one of them alone. Thus, the present invention has been accomplished.
That is, the present invention relates to the following processes (1) to (14). the following general formula (1): ##STR2## wherein each of R1 and R2 is a hydrogen atom or an amino-protecting group, and the configurations relating to the carbon atoms at the *2-position and *3-position are as follows: in the case of the carbon atom at the *2-position being in R-configuration, the carbon atom at the *3-position is in S-configuration, and in the case of the carbon atom at the *2-position being in S-configuration, the carbon atom at the *3-position is in R-configuration, which comprises treating a mixture of diastereomers of an N-(protected)-3-amino-2-hydroxy-4-phenylbutyronitrile in the presence of an amine and an organic solvent. amine used is 0.1 to 10 mol % based on the number of moles of the mixture of diastereomers of an N-(protected)-3-amino-2-hydroxy-4-phenylbutyronitrile, and the treatment temperature ranges from 0.degree. C. to reflux temperature. solvent is a single ether solvent, a mixed solvent of an ether solvent and an aliphatic hydrocarbon solvent, a single aromatic hydrocarbon solvent, or a mixed solvent of an aromatic hydrocarbon solvent and an aliphatic hydrocarbon solvent. mixing ratio of the ether solvent to the aliphatic hydrocarbon solvent and that of the aromatic hydrocarbon solvent to the aliphatic hydrocarbon solvent is 1:0-6. is isopropyl ether, the aliphatic hydrocarbon solvent is n-heptane, and the a
REFERENCES:
patent: 5157143 (1992-10-01), Pellacini et al.
patent: 5493047 (1996-02-01), Brussee et al.
Tetrahedron Lett. 1988, vol. 29, No. 27; pp. 3295-3298; M. T. Reetz, et al.; "Stereoselective Cyanohydrin-Forming reactions of Chiral .alpha.-Amino Aldehydes".
J. Antibiot. 1976, vol. 29, No. 5 pp. 600-601, "The Chemical Synthesis of Bestatin".
Chem. Lett. 1992, No. 7, pp. 1169-1172; Jin-Hua Gu, et al.; "Unique Stereocontrol in Europium (III)-Catalyzed Cyanosilylation of Chiral .alpha.-Amino Aldehydes".
Tetrahedron Lett. vol. 33, pp. 5029-5032, 1992; M. Robert Leanna, etal.; "Synthesis of .alpha.-Amino and .alpha.-Alkoxy Aldehydes via Oxoammonium Oxidation".
Org. Syn., vol. 69, pp. 212-219; Pier Lucio Anelli,et al.; "A General Synthetic Method for the Oxidation of Primary Alcohols to Aldehydes: (S)-(+)-2-Methylbutanal (Butanal, 2-methyl-, (S)-)".
Koshigoe Taichi
Miyazawa Yoshinobu
Ohkawa Kouichi
Saeki Shinichiro
Sekine Jouji
Lambkin Deborah
Murray Joseph
Nippon Kayaku Kabushiki Kaisha
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