Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1992-10-05
1994-06-21
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
560 29, 560115, 564 92, 564 93, 564210, 564213, 564342, 564360, 564391, C07C21300, C07C21520
Patent
active
053229630
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel method for preparing compounds represented by the formulas [III], [IV]. ##STR2## (where R.sup.1 is a protective group on the amino group, R.sup.4 is a cyclohexyl group or a phenyl group, and R.sup.2 is a lower alkyl group which may be branched). The compounds are useful as starting materials for preparing desired compounds which have human renin inhibiting activity and are useful as hypertension remedies, examples of the desired compounds being amino acid derivatives (see EP 0396065Al) represented by following formulas [I]and [II]. More particularly, the compounds [III] and [IV] are useful as starting material for the synthesis of the A4 parts of the desired compounds [I] and [II]. ##STR3## (where R.sup.2 is a lower alkyl group which may be branched)
BACKGROUND ART
Both the .alpha.-amino-.beta.-hydroxy-.delta.-ketone derivative (hereinafter called amino hydroxy ketone derivative) represented by formula [III] and the .alpha.amino-.beta., .delta.-diol derivative (hereinafter called amino diol derivative) represented by formula [IV] are known, and the amino diol derivative [IV] is prepared by reducing the amino hydroxy ketone derivative [III].
As the method for preparing the amino hydroxy ketone derivative [III], for example, the following methods are known.
1 A method wherein .alpha.-amino aldehyde derivative [V] is reacted and condensed with a ketone derivative such as isopropyl methyl ketone, in the presence of a base such as lithium diisopropyl amide (EP 0396065Al). ##STR4##
2 A method wherein oxazolidine derivative [VI] having a dithiohetero cyclic group is converted to a corresponding amino hydroxy ketone [III] (EP 0396065Al), by turning the dithiohetero part of the starting derivative [VI] into an oxo form, and opening the oxazolidine ring. ##STR5##
3 A method wherein lactam derivative [VII] having the amino group protected with a tert-butoxycarbonyl group is reacted with Glignard's reagent to open the lactam ring, thereby synthesizing amino hydroxy ketone derivative III] (W090/07521). ##STR6## (where THP denotes a tetrahydropyranyl group)
However, the amino hydroxy ketone derivative [III] has the configuration about the hydroxyl group in type (a) shown below, and there is a stereoisomer (b) with respect to the hydroxyl group. ##STR7##
The conventional method 1 does not satisfy the stereoselectivity about the hydroxyl group. The method 2 is large in the number of steps, including introduction of the dithio hetero ring group and opening of the oxazolidine ring, and is complicated so that the method is not practicable. The method 3 is also complicated for practical use, requiring many steps in preparing the lactam derivative which is the starting compound.
On the other hand, there is also known a method for preparing amino diol derivative [IV] by reducing the amino hydroxy ketone derivative [III] (EP0396065Al, W090/07521). However, the configuration of this amino diol derivative [IV] is of the following type (A), while there are also three other types (B), (C), (D) of configuration about the hydroxyl group, and therefore, it is extremely difficult to selectively prepare the derivative of (A) having the desired configuration. ##STR8##
In addition, the reduction reaction of .alpha.-hydroxy-.delta.-ketone derivative using tetramethyl ammonium borohydride is generally lowered in stereoselectivity at high temperature, and tends to be worse in the yield of the desired compound. Conventionally, acetic acid, acetonitrile/acetic acid and the like were used as a solvent, but acetic acid freezes at 16.degree. C. or less, and acetonitrile/acetic acid is not sufficient in the stereoselectivity although it is satisfactory in reaction at 16.degree. C. or less.
On the other hand, a method is also known for preparing .alpha.-amino aldehyde derivative [V] which is used as starting material in the present invention (Unexamined Japanese Patent Publication 2-60595). In this method, 2-amino-1-cyclohexyl propanol is oxidized in a solvent to obtain an .alpha.-amino al
REFERENCES:
An Expeditious Synthesis of (3S,4S)-Statine and (3S-4S)-Statine and (3S,4S)-Cyclohexylstatine, Tetrahedron Letters, vol. 31, No. 2, pp. 217-218, 1990.
Angew. Chem. Int. Ed. Engl 26, pp. 1141-1143, 1987.
J. Am. Chem. Soc. 1988, 110, pp. 3560-3578.
Ando Koji
Shibata Saizo
Shirakawa Eiji
Uchida Itsuo
Yamada Yasuki
Japan Tobacco Inc.
Raymond Richard L.
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