Process for the preparation of optically active amino alcohols

Details Process for the preparation of optically active amino alcohols Process for the preparation of optically active amino alcohols

2001-07-17

2002-06-25

Shippen, Michael L. (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S022000, C560S024000, C560S028000, C560S029000, C560S030000, C560S115000, C560S157000, C560S166000, C564S082000, C564S083000, C564S098000, C564S099000, C564S159000, C564S184000, C564S185000, C564S186000, C564S218000, C564S219000, C564S224000, C564S382000, C568S880000

Reexamination Certificate

active

06410749

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to a process to highly enantioselectively and highly diastereoselectively prepare optically active &bgr;-amino alcohols useful as an intermediate for synthesizing pharmaceutical active ingredients and agricultural chemicals at a high yield by using a racemic &agr;-aminocarbonyl compound as the starting material.
BACKGROUND ART
Optically active &bgr;-amino alcohols are considered as an important intermediate for synthesizing pharmaceutical active ingredients and agricultural chemicals. As references wherein processes for preparing such optically active &bgr;-amino alcohols have been disclosed, the followings may be given as examples.
1 Process in which the reaction of &agr;-(substituted-amino)aldehyde and a metal reagent is employed.
i) JP laid-open No. 50-137911 gazette
* (Anti-isomer/Syn-isomer=4.3-2.5/1)
ii) J. Org. Chem., 55, 1439 (1990)
2 Process in which diastereoselective reduction of optically active &agr;-amino ketone is employed.
Tetrahedron. Lett., 35, 547 (1994)
3 Process in which diastereoselective reduction of optically active &agr;-alkoxyimine is employed.
J. Chem. Soc. Chem. Commun., 746 (1987)
4 Process in which diastereoselective hydrogenation of &agr;-amino-&bgr;-keto acid is employed.
i) J. Am. Chem. Soc., 111, 9134 (1989)
ii) J. Am. Chem. Soc., 115, 144 (1993)
5 Process in which asymmetric reduction of keto oxime is employed.
JP laid-open No. 10-45688 gazette
Among the processes in the past as described above, the diastereoselctivity in the processes {circle around (1)} and {circle around (5)} are low. The processes {circle around (2)} and {circle around (3)} require to prepare the raw material for the optically active compound beforehand and are thus complicated, the process {circle around (4)} allows to prepare highly diastereoselective optically active amino alcohol when a substrate containing a functional group, such as carboxyl, in the molecule is used, however, it is difficult to prepare optically active compounds according to the process {circle around (4)} when simple amino alcohol containing no functional group in the molecule is used.
Because of the difficulty as described above, development of selective production process of optically active &bgr;-amino alcohols by using the racemic modification, which is more commonly-useful and can produce the desired products at high yields, has been desired.
In the present invention, the syn-isomer is defined as the one having a steric configuration wherein both amino group and hydroxy group to be respectively substituted in a vertical direction of carbon atoms in chain face toward the same plane when the carbon atoms in chain are fixed as the central axis and the steric configuration is laid in a horizontal direction, while the anti-isomer is defined as the one having a steric configuration wherein both amino group and hydroxy group face toward the contrary planes with each other.
DISCLOSURE OF INVENTION
It is an object of the present invention to provide practical manufacturing process for optically active &agr;-amino alcohols by using one of widely-available racemic &agr;-aminocarbonyl compounds as the starting material.
For achieving the object described above, the present invention provides a process for the preparation of optically active &bgr;-amino alcohols represented by the general formula (2); Ra—C*H(OH)—C*H(Rb)—Rc, wherein Ra and Rc are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted aryl, Rb is one member selected from among groups represented by the following general formulae; (3) R1CO(R2)N—, (4) R1CO(R1′CO)N—, (5) R1CO(R1′SO
2
)N—, and (6) R1SO
2
(R2)N—, wherein R1, R1′ and R2 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted aryl or optionally substituted aryloxy, or alternatively R1 and R2 or R1 and R1′ may be united to form a five- to eight-membered nitrogenous heterocycle, and C* is an asymmetric carbon atom, characterized by reacting a racemic &agr;-aminocarbonyl compound represented by the general formula (1); Ra—CO—CH(Rb)—Rc, wherein Ra, Rb and Rc are each as defined above, with hydrogen or a hydrogen donor in the presence of an optically active transition metal compound and a base.
In the preparation process of optically active &bgr;-amino alcohols according to the present invention, it is preferable that the optically active transition metal compound is a homogeneous system optically active hydrogenation catalyst.
And, it is further preferable that the homogeneous system optically active hydrogenation catalyst is an optically active transition metal compound represented by the following general formula;
MaXY(Px)
m
(Nx)
n
  (7)
wherein Ma represents a metal atom belonging to VIII-group metals, X and Y represent each independently hydrogen, halogeno, carboxyl, hydroxide or alkoxy, Px represents phosphine ligand, Nx represents amine ligand, and at least either of Px or Nx is optically active, and m and n are an integer of 1 through 4.
Further, in the preparation process of optically active &bgr;-amino alcohols according to the present invention, it is preferable to use a compound represented by the following general formula (8);
Mb
m
′Z
n′,
wherein Mb represents either an alikali metal ion or an alkaline earth metal ion, Z represents OH
−
, RO
−
, wherein R is C
1-6
alkyl, an aromatic anion, HS
−
or CO3
2−
, and m′ and n′ are an integer of 1 through 3, as the base described above. However, a quaternary amine salt compound may be used as the base as well.
According to the preparation process of optically active &bgr;-amino alcohols of the present invention, optically active &bgr;-amino alcohols useful as the intermediate for the synthesis of pharmaceutical active ingredients and agricultural chemicals and represented by the general formula (2) can be prepared highly selectively and at a high yield.
Now, the embodiments for carrying out the present invention are explained in the following.
As the raw material to be used in the process of the present invention, a compound represented by the following general formula (1);
Ra—CO—CH(Rb)—Rc  (1)
is used.
In the general formula (1), Ra and Rc each independently represent hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted aryl.
In addition to the groups as described above, any of alkyl, alkenyl, aralkyl and aryl may be used as far as that may give no inhibitory effect on the reactions in the process of the present invention.
As substituents for the optionally substituted alkyl, the optionally substituted cycloalkyl, the optionally substituted alkenyl, the optionally substituted aralkyl and the optionally substituted aryl described above, any ones giving no inhibitory effect on the reactions in the process of the present invention may be used without limitation in terms of substitution position, type of substituent, numbers of substituents, etc.
As examples for the substituents, hydroxy, amino, nitro, alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl and hexyl; alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy; alkoxycarbonyl, such as methoxycarbonyl, ethoxycabonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl; phenoxycarbonyl, phenyl optionally substituted at the arbitrary position on the benzene ring, naphthyl optionally substituted at the arbitrary position on the naphthalene ring, such as 1-naphthyl and 2-naphthyl, a heterocyclic group optionally substituted at the arbitrary position on the ring, such as furan, pyran, dioxolane, d

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