Process for reducing &agr;-amino ketones

Details Process for reducing &agr;-amino ketones Process for reducing &agr;-amino ketones

1999-09-29

2001-07-03

Richter, Johann (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C560S017000, C560S029000, C568S305000, C568S306000, C568S307000, C568S704000, C568S705000, C568S713000

Reexamination Certificate

active

06255522

ABSTRACT:

FIELD OF THE INVENTION
This application is a 371 of PCT/JP98/02444 filed Jun. 3, 1998.
The present invention relates to a method for stereoselectively reducing &agr;-aminoketone derivatives, in particular &agr;-aminohaloketorle derivatives.
The reduction products, namely &agr;-aminoalcohol derivatives, in particular &agr;-aminohalohydrin derivatives, are compounds useful as intermediates for the production of medicinal compounds, for example HIV protease inhibitors (Japanese Kokai Publication Hei-8-99959: Japanese Kokai Publication Hei-5-170722).
BACKGROUND ART
Reduction of carbonyl compounds is a very important technology in various fields, inclusive of the production of medicinal compounds and agrochemicals, and various methods have been utilized to answer respective specific purposes. Among them, the technology of converting optically active &agr;-aminoketone derivatives to &agr;-aminoalcohol derivatives by stereoselective reduction is required to be high in operability and efficient for industrialization since such &agr;-aminoalcohol derivatives having an erythro configuration are important as intermediates of anti-HIV drugs, among others.
The “erythro” form means an isomer in which the amino group and hydroxy group bound to the adjacent carbon atoms have the relative configuration shown below. In the following formula, Z
1
and Z
2
represent the remaining chemical structure moieties.
A prior art technology for reducing &agr;-aminoketone derivatives comprises, for example, reducing them with diisobutylaluminum hydride (DIBAH), sodium borohydride, lithium tri-secondary-butylborohydride (L-Selectride) or the like at −78° C. [Tetrahedron Letters, 36, 5453 (1995)].
The reduction technology using DIBAH is excellent in reactivity and economy and is a very useful method from the( industrial viewpoint. This method is used in reducing, for example, &agr;-aminochloroketone derivatives derived from leucine. When said &agr;-aminochloroketone derivatives are reduced with DIBAH at −78° C., the erythro forms can be obtained preferentially with a diastereomer excess of about 75%.
However, this method requires an extremely low temperature of −78° C. for achieving high selectivity.
In Japanese Kokai Publication Hei-8-99959, a technology is disclosed which uses an aluminum trialkoxide as the reducing agent.
However, the technology disclosed in the above publication requires heating at a temperature not lower than 50° C. to raise the rate of reaction although the stereoselectivity is high. Thus, said technology still has problems to be solved; for instance, it is not suited for reducing thermally unstable substrates. Therefore, a practical technology has been demanded by which carbonyl compounds, in particular optically active &agr;-aminoketone derivatives can be converted to erythro-form &agr;-aminoalcohol derivatives by stereoselective reduction under mild conditions.
DISCLOSURE OF THE INVENTION
In the light of the above mentioned state of things, it is an object of the present invention to provide a method for reducing &agr;-aminoketone derivatives, in particular &agr;-aminohaloketone derivatives, under mild conditions to give &agr;-aminoalcohol derivatives, in particular &agr;-aminohalohydrin derivatives, with high stereoselectivity.
The present invention lies in a method for reducing &agr;-aminoketones which comprises reacting an &agr;-aminoketone derivative of the general formula (1);
wherein R
1
represents one member selected from the group consisting of a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group containing 7 to 20 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 20 carbon atoms, and a hydrogen atom: R
2
represents either a group of the general formula (2);
CH
n
X
3−n
  (2)
wherein X represents a halogen atom and n represents an integer of 0 to 2, or a group of the general formula (3);
wherein Y represents one member selected from the group consisting of an alkoxyl group, an aralkyloxyl group, a substituted or unsubstituted amino group, and an alkylthio group, P
1
and P
2
each independently represents a hydrogen atom or an amino-protecting group, exclusive of the case where P
1
and P
2
are the same and each represents a hydrogen atom,
with a compound prepared from an organoaluminum compound of the general formula (4);
wherein R
3
, R
4
and R
5
each independently represents a substituted or unsubstituted alkyl group containing 1 to 10 carbon atoms, or a hydrogen atom, on condition that at most one of R
1
, R
4
and R
5
represents a hydrogen atom, a sulfonic acid derivative of the general formula (5);
R
6
SO
3
H  (5)
wherein R
6
represents one member selected from the group consisting of a substituted or unsubstituted alkyl group containing 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group containing 7 to 20 carbon atoms, and a substituted or unsubstituted aryl group containing 6 to 20 carbon atoms, and
an alcohol compound of the general formula (6):
R
7
OH  (6)
wherein R
7
represents a substituted or unsubstituted, primary or secondary alkyl group containing 1 to 20 carbon atoms, or a substituted or unsubstituted, primary or secondary aralkyl group containing 7 to 20 carbon atoms, to give an &agr;-aminoalcohol derivative of the general formula (7):
wherein R
1
, R
2
, P
1
and P
2
are as defined above.


REFERENCES:
patent: 0 827 943 A1 (1998-03-01), None
patent: 0 969 000 A1 (2000-01-01), None
patent: WO98/11057 (1998-03-01), None
Akamanchi et al, Truly Catalytic Meerwein-Ponndorf-Verley (MPV) Reduction, Tetrahedron Letters, vol. 36, No. 28, pp. 5085-5088, 1995.
Akamanchi et al, Aluminium Isopropoxide—TFA, a Modified Catalyst for Highly Accelerated Meerwein-Ponndorf-Verley (MPV) Reduction, Tetrahedron Letters, vol. 36, No. 20, pp. 3571-3572, 1995.
Akamanchi et al, Diisopropoxyaluminium Trifluoroacetate: A New off the Shelf Metal Alkoxide Type Reducing Agent for Reduction of Aldehydes and Ketones, Synlett, Apr. 1997, pp. 371-372.
Kow et al, Rate Enhancement of the Meerwein-Ponndorf-Verley-Oppenhauer Reaction in the Presence of Proton Acids, J. Org. Chem., vol. 42, No. 5, 1977, pp. 826-827.
Database CAPLUS on STN, Acc. No. 1994:654933, Cha et al., ‘Reaction of dipyrrolidinoaluminum hydride in THF with selected organic compounds containing representative functional groups.’ Bull. Korean Chem. Soc. (1994), 15(8), pp. 644-649. (abstract).*
Database CAPLUS on STN, Acc. No. 1994:243631, Cha et al., ‘Reaction of bis (diethylamino)aluminum hydride in THF with selected organic compounds containing representative functional groups.’ Bull. Korean Chem. Soc. (1994), 15(2), pp. 132-138. (abstract).

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