Process for the purification or isolation of (2S,3R)-1-halo-2-hy

Details Process for the purification or isolation of (2S,3R)-1-halo-2-hy Process for the purification or isolation of (2S,3R)-1-halo-2-hy

1999-05-14

2000-08-22

Barts, Samuel

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

Organic compounds

Carboxylic acid esters

564185, 564341, C07C26100

Patent

active

061075116

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a method of purifying and isolating an N-protected (2S,3R)-1-halo-2-hydroxy-3-amino-4-phenylthiobutane of the following general formula (1) or its enantiomer. The following compound is useful as an intermediate for the production of medicinal compounds, particularly an HIV protease inhibitor (Viracept.TM. already on the market) which is described inter alia in EP 604185 A1. ##STR2## (wherein X represents a halogen atom; one of P.sup.1 and P.sup.2 represents a hydrogen atom and the other represents an amino-protecting group, or P.sup.1 and P.sup.2 taken together represents an amino-protecting group).


PRIOR ART

The N-protected (2S,3R)-1-halo-2-hydroxy-3-amino-4-phenylthiobutane of the above general formula (1) (hereinafter referred to sometimes as Compound (1)) can be synthesized by, for example, the process described in WO 95/09843 or the process described in WO 96/23756 or the like.
In the process according to WO 95/09843, (2R)-2-N-(benzyloxycarbonyl)amino-3-phenylthiopropanoic acid is first converted to (3S)-1-diazo-2-oxo-3-N-(benzyloxycarbonyl)amino-4-phenylthiobutane, then converted to the haloketone compound (3R)-1-chloro-2-oxo-3-N-(benzyloxycarbonyl)amino-4-phenylthiobutane and, in turn, it is reduced to the (2S,3R)-1-chloro-2-hydroxy-3-N-(benzyloxycarbonyl) amino-4-Phenylthiobutane.
According to the process described in WO 96/23756, a (2R)-2-N-(benzyloxycarbonyl)amino-3-phenylthiopropanoic ester is converted to the haloketone compound (3R)-1-chloro-2-oxo-3-N-(benzyloxycarbonyl)amino-4-phenylthiobutane, and it is then reduced to the (2S,3R)-1-chloro-2-hydroxy-3-N-(benzyloxycarbonyl) amino-4-phenylthiobutane.
The compound (1) thus obtained is not necessarily thermally stable and, moreover, because of the decompositions and side reactions involved in the course of production, the product is liable to contain various contaminants. Particularly, the N-protected (2R,3R)-1-halo-2-hydroxy-3-amino-4-phenylthiobutane of the following general formula (2) (hereinafter referred to sometimes as compound (2)), the N-protected (3R)-1-phenylthio-2-hydroxy-3-amino-4-phenylthiobutane of the following general formula (3) (hereinafter referred to sometimes as compound (3)), and the N-protected (2R,3S)-1-haro-2-hydroxy-3-amino-4-phenylthiobutane of the following general formula (4) (hereinafter referred to sometimes as compound (4)) tend to form in appreciable amounts as the byproducts of the compound (1) and in order that the objective compound of high quality can be obtained, those byproduct impurities must be somehow eliminated. ##STR3## wherein X, P.sup.1 and P.sup.2 are defined above.
The above compound (2) is an diastereomer of the objective compound (1) and its byproduction is predicated on the selectivity of reduction of the precursor (haloketone) (3R)-1-halo-2-oxo-3-amino-4-phenylthiobutane.
The above compound (3) is a compound obtained by substitution of a phenylthio group for the 1-halogen atom of the objective compound (1) and its byproduction is apparently attributable to a substitution reaction involving the liberated phenylthio group or its equivalent.
The above compound (4) is an enantiomer of the objective compound (1) and its byproduction is derived from the (S)-formed haloketone which is present with a precursor (haloketone) of the (R)-compound, (3R)-1-halo-2-oxo-3-amino-4-phenylthiobutane and which is an enantiomer thereof. This (S)-formed compound can be produced when the optical purity of (2R)-2-N-(benzyloxycarbonyl)amino-3-phenylthiopropanoic acid or (2R)-2-N-(benzyloxycarbonyl)amino-3-phenylthio-propanoic ester or the like which is a starting material of the methods disclosed in above-mentioned WO95/09843 or WO96/23756 is not entirely high.
As is generally known, it is difficult to remove structurally analogous impurities (related compounds) and in order that such impurities may be removed to provide an objective compound of high quality, there must be established an effective purification and isolation technology.
As the purification and isolati

REFERENCES:
patent: 5484926 (1996-01-01), Dressman et al.

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