Process for the synthesis of chirally pure beta-amino-alcohols

Details Process for the synthesis of chirally pure beta-amino-alcohols Process for the synthesis of chirally pure beta-amino-alcohols

2002-11-26

2004-10-05

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C564S302000, C564S487000, C564S489000

Reexamination Certificate

active

06800764

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a novel process of producing chirally pure &bgr;-amino-alcohols, as well as intermediates thereof including &agr;-amino acids. Compounds of the present invention are useful for a variety of purposes, including for use in pharmaceutical compositions.
A variety of techniques have been described for production of a preferred enantiomer from &agr;-amino acids. These techniques require the use of either resolution procedures or asymmetric syntheses at some point in the synthesis to prepare the target compounds. More efficient means for producing chirally pure target compounds are needed.
SUMMARY OF THE INVENTION
In one aspect, the present invention comprises a process for preparing chirally pure S-enantiomers of &agr;-amino acids.
In a further aspect, a process is provided for preparing chirally pure S-enantiomers of &bgr;-amino alcohols.
In yet another aspect, a process is provided for preparing chirally pure S-enantiomers of N-sulfonyl &bgr;-amino alcohols.
These and other aspects of the invention will be apparent to one of skill in the art upon reading of the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a process for the preparation of chiral &agr;-amino acids of the formula (R)
2
CH(CH
2
)
n
CH(NH
2
)C(═O)OH, where n is 0 to about 10; chiral &bgr;-amino alcohols of the formula (R)
2
CH(CH
2
)
n
CH(NH
2
)CH
2
OH; and chiral S enantiomers of N-sulfonyl &bgr;-amino alcohols of the formula (R)
2
CH(CH
2
)
n
CH(CH
2
OH)NH—S(O)
2
-2-C
4
H
2
S-5-Cl, wherein R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH
2
cycloalkyl, CH
2
-3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, or CH(OH)-4-SCH
3
-phenyl.
Both natural and unnatural &agr;-amino acids, natural and unnatural &bgr;-amino alcohols, and intermediates thereof, may be prepared according to the present invention. Such &agr;-amino acids and &bgr;-amino alcohols may also be referred to as 2-amino acids or 2-amino alcohols.
As used herein, the term “chirally pure” refers to compounds which are in 100% S-enantiomeric form as measured by chiral high performance liquid chromatography (HPLC). Other methods of measuring chiral purity include conventional analytical methods, including specific rotation, and conventional chemical methods. However, the technique used to measure chiral purity is not a limitation on the present invention.
As described herein, the method of the invention affords chirally pure &agr;-amino acids or &bgr;-amino alcohols following the recrystallization step in the method. Where chiral purity is not a requirement, the method of the invention may also be used to provide chiral &agr;-amino acids or &bgr;-amino alcohols which contain some percentage of a mixture of enantiomeric forms, e.g., which may be composed of about 90 to about 99% S-enantiomers, by following the method of the invention in the absence of recrystallization.
In one embodiment, the present invention is directed toward a process for preparing chiral S-enantiomers of &agr;-amino acids, which involves preparing an organometallic reagent from an alkyl halide of the formula (R)
2
CH(CH
2
)
n
CH
2
X, wherein X is Cl, Br or I and n is 0 to about 10; adding the organometallic reagent to carbon dioxide to afford a carboxylic acid; activating the carboxylic acid with an acid halide, phosphorus trichloride, acid anhydride, or thionyl chloride in the presence of a tertiary amine base; reacting the product of the activating step with an alkali metal salt of S-4-benzyl-2-oxazolidinone; treating the product of the alkali metal step with a strong non-nucleophilic base to form an enolate anion; trapping the enolate anion with 2,4,6-triisopropylbenzenesulfonyl azide to afford an oxazolidinone azide; hydrolyzing the oxazolidinone azide with an aqueous base to afford an &agr;-azido acid; reducing the &agr;-azido acid to the &agr;-amino acid; and recrystallizing the &agr;-amino acid to afford the chirally pure &agr;-amino acid.
In another embodiment, the present invention is directed toward a process for preparing chiral S enantiomers of &bgr;-amino alcohols, which involves preparing an &agr;-amino acid as described above, reducing the &agr;-amino acid to the &bgr;-amino alcohol, and recrystallizing the &bgr;-amino alcohol to afford the chirally pure &bgr;-amino alcohol.
In a further preferred embodiment, the present invention is directed toward a process for preparing chiral S enantiomers of N-sulfonyl &bgr;-amino alcohols of the general formula:
wherein R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH
2
cycloalkyl, CH
2
-3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, or CH(OH)-4-SCH
3
-phenyl and n is 0 to about 10. This process involves reducing an &agr;-amino acid to an &bgr;-amino alcohol of the formula (R)
2
CH(CH
2
)
n
CH(NH
2
)CH
2
OH; sulfonylating the &bgr;-amino alcohol with 5-chloro-thiophene-2-sulfonyl halide; and recrystallizing the product of the sulfonylation step to afford the chirally pure N-sulfonyl &bgr;-amino alcohols.
In one embodiment, the compounds of the invention contain one chiral carbon center, where R in the above-noted structures is the same. In certain desired embodiments, the R groups are methyl, ethyl, and n-propyl, and most preferably the R groups are ethyl. However, the invention further encompasses producing &agr;-amino acids and &bgr;-amino alcohols of the general formulae provided herein where the R groups are different. In these compounds one or more additional chiral centers may be present; however, the additional chiral centers must be optically pure and must not interfere with the production of the chirally pure &agr;-amino acids, &bgr;-amino alcohols, and pure S enantiomers of N-sulfonyl &bgr;-amino alcohols of the present invention.
In another preferred embodiment, the chiral carbon center is of S-stereochemistry which gives rise to enantiomerically pure products.
Thus, the process of the invention provides an efficient route to the synthesis of chirally pure S enantiomers of &bgr;-amino alcohols, and intermediates thereof, which are useful for a variety of purposes. For example, the exemplary compounds provided herein, the N-sulfonyl &bgr;-amino alcohols are useful for inhibition of &bgr;-amyloid production, which is implicated in amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Alzheimer's Disease (AD), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, Down's syndrome, among others.
As used herein, the term “pharmaceutically useful” refers to compounds having a desired biological effect, whether as a therapeutic, immune stimulant or suppressant, adjuvant, or vaccinal agent. Similarly, a variety of compounds which are suitable for use in non-pharmaceutical applications, e.g., a diagnostic, a marker, among others may be produced by the method of the invention. However, other pharmaceutically useful compounds may be produced by this method.
The term “alkyl” is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms, preferably one to eight carbon atoms and, most preferably, one to six carbon atoms; “alkenyl” is intended to include both straight- and branched-chain alkyl groups with at least one carbon—carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms; and “alkynyl” group is intended to cover both straight- and branched-chain alkyl groups with at least one carbon—carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms. As used herein, the term “lower” refers to any of th

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