Preparation of S-aryl-cysteine and its derivatives

Details Preparation of S-aryl-cysteine and its derivatives Preparation of S-aryl-cysteine and its derivatives

2000-11-14

2004-07-20

Wilson, James O. (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S155000, C560S157000, C562S426000

Reexamination Certificate

active

06765109

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for preparing an enantiomerically enriched S-aryl cysteine and its derivatives. Specifically, the process of the present invention provides S-aryl cysteine and its derivatives in enantiomeric excess of greater than about 96%.
BACKGROUND OF THE INVENTION
S-aryl cysteines are useful compounds in the biological study of metabolism, and they are useful intermediates in a synthesis of a variety of pharmaceutically active compounds. For example, S-aryl cysteine derivatives (mercapturic acids) are useful for studying the xenobiotics metabolic pathways. L. F. Chasseaud,
Drug Metab. Rev
., 1973, 2, 185. In addition, chiral S-aryl-L-cysteines have been used successfully to target the human immunodeficient virus (HIV) as a therapy for the treatment of AIDS. Kaldor et al.,
J. Med. Chem
. 1997, 40 (24), 3979-3985.
Many currently available synthetic methods for S-aryl cysteine involve preparation of racemic mixtures. There are, however, a number of disadvantages associated with racemic mixtures of such compound. A racemic mixture of S-aryl cysteine results in production of racemic drugs. It is well known that certain physiological properties of chiral drugs are dependent upon stereochemistry of the drug and the undesired side-effects to are often attributed to the presence of the undesired stereoisomer of the chiral drug. Accordingly, a high enantioselective synthesis of a chiral drug will result in a drug having a desired therapeutic activity with a reduced amount of undesired side-effects. Of course, the synthesis of a chiral drug can include a step of separating a racemic mixture; however, this is often time consuming and costly. In addition, racemic synthesis requires discarding one half of the compound unless the undesired isomer can be converted to a desired isomer. Moreover, not all racemic compounds can be resolved to provide a satisfactory yield of a desired enantiomer.
Current methods for enantioselective synthesis of S-aryl cysteine involve enzymatic methods (See, for example, Japanese Patent No. 58,146,287 and European Patent Application No. EP 754,759, which are assigned to Mitsui Toatsu Chemicals, Inc.) and are applicable to preparation of only a limited number of S-aryl cysteines.
Most of the current chemical synthetic methods for enantioselective preparation of S-aryl cysteine result in a racemic mixture, use elaborate reagents dramatically increasing the overall cost, or result in unacceptable levels of enantioselectivity to be useful in a pharmaceutical process.
Recently, Knight and Sibley (D. W. Knight and A. W. Sibley,
J. Chem. Soc., Perkin Trans
. 1, 1997, 2179-2187) reported that the displacement of N-benzyloxycarbonyl-O-p-toluenesulfonyl serine methyl ester (or methyl (S)-2-benzyloxycarbonylamino-3-methylsulfonyloxypropanoate) with freshly prepared sodium thiophenylate in DMF at about 0° C. afforded the desired N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester (or methyl (R)-2-benzyloxycarbonylamino-3-phenylthiopropanoate) in 98% yield providing a reported optical rotation of [&agr;]
20
D
−17.2 (c, 1.8; MeOH). No enantiomeric ratio of the product was reported. Furthermore, the use of sodium phenolate, prepared from sodium hydride, thiophenol and DMF is not amenable to large scale manufacture.
Therefore, there is a need for an efficient, concise and enantioselective method suitable for the large scale manufacture of S-aryl cysteine using relatively inexpensive reagents.
SUMMARY OF THE INVENTION
The present invention is directed to a method for preparing S-aryl cysteines of the formula:
where Ar is an aryl, P
1
is H or an amine protecting group and P
2
is H or a carboxylic acid protecting group.
Preferably Ar is C
5
-C
20
aryl.
Preferably P
1
is an amine protecting group, and more preferably P
1
is benzyloxycarbonyl (i.e., —C(═O)OCH
2
C
6
H
5
) or methoxycarbonyl (i.e., —C(C═O)OCH
3
).
Preferably P
2
is a carboxylic acid protecting group, and more preferably P
2
is methyl.
In one embodiment of the present invention, a thiolate of the formula:
is reacted with an aryl halide of the formula Ar—X
1
, where M is a metal, X
1
is a halide and Ar is an aryl as defined above.
The thiolates of compound II can be generated by contacting cystine or cysteine with a coupling reagent. A coupling reagent is selected from the group consisting of a metal, metal oxide, metal salt and mixtures thereof. Preferably the coupling agent is selected from the group consisting of copper, copper halide, copper oxide, zinc, zinc halide, zinc oxide, aluminum, aluminum halide, aluminum oxide, iron, iron oxide, iron halide, cobalt, cobalt oxide, cobalt halide, tin, tin oxide, tin halide, potassium, potassium oxide, potassium halide, sodium, sodium oxide, sodium halide and mixtures thereof. More preferably, the coupling agent is selected from the group consisting of copper, copper halide, copper oxide and mixtures thereof. And most preferably, the coupling agent is selected from the group consisting of copper, cupric bromide, cupric oxide, cupric chloride, cupric iodide, cuprous bromide, cuprous chloride, cuprous iodide and mixtures thereof. Typically, the thiolate is generated in situ and is used without further purification.
A variety of aryl halides can be reacted with the thiolate to produce S-aryl cysteine compounds. Preferably, aryl halide is phenyl bromide.
The reaction may be conducted in the presence of a reaction solvent. Preferably, the reaction solvent is selected from the group consisting of dimethylacetamide, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), diethylacetamide, dimethylbutyramide, and N-methyl-2-pyrrolidone.
In another embodiment of the present invention, a compound of the formula:
where X is a halide, mesylate or tosylate, is contacted with an aryl thiol (i.e., Ar—SH) in the presence of a base. Preferably the base is selected from the group consisting of sodium hydroxide, sodium bicarbonate, and potassium carbonate. X is a leaving group which is displaced by the sulfur group of the aryl thiol. Preferably, X is mesylate or tosylate. In a particular aspect of the present invention, the compound is prepared from serine. For example, protection of the amine group and the carboxylic acid group followed by conversion of the hydroxy group to a leaving group produces the desired compound, which can undergo a substitution reaction with an aryl thiol to produce the desired S-aryl cysteine.
The method may further involve the addition of a phase transfer catalyst. Preferably, the phase transfer catalyst is selected from the group consisting of Aliquat® 336 (i.e., tricaprylylmethylammonium chloride, a mixture of C
8
and C
10
chains with C
8
predominating), TBAB, and TBPB.
Preferably, the method of the present invention produces S-aryl cysteine enantioselectively. More preferably, the method produces S-aryl cysteine in enantiomeric excess of greater than about 96%, still more preferably greater than about 98%, and most preferably greater than about 99.5%.


REFERENCES:
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patent: 6130348 (2000-10-01), Hilpert
patent: 0 897 911 (1999-02-01), None
patent: WO 98/45271 (1998-10-01), None
Chenault, H. K. et al “Kinetic resolution of unnatural and rarely occurring amino acids” J. Am. Chem. Soc. vol 111, no 16, pp. 6354-6364, 1989.*
Liu, J., et al “Total synthesis of (-)-eudistomin F” Heterocycles, vol 31, no 2, pp. 229-232, 1990.*
Sasaki et al., “A Novel Approach to the Synthesis of Optically Pure Now Protein &agr;-Amino Acids in Both L and D Configurations from L-Serine,”Tetrahedron Letters, 1987, v. 28, pp. 6069-6072.
Marzoni et al., “A Convenient, Large Scale Synthesis of N-CBZ-(S-Phenyl)-L-Cysteine,”Synthetic Communications, 1995, v. 25(16), pp. 2475-2482.
Hichman et al., “Synthesis of Aromatic S-Substituted Derivatives of N-Acetyl-L-Cysteine,”Aust. J. Chem., 1985, v. 38, pp. 899-904.
Knight and Sibley, “Total Synthesis of (-)-Slaframine from (2R,3S)-3-Hydroxyproline,”J. Chem. Soc., Perkin Trans. I, 1997, pp. 2179-2187.
Nakamura et al., A

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