Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2001-09-17
2003-05-13
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C560S011000
Reexamination Certificate
active
06562994
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,636,505 describes N-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds, methods for their preparation, and their utility in the treatment of malignant or benign prostatic disease or of androgen dependent disease conditions such as acne, hirsutism or seborrhoea. Bicalutamide, (±)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide, is a particularly preferred specie of the above compounds. Bicalutamide is an effective, well-tolerated and convenient non-steroidal antiandrogen for use in the treatment of advanced prostate cancer. Preclinical and clinical studies have also indicated its potential as monotherapy, with quality of life advantages compared with castration (Schellhammer, Exp. Opin. Invest. Drugs, 8, p. 849 (1999)).
Bicalutamide has been prepared by reacting 3-trifluoromethyl-4-cyanoanaline with methacryloyl chloride followed by epoxidation of the resultant N-(3-trifluoromethyl-4-cyanophenyl)methacrylamide and subsequent epoxide ring opening with thiol and sulfone formation (U.S. Pat. No. 4,636,505; Tucker et al., J. Med. Chem., 31, p. 954 (1988)). Although that process is relatively straight forward, chromatographic separations required in the process makes it undesirable for use on a commercial scale. In addition, that process requires the use of relatively expensive starting materials.
Accordingly, what is needed in the art is a process for the preparation of N-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds which does not require the use of chromatographic separations and uses less expensive starting materials.
It is, therefore, an object of the present invention to provide an improved process for the preparation of N-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds which does not require the use of chromatographic separations and uses relatively less expensive starting materials compared to the art processes.
This and other objects and features of the present invention are described hereinbelow in more detail.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of an N-(substituted phenyl)-3-alkyl-, aryl- or heteroarylsulfonyl-2-hydroxy-2-alkyl- or haloalkylpropanamide of formula I
wherein
Y is cyano, nitro, perfluoroalkyl, alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl;
R is perfluoroalkyl, cyano, nitro, alkylcarbonyl, alkoxycarbonyl, alkyl or alkoxy;
R
1
is alkyl or haloalkyl; and
R
2
is alkyl, aryl or heteroaryl,
which process comprises:
(a) reacting a substituted benzene of formula II (II)
wherein Y and R are as described above, X is F, Cl, Br, I or —OSO
2
R
3
, and R
3
is alkyl or aryl with an &agr;,&bgr;,-unsaturated propanamide of formula III
wherein R
1
is as described above in the presence of a first base to form an N-(substituted phenyl)-&agr;,&bgr;-unsaturated propanamide of formula IV
(b) reacting the formula IV propanamide with an epoxidizing agent to form an epoxide of formula V
(c) reacting the formula V epoxide with a thiol of formula VI
R
2
SH (VI)
wherein R
2
is as described above in the presence of a second base to form a sulfide of formula VII
(d) reacting the formula VII sulfide with an oxidizing agent.
The present invention also relates to improved processes for the preparation of N-(substituted phenyl)-&agr;,&bgr;-unsaturated propanamides of formula IV, epoxides of formula V, and sulfides of formula VII.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention preferably comprises reacting a substituted benzene of formula II with an &agr;,&bgr;-unsaturated propanamide of formula III in the presence of a first base and an aprotic solvent, preferably in a temperature range from about −40° C. to 155° C., to form an N-(substituted phenyl)-&agr;,&bgr;-unsaturated propanamide of formula IV; reacting the formula IV propanamide with an epoxidizing agent in the presence of an aprotic solvent, preferably in a temperature range from about −78° C. to 155° C., to form an epoxide of formula V; reacting the formula V epoxide with a thiol of formula VI in the presence of a second base and an aprotic solvent, preferably in a temperature range from about −78° C. to 155° C., to form a sulfide of formula VII; and reacting the formula VII sulfide with an oxidizing agent in the presence of an aprotic solvent, preferably in a temperature range from about −78° C. to 155° C.
Aprotic solvents suitable for use in this invention include, but are not limited to, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, and the like; hydrocarbons such as hexane, heptane, and the like; aromatic hydrocarbons such as benzene, toluene, a xylene, mesitylene, and the like; halogenated aromatic hydrocarbons such as fluorobenzene, chlorobenzene, bromobenzene, a dihalobenzene, and the like; an ether such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, and the like; an ester such as ethyl acetate, and the like; and an amide such as N,N-dimethylformamide, and the like; and mixtures thereof. In a preferred embodiment of the present invention, step (a) is conducted in the presence of an amide, preferably N,N-dimethylformamide; step (b) is conducted in the presence of a halogenated hydrocarbon, preferably dichloromethane; step (c) is conducted in the presence of an ether, preferably tetrahydrofuran; and step (d) is conducted in the presence of a halogenated hydrocarbon, preferably dichloromethane.
First and second bases useful in the processes of this invention include, but are not limited to, alkali metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, and the like; alkali metal amides such as sodium amide, and the like; and alkyllithiums such as butyllithium, and the like. Preferred first and second bases include sodium hydride, potassium t-butoxide, sodium amide, and butyllithium with sodium hydride being more preferred.
Epoxidizing agents suitable for use in the present invention include conventional epoxidizing agents known in the art. Conventional epoxidizing agents particularly useful in the processes of this invention include, but are not limited to, peracids such as peracetic acid, trifluoroperacetic acid, 3-chloroperbenzoic acid, and the like; and dioxiranes such as dimethyldioxirane, methyltrifluoromethyldioxirane, and the like. Preferred epoxidizing agents include peracids with trifluoroperacetic acid being more preferred.
Oxidizing agents suitable for use in the oxidation of the formula VII sulfides of this invention include conventional oxidizing agents known in the art. Conventional oxidizing agents particularly useful for the oxidation of the formula VII sulfide of the present invention include, but are not limited to, peracids such as peracetic acid, trifluoroperacetic acid, 3-chloroperbenzoic acid, and the like; dioxiranes such as dimethyldioxirane, methyltrifluoromethyldioxirane, and the like; hydrogen peroxide; sodium periodate; N-methylmorpholine N-oxide; and oxone. Preferred oxidizing agents include peracids with trifluoroperacetic acid being more preferred.
The peracids utilized in the epoxidation and oxidation steps of the present invention may be conveniently prepared in situ from hydrogen peroxide and the corresponding acid anhydride. For example, trifluoroperacetic acid is preferably formed in situ from hydrogen peroxide and trifluoroacetic anhydride.
In a preferred process of the present invention, R
3
is trifluoromethyl. In another preferred process of this invention, X is F, Cl, Br or I, more preferably F.
Preferred formula I compounds produced by the process of the present invention are those wherein
Chen Bang-Chi
Sundeen Joseph E.
Zhao Rulin
Baxam Deanna L.
Bristol-Myers Squibb Co.
Richter Johann
Zucker Paul A.
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