Process for preparing benzyl-substituted rhodanine derivatives

Details Process for preparing benzyl-substituted rhodanine derivatives Process for preparing benzyl-substituted rhodanine derivatives

1999-06-10

2001-03-13

Gerstl, Robert (Department: 1613)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06201127

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for preparing certain benzyl-substituted rhodanine derivatives useful for treating inflammation, inflammatory bowel disease, allergies, arthritis, hypoglycemia and muscular dystrophy and in preventing ischemia induced cell damage.
BACKGROUND OF THE INVENTION
Benzyl-substituted rhodanine derivatives are known to be active in treating inflammation, inflammatory bowel disease (hereinafter IBD), allergies, arthritis, hypoglycemia and muscular dystrophy and in preventing ischemia induced cell damage. For example, U.S. Pat. No. 5,216,002 discloses that certain benzyl-substituted rhodanine derivatives are useful for treating IBD; U.S. Pat. No. 5,158,966 discloses the use of such compounds for treating Type I diabetes; EPO Publication No. 391644 discloses the effectiveness of such compounds for treating inflammation, arthritis and muscular dystrophy, and for preventing ischemia induced cell damage; EPO Publication No. 343643 describes the use of such compounds for treating allergies and inflammation; while EPO Publication No. 587377 discloses these compounds as being effective in treating hypoglycemia.
All of the above patents and publications describe various processes for making the benzyl-substituted rhodanine derivatives disclosed therein. For example, U.S. Pat. No. 5,158,966, herein incorporated by reference, discloses a process for preparing benzyl-substituted rhodanine derivatives comprising reacting 3,5-di-tert-butyl-4-hydroxy benzaldehyde with rhodanine in acetic acid to form 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-2-thioxo-4-thiazolidinone, and reducing the resultant 2-thioxo-4-thiazolidinone with hydrogen using palladium on carbon as a catalyst.
Alternately, the alkene of the 2-thioxo-4-thiazolidinone can be reduced by refluxing with diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, followed by reduction of the thioxo group with hydrogen and palladium on carbon. In another process, reduction of the thioxo group may be accomplished by heating the methyl-2-thioxo-4-thiazolidinone in a mixture of acetic acid in the presence of zinc.
The current processes for preparing benzyl-substituted rhodanine derivatives, as set forth above, have utility. However, these processes require either large amounts of expensive catalyst or generate excessive amounts of environmentally hazardous zinc waste.
The present invention provides an improved process for preparing benzyl-substituted rhodanine derivatives. The process of the present invention can be performed with inexpensive, readily available reagents and eliminates the generation of zinc waste. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing a compound of the formula
wherein:
Ar is (i) phenyl, (ii) phenyl substituted with from one to three substituents independently selected from C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
8
alkoxy, C
1
-C
8
alkylthio, trifluoromethyl, C
1
-C
4
alkylphenyl, phenyl, F, Cl, hydroxy, phenoxy, C
1
-C
4
alkyloxyphenyl, thiophenyl, C
1
-C
4
alkylthiophenyl, N(R
4
)
2
where each R
4
is independently C
1
-C
6
alkyl or (iii) 1- or 2-napthyl;
R
1
is H, C
1
-C
6
alkyl, C
1
-C
4
alkylphenyl, phenyl or phenyl-substituted with one or two substituents independently selected from Cl, F, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoromethyl, —N(C
1
-C
4
alkyl)
2
or C
1
-C
4
alkylthio;
R
2
is H, C
1
-C
6
alkyl, benzyl or &agr;-methylbenzyl; and
R
3
is (i) H, (ii) C
1
-C
6
alkyl, (iii) phenyl, (iv) phenyl substituted with from one to three substituents independently selected from C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
8
alkoxy, C
1
-C
8
alkylthio, trifluoromethyl, C
1
-C
4
alkylphenyl, phenyl, F, Cl, hydroxy, phenoxy, C
1
-C
4
alkyloxyphenyl, thiophenyl, C
1
-C
4
alkylthiophenyl, N(R
4
)
2
where each R
4
is independently C
1
-C
6
alkyl or (v) 1- or 2-napthyl;
which process comprises reacting a compound of the formula III
wherein:
Ar, R
1
and R
2
are as defined above, and
X is S, NH, or 0; with with an aldehyde of the formula
where R
3
is as defined above,
wherein said reaction is conducted in the presence of an amine of the formula H
2
NR
6
where R
6
is H, C
1
-C
6
alkyl, benzyl or &agr;-methylbenzyl.
The present invention, further, provides new intermediate compounds of the formula II
wherein:
Ar is (i) phenyl, (ii) phenyl substituted with from one to three substituents independently selected from C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
8
alkoxy, C
1
-C
8
alkylthio, trifluoromethyl, C
1
-C
4
alkylphenyl, phenyl, F, Cl, hydroxy, phenoxy, C
1
-C
4
alkyloxyphenyl, thiophenyl, C
1
-C
4
alkylthiophenyl, N(R
4
)
2
where each R
4
is independently C
1
-C
6
alkyl or (iii) 1- or 2-naphthyl;
R
1
is H, C
1
-C
6
alkyl, C
1
-C
4
alkylphenyl, phenyl or phenyl-substituted with one or two substituents independently selected from Cl, F, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoromethyl, —N(C
1
-C
4
alkyl)
2
or C
1
-C
4
alkylthio;
R
2
is H, C
1
-C
6
alkyl, benzyl or &agr;-methylbenzyl; and
R
5
is H, —CHR
3
OH, where R
3
is (i) H, (ii) C
1
-C
6
alkyl, (iii) phenyl, (iv) phenyl substituted with from one to three substituents independently selected from C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
8
alkoxy, C
1
-C
8
alkylthio, trifluoromethyl, C
1
-C
4
alkylphenyl, phenyl, F, Cl, hydroxy, phenoxy, C
1
-C
4
alkyloxyphenyl, thiophenyl, C
1
-C
4
alkylthiophenyl, N(R
4
)
2
where each R
4
is independently C
1
-C
6
alkyl or (v) 1- or 2-napthyl.
The compounds of formula II are useful as intermediates in preparing the compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “C
1
-C
8
alkyl” refers to straight and branched chain aliphatic radicals of 1-8 carbon atoms. Typical C
1
-C
8
alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentane, iso-pentane, n-hexane, iso-hexane and the like. The term “C
1
-C
8
alkyl” includes within its definition the terms “C
1
-C
4
alkyl” and “C
1
-C
6
alkyl”.
The term “C
1
-C
8
alkoxy” represents a straight or branched alkyl chain having 1 to 8 carbon atoms which chain is attached to the remainder of the molecule by an oxygen atom. Typical C
1
-C
8
alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like. The term “C
1
-C
8
alkoxy” includes within its definition “C
1
-C
4
alkoxy”.
The term “C
2
-C
6
alkenyl” refers to straight and branched chains of 2 to 6 carbon atoms, both inclusive, having a double bond. As such, the term includes ethylene, propylene, isopropylene, 1-butene, 2-butene, 2-methyl-1-propene, 1-pentene, 2-pentene, 2-methyl-2-butene and the like.
The term “C
2
-C
6
alkynyl” refers to straight and branched chains of 2 to 6 carbon atoms, both inclusive, having a triple bond. As such, the term includes acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 3-methyl-1-butyne, 1-hexyne, 2-hexyne, 3-hexyne and the like.
The term “C
1
-C
8
alkylthio” represents a straight or branched alkyl chain having one to eight carbon atoms, which chain is attached to the remainder of the molecule by a sulfur atom. Typical C
1
-C
8
alkylthio groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and the like. The term “C
1
-C
8
alkylthio” includes within its definition “C
1
-C
4
alkylthio”.
“C
1
-C
4
alkylphenyl” represents a straight or branched chain alkyl group having from one to four carbon atoms attached to a phenyl ring. Typical C
1
-C
4
alkylphenyl groups include methylphenyl, ethylphenyl, n-propylphenyl, isopropylphenyl, n-butylphenyl, isobutylphenyl, and tert-butylphenyl.
The term “C
1
-C
4
alkylthiophenyl” represents a straight or branched chain alkyl group having from one to four carbon atoms a

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