Methods for the preparation of biphenyl isoxazole sulfonamides

Details Methods for the preparation of biphenyl isoxazole sulfonamides Methods for the preparation of biphenyl isoxazole sulfonamides

2000-03-20

2001-11-06

Powers, Fiona T. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S245000, C548S246000

Reexamination Certificate

active

06313308

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods for the preparation of biphenyl isoxazole sulfonamides and intermediates thereof. The present invention also relates to the novel intermediates prepared by these methods. The biphenyl isoxazole sulfonamides prepared by the present methods are endothelin antagonists useful, inter alia, for the treatment of hypertension.
BRIEF DESCRIPTION OF THE INVENTION
The present methods allow preparation of biphenyl sulfonamides of the following formula I:
where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups, enantiomers and diastereomers, and salts, preferably pharmaceutically acceptable salts, thereof. Preferred substituent groups for the biphenyl group include those groups R
11
to R
14
described herein and especially, when the biphenyl group is a 2-biphenyl
group, the group
in the 4′-position.
Preferred methods of the present invention allow preparation of compounds of the following formula Ia:
enantiomers and diastereomers, and salts, preferably pharmaceutically acceptable salts, thereof. Throughout this specification, the above symbols are defined as follows:
one of X and Y is N and the other is O;
R
1
, R
2
, R
3
and R
4
are each directly bonded to a ring carbon and are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z
1
, Z
2
and Z
3
;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) —C(O)H or —C(O)R
5
;
(h) —CO
2
H or —CO
2
R
5
;
(i) −Z
4
—NR
6
R
7
;
(j) —Z
4
—N(R
10
)—Z
5
—NR
8
R
9
; or
(k) R
3
and R
4
together may also be alkylene or alkenylene, either of which may be substituted with Z
1
, Z
2
and Z
3
, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;
R
5
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and z
3
;
R
6
, R
7
, R
8
, R
9
and R
10
are each independently
(a) hydrogen; or
(b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
; or
R
6
and R
7
together may be alkylene or alkenylene, either of which may be substituted with Z
1
, Z
2
and Z
3
, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R
8
, R
9
and R
10
together are alkylene or alkenylene, either of which may be substituted with Z
1
, Z
2
and Z
3
, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
R
11
, R
12
, R
13
and R
14
are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z
1
, Z
2
and Z
3
,
(c) heterocycle, substituted heterocycle or heterocyclooxy;
(d) halo;
(e) hydroxyl;
(f) cyano;
(g) nitro;
(h) —C(O)H or —C(O)R
5
;
(i) —CO
2
H or —CO
2
R
5
;
(j) —SH, —S(O)
n
R
5
, —S(O)
m
—OH, —S(O)
m
—OR
5
, —O—S(O)m—OR
5
, —O—S(O)
m
OH or —O—S(O)
m
—OR
5
;
(k) —Z
4
—NR
6
R
7
; or
(l) —Z
4
—N(R
10
)—Z
5
—NR
8
R
9
;
Z
1
, Z
2
and Z
3
are each independently
(a) hydrogen;
(b) halo;
(c) hydroxy;
(d) alkyl;
(e) alkenyl;
(f) aryl;
(g) aralkyl;
(h) alkoxy;
(i) aryloxy;
(j) aralkoxy;
(k) heterocycle, substituted heterocycle or heterocyclooxy;
(l) —SH, —S(O)
n
Z
6
, —S(O)
m
—OH, —S(O)
m
—OZ
6
, —O—S(O)
m
—Z
6
, —O—S(O)
m
OH or —O—S(O)
m
—OZ
6
;
(m) oxo;
(n) nitro;
(o) cyano;
(p) —C(O)H or —C(O)Z
6
;
(q) —CO
2
H or —CO
2
Z
6
;
(r) —Z
4
—NZ
7
Z
8
;
(s) —Z
4
—N(Z
11
) —Z
5
—H;
(t) —Z
4
—N(Z
11
) —Z
5
—Z
6
; or
(u) —Z
4
—N(Z
11
) —Z
5
—Nz
7
Z
8
;
Z
4
and Z
5
are each independently
(a) a single bond;
(b) —Z
9
—s(O)
n
—Z
10
—;
(c) —Z
9
—C(O) —Z
10
—;
(d) —Z
9
—C(s)—Z
10
—;
(e) —Z
9
—O—Z
10
—;
(f) —Z
9
—S—Z
10
—;
(g) —Z
9
—O—C(O)—Z
10
—; or
(h) —Z
9
—C(O)—O—Z
10
—;
Z
6
is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycloalkenylalkyl; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocycle or substituted heterocycle;
Z
7
and Z
8
are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, or Z
7
and Z
8
together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;
Z
9
and Z
10
are each independently a single bond, alkylene, alkenylene or alkynylene;
Z
11
is
(a) hydrogen; or
(b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl;
or any two of Z
7
, Z
8
and Z
11
together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
J is O, S, N or NR
15
;
K and L are N or C, provided that at least one of K or L is C;
R
15
is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl;
each m is independently 1 or 2;
each n is independently 0, 1 or 2; and
p is 0 or an integer from 1 to 2.
In accordance herewith, a compound of the formula I or salt thereof may be prepared by a method comprising the steps of:
(a) contacting an arylboronic acid of the formula II:
 or pinacol ester or salt thereof, wherein R is an alkyl group and where the phenyl ring of said formula II may be further substituted, such as with one or more groups described for the groups R
11
to R
14
herein, with a halophenyl compound of the formula III or salt thereof:
 wherein the halo group is preferably bromo or iodo and wherein the phenyl ring of said formula III may be further substituted, such as with one or more groups described for the groups R
11
to R
14
herein, and especially, when the biphenyl group of said compound of the formula I or salt thereof is a 2-biphenyl, the group
 para to the halo group, in the presence of a palladium(0) catalyst and a base containing an alkali metal atom selected from sodium, potassium or lithium, to form a compound of the formula IV or salt thereof:
 and converting said compound IV or salt thereof to a compound V or salt thereof with a chlorinating agent:
 where the phenyl rings of the biphenyl groups of formulae IV or V may independently be unsubstituted or substituted with one or more substituent groups; and M is sodium, potassium or lithium; and
(b) coupling the compound of formula V or salt thereof with a compound of formula VI
in the presence of a base to form said formula I or salt thereof.
 In a preferred embodiment, a compound of the formula Ia or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a boronic acid of the formula IIa or salt thereof:
 wherein R is an alkyl group, with a halophenyl compound of the formula IIIa or salt thereof:
 in the presence of a palladium(0) catalyst and a base containing an alkali metal atom selected from sodium, potassium or lithium, to form a compound of formula IVa or salt thereof:
 wherein M is lithium, sodium or potassium; and converting compound IVa to compound Va with a chlorinating agent:
 and
(b) coupling said formula Va compound or salt thereof with a compound of formula VI in the presence of a base to form said compound of the formula Ia or salt thereof.
The present methods for preparing a compound of the formula I or salt thereof are advantageous in that they provide high yields with minimal o

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