US2004059123A1PendingUtilityA1
Methods for the preparation of biphenyl isoxazole sulfonamides
Priority: Oct 17, 2000Filed: Aug 12, 2003Published: Mar 25, 2004
Est. expiryOct 17, 2020(expired)· nominal 20-yr term from priority
C07F 5/025C07D 413/12A61P 9/12C07D 261/16C07D 261/14
43
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for the preparation of a biphenyl sulfonamide 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 thereof, wherein
one of X and Y is N and the other is O;
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;
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;
each m is independently 1 or 2; and
each n is independently 0, 1 or 2;
comprising the steps of
(a) contacting a pinacol ester of the formula II or salt thereof
where the phenyl ring of said formula II may be further substituted, and where “prot” denotes an alkoxymethyl nitrogen-protecting group,
with a compound of the formula III or salt thereof
where R 16 is halogen or a group —O-Q where
Q is —SO 2 CF 3 , —SO 2 CH 3 or
and where the phenyl ring of said formula III may be further substituted,
in the presence of a palladium(0) catalyst and, optionally, a base, to form a compound of the formula IV or salt thereof
where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups; and
(b) deprotecting the nitrogen of said compound of the formula IV or salt thereof to form said compound of the formula I or salt thereof.
2 . The method of claim 1 , for the preparation of a compound of the following formula Ia
and enantiomers and diastereomers, and salts thereof, wherein
R 1 and R 2 are each directly bonded to a ring carbon and are each independently selected from those groups (a) through (j) recited in claim 1 for R 3 and R 4 ;
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 ;
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; and
p is 0 or an integer from 1 to 2;
comprising the steps of:
(a) contacting a pinacol ester of the formula IIa or salt thereof
with a compound of the formula IIIa or salt thereof
in the presence of a palladium(0) catalyst and, optionally, a base, to form a compound of the formula IVa or salt thereof
(b) deprotecting the nitrogen of said formula IVa compound or salt thereof to form said compound of the formula Ia or salt thereof.
3 . The method of claim 2 , wherein said palladium(0) catalyst is a palladium (II) salt and triphenylphosphine.
4 . The method of claim 3 , wherein said palladium (II) salt is palladium acetate.
5 . The method of claim 2 , wherein said base is aqueous potassium carbonate or sodium carbonate.
6 . The method of claim 2 , wherein “prot” is methoxymethyl.
7 . The method of claim 2 , wherein the halo group in said compound of the formula IIIa or salt thereof is bromo, chloro, or iodo.
8 . The method of claim 2 , wherein said compound of the formula Ia or salt thereof is crystallized from solution subsequent to step (b).
9 . The method of claim 2 , wherein residual palladium is removed subsequent to step (a) by use of a chelating agent.
10 . The method of claim 2 , wherein said compound of the formula IIa or salt thereof is N-[methoxymethyl]-N-(4,5-dimethyl-3-isoxazolyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfanamide, and said compound of the formula IIIa or salt thereof is 2-[4-Bromo-3-(formyl)phenyl]oxazole.
11 . A compound of the formula II or salt thereof
where the phenyl ring of said formula II may be further substituted, and where “prot” denotes an alkoxymethyl nitrogen-protecting group, and wherein
one of X and Y is N and the other is 0;
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;
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;
each m is independently 1 or 2; and
each n is independently 0, 1 or 2.
12 . A compound of claim 11 of the formula IIa or salt thereof
wherein
“prot” is methoxymethyl;
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—OS(O) m —OR 5 ;
(k)-Z 4 -NR 6 R 7 ; or
(l)-Z 4 -N(R 10 )-Z 5 -NR 8 R 9 .
13 . The compound of claim 12 , which is N-[methoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.
14 . A method for the preparation of a pinacol ester of the formula II or salt thereof
where the phenyl ring of said formula II may be further substituted, where “prot” denotes an alkoxymethyl nitrogen-protecting group, and wherein
one of X and Y is N and the other is 0;
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;
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;
each m is independently 1 or 2; and
each n is independently 0, 1 or 2;
comprising the steps of
(a) contacting a compound of the formula V or salt thereof
where the phenyl group of said formula V may be further substituted,
with an amine of the formula VI or salt thereof
in the presence of an organic base and optionally an organic solvent, to form a compound of the formula VII or salt thereof
where the phenyl group of said formula VII may be further substituted;
(b) protecting the nitrogen of said compound of the formula VII or salt thereof by contacting the compound of formula VII with a compound of formula XX
where R 17 is alkoxy or halogen, and R 18 is alkoxy,
in the presence of a Lewis or protic acid when R 17 is alkoxy, or in the presence of a base when R 17 is halo, to form a compound of the formula VIII or salt thereof
where the phenyl group of said formula VIII may be further substituted;
(c) lithiating said compound of the formula VIII or salt thereof with an alkyl or aryl lithium compound and contacting the lithiated product formed with a trialkylborate, followed by hydrolysis, to form a boronic acid of the formula IX or salt thereof
where the phenyl group of said formula IX may be further substituted; and
(d) contacting said compound of the formula IX or salt thereof with pinacol, with removal of water, thereby forming said compound of the formula II or salt thereof.
15 . The method of claim 14 for the preparation of a pinacol ester of the formula IIa or salt thereof,
where R 13 and R 14 are as defined in claim 2 , and “prot” is methoxymethyl,
comprising the steps of
(a) contacting a compound of the formula Va or salt thereof
with an amine of the formula VIa or salt thereof
in the presence of an organic base and optionally an organic solvent, to form a compound of the formula VIIa or salt thereof
(b) protecting the nitrogen of said compound of the formula VIIa or salt thereof by contacting the compound of formula VII with a compound of formula XX
where R 17 and R 18 are each methoxy, in the presence of a Lewis or protic acid to form a compound of the formula VIII or salt thereof:to form a compound of the formula VIIIa or salt thereof
(c) lithiating said compound of the formula VIIIa or salt thereof with an alkyl or aryl lithium compound and contacting the lithiated product formed with a trialkylborate, followed by hydrolysis, to form a boronic acid of the formula IXa or salt thereof
(d) contacting said compound of the formula IXa or salt thereof with pinacol, with removal of water, thereby forming said compound of the formula IIa or salt thereof.
16 . The method of claim 15 , wherein X is N and Y is O.
17 . The method of claim 15 , wherein the halo group of the compound of the formula Va or salt thereof is bromo, chloro or iodo.
18 . The method of claim 15 , wherein said leaving group is halo.
19 . The method of claim 18 , wherein said leaving group is chloro.
20 . The method of claim 15 , wherein the organic base in step (a) is an amine.
21 . The method of claim 20 , wherein said organic base is pyridine or a trialkylamine.
22 . The method of claim 15 , wherein said organic base also functions as an organic solvent.
23 . The method of claim 15 , wherein the alkyl or aryl lithium compound is n-butyl lithium or phenyl lithium.
24 . The method of claim 15 , wherein said lithiation and/or contact with said trialkylborate is conducted at temperatures from about −40° C. to about −105° C.
25 . The method of claim 15 , wherein said trialkylborate is triisopropylborate or trimethylborate.
26 . The method of claim 15 , wherein said removal of water is conducted by the addition of a drying agent, or by azeotropic removal of water by heating with a solvent.
27 . The method of claim 15 , wherein said compound of the formula IIa or salt thereof is N-[methoxymethyl]-N-(4,5-dimethyl-3-isoxazolyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, said compound of the formula Va or salt thereof is 2-bromobenzenesulfonyl chloride, and said amine of the formula VIa or salt thereof is 3-amino-4,5-dimethylisoxazole.
28 . A method for the preparation of a compound of the formula I or salt thereof
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 thereof,
wherein
one of X and Y is N and the other is 0;
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;
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;
each m is independently 1 or 2; and
each n is independently 0, 1 or 2;
comprising the steps of
(a) contacting a boronic acid of the formula IX or salt thereof
where the phenyl group of said formula IX may be further substituted, and wherein “prot” is an alkoxymethyl nitrogen-protecting group,
with a compound of formula III or salt thereof
where R 16 is halogen or a group —O-Q where Q is —SO 2 CF 3 , —SO 2 CH 3 , or
and where the phenyl ring of said formula III may be further substituted,
in the presence of a palladium(0) catalyst and, optionally a base, to form a nitrogen-protected compound of the formula IV or salt thereof
where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups; and
(b) deprotecting the nitrogen of said compound of the formula IV or salt thereof to form said compound of the formula I or salt thereof.
29 . The method of claim 28 , for the preparation of a compound of the following formula Ia
and enantiomers and diastereomers, and salts thereof, wherein
R 1 and R 2 are each directly bonded to a ring carbon and are each independently selected from those groups (a) through (j) recited above for R 3 and R 4 ;
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 ;
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; and
p is 0 or an integer from 1 to 2;
comprising the steps of:
(a) contacting a boronic acid of the formula IXa or salt thereof
where “prot” is methoxymethyl, with a compound of the formula IIIa or salt thereof
in the presence of a palladium(0) catalyst and, optionally a base, to form a nitrogen-protected compound of the formula IVa or salt thereof
(b) deprotecting the nitrogen of said formula IVa compound or salt thereof to form said compound of the formula Ia or salt thereof.
30 . A method for the preparation of an oxazole phenyl halide of the formula IIIa(1) or salt thereof
Where R 11 and R 12 are as defined in claim 2 and R 16 is halogen or a group —O-Q where Q is —SO 2 CF 3 , —SO 2 CH 3 or
comprising the steps of
(a) contacting a phenyl acid halide compound of formula X or salt thereof
with either triazole in the presence of a base, or an N-trimethylsilyl derivative of triazole, to form a triazole amide the formula XI or salt thereof
(b) effecting a nitrogen elimination rearrangement of the triazole amide of formula XI or salt thereof, to form an oxazole of the formula IIIa(1) or salt thereof.
31 . The method of claim 30 , wherein, in said compound of formula X, the halo group of the acid halide moiety is chloro, and R 16 is chloro, bromo, or iodo.
32 . The method of claim 31 , wherein R 11 is dihalomethyl and R 12 is hydrogen.
33 . The method of claim 30 wherein the compound of formula X is contacted with triazole in the presence of sodium hydride.
34 . A method for the preparation of compounds of the formula IIIa(2) or salts thereof.
comprising the step of
(a) hydrolyzing a compound of formula IIIb or salt thereof
where *R 11 is dihalomethyl,
in the presence of a nucleophilic base to form a compound of formula IIIa(2).
35 . The method of claim 34 wherein the compound of formula IIIb is prepared by a method comprising the steps of
(a) contacting a compound of formula XXI
with a suitable halogenating agent to form a compound of the formula XXII
(b) converting said compound of formula XXII to an aryl acid halide compound of formula Xa
(c) converting said compound of formula Xa to a compound of formula IIIb by either of the following processes (i) or (ii)
(i) contacting the compound of formula Xa with either triazole in the presence of a base, or an N-trimethylsilyl derivative of triazole, to form a triazole amide the formula XI or salt thereof
and effecting a nitrogen elimination rearrangement of the triazole amide of formula XI or salt thereof, to form an oxazole of the formula IIIb; or
(ii) contacting the compound of formula Xa with with an amine acetal of the formula
in the presence of a base and a solvent, to form an amide acetal of the formula
and cyclizing the amide acetal in the presence of a cyclization agent, to form a compound of the formula IIIb.
36 . The method of claim 34 where R 16 is bromo or iodo, and *R 11 is dibromomethyl.
37 . The method of claim 35 where R 16 is bromo or iodo, and *R 11 is dibromomethyl.
38 . The method of claim 35 where the compound of formula Xa is converted to the compound of formula IIIb using the process (i).
39 . The method of claim 35 where the compound of formula XXIII is converted to the compound of formula IIIb using the process (ii).
40 . A method for the preparation of compounds of the formula Ia or salts thereof
wherein
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 (1)-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;
comprising the steps of
(a) lithiating a compound of the formula IIIa or salt thereof
with an alkyl or aryl lithium compound in the presence of a trialkylborate, followed by hydrolysis, to form a boronic acid of the formula XIII or salt thereof
(b) contacting the boronic acid of the formula XIII or salt thereof with a compound of the formula VIII or salt thereof
in the presence of a palladium(0) catalyst and, optionally a base, to form a compound of the formula IVa or salt thereof.
(c) deprotecting the nitrogen of said formula IVa compound or salt thereof to form said compound of the formula Ia or salt thereof.
41 . The compound N-(4,5-Dimethyl-3-isoxazolyl)-2′-formyl-N-[methoxymethyl]4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide.
42 . A high melt polymorph of the compound N-[[2′-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1′-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide having a melting point of about 166-168° C.
43 . A high melt polymorph of the N-[[2′-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1′-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide having a melting point of about 156-158° C.
44 . A high melt polymorph of the compound N-[[2′-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1′-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide having a melting point of about 116-118° C.Join the waitlist — get patent alerts
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