Process for preparing 2-phenyl-3-aminopyridine, substituted...

Details Process for preparing 2-phenyl-3-aminopyridine, substituted... Process for preparing 2-phenyl-3-aminopyridine, substituted...

2000-05-11

2001-11-13

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S308000, C546S312000, C568S001000

Reexamination Certificate

active

06316632

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a method for preparing 2-phenyl-3-aminopyridine, its substituted phenyl derivatives, and salts thereof. 2-phenyl-3-aminopyridine and its substituted derivatives are useful in the preparation of compounds that have utility as substance P antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, members of which exert prompt stimulatory action on smooth muscle tissue. Substance P is a pharmaceutically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is described in U.S. Pat. No. 4,680,283. The involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For example, substance P has been shown to be involved in the transmission of pain or migraine, as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, and in gastrointestinal disorders such as ulcerative colitis, irritable bowel syndrome, and Crohn's disease. Tachykinin antagonists have been reported as useful in treating these conditions and in treating cardiovascular diseases, allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera, senile dementia of the Alzheimer type, emesis, sunburn, and Helicobacter pylori infection.
A variety of substance P antagonists can be prepared from 2-phenyl-3-aminopyridine. For example, U.S. Pat. No. 5,323,929 describes substance P antagonists of the formula
where R
3
is a substituted, or unsubstituted aryl, heteroaryl, or cycloalkyl group. These antagonists can be prepared by reduction of 2-phenyl-3-aminopyridine, followed by reductive amination of the resulting 2-phenyl-3-aminopiperidine using an appropriate aldehyde of the formula R
3
CHO. Alternately, these substance P antagonists can be obtained by reacting 2-phenyl-3-aminopyridine with a compound of the formula R
3
CHO or R
3
CH
2
X, where X is a leaving group, to produce the pyridine analog of the substance P antagonist. The pyridine analog is then reduced to obtain the final product.
Additional substance P antagonists that can be prepared from 2-phenyl-3-aminopyridine are described in U.S. Pat. No. 5,773,450, and in WO 97/08144 and PCT/IB97/01466. Methods employing 2-phenyl-3-aminopyridine to make substance P antagonists are also described in U.S. Pat. No. 5,232,929.
However, the conventional method employed to prepare 2-phenyl-3-aminopyridine, described by Miller and Farrell (Tetrahedron Letters, 1998, 39: 6441-6444) is air sensitive and results in a relatively low yield.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing 2-phenyl-3-aminopyridine substituted phenyl derivatives thereof, and salts thereof. In one aspect, the invention comprises reacting a compound of the formula
in a reaction inert solvent in the presence of a base and a palladium catalyst to obtain a compound of the formula
wherein:
X is Cl, Br, or I;
Z is H, (C
1
-C
4
) alkyl, methoxy, trifluoromethoxy, F, or Cl;
Ar is (C
6
-C
10
) aryl optionally substituted by from 1 to 3 R
5
groups;
R
1
is (C
1
-C
6
) straight or branched alkyl, (C
3
-C
7
) cycloalkyl, or (C
6
-C
10
) aryl, said alkyl, cycloalkyl, and aryl groups beings optionally substituted by from 1 to 3 R
5
groups;
R
3
and R
4
are independently selected from H, and (C
1
-C
6
) alkyl, wherein when R
3
and R
4
are (C
1
-C
6
) alkyl they may be fused together to form a ring structure; and
each R
5
is independently selected from halo, cyano, nitro, (C
1
-C
6
) halosubstituted alkyl, (C
1
-C
6
) alkoxy, (C
6
-C
10
) aryloxy, (C
1
-C
6
) halosubstituted alkoxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
2
-C
6
) alkynyl, (C
1
-C
6
) alkylthio, (C
1
-C
6
) alkylsulfinyl, (C
1
-C
6
) alkylsulfonyl, (C
1
-C
6
) alkyl-OC(O)—, (C
1
-C
6
) alkyl-OC(O)—(C
1
-C
6
) alkyl-, (C
1
-C
6
) alkyl-C(O)O—, (C
1
-C
6
) alkyl-C(O)—(C
1
-C
6
) alkyl-O—, (C
1
-C
6
) alkyl-C(O)—, (C
1
-C
6
) alkyl-C(O)—(C
1
-C
6
) alkyl-, (C
6
-C
10
) aryl-, (C
6
-C
10
) aryl-(C
1
-C
6
) alkyl-, and (C
3
-C
7
) cycloalkyl wherein one or two of the carbon atoms of said cycloalkyl may optionally be replaced by nitrogen, oxygen, or sulfur.
In a preferred embodiment, the compound of formula III or VII is prepared by reacting a compound of the formula
in a reaction inert solvent,
wherein:
Y is Cl, Br, I, or —C(O)R
2
;
and R
2
(C
1
-C
6
) is straight or branched alkyl, (C
3
-C
7
) cycloalkyl, or (C
6
-C
10
) aryl, said alkyl, cycloalkyl, and aryl groups beings optionally substituted by from 1 to 3 R
5
groups, wherein said reaction of compound III or VIII with compound IV occurs substantially simultaneously with, or subsequent to, said reaction of compound I with compound II or VII.
The compound of formula V is preferably deprotected in aqueous acid to obtain a salt of compound X.
In one aspect of the above-described method, the invention involves the steps of:
(a) reacting a compound of the formula
in a reaction inert solvent in the presence of a base to obtain a compound of the formula
(b) reacting the compound of formula III with a compound of the formula
in a reaction inert solvent in the presence of a base and a palladium catalyst to obtain a compound of the formula
and
(c) deprotecting the compound of formula V in aqueous acid to obtain a salt of a compound of the formula
wherein:
X, Y, Z, R
1
, R
2
, R
3
, R
4
, and R
5
are defined as described above. In another aspect of the above described method, the invention involves the steps of
(a) reacting a compound of the formula
with a compound of the formula ARCHO VII
in a reaction inert solvent to obtain a compound of the formula
and
(b) substantially simultaneously with, or subsequent to, step (a), reacting the compound of formula VIII with a compound of the formula
in a reaction inert solvent in the presence of a base and a palladium catalyst to obtain a compound of the formula
wherein step (a) is further conducted in the presence of a base where steps (a) and (b) are conducted substantially simultaneously,
and wherein Ar, X, Z, R
3
, R
4
, and R
5
are defined as described above.
In preferred embodiments of the invention, X is Cl, Z is H, and, where relevant, Y is Cl.
In a preferred embodiment, Ar is selected from phenyl and naphthyl optionally substituted by from 1 to 3 R
5
groups.
In other embodiments of the invention, R
1
and R
2
are the same, and preferably are both methyl.
In other embodiments, R
1
is methyl and R
2
is t-butyl.
In another embodiment, R
1
and R
2
are independently selected from (C
1
-C
6
) straight or branched alkyl, and phenyl.
In a further preferred embodiment, R
3
and R
4
are H.
In another preferred embodiment, each R
5
is independently selected from (C
1
-C
6
) straight or branched alkyl, phenyl, benzyl, trifluoromethyl, (C
1
-C
6
) alkoxy, F, Cl, and trifluoromethoxy.
In a further preferred embodiment, Z is H; R
1
and R
2
are the same, are independently selected from (C
1
-C
6
) straight or branched alkyl, and phenyl, and are optionally substituted by from 1 to 3 R
5
groups; R
3
and R
4
are H; and each R
5
is independently selected from (C
1
-C
6
) straight or branched alkyl, phenyl, benzyl, trifluoromethyl, (C
1
-C
6
) alkoxy, and trifluoromethoxy.
The term “alkyl” is used herein, unless otherwise indicated, to refer to a saturated monovalent hydrocarbon radical, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl.
The term “alkenyl” is used herein, unless otherwise indicated, to refer to a monovalent hydrocarbon radical having at least one carbon-carbon double bond, including but not limited to, vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, and encompassing E and Z isomers of such alkenyl radicals.
The term “alkynyl” is used herein, unless otherwise indicated, to refer to a monovalent hydrocarbon radical having at least on

Affiliated with

Also associated with

Rating

Process for preparing 2-phenyl-3-aminopyridine, substituted... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for preparing 2-phenyl-3-aminopyridine, substituted..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing 2-phenyl-3-aminopyridine, substituted... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2568375