Synthesis for 4-aryl-5-pyrimidine imidazole substituted...

Details Synthesis for 4-aryl-5-pyrimidine imidazole substituted... Synthesis for 4-aryl-5-pyrimidine imidazole substituted...

1998-12-16

2001-05-29

Higel, Floyd D. (Department: 1613)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S333500

Reexamination Certificate

active

06239279

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel method for synthesizing imidazole derivatives having 4-aryl, 5-pyrimidine heterocyclic rings.
BACKGROUND OF THE INVENTION
The present invention describes a novel, and general method to prepare 5-pyrimidinyl substituted imidazoles. Previous syntheses of this class of molecules utilized the van Leusen reaction (van Leusen, A. M., et. al.
J. Org. Chem.
1977, 42, 1153), which involves the cycloaddition of an imine and a tosylisonitrile. Difficulties in preparing the aldehyde precursors to the desired imines limited the scope of this approach. In Adams et al., WO 95/02591 an improvement on the cycloaddition reaction is shown for similar compounds. However addition of a pyrimidine ring in an environmentally favourable and commercially feasible manner is still needed. The present invention employs a novel method of cycloaddition of a tosylisonitrile with an &agr;-ketoaldimine to produce a 5-keto imidazole derivative. The 5-keto group serves as an excellent precursor for addition of the optionally substituted pyrimidine ring.
SUMMARY OF THE INVENTION
The present invention is to a process of making compounds of Formula (I),
wherein
R
1
is an optionally substituted pyrimidin-4-yl ring;
R
4
is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring;
m is 0, or the integer 1 or 2;
m′ is an integer having a value of 1 or 2,
R
2
is —(CR
10
R
20
)
n′
OR
9
, heterocyclyl, heterocyclylC
1-10
alkyl, C
1-10
alkyl, halo-substituted C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-10
alkyl, C
5-7
cycloalkenyl, C
5-7
cycloalkenyl-C
1-10
-alkyl, aryl, arylC
1-10
alkyl, heteroaryl, heteroaryl-C
1-10
-alkyl, (CR
10
R
20
)
n
OR
11
, (CR
10
R
20
)
n
S(O)
m
R
18
, (CR
10
R
20
)
n
NHS(O)
2
R
18
, (CR
10
R
20
)
n
NR
13
R
14
, (CR
10
R
20
)
n
NO
2
, (CR
10
R
20
)
n
CN, (CR
10
R
20
)
n′
SO
2
R
18
, (CR
10
R
20
)
n
S(O)
m′
NR
13
R
14
, (CR
10
R
20
)
n
C(Z)R
11
, (CR
10
R
20
)
n
OC(Z)
11
, (CR
10
R
20
)
n
C(Z)OR
11
, (CR
10
R
20
)
n
C(Z)NR
13
R
14
, (CR
10
R
20
)
n
C(Z)NR
11
OR
9
, (CR
10
R
20
)
n
NR
10
C(Z)R
11
, (CR
10
R
20
)
n
NR
10
C(Z)NR
13
R
14
, (CR
10
R
20
)
n
N(OR
6
)C(Z)NR
13
R
14
, (CR
10
R
20
)
n
N(OR
6
)C(Z)R
11
, (CR
10
R
20
)
n
C(═NOR
6
)R
11
, (CR
10
R
20
)
n
NR
10
C(═NR
19
)NR
13
R
14
, (CR
10
R
20
)
n
OC(Z)NR
13
R
14
, (CR
10
R
20
)
n
NR
10
C(Z)NR
13
R
14
, (CR
10
R
20
)
n
NR
10
C(Z)OR
10
, 5-(R
18
)-1,2,4-oxadiazol-3-yl or 4-(R
12
)-5-(R
18
R
19
)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;
n is an integer having a value of 1 to 10;
n′ is 0, or an integer having a value of 1 to 10;
Z is oxygen or sulfur,
R
3
is heterocyclyl, heterocyclylC
1-10
alkyl or R
8
;
R
6
is hydrogen, a pharmaceutically acceptable cation, C
1-10
alkyl, C
3-7
cycloalkyl, aryl, arylC
1-4
alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C
1-10
alkanoyl;
R
8
is C
1-10
alkyl, halo-substituted C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-7
cycloalkyl, C
5-7
cycloalkenyl, aryl, arylC
1-10
alkyl, heteroaryl, heteroarylC
1-10
alkyl, (CR
10
R
20
)
n
OR
11
, (CR
10
R
20
)
n
S(O)
m
R
18
, (CR
10
R
20
)
n
NHS(O)
2
R
18
, (CR
10
R
20
)
n
NR
13
R
14
; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;
R
9
is hydrogen, —C(Z)R
11
or optionally substituted C
1-10
alkyl, S(O)
2
R
18
, optionally substituted aryl or optionally substituted aryl-C
1-4
alkyl;
R
10
and R
20
is each independently selected from hydrogen or C
1-4
alkyl;
R
11
is hydrogen, C
1-10
alkyl, C
3-7
cycloalkyl, heterocyclyl, heterocyclyl C
1-10
alkyl, aryl, arylC
1-10
alkyl, heteroaryl or heteroarylC
1-10
alkyl;
R
12
is hydrogen or R
16
;
R
13
and R
14
is each independently selected from hydrogen or optionally substituted C
1-4
alkyl, optionally substituted aryl or optionally substituted aryl-C
1-4
alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR
9
;
R
16
is C
1-4
alkyl, halo-substituted-C
1-4
alkyl, or C
3-7
cycloalkyl;
R
18
is C
1-10
alkyl, C
3-7
cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C
1-10
alkyl, heteroaryl or heteroarylalkyl; and
R
19
is hydrogen, cyano, C
1-4
alkyl, C
3-7
cycloalkyl or aryl;
which process comprises:
a) reacting a compound of formula (II), as defined below
 wherein R is the optional substituent on the pyrimidinyl (R
1
) moiety in Formula (I), or is hydrogen, an optionally substituted alkyl or an optionally substituted aryl, with a compound of the Formula R
2
NH
2
(III), wherein R
2
is as defined for Formula (I), to yield a compound of Formula (IV)
 wherein R and R
2
are as defined above; and
b) reacting a compound of Formula (IV) with a compound of Formula (V) and a suitable base,
 wherein Ar is an optionally substituted aryl; and R
4
is as defined for Formula (I); to yield a compound of Formula (VI)
 wherein R, R
2
and R
4
are as defined above; and
c) reacting a compound of Formula (VI) with a compound of Formula VII
 wherein R
a
is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl group all of which are unsubstituted or substituted; and R
b
is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl group all of which may be optionally substituted; to yield a compound of Formula (VIII)
 wherein R
b
is as defined above for Formula (VII), R is as defined above, and R
2
and R
4
are defined as for Formula (I);
d) reacting a compound of Formula (VIII) with a compound of Formula (IX)
 wherein
Z is N(R
d
)
2
, SR
e
, OR
e
, or R
d
,
R
d
is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl;
R
e
is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl; and
Y is O, S, or NH;
 to yield a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention are the novel compounds of Formula (VI), and (VIII) as defined herein.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel synthesis of a group of imidazole compounds, whose general structure is shown above in Formula (I) above, and further as described in Adams et al., WO 95/02591; Adams et al., WO 96/21452, published Jul. 18, 1996; Adams et al., WO 96/21654, published Jul. 18, 1996; and Adams et al., U.S. Ser. No. 08/659,102 filed Jun. 3, 1996 whose disclosures are all incorporated herein by reference.
Preferred compounds of Formula (I) have the structure:
wherein
R
1
is pyrimidin-4-yl which ring is optionally substituted with one or two substituents each of which is independently selected from optionally substituted C
1-10
alkyl, optionally substituted aryl, halogen, hydroxyl, thiol, C
1-10
alkoxy, C
1-10
alkylthio, C
1-10
alkylsulfinyl, CH
2
OR
12
, amino, mono or di-C
1-10
alkyl substituted amino, NHR
21
, N(R
10
)C(O)R
a
or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR
15
;
R
4
is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring;
m is 0, or the integer 1 or 2;
m′ is an integer having a value of 1 or 2,
m″ is 0, or an integer having a value of 1 to 5;
R
2
is —(CR
10
R
20
)
n′
OR
9
, heterocyclyl, heterocyclylC
1-10
alkyl, C
1-10
alkyl, halo-substituted C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-10
alkyl, C
5-7
cycloalkenyl, C
5-7
cycloalkenyl-C
1-10
-alkyl, aryl, arylC
1-10
alkyl, heteroaryl, heteroaryl-C
1-10
-alkyl, (CR
10
R
20
)
n
OR
11
, (CR

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