Efficient method for the conversion of nitriles to amidines

Details Efficient method for the conversion of nitriles to amidines Efficient method for the conversion of nitriles to amidines

2002-04-25

2003-08-26

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S247000

Reexamination Certificate

active

06610858

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to processes for the conversion of cyano groups into amidines for the purpose of producing compounds which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex. These compounds may be used for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
BACKGROUND
There are several methods to convert cyano groups into amidine groups (S. Patai, Z. Rappoport, The Chemistry of Amidines and Imidates, 1991, John Wiley & Sons Ltd.). One of the most widely used methods for the preparation of amidines is the Pinner synthesis (R. Roger, D. G. Neilson,
Chem. Rev.
1961, 61, 179-211), which proceeds in two steps through an imidate intermediate.
Abood et al, in U.S. Pat. No. 5,484,946, discusses formation of the amidine moiety from a nitrile group through an amidoxime intermediate. Jendrall et al, in
Tetrahedron
1995, 51, 12047-12068, used a similar process to convert a cyano group into the amidinium functionality. Eloy and Leners, in
Chem. Rev.,
1962, 62, 155-183, review the preparation of amidoximes from nitriles. Chio and Shine, in
J. Heterocyclic Chem.,
1989, 26, 125-128, reported that these amidoximes can be transformed into 1,2,4-oxadiazole derivatives. Judkins et al, in
Synthetic Commun.
1996, 26, 4351, describe formation of amidine moiety from nitrile through an amidoxime intermediate under acetylation or acylation conditions.
This literature however, does not disclose any regioselectivity between an amidoxime and an isoxazoline. In fact, Mueller et al,
Angew. Chem.,
1994, 106, 1305-1308, report that hydrogenation with 10% Pd/C will reduce a isoxazoline ring system. There is also no precedent for the transformation of a cyano group into an amidine functionality through a 1,2,4-oxadiazole moiety, and therefore the conversion of a 1,2,4-oxadiazole into amidine directly through catalytic hydrogenation is not taught.
Compounds of generic form (I) are antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex which are currently being evaluated for the inhibition of platelet aggregation, as thrombolytics, and for the treatment of thromboembolic disorders. Consequently, large quantities of these compounds are needed to support drug development studies.
The preparation of compounds of generic form (I) have been disclosed in U.S. Pat. No. 5,446,056, PCT international publication WO 95/14683, PCT international publication WO 96/38426, pending and commonly owned U.S. application Ser. No. 08/700,906, and in
J. Med. Chem.,
Xue et al, 1997, 40, 2064-2084. The preparation of (X) has been disclosed by Zhang et al in
Tetrahedron Lett.
1996, 37, 4455-4458 and
J. Org. Chem.
1997, 62, 2466-2470, which describe amidine formation from a nitrile using the Pinner reaction. Although this process has been able to produce compounds of formula (X) on a multikilogram scale, employing the Pinner reaction on a commercial scale poses several disadvantages. The Pinner approach involves the use of an excess of hydrogen chloride gas which is environmentally unfriendly, and removal of the inorganic salts generated during the Pinner process requires extensive purification protocols. It was therefore necessary to develop an efficient, safer process to produce compounds of formula (I) on large scale.
SUMMARY OF THE INVENTION
The present invention relates generally to processes for the conversion of cyano groups into amidines for the purpose of producing compounds, and intermediates therefore, which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex. These compounds may be used for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
There is provided by this invention a process for the preparation of compounds of formula (I), (III), (IV), (V) and (VI):
wherein:
R
1
is selected from H or NHR
1a
;
R
1a
is selected from the group consisting of:
—C(═O)—O—R
1b
,
—C(═O)—R
1b
,
—C(═O)N(R
1b
)
2
,
—C(═O)NHSO
2
R
1b
,
—C(═O)NHC(═O)R
1b
,
—C(═O)NHC(═O)OR
1b
,
—C(═O)NHSO
2
NHR
1b
,
—C(═S)—NH—R
1b
,
—NH—C(═O)—O—R
1b
,
—NH—C(═O)R
1b
,
—NH—C(═)—NH—R
1b
,
—SO
2
—O—R
1b
,
—SO
2
—R
1b
,
—SO
2
—N(R
1b
)
2
,
—SO
2
—NHC(═O)OR
1b
,
—P(═S)(OR
1b
)
2
,
—P(═O)(OR
1b
)
2
,
—P(═S)(R
1b
)
2
,
—P(═O)(R
1b
)
2
, and
R
1b
is selected from the group consisting of:
C
1
-C
8
alkyl substituted with 0-2 R
1c
,
C
2
-C
8
alkenyl substituted with 0-2 R
1c
,
C
2
-C
8
alkynyl substituted with 0-2 R
1c
,
C
3
-C
8
cycloalkyl substituted with 0-2 R
1c
,
aryl substituted with 0-4 R
1c
,
aryl(C
1
-C
6
alkyl)-substituted with 0-4 R
1c
,
a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R
1c
, and
C
1
-C
6
alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4R
1c
;
R
1c
is H, halogen, CF
3
, CN, NO
2
, C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
3
-C
11
cycloalkyl, C
4
-C
11
cycloalkylalkyl, aryl, aryl(C
1
-C
6
alkyl)-, C
1
-C
6
alkoxy, and C
2
-C
5
alkoxycarbonyl;
R
2
is selected from H or C
1
-C
10
alkyl;
R
3
and R
4
are independently selected from the group consisting of H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
7
cycloalkyl, and aryl substituted with 0-2 R
3a
;
R
3a
is selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo, CF
3
, NO
2
, and NR
3b
R
3c
;
R
3b
and R
3c
are each independently selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
alkoxycarbonyl, C
2
-C
10
alkylcarbonyl, C
1
-C
10
alkylsulfonyl, heteroaryl(C
1
-C
4
alkyl)sulfonyl, aryl(C
1
-C
10
alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 R
3d
;
R
3d
is selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo, CF
3
, and NO
2
;
R
5
is selected from the group consisting of:
hydroxy, C
1
-C
10
alkyloxy, C
3
-C
11
cycloalkyloxy,
C
6
-C
10
aryloxy, C
7
-C
11
arylalkyloxy,
C
3
-C
10
alkylcarbonyloxyalkyloxy,
C
3
-C
10
alkoxycarbonyloxyalkyloxy,
C
3
-C
10
alkoxycarbonylalkyloxy,
C
5
-C
10
cycloalkylcarbonyloxyalkyloxy,
C
5
-C
10
cycloalkoxycarbonyloxyalkyloxy,
C
5
-C
10
cycloalkoxycarbonylalkyloxy,
C
8
-C
11
aryloxycarbonylalkyloxy,
C
8
-C
12
aryloxycarbonyloxyalkyloxy,
C
8
-C
12
arylcarbonyloxyalkyloxy,
C
5
-C
10
alkoxyalkylcarbonyloxyalkyloxy,
5-(C
5
-C
10
alkyl)-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, and
(R
5a
)HN-(C
1
-C
10
alkoxy)-;
R
5a
is selected from the group consisting of H, C
1
-C
4
alkyl, aryl(C
1
-C
10
alkoxy)carbonyl, C
2
-C
10
alkoxycarbonyl, and C
3
-C
6
alkenyl;
R
6
is selected from the group consisting of H, CF
3
, CF
2
CF
3
, CF
2
CF
2
CF
3
, CF
2
CF
2
CF
2
CF
3
, C
1
-C
8
alkyl, C
1
-C
8
perfluoroalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
11
cycloalkyl, C
4
-C
11
cycloalkylalkyl, aryl(C
1
-C
6
alkyl)-, C
1
-C
6
alkoxy, C
7
-C
10
arylalkyloxy, aryloxy and aryl substituted with 0-5 R
6c
;
R
6c
is selected from the group consisting of H, halo, CF
3
, CN, NO
2
, NR
6d
R
6e
, C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
3
-C
11
cycloalkyl, C
4
-C
11
cycloalkylalkyl, aryl, aryl(C
1
-C
6
alkyl)-, C
1
-C
6
alkoxy, and C
2
-C
5
alkoxycarbonyl;
R
6d
and R
6e
are independently selected from the group consisting of H, C
1
-C
10
alkyl, C
2
-C
10
alkoxycarbonyl, C
2
-C
10
alkylcarbonyl, C
1
-C
10
alkylsulfonyl, aryl, aryl(C
1
-C
10
alkyl)sulfonyl, arylsulfonyl, heteroaryl(C
1
-C
4
alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, or heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 substituents selected from the group

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