Synthesis of 1,3,5-trisubstituted pyrazoles

Details Synthesis of 1,3,5-trisubstituted pyrazoles Synthesis of 1,3,5-trisubstituted pyrazoles

2001-12-03

2002-10-15

Solola, T A (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

54

Reexamination Certificate

active

06465656

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to processes for the preparation of 1,3,5-trisubstituted pyrazoles and intermediates for the synthesis of the same, such pyrazoles being useful as factor Xa inhibitors.
BACKGROUND OF THE INVENTION
1,3,5-Trisubstituted-pyrazole compounds of the type shown below are currently being studied as factor Xa inhibitors in clinical settings. As one of ordinary skill in the art understands, clinical trials and NDA submissions require practical, large-scale synthesis of the active drug.
Consequently, it is desirable to find new synthetic procedures for making 1,3,5-trisubstituted pyrazoles.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide a novel process for making 1,3,5-trisubstituted pyrazoles.
It is another object of the present invention to provide novel intermediates for the syntheses of the same 1,3,5-trisubstituted pyrazoles.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula I can be formed from aryl hydrazines.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in a first embodiment, the present invention provides a novel process for preparing a compound of formula I:
wherein ring D is selected from 2-(aminomethyl)phenyl, 3-(aminomethyl)phenyl, and (3-amino)benz[d]isoxazol-6-yl; and
B is 2-MeSO
2
-phenyl or 2-NH
2
SO
2
-phenyl, the process comprising:
(a) acylating a hydrazine of formula II to form a compound of formula III:
 wherein ring D is selected from 2-cyanophenyl, 3-cyanophenyl, 3-cyano-4-fluorophenyl, 2-(PgNHCH
2
)phenyl, and 3-(PgNHCH
2
)phenyl, and Pg is an amine protecting group;
(b) converting a compound of formula III to a compound of formula IV, wherein X is selected from Cl, OMs, Br, OSO
2
Ph, and OTs;
(c) contacting a compound of formula IV with a base to form a dipolar compound of formula V:
(d) contacting a compound of formula V in situ with a dipolarophile of formula VI to form a compound of formula VII, wherein Y is selected from Br, 2-MeSO
2
-phenyl, 2-MeS-phenyl, 2-NH
2
SO
2
-phenyl, and 2-PgNHSO
2
-phenyl;
(e) converting a compound of formula VII to a compound of formula I by subjecting it to the following reactions, which may be performed, when applicable, in any order:
(e1) oxidizing the pyrazoline to a pyrazole;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO
2
Me-phenyl, or 2-SO
2
NH
2
-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO
2
—;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH
2
)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz [d]isoxazol-6-yl; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, step (b) is performed by contacting a compound of formula III with a sulfonyl chloride in the presence of an amine base, wherein the amine base is capable of forming a tertiary amine hydrogen chloride in situ and delivering a chloride in situ to form a compound of formula IV wherein X is Cl;
wherein the sulfonyl chloride is selected from methylsulfonyl chloride, phenylsulfonyl chloride and toluenesulfonyl chloride, the amine base is selected from triethylamine, diisopropylethylamine, and N-methylmorpholine.
In another embodiment, the sulfonyl chloride is phenylsulfonyl chloride and the amine base is diisopropylethylamine.
In another embodiment, step (b) is performed by contacting a compound of formula III with a sulfonyl chloride in the presence of an amine base, followed by contacting the resultant sulfonyl compound with a tertiary amine hydrogen chloride to form a compound of formula IV wherein X is Cl;
wherein the sulfonyl chloride is selected from methylsulfonyl chloride, phenylsulfonyl chloride and toluenesulfonyl chloride, the amine base is selected from triethylamine, diisopropylethylamine, and N-methylmorpholine.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e1) oxidizing the pyrazoline to a pyrazole;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO
2
Me-phenyl, or 2-SO
2
NH
2
-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO
2
—;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH
2
)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e1) oxidizing the pyrazoline to a pyrazole;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH
2
)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO
2
Me-phenyl, or 2-SO
2
NH
2
-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO
2
—; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO
2
Me-phenyl, or 2-SO
2
NH
2
-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO
2
—;
(e1) oxidizing the pyrazoline to a pyrazole;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH
2
)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e2a) when Y=Br, converting the Br group to 2-SO
2
Me-phenyl or 2-SO
2
NH
2
-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO
2
—;
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH
2
)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e1) oxidizing the pyrazoline to a pyrazole; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH
2
)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e1) oxidizing the pyrazoline to a pyrazole;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO
2
Me-phenyl, or 2-SO
2
NH
2
-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO
2
—; and,
(e4) when Pg is present, removing the protecting group.
In another embodiment, in (e) the compound of formula VII is converted to a compound of formula I by subjecting compound VII to the following reactions, that are performed, when applicable, in the order shown:
(e3a) when ring D is cyanophenyl, converting this group to aminomethylphenyl or (PgNHCH
2
)phenyl;
(e3b) when ring D is 3-cyano-4-fluorophenyl, converting this ring to (3-amino)benz[d]isoxazol-6-yl;
(e2a) when Y=Br, converting the Br group to 2-MeS-phenyl, 2-SO
2
Me-phenyl, or 2-SO
2
NH
2
-phenyl;
(e2b) when Y=2-MeS-phenyl, converting the MeS-group to MeSO
2
—;
(e1

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