Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-27
2003-11-11
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06646128
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to processes for the regioselective preparation of heterocyclo-alkylsulfonyl pyrazole derivatives and their synthetic intermediates. The pyrazole compounds prepared by the processes of this invention are useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. It is believed that the pyrazole compounds prepared by the processes of this invention inhibit the biosynthesis of prostaglandins by intervention of the action of the enzyme cyclooxygenase on arachidonic acid.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in treating pain and the signs and symptoms of arthritis because of their analgesic and anti-inflammatory activity. It is accepted that common NSAIDs work by blocking the activity of cyclooxygenase (hereinafter referred to as “COX”), also known as prostaglandin G/H synthase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandins, especially prostaglandin E
2
(PGE
2
), which is the predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of the biosynthesis of prostaglandins has been a therapeutic target of anti-inflammatory drug discovery.
A variety of sulfonylbenzene compounds which inhibit COX have been disclosed in patent publications (WO 97/16435, WO 97/14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO 96/936617, WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845, and EP 554829). International Publication Number WO 97/11704 discloses pyrazole compounds substituted by optionally substituted aryl.
The production of the compounds of formula 1 with a yield and purity suitable for commercial use has presented several difficulties. As described in detail below, the use of previously disclosed methods results in the production of significant amounts of the regioisomer of the compound of formula 1, which is difficult to separate from the compound of formula 1 without significant loss of yield. Applicants' investigations have revealed that preparing the compound of formula 1 at low temperatures favors the regioselective production of the compound of formula 1 but provides poor yields and the presence of an intermediate as a major impurity. On the other hand, maintaining the reaction temperature high enough to allow the consumption of the intermediates causes another problem, namely, the production of the regioisomer of the compound of formula 1.
Applicants solved these problems by discovering unexpectedly that the use of water as a co-solvent in the reaction provided the following benefits: (1) the production of the regioisomer of the compound of formula 1 is minimized, thereby resulting in the formation of the compound of formula 1 with high regioselectivity; and (2) the compound of formula 1 is formed with high yield. In addition, the use of water allows the regioselective production of the compound of formula 1 over a broad range of temperatures.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of formula 1:
which comprises combining
(a) a compound of formula 2:
(b) a compound of formula 3:
(c) one or more acids;
(d) one or more water-miscible organic solvents; and
(e) water;
wherein
R
1
is phenyl optionally substituted by 1-3 substituents independently selected from the group consisting of halo, hydroxy, cyano, mercapto, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
1
-C
6
)alkoxy, —OCF
3
, (C
1
-C
6
)alkyl-S—, (C
1
-C
6
)alkyl-S(═O)—, (C
1
-C
6
)alkyl-SO
2
—, amino, (C
1
-C
6
)alkylamino, di[(C
1
-C
6
)alkyl]amino, H
2
N—(C↑O)—, (C
1
-C
6
)alkyl-NH—(C═O)— and formyl;
R
2
is hydrogen, halo or (C
1
-C
6
)alkyl;
R
3
is (C
1
-C
6
)alkyl optionally substituted with from one to three halo atoms; and
R
4
is (C
1
-C
6
)alkyl.
In an embodiment of the invention, R
1
is phenyl optionally substituted with one or two substituents independently selected from halo, hydroxy, mercapto, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy and (C
1
-C
6
)alkyl-S—. In a preferred embodiment of the invention, R
1
is unsubstituted phenyl.
In another embodiment of the invention, R
2
is chloro or fluoro. In a preferred embodiment of the invention, R
2
is chloro. In another preferred embodiment of the invention, R
2
is (C
1
-C
6
)alkyl; in a more preferred embodiment of the invention, R
2
is hydrogen or methyl. In a particularly preferred embodiment of the invention, R
2
is hydrogen.
In another embodiment of the invention, R
3
is (C
1
-C
6
)alkyl substituted with from one to three halo atoms. In a preferred embodiment of the invention, R
3
is (C
1
-C
3
)alkyl substituted with from one to three fluoro atoms. In a more preferred embodiment of the invention, R
3
is difluoromethyl or trifluoromethyl. In a particularly preferred embodiment of the invention, R
3
is difluoromethyl. In another particularly preferred embodiment of the invention, R
3
is trifluoromethyl.
In another preferred embodiment of the invention, R
4
is (C
1
-C
3
)alkyl. In a more preferred embodiment of the invention, R
4
is methyl.
In another embodiment of the invention, R
1
is unsubstituted phenyl and R
2
is hydrogen. In another embodiment of the invention, R
1
is unsubstituted phenyl, R
2
is hydrogen, R
3
is methyl substituted with one, two or three fluoro and R
4
is methyl. In a preferred embodiment of the invention, R
1
is unsubstituted phenyl, R
2
is hydrogen, R
3
is difluoromethyl or trifluoromethyl and R
4
is methyl. In a particularly preferred embodiment of the invention, R
1
is unsubstituted phenyl, R
2
is hydrogen, R
3
is difluoromethyl and R
4
is methyl.
In this application, the term “compound of formula 1” includes a compound of formula 1 as well as a compound of formula 1a, wherein R
3
is trifluoromethyl or difluoromethyl, and a compound of formula 1b:
The compounds of formula 1a and formula 1b are preferred embodiments of the compound of formula 1, to which all of the embodiments, preferred embodiments and particularly preferred embodiments of the processes described herein apply. The compound of formula 1a is a particularly preferred embodiment of the compound of formula 1, to which all of the embodiments, preferred embodiments and particularly preferred embodiments of the processes described herein apply. Accordingly, for the sake of brevity, the phrase “process for preparing a compound of formula 1” is to be understood for the purposes of this application as interchangeable with the phrase “process for preparing the compound of formula 1a” or the phrase, “process for preparing the compound of formula 1b.” It is to be further understood that the compounds of formula 2 and formula 3 used in the processes of the invention for preparing the compounds of formula 1a and formula 1b are to be understood as including the corresponding respective preferred substituents. For example, in a process for preparing a compound of formula 1a, in the compound of formula 2, R
1
is unsubstituted phenyl, R
2
is hydrogen and R
3
is difluoromethyl, while in the compound of formula 3, R
4
is methyl. Correspondingly, in a process for preparing the compound of formula 1b, in the compound of formula 2, R
1
is unsubstituted phenyl, R
2
is hydrogen and R
3
is trifluoromethyl, while in the compound of formula 3, R
4
is methyl.
It is to be noted that the term “mixture”, as used herein, unless otherwise indicated, is used without regard to the state of dispersion of the components thereof.
The term “miscible” as used herein with respect to two or more substances, unless otherwise indicated, means that the two or more substances are capable of forming a “true solution” as that term is understood in the art (see, e.g.,
Hawley's Condensed Chemical Dictionary,
13
th
ed. John Wiley & Sons, New York (1997), p. 103
Bourassa Dennis E.
Castaldi Michael J.
Ripin David B.
Benson Gregg C.
Morris Patricia L.
Munchhof Martha G.
Pfizer Inc.
Richardson Peter C.
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