Processes for the preparation of 1,5-diarylpyrazoles

Details Processes for the preparation of 1,5-diarylpyrazoles Processes for the preparation of 1,5-diarylpyrazoles

2002-09-18

2003-06-17

Ramsuer, Robert W. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06579988

ABSTRACT:

The present invention relates to processes for the preparation of 1,5-diarylpyrazoles, and chemical intermediates that serve as useful intermediates in the preparation of 1,5-diarylpyrazoles. 1,5-Diarylpyrazoles are particularly useful in the treatment of inflammation and inflammation-related disorders, including arthritis.
Selective inhibitors of cyclooxygenase-2 (COX-2) have demonstrated effective anti-inflammatory activity with reduced gastrointestinal side effects, as compared to other antiinflammatory agents, e.g., NSAIDs, that inhibit both the constitutive form of cyclooxygenase (COX-1), and the inducible form of the enzyme, COX-2. A particularly effective structural class of selective COX-2 inhibitors are the 1,5-diarylpyrazoles. For example, the compound, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (celecoxib®) has been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis and osteoarthritis.
Penning et al. (
J. Med. Chem.
1997, 40, 1347-1365) discloses that 1,5-diarylpyrazoles can be prepared by condensation of 1,3-dicarbonyl adducts with aryl hydrazines. The 1,3-dicarbonyl adducts can be prepared by Claisen condensations of aryl methyl ketones with carboxylic acid esters. In an alternate preparation, the 1,5-diarylpyrazoles can be synthesized by epoxidation of &bgr;-aryl-&agr;,&bgr;-unsaturated ketones, followed by condensation of the resulting epoxides with aryihydrazines.
SUMMARY OF THE INVENTION
In one embodiment, the invention relates to a process for preparing a compound of the formula
R
1
, R
3
and R
4
are independently selected from the group consisting of hydrogen; halogen; preferably fluoro, chloro, bromo or iodo; hydroxyl; nitro; C
1
to C
6
alkyl, preferably C
1
to C
3
alkyl; C
1
to C
6
alkoxy, preferably C
1
to C
3
alkoxy, more preferably methoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, more preferably trifluoromethyl; and cyano.
R
2
is amino; or lower alkyl, preferably C
1
to C
3
alkyl.
In preferred aspects, the invention relates to the process for preparing a compound having the formula
Preferably R
1
is methyl, particularly where R
2
is amino.
The process includes the step of condensing an alkyne of formula
with a phenyl hydrazine of the formula
or a salt thereof.
In some embodiments, the alkyne of the formula 3 is prepared by:
(i) adding bromine to a compound of formula
(ii) contacting the product of step (i) with a base.
In one embodiment, the compound of the formula 2 can be prepared by treating a compound of the formula
with trimethyl(trifluoromethyl)silane in the presence of cesium fluoride.
In an alternative embodiment, the compound of formula 3 can be prepared by a process that includes:
i) contacting a phenylacetylene of the formula
 with carbon monoxide, oxygen, and methanol, in the presence of a palladium (II) catalyst to provide a propargylic ester of the formula
(ii) treating the propargylic ester of the formula 9 with trimethyl(trifluoromethyl)silane in the presence of cesium fluoride to give the compound of formula 3.
In another aspect, the invention relates to a compound of the formula
R
1
, R
3
and R
4
are independently selected from the group consisting of hydrogen halogen; preferably fluoro, chloro, bromo or iodo; hydroxyl; nitro; C
1
to C
6
alkyl, preferably C
1
to C
3
alkyl; C
1
to C
6
alkoxy, preferably C
1
to C
3
alkoxy, more preferably methoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, more preferably trifluoromethyl; and cyano.
In a preferred embodiment, the compound has the formula
wherein R
1
is lower alkyl, preferably methyl.
DETAILED DESCRIPTION OF THE INVENTION
The following terms shall have, for the purposes of this application, the respective meanings set forth below.
“lower alkoxy” shall include linear or branched C
1
to C
6
alkoxy groups, unless otherwise specified.
“lower alkyl” shall include linear or branched C
1
to C
6
alkyl groups, unless otherwise specified.
In accordance with the present invention, novel processes and synthetic intermediates for the preparation of 1,5-diarylpyrazoles are provided. The processes of the invention have been developed from readily available and inexpensive starting materials. Furthermore, the processes provide high yields of 1,5-diarylpyrazoles, and simplify isolation and purification steps.
One embodiment of the invention is depicted in Scheme 1, wherein R
1
-R
4
are as described above for the compound of formula 1, and Y is a halide, preferably chloride. An alkyne of the formula 3, is condensed with a phenyl hydrazine compound of the formula 4 to provide a 1,5-diaryl-3-trifluoromethylpyrazole of the formula 1. Preferably, the phenyl hydrazine compound of the formula 4 is provided as a salt, e.g., a hydrochloride salt. The reaction can be completed in a protic solvent such as ethanol, n-propanol, isopropanol, butanol or acetic acid at an elevated temperature, e.g. ethanol at reflux. Typically a slight excess of phenyl hydrazine is used, from about 1.05 to about 1.3 molar equivalents. The reaction provides high regioselectivity with respect to the ratio of products obtained of the 1,5-diaryl type (i.e. compound of the formula 1) to the 1,3-diaryl type (not shown). Typically, the ratio of the desired 1,5-diaryl pyrazole to the undesired 1,3-isomer is greater than 9 to 1. Purification of the compound of formula 1 can be conveniently carried out by recrystallization from alcohol solvents, e.g., ethanol.
Various acid addition salts of the compound of the formula 1 can be prepared by treatment with an organic or inorganic acid. Preferably, the acid addition salts formed are pharmaceutically acceptable salts, such as those described in U.S. Pat. No. 5,563,165, the disclosure of which is herein incorporated by reference. Suitable base addition salts of the compound of formula 1, wherein the phenyl group at the 5-position of the pyrazole ring incorporates a carboxy or hydroxyl substituent. Base addition salts include metallic addition salts, e.g, sodium, potassium, and organic base addition salts, e.g, organic amines. Other pharmaceutically acceptable acid addition salts are detailed in U.S. Pat. No. 5,563,165.
The phenyl hydrazine compound of the formula 4 can be prepared from substituted anilines of the formula 11, wherein R
2
is amino or lower alkyl as shown in Scheme 2. Preferably, the aniline contains the amidosulfonyl or alkylsulfonyl group in the para position as shown in the structural formula for 11. A diazonium salt is formed from the substituted aniline by treatment with nitrous acid (e.g., formed from hydrochloric acid and sodium nitrite). For example, an aqueous mixture of sulfanilamide and hydrochloric acid is treated with a solution of sodium nitrite at temperatures below about 5° C. to form the corresponding diazonium salt. The cold diazonium salt is then treated with a reducing agent, e.g., stannous chloride, to provide the substituted phenyl hydrazine compound. It will be appreciated that alternative well-known preparations of phenyl hydrazine compounds can also be used, for example, preparation from phenyl halides by nucleophilic displacement by hydrazine.
The alkyne of the formula 3 can be prepared by synthetic methods that are depicted in Schemes 3 and 4. In one embodiment, the alkyne of the formula 3 is obtained from an &agr;,&bgr;-unsaturated ketone precursor, the compound of formula 2 (Scheme 3). The compound of formula 2, for example, is first treated with bromine in a suitable inert organic solvent, e.g. chloroform, at room temperature for a sufficient amount of time to form an &agr;,&bgr;-dibromo intermediate. The crude product obtained from the bromination reaction is subsequently treated with a base such an alkali metal hydroxide, e.g., potassium, sodium, or lithium hydroxide, to effect elimination of HBr and provide the alkyne of formula 3. The alkyne of the formula 3 can be further purified by, for example, recrystallization from suitable solvents, e.g., alcohols, when the compound is a solid. Alternat

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