Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-01
2003-09-02
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
06613914
ABSTRACT:
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The invention relates to a process of preparing 1,5-diaryl-3-substituted pyrazoles of the formula
wherein
R
1
, R
2
, R
3
and R
4
are the same or different and are individually selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, amino, acetamido, phenyl, halo, hydroxy, lower alkylsulfonyl, lower alkylthio, nitro, trifluoromethyl, omega-trifluoromethyl lower alkoxy, or where R
1
, R
2
or R
3
, R
4
taken together with the phenyl group to which they are attached, form a naphthyl or substituted naphthyl group.
In a preferred embodiment, the invention relates to a process of making 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide, a compound of formula Ia, known as tepoxalin.
The compounds of formula I and method of making and using the compounds of formula I are described in U.S. Pat. No. 4,826,868, issued May 2, 1989, incorporated by reference herein.
Tepoxalin is a potent inhibitor of both the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade (U.S. Pat. No. 4,826,868 and Robinson, C., Drugs of the Future, 15, 9. 902 (1990)).
Known methods of synthesizing tepoxalin include the following. U.S. Pat. No. 4,826,868 describes reacting the alcohol, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanol with Jones reagent to form the acid, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid, which is reacted with dimethylformamide and oxalyl chloride in tetrahydrofuran (“THF”) which is then reacted with methylhydroxylamine hydrochloride and triethylamine in THF.
U.S. Pat. No. 4,898,952 describes a process for making tepoxalin which comprises reacting a hydrazine with a diketoacid to form a pyrazole acid which is reacted with dimethylformamide and oxalyl chloride to yield the pyrazole acid chloride which is reacted with methyl hydroxylamine hydrochloride and triethylamine to yield tepoxalin. The diketoacid is prepared by adding an appropriately substituted acetophenone to a solution of lithium diisopropylamide (LDA made from diisopropylamine and n-butyllithium in THF at low temperature). Alternatively, lithium hexamethyl disilazide may be employed as the base in place of lithium diisopropylamide. Succinic anhydride is then added to this solution to produce the diketoacid.
U.S. Pat. No. 5,117,054 describes a process wherein p-chloroacetophenone is reacted with succinic anhydride to form 4-chloro-&ggr;,&egr;-dioxo-benzenehexanoic acid which is reacted with acetic anhydride or acetyl chloride to yield 5-[2-(4-chlorophenyl)-2-oxoethylidene]dihydro-2(3H)-furanone. This compound is then added to a mixture of N-methylhydroxylamine hydrochloride and an amine base such as triethylamine, Hunig's base, pyridine or lutidine and a solvent such as methylene chloride or chloroform to form 4-chloro-N-hydroxy-N-methyl-&ggr;,&egr;-dioxo-benzenehexanamide which is combined with 4-methoxyphenyl hydrazine hydrochloride, an amine base as described above in an alcoholic solvent such as methanol, ethanol or propanol.
The preparation of 4-chloro-&ggr;,&egr;-dioxo-benzenehexanoic acid from p-chloroacetophenone utilizing various bases selected from lithium diisopropylamide (LDA); LDA.LiCl; magnesium diisopropylamide (MDA); MDA.lLiBr; MDA.2LiB
R
or lithium bis(trimethylsilyl) amide was disclosed in Murray et al, Synthesis 1991, p. 18-20.
Due to cost, toxicity, and hazard considerations, it is desirable to be able to synthesize 1,5-diaryl-3-substituted pyrazoles, particularly tepoxalin, without the reagents lithium hexamethyl disilazide, oxalyl chloride and methylene chloride and without excess p-chloroacetophenone.
The current invention produces tepoxalin in a much higher over-all yield and at a decreased cost than the known processes.
BRIEF SUMMARY OF THE INVENTION
The invention relates to a process for preparing a compound of the formula I
wherein
R
1
, R
2
, R
3
and R
4
are the same or different and are individually selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, amino, acetamido, phenyl, halo, hydroxy, lower alkylsulfonyl, lower alkylthio, nitro, trifluoromethyl, omega-trifluoromethyl lower alkoxy, or where R
1
, R
2
or R
3
, R
4
taken together with the phenyl group to which they are attached, form a naphthyl or substituted naphthyl group;
comprising reacting a compound of formula II
wherein R
3
and R
4
are as described above, with succinic anhydride and an alkoxide base to form the corresponding compound of formula III
wherein R
3
and R
4
are as described above, which is reacted with a compound of formula IV
wherein R
1
and R
2
are as described above, to form a corresponding compound of formula V
wherein R
1
, R
2
, R
3
and R
4
are as described above, reacting the compound of formula V with an alcohol to form the corresponding ester of formula VI
wherein R
1
, R
2
, R
3
and R
4
are as described above and R is lower alkyl or cycloalkyl, and reacting the ester of formula VI with N-methylhydroxylamine hydrochloride and a base to form the corresponding compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
In the above formula, R
1
, R
2
, R
3
and R
4
are substituents on phenyl rings, where phenyl rings substitute for hydrogen atoms at positions 1 and 5 of the pyrazole ring. It is preferred that at least one of R
1
and R
2
, and one of R
3
and R
4
be substituted at the 4-positions of their respective phenyl rings.
Lower alkyl radicals include, for example, methyl ethyl, propyl, isopropyl, n-butyl, sec-butyl, E-butyl, n-pentyl, 2-methul-3-butyl, 1-methylbutyl, 2-methylbutyl, reopertyl, n-hexyl, 1-methylpenthyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl, and the like.
Lower alkoxy shall mean oxygen ethers formed from a before-described lower alkyl group. Exemplary radicals include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, and the like.
Lower alkylthio radicals of R
1
, R
2
, R
3
and R
4
are thio ethers and are thus analogous to the ethers described above.
Halo radicals preferably include chloro and bromo, as well as fluoro and iodo.
Lower alkylsulfonyl radicals contain a before-described lower alkyl radical bonded to an SO
2
moiety that is itself also bonded to a phenyl ring. Exemplary lower alkylsulfonyl radicals thus include methylsulfonyl, ethylsulfonyl, 2-ethylbutylsulfonyl and the like.
An omega-trifluoromethyl lower alkoxy radical is a lower alkoxy radical as before described that additionally includes a trifluoromethyl group at a position farthest on the alkyl chain from the place of bonding to the phenyl ring. Exemplary of such radicals are the 2,2,2-trifluoroethoxy.
Naphthyl and substituted naphthyl radicals can replace an aryl group herein at either the 1- or 2-positions to provide 1-naphthyl or 2-naphththyl substituents respectfully. Substituents on the naphthyl radicals can be any of those described herein as being useful aryl substituents. Exemplary substituted 1- and 2-naphthyls include 6-methoxy-2-naphthyl and the like.
As used herein, unless otherwise noted, the term “lower” when used with alkyl or alkoxy means a carbon chain composition of 1-6 carbon atoms.
The term “alkoxide base” refers to a lower primary alkoxide, secondary alkoxide, or tertiary alkoxide such as, methoxide, ethoxide, 2-propoxide, tert-butoxide and the like. The preferred base is a tertiary alkoxide and preferably potassium tert-butoxide.
The invention relates to a process of preparing a compound of the formula I
comprising reacting a compound of formula II
with succinic anhydride and an alkoxide base to form a corresponding compound of formula III
which is reacted with a compound of formula IV
to form a corresponding compound of formula V
reacting the compound of formula V with an alcohol to form the corresponding ester of formula VI
wherein R is lower alkyl, such as methyl, ethyl, isopropyl, preferably ethyl, or aryl, and reacting the ester of formula VI with N-methylhydroxylamine hydrochloride and an appropriate base, such as an alkoxide base, amine base or inorg
Abdel-Magid Ahmed F.
Harris Bruce D.
Maryanoff Cynthia A.
Ortho-McNeil Pharmaceutical , Inc.
Ramsuer Robert W.
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