Methods for the synthesis of dioxoalkanoic acid compounds

Details Methods for the synthesis of dioxoalkanoic acid compounds Methods for the synthesis of dioxoalkanoic acid compounds

2001-11-07

2003-07-08

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S012000, C560S017000, C560S042000, C560S045000, C560S047000, C560S053000, C560S104000, C560S014000, C562S429000, C562S459000, C562S463000

Reexamination Certificate

active

06590119

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to methods for the synthesis of dioxoalkanoic acid compounds and derivatives useful as intermediates for diarylpyrrole therapeutic agents. More particularly, the present invention is directed to the treatment of benzoylcyclohexanone compounds with an alcohol to provide improved yields of purified 7-aryl4,7-dioxoheptanoic acid derivatives.
BACKGROUND OF THE INVENTION
Aryl dioxoalkanoic acid compounds are useful intermediates for the synthesis of diarylpyrrole alkanoic acid therapeutic agents. U.S. Pat. No. 5,219,856 describes a process for preparing pyrrole compounds with activity as angiotensin-II inhibitors. U.S. Pat. No. 5,032,590 describes intermediate diphenyl isopropylpyrroles used to prepare substituted pyrrole compounds.
WO 9825896 and Collins, P. W., et al., 1,2-Diarylpyrroles as Potent and Selective Inhibitors of Cyclooxygenase-2,
J. Med Chem.,
1997, 40, 1619-1633 disclose the preparation of 7-aryl-4,7-dioxoheptanoic acid compounds of the formula:
from acetophenones and furfural. These diketones have been used to prepare diarylpyrrole alkanoic acid therapeutic agents of the formula:
These references, however, teach the preparation of the diketone compounds using starting materials and processes that differ from that of the present invention and having yields of about 33%.
Diketone compounds have also been produced from aryloxo and aryldioxo pentanoic, hexanoic and heptanoic acid compounds. Kapoor, V. M., et al., Steroid Intermediates, Synthesis and Transformations of 7-Aryl4,7-dioxoheptanoic Acids,
J. Chem. Soc,
Perkin, 1973, 2420-2424. This reference discloses a process of preparing the aryldioxoheptanoic acid compounds using acid hydrolysis of furfurylidene compounds wherein the yields of the diketone compounds varied depending on the substituents used.
Similarly, aryl dioxoalkanoic acid compounds, such as aroyloxohexanoic acid, have been used as intermediates in the preparation of compounds with antiinflammatory activity. Short, F. W., et al., Synthesis and Interconversion of 6-Aroyl4-oxohexanoic Acids and 5-Aryl-2-furanpropionic Acids. Antiinflammatory Agents,
J. Heterocyclic Chem.,
1969, 6, 713-722 describes the preparation of the aroyloxohexanoic acid compounds using acid catalyzed solvolysis. This reference teaches a process and starting materials that result in varying amounts of the desired diketone compounds.
The current methods used to prepare dioxoalkanoic acid compounds generally suffer from either the formation of the desired product in low yield, inseparable or hard to separate mixtures of the desired product and a different product or different products entirely. An object of the present invention is to provide a more efficient process to prepare purified diketone compounds with improved yields.
SUMMARY OF THE INVENTION
The present invention is directed to an efficient method for the synthesis of purified diketone compounds with improved yields. The process involves the treatment of benzoylcyclohexanone ketal compounds with an alcohol to unexpectedly produce mono-protected 1,4-diketone compounds such as 7-aryl-7,4-dioxoheptanones with surprisingly improved yields. More particularly, the invention provides a method of preparing a diketone compound of the general formula (I):
wherein:
R
1
is independently selected from the group consisting of hydrogen, halogen, —S—CH
3
, —SO—CH
3
, —SO
2
—CH
3
, —SO
2
—NH
2
,(C
1
-C
6
)alkyl or substituted (C
1
-C
6
)alkyl;
wherein the alkyl substituents are selected from —S—CH
3
, —SO—CH
3
, —SO
2
—CH
3
or —SO
2
—NH
2
, (C
1
-C
6
)alkoxy, cycloalkyl, aryl, aralkyl, nitro, amino, hydroxy or trifluoro;
R
2
is independently selected from the group consisting of (C
1
-C
6
)alkyl or substituted (C
1
-C
6
)alkyl; and,
n is an integer selected from 1, 2 or 3; which method comprises,
treatment of a compound of the general formula (II):
with an alcohol, wherein R
1
is as described above, to provide the diketone compounds of the general formula (I). Preferably, the alcoholysis is carried out in refluxing alcohol. More preferably, the alcoholysis of the compound of the general formula (II) is carried out in the presence of a catalytic amount of sodium methoxide.
In an additional method of synthesis embodied in this invention, purified 7-aryl4,7-dioxoheptanoic acid compounds of the general formula (III) are produced with improved yields;
wherein R
1
, R
2
and n are as recited above; which method comprises, transketalyzing or mildly hydrolyzing a diketone compound of the general formula (I) to prepare a 7-aryl4,7-dioxoheptanoic acid compound of the general formula (III).
Aryl dioxoalkanoic acid compounds of the general formula (III) are demonstrated as useful intermediates in the preparation of diarylpyrrole therapeutic compounds of the general formula (IV), such as 1,5-diaryl-1H-pyrrole-2-propionic acids known to possess antiinflammatory activity;
wherein;
wherein R
1
and R
2
are as recited above; and,
R
3
is independently selected from the group consisting of hydrogen, halogen, —S—CH
3
, —SO—CH
3
, —SO
2
—CH
3
, —SO
2
—NH
2
, (C
1
-C
6
)alkyl or substituted (C
1
-C
6
)alkyl;
wherein the alkyl substituents are selected from —S—CH
3
, —SO—CH
3
, —SO
2
—CH
3
or —SO
2
—NH
2
, (C
1
-C
68
)alkoxy, cycloalkyl, aryl, aralkyl; nitro, amino, hydroxy or trifluoro;
and the pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Relative to the above generic description, certain compounds of the general formulae (I) and (III) are preferred. Particularly preferred embodiments are those compounds wherein;
R
1
is independently selected from the group consisting of hydrogen, halogen, —S—CH
3
, —SO—CH
3
, —SO
2
—CH
3
, —SO
2
—NH
2
or (C
1
-C
4
)alkyl;
R
2
is independently selected from the group consisting of (C
1
-C
4
)alkyl or substituted (C
1
-C
4
)alkyl; and,
n is an integer selected from 2 or 3;
and the pharmaceutically acceptable salts thereof.
Definitions
The terms used in describing the invention are commonly used and known to those skilled in the art. However, the terms that could have other meanings are hereinafter defined. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
Accordingly, the term “alkyl” refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms. “Independently” means that when there are more than one substituent, the substituents may be different. The term “alkoxy” refers to O-alkyl where alkyl is as defined supra.
Unless otherwise specified, the term “substituted alkyl” refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyl, cycloalkyoxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO
2
NH
2
), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH
2
), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above that the substituent is further substituted, such substitutions will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “aryl” refers to monocyclic or bicyc

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