Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-11-20
2004-06-22
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S284000
Reexamination Certificate
active
06753428
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a process for racemizing one of the enantiomers, or an enantiomerically enriched mixture, of an optically active compound. This invention more specifically relates to racemization of quinazolinone derivatives.
BACKGROUND OF THE INVENTION
Interest in the medicinal chemistry of quinazoline derivatives was stimulated in the early 1950′s with the elucidation of the structure of a quinazoline alkaloid, 3-[&bgr;-keto-&ggr;-(3-hydroxy-2-piperidyl)-propyl]-4-quinazolone, from an Asian plant known for its antimalarial properties. In a quest to find additional antimalarial agents, various substituted quinazolines have been synthesized. Of particular import was the synthesis of the derivative 2-methyl-3-o-tolyl-4-(3H)-quinazolinone. This compound, known by the name methaqualone, though ineffective against protozoa, was found to be a potent hypnotic.
Since the introduction of methaqualone and its discovery as a hypnotic, the pharmacological activity of quinazolinones and related compounds has been investigated. Quinazolinones and derivatives thereof are now known to have a wide variety of biological properties including hypnotic, sedative, analgesic, anticonvulsant, antitussive and anti-inflammatory activities.
Quinazolinones are among a growing number of therapeutic agents used to treat cell proliferative disorders, including cancer. For example, PCT WO 01/30768, which is incorporated herein by reference in its entirety, describes a pharmaceutical composition containing quinazolinone derivatives which are inhibitors of the mitotic kinesin KSP and are useful in the treatment of cellular proliferative diseases, for example cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders and inflammation. Certain of the compounds described therein have the following formula:
wherein
R
1
is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, and substituted heteroaralkyl;
R
2
and R
2
′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, and substituted heteroaralkyl; or R
2
and R
2
′ taken together form a 3- to 7-membered ring;
R
3
is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, substituted heteroaralkyl, oxaalkyl, oxaaralkyl, substituted oxaaralkyl, R
15
O— and R
15
—NH—;
R
3a
is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R
15
—NH—;
R
3b
is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R
4
is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, substituted heteroaralkyl, and R
16
-alkylene-;
R
5
, R
6
, R
7
and R
8
are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heretoaryl;
R
15
is chosen from alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, and substituted heteroaralkyl; and
R
16
is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl.
These quinazolinone derivatives have an asymmetric carbon atom (i.e., the stereogenic center to which R
2
and R
2′
, are attached) that may exist as a racemic mixture of these compounds, i.e., a mixture of both the (+) and (−) or dextro and levo rotary forms. These compounds can be produced as racemates and administered in this form. However, it is known that the physiological utility of racemic mixtures often is focused on one enantiomer, the other having either little or no effect or even diminishing the effect of the active enantiomer.
A generic synthetic scheme for the preparation of quinazolinone compounds of Formula I(a)-(d) above is described in PCT WO 01/30768 and is shown in
FIGS. 1 and 2
. An asymmetric synthesis of the quinazolinone compounds of Formula I using optically active reagents is shown in FIG.
3
. Disposal of the undesired enantiomer of an intermediate is not environmentally or economically desirable. Thus an efficient method of converting the inactive or undesirable enantiomer into the other usable, desirable enantiomer is a commercially important objective. This invention makes it possible to achieve this objective.
The references discussed herein are provided solely for their disclosure prior to the filing date of the present application and are each incorporated herein by reference. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.
SUMMARY OF THE INVENTION
The present invention provides a method for racemizing one of the enantiomers, or an enantiomerically enriched mixture, of an optically active compound of the formula:
comprising:
contacting said compound with an alkali alkoxide of a C
1
-C
6
primary alcohol; and
isolating the resulting racemic compound,
wherein
R
1
is chosen from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, and substituted heteroaralkyl;
R
2
is alkyl, oxaalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, and substituted heteroaralkyl; and
R
5
, R
6
, R
7
and R
8
are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heretoaryl.
The process is characterized in that one of the enantiomers, or an enantiomerically enriched mixture, of enantiomers is contacted with an alkali metal alkoxide of a primary alcohol. Preferably, the reaction mixture comprises the primary alcohol from which the alkali metal alkoxide was derived. The racemic compounds can then be isolated by conventional methods.
The alkali metal alkoxide of a primary alcohol will generally be derived from a primary aliphatic alcohol with 1-6 C-atoms, preferably methanol or ethanol, and more preferably, ethanol. Preferably, the reaction is carried out under reflux temperature.
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Bergnes Gustave
Morgans, Jr. David
Smith Whitney W.
Yao Bing
Cytokinetics Inc.
Ford John M.
Swiss Law Group
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