Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1998-11-06
2001-01-30
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S470000, C562S491000
Reexamination Certificate
active
06180823
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a chemical process for preparing &agr;-alkylphenylglycolic acids and to intermediates in that process.
BACKGROUND OF THE INVENTION
Cyclohexylphenyl glycolic acid (also referred to herein as “CHPGA”) is used as a starting material for manufacturing compounds that have important biological and therapeutic activities. Such compounds include, for example, oxphencyclimine, oxyphenonium bromide, oxypyrronium bromide, oxysonium iodide, oxybutynin (4-diethylamino-2-butynyl phenylcyclohexylglycolate) and its metabolites, such as desethyloxybutynin (4-ethylamino-2-butynyl phenylcyclohexylglycolate).
The important relation between stereochemistry and biological activity is well known. For example, the (S)-enantiomers of oxybutynin and desethyloxybutynin have been shown to provide a superior therapy in treating urinary incontinence, as disclosed in U.S. Pat. Nos. 5,532,278 and 5,677,346. The (R) enantiomer of oxybutynin has also been suggested to be a useful drug candidate. [Noronha-Blob et al.,
J. Pharmacol. Exp. Ther.
256, 562-567 (1991)].
Racemic CHPGA is generally prepared by one of two methods: (1) selective hydrogenation of phenyl mandelic acid or of phenyl mandelate esters, as shown in Scheme 1; or (2) cyclohexyl magnesium halide addition to phenylglyoxylate as shown in Scheme 2.
Asymmetric synthesis of individual enantiomers of CHPGA has been approached along the lines of Scheme 2, by Grignard addition to a chiral auxiliary ester of glyoxylic acid to give a diastereomeric mixture of esters. In addition, a multiple step asymmetric synthesis of (R)-CHPGA from (D)-arabinose using Grignard reagents has been reported.
As outlined in Scheme 3 below, the simple chiral ester wherein R* is the residue of a chiral alcohol, can be directly converted to chiral drugs or drug candidates by trans-esterification (R′=acetate), or hydrolyzed to yield chiral CHPGA and then esterified (R′=H).
While the aforementioned asymmetric synthetic methods are adequate for many purposes, the chemical yields are in some cases poor, and the stereoselectivity is not always high. Also, the chiral auxiliary reagents that give good yields and higher stereoselectivity are often quite expensive. Thus, these processes are often cost prohibitive for use in commercial scale production of chiral pharmaceutical compounds.
A potential alternative to asymmetric synthesis is resolution of racemic CHPGA. This has been accomplished on an analytical scale using resolving agents such as ephedrine, quinine, and (+) and (−)-amphetamine. However, such resolving agents are expensive, making known processes for resolution as impractical as known asymmetric syntheses. In addition, resolution processes using these agents provide poor stereoselectivity. The poor stereoselectivity necessitates multiple recrystallization steps to isolate the single CHPGA enantiomer, which adds to the production costs of chiral pharmaceuticals made from these precursors.
A more efficient and economic method for producing &agr;-alkylphenylglycolic acids, particularly single enantiomers of &agr;-alkylphenylglycolic acids, on an industrial scale is therefore desirable. Such a method should provide high purity compounds in high chemical yields with few processing steps.
SUMMARY OF THE INVENTION
The above need is satisfied, the limitations of the prior art overcome, and other benefits realized in accordance with the principles of the present invention, which in one aspect relates to a process for preparing an alkyl phenylglycolic acid enriched in one enantiomer, comprising the sequential steps of:
(a) condensing a substituted acetaldehyde with a single enantiomer of mandelic acid to provide a 5-phenyl-1,3-dioxolan-4-one;
(b) condensing said 5-phenyl-1,3-dioxolan-4-one with an alkyl ketone or aldehyde to provide a 5-(1-hydroxyalkyl)-5-phenyl-1,3-dioxolan-4-one;
(c) exposing said 5-(1-hydroxyalkyl)-5-phenyl-1,3-dioxolan-4-one to dehydrating conditions to provide a 5-(1-alkenyl)-5-phenyl-1,3-dioxolan-4-one;
(d) hydrolyzing said 5-(1-alkenyl)-5-phenyl-1,3-dioxolan-4-one to provide an &agr;-alkenylphenylglycolic acid; and
(e) reducing said &agr;-alkenylphenylglycolic acid to an &agr;-alkylphenylglycolic acid.
In an alternative embodiment, the last two steps (hydrolysis and reduction) can be reversed:
(d) reducing said 5-(1-alkenyl)-5-phenyl-1,3-dioxolan-4-one to provide a 5-alkyl-5-phenyl-1,3-dioxolan-4-one; and
(e) hydrolyzing said 5-alkyl-5-phenyl-1,3-dioxolan-4-one to an &agr;-alkylphenylglycolic acid.
In particular, preferred embodiments, the substituted acetaldehyde is pivaldehyde, the alkyl ketone is cyclohexanone, the mandelic acid is (S)-(+)-mandelic acid or (R)-(−)-mandelic acid and cyclohexylphenylglycolic acid enriched in either the S or the R enantiomer, respectively, is produced.
In another aspect, the invention relates to a process for preparing a racemic alkyl phenylglycolic acid, comprising a first step of:
(a) condensing acetaldehyde or a symmetrical dialkyl ketone with racemic mandelic acid to provide a 5-phenyl-1,3-dioxolan-4-one;
followed by the same process described above for single enantiomers. The condensation of the acetaldehyde, symmetrical dialkyl ketone or substituted acetaldehyde with mandelic acid may be accomplished in the presence of an acid catalyst; the condensation of the 5-phenyl-1,3-dioxolan-4-one with an alkyl ketone or aldehyde may be accomplished under basic conditions.
In another aspect, the invention relates to a compound chosen from the group consisting of:
wherein R
1
is alkyl of 1 to 10 carbons or substituted alkyl of 4 to 20 carbons in total. The compounds are novel intermediates in the synthesis of CHPGA.
DETAILED DESCRIPTION
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr
J. Chem. Ed.
62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, for example, the formula 5 is intended to encompass either one of the optically pure 5-cyclohexyl-5-phenyldioxol-2-ones:
The term “enantiomeric excess” is well known in the art and is defined for a resolution of ab→a+b as
ee
a
=
(
conc
.
of
a
-
conc
.
of
b
conc
.
of
a
+
conc
.
of
b
)
×
100
The term “enantiomeric excess” is related to the older term “optical purity” in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee.; in other words, a 90% e.e. reflects the presence of 95% of one enantiomer and 5% of the other in the material in question. The term “diastereomeric excess (d.e.) is similarly defined as
de
p
=
{
conc
.
of
p
-
conc
.
of
q
conc
of
p
+
conc
of
q
}
×
100
in which p and q are diastereomers, and 90% de reflects 95% of p and 5% of q. The diastereomeric excess is a measure of the diastereoselectivity of a reaction or process.
“Substituted acetaldehyde” means acetaldehyde in which one or more hydrogens is replaced so as to provide an aldehyde which, when incorporated into the dioxolone ring, is base-inert. For syntheses in which enantioselectivity is important, a bulky, base-inert aldehyde is needed. A “bulky, base-inert aldehyde” as the term is used herein refers to an aldehyde
Grover Paul T.
Senanayake Chris Hugh
Heslin & Rothenberg, P.C.
Killos Paul J.
Oh Taylor Victor
Sepracor Inc.
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