Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 3~ 3
X-7626
METHOD OF RESOLVING CIS 3-AMINO-4-[2-(2-FURYL)ETH-l-YL]-
l-METHOXYCARBONYLMEI~YL-AZETIDIN-2-ONE AND
MALIC ACID SALTS THEREOF
An important clinical trial candidate, (6R,7S)
7 (R)-phenylglycylinamido-3-chloro-l~azabicyclo[4.2.0]-
oct-2-en-8-on-2-carboxylic acid (loracarbef) may be
synthesized by various routes. One of the more note-
worthy total syntheses of loracarbef is that madepossible by Evans and Sjogren, U.S. Patent 4,665,171.
The Evans and Sjogren methodology provides a chiral 2+2
(ketene plus imine) cycloaddition, and accordingly,
entry to a wide variety of chiral cis ~-lactams.
However, the Evans and Sjogren methodology provides for
the utilization of a chiral auxiliary of the formula
Il
20 ~
O N~CH2(~C~X'
Ar
in the 2+2 cycloaddition with a Schiff's base, wherein
X' is chloro, bromo, trifluoroacetoxy, or -OP(=)X2,
wherein X is halogen. The above chiral auxiliary is
s~nthesized in seven steps from L-phenylglycine. The
r
~2~3~2
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resulting cycloaddition provides compo-unds of the
formula
Ar
S ~ H
y~
O ,~N~
0 C:~ ~
whexein Ar is phenyl, C1-C4 alkylphenyl, halophenyl,
C1 C~ alkox~phenyl, naphthyl, thienyl, furyl,
benzothienyl, or benzofuryl; R is phenyl, C1 -C4
alkylpherlyl, C1-C~ alkoxyphenyl, or halophenyl; Y is
-CH=CH-, or CH2-CH2-; and R' is phenyl, C1-C~
alkylphenyl, C1-C4 alkoxyphenyl, halophenyl, furyl or
naphthyl.
The obvious shortcomings of the Evans and
Sjogren route are that a very expensive starting
material, L phenylglycine, is used, -the chiral auxiliary
is synthesized in several steps in linear fashion; and
further, the chiral auxiliary is removed and discarded
using Li/N~I3/t-C4HgOH to provide a free 3~amino-
azetidinone.
As an achiral alternative, Hatanaka et al.,
Tetrahedron Letters Vol. 24, No. 49, pp 4837-4838
~1983), provides a method of preparing a 3-hydroxy(i~-1-
carbacephalosporin via a 2+2 cycloaddition much in the
X-7626 - 3 -
same fashion as that of Evans and Sjogren, but without
the use of a chiral auxiliary as the ketene source. The
Hatanaka methodology provides many of the same inter-
mediates as does the Evans and Sjogren synthesis, albeit
in achiral form. The advantage of the achiral synthesis
is economy of steps and starting material.
The present inven-tion affords a useful alter-
native to the challenge of synthesizing l-carba(1-
dethia~cephalosporins by providing a method for resolu-
tion of a key achiral cis-azetidinone intermediate
provided by achiral cis-2+2 cycloaddition. In partic-
ular, the present invention provides a method for
resolution of a crucial achiral intermediate in the
total synthesis of l-carba(1-dethia)cephalsoporins using
L-malic acid.
Cis 3-amino-4-[2-(2-furyl)eth-l yl]-1-methoxy-
carbonylme-thyl-azetidin-2-one is resolved by the practice
of this invention into its enantiomeric cis ~,~ and cis
~,~ components whereby the desired cis ~,~ enantiomer is
selectively crystallized from solution using S(-)-malic
acid.
The present invention provides a method for
resolving cis ~ -3~amino-4-~2-(2-furyl)eth-1-yl]-1-
methoxycarbonylmethyl-azetidin-2-one into its component
enantiomers, which comprises the steps:
(a) con-tacting a polar organic solution of the
cis ~ racemate with at least about 0.5
mole-equivalents of an optically active malic
acid; and
(b) separating the insoluble salt formed thereby.
According to this invention the cis ~
azetidinone mixture is represented by -the following two
enantiomers:
~2~ 3Z
X-7626 - 4 -
2N,
N CO2~3
\v~ and ~ N~V~CO2CH3
(I) (II)
(~
to yield optically pure isomers, each free of the
other. This resolution is accomplished by dissolving a
racemic mixture of I and II in 2 polar organic solvent,
preferably tetrahydrofuran, and warming the solution to
approximately 50C or at least a temperature sufficient
to dissolve the racemate (I and II) and the malic acid.
S~ malic acid is then added and the solutions allowed
to cool to room temperatuxe gradually overnight, thus
~orming the diasteromenic S(-)-malic acid salt of (I)
in excellent yield and outstanding optical purity. The
resulting free amino enantiomer (I) is then provided by
standard acid/base workup. Order of addition to the
polar organic solution is, of course, not critical.
The corresponding ~,~ enantiomer (II) is
provided by -the same manipulations as above by merely
substituting R-(+) malic acid for S(-)-malic acid.
Alterna~ively, in a method to provide
optically pure cis ~,~ isomer, one could use R-(+)-
malic acid as the resolving agent and exhaustively
crystallize the cis ~,~ isomer away from the solution,
~2~ 3~
X-7626 5 -
thereby leaving the mother liquors with an enhanced
concentration of cis ~,~ isomer.
As a urther aspect of the presen-t invention,
in addition to the process for resolving the racemic
mixture of I and II above, there is provided the S(-)-
malic acid salt of (I~ and the R(~)-malic acid salt of
(II~.
The diastereomeric salt formed is separated
from the resolution mixture and the free amino azeti-
dinone is recovered from the salt form by conventionalmethods. For example, the salt is treated in an aqueous
medium with a base to form the free amine which can be
extracted from the aqueous phase with a water immiscible
solvent such as ethyl acetate. The process provides a
high degree of separation of the two enantlomeric
azetidinones as reflected by the observed enantiomeric
excess (ee) of the product.
It is noteworthy that a number of optically
active acids were tried as potential resolving agents
albeit none were successful except for malic acid.
These acids include: D-(-)-mandelic acid, d-10-camphor-
sulfonic acid, (+)-tartaric acid, dibenzoyl~(l)-
tartaric, ditoluyl-(D)-tartaric, N-benzoyl alanine (L),
guinic acid, ~-camphoric, L-pyroglutamic, (-~pinane
carboxylic acid, and abietic acid. Thus, the two
optically pure malic acids ((+) and (-)) appear to be
unique as readily available, efficient resolving agen-ts
for cis-3~amino-4-[2-(2-furyl)eth-1-yl]-1-methoxy-
carbonylmethyl-azetidin-2 one.
In each of the resolution attempts, four
solvents were evaluated: tetrahydrofuran, ethyl
acetate, acetonitrile, and 1,2-dichloroethane. As noted
3Z
X-76~6 - 6 -
above, only malic acid was shown to be an effective
resolving agent, and further, only in tetrahydrofuran.
However, one skilled in the art will recognize that the
possibility exists that the diaskereomer formed by
admixture of S(-)-malic acid and (I) (or R(+)-malic and
II) may also selectively crystallize from other solvents
of like polarity and solvent effects. In this regard,
it must be emphasized that the choice of solvent systems
in the above is by no means exhaustive and others may be
considered to be equivalent in their utility.
One skilled in the art will appreciate that
the selective crystallization of one diastereomer from
a polar organic solution is also affected by concentra-
tion. A relatively low concentration provides pure
diastereomer of generally higher purity but lower yield,
while the utilization of a higher concentration of
racemate and resolving agent will normally provide
higher yields of solid, many times at the expense of
optical purity. Thus, the preferred concentration range
for the present invention in tetrahydrofuran is about
0.25 M to about 0.75 M, preferably about 0.5 M.
The invention is further described by the
following examples but is not to be construed as
limiting any aspect of the invention.
Example 1
A 0.5 g portion of the oxalate salt of cis
~ , 3-amino-4-[2-(furyl)ethyl]-1-methoxycarbonyl-
azetidin-2-one was slurried in 10 ml of water, neutral-
ized to pH = 7.5 with saturated Na~CO3 solution and
extracted with CH2Cl2. The CH2C12 solution was dried
3~3f~
X-7626 - 7 -
over anhydrous MgSO4, filtered, and concentrated in
vacuo to provide the racemic free-amine.
A 0.232 g sample of the resulting racemic free
amine was then dissolved in tetrahydrofuran (2 ml) and
heated to about 50C. A 0.134 g portion of S(-)-malic
acid was then added and the resulting solu-tion was
allowed to stand overnight.
The containing vessel was wrapped in insulation,
thereby allowing the solution to gradually cool to room
temperature. The resulting crystalline solid was then
filtered and washed with l ml te-trahydrofuran to provide
40 mg (22% yield) of the S( )-malic acid salt of cis
~ 3-amino-4-[2-(2-furyl)eth-1-yl]-1-methoxycarbonyl-
methyl-azetidin-2-one.
5 mg (14 ~m) of the L-malic salt was
dissolved in a mixture of 1 ml H20, 3.5 mg (3 meq)
NaHCO3, and 1 ml acetonitrile. 3.2 mg (14 ~m) 3,5-di-
nitrobenzoyl chloride was added and the reaction
stirred for 16 hr at room temperature. After 5 ml H20
~as added, the reacti.on was vacuum filtered and washed
with ~2 0 (2 x 1 ml portions), cold isopropanol (2 x 1 ml
portions) and diethyl ether (2 x 2 ml) to isolate 2.5
mg of the 3,5-dinitrobenzamide (85 area % by gradient
reverse phase HPLC).
The amide solution in te-trahydrofuran was
injected on both a YMC-AK03S-5300A, 25 cm, 4.6 mm OD
chiral column (YMC Corporation) and a Pirkle covalent
D-naph-thylalanine chiral column ~egis~ to show a 99%
ee (enantiomeric excess). Also, the ~-DNB amide made
from a chiral ~-lactam made by -the Evans and Sjogren
route and the analogous racemic DNB amide was injected
~-7626 - 8 -
on both systems to confirm the retention times of both
the ~- and the ~-DNB amides.
Example 2
Th~ procedure for isolation of the ~,~ isomer
was identical to that of Example 1, substituting R(+)-
malic acid as resolving agent to provide the a,~ isomer
(27% yield, 99% ee).
