Note: Descriptions are shown in the official language in which they were submitted.
CA 02536608 1995-12-01
30725-117D
New highly selective process for the preparation of
enantiomerically pure phenyl-substituted 1,4-dihydropyridine-
3,5-dicarboxylic acid derivatives
This application is a divisional application of
copending application 2,164,276, filed December 1, 1995.
The present invention relates to a new selective
process for the preparation of enantiomerically pure phenyl-
substituted 1,4-dihydropyridine-3,5-dicarboxylic acid
derivatives.
The publication Angew. Chem. 103, 1991, 1587-1605
describes the high importance of the absolute
stereochemistry of 1,4-dihydropyridines for their
pharmacological action as calcium antagonists or calcium
agonists and provides a list of the processes available to
date for preparing them in enantiomerically pure form. All
these processes emphasize the separation of diastereomeric
esters using chiral pool auxiliaries, the selection of which
being essentially a trial-and-error method with regard to
the substantial difficulties often encountered in their
preparation and the introduction and elimination into, or
from, the molecules. In particular the elimination of a
large number of auxiliaries is frequently complicated from
the technical and chemical point of view, and this, in turn,
results in a decreased yield.
Surprisingly, there has now been found a highly
selective method by using maleimides as auxiliaries.
This divisional application provides use of a
derivative of an optically active maleimide of the general
formula (VII):
- 1 -
CA 02536608 2007-01-24
30725-I17D
O
~
* N-A (VII)
HO \
0
*R,S
wherein:
A represents: (i) H or straight-chain or branched
alkyl having up to 8 carbon atoms, or (ii) phenyl or benzyl
which are optionally up to trisubstituted by identical or
different substituents selected from the group consisting of
hydroxyl, nitro, a halogen atom, cyano, carboxyl,
trifluoromethyl, trifluoromethoxy, straight-chain or
branched alkoxy having up to 6 carbon atoms and a group of
the general formula: -NR6R' or -SOZRB, wherein:
R6 and R' are identical or different and represent
H, phenyl or straight-chain or branched alkyl having up to
5 carbon atoms, and
R8 represents straight-chain or branched alkyl
having up to 4 carbon atoms or phenyl,
in the preparation of the diastereomerically pure 1,4-
dihydropyridines of the general formulae (IVa) and (IVb):
0
O 2
R N-A
R2
N-q R~02C * CO~1 R'02C C02 O
0 I I
H3c N CH3 H3C H CH3
H
(IVa) (R/b)
- la -
CA 02536608 2007-01-24
30725-117D
wherein:
A is as defined above;
R1 represents: (i) straight-chain or branched alkyl having up
to 8 carbon atoms which is optionally substituted by
straight-chain or branched alkoxy having up to 6 carbon
atoms or hydroxyl, or (ii) cycloalkyl having 3 to 7 carbon
atoms; and
R4
R2 represents the radical R5
wherein
R4 and R5 are identical or different and represent: (i) a
halogen atom, cyano, ethinyl, trifluoromethoxy, methylthio,
nitro or trifluoromethyl, or (ii) straight-chain or branched
alkyl, alkenyl, alkinyl or alkoxy having up to 4 carbon
atoms, and one of the substituents optionally represents H;
and a salt thereof.
The invention relates to a new highly selective
process for the preparation of enantiomerically pure phenyl-
substituted 1,4-dihydropyridine-3,5-dicarboxylic acid
derivatives of the general formula (I)
- lb -
CA 02536608 1995-12-01
R2
R'02C * C02R 3
e 1
H3C N CH3 a)
I
H
R and S
in which
R' and R3 are identical or different and represent straight-chain or branched
alkyl
having up to 8 carbon atoms which is optionally substituted by straight-chain
or
branched alkoxy having up to 6 carbon atoms or hydroxyl, or
represent cycloalkyl having 3 to 7 carbon atoms,
and
R4
RZ represents the radical R 5
in which
R4 and RS are identical or different and
denote halogen, cyano, ethinyl, trifluoromethoxy, methylthio, nitro,
trifluoromethyl or straight-chain or branched alkyl, alkenyl, alkinyl or
alkoxy having up to 4 carbon atoms, and one of the substituents
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CA 02536608 1995-12-01
optionally represents hydrogen,
and their salts,
characterized in that the enantiomerically pure benzylidene compounds of the
general
formula (II) or the benzylidene compounds of the general formula (IIa)
R2 O R2
(II) C02R (ila)
COZ N-A
O O O CH3
CH3
' R, S
in which
R' and RZ have the abovementioned meanings
and
A represents hydrogen or straight-chain or branched alkyl having up to 8
carbon
atoms, or
represents phenyl or benzyl which are optionally up to trisubstituted by
identical
or different substituents from the series consisting of hydroxyl, nitro,
halogen,
cyano, carboxyl, trifluoromethyl, trifluoromethoxy, straight-chain or branched
alkoxy having up to 6 carbon atoms or by a group of the formula -NR6R' or
-SOzRg
in which
R6 and R' are identical or different and
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CA 02536608 1995-12-01
denote hydrogen, phenyl or straight-chain or branched alkyl having up
to 5 carbon atoms
and
Rg denotes straight-chain or branched alkyl having up to 4 carbon atoms or
phenyl,
are converted, by reaction,
in the case of the enantiomerically pure benzylidene compounds of the general
formula
(II), with aminocrotonic esters of the general formula (III) and, in the case
of the
benzylidene compounds of the general formula (IIa), with the corresponding
enantiomerically pure aminocrotonic esters of the general formula (IIIa)
0
NHZ
NH N-A (Illa)
CO2R' (III) or z *
COZ
O
'R,S
in which
R' and A have the abovementioned meanings
in inert solvents, if appropriate in the presence of a base,
to the diastereomerically pure 1,4-dihydropyridines of the general formulae
(IVa) and
(IVb)
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O O
R2 Rz
N-A = # N-A
R O2C CO2 " R O2C CO2 " .. 4
O ~ ~ O
H3C N CH3 H3C N CH3
I I
H H
(IVa) (IVb)
in which
R', R2 and A have the abovementioned meanings
and the maleimide radical subsequently eliminated with weak bases under mild
conditions, if appi=opriate isolating the free acid, and the carboxyl function
is esterified
by customary methods.
The process according to the invention can be illustrated by way of example by
the
formulae of the following scheme:
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CA 02536608 1995-12-01
CN
[A]
0 ci
NH2 N-CH2 C6H5 + CH
CO2 C-C02 (CH2)2 OCH3
O
CO-CH3
CN
0
cl
H3C0-(CH2)2 02C COZ 4N-CHZ C6H5
i-propanol, e _ I I
O
H3C N CH3
H
CN
1.DBU
2. carbonyldiimidazole Ci
3. i-propanol H3C0-(CH2)2 02C COZ CH(CH3)2
,
DMAP I I
H3C N CH3
H
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CA 02536608 1995-12-01
[B] CN
NH2
CI
N-CHz C6H5 + C02-(CH2)2 OCH3
COzi
O
O CH3
CN
I O
CI
i-propanol, A 10 H3CO-(CHz)zOzC CO2i~..= 4N-CHZ C6H5 _=
~ ~ O
H3C N CH3
H
CN
~
~
i
1.DBU = CI
2. carbonyldiimidazole H3C0-(CH2)2-02C C02 CH(CH3)2 10 3. i-propanol, DMAP ~ ~
H3C N CH3
1
H
Surprisingly, the process according to the invention gives the chiral
compounds of the
general formula (I) in a sophisticated manner in very high enantiomeric purity
combined with very high yields.
In contrast to the abovementioned prior art, the process according to the
invention
provides a highly enantioselective route for the synthesis of enantiomerically
pure
substituted 4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid derivative by
using
maleimide radicals in the compounds of the general formula (IV) and (IVa) as
auxiliaries, these existing in both enantiomerically pure forms. The
maleimides, in turn,
can be obtained from the corresponding (R)- or (S)- maleic acid via a single,
simple
chemical reaction. The process according to the invention is also
distinguished by the
fact that, in contrast to the prior art, the maleimides, as auxiliaries, can
be introduced
readily into the benzylidene compounds of the general formula (II) or into the
aminocrotonic esters of the general formula (IIIa). Moreover, the maleimide
radicals
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CA 02536608 1995-12-01
can be eliminated selectively from all compounds in a highly sophisticated
manner
under very mild conditions, using weak bases. Moreover, simply and
systematically
varying the radical A in the maleimides of the general formulae (IV) and (IVa)
allows
the problem to be solved in an optimal fashion with a view to the
dihydropyridine in
question. Due to the rigid, cyclic structure of the maleimides, the
corresponding
diastereomerically pure dihydropyridines of the general formula (IV/IVa) not
only
crystallize in very high yields but are also distinguished by substantially
different
crystallization behaviours.
These advantages, which, in the end, also make possible the very high yields
of the
compounds of the general formula (I) according to the invention, are not
achieved by
any known auxiliary.
A further advantage of the process according to the invention, in particular
with a view
to costs, is the fact that the entire reaction sequence is very short and
presents few
complications and that even the various intermediates can be obtained in very
good
yields and with high diastereomeric or enantiomeric purity.
The process according to the invention is suitable in principle for the
synthesis of
enantiomerically pure dihydropyridine-3,5-dicarboxylic acid derivatives.
Suitable solvents for the reaction of the compounds of the formulae (IIa) and
(IIIa) are
generally all inert organic solvents which do not undergo changes under the
reaction
conditions. These preferably include alcohols, such as methanol, ethanol,
propanol or
isopropanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuran,
glycol dimethyl
ether or diethylene glycol dimethyl ether, acetonitrile, or amides, such as
hexamethylphosphoric triamide or dimethylformamide, or acetic acid or esters,
such as
ethyl acetate, or halogenated hydrocarbons, such as methylene chloride, carbon
tetrachloride or hydrocarbons such as benzene, xylene or toluene. Equally, it
is possible
to use mixtures of the abovementioned solvents. Isopropanol is preferred.
The reaction temperatures can be varied within a substantial range. In
general, the
process is can'ied out between 20 C and 120 C, preferably between 60 C and 90
C.
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CA 02536608 1995-12-01
The reactions can be carried out under atomospheric pressure, but also under
elevated
or reduced pressure (for example 0.5 to 80 bar). In general, it is carried out
under
atmospheric pressure.
Suitable solvents for the reaction of the compounds of the formulae (II) and
(III) are
ethyl acetate or isopropanol.
Some of the compounds of the general formula (IIa) are known or can be
prepared by
customary methods, for example by reacting the corresponding aldehydes with
2-alkoxyalkyl acetoacetates.
The compounds of the general formula (III) are known per se.
The enantiomerically pure benzylidene compounds of the general formula (II)
are new
and can be prepared by reacting
aldehydes of the general formula (V)
Rz-CHO (V)
in which
RZ has the abovementioned meaning
with enantiomerically pure acetoacetic esters of the general formula (VI)
0
O O
*
H3C 0 N-A
(VI)
O
* R, S
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CA 02536608 1995-12-01
in whlch
A has the abovementioned meaning
in inert solvents and in the presence of a base and of a carboxylic acid.
Suitable solvents for the fust step are all inert organic solvents which do
not undergo
changes under the reaction conditions. These preferably include alcohols, such
as
methanol, ethanol, propanol or isopropanol, or ethers, such as diethyl ether,
dioxane,
tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether,
acetonitrile,
or amides, such as hexamethylphosphoric triamide or dimethylformamide, or
acetic acid
or esters, such as ethyl acetate, or halogenated hydrocarbons, such as
dichloromethane,
carbon tetrachloride or hydrocarbons such as benzene or toluene. Equally, it
is possible
to use mixtures of the abovementioned solvents. Dichloromethane is preferred.
Bases which are preferably suitable for the fust step are cyclic amines, such
as, for
example, piperidine, Cl-C3-tri- and dialkylamines, such as, for example, di-
and
triethylamine or pyridine or dimethylaminopyridine. Piperidine is preferred.
In general, the base is employed in an amount of 0.01 mol to 0.10 mol,
preferably from
0.05 mol to 0.08 mol, per mole of the aldehyde.
Preferably suitable acids are CI-C4-alkylcarboxylic acid, such as, for
example, acetic
acids.
In general, the acid is employed in an amount of 0.01 mol to 0.10 mol,
preferably from
0.05 mol to 0.08 mol, per mole of the aldehyde.
The reaction temperature in the first step can be varied within a substantial
range. In
general, the process is carried out in the range from 20 C to 120 C,
preferably from
C to 60 C.
The processes can be cairied out under atmospheric pressure, elevated pressure
or
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CA 02536608 1995-12-01
reduced pressure (for example from 0.5 to 5 bar), preferably under atmospheric
pressure.
The aldehydes of the general formula (V) are known or can be prepared by
customary
methods.
The enantiomerically pure compounds of the general formula (VI) are new and
can be
prepared by reacting
(S)- or (R)- maleimides of the general formula (VII)
0
' N-A
HO (VII)
O
*R,S
in which
A has the abovementioned meaning
with diketene or diketene/acetone addition product (2,2,6-trimethyl-1,3-dioxin-
4-one)
in inert solvents.
Generally suitable solvents are hydrocarbons, such as, for example, benzene,
toluene or
xylene. Toluene is preferred.
The reactions are carried out in a temperature range from 90 C to 140 C,
preferably
from 100 C to 110 C.
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The reactions are generally carried out under atmospheric pressure. However,
it is also
possible to carry out the reactions under superatmospheric or subatmospheric
pressure
(for example in the range from 0.5 to 5 bar).
Some of the enantiomerically pure imides of the general formula (VII) are
known [c~,
for example, THI.,1990, 4949; J. Am. Chem. Soc., 2589, 1989] or can be
prepared by
reacting (S)-(-)- or (R)-(-)-maleic acid with the corresponding amines in one
of the
abovementioned solvents, preferably xylene, in a temperature range from 100 C
to
180 C, preferably from 130 C to 150 C.
Diketene and 2,2,6-triethyl-1,3-dioxin-4-one are known.
The enantiomerically pure aminocrotonic esters of the general formula (IIIa)
are new
and can be prepared, for example, by adding ammonia or ammonium salts in situ
in the
preparation of the abovementioned acetoacetic esters of the general formula
(VI).
Suitable solvents are those which have been mentioned in the preparation of
the
compound of the general formula (VI). The reaction with the ammonium salts is
carried out in toluene in a water separator under reflux.
The reactions are carried out in a temperature range from 50 C to 120 C,
preferably
from 5 C to 80 C.
The reactions are generally carried out under a subatmospheric pressure of 0.1
to
0.5 bar. However, it is also possible to carry out the reactions under
atmospheric or
superatmospheric pressure (for example in the range from 1 to 5 bar).
Suitable ammonium salts are generally ammonium salts of organic or inorganic
acids,
such as, for example ammonium acetate or ammonium formate. Ammonium acetate is
preferred.
The enantiomerically pure compounds of the general formula (1V) are new and
can be
prepared as described above.
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The substituted pyrrolidine-2,5-dion-3-yl radical is eliminated from the
enantiomerically
pure 1,4-dihydropyridines of the general formula (IV) in one of the
abovementioned
inert solvents. Preferred are ethyl acetate, tetrahydrofuran or mixtures of
these two.
Suitable bases are generally alkali metal carbonates, such as, for example,
sodium
carbonate or potassium carbonate, or organic bases, such as trialkylamines,
for example
triethylamine, N-ethylmorpholine, N-methylpiperidine or diisopropylethylamine
or
dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or
1,5-diazabicyclo[4.3.0]non-5-ene (DBN). 1,8-diazabicyclo[5.4.0]undec-7-ene is
preferred.
The base is applied in an amount of 1 mol to 5 mol, preferably 1 mol to 2 mol,
in each
case per mole of the enantiomerically pure compounds of the general formula
(IV).
The reaction is carried out in a temperature range from 0 C to 50 C,
preferably at
room temperature.
The reaction is generally carried out under atomospheric pressure. However, it
is also
possible to cairy out the reaction under superatmospheric or subatmospheric
pressure
(for example in the range from 0.5 to 5 bar).
Without isolating the free enantiomerically pure acid, the compounds of the
general
formulae (IV) or (IVa) are subsequently converted to the enantiomerically pure
compounds of the general formula (VIII)
R2
R'O2C CO-D
R, S (VIII)
H3C N CH3
I
H
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in which
R' and RZ have the abovementioned meanings
and
D represents an activating radical, for example imidazolyl,
by means of activation with an auxiliary in one of the abovementioned solvents
in the
presence of ethyl acetate, and, in a last step, the pro(lucts are reacted with
a suitable
alcohol (R3-OH) in the presence of one of the abovementioned bases, preferably
N,N-dimethylaminopyridine, at the reflux temperature of the alcohol in
question, to
give the enantiomerically pure compounds of the general formula (I) according
to the
invention.
Auxiliaries which are preferably employed for activating the carboxylic acid
are
condensing agents. Condensing agents which are preferably employed are the
customary condensing agents, such as carbodiimides, for example N,N-diethyl-,
N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide,
N-(3-dimethylaminoisopropyl)-N-ethylcarbodiimide hydrochloride, or carbonyl
compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such as
2-ethyl-5-phenyl-1,2-oxazolium 3-sulphonate or 2-tert-butyl-5-methyl-
isoxazolium
perchlorate, or acylamino compounds, such as 2-ethoxy-l-ethoxycarbonyl-
1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl
chloroformate, or
benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphonate. N,N-di-
cyclohexylcarbodiimide and carbonyldiimidazole are preferred.
In general, the auxiliaries are employed in an amount of 1 mol to 3 mol,
preferably
1 mol to 1.5 mol, in each case per mole of the free carboxylic acid.
The processes can be carried out under atmospheric pressure, elevated or
reduced
pressure (for example from 0.5 to 5 bar), preferably under atmospheric
pressure.
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The activated enantiomerically pure 1,4-dihydropyridines of the general
forlnula (VIII)
are lrnown or can be prepared as described above.
Preferred enantiomerically pure compounds of the general formula (1) which are
prepared by the process according to the invention are those
in which
R' and R3 are identical or different and
represent straight-chain or branched alkyl having up to 8 carbon atoms which
is optionally substituted by straight-chain or branched alkoxy having up to 5
carbon atoms or hydroxyl, or represents cyclopropyl, cyclopentyl, cyclohexyl
or
cycloheptyl,
and
R4
RZ represents the radical R
in which
R4 and RS are identical or different and in each case
denote fluorine, bromine, chlorine, cyano, ethinyl, trifluoromethoxy, methyl,
nitro, methylthio, trifluoromethyl or straight-chain or branched alkoxy having
up
to 3 carbon atoms, and, if appropriate, one of the substituents represents
hydrogen,
and salts thereof.
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Particularly preferred compounds of the general formula (I) which are prepared
by the
process according to the invention are those:
in which
R' and R3 are identical or different and represent
straight-chain or branched alkyl having up to 8 carbon atoms which is
optionally substituted by methoxy or hydroxyl,
or represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl,
and
R4
~
RZ represents the radical I R
i
in which
R4 and RS are identical or different and denote
fluorine, chlorine, cyano, ethinyl, trifluoromethoxy, methyl, methylthio,
nitro,
trifluoromethyl or straight-chain or branched alkoxy having up to 3 carbon
atoms, and, if appropriate, one of the substituents represents hydrogen,
and salts thereof.
Enantiomerically pure compounds which are very particularly preferably
prepared by
the process according to the invention are (4R)- and (4S)-isopropyl-(2-
methoxyethyl)-
4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-
dicarboxylate.
The process according to the invention allows access to the enantiomerically
pure
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halogenphenyl-substituted 1,4-dihydropyridines of the general formula (I),
which are
valuable cerebrally active pharmaceuticals, in a highly enantioselective
manner
combined with a very high yield.
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StdYfing COnlilOu[IdS
Example I (formula VI)
(3 S)-1-Benzyl-3-(3-oxobut)ryloxy)-pyrrolidine-2, 5-dione
O
O O / \
/'~I I' N-CHZ -
1~ 0
O
2,2,6-Trimethyl-1,3-dioxine-4-one (6.6 g, 4.38 mmol, 95% pure) is added
dropwise to
a solution of N-benzyl-(S)-maleimide (9.0 g, 43.8 mmol) [THI, B90, 4949] in
xylene
(18 ml) at 130 C. The acetone which fon ns is distilled off from the reaction
mixture.
Stirring is continued for 2 hours at 130 C, the reaction solution is cooled to
50 C, and
the solvent is stripped off in vacuo. The residue is purified by column
chromatography
on silica gel (eluent: diethyl ether). After the product fractions have been
concentrated,
11.8 g (93%) of the title compound are obtained.
'H NMR (CDCl3): 6= 2.28 (s, 3H); 2.77 (dd, J = 18 Hz, 5 Hz, 1 H); 3.19 (dd, J
18 Hz, 8 Hz, 1H); 3.56 (s, 2H); 4.68 (AB system, 2H); 5.49 (dd, J = 8 Hz, 5
Hz, 1H);
7.25-7.42 ppm (m, 5H); enol H: weak singulet at 11.68 ppm).
Example II -
(3 S)-3-(3-Aminocrotonyloxy)-1-benzyl-pyrrolidine-2, 5-dione
O
NH2 O ~ \
/~ I II N-CHz
O
O
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A suspension of N-benzyl-(S)-maleimide (1700 g, 8.28 mol) in toluene (6.8 1)
is heated
at 105 C, and 2,2,6-trimethyl-1,3-dioxin-4-one (85% pure, 1447 g, 8.65 mol)
are run
in in the course of approximately 20 minutes, the acetone which forms being
distilled
off together with toluene. Stirring is continued for 2 hours at 100-105 C,
more
acetone/toluene being distilled off. Toluene (1 1) is run into the reaction
solution, and
the batch is cooled to 70 C. After ammonium acetate (1207 g, 15.7 mol) has
been
added, the mixture is refluxed in a water separator at 65 C and 250-300 mbar
for
3 hours. Ethyl acetate (3.4 1) is run in, the batch is cooled to room
temperature and
washed with saturated aqueous NaHCO3 solution, the organic phase is dried over
Na2SO4, and the solvent is distilled off in vacuo at 35-40 C. The residue is
taken up in
isopropanol (4.2 1), and the solvent is distilled off in vacuo at 25-65 C. The
residue is
again taken up in isopropanol (2.5 1). The suspension is refluxed, during
which process
the solid dissolves. After the mixture has cooled to 5-7 C, water (1.8 1) is
run in,
precipitated product is filtered off and washed with isopropanol/water (1:1,
3.4 1), and
the product is dried in vacuo at 50 C.
Yield 1990 g (83%)
m.p.: 104-105 C
'H NMR (CDC13): 8= 1.94 (s, 3H); 2.71 (dd, J = 18 Hz, 5 Hz, 1 H); 3.12 (dd, J
18 Hz, 8 Hz, 1 H); 4.57 (s, 1 M; 4.71 (AB system, 2H); 4.74 (s, broad, 1 H);
5.40 (dd,
J = 8 Hz, 5 Hz, 1 H); 7.20-7.44 (m, 514); 7.88 ppm (s, broad, 1 H).
Example lII (formula II)
1-Benzylpyrrolidine-2,5-dion-3-yl (3'S)-2-acetyl-3-(2-chloro-3-cyanophenyl)-
2-propenoate
CN
CI
O
CH
H3C-OC ~CO-O 4NO
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A solution of the compound of Example I(12.6 g, 43.6 mmol) and 2-chloro-3-
cyano-
benzaldehyde (7.2 g, 43.6 mmol) in dichloromethane (80 ml) is treated with
piperidine
(246 mg, 2.8 mmol) and glacial acetic acid (168 mg, 2.8 mmol), and the mixture
is
refluxed in a water separator for 18 hours. After the dichloromethane solution
has
cooled to room temperature, it is washed with water (40 ml), dried over Na2SO4
and
concentrated in vacuo. The residue is purified by column chromatography on
silica gel
(eluent: ether). After concentrating the product fractions, 13.0 g (68%) of
the title
compound are obtained as a mixture of E/Z isomers.
'H NMR (CDC13): S= 2.30, 2.51 (2s, 3H); 2.70-2.87 (m, 1H); 3.08-3.33 (m, 1H);
4.63-4.80 (m, 2H); 5.51-5.69 (m, 1H); 7.27-7.92 (m, 9H).
Example IV (formula IV)
(4R,3' S)-(1-B enzyl-pyrroli dine-2,5-dion-3-yl)-(2-methoxyethyl)-4-(2-chloro-
3 -cyano-
phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarb oxylate
c(o
0
H3CO 0 0 0 4N-CH2--O
\/ I I 0
H3C N CH3
H
Variant A:
The compound of Example II (80.0 g, 0.244 mol) and 2-methoxyethyl 2-acetyl-
3-(2-chloro-3-cyano-phenyl)-2-propenoate (83.29 g, 0.243 mol) are treated with
isopropanol (1100 ml), and the mixture is refluxed for 8.5 hours. It is cooled
to room
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temperature, and the crude product, which has precipitated, is washed twice
using in
each case 100 ml of isopropanol and dried in vacuo at 40 C. The crude product
is
suspended in ethyl acetate (200 ml), and the supension is refluxed for 1 hour.
After the
mixture has cooled to room temperature, the product is filtered off, washed
with ethyl
acetate (40 ml) and dried in vacuo at 50 C.
Yield: 57.8 g (41%)
Diastereomeric excess _ 99.5% (HPLC, Chiracel OD-H)
m.p.: 239-240 C
'H NMR (d6DMSO): S= 2.26 (s, 6H); 2.68 (dd, J = 18 Hz, 5 Hz, 1 H); 3.09 (dd, J
18 Hz, 8 Hz, 1H); 3.16 (s, 3H); 3.37-3.50 (m,2H); 3.95-4.12 (m, 2H); 4.52,
4.64 (AB
signal, JAB = 15 Hz, 2H); 5.25 (s, 1H); 5.53 (dd, J = 8 Hz, 5 Hz, 1H); 7.22-
7.77 (m,
8H).
Variant B (via lI and III)
The compound of Example III (3.0 g, 6.9 mmol) and 2-methoxyethyl 3-
aminocrotonate
(l.l g, 6.9 mmol) are treated with ethyl acetate (38 ml), and the mixture is
refluxed for
5 hours. The product which has precipitated is filtered off, washed with ethyl
acetate
(3 ml) and dried in vacuo at 40 C.
Yield: 1.3 g (33%)
Diastereomeric excess _ 99.5% (HPLC, Chiracel OD-H)
Example V
(4R)-Imidazolyl-2-methoxy ethyl-4-(2-chl oro-3 -cy ano-phenyl)-1,4-dihy dro-2,
6-dim ethy l-
pyridine-3,5-dicarboxylate
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CN
CI
0 0
H3CO0 ,,,,--,,O N-\\
N
~
H3C N CHs
H
The compound of Example IV (73.9 g, 0.128 mol) is suspended in ethyl acetate
(480 ml) and tetrahydrofuran (96 ml), and the suspension is treated with
1,8-diazabicyclo[5.4.0]undeo-7-ene (DBU, 29.0 ml, 0.192 mol) and stirred at
room
temperature for 12 hours. Then, 1 N HCl (300 ml) is added, and the mixture is
stin-ed
vigorously for 15 minutes. The ethyl acetate phase is separated off, washed in
each
case once using 1 N HCl (150 ml) and saturated aqueous NaCI solution and dried
over
Na2SO4. The solvent is stripped off in vacuo and the residue is taken up in
ethyl
acetate (420 ml). After an addition of N,N-carbonyldiimidazole (25.0 g, 0.154
mol),
the mixture is stirred at room temperature for 12 hours and at 0-5 C for 30
minutes.
The product which has precipitated is filtered off, washed with ethyl acetate
(25 ml)
and dried in vacuo.
Yield: 42.6 g (76%)
m.p.: 180 C
'H NMR (CDC13): 8 =1.90 (s, 31-1); 2.48 (s, 3H); 3.22 (s, 31-1); 3.40-3.52 (m,
2H); 4.10
(t,214); 5.58 (s, 111); 6.02 (s, 1H); 7.08 (d, 1H); 7.25-7.58 (m, 4H); 7.91
(s, 11-1).
Dihydrvpyridines of the foimnla (I)
(4R)-Isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-
dimethyl-
pyridine-3,5-dicarboxylate
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CN
CI
0 0
H3CO0 O-CH(CH3)2
H3C N CH3
H
The compound of Example V (73.2 g, 166 mmol) and N,N-dimethylaminopyridine
(0.93 g, 7.6 mmol) are refluxed in isopropanol (530 ml) for 20 hours. The
reaction
mixture is slowly cooled to 0-5 C and stirred at 0-5 C for 1 hour. Crude
product which
has crystallized is filtered off, washed with cold isopropanol (35 ml) and
dried in
vacuo. After recrystallization of the crude product from ethyl acetate
(150 ml)/cyclohexane (450 ml), 53.2 g (74%) of the title compound are
obtained.
m.p.: 138-140 C
[a]D = +13.9 (c = 1, CHCl3 )
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