Note: Descriptions are shown in the official language in which they were submitted.
CA 02438891 2003-08-20
Case 1/1189-ff-text BOEHRINGER INGELHEIM PHARMA KG
75112fft.204
Process for preparing optically active dihydropyrones
The invention relates to a new process for preparing optically active
dihydropyrones,
new intermediate products which can be obtained by this method of synthesis,
and
their use as starting compounds in the preparation of pharmaceutically active
compounds.
Background to the invention
io 5,6-Dihydro-4-hydroxy-2-pyrones are important structural elements in a
number of
pharmaceutically active compounds. One category of particular interest
comprises
the 5,6-dihydro-4-hydroxy-2-pyrone-sulphonamides, which may be used as non-
peptidic HIV-protease inhibitors. A particularly effective example of a potent
and
orally bioavailable HIV-protease inhibitor in this category of substances is
the
compound tipranavir (PNU-140690), which has the following structure
OH fMe
H
N, go2
O O N
\ I /
Me C F3
This and other structurally similar compounds are known from the prior art
(cf. for
example J. Med. Chem. 1998, 41, 3467-3476).
A key step in the synthesis of the abovementioned compounds and those
structurally
similar thereto is the reaction of 5,6-dihydro-4-hydroxy-2-pyrones 1 with
suitably
substituted carbonyl compounds 2 to form the condensation products 3, as
illustrated
in Diagram 1.
OH O R
O R~
+ -~
R1 zO O R R R2 O O
Diagram 1: R 1 ? R 3
CA 02438891 2003-08-20
2
The meanings of the groups Rl and R2 which are different from one another can
be
found in the detailed description of the invention which follows. The groups
may vary
in their meanings depending on the substitution pattern of the respective
target
compounds, as described in the prior art.
It is significant according to the invention that the chiral information
contained in the
starting compounds 1 is retained in the subsequent reaction shown in Diagram
1, as
a result of which the compounds 1 have a central importance in the synthesis
of the
abovementioned pharmaceutically active compounds.
The aim of the present invention is therefore to provide a process which
allows 1 to
be synthesised in high yields, with high enantiomeric purity, at the lowest
possible
technical cost and in a high space/time yield.
Detailed description of the invention
Surprisingly, it has been found that these objectives of the present invention
as
outline above can be achieved if the chiral 5,6-dihydro-4-hydroxy-2-pyrones I
are
prepared according to the procedure illustrated in Diagram 2.
OH 3 o
HO ' R ~ HO R
~ 3
+ R4 a
R~ R20 O H 2 N Ra Ri', 2 O O H3N XRa
R
1-rac 4 1-salt
OH
RR2 O O
Diagram 2:
For this, racemic 5,6-dihydro-4-hydroxy-2-pyrones 1-rac are converted with
chiral
aminoalcohols 4 into the salts 1-salt. Surprisingly, the latter can be
obtained in the
form of crystallising compounds and thus isolated in good yields and with a
high
degree of purity. Depending on the choice of the optically active
aminoalcohols 4 the
salts 1-salt of the R- or S-configured compounds 1 are crystallised. The salts
1-salt'
of the unwanted enantiomers of 1 stay in solution during this reaction step.
The
optically active target compounds are liberated from the crystallised salts 1-
salt.
CA 02438891 2003-08-20
3
Within the scope of the present invention any reference to compounds of
formula I
should always be taken as a reference to the optically active compounds 1,
whereas
any reference to compounds of formula 1-rac should be taken as a reference to
the
racemic mixture of the compounds of formula 1.
Accordingly, the present invention relates to a process for preparing a
compound of
formula I
OH
~ 1
R2O O
1o optionalfy in the form of the tautomers thereof,
wherein
Rl and R2 independently of one another denote hydrogen or a group selected
from among C1 -Cq,-alkyl, C3-C8-cycloalkyl, C6-C1 p-aryl and -C1 -C4-alkylene-
C6-C10-aryl, which may optionally be mono-, di- or trisubstituted by one or
more groups selected from among hydroxy, halogen, Cl-C4-alkoxy and CF3,
with the proviso that Rl and R2 cannot simultaneously have the same
meaning,
characterised in that in a first step a compound of formula 1-rac
OH
\ 1-rac
RI R2 O O
wherein Rl and R2 may have the meanings given hereinbefore,
is reacted in a suitable solvent with one or more, preferably one chiral
aminoalcohol
of formula 4
R3
HO ,~ R3'
JR4 4
H2N R4'
wherein
R3, RT, R4 and R4'which may be identical or different denote hydrogen or a
group
selected from among Cl-C4-alkyl, C3-C8-cycloalkyl, Cg-Clo-aryl and
-Cl-Cq,-alkylene-Cg-Clp-aryl, which may optionally be mono-, di- or
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4
trisubstituted by one or more groups selected from among hydroxy, halogen,
CI-C4-alkoxy, -S-Cl-C4-alkyl, -S02-Cl-C4-alkyl, NO2 and CF3,
with the proviso that if R3 and R3' have the same meaning, the groups R4 and
R4'cannot have the same meaning, and
with the proviso that if R4 and R4' have the same meaning, the groups R3 and
R3' cannot have the same meaning,
to form a salt of formula 1-salt
O R3
--I HO :R3'
+ Ra
.
11salt
[R1*SO H 3 N R4,
lo wherein the groups Rl, R2, R3, R3', R4 and R4'may have the meanings given
hereinbefore, the resulting crystalline compound I-salt is isolated and the
target
compound is liberated therefrom.
A preferred process according to the invention is a process for preparing a
compound of formula 1 optionally in the form of the tautomers thereof,
wherein
Rl and R2 independently of one another denote a group selected from among
methyl, ethyl, propyl, butyl, phenyl, benzyl, phenylethyl and phenylpropyl
which may optionally be monosubstituted by a group selected from among
hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy and CF3
with the proviso that Rl and R2 cannot simultaneously have the same
meaning,
characterised in that in a first step a compound of formula 1-rac wherein Rl
and R2
may have the meanings given hereinbefore is reacted in a suitable solvent with
one
or more, preferably one chiral aminoalcohol of formula 4 wherein
R3, RT, R4 and R4' which may be identical or different denote hydrogen or a
group
selected from among methyl, ethyl, propyl, phenyl, benzyl and phenylethyl,
which may optionally be mono- or disubstituted by one or two groups selected
from among hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy, Me-S-,
Me-SO2-, Et-S-, Et-S02-, NO2 and CF3,
with the proviso that if R3 and R3' have the same meaning, the groups R4 and
R4' cannot have the same meaning, and
with the proviso that if R4 and R4' have the same meaning, the groups R3 and
R3' cannot have the same meaning,
CA 02438891 2003-08-20
to form a salt of formula 1-sait, wherein the groups Rl, R2, R3, RT, R4 and
R41 may
have the meanings given hereinbefore, the resulting crystalline compound 1-
salt is
isolated and the target compound 1 is liberated therefrom.
5 Particularly preferred according to the invention is a process for preparing
a
compound of formula 1 optionally in the form of the tautomers thereof,
wherein
Rl and R2 independently of one another denote a group selected from among
methyl, ethyl, propyl, butyl, phenyl, benzyl, phenylethyl and phenylpropyl,
with the proviso that Rl and R2 cannot simultaneously have the same
meaning,
characterised in that in a first step a compound of formula 1-rac,
wherein Rl and R2 may have the meanings given hereinbefore,
is reacted in a suitable solvent with one or more, preferably one chiral
aminoalcohol
of formula 4
wherein
R3, RT, R4 and R4'which may be identical or different denote hydrogen or a
group
selected from among methyl, ethyl, propyl, phenyl and benzyl, which may
optionally be monosubstituted by a group selected from among hydroxy,
methoxy, Me-S-, Me-SO2- and NO2,
with the proviso that if R3 and RT have the same meaning, the groups R4 and
R4' cannot have the same meaning, and
with the proviso that if R4 and R4'have the same meaning, the groups R3 and
R3'cannot have the same meaning,
to form a salt of formula 1-salt, wherein the groups Rl, R2, R3, RT, R4 and
R4' may
have the meanings given hereinbefore, the resulting crystalline compound 1-
sait is
isolated and the target compound 1 is liberated therefrom.
Also preferred is a process for preparing a compound of formula 1
optionally in the form of the tautomers thereof, wherein
Rl and R2 independently of one another denote a group selected from among
ethyl,
propyl, butyl, benzyl, phenylethyl and phenylpropyl,
with the proviso that Rl and R2 cannot simultaneously have the same
meaning,
characterised in that in a first step a compound of formula 1-rac,
wherein Rl and R2 may have the meanings given hereinbefore,
is reacted in a suitable solvent with one or more, preferably one chiral
aminoalcohol
of formula 4, wherein
CA 02438891 2003-08-20
6
R3 and R3' which may be identical or different denote hydrogen or a group
selected
from among phenyl, hydroxyphenyl, methylthiophenyl and nitrophenyl, and
R4 and R4' which may be identical or different denote hydrogen or a group
selected
from among methyl, hydroxymethyl and phenyl,
with the proviso that if R3 and RT have the same meaning, the groups R4 and
R4' cannot have the same meaning, and with the proviso that if R4 and R4'
have the same meaning, the groups R3 and R3'cannot have the same
meaning,
to form a salt of formula 1-salt , wherein the groups Rl, R2, R3, RT, R4 and
R4'
io may have the meanings given hereinbefore, the resulting crystalline
compound
1-salt is isolated and the target compound 1 is liberated therefrom.
Particularly preferred according to the invention is a process for preparing a
compound of formula 1, optionally in the form of the tautomers thereof,
wherein Rl denotes phenylethyl and R2 denotes propyl,
characterised in that in a first step a compound of formula 1-rac wherein Rl
and R2
may have the meanings given hereinbefore
is reacted in a suitable solvent with one or more, preferably one chiral
aminoalcohol
of formula 4
wherein
R3 and RT which may be identical or different denote hydrogen or a group
selected
from among phenyl, methylthiophenyl and nitrophenyl, and
R4 and R4' which may be identical or different denote hydrogen or a group
selected
from among methyl, hydroxymethyl and phenyl,
with the proviso that if R3 and RT have the same meaning, the groups R4 and
R4' cannot have the same meaning, and with the proviso that if R4 and R4'
have the same meaning, the groups R3 and RT cannot have the same
meaning,
to form a salt of formula 1-salt, wherein the groups R1, R2, R3, RT, R4 and
R4' may
have the meanings given hereinbefore, the resulting crystalline compound 1-
salt is
isolated and the target compound 1 is liberated therefrom.
The following procedure may be used to carry out the process according to the
invention. To prepare 1-saltthe racemic mixture 1-rac is dissolved in a
suitable
organic solvent, preferably in an anhydrous organic solvent, most preferably
in a
non-polar organic solvent. Preferred solvents according to the invention are
acetonitrile, propionitrile, butyronitrile, methylene chloride, chloroform,
methyl
acetate, ethyl acetate, n-butyl acetate, tert-butylmethylether, isopropanol,
tetrahydrofuran, dioxane, methanol or mixtures thereof, more preferably
acetonitrile,
CA 02438891 2003-08-20
7
propionitrile, butyronitrile, methylene chloride, n-butyl acetate or mixtures
thereof,
most preferably acetonitrile, propionitrile, butyronitrile or mixtures
thereof.
At a temperature of -10 C to 50 C, preferably 0 C to 40 C, more preferably 10-
30 C,
most preferably 20-25 C the chiral amine 4 is added and the resulting mixture
is
mixed thoroughly by stirring for a period of 1-12 h, preferably 3-8 h, more
preferably
4-6 h at constant temperature. Between 0.3 - 2.0 mol, preferably 0.4 - 1.0
mol, most
preferably about 0.45 - 0.55 mol of amine 4 are used per mol of 1-rac put in.
It may
be helpful in some cases to add seed crystals to accelerate crystallisation or
to use
io other methods known in the art for increasing the tendency to
crystallisation.
The reaction mixture is then brought to a temperature of -40 C to 30 C,
preferably
-20 C to 20 C, more preferably -10 C to 15 C, most preferably 0 C to 10 C and
the
crystalline 1-salt is separated off. The salt which is diastereomeric to 1-
salt may be
obtained from the remaining solution analogously using methods known in the
prior
art. The crystals thus obtained are then washed with one of the abovementioned
organic solvents, preferably with the organic solvent which is used to carry
out the
reaction, and dried in vacuo.
The following procedure may be used according to the invention to liberate the
compounds of formula 1 from the 1-satt salts. The 1-salt compounds are taken
up in
a suitable solvent, preferably a polar solvent, more preferably in water. An
organic
solvent, preferably an organic, water-immiscible solvent is used for this.
This solvent
is preferably selected from among toluene, methyl tert.-butylether, methylene
chloride, chloroform, methyl acetate, ethyl acetate, n-butyl acetate and
mixtures
thereof, more preferably selected from toluene, methyl tert.-butyiether, ethyl
acetate,
n-butyl acetate and mixtures thereof, toluene and methyl tert.-butylether
being of
particular importance. According to the invention, the ratio in which the
abovementioned polar solvent and the abovementioned water-immiscible solvent
are
used is in the range from 1:10 (v/v) to 10:1 (v/v), preferably 1:5 (v/v) to
5:1 (v/v),
more preferably 3:1 (v/v) to 1:3 (v/v). An organic or inorganic acid is then
added to
this mixture, while according to the invention the use of inorganic mineral
acids is
preferred. The following acids are preferably used as inorganic acids:
hydrochloric
acid, sulphuric acid, nitric acid, formic acid, acetic acid or phosphoric
acid, preferably
hydrochloric acid, sulphuric acid or phosphoric acid, most preferably
hydrochloric
acid and sulphuric acid, while sulphuric acid is of particular importance
according to
the invention for performing this step of the process. The acid may be
dissolved in
dilute or concentrated form, in the form of aqueous solutions or in organic
solvents,
optionally also in gaseous form, where technically possible. If sulphuric acid
is used,
CA 02438891 2003-08-20
8
for example, 30% sulphuric acid (aq) may be used. It is clear to anyone
skilled in the
art that at least stoichiometric amounts of acid are necessary in order to
liberate I
completely from 1-salt. It is preferable according to the invention for the
acid to be
added in excess. In this way, a pH of <5, preferably a pH of 0.5-3, more
preferably a
pH of about 1-2 is obtained according to the invention.
After all the acid has been added, the mixture is stirred for between 0.25 - 5
h,
preferably 0.5-3 h, more preferably 0.75-1.5 h. Two phases are formed. The
aqueous
phase is separated off and the remaining organic phase is optionally washed
another
one to five times with water and finally the solvent is distilled off in
vacuo. As a rule,
no further purification of the products is necessary. Depending on the
crystallisation
tendency of I in the solvent in question, the target compounds may also be
isolated
by crystallisation. By working up the organic phase, e.g. by adding a base,
the
amines 4 initially used in the synthesis can be recovered and recycled into a
new
reaction with 1-rac.
As is clear from the foregoing description of the process according to the
invention,
the compounds of formula 1-salt are of particular importance, due for example
to the
surprisingly high crystallisation tendency of these salts.
Accordingly, in another aspect, the present invention relates to the compounds
of
formula I-salt
O R3
HO : R3'
+ R4
R R2 O O H3N R4,
11salt
wherein
R1 and R2 independently of one another denote hydrogen or a group selected
from among C1-C4-alkyl, C3-C8-cycloalkyl, C6-C10-aryl and -C1-C4-alkylene-
C6-C10-aryl, which may optionally be mono-, di- or trisubstituted by one or
more groups selected from among hydroxy, halogen, C1-C4-alkoxy and CF3;
3o R3, R3', R4 and R4'which may be identical or different denote hydrogen or a
group
selected from among C1-C4-alkyl, C3-C8-cycloalkyl, C6-C10-aryl and -C1-C4-
alkylene-C6-C10-aryl, which may optionally be mono-, di- or trisubstituted by
one or more groups selected from among hydroxy, halogen, C1-C4-alkoxy,
-S-C1-C4-alkyl, -SO2-C1-C4-alkyl, NO2 and CF3,
CA 02438891 2003-08-20
9
optionally in the form of the tautomers thereof,
with the proviso that Rl and R2 cannot simultaneously have the same meaning,
with the proviso that if R3 and RT have the same meaning, the groups R4 and
R4'
cannot have the same meaning, and
with the proviso that if R4 and R4' have the same meaning, the groups R3 and
RT
cannot have the same meaning.
Preferred compounds are those of formula 1-salt
wherein
9o Rl and R2 independently of one another denote a group selected from among
methyl, ethyl, propyl, butyl, phenyl, benzyl, phenylethyl and phenylpropyl
which may optionally be monosubstituted by a group selected from among
hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy and CF3;
R3, RT, R4 and R4'which may be identical or different denote hydrogen or a
group
selected from among methyl, ethyl, propyl, phenyl, benzyl and phenylethyl,
which may optionally be mono- or disubstituted by one or two groups selected
from among hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy, Me-S-,
Me-S02-, Et-S-, Et-S02-, NO2 and CF3,
optionally in the form of the tautomers thereof,
with the proviso that Rl and R2 cannot simultaneously have the same meaning,
with the proviso that if R3 and RT have the same meaning, the groups R4 and
R4,
cannot have the same meaning, and
with the proviso that if R4 and R4' have the same meaning, the groups R3 and
RT
cannot have the same meaning.
Particularly preferred are compounds of formula 1-salt
wherein
Rl and R2 independently of one another denote a group selected from among
methyl, ethyl, propyl, butyl, phenyl, benzyl, phenylethyl and phenylpropyl,
R3, RT, R4 and R4'which may be identical or different denote hydrogen or a
group
selected from among methyl, ethyl, propyl, phenyl and benzyl, which may
optionally be monosubstituted by a group selected from among hydroxy,
methoxy, Me-S-, Me-SO2- and NO2,
optionally in the form of the tautomers thereof,
with the proviso that Rl and R2 cannot simultaneously have the same meaning,
with the proviso that if R3 and RT have the same meaning, the groups R4 and
R4'
cannot have the same meaning, and
with the proviso that if R4 and R4' have the same meaning, the groups R3 and
RT
cannot have the same meaning.
CA 02438891 2003-08-20
Also preferred are compounds of formula 1-salt
wherein
R1 and R2 independently of one another denote a group selected from among
ethyl,
5 propyl, butyl, benzyl, phenylethyl and phenylpropyl,
R3 and RT which may be identical or different denote hydrogen or a group
selected
from among phenyl, hydroxyphenyl, methylthiophenyl and nitrophenyl;
R4 and R4' which may be identical or different denote hydrogen or a group
selected
from among methyl, hydroxymethyl and phenyl,
10 optionally in the form of the tautomers thereof,
with the proviso that R1 and R2 cannot simultaneously have the same meaning,
with the proviso that if R3 and RT have the same meaning, the groups R4 and
R4cannot have the same meaning, and
with the proviso that if R4 and R4' have the same meaning, the groups R3 and
RT
cannot have the same meaning.
Also particularly preferred according to the invention are compounds of
formula
1-salt
wherein
R1 denotes phenylethyl and R2 denotes propyl,
R3 and R3' which may be identical or different denote hydrogen or a group
selected
from among phenyl, methylthiophenyl and nitrophenyl,
and
R4 and R4' which may be identical or different denote hydrogen or a group
selected
from among methyl, hydroxymethyl and phenyl,
optionally in the form of their tautomers, with the proviso that if R3 and RT
have the
same meaning, the groups R4 and R4'cannot have the same meaning, and
with the proviso that if R4 and R4' have the same meaning, the groups R3 and
RT cannot have the same meaning.
Because of the central importance of the compounds of formula 1-salt as
starting
compounds for synthesising optically active, pharmaceutically active
compounds, in
a further aspect the invention relates to the use of compounds of general
formula 1-
salt for preparing pharmaceutically active compounds. Preferably, the present
invention relates to the use of compounds of formula 1-salt for preparing
tipranavir.
The present invention further relates to processes for preparing
pharmaceutically
active compounds which are characterised in that compounds of formula 1-salt
are
CA 02438891 2003-08-20
11
used which may be obtained by the process according to the invention for
preparing
1-salt.
The present invention preferably relates to processes for preparing tipranavir
which
are characterised in that compounds of formula 1-salt are used which may be
obtained by the process for preparing 1-salt according to the invention.
Moreover, one aspect of the present invention relates to the use of compounds
of
general formula 1 which are obtained according to the present invention for
preparing pharmaceutically active compounds. The present invention preferably
io relates to the use of compounds of formula 1 which are obtained according
to the
present invention for the preparation of tipranavir.
The present invention further relates to methods of preparing pharmaceutically
active
compounds which are characterised in that compounds of formula 1 are used
which
are obtained by the process according to the invention for preparing 1.
The present invention preferably relates to processes for preparing tipranavir
which
are characterised in that compounds of formula 1 are used which are obtained
by the
process according to the invention for preparing 1.
According to the invention, the compounds 1-salt may be synthesised starting
from
the compounds of formula 1-rac. The latter may be obtained by the procedure
outlined in Diagram 3.
OH
O O O
+
R~ R2 OR5 Rl R2 O O
5 6 1-rac
Diagram 3:
For this, a suitably substituted carbonyl compound 5 wherein the groups R1 and
R2
may have the meanings given hereinbefore is reacted with an acetoacetic acid
derivative 6 wherein R5 denotes Cl-Cq,-alkyl or a cation selected from among
lithium, sodium and potassium, preferably sodium, preferably methyl, ethyl,
propyl or
sodium, most preferably ethyl or sodium, to obtain the compound 1-rac, wherein
the
groups R1 and R2 may have the meanings given hereinbefore.
This reaction is carried out in the presence of organic or inorganic bases,
preferably
in the presence of organic, sterically demanding bases. VVithin the scope of
the
CA 02438891 2003-08-20
12
present invention it is preferable to use organic bases which are selected
from
among DBU and DBN. Sterically demanding organic bases in the sense of the
present invention also include organometallic compounds such as lithium,
sodium
and potassium salts of secondary amines. Preferred bases of this type are
selected
from among lithium diisopropylamine, lithium diethylamine, lithium
hexamethyldisilazane, sodium hexamethyldisilazane, potassium
hexamethyldisilazane or lithium tert.-butoxide, preferably lithium
diisopropylamine,
lithium diethylamine, lithium hexamethyldisilazane, sodium
hexamethyldisilazane,
potassium hexamethyldisilazane, particularly preferably lithium
diisopropylamine, and
lithium diethylamine. These latter bases are either commercially obtainable or
may
be synthesised by methods known in the art.
In order to prepare the compounds of formula 1-rac according to the invention,
one
of the abovementioned bases, which is either generated in situ or used
directly, is
placed in a suitable organic solvent, preferably in an organic anhydrous
solvent. The
solvents used are preferably ethereal solvents such as tetrahydrofuran (THF),
methylethylether, diethylether, dioxane or other non-polar organic solvents
such as
toluene, hexane or heptane. If desired, the ethereal solvents may also be used
in
admixture with the abovementioned non-polar solvents. It is preferable to use
the
2o abovementioned ethereal solvents. The solvent THF and mixtures containing
it,
preferably THF/hexane or THF/toluene, are of particular importance.
The solution thus obtained is cooled, preferably to a temperature of below 0
C,
preferably below -10 C, more preferably below -20 C. According to the
invention, it is
particularly preferred to carry out the reaction in a range from -78 C to -40
C. If one
of the abovementioned solvents is not in a liquid aggregate state at these
temperatures, the lowest possible reaction temperature is determined by the
flow
point of the solvent used, as will be clear to anyone skilled in the art. The
acetoacetic acid derivative 6, in which R5 may be as hereinbefore defined, is
then
added to the cooled solution of the base in one of the abovementioned
solvents. At
most stoichiometric amounts of 6 are added per mol of base used. Preferably,
substoichiometric amounts of 6 are used, the molar ratio of 6 to the base used
preferabiy being in the range from 0.9:1 to 0.2:1, more preferably 0.7:1 -
0.3:1, most
preferably 0.6:1 - 0.4:1.
After the addition of 6 the mixture is stirred at constant temperature for a
period of
about 5 minutes to 1 h and a solution of 5 in one of the abovementioned
solvents,
preferably in the same organic solvent, is slowly added dropwise thereto. A
maximum of 1 moi of 5 is used per mol of compound 6 used. Preferably,
CA 02438891 2003-08-20
13
substoichiometric amounts of 5 are used, the molar ratio of 5 to 6 preferably
being in
the range from 0.9:1 - 0.2:1, more preferably 0.8:1 - 0.3:1, most preferably
0.7:1 -
0.5:1. After the addition is complete, stirring is continued either at
constant
temperature or at slightly elevated temperature. If the temperature is
increased it is
still preferably kept below 0 C, preferably below -10 C, more preferably below
-20 C.
It is particularly preferable according to the invention to carry out the
reaction in a
range from -40C to -20 C. According to the invention, the reaction lasts in
the region
of 0.5 - 8 h, preferably 1- 5 h, most preferably 1.5 - 3 h.
io The reaction may be stopped by methods known in the art, e.g. by the
addition of
aqueous solutions, e.g. aqueous ammonium chloride solution. The reaction
mixture
is also worked up analogously to the procedures known in the prior art.
Examples of alkyl groups (including those which are part of other groups)
include,
unless otherwise specified, branched and unbranched alkyl groups with 1 to 4
carbon atoms. The following hydrocarbon groups are mentioned by way of
example:
methyl, ethyl, propyl, 1-methylethyl (lsopropyl), n-butyl, 1-methylpropyl, 2-
methylpropyl, 1,1-dimethylethyl (tert.butyl). The definitions propyl and butyl
in each
case include the associated isomeric groups. In some cases, the common
abbreviations Me for methyl, Et for ethyl, Prop for propyl and But for butyl
are used
for the abovementioned alkyl groups.
Examples of alkylene groups include branched and unbranched alkylene bridges
with 1 to 4 carbon atoms. These may be, for example: methylene, ethylene,
propylene and butylene. Unless otherwise specified, the terms propylene and
butylene used above also include all the possible isomeric forms. Accordingly,
the
term propylene includes the isomeric bridges n-propylene, methylethylene and
dimethylmethylene and the term butylene includes the isomeric bridges n-
butylene,
1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-
dimethylethylene.
Cycloalkyl generally denotes a saturated cyclic hydrocarbon group with 3 to 8
carbon
atoms. Cyclic hydrocarbons with 3 to 6 carbon atoms are preferred.
Cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are mentioned
as
examples.
Alkyloxy, which may optionally also be referred to as alkoxy, generally
denotes a
straight-chain or branched alkyl group with 1 to 4 carbon atoms bound via an
oxygen
atom. The methoxy group is particularly preferred.
CA 02438891 2003-08-20
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14
The term aryl denotes an aromatic ring system with 6 to 10 carbon atoms.
Preferred
aryi groups are naphthyl and phenyl, the phenyl group being particularly
preferred.
Naphthyl may be abbreviated to Naph and phenyl to Ph.
By aryl-alkylene or alkylene-aryl are meant, for the purposes of the
invention, aryl
groups linked by an alkylene bridge, the alkylene groups and aryl groups being
defined as mentioned above. Unless otherwise specified, preferred alkylene-
aryl
groups according to the invention are benzyl, 2-phenylethyl and 3-
phenylpropyl.
Halogen within the scope of the present invention denotes fluorine, chlorine,
bromine
or iodine, of which fluorine, chlorine and bromine are preferred, unless
otherwise
specified.
Within the scope of the present invention any reference to compounds of
formula 1
should be taken as a reference to the compound in an optically active form.
The
particular optically active form is determined by the definition of the groups
R1 and
R2 in each case. Any reference to I includes all the enantiomeric mixtures of
the two
possible enantiomers of 1 which are not racemic. Racemic mixtures are referred
to
as 1-rac , as hereinbefore defined. Any reference to I also includes the
particular
tautomeric forms of J.
Within the scope of the present invention any reference to compounds of
formula 1-
sait should be taken as a reference to the compound in an optically active
form. The
particular optically active form is determined by the definition of the groups
RI, R29
R3, R3', R4 and, R4~. Any reference to 1-sait includes all the diastereomeric
mixtures
of the possible diastereomers of 1-sait which are not racemic. Any reference
to 1-
sait also includes the particular tautomeric forms of 1-sa
The following Examples serve to illustrate some methods of synthesis carried
out by
way of example for preparing a compound of formula 1. They are to be
understood
only as descriptions of possible methods given as examples, without
restricting the
invention to their contents.
Preparation of the comQound of formula 1-rac
(wherein R1 denotes 2-phenylethyl and R2 denotes n-propy!)
104 ml (1.00 mol) of diethylamine in 160 mi THF are cooled to -50 C. Wrthin 10
minutes, 400 ml (1.00 mol) of a 2.5 M n-BuLi solution in n-hexane are added to
this
CA 02438891 2003-08-20
solution. After it has all been added, stirring is continued for another 10
min and 63
ml (0.500 mol) of acetoacetic acid ester are then added. After 10 minutes, 60
g
(0.340 mol) of 1-phenylhexan-3-one in 80 ml of THF are added dropwise over 30
min
at -500C. The mixture is heated to -30 C and stirred for another 2 h. The
reaction
5 solution is added to 1200 ml of saturated NH4CI solution, the aqueous phase
is
separated off and the organic phase is washed with 400 ml of saturated NH4CI
solution and 200 ml of 2N HCI. Then the organic phase is washed until neutral
with
NaHCO3 solution, separated off and the solvent is distilled off in vacuo. The
oil
obtained (118 g) is combined at ambient temperature with a solution of 29.4 g
(1.20
1o mol) of KOH (85%) in 140 ml of MeOH. After the reaction has ended (about
10h) the
MeOH is separated off by distillation. The residue is taken up in 400 ml of
water and
400 ml of toluene and after phase separation the aqueous phase is extracted
again
with 400 ml of toluene. The aqueous phase is adjusted to pH < 2 with 136 ml of
30 %
H2SO4 and extracted with 400 ml of toluene. The toluene phase is washed three
15 times with 200 ml of water. The toluene is evaporated down to about half
the volume.
The residue is mixed with 500 ml of octane and stirred until crystallisation
occurs.
67.5 g (76%) of the compound 1-rac are obtained.
Preparation of the compound of formula 1-salt
(wherein R1 denotes 2-phenylethyl, R2 denotes n-propyl, R3 denotes hydrogen,
R3,
denotes 4-methylthiophenyl, R4 denotes hydroxymethyl and R4, denotes hydrogen)
29 g (110 mmol) of the compound 1-rac obtained by the above method are
dissolved
in 250 ml of acetonitrile. After the addition of 10.6 g (50.0 mmol) of (+)-
thiomicamine
4 a solution is formed. It is stirred for 5 hours at ambient temperature,
cooled to
about 5 C and the crystals are suction filtered through a Biichner funnel. The
crystals obtained are washed with 150 ml of acetonitrile. The crystals are
dried in a
vacuum drying cupboard for 12 h. 21.3 g (90% yield based on the amine 4 used)
of
colourless crystals are obtained. The ratio of diastereomers is about 90:10
without
any further crystallisation. If necessary, the optical purity can be increased
by a
further crystallisation step.
Preparation of the compound of formula I
(wherein R1 denotes 2-phenylethyl and R2 denotes n-propyl)
29 g (110 mmol) of the compound 1-salt obtained by the method described above
are combined with 290 methyl-tert.-butylether in 290 ml of water. 15 ml of 30%
sulphuric acid are added thereto (pH =1.5). After one hour's stirring, two
phases are
formed. The aqueous phase is separated off. The organic phase is washed three
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16
times with 100 ml of water. Then the organic phase is evaporated down in vacuo
to
leave a residue.
14.0 g (yield 88%) of compound 1 are obtained.
Table 1 lists the compounds of formula 1-salt obtained by the method according
to
the invention.
Table 1:
O Rs
.~ HO R
1-salt
+ R4
x R'.= R20 O H3N R4,
Exa- R1 R2 R3 RT R4 R41
mple
1 Ph-ethyl- n-propyl- H 4-MeS-Ph- HO-methyl- H
2 n-propyl- Ph-ethyl- Ph H Me H
3 n-propyl- Ph-ethyl- H Ph H Me
4 Ph-ethyl- n-propyl- H H H Ph
5 Ph-ethyl- n-propyl- H H Ph H
6 Ph-ethyl- n-propyl- H Ph HO-methyl- H
7 Ph-ethyl- n-propyl- Ph H H HO-methyl-
8 Ph-ethyl- n-propyl- H 4-N02-Ph HO-methyl- H
9 Ph-ethyl- n-propyl- 4-N02-Ph H H HO-methyl-
10 n-propyl- Ph-ethyl- Ph H Ph H
11 n-propyl- Ph-ethyl- H Ph H Ph
