Note: Descriptions are shown in the official language in which they were submitted.
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80897pct.211
Industrial process for preparing tropenol
The invention relates to a new industrially useable process for preparing
tropenol, optionally in the form of the acid addition salts thereof.
Background to the invention
The compound tropenol is known from the prior art and has the following
chemical structure:
Me
N
\\ , H
OH ~I
The compound may be used as a starting compound for preparing
pharmacologically valuable compounds. For example, the compounds
tiotropium bromide, ipratropium bromide or also BEA2108 may be mentioned
in this context. These pharmacologically valuable substances are
characterised by the following chemical structures:
+ Me + Me
Me,N, Me Me,N,
O _ Me~N~Me Br
O ~H Br / O ~H Br
S O ~ ~ S O
/ OH ~ OH I / OH
/~S v / ~S
tiotropium bromide ipratropium bromide BEA2108
Because of the high degree of efficacy of the above compounds they have to
be made available in as pure form as possible using efficient methods of
synthesis. The stringent purity requirements, in particular, with which
compounds intended for therapeutic use generally have to comply, demand
the lowest possible levels of contaminant in the starting compounds. If
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materials which contain relatively high levels of impurities are used as
starting
compounds, purification of the end product is often difficult as any
impurities
introduced at the beginning often cannot easily be removed at later stages of
synthesis or only at the expense of substantial losses of yield. This is
particularly the case when the by-products or impurities present only differ
slightly structurally from the main products in question.
Against this background the problem of the present invention is to provide a
method of synthesis which allows industrial production of tropenol, preferably
in the form of one of the acid addition salts thereof, in a good yield and
particularly with a high degree of purity.
Detailed description of the invention
The problem defined above is solved by the invention described hereinafter.
The present invention accordingly relates to an industrial process for
preparing tropenol of formula (I)
Me
N
\\ , H
OH (I)
optionally in the form of the acid addition salts thereof, characterised in
that a
compound of formula (II)
Me
E
HO H
/R
O (II)
wherein
R denotes a group selected from C~-C4-alkyl, C2-C6-alkenyl and C~-C4-
alkylene-phenyl, each of which may be substituted by hydroxy or
C ~ -C4-alkoxy,
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optionally in the form of the acid addition salts thereof as well as
optionally in
the form of the hydrates thereof in a suitable solvent, is reacted with a
formamide-acetal of formula (III)
R"
R"iN ~OR~
OR' (III)
wherein
R' denotes C1-C4-alkyl and R" denotes a group selected from C1-C4-alkyl
and C1-C4-alkylene-phenyl, to obtain a compound of formula IV
Me
N
R~~~N O O H
R"
O\ /R
O (IV)
wherein the groups R, R' and R" may have the meanings given above,
this is then converted by decarboxylation into an ester of formula (V)
Me
N
\\ , H
O\ /R
O (V)
wherein R may have the meanings given above, and lastly this ester is
saponified to obtain the compound of formula (I) which is optionally converted
into an acid addition salt by reaction with a suitable acid. . .
Preferably, the present invention relates to an industrial process for
preparing
tropenol of formula (I), optionally in the form of the acid addition salts
thereof,
which is characterised in that a compound of formula (II) wherein R denotes
C1-C4-alkyl or C2-Cq.-alkenyl is used as starting material, optionally in the
form of the acid addition salts thereof and optionally in the form of the
hydrates thereof, and wherein, in the formamide-acetal of formula (III) used,
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the groups R' denote methyl or ethyl and the groups R" represent methyl,
ethyl or propyl.
Most preferably, the present invention relates to an industrial process for
preparing tropenol of formula (I), optionally in the form of the acid addition
salts thereof, preferably in the form of its hydrochloride, which is
characterised
in that a compound of formula (II) wherein R denotes 1-propenyl, 2-propenyl,
1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl or 2-
buten-
2-yl is used as starting material, optionally in the form of the acid addition
salts
thereof as well as optionally in the form of the hydrates thereof and wherein
in
the formamide-acetal of formula (III) used the groups R' and R" represent
methyl or ethyl, preferably methyl.
Most preferably, the compound of formula (II) used is the compound wherein
R denotes 2-buten-2-yl. This compound is also known by the name meteloidin
in the prior art.
The term C1-C4-alkyl within the scope of the present invention denotes
branched or unbranched alkyl groups with up to 4 carbon atoms. Examples
include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and
tert-
butyl. The term C1-C4-alkylene-phenyl within the scope of the present
invention denotes phenyl which is linked via a branched or unbranched
alkylene bridge having up to 4 carbon atoms. Examples include benzyl,
phenyl-2-ethyl, phenyl-1-ethyl, phenyl-3-propyl, phenyl-2-propyl- etc. Both
the
C1-C4-alkyl groups and also the C1-C4-alkylene-phenyl groups may, unless
otherwise specified, be substituted by one or more hydroxy and/or C1-C4-
alkyloxy groups.
By C2-C6-alkenyl are meant within the scope of the present invention
branched or unbranched alkenyl groups with 2 to 6 carbon atoms which have
at least one double bond. Examples include vinyl, 1-propenyl, 2-propenyl, 1-
buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-
yl,
butadien-1-yl, butadien-2-yl etc.
Unless otherwise stated, within the scope of the present invention the term
acid addition salts refers to the salts formed with the acids hydrochloric
acid,
hydrobromic acid, phosphoric acid, sulphuric acid, tetrafluoroboric acid or
hexafluorophosphoric acid, preferably hydrochloric acid or hydrobromic acid.
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According to the invention, the following procedure may be followed for
pertorming the process for preparing tropenol according to the invention.
The compound of formula (III) is placed in a suitable reaction vessel.
Usually at least 1 mol of the compound (Ill) is used per mol of the compound
of formula (II) to be reacted. Preferably, between 1.01 and 5.0 mol,
preferably
between 1.1 and 4.0 mol, most preferably between 1.5 and 3.0 mol of the
compound (III) are put in per mol of the compound (III) to be reacted. Then
the compound of formula (II) is added batchwise with stirring. After the
addition has ended the mixture obtained is heated preferably to a temperature
of above 40°C, preferably more than 50°C, most preferably more
than 60°C.
In the course of the reaction the alcohol R'-OH is released. It is preferably
removed from the reaction equilibrium by distillation. This distillation may
optionally be carried out under reduced pressure. If the compound of formula
(III) used is the compound wherein R' denotes methyl, the temperature is
preferably adjusted to a range from about 55-90°C, more preferably from
about 60-85°C. After the reaction has ended the compound of formula
(III)
which was optionally used in excess is removed by distillation under reduced
pressure. To do this the mixture obtained is preferably heated to a
temperature of above 40°C, preferably above 50°C, and a vacuum
of 100
mbar or less, preferably 60 mbar or less, most preferably 40 mbar or less is
applied.
The residue remaining (crude product of general formula (IV)) is then taken up
with stirring in a suitable solvent, preferably in a polar organic solvent,
most
preferably in a solvent selected from the group consisting of
dimethylformamide, acetonitrile, dimethylacetamide and N-
methylpyrrolidinone, most preferably dimethylformamide. For example 0.001
to 10 L, preferably 0.01 to 5 L, most preferably 0.05 to 1 L of s~ivent may be
used per mol of the compound of formula (II) used in order to prepare this
solution. Preferably at this point about 0.07 to 0.5 L of solvent are used per
mol of the compound of formula (II) originally put in.
The solution thus obtained is then added, over a period of for example 10
minutes to 3 hours, preferably 20 minutes to 2 hours, to stirred acetic
anhydride heated to a temperature of more than 70°C, preferably more
than
80°C, preferably more than 90°C, but not more than 139°C.
Most preferably,
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the acetic anhydride used is heated to a temperature of about 120-
135°C.
According to the invention, for example, 1 to 10 mol, preferably 2 to 8 mol,
most preferably about 3 to 6 mol of acetic anhydride are used per mol of the
compound of formula (II) originally put in. Preferably, according to the
invention, about 4 to 5 mol of acetic anhydride are used per mol of the
compound of formula (II) put in. During this reaction C02 is given off. After
the addition has ended for example a further 0.0005 to 5 L, preferably 0.005
to 2.5 L, most preferably 0.025 to 0.5 L of the above-mentioned solvent are
added to the solution containing the compound of formula (IV) and the
resulting mixture is stirred at constant temperature for a further 10 minutes
to
6 hours, for example, preferably a further 30 minutes to 3 hours, most
preferably a further 1 to 2 hours. Then all the liquid ingredients of the
reaction
mixture are eliminated by distillation at at least 40°C, preferably at
least 50°C,
most preferably at about 55-70°C under reduced pressure, preferably at
about
20 mbar or less, preferably at about 10 mbar or less.
The residue remaining is then taken up in a suitable solvent, preferably in
water and/or a lower alcohol, selected from the group consisting of methanol,
ethanol and isopropanol, most preferably water, ethanol or a mixture thereof.
At this point preferably 0,1 to 3 L, most preferably about 0.5 to 2 L of one
of
the abovementioned alcohols mixed with for example 0.01 to 1 L, preferably
0.05 to 0.5 L of water are used as solvent, per mol of the compound of
formula (II) originally put in.
To saponify the ester function of the compound of formula (V) now present in
dissolved form this is combined with a suitable base. Suitable bases are
preferably inorganic bases, selected from among the alkali or alkaline earth
metal carbonates, alkali or alkaline earth metal alkoxides and alkali or
alkaline
earth metal hydroxides. Particularly preferred are the hydroxides of lithium,
sodiuiii~, -potassium and calcium, most preferably sodium or calcium.
According to the invention sodium hydroxide is most preferably used as the
base. The abovementioned bases may be used in pure form or, more
preferably, in the form of aqueous concentrated solutions. If, for example,
sodium hydroxide is used, which is the particularly preferred base, it is
preferably added in the form of aqueous solutions with a concentration of at
least 40 wt.%. It is essential to use at least stoichiometric amounts of base
per
mol of the eompQUnd of formula (II) originally put in. However, it is also
possible to use the base in excess. Preferably, about 1.1 to 4 mol, preferably
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1.5 to 3 mol, most preferably about 1.7 to 2.5 mol of the abovementioned
base are used per mol of the compound of formula (II) originally used. The
base may be added to the solution of the ester of formula (V) for example at a
temperature in the range from 0 to 50°C. However, after the base has
been
added it is preferable to heat the resulting reaction mixture to a temperature
above 50°C, most preferably above 60°C. In a particularly
preferred
embodiment of the present invention, after all the base has been added, the
reaction mixture obtained is refluxed with stirring for a period of about 15
minutes to 4 hours, preferably 30 minutes to 3 hours, most preferably 1 to 2
hours. Then the solvent is eliminated by distillation at at least 40°C,
preferably
at least 50°C, most preferably at about 50-60°C under reduced
pressure,
preferably at about 80 mbar or less, preferably at about 60 mbar or less, most
preferably at about 50 mbar or less.
The residue obtained is taken up in water. About 0.01 to 1, preferably about
0.1 to 1 L of water are used per mol of the compound of formula (II)
originally
put in. The tropenol is extracted from this mixture by means of a suitable,
water-immiscible organic solvent, preferably using a solvent selected from the
group consisting of toluene, methyl-tent-butylether, dichloromethane,
chloroform, preferably dichloromethane. According to the invention, a total of
between 0.5 and 5, preferably between 0.75 and 4 litres of organic solvent are
used for the extraction per mol of the compound of formula (II) used. The
extraction is carried out according to the invention between 3 and 8,
preferably 4 to 6 times. After the extraction has ended the organic phases are
combined and the organic solvent is distilled off in vacuo.
The crude product remaining is taken up in an organic solvent selected from
among methanol, ethanol and isopropanol, preferably isopropanol. According
to the invention between 0.1 and 4.0 litres, preferably between about 1 and 2
litres of this abovementioned sclve~ ~i are used per mol of the compound of
formula (II) originally used. The solution obtained is optionally filtered.
The
filtrate contains tropenol of formula (I) in the form of its free base. If the
free
base is to be used in the next reaction, the solvent is distilled off in vacuo
at
this point. The remaining free base can then be used in the next steps of the
synthesis, without further purification. According to the invention, however,
the
free base of tropenol is preferably converted into one of the acid addition
salts. By the acid addition salts of tropenol-are meant, for the purposes of
the
present invention, the salts selected from among the hydrochloride,
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hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate or
hexafluorophosphate. The hydrobromide and hydrochloride salts are
particularly preferred, while tropenol hydrochloride is of particular
importance
according to the invention. To prepare the acid addition salts the filtrate is
cooled to a temperature in the range from -20°C to 20°C,
preferably in the
range from -10°C to 15°C. The suspension thus obtained is then
combined
with the corresponding acid needed to form the acid addition salts, namely the
hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate,
tetrafluoroborate or hexafluorophosphate. At least 1 mol of the acid in
question should be used per mol of the compound of formula (II) originally
used. It may be possible, within the scope of the processes according to the
invention, to use the acid in excess (i.e. 1.1 to about 2-3 mol per mol of the
base (II) originally used). According to the invention the hydrochloride of
tropenol is preferably prepared. The hydrochloric acid required for this may
be
added either in the form of a solution or in gaseous form. Preferably,
hydrogen chloride in gaseous form is used. One of the abovementioned
acids is added to the solution of the free base of the tropenol (I) until a pH
of 1
to 5, preferably 1.5 to 4, is obtained. After all the acid has been added
stirring
may optionally continue at constant temperature for a further 0.5 to 2 hours.
Finally, the precipitated acid addition salt of tropenol is separated off and
optionally washed with a solvent selected from among acetone,
methylisobutylketone and methylethylketone, preferably acetone, and dried in
vacuo or under an inert gas (such as nitrogen), optionally at elevated
temperature.
As mentioned in the introduction, tropenol, which may be obtained by the
preparation process according to the invention, is a valuable starting
compound for preparing therapeutically active compounds such as for
example tiotropium bromide, ipratropium bromide or BEA2108. Because of
the high purity in which tropenol can be obtained according to the~present
invention, it is possible to prepare the abovementioned active substances in
the specifications required for pharmaceutical use.
Accordingly, the present invention further relates to the use of tropenol,
optionally in the form of the acid addition salts thereof, as a starting
material
for preparing therapeutically active compounds such as for example
_ . _ tiotropium bromide, ipratropium bromide or BEA2108, preferably
tiotropium
bromide.
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The present invention further relates to the use of compounds of formula (II)
Me
N
HO
HO \\ ,H
O~R
O (II)
wherein R may have the meanings given above, optionally in the form of the
acid addition salts thereof as well as optionally in the form of the hydrates
thereof, as a starting material for preparing therapeutically active compounds
such as for example tiotropium bromide, ipratropium bromide or BEA2108,
preferably tiotropium bromide.
Preferably, the present invention relates to the use of meteloidin, optionally
in
the form of the acid addition salts thereof, as well as optionally in the form
of
its hydrates, as a starting material for preparing therapeutically active
compounds such as for example tiotropium bromide, ipratropium bromide or
BEA2108, preferably tiotropium bromide.
The procedure illustrated in Diagram 1 may be used to prepare tiotropium
bromide starting from tropenol.
Me
Me O N'
N
S OMe
+ I / OH ~ O H
) /\S S O
OH
(I) (VI) ( / OH
Me ~S (VII)
+ Me N,
Me,N,
_,. O
O \\ , H
~H Br- E ~'O
O S O
S O I / OH (VIII)
I / OH / S
/ ~S
Diagram 1:
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Starting from the tropenol (I) which may be obtained according to the
invention, first tropenol di-(2-thienyl)-glycolate (VII) is formed by reacting
with
di-(2-thienyl)-glycolic acid derivatives (VI). This ester is converted by
epoxidation of the olefinic double bond into the corresponding scopine ester
(VIII), from which tiotropium bromide can be obtained by reacting with methyl
bromide.
Therefore, in a particularly preferred aspect, the present invention relates
to a
process for preparing tiotropium bromide
+ Me
Me~N,
O
H Br_
O
S O
/ OH
/ ~S
characterised in that in a first step a compound of formula (II)
Me
N
HO
HO \\ ,H
O\ /R
O (II)
wherein R may have the meanings given above, optionally in the form of the
acid addition salts thereof as well as optionally in the form of the hydrates
thereof, is reacted in a suitable solvent with a formamide-acetal of formula
(III)
R"
I
R"iN ~OR~
OR' (III)
wherein
R' and R" may have the abovementioned meanings, to obtain a compound of
formula IV
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Me
N
R"~N O O H
R"
O R
O (IV)
wherein the groups R, R' and R" may have the meanings given above,
then this is converted by decarboxylation into an ester of formula (V)
Me
N
\\ , H
O\ /R
O (V)
wherein R may have the meanings given above, and this ester is saponified to
obtain tropenol of formula (I), which is reacted, optionally in the form of
the
acid addition salts thereof, in a second step with an ester of formula (VI)
0
S OMe
/ OH
/ ~S
(VI)
to obtain the tropenol ester of formula (VII)
Me
N
\\ , H
~'O
S O
OH
/ ~S
(VII)
which is epoxidised in a third step to obtain the scopine ester of formula
(VIII)
_1
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Me
N
O
H
O
S O
OH
/ ~S
(VIII)
and this is then quaternised in a fourth step using methylbromide to obtain
tiotropium bromide.
The Examples that follow serve to illustrate some methods of synthesis
carried out by way of example in order to prepare tropenol and the tiotropium
bromide which may be obtained therefrom. They are intended solely as
possible procedures, provided as an illustration, without restricting the
invention to their content.
Example 1:
Preparation of tropenol (I) in the form of its hydrochloride
19.5 kg of dimethylformamide dimethylacetal are placed in a suitably sized
stirred apparatus and 20.9 kg of meteloidin are added batchwise. After the
addition has ended the resulting mixture is slowly heated to a temperature of
about 80°C with stirring. The methanol liberated in the course of the
reaction
is distilled off. After the reaction has ended the excess dimethylformamide
dimethylacetal is distilled off at about 50-60°C under reduced pressure
(30mbar or less). Then 8 L dimethylformamide are added to the residue
remaining and the solution obtained is cooled to about 45-50°C with
stirring.
This solution is then added, over a period of about 30-70 minutes at about
125-135°C, to 37.7 kg of stirred acetic anhydride heated to
125°C. Gaseous
C02 is given off. After the addition has ended a further 4 L dimethylformamide
are added and the whole reaction mixture is stirred for a further 1.5 hours at
about 125-135°C. Once the reaction has ended all the liquid
constituents are
distilled off by heating to about 60°C under reduced pressure (about 5
mbar or
less). The residue remaining is taken up in 71 L ethanol and cooled to about
25°C with stirring. After the addition of 8 L water and another 10 L
ethanol,
45% sodium hydroxide solution (18.3 kg) is added to the resulting mixture.
The mixture obtained is refluxed for about 1.5 hours with stirring. The
solvent
is then distilled off at about 50-60°C under reduced pressure (about 40
mbar)
and the residue remaining is taken up in 31 L water. In order to extract the
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product 62 L methylene chloride are added. After separation of the organic
phase the aqueous phase remaining is extracted twice more with 30 L
methylene chloride and 3 times with 21 L methylene chloride. The organic
phases obtained are combined and the solvent is removed by distillation. The
residue remaining is then taken up in about 35 kg of isopropanol, combined
with 1.6 kg of Clarcel and the resulting mixture is stirred and filtered. Then
at
an internal temperature of about -10°C to +10°C gaseous hydrogen
chloride is
piped into the resulting solution until a pH of about 2-3 is obtained (approx.
3.0 kg of HCI gas). Once all the gas has been added the mixture is stirred for
another hour or so at constant temperature. The solid formed, tropenol
hydrochloride, is separated off and dried at about 40-45°C under
nitrogen.
Yield: 11.5 kg of tropenol-hydrochloride (80% based on the meteloidin used)
Example 2: Preparation of tiotropium bromide
a) Preparation of the tropenol ester (VII)
Ammonia (1.8 kg) is piped into 10.9 kg of tropenol hydrochloride (obtainable
according to Example 1 ) in toluene (95 L) at 25°C. The resulting
suspension is
stirred for about 1 h at constant temperature. Then the ammonium
hydrochloride formed is filtered off and rinsed with toluene (26 L). At a
jacket
temperature of about 50°C some of the toluene (about 60 L) is distilled
off in
vacuo. After cooling to about 25°C 15.8 kg of methyl di-(2-
thienyl)glycolate
are added and the resulting mixture is heated to 50°C to dissolve it.
Toluene
(40 L) is placed in another apparatus and sodium hydride (2.7 kg) is added
thereto at about 25°C. The previously formed solution of tropenol and
methyl
di-(2-thienyl)-glycolate is added to this solution at 30°C within 1 h.
After the
addition has ended, the mixture is heated to 75°C under reduced
pressure for
about 7 hours with stirring. The methanol formed is distilled off. The mixture
remaining is cooled and added to a mixture of water (958 L) and 36
hydrochloric acid (13.2 kg). The aqueous phase is then separated off and
washed with methylene chloride (56 L). AftEr more methylene chloride has
been added (198 L) the mixture thus obtained is adjusted to pH 9 with
prepared soda solution (9.6 kg of soda in 45 L of water). The methylene
chloride phase is separated off and the aqueous phase is stirred with
methylene chloride (262 L). The methylene chloride phase is evaporated
down to the residue at 65°C. The residue is taken up in toluene (166 L)
and
heated to 95°C. The toluene solution is cooled to 0°C. The
crystals obtained
are separated off, washed with toluene (33 L) and dried at about 50°C
for
max. 24 hours in a nitrogen current.
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Yield: 18.6 kg (83%);melting point: about 160°C (determined by TLC at
a
heating rate of 10 K/m in);
b) Preparation of the scopine ester (VIII)
260 L of DMF are placed in a suitable reaction apparatus and heated to
50°C.
Then 16.2 kg of tropenol ester (IV) are added and the mixture is stirred until
a
clear solution is obtained. After cooling to 40°C, hydrogen peroxide-
urea
complex (10.2 kg), water (13 L) and vanadium-(V)-oxide (0.7 kg) are added
successively batchwise and the contents of the apparatus are heated to
about 50°C. After 2 - 3 h stirring at constant temperature the mixture
is cooled
to about 20°C. The reaction mixture obtained is adjusted to about pH
4.0 with
hydrochloric acid (36 %). Prepared sodium bisulphite solution (2.4 kg in 24 L
of water) is added. At an internal temperature of 35°C the solvent is
partially
distilled off in vacuo (about 210 L). It is cooled to about 20°C again
and
combined with Clarcel (3.2 kg). The pH is adjusted to about 2.0 with dilute
hydrochloric acid (36%, 0.8 kg in about 440 L of water). The resulting
solution
is filtered and extracted with methylene chloride (58 L). The methylene
chloride phase is discarded. Methylene chloride (130 L) is again added to the
aqueous phase and the pH is adjusted to about 10.0 with a prepared soda
solution (11.0 kg in 51 L of water). The methylene chloride phase is separated
off and the aqueous phase is extracted with methylene chloride (136 L).
Methylene chloride (about 175 L) is distilled off from the combined methylene
chloride phases in a weak vacuum (600 - 700 mbar) at 40°C. The contents
of
the apparatus are cooled to 20°C, acetyl chloride (about 0.5 kg) is
added and
the mixture is stirred for about 40 minutes at 20°C. The reaction
solution is
transferred into a second apparatus. The pH is adjusted to 2.0 with a
prepared hydrochloric acid solution (4.7 kg of 36 % hydrochloric acid in 460 L
of water) at 20°C. The methylene chloride phase is separated off and
discarded. The aqueous phase is washed with methylene chloride (39 L).
Then methylene chloride (130 L) is added and the pH is adjusted to 10.0 with
a prepared soda solution (7.8 kg of soda in 38 L of water) at 20°C.
After 15
min. stirring the organic phase is separated off and the aqueous phase is
washed twice with methylene chloride (97 L and 65 L). The methylene
chloride phases are combined and some of the methylene chloride (90 L) is
distilled off in a weak vacuum at a temperature of 30 - 40°C. Then
dimethylformamide (114 kg) is added and the remainder of the methylene
_ _ __chloride is distilled off in vacuo at 40°C. The contents of the
apparatus are
cooled to 20°C.
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c) Preparation of the tiotropium bromide
Methyl bromide (5.1 kg) is piped into the scopine ester solution obtained by
the method described above at 20°C. The contents of the apparatus are
stirred at 30°C for about 2.5 days. 70 L of DMF are distilled off at
50°C in
vacuo. The solution is transferred into a smaller apparatus. It is rinsed with
DMF (10 L). Additional DMF is distilled off at 50°C in vacuo until
a total
amount of distillate of about 100 L is obtained. This is cooled to 15°C
and
stirred for 2 hours at this temperature. The product is isolated using a
suction
filter drier, washed with 15°C cold DMF (10 L) and 15°C cold
acetone (25 L).
It is dried at max. 50°C for max. 36 hours in a nitrogen current.
Yield: 13.2 kg (88 %);
Melting point: 200-230°C (depending on the purity of the starting
product);
The crude product thus obtained (10.3 kg) is added to methanol (66 L). The
mixture is refluxed to dissolve it. The solution is cooled to 7°C and
stirred for
1.5 h at this temperature. The product is isolated using a suction filter
drier,
washed with 7°C cold methanol (11 L) and dried for max. 36 h at about
50°C
in a nitrogen current.
Yield: 9.9 kg (96 %);
Melting point: 228°C (determined by TLC at a heating rate of 10
K/min).
If desired, the product thus obtained may be converted in the crystalline
monohydrate of tiotropium bromide. The following method may be used.
15.0 kg of tiotropium bromide are added to 25.7 kg of water in a suitable
reaction vessel. The mixture is heated to 80-90°C and stirred at
constant
temperature until a clear solution is formed. Activated charcoal (0.8 kg),
moistened with water, is suspended in 4.4 kg of water, this mixture is added
to
the solution containing tiotropium bromide and rinsed with 4.3 kg of water.
The mixture thus obtained is stirred for at least 15 min. at 80-90°C
and then
filtered through a heated filter into an apparatus which has been preheated to
an outer temperature of 70°C. The filter is rinsed with 8.6 kg of
water. The
contents of the apparatus are cooled to a temperature of 20-25°C at a
rate of
3-5°C every 20 minutes. Using cold water the apparatus is cooled
further to
10-15°C and crystallisation is completed by stirring for at least
another hour.
The crystals are isolated using a suction filter drier, the crystal slurry
isolated
CA 02487672 2004-11-29
WO 03/101986 16 PCT/EP03/05158
is washed with 9 L of cold water (10-15°C) and cold acetone (10-
15°C). The
crystals obtained are dried at 25°C for 2 hours in a nitrogen current.
Yield: 13.4 kg of tiotropium bromide monohydrate (86 % of theory).
Melting point: 230°C (determined by TLC at a heating rate of 10
Klmin).
