U.S. patent application number 11/827443 was filed with the patent office on 2008-02-28 for process for the preparation of tiotropium bromide.
This patent application is currently assigned to Sicor Inc.. Invention is credited to Jonathan Busolli, Nicola Diulgheroff, Alessandro Pontiroli, Francesca Scarpitta, Roberta Volonte.
Application Number | 20080051582 11/827443 |
Document ID | / |
Family ID | 39197541 |
Filed Date | 2008-02-28 |
United States Patent
Application |
20080051582 |
Kind Code |
A1 |
Busolli; Jonathan ; et
al. |
February 28, 2008 |
Process for the preparation of tiotropium bromide
Abstract
The invention is directed to improved processes for preparing
Tiotropium bromide.
Inventors: |
Busolli; Jonathan; (Carisio
(VC), IT) ; Diulgheroff; Nicola; (Torino, IT)
; Scarpitta; Francesca; (Ivrea (TO), IT) ;
Volonte; Roberta; (Rovellasca (CO), IT) ; Pontiroli;
Alessandro; (S. Maria della Versa (PV), IT) |
Correspondence
Address: |
LERNER, DAVID, LITTENBERG,;KRUMHOLZ & MENTLIK
600 SOUTH AVENUE WEST
WESTFIELD
NJ
07090
US
|
Assignee: |
Sicor Inc.
Irvine
CA
|
Family ID: |
39197541 |
Appl. No.: |
11/827443 |
Filed: |
July 10, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60835200 |
Aug 3, 2006 |
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60835201 |
Aug 3, 2006 |
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60836037 |
Aug 7, 2006 |
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60830231 |
Jul 10, 2006 |
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Current U.S.
Class: |
546/116 |
Current CPC
Class: |
C07D 491/18
20130101 |
Class at
Publication: |
546/116 |
International
Class: |
C07D 491/044 20060101
C07D491/044 |
Claims
1. A scopine salt of formula II-s ##STR26## comprising a salt
content of about 0.5% to about 40% by weight; wherein X is selected
from the group consisting of Br, Cl, SO4, MeCOO, PO4, MeSO3,
tartrate, fumarate, citrate, maleate, succinate, p-toluene
sulphonate and amidosulphonate.
2. The scopine salt of claim 1, wherein X is Br.
3. The scopine salt of claim 1, wherein said salt content is about
0.5% to about 20% by weight.
4. The scopine salt of claim 1, wherein said scopine salt is
selected from the group consisting of an HBr, HCl, H.sub.2SO4,
CH.sub.3COOH, H.sub.3PO.sub.4, MeSO.sub.3H, tartrate, fumarate,
citrate, maleate, succinate, maliate, p-toluenesulphonate, borate
and amidosulphonate scopine salt.
5. A process of preparing said scopine salt of claim 1, comprising:
a. filtering a reaction mixture containing said scopine salt to
produce a filtrate, b. adding water to said filtrate to precipitate
insoluble salts; c. filtering said insoluble salts from said
filtrate; d. adding an acid to said filtrate to precipitate said
scopine salt; and e. collecting said precipitated scopine salt.
6. The process of claim 5, wherein said acid is HBr.
7. The process of claim 5, further comprising washing said
precipitated scopine salts with a polar organic solvent.
8. The process of claim 7, wherein said polar organic solvent is
selected from the group consisting of a C.sub.1-6 alcohol, a
C.sub.4-8 ether, a C.sub.3-10 ketone, a C.sub.2-4 nitrile, and
mixtures thereof.
9. The process of claim 8, wherein said polar organic solvent is
selected from the group consisting of methanol, ethanol,
isopropanol, 1,4-dioxane, acetone, acetonitrile, and mixtures
thereof.
10. A process for preparing Tiotropium bromide comprising preparing
a scopine salt of formula II-s containing about 0.5% to about 40%
by weight of salts by the process of claim 5, and converting it to
Tiotropium bromide.
11. A process for the preparation of N-demethyl-tiotropium of
formula III, ##STR27## comprising reacting
methyl-di-(2-thienyl)-glycolate of formula I, ##STR28## with a
scopine salt as defined in claim 1.
12. The process of claim 11, wherein said
methyl-di-(2-thienyl)-glycolate of formula I, ##STR29## is combined
with a weak inorganic base, a polar organic solvent, and a scopine
salt of formula II-s containing about 0.5% to about 40% by weight
of salts to obtain a mixture, and heating said mixture.
13. The process of claim 12, wherein said scopine salt is suspended
in a polar organic solvent prior to said combination.
14. The process of claim 13, wherein said weak inorganic base is
added to said suspension providing a new suspension.
15. The process of claim 14, wherein said weak inorganic base is
anhydrous.
16. The process of claim 15, wherein said weak inorganic base has a
pKa of about 8 to about 12.
17. The process of claim 16, wherein said weak inorganic base is
selected from the group consisting of K.sub.2CO.sub.3, NaHCO.sub.3,
Li.sub.2CO.sub.3, CS.sub.2CO.sub.3, t-ButOK, and t-ButOLi.
18. The process of claim 17, wherein said weak inorganic base is
K.sub.2CO.sub.3.
19. The process of claim 14, wherein after said addition of said
weak inorganic base, a mixture of said
methyl-di-(2-thienyl)-glycolate and another portion of said weak
inorganic base are added to said new suspension to provide a
mixture.
20. The process of claim 12, wherein said
methyl-di-(2-thienyl)-glycolate is added in solution in a polar
organic solvent.
21. The process of claim 12, wherein said polar organic solvent is
selected from a group consisting of C.sub.1-C.sub.4 amides,
C.sub.2-C.sub.4 sulfoxides, C.sub.2-C.sub.4 sulfones,
C.sub.7-C.sub.8 aromatic hydrocarbons, and C.sub.2-C.sub.4
nitrites.
22. The process of claim 21, wherein said polar organic solvent is
dimethylformamide.
23. The process of claim 12, wherein an amount of said weak
inorganic base is about 0.45 to about 2.5 moles per mole equivalent
of said scopine salt.
24. The process of claim 14, wherein said addition of said weak
inorganic base is performed at a temperature of about 25.degree. C.
to about 65.degree. C.
25. The process of claim 24, wherein said mixture is heated to a
temperature of less than about 70.degree. C.
26. The process of 12, further comprising recovering said
N-demethyl-tiotropium.
27. A process for the preparation of N-demethyl-tiotropium of
formula III, ##STR30## comprising reacting
methyl-di-(2-thienyl)-glycolate of formula I, ##STR31## with a
scopine base.
28. The process of claim 27, wherein said
methyl-di-(2-thienyl)-glycolate is combined with a scopine base,
about 1 to about 1.5 mole equivalents of a weak inorganic base per
mole equivalent of said scopine base, and a polar organic solvent
to obtain a mixture, and heating said mixture.
29. A process for the preparation of Tiotropium bromide comprising
the steps of: a. preparing N-demethyl-tiotropium by a process as
defined in claim 11; and b. reacting said N-demethyl-tiotropium
with methylbromide in an organic solvent to form Tiotropium
bromide.
30. The process of claim 29, wherein said organic solvent is
selected from the group consisting of a C.sub.2-4 nitrile, a
C.sub.4-8 linear or cyclic ether, a mixture of a C.sub.2-4 nitrile
and a C.sub.4-8 linear or cyclic ether, a mixture of a C.sub.7-8
aromatic hydrocarbon and a C.sub.2-4 nitrile, and a mixture of a
C.sub.2-4 nitrile and a C.sub.3-10 ketone.
31. The process of claim 30, wherein said organic solvent is
selected from the group consisting of acetonitrile,
tetrahydrofuran, a mixture of acetonitrile and tetrahydrofuran, a
mixture of toluene and acetonitrile, and a mixture of acetone and
acetonitrile.
32. The process of claim 31, wherein said organic solvent is
acetonitrile.
33. Use of a scopine salt as defined in any of claims 1 to 5 in a
process for the manufacture of N-demethyl tiotropium of Formula III
or Tiotropium bromide.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the filing date of
U.S. Provisional Patent Application No. 60/830,231 filed Jul. 10,
2006; U.S. Provisional Patent Application No. 60/835,201, filed
Aug. 3, 2006; U.S. Provisional Application No. 60/835,200, filed
Aug. 3, 2006; and U.S. Provisional Application No. 60/836,037,
filed Aug. 7, 2006, the disclosures of which are hereby
incorporated herein by reference. This application is also related
to U.S. patent application Ser. No. 11/643,013, filed Dec. 19,
2006.
FIELD OF THE INVENTION
[0002] The invention is directed to improved processes for
preparing Tiotropium bromide.
BACKGROUND
[0003] Tiotropium bromide,
(1.alpha.,2.beta.,4.beta.,5.alpha.,7.beta.)-7-[(hydroxydi-2-thienylacetyl-
)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]nonane bromide or
6.beta.,7.beta.-epoxy-3.beta.-hydroxy-8-methyl-1.alpha.H,5.alpha.H-tropan-
ium bromide, di-2-thienylglycolate, has the following chemical
structure: ##STR1## It is an anticholinergic drug with specificity
for muscarinic receptors. As a bronchodilator it provides
therapeutic benefit in the treatment of asthma or chronic
obstructive pulmonary disease (COPD). This active pharmaceutical
ingredient is administered by inhalation, and is available
commercially as SPIRIVA.RTM. HandiHaler.RTM..
[0004] Tiotropium bromide was first disclosed in U.S. Pat. No.
5,610,163 where it was synthesized via N-demethyl tiotropium of
formula III, ##STR2## which was obtained by a reaction of methyl
di(2-thienyl)glycolate of formula I and Scopine of formula II using
sodium metal in melt or sodium methoxide in melt. Because of the
dangerous reaction conditions, this method is not suitable for
industrial scale preparation. The quaternization of
N-demethyl-tiotropium is then carried out in a mixture of
acetonitrile and methylene chloride using methyl bromide as a
quaternizing agent. The process is illustrated in the following
scheme: ##STR3## The product was then crystallized from a mixture
of acetone and methanol.
[0005] Also described in the prior art is the preparation of
Scopine HCl, which was first disclosed in GB 1469781, wherein it
was prepared by reduction of scopolamine using sodium borohydride,
followed by addition of HCl to the reaction mixture, a process
illustrated by the following scheme: ##STR4## This salt of scopine
can be used as a precursor for scopine base, however a process to
remove inorganic salts from the desired product is not
reported.
[0006] U.S. Pat. Nos. 6,486,321 and 6,506,900 disclose a synthesis
of Tiotropium and analogues via tropenol derivatives by introducing
an additional epoxidation step, as described by the following
scheme. ##STR5##
[0007] U.S. Pat. No. 6,747,154, refers to formal approaches by
stating "These processes known in the art may also be used to
prepare the compounds of formula 1. ##STR6##
[0008] However, these methods of synthesis are more complex
procedures involving a number of synthetic steps." Therefore a
different synthetic approach was developed, where the coupling is
carried out using scopine methobromide rather than scopine, but
details, including the yield, of this coupling reaction are not
reported. ##STR7##
[0009] United States Patent Publication No 2006/0047120 describes
yet another approach, coupling scopine methobromide with
trimethylsilyl-protected sodium dithienyl glycolate which is
obtained in situ. ##STR8##
[0010] This application, provides that this approach was developed
to improve the prior art synthesis for Tiotropium bromide.
[0011] Hence, an improved process to prepare Tiotropium bromide is
needed.
SUMMARY OF THE INVENTION
[0012] In one embodiment, the present invention encompasses scopine
salt of formula II-s: ##STR9## containing about 0.5% to about 40%
by weight of salts; wherein X is Br, Cl, SO.sub.4, MeCOO, PO.sub.4,
MeSO.sub.3, tartrate, fumarate, citrate, maleate, succinate,
p-toluene sulphonate or amidosulphonate.
[0013] In another embodiment, the present invention encompasses a
process to convert scopine salt of formula II-s containing about
0.5% to about 40% by weight of salts to Tiotropium bromide of
formula IV. ##STR10##
[0014] In yet another embodiment, the present invention encompasses
the preparation of N-demethyl-tiotropium of formula III, ##STR11##
comprising combining methyl-di-(2-thienyl)-glycolate of formula I,
##STR12## a weak inorganic base, a polar organic solvent and
scopine salt of formula II-s ##STR13## containing about 0.5% to
about 40% by weight of salts to obtain a mixture, and heating the
mixture.
[0015] In one embodiment, the present invention encompasses a
process for the preparation of Tiotropium bromide comprising a)
combining methyl-di-(2-thienyl)-glycolate of formula I, ##STR14## a
weak base, a polar organic solvent, and scopine salt of formula
II-s containing about 0.5% to about 40% by weight of salt to obtain
a mixture; b) heating the mixture providing N-demethyl-tiotropium
of formula III; c) recovering the N-demethyl-tiotropium of formula
III; d) combining N-demethyl-tiotropium of formula III with
methylbromide (MeBr) and an organic solvent to yield Tiotropium
bromide.
[0016] In another embodiment, the present invention encompasses a
process to prepare Tiotropium bromide, by preparing
N-demethyl-tiotropium of formula III by the process of the present
invention, and further converting it to Tiotropium bromide.
DETAILED DESCRIPTION OF THE INVENTION
[0017] As used herein, the term "room temperature" refers to a
temperature ranging from about 20.degree. C. to about 26.degree.
C.
[0018] The present application discloses a novel approach to the
synthesis of Tiotropium bromide, in particular from a Scopine
hydrohalide of formula II-s, and even more specifically, from
scopine HBr of the formula ##STR15## that contains a low level of
salts, as compared to the process disclosed in GB '781, where the
obtained scopine HCl contained a high level of more than 60% by
weight of inorganic salts. These salts are insoluble in water, and
thus cannot be removed by a simple washing operation.
[0019] Typically, scopine hydrohalide containing low level of salts
refers to scopine salt with less than 40% by weight of salts.
Typically, the measurement of the salts content is done by sulfuric
ashes, as exemplified in example 1.
[0020] Moreover, the inventors of this application have found that
the purity of the scopine salt affects the purity and the yield of
N-demethyl-tiotropium of formula III, a key intermediate in the
synthesis of Tiotropium bromide. ##STR16## For example, without
restricting the invention, using pure scopine salt leads to higher
yield and purity, as will be further demonstrated.
[0021] The present invention encompasses scopine salt of formula
II-s ##STR17## containing about 0.5% to about 40% by weight of
salts; wherein X is Br, Cl, SO.sub.4, MeCOO, PO.sub.4, MeSO.sub.3,
tartrate, fumarate, citrate, maleate, succinate, p-toluene
sulphonate or amidosulphonate.
[0022] Preferably, scopine salt of formula II-s contains about 0.5%
to about 20% by weight of salts, more preferably of about 0.5% to
about 15% by weight, even more preferably of about 0.5% to about 5%
by weight, and most preferably of about 0.5% to about 1% by weight.
As mentioned before, the content of the salts can be determined by
sulfuric ashes.
[0023] Preferably, the scopine salt is selected from a group
consisting of HBr, HCl, H.sub.2SO.sub.4, CH.sub.3COOH,
H.sub.3PO.sub.4, MeSO.sub.3H, tartrate, fumarate, citrate, maleate,
succinate, maliate, p-toluenesulphonate, and amidosulphonate. More,
preferably, the salt is HBr.
[0024] The above scopine salt of formula II-s is obtained by
filtration of the reaction mixture prior to the addition of acid.
The process comprises: a) filtering solids from the reaction
mixture containing scopine base and insoluble inorganic salts, such
as borate salts, to produce a filtrate; b) washing the solids with
a polar organic solvent; c) adding water to the filtrate to
precipitate insoluble inorganic salts; d) filtering the filtrate to
remove any precipitated salts; e) washing the inorganic salts with
a polar organic solvent; and f) adding an acid and a polar organic
solvent to the filtrate to obtain the scopine salt of formula
II-s.
[0025] The addition of water in the above process causes the
remaining insoluble salts to precipitate. Preferably, after the
addition of water the filtrate is stirred for about 0.5 hour to
about 2 hours, more preferably for about 1 to about 1.5 hours.
[0026] Typically, the addition of water results in a precipitate
formation and thus a suspension. The suspension is concentrated
under vacuum, to remove water, thus increasing the yield.
Preferably, the suspension is concentrated at a temperature of no
more than 55.degree. C., more preferably of about 25.degree. C. to
about 55.degree. C., most preferably of about 30.degree. C. to
about 35.degree. C.
[0027] After the suspension is concentrated, it is filtered, and
washed twice with a polar organic solvent. Preferably, the polar
organic solvent is selected from a group consisting of C.sub.1-6
alcohol, C.sub.4-8 ether, C.sub.3-10 ketone, C.sub.2-4 nitrile, and
mixtures thereof. Preferably, the C.sub.1-6 alcohol is C.sub.1-4
alcohol, more preferably C.sub.1-3 alcohol. Preferably, the
C.sub.1-3 alcohol is methanol, ethanol or isopropanol. Moreover,
absolute ethanol may be used. A preferred C.sub.4-8 ether is
C.sub.4-6 ether, more preferably C.sub.4-5 ether. A preferred
C.sub.4-5 ether is either tetrahydrofuran or 1,4-dioxane.
Preferably, the C.sub.3-10 ketone is C.sub.2-3 ketone. Preferably,
the C.sub.2-3 ketones acetone. A preferred C.sub.2-4 nitrile is
C.sub.1-2 nitrile. Preferably, the C.sub.1-2 nitrile is
acetonitrile. Most preferably, the solvent is ethanol.
[0028] Preferably, the acid is HBr.
[0029] The obtained scopine salt of formula II-s is then converted
to Tiotropium bromide of formula IV. The conversion will be
illustrated below.
[0030] The novel approach, also comprises a process for the
preparation of Tiotropium bromide comprising: a) combining
methyl-di-(2-thienyl)-glycolate of formula I, ##STR18## a weak
inorganic base, a polar organic solvent, and scopine salt of
formula II-s containing about 0.5% to about 40% by weight of salt
to obtain a mixture; b) heating the mixture providing
N-demethyl-tiotropium of formula III; c) recovering the
N-demethyl-tiotropium of formula III; d) combining
N-demethyl-tiotropium of formula III with methylbromide (MeBr) and
an organic solvent to yield Tiotropium bromide.
[0031] The process is illustrated by the following scheme:
##STR19## wherein X is Br, Cl, SO.sub.4, MeCOO, PO.sub.4,
MeSO.sub.3, tartrate, fumarate, citrate, maleate, succinate,
p-toluene sulphonate or amidosulphonate.
[0032] The glycolate of formula I may be prepared by combining
2-bromo-tiophene of the following formula, ##STR20## Mg, and an
ethereal solvent; combining with dimethyloxalate of the following
formula ##STR21## and quenching.
[0033] Combining 2-bromo-thiophene, Mg, and an ethereal solvent
provides a Grignard reagent that can be prepared, for example,
according to the process disclosed in Nyberg, K. Acta Chemica
Scandinavica, 24, 1970, 1590-1596.
[0034] Methyl di-(2-thienyl)glycolate of formula I may be purified
by crystallization from a mixture of ethanol and heptane, absolute
ethanol and heptane, isopropanol and heptane, and from toluene and
heptane.
[0035] N-demethyl-tiotropium of formula III ##STR22## is prepared
under conditions, which are not dangerous, are suitable for
industrial scale preparation, and which provide a satisfactory
yield. Moreover, the use of scopine salt instead of scopine base,
and applying mild conditions in the preparation of
N-demethyl-tiotropium of formula III, decrease significantly the
conversion of scopine to scopoline, a side product that occurs in
basic media, as illustrated in the following scheme: ##STR23##
[0036] The preparation of N-demethyl-tiotropium of formula III,
##STR24## comprises combining methyl-di-(2-thienyl)-glycolate of
formula I, ##STR25## a weak inorganic base, a polar organic
solvent, and scopine salt of formula II-s, containing about 0.5% to
about 40% by weight of salts to obtain a mixture, and heating the
mixture.
[0037] Initially, scopine salt of formula II-s is suspended in a
polar organic solvent. Preferably, the salt is an HBr salt. The
polar organic solvent is selected from a group consisting of
amides, sulfoxides, sulfones, aromatic hydrocarbons, nitrites, and
mixtures thereof. Preferably, the polar organic solvent is selected
from the group consisting of C.sub.1-C.sub.4 amide, C.sub.2-C.sub.4
sulfoxide, C.sub.2-C.sub.4 sulfones, C.sub.7-C.sub.8 aromatic
hydrocarbon, and C.sub.2-C.sub.4 nitrile. A preferred
C.sub.1-C.sub.4 amide is dimethylformamide, N-methyl-2-pyrrolidone,
or dimethylacetamide. A preferred C.sub.2-C.sub.4 sulfoxide is
dimethylsulfoxide. Preferably, the C.sub.2-C.sub.4 sulfone is
sulfolane. Preferably, the C.sub.2-C.sub.4 nitrile is acetonitrile.
Preferably, the C.sub.7-C.sub.8 aromatic hydrocarbon is toluene.
More preferably, the polar organic solvent is
dimethylformamide.
[0038] Then, the weak inorganic base is added to the suspension
providing a new suspension. Typically, an anhydrous weak inorganic
base, i.e. having <0.5% of water by weight, is used in such
reactions to obtain the free base form of scopine. Preferably, the
weak inorganic base has a pKa of about 8 to about 12, even more
preferably of about 9 to about 10. Preferably, the weak inorganic
base is selected from a group consisting of: K.sub.2CO.sub.3,
NaHCO.sub.3, Na.sub.2CO.sub.3, Li.sub.2CO.sub.3, Cs.sub.2CO.sub.3,
t-ButOK, and t-ButOLi. More preferably, the weak inorganic base is
K.sub.2CO.sub.3.
[0039] After the addition of the base, a mixture of
Methyl-di-(2-thienyl)-glycolate of formula I and another portion of
the weak inorganic base are added to the new suspension, providing
the mixture.
[0040] Methyl-di-(2-thienyl)-glycolate of formula I can be added as
solid or in solution. Preferably, methyl-di-(2-thienyl)-glycolate
of formula I is in solution in the polar organic solvent.
[0041] Preferably, the weak inorganic base is present in the
mixture in an amount of about 0.45 to about 2.5, more preferably,
of about 2 to about 2.5 mole equivalent per mole equivalent of
scopine salt of formula II-s. The weak inorganic base is added in
two portions to prevent decomposition of scopine and to provide
favorable reaction conditions.
[0042] Preferably, the mixture of the weak inorganic base and
methyl-di-(2-thienyl)-glycolate of formula I are added at a
temperature of about 25.degree. C. to about 65.degree. C., more
preferably at about 60.degree. C. to about 65.degree. C.
[0043] Typically, the said mixture is heated in order to provide
N-demethyl-tiotropium of formula III. Preferably, the said mixture
is heated to a temperature of below 70.degree. C., more preferably,
of about 25.degree. C. to about 65.degree. C., even more preferably
of about 60.degree. C. to about 65.degree. C., and most preferably
of about 63.degree. C. to about 65.degree. C. Preferably, heating
is done for about 17 to about 24 hours, more preferably for about
18 to about 20 hours.
[0044] Preferably, heating is done under reduced pressure. Usually,
the term "reduced pressure" refers to a pressure of about 70 to
about 100 millibar.
[0045] Usually, such reactions are done under inert conditions,
such as under an atmosphere of nitrogen. Inert conditions are
provided by bubbling an inert gas, such as nitrogen and/or argon,
during the reaction, through a second inlet. Preferably, nitrogen
is bubbled in a rate of about 1.8 to about 2.6 L/min, more
preferably, of about 2.0 to about 2.4 L/min, and even more
preferably of about 2.2 to about 2.4 L/min.
[0046] The heating under reduced pressure, while bubbling nitrogen
from a second inlet, assists in evaporating methanol, which is
formed during the reaction, hence, shifting the reaction towards
the formation of the product.
[0047] N-demethyl-tiotropium of formula III may be recovered by
cooling the mixture; adding an acid to the cooled mixture providing
a two phase system comprising of an organic and aqueous phases;
extracting the aqueous phase with an organic solvent; adding a base
to the aqueous phase to precipitate N-demethyl-tiotropium of
formula III; filtering the precipitate N-demethyl-tiotropium of
formula III; washing and drying the N-demethyl-tiotropium.
Preferably, the acid is HBr.
[0048] Preferably, the heated mixture is cooled to a temperature of
about 10.degree. C. to about -10.degree. C., more preferably to
about 5.degree. C. to about 0.degree. C.
[0049] Preferably, the addition of the acid provides a pH of about
2 to about 3.5. Preferably, the organic solvent is toluene.
[0050] Preferably, the weak inorganic base is added at a
temperature of about 0.degree. C. to about 5.degree. C. Preferably,
the weak inorganic base is selected from a group consisting of:
K2CO3, NaHCO3, Na2CO3, Li2CO3, Cs2CO3, t-ButOK, and t-ButOLi.
Preferably, the weak inorganic base is K2CO3.
[0051] Preferably, the precipitate is washed with water to obtain
pH of about 7.
[0052] Optionally, scopine base may be used instead of scopine
salt. When scopine base is used, typically, a smaller amount of the
weak inorganic base is required. Preferably, about 1 to 1.5 mole
equivalent of weak inorganic base per mole equivalent of scopine
base may be used.
[0053] The obtained N-demethyl-tiotropium of formula III may then
be converted to Tiotropium bromide. The conversion can be done, for
example, by the process disclosed in U.S. Pat. No. 5,610,163 or by
the process of the present invention described below.
[0054] The conversion of N-demethyl-tiotropium of formula III to
Tiotropium bromide can be done by reacting N-demethyl-tiotropium of
formula III with methyl bromide in an organic solvent.
[0055] Initially, N-demethyl-tiotropium of formula III and the
organic solvent are combined to obtain a suspension. Preferably,
the organic solvent is selected from a group consisting of
C.sub.2-4 nitrile, C.sub.4-8 linear or cyclic ether, mixtures of
C.sub.2-4 nitrile and C.sub.4-8 linear or cyclic ether, mixtures of
C.sub.7-8 aromatic hydrocarbon and C.sub.2-4 nitrile, and mixtures
of C.sub.2-4 nitrile and C.sub.3-10 ketone. Preferably, the
C.sub.2-4 nitrile is acetonitrile. A preferred C.sub.4-8 linear or
cyclic ether is tetrahydrofuran. Preferably, a mixture of C.sub.2-4
nitrile and C.sub.4-8 linear or cyclic ether is that of
acetonitrile and tetrahydrofuran. A preferred mixture of C.sub.7-8
aromatic hydrocarbon and C.sub.2-4 nitrile is that of toluene and
acetonitrile. Preferably, a mixture of C.sub.2-4 nitrile and
C.sub.3-10 ketone is that of acetone and acetonitrile. Most
preferably, the solvent is acetonitrile.
[0056] Methyl bromide is then added to the suspension to provide a
mixture. Methyl bromide can be used as a gas or in solution.
Preferably, methyl bromide is used in solution, where the solvent
is an organic solvent that is described above.
[0057] The mixture is the maintained at a temperature of about
20.degree. C. to about 40.degree. C. Preferably, the mixture is the
maintained at a temperature of about 20.degree. C. to about
25.degree. C.
[0058] Typically, the mixture is maintained to allow the formation
of Tiotropium bromide. Preferably, the mixture is maintained for
about 12 to about 64 hours, more preferably for about 18 to about
22 hours.
[0059] Tiotropium bromide may then be recovered by any method known
in the art, such as filtering and drying. Tiotropium bromide may
then be purified by crystallization from ethanol. Preferably, crude
Tiotropium bromide is dissolved in ethanol. More preferably, the
ethanol is absolute ethanol. Preferably, the dissolution is done by
heating to a temperature of about 75 to about 78.degree. C.
Typically, after dissolution, the solution is cooled to a
temperature of about 22 to about 25.degree. C. to induce
precipitation of Tiotropium bromide. Preferably, cooling is done
over a period of about 6 to about 8 hours.
[0060] The precipitate is recovered from the suspension by
filtration, washed with absolute ethanol, and dried.
[0061] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the preparation of the composition and methods
of use of the invention. It will be apparent to those skilled in
the art that many modifications, both to materials and methods, may
be practiced without departing from the scope of the invention.
EXAMPLES
Sulfuric Ashes Methodology for Determining the Level of Salts in
Scopine HBr
[0062] 1 g (exactly weighted) of scopine HBr was placed in a
platinum melting pot. Sulphuric acid 96% was added, and then placed
in an oven at 600.degree. C. until a constant weight was achieved.
The melting pot, with the organic residue inside, was weighted to
afford the percent of inorganic salts present in the original
material.
Example 1
Comparative Example: Preparation of Scopine Hydrochloride According
to GB '781
[0063] 10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate
was suspended in 100 mL of absolute ethanol, and cooled to about
0.degree. C. Sodium borohydride (4.0 g, 105.7 mmol) was then added
portion-wise while maintaining the temperature at a maximum of
30.degree. C. 4.8 mL of water was then added to the reaction
mixture. After 3.5 hours, the reaction was completed and 50 mL of
diethyl ether was then added. The reaction was then cooled to
0.degree. C., and acidified with 2M hydrochloric acid in diethyl
ether to a pH of about 2. The suspension was stirred at room
temperature for 30 minutes and then filtered on GochP3. The white
solid was dried at 45.degree. C. under vacuum for 4 hours, yielding
9 g of product containing 79% of salts determined by sulphuric
ashes.
Example 2
Preparation of Methyl di-(2-thienyl)glycolate
[0064] 1050 mL of tetrahydrofuran was loaded in a 2 L round
bottomed flask. 22.6 g (0.93 mol) of magnesium turnings were then
added, and the mixture was kept at 35.degree. C., while catalytic
bromoethane (200 mg, 1.84 mmol) was loaded. 150 g (0.92 mol) of
2-bromothiophene was added dropwise, and after about 15% (13 ml) of
reagent was exothermicity was observed. The temperature was
maintained at a maximum of 50-55.degree. C., and the remaining
2-bromothiophene was then added. At the end of the addition, the
reaction mixture was heated to 65.degree. C. for 1.5 hours to 2
hours, and then cooled to 25.degree. C.
[0065] The Grignard solution thus formed was added drop-wise, in
about 2.5 hours to 3 hours, into a solution of dimethyl oxalate
(54.3 g, 0.46 mol) dissolved in 300 mL of tetrahydrofuran, while
maintaining the temperature at maximum 5-10.degree. C. via cooling
bath.
[0066] The solution was kept under stirring for 0.5 hours to 1.0
hours at 5-10.degree. C., and then saturated ammonium chloride
(1400 mL of a mixture of 650 g solid ammonium chloride and 2000 mL
water) was added at 0.degree. C., while monitoring the temperature
(maximum 15-20.degree. C.). Then, 150 mL of water and 625 mL of
toluene were added. The separated organic phase was washed with
water (900 mL), and then with brine (900 mL).
[0067] To the organic phase 7.5 g of charcoal was added, and the
mixture was heated to 40.degree. C. and stirred at this temperature
for one hour.
[0068] The mixture was then filtered on decalite pad, and washed
three times with toluene (3.times.150 mL)
[0069] This solution was concentrated at 50-55.degree. C. under
vacuum (about 30 mmHg) to 270 mL, heated to 65.degree. C., and then
720 mL n-heptane was added drop-wise over 2.5 hours.
[0070] The solution was stirred for one hour at 65.degree. C., and
then cooled in 3 hours to 25.degree. C. (about 1.degree. C./5 min).
It was then left stirring at this temperature for at least 8 hours,
filtered on GochP3, and washed once with 150 mL n-heptane.
[0071] The creamy solid obtained was dried under vacuum at
45.degree. C. for 7 hours yielding 73.6 g (63% overall yield, HPLC
purity 99.8 area %).
Example 3
Crystallization of Methyl di-(2-thienyl)glycolate in Ethanol
96%/n-heptane
[0072] Crude methyl di-(2-thienyl)glycolate (2.0 g) was dissolved
in ethanol 96% (8.0 ml) at 45.degree. C. 16.0 mL of n-heptane were
then added drop-wise at 45.degree. C. in 20 minutes. The solution
was maintained at 45.degree. C. for hour, and then it was cooled to
0.degree. C. in 1 hour, and left at this temperature for another
hour. The solid was filtered on a sintered glass funnel and it was
washed once with n-heptane (2 mL). Drying for 6 hours at 50.degree.
C. under vacuum yielded 1.4 g of methyl di-(2-thienyl)glycolate
(70%)
Example 4
Crystallization of Methyl di-(2-thienyl)glycolate in Absolute
Ethanol/n-heptane
[0073] Crude methyl di-(2-thienyl)glycolate (10.0 g) was dissolved
in absolute ethanol (30.0 mL) at 55.degree. C. 80.0 mL of n-heptane
was then added drop-wise at 55.degree. C. in 30 minutes. The
solution was maintained at 55.degree. C. for 1 hour, and then it
was cooled to room temperature over 3 hours, and left at this
temperature for 6 hours. The solid was filtered on a sintered glass
funnel and it was washed once with n-heptane (10.0 mL). Drying for
18 hours at 50.degree. C. under vacuum yielded 8.0 g of Methyl
di-(2-thienyl)glycolate (80%).
Example 5
Crystallization of Methyl di-(2-thienyl)glycolate in
Isopropanol/n-heptane
[0074] Crude methyl di-(2-thienyl)glycolate (5.0 g) was dissolved
in isopropanol (20.0 mL) at 60.degree. C. 40.0 mL of n-heptane was
then added drop-wise at 60.degree. C. in 30 minutes. The solution
was maintained at 45.degree. C. for 1 hour, and then it was cooled
to 0.degree. C. in 1 hour, and left at this temperature for another
hour. The solid was filtered on a sintered glass funnel, and it was
washed once with n-heptane (5.0 ml). Drying for 12 hours at
50.degree. C. under vacuum yielded 3.6 g of methyl
di-(2-thienyl)glycolate (72%).
Example 6
Crystallization of Methyl di-(2-thienyl)glycolate in
Toluene/n-heptane
[0075] Crude methyl di-(2-thienyl)glycolate (250.0 g) was dissolved
in toluene (500 mL) at 55.degree. C. 1750 mL of n-heptane was then
added drop-wise at 55.degree. C. in 2.5 hours. The solution was
maintained at 55.degree. C. for 1 hour, and then it was left to
cool to room temperature over 16 hours, and then cooled to
0.degree. C., and left at this temperature for 2 hours. The solid
was filtered on a sintered glass funnel and it was washed twice
with n-heptane (2.times.150 mL). Drying for 16 hours at 50.degree.
C. under vacuum yielded 184.1 of methyl di-(2-thienyl)glycolate
(73.6%)
Example 7
Preparation of Scopine Hydrobromide in Ethanol 96%
[0076] 100 g (0.228 mol) of scopolamine hydrobromide trihydrate was
suspended in 1000 mL of ethanol 96%, and cooled to 0.degree. C.
Well ground sodium borohydride (30.23 g, 0.80 mol) was then added
portion-wise, while maintaining the temperature at maximum
25-30.degree. C., gas evolution was noticed.
[0077] The reaction mixture was left stirring at room temperature
for 16 hours, and then filtered on decalite pad, and washed twice
with 100 mL of ethanol 96%. Water (19 mL) was added to the filtered
solution, it was left stirring for 1.5 hours, and the obtained
white suspension was concentrated under vacuum (about 30 mmHg) at
maximum 55.degree. C. to give a residue of 300 mL. After 30 minutes
at room temperature, the residue was filtered on GochP3, and washed
twice with 50 mL of ethanol 96%.
[0078] The solution was then cooled to 0.degree. C., and acidified
with 30 mL hydrobromic acid 48% to a pH of 1. 700 mL
tetrahydrofuran was added drop-wise, in 3 hours, to the reaction
mixture at 0.degree. C., and it was maintained at 0.degree. C. for
5 hours. The white solid was then filtered on Goch P3, washed with
100 mL tetrahydrofuran, and dried at 50.degree. C. under vacuum for
16 hours, yielding 33.2 g (64% yield, sulphuric ashes 0.7%).
Example 8
Preparation of Scopine Hydrobromide in Abs. Ethanol with
Precipitation in HBr 48%
[0079] 5 g (11.4 mmol) of scopolamine hydrobromide trihydrate was
suspended in 50 mL of absolute ethanol, and cooled to 0.degree. C.
Well ground sodium borohydride (1.73 g, 45.7 mmol) was then added
portion-wise while maintaining the temperature at a maximum of
30.degree. C.
[0080] 4.0 ml water was then added to the reaction mixture, and
then after 30 minutes, the suspension was filtered on decalite pad,
and washed with 30 mL of absolute ethanol.
[0081] The obtained solution was concentrated under vacuum at
40.degree. C. to residual 15 mL and, after 2 hours at room
temperature, filtered on GochP3, and washed with 4 mL of absolute
ethanol.
[0082] The solution was then cooled to 0.degree. C., and acidified
with hydrobromic acid 48% in water to obtain a pH of 1.
[0083] 15 mL tetrahydrofuran was then added drop-wise to the
reaction mixture at 0.degree. C., and it was maintained at
0.degree. C. for 2 hours and then at room temperature for 2 days.
The white solid was filtered on Goch P3, and dried at 50.degree. C.
under vacuum for 16 hours, yielding 1.4 g (52%). The other 40 mL
THF ("tetrahydrofuran") added to the mother liquor at 0.degree. C.
led to obtain other 700 mg product, containing 0.72% of salts.
Example 9
Preparation of Scopine Hydrobromide in Abs. Ethanol (5 Vol) with
Precipitation in HBr 48%
[0084] 10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate
was suspended in 50 mL of absolute ethanol, and cooled to 0.degree.
C. Sodium borohydride (3.46 g, 68.6 mmol) was then added
portion-wise while maintaining the temperature at a maximum of
30.degree. C.
[0085] 4.8 ml of water was then added to the reaction mixture, and
after 30 minutes the suspension was filtered on decalite pad, and
washed with 10 mL of absolute ethanol.
[0086] The solution was then cooled to 0.degree. C., and acidified
with hydrobromic acid 48% in water to obtain a pH of 1.
[0087] 100 mL tetrahydrofuran was added drop-wise to the reaction
mixture at 0.degree. C., and it was maintained at 0.degree. C. for
8 hours
[0088] The white solid was filtered on Goch P3, and dried at
50.degree. C. under vacuum for 16 hours, yielding 12.8 g (52%),
containing 0.65% of salts.
Example 10
Preparation of Scopine Hydrobromide in Ethanol with Precipitation
in HBr 48%
[0089] 100 g (0.22 mol) of scopolamine hydrobromide trihydrate was
suspended in 1000 mL of ethanol 1 96% and cooled to 0.degree. C.
Well ground sodium borohydride (30.23 g, 0.80 mol) was then added
portion-wise maintaining the temperature at maximum 25-30.degree.
C., gas evolution was noticed. The reaction mixture was left
stirring at room temperature for 16 hours and then filtered on
decalite pad, and washed twice with 100 mL of Ethanol 96%. 19 mL
water was added to the filtered solution, and it was left stirring
for 1.5 hours. The obtained white suspension was concentrated under
vacuum (about 30 mmHg) at maximum 55.degree. C. to residual 300 mL
and, after 30 minutes at room temperature, filtered on GochGoch P3
and washed twice with 50 mL of Ethanol 96%. The solution was then
cooled to 0.degree. C. and acidified with 30 mL hydrobromic acid
48% to a pH of 1. 1000 mL tetrahydrofuran was added drop-wise to
the reaction mixture at 0.degree. C. in 3 hours and maintained at
0.degree. C. for 4-5 hours. The white solid was then filtered on
Goch P3, washed with 100 mL tetrahydrofuran and dried at 50.degree.
C. under vacuum for 16 hours, yielding 45.9 g (85.6% yield,
sulphuric ashes 12.7%).
Example 11
Preparation of N-demethyl-tiotropium
[0090] 15 g (0.064 mol) of scopine hydrobromide was suspended in
165 mL of dimethylformamide at 25.degree. C., then 17.6 g (0.127
mol) of anhydrous potassium carbonate were added, and the mixture
was stirred at room temperature for about 60 minutes. 16.2 g (0.064
mol) of methyl di-(2-thienyl)glycolate were dissolved in 30 mL of
dimethylformamide, and, with 4.4 g (0.032 mol) of anhydrous
potassium carbonate, they were added to the reaction mixture at
about 60-65.degree. C. The suspension was heated to 65.degree. C.,
under vacuum (70-100 mbar), and under nitrogen stripping (2.2-2.4
L/min) for 18 hours. At the end of the reaction the distilled DMF
("dimethylformamide") was reintroduced to the reaction mixture and
another 2 volumes of DMF, for a total of 15 volumes (225 mL), were
added. The reaction mixture was cooled to 0.degree. C., and
acidified to pH 3 with about 168 mL of 2M HBr (the temperature
during the addition below 20.degree. C.). The obtained solution was
extracted twice with 85 mL toluene, and the combined aqueous phases
were then cooled to 0-5.degree. C., and basified with 8.5 g of
solid potassium carbonate to a pH of 9. After one hour at 0.degree.
C. the solid was filtered on Goch P3, and washed five times with 60
mL of water to obtain a pH of 7. The solid was dried under vacuum
at 45.degree. C. for 16 hours yielding 16.5 g (69% yield, 98.3%
HPLC purity)
Example 12
Preparation of N-demethyl-tiotropium with a Scopine Containing High
Percent of Salts
[0091] 3.0 g (0.012 mol) of scopine hydrobromide containing 69%
inorganic salts was suspended at room temperature in 27 mL of
dimethylformamide, then 3.4 g (0.025 mol) of anhydrous potassium
carbonate were added, and the mixture was stirred at room
temperature for about 60 minutes. 3.1 g (0.012 mol) of methyl
di-(2-thienyl)glycolate were dissolved in 9 mL of
dimethylformamide, and, with 0.85 g (0.006 mol) of anhydrous
potassium carbonate, they were added to the reaction mixture at
about 60-65.degree. C. The suspension was heated to 65.degree. C.,
under vacuum (70-100 mbar), and under nitrogen stripping (2.2-2.4
L/min) for 18 hours. At the end of the reaction, the distilled DMF
was re-added to the reaction mixture and other 2 volumes of DMF,
for a total of 15 volumes (45 mL), were added. The reaction mixture
was cooled to 0.degree. C., and acidified to pH 3 with 33 mL of HBr
2M (temperature during addition below 20.degree. C.). The obtained
solution was extracted twice with 15 mL toluene, and the combined
aqueous phases were then cooled to 0-5.degree. C., and basified
with 7.1 g of solid potassium carbonate to a pH of 9. After one
hour at 0.degree. C., the solid was filtered on Goch P3, and washed
five times with 30 mL of water to obtain a pH of 7. The solid was
dried under vacuum at 45.degree. C. for 16 hours yielding 1.8 g
(37.5% yield, 70% HPLC purity).
Example 13
Preparation of N-demethyl-tiotropium from Scopine Base and a Weak
Inorganic Base
[0092] 5.45 g (0.023 mol) of scopine hydrobromide was suspended in
30 mL of DCM, and then 5 g (0.036 mol) of potassium carbonate was
added. The reaction mixture was stirred at room temperature for one
hour and then filtered on Goch P3 and washed with acetonitrile
several times, (using about 10 ml of acetonitrile). After
evaporation of the filtered solution, 2.78 g of scopine base was
obtained (77.5% yield). 3.0 g (0.02 mol) of scopine base was
suspended at room temperature in 27 mL of dimethylformamide, then
2.7 g (0.02 mol) of anhydrous potassium carbonate was added, and
the mixture was stirred at room temperature for about 60 minutes.
4.9 g (0.02 mol) of methyl di-(2-thienyl)glycolate were dissolved
in 9 mL of dimethylformamide, and, with 1.33 g (0.0096 mol) of
anhydrous potassium carbonate, they were added to the reaction
mixture at about 60-65.degree. C. The suspension was heated to
65.degree. C., under vacuum (70-100 mbar), and under nitrogen
stripping (2.2-2.4 L/min) for 18 hours. At the end of the reaction
the distilled DMF was re-added to the reaction mixture and other 2
volumes of DMF, for a total of 15 volumes (45 mL), were added. The
reaction mixture was cooled to 0.degree. C., and acidified to a pH
of 3 with 33 mL of 2M HBr (temperature during addition below
20.degree. C.). The obtained solution was extracted twice with 15
mL toluene, and the combined aqueous phases were then cooled to
0-5.degree. C., and basified with 7.1 g of solid potassium
carbonate to a pH of 9. After one hour at 0.degree. C., the solid
was filtered on Goch P3, and washed five times with 30 mL of water
to obtain a pH of 7. The solid was dried under vacuum at 45.degree.
C. for 16 hours yielding 5.1 g (69.5% yield, 98.5% HPLC purity)
Example 14
Preparation of Tiotropium Bromide
[0093] 0.5 g of N-demethyl tiotropium (1.33 mmol) was suspended in
a flask under nitrogen with 5 mL of CH.sub.3CN. 0.525 g of
CH.sub.3Br 48% w/w solution in CH.sub.3CN (0.00266 mol) was loaded
and the suspension was left under stirring at 22.degree. C. for 20
hours. The product was filtered and washed with 1 mL of CH.sub.3CN.
375 mg of Tiotropium was obtained (HPLC purity 92.21%, starting
material 7.68%).
Example 15
Preparation of Tiotropium Bromide
[0094] 0.52 g of N-demethyl tiotropium (1.39 mmol) was suspended in
a flask under nitrogen with 5.23 g of CH.sub.3CN. 1.35 g of
CH.sub.3Br 50% w/w solution in CH.sub.3CN (0.0071 mol) was loaded,
and the suspension was left under stirring at 22.degree. C. for 12
hours. The product was filtered and washed with 1 mL of CH.sub.3CN.
572 mg of wet Tiotropium was obtained (HPLC purity 99.89%, starting
material 0.07%).
Example 16
Preparation of Tiotropium Bromide
[0095] 4.96 g of N-demethyl tiotropium (13.2 mmol) were loaded in a
flask under nitrogen with 49.6 mL of CH.sub.3CN. A suspension was
obtained. 12.61 g of CH.sub.3Br 50% w/w --CH.sub.3CN solution-
(0.066 mol) were loaded. The suspension was left under stirring at
22.degree. C. for 64 hours. The product was filtered and washed
with 2 mL of CH.sub.3CN. 6.93 g of wet Tiotropium was obtained, and
dried under vacuum at 45.degree. C. for 22 h (residual pressure 4
mbar). 5.9 g of dry product (purity 99.8%, start 0.107%) was
obtained.
Example 17
Crystallization of Tiotropium Bromide
[0096] Crude Tiotropium bromide (1.00 g) was dissolved in absolute
ethanol (65 mL) at 78.degree. C. The solution was heated to
78.degree. C. for about 30 min, and then was cooled to 22.degree.
C. in at least 6 hours. The obtained suspension was maintained at
22.degree. C. for at least 3 hours, and then was filtered on a
sintered glass funnel, and the solid was washed twice with absolute
ethanol (2.times.1.0 mL). The solid was dried for 30 min. at
22.degree. C. under N.sub.2 flow, and then for 9 hours at
60.degree. C. under reduced pressure (17 mbar). 0.66 g of
Tiotropium bromide was obtained.
Example 18
Preparation of Tiotropium Bromide Monohydrate from Tiotropium
Bromide Ethanolate
[0097] 13.45 g of dry Tiotropium bromide from example 16 was
suspended in 80.7 mL of water and the suspension was stirred at
room temperature for 4 h. After it was filtered washing with 10 mL
of water was conducted. The product was left on the filter under
vacuum and under nitrogen at room temperature for 15 min. 11.66 g
of monohydrate was obtained. The content of water on the sample was
4.3% (TGA analysis).
Example 19
Comparative Preparation of Tiotropium Bromide from
N-demethyltiotropium According to U.S. Pat. No. 5,610,163
[0098] 10.0 g (0.0265 mole) of scopine di-(2-thienyl)glycolate was
dissolved in a mixture comprising 20 mL of anhydrous methylene
chloride and 30 mL of anhydrous acetonitrile and treated with 12.8
g (0.1325 mole) of methyl bromide (as 50% strength solution in
anhydrous acetonitrile), and the reaction mixture was allowed to
stand for 24 hours at room temperature in a tightly sealed reaction
vessel. Crystals were precipated during this time. They are
filtered off under suction, washed using methylene chloride and
dried at 35.degree. C.--under reduced pressure. White crystals were
obtained (from methanol/acetone), m.p. 217.8 C. (decomposition)
after drying at 111.degree. C. under reduced pressure.
Example 20
Preparation of Scopine Hydrochloride in Absolute Ethanol (5 Vol)
with Precipitation in HCl 37%
[0099] 10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate
was suspended in 50 mL of absolute ethanol, and cooled to 0.degree.
C. Sodium borohydride (3.46 g, 68.6 mmol) was then added
portion-wise while maintaining the temperature at a maximum of
30.degree. C.
[0100] 4.8 mL of water was then added to the reaction mixture, and
after 30 minutes the suspension was filtered on decalite pad, and
washed with 10 mL of absolute ethanol.
[0101] The solution was then cooled to 0.degree. C., and acidified
with hydrochloric acid 37% in water to obtain a pH of 1.
[0102] 100 mL of tetrahydrofuran was added drop-wise to the
reaction mixture at 0.degree. C., and it was maintained at
0.degree. C. for 8 hours
[0103] The white solid was filtered on Goch P3, and dried at
50.degree. C. under vacuum for 16 hours, yielding 12.8 g (52%).
Example 21
Preparation of N-demethyl-tiotropium
[0104] 13.2 g (0.064 mol) of scopine hydrochloride was suspended in
165 mL of dimethylformamide at 25.degree. C., then 17.6 g (0.127
mol) of anhydrous potassium carbonate were added, and the mixture
was stirred at room temperature for about 60 minutes. 16.2 g (0.064
mol) of methyl di-(2-thienyl)glycolate was dissolved in 30 mL of
dimethylformamide, and with 4.4 g (0.032 mol) of anhydrous
potassium carbonate, they were added to the reaction mixture at
about 60-65.degree. C. The suspension was heated to 65.degree. C.,
under vacuum (70-100 mbar), and under nitrogen stripped (2.2-2.4
L/min) for 18 hours.
[0105] At the end of the reaction, the distilled DMF was
re-introduced to the reaction mixture and the other 2 volumes of
DMF, for a total of 15 volumes (225 mL), were added. The reaction
mixture was cooled to 0.degree. C., and acidified to a pH of 3 with
about 168 mL of 2M HBr (temperature during addition was below
20.degree. C.). The obtained solution was extracted twice with 85
mL of toluene, and the combined aqueous phases were then cooled to
0-5.degree. C., and basified with 8.5 g of solid potassium
carbonate to a pH of 9. After one hour at 0.degree. C., the solid
was filtered on Goch P3, and washed five times with 60 mL of water
to obtain a pH of 7. The solid was dried under vacuum at 45.degree.
C. for 16 hours yielding 16.5 g (69% yield, 98.3% HPLC purity).
* * * * *