U.S. patent application number 12/779216 was filed with the patent office on 2010-11-18 for method for preparing high-purity fesoterodine fumarate.
This patent application is currently assigned to CHEMI S.P.A.. Invention is credited to Umberto Ciambecchini, Stefano Turchetta, Elio Ullucci, Maurizio Zenoni.
Application Number | 20100292502 12/779216 |
Document ID | / |
Family ID | 41491573 |
Filed Date | 2010-11-18 |
United States Patent
Application |
20100292502 |
Kind Code |
A1 |
Ciambecchini; Umberto ; et
al. |
November 18, 2010 |
Method for preparing high-purity fesoterodine fumarate
Abstract
A process is described for preparing fesoterodine fumarate
comprising the salification reaction of fesoterodine with fumaric
acid in an organic solvent, preferably a ketone, at a temperature
not greater than 45.degree. C. Such process allows obtaining
products with high yields and purities, and in particular a product
having a content of
(2E)-4-[(3-(3-diisopropylamino-1-phenylpropyl)-4-(2-isobutyroyloxyphenyl)-
methoxy]-4-oxobut-2-enoic acid less than or equal to 0.15% by
mole.
Inventors: |
Ciambecchini; Umberto;
(Patrica, IT) ; Ullucci; Elio; (Patrica, IT)
; Turchetta; Stefano; (Patrica, IT) ; Zenoni;
Maurizio; (Patrica, IT) |
Correspondence
Address: |
LUCAS & MERCANTI, LLP
475 PARK AVENUE SOUTH, 15TH FLOOR
NEW YORK
NY
10016
US
|
Assignee: |
CHEMI S.P.A.
Cinisello Balsamo (MI)
IT
|
Family ID: |
41491573 |
Appl. No.: |
12/779216 |
Filed: |
May 13, 2010 |
Current U.S.
Class: |
560/140 |
Current CPC
Class: |
C07C 227/16 20130101;
C07C 219/28 20130101; C07C 59/40 20130101 |
Class at
Publication: |
560/140 |
International
Class: |
C07C 69/017 20060101
C07C069/017 |
Foreign Application Data
Date |
Code |
Application Number |
May 15, 2009 |
IT |
MI2009A000845 |
Claims
1. Process for preparing fesoterodine fumarate comprising reacting
fesoterodine with fumaric acid, wherein said reaction step is
carried out in at least one organic solvent at a temperature not
higher than 45.degree. C.
2. Process according to claim 1, wherein said temperature is
comprised between 30 and 40.degree. C.
3. Process according to claim 2, wherein said temperature is about
35.degree. C.
4. Process according to claim 1, further comprising heating a
mixture of fesoterodine and fumaric acid in said at least one
organic solvent until complete dissolution, and cooling the
solution thus obtained at a temperature lower than 25.degree.
C.
5. Process according to claim 4, wherein said heating step is
carried out for a period comprised between 10 minutes and two
hours.
6. Process according to claim 5, wherein said heating step is
carried out for a period comprised between 30 minutes and one
hour.
7. Process according to claim 4, wherein said cooling step is
carried out at a temperature comprised between 5 and 20.degree.
C.
8. Process according to claim 7, wherein said cooling step is
carried out at a temperature comprised between 15 and 20.degree.
C.
9. Process according to claim 1, wherein said at least one organic
solvent is a polar aprotic organic solvent.
10. Process according to claim 1, wherein said at least one organic
solvent is a ketone.
11. Process according to claim 10, wherein said ketone has from
three to six carbon atoms.
12. Process according to claim 10, wherein said ketone is
methylethylketone.
13. Process according to claim 1, wherein said fumaric acid is used
in molar ratios comprised between 0.9 and 1.5 with respect to
fesoterodine.
14. Process according to claim 13, wherein said fumaric acid is
used in molar ratios comprised between 1.0 and 1.1 with respect to
fesoterodine.
15. Process according to claim 1, wherein said fesoterodine is used
in a weight/volume ratio comprised between 2 and 50 with respect to
said at least one organic solvent.
16. Process according to claim 15, wherein said fesoterodine is
used in a weight/volume ratio comprised between 3 and 10 with
respect to said at least one organic solvent.
17. Process according to claim 1, wherein the fesoterodine fumarate
thus obtained is filtered, washed, dried under vacuum and/or
micronized.
18. Process according to claim 17, wherein the fesoterodine
fumarate is micronized until obtaining a PSD with d (0.9).ltoreq.20
micron.
19. Fesoterodine fumarate having a content of
(2E)-4-[(3-(3-diisopropylamino-1-phenylpropyl)-4-(2-isobutyroyloxyphenyl)-
methoxy]-4-oxobut-2-enoic acid less than or equal to 0.15% by
mole.
20. Micronized fesoterodine fumarate having a content of
(2E)-4-[(3-(3-diisopropylamino-1-phenylpropyl)-4-(2-isobutyroyloxyphenyl)-
methoxy]-4-oxobut-2-enoic acid less than or equal to 0.15% by mole
and a PSD with d (0.9).ltoreq.20 micron.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and benefit of Italian
Application No. MI2009A000845 filed on May 15, 2009, the content of
which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The object of the present invention is a process for
preparing fesoterodine fumarate comprising the salification
reaction of fesoterodine with fumaric acid in an organic solvent,
preferably a ketone, at a temperature not greater than 45.degree.
C.
BACKGROUND OF THE INVENTION
[0003] Fesoterodine fumarate is the international nonproprietary
name (INN) of the active principle
2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl)phenyl
isobutyrate hydrogen fumarate, whose structure formula is reported
hereinbelow.
##STR00001##
[0004] Fesoterodine fumarate was approved in Europe and in the
U.S.A. for the treatment of overactive bladder syndrome with the
commercial name of TOVIAZ.RTM..
[0005] Fesoterodine fumarate was described for the first time in
U.S. Pat. No. 6,858,650, which reports the preparation of the
active ingredient by the salification of fesoterodine with fumaric
acid, according to scheme 1 reported below.
##STR00002##
[0006] In turn, fesoterodine (also called fesoterodine base) is
described in U.S. Pat. No. 6,713,464, where it is prepared starting
from a deacylated precursor, (R)-feso deacyl, i.e.
(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol,
according to scheme 2 reported hereinbelow.
##STR00003##
[0007] The preparation of (R)-feso deacyl is instead described in
U.S. Pat. No. 5,559,7269.
DETAILED DESCRIPTION OF THE INVENTION
[0008] During the salification experiments of fesoterodine with
fumaric acid, it was found that in the salification reaction,
variable quantities of a by-product can be formed that is not
reported in the literature. Such by-product was identified as a
fesoterodine monofumarate, i.e.
(2E)-4-[(3-(3-diisopropylamino-1-phenylpropyl)-4-(2-isobutyroyloxyphenyl)-
methoxy]-4-oxobut-2-enoic acid, whose structure formula is reported
hereinbelow.
##STR00004##
[0009] Such impurity, named "feso fumaric ester" impurity for
convenience, can increase up to values greater than 1% if the
salification conditions are not suitable controlled.
[0010] The feso fumaric ester impurity has been synthesized and
characterized, and salification conditions of fesoterodine with
fumaric acid have been identified (constituting the object of the
present invention) such that the quantity of feso fumaric ester
impurity in the finished product is maintained below the ICH limits
allowed for known impurities (.ltoreq.0.15% by mole).
[0011] Both the process for the preparation of fesoterodine
fumarate via salification of fesoterodine with fumaric acid and the
fesoterodine fumarate thus obtained constitute the object of the
present invention; and in particular, a fesoterodine fumarate
having a content of feso fumaric ester impurity below 0.15% by
mole.
[0012] The process according to the present invention comprises the
salification reaction of fesoterodine with fumaric acid in at least
one suitable organic solvent at a temperature not higher than
45.degree. C., preferably at a temperature comprised between 30 and
40.degree. C., still more preferably at about 35.degree. C.
[0013] In practice, such salification reaction is carried out by
heating a mixture of fesoterodine and fumaric acid at the aforesaid
temperature in the aforesaid at least one organic solvent, until
complete dissolution; such operation normally requires from 10
minutes to two hours, preferably from 30 minutes to one hour. The
solution thus obtained is then cooled at a temperature lower than
25.degree. C., preferably comprised between 5 and 20.degree. C.,
still more preferably between 15 and 20.degree. C.
[0014] The precipitation of the salt can be triggered with methods
known in the art, for example via addition of a crystalline
fesoterodine fumarate seed or by means of addition of solid
fesoterodine fumarate obtained via lyophilization of an aqueous
solution of fesoterodine fumarate.
[0015] The fesoterodine usable in the process of the present
invention can be obtained according to one of the methods reported
in the literature, for example according to the method reported in
U.S. Pat. No. 6,713,464, incorporated herein by reference; it can
also be used either in pure or crude form.
[0016] According to one aspect of the invention, the organic
solvent is preferably a polar aprotic organic solvent, preferably a
ketone, still more preferably a ketone having from three to six
carbon atoms; according to the more preferred embodiment, such
ketone is methylethylketone (i.e. 2-butanone).
[0017] According to a further aspect of the invention, fumaric acid
is used in molar ratios comprised between 0.9 and 1.5 (preferably
between 1.0 and 1.1) with respect to fesoterodine; fesoterodine, in
turn, is used in a weight/volume ratio (g/l) comprised between 2
and 50, preferably between 3 and 10, with respect to said at least
one organic solvent.
[0018] Fesoterodine fumarate thus obtained can then be isolated
with conventional methods; it is preferably filtered, washed
(generally with the same solvent used in the salification reaction)
and then dried under vacuum.
[0019] The product thus obtained is therefore preferably micronized
by using conventional techniques, until a PSD is obtained with d
(0.9).ltoreq.20 microns, i.e. a Particle Size Distribution in which
90% of the particles have a size that does not exceed 20
microns.
[0020] In the following tables, the results of two stability tests
are reported that were conducted on samples of fesoterodine
fumarate obtained by following the teachings of example 1.
[0021] In detail, the experiment related to Table 1 consists of
dissolving fesoterodine fumarate in methylethylketone at 40.degree.
C., drawing samples of the freshly dissolved solution (time 0),
after 1, 3 and 20 hours of maintenance at 40.degree. C. and
analyzing them in HPLC in order to verify their purity.
TABLE-US-00001 TABLE 1 Solution stability in methylethylketone at T
= 40.degree. C. HPLC Purity (R)-feso- Impurity Impurity Feso
fumaric ester Diester Area % deacyl RRt = 1.05 RRt = 1.34 impurity
impurity RRt = 1.86 t = 0 99.87 n.d. n.d. 0.06 0.07 -- -- t = 1
hour 99.85 n.d. n.d. 0.06 0.09 -- -- t = 3 hours 99.77 0.01 n.d.
0.06 0.12 0.04 -- t = 20 hours 99.70 0.02 n.d. 0.08 0.14 0.06 n.d.
RRt = Relative Retention time (HPLC) n.d. = not detectable
[0022] From the conducted test, it was observed that the feso
fumaric ester impurity increases over time until it stabilizes at
about 0.14% by mole, i.e. below the specification limit, after 20
hours.
[0023] In confirmation thereof, another stability test was carried
out at 60.degree. C. on the crystallized solid product, whose
results are reported in Table 2. In detail, the experiment consists
of introducing a sample of fesoterodine fumarate in an oven capable
of maintaining a temperature of 60.degree. C. and 60% relative
humidity, drawing samples of the freshly introduced substance (time
0) after 24, 48, 72 and 144 hours staying in such conditions, and
analyzing them in HPLC in order to verify their purity.
TABLE-US-00002 TABLE 2 Solid stability at T = 60.degree. C. in
atmosphere with 60% relative humidity HPLC Purity (R)-feso-
Impurity Impurity Feso fumaric ester Diester Area % deacyl RRt =
1.05 RRt = 1.34 impurity impurity RRt = 1.86 t = 0 99.85 0.02 n.d.
n.d. 0.09 0.04 n.d. t = 24 h 99.83 0.02 n.d. n.d. 0.11 0.04 n.d. t
= 48 h 99.74 0.02 n.d. 0.08 0.12 0.04 n.d. t = 72 h 99.72 0.03 0.02
0.06 0.13 0.04 n.d. t = 144 h 99.64 0.05 0.03 0.07 0.14 0.04 0.03
RRt = Relative Retention time (HPLC) n.d. = not detectable
[0024] Also from this stability test, it is confirmed that
crystalline fesoterodine fumarate maintained at 60.degree. C. loses
purity over time via formation of the feso fumaric ester impurity,
which stabilizes after 144 hours (6 days) at around 0.14% by
mole.
[0025] The following examples clarify in detail the conditions used
for obtaining high-purity fesoterodine fumarate according to the
present invention; such examples are intended as non-limiting and
exemplifying of the present invention.
Example 1
Preparation of Fesoterodine Fumarate
[0026] In a 2-liter reactor, 31.2 g of sodium bicarbonate and 1250
ml of deionized water (pH 8.1) are charged. Stirring is performed
until complete dissolution of the salt. In a 10-liter reactor, 250
g of (R)-Feso deacyl and 7500 ml of dichloromethane are charged.
Stirring is performed until a complete solution is obtained. Then,
the aqueous bicarbonate solution is added to the organic solution
and the biphasic mixture is cooled at 5.degree. C. 86 g of
isobutyryl chloride are then added dropwise to the mixture, which
is once again stirred for one hour from the end of the addition.
Then, 1250 ml of a solution of 5% w/w sodium bicarbonate in water
are added to the reaction mixture and the mixture is heated at
20.degree. C., still under stirring. The lower organic phase is
separated and is first washed with 2500 ml of a solution of 5% w/w
sodium bicarbonate in water then twice with 2.times.2500 ml of
deionized water. The obtained organic phase is concentrated to a
small volume and 1000 ml of 2-butanone are added thereto. The
mixture is once again evaporated to half the initial volume, then
1000 ml of 2-butanone are added again and 80.4 g fumaric acid are
added to the solution. The suspension is heated at 35.degree. C.
until complete dissolution is obtained. It is cooled at 20.degree.
C.; the crystallization is triggered with crystalline fesoterodine
fumarate seeds. Stirring is maintained for 1 hour at 20.degree. C.
and for 2 hours at 0.degree. C. The suspension is then filtered
over a Buchner funnel and the pad is washed with 600 ml of
2-butanone. 621 g of moist product are obtained, which are dried at
t=35.degree. C. for 15 hours, obtaining 331 g of crystalline
fesoterodine fumarate (85.7% yield). The purity of the product is
99.8%, with (R)-feso deacyl not detectable, diester impurity 0.10%
and feso fumaric ester impurity 0.07%.
Example 2
Preparation of Fesoterodine Fumarate
[0027] In a 250 milliliter flask, 3.0 g of (R)-Feso deacyl and 60
ml of dichloromethane are charged. Stirring is performed until a
complete solution is obtained. The temperature of the solution is
brought to 0-5.degree. C. 1.02 g of isobutyryl chloride dissolved
in 30 ml of dichloromethane are added dropwise on the mixture and
the mixture is again stirred for ten minutes from the end of the
addition. Then, 15 ml of a solution of 2.5% w/w sodium bicarbonate
in water (pH 8.1) are added to the reaction mixture and the mixture
is stirred at 0-5.degree. C. for another 2 hours. It is then left
to warm at room temperature and the lower organic phase is
separated, washing it first with 30 ml of a solution of 5% w/w
sodium bicarbonate in water and then twice with 2.times.50 ml of
deionized water. The obtained organic phase is concentrated to
small volume and 30 ml of 2-butanone are added thereto. The mixture
is once again evaporated to half the initial volume, then another
30 ml of 2-butanone are added, and 0.9 g of fumaric acid are added
to the solution. The suspension is heated at 35.degree. C. until
complete dissolution is obtained. It is cooled at 20.degree. C.;
the crystallization is triggered with seeds of crystalline
fesoterodine fumarate. Stirring is maintained for 1 hour at
20.degree. C. and for 2 hours at 0.degree. C. Then, the suspension
is filtered over a Buchner filter and the pad is washed with 10 ml
of 2-butanone. 3.41 g of moist product are obtained, which are
dried at t=35.degree. C. for 15 hours, obtaining 3.13 g of
crystalline fesoterodine fumarate (85.7% yield). The purity of the
product is 99.8%, with (R)-feso deacyl 0.12%, diester impurity
0.07% and feso fumaric ester impurity 0.02%.
[0028] The fesoterodine thus obtained can be recrystallized by
dissolving it in 21 ml of methylethylketone, bringing the mixture
to 40.degree. C. (with dissolution of the suspended material),
cooling the solution at 20.degree. C., and seeding the solution
with 2 mg of crystalline fesoterodine fumarate. After further
cooling at 0-5.degree. C. and keeping in such conditions for two
hours, the obtained solid is filtered and washed with
methylethylketone, obtaining 3.03 g of moist fesoterodine fumarate,
which is dried at 35.degree. C. for 15 hours, obtaining 2.75 g of
fesoterodine fumarate (89% yield), having HPLC purity equal to
99.9%, containing (R)-feso deacyl 0.09%, non-detectable diester
impurity and feso fumaric ester impurity 0.03%.
Example 3
Preparation of Micronized Fesoterodine Fumarate
[0029] 30 g of fesoterodine fumarate prepared according to example
1 are inserted into a Mc One.RTM. Fluid Jet Mill micronization
apparatus at a nitrogen pressure of the micronization chamber of 4
atmospheres and at a nitrogen pressure of the Venturi tube of 6
atmospheres. The recovered product is subjected to Particle Size
Distribution analysis by using a Malvern Mastersizer 2000 Ver.
5.22, Tegiloxan 3 instrument as dispersing agent and a dispersing
speed in the instrument of 3000 rpm. The d(0.9) of the product is
equal to 24 microns. The product is analyzed for HPLC purity and
has identical purity to the starting product (99.8%, with (R)-feso
deacyl not detectable, diester impurity 0.10% and feso fumaric
ester impurity 0.07%.). The obtained product is also analyzed by
means of X ray diffraction of powders and the analysis confirms
that the micronized material has the same crystalline form as the
starting material.
[0030] A second 30 g aliquot of the product prepared according to
the example 1 is micronized in the same above-described apparatus,
at a nitrogen pressure of the micronization chamber of 6
atmospheres and at a nitrogen pressure of the Venturi tube of 8
atmospheres. The recovered product is subjected to Particle Size
Distribution analysis by using a Malvern 2000 instrument. The
d(0.9) of the product is equal to 15 microns and the purity of the
product remains unchanged with respect to the material inserted in
the micronizer. The obtained product is also analyzed by means of X
ray diffraction of powders and the analysis confirms that the
micronized material has the same crystalline form as the starting
material.
Example 4
Preparation of Fesoterodine Fumaric Ester Impurity
[0031] 5 g of fesoterodine fumarate prepared as in example 1 are
dissolved in 150 ml of methylethylketone and the mixture is heated
under reflux for a week. At the end, the HPLC analysis detects
shows a content of feso fumaric ester impurity of 15%. The solvent
is evaporated and the residue is chromatographed on silica gel
column, eluting with a mobile phase constituted by 80%
dichloromethane and 20% methanol. The column fractions containing
the desired impurity are collected and by drying the pooled
fractions, 600 mg of the desired impurity are obtained. The
spectroscopic data reported below, related to the isolated
impurity, confirm the identity of the obtained product.
[0032] .sup.1H-NMR: 6 (DMSOd.sup.6): 6.60-7.45 (m, 10H); 5.15 (d,
2H); 4.01 (m, 1H); 3.59-3.52 (m, 4H); 2.87-2.71 (m, 5H); 1.35-1.24
(m, 18H).
[0033] .sup.13C-NMR: 6 (DMSOd.sup.6): 175.86, 169.55, 166.25,
148.68, 142.19, 141.28, 135.42, 134.79, 129.05, 128.99, 128.08,
127.87, 127.69, 127.17, 123.05, 65.86, 54.54, 46.17, 41.74, 34.37,
31.91, 19.38, 19.23, 18.04, 17.83.
[0034] MS (positive ionization): (M+1) 510.54 (100%), 511.40 (36%),
512.35 (7%). Calculated for C.sub.30H.sub.39NO.sub.6: 510.29 (100),
511.29 (36%), 510.29 (7%).
* * * * *