PROCEDE AMELIORE PERMETTANT LA PREPARATION DE CHLORHYDRATE DIHYDRATE D'ONDANSETRON

AN IMPROVED PROCESS FOR PREPARING PURE ONDANSETRON HYDROCHLORIDE DIHYDRATE

Abrégé français

L'invention concerne un procédé amélioré permettant la préparation de diméthylamino-méthyl-carbazolone et d'une base d'ondansetron, et un processus de recristallisation permettant la préparation d'un chlorhydrate dihydraté d'ondansetron pur présentant une pureté d'au moins 99,0 %.

Abrégé anglais

An improved method for preparing dimethylamino-methyl-carbazolone and
ondansetron base. A recrystallization process for preparing pure ondansetron
hydrochloride dihydrate with a purity of at least 99.0% is also disclosed.

Revendications

11
WHAT IS CLAIMED IS:
1. Ondansetron hydrochloride dehydrate having a purity of at least 99.0%.
2. Ondansetron hydrochloride dehydrate having a purity of at least 99.5%.
3. Ondansetron hydrochloride dehydrate having a purity of at least 99.9%.
4. A process for preparing dimethylamino-methyl-carbazolone comprising
the steps of:
a) preparing a solution of methyl-carbazolone having the formula:
<IMG>
b) heating the solution in the presence of dimethylamine hydrochloride and
paraformaldehyde;
c) basifying the solution to form a precipitate;
d) separating the precipitate from the solution;
e) drying the precipitate.
5. The process according to claim 4, wherein R is methyl.
6. The process according to claim 4, wherein the heating step is performed at
a temperature of about 70°C to about 100°C.
7. The process according to claim 4, wherein the heating step is performed at
a temperature of about 80°C to about 90°C.
8. The process according to claim 4, wherein the heating step is performed
for about 6 to about 24 hours.
9. The process according to claim 4, wherein the heating step is performed
for about 6 to about 12 hours.

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10. The process according to claim 4, wherein the heating step is performed in
acetic acid.
11. The process according to claim 4, wherein about one equivalent methyl-
carbazolone is heated in the presence of about 1.1 to about 1.5 equivalents
of dimethylamine hydrochloride and paraformaldehyde.
12. The process according to claim 4, wherein about one equivalent methyl-
carbazolone is heated in the presence of about 1.2 equivalents of
dimethylamine hydrochloride and formaldehyde.
13. The process according to claim 4, wherein about one equivalent methyl-
carbazolone is heated in the presence of about 1.1 to about 1.5 equivalents
of dimethylamine hydrochloride and formaldehyde.
14. The process according to claim 4, wherein about one equivalent methyl-
carbazolone is heated in the presence of about 1.2 equivalents of
dimethylamine hydrochloride and formaldehyde.
15. The process according to claim 4, wherein about one equivalent methyl-
carbazolone is heated in the presence of about 4 to about 6 volumes of
acetic acid.
16. The process according to claim 4, wherein about one equivalent methyl-
carbazolone is heated in the presence of about 4 volumes of acetic acid.
17. The process according to claim 4, wherein the solution of methyl-
carbazolone is basified by about 45% sodium hydroxide.
18. The process according to claim 17, wherein the solution is basified to a
pH
of about 13 to about 14.

13
19. The process according to claim 17 or 18, wherein the basifying step is
performed in the presence of 10% celite.
20. A process for preparing ondansetron base, comprising the steps of:
a) preparing a solution of methyl-imidazole and dimethylamino-methyl-
carbazolone of the formula
<IMG>
b) heating the solution;
c) removing a precipitate containing ondasetron base from the
solution;
d) washing the precipitate;
e) drying precipitate to obtain ondansetron base.
21. The process according to claim 20, wherein the solution is prepared by
adding about 4 to about 6 equivalents methyl-imidazole to one equivalent
dimethylamino-methyl-carbazolone.
22. The process according to claim 20, wherein the solution is prepared by
adding about 5 equivalents methyl-imidazole to one equivalent
dimethylamino-methyl-carbazolone.
23. The process according to claim 20, wherein the solution is prepared in the
presence of 10% celite.
24. The process according to claim 20, further comprising the step of:
recrystallizing ondansetron base.
25. The process according to claim 24, wherein the recrystallizing step is

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performed in the presence of activated carbon and methanol.
26. A process of preparing pure ondansetron hydrochloride dihydrate
comprising the steps of:
a) preparing a solution of ondansetron base;
b) acidifying the solution with hydrogen chloride to form a
precipitate;
c) washing the precipitate; and
d) crystallizing pure ondansetron hydrochloride dihydrate.
27. The process according to claim 26 wherein about 3 to about 7 volumes of
water is added to ondansetron base to prepare a solution of ondansetron
base.
28. The process according to claim 26 wherein about 5 volumes of water is
added to ondansetron base to prepare a solution of ondansetron base.
29. The process according to claim 26 wherein about 1.0 to about 1.4
equivalents of about 32% (v:v) hydrochloric acid is added to acidify the
solution to induce precipitation.
30. The process according to claim 26 wherein about 1.1 equivalents of about
32% (v:v) hydrochloric acid is added to acidify the solution to induce
precipitation.
31. The process of claims 29 or 30, wherein the solution is acidified to a pH
about 1 to about 4.
32. The process of claims 29 or 30, wherein the solution is acidified to a pH
about 3.
33. The process according to claim 26, wherein the precipitate is washed with
about 5 to about 15 ml of isopropanol.

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34. The process according to claim 26, wherein the precipitate is washed with
about 10 ml of isopropanol.
35. The process according to claim 26, wherein the crystallizing step is
achieved by adding about 3 to about 5 volumes of water to induce
crystallization.
36. The process according to claim 26, wherein the crystallizing step is
achieved by adding about 4 volumes of water to induce crystallization.
37. The process according to claim 26, wherein the crystallization step is
repeated two times.
38. The process according to claim 26, wherein the crystallizing step is
achieved in the presence of activated carbon.
39. The process according to claim 36, wherein the activated carbon is
selected
from the group consisting of SX-2, CA-1, CXV and SX-1.
40. The process according to claim 39, wherein the activated carbon is about 5
to about 15% SX-1.
41. The process according to claim 39, wherein the activated carbon is about 5
to about 10% SX-1.
42. Ondansetron hydrochloride dehydrate as prepared in accordance with a
process of claim 26, wherein the ondansetron hydrochloride dehydrate has
a purity of at least about 99.0%.
43. Ondansetron hydrochloride dehydrate as prepared in accordance with a
process of claim 26, wherein the ondansetron hydrochloride dehydrate have
a purity of at least about 99.5%.

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44. Ondansetron hydrochloride dehydrate as prepared in accordance with a
process of claim 26, wherein the ondansetron hydrochloride dehydrate has
a purity of at least about 99.9%.
45. A pharmaceutical formulation comprising ondansetron hydrochloride
dihydrate as prepared in accordance with a process of claim 26, wherein
the ondansetron hydrochloride dehydrate has a purity of at least about
99.0%.
46. A pharmaceutical formulation comprising ondansetron hydrochloride
dihydrate as prepared in accordance with a process of claim 26, wherein
the ondansetron hydrochloride dehydrate has a purity of at least about
99.5%.
47. A pharmaceutical formulation comprising ondansetron hydrochloride
dihydrate as prepared in accordance with a process of claim 26, wherein
the ondansetron hydrochloride dehydrate has a purity of at least about
99.9%.

Description

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1
AN IMPROVED PROCESS FOR PREPARING PURE ONDANSETRON
HYDROCHLORIDE DIHYDRATE
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of Provisional Application Serial No.
601261,051, filed January 11, 2001, the disclosure of which is incorporated by
reference in its entirety herein.
FIELD OF THE INVENTION
The present invention relates to an improved process for preparing
dimethylamino-methyl-carbazolone. The present invention relates to an improved
process for preparing ondansetron base. The present invention also relates to
an
improved process for recrystallizing ondansetron hydrochloride dihydrate to
obtain pure ondansetron hydrochloride dihydrate.
BACKGROUND OF THE INVENTION
Ondansetron, also known as 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-
imidazol-1-yl) methyl]-4H-carbazol-4-one is a potent and highly selective
serotonin (5-HT3, 5-hydroxytrptamine receptor 3) antagonist and has the
following
formula:
O CH3
N
CH3
Ondansetron is currently available as an anti-emetic agent, particularly in
cancer chemotherapy, and in some other uses such as anti-depressive, anti-
migraine and anti-psychotic. It is commonly used in the alleviation of
cognitive
disorders as in Alzheimer disease, in treatment of rhinitis, psychiatric
disorders
and for increased vigilance and for control of dependence on narcotics.
U.S. Patent No. 4,695,578, assigned to the Glaxo Group Limited, describes
a process of preparing ondansetron and uses thereof. However, ondansetron

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prepared according to said process contains impurities and by-products such as
1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one.
There is a continuing need for improving the method of preparing
ondansetron with high purity that meets the standard for clinical uses.
OBJECTS AND SUMMARY OF THE INVENTION
The known methods of preparing ondansetron do not achieve a
pharmaceutically describe high purity and color. An object of the present
invention is to meet a need in the art for a high purity (i.e., at least about
99.0%)
and improved color
Another object of the present invention is to prepare pure ondansetron
hydrochloride dihydrate substantially free of any impurities and by-product
such
as 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one (e.g., the exo-
methylene by-product).
Another object of the present invention is to prepare ondansetron
hydrochloride dihydrate that has a purity of at least about 99.0%. Preferably,
the
ondansetron hydrochloride dihydrate has a purity of at least about 99.5%. Most
preferably, the ondansetron hydrochloride dehydrate has a purity of at least
about
99.9%.
Another object of the present invention is to provide a process for
preparing dimethylamino-methyl-carbazolone, the process comprising the steps
of:
a) preparing a solution of methyl-carbazolone;
b) heating the solution in the presence of dimethylamino hydrochloride
and paraformaldehye;
c) basifying the solution to form a precipitate;
d) separating the precipitate from the solution to obtain dimethylamino-
methyl-carbazolone; and
e) drying the dimethylamino-methyl-carbazolone.

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Another obj ect of the present invention is a process for preparing
ondansetron base, the process comprising the steps of
a) preparing a solution of methyl-imidzole and dimethylamino-methyl-
carbazolone;
b) heating the solution;
c) removing a precipitate containing ondansetron base;
d) washing the precipitate; and
e) drying the precipitate to obtain pure ondansetron base.
Preferably, step e) is followed by recrystallizing the ondansetron base in
the presence of activated carbon and methanol.
Another obj ect of the present invention is a process for preparing
ondansetron hydrochloride dihydrate, the process comprising the steps of:
a) preparing a solution of ondansetron base;
b) acidifying the solution with hydrogen chloride to form a
precipitate;
c) washing the precipiate; and
d) crystallizing ondansetron hydrochloride dihydrate.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "exo-methylene by-product" refers to 1,2,3,9-
tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one. It represents one of the
main impurity in ondansetron preparation. Another impurity in ondansetron
preparation is dimeric exo-methylene by-product.
Unless otherwise specified, "%" refers to % wt.
As used herein, the term "pure ondansetron" refers to ondansetron that is
substantially free of exo-methylene by-product and has a high purity of at
least
about 99.0%.
As used herein, the term "hydrogen chloride" refers to either a gaseous
hydrogen chloride or a solution of hydrogen chloride gas in water.

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As used herein, the term "equivalent" refers to molar equivalent.
As used herein, the term "vacuum distillation" refers to the separation of
solids from liquids by passing the mixture through a vacuum filter.
As used herein, the term "reflux" refers to during a chemical process, part
of the product stream may be returned to the process to assist in giving
increased
conversion or recovery, as in distillation or liquid-liquid extraction.
As used herein, the term "filter cake" refers to a concentrated solid or
semisolid material that is separated from a liquid and remains on the filter
after
pressure filtration.
The present invention is an improved method of preparing a pure
ondansetron hydrochloride dehydrate with purity at least 99.0%. More
preferably,
the ondansetron hydrochloride dehydrate purity is at least 99.5%. Most
preferably,
the ondansetron hydrochloride dehydrate purity is at least 99.9%.
The present invention provides an improved method of preparing
dimethylamino-methyl-carbazolone. The present invention further provides an
improved method of preparing ondansetron base. The present invention fizrther
provides an improved method of preparing pure ondansetron hydrochloride
dehydrate.
Preparation of Dimethylamino-Methyl-Carbazolone
The present invention provides a process for preparing dimethyl amino-
methyl-carbazolone comprising the steps of
a) preparing a solution of methyl-carbazolone having the formula:
(where R = C 1-4, alkyd

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b) heating the solution in the presence of dimethylamino hydrochloride and
paraformaldehyde;
c) basifying the solution to form a precipitate;
d) separating the precipitate from the solution to obtain dimethylamino-
methyl-carbazolone; and
e)drying the dimethylamino-methyl-carbazolone.
During the heating step, the solution is heated in the presence of
dimethylamine hydrochloride and paraformaldehyde in an organic solvent.
Preferably, the organic solvent is acetic acid.
Preferably, one equivalent methyl-carbazolone is refluxed with about 1.1
to about 1.5 equivalents of dimethylamine-hydrochloride and paraformaldehyde.
Most preferably, one equivalent methyl-carbazolone is refluxed with about 1.2
equivalents of dimethylamine-hydrochloride and paraformaldehyde. During the
heating step, formaldehyde can be used to substitute for paraformaldehyde in
the,
reflux reaction.
Preferably, one equivalent methyl-carbazolone is refluxed with about 4 to
about 16 volumes of acetic acid. Most preferably, one equivalent methyl-
carbazolone is refluxed with about 4 volumes of acetic acid.
Preferably, the heating step is performed at a temperature of about
70°C to
about 100°C. Most preferably, the heating step is performed at a
temperature of
about 80° to about 90° C.
Preferably, the heating step is performed for about 6 to about 24 hours.
Most preferably, the heating step is performed for about 6 to about I2 hours.
Preferably, the separating step is performed using filtration.
Preferably, the heating step is performed Without the use of vacuum

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distillation or extraction. The heating step performed in the absence of
vacuum
distillation or extraction consistently yields a better pure dimethylamino-
methyl-
carbazolone.
The present invention also provides a process of preparing pure
dimethylamino-methyl-carbazolone fizrther comprises dissolving the filter cake
in
acetone and treating with activated carbon and hydrogen chloride.
Preferably, water is added at the basifying step thereafter rendering the
solution basic by about 45% sodium hydroxide (NaOH) to a pH range of about 13
to about 14. Preferably, the basifying step is performed in the presence of
celite
(10%), filter and dry.
Preferably, the dry cake is dissolved in acetone. Preferably, the dissolved
cake is treated with activated carbon and hydrogen chloride to precipitate
dimethylamino-methyl-carbazolone.
Preuaration of Ondansetron Base
The present invention provides a process for the synthesis of ondansetron
base comprising the steps of
a) preparing a solution of methyl-imidazole and dimethylamino-methyl-
carbazolone of the formula
O
~N(Me)2 . HC1 (where R= C1_4~ alkyl)
N
R
b) heating the solution;
c) removing a precipitate containing containing ondasetron base from
the solution;
d) washing the precipitate;
e) drying precipitate to obtain ondansetron base.

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The present invention further provides a process for the synthesis of
substantially pure ondansetron base, further comprising the steps of
recrystallizing in the presence of activated carbon and methanol.
During the solution preparation step of methyl-imidazole and
dimethylamino-methyl-carbazolone, about 4 to about 6 equivalents methyl-
imidazole is preferably added to one equivalent dimethylamino-methyl-
carbazolone. Most preferably, about 5 equivalents of methyl-imidazole is added
to one equivalent dimethylamino-methyl-carbazolone.
Preferably, the preparation step is performed in the presence of 10% celite.
Preferably, the present invention provides a process for preparing
ondansetron base further comprising (after step e) a step of recrystallizing
ondansetron base in the presence of activated carbon and methanol.
Crystallization to Prepare Pure Ondansetron Hydrochloride Dehydrate
The present invention provides an improved method of preparing a pure
ondansetron hydrochloride dehydrate. Specifically, the preparation involves
crystallization of ondansetron hydrochloride dehydrate from ondansetron base
with
water and activated carbon and in the absence of an organic solvent.
The crystallization process of the present invention greatly increases the
purity of ondansetron hydrochloride dehydrate and dramatically lowers the
content
of the exo-methylene by-product impurity. Preferably, the crystallization step
is
performed 1-3 times. Most preferably, the crystallization step is performed
two
times.
The present invention provides a method of crystallization of ondansetron
hydrochloride dehydrate comprising the steps of:
a) preparing a solution of ondansetron base;
b) acidifying the solution with hydrogen chloride to form a

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8
precipitate;
c) washing the precipitate; and
d) crystallizing pure ondansetron hydrochloride dihydrate.
Preferably, the solution preparation step is achieved by adding about 3 to
about 7 volumes of water to ondansetron base. Most preferably, the solution
preparation step is achieved by adding about 5 volumes of water to ondanseton
base.
Preferably, the acidifying step is achieved by adding hydrochloric acid.
Preferably, about 1.0-1.4 equivalents of about 32% (v:v) hydrochloric acid is
added to induce precipitation. Most preferably, about 1.1 equivalents of about
32% (v:v) hydrochloric acid is added to induce precipitation. More preferably,
the
acidifying step is achieved at a pH about 1 to about 4. Most preferably, the
acidifying step is achieved at a pH about 3.
Preferably, the washing step is achieved by using isopropanol. Preferably,
about 5 to about 15m1 of isopropanol is used to wash the precipitates. Most
preferably, about 10 ml of isopropanol is used to wash the precipitates.
Preferably, the crystallizing step is achieved by adding about 3 to about 5
volumes of water to induce crystallization. Most preferably, about 4 volumes
of
water is used to induce crystallization.
Preferably, the crystallizing step is performed in the presence of activated
carbon. Preferably, the activated carbon is selected from the group consisting
of
SX-2, CA-1, CXV, and SX-1.
Preferably, the crystallizing step is performed in the presence of about 5 to
about 15% SX-1 activated carbon. Most preferably, the crystallizing step is
performed in the presence of about 10% SX-1 activated carbon.
The present invention is further explained by the following examples. The

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present invention is by no means restricted to these specific examples. One of
ordinary skill in the art will understand how to vary the exemplified
preparations
to obtain the desired results.
EXAMPLES
Example 1: Preparation of Pure Dimethylamino- Methyl-Carbazolone Salt
Into 180 ml glacial acetic acid 45 gram (0.226 mole,1.0 eq) of methyl-
carbazolone, 22.4 gram ( 0.275 mole, 1.22 eq) of dimethylamine hydrochloride
and 9 gram (0.3 mole, 1.33 eq) of paraformaldehyde were added.
The reaction was kept at about 80 ~ 2°C during 12 hours, then 540
ml of
water and 4.5 gram of highflow are introduced into the reactor, the batch was
cooled to about 10°C and rendered basic with about 45% NaOH to about pH
13 to
about 14 while the batch temperature did not exceed about 25°C.
Then the batch was stirred at about 5 to about 10° C for an
additional 1
hour, the precipitate that formed along with the highflow were collected and
dried
in vacuum oven at about 60°C until constant weight to obtain crude
product
containing highflow.
The crude product was treated with 3.3 gram activated carbon type SX-1
(by NORIT) in 990 ml acetone, filtered, cooled to about 25°C and
hydrochloric
acid was bubbled through the acetone solution until pH was about 3, the batch
was
cooled to about 0 to about 5° C, kept at this temperature for half an
hour, filtered,
washed with about 20 ml acetone and dried in an oven at about 50°C
until constant
weight to give 49.6 gram dimethylamino-methyl-carbozolone-HCl.
Example 2: Preparation of Pure Ondansetron Base
Into 330 ml water 33 gram (0.112 mole, 1 eq.) dimethylamino-methyl-
carbozolone-HCI, 3.3 gram highflow, 46.3 gram (0.563 mole, 5 eq) methyl-
imidazole were added.

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The reaction was heated at reflux during 12 hours and cooled to about 5 to
about 10° C, the precipitate was filtered, washed with 3 x 300m1 water
and dried in
a vacuum oven at about 60° C until constant weight to give crude
compound
containing highflow.
5 The crude compound was treated with 1.5 gram activated carbon type SX-
1 (by NORIT) in 930 ml methanol, filtered (hot filtration) from the highflow
and
activated carbon and crystallized at 0 to about 5°C during one hour.
Hot filtration
was around 60°C and was done with methanol near its boiling point
(i.e., 65°C).
The precipitate was collected by filtration, washed with 2 x 20 ml cold
methanol
10 and dried in vacuum oven at about 60°C until constant weight to give
21.3 gram
ondansetron-base.
Example 3: Preparation of Pure Ondansetron Hydrochloride Dih
Into 100 ml of water 20 gram ondansetron-base were introduced. To the
stirred suspension 7.5 ml (1.1 equivalents) of about 32% hydrochloric acid
(HCl)
was added. A slightly exothermic reaction occurred, the suspension turned
almost
clear and a precipitate began to form.
The reaction was cooled down and kept at about 3-5°C for an
additional 1
hour filtered, washed, with about 10 ml cold isopropanol and dried at about
50°C
under vacuum.
Example 4: Recrystallization of Ondansetron Hydrochloride Dihydrate
Ondansetron-HCl-2H20 was crystallized twice from 1:4 w/v water and
about 10% w/w activated carbon type SX-1 (by NORIT) at about 95°C
during half
an hour, filtered (hot filtration), washed with 1 volume of hot water, cooled
to
about 5°C and kept at this temperature for about 1 hour. The crystals
was
collected, washed with about 10 ml cold isopropanol and dried to give pure
ondansetron-HCl-2H20. The obtained pure ondansetron hydrochloride dihydrate
was determined by HPLC to be at least greater than 99.0%. The obtained pure
ondansetron hydrochloride dihydrate contained less than 0.01% exo-methylene by-
product or undetectable.