US 2002O115707A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2002/0115707 A1
Lidor-Hadas et al. (43) Pub. Date: Aug. 22, 2002
(54) PROCESS FOR PREPARING PURE Related U.S. Application Data
ONDANSETRON HYDROCHLORIDE
DIHYDRATE (60) Provisional application No. 60/261,051, filed on Jan.
11, 2001.
(76) Inventors: Rami Lidor-Hadas, Kfar Saba (IL);
Eliezer Bachar, Tel Aviv (IL) Publication Classification
Correspondence Address: (51) Int. Cl." ...................... A61K 31/403; CO7D 209/82
KENYON & KENYON (52) U.S. Cl. ............................................ 514/411; 548/440
ONE BROADWAY
NEW YORK, NY 10004 (US) (57) ABSTRACT
An improved method for preparing dimethylamino-methyl
(21) Appl. No.: 10/045,970 carbazolone and Ondansetron base. A recrystallization pro
ceSS for preparing pure ondansetron hydrochloride dihydrate
(22) Filed: Jan. 11, 2002 with a purity of at least 99.0% is also disclosed.
US 2002/0115707 A1 Aug. 22, 2002

PROCESS FOR PREPARING PURE 0008 Another object of the present invention is to pre
ONDANSETRON HYDROCHLORIDE DIHYDRATE pare pure ondansetron hydrochloride dihydrate Substantially
free of any impurities and by-product Such as 1,2,3,9-
CROSS REFERENCE TO RELATED tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one (e.g.,
APPLICATION the exo-methylene by-product).
0001. This application claims the benefit of Provisional 0009. Another object of the present invention is to pre
Application Ser. No. 60/261,051, filed Jan. 11, 2001, the pare ondansetron hydrochloride dihydrate that has a purity
disclosure of which is incorporated by reference in its of at least about 99.0%. Preferably, the ondansetron hydro
entirety herein. chloride dihydrate has a purity of at least about 99.5%. Most
preferably, the Ondansetron hydrochloride dihydrate has a
FIELD OF THE INVENTION purity of at least about 99.9%.
0002 The present invention relates to an improved pro 0010 Another object of the present invention is to pro
ceSS for preparing dimethylamino-methyl-carbazolone. The vide a process for preparing dimethylamino-methyl-carba
present invention relates to an improved proceSS for prepar Zolone, the proceSS comprising the Steps of:
ing ondansetron base. The present invention also relates to 0011) a) preparing a solution of methyl-carbazolone;
an improved process for recrystallizing Ondansetron hydro
chloride dihydrate to obtain pure ondansetron hydrochloride 0012 b) heating the solution in the presence of
dihydrate. dimethylamino hydrochloride and paraformaldehye;
0013 c) basifying the solution to form a precipitate;
BACKGROUND OF THE INVENTION
0014 d) separating the precipitate from the solution
0.003 Ondansetron, also known as 1,2,3,9-tetrahydro-9- to obtain dimethylamino-methyl-carbazolone; and
methyl-3-(2-methyl-1H-imidazol-1-yl) methyl-4H-carba
Zol-4-One is a potent and highly selective Serotonin (5-HT, 0015 e) drying the dimethylamino-methyl-carba
5-hydroxytrptamine receptor 3) antagonist and has the fol Zolone.
lowing formula: 0016. Another object of the present invention is a process
for preparing ondansetron base, the process comprising the
Steps of
CH
0017 a) preparing a solution of methyl-imidzole
and dimethylamino-methyl-carbazolone;
0018 b) heating the solution;
0.019 c) removing a precipitate containing
CH Ondansetron base;
0020 d) washing the precipitate; and
0004 Ondansetron is currently available as an anti 0021 e) drying the precipitate to obtain pure
emetic agent, particularly in cancer chemotherapy, and in Ondansetron base.
Some other uses Such as anti-depressive, anti-migraine and 0022 Preferably, step e) is followed by recrystallizing the
anti-psychotic. It is commonly used in the alleviation of Ondansetron base in the presence of activated carbon and
cognitive disorders as in Alzheimer disease, in treatment of methanol.
rhinitis, psychiatric disorders and for increased vigilance
and for control of dependence on narcotics. 0023. Another object of the present invention is a process
for preparing ondansetron hydrochloride dihydrate, the pro
0005 U.S. Pat. No. 4,695,578, assigned to the Glaxo ceSS comprising the Steps of
Group Limited, describes a process of preparing
Ondansetron and uses thereof. However, Ondansetron pre 0024 a) preparing a Solution of Ondansetron base;
pared according to Said process contains impurities and
by-products such as 1,2,3,9-tetrahydro-9-methyl-3-methyl 0025 b) acidifying the solution with hydrogen chlo
ene-4H-carbazol-4-One. ride to form a precipitate;
0006 There is a continuing need for improving the 0026 c) washing the precipiate; and
method of preparing ondansetron with high purity that meets 0027 d) crystallizing ondansetron hydrochloride
the Standard for clinical uses. dihydrate.
OBJECTS AND SUMMARY OF THE DETAILED DESCRIPTION OF THE
INVENTION INVENTION
0007. The known methods of preparing ondansetron do 0028. As used herein, the term “exo-methylene by-prod
not achieve a pharmaceutically describe high purity and uct” refers to 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H
color. An object of the present invention is to meet a need in carbazol-4-One. It represents one of the main impurity in
the art for a high purity (i.e., at least about 99.0%) and Ondansetron preparation. Another impurity in Ondansetron
improved color. preparation is dimeric eXO-methylene by-product.
US 2002/0115707 A1 Aug. 22, 2002

0029. Unless otherwise specified, “%” refers to % wt. 0043 e) drying the dimethylamino-methyl-carba
Zolone.
0.030. As used herein, the term “pure ondansetron” refers
to Ondansetron that is Substantially free of eXO-methylene 0044. During the heating step, the solution is heated in
by-product and has a high purity of at least about 99.0%. the presence of dimethylamine hydrochloride and paraform
0.031 AS used herein, the term “hydrogen chloride” aldehyde in an organic Solvent. Preferably, the organic
refers to either a gaseous hydrogen chloride or a Solution of Solvent is acetic acid.
hydrogen chloride gas in water.
0032. As used herein, the term “equivalent” refers to 0045 Preferably, one equivalent methyl-carbazolone is
molar equivalent. refluxed with about 1.1 to about 1.5 equivalents of dimethy
lamine-hydrochloride and paraformaldehyde. Most prefer
0.033 AS used herein, the term “vacuum distillation” ably, one equivalent methyl-carbazolone is refluxed with
refers to the Separation of Solids from liquids by passing the about 1.2 equivalents of dimethylamnine-hydrochloride and
mixture through a vacuum filter. paraformaldehyde. During the heating Step, formaldehyde
0034. As used herein, the term “reflux' refers to during a can be used to Substitute for paraformaldehyde in the reflux
chemical process, part of the product Stream may be returned reaction.
to the process to assist in giving increased conversion or
recovery, as in distillation or liquid-liquid extraction. 0046 Preferably, one equivalent methyl-carbazolone is
refluxed with about 4 to about 16 volumes of acetic acid.
0035. As used herein, the term “filter cake” refers to a Most preferably, one equivalent methyl-carbazolone is
concentrated Solid or Semisolid material that is separated
from a liquid and remains on the filter after pressure filtra refluxed with about 4 volumes of acetic acid.
tion.
0047 Preferably, the heating step is performed at a tem
0.036 The present invention is an improved method of perature of about 70° C. to about 100° C. Most preferably,
preparing a pure ondansetron hydrochloride dihydrate with the heating Step is performed at a temperature of about 80
purity at least 99.0%. More preferably, the ondansetron to about 90° C.
hydrochloride dihydrate purity is at least 99.5%. Most
preferably, the Ondansetron hydrochloride dihydrate purity 0048 Preferably, the heating step is performed for about
is at least 99.9%. 6 to about 24 hours. Most preferably, the heating step is
0037. The present invention provides an improved performed for about 6 to about 12 hours.
method of preparing dimethylamino-methyl-carbazolone.
The present invention further provides an improved method 0049 Preferably, the separating step is performed using
of preparing Ondansetron base. The present invention further filtration.
provides an improved method of preparing pure ondansetron 0050 Preferably, the heating step is performed without
hydrochloride dihydrate.
the use of vacuum distillation or extraction. The heating Step
Preparation of Dimethylamino-Methyl-Carbazolone performed in the absence of vacuum distillation or extrac
tion consistently yields a better pure dimethylamino-methyl
0.038. The present invention provides a process for pre carbazolone.
paring dimethyl amino-methyl-carbazolone comprising the
Steps of: 0051. The present invention also provides a process of
preparing pure dimethylamino-methyl-carbazolone further
0039 a) preparing a solution of methyl-carbazolone comprises dissolving the filter cake in acetone and treating
having the formula: with activated carbon and hydrogen chloride.
0052 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.
0053 Preferably, the dry cake is dissolved in acetone.
Preferably, the dissolved cake is treated with activated
(where R = C14, alkyl) carbon and hydrogen chloride to precipitate dimethylamino
methyl-carbazolone.

0040 b) heating the solution in the presence of Preparation of Ondansetron Base

dimethylamino hydrochloride and paraformalde 0054 The present invention provides a process for the
hyde;
Synthesis of Ondansetron base comprising the Steps of:
0041 c) basifying the solution to form a precipitate; 0055) a) preparing a solution of methyl-imidazole
0042 d) separating the precipitate from the solution and dimethylamino-methyl-carbazolone of the for
to obtain dimethylamino-methyl-carbazolone; and mula
US 2002/0115707 A1 Aug. 22, 2002

0071 d) crystallizing pure ondansetron hydrochlo

ride dihydrate.
0072 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.
0073 Preferably, the acidifying step is achieved by add
(where R = C14, alkyl) ing 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
0056 b) heating the solution; about 32% (v:v) hydrochloric acid is added to induce
precipitation. More preferably, the acidifying Step is
0057 c) removing a precipitate containing contain achieved at a pH about 1 to about 4. Most preferably, the
ing ondasetron base from the Solution; acidifying Step is achieved at a pH about 3.
0.058 d) washing the precipitate; 0074 Preferably, the washing step is achieved by using
0059) e) drying precipitate to obtain ondansetron isopropanol. Preferably, about 5 to about 15 ml of isopro
base. panol is used to wash the precipitates. Most preferably, about
10 ml of isopropanol is used to wash the precipitates.
0060. The present invention further provides a process
for the Synthesis of Substantially pure ondansetron base, 0075 Preferably, the crystallizing step is achieved by
further comprising the Steps of: adding about 3 to about 5 volumes of water to induce
0061 recrystallizing in the presence of activated crystallization. Most preferably, about 4 volumes of water is
carbon and methanol.
used to induce crystallization.
0.062. During the solution preparation step of methyl 0076 Preferably, the crystallizing step is performed in
imidazole and dimethylamino-methyl-carbazolone, about 4 the presence of activated carbon. Preferably, the activated
to about 6 equivalents methyl-imidazole is preferably added carbon is Selected from the group consisting of SX-2, CA-1,
to one equivalent dimethylamino-methyl-carbazolone. Most CXV, and SX-1.
preferably, about 5 equivalents of methyl-imidazole is added 0077 Preferably, the crystallizing step is performed in
to one equivalent dimethylamino-methyl-carbazolone. the presence of about 5 to about 15% SX-1 activated carbon.
0.063 Preferably, the preparation step is performed in the Most preferably, the crystallizing Step is performed in the
presence of 10% celite. presence of about 10% SX-1 activated carbon.
0.064 Preferably, the present invention provides a process 0078. The present invention is further explained by the
for preparing ondansetron base further comprising (after following examples. The present invention is by no means
Step e) a step of recrystallizing ondansetron base in the restricted to these specific examples. One of ordinary skill in
presence of activated carbon and methanol. the art will understand how to vary the exemplified prepa
rations to obtain the desired results.
Crystallization to Prepare Pure Ondansetron
Hydrochloride Dihydrate EXAMPLES
0065. The present invention provides an improved Example 1:
method of preparing a pure ondansetron hydrochloride dihy
drate. Specifically, the preparation involves crystallization Preparation of Pure
of Ondansetron hydrochloride dihydrate from ondansetron Dimethylamino-Methyl-Carbazolone Salt
base with water and activated carbon and in the absence of
an organic Solvent. 0079 Into 180 ml glacial acetic acid 45 gram (0.226
0.066 The crystallization process of the present invention mole, 1.0 eq) of methyl-carbazolone, 22.4 gram (0.275
greatly increases the purity of Ondansetron hydrochloride mole, 1.22 eq) of dimethylamine hydrochloride and 9 gram
dihydrate and dramatically lowers the content of the eXo (0.3 mole, 1.33 eq) of paraformaldehyde were added.
methylene by-product impurity. Preferably, the crystalliza 0080. The reaction was kept at about 80+2 C. during 12
tion step is performed 1-3 times. Most preferably, the hours, then 540 ml of water and 4.5 gram of highflow are
crystallization Step is performed two times. introduced into the reactor, the batch was cooled to about
0067. The present invention provides a method of crys 10° C. and rendered basic with about 45% NaOH to about
tallization of Ondansetron hydrochloride dihydrate compris pH 13 to about 14 while the batch temperature did not
ing the Steps of exceed about 25 C.
0068) a) preparing a Solution of Ondansetron base; 0081. Then the batch was stirred at about 5 to about 10
0069 b) acidifying the solution with hydrogen chlo C. for an additional 1 hour, the precipitate that formed along
ride to form a precipitate; with the highflow were collected and dried in vacuum oven
at about 60° C. until constant weight to obtain crude product
0070) c) washing the precipitate; and containing highflow.
US 2002/0115707 A1 Aug. 22, 2002

0082 The crude product was treated with 3.3 gram What is claimed is:
activated carbon type SX-1 (by NORIT) in 990 ml acetone, 1. Ondansetron hydrochloride dihydrate having a purity
filtered, cooled to about 25 C. and hydrochloric acid was of at least 99.0%.
bubbled through the acetone solution until pH was about 3, 2. Ondansetron hydrochloride dihydrate having a purity
the batch was cooled to about 0 to about 5 C., kept at this of at least 99.5%.
temperature for half an hour, filtered, washed with about 20 3. Ondansetron hydrochloride dihydrate having a purity
ml acetone and dried in an oven at about 50 C. until of at least 99.9%.
constant weight to give 49.6 gram dimethylamino-methyl 4. A proceSS for preparing dimethylamino-methyl-carba
carbozolone-HCl.
Zolone comprising the Steps of:
Example 2: a) preparing a Solution of methyl-carbazolone having the
formula:
Preparation of Pure Ondansetron Base
0083) Into 330 ml water 33 gram (0.112 mole, 1 eq.)
dimethylamino-methyl-carbozolone-HCl, 3.3 gram high
flow, 46.3 gram (0.563 mole, 5 eq) methyl-imidazole were
added.
0084. The reaction was heated at reflux during 12 hours
and cooled to about 5 to about 10 C., the precipitate was
filtered, washed with 3x300 ml water and dried in a vacuum
oven at about 60° C. until constant weight to give crude (where R = C14, alkyl)
compound containing highflow.
0085. The crude compound was treated with 1.5 gram
activated carbon type SX-1 (by NORIT) in 930 ml methanol, b) heating the Solution in the presence of dimethylamine
filtered (hot filtration) from the highflow and activated hydrochloride and paraformaldehyde;
carbon and crystallized at 0 to about 5 C. during one hour.
Hot filtration was around 60° C. and was done with metha c) basifying the Solution to form a precipitate;
nol near its boiling point (i.e. 65 C.). The precipitate was d) Separating the precipitate from the Solution;
collected by filtration, washed with 2x20 ml cold methanol
and dried in vacuum oven at about 60° C. until constant e) drying the precipitate.
weight to give 21.3 gram ondansetron-base. 5. The process according to claim 4, wherein R is methyl.
Example 3: 6. The process according to claim 4, wherein the heating
step is performed at a temperature of about 70° C. to about
Preparation of Pure Ondansetron Hydrochloride 100° C.
Dihydrate 7. The process according to claim 4, wherein the heating
step is performed at a temperature of about 80° C. to about
0.086 Into 100 ml of water 20 gram ondansetron-base 90° C.
were introduced. To the stirred suspension 7.5 ml (1.1 8. The process according to claim 4, wherein the heating
equivalents) of about 32% hydrochloric acid (HCl) was step is performed for about 6 to about 24 hours.
added. A Slightly exothermic reaction occurred, the Suspen 9. The process according to claim 4, wherein the heating
Sion turned almost clear and a precipitate began to form. step is performed for about 6 to about 12 hours.
0087. The reaction was cooled down and kept at about 10. The process according to claim 4, wherein the heating
3-5 C. for an additional 1 hour filtered, washed, with about Step is performed in acetic acid.
10 ml cold isopropanol and dried at about 50° C. under 11. The process according to claim 4, wherein about one
WCUU. equivalent methyl-carbazolone is heated in the presence of
about 1.1 to about 1.5 equivalents of dimethylamine hydro
Example 4: chloride and paraformaldehyde.
12. The proceSS according to claim 4, wherein about one
Recrystallization of Ondansetron Hydrochloride equivalent methyl-carbazolone is heated in the presence of
Dihydrate about 1.2 equivalents of dimethylamine hydrochloride and
0088 Ondansetron-HC1-2HO was crystallized twice formaldehyde.
from 1:4 w/v water and about 10% w/w activated carbon 13. The proceSS according to claim 4, wherein about one
type SX-1 (by NORIT) at about 95°C. during half an hour, equivalent methyl-carbazolone is heated in the presence of
filtered (hot filtration), washed with 1 volume of hot water, about 1.1 to about 1.5 equivalents of dimethylamine hydro
cooled to about 5 C. and kept at this temperature for about chloride and formaldehyde.
1 hour. The crystals was collected, washed with about 10 ml 14. The proceSS according to claim 4, wherein about one
cold isopropanol and dried to give pure ondansetron-HCl equivalent methyl-carbazolone is heated in the presence of
2HO. The obtained pure ondansetron hydrochloride dihy about 1.2 equivalents of dimethylamine hydrochloride and
drate was determined by HPLC to be at least greater than formaldehyde.
99.0%. The obtained pure ondansetron hydrochloride dihy 15. The proceSS according to claim 4, wherein about one
drate contained less than 0.01% exo-methylene by-product equivalent methyl-carbazolone is heated in the presence of
or undetectable. about 4 to about 6 volumes of acetic acid.
US 2002/0115707 A1 Aug. 22, 2002

16. The proceSS according to claim 4, wherein about one 28. The process according to claim 26 wherein about 5
equivalent methyl-carbazolone is heated in the presence of Volumes of water is added to Ondansetron base to prepare a
about 4 volumes of acetic acid. Solution of Ondansetron base.
17. The process according to claim 4, wherein the Solution 29. The process according to claim 26 wherein about 1.0
of methyl-carbazolone is basified by about 45% sodium to about 1.4 equivalents of about 32% (v:v) hydrochloric
hydroxide. acid is added to acidify the Solution to induce precipitation.
18. The process according to claim 17, wherein the 30. The process according to claim 26 wherein about 1.1
solution is basified to a pH of about 13 to about 14. equivalents of about 32% (v:v) hydrochloric acid is added to
19. The process according to claim 17 or 18, wherein the acidify the Solution to induce precipitation.
basifying Step is performed in the presence of 10% celite. 31. The process of claims 29 or 30, wherein the solution
20. A process for preparing ondansetron base, comprising is acidified to a pH about 1 to about 4.
the Steps of: 32. The process of claims 29 or 30, wherein the solution
a) preparing a Solution of methyl-imidazole and dimethy is acidified to a pH about 3.
lamino-methyl-carbazolone of the formula 33. The process according to claim 26, wherein the
precipitate is washed with about 5 to about 15 ml of
isopropanol.
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
(where R = C14, alkyl) 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
b) heating the Solution; crystallizing Step is achieved in the presence of activated
c) removing a precipitate containing ondasetron base from carbon.
the Solution; 39. The process according to claim 36, wherein the
d) washing the precipitate; activated carbon is Selected from the group consisting of
SX-2, CA-1, CXV and SX-1.
e) drying precipitate to obtain ondansetron base. 40. The process according to claim 39, wherein the
21. The process according to claim 20, wherein the activated carbon is about 5 to about 15% SX-1.
Solution is prepared by adding about 4 to about 6 equivalents 41. The process according to claim 39, wherein the
methyl-imidazole to one equivalent dimethylamino-methyl activated carbon is about 5 to about 10%. SX-1.
carbazolone. 42. Ondansetron hydrochloride dihydrate as prepared in
22. The process according to claim 20, wherein the accordance with a process of claim 26, wherein the
Solution is prepared by adding about 5 equivalents methyl Ondansetron hydrochloride dihydrate has a purity of at least
imidazole to one equivalent dimethylamino-methyl-carba about 99.0%.
Zolone. 43. Ondansetron hydrochloride dihydrate as prepared in
23. The process according to claim 20, wherein the accordance with a process of claim 26, wherein the
Solution is prepared in the presence of 10% celite. Ondansetron hydrochloride dihydrate have a purity of at least
24. The process according to claim 20, further comprising about 99.5%.
the step of: 44. Ondansetron hydrochloride dihydrate as prepared in
recrystallizing ondansetron base. accordance with a process of claim 26, wherein the
25. The process according to claim 24, wherein the Ondansetron hydrochloride dihydrate has a purity of at least
recrystallizing Step is performed in the presence of activated about 99.9%.
carbon and methanol. 45. A pharmaceutical formulation comprising
26. A process of preparing pure ondansetron hydrochlo Ondansetron hydrochloride dihydrate as prepared in accor
ride dihydrate comprising the Steps of: dance with a process of claim 26, wherein the Ondansetron
hydrochloride dihydrate has a purity of at least about 99.0%.
a) preparing a Solution of Ondansetron base; 46. A pharmaceutical formulation comprising
b) acidifying the solution with hydrogen chloride to form Ondansetron hydrochloride dihydrate as prepared in accor
a precipitate; dance with a process of claim 26, wherein the Ondansetron
hydrochloride dihydrate has a purity of at least about 99.5%.
c) washing the precipitate; and 47. A pharmaceutical formulation comprising
d) crystallizing pure ondansetron hydrochloride dihy Ondansetron hydrochloride dihydrate as prepared in accor
drate. dance with a process of claim 26, wherein the Ondansetron
27. The process according to claim 26 wherein about 3 to hydrochloride dihydrate has a purity of at least about 99.9%.
about 7 volumes of water is added to ondansetron base to
prepare a Solution of Ondansetron base. k k k k k