U.S. patent application number 11/285995 was filed with the patent office on 2006-04-06 for process for the preparation of citalopram.
This patent application is currently assigned to Pharmachem Technologies Limited. Invention is credited to Olivier Dapremont, DerShing Huang, Aslam A. Malik, Hasan Palandoken, Antonio Romero, Joy A. Stringer.
Application Number | 20060074253 11/285995 |
Document ID | / |
Family ID | 26935001 |
Filed Date | 2006-04-06 |
United States Patent
Application |
20060074253 |
Kind Code |
A1 |
Malik; Aslam A. ; et
al. |
April 6, 2006 |
Process for the preparation of citalopram
Abstract
The present invention provides, inter alia, a novel process for
the preparation of Citalopram, a known antidepressant.
Inventors: |
Malik; Aslam A.; (Cameron
Park, CA) ; Palandoken; Hasan; (Woodland, CA)
; Stringer; Joy A.; (West Sacramento, CA) ; Huang;
DerShing; (Folsom, CA) ; Romero; Antonio;
(Irvine, CA) ; Dapremont; Olivier; (Folsom,
CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Pharmachem Technologies
Limited
Bristol
GB
|
Family ID: |
26935001 |
Appl. No.: |
11/285995 |
Filed: |
November 22, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10242322 |
Sep 11, 2002 |
6967259 |
|
|
11285995 |
Nov 22, 2005 |
|
|
|
60324821 |
Sep 24, 2001 |
|
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|
Current U.S.
Class: |
549/467 |
Current CPC
Class: |
C07D 307/87 20130101;
A61P 25/24 20180101 |
Class at
Publication: |
549/467 |
International
Class: |
C07D 307/87 20060101
C07D307/87 |
Claims
1. A method for preparing a compound of Formula IV having the
following structure: ##STR15## said method comprising: (a)
contacting a salt of the compound of Formula III having the
following structure: ##STR16## with about 2 to about 10 equivalents
of phosphoric acid to form a reaction mixture; (b) adding an
organic solvent to said reaction mixture; and (c) quenching said
reaction mixture with base to form a product mixture comprising
said compound of Formula IV.
2. The method of claim 1, wherein said salt of the compound of
Formula III is a HCl salt.
3. The method of claim 1, wherein said phosphoric acid is 20%
phosphoric acid.
4. The method of claim 1, wherein said compound of Formula III is
contacted with about 6 to about 9 equivalents of 20% phosphoric
acid.
5. The method of claim 1, wherein said compound of Formula III is
contacted with about 9 equivalents of 20% phosphoric acid.
6. The method of claim 1, wherein said organic solvent in step (b)
is a member selected from the group consisting of toluene, benzene,
xylene, diethylether, t-butylmethylether, dioxane, and mixtures
thereof.
7. The method of claim 1, wherein said organic solvent in step (b)
is toluene.
8. The method of claim 1, wherein said base is a member selected
from the group consisting of ammonium hydroxide, sodium hydroxide
and potassium hydroxide.
9. The method of claim 1, wherein said base is aqueous ammonium
hydroxide.
10. The method of claim 1, further comprising: (c) isolating said
compound of Formula IV from said product mixture.
11. The method of claim 10, wherein step (c) comprises: (i)
separating the organic phase and the aqueous phase; (ii)
re-extracting the aqueous phase with toluene; (iii) combining the
organic phases to form a combined organic phase and washing said
combined organic phase with water; and (iv) distilling said washed
organic phase to obtain the compound of Formula IV.
12. A method for preparing a compound of Formula V having the
following structure: ##STR17## said method comprising: (a)
contacting a compound of Formula IV having the following structure:
##STR18## with a mixture of cuprous cyanide and sodium cyanide to
form a reaction mixture; (b) heating said reaction mixture until
the reaction is complete; and (c) quenching said reaction mixture
to form a product mixture comprising said compound of Formula
V.
13. The method of claim 12, wherein said compound of Formula IV is
in a first organic solvent.
14. The method of claim 13, wherein said first organic solvent is a
member selected from the group consisting of toluene, benzene,
xylene, diethylether, t-butylmethylether, dioxane, and mixtures
thereof.
15. The method of claim 14, wherein said first organic solvent is
toluene.
16. The method of claim 12, wherein said mixture of cuprous cyanide
and sodium cyanide is in a second organic solvent.
17. The method of claim 16, wherein said second organic solvent is
a member selected from the group consisting of
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidione,
quinoline, collidine, xylene, dimethylsulfone,
hexamethylphosphoramide and trifluoromethylchlorobenzene.
18. The method of claim 16, wherein said second organic solvent is
N,N-dimethylformamide.
19. The method of claim 12, wherein the ratio of cuprous
cyanide:sodium cyanide in said mixture of cuprous cyanide and
sodium cyanide is about 2.5:1.0 to about 1:2.5.
20. The method of claim 12, wherein the ratio of cuprous
cyanide:sodium cyanide in said mixture of cuprous cyanide and
sodium cyanide is about 0.50:1.0 to about 2.5:1.
21. The method of claim 12, wherein the ratio of cuprous
cyanide:sodium cyanide in said mixture of cuprous cyanide and
sodium cyanide is about 0.75:1.0 to about 1.0:1.0.
22. The method of claim 13, wherein said first organic solvent is
removed from said reaction mixture prior to step (b).
23. The method of claim 12, wherein said reaction mixture is
quenched with a member selected from the group consisting of
aqueous sodium cyanide and aqueous potassium cyanide.
24. The method of claim 20, wherein said reaction mixture is
quenched with 10% aqueous sodium cyanide.
25. The method of claim 12, further comprising: (d) isolating said
compound of Formula V from said product mixture.
26. The method of claim 21, wherein step (d) comprises: (i) adding
ethylenediamine and a first organic solvent to said reaction
mixture and separating the organic phase and the aqueous phase;
(ii) re-extracting the aqueous phase with said first organic
solvent; (iii) combining the organic phases to form a combined
organic phase and back-extracting the combined organic phase with
an acid to form an acid extract; (iv) neutralizing said acid
extract with a base to a pH of about 8.5 to about 11 to form a
neutralized extract; (v) extracting said neutralized extract with a
second organic solvent to form a second organic solvent extract;
(vi) treating said second organic solvent extract with charcoal and
removing said second organic solvent to generate the compound of
Formula V.
27. The method of claim 26, wherein said first and second organic
solvents are independently selected from the group consisting of
toluene, benzene, xylene, diethylether, t-butylmethylether,
dioxane, and mixtures thereof.
28. The method of claim 27, wherein said first and second organic
solvents are both toluene.
29. The method of claim 26, wherein said acid in step (iii) is a
member selected from the group consisting of HCl, HBr,
H.sub.2SO.sub.4, H.sub.3PO.sub.4, trifluoroacetic acid and acetic
acid.
30. The method of claim 29, wherein said acid in step (iii) is 20%
aqueous acetic acid.
31. The method of claim 26, wherein said base in step (iv) is a
member selected from the group consisting of sodium hydroxide,
potassium hydroxide and sodium carbonate.
32. The method of claim 26, wherein said base in step (iv) is
sodium hydroxide.
33. The method of claim 26, wherein in step (iv) said acid extract
is neutralized with said base to a pH of about 9 to about 10.
34. The method of claim 26, wherein said compound of Formula V is
further purified using simulated moving bed chromatography having a
stationary phase and a mobile phase.
35. The method of claim 34, wherein the stationary phase is a
reverse phase silica gel and the mobile phase is an organic
solvent/water mixture.
36. The method of claim 35, wherein said reverse phase silica gel
is a C.sub.18-derivatized silica gel.
37. The method of claim 35, wherein the pH of the mobile phase is
about 1.5 to about 4.0.
38. The method of claim 37, wherein the pH of the mobile phase is
about 2.5.
39. The method of claim 37, wherein the pH of the mobile phase is
maintained by the addition of 0.1 to 2% trifluoroacetic acid.
40. The method of claim 35, wherein said organic solvent in the
mobile phase is methanol.
41. The method of claim 35, wherein said organic solvent in the
mobile phase is ethanol.
42. The method of claim 35, wherein said organic solvent in the
mobile phase is acetonitrile.
43. The method of claim 34, wherein the stationary phase is a
normal phase silica gel and the mobile phase is an organic solvent
mixture.
44. The method of claim 42, wherein said organic solvent mixture is
a mixture of an alcohol, a hydrocarbon and an organic base.
45. The method of claim 43, wherein said alcohol is a member
selected from the group consisting of methanol, ethanol, n-propanol
and isopropanol.
46. The method of claim 43, wherein said hydrocarbon is a member
selected from the group consisting of heptane, n-heptane, hexane,
isohexane, toluene, cyclohexane, benzene and combinations
thereof.
47. The method of claim 43, wherein said organic base is a member
selected from the group consisting of triethylamine, diethylamine,
trimethylamine, dimethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine and
diethylisopropylamine.
48. The method of claim 43, wherein said organic base is present in
said organic solvent mixture at about 0.05 to about 5%.
49. The method of claim 48, wherein said organic base is present in
said organic solvent mixture at about 0.1 to about 0.5%.
50. The method of claim 48, wherein said organic base is present in
said organic solvent mixture at about 0.2 to about 0.4%.
51. The method of claim 43, wherein said organic solvent mixture is
a mixture of ethanol, heptane and triethylamine.
52. The method of claim 34, wherein the stationary phase is a
chiral phase silica gel and the mobile phase is an organic solvent
mixture.
53. The method of claim 52, wherein said organic solvent mixture is
a mixture of an alcohol, a hydrocarbon and an organic base.
54. The method of claim 53, wherein said alcohol is a member
selected from the group consisting of methanol, ethanol, n-propanol
and isopropanol.
55. The method of claim 53, wherein said hydrocarbon is a member
selected from the group consisting of heptane, n-heptane, hexane,
isohexane, toluene, cyclohexane, benzene and combinations
thereof.
56. The method of claim 53, wherein said organic base is a member
selected from the group consisting of triethylamine, diethylamine,
trimethylamine, dimethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine and
diethylisopropylamine.
57. The method of claim 53, wherein said organic base is present in
said organic solvent mixture at about 0.05 to about 5%.
58. The method of claim 57, wherein said organic base is present in
said organic solvent mixture at about 0.1 to about 0.5%.
59. The method of claim 57, wherein said organic base is present in
said organic solvent mixture at about 0.2 to about 0.4%.
60. The method of claim 26, wherein said compound of Formula V is
further purified using single column chromatography having a
stationary phase and a mobile phase.
61. A method for preparing a compound of Formula VI having the
following structure: ##STR19## said method comprising: (a)
dissolving a compound of Formula V having the following structure:
##STR20## in an organic solvent to form a reaction mixture; and (b)
contacting said reaction mixture with HBr to form a product mixture
comprising said compound of Formula VI.
62. The method of claim 50, wherein said organic solvent in step
(a) is a member selected from the group consisting of acetone,
methylethylketone, ethylacetate, toluene, benzene, xylene,
diethylether, t-butylmethylether, dioxane, and mixtures
thereof.
63. The method of claim 51, wherein said organic solvent in step
(a) is diethylether.
64. The method of claim 51, wherein said organic solvent in step
(a) is acetone.
65. The method of claim 51, wherein said HBr is gaseous HBr.
66. The method of claim 51, wherein said HBr is aqueous HBr.
67. The method of claim 50, further comprising: (c) isolating said
compound of Formula VI from said product mixture.
68. The method of claim 50, wherein step (c) comprises: (i) cooling
the product mixture and filtering said product mixture to obtain
the compound of Formula VI as a precipitated solid; (ii) washing
said precipitated solid with an organic solvent; and (iii) drying
said precipitated solid to obtain the compound of Formula VI.
69. The method of claim 55, further comprising (iv) recrystallizing
the compound of Formula VI.
70. The method of claim 56, wherein said compound of Formula VI is
recrystallized from a solvent mixture of toluene and methanol.
71. The method of claim 56, wherein step (iv) comprises: (i')
combining said precipitated solid with toluene and methanol to form
a mixture and heating said mixture; (ii') filtering said mixture
through Celite and slowly cooling said mixture; (iii') filtering
said mixture to obtain the crystallized solid, washing the
crystallized solid with toluene, and drying said crystallized solid
to obtain the compound of Formula VI.
72. The method of claim 58, wherein in step (ii') said mixture is
cooled to about ambient temperature.
73. The method of claim 58, wherein in step (ii') said mixture is
cooled to about 0.degree. C. to about 5.degree. C.
74. The method of claim 56, wherein step (iv) comprises: (i')
combining said precipitated solid with methanol and
isopropylalcohol to form a mixture and heating said mixture; (ii')
filtering said mixture through Celite and slowly cooling said
mixture; (iii') filtering said mixture to obtain the crystallized
solid, washing the crystallized solid with isopropylalcohol, and
drying said crystallized solid to obtain the compound of Formula
VI.
75. A method for removing demethyl- and/or didemethyl-impurities
from a mixture of Citalopram containing demethyl- and/or didemethyl
impurities in a solvent, said method comprising: (a) contacting
said mixture of Citalopram with a scavenger resin having a
functional group that is reactive with a primary or secondary amine
to form resin-bound demethyl- and/or didemethyl impurities, wherein
said scavenger resin is insoluble in said solvent; and (b)
filtering said resin-bound demethyl- and/or didemethyl-impurities,
thereby removing said demethyl and/or didemethyl-impurities from
said mixture of Citalopram.
76. The method of claim 75, wherein said functional group is a
member selected from the group consisting of isocyanates,
isothiocyanates, acid chlorides, esters and anhydrides.
77. The method of claim 75, wherein said scavenger resin is a
polystene-based resin.
78. The method of claim 75, wherein said scavenger resin is a
silica gel-based resin.
79. The method of claim 77, wherein said polystene-based resin has
the following structure: ##STR21## wherein R is a member selected
from the group consisting of isocyanates, isothiocyanates, acid
chlorides, esters and anhydrides.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application claims priority to U.S. Provisional
Patent Application No. 60/324,821, filed Sep. 24, 2001, the
teachings of which are incorporated herein by reference for all
purposes.
BACKGROUND OF THE INVENTION
[0002] Citalopram is an antidepressant drug that is widely used in
both the United States and Europe. Its mode of action and activity
have been described in various publications. The active ingredient
is an HBr or oxalate salt, preferably an HBr salt. Citalopram has
the following structure: ##STR1##
[0003] Several processes have been described in the literature for
preparing Citalopram (see, Drugs of Future, 25(6):620 (2000).
Citalopram was first disclosed in German Patent 2,657,271, which is
the German equivalent of now expired U.S. Pat. No. 4,136,193. In
this patent, 5-bromophthalide (5-BP) was converted via a five-step
reaction sequence to Citalopram. This route for preparing
Citalopram is depicted in FIG. 1, and constitutes the basis of
several patents and patent applications.
[0004] Attempts to reproduce the process described in U.S. Pat. No.
4,136,193 for the preparation of Citalopram in the quality
specifications required for its use in pharmaceutical applications
have been unsuccessful. It is noted that the quality specifications
for pharmaceutical quality Citalopram are extremely stringent and
require material with purity in excess of 99.7%. Difficulty
encountered in manufacturing Citalopram of the required purity by
the process described in German Patent No. 2,657,013, U.S. Pat. No.
4,136,193 and PCT International Publication Nos. WO 00/11926 and WO
00/13648 was recently described by Lundbeck in WO 01/45483 A2 (see,
page 2, line 26).
[0005] Following is the detailed description of the process
described in U.S. Pat. No. 4,136,193. It is noted that the
experimental process described in U.S. Pat. No. 5 4,136,193 is for
the 4-chlorophenyl analog, but it is noted therein that the process
is applicable to the 4-fluorophenyl derivative as well. As
illustrated in FIG. 1, the process described in U.S. Pat. No.
4,136,193 involves a 5-step conversion of 5-bromophthalide to
Citalopram.
[0006] In the first step, a compound of Formula I ("5-BP") is
reacted with p-fluorophenyl-magnesium halide; in the second step,
the intermediate of a compound of Formula II is isolated and
reacted with N,N-dimethylaminopropylmagnesium halide to give the
diol of Formula III ("Br-Diol"). The Grignard reaction is conducted
in traditional solvents, such as diethyl ether and THF.
Unfortunately, the work-up is very complex and involves excessive
handling of a flammable liquid, i.e., diethyl ether. The work-up
involves the following steps: [0007] The reaction mixture is
quenched into ice water; [0008] An aqueous saturated ammonium
chloride solution is added; [0009] The mixture is extracted with
diethyl ether; [0010] The ether phase is then extracted with 20%
aqueous acetic acid; [0011] The acid phase is made alkaline with 10
N aqueous sodium hydroxide; [0012] The aqueous phase is extracted
with diethyl ether (2.times.); [0013] The combined ethereal
extracts are dried over anhydrous K.sub.2CO.sub.3; [0014] The ether
extract is treated with activated carbon; and [0015] The solvent is
evaporated in vacuum to give Br-Diol, an oil.
[0016] The above work-up process is very laborious and is not
suited for large-scale production. Again, it involves the excessive
handling of flammable solvents, such as diethyl ether, and it
involves numerous unit operations, thereby reducing productivity.
Moreover, it is noted that Br-Diol is isolated as the free amine
and is an oil. The physical characteristics of Br-Diol are
important. Since Br-Diol is an oil, it cannot be isolated as a
crystalline solid and, thus, it cannot be purified by techniques
such as crystallization/recrystallization. Purification of this oil
by crystallization or similar techniques is not described. It is
believed that this is one of the major reasons why the process
described in U.S. Pat. No. 4,136,193 fails to provide Citalopram in
the quality, i.e., purity, required for drug applications. In
addition, in order to meet the tight specifications for Citalopram,
it is critical that purity is established at this stage.
[0017] In step three, Br-Diol is subjected to a ring closure
reaction with 60% aqueous phosphoric acid. In a typical reaction,
5-bromophthalide is heated with excess (30 equivalents) 60% aqueous
phosphoric acid for 3 h and then neutralized with saturated aqueous
ammonia. The resulting mixture is then extracted with diethyl
ether, and the ether extract is dried over potassium carbonate. The
ether extract is then treated with activated charcoal and stripped
of solvent under reduced pressure to give the compound of Formula
IV ("5-Br").
[0018] As mentioned above, step three employs a large excess of 60%
aqueous phosphoric acid. This is troublesome because on reaction
completion excess phosphoric acid has to be neutralized with
ammonia. Neutralization is an extremely exothermic process and heat
management becomes a major issue in the commercial-scale production
of this material. In addition, the use of such a large excess of
phosphoric acid increases the cost of commercial scale operations
due to the use of excess reagents, longer cycle times and reduced
loading. Moreover, from a safety point of view, the use of
flammable solvents, such as diethyl ether, is discouraged for the
commercial-scale production of organic compounds.
[0019] In step four, 5-Br is reacted with cuprous cyanide in DMF to
give, after the work-up, Citalopram. The reaction conditions and
work-up for the process described in U.S. Pat. No. 4,136,193 is as
follows: [0020] 5-Br is reacted with CuCN in DMF at reflux for 4 h;
[0021] The reaction mixture is cooled to 55.degree. C. and quenched
into an aqueous solution of ethylene diamine; [0022] The oily layer
is separated and the aqueous layer is extracted with benzene;
[0023] The combined organic phases are washed with 10% aqueous
sodium cyanide; [0024] The organic layer is dried, treated with
activated carbon, and concentrated under vacuum to give an oil;
[0025] The oil is dissolved in ether and extracted with aqueous
acetic acid; [0026] The acetic acid layer is made alkaline with 10
N aqueous sodium hydroxide and extracted with ether; and [0027] The
ethereal extract is dried over K.sub.2CO.sub.3, treated with
activated charcoal, and stripped of solvent to give Citalopram.
[0028] Unfortunately, there are numerous problems with step four.
First, the reaction does not go to completion in 4 h; in reality,
conversion after 4 h is <10%. Removal 5 of unreacted 5-Br is
difficult and normal purification techniques, such as extraction,
crystallization, etc., are not effective. When the reaction is
pushed to achieve higher conversion, formation of numerous
unidentified side-products is observed. In short, the process
described in U.S. Pat. No. 4,136,193 does not work to provide
acceptable quality Citalopram. Moreover, the work-up is laborious
and involves the use of undesirable solvents such as benzene and
diethyl ether.
[0029] In the fifth and final step of the process described in U.S.
Pat. No. 4,136,193, Citalopram is converted to Citalopram-HBr or
the oxalate salt in the conventional manner-a process is not
described for this conversion.
[0030] Another route for the preparation of Citalopram has been
described in U.S. Pat. No. 4,650,884. This process is based on
5-cyanophthalide ("5-CN"). In this process, 5-CN is reacted with
4-fluorophenylmagnesium halide and N,N-dimethylaminopropylmagnesium
halide to give the corresponding hydroxy intermediate that is then
dehydrated with sulfuric acid to give Citalopram.
[0031] Although a number of processes have been described for the
preparation of Citalopram, there remains a need in the art for
additional processes that can be prepared in high yield, at the
quality specifications required for use in pharmaceutical
applications and without the limitations of the prior art method
disclosed in now expired U.S. Pat. No. 4,136,193. Quite
surprisingly, the present invention fulfills these and other
needs.
SUMMARY OF THE INVENTION
[0032] The present invention provides a novel process for the
preparation of Citaopram and, in particular, Citalopram.HBr. Using
the process of the present invention, Citalopram.HBr can be readily
prepared in high yields, at the quality specifications required for
use in pharmaceutical applications (i.e., greater than 99.7% pure)
and without the limitations of the prior art methods.
[0033] Other features, objects and advantages of the invention and
its preferred embodiments will become apparent from the detailed
description which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 illustrates a prior art process used to prepare
Citalopram. This process was originally disclosed in now expired
U.S. Pat. No. 4,136,193.
[0035] FIG. 2 illustrates a process in accordance with one aspect
of the present invention that can be used to prepare Citalopram in
high yield and at the quality specifications required for use in
pharmaceutical applications.
[0036] FIG. 3 illustrates an example of a feed composition to be
purified.
[0037] FIGS. 4 illustrates that the product contained in the
extract, i.e., the recovered extract, does not contain any
detectable amounts of 5-Br.
[0038] FIG. 5 illustrates the recovered raffinate.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0039] The present invention provides a process for the preparation
of Citalopram and, in particular, Citalopram.HBr. FIG. 2
illustrates an exemplary process for the preparation of
Citalopram.HBr in accordance with the present invention.
[0040] As illustrated in FIG. 1, the present invention provides a
salt of the compound of Formula III, which can be isolated as a
crystalline material, and a novel, simplified process for preparing
such salt. The ability to isolate a salt of the compound of Formula
III allows one to set the purity at this step by allowing one to
get rid of impurities that would otherwise be carried through the
process, making it impossible to prepare high quality
Citalopram.
[0041] As such, in one embodiment, the present invention provides a
crystalline salt of the compound of Formula III having the
following structure: ##STR2## In a presently preferred embodiment,
the crystalline salt is an acid salt. Suitable acid salts include,
but are not limited to, a HCl salt, a HBr salt, a H.sub.2SO.sub.4
salt, a H.sub.3PO.sub.4 salt, a methanesulfonic acid salt, a
trifluoroacetic acid salt, an acetic acid salt, a fumaric acid salt
and a citric acid salt. In a presently preferred embodiment, the
crystalline salt is an HCl salt having the following structure:
##STR3##
[0042] In another aspect, the present invention provides a method
for preparing the salt of the compound of Formula III, the process
comprising: (a) contacting a compound of Formula I having the
following structure: ##STR4## with 4-fluorophenyl magnesium bromide
to form an intermediate of Formula II having the following
structure: ##STR5## (b) contacting the intermediate of Formula II
with dimethylaminopropyl magnesium chloride in an organic solvent
to form a reaction mixture; and (c) quenching the reaction mixture
with an acid to form a product mixture comprising the salt of the
compound of Formula III. In one embodiment of the above process,
the crystalline salt is an acid salt. Suitable acid salts include,
but are not limited to, a HCl salt, a HBr salt, a H.sub.2SO.sub.4
salt, a H.sub.3PO.sub.4 salt, a methanesulfonic acid salt, a
trifluoroacetic acid salt, an acetic acid salt, a fumaric acid salt
and a citric acid salt. In a presently preferred embodiment, the
crystalline salt is an HCl salt having the following structure:
##STR6## In connection with this particular embodiment, it has been
surprisingly found that depending on the isolation and
recrystallization procedures used to isolate the HCl salt of the
compound of Formula III, different polymorphs are obtained. For
instance, the crude HCl salt of the compound of Formula III,
isolated from a mixture of THF/toluene/aqueous HCl has one melting
point, whereas the crude HCl salt of the compound of Formula III
recrystallized from butanol has a second melting point.
[0043] As such, in one embodiment, the acid used in step (c) is a
member selected from the group consisting of HCl, HBr,
H.sub.2SO.sub.4, H.sub.3PO.sub.4, methanesulfonic acid,
trifluoroacetic acid, acetic acid, fumaric acid and citric acid.
Again, in a preferred embodiment, the acid is aqueous HCl.
[0044] In one embodiment, the solvent used in step (b) is an
organic solvent.
[0045] Suitable organic solvents include, but are not limited to,
diethylether, t-butylmethylether, THF, dioxane, toluene, xylene and
mixtures thereof. In a preferred embodiment, the organic solvent
used in step (b) is a mixture of THF and toluene.
[0046] In a preferred embodiment, the above method further
comprises: (d) isolating the salt of the compound of Formula III
from the product mixture. In one embodiment, step (d) comprises:
(i) filtering the product mixture to obtain the salt of the
compound of Formula III. In another embodiment, step (d) further
comprises: (ii) washing the salt of the compound of Formula III
with water and toluene. In yet another embodiment, step (d) further
comprises: (iii) recrystallizing the salt of the compound of
Formula III from a member selected from the group consisting of
1-butanol, 2-butanol and water. In a preferred embodiment, the salt
of the compound of Formula III is recrystallized from
2-butanol.
[0047] In another aspect, the present invention provides a method
for preparing a compound of Formula IV having the following
structure: ##STR7## the method comprising: (a) contacting a salt of
the compound of Formula III having the following structure:
##STR8## with about 2 to about 10 equivalents of phosphoric acid to
form a reaction mixture; (b) adding an organic solvent to said
reaction mixture; and (c) quenching said reaction mixture with base
to form a product mixture comprising said compound of Formula
IV.
[0048] With respect to this method, the patent literature (e.g.,
U.S. Pat. No. 4,136,193) teaches that an excess of 60% phosphoric
acid (.about.30 equivalents) is required in order to achieve ring
closure. However, it has now been surprisingly found that ring
closure can be achieved with significantly fewer equivalents of
phosphoric acid (e.g., about 2 to about 10 equivalents). This
finding gives rise to a purer product and numerous other
advantages. For instance, one of the problems associated with the
process disclosed in U.S. Pat. No. 4,136,193 for making Citalopram
is neutralization of excess phosphoric acid with ammonia. As
expected, this reaction is very exothermic and takes a long time to
neutralize the reaction mixture. Long neutralization time equates
to longer cycle time, which in turn means lower productivity. Since
fewer equivalents of phosphoric acid are used and the amount of
ammonia needed to quench the excess phosphoric acid is reduced, the
overall batch size is higher than the normal batch size by nearly
20%. As such, the method of the present invention provides purer
product, is more suited for commercial scale production, and has
much higher productivity.
[0049] In one embodiment, the salt of the compound of Formula III
is a HCl salt. In another embodiment, the phosphoric acid is about
20% to about 60% phosphoric acid. In a preferred embodiment, the
compound of Formula III is contacted with about 6 to about 9
equivalents of 20% phosphoric acid. In another preferred
embodiment, the compound of Formula III is contacted with about 9
equivalents of 20% phosphoric acid. It will be readily apparent to
those of skill in the art that other acids can be used in place of
phosphoric acid. Suitable acids include, but are not limited to,
HCl, HBr, sulfuric acid, trifluoroacetic acid,and methane sulfonic
acid, etc.
[0050] In another embodiment, the organic solvent in step (b) is a
member selected from the group consisting of toluene, benzene,
xylene, diethylether, t-butylmethylether, dioxane, and mixtures
thereof. In a preferred embodiment, the organic solvent in step (b)
is toluene.
[0051] In another embodiment, the base is a member selected from
the group consisting of ammonium hydroxide, sodium hydroxide and
potassium hydroxide. In a presently preferred embodiment, the base
is aqueous ammonium hydroxide.
[0052] In a preferred embodiment, the above method further
comprises: (c) isolating the compound of Formula IV from the
product mixture. In one embodiment, step (c) comprises: (i)
separating the organic phase and the aqueous phase; (ii)
re-extracting the aqueous phase with toluene; (iii) combining the
organic phases to form a combined organic phase and washing the
combined organic phase with water; and (iv) distilling the washed
organic phase to obtain the compound of Formula IV.
[0053] In a preferred embodiment, the above method is carried out
at a temperature of about 80.degree. C..+-.10.degree. C.
[0054] In another aspect, the present invention provides a method
for preparing a compound of Formula V having the following
structure: ##STR9## the method comprising: (a) contacting a
compound of Formula IV having the following structure: ##STR10##
with a mixture of cuprous cyanide and sodium cyanide to form a
reaction mixture; (b) heating the reaction mixture until the
reaction is complete; and (c) quenching the reaction mixture to
form a product mixture comprising the compound of Formula V. It has
been found that a mixture of cyanating agents works surprisingly
well for carrying out this method.
[0055] In one embodiment, the compound of Formula IV is in a first
organic solvent. Suitable first organic solvents include, but are
not limited to, toluene, benzene, xylene, diethylether,
t-butylmethylether, dioxane, and mixtures thereof. In a preferred
embodiment, the first organic solvent is toluene. In another
embodiment, the mixture of cuprous cyanide and sodium cyanide is in
a second organic solvent. Suitable second organic solvents include,
but are not limited to, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidione, quinoline, collidine,
xylene, dimethylsulfone, hexamethylphosphoramide and
trifluoromethylchlorobenzene. In a preferred embodiment, the second
organic solvent is N,N-dimethylformamide.
[0056] It will be readily apparent to those of skill in the art
that the ratio of cuprous cyanide:sodium cyanide in the mixture of
cuprous cyanide and sodium cyanide can be varied. In a presently
preferred embodiment, the ratio of cuprous cyanide:sodium cyanide
in the mixture of cuprous cyanide and sodium cyanide is about
2.5:1.0 to about 1:2.5. In a presently preferred embodiment, the
ratio of cuprous cyanide:sodium cyanide in the mixture of cuprous
cyanide and sodium cyanide is about 0.50:1.0 to about 2.5:1. In
another preferred embodiment, the ratio of cuprous cyanide:sodium
cyanide in the mixture of cuprous cyanide and sodium cyanide is
about 0.75:1.0 to about 1.0:1.0. It will be readily apparent to
those of skill in the art that other mixtures of cyanating agents
(e.g., KCN:CuCN or Metal-CN:CuCN complexes) can be used in the
above method of the present invention.
[0057] In one embodiment, the first organic solvent is removed from
the reaction mixture prior to step (b). In another embodiment, the
reaction mixture is quenched with a member selected from the group
consisting of aqueous sodium cyanide and aqueous potassium cyanide.
In a preferred embodiment, the reaction mixture is quenched with
10% aqueous sodium cyanide.
[0058] In a preferred embodiment, the above method further
comprises: (d) isolating the compound of Formula V from the product
mixture. In one embodiment, step (d) comprises: (i) adding
ethylenediamine and a first organic solvent to the reaction mixture
and separating the organic phase and the aqueous phase; (ii)
re-extracting the aqueous phase with the first organic solvent;
(iii) combining the organic phases to form a combined organic phase
and back-extracting the combined organic phase with an acid to form
an acid extract; (iv) neutralizing the acid extract with a base to
a pH of about 8.5 to about 11 to form a neutralized extract; (v)
extracting the neutralized extract with a second organic solvent to
form a second organic solvent extract; (vi) treating the second
organic solvent extract with charcoal and removing the second
organic solvent to generate the compound of Formula V.
[0059] In a preferred embodiment of step (d), the first and second
organic solvents are independently selected from the group
consisting of toluene, benzene, xylene, diethylether,
t-butylmethylether, dioxane, and mixtures thereof. In another
preferred embodiment, the first and second organic solvents are
both toluene.
[0060] In one embodiment, the acid in step (iii) is a member
selected from the group consisting of HCl, HBr, H.sub.2SO.sub.4,
H.sub.3PO.sub.4, trifluoroacetic acid and acetic acid. In a
preferred embodiment, the acid in step (iii) is 20% aqueous acetic
acid. In one embodiment, the base in step (iv) is a member selected
from the group consisting of sodium hydroxide, potassium hydroxide
and sodium carbonate. In a preferred embodiment, the base in step
(iv) is sodium hydroxide. In one embodiment, the acid extract in
step (iv) is neutralized with the base to a pH of about 9 to about
10.
[0061] In another aspect, the above method further comprises
purifying the compound of Formula V using simulated moving bed
(SMB) chromatography having a stationary phase and a mobile phase.
It has been found that SMB chromatography works surprisingly well
for removing non-polar impurities found in the reaction mixture. In
one embodiment, the stationary phase is a reverse phase silica gel
and the mobile phase is an organic solvent/water mixture. A
C18-derivatized silica gel is an example of a suitable reverse
phase silica gel. Typically, the pH of the mobile phase is about
1.5 to about 4.0, more preferably about 2.5. The pH of the mobile
phase can be maintained by, for example, the addition of 0.1 to 2%
trifluoroacetic acid. In a preferred embodiment, the organic
solvent in the mobile phase is methanol. In another preferred
embodiment, the organic solvent in the mobile phase is ethanol. In
another preferred embodiment, the organic solvent in the mobile
phase is acetonitrile.
[0062] In another embodiment, the stationary phase is a normal
phase silica gel and the mobile phase is an organic solvent
mixture. In one embodiment, the organic solvent mixture is a
mixture of an alcohol, a hydrocarbon and an organic base. Suitable
alcohols include, but are not limited to, methanol, ethanol,
n-propanol and isopropanol. Suitable hydrocarbons include, but are
not limited to, heptane, n-heptane, hexane, isohexane, toluene,
cyclohexane, benzene and combinations thereof. Suitable organic
bases include, but are not limited to, triethylamine, diethylamine,
trimetylamine, dimethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine and diethylisopropylamine.
In a preferred embodiment, the organic base is present in the
organic solvent mixture at about 0.05 to about 5%, more preferably
at about 0.1 to about 0.5% and, even more preferably, at about 0.2
to about 0.4%. In a preferred embodiment, the organic solvent
mixture is a mixture of ethanol, heptane and triethylamine.
[0063] In another embodiment, the stationary phase is a chiral
phase silica gel and the mobile phase is an organic solvent
mixture. Suitable chiral phase silica gel stationary phases
include, but are not limited to, CHIRALPAK.RTM. AD.TM.;
CHIRALPAK.RTM. AS.TM.; CHIRALCEL.RTM. OD.TM.; and CHIRALCEL.RTM.
OJ.TM., all of which are commercially available from Daicel,
through its subsidiary, Chiral Technologies Inc. In one embodiment,
the organic solvent mixture is a mixture of an alcohol (which may
or may not be denatured with, for example, a hydrocarbon such as
n-heptane), a hydrocarbon and an organic base. Suitable alcohols
include, but are not limited to, methanol, ethanol, n-propanol and
isopropanol. Suitable hydrocarbons include, but are not limited to,
heptane, n-heptane, hexane, isohexane, toluene, cyclohexane,
benzene and combinations thereof. Suitable organic bases include,
but are not limited to, triethylamine, diethylamine, trimetylamine,
dimethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine and diethylisopropylamine.
In a preferred embodiment, the organic base is present in the
organic solvent mixture at about 0.05 to about 5%, more preferably
at about 0.1 to about 0.5% and, even more preferably, at about 0.2
to about 0.4%. In a preferred embodiment, the organic solvent
mixture is a mixture of ethanol, heptane and triethylamine.
[0064] In another embodiment, the compound of Formula V is further
purified using single column chromatography having a stationary
phase and a mobile phase. It has been found that single column
chromatography works surprisingly well for removing any non-polar
impurities found in the reaction mixture. Suitable stationary and
mobile phases are similar to those described above in connection
with the SMB chromatography.
[0065] In another aspect, the present invention provides a method
for preparing a compound of Formula VI having the following
structure: ##STR11## the method comprising: (a) dissolving a
compound of Formula V having the following structure: ##STR12## in
an organic solvent to form a reaction mixture; and (b) contacting
the reaction mixture with HBr to form a product mixture comprising
the compound of Formula VI.
[0066] In one embodiment, the organic solvent in step (a) is a
member selected from the group consisting of acetone,
methylethylketone, ethylacetate, toluene, benzene, xylene,
diethylether, t-butylmethylether, dioxane, and mixtures thereof. In
a preferred embodiment, the organic solvent in step (a) is
diethylether. In another preferred embodiment, the organic solvent
in step (a) is acetone.
[0067] In one embodiment, the HBr is gaseous HBr. In an example of
this embodiment, the method comprises bubbling gaseous HBr into the
reaction mixture to form a product mixture comprising the compound
of Formula VI. In another embodiment, the HBr is aqueous HBr and
the reaction mixture is contacted with aqueous HBr to form a
product mixture comprising the compound of Formula VI.
[0068] In a preferred embodiment, the above method further
comprises: (c) isolating the compound of Formula VI from the
product mixture. In one embodiment, step (c) comprises: (i) cooling
the product mixture and filtering the product mixture to obtain the
compound of Formula VI as a precipitated solid; (ii) washing the
precipitated solid with an organic solvent; and (iii) drying the
precipitated solid to obtain the compound of Formula VI. In one
embodiment, step (c) further comprises: (iv) recrystallizing the
compound of Formula VI. In one embodiment, the compound of Formula
VI is recrystallized from a solvent mixture of toluene and
methanol. In another embodiment, the compound of Formula VI is
recrystallized from a solvent mixture of methanol and
isopropylalcohol (IPA).
[0069] In another embodiment, step (iv) comprises: (i') combining
the precipitated solid with toluene and methanol to form a mixture
and heating the mixture; (ii') filtering the mixture through Celite
and slowly cooling the mixture; and (iii') filtering the mixture to
obtain the crystallized solid, washing the crystallized solid with
toluene, and drying the crystallized solid to obtain the compound
of Formula VI. In one embodiment, in step (ii'), the mixture is
cooled to about ambient temperature. In another embodiment, in step
(ii'), the mixture is cooled to about 0.degree. C. to about
5.degree. C.
[0070] In yet another embodiment, step (iv) comprises: (i')
combining the precipitated solid with methanol and isopropylalcohol
(IPA) to form a mixture and heating the mixture; (ii') filtering
the mixture through Celite and slowly cooling the mixture; and
(iii') filtering the mixture to obtain the crystallized solid,
washing the crystallized solid with isopropylalcohol, and drying
the crystallized solid to obtain the compound of Formula VI. In one
embodiment, in step (ii'), the mixture is cooled to about ambient
temperature. In another embodiment, in step (ii'), the mixture is
cooled to about 0.degree. C. to about 5.degree. C.
[0071] In another embodiment, the present invention provides a
process for the removal of demethyl- (A) and didemethyl- (B)
impurities from crude Citalopram mixtures, wherein the demethyl-
and didemethyl-impurities have the following structures: ##STR13##
Demethyl- (A) and didemethyl- (B) impurities are common impurities
formed at various stages during the preparation of Citalopram.
Unfortunately, these troublesome impurities present a challenge in
removal due to their structural proximity to Citalopram.
[0072] As such, the present invention provides a method for
removing demethyl- and didemethyl-impurities from a crude
Citalopram mixture containing demethyl- and didemethyl-impurities
in a solvent, the method comprising: (a) contacting the mixture of
Citalopram with a scavenger resin having a functional group that is
reactive with a primary or secondary amine to form resin-bound
demethyl- and/or didemethyl-impurities, wherein the scavenger resin
is insoluble in the solvent; and (b) filtering the resin-bound
demethyl- and/or didemethyl-impurities, thereby removing the
demethyl and/or didemethyl-impurities from the mixture of
Citalopram.
[0073] In one embodiment of the above method, the functional group
on the scavenger resin includes, but is not limited to,
isocyanates, isothiocyanates, acid chlorides, esters and
anhydrides. In some embodiment, the scavenger resin can have more
than one functional group and, in this case, the functional groups
can be the same or different. It has been found that such
functional groups react with the primary and/or secondary amine
functionalities present in impurities A and B, virtually in an
irreversible fashion, thereby attaching impurities A and B to the
scavenger resin. The attachment of impurities A and B to the
scavenger resin renders such impurities insoluble as well.
[0074] The scavenger resin can be any resin that (1) is insoluble
in the solvent in which the product is dissolved; (2) is
non-reactive with the solvent in which the product is dissolved;
and (3) contains a functional group that is reactive with a primary
and/or a secondary amine. In one embodiment, the scavenger resin is
a polystyrene-based resin. In another embodiment, the scavenger
resin is a silica gel-based resin. In a preferred embodiment, the
scavenger resin is a polystyrene-based resin having the following
structure: ##STR14## wherein: R is a functional group that is
reactive with a primary and/or secondary amine such as those
described above.
[0075] The above method is typically carried out by stirring a
crude Citalopram mixture containing A and/or B in an appropriate
solvent with a scavenger resin having a functional group that is
reactive with the primary and/or seconday amine functionalities
present in A and B, respectively. Suitable solvents include, but
are not limited to, toluene, benzene, xylene, diethylether,
t-butylmethylether, dioxane, and mixtures thereof. The resulting
mixture is a heterogeneous mixture as the scavenger resin is also
insoluble in the solvent. It is thought that impurities A and B,
but not Citalopram, attach to the resin by making a covalent bond
between a primary or secondary amine functionality and the
functional group on the scavenger resin, thereby rendering them
insoluble. A simple filtration of the resin-bound, i.e., insoluble,
impurities A and B affords a purified Citalbpram solution virtually
free of impurities A and B.
[0076] The above method has a number of significant advantages
including, but not limited to, the following: (1) it selectively
renders otherwise soluble impurities A and B insoluble by binding
them to the insoluble resin through the reaction of the reactive
end groups of the scavenger resin and the primary and secondary
amine functionalities present in impurities A and B; (2) the
scavenger resin will bind any other impurity containing a primary
or secondary amine functionalities and render them insoluble as
well; (3) the scavenger resin cannot react with the desired
Citalopram, which has a tertiary amine functionality; (4) once the
resin binds to the impurities A, B (or any other impurity
containing a primary or secondary amine functionality) rendering
them insoluble, only a simple filtration is required to remove
these impurities, thereby minimizing any loss (i.e., any loss due
to the acid/base wash and/or crystallization and recrystallization
utilized in the method disclosed in PCT Patent Publication No. WO
01/45483 A2); and (5) once the filtration is performed, a purified
Citalopram solution is obtained and the purified Citalopram can be
recovered by a simple evaporation of the solvent.
[0077] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of non-critical parameters which can be changed or modified
to yield essentially the same results.
EXAMPLES
[0078] A. Preparation of Dimethylaminopropyl Magnesium Chloride
[0079] A 30% aqueous sodium hydroxide (1.04 kg, 7.80 mol, 1.10 eq.)
solution was added to a mixture of 65% aqueous dimethylaminopropyl
chloride hydrochloride (1.71 kg, 7.04 mol, 1.00 eq.) and toluene
(0.167 kg) at <20.degree. C. [0080] The phases were separated.
[0081] The organic phase was combined with THF (0.600 kg) and dried
over molecular sieves (Siliporite NK10, 0.227 kg). [0082]
Approximately 5% of the dried dimethylaminopropyl chloride solution
was added to a mixture of magnesium (0.170 kg, 7.00 mol, 1.00 eq.),
ethyl bromide (0.0038 kg, 0.035 mol, 0.0050 eq.), and THF (1.60
kg). [0083] The resulting mixture was heated to reflux
(>68.degree. C.) and the remaining dimethylaminopropyl chloride
solution was added over 1.5 h. [0084] Reflux (>68.degree. C.)
was maintained throughout the addition period by adjusting the
addition rate and heating and/or cooling as necessary. [0085] The
mixture was refluxed (>70.degree. C.) for 1 h, then cooled to
ambient temperature and stored under a dry nitrogen atmosphere.
[0086] B. Preparation of
(4-Bromo-2-hydroxymethyl)phenyl-(4-fluorophenyl)-(3-dimethylaminopropyl)
methanol hydrochloride [0087] A solution of 1.1 M 4-fluorophenyl
magnesium bromide in THF (5.57 kg, 6.01 mol, 1.28 eq.) was added to
a mixture of 5-bromophthalide (1.00 kg, 4.69 mol, 1.00 eq), and
toluene (6.25 kg) at <20.degree. C. over 1 h. [0088] The mixture
was stirred at <20.degree. C. for 0.5 h. [0089] A solution of
1.8 M dimethylaminopropyl magnesium chloride (3.90 kg, 7.02 mol,
1.50 eq.) was added to the mixture over 2 h, maintaining
<30.degree. C. with cooling. [0090] The resulting mixture was
stirred ambient temperature for 16 h. [0091] The mixture was
quenched into 6.23% aqueous hydrochloric acid (9.9 kg, 19.3 mol,
4.1 eq.). [0092] The slurry was stirred at ambient temperature for
1 h and filtered. [0093] The product was then washed with water
(2.00 kg) and toluene (4.00 kg). [0094] The off-white solids were
dried at 35-40.degree. C. under vacuum to yield 1.63 kg (80.4%
yield) of crude bromodiol*HCl.
[0095] C. Purification of Bromodiol HCl [0096] A mixture of crude
bromodiol*HCl (1.60 kg) and 2-butanol (8.00 kg) was heated to
70.degree. C. to form a hazy solution and filtered through a bed of
celite. [0097] The resulting solution was cooled slowly to
5.degree. C. to precipitate the product. [0098] The resulting
slurry was filtered and washed with 2-butanol (1.60 kg). [0099] The
off-white solids were dried at 35-40.degree. C. under vacuum to
yield 1.18 kg (73.8% recovery from crude) of bromodiol*HCl.
[0100] The properties of the Bromodiol*HCl are as follows: [0101]
HPLC area % purity: 99.9% [0102] mp (DSC): 183.degree. C. [0103]
.sup.1H NMR (d-DMSO): .delta.10.19 (s, 1H), .delta.7.0-7.8 (m, 7H),
.delta.5.90 (s, 1H), .delta.5.17 (s, 1H), .delta.4.49 (d, 1H),
.delta.3.97 (d, 1H), .delta.3.02 (m, 2H), .delta.2.65 (s, 6H),
.delta.2.21 (m, 2H), .delta.1.65 (m, 1H), .delta.1.36 (m, 1H).
[0104] D. Preparation of
5-Bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-phthalan
("5-Br") [0105] A mixture of bromodiol*HCl (1.12 kg, 2.59 mol, 1.00
eq.) and 60% phosphoric acid (12.7 kg, 77.8 mol, 30.0 eq.) was
heated to 90.degree. C. for 1 h. [0106] The mixture was cooled to
<10.degree. C. [0107] Toluene (6.72 kg) and water (8.96 kg) were
added to the solution and the mixture was quenched with 28% aqueous
ammonium hydroxide (9.37 kg, 74.9 mol, 28.9 eq.), maintaining
<25.degree. C. [0108] The phases were separated and the aqueous
layer was re-extracted with toluene (4.48 kg). [0109] The organic
phases were combined and washed with water (4.0 kg). [0110] The
solvent was distilled from the washed organic extracts to yield 977
g (99.2% yield, 95.2% yield corrected for residual solvents) of
5-Br as an orange oil.
[0111] The properties of 5-Br are as follows: [0112] HPLC area %
purity: 99.0% [0113] .sup.1H NMR (d-DMSO): .delta.7.1-7.6 (m, 7H),
.delta.5.10 (m, 2H), .delta.2.51 (m, 2H), .delta.2.11 (m, 2H),
.delta.2.01 (s, 6H), .delta.1.23 (m, 2H).
[0114] E. Modified Process for the Preparation of 5-Br [0115] A
mixture of bromodiol*HCl (0.200 kg, 0.462 mol, 1.00 eq.) and 20%
phosphoric acid (2.04 kg, 4.16 mol, 9.00 eq.) was heated to
90.degree. C. for 2.5 h. [0116] The mixture was cooled to
<10.degree. C. [0117] Toluene (1.20 kg) was added to the
solution and the mixture was quenched with 28 % aqueous ammonium
hydroxide (0.574 kg, 4.59 mol, 9.93 eq.), maintaining
<25.degree. C. [0118] The phases were separated and the aqueous
layer was re-extracted with toluene (0.800 kg). [0119] The organic
phases were combined and washed with water (0.800 kg). [0120] The
solvent was distilled from the washed organic extracts to yield 164
g (93.6% yield) of 5-Br as an orange oil.
[0121] The properties of 5-Br are as follows: [0122] HPLC area %
purity: 99.2% [0123] .sup.1H NMR (d-DMSO): .delta.7.1-7.6 (m, 7H),
.delta.5.10 (m, 2H), .delta.2.51 (m, 2H), .delta.2.11 (m, 2H),
.delta.2.01 (s, 6H), .delta.1.23 (m, 2H).
[0124] F. Process for the Preparation of
5-Cyano-1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)phthalane
("Citalopram" or "5-CN") [0125] A solution of
5-bromo-1-(3-dimethylaminopropyl)1-(p-fluorophenyl)phthalane (100.5
g, 0.266 mol) in toluene was added to a mixture of cuprous cyanide
(50.0 g, 0.558 mol) and sodium cyanide (9.8 g, 0.200 mol) in of
N,N-dimethylformamide (450 mL) [0126] Toluene was removed by
distillation and the resulting mixture was heated to
154-159.degree. C. under nitrogen until the desired conversion was
achieved. [0127] The reaction mixture was then chilled to
60-70.degree. C. and quenched with a 10% aqueous NaCN solution (350
g). [0128] Aqueous ethylenediamine (41% solution, 140 g) and
toluene (500 mL) were added and the mixture was filtered. [0129]
The organic layer was separated and the aqueous layer was extracted
with toluene (2.times.100 mL). [0130] The combined organic extracts
were washed with water (2.times.100 mL). [0131] The organic extract
was then extracted with 20% acetic acid solution (2.times.250 mL).
[0132] The combined acetic acid extracts were neutralized with
16.6% aqueous NaOH to a pH of about 9 to about 10 and extracted
with toluene (3.times.300 mL). [0133] The combined toluene extracts
were treated with activated charcoal (16.1 g) and stripped of
solvent under reduced pressure to give crude Citalopram (72.3 g,
84%) as a light brown oil.
[0134] The properties of 5-CN are as follows: [0135] HPLC purity:
95% with 5% unreacted 5-Br [0136] .sup.1H NMR (DMSO-d.sub.6):
.delta. 7.6 (s, 1H, 4-H aromatic proton), 6.98 to 7.52 (m, 6H,
aromatic protons), 5.25 (d, 1H, 3-H.sub.a), 5.15 (d, 1H,
3-H.sub.b), 3.08 (t, 2H, 3'-CH.sub.2), 2.71 (s, 6H,
--N(CH.sub.3).sub.2), 2.49 to 2.27 (m, 2H, 1'-CH.sub.2), 1.82 to
1.71 (m, 2H, 2'-CH.sub.2); [0137] LC/MS: m/z, 325 (M+1).
[0138] G. Process for the Purification of Crude 5-CN
[0139] The crude 5-CN product is dissolved in a mixture of
heptane/ethanol/TEA (90%: 10%:0.1%), and separated using
Multi-Column Chromatography (MCC) equipment (SMB) to provide 5-CN
with <0.1% 5-Br. The mobile phase is heptane/ethanol/TFA. The
stationary phase is CHIRALCEL OD.TM.. MCC separation has been
demonstrated on 400 g scale and the product isolated from the
separation was >99.9% pure. The product was so pure that when it
was converted to the HBr salt, it maintained its purity and did not
require additional purification--a 20% savings in the yield.
[0140] H. Process for the Preparation of
5-Cyano-1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)phthalane HBr
(Citalopram-HBr) [0141] HBr gas (18.0 g, 0.223 mol) was bubbled
into a stirred solution of pure 5-CN (72.3 g, 0.223 mol) in 723 mL
acetone at 20-25.degree. C. [0142] The resulting slurry was cooled
to 0-5.degree. C. and filtered. [0143] The product was washed with
cold acetone (3.times.100 mL) and dried in vacuo (60-80.degree. C.
at 5-10 mmHg) to give Citalopram-HBr (69.8 g, 77.3%), a white
solid.
[0144] L Purification of Citalopram-HBr [0145] A mixture of the
crude product (69.8 g), toluene (1117 g), and methanol (138 g) was
heated to 60-70.degree. C. [0146] The resulting solution was
filtered through celite and slowly cooled to ambient temperature.
[0147] The crystallized solid was filtered, washed with 100 mL
toluene, and dried in vacuo (60-80.degree. C. at 10 mmHg) to give
pure Citalopram-HBr (53.2 g, 76.2%), a white solid.
[0148] The properties of Citalopram-HBr are as follows: [0149] mp
(DSC): 186.degree. C. [0150] HPLC Purity: 99.8% [0151] IR (KBr):
2931, 2655, 2229,1507, 1217, 1028, 1013, 835 cm.sup.-1; [0152]
.sup.1H NMR (DMSO-d.sub.6): .delta. 9.15 (s, 1H,
--NH(CH.sub.3).sub.2), 7.71 to 7.91 (m, 3H, aromatic protons), 7.52
to 7.64 (m, 2H, aromatic protons), 7.06 to 7.27 (m, 2H, aromatic
protons), 5.08 to 5.28 (q, 2H, 3-H), 3.3 (t, 2H, 3'-CH.sub.2), 2.65
(s, 6H, --NH(CH.sub.3).sub.2), 2.2 (t, 2H, 1'-CH.sub.2), 1.29 to
1.60 (m, 2H, 2'-CH.sub.2).
[0153] J. Process for the Preparation of
5-Cyano-1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)phthalane HBr
(Citalopram-HBr)
[0154] In addition to the foregoing method, Citalopram-HBr can be
prepared using aqueous HBr. It has been found that the resulting
product prepared using aqueous HBr is equivalent to that prepared
using gaseous HBr in both yield and purity.
[0155] C.HBr Salt Formation [0156] 48% HBr (aq) (54.1 g, 0.321 mol)
is added to a stirred solution of 5-CN (104.1 g, 0.31 mol) in
Toluene (366 g) at 5-10.degree. C. [0157] The resulting slurry is
cooled to 0-5.degree. C. and filtered. [0158] The product is washed
with cold Toluene (2.times.107 mL) and dried in vacuo
(60-80.degree. C. at 5-10 mm Hg) to afford C-HBr (97.5 g, 93.6%) as
a white solid.
[0159] Recrystallization/Purification
[0160] A recrystallization is not necessary when using 5-CN
purified by SMB chromatography. However, the following can be
performed if further purification is required or desired. [0161] A
mixture of C-HBr (97.5 g, 0.301 mol), methanol (103.6 g) and
isopropanol (207.2 g) is heated to 60-70.degree. C. [0162] The
resulting solution was cooled to 0.degree. C. and filtered. [0163]
The recrystallized product was washed with cold isopropanol
(2.times.75 mL) and dried in vacuo (60-80.degree. C. at 5-10 mm Hg)
to afford C-HBr (88.6 g, 85.1%) as a white solid.
[0164] The properties/characterization of pure C-HBr are as
follows: [0165] mp (DSC): 187.degree. C. [0166] HPLC Purity: 99.8%
[0167] 5-Br: None detected [0168] Total Impurities: .ltoreq.0.2%
[0169] Unknown Inpurities .ltoreq.0.1%: None detected [0170]
IR(KBr): 2931, 2655, 2229, 1507, 1217, 1028, 1013, 835 cm.sup.-1;
[0171] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.15 (s, 1H,
--NH(CH.sub.3).sub.2), 7.71 to 7.91 (m, 3H, aromatic protons), 7.52
to 7.64 (m, 2H, aromatic protons), 7.06 to 7.27 (m, 2H, aromatic
protons), 5.08 to 5.28 (q, 2H, 3-H), 3.3 (t, 2H, 3'-CH.sub.2), 2.65
(s, 6H, --NH(CH.sub.3).sub.2), 2.2 (t, 2H, 1'-CH.sub.2), 1.29 to
1.60 (m, 2H, 2'-CH.sub.2).
[0172] K. Removal of Demethyl and Didemethyl Impurites from a Crude
Citalopram Mixture [0173] Methylisocyanate polystyrene resin (0.34
g, 0.18 mol isocyanate) is added to a solution of 5-CN (0.92 g) in
Toluene (10 g) and stirred at room temperature. [0174] After 2 h at
room temperature, the resin was filtered and Toluene was evaporated
in vacuo (50-60.degree. C. at 5-10 mm Hg) to afford product with
70% less demethyl impurity (A).
[0175] L SMB Purification of Citalopram-HBr
Experimental
[0176] The feed mixture is an oil recovered from the cyanation step
and contains several impurities (polar and non-polar). These
impurities can mostly be removed by standard reworking of the
product (e.g., by crystallization and solvent exchange). However,
one impurity is not removed by these techniques. This impurity is
the starting material of the previous step. It is the 5-Br
intermediate that is converted into Citalopram during the cyanation
step.
[0177] The separation of a mixture of Citalopram and 5-Br
intermediate in the proportion 95/5 (HPLC area % at 232-nm) was
examined by chromatography and more specifically by the simulated
moving bed technique. FIG. 3 (reverse phase analysis) gives an
example of the feed composition. The largest peak is the Citalopram
peak. The second largest peak is the 5-Br intermediate. The other
peaks are of lesser interest for the chromatographic
separation.
[0178] The following equipment was used for the experiment. SMB
unit: Licosep laboratory unit from NOVASEP (Brabois (54), France)
equipped with 8 axial compression columns from MERCK (Darmstadt,
Germany). Each column was 50-mm internal diameter and was prepared
using 110-g of CHIRALCEL OD.TM. 20-.mu.m chiral stationary phase
(Chiral Technologies Inc, Exton, USA). The average column length
was 10.3-cm. The mobile phase used for the separation was a mixture
of ethanol (denatured with n-heptane) and n-heptane in the
proportion 10/90 % (v/v.). Triethylamine was added as a modifier
(0.2% total volume). The separation was conducted at 30.degree. C.
Under such conditions, the compound of interest (Citalopram) is the
second eluting compound and will be designed as the Extract, 5-Br
will be the Raffinate.
[0179] Each column was individually tested with a diluted solution
of the mixture to be separated (14.2-g/1). The injected volume was
0.5-ml. Detection was performed at 254-nm and the flow rate was
100-ml/min. The 5-Br average elution time is 1.92-min while the
Citalopram has an averaged elution time of 3.10-min. The average to
(or dead volume) of the column was 1.51-min. The average retention
factor for the 5-Br was 0.27 and was 1.04 for the Citalopram. The
average selectivity of the separation was 3.84.
Separation Parameters
[0180] The separation was conducted using 703.1 g of a mixture of
Citalopram and 5-Br prepared according to the cyanation procedure.
The feed composition is 95% of Citalopram and 5% of 5-Br (area % by
HPLC at 232-nm). The feed contains other impurities, but they were
not taken into account in the calculation of the feed composition.
The feed concentration for this step was 22.7-g/l.
[0181] The set of parameters used for the separation was:
TABLE-US-00001 Zone I Period Eluent (recycle) Extract Zone II Feed
Zone III Raffinate Zone IV min ml/min ml/min ml/min ml/min ml/min
ml/min ml/min ml/min 1.65 86.7 190 76.7 113.3 40 @ 153.3 50 103.3
22.7 g/l
Product Recovery
[0182] Each recovered fraction (extract and raffinate) was
evaporated in 20-L rotary evaporators (Genser, Germany). The
Extract fraction was evaporated to dryness and the product was
recovered as a crystal. The evaporation step was conducted at
40.degree. C. (waster bath) and under vacuum (1 50-mbar to start
the process and down to 80-mbar for drying the product) with 50-rpm
for the flask speed.
[0183] The solvent recovered was sampled and tested and acceptable
low amount of product was detected (traces).
[0184] The raffinate was re-dissolved in a small amount of ethanol
denatured and evaporated in a 1-L flask using the laboratory
evaporator (Buchii). The raffinate product (5-Br) was recovered as
a viscous oil.
[0185] A sample of each recovered fraction was analyzed using a
C.sub.18 column (reverse phase) and a gradient of water with TFA
(trifluoroaceticacid) and acetonitrile with TFA.
Separation Performance
[0186] The total quantity of product recovered is 675.3-g (all
fractions included), which gives an overall yield for the process
of 96%. The 4% loss is due to product loss in the equipment (tanks
walls, tubing, SMB unit) and when recovering the fractions.
[0187] The expected quantity of 5-CN to be recovered was 641.5-g.
The total extract collected was 576.2-g representing a recovery
yield of 89.8%.
[0188] The product obtained in the extract does not contain
detectable amount of 5-Br (see, FIGS. 4 and 5).
[0189] Based on these experimental data, the production rate for
the separation is 1.31 -kg/d of 5-CN at 17 bars. This corresponds
to a productivity of 1.49 kg of Citalopram per day per kg of CSP at
17 bars (free of 5-Br).
[0190] Let's Discuss Whether or Not to Include the Loading Study as
Well as the Other Information in the Discussion Section]
[0191] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference for all purposes.
* * * * *