U.S. patent application number 10/046126 was filed with the patent office on 2002-08-29 for method for the preparation of pure citalopram.
This patent application is currently assigned to H. Lundbeck A/S. Invention is credited to Dancer, Robert, Sbrogio, Federico, Villa, Marco.
Application Number | 20020120005 10/046126 |
Document ID | / |
Family ID | 8159922 |
Filed Date | 2002-08-29 |
United States Patent
Application |
20020120005 |
Kind Code |
A1 |
Villa, Marco ; et
al. |
August 29, 2002 |
Method for the preparation of pure citalopram
Abstract
The present invention relates to the process for the preparation
and purification of citalopram (I) 1 in which a compound of formula
(II) 2 wherein Z is iodo, bromo, chloro or
CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--- O--, n being 0, 1, 2, 3, 4,
5, 6, 7 or 8, is subjected to a cyanide exchange reaction with a
cyanide source; the resultant crude citalopram product is
optionally subjected to some initial purification and subsequently
treated with an amide or an amide-like group forming agent; the
reaction mixture is then subjected to an acid/base wash and/or
crystallisation and recrystallisation of citalopram in order to
remove the amides formed from the crude citalopram mixture; and the
resulting citalopram product is optionally further purified, worked
up and isolated as the base or a pharmaceutically acceptable salt
thereof.
Inventors: |
Villa, Marco; (Padova,
IT) ; Sbrogio, Federico; (Favaro Veneto, IT) ;
Dancer, Robert; (Frederiksberg C, DK) |
Correspondence
Address: |
DARBY & DARBY P.C.
805 Third Avenue
New York
NY
10022
US
|
Assignee: |
H. Lundbeck A/S
Valby-Copenhagen
DK
|
Family ID: |
8159922 |
Appl. No.: |
10/046126 |
Filed: |
January 8, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10046126 |
Jan 8, 2002 |
|
|
|
PCT/DK01/00147 |
Mar 7, 2001 |
|
|
|
Current U.S.
Class: |
514/466 ;
549/467 |
Current CPC
Class: |
A61P 25/24 20180101;
C07D 307/87 20130101 |
Class at
Publication: |
514/466 ;
549/467 |
International
Class: |
A61K 031/36; C07D
37/81 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 2000 |
DK |
PA 2000 01929 |
Claims
1. A process for the preparation of citalopram 9in which a compound
of formula II 10wherein Z is iodo, bromo, chloro or
CF.sub.3--(CF.sub.2).su- b.n--SO.sub.2--O--, n being 0, 1, 2, 3, 4,
5, 6, 7 or 8, is subjected to a cyanide exchange reaction with a
cyanide source; the resultant crude citalopram product is
optionally purified and subsequently treated with an amide or an
amide-like group forming agent selected from the compounds of
Formulas (a), (b) or (c): 11where X is halogen or a group
O--CO--R', Hal is halogen, Y is O or S, W is O, N or S and R, R',
R" and R'" are each selected from the group consisting of hydrogen,
alkyl, and optionally substituted aryl or aralkyl; the reaction
mixture is then subjected to an acid/base wash or crystallisation
and recrystallisation of citalopram in order to remove amides
formed from the crude citalopram mixture; and the resulting
citalopram product is optionally purified and isolated as the base
or a pharmaceutically acceptable salt thereof.
2. The process of claim 1 wherein the amide or amide-like group
forming agent is a compound of formula R--CO--X, wherein R and X
are as defined in claim 1.
3. The process of claim 2 wherein the amide or amide-like group
forming agent is a carboxylic acid anhydride or an acyl
halogenide.
4. The process of claim 3 wherein the amide or amide-like group
forming agent is acetic acid anhydride.
5. The process of claim 3 wherein the amide or amide-like group
forming agent is an acylchloride.
6. The process of claim 5, wherein the acylchloride is
acetylchloride.
7. The process of one of claims 1-5 wherein Z is Br and the cyanide
reaction is carried out by reaction with cuprous cyanide in a
solvent.
8. The process of one of claims 1-5 wherein Z is iodo, bromo,
chloro or CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O--, being 0,1, 2,
3, 4, 5, 6, 7 or 8, and the cyanide exchange reaction is carried
out by reaction with a cyanide source in the presence of a
palladium catalyst and a catalytic amount of Cu.sup.+ or
Zn.sup.2+.
9. The process of one of claims 1-5 wherein Z is iodo, bromo,
chloro or CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O--, n being 0,1,
2, 3, 4, 5, 6, 7 or 8, and the cyanide exchange reaction is carried
out with Zn(CN).sub.2 in the presence of a palladium catalyst.
10. The process of claim 9 wherein Z is Br.
11. The process of one of claims 1-5 wherein Z is Cl or Br and the
cyanide exchange reaction is carried out with a cyanide source in
the presence of a nickel catalyst, optionally in the presence of a
catalytic amount of Cu.sup.+ or Zn.sup.2+.
12. The process of claim 11 wherein Z is Cl.
Description
[0001] The present invention relates to a process for the
manufacture of the well-known antidepressant drug citalopram,
1-[3-(dimethylamino)propyl-
]-1-(4fluorophenyl)-1,3dihydro-5-isobenzofuran-carbonitrile, in
particular a process for preparing pure citalopram by cyanide
exchange.
BACKGROUND OF THE INVENTION
[0002] Citalopram is a well-known antidepressant drug that has now
been on the market for some years and has the following structure:
3
[0003] It is a selective, centrally acting serotonin
(5-hydroxytryptamine; 5-HT) reuptake inhibitor, which has further
been disclosed to show effects in the treatment of dementia and
cerebrovascular disorders, cf. EP-A-474580.
[0004] Citalopram was first disclosed in DE 2,657,013,
corresponding to U.S. Pat. No. 4,136,193. This patent publication
i.a. outlines a process for preparation of citalopram from the
corresponding 5-bromo-derivative by reaction with cuprous cyanide
in a suitable solvent Further processes for the preparation of
citalopram by exchange of 5-halogen or
5-CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O-- with cyano are
disclosed in WO 0011926 and WO 0013648.
[0005] Other processes involve:
[0006] Conversion of a 5-amido or 5-ester group to a 5-cyano group
(WO 9819513)
[0007] Conversion of a 5-amino group to a 5-cyano group (WO
9819512)
[0008] Conversion of a 5-formyl group to a 5-cyano group (WO
9900548)
[0009] Conversion of a 5-oxazolinyl or 5-thiazolinyl group to a
5-cyano group (WO 0023431)
[0010] It has turned out that it is difficult to manufacture
citalopram in the required quality. The processes of DE 2,657,013,
WO 0011926 and WO 0013648 comprising exchange of 5-halogen with
cyano as described above have been found to give the
desmethyl-citalopram derivative in unacceptable amounts. This
impurity is difficult to remove by usual working up procedures
leading to extensive and expensive purification processes.
[0011] Thus, a process for the removal of impurities formed during
the preparation of citalopram by cyanide exchange reaction i.e. the
exchange of 5-halogen or the like with 5-cayno, is necessary in
order to obtain a commercially attractive manufacture of
citalopram.
[0012] It has now been found that the desmethyl-citalopram impurity
may be removed by reaction with an amide-forming group or a similar
group. The amide formed may be separated from the final product by
conventional work-up procedures.
SUMMARY OF THE INVENTION
[0013] Accordingly, the present invention provides a novel process
for the preparation of citalopram of formula 4
[0014] in which a compound of Formula II 5
[0015] wherein Z is iodo, bromo, chloro or
CF.sub.3--(CF.sub.2).sub.n--SO.- sub.2--O--, n being 0, 1, 2, 3, 4,
5, 6, 7 or 8, is subjected to a cyanide exchange reaction with a
cyanide source;
[0016] the resultant crude citalopram product is optionally
subjected to some initial purification and subsequently treated
with an amide or an amide-like group forming agent selected from
the agents of formulas (a), (b) or (c): 6
[0017] where X is halogen or a group O--CO--R', Hal is halogen, Y
is O or S, W is O, N or S and R, R', R" and R'" are each
independently selected from the group consisting of hydrogen, alkyl
optionally substituted aryl or aralkyl;
[0018] the reaction mixture is then subjected to an acid/base wash
and/or crystallisation and recrystallisation of citalopram in order
to remove the amides formed from the crude citalopram; and
[0019] the resulting citalopram product is optionally further
purified, worked up and/or isolated as the base or as a
pharmaceutically acceptable salt thereof.
[0020] In the further aspect, the invention relates to the above
process in which the compound of formula II is the S-enantiomer and
the product obtained is escitalopram.
[0021] In yet another aspect, the present invention relates to an
antidepressant pharmaceutical composition comprising citalopram
manufactured by the process of the invention.
[0022] According to the process of the invention, the desmethyl
citalopram impurity of formula III 7
[0023] is reacted with the amide or amide-like group forming
reagent of formula (a), (b) or (c) to form an amide or an
amide-like compound of formula IV: 8
[0024] wherein A is a group R--CO--, R'--CO--, R"--W--CY-- or
R'"--SO.sub.2--, wherein R, R', R" and R'", W and Y are as defined
above. The reaction product of formula IV may be removed by
acid/base wash or crystallisation and discarded, and citalopram may
be obtained as a pure product fulfilling the requirements of the
health authorities. Furthermore, the reaction may be carried out
under convenient conditions.
[0025] Throughout this specification with claims, halogen means
chloro, bromo or iodo.
[0026] The term alkyl refers to a branched or unbranched alkyl
group, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,
2-methyl-2-propyl, and 2-methyl-1-propyl.
[0027] The term aryl refers to a carbocyclic aromatic group, such
as phenyl. Aralkyl refers to a aryl-alkyl group wherein aryl and
alkyl are as defined above. The aryl and aralkyl groups may
optionally be substituted, e.g. with alkyl groups, forming for
example tolyl.
[0028] The cyanide exchange reaction is a reaction where the
substituent Z in the compound of formula II is exchanged with a
cyano group. The cyanide exchange reaction may be carried out:
[0029] When Z is Br, by reaction with cuprous cyanide in a suitable
solvent as described in U.S. Pat. No. 4,136,193,
[0030] When Z is iodo, bromo, chloro or
CF.sub.3--(CF.sub.2).sub.n--SO.sub- .2--O--, n being 0, 1, 2, 3, 4,
5, 6, 7 or 8, by reaction with a cyanide source in the presence of
a palladium catalyst and a catalytic amount of Cu.sup.+ or
Zn.sup.2+ as described in WO 0013648. Preferred cyanide sources are
KCN, NaCN or ((R.sup.2).sub.4N)CN where (R.sup.2).sub.4 indicates
four grows which may be the same or different and are selected from
hydrogen and straight chain or branched alkyl. Alternatively the
reaction may be carried out with Zn(CN).sub.2 in the presence of a
palladium catalyst
[0031] The palladium catalyst may be any suitable Pd(0) or Pd(II)
containing catalyst, such as Pd(PPh.sub.3).sub.4, Pd2(dba).sub.3,
Pd(PPh).sub.2Cl.sub.2, etc. The catalysts, the reaction conditions,
Cu.sup.+ and Zn.sup.++ sources, etc are further described in WO
0013648.
[0032] The palladium catalysed process is in particular convenient
when Z is Br.
[0033] When Z is Cl or Br, with a with a cyanide source in the
presence of a nickel catalyst, as described in WO 0011926.
Preferred cyanide sources are KCN, NaCN or ((R.sup.2).sub.4N)CN
where R.sup.2).sub.4 indicates four groups which may be the same or
different and are selected from hydrogen and straight chain or
branched alkyl. The reaction may optionally be carried out in the
presence of a catalytic amount of Cu.sup.+ or Zn.sup.2+.
[0034] The nickel catalyst may be any suitable Ni(0) or Ni(II)
containing complex which acts as a catalyst, such as
Ni(PPh.sub.3).sub.3, (.sigma.-aryl)-Ni(PPh.sub.3).sub.2Cl, etc and
it is preferably prepared in situ. The nickel catalysts and the
reaction conditions are further described in WO 0011926.
[0035] The nickel catalysed process is in particular convenient
when Z is Cl.
[0036] The intermediate of formula II wherein Z is bromo or chloro
may be prepared from bromo- and chlorophthalide, respectively, as
described in DE 2,657,013. The compound wherein Z is iodo or Z is
CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O-- may be prepared as
described in WO 0013648. Preferably the intermediate wherein Z is
Br is used.
[0037] The amide or amide-like group forming agent used in the
process of the invention is preferably a compound of Formula (a),
more preferably an acid anhydride or an acid halogenide, most
preferably acetic anhydride or acetyl chloride. This agent is used
in an amount of up to 10 mol/mol % of the amount of citalopram
dependent on the content of the desmethyl-impurity of formula
III.
[0038] The crude citalopram product resulting from the cyanide
exchange reaction may be subjected to some initial purification
before the citalopram product is reacted with an amide or an
amide-like group forming agent, e.g. extraction, crystalisation,
washing with a mixture of an aqueous and an organic solvent in
order to remove metal salts.
[0039] The acid/base wash may be performed by:
[0040] Dissolving the crude citalopram product comprising the amide
or amide like product of formula IV in a proper solvent, e.g.
toluene,
[0041] then adding an aqueous acid until the mixture is acidic
(e.g. until pH is about 0.5-3, more preferably about 1) and
separating the aqueous phase containing citalopram,
[0042] discarding the organic phase comprising the amide or
amide-like product of formula IV, and
[0043] then making the aqueous phase basic by addition of a base,
and dissolving the mixture in an organic solvent.
[0044] Then collecting the organic phase
[0045] The crude citalopram may be dissolved in any convenient
solvent, preferably toluene.
[0046] The acid used may be any mineral acid, for example HCl, HBr,
H.sub.2SO.sub.4 or H.sub.3PO.sub.4 or a carboxylic acid such as
acetic acid, and the base used may be any convenient base,
preferably NH.sub.3 or NaOH. The second organic solvent may be any
suitable solvent preferably the same as used in the first step of
the acid/base wash.
[0047] Further removal of the amide or amide-like product of
formula IV and other impurities may if necessary be carried out by
crystallisation and/or recrystallisation of the citalopram base
(cf. Dutch patent No 1016435) and/or crystallisation and
re-crystallisation of a pharmaceutically acceptable salt of
citalopram.
[0048] According to one preferred embodiment of the invention:
[0049] 5-Bromo citalopram is reacted with a cyanide source as
described above;
[0050] the resulting crude citalopram is isolated as the base in
the form of an oil;
[0051] the reaction mixture is washed with a mixture of an aqueous
solvent and an organic solvent, e.g. a mixture of
H.sub.2O/ethylenediamine and toluene or of an aqueous EDTA-solution
and toluene, in order to remove metal salt (originating from the
cyanide,source);
[0052] up to 10 mol/mol % acetic anhydride is added;
[0053] the reaction between the acetic anhydride and the
desmethyl-citalopram impurity is allowed to take place, either neat
or in a solvent;
[0054] the reaction mixture is acidified by addition of
hydrochloric acid;
[0055] the aqueous phase containing the citalopram product is
separated from the organic phase containing the acetamide impurity
of formula IV (A=acetyl);
[0056] The organic phase is discarded;
[0057] The aqueous phase is made basic by addition of NH.sub.3 or
NaOH and an organic solvent is added;
[0058] The organic phase is collected and the free base is
crystallised;
[0059] Thereafter, a pharmaceutically acceptable salt of
citalopram, such as the hydrobromide or hydrochloride, may be
prepared by methods known in the art.
[0060] Thus, the crystalline base may be reacted with either the
calculated amount of acid in a water miscible solvent, such as
acetone or ethanol, with subsequent isolation of the salt by
concentration and cooling, or with an excess of the acid in a water
immiscible solvent, such as ethylether, ethylacetate or
dichloromethane, with the salt separating spontaneously. The
hydrobromide or hydrochloride of citalopram obtained by the method
of the invention has a very high purity, preferably more than 99.7%
pure, most preferably more than 99.8% purity. Other salts of
citalopram, e.g. the oxalate, may also be obtained in a very pure
form by this process.
[0061] The pharmaceutical compositions of the invention may be
administered in any suitable way and in any suitable form, for
example orally in the form of tablets, capsules, powders or syrups,
or parenterally in the form of usual sterile solutions for
injection.
[0062] The pharmaceutical formulations of the invention may be
prepared by conventional methods in the art For example, tablets
may be prepared by mixing the active ingredient with ordinary
adjuvants and/or diluents and subsequently compressing the mixture
in a conventional tabletting machine. Examples of adjuvants or
diluents comprise: Corn starch, potato starch, talcum, magnesium
stearate, gelatine, lactose, gums, and the like. Any other adjuvant
or additive, colourings, aroma, preservatives etc. may be used
provided that they are compatible with the active ingredients.
[0063] Solutions for injections may be prepared by solving the
active ingredient and possible additives in a part of the solvent
for injection, preferably sterile water, adjusting the solution to
the desired volume, sterilising the solution and filling it in
suitable ampoules or vials. Any suitable additive conventionally
used in the art may be added, such as tonicity agents,
preservatives, antioxidants, etc.
[0064] Finally, it has been found that the base may be formulated
into very good and stable solid formulations with good release
properties (cf. Dutch patent No 1016435).
[0065] The invention is further illustrated by the following
examples.
EXAMPLE 1
Preparation of Crude Citalopram Base
(1-[3-(dimethylamino)propyl]-1-(4-flu-
orophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile)
[0066] Cu(I)CN (197 g, 2.2 mol) is added to a solution of
1-[3-dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromo-isobenz-
ofurane (720 g, 1.9 mol) in sulfolane (250 mL). After the reaction
mixture has been heated to 150.degree. C. for a period of 5 hours,
sulfolane (500 mL) is added. The reaction mixture is cooled to
80.degree. C. where ethylenediamine (aq, 50% w/v) is added. Toluene
(2 L) is added and the phases are separated.
[0067] The organic phase is further washed with EDTA (aq, 500 mL,
5% w/v) and water (2.times.500 mL). The volatile materials from the
organic phase are removed in vacuo.
[0068] 540 g of crude Citalopram base is isolated as an oil. Purity
approx. 85% by HPLC (Peak area)
EXAMPLE 2
Purification of Crude Citalopram by Removing
1-[3-(methylamino)propyl]-1-(-
4-fluorophenyl)-1,3dihydro-5-isobenzofurancarbonitrile as its
acetamide.
[0069] Crude citalopram base from Example 1 (324 g, 1 mol) having a
content of approx. 2.5% mol/mol of
1-[3-(methylamino)propyl]-1-(4-fluorop-
henyl)-1,3-(dihydro-5-isobenzofurancarbonitrile is dissolved in
toluene (1.5 L). Acetic anhydride (10 g, 0.1 mole) is added and the
reaction mixture is heated to 60.degree. C. for 30 min. Water (2 L)
is added, the pH is adjusted to 1 by adding cone. HCl (aq, 12 M)
and the phases are separated The organic phase is discarded and the
pH of the aqueous phase is adjusted to 9 with the addition of
ammonia (aq, 25% w/v). Toluene (1.5 L) is added and phases are
separated. The aqueous phase is discarded and the solvents are
removed from the organic phase in vacuo. A yield of 330 g of an oil
containing crude free base of citalopram and toluene is isolated.
The content of 1-[3-(methylamino)propyl]-1-(4-fluorophenyl)-1,3-
-dihydro-5-isobenzofuran-carbonitrile is <0.1% mol/mol.
* * * * *