Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-08
2002-09-24
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06455710
ABSTRACT:
The present invention relates to a process for the manufacture of the well-known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4fluorophenyl)-1,3 -dihydro-5-isobenzofuran-carbonitrile, in particular a process for preparing pure citalopram by cyanide exchange.
BACKGROUND OF THE INVENTION
Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure:
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.
Citalopram was fist 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′
3
—(CF
2
)
n
—SO
2
—O— with cyano are disclosed in WO 001 1926 and WO 0013648.
Other processes involve:
Conversion of a 5-amido or 5-ester group to a 5-cyano group (WO 9819513)
Conversion of a 5-amino group to a 5-cyano group (WO 9819512)
Conversion of a 5-formyl group to a 5-cyano group (WO 9900548)
Conversion of a 5-oxazolinyl or 5-thiazolinyl group to a 5-cyano group (WO 0023431)
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.
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-cyano, is necessary in order to obtain a commercially attractive manufacture of citalopram.
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
Accordingly, the present invention provides a novel process for the preparation of citalopram of formula
in which a compound of Formula II
wherein Z is iodo, bromo, chloro or CF
3
—(CF
2
)
n
—SO
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 selected from the agents of formulas (a), (b) or (c):
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;
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
the resulting citalopram product is optionally further purified, worked up and/or isolated as the base or as a pharmaceutically acceptable salt thereof.
In a 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.
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
According to the process of the invention, the desmethyl citalopram impurity of formula III
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:
wherein A is a group R—CO—, R′—CO—, R″—W—CY— or R′″—SO
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.
Throughout this specification with claims, halogen means chloro, bromo or iodo.
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.
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.
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:
When Z is Br, by reaction with cuprous cyanide in a suitable solvent as described in U.S. Pat. No. 4,136,193,
When Z is iodo, bromo, chloro or CF
3
—(CF
2
)
n
—SO
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
+
or Zn
2+
as described in WO 0013648. Preferred cyanide sources are KCN, NaCN or ((R
a
)
4
N)CN where (R
a
)
4
indicates four groups 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)
2
in the presence of a palladium catalyst.
The palladium catalyst may be any suitable Pd(0) or Pd(II) containing catalyst, such as Pd(PPh
3
)
4
, Pd
2
(dba)
3
, Pd(PPh)
2
Cl
2
, etc. The catalysts, the reaction conditions, Cu
+
and Zn
++
sources, etc are further described in WO 0013648.
The palladium catalysed process is in particular convenient when Z is Br.
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
a
)
4
N)CN where (R
a
)
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
+
or Zn
2+
.
The nickel catalyst may be any suitable Ni(0) or Ni(II) containing complex which acts as a catalyst, such as Ni(PPh
3
)
3
, (&sgr;-aryl)-Ni(PPh
3
)
2
Cl, etc and it is preferably prepared in situ. The nickel catalysts and the reaction conditions are further described in WO 0011926.
The nickel catalysed process is in particular convenient when Z is Cl.
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
3
—(CF
2
)
n
—SO
2
—O— may be prepared as described in WO 0013648. Preferably the intermediate wherein Z is Br is used.
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.
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, crystallisation, washing with a mixture of an aqueous and an organic solvent in order to remove metal salts.
The acid/base wash may be performed by:
Dissolving the crude citalopram product comprising the amide or amide like product of formula IV in a pr
Dancer Robert
Sbrogiò Federico
Villa Marco
H. Lundbeck A/S
Owens Amelia
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