U.S. patent application number 13/162059 was filed with the patent office on 2011-10-13 for process for preparation of citalopram and enantiomers.
This patent application is currently assigned to SUN PHARMA GLOBAL FZE. Invention is credited to Periyandi NAGARAJAN, Thennati RAJAMANNAR, Kilaru SRINIVASU.
Application Number | 20110251410 13/162059 |
Document ID | / |
Family ID | 39641935 |
Filed Date | 2011-10-13 |
United States Patent
Application |
20110251410 |
Kind Code |
A1 |
NAGARAJAN; Periyandi ; et
al. |
October 13, 2011 |
PROCESS FOR PREPARATION OF CITALOPRAM AND ENANTIOMERS
Abstract
The present invention provides a process for preparation of
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n car-bonitrile comprising reacting a compound of formula IVa, in
the presence of a base with a compound of formula RX, ##STR00001##
wherein R is selected from alkyl, alkenyl, aryl and heteroaryl
which may be optionally substituted with electron withdrawing
groups and X is selected from F, Cl, Br, I, CN, OTf and OR.sub.1,
wherein Tf represents trifluoromethanesulfonyl group, and R.sub.1
is optionally substituted alkyl, Z is a cyano group or a group that
may be converted to a cyano group; further wherein RX is selected
such that an intermediate ether derivative, a compound of formula
Va formed from said reaction cyclizes to a compound of formula VI,
##STR00002## and where Z is not a cyano group, conversion of the
group Z in the compound of formula VI to a cyano group to form
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile. The present invention also provides novel ether
compound, a compound of formula Va and a process for preparation
thereof.
Inventors: |
NAGARAJAN; Periyandi;
(Baroda, IN) ; SRINIVASU; Kilaru; (Baroda, IN)
; RAJAMANNAR; Thennati; (Baroda, IN) |
Assignee: |
SUN PHARMA GLOBAL FZE
Sharjah
AE
|
Family ID: |
39641935 |
Appl. No.: |
13/162059 |
Filed: |
June 16, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12024492 |
Feb 1, 2008 |
7989645 |
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13162059 |
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11660742 |
Feb 22, 2007 |
7790935 |
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PCT/IN2005/000276 |
Aug 12, 2005 |
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12024492 |
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Current U.S.
Class: |
549/467 |
Current CPC
Class: |
C07D 307/87
20130101 |
Class at
Publication: |
549/467 |
International
Class: |
C07D 307/87 20060101
C07D307/87 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 23, 2004 |
IN |
912/MUM/2004 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-i-
sobenzofuran carbonitrile or Escitalopram with HPLC purity greater
than 99.5% and a chiral purity greater than 99.5% obtained without
chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile, in more than 50% yield based on the
S-enantiomer of the compound of formula IVa, ##STR00022## wherein Z
is a cyano group or a group that may be converted to a cyano group
selected from the group consisting of halogen, --OH, --CHO,
--CH.sub.2OH, --CH.sub.2NH.sub.2, --CH.sub.2NO.sub.2, --CH.sub.3,
--CH.sub.2Cl, --CH.sub.2Br, --NHR.sub.2, --COOR.sub.3,
--CONR.sub.3R.sub.4 and CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O--
wherein n is 0-8, R.sub.2 is hydrogen or C1 to C6 alkylcarbonyl and
R.sub.2 and R.sub.3 are selected from hydrogen, optionally
substituted C1 to C6 alkyl or aryl and, a group of formula VII:
##STR00023## wherein Y is O or S; R.sub.5 and R.sub.6 are each
independently selected from hydrogen and C1 to C6 alkyl or R.sub.5
and R.sub.6 together form a C2 to C5 alkylene chain thereby forming
a spiro ring; R.sub.7 is selected from hydrogen, C1 to C6 alkyl,
R.sub.8 is selected from hydrogen, C1 to C6 alkyl, a carboxy group
or a precursor group thereof, or R.sub.7 and R.sub.8 together form
a C2 to C5 alkylene chain thereby forming a spiro ring.
5.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-i-
sobenzofuran carbonitrile or Escitalopram according to claim 4,
wherein the escitalopram has a chiral purity greater than
99.7%.
6.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-i-
sobenzofuran carbonitrile or Escitalopram according to claim 4,
wherein the escitalopram has a HPLC purity greater than 99.7%.
7.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-i-
sobenzofuran carbonitrile or Escitalopram according to claim 4,
wherein the escitalopram has a chiral purity greater than 99.7% and
an HPLC purity greater than 99.7%.
8.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-i-
sobenzofuran carbonitrile as claimed in claim 4, wherein the yield
represents a quantity greater than 10 kg escitalopram.
9.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-i-
sobenzofuran carbonitrile as claimed in claim 4, wherein the yield
represents a quantity greater than 30 kg escitalopram.
10.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram with an HPLC purity
greater than 99.2% and chiral purity greater than 99.8% obtained
without chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile, in more than 50% yield based on the
S-enantiomer of the compound of formula IVa, ##STR00024## wherein Z
is a cyano group or a group that may be converted to a cyano group
selected from the group consisting of halogen, --OH, --CHO,
--CH.sub.2OH, --CH.sub.2NH.sub.2, --CH.sub.2NO.sub.2, --CH.sub.3,
--CH.sub.2Cl, --CH.sub.2Br, --NHR.sub.2, --COOR.sub.3,
--CONR.sub.3R.sub.4 and CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O--
wherein n is 0-8, R.sub.2 is hydrogen or C1 to C6 alkylcarbonyl and
R.sub.2 and R.sub.3 are selected from hydrogen, optionally
substituted C1 to C6 alkyl or aryl and, a group of formula VII:
##STR00025## wherein Y is O or S; R.sub.5 and R.sub.6 are each
independently selected from hydrogen and C1 to C6 alkyl or R.sub.5
and R.sub.6 together form a C2 to C5 alkylene chain thereby forming
a Spiro ring; R.sub.7 is selected from hydrogen, C1 to C6 alkyl,
R.sub.8 is selected from hydrogen, C1 to C6 alkyl, a carboxy group
or a precursor group thereof, or R.sub.7 and R.sub.8 together form
a C2 to C5 alkylene chain thereby forming a spiro ring.
11.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile as claimed in claim 10, wherein the
yield represents a quantity greater than 10 kg escitalopram.
12.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile as claimed in claim 10, wherein the
yield represents a quantity greater than 30 kg escitalopram.
13.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram according to claim 10,
wherein the escitalopram has a HPLC purity greater than 99.5%.
14.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram according to claim 10,
wherein the escitalopram has a HPLC purity greater than 99.7%.
15.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram according to claim 11,
wherein the escitalopram has a HPLC purity greater than 99.5%.
16.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram according to claim 11,
wherein the escitalopram has a HPLC purity greater than 99.7%.
17.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram according to claim 12,
wherein the escitalopram has a HPLC purity greater than 99.5%.
18.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram according to claim 12,
wherein the escitalopram has a HPLC purity greater than 99.7%.
19.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile or Escitalopram with a sum of chiral
impurity and HPLC impurity no greater than 0.8% obtained without
chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile, in more than 50% yield based on the
S-enantiomer of the compound of formula IVa, ##STR00026## wherein Z
is a cyano group or a group that may be converted to a cyano group
selected from a group consisting of halogen, --OH, --CHO,
--CH.sub.2OH, --CH.sub.2NH.sub.2, --CH.sub.2NO.sub.2, --CH.sub.3,
--CH.sub.2Cl, CH.sub.2Br, --NHR.sub.2, --COOR.sub.3,
--CONR.sub.3R.sub.4 and CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O--
wherein n is 0-8, R.sub.2 is hydrogen or C1 to C6 alkylcarbonyl and
R.sub.2 and R.sub.3 are selected from hydrogen, optionally
substituted C1 to C6 alkyl or aryl and, a group of formula VII:
##STR00027## wherein Y is O or S; R.sub.5 and R.sub.6 are each
independently selected from hydrogen and C1 to C6 alkyl or R.sub.5
and R.sub.6 together form a C2 to C5 alkylene chain thereby forming
a spiro ring; R.sub.7 is selected from hydrogen, C1 to C6 alkyl,
R.sub.8 is selected from hydrogen, C1 to C6 alkyl, a carboxy group
or a precursor group thereof, or R.sub.7 and R.sub.8 together form
a C2 to C5 alkylene chain thereby forming a Spiro ring.
20.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile as claimed in claim 19, wherein the
yield represents a quantity greater than 10 kg escitalopram.
21.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile as claimed in claim 19, wherein the
yield represents a quantity greater than 30 kg escitalopram.
22.
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5--
isobenzofuran carbonitrile as claimed in any of the claims 19 to
21, wherein the sum of chiral impurity and HPLC impurity is not
greater than 0.5%.
Description
[0001] This is a Continuation application of U.S. application Ser.
No. 12/024,492, which is a Continuation-in-Part of application Ser.
No. 11/660,742 filed Feb. 22, 2007, which is a National Stage
Application filed under .sctn.371 of PCT Application No.
PCT/IN2005/000276 filed Aug. 12, 2005 which claims benefit of
priority to IN 912/MUM/2004 filed Aug. 23, 2004, the entire
disclosure(s) of the prior application(s), application Ser. No.
11/660,742 is considered part of the disclosure of the accompanying
continuation-in-part application and is hereby incorporated by
reference.
[0002] The invention provides a process for preparation of
(RS)-(.+-.)-1-[3-(di-methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-
-isobenzofuran carbonitrile (a compound of formula I, INN name for
the compound is citalopram) and its enantiomers viz.,
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile (a compound of formula II, known as
(S)-(+)-citalopram or escitalopram) and
(R)-(-)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran car-bonitrile (a compound of formula III) and acid
addition salts thereof.
##STR00003##
[0003] More particularly, the invention provides a process for
preparation of citalopram or its enantiomers via novel ether
intermediate compounds.
[0004] Citalopram was first disclosed in U.S. Pat. No. 4,136,193
and (S)-(+)-citalopram in USRE 34,712 (the '712 patent).
[0005] U.S. Pat. No. 4,650,884 teaches use of the diol, viz.,
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)-benzonitrile, a compound of formula IV in racemic form, which
is cyclized in presence of H.sub.2SO.sub.4 to obtain citalopram
(Scheme I).
##STR00004##
[0006] The '712 patent teaches preparation of (S)-(+)-citalopram, a
compound of formula II by using the enantiomeric diol compound of
formula IV, viz.,
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-but-
yl]-3-(hydroxymethyl)-benzonitrile, which is derivatized to obtain
a labile ester thereof like methanesulfonyl, p-toluenesulfonyl,
10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl.
The labile ester derivative is cyclized stereoselectively, in
presence of a base to obtain the (+)-isomer, namely
(S)-(+)-citalopram (Scheme II). When the '712 process was followed
by us escitalopram oxalate was obtained with chiral purity of less
than 99.2%.
##STR00005##
[0007] Lundbeck's patent U.S. Pat. No. 7,112,686 discloses a ring
closure of R-cyano diol (R isomer of compound of Formula IV) under
acidic conditions resulting in a mixture of isomers of compound of
Formula I with a surplus of S isomer. In accordance with the claims
in the patent, upon subjecting the mixture to repeated
crystallization, racemic citalopram is separated, leaving behind
almost pure escitalopram in the mother liquor. In examples
escitalopram having a chiral purity of 99.9% can be obtained and is
disclosed. However, apparently the product of first crystallization
is mixture of isomers or after repeated crystallizations a racemic
citalopram and escitalopram yields from the mother liquor are
therefore low. Therefore this is not a commercially feasible route
for the commercial preparation of escitalopram in high yields.
[0008] Lundbeck's US patent application US 2005/0065207 claims
liquid chromatographic separation of enantiomers of citalopram or
intermediates thereof using chiral stationary phase. It discloses
separation of (S) bromodiol from the racemic bromodiol and
separation of (S) bromocitalopram from the racemic bromocitalopram
using chiral chromatography. However, chiral chromatographic
separations are tedious and normally avoided on industrial scale.
Example 5 discloses cyanation of (+)bromocitalopram derivative to
obtain escitalopram of 99.6% e.e with 80% yield in this step.
[0009] WO 03/051861 (assignee: Lundbeck) claims methods of
resolving diols other than cyanodiol for example bromodiol. WO
05/047274 discloses and claims a process for preparation of
escitalopram.
[0010] The prior art strategies are based on cyclization of the
diol under acidic conditions to obtain citalopram or derivatization
through a labile ester derivative and cyclization in presence of a
base to obtain (S)-(+)-citalopram. These processes of prior art
have following disadvantages when the process is to be scaled-up
for industrial use: [0011] 1. Cyclization of the diol at higher
temperature using acids generates amide, acid, indene by-products
leading to formation of impure product. [0012] 2. Use of the labile
esters demonstrated for making enantiomers of citalopram requires
use of a reactive agents like methanesulfonyl chloride which could
give rise bismesylates and thus could lead to the formation of
undesired impurities. [0013] 3. For preparation of the labile
esters, organic bases like triethylamine, pyridine are used as
proton scavengers, the undesired labile esters of tertiary alcohol
group formed under the reaction condition can proceed via
non-concerted manner resulting in chirality perturbation and
impurity formation. The excess of base employed can also
participate in displacing the reactive ester to form the
corresponding ammonium derivatives due to its inherent
nucleophilicity. [0014] 4. The labile ester is sensitive to
moisture, temperature, resulting in decomposition.
[0015] There is a need for a convenient, robust process for
efficient preparation of citalopram and enantiomers thereof. The
present invention provides such a process for preparation of
citalopram and enantiomers thereof by use of the racemic or
enantiomeric diol intermediate, which is derivatized to obtain an
ether derivative thereof, which can be cyclised in-situ to obtain
citalopram or enantiomers thereof. The ether derivatives are formed
at the primary alcohol group of the diol intermediate by reacting
with aryls, heteroaryls or alkyls optionally substituted with
electron withdrawing groups.
[0016] None of the prior arts provide
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile or Escitalopram with chiral purity greater
than 99.8% obtained in more than 50% yield based on
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile or an equivalent precursor thereof, without
chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile or its precursors. We have found that the
process of the present invention provides such escitalopram of high
chiral purity in high yields without the need for chiral
chromatographic separation.
SUMMARY OF THE PRESENT INVENTION
[0017] The present invention provides a process for preparation of
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile comprising reacting a compound of formula IVa, in
the presence of a base with a compound of formula RX,
##STR00006##
[0018] wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and
OR.sub.1, wherein Tf represents trifluoromethanesulfonyl group, and
R.sub.1 is optionally substituted alkyl, Z is a cyano group or a
group that may be converted to a cyano group; further wherein RX is
selected such that an intermediate ether derivative, a compound of
formula Va formed from said reaction cyclizes to a compound of
formula VI,
##STR00007##
and where Z is not a cyano group, conversion of the group Z in the
compound of formula VI to a cyano group to form
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile.
[0019] The present invention in one embodiment provides a process
for preparation of
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile comprising reacting
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)benzonitrile, in the presence of a base, with a compound of
formula RX, wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and
OR.sub.1, wherein Tf represents trifluoromethanesulfonyl group, and
R.sub.1 is optionally substituted alkyl; further wherein RX is
selected such that an intermediate ether derivative, a compound of
formula V formed from said reaction,
##STR00008##
cyclizes to
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile.
[0020] The present invention provides novel ether compound, a
compound of formula Va, or acid addition salt thereof,
##STR00009##
[0021] wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups and Z is a cyano group or a group that may be
converted to a cyano group.
[0022] The present invention in one embodiment provides novel ether
compound, a compound of formula V or acid addition salt
thereof,
##STR00010##
[0023] wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups.
[0024] The present invention provides a process for preparation of
a compound of formula Va, comprising reacting a compound of formula
IVa, in the presence of a base with a compound of formula RX,
##STR00011##
[0025] wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and
OR.sub.1, wherein Tf represents trifluoromethanesulfonyl group, and
R.sub.1 is optionally substituted alkyl, Z is a cyano group or a
group that may be converted to a cyano group.
[0026] The present invention in one embodiment provides a process
for preparation of a compound of formula V,
##STR00012##
comprising reacting
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)benzonitrile, in the presence of a base, with a compound of
formula RX, wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and
OR1, wherein Tf represents trifluoromethanesulfonyl group, and R1
is optionally substituted alkyl.
[0027] The present invention also provides
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile or Escitalopram with chiral purity greater
than 99.8% obtained in more than 50% yield based on
(S)-(-)-1-[3-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile or an equivalent precursor thereof, without
chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile or its precursors. Particularly the present
invention can provide escitalopram with chiral purity greater than
99.8% in more than 50% yield, without use of chiral chromatographic
separation, and in commercial batch sizes of greater than 10 Kg
escitalopram, particularly in large batches greater than 30 Kg
escitalopram.
DETAILS OF THE PRESENT INVENTION
[0028] As used herein
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile may represent a racemic or an enantiomeric compound,
especially (S)-(+)-isomer thereof, unless otherwise specified.
[0029] The compound of formula IVa, the compound of formula Va or
the compound of formula VI represents a racemic or an enantiomeric
compound, unless otherwise specified. Z is a cyano group or a group
that may be converted to a cyano group. Such groups, Z, may be
selected from halogen, --OH, --CHO, --CH.sub.2OH,
--CH.sub.2NH.sub.2, --CH.sub.2NO.sub.2, --CH.sub.3, --CH.sub.2Cl,
--CH.sub.2Br, --NHR.sub.2, --COOR.sub.3, --CONR.sub.3R.sub.4,
CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O-- wherein n is 0-8, R.sub.2
is hydrogen or C1to C6 alkylcarbonyl and R.sub.2 and R.sub.3 are
selected from hydrogen, optionally substituted C1 to C6 alkyl or
aryl and, a group of formula VII:
##STR00013##
[0030] wherein Y is O or S; R.sub.5 and R.sub.6 are each
independently selected from hydrogen and C1 to C6 alkyl or R.sub.5
and R.sub.6 together form a C2 to C5 alkylene chain thereby forming
a spiro ring; R.sub.7 is selected from hydrogen, C1 to C6 alkyl,
R.sub.8 is selected from hydrogen, C1 to C6 alkyl, a carboxy group
or a precursor group thereof, or R.sub.7 and R.sub.8 together form
a C2 to C5 alkylene chain thereby forming a spiro ring.
[0031] When Z is halogen, in particular bromo or chloro, conversion
of the compound of formula VI to form
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile may be carried out by any process as known in the
art, for example as described in U.S. Pat. No. 4,136,193, PCT
publications WO 00/13648, WO 00/11926 or WO 01/02383.
[0032] Compounds of formula VI, wherein the group Z is
CF.sub.3--(CF.sub.2).sub.n--SO.sub.2--O--, wherein n is 0-8, may be
converted to
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile by methods analogous to those described in PCT
publication WO 00/13648.
[0033] Compounds of formula VI, wherein the group Z is --CHO, may
be converted to
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile by methods analogous to those described in PCT
publication WO 99/30548.
[0034] Compounds of formula VI, wherein the group Z is --NHR.sub.2,
wherein R.sub.2 is hydrogen or alkylcarbonyl, may be converted by
to
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile by methods analogous to those described in PCT
publication WO 98/19512.
[0035] Compounds of formula VI, wherein the group Z is --COOR.sub.3
or --CONR.sub.3R.sub.4, wherein R.sub.3 and R.sub.4 are selected
from hydrogen and optionally substituted alkyl or aryl may be
converted to
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile by methods analogous to those described in PCT
publications WO 98/19511 and WO 98/19513.
[0036] Compounds of formula VI, wherein the group Z is a group of
formula VII may be converted to
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile by methods analogous to those described in PCT
publication WO 00/23431.
[0037] Compounds of formula VI, wherein Z is OH, --CH.sub.2OH,
--CH.sub.2NH.sub.2, --CH.sub.2NO.sub.2, --CH.sub.2Cl, --CH.sub.2Br,
--CH.sub.3 or any of the groups above, may be converted to
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile by methods analogous to those described in PCT
publications WO 01/68632 and WO 01/85712.
[0038] Starting materials of formula IVa may be prepared according
to the above mentioned patents and patent applications, which are
incorporated herein by reference or by analogous methods known in
the art.
[0039] The compound RX is a compound, which can react with a
compound of formula IVa such as,
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)benzonitrile to form a ether derivative, a compound of formula
Va, via addition-elimination type reaction, X being any suitable
leaving group. A suitable leaving group is any group which upon
reaction of a compound of formula IVa with the compound RX,
facilitates formation of an ether derivative represented by a
compound of formula Va.
[0040] In a preferred embodiment RX is a compound of formula,
wherein R is selected from alkyl, alkenyl, aryl and heteroaryl
which may be optionally substituted with electron withdrawing
groups and X is selected from F, Cl, Br, I, CN, OTf and OR.sub.1,
wherein Tf represents trifluoromethanesulfonyl group, and R.sub.1
is alkyl optionally substituted with electron withdrawing
groups.
[0041] RX is further selected from compounds capable of forming an
ether derivative, a compound of formula Va.
[0042] In the process of the invention, a compound of formula Va is
formed by reaction of compound of formula IVa with a compound of
formula RX, in presence of a base. The compound of formula Va can
in-situ cyclize to form a compound of formula VI. If desired it can
be isolated and then subjected to cyclization in presence of a
base.
[0043] In a preferred embodiment, the ether derivative compound of
formula V, formed by reaction of
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)benzonitrile with a compound of formula RX, in presence of a
base, cyclizes in-situ to directly form
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile. However, if it is so desired, the ether derivative
compound of formula V may be isolated and subjected to cyclization
in presence of a base.
[0044] Further, preferably, the compound RX is not labile like
methanesulfonyl chloride used in the prior art, the '712 patent,
and thus resulting in an advantage of easier handling and storage
and leading to preparation of chirally pure S-(+)-citalopram end
product. The use of methanesulfonyl chloride may give rise to
bismesylates leading to formation of undesired impurities with
chirality perturbation.
[0045] The present invention provides novel ether compound, a
compound of formula Va, or acid addition salt thereof,
##STR00014##
and a process for preparation thereof comprising reacting a
compound of formula IVa, in the presence of a base, with a compound
of formula RX,
[0046] wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and
OR.sub.1, wherein Tf represents trifluoromethanesulfonyl group, and
R.sub.1 is optionally substituted alkyl, Z is a cyano group or a
group that may be converted to a cyano group.
[0047] The present invention in one embodiment provides novel ether
compound, a compound of formula V, or acid addition salt
thereof,
##STR00015##
and a process for preparation thereof comprising reacting
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxy
methyl)benzonitrile, in the presence of a base, with a compound of
formula RX,
[0048] wherein R is selected from alkyl, alkenyl, aryl and
heteroaryl which may be optionally substituted with electron
withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and
OR.sub.1, wherein Tf represents trifluoromethanesulfonyl group, and
R.sub.1 is optionally substituted alkyl.
[0049] In a preferred embodiment, the present invention provides
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-c-
hlorophenoxymethyl)benzonitrile, a compound of formula VIII, or
acid addition salt thereof,
##STR00016##
and a process for preparation thereof comprising reacting
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)-benzonitrile, in the presence of a base, with
2,5-dichloronitrobenzene.
[0050] In a more preferred embodiment, the present invention
provides novel
(S)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-
-nitro-4-chlorophenoxymethyl)benzonitrile or an acid addition salt
thereof for example, hydrochloride salt.
[0051] In a particularly preferred embodiment, the present
invention provides
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-buty-
l]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrile hydrochloride.
[0052] The acid addition salt of compound of formula V, Va or VIII
may be prepared by any standard method of contacting the compound
of formula V, Va or VIII with an acid, for example inorganic acid
like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid and the like or organic acid like oxalic
acid, citric acid, succinic acid, cinnamic acid, p-toluenesulfonic
acid and the like.
[0053] As used herein, "alkyl" may be any straight, branched, or
cyclic alkyl group of C1 to C6 atoms, optionally substituted with
one or more electron withdrawing groups selected from nitro, halo,
cyano, 4-trifluoroalkyl, 2,4-bis(trifluoroalkyl),
2,6-bis(trifluoroalkyl), --CHO, --COOR.sub.9, wherein R.sub.9 may
be alkyl, aryl or heteroaryl.
[0054] As used herein, "alkenyl" may be any straight, branched, or
cyclic alkyl group of C1 to C6 atoms, optionally substituted with
one or more electron withdrawing groups selected from nitro, halo,
cyano, 4-trifluoroalkyl, 2,4-bis(trifluoroalkyl),
2,6-bis(trifluoroalkyl), --CHO, --COOR.sub.9, wherein R.sub.9 may
be alkyl, aryl or heteroaryl.
[0055] As used herein, "aryl" may be a mono-, bi- or polycyclic
aromatic system, for example phenyl, naphthyl, optionally
substituted with one or more electron withdrawing groups selected
from nitro, halo, cyano, 4-trifluoroalkyl, 2,4-bis(trifluoroalkyl)
or 2,6-bis(trifluoroalkyl), --CHO, --COOR.sub.9, wherein R.sub.9
may be alkyl, aryl or heteroaryl.
[0056] As used herein, "heteroaryl" may be a mono-, bi- or
polycyclic aromatic system containing one or more hetero atom which
may be same or different, for example quinolinyl, isoquinolinyl,
pyridinyl, indanyl, fluorenyl, oxazolyl, pyrazinyl, thienyl,
quinazolinyl, benzimidazolyl and the like optionally substituted
with one or more electron withdrawing groups selected from nitro,
halo, cyano, 4-trifluoroalkyl, 2,4-bis(trifluoroalkyl) or
2,6-bis(trifluoroalkyl), --CHO, --COOR.sub.9, wherein R.sub.9 may
be alkyl, aryl or heteroaryl.
[0057] As used herein, "hetero atom" may preferably be selected
from N, O, S or P.
[0058] The base used may be selected from an alkoxide, wherein the
alkyl residue is C1 to C6 linear, branched or cyclic alkyl and the
counter ion is an alkali or alkaline earth metal; alkali or
alkaline earth metal oxide, hydroxide, carbonate or bicarbonate or
an amine base. The amine base may be selected from aliphatic or
aromatic amines, cyclic or acyclic amines, for example
isoquinolines, quinolines, dialkylarylamines, pyridine, substituted
pyridines. The base may be selected from moderate bases that do not
favor the formation of bisalkoxides thus providing control over the
derivatization of the primary alcohol group of the diol.
[0059] The ether derivative compounds represented by a compound of
formula V or Va can cyclize to form citalopram or enantiomers
thereof. When the diol compound, viz., a compound of formula IV or
IVa is used in enantiomeric form, derivatized to form an ether
derivative thereof, a compound of formula V or Va, it cyclizes
stereoselectively to afford enantiomerically pure citalopram.
[0060] In a preferred embodiment, the group R is:
##STR00017##
[0061] wherein one or more of a, b and c may be carbon or hetero
atom which may be same or different, P and Q may be selected from
electron withdrawing groups like NO.sub.2, CF.sub.3, CN, halogen,
COOR.sub.9, CHO and the like, wherein R.sub.9 is alkyl, aryl or
heteroaryl.
[0062] In another preferred embodiment the compound of formula RX
is selected from the group consisting of the following
compounds:
##STR00018##
[0063] In one embodiment the present invention provides a process
for preparation of racemic
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile comprising reacting racemic
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)-benzonitrile, with a compound of formula RX, in presence of a
base. Preferably the compound of formula RX is
dichloronitrobenzene.
[0064] In another embodiment the present invention provides a
process for preparation of enantiomeric
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile comprising reacting enantiomeric
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)-benzonitrile, with a compound of formula RX, in presence of a
base. Preferably the compound of formula RX is
dichloronitrobenzene.
[0065] In another preferred embodiment the present invention
provides a process for preparation of
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile comprising reacting
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile, with a compound of formula RX, in presence
of a base. Preferably the compound of formula RX is
dichloronitrobenzene.
[0066] In a particularly preferred embodiment the present invention
provides a process for preparation of
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile comprising reacting
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile with 2,5-dichloronitrobenzene, in presence
of a base to form a compound of formula VIII,
##STR00019##
and cyclization of compound of formula VIII.
[0067] The embodiment of the process of the present invention
whereby
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile, is reacted with a compound of formula RX,
in presence of a base has been found to be surprisingly
advantageous over the processes known in the art. This process is
capable of providing
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile or Escitalopram with chiral purity greater
than 99.8% obtained in more than 50% yield based on
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)-benzonitrile or an equivalent precursor thereof,
without chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile or its precursors. Particularly the process
can provide escitalopram with chiral purity greater than 99.8% in
more than 50% yield, without use of chiral chromatographic
separation, and in commercial batch sizes of greater than 10 Kg
escitalopram, particularly in large batches greater than 30 Kg
escitalopram.
[0068] As defined above the yield of escitalopram is based on the
precursor particularly
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile. Equivalent precursors that may be used in
the process of the present invention and from which the yields of
escitalopram may thereby be calculated include compounds of formula
IV a'
##STR00020##
Z, may be selected from halogen, --OH, --CHO, --CH.sub.2OH,
--CH.sub.2NH.sub.2, --CH.sub.2NO.sub.2, --CH.sub.3, --CH.sub.2Cl,
--CH.sub.2Br, --NHR.sub.2, --COOR.sub.3, --CONR.sub.3R.sub.4,
CF.sub.3--(CF.sub.2).sub.nSO.sub.2--O-- wherein n is 0-8, R.sub.2
is hydrogen or C1 to C6 alkylcarbonyl and R.sub.2 and R.sub.3 are
selected from hydrogen, optionally substituted C1 to C6 alkyl or
aryl and, a group of formula VII:
##STR00021##
[0069] wherein Y is O or S; R.sub.5 and R.sub.6 are each
independently selected from hydrogen and C1 to C6 alkyl or R.sub.5
and R.sub.6 together form a C2 to C5 alkylene chain thereby forming
a spiro ring; R.sub.7 is selected from hydrogen, C1 to C6 alkyl,
R.sub.8 is selected from hydrogen, C1 to C6 alkyl, a carboxy group
or a precursor group thereof, or R.sub.7 and R.sub.8 together form
a C2 to C5 alkylene chain thereby forming a spiro ring.
[0070] The process of the present invention may be carried out in
any suitable solvent. Examples of solvents that may be used are
alcohol solvents like methanol, ethanol, t-butanol,
polyethyleneglycol; ketone solvents like acetone, methyl iso-butyl
ketone; ether solvents like tetrahydrofuran, dioxane; ester
solvents like ethylacetate, butylacetate; amide solvents like
dimethylformamide, dimethylacetamide; nitrile solvents like
acetonitrile; dipolar aprotic solvents like dimethylsulfoxide,
sulfolane; hydrocarbon and aromatic hydrocarbon solvents having a
boiling point greater than 70.degree. C.
[0071] The process of the present invention can be carried out in a
suitable solvent with a base at temperature ranging from ambient to
the reflux temperature of the selected solvent. The reaction may be
completed in 0.5 to 40 hours, preferably 0.5 to 20 hours depending
on the selected solvent and base.
[0072] In a typical procedure, the reaction may be worked-up by
quenching by addition of 2 to 10 volumes, preferably 3 to 8 volumes
of water to the reaction solvent, depending on the product
solubility in the selected solvent, at temperature between the
range of 0.degree. C. to 100.degree. C., preferably 20.degree. C.
to 60.degree. C. The reaction mixture may be extracted with a
suitable water-immiscible solvent like toluene, ether,
ethylacetate.
[0073] If desired,
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofura-
n carbonitrile may be converted to a pharmaceutically acceptable
acid addition salt thereof by treatment with organic or inorganic
acid. Examples of organic acids are oxalic, fumaric, succinic
mandelic, benzoic, p-toluenesulfonic acid and the like. Examples of
inorganic acids are hydrobromic, hydrochloric, sulfuric,
phosphoric, nitric and the like. The preparation of salt formation
may be carried out in a solvent like acetone, water, methanol,
isopropanol, dimethylformamide or mixture thereof.
[0074] The worked out examples given below illustrate the process
and not to be construed as limiting.
EXAMPLES
Example 1
Preparation of citalopram oxalate
[0075] To a solution of 10 gm of (RS)-(+)
4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymeth-
yl)-benzonitrile in 50 ml of dimethylsulfoxide (DMSO) at room
temperature was added 12 gm of anhydrous K.sub.2CO.sub.3 and 6.73
gm of 2,5-dichloronitrobenzene was added to the above reaction
mixture at room temperature and stirred at 100.degree. C. for 15
hours. To the reaction mixture, 250 ml of water was added and
extracted with toluene, the toluene layer was washed with water and
5% sodium hydroxide solution and after acid base treatment yielded
an oily product. The oil was dissolved in 40 ml of acetone at
30.degree. C. and 3.4 gm of oxalic acid dihydrate was added to it,
stirred, cooled, filtered and dried at 60.degree. C.
[0076] Dry wt: 7.8 gm.
Example 2
Preparation of (S)-(+)-citalopram oxalate
[0077] To a solution of 6 gm of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 60 ml tetrahydrofuran (THF) was added
4.33 gm of potassium tertiary butoxide at 0-10.degree. C. and
stirred for 30 minutes. A solution of 4.04 gm of
2,5-dichloronitrobenzene in 30 ml THF at 0-10.degree. C. was added
to it and stirred for 10-15 hours at room temperature, followed by
addition of 250 ml of water. The reaction mixture was extracted
with toluene, the toluene layer was washed with water and 5% sodium
hydroxide solution and after acid base treatment yielded an oily
product. The oil was dissolved in 16 ml of acetone at 30.degree. C.
and 1.75 gm of oxalic acid dihydrate in 8 ml acetone was added to
it, stirred, cooled, filtered and dried at 60.degree. C. to get the
oxalic acid salt of (S)-(+)-1-[3-(dimethylamino)
propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran
carbonitrile.
[0078] Dry wt: 4.3 gm, [.alpha.].sub.D=+11.8.degree. (c=1,
methanol).
[0079] Chiral HPLC: R-isomer content: 0.64%
Example 3
Preparation of (S)-(+)-citalopram oxalate
[0080] To a solution of 6.0 gm of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 30 ml of DMSO at room temperature was
added 7.3 gm of anhydrous K.sub.2CO.sub.3 and 4.04 gm of
2,5-dichloronitrobenzene was added to the above reaction mixture at
room temperature and stirred at 100.degree. C. for 15.0 hours. To
the above reaction mixture, 120 ml of water was added, and
extracted with toluene. The toluene layer was washed with water and
5% sodium hydroxide solution and after acid base treatment yielded
an oily product. The oil was dissolved in 16 ml of acetone at
30.degree. C. and 1.9 gm of oxalic acid dihydrate in 8 ml of
acetone was added to it, stirred, cooled, filtered and dried at
60.degree. C.
[0081] Dry wt: 4.1 gm, [.alpha.].sub.D=+12.62.degree. (c=1,
methanol).
[0082] Chiral HPLC: R-isomer content: 0.2%
Example 4
Preparation of (S)-(+)-citalopram oxalate
[0083] To a solution of 64 Kg of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 300 lit DMSO was added 77.48 Kg of
anhydrous K.sub.2CO.sub.3 and 43.06 Kg of 2,5-dichloronitrobenzene
at room temperature and stirred for 16 hours at 100-105.degree. C.
To the reaction mixture 3000 ml of water was added at about
30.degree. C. The reaction mixture was extracted with toluene, the
toluene layer was washed with water and 5% sodium hydroxide
solution and after acid base treatment yielded an oily product. The
oil was dissolved in 510 lit of isopropanol at about 30.degree. C.
and 20.4 lit water added, stirred for 10 minutes and 20.8 Kg of
oxalic acid dihydrate was added and heated to about 70-75.degree.
C., stirred, charcolised, cooled and filtered. The filtrate was
cooled to 5-10.degree. C. slowly and the resultant solid was
filtered, dried at 60.degree. C. and micronised to get the oxalic
acid salt of
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydr-
o-5-isobenzofuran carbonitrile.
[0084] Dry wt: 61.5 Kg, [.alpha.].sub.D=+13.85.degree. (c=1,
methanol).
[0085] Chiral HPLC: R-isomer content: 0.38%.
[0086] Purity by HPLC: 99.25%.
Example 5
Preparation of
S-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nit-
ro-4-chlorophenoxymethyl)-benzonitrile hydrochloride
[0087] To a solution of 5.6 gm of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 85 ml THF was added 2.02 gm of potassium
tertiary butoxide at 0-10.degree. C. and stirred for 10 min. 3.14
gm of 2,5-dichloronitrobenzene was added to the reaction mixture at
0-10.degree. C. and stirred for 10-15 hrs at RT (30-35.degree. C.),
solvent distilled under vacuum and 40 ml of water was added, and
extracted with toluene, toluene layer was washed with water and 10%
sodium hydroxide solution and distilled to get an oily product,
which is purified by column chromatography using silica gel and
ethylacetate, Wt: 500 mg. The above oily product was dissolved in
10 ml of isopropanol (IPA) at 30.degree. C. and 2.0 ml of IPA-HCl
was added, stirred and solvent distilled under vacuum and
crystallized in IPA to get
(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-
-4-chlorophenoxymethyl)-benzonitrile hydrochloride whose structure
was confirmed by IR, NMR and Mass spectral data.
[0088] Dry wt: 300 mg, [.alpha.].sub.D=-46.8.degree. (c=1,
methanol).
[0089] Analysis calculated for C26H26N3O4Cl2F: C, 58.44; H, 4.90;
N, 7.86; found: C, 57.42; H, 4.65; N, 7.33.
[0090] .sup.1HNMR (400.13 MHz, DMSO-d6) .delta.1.42-1.43 (broad m,
1H); 1.75-1.76(broad m,1H); 2.32-2.47(m, 2H); 2.70(s,6H);
3.00-3.13(m, 2H); 5.03(d, J=14.01 Hz, 1H); 5.43(d, J=14.04 Hz,1H);
6.43(s,1H); 6.52(d, J=9.09 Hz, 1H,); 7.18(t, J=8.85 Hz, 2H);
7.39(dd, J.sub.1=8.71 Hz, J.sub.2=5.41 Hz, 2H); 7.54(dd,
J.sub.1=8.97 Hz, J.sub.2=2.63 Hz, 1H); 7.90(s, 1H); 7.96(d, J=8.25
Hz,1H); 8.03(d, J=8.25 Hz, 1H,); 8.08(d, J=2.63 Hz, 1H); 10.36(s,
1H).
[0091] .sup.13CNMR (100.61 MHz, DMSO-d6) .delta.18.44 (t); 38.87
(t); 41.86 (2q); 56.47 (t); 67.83 (t); 76.63(s); 110.49(s);
114.84(2d, J=21.23 Hz); 116.11(d); 124.93(d); 118.48(s); 124.17(s);
127.57(d); 127.88(2d, J=8.02 Hz); 130.99(d); 131.31(d); 133.84(d);
136.47(s); 139.55(s); 140.89[s(d, J=2.80 Hz)]; 149.27(s);
149.45(s); 160.91[s(d, J=243.67 Hz)].
[0092] Mass: CI Mode, M.sup.+=498.20(0.87%);
(M-173)=325.30(100.0%).
[0093] IR (KBr): cm-.sup.1 735.02, 747.45; 1162.70, 1230.44;
1507.93, 1603.51; 1283.12, 1528.82; 2226.34; 2935.53, 3039.88,
3062.31; 3249.93.
Example 6
Preparation of (S)-(+)-citalopram
[0094] To a solution of 100 mg of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-n-
itro-4-chlorophenoxymethyl)benzonitrile hydrochloride in 2.0 ml of
DMSO was added 64.5 mg of potassium carbonate at 30-35.degree. C.
and stirred for 30 min at 95-100.degree. C. After reaction
completion which is monitored by TLC, 40 ml of water was added, and
extracted with toluene, toluene layer was washed with water and 10%
sodium hydroxide solution and distilled out toluene to get an oily
product.
[0095] Wt: 65.0 mg
[0096] Chiral HPLC: S-isomer content: 100%.
[0097] .sup.1HNMR (400.13 MHz, CDCl.sub.3) .delta.1.27-1.38 (m,1H);
1.41-1.53 (m,1H); 2.13(s, 6H);2.09-2.25(m, 4H); 5.15(d, J=12.96 Hz,
1H); 5.19(d, J=12.96 Hz, 1H); 6.98-7.02(m, 2H); 7.38-7.49(m, 4H);
7.58(d, J=7.77 Hz, 1H).
Example 7
Preparation of (S)-(+)-citalopram
[0098] Given Below in Table I is the Comparison Between
(S)-(+)-citalopram oxalate Prepared by:
[0099] A] the prior art process using the methanesulfonyl ester
derivative (Experiments A(1), A(2) and A(3)) and
[0100] B] the process of the present invention using the ether
derivative compound VIII (Experiments B(1), B(2) and B(3)):
TABLE-US-00001 TABLE I (S)-(+)-citalopram oxalate Chiral HPLC Input
Batch purity % Specific optical HPLC Experiment No. of the S- R-
rotation Unknown No. Batch No. starting diol isomer isomer (1%
methanol) Purity % impurity % A(1) 1511- PN 42701 98.96 1.04
+13.1.degree. 99.59 0.18 S/F/771/15 A(2) 1511- PN 41864 99.16 0.84
+13.0.degree. 99.69 0.09 S/F/771/16 A(3) 1511- 1511- 99.15 0.85
+12.9.degree. 98.95 0.6 S/F/771/20 S/II/771/10A B(1) 1511- PN 42701
99.66 0.34 +13.2.degree. 99.76 0.05 S/F/771/17 B(2) 1511- PN 41864
99.62 0.38 +13.1.degree. 99.77 0.05 S/F/771/18 B(3) 1511- 1511-
99.77 0.23 +13.4.degree. 99.76 0.03 S/F/771/19 S/II/771/10A
Experiment A(1):
[0101] To a solution of 16 gm of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 128 ml dichloromethane was added 14.2 gm
of triethylamine, stirred and cooled and 8.0 gm of
methanesulfonylchloride was added at below 10.degree. C. and
stirred at less than 10.degree. C. for 1.0 hr. To the reaction
mixture 65 ml of water was added and extracted with
dichloromethane. The dichloromethane layer was washed with water
and distilled and dissolved the material in toluene, the toluene
layer was washed with water and distilled to get an oily product.
The oil was dissolved in 50 ml acetone and 5.12 gm of oxalic acid
dihydrate in 50 ml acetone was added to it at room temperature,
stirred and cooled. The filtrate was cooled to 5-10.degree. C.
slowly and the resultant oxalate salt was filtered, dried at
60.degree. C. and purified by dissolving in 420 ml acetone, heated
to reflux temperature, stirred to get clear solution, charcolized
and distilled to a residual volume of 75 ml, cooled to 5-10.degree.
C. slowly and the resultant solid was filtered, dried at 60.degree.
C. to get the oxalic acid salt of
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile.
[0102] Dry wt: 9.4 gm
[0103] [.alpha.].sub.D=+13.1.degree. (c=1, methanol).
[0104] Chiral HPLC: R-isomer content: 1.04%.
[0105] Purity by HPLC: 99.59%.
[0106] Experiments A(2) and A(3) have been carried out in similar
way as in Experiment No. A(1). Comparative Experiments A(1), A(2)
and A(3) have been carried out according to the teaching of prior
art, U.S. Pat. No. Re 34712, which is incorporated herein by
reference.
Experiment B(1):
[0107] To a solution of 16 gm of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 75 ml DMSO was added 19.3 gm of
anhydrous K.sub.2CO.sub.3 and 10.8 gm of 2,5-dichloronitrobenzene
at room temperature and stirred for 15 hours at 100-105.degree. C.
To the reaction mixture 750 ml of water was added at about
30.degree. C. The reaction mixture was extracted with toluene, the
toluene layer was washed with water and 5% sodium hydroxide
solution and after acid base treatment yielded an oily product. The
oil was dissolved in a mixture of 125 ml IPA and 5 ml water at
30.degree. C. and 5.3 gm of oxalic acid dihydrate was added to it,
heated to 70-75.degree. C., stirred and charcolized to get clear
solution, cooled to 5-10.degree. C. slowly and the resultant
oxalate salt was filtered, dried at 60.degree. C. and purified by
dissolving in a mixture of 140 ml isopropanol and 5.6 ml water at
30.degree. C. heated to 70-75.degree. C., stirred to get a clear
solution, cooled to 5-10.degree. C. slowly and the resultant solid
was filtered, dried at 60.degree. C. to get the oxalic acid salt of
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile.
[0108] Dry wt: 13.3 gm
[0109] [.alpha.].sub.D=+13.2.degree. (c=1, methanol).
[0110] Chiral HPLC: R-isomer content: 0.34%.
[0111] Purity by HPLC: 99.76%.
[0112] Experiments B(2) and B(3) have been carried out in similar
way as in Experiment No. B(1), which illustrate the process of the
present invention.
[0113] It is evident from the data presented in Table I and the
worked out examples, that (S)-(+)-citalopram prepared by the
process of the present invention contains R-isomer in the range of
0.00 to 0.38%, whereas (S)-(+)-citalopram prepared by the prior art
process of methanesulfonyl ester derivative contains R-isomer in
the range of 0.84 to 1.04%.
Example 8
Preparation of (S)-(+)-citalopram oxalate
[0114] To a solution of 54.5 kg of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 255 lit DMSO was added 66.0 kg of
anhydrous K.sub.2CO.sub.3 and 36.7 kg of 2,5-dichloronitrobenzene
at room temperature and stirred for 16 hours at 100-105.degree. C.
To the reaction mixture 2550 lit of water was added at about
30.degree. C. The reaction mixture was extracted with toluene, the
toluene layer was washed with water and 5% sodium hydroxide
solution and after acid base treatment yielded an oily product. The
oil was dissolved in 435 lit IPA at 30.degree. C. and 17.7 kg of
oxalic acid dihydrate was added to it, heated to 70-75.degree. C.,
stirred and charcolised the clear solution, cooled, The filtrate
was cooled to 5-10.degree. C. slowly and the resultant solid was
filtered, dried at 60.degree. C. and micronised to get the oxalic
acid salt of
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile.
[0115] Dry wt: 44.2 kg (% Yield=67%),
[.alpha.].sub.D=+12.94.degree. (c=1, methanol).
Chiral HPLC: R-Isomer Content: 0.08%.
[0116] Purity by HPLC: 99.56%.
[0117] It is seen that this example provides
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile or Escitalopram with chiral purity greater
than 99.8% obtained in more than 50% yield based on
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile or an equivalent precursor thereof, without
chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile or its precursors, and in commercial batch
size of greater than 30 Kg escitalopram.
Example 9
Preparation of (S)-(+)-citalopram oxalate
[0118] To a solution of 54.5 kg of
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile in 255 lit DMSO was added 66.0 kg of
anhydrous K.sub.2CO.sub.3 and 36.7 kg of 2,5-dichloronitrobenzene
at room temperature and stirred for 16 hours at 100-105.degree. C.
To the reaction mixture 2550 lit of water was added at about
30.degree. C. The reaction mixture was extracted with toluene, the
toluene layer was washed with water and 5% sodium hydroxide
solution and after acid base treatment yielded an oily product. The
oil was dissolved in 435 lit IPA at 30.degree. C. and 17.7 kg of
oxalic acid dihydrate was added to it, heated to 70-75.degree. C.,
stirred and charcolised the clear solution, cooled, The filtrate
was cooled to 5-10.degree. C. slowly and the resultant solid was
filtered, dried at 60.degree. C. and micronised to get the oxalic
acid salt of
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile.
[0119] Dry wt: 46.10 kg, [.alpha.].sub.D=+13.28.degree. (c=1,
methanol).
[0120] Chiral HPLC: R-isomer content: 0.05%.
[0121] Purity by HPLC: 99.62%.
[0122] It is seen that this example provides
(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isob-
enzofuran carbonitrile or Escitalopram with chiral purity greater
than 99.8% obtained in more than 50% yield based on
(S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hyd-
roxymethyl)benzonitrile or an equivalent precursor thereof, without
chiral chromatographic separation of
(.+-.)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobe-
nzofuran carbonitrile or its precursors, and in commercial batch
size of greater than 30 Kg escitalopram.
* * * * *