Improved syntheses of N-desmethylcitalopram and N,N-didesmethylcitalopram

Article abstract of DOI:10.1080/00397910601163745

An improved and efficient synthesis of N-desmethylcitalopram (2) and N,N-didesmethylcitalopram (3) is presented. The method involved N-demethylation of citalopram (1) using 1-chloroethyl chloroformate to give 2 in 87% yield. Synthesis of 3 was accomplished by alkylation of 8 with 1-(3-bromopropyl)-2,2,5, 5-tetramethyl-1-aza-2,5-disilacyclopentane (9). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601163745

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Improved Syntheses of
N‐Desmethylcitalopram and
N,N‐Didesmethylcitalopram
Chunyang Jin a , Karl G. Boldt a , Kenneth S. Rehder a & George A. Brine a
a Organic and Medicinal Chemistry, Science and Engineering Group, Research
Triangle Institute, Research Triangle Park, North Carolina, USA
Version of record first published: 24 Feb 2007.
To cite this article: Chunyang Jin, Karl G. Boldt, Kenneth S. Rehder & George A. Brine (2007): Improved
Syntheses of N‐Desmethylcitalopram and N,N‐Didesmethylcitalopram, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:6, 901-908
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Synthetic Communicationsw, 37: 901–908, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601163745
Improved Syntheses
of N-Desmethylcitalopram
and N,N-Didesmethylcitalopram
Chunyang Jin, Karl G. Boldt, Kenneth S. Rehder,
and George A. Brine
Organic and Medicinal Chemistry, Science and Engineering Group,
Research Triangle Institute, Research Triangle Park, North Carolina, USA
Abstract: An improved and efficient synthesis of N-desmethylcitalopram (2) and N,N-
didesmethylcitalopram (3) is presented. The method involved N-demethylation of cita-
lopram (1) using 1-chloroethyl chloroformate to give 2 in 87% yield. Synthesis of 3
was accomplished by alkylation of 8 with 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-
aza-2,5-disilacyclopentane (9).
Keywords: citalopram, N-desmethylcitalopram, N,N-didesmethylcitalopram, N-
demethylation
INTRODUCTION
Citalopram (CIT, 1, Figure 1), a selective serotonin reuptake inhibitor (SSRI),
is one of the most widely used antidepressants for the treatment of anxiety,
obsessional, and control disorder.[1] CIT is metabolized mainly in the liver
by cytochrome P450 (CYP2C19, CYP2D6, and CYP3A4 subtypes), and its
most abundant active metabolites are N-desmethylcitalopram (DCIT, 2) and
N,N-didesmethylcitalopram (DDCIT, 3).[2] To monitor citalopram and its
metabolites in biological fluids by analytical methods (e.g., liquid chromato-
graphy and capillary electrophoresis), the authentic samples of DCIT and
Received in the USA July 27, 2006
Address correspondence to Chunyang Jin, Organic and Medicinal Chemistry,
Science and Engineering Group, Research Triangle Institute, P.O. Box 12194,
Research Triangle Park, NC 27709, USA. E-mail: cjin@rti.org
901

902
C. Jin et al.
Figure 1. Structures of citalopram (1), N-desmethylcitalopram (2) and N,N-dides-
methylcitalopram (3).
DDCIT were needed as standards. In 1977, Bigler and coworkers reported the
first syntheses of DCIT and DDCIT.[3] DCIT was prepared by N-demethylation
of citalopram using trichloroethyl chloroformate followed by zinc reduction in
acetic acid. However, the yield of this demethylation was only 43%, and zinc
dust is difficult to handle in a large-scale reaction and the subsequent workup
process. In the case of DDCIT, experimental details of the key step, alkylation
of 1-(4-fluoropheny1)-5-phthalancarbonitrile with 3-chloropropyl amine, were
not given in the article. As a part of an ongoing research program, we needed to
synthesize samples of DCIT and DDCIT. In this article, we report on an
improved and efficient synthesis of DCIT and DDCIT.
RESULTS AND DISCUSSION
The N-demethylation of tertiary methylamines has been accomplished in
several ways. These include reaction with cyanogen bromide (von Braun
reaction)[4] or a substituted chloroformate[5] followed by cleavage of the
resultant cyanamide or carbamate. Among those reported chlorofomates[6,7]
1-chloroethyl chloroformate (ACE-Cl) is one of the most selective and
effective reagents for the N-demethylation reaction.[8] The application of
ACE-Cl for N-demethylation of citalopram in 1,2-dichloroethane was first
investigated. Citalopram (1) was treated with 4 equivalents of ACE-Cl in
refluxing 1,2-dichloroethane for 24 h. Surprisingly, no N-demethylation
1
product was observed based on H NMR and MS spectral analyses of the
crude product mixture. The starting material 1 was recovered in 81% yield.
After extensive optimization, it was found that treatment of 1 with neat
ACE-Cl (20 equivalents) at 1308C for 6 h generated carbamate 4, which

Syntheses of DCIT and DDCIT
903
was hydrolyzed without purification in boiling methanol to give crude N-des-
methylcitalopram (2) (Scheme 1). This hydrolysis process also produced a
small amount of methyl ester 5, a by-product of an acid-catalyzed methanoly-
sis of 2. Column chromatography to separate 2 from 5 failed because of their
similar polarities. Therefore, the ester 5 was converted to its carboxylate salt
by treatment of the mixture with 1 N NaOH in THF. Subsequent chloromato-
graphy provided pure N-desmethylcitalopram (2) in 87% yield.
Synthesis of N,N-didesmethylcitalopram (3) was accomplished following
the route outlined in Scheme 2. 1-(4-Fluorophenyl)-5-phthalancarbonitrile (8)
was prepared in 58% yield from commercial 5-bromophthalide (6) following
the literature report,[3] although a modification of the workup conditions was
required for the last step. Thus, in our hands, 5-bromo-1-(4-fluorophe-
nyl)phthalan (7) was treated with copper(I) cyanide in refluxing N,N-
dimethylformamide for 6 h. Afterward, the reaction mixture was diluted
with concentrated aqueous NH4OH followed by bubbling the solution with
a steam of air to remove copper(I). This avoided the use of highly toxic
sodium cyanide in the workup. According to Bigler et a1.,[3] alkylation of 8
with 3-chloropropyl amine would produce N,N-didesmethylcitalopram (3).
However, because the experimental detail and yield of this key step
Scheme 1.

904
C. Jin et al.
Scheme 2.
were not given in their paper, we decided to use a suitable N-protected 3-bro-
mopropyl amine instead of the unprotected 3-chloropropyl amine because of
the basic and nucleophilic nature of free NH2 group. Double N-protected
groups for primary amines including N,N-di(t-butoxycarbonyl), phthalimide,
N,N-dibenyzl, and N,N-diallyl groups are well-documented in the literature.[9]
However, these protecting groups meet with limitations or incompatibilities
with regard to the alkylation procedure (e.g., phthalimide derivative[10] or
the deprotection step (e.g., N,N-dibenyzl[11] and N,N-diallyl)[12]. Treatment
of 8 with sodium methylsufinylmethide and N-(3-bromopropyl)phthalimide
(11) gave 13 in 47% yield as the only isolated product.
It has been reported that the cyclic tetramethyldisilazane protecting
group is stable in n-BuLi or lithium diisopropylamine (LDA) conditions
required for alkylation.[13] The silyl protecting group can be easily removed
using tetrabutylammonium fluoride (TBAF). Thus, 1-(4-fluoropheny1)-5-
phthalancarbonitrile (8) was treated with sodium methylsufinylmethide,
generated from sodium hydride and dimethylsulfoxide, followed by the addition

Syntheses of DCIT and DDCIT
905
of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (9).
Surprisingly, the desired product 10 was not isolated after aqueous workup.
Instead, N,N-didesmethylcitalopram (3), the desilylated product, was
obtained pure in almost quantitative yield.
In summary, we report an improved and efficient synthesis of N-des-
methylcitalopram (2) and N,N-didesmethylcitalopram (3). The method
involved N-demethylation of citalopram (1) using 1-chloroethyl chlorofor-
mate to give 2 in 87% yield. N,N-Didesmethylcitalopram (3) was prepared
in 57% yield from 5-bromophthalide.
EXPERIMENTAL
Melting points were determined on a Mel-Temp II capillary melting-point
apparatus and are uncorrected. NMR (1H and 13C) spectra were obtained
using a Bruker Avance DPX 300-MHZ NMR spectrometer. Chemical shifts
are reported in parts per million (ppm) with reference to internal solvent.
High resolution mass spectrum (HRMS) were recorded on a Waters Autospec
Ultima mass spectrometer. Elemental analyses were done by Atlantic
Microlab Inc., Norcross, GA. Analytical thin-layer chromatography (TLC)
was carried out using EMD silica-gel 60 F254 TLC plates. Flash-column chrom-
atography was done on a CombiFlash Companion system using Isco prepacked
silica-gel columns. Reagents were normally obtained from Aldrich Chemical
Company and used as received unless otherwise noted.
N-Desmethylcitalopram (2)
To a mixture of citalopram hydrobromide (0.55 g, 1.36 mmol) in EtOAc
(50 mL), dilute aqueous NH4OH (10 mL) was added. The EtOAc layer was
separated, washed with brine (3 ꢀ 10 mL), dried (Na2SO4), and concentrated
in vacuo. The resultant free base was dissolved in 1-chloroethyl chloroformate
(2.96 mL, 2.72 mmol). The reaction mixture was heated 6 h at 1308C, cooled
to room temperature, and then concentrated in vacuo. The residue was taken
up in MeOH (15 mL) and refluxed for 5 h. After this time, the solvent was
evaporated, and the residue was vacuum dried. The resultant crude product
was dissolved in THF (5 mL), and 1 N NaOH (5 mL), was added to the
solution. After stirring overnight, the reaction mixture was diluted with
EtOAc (50 mL), washed with brine (3 ꢀ 10 mL), dried (Na2SO4), and con-
centrated in vacuo. Chromatography (12 g of Isco silica-gel column) using
0 ! 50% MeOH-CH2Cl2 afforded 2 (0.31 g, 87%) as an oil: 1H NMR
(300 MHz; CDC13) d 1.25–1.55 (2H, m), 2.10–2.30 (2H, m), 2.39 (3H, s),
2.61 (2H, t, J ¼ 6.0 Hz), 2.96 (1H, br s), 5.14 (1H, d, J ¼ 12 Hz), 5.21 (1H,
d, J ¼ 12 Hz), 6.95–7.05 (2H, m), 7.36–7.48 (3H, m), 7.50 (1H, s), 7.66–
7.75 (1H, m); 13C NMR (75 MHz; CDCl3) d 23.7, 35.7, 38.8, 51.4, 71.3,

906
C. Jin et al.
91.1, 111.7, 115.3 (d, JC-F ¼ 21 Hz), 118.6, 122.8, 125.2, 126.8 (d, JC-F
¼
8 Hz), 131.9, 139.5 (d, JC-F ¼ 3 Hz), 140.3, 149.3, 162.0 (d, JC-F ¼ 245 Hz).
The free base was converted to the oxalate salt as a white solid: mp 139–
1
1418C; H NMR (300 MHz; CD3OD) d 1.40–1.65 (2H, m), 2.10–2.32 (2H,
m), 2.54 (3H, s), 2.91 (2H, t, J ¼ 7.7 Hz), 5.09 (1H, d, J ¼ 13.2 Hz), 5.17
(1H, d, J ¼ 13.2 Hz), 6.94–7.04 (2H, m), 7.43–7.65 (5H, m); Anal. calcd.
for C21H21FN2O5: C, 62.99; H, 5.29; N, 7.00. Found: C, 62.65; H, 5.26; N,
6.96.
1-(4-Fluorophenyl)-5-phthalancarbonitrile (8)
A mixture of 7 (7.14 g, 24.0 mmol) and CuCN (2.58 g, 28.8 mmol) in DMF
was refluxed 6 h under nitrogen. After being cooled to room temperature,
the mixture was poured into concentrated aqueous NH4OH (100 mL), and a
strong steam of air was bubbled through the solution for 15 min. The
resultant blue solution was extracted with benzene (3 ꢀ 50 mL). The
combined benzene extracts were washed with NH4OH (2 ꢀ 30 mL) and
brine (3 ꢀ 30 mL), dried (Na2SO4, and concentrated in vacuo. Chromato-
graphy (80 g of Isco silica-gel column) using 0 ! 20% EtOAc–hexanes
afforded 2.44 g of the title compound. The recovered starting material 7
(3.80 g) was recycled to produce an additional product (2.13 g) that was
combined with the previous sample to give 8 (4.57 g, 79% for two cycles)
1
as a white solid: mp 95–978C; H NMR (300 MHz; CDCl3) d 5.20 (1H, d,
J ¼ 12.3 Hz), 5.34 (1H, dd, J ¼ 12.3, 2.4 Hz), 6.16 (1H, s), 7.00–7.14 (3H,
m), 7.20–7.32 (2H, m), 7.55 (1H, d, J ¼ 7.8 Hz), 7.60 (1H, s); 13C NMR
(75 MHz; CDCl3) d 72.5, 85.3, 111.8, 115.6 (d, JC-F ¼ 21 Hz), 118.7,
123.2, 125.1, 128.7 (d, JC-F ¼ 8 Hz), 131.8, 136.6 (d, JC-F ¼ 3 Hz), 140.4,
147.0, 162.7 (d, JC-F ¼ 245 Hz); EI HRMS calcd. for C15H10FNO (Mþ):
239.0746. Found: 239.0736.
N,N-Didesmethylcitalopram (3)
A mixture of NaH (60% in mineral oil, 0.62 g, 15.4 mmol) in DMSO (28 mL)
was heated at 658C under nitrogen for 20 min and then cooled to room
temperature. A solution of 8 (3.35 g, 14.0 mmol) in DMSO (28 mL) was
then added and stirred for 20 min. Afterward, 1-(3-bromopropyl)-2,2,5,5-
tetramethyl-1-aza-2,5-disilacyclopentane (3.49 mL, 14.0 mmol) was added
all at once, and the resultant reaction mixture was stirred at room temperature
for 1 h. The mixture was then poured into ice water (100 mL), stirred 30 min,
and extracted with EtOAc (3 ꢀ 100 mL). The combined EtOAc extracts were
dried (Na2SO4) and concentrated in vacuo. The resultant residue was
dissolved in 2N HCl (200 mL) and washed with Et2O (3 ꢀ 50 mL). The
aqueous layer was made basic using NH4OH and extracted with EtOAc

Syntheses of DCIT and DDCIT
907
(3 ꢀ 100 mL). The combined EtOAc extracts were washed with brine
(3 ꢀ 50 mL) and dried (Na2SO4). Removal of solvent in vacuo afforded 3
1
(4.11 g, 99%) as an oil: H NMR (300 MHz; CDC13) d 1.12 (2H, br s),
1.21–1.54 (2H, m), 2.06–2.30 (2H, m), 2.68 (2H, t, J ¼ 7.1 Hz), 5.14 (1H,
d, J ¼ 13.5 Hz), 5.21 (1H, d, J ¼ 13.5 Hz), 6.94–7.06 (2H, m), 7.35–7.47
(3H, m), 7.51 (1H, s), 7.60 (1H, d, J ¼ 7.8 Hz); 13C NMR (75 MHz;
CDCl3) d 27.9, 38.3, 41.8, 70.9, 90.7, 111.2, 114.9 (d, JC-F ¼ 21 Hz),
118.4, 122.4, 124.9, 126.5 (d, JC-F ¼ 8 Hz), 131.5, 139.5 (d, JC-F ¼ 3 Hz),
140.0, 149.0, 161.6 (d, JC-F ¼ 245 Hz); ESI HRMS calcd. for C18H17FN2O
[M þ H]þ: 297.1403. Found: 297.1400.
The free base was converted to the oxalate salt as a white solid: mp 155–
1
1578C; H NMR (300 MHz; CD3OD) d 1.48–1.72 (2H, m), 2.18–2.40 (2H,
m), 2.93 (2H, t, J ¼ 7.2 Hz), 5.18 (1H, d, J ¼ 13.2 Hz), 5.25 (1H, d,
J ¼ 13.2 Hz), 7.00–7.11 (2H, m), 7.51–7.72 (5H, m); Anal. calcd. for
.
C20H19FN2O5 0.25H2O: C, 61.46; H, 5.03; N, 7.17. Found: C, 61.48; H,
5.05; N, 7.00.
ACKNOWLEDGMENT
This work was supported by the National Institute of Mental Health under
Contract N01-MH-32005. We thank James Windak, Chemistry Department,
University of Michigan, Ann Arbor, Michigan, for the high-resolution mass
spectral analyses.
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