studies on the synthesis of anti-depressant drug,...
TRANSCRIPT
Chapter VI
NC
N
F
O
Studies on the synthesis of
anti-depressant drug,
Escitalopram
INTRODUCTION:
Depression or feelings of unhappiness or disappointment is an extremely common state affecting
up to one-third of all people at some time. However, when these feelings become exaggerated,
pervasive and interfere with the normal functioning of everyday life, they are considered
pathological depression.[1]
Depressive disorders encompass a variety of conditions. These
disorders affect more than 19 million adults in the US each year and the World Health
Organization predicts that depression will be the second leading cause of disability worldwide by
the year 2020.[1,2]
However, it is generally accepted that neurochemical abnormalities are
ultimately responsible for the emergence of depressive symptoms.[1]
Although depression can represent an extreme disability, with appropriate treatment up to 80% of
all individuals affected can improve and return to their normal daily life activities. In addition to
non-pharmacological treatment (e.g., cognitive, behavioral and psychodynamic therapies), there
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 405
Chapter - VI
are currently three major classes of drugs available for the treatment of depression. Table-6.1
details the broad classification of antidepressants.
Table-6.1
Specific
reuptake
inhibitors (RIs),
enhancers (REs)
and releasing
agents (RAs)
Selective serotonin reuptake inhibitors (SSRIs) (Alaproclate, Citalopram,
Escitalopram, Femoxetine, Fluoxetine, Fluvoxamine, Indalpine, Ifoxetine,
Litoxetine, Lubazodone, Omiloxetine, Panuramine, Paroxetine,
Pirandamine, Seproxetine, Sertraline)
Serotonin-norepinephrine reuptake inhibitors (SNRIs) (Clovoxamine,
Desvenlafaxine, Duloxetine, Levomilnacipran, Eclanamine, Milnacipran,
Sibutramine, Venlafaxine)
Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs)
(Amitifadine, Bicifadine, Brasofensine, Cocaine, Diclofensine,
Fezolamine, Pridefine, Tesofensine)
Norepinephrine reuptake inhibitors (NRIs) (Amedalin, Atomoxetine /
Tomoxetine, Binedaline, Ciclazindol, Daledalin, Edivoxetine,
Esreboxetine, Lortalamine, Mazindol, Nisoxetine, Reboxetine, Talopram,
Talsupram, Tandamine, Viloxazine)
Dopamine reuptake inhibitors (DRIs) (Medifoxamine, Vanoxerine)
Norepinephrine-dopamine reuptake inhibitors (NDRIs) (Amineptine,
Bupropion/Amfebutamone, Cilobamine, Manifaxine, Methylphenidate,
Nomifensine, Radafaxine, Tametraline)
Norepinephrine-dopamine releasing agents (NDRAs) (Amphetamine,
Befuraline, Lisdexamfetamine, Methamphetamine, Phenethylamine,
Piberaline, Tranylcypromine)
Serotonin-norepinephrine-dopamine releasing agents (SNDRAs) (4-
Methyl-αMT, αET/Etryptamine, αMT/Metryptamine)
Selective serotonin reuptake enhancers (SSREs) (Tianeptine)
Others (Indeloxazine, Teniloxazine, Tramadol, Viqualine)
Receptor
antagonists
and/or reuptake
inhibitors
Serotonin antagonists and reuptake inhibitors (SARIs) (Etoperidone,
Nefazodone, Trazodone)
Nonadrenergic and specific serotonergic antidepressants (NaSSAs)
(Aptazapine, Esmirtazapine, Mianserin, Mirtazapine,
Setiptiline/Teciptiline)
Norepinephrine-dopamine disinhibitors (NDDIs) (Agomelatine)
MD. UMAR KHAN Thesis
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Chapter - VI
Serotonin modulators and stimulators (SMSs) (Vortioxetine)
Others (Tedatioxetine, Vilazodone)
Heterocyclic
antidepressants
Bicyclics (Tiazesim, Tofenacin)
Tricyclics (Amezepine, Amineptine, Amitriptyline, Amitriptylinoxide,
Azepindole, Butriptyline, Cianopramine, Clomipramine, Cotriptyline,
Cyanodothiepin, Demexiptiline, Depramine/Balipramine, Desipramine,
Dibenzepin, Dimetacrine, Dosulepin/Dothiepin, Doxepin, Enprazepine,
Fluotracen, Hepzidine, Homopipramol, Imipramine, Imipraminoxide,
Intriptyline, Iprindole, Ketipramine, Litracen, Lofepramine, Losindole,
Mariptiline, Melitracen, Metapramine, Mezepine, Naranol, Nitroxazepine,
Nortriptyline, Noxiptiline, Octriptyline, Opipramol, Pipofezine,
Propizepine, Protriptyline, Quinupramine, Tampramine, Tianeptine,
Tienopramine, Trimipramine)
Tetracyclics (Amoxapine, Aptazapine, Azipramine, Ciclopramine,
Esmirtazapine, Maprotiline, Mazindole, Mianserin, Mirtazapine,
Oxaprotiline, Setiptiline/Teciptiline)
Monoamine
oxidase
inhibitors
(MAOIs)
Nonselective (Irreversible: Benmoxin, Carbenzide, Cimemoxin,
Domoxin, Echinopsidine, Iproclozide, Iproniazid, Isocarboxazid,
Mebanazine, Metfendrazine, Nialamide, Octamoxin, Phenelzine,
Pheniprazine, Phenoxypropazine, Pivalylbenzhydrazine, Safrazine,
Tranylcypromine.; Reversible: Caroxazone, Paraxazone, Quercetin)
MAOA-Selective (Irreversible: Clorgiline.; Reversible: Amiflamine,
Bazinaprine, Befloxatone, Berberine, Brofaromine, Cimoxatone,
Esuprone, Eprobemide, Harmala Alkaloids, Methylene Blue,
Metralindole, Minaprine, Moclobemide, Pirlindole, Sercloremine,
Tetrindole, Toloxatone, Tyrima)
MAOB-Selective (Irreversible: Ladostigil, Mofegiline, Pargyline,
Rasagiline, Selegiline.; Reversible: Lazabemide, Milacemide)
Azapirones and
other 5-HT1A
receptor agonists
Alnespirone, Aripiprazole, Befiradol, Buspirone, Eptapirone, Flesinoxan,
Flibanserin, Gepirone, Ipsapirone, Oxaflozane, Tandospirone, Vilazodone,
Zalospirone
Tricyclic antidepressants (TCAs), which act by altering the balance of norepinephrine and
serotonin in the brain, were first introduced in the late 1950’s and have been the standard
treatment for depression despite their slow action and unpleasant and often serious side effects.
A second class of compounds are the Monoamine Oxidase (MAO) inhibitors, which slow the
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 407
Chapter - VI
breakdown of norepinephrine and serotonin (5-HT) in the brain allowing prolonged activity of
these neurotransmitters. Since the late 1980’s, selective serotonin reuptake inhibitors (SSRIs)
have overtaken TCAs in the market. The result is considerably fewer side effects as compared to
TCAs and MAO inhibitors.[1]
Since the launch of the first SSRI in 1985, SSRIs have become widely used due to their reactive
safety in overdose situation and their overall superior safety profiles.[1,3]
SSRI, therefore, remain
an attractive treatment for anxiety and depression and investigation to find newer, more effective
SSRIs continues.
Citalopram is an SSRI launched in 1989 for the treatment of depression, is a racemic mixture of
(S)-(+)- and (R)-(-)-Citalopram, is a well-known antidepressant drug available in the market for
some years as tablets or an oral suspension.[4,5]
It has been used in more than 65 countries, with a
total estimated worldwide exposure of 8 million persons. Citalopram is widely used as an
alternative to the older tricyclics as it has fewer side-effects and is safer in over dosage.[6-13]
It
was shown to surprise that almost the entire 5-HT uptake inhibition resides in (S)-(+)-Citalopram
enantiomer.[14]
Escitalopram was twice as effective as the Racemate and over 100-fold more
potent than the (R)-(-)-enantiomer in inhibiting 5-HT reuptake in vitro study.[15-17]
Several
reports have been published describing Citalopram and its enantiomer, S-(+)-1, which has ~30
fold higher binding affinity at serotonin transporter than its R-(-)-enantiomer.[18,19]
Lexapro® (escitalopram oxalate) is an orally administered selective serotonin reuptake
inhibitor (SSRI). Escitalopram is the pure S-enantiomer (single isomer) of the racemic bicyclic
phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1-[3-(dimethyl-
amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural
formula:
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 408
Chapter - VI
NC
N
F
O
COOH
COOH
The molecular formula is C20H21FN2O • C2H2O4 and the molecular weight is 414.40.
Escitalopram oxalate occurs as a fine, white to slightly-yellow powder and is freely soluble in
methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble
in water and ethanol, slightly soluble in ethyl acetate and insoluble in heptane.
Lexapro (escitalopram oxalate) is available as tablets or as an oral solution.
Lexapro tablets are film-coated, round tablets containing escitalopram oxalate in strengths
equivalent to 5 mg, 10 mg, and 20 mg escitalopram base. The 10 and 20 mg tablets are scored.
The tablets also contain the following inactive ingredients: talc, croscarmellose sodium,
microcrystalline cellulose/colloidal silicon dioxide, and magnesium stearate. The film coating
contains hypromellose, titanium dioxide, and polyethylene glycol.
Lexapro oral solution contains escitalopram oxalate equivalent to 1 mg/mL escitalopram base. It
also contains the inactive ingredients: sorbitol, purified water, citric acid, sodium citrate, malic
acid, glycerin, propylene glycol, methylparaben, propylparaben, and natural peppermint flavor.
In the treatment of depression, the initial dosage of Citalopram is 20 mg daily by mouth, which
can be increased 40 mg once daily generally. Citalopram hydrochloride has also been given by
intravenous infusion in similar doses when oral route is impracticable. In the treatment of panic
disorder with or without agoraphobia, the initial dose of Citalopram is 10 mg daily by mouth
increasing to 20 mg daily after one week. Developed by Lundbeck, it rapidly achieved
blockbuster status generating over $2.1 Billion sales in 2012.[20]
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 409
Chapter - VI
Table-6.2
Sr.
no.
Generic name
Systematic (IUPAC) name Structure
1
Escitalopram (1)
(S)-1-[3-(Dimethylamino)propyl]-1-(4-
fluorophenyl)-1,3-dihydroisobenzofuran-5-
carbonitrile
NC
N
F
O
2
Zimelidine (2)
(Z)-3-(4-bromophenyl)-N,N-dimethyl-3-
(pyridin-3-yl)prop-2-en-1-amine
N
Br
N
3
Pirandamine (3)
N,N-dimethyl-2-(1-methyl-4,9-dihydro-3H-
indeno[2,3-c]pyran-1-yl)ethanamine
O
N
4 Litoxetine (4)
4-(naphthalen-2-ylmethoxy)piperidine O
NH
5
Fluoxetine (5)
(RS)-N-methyl-3-phenyl-3-[4-
(trifluoromethyl)phenoxy]propan-1-amine
F3C
O NH
6
Paroxetine (6)
(3S,4R)-3-[(2H-1,3-benzodioxol-5-
yloxy)methyl]-4-(4-fluorophenyl)piperidine
HN
F
OO
O
H
H
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 410
Chapter - VI
7
Sertraline (7)
(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-
1,2,3,4-tetrahydronaphthalen-1-amine
Cl
Cl
HNH
H
8
Lubazodone (8)
(2S)-2-[(7-fluoro-2,3-dihydro-1H-inden-4-
yl)oxymethyl]morpholine
F
OO
HN
REVIEW OF LITERATURE:
Number of methods have been developed for the synthesis of Citalopram and Escitalopram.
Citalopram or Escitalopram can be prepared by
i. alkylation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile,[21-37]
ii. cyanide exchange in the final step, from bromo,[38-58]
iodo,[59-61]
chloro,[62]
trifluoromethane sulfonate[45]
Citalopram and aryl magnesium bromide cyanation,[63]
iii. functional group transformation to nitrile in the final step, from amino,[64-65]
carboxy,[66-69]
carboxamide,[70]
substituted carboxamide,[66]
formyl,[71-74]
substituted formyl,[75-76]
aminomethyl Citalopram,[70]
iv. elaboration of an alcohol,[77-81]
aldehyde[82]
or amine[83-84]
to complete the
dimethylaminopropyl side chain in the final step,
v. diol preparation and / or cyclization in the final step,[42,85-105]
vi. classical resolution of citalopram,[84,106-108]
desmethyl citalopram,[109]
didesmethyl
citalopram,[84,110]
citalopram diol[111-119]
and bromo citalopram diol,[40-41]
vii. chemoenzymatic resolution of citalopram diol,[120-122]
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 411
Chapter - VI
viii. asymmetric addition of 3-dimethylaminopropylmagnesium chloride to 4-(4-
fluorobenzoyl)-3-(hydroxymethyl)benzonitrile,[123]
ix. Escitalopram diol cyclization,[124-130]
x. Diels-Alder approach,[131]
and
xi. phthalic anhydride analogs.[132-134]
9 10
Br
O
O
MgBr
F
+THF, ether
Br
OH
O
F
Br
OH
OH
F
Br
O
F
NC
O
F
NaH, DMSO
Cl N
Br
OH
OH
F
N
Br
N
F
O
NC
N
F
O
1
ClMg N
THF, ether,NH4Cl
AcOH, NaOH
H3PO4
ammonia
CUCN, DMF,
ethylene diamine
NH4Cl, water
LAHether
ether, AcOH,
NaOH
H3PO4
ammonia
CUCN, DMF,
ethylene diamine
ether, AcOH,
NaOH
11
12
13 14
15
16
17
15
…..Scheme-6.1
Citalopram 1 was first synthesized by Bogeso and Toft in 1978.[38]
This patent discloses the
preparation of Citalopram by cyanide exchange in final step. It starts from 5-bromophthalide 9 by
successive Grignard reactions followed by cyclization with an acid and subsequently cyanation
reaction using cuprous cyanide. Finally the crude product was purified by distillation under
reduced pressure and converted into Citalopram salts. Further, this patent also discloses
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 412
Chapter - VI
preparation of 1 from Grignard adduct-I 11 by successive reduction, cyclization, cyanation and
finally alkylation with N,N-dimethyl-aminopropyl chloride 15 (Scheme-6.1).
Citalopram can also be prepared from 5-cyanophthalide, 18 as shown in scheme-6.2,[85]
by
successive Grignard reactions with 4-fluorophenylmagnesium bromide 10 and N,N-
dimethylaminopropylmagnesium chloride 15 to get 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-
hydroxybutyl]-3-(hydroxymethyl) benzonitrile, 20 which was converted into Citalopram by ring
closure (diol cyclization) in the final step with sulfuric acid.
18
19
20
10
NC
O
O
MgBr
F
+THF
NC
O
F
OMgBr
NC
OMgBr
O
F
ClMg N
THF
15
NC
OMgBr
OMgCl
F
N
NC
OH
OH
F
NAcOH, water
NC
N
F
O70% H2SO4
1
…..Scheme-6.2
Boegesoe and Perregaard[111]
at Lundbeck developed the first patented process which discloses
the preparation of pure enantiomer of Citalopram by Classical resolution of Citalopram diol 20
(Scheme-6.3). The racemic mixture of penultimate diol 20 was resolved using (+)-di-p-
toloyltartaric acid and the resolved diol 22 was subjected to stereoselective ring closure to
prepare pure enantiomer of Citalopram. Further, according to the invention, 20 was reacted with
an enantiomeric pure acid chloride 23. The diastereoisomers were subsequently separated by
HPLC or fractional crystallization. The thus-purified diastereoisomers were finally treated with
strong base in an inert solvent e.g. toluene yielding the pure Citalopram enantiomers respectively.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 413
Chapter - VI
21
22
23
24
20
NC
OH
OH
F
N
NC
OH
OH
F
N
NC
N
F
O
NC
O
OH
F
N
O
CF3Ph
O
NC
O
OH
F
N
O
CF3Ph
O
(+)
(+)
(+)-DI-P-TOLUOYL-
TERTARIC ACID
IPA
TOLUENE
TEA, MSCl
O
CF3Ph
O
(+)
Cl
MDC, TEA
toluene,
KOtBu
HPLC separation
toluene,
KOtBu
25
1
…..Scheme-6.3
26 27
18
10
NC
O
O
MgBr
F
+THF
NC
OH
O
F
NC
OH
OH
F
NC
O
F14
NC
N
F
O
1
NaBH4
THF, EtOH
H3PO4
n-BuLi, DIPA
1,2-dimethoxyethane
Cl N
15
…..Scheme-6.4
Petersen et al[21]
put forward a method for the preparation of citalopram which described
reduction of the oxo group of a compound of formula 26 (Grignard adduct-I), with sodium
borohydride and subsequent cyclization gives 5-carbonitrile derivative 14 (Scheme-6.4). Further
alkylation of 5-carbonitrile derivative was carried out with 3-dimethylaminopropyl chloride 15 in
basic conditions.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 414
Chapter - VI
Dall'asta et al[75]
prepared escitalopram from 5-carboxy phthalide by functional group
transformation to nitrile in the final step. The chlorination of 5-carboxy phthalide 28 with
refluxing SOCl2 gave the acyl chloride 29, which was condensed with 2-amino-2-methyl-1-
propanol 30 in THF to yield the corresponding amide 31. The cyclization of 31 by means of
SOCl2 afford the oxazoline 32, which was treated with 10 in THF to give the benzophenone 33.
This compound 33, without isolation, was treated with 15 in the same solvent to provide the
carbinol 34, which was submitted to optical resolution with (+)- or (-)-tartaric acid, or (+)- or (-) -
camphor-10-sulphonic acid (CSA) to give the desired (S)-enantiomer 35. Cyclization of 35 by
means of methanesulfonyl chloride and TEA in MDC yields the chiral isobenzofuran 36, which
was finally treated with POCl3 in refluxing pyridine to yield 1(Scheme-6.5).
28 29
30
31 32
33 34
35 36
O
O
O
HOO
O
O
ClO
O
O
NH
HO
O
O
O
N
O
N OH
O
F
O
N OHOH
F
N
O
N OHOH
F
N
O
N
F
N
O
NC
N
F
O
1
SOCl2 NH2
HOSOCl2
10
MgBr
FClMg N 15
tartaric acid /
CSA
TEA
MSCl POCl3
…..Scheme-6.5
Rock et al[77]
prepared Citalopram by elaboration of alcohol 39 to complete the dimethyl-
aminopropyl side chain in the final step (Scheme-6.6).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 415
Chapter - VI
37
38
39 40
NC
O
F14
NC
O
F
O
NC
O
F
OH
NC
O
F
OS
O O
NC
N
F
O
1
NH
TEA, DMF
TsCl, TEA
toluene
OBr
THF, LDA
1,4-CYCLOHEXADIENE
Pd, EtOH
41
…..Scheme-6.6
The two strategies[120,122]
for chemoenzymatic resolution of the (RS)-diol 20 were based on the
selective reactivity of an (R)-diol monoester or (R)-diol with a lipase. The (R)- and (S)-diols 20
were converted to monoacetates and the (R)-diol monoacetate 42 was selectively hydrolyzed
using a lipase (Scheme-6.7). Alternatively, the (R)-diol in the mixture of (R)- and (S)-diols 20
was selectively esterified with vinyl butyrate using an esterase. In both cases, the mixture of diol
22 and diol monoacetate 42 could be separated by crystallization. 22 could be converted to 1 by
conventional way.
4220
NC
OH
OH
F
N
NC
OAc
OH
F
N
22
NC
OH
OH
F
N
NC
N
F
O
1
OAc
Lipase, ACN
NaOH,
Water
MeOH
MsCl, TEA
MDC
…..Scheme-6.7
Albert et al[123]
came with an asymmetric addition of 3-dimethylaminopropylmagnesium chloride
15 to 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile 44 would produce the (S)-diol 22
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 416
Chapter - VI
directly, eliminating the need for the resolution (Scheme-6.8). The concept for inducing
asymmetry was to use the neighboring hydroxymethyl group to anchor a boron complex
containing a chiral amino alcohol. The close proximity of this complex to the ketone induces
asymmetry during the addition of 3-dimethylaminopropylmagnesium chloride. Screening of
conditions for the asymmetric addition was best done starting with the pure ketone 26.
43
44
26
18
10
NC
O
O
MgBr
F
+ THF
NC
OH
O
F
1,2-dimethoxyethane
OH
N
(i-PrO)2BCH3
Toluene
NC
O
O
F
BO
N
ClMg N 15
THF
22
NC
OH
OH
F
N
21
22
NC
OH
OH
F
N
(+)-DI-P-TOLUOYL-
TERTARIC ACID
IPA
(+)-DPTTA
…..Scheme-6.8
Inversion with significant racemization was observed in cyclization using sulfuric acid at
elevated temperature. Cotticelli et al[129]
described (S)-diol cyclizations using Mitsunobu
conditions (Scheme-6.9).
22
NC
OH
OH
F
N
NC
N
F
O
1
NC
N
F
O
COOH
COOH
DEAD, PPh3
NaOtBu, THF
oxalic acid
acetone
…..Scheme-6.9
Paulon et al[131]
proposed diels-alder approach for the preparation of citalopram which started
from 2-furaldehyde diethyl acetal 45 (Scheme-6.10). Ring metallation and capture of the
aryllithium with 4-fluorobenzaldehyde affords secondary alcohol 47. Construction of the chiral
carbon follows a now-familiar path: oxidation of secondary alcohol 47 to the ketone 48 and
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 417
Chapter - VI
condensation of ketone 48 with 3-dimethylaminopropylmagnesium chloride. The (R)- and (S)-
alcohols 49 were separated by chromatography. (S)-Alcohol 50 was converted to the allyl ether
51. Heating allyl ether 51 induces the intramolecular [4 + 2]-cycloaddition. Hydrolysis of the
cycloadduct 52 under acidic conditions affords 1-(3-dimethylamino)propyl)-1-(4-fluorophenyl)-
1,3-dihydroisobenzofuran-5-carbaldehyde 53. Aldehyde 53 was converted to the oxime 54 and
dehydrated with acetic anhydride to produce Escitalopram 1.
45
46
47 48
49
O
O
O
CHO
O
O
OOH
F
FO
O
OO
F
ClMg N 15
THF
O
O
O
OH
F
NO
O
O
OH
F
NO
O
O
O
F
N
F
N
OO
O
O
N
F
OH
O
N
F
OH
NOH
NC
N
F
O
1
50 51
52 53
54
…..Scheme-6.10
PRESENT WORK:
The object of the present work was to uncover and overcome the many disadvantages of the prior
art. Present work details the journey towards development of a simple, safe, productive, eco-
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 418
Chapter - VI
friendly and easy to handle commercial process for preparing Escitalopram. Hence, we have
developed and optimized the process, impurities formed in the process were identified, prepared
and characterized. Additionally, force degradation study of Escitalopram was also investigated. A
mechanistic rationale for the formation of the various process impurities and degradation
products has been provided.
RESULTS AND DISCUSSION:
Two synthetic approaches are described herein, among which approach A deals with 5-synthetic
steps preparation of Escitalopram, having chromatographic purity control from Citalopram diol
oxalate salt and steric controls via classical resolution of Citalopram diol, by Di-p-toluoyl-D-
tartaric acid reagent for commercial scale synthesis of Escitalopram 1. Approach B discloses a
new manufacturing process comprises de-methylation of Citalopram to produce desmethyl
Citalopram, separating the enantiomers from the pure desmethyl Citalopram with an optically
active acid and finally methylating an enantiomerically pure compound using suitable
methylating agent to produce Escitalopram 1. Additionally, force degradation study of
Escitalopram was also carried out. A mechanistic rationale for the formation of the various
impurities and degradation products has also been provided.
APPROACH A:
Escitalopram 1 was first synthesized by Boegesoe and Perregaard in 1989.[111]
According to this
patent reference, attempts to resolve Citalopram enantiomers to produce Escitalopram were not
successful. Therefore, resolution of enantiomers of the diol 20 with optically active selective
precipitant, Di-p-toluoyl-D-tartaric acid 21, has been carried out to obtain (S)-Enantiomer of diol
prior to ring closure in a stereospecific manner to obtain Escitalopram 1 as shown in Scheme-6.3.
The resolution of enantiomers requires high purity of Diol 20 to selectively precipitate out (S)-
Diol hemi Di-p-toluoy1-D-tartaric acid salt having substantially high chiral purity. The Diol 20,
obtained as described by Bogeso,[85]
was not sufficiently pure and extensive purification steps
have been described in this reference, which involve repeated charcoal and silica gel treatment of
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 419
Chapter - VI
the Diol. Further, purification of Diol compound has been carried out by preparing hydrobromide
salt and subsequently by crystallization, first from water and thereafter from 2-propanol/ethanol.
The present investigation provides a simple and economical process for the purification of Diol
20, which can be used for commercial production of Escitalopram.
55
18
20
10
NC
O
O
MgBr
F
+THF
NC
OMgBr
O
F
ClMg N
THF
15
NC
OMgBr
OMgCl
F
N
NC
OH
OH
F
NAcOH, water oxalic acid / EtOH
NC
OH
OH
F
NCOOH
COOH
56
Toluene
aq. ammonia
20
NC
OH
OH
F
N
21
22
NC
OH
OH
F
N
(+)-DI-P-TOLUOYL-
TERTARIC ACID
IPA
NC
OH
OH
F
N
2.
HO
OH
O
O
OO
O
O
MDC
NaOH
NC
N
F
OMDC
TEA, MSCl
1
Oxalic acid
acetone
NC
N
F
O
1
COOH
COOH
Adduct I Adduct II
…..Scheme-6.11
The Diol 20, was synthesized from 5-cyanophthalide 18 by two successive Grignard reactions
with 4-fluoro-phenylmagnesium bromide 10 and 3-(N,N-dimethylamino) propylmagnesium
chloride 15 (Scheme-6.11). Oxalate salt of 20 was prepared by treating Diol with oxalic acid
dihydrate in an alcohol. This highly pure Diol oxalate 55 was basified and treated with 21 to
selectively precipitate out (S)-Diol hemi Di-p-toluoy1-D-tartaric acid salt 56 having substantially
high chiral purity, which further converted to 22 and cyclized.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 420
Chapter - VI
PROCESS DEVELOPMENT AND IMPURITY PROFILE:
Preparation of citalopram diol oxalate 55: To prepare 20, the Grignard reagent 10 was prepared
as usual by reacting it with magnesium in tetrahydrofuran. This was added to 5-cyanophthalide
18 in tetrahydrofuran and reaction was monitored by qualitative HPLC analysis, which showed
~19% w/w of unreacted 18 and several other impurities. This reaction was carried out with 1.1
m. eq. of 10 w.r.t. 18. In the same experiment, additional quantities of 10 was added in portion
wise. Thus, after adding 0.1 m. eq. extra Grignard reagent (Total: 1.2 m. eq.), the unreacted 18
was 7.59% and after adding 0.12 m. eq. (Total: 1.32 m. eq.) 10, the unreacted 18 was 1.23%, with
product formation of 76.86% only.
Subsequent to this experiment, another reaction was repeated wherein 1.30 m. eq. of 10 in
tetrahydrofuran, was added to 18 in 5.5 h. In this reaction 18 left unreacted was 15.52%, with
product formation ~64%.
Another experiment was performed wherein 10 was used in the molar ratio 1.5 m. eq. and was
added in 3 h 30 min to 18. This reaction results in the formation of ~74% adduct I intermediate
with 18 left unreacted 0.90% and a single highest impurity ~24%. This impurity was later
identified as Bis(4-Fluorophenyl)Diol Impurity 57.
57
NC
OH
OH
F
F
The origin of this impurity was the successive addition of 10 on 18 as given in the Scheme-6.12.
57
NC
OH
OH
F
F18
10
NC
O
O
MgBr
F
+THF
NC
OMgBr
O
F10
MgBr
F
+THF
AcOH,
water
Adduct I
…..Scheme-6.12
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 421
Chapter - VI
To minimize the formation of this impurity, an experiment was designed wherein the controlled
addition of 10 was carried out as per the parameter established in previous experiment. After
addition of 1.32 m. eq. of 10 in 8h, 18 left unreacted was 0.38% with product formation (adduct
I) was 78.65% and Bis(4-Fluorophenyl)diol impurity 57 was 17.90%.
Based on these observations, several other experiments were carried out to maximize adduct I,
with lesser amount of unreacted 18 and a minimum formation of 57. These studies concluded
that, 1.32 m. eq. 10 was the suitable quantity to be added to 18 in tetrahydrofuran, wherein we
can obtain unreacted 18 < 3%, and Bis(4-Fluorophenyl)diol impurity 57 in the range of 15-17%.
The remaining being mostly adduct I. Subsequently to the preparation of adduct I, the second
Grignard reaction with 3-(N,N-dimethylamino)propyl magnesium chloride 15 proceeds smoothly
to convert quantitatively adduct I into adduct II at lower temperature and at a slow addition rate.
In one experiment, Grignard Reagent II 15 was added to Adduct I in 3h. Adduct I left unreacted
was 1.24% with formation of adduct II was 80.17%. In this experiment formation of one
impurity (~2%) was observed due to reaction of 15 with cyano group of adduct II in the
following manner (Scheme-6.13).
58
NC
OMgBr
OMgCl
F
N
Adduct II
ClMg N
THF
15
OH
OH
F
N
AcOH,
water
O
N
…..Scheme-6.13
So based on the above observations, it was observed that 15 should also be added at a slow rate to
adduct I to avoid the formation of above said impurity 58. An experiment was designed, wherein
the controlled addition of 15 was carried out at 0-5°C. After 7h 30min, the adduct I left
unreacted was 1.23% with the conversion to adduct II was 78.64% by HPLC and formation of 58
Impurity at RRT 0.42 was found absent.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 422
Chapter - VI
Having understood the nature of the major impurity present in the reaction mass, a work-up
procedure was followed wherein (±)-Citalopram diol product 20 containing the basic amino
group in the structure was extracted into water as its acetic acid salt. This practice would
routinely eliminate the Bis(4-Fluorophenyl)diol impurity 57, unreacted adduct I, as these were
unable to make acetate salt because of absence of amino group in its structure and therefore,
would remain in the organic layer. This way we could obtain the (±)-Citalopram diol 20 having
more than 97% HPLC chromatographic purity.
Further, in oxalate salt preparation of 20 with oxalic acid dihydrate in an alcohol solvent selected
from methanol, ethanol, isopropanol, butanol, isobutanol etc., and preferably ethanol, non salt
forming impurities were getting removed and remain in mother liquor. This way we could obtain
the (±)-Citalopram diol oxalate intermediate having more than 99.5% chromatographic purity by
HPLC and melting range 168-171°C.
Throughout, during the process optimization, there has been an emphasis to have minimum
quantity of unreacted 18, which carrying out the Grignard reaction to preparation. This was due
to fact that unreacted 18 react with 15 in the subsequent reaction to form the following impurity.
NC
OH
OH
N
N
59
It was evident from its structure, this impurity was not easy to remove as compared to Bis(4-
Fluorophenyl)diol impurity 57 by acetate salt formation. Similarly, this also explains that
sequence of Grignard reaction can be altered.
Preparation of adduct I was studied by varying temperature of reaction (~10 to -15°C; -15°C to
20°C). It was observed that slow addition of 10 at -2 to -8°C gives to best results, wherein adduct
I product in the range of 73-78%, Bis(4-Fluorophenyl)diol impurity 57 was 14-18% and 5-
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 423
Chapter - VI
cyanophthalide 18 left unreacted < 3%. Similarly, slow addition of Grignard reagent II 15 to
adduct I reaction mass at 0-5°C gives better results within product formation in the range of (73-
78%) and adduct I < 2% was observed.
Resolution of Citalopram diol enantiomer 22: It was well documented in chemical literature
that, the best of all the methods was the resolution of 20, consists in converting the enantiomer in
a racemic modification into diastereoisomers. Because of their different solubilities, the
diastereoisomers may be separated by fractional crystallization. After separation, the acids may
be regenerated by hydrolysis with inorganic acids or with alkali.
(±)-Citalopram diol 20 was set free from 55 by suspending it in a mixture of water and toluene
and then adding aqueous ammonia base. The toluene was distilled and concentrated, highly pure
20 thus obtained was dissolved in isopropyl alcohol, a class 3 solvent. Then it was treated with
optically active selective precipitants (+)-Di-p-toluoyl-D-tartaric acid 21 to isolate the less
soluble (S)-(-)-Citalopram diol hemi(+)-Di-p-toluoyl-D-tartaric acid salt 56.
Initially, one experiment was designed using 0.5 m. eq. of 21 and isopropyl alcohol as solvent.
After stirring at 25-30°C for 96h slight turbidity appears. But after seeding the solution, 56
crystallized out immediately. After analysis by 1H NMR, SOR, Mass, structure of the product
was confirmed.
In another experiment, 1.0 m. eq. of 21 was added to 20. After 7 days stirring also no
precipitation was observed. Further, the same reaction mass was seeded with 56, but again no
precipitation was observed even after 48 h of stirring. In one experiment, 21 was used 0.25 m. eq.
of 20. The obtained product was in a very low yield. But from 1H NMR it was confirmed that
precipitated product was 56 only. From the above experiment, it was clear that 20 forms only 56
not of 1:1 mixture salt form.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 424
Chapter - VI
(S)-(-)-Citalopram diol hemi DPTTA salt 56, thus obtained was having chromatographic purity ≥
99% by HPLC and chiral purity ~95%. After cyclization of the obtained 22 from 56 gives
Escitalopram oxalate 1 of lower chiral purity as evident from the Table-6.3.
Table-6.3
BATCH No. (S)-(-)-CITALOPRAM DIOL DPTTA
SALT, 56 ESCITALOPRAM OXALATE, 1
MK(426)146 96.91 95.04
MK(426)174 99.11 98.08
So, there was a need to purify (S)-(-)-Citalopram diol hemi DPTTA salt to obtain Escitalopram
oxalate of high chiral purity.
In few experiments, 56 was purified using isopropyl alcohol; (i) by preparing slurry.; (ii) by re-
crystallization. It was observed that re-crystallization of 56 gives better and consistent result in
comparison to purifying it by preparing its slurry, which is revealed by the following
experiments.
Purification by Slurry Formation: Table-6.4
BATCH No.
(R)-(+)-CITALOPRAM DIOL DPTTA CONTENT
CRUDE PURIFIED REPURIFICATION
MK(426)174 1.68% 0.89% -
MK(426)168 8.81% 3.20% 0.81%
MK(426)164 4.65% 2.53% 0.57%
MK(426)158 9.97% 2.30% 0.62%
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 425
Chapter - VI
Purification By Re-crystallization: Table-6.5
BATCH No.
(R)-(+)-CITALOPRAM DIOL DPTTA CONTENT
INPUT AFTER RECRYSTALLISATION
VK(484)65 3.51% 0.26%
VK(484)54 3.09% 0.30%
VK(484)55 8.81% 0.68%
Above study clearly indicates that crystallization was the better approach to achieve chiral purity
≥ 99% [(R)-(+)-Citalopram diol DPTTA salt < 1%].
NC
OH
OH
F
N
HO
OH
O
O
OO
O
O
NC
O
OH
F
N
HO O
O
OO
O
O
60
…..Scheme-6.14
In contrast to chiral purity, chromatographic purity decreases after crystallization. The major
impurity, which increases during crystallization, was as shown in Scheme-6.14.
This related substance of 56 has been identified by LCMS study. However, this impurity arising
during crystallization does not affect the Escitalopram oxalate purity in next step and remains in
mother liquor.
Preparation of Escitalopram oxalate 1: It was well documented in literature that cyclization of
(S)-(-)-Citalopram diol 22, was a facile reaction. These were two ways of cyclization for 22.
(i) Acidic cyclization;
(ii) Basic cyclization;
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 426
Chapter - VI
It was also reported that retention by configuration cannot be attained by acid ring closure. For
retention of configuration in ring closure, methanesulfonyl chloride in presence of base i.e.
triethylamine has been used widely in literature.
So, 56 was treated with aqueous sodium hydroxide to obtain 22, which was extracted into toluene
/ methylene chloride and then subjected to ring closure with retention of configuration using
methanesulfonyl chloride in the presence of triethylamine to obtain Escitalopram base.
In the initial experiments, 22 has been extracted in toluene and ring closure was carried out using
2.8 m. eq. of triethylamine and 1.15 m. eq. as methanesulfonyl chloride at -5 to -10°C and
methanesulfonyl chloride addition was carried out in 1 h. After work-up, isolated product shows
chromatographic purity of 92.36% and a single higher impurity 6.74%. When same experiment
was repeated using 1.1 m. eq. of methanesulfonyl chloride and addition was carried out in 3 h,
formation of number of impurities has been observed. Isolated product i.e. Escitalopram base
shows chromatographic purity of 93.36% and a single highest impurity 9.24%. This impurity
reduces to 0.36% in oxalate salt preparation.
To minimize the formation of these impurities, an experiment was designed wherein methylene
chloride was used as a solvent. 1.1 m. eq. of methanesulfonyl chloride was added in 1 h at -2 to -
5°C. After addition, starting material (S)-(-)-Citalopram diol left unreacted was 3.62%, while
product formation was only ~79% and highest individual impurity of 7.46% was observed. Even
after 3h of stirring the reaction, did not proceed further. This 7.46% impurity was later identified
as Benzazocinium Impurity.
NC
O
F
N
S
O
O
62
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 427
Chapter - VI
This impurity originates with intramolecular nucleophilic displacement of the primary
methanesulfonate by dimethylamino group and further, sulfonyl group induced due to
dehydration of the benzylic tert-carbonitrile Scheme-6.15.
NC
OH
OH
F
N
NC
O
O
F
N
MDC
TEA, MSCl
S
O
O
S
O
OH
NC
O
F
S
O
O
NC
O
F
N
S
O
O
2261 62
N
…..Scheme-6.15
Having understood the nature of the major impurities present in reaction mass, a work-up
procedure was followed wherein the product Escitalopram remains in organic layer and
impurities separates out in aqueous due to its high solubility in water. This practice would
routinely eliminate the benzazocinium impurity 62. This way we could obtain Escitalopram base
having more than 95% as HPLC purity. Based on the observation, several other experiments of
ring closure to maximize the escitalopram base formation in reaction mass and smallest amount
of unreacted (S)-(-)-Citalopram diol and minimum of benzazocinium and other impurities were
carried out.
To minimize the formation of impurity, an experiment was designed wherein the controlled
addition of methanesulfonyl chloride was carried out as per the parameters established in the
performance. After addition of 1.0 m. eq. as methanesulfonyl chloride, unreacted (S)-(-)-
Citalopram diol was found to be 4.46%, while the product formation was 93.24%. After addition
of 1.05 m. eq. as methanesulfonyl chloride, starting material left unreacted was nil, while the
product formed was 94.29%. After work-up escitalopram base in organic layer was having
chromatographic purity of 97.57%.
It was observed that after concentration, one impurity has been increased ~1% level, which was
identified to be Chloromethyl Citalopram (Scheme-6.16). Which was formed due to nucleophilic
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 428
Chapter - VI
displacement of the chloride group in methylene chloride by the dimethylamino group of
Citalopram.
63
NC
N
F
O
Cl
.Cl
A sample of Citalopram base was stirred in methylene chloride at 25-30°C. It was found that
content of Chloromethyl citalopram impurity increased with time.
Table-6.6
CHLOROMETHYL CITALOPRAM
CITALOPRAM BASE (Initial) Not detected
(After 7 h) 2.88%
(After 20 h) 7.91%
63
NC
N
F
O
Cl
.Cl
NC
N
F
O
1
MDC
…..Scheme-6.16
Subsequent to this observation after work-up methylene chloride was removed at lower
temperature and finally co-distilled with acetone to remove the traces of methylene chloride from
the concentrated mass before preparation of its oxalate. It was also observed that chloromethyl
citalopram impurity was getting eliminated in oxalate preparation Table-6.7.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 429
Chapter - VI
Table-6.7
CHLOROMETHYL CITALOPRAM
ESCITALOPRAM BASE 2.38%
ESCITALOPRAM OXALATE 0.07%
Few experiments were carried out to understand the manner in which (S)-(-)-Citalopram diol
behave, further if it left unreacted in reaction Table-6.8. In these experiments (S)-(-)-Citalopram
diol was left unreacted at different levels and converted to the oxalate salt.
Table-6.8
BATCH NO.
(S)-(-)-CITALOPRAM DIOL
In reaction mass Escitalopram base Escitalopram oxalate
MK(507)3 3.34% 2.88% 0.27%
MK(507)7 1.02% 0.83% 0.09%
MK(426)188 0.88% 0.59% 0.04%
Above study clearly indicated that (S)-(-)-Citalopram diol should be controlled ‘Not More Than
< 0.5%’ in reaction monitoring to remove it completely from the final product.
Other impurity, which was potentially formed in Escitalopram base preparation, was Citalopram
Alkene Dimer having the following structure.
NC
F N
CNO
F
N
65
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 430
Chapter - VI
This impurity originates with intermolecular nucleophic displacement of primary
methanesulfonate by dimethylamino group of 1 and further due to dehydration of the benzylic
tert-carbinol as given in Scheme-6.17.
64
NC
F N
CNO
F
N
NC
OH
OH
F
N
NC
O
O
F
N
MDC
TEA, MSCl
S
O
O
S
O
OH
22
NC
O
F
S
O
O
N
CN
O
F
N
1
65
…..Scheme-6.17
Table-6.9
BATCH NO.
CITALOPRAM ALKENE DIMER
Base Remarks Oxalate
MK(426)181 0.65 Fast addition / mix 0.06
MK(426)183 0.75 Fast addition / mix 0.06
MK(426)187 2.07 Fast addition / toluene 0.15
MK(484)66 0.40 Controlled addition 0.02
MK(507)5 0.38 Controlled addition 0.05
MK(507)7 0.18 Controlled addition Not detected
It was observed that controlled addition of methanesulfonyl chloride restricts the formation of
Citalopram alkene dimer (Table-6.9).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 431
Chapter - VI
Following impurities were also prepared and characterized which were listed in the
pharmacopoeia (Table-6.10).
Table-6.10
N
F
O
71
H2N
O
NC
N
O
72
NC
N
F
O
73
O
Br
N
F
O
17
NC
N
F
O
74
OH
67
NC
NH
F
O
75
O
F
N
O
N
N
F
O
76
HO
O
NC
N
O
77F
NC
N
F
O
78
O
N
F
O
79
NC
OH
F 80
N
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 432
Chapter - VI
Escitalopram oxalate formation step does not involve any complexity and proceeds smoothly.
This step take care of Chloromethyl citalopram 63, Citalopram alkene dimer 65 and (S)-(-)-
Citalopram diol 22 present in 1. No new impurity formation has been observed during
preparation of Escitalopram oxalate. This process of the present investigation provides
Escitalopram oxalate with HPLC purity more than 99.8%.
APPROACH B:
The new approach relates to a novel process for the preparation of Escitalopram 1, which
comprises (i) de-methylating (±)-1-[3-(dimethylamino)propyl]-1-(4-fluoropheny1)-1,3- dihydro-
5-isobenzofurancarbonitrile (Citalopram, (±)-1) to produce (±)-1-[3-(methylamino) propy1]-1-(4-
fluoropheny1)-1,3-dihydro-5-isobenzofurancarbonitrile (Desmethyl citalopram, 67), (ii)
separating the enantiomers from the pure desmethyl Citalopram 67 with an optically active acid
21 to obtain (S)-(+)-1-[3-(methylamino)propy1]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzo-
furancarbonitrile 69, (iii) methylating an enantiomerically pure compound 69 using suitable
methylating agent to produce Escitalopram 1 (Scheme-6.18).
66
67
NC
N
F
O
1
NC
NH
F
O
NC
NH2
F
O HO
O
O
O
OO
O
O
NC
NH
F
O
NC
N
F
O
Cl O
O
Cl
ethylenedichloride,
21
(+)-DI-P-TOLUOYL-
TERTARIC ACID
methanol
water, toluene
NaOH
HCHO,
HCOOH
68
69
70(±)-1
NC
N
F
O
O
O Cl methanol
…..Scheme-6.18
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 433
Chapter - VI
RESULTS AND DISCUSSION:
The N-demethylation of tertiary methylamines has been accompalished in several ways. These
include reaction with cyanogen bromide (von Braun reaction)[135]
or a substituted
chloroformate[136,137]
followed by cleavage of the resultant cyanamide or carbamate.
(±)-1-[3-(Dimethylamino)propyl]-1-(4-fluoropheny1)-1,3-dihydro-5-isobenzofurancarbonitrile
[Citalopram, (±)-1], used as a starting material in the process of the present invention, was
synthesized from 5-cyanophthalide 18 by two successive Grignard reactions with 4-fluoro-
phenylmagnesium bromide 10 and 3-(N,N-dimethylamino)propylmagnesium chloride 15 to
produce citalopram diol, 20 which was cyclised to produce Citalopram. Also it was well known
in the chemical literature that methyl group can be replaced conveniently with the chloromethyl
chloroformate Scheme-6.19.
NC
N
F
O
+ Cl O
O
Cl
NC
N
F
O
O Cl
O
.Cl
-CH3Cl
NC
N
F
O
O
O
OMeCl
NC
NH
F
O
+ CO2 + CH2(OCH3)2
(±)-1
70 67
…..Scheme-6.19
According to the present study, demethylation of racemic (±)-1 was carried out using
haloformates selected from 1-chioroethyl chloroformate, 1-chloromethyl chloroformate, phenyl
chloroformate, ethyl chloroformate, benzoyl chloroformate; phosgene derivatives; carbonyl
analogues and carbonates selected from dimethylcarbonate, diethylcarbonate or mixture thereof
in an organic solvent selected from ethylene dichloride, methylene chloride, propylene chloride,
toluene, xylene, cyclohexane, heptane preferably ethylene dichloride. After completion of
reaction, the reaction mass was concentrated at about 40-100 °C under reduced pressure and DM
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 434
Chapter - VI
water was added to the residue at 20-25 °C and the product was extracted into organic solvent
selected from toluene or ethyl acetate. The organic layer was concentrated at about 50-55°C
under reduced pressure. The residue obtained was treated with aqueous acidic, alkaline solutions
or alcoholic solution such as ethanol, methanol, isoprapanol at temperature of 40-100°C to
produce desmethyl Citalopram 67.
In an alternative method desmethyl citalopram 67 can also be prepared by reacting 1-(4-
fluoropheny1)-1,3-dihydro-5-isobenzofurancarbonitrile with (3-bromopropoxy)-terbutyl-
dimethylsilane in presence of LDA in a solvent selected from tetrahydrofuran at a temperature of
about -60 to -80°C, followed by removal of silyl protecting group to produce 1-(4-fluoropheny1)-
1-(3-hydroxypropy1)-1,3-dihydro-5-isobenzofurancarbonitrile, which was further reacted with
methanesulfonyl chloride in presence of base selected from triethylamine in a solvent selected
from tetrahydrofuran to produce 1-(4-fluoropheny1)-1-[(3-methanesulfonyloxy)propyl]-1,3-
dihydro-5-isobenzofurancarbonitrile. 1-(4-Fluoropheny1)-1[(3-methanesulfonyloxy)propyl]-1,3-
dihydro-5-isobenzofurancarbonitrile was further reacted with methylamine in a solvent selected
from methanol, ethanol, isopropanol, tetrahydrofuran or mixtures thereof to produce desmethyl
citalopram.
In another embodiment of the present study, desmethyl Citalopram 67 obtained from the above
methods, was optionally purified by adding DM water to the desmethyl Citalopram 67 and
washed with organic solvent selected from toluene, ethyl acetate, chloroform, methylene
chloride, preferably in toluene to remove undesired impurities, followed by adjusting the pH of
aqueous layer containing pure desmethyl Citalopram 67 to a value of about 9 to 9.5 using a base
such as aqueous ammonia. The compound was extracted from the basified aqueous layer with a
suitable organic solvent selected from toluene, ethyl acetate, chloroform, methylene chloride,
preferably in toluene and distilling the solvent to produce pure desmethyl Citalopram base.
In another embodiment of the present invention, desmethyl Citalopram 67 was optionally
converted into its corresponding acid addition of salts such as hydrochloride, hydrobromide, and
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-depressant drug, Escitalopram 435
Chapter - VI
oxalate by treating with suitable acidic reagent in a suitable organic solvent. Hydrolyzing the salt
in presence of base in water and organic solvent mixture to produce pure desmethyl Citalopram
67.
67 was treated with optically active acid selected from dibenzoyl tartaric acid, bisnaphthyl-
phosphoric acid, 10-camphorsulphonic acid, di-(p-toluoyl)tartaric acid, in a solvent selected from
alcohol such as methanol, ethanol, isopropanol , butanol or mixtures thereof to resolve 67
enantiomers to obtain 69. Preferably Di-p-toluoyl-D-tartaric acid 21 was used to obtain (S)-
enantiomer of desmethyl Citalopram 69 having HPLC chiral purity of more than 98%.
69 was reacted with methylating reagent selected from methyl iodide, dimethyl sulfate, formic
acid/formaldehyde more preferably formic acid/formaldehyde at a temperature of about 80-95°C
to produce Escitalopram 1. Optionally methylation was carried out in a solvent selected from
toluene, xylene, ethylene dichloride. After completion of reaction, the reaction mass was
concentrated to residue. DM water and toluene was added to the obtained residue and pH of the
aqueous layer was adjusted to 9 to 9.5 using aqueous ammonia and the product was extracted
with toluene and the toluene layer was concentrated to produce Escitalopram base.
Escitalopram base thus obtained was dissolved in an organic solvent selected from acetone,
acetonitrile, ethanol, methanol, isopropanol, tetrahydrofuran, toluene, cyclohexane, isopropyl
ether etc., and preferably in acetone and was treated with oxalic acid dihydrate to obtain
Escitalopram oxalate, which was isolated and dried by conventional methods. This process of the
present study provides Escitalopram oxalate with HPLC purity more than 99.5 %.
CONCLUSION:
We have developed and optimized two process, impurities formed in the process were identified,
prepared and characterized. Additionally, force degradation study of Escitalopram was also
investigated. A mechanistic rationale for the formation of the various process impurities and
degradation products has been provided.
MD. UMAR KHAN Thesis
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Chapter - VI
EXPERIMENTAL:
(±)4-[4-Dimethylamino)-1-(4-fluoropheny1)-1-Hydroxybutyl]-3-(Hydroxymethyl)-Benzonitrile
[(±)-Citalopram Diol, 20]
Magnesium turnings (40.64 g, 1.69 mol) were taken along with THF (160 ml) in a vessel at 25-
35°C under inert atmosphere. The mass was heated to 62-65°C and iodine (1 g, 0.004 mol) was
added followed by a solution of 1-bromo-4-fluorobenzene (290.60 g, 1.66 mol) in THF (600 ml)
was added slowly at 60-65°C. The reaction mass was maintained at 60-65°C for about 1 h for the
formation of Grignard reagent (GR-I, 10). This was diluted with THF (300 ml) and cooled to 25-
35°C. Likewise, magnesium turnings (36.94 g, 1.54 mol) were taken along with THF (100 ml) in
a vessel at 25-35°C under inert atmosphere. The mass was heated to 62-65°C and iodine (1 g,
0.004 mol) was added followed by a solution of N,N-dimethyl-3-chloropropylamine (183.40 g,
1.51 mol) in THF (400 ml) was added slowly at 60-65°C. The reaction mass was maintained at
60-65°C for about 2 h for the formation of Grignard reagent (GR-II, 15). This was diluted with
THF (500 ml) and cooled to 25-35°C. In another flask were charged 5-cyanophthalide, 18 (200 g,
1.258 mol) and THF (940 ml) under inert atmosphere and were cooled to -5±3°C. Thereafter, 10
was added slowly at -5±3°C and stirred for 1 h. After completion of reaction, 15 was added
slowly at -0±2°C and stirred for the completion of reaction. The reaction mass was then added to
precooled water (2400 ml) at < 20°C. Adjusted the pH to 7.0±0.2 by adding glacial acetic acid
and concentrated at 40-55°C under reduced pressure to distil THF. After acid-base treatment with
acetic acid and ammonia, product extracted in toluene and concentrated to obtain 20 as a
yellowish green, viscous liquid that contains 5-10% w/w toluene. Yield: 200 g; Chromatographic
purity: 91.35%; Assay (% w/w, by titrimetry): 90.0. Molecular Formula: C20H23FN2O2;
Molecular Weight: 342; Mass (ESI, in +ve ion mode): 343 [(MH)+];
1H NMR (DMSO-d6, 300
MHz, δ ppm): 1.20 & 1.39 (2m, 2H, CH2); 2.01 (s, 6H, 2CH3); 2.15 (t, 2H, CH2); 2.23-2.26 (2m,
2H, CH2); 4.04 & 4.57 (2dd each, 2H, CH2); 5.16 & 6.50 (2brs, 2H, 2OH); 7.07-7.89 (m, 7H,
Ar-H).
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(±)4-[4-Dimethylamino)-1-(4-fluoropheny1)-1-Hydroxybutyl]-3-(Hydroxymethyl)-Benzonitrile,
Oxalate [(±)-Diol Oxalate Salt, 55]
(±)-Diol compound (20) (12 g. 0.035 mol) and oxalic acid dihydrate (4.64 g, 0.0368, 1.05 mol)
were added to methanol (36 ml) and heated the contents to 55-60°C, to obtain a clear solution.
The obtained solution was cooled to 25-30°C. and stirred for 3 h to complete the crystallization.
Product was filtered and thereafter, dried at 50-60°C, under reduced pressure to yield 11 g of diol
oxalate salt (55) with HPLC purity 99.93%. Molecular Formula: C20H23FN2O2.C2H2O4;
Molecular Weight: 432; Mass (ESI, in +ve ion mode): 343 [(MH)+- C2H2O4]; IR (KBr, cm
-1):
3242, 3065, 2952, 2899, 2650, 2519, 2476, 2233, 1770, 1732, 1716, 1652, 1603, 1506, 1488,
1472, 1440, 1412, 1397, 1300, 1279, 1215, 1157, 1024, 1006, 969, 840. 1H NMR (DMSO-d6,
300 MHz, δ ppm): 1.35-1.59 (brm, 2H, CH2); 2.15-2.28 (m, 2H, CH2); 2.63 (s, 6H, 2CH3); 2.96-
2.97 (d, 2H, CH2); 4.02 & 4.53 (2d each, 2H, CH2); 7.02-7.89 (m, 7H, Ar-H).
(±)-4-[4-Dimethylamino)-1-(4-Fluorophenyl)-1-Hydroxybuty1]-3-(Hydroxymethyl)-Benzonitrile,
Oxalate [(±)-Diol Oxalate Salt, 55]
(±)-Diol compound (20) (360 g, 1.05 mol) was dissolved in ethanol (1400 ml) and heated to 50-
55°C, to obtain a clear solution. Oxalic acid dihydrate (164.40 g, 1.3 mol) was added slowly and
cooled the obtained solution to 15-20°C and stirred for 4 hrs to complete the crystallization.
Product formed was filtered and dried at 50-60°C, under vacuum to yield 360 g of Diol oxalate
salt (55), with HPLC purity of 99.95%. (Melting Range: 168-171°C).
(±)-4-[4-Dimethylamino)-1-(4-Fluorophenyl)-1-Hydroxybuty1]-3-(Hydroxymethyl)-Benzonitrile,
Oxalate [(±)-Diol Oxalate Salt, 55]
(±)-Diol compound 20 (7 g, 0.0205 mol) and oxalic acid dihydrate (2.83 g, 0.0225 mol) were
added to isopropyl alcohol (77 ml) and heated the contents to 75-80°C to obtain a clear solution.
The obtained solution was cooled to 10-15°C. and stirred for 2 h to complete the crystallization.
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The product was filtered, and thereafter dried at 50-60°C under reduced pressure for 6 h to give
8.6 g of diol oxalate salt (55), with HPLC purity of 99.94%.
(±)-4-[4-Dimethylamino)-1-(4-Fluorophenyl)-1-Hydroxybuty1]-3-(Hydroxymethyl)-Benzonitrile,
Oxalate [(±)-Diol Oxalate Salt, 55]
(±)-Diol compound 20 (7 g, 0.0205 mol) and oxalic acid dihydrate (2.96 g, 0.0235 mol) were
added to n-butanol (77ml) and the contents were heated to 80-85°C to obtain a clear solution.
Obtained solution was cooled slowly to 15-20°C and stirred for 3 h to complete the
crystallization. The product formed was filtered and washed with n-butanol (2x7 ml). Thereafter,
product was dried at 50-60°C under reduced pressure to give 8.5 g of diol oxalate salt (55), with
HPLC purity of 99.93%.
(S)-(-)-4-[4-(Dimethylamino)-1-(4-Fluorophenyl)-1-Hydroxybutyl]-3-(Hydroxymethyl)
Benzonitrile, Hemi (+)-Di-P-Toluoyl-D-Tartaric Acid Salt [(S)-(-)-Diol Dptta Salt, 56]
(±)-Diol oxalate 55 (225 g, 0.52 mol) was suspended in a mixture of DM water (2250 ml) and
toluene (2250 ml) at 30-35°C and pH was raised to 9.8 using aqueous ammonia solution. The
organic layer was separated, was washed with DM water and concentrated at 50-55°C under
reduced pressure. The obtained residue was dissolved in isopropyl alcohol (1125 ml) at 50-55°C,
(+)-Di-p-toluoyl-D-tartaric acid (105 g, 0.27 mol) was added and slowly cooled to 25-30°C and
stirred for 10 h. The crystals formed in the reaction mixture were filtered and washed with
isopropyl alcohol (2x110 ml) to obtain 180 g product (chiral purity: > 96%). The above salt was
suspended in isopropyl alcohol (1500 ml) and heated to 80°C. to obtain a clear solution. The
resulting solution was cooled to 20-25°C and stirred for 1 hr. The solids were filtered and washed
with isopropyl alcohol (2x50 ml) and thereafter dried to yield 102 g of the above salt. Chiral
purity (by HPLC): 99.94%; [α]D25
+8.0 (c=1, in methanol, on anhydrous basis). Molecular
Formula: (C20H23FN2O2).C20H18O8; Molecular Weight: 1070; Mass (ESI, in +ve ion mode): 343
[(MH)+]; IR (KBr, cm
-1): 3292, 3076, 2964, 2872, 2229, 1717, 1614, 1507, 1484, 1457, 1410,
1380, 1337, 1267, 1223, 1183, 1156, 1111, 1039, 1011, 839. 1H NMR (DMSO-d6, 300 MHz, δ
MD. UMAR KHAN Thesis
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ppm): 1.25-1.48 (m, 2H, CH2); 2.13-2.28 (m, 2H, CH2); 2.33-2.35 (2s, 6H, 2CH3); 2.58-2.60 (t,
2H, CH2); 4.02 & 4.55 (2d each, 2H, CH2); 5.62 (s, 1H, CH); 7.07-7.89 (m, 7H, Ar-H).
preparation of 1:
(S)-(-)-Diol DPTTA salt (80 g, 0.075 mol) was suspended in a mixture of DM water (800 ml)
and methylene chloride (800 ml) at 20-25°C. The pH of the resulting solution was adjusted to
10.1 using aqueous sodium hydroxide solution at 20-25°C. Organic layer was separated and
washed with DM water (1x300 ml). Thereafter, the organic layer was partially concentrated at
atmospheric pressure at 35-39°C and the resulting concentrated mass was cooled to -5°C to -
10°C. Triethylamine (42.30 g, 0.41 mol) was added under nitrogen atmosphere, followed by
addition of methanesulfonyl chloride (18 g, 0.16 mol) slowly at -5°C to -10°C over a period of 3
h and progress of the reaction was monitored by qualitative HPLC analysis. After completion of
the cyclization, the reaction mass was washed with 0.5% w/w aqueous sodium hydroxide
solution followed by DM water at 0-10°C. Methylene chloride was distilled from reaction mass
at 20-30°C in vacuum to get Escitalopram base. Chiral purity: 99.12%; Chromatographic purity
(by HPLC): 98.42%.1HNMR (DMSO-d6, 300 MHz, δ ppm): 1.23 (m, 2H, CH2); 2.01 (s, 6H,
2CH3); 2.13 (m, 4H, 2CH2); 5.16 (q, 2H, CH2); 7.14 (t, 2H, Ar-H); 7.58 (m, 2H, Ar-H); 7.77 (m,
3H, Ar-H).
The oxalate salt of the above base was obtained by treating it with oxalic acid dihydrate in
acetone. Chiral purity: 99.01%; Chromatographic purity: 99.85%; [α] D25
+13.4 (c= I , in
methanol, on anhydrous basis). Molecular Formula: C20H21FN2O.C2H2O4; Molecular Weight:
414.4; Mass (ESI, in +ve ion mode): 325.3 [(MH)+-C2H2O4]; IR (KBr, cm
-1): 3444, 3022, 2958,
2911 & 2858, 2231, 1720, 1601, 1507, 1478, 1441, 1403, 1222, 1028, 837, 719. 1HNMR
(DMSO-d6, 300 MHz, δ ppm): 1.49 (m, 2H, CH2); 2.24 (t, 2H, CH2); 2.63 (s, 6H, 2CH3); 2.98 (t,
2H, CH2); 5.16 & 5.25 (ABq, 2H, CH2); 7.14-7.82 (m, 7H, Ar-H); 9.73 (brs, 2H, COOH). 13
C
NMR(DMSO-d6) (proton decoupled) in δppm: 19.9, 37.8, 42.8, 57.2, 72.0, 91.2, 116.0, 124.0,
126.6, 132.9, 127.9, 111.5, 119.6, 140.7, 140.9, 149.7, 160.6, 163.8, 166.0.
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preparation of 57:
Molecular Formula: C21H15F2NO2; Molecular Weight: 351; Mass (ESI, in -ve ion mode): 350.2
[(M-H)-];
1H NMR (DMSO-d6, 300 MHz, δ ppm): 4.37 (s, 2H, CH2); 5.20 (brs, 1H, OH); 6.70 (d,
1H, Ar-H); 6.97 (d, 1H, Ar-H); 7.17 (m, 8H, Ar-H); 7.61 (dd, 1H, Ar-H); 7.99 (brs, 1H, OH).
preparation of 62:
An off-white gummy solid. Molecular Formula: [C20H20FN2]+.CH3COO
- ; Molecular Weight:
366; Mass (ESI, in +ve ion mode): 307.0 [(MH)+- CH3COO
-];
1H NMR (CDCl3, 300 MHz, δ
ppm): 1.85 (s, 3H, CH3); 2.15 & 2.73 (2m, 1H each, CH2); 3.28 & 3.67 (2s, 6H, 2CH3); 3.45 &
3.74 (2m, 1H each, CH2); 4.45 & 5.20 (2d, 1H each, CH2); 6.38 (t, 1H, CH); 6.96-7.07 (m, 4H,
Ar-H); 7.22 (d, 1H, Ar-H); 7.66 (d, 1H, Ar-H); 8.49 (s, 1H, Ar-H); 13
C NMR(DMSO-d6) (proton
decoupled) in δppm: 22.73, 45.76, 49.85, 57.31, 60.08, 73.35, 75.60, 116.12, 120.68, 128.18,
128.27, 128.37, 129.32, 129.93, 130.04, 130.75, 131.78, 132.20, 133.27, 134.09, 138.54.
preparation of 63:
A white powder. Molecular Formula: [C21H23FN2OCl]+.Cl
- ; Molecular Weight: 409; Mass (ESI,
in +ve ion mode): 373.2 [(MH)+- Cl
-] and 375.1 [(M+2H)
+- Cl
-];
1H NMR (DMSO-d6, 300 MHz,
δ ppm): 1.55 (m, 2H, CH2); 2.25 (t, 2H, CH2); 3.06 (s, 6H, 2CH3); 3.44 (m, 2H, CH2); 5.17 &
5.28 (ABq, 2H, CH2); 5.31 (s, 2H, CH2); 7.16-7.84 (m, 7H, Ar-H).
preparation of 65:
A cream colour powder. Molecular Formula: [C40H41F2N4O]+.CH3COO
- ; Molecular Weight:
690; Mass (ESI, in +ve ion mode): 631.4 [(MH)+-CH3COO
-];
1H NMR (DMSO-d6, 300 MHz, δ
ppm): 1.45 (m, 2H, CH2); 1.51 (s, 3H, CH3); 2.02 (s, 6H, 2CH3); 2.15 (m, 2H, CH2); 2.38 (m, 4H,
2CH2); 2.85 & 2.87 (2s, 6H, 2CH3); 3.26 (t, 2H, CH2); 4.16 (s, 2H, CH2); 5.17 & 5.22 (ABq, 2H,
CH2); 5.90 (t, 1H, CH); 7.16-8.07 (m, 14H, Ar-H).
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preparation of 67:
Citalopram base (150 g, 0.46 mol) was dissolved in ethylene dichloride (750 ml) and
chloromethyl chloroformate (89.54 g, 0.69 mol) was added at 0-5°C. The contents were heated
slowly to 85-90°C and stirred at the same temperature to complete the reaction. After completion
of reaction, the reaction mass was concentrated at 50-55°C under reduced pressure (200-10 mm
Hg). Thereafter, DM water (300 ml) was added to the reaction mass at 20-25°C and the obtained
product was extracted into toluene at the same temperature. The organic layer was concentrated
at 50-55°C under reduced pressure (200-10 mm Hg) till no more solvent distils. Methanol
(450 ml) was added to the concentrated mass containing the product and heated the reaction mass
to 60-65°C and stirred to complete the reaction (by HPLC). After completion, methanol was
removed by distillation at 50-55°C under reduced pressure (200-10 mm Hg). DM water (450 m1)
was added to the concentrated mass at 20-35°C and washed it with toluene to remove non salt
forming impurities. pH of the aqueous layer was adjusted to 9.5 using aqueous ammonia solution
at 20-35°C and thereafter, product was extracted into toluene. Finally, the organic layer was
concentrated at 50-55°C under reduced pressure (200-10 mm Hg) to produce titled compound
desmethyl citalopram base. yield : 118.3 g; Molecular Formula: C19H19FN2O; Molecular Weight:
310; Mass (ESI, in +ve ion mode): 311.2 [(MH)+]; IR (neat, cm
-1): 3330, 3063, 2946, 2852, 2794,
2230, 1615, 1601, 1508, 1477, 1446, 1426, 1359, 1268, 1226, 1160, 1144, 1117, 1074, 1032,
1014, 884, 835. 1H NMR (DMSO-d6, 300 MHz, δ ppm): 1.18-1.32 (m, 2H, CH2); 2.17 (s, 3H,
CH3); 2.21 (t, 2H, CH2); 2.38 (t, 2H, CH2); 5.16 (ABq, 2H, CH2); 7.15 (m, 2H, Ar-H); 7.58 (m,
2H, Ar-H); 7.75 (m, 3H, Ar-H).
Desmethyl citalopram base was dissolved in ethyl acetate (600 m1) at 20-25 °C and pH was
adjusted to 3.5 with aqueous hydrochloric acid. The reaction mass was stirred for 4 hrs at
10-15°C to complete the precipitation. The product was filtered and dried at 40-45°C under
vacuum to yield 120 g of desmethyl citalopram hydrochloride, with HPLC purity of 99.5%.
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preparation of 68:
Racemic desmethylcitalopram (20 g, 0.0645 mol) was dissolved in methanol (200 m1) at 20-
35°C. Di-p-toluoyl-D-tartaric acid (25 g, 0.0648 mol) was added and slowly cooled to 25-30°C
and stirred for 12 hrs. The crystals formed in the reaction mixture were filtered and washed with
methanol to obtain titled product (Chiral purity >90%). The above salt was suspended in
methanol (140 ml) and heated to 55-60°C to obtain a clear solution. The resulting solution was
cooled to 25-30°C and stirred for 15 hrs. The solids were filtered and washed with methanol and
thereafter dried to yield (S)-(+) Desmethyl DPTTA Salt. Molecular Formula: C19H20FN2O+.
C20H17O8-; Molecular Weight: 696.26; Mass (ESI, in +ve ion mode): 311.2 [(MH)
+-C20H17O8
-];
IR (KBr, cm-1
): 3426, 3040, 2961, 2859, 2230, 1718, 1612, 1508, 1468, 1443, 1427, 1408, 1379,
1335, 1267, 1231, 1178, 1161, 1123, 1111, 1034, 1021, 956, 838. 1H NMR (DMSO-d6, 300
MHz, δ ppm): 1.33-1.46 (m, 2H, CH2); 2.16 (t, 2H, CH2); 2.36 (s, 9H, 3CH3); 2.75 (t, 2H, CH2);
3.18 (s, 2H, CH2); 5.16 (ABq, 2H, CH2); 5.64 (s, 2H, CH); 7.15 (t, 2H, Ar-H); 7.30 (d, 4H, Ar-H);
7.55 (m, 2H, Ar-H); 7.67-7.77 (m, 3H, Ar-H); 7.85 (d, 4H, Ar-H); 9.08 (brs, 2H, COOH).
preparation of 69:
(S)-(+)-Desmethyl DPTTA salt (2.5 g, 0.0036 mol) was suspended in a mixture of DM water (25
ml) and toluene (25 ml) at 25-30°C. The pH of the resulting solution was adjusted to 10 using
aqueous sodium hydroxide solution at 25-30°C. Organic layer was separated, washed and
partially concentrated at 50-55°C under reduced pressure to produce S-(+)-desmethyl citalopram
base as a residue. Molecular Formula: C19H19FN2O; Molecular Weight: 310; Mass (ESI, in +ve
ion mode): 311.2 [(MH)+]; IR (neat, cm
-1): 3330, 3063, 2946, 2852, 2794, 2230, 1615, 1601,
1508, 1477, 1446, 1426, 1359, 1268, 1226, 1160, 1144, 1117, 1074, 1032, 1014, 884, 835. 1H
NMR (DMSO-d6, 300 MHz, δ ppm): 1.14-1.33 (m, 2H, CH2); 2.17 (s, 3H, CH3); 2.21 (t, 2H,
CH2); 2.38 (t, 2H, CH2); 5.16 (ABq, 2H, CH2); 7.15 (m, 2H, Ar-H); 7.58 (m, 2H, Ar-H); 7.75
(m, 3H, Ar-H).
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preparation of 1:
Formic acid (0.45 g, 0.0097 mol) and formaldehyde (0.78 g, 0.026 mol) were added to the above
obtained residue containing S-(+)-desmethyl citalopram and heated to 90-95°C for 2 hrs. After
completion of reaction the reaction mass was concentrated at 50-55°C under reduced pressure.
2N Hydrochloric acid (5 ml) and toluene/MDC were added to the concentrated mass at 25-30°C
and separated the organic layer. The pH of the aqueous layer was adjusted to 9.5 using aqueous
ammonia solution at 20-35°C and thereafter, product was extracted with methylene chloride.
Finally, the organic layer was concentrated at 50-55°C (200-10 mm Hg) to obtain Escitalopram
base. The oxalate salt of the above base was obtained by treating it with oxalic acid dihydrate in
acetone. Chiral purity: 99.01%; Chromatographic purity: 99.85%; [α] D25
+13.4 (c= I , in
methanol, on anhydrous basis). Molecular Formula: C20H21FN2O.C2H2O4; Molecular Weight:
414.4; Mass (ESI, in +ve ion mode): 325.3 [(MH)+-C2H2O4]; IR (KBr, cm
-1): 3444, 3022, 2958,
2911 & 2858, 2231, 1720, 1601, 1507, 1478, 1441, 1403, 1222, 1028, 837, 719. 1HNMR
(DMSO-d6, 300 MHz, δ ppm): 1.49 (m, 2H, CH2); 2.24 (t, 2H, CH2); 2.63 (s, 6H, 2CH3); 2.98 (t,
2H, CH2); 5.16 & 5.25 (ABq, 2H, CH2); 7.14-7.82 (m, 7H, Ar-H); 9.73 (brs, 2H, COOH). 13
C
NMR(DMSO-d6) (proton decoupled) in δppm: 19.9, 37.8, 42.8, 57.2, 72.0, 91.2, 116.0, 124.0,
126.6, 132.9, 127.9, 111.5, 119.6, 140.7, 140.9, 149.7, 160.6, 163.8, 166.0.
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SPECTRA:
…..1H NMR SPECTRUM OF COMPOUND 20
…..IR AND 1H NMR SPECTRUM OF COMPOUND 55
MD. UMAR KHAN Thesis
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…..MASS SPECTRUM OF COMPOUND 55
…..IR AND 1H NMR SPECTRUM OF COMPOUND 56
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…..1H NMR SPECTRUM OF COMPOUND 1 BASE
…..IR AND 1H NMR SPECTRUM OF COMPOUND 1
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….. 13
C NMR AND MASS SPECTRUM OF COMPOUND 1
…..MASS SPECTRUM OF COMPOUND 57
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…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 67
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…..IR and 1H NMR SPECTRUM OF COMPOUND 68
….. 1H NMR SPECTRUM OF COMPOUND 57
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…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 63
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…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 65
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….. 1H NMR,
13C NMR AND MASS SPECTRUM OF COMPOUND 65
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REFERENCES:
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