Studies on the synthesis of anti-depressant drug,...

59
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

Transcript of Studies on the synthesis of anti-depressant drug,...

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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

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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)

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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

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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:

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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]

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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

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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]

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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

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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.

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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.

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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).

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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

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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

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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-

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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

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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.

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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

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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.

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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-

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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.

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(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%

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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;

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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

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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

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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.

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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

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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).

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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

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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

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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

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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

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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.

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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

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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

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…..MASS SPECTRUM OF COMPOUND 55

…..IR AND 1H NMR SPECTRUM OF COMPOUND 56

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MD. UMAR KHAN Thesis

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Chapter - VI

…..1H NMR SPECTRUM OF COMPOUND 1 BASE

…..IR AND 1H NMR SPECTRUM OF COMPOUND 1

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MD. UMAR KHAN Thesis

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Chapter - VI

….. 13

C NMR AND MASS SPECTRUM OF COMPOUND 1

…..MASS SPECTRUM OF COMPOUND 57

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Chapter - VI

…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 67

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Chapter - VI

…..IR and 1H NMR SPECTRUM OF COMPOUND 68

….. 1H NMR SPECTRUM OF COMPOUND 57

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Chapter - VI

…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 63

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Chapter - VI

…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 65

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Chapter - VI

….. 1H NMR,

13C NMR AND MASS SPECTRUM OF COMPOUND 65

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