N-desmethylation reaction for the synthesis and ...gmail.com Chemical process involves the synthesis of a single product or several products by mixing compounds at certain proportions

IJIPBART (2015) Volume 2, Issue (3), pp: 217-227 ISSN: 2349-865X

OPEN ACCESS

International Journal of Innovation in Pharma

Biosciences and Research Technology (IJIPBART)

Original Research Article

www.refsynjournals.com 217

One step N-desmethylation reaction for the synthesis and

characterization of the N-desmethyl Escitalopram from

Escitalopram oxalate

V.Saranya1, G.Vanaja

1*,

C.Premalatha

1, J.Nowsath ali

2

1Department of Chemistry, Dhanalakshmi Srinivasan College of Arts and Science for Women, Perambalur-

621212, India 2 R&D Department, Refsyn Biosciences Pvt. Ltd, Puducherry-605005, India.

ABSTRACT

INTRODUCTION

Synthetic chemistry is a branch of chemistry where chemical reactions are purposefully

employed to obtain a product or several products and this field has evolved to a greater extent.

Synthetic methods which can provide the expected product in high standards of chemical yield,

selectivity and purity as in biochemical methods are needed. A chemical substance used in the

treatment, cure, prevention, or diagnosis of a disease is called a drug. Any component that is not the

chemical entity of the drug substance and affects the purity of active ingredient or drug substance is

called an Impurity, as defined by the International Conference on Harmonization (ICH) Guidelines

(US FDA, 2003). Degradants are chemical substances formed as a result of breakdown of drugs

during longer storage conditions.

The chemical process in which methyl group is removed from a molecule is called

demethylation. N-demethylation is a chemical transformation of major importance in the synthesis of

drugs, intermediates of pharmaceutical compounds and metabolites. N-demethylation of tertiary N-

Article received

July 28, 2015

Article accepted

August 08, 2015

Article published

September 30, 2015

*Corresponding Author:

G. VANAJA,

Dept. of Chemistry,

Dhanalakshmi Srinivan College

of Arts and Science for Women,

Perambalur-621212, India.

[email protected]

Chemical process involves the synthesis of a single product or several

products by mixing compounds at certain proportions and conditions.

In the present study, Escitalopram oxalate is used to synthesize and

characterize N-desmethyl escitalopram by a one step N-

desmethylation reaction. The synthesized impurity N-desmethyl

escitalopram was purified by column chromatography. The purified

impurity was analyzed by HPLC. The functional group in the

compound was analyzed using FT-IR and its molecular weight was

determined by LC-MS. The structure of the purified compound was

determined by 1HNMR spectroscopy and

13CNMR spectroscopy

analysis respectively.

Keywords: Synthetic chemistry, Escitalopram oxalate, Escitalopram,

demethylation, N-desmethyl Escitalopram

Vanaja et al IJIPBART (2015) Volume 2, Issue (3), pp: 196-206


methylamines has been studied extensively and a variety of methods for this process have been

reported (Thavaneswaran, 2006). N-demethylated products can be synthesized using different

methods. Yan-jie et al., (2013) purified impurities in azithromycin drug, 3’-N-demethyl azithromycin

and 3’-N-demethyl 3

’-N-formyl azithromycin by chromatographic separation technique. Reaction

conditions were optimized with HPLC method and the structures of the derivatives were identified by

H1

NMR and MS. Similarly, the N-demethylation of Sildenafil was studied and the purity of the

compound was analyzed by HPLC and characterized using FT-IR and MS (Suganthi et al., 2015). In

another study, Le Tourneau et al., (2012) studied the structural factors behind macrolide resistance

through the synthesis of new macrolide derivates possessing truncated desosamine sugar moieties and

subsequent determination of their anti-bacterial activity. Similarly, the impurities in the synthesis of

Tramadol hydrochloride and clozapine were also studied (Venkanna et al., 2012; Garipelli et al.,

2010).

Characteraization of impurities using HPLC, LC-MS, FT-IR and NMR were reported in many

studies. Topalli et al., (2012) developed a simple, sensitive and rapid reversed phase HPLC (RP-

HPLC) method for the separation and quantitative determination of related substances of

Clarithromycin in Clarithromycin powder. Asnawi et al., (2011) obtained demethylated quinine by

mild and selective demethylation of quinine using anhydrous aluminium trichloride to prevent the

addition reaction of allyl group. The compound was characterized by FT-IR and HPLC. Sharma et al.,

(2010) developed a new method for N-methylation of aromatic diamines using dimethyl carbonate

(DMC) and investigated the effects of various functional groups on the aromatic ring. Radhkrishna et

al., (2008) detected three unknown impurities in rosiglitazone maleate by simple RP-HPLC. These

impurities were preliminarily identified with LC-MS and characterized by mass number of the

impurities. Kaleemullaha et al., (2011) used a simple and rapid HPLC method to quantify di-p-

Toluoyl-d-Tartaric acid (DPTTA) at very low levels in Escitalopram oxalate. Gangula et al., (2011)

studied the synthesis and identification of five process-related impurities of escitalopram by

employing LC-MS and characterized them using IR and NMR. Mondal et al., (2013) developed a RP-

HPLC method for the simultaneous determination of Escitalopram oxalate and Etizolam.

Escitalopram oxalate is an antidepressant under the group of selective serotonin reuptake

inhibitors (SSRI). N-demthylation of Escitalopram was reported using Chloromethyl chloroformate

(Vipin, Kumar Kaushik, et al., 2006). In this present study, the synthesis of N-desmethyl citalopram

from Escitalopram oxalate by simple one step method and purify the column and characterize by LC-

MS, 1H and

13C NMR and FT-IR.



METHODS

Escitalopram oxalate was gifted from Refsyn Biosciences Pvt. Ltd. All the solvents used were

of analytical grade.

Conversion of Escitalopram Oxalate to Escitalopram free base

Escitalopram oxalate was dissolved in water. The pH of the solution was adjusted to 8-9 with

saturated sodium carbonate for converting free base. The compound was extracted with chloroform.

The organic layer was dried and filtered under anhydrous sodium sulphate. The resulting solution was

concentrated under reduced pressure using rotary vacuum evaporator. The weight of crude material

was noted and the material was stored at -20°C until further use. The crude material was analysed by

TLC. Readymade TLC plate (Merck, Silica gel 60 F254) was used as the stationary phase and

chloroform: methanol (9:1, v/v) was used as the mobile phase. The spots were visualized under UV

chamber (short UV- 254nm).

Synthesis of N-Desmethyl Escitalopram

1.0 equivalent of Escitalopram free base was dissolved in 10ml of methanol. 6.9 equivalents

of sodium acetate was added to the reaction mixture and mixed until the compound was dissolved

completely. Then, 1.7 equivalent of iodine was added to the reaction mixture at regular intervals and

the pH was checked and maintained between 8.5 and 9.5 in the reaction mixture by adding 0.1N

sodium hydroxide in drops. The reaction was continued and the pH and TLC were checked every

hour. The reaction was continued over night. The reaction was continued until clear solution. The

reaction was monitored by TLC in the solvent system Chloroform: Methanol (9.8:0.2, v/v).

Visualization of the spots was observed by UV light at 254 nm. After the reaction was completed, 100

ml of dichloromethane was added to the reaction mixture. The organic and aqueous layers were

separated. The organic layer was filtered under anhydrous sodium sulfate and dried. The resulting

solution was concentrated under reduced pressure using rotary vacuum evaporator. The weight of the

crude material was analysed by MASS and purified by column chromatography.

Column Purification of the crude material

1.7g of crude material was taken with 5g of silica gel (for column chromatography 60-120

mesh) and suspended in 10 ml chloroform. The mixture was heated gently until the silica gel becomes

free flowing. A cylindrical glass column (1.5×15 mm) was taken and 20g of fresh silica gel was added

with 100ml of chloroform to make silica slurry. The slurry was transferred and packed in the column

to three-fourth proportion. The adsorbed crude material slurry was poured into the solvent layer above

the silica gel in the packed column. The column elution was started with 100% chloroform and the

polarity was increased using chloroform: methanol in a proportion of 100% chloroform and 99.5:0.5,

99:1, 98.5:1.5,98:2,97:3,96:4,95:5 etc. Individual fractions were monitored for TLC. Same spot

fractions were mixed and concentrated using roteva (super rotavap) at 60oC under vacuum pressure.

The fractions were analyzed for maximum absorbance using UV Spectrophotometer (HITACHI, U-



2010). The purified fractions were scanned at wavelengths between 200 and 400 nm and compared

with free base and escitalopram oxalate.

Characterization of N-Desmethyl Escitalopram

Functional group analysis by FT-IR

The fraction collected from the column separation was analyzed to identify the functional

group using FT-IR spectroscopy. 1% of the compound was mixed thoroughly with 99% of Potassium

Bromide and made as a pellet and analyzed using FT-IR (Nicolet IS 5, Thermofischer, USA). The

functional group was identified from the spectral data.

Molecular weight determination by LC-MS

LC-MS/MS analysis was performed using LCMS (LC-2010EV model) with APCI coupled

with HPLC system consisting of Agilent 1100 series low pressure quaternary gradient pump along

with dampener/ degasser, auto sampler and the column oven (Shimadzu, Japan). The analysis was

done in positive electro spray ionization (ESI) mode with turbo ion spray interface. An Inertsil C18

(250x4.6 mm, 5µl, GL Sciences, Japan) column was used for separation. The column eluent was

introduced into the electron spray ionization (ESI) chamber of the mass spectrometer with the split

ratio of 3:7. Mass fragmentation studies were carried out by maintaining normalized collision energy

at 35 eV with the m/z range of 50-300 amu.

Structural determination of purified compound by 1H NMR and

13C NMR

The structure of the purified compound was determined by 1H NMR and

13C NMR using Jeol

400-MHz NMR spectrophotometer with multiple probe facility for 1H,

11B,

13C,

17O,

19F,

31P, Model-

JNM-400.

RESULTS AND DISCUSSION

Synthesis of N-Desmethyl Escitalopram

Reaction setup for the Escitalopram free base was shown in Figure 1. The conversion of free

base from salt makes the reaction faster and effective. The free base obtained from salt was used for

N-demethylation reaction.

Figure 2 shows the reaction setup for the synthesis of N- desmethyl Escitalopram after

addition of Iodine. The reaction was continued for a day. Thin Layer Chromatograms of the reaction

mixture at 2, 16 hour and 24 hours were shown in Figure 2 which was visualized under UV chamber.

After 24 hours, the disappearance of starting material was almost 93%. The formation of N-desmethyl

Escitalopram and disappearance of Escitalopram free base indicated completion of the reaction. Taha

et al., (2009) used thin layer chromatography for the determination of (±) Citalopram and its S-

enantiomer Escitalopram. Sundar (2011) developed and validated liquid chromatographic method for

estimation of Escitalopram oxalate in tablet dosage forms. To conform the formation of N-desmethyl

compound MASS analysis was performed. The N-demethylated citalopram product peak was visible

at a m/z ratio of 311 and the citalopram product peak was visible at a m/z ratio of 324 (Figure 3).

Vanaja et al

www.refsynjournals.com

Figure1. Reaction setup for E

of Es

Figure 2. Reaction setup and TLC monitoring of N

Figure

Column Purification

The crude material of N

(Figure 4). Chloroform: methanol in the mobile phase was used for elution. The purified fraction was

utilized for further characterization.

purified compound was further characterized by FT

identified using FT-IR. FT-IR results of Escitalopram and N

IJIPBART (2015) Volume 2,

Reaction setup for Escitalopram Free base (A & B), extraction (C)

scitalopram Free base using Roteva (D)

Reaction setup and TLC monitoring of N-demethylation reaction

Figure 3. Mass analysis of the crude compound

The crude material of N-desmethylated product was purified by column chromatography


utilized for further characterization. In the fractions 184 to 229, the pure compound was obtained. The

purified compound was further characterized by FT-IR, HPLC and NMR. The functional group was

IR results of Escitalopram and N-desmethylated Escitalopram compounds

IJIPBART (2015) Volume 2, Issue (3), pp: 196-206

221

and concentration

demethylation reaction

desmethylated product was purified by column chromatography


pure compound was obtained. The

The functional group was

desmethylated Escitalopram compounds

Vanaja et al


were shown in Figure 5. Abdouss

serum and urine

Figure 4. Column purification of N

Figure 5. FT-IR analysis of Escitalopram oxalate and N

Table1. FT-IR analysis results of Escitalopram oxalate and N

Escitalopram oxalate

Frequency

range

3427.99

3020.549

2956.15

2856.14

2698.63

2230.59

1719.53

1600.67

1506.67

1477.64

1403.77

1278.56

12225.9

1103.99

1073.63

1027.34

961.46

881.32

836.99

751.11

719.35


Abdouss et al., (2012) used FT-IR to characterize citalopram

olumn purification of N-desmethyl Escitalopram (A) Slurry & (B)

IR analysis of Escitalopram oxalate and N-desmethyl Escitalopram

IR analysis results of Escitalopram oxalate and N-desmethyl Escitalopram

Escitalopram oxalate N-desmethyl escitalopram

Frequency Functional

group

Frequency

range

Functional

group

O-H

C-H

C-H

C-H

O-H

N-H

C=O

N-H

C=C

C-H

C-H

C-F

C-O

C-O

C-O

C-O

C-H

C-H

C-H

C-H

C-H

3446.94

2923.98

2852.72

2229.69

1600.55

1507.59

1465.42

1224.02

1160.11

1028.75

953.75

835. 27

756. 20

O-H

C-H

C-H

C-N

N-H

C=C

C-H

C-F

C-O

C-O

C-H

C-H

C-H


222

citalopram from human

(B) Column Packed

desmethyl Escitalopram


desmethyl escitalopram

Functional

Vanaja et al


UV-Visible Spectrocopy Analysis

Figure 6 shows the λmax

desmethyl Escitalopram before column purification and Figure 6 shows the

Escitalopram free base and N-desmethyl Escitalopram after column purification. Gandhi

employed spectrophotometric analysis for the determination of Escitalopram Oxalate in combined

tablet dosage form. Chaudhari and Parmar (2010) used spectrophotometric method for the

determination of Escitalopram Oxalate from tablet formulation.

Figure6. λmax values of Escitalopram oxalate, Escitalopram free base and N

Escitalopram before and after column purification

The λmax VALUE of Escitalopram oxalate is 237 & 284.5, for Escitalopram free base was 287 &

239.5 and for N-desmethyl citalopram was 284, 236.5

LC-MS Spectroscopy analysis

Dhavale et al., (2008) used HPTLC for the determination of escitalopram oxalate and

clonazepam in combined tablets. Similarly, Kakde

the simultaneous estimation of escitalopram oxalate and clonazepam in tablet dosage. Samanta

(2011) used RP-HPLC method for the estimation of escitalopram in bulk and in dosage forms.

Greiner et al., (2007) used column

the determination of citalopram and escitalopram together with their active main metabolites

desmethyl (es-)citalopram in human serum.


Visible Spectrocopy Analysis

max values of Escitalopram oxalate, Escitalopram free base and N

desmethyl Escitalopram before column purification and Figure 6 shows the

desmethyl Escitalopram after column purification. Gandhi

yed spectrophotometric analysis for the determination of Escitalopram Oxalate in combined


determination of Escitalopram Oxalate from tablet formulation.

values of Escitalopram oxalate, Escitalopram free base and N

Escitalopram before and after column purification

VALUE of Escitalopram oxalate is 237 & 284.5, for Escitalopram free base was 287 &

desmethyl citalopram was 284, 236.5

(2008) used HPTLC for the determination of escitalopram oxalate and

clonazepam in combined tablets. Similarly, Kakde et al., (2009) used spectrophotometric met

the simultaneous estimation of escitalopram oxalate and clonazepam in tablet dosage. Samanta

HPLC method for the estimation of escitalopram in bulk and in dosage forms.

(2007) used column-switching high performance liquid chromatography (HPLC) for


)citalopram in human serum.


223

values of Escitalopram oxalate, Escitalopram free base and N-

desmethyl Escitalopram before column purification and Figure 6 shows the λmax values of

desmethyl Escitalopram after column purification. Gandhi et al., (2008)

yed spectrophotometric analysis for the determination of Escitalopram Oxalate in combined


values of Escitalopram oxalate, Escitalopram free base and N-desmethyl

VALUE of Escitalopram oxalate is 237 & 284.5, for Escitalopram free base was 287 &

(2008) used HPTLC for the determination of escitalopram oxalate and

(2009) used spectrophotometric method for

the simultaneous estimation of escitalopram oxalate and clonazepam in tablet dosage. Samanta et al.,

HPLC method for the estimation of escitalopram in bulk and in dosage forms.

mance liquid chromatography (HPLC) for


Vanaja et al


Figure 7. LC

The LC-MS results of

approximately 1 min as depicted in Figure 7. By using atmospheric pressure chemical ionization, MS

spectra was produced consisting predominantly of the protonated [M+H]

showed a m/z ratio of 311.1 indicating desmethyl escitalopram. Singh

method for the determination of escitalopram in human plasma. In another study, the structural

elucidation of process-related impurities in escitalopram was performed by LC/ESI

(Raman et al., 2010). Dhaneshwar

degradation behavior of Escitalopram Oxalate.

demethylated metabolites of Escitalopram by LC

1H NMR Spectroscopy analysis and

Figure 8. H

1 NMR and C

1H NMR analysis of N-desmethyl citalopram was performed for the identification of protons.

NMR (DMSO-d6) δ ppm 1.17-1.31 (m, 2H), 2.17

7.12-7.18 (t, 2H), 7.56-7.61 (q, 2H), 7.72

2.10-2.30 (m, 2H), 2.35 (s, 3H), 2.53

(m, SH) (Figure 8). Chemical Shift in

spectrum. Each carbon nucleus has its own electronic environment, different from the environment of

other non-equivalent nuclei; it feel

strength. 13

C NMR 23.9, 35.9, 38.8, 51.4, 71.2, 90.9, 111.5, 115.0, 115.3, 118.5, 122.7, 125.1, 126.6,

126.7, 131.7, 139.4, 140.2, 149.2, 160.2, 163.5. M+ 310.9 (Figure 8).


LC-MS analysis of N-desmethyl Escitalopram

MS results of N-desmethyl escitalopram, eluted from the analytical column at


spectra was produced consisting predominantly of the protonated [M+H]+

ion. The precursor ions

311.1 indicating desmethyl escitalopram. Singh et al., (2004) used LC


related impurities in escitalopram was performed by LC/ESI

2010). Dhaneshwar et al., (2009) used column LC-MS to evaluate the stress

degradation behavior of Escitalopram Oxalate. In another study, Frison et al., (2008) quantified the

demethylated metabolites of Escitalopram by LC-MS.

H NMR Spectroscopy analysis and 13

C NMR Spectroscopy analysis

NMR and C13

NMR spectroscopy analysis of N-desmethyl Escitalopram

desmethyl citalopram was performed for the identification of protons.

1.31 (m, 2H), 2.17-2.20 (d, 5H), 2.35-2.40 (t, 2H), 5.10

7.61 (q, 2H), 7.72-7.79 (q, 3H). 1H NMR (CDC13, b): 1.30

2.30 (m, 2H), 2.35 (s, 3H), 2.53-2.60 (m, 2H), 5.10-5.25 (m, 2H), 6.94-7.05 (m, 2H), 7.40

(m, SH) (Figure 8). Chemical Shift in 13

C NMR spectrum arises in the same way as in proton NMR


equivalent nuclei; it feels a different magnetic field, and absorbs at different applied field

C NMR 23.9, 35.9, 38.8, 51.4, 71.2, 90.9, 111.5, 115.0, 115.3, 118.5, 122.7, 125.1, 126.6,

126.7, 131.7, 139.4, 140.2, 149.2, 160.2, 163.5. M+ 310.9 (Figure 8). Zhong-hu and


224

desmethyl escitalopram, eluted from the analytical column at


ion. The precursor ions

(2004) used LC-ESI/MS


related impurities in escitalopram was performed by LC/ESI-MS and NMR

MS to evaluate the stress

(2008) quantified the


desmethyl citalopram was performed for the identification of protons. 1H

2.40 (t, 2H), 5.10-5.21 (dd, 2H),

H NMR (CDC13, b): 1.30-1.66 (m, 2H),

7.05 (m, 2H), 7.40 -7:62

C NMR spectrum arises in the same way as in proton NMR


s a different magnetic field, and absorbs at different applied field

C NMR 23.9, 35.9, 38.8, 51.4, 71.2, 90.9, 111.5, 115.0, 115.3, 118.5, 122.7, 125.1, 126.6,

hu and Xue-wu (2013)



used NMR analysis for the structure identification of unknown impurity in escitalopram. Similarly,

Charde (2012) employed NMR spectroscopy to characterize process related impurities in

escitalopram oxalate.

CONCLUSION

N-demethylation of Escitalopram was performed with the basic simple, cost effective and less

time consuming method by using sodium acetate and iodine. This showed that the N-demethylated

impurities of pharmaceutical drugs can be synthesized by simple method and can avoid the

carcinogenic agent. These compounds can be utilized for future drug discovery, drug developmental

studies as well as reference standards for pharmaceutical and toxicological studies.

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IJIPBART, 2(03); 196-206.

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The authors declare that they have no conflict of interests regarding the publication of this paper.

Copyright © 2015 by authors. This is an open access article distributed under the Creative Commons Attribution License, which

permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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