Synthesis and characterization of potential impurities of the antimigraine drug, rizatriptan benzoate

Article abstract of DOI:10.1080/00397910701798051

Rizatriptan benzoate is a recently developed antimigraine drug used for the treatment of migraines and severe headaches. In the synthesis of rizatriptan benzoate in bulk,various impurities are formed. The present work details the development of a simple a

Full text of DOI:10.1080/00397910701798051

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Synthesis and Characterization of Potential
Impurities of the Antimigraine Drug,
Rizatriptan Benzoate
P. Seetharama Sarma a , C. Nageswar Rao a , M. V. Surayanarayana a , Padi
Pratap Reddy a , M. Khalilluah b & Cherukupally Praveen a
a Research and Development Centre, Integrated Product Development
Organization‐Active Pharmaceutical Ingredients, Dr. Reddy's Laboratories
Ltd. , Bachupally, Hyderabad, Andhra Pradesh, India
b Department of Chemistry , Institute of Science and Technology, JNT
University , Kukatpally, Hyderabad, India
Published online: 27 Feb 2008.
To cite this article: P. Seetharama Sarma , C. Nageswar Rao , M. V. Surayanarayana , Padi Pratap Reddy ,
M. Khalilluah & Cherukupally Praveen (2008) Synthesis and Characterization of Potential Impurities of the
Antimigraine Drug, Rizatriptan Benzoate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:4, 603-612, DOI: 10.1080/00397910701798051
To link to this article: http://dx.doi.org/10.1080/00397910701798051
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Synthetic Communicationsw, 38: 603–612, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701798051
Synthesis and Characterization of Potential
Impurities of the Antimigraine Drug,
Rizatriptan Benzoate
P. Seetharama Sarma,1 C. Nageswar Rao,1
M. V. Surayanarayana,1 Padi Pratap Reddy,1 M. Khalilluah,2
and Cherukupally Praveen1
1Research and Development Centre, Integrated Product Development
Organization-Active Pharmaceutical Ingredients, Dr. Reddy’s Labora-
tories Ltd., Bachupally, Hyderabad, Andhra Pradesh, India
2Department of Chemistry, Institute of Science and Technology, JNT
University, Kukatpally, Hyderabad, India
Abstract: Rizatriptan benzoate is a recently developed antimigraine drug used for the
treatment of migraines and severe headaches. In the synthesis of rizatriptan benzoate in
bulk,various impurities are formed. The present work details the development of a
simple and novel process for the preparation of hydrazone impurity (6), rizatriptan
N-oxide (7), rizatriptan dimer (9), desmethyl rizatriptan (13), 5-(1H-1,2,4-triazol-1-
yl-methyl)-1H-indole-3-ethanamine hydrochloride (14), N-methyl rizatriptan oxalate
(15), and impurities.
Keywords: impurities, maxalt, migraines, rizatriptan benzoate, serotonin agonist
INTRODUCTION
Rizatriptan benzoate is described chemically as N,N-dimethyl-5-(1H-1,2,4-
triazol-1-yl-methyl)-1H-indole-3-ethanamine monobenzoate (1). It is used
Received in India August 22, 2007
DRL Communication No -IPDO-IPM00063
Address correspondence to Cherukupally Praveen, Research and Development
Centre, Integrated Product Development Organization-Active Pharmaceutical Ingredi-
ents, Dr. Reddy’s Laboratories Ltd., Bachupally, Hyderabad 500 072, India. E-mail:
praveench@drreddys.com
603

604
P. S. Sarma et al.
in the treatment of migraines.[1–4] Rizatriptan benzoate binds to serotonin
receptors in the brain, which causes the blood vessels to narrow. By decreas-
ing the width of blood vessels in the brain, rizatirptan relieves the pain.
Rizatriptan is available as an orally disintegrating tablet with a brand
name Maxalt.
The literature survey revealed various synthetic methods for rizatriptan
benzoate.[5–9] It was synthesized according to the Scheme 1, with slight modi-
fications to make it simpler and commercially viable. Reaction of 1-(4-
hydrazino phenyl) methyl-1,2,4-triazole dihydrochloride 5 with 4-N,N-
dimethyl amino butanal dimethyl acetal 4 in presence of 4–5% hydrochloric
acid gave 3, which undergoes cylization under reflux conditions to afford riza-
triptan base 2. Addition of benzoic acid to the base 2 gave the title compound
N,N-dimethyl-5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-ethanaminemono
benzoate (1).
During the analysis of laboratory batches of rizatriptan benzoate, six
impurities were detected by high performance liquid chromatography
(HPLC). A literature survey revealed that the HPLC method was
described for rizatriptan benzoate along with three impurities.[10] The
study did not mention the synthesis and characterization of impurities.
The presence of impurities in an active pharmaceutical ingredient (API)
can have a significant impact on the quality and safety of the drug.
Therefore, it is necessary to study the impurity profile of the API to be
used in the manufacturing of a drug product. International Conference on
Harmonization (ICH) guidelines recommend identifying and characterizing
all impurities that are present at a level of 0.10% or more.[11,12] This
became essential in the wake of stringent purity requirements from regulat-
ory authorities. In this context, a comprehensive study was undertaken to
synthesize and characterize all six impurities: hydrazone impurity (6),
Scheme 1. Synthesis of Rizatriptan benzoate (1). Reagents and conditions: (a) 4–5%
HCl solution, 0 8C, 1 hr. (b) 4–5% HCl solution, reflux, 2 h, 40%. (c) Benzoic acid,
isopropanol, rt, 1 h, 80%.

Impurities of Rizatriptan Benzoate
605
rizatriptan N-oxide (7), rizatriptan dimer (9), desmethyl rizatriptan (13),
5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-ethanamine hydrochloride (14),
and N-methyl rizatriptan oxalate (15) by spectroscopic and spectrometric
techniques. Results are presented in this article.
DISCUSSIONS
In this article, we herewith disclose our work regarding the synthe-
sis and characterization of the various potential impurities of rizatriptan
benzoate.
1-(4-(2-(4-(Dimethylamino)butylidene)-hydrazino)phenyl)-methyl-
1,2,4-triazole (6)
Preparation of 1-(4-(2-(4-(dimethyl amino) butylidene)-hydrazino)phenyl)-
methyl-1,2,4-triazole (6) involves condensation of 1-(4-hydrazinophenyl)-
methyl-1,2,4-triazole dihydrochloride 5 with 4-N,N-dimethylamino butanal
dimethyl acetal 4 in the presence of aqueous HCl as an acid catalyst.
This was an insitu intermediate in the synthesis of rizatriptan benzoate.
The protonated molecular ion of 6 appeared as the base peak at 287.4 in
mass spectrum. The presence of NH stretching (3430 cm21), aromatic
C-H stretching (3033 cm21), aliphatic C-H stretching (2945, 2863 cm21),
and C55N stretching (1613 cm21) was evident in the infrared spectrum.
1
In the H NMR spectrum, NH appeared as a singlet at 7.0d, which disap-
peared on D2O exchange. The N-CH3 protons appeared as a singlet at
2.34 d, and the benzylic methyl protons attached to 1,2,4-triazole appeared
as a sixnglet at 5.66 d.
N,N-Dimethyl-5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-
ethanamine N-Oxide (7)
This N-oxide impurity was formed by the air oxidation of rizatriptan base
during the process. rizatriptan base 2 on treatment with meta-chloroperbenzoic
acid (m-CPBA) in dichloromethane smoothly afforded rizatriptan N-oxide in
quantitative yields. The protonated molecular ion of 7 appeared as the base
peak at 286.2 in mass spectrum. The IR spectrum showed the presence of
aromatic C-H stretching (3042 cm21), aliphatic C-H stretching (2946,
1
2924 cm21), and C55N stretching (1504 cm21). In the H NMR spectrum
dimethyl sulfoxide (DMSO), NH appeared as a singlet at 11.3 d, which disap-
peared on D2O exchange. The N-CH3 protons appeared as a singlet at 2.34 d.
The benzylic methyl protons attached to 1,2,4-triazole appeared as a singlet at
5.5 d.

606
P. S. Sarma et al.
[3-[2-(N,N-Dimethylamino)ethyl-2-[[3-[2-(N,N-dimethylamino)ethyl]-1H-
indol-5-yl]methyl]-1H-indol-5-yl]methyl-1H-1,2,4-triazolebenzoate (9)
This impurity was formed by the self-condensation of two molecules of riza-
triptan base with the elimination of one triazole ring, catalyzed by acid during
the formation of rizatriptan base. This was further converted into benzoate
salt. Preparation of this impurity involves treating rizatriptan base with
dilute hydrochloric acid under reflux conditions. The protonated molecular
ion of 9 appeared as the base peak at 470.5 in the mass spectrum. IR
spectrum showed the presence of NH stretching (3287 cm21), aliphatic C-H
stretching (2957, 2924 cm21), and aromatic C55C and C55N stretching
(1599,1571 cm21) respectively. In the 1H NMR spectrum (DMSO), two
singlets appeared at 10.9 d and 10.7 d, corresponding to two indole NH
protons, which disappeared on D2O exchange. Two sets of two benzylic
protons appeared as singlets at 5.4 d and 4.1d respectively. Twelve protons
of N-methyl appeared as a singlet at 2.3 d.
N-Methyl-5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-ethanamine (13)
This impurity is formed during the Fisher indole cyclization of 1-(4-hydrazi-
nophenyl)methyl-1,2,4-triazole dihydrochloride 5 with 4-N,N-dimethylamino
butanal dimethyl acetal 4 in the presence of aqueous HCl under reflux con-
ditions. Preparation of this impurity involves condensation of 1-(4-hydrazino-
phenyl)methyl-1,2,4-triazole dihydrochloride
5 with sodium salt of
4-chlorobutanal bisulfite adduct 10 to afford 11, which undergoes
immediate cyclization in the presence of polyphosphoric acid isopropyl
ester, to give the chloro indole derivative 12. This was further reacted with
aqueous mono methylamine solution to give the title compound 13. The pro-
tonated molecular ion of 13 appeared as the base peak at 256.5 in mass
spectrum. IR spectrum (neat) showed the presence of NH stretching
(3421 cm21), aromatic C-H stretching (3042 cm21), aliphatic C-H stretching
(2946, 2924 cm21), -N-H bending (1595 cm21), and aromatic C-H bending
1
(807, 743 cm21). In the H NMR spectrum (DMSO), indole NH appeared
as a singlet at 10.9 d and des-methyl NH appeared broad at 3.8 d, which dis-
appeared on D2O exchange. The N-CH3 protons appeared as a doublet at
2.4 d. The benzylic methyl protons attached to 1,2,4-triazole appeared as a
singlet at 5.43 d.
5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-ethanamine
Hydrochloride (14)
This impurity is formed during the synthesis of rizatriptan benzoate. Preparation
of this impurity involves condensation of 1-(4-hydrazinophenyl)methyl-1,2,

Impurities of Rizatriptan Benzoate
607
4-triazole dihydrochloride (3) with sodium salt of 4-chloro butanal bisulfite
adduct in the presence of aqueous isopropyl alcohol as a solvent medium
and triethyl amine as a base under reflux conditions. The protonated
molecular ion of 14 appeared as the base peak at 242 in mass spectrum. IR
spectrum showed the presence of NH stretching (3400 cm21), aromatic C-H
stretching (3033 cm21), aliphatic C-H stretching (2946, 2924 cm21), and
1
aromatic C-H bending (820, 716 cm21). In the H NMR spectrum (DMSO),
indole NH appeared as a singlet at 11.1 d, and free amine protons appeared
as a broad singlet at 6.0 d, which disappeared upon adding deuterium oxide.
The benzylic methyl protons attached to 1,2,4-triazole appeared as a singlet
at 5.43 d.
N,N-Dimethyl-5-(1-methyl-1,2,4-triazol-1-yl-methyl)-1H-indole-3-
ethanamine Oxalate (15)
This impurity is formed during the Fisher indole cyclization of 1-(4-hydrazi-
nophenyl)methyl-1,2,4-triazole dihydrochloride (3) with 4-N,N-dimethyla-
mino butanal dimethyl acetal in the presence of aqueous HCl under reflux
conditions. Preparation of this impurity involves N-methylation on a rizatrip-
tan base with methyl iodide in presence of potassium ter-butoxide as a base in
DMF. The protonated molecular ion of 15 appeared as the base peak at 284 in
mass spectrum. IR spectrum showed the presence of aliphatic C-H stretching
(3008, 2937 cm21); C55O (1639 cm21) corresponds to carboxylic acid. In the
1H NMR spectrum (DMSO), indole N-CH3 and six protons of tryptamine
appeared as a mulitplet at 2.8 d, and benzylic methyl protons attached to
1,2,4-triazole appeared as singlet at 5.4 d.
CONCLUSIONS
Information on the different possible potential impurities and their synthetic
routes is a prerequisite for better understanding the impurity formation
pathway of the antimigraine drug rizatriptan benzoate. Keeping in view the
regulatory importance of rizatriptan benzoate impurities, our efforts to syn-
thesize and characterize them effectively prove to be valuable.
EXPERIMENTAL
Materials and Instruments
All solvents and reagents were purchased from the suppliers and used
without further purification. The 1H NMR spectra were recorded in
DMSO-d6 at 200 MHz on
a Varian Gemini 200-MHz FT NMR

608
P. S. Sarma et al.
spectrometer. The chemical shifts were reported in parts per million (d ppm)
relative to TMS. The IR spectra were recorded in the solid state as KBr dis-
persion using a Perkin-Elmer FT-IR spectrophotometer. The mass spectra
were recorded on Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap
LC-MS/MS.
1-(4-(2-(4-(Dimethylamino)butylidene)-Hydrazino)phenyl)-methyl-
1,2,4-triazole (6)
To a mixture of 1-(4-hydrazinophenyl)methyl-1,2,4-triazole dihydrochloride
3 (20.0 g, 0.076 mol) and water (200.0 mL), concentrated hydrochloric acid
solution (15.8 mL) was added slowly at 0–58C and stirred for 30 min at
0–58C. 4-N,N-Dimethyl aminobutanal dimethyl acetal 4 (14.7 g, 0.091 mol)
was added to the reaction mixture at 0–58C and stirred for 60 min for the
reaction completion. Caustic lye (25.0 mL) was added slowly dropwise to
the reaction mass up to pH 6.0–7.0. The product was extracted twice with
ethyl acetate (60.0 mL). The organic phase was dried over sodium sulfate
and evaporated under vacuum. The resultant solid was dried aerially to a
constant weight to afford the title compound 6 (yield 15.0 g, 68.6%, purity
by HPLC 97.6%).
IR (KBr, cm21): 3430 (N-H), 3033 (Ar-H), 2945, 2863 (Ali-H), 1613
1
(C55N). H NMR (DMSO, d ppm): 9.7 (s, 1H), 8.6 (s, 1H), 8.0 (s, 1H),
7.0–7.2 (m, 4H), 6.8 (d, 1H), 5.2 (s, 2H), 2.2 (m, 4H), 2.0 (s, 6H), 1.6
(m, 2H). Mass: 287.4 (Mþ þ 1).
N,N-Dimethyl-5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-
ethanamine N-Oxide (7)
A mixture of rizatriptan base 2 (17 g, 0.062 mol), dichloromethane
(100.0 mL), and meta-chloro per benzoic acid (10.86 g, 0.062 mol) was
stirred for 3–4 h for reaction completion. The mixture was placed in an
ice-water bath, and a saturated solution of sodium sulfite (25.0 mL)
was added. The reaction mixture was stirred at room temperature for
15 min. Starch/iodine paper test showed the absence of peroxide.
The organic and aqueous layers were separated. The organic layer was
concentrated under vacuum at 408C to get the residue. The residue was
chromatographed on silica gel eluting with CH2Cl2/methanol/NH3
(30:8:1) to afford the title compound 7 (yield 10.0 g, 55.5%, purity by
HPLC 97.0%).
IR (KBr, cm21): 3358 (N-H), 3042 (Ar-H), 2946, 2924 (Ali-H), 1504
1
(C55N). H NMR (DMSO, d ppm): 11.3 (s, 1H), 8.6 (s, 1H), 8.0 (s, 1H),
7.6 (s, 1H), 7.3 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 5.4 (s, 2H), 3.4 (m, 4H) 3.2
(d, 6H). Mass: 286.2 (Mþ þ1).

Impurities of Rizatriptan Benzoate
609
[3-[2-(N,N-Dimethylamino)ethyl-2-[[3-[2-(N,N-dimethylamino)ethyl]-
1H-indol-5-yl]methyl]-1H-indol-5-yl]methyl-1H-1,2,4-
triazolebenzoate (9)
A solution of rizatriptan base 2 (67.0 g, 0.248 mol), water (670.0 mL),
and HCl (88.0 mL) was added, and the reaction mixture was refluxed for
4 h. The pH of the aqueous layer was adjusted to 10–11 using caustic
lye (60.0 mL). The product was extracted twice with ethyl acetate
(200.0 mL) and dried over sodium sulfate. The organic layer was con-
centrated under vacuum at 408C to get the residue. The residue was
chromatographed on silica gel eluting with CH2Cl2/Methanol/NH3
(30:8:1) to give it as a yellow oil (16.0 g, 13.7%). The benzoate salt was
prepared by addition of a solution of benzoic acid (4.16 g, 0.034 mol) in
acetone (10.0 mL) to a solution of the yellow oil (16.0 g, 0.034 mol) in
acetone (10.0 mL). The precipitated solid was filtered, washed with
acetone (5.0 mL), and dried to a constant weight at 40–508C to yield
dimer of rizatriptan benzoate 9 (yield 16.0 g, 79.3%, purity by HPLC
96.5%).
IR (KBr, cm21): 3287 (N-H), 2957, 2924 (Ali C-H), 1599, 1571
1
(Ar C55C, C55N), 725 (Ar C-H). H NMR (DMSO, d ppm): 10.9 (s, 1H,
Ar N-H), 10.7 (s, 1H, Ar N-H), 8.6 (s, 1H Ar C-H), 8.0 (m, 5H,
Ar C-H), 7.6 (m, 2H, Ar C-H), 7.5 (m, 3H, Ar C-H), 7.4 (m, 2H), 7.1
(s, 1H, Ar C-H), 6.9 (m, 2H, Ar C-H), 5.4 (s, 2H, Ali CH2), 4.1
(s, 2H), 2.8 (m, 4H), 2.6 (m, 2H, CH2), 2.3 (s, 12H, CH3). Mass: 486
(Mþ þ1).
N-Methyl-5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-ethanamine (15)
Stage 1
To a mixture of sodium bicarbonate (19.2 g) and water (100.0 mL),
1-(4-hydrazinophenyl) methyl-1,2,4-triazole dihydrochloride
3 (20.0 g,
0.076 mol) was added at room temperature. The reaction mass was cooled
to 0–58C, and sodium salt of 4-chloro butanal bisulfate adduct 10
(17.6 g, 0.839 mol) was added. The reaction mass was stirred for 60 min
for the completion of the reaction. To the reaction mass, ethyl acetate
(100.0 mL) was added and stirred for 15 min. The organic and aqueous
layers were separated. The aqueous layer was extracted with ethyl acetate
(50.0 mL), combined with the total organic layer, dried over sodium
sulfate, and evaporated under vacuum. The resultant solid was dried
aerially to
a constant weight to afford 1-(4-(2-(4-chlorobutylidene)-
hydrazino)phenyl)-methyl-1,2,4-triazole 11 (yield 15.2 g, 71.7%). IR (KBr,
cm21): 3430 (N-H), 3033 (Ar-H), 2945, 2863 (Ali-H), 1613 (C55C,
C55N). Mass: 209 (Mþ 269).

610
P. S. Sarma et al.
Stage 2
A mixture of 1-(4-(2-(4-chloro butylidene)-hydrazino)phenyl)-methyl-1,2,4-
triazole 11 (10.0 g, 0.036 mol) and polyphosphoric isopropyl ester (40.0 g)
in chloroform (100.0 mL) was added, heated to 55–608C, and maintained
for 6 h for reaction completion. The reaction mass was cooled to
25–358C, and water (60.0 mL) was added. The organic and aqueous
layers were separated. The Aqueous layer was extracted with chloroform
(60.0 mL). Combined organic layers were washed twice with 5% sodium
bicarbonate solution (60.0 mL) and evaporated. To the resultant residue
12, methanol (100.0 mL) was added, followed by KI (7.5 g) and aqueous
methylamine solution (50.0 mL). The reaction mass was heated to
50–608C and maintained for 5 h until reaction completion. To the
reaction mixture, water (50.0 mL) was added and extracted twice with
ethyl acetate (50.0 mL). The total organic fractions were dried over
sodium sulfate and evaporated under vacuum. The residue was chroma-
tographed on silica gel, eluting with CH2Cl2/Methanol/NH3 (30:8:1)
to afford the title compound 13 (yield 10.0 g, 55.5%, purity by HPLC
95.7%).
IR (KBr, cm21): 3421 (N-H), 3042 (Ar-H), 2946, 2924 (Ali-H), 1595.1
(-Nþ-H, bending), 1433,1363 (Ali C-H bending), 807,743 (aromatic C-H
1
bending). H NMR (DMSO, d ppm): 10.9 (s, 1H, Ar N-H), 8.60 (s, 1H)
7.95 (s, 1H) 7.55 (s, 1H), 7.30 (d, 1H), 7.18 (s, 1H) 7.03 (d, 1H), 5.43
(s, 2H), 3.8 (br-s, 1H), 2H (m, 2.86), 2H (m, 2.66), 2.4 (d, 3H, N-CH3).
Mass: 256.5 (Mþ þ1).
5-(1H-1,2,4-Triazol-1-yl-methyl)-1H-indole-3-ethanamine
Hydrochloride (14)
To mixture of 1-(4-hydrazinophenyl)methyl-1,2,4-triazole dihydrochloride 3
(10.0 g, 0386 mol) and 50% aqueous isopropyl alcohol (100.0 mL), sodium
salt of 4-chloro butanal bisulfate adduct 10 (12.0 g, 0.057 mol) was added.
The pH of the reaction mass was adjusted to 3.5 with triethyl amine
(12.0 mL). The reaction mass was heated to 75–808C and maintained for
2 h for reaction completion. The reaction mass was cooled to 25–358C and
evaporated under reduced pressure at 50–608C. The residue was dissolved
in water (100.0 mL) and filtered through a Celitew bed. The product was
extracted twice with dichloromethane (50.0 mL) and evaporated under
reduced pressure. The crude product was dissolved in isopropyl alcohol
(20.0 mL), and HCl in isopropyl alcohol (20.0 mL) was added at room temp-
erature. The precipitated solid was filtered, washed with isopropyl alcohol
(10.0 mL), and dried to a constant weight at 40–508C to yield 5-(1H-1,2,4-
triazol-1-yl-methyl)-1H-indole-3-ethanamine hydrochloride 14 (5.0 g, 47%,
purity by HPLC 96.8%).

Impurities of Rizatriptan Benzoate
611
IR (KBr, cm21): 3400 (N-H), 3033 (Ar C-H), 1556.1 (-Nþ-H, bending),
1
1430, 1382 (Ali C-H bending), 820, 716 (aromatic C-H bending). H NMR
(DMSO, d ppm): 11.1 (s, 1H), 9.0 (s, 1H), 8.3 (s, 1H), 7.55 (s, 1H), 7.40
(d, 1H), 7.20 (d, H), 7.17 (s, 1H), 6.0 (br-s, 2H), 5.43 (s, 2H), 2.86 (m, 2H),
2.66 (s, 2H). Mass: 242 (Mþ þ1).
N,N-Dimethyl-5-(1-methyl-1,2,4-triazol-1-yl-methyl)-1H-indole-3-
ethanamine oxalate (15)
To a solution of rizatriptan base 2 (17.0 g, 0.063 mol) in THF (100.0 ml)
potassium tert butoxide (14.2 g, 0.126 mol) was added at room temperature.
Methyl iodide (6.1 mL, 0.094 mol) was added dropwise at room temperature,
and the reaction mass was maintained for 2 h. Water (150.0 mL) was added
to the reaction mixture. The product was extracted twice with dichloromethane
(100.0 mL) and evaporated. The oxalate salt was prepared by addition of a
solution of oxalic acid (4.4 g, 0.035 mol) in isopropyl alcohol (10.0 mL) to
the residue in isopropyl alcohol (20.0 mL). The precipitated solid was
filtered, washed with isopropyl alcohol (5.0 mL), and dried to a constant
weight at 40–508C to afford the title compound 15 (yield 11.3 g, 48.0%,
purity by HPLC 97.5%). IR (KBr, cm21): 3008, 2937 (Ali C-H), 1639
(C55O), 1466, 1404 (Ali C-H, bending), 1137 (-C-N).1H NMR (DMSO, d
ppm): 8.60 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1H), 7.18 (s, 1H), 7.03
(d, 1H), 5.40 (s, 2H), 3.30 (m, 2H) 3.0 (m, 2H) 2.8 (s, 9H). Mass: 284 (Mþ þ1).
ACKNOWLEDGMENTS
The authors thank the management of Dr. Reddy’s Laboratories Ltd. for sup-
porting this work.
REFERENCES
1. Wolf, H. G. The pathophysiology of headache. Int. J Neurol. 1963, 3 (1), 287.
2. Lance, J. W. In Mechanism and Management of Headache; 2nd edn.; Butterworth:
London, 1973.
3. Fozard, J. The animal pharmacology of drugs in the treatment of migraine.
J. Pharm. Pharmacol 1975, 27, 297–321.
4. Lance, J. W. 5-Hydroxytryptamine and its role in migraine. Eur. Neurol. 1991,
31 (5), 279–281.
5. Rabasseda, X.; Mealy, N.; Castaner, J. Synthesis of MK-0462. Drugs of Future
1995, 20 (7), 676–679.
6. Remuzon, P.; Dunny, C.; Jacquet, J. P.; Soumeillant, M.; Bouzard, D. 4-Hydroxy-
2-methyl-3(2H)-isothiazolone-1,1-dioxide as protecting group of 4-(N-methylami-
nousulfonyl) methylphenylhydrazine during fischer indole synthesis. Tetrahedron
Lett. 1995, 36 (35), 6227–6230.

612
P. S. Sarma et al.
7. Chen, C.-Y.; Senanayake, C. H.; Billy, T. J.; Larsen, R. D.; Verhoeven, T. R.;
Redider, P. J. J.Org.Chem. 1994, 59, 3738.
8. Street, L. J.; Baker, R.; Davey, W.; Guiblin, A. R.; Jelly, R. A.; Reeve, A. J.;
Routledge, H.; Sternfled, F.; Watt, A. P.; Beer, M. S.; Middlemiss, D. N;
Noble, A. J.; Stanton, J. A.; Scholey, K.; Hargreaves, R. J; Sohal, B.;
Graham, M. I.; Matassa, G. Synthesis and serotonergic activity of N,N-dimethyl-
2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyamine and anologues. Potent
agonists for 5-HT1D receptors. J. Med. Chem. 1995, 38, 1799.
9. Baker, R.; Hadham, M.; Matassa, V. G.; Pelham, F.; Street, L. J.; Harlow. Triazole
containing indole derivatives. US Patent. 5,298,520, 1994.
10. Mallikarjuna, R. B; Sangaraju, S. Srinivasu, M. K; Madhavan, P.; Lalitha
Devi, M.; Rajendrakumar, P.; Chandrasekhar, K. B; Arpita, Ch.; Satya Balaji, T.
Development of validation of a specific stability indicating high performance
liquid chromatographic method for rizatriptan benzonate. J. Pharm. Biomed.
Anal. 2006, 41, 1146–1152.
11. ICH Guidelines, Q3A (R) Impurities in New Drug Substances, The quality guide-
lines for Active Pharmaceutical Ingredients related to impurities according to the
International Conference of Horminization. February 2002.
12. ICH Guidelines, Q3B (R) Impurities in New Drug Products, The quality guidelines
for Active Pharmaceutical Ingredients related to impurities according to the Inter-
national Conference of Horminization. February 2002.