Efficient synthesis of impurity-C of antimigraine agent Rizatriptan benzoate

Article abstract of DOI:10.1021/op200284m

During the commercial manufacturing of antimigraine drug Rizatriptan benzoate, several impurities are reported to be formed. This present work demonstrates a convergent and short synthesis of the most critical impurity (C) of Rizatriptan, [2-(5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indole-2-yl)-N,N- dimethylethanamine (1)], recently reported in U.S. Pharmacopeia.

Full text of DOI:10.1021/op200284m

Communication
pubs.acs.org/OPRD
Efficient Synthesis of Impurity-C of Antimigraine Agent Rizatriptan
Benzoate
Chinmoy Pramanik,* Rahul Bhumkar, Ganesh Karhade, Pravinkumar Khairnar,
Narendra Kumar Tripathy, and Mukund K. Gurjar
API R&D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjewadi, Pune-411057, India
S
* Supporting Information
which is basically a regio-isomer of the parent API. To the best
ABSTRACT: During the commercial manufacturing of
antimigraine drug Rizatriptan benzoate, several impurities
are reported to be formed. This present work demon-
strates a convergent and short synthesis of the most critical
impurity (C) of Rizatriptan, [2-(5-((1H-1,2,4-triazol-1-
yl)methyl)-1H-indole-2-yl)-N,N-dimethylethanamine
(1)], recently reported in U.S. Pharmacopeia.
of our knowledge, there is no commercial vendor for this new
impurity and also there is no literature reported synthesis of 1.
For the impurity profile study for our bulk API Rizatriptan
benzoate, we planned to investigate the synthesis of 1. Herein
we wish to report a short synthesis which we believe will be of
immense help to organic chemists from pharmaceutical
companies from all over the world. Moreover, our approach
would provide an easy access to the synthesis of 2-substituted
indole derivatives.
After extensive literature study on the synthesis of 2-
substituted indole derivatives, we decided to approach the
indole formation by using the well-known Sonogashira
coupling5 (iodo-aniline 5 with homopropargyl alcohol (4)
followed by in situ indocyclization6 as key steps which would
provide the critical indole moiety 27 (Scheme 1)). Then
onwards the synthesis of the target compound 1 can be easily
accomplished from the critical alcohol intermediate 2 by using a
couple of straightforward conversions. 5 can be obtained from
commercially available nitro-compound 7, following literature
procedures.8
INTRODUCTION
Rizatriptan benzoate [Figure 1; brand name: MAXALT, Merck
and Co. Inc., USA; a selective 5-hydroxytryptamine1B/1D (5-
■
RESULTS AND DISCUSSION
Figure 1.
■
As per our strategy, 4-nitrobenzyl bromide (7) was reacted with
the sodium salt of triazole to afford the nitro derivative (8).
Reduction of the nitro group of 8 followed by controlled
iodination9 of the resulting aniline 6 using I2 and aqueous
NaHCO3 furnished the desired iodo-aniline 5 in good yield
(Scheme 2).
The critical Sonogashira coupling of iodo compound 5 with
homopropargyl alcohol followed by in situ indole formation
was attempted under various reported conditions, but it failed
to give us the desired indole moiety 2, instead the uncyclized
condensed intermediate 310 was isolated in most of the cases
(Scheme 3). Our efforts to cyclize 3 under various conditions
(using various metal alkoxides, fluorides, and Lewis acids even
at elevated temperature)11 proved to be ineffectual.
At this stage we decided to examine the endocyclization by
protecting the alcohol group of 3. Accordingly, THP-protected
9 was prepared by the coupling of iodo compound 5 with the
THP-protected alcohol 1012 under Sonogashira conditions.
Intermediate 9 was subjected to endocyclization under various
conditions, but again all our efforts were in vain in arriving at
the desired indole moiety (Scheme 4).
HT1B/1D) receptor antagonist], chemically known as N,N-
dimethyl-5-(1H-1,2,4-triazol-1-yl-methyl)-1H-indole-3-ethan-
amine monobenzoate, is used for the treatment of migraine and
severe headaches. By binding with serotonium receptors in the
brain, rizatriptan benzoate makes the blood vessels in the brain
narrower, which results in relieving the pain.1,2
Impurity profiling (i.e., identification as well as quantification
of impurities) of an active pharmaceutical ingredient is of
fundamental significance for medical safety reasons and also for
the drug effectiveness and is now receiving vital attention from
regulatory authorities. The International Conference of
Harmonization (ICH) has published guidelines on impurities
in new drug substances, products, and residual solvents.3 The
level of total impurities must be reduced typically to less than
1.0%, and each individual impurity of 0.1% or above must be
identified. Hence, there is a good demand for considerable
quantity of the impurity reference standards for both regulatory
authorities and pharmaceutical companies, as each impurity
needs to be quantified in the drug substances. A literature
survey on Rizatriptan benzoate revealed that nine process
related impurities have been identified, and few of them have
been synthesized.4 Recently, the U.S. Pharmacopeia reported a
new process related impurity (1) for Rizatriptan benzoate
Received: October 12, 2011
Published: February 21, 2012
© 2012 American Chemical Society
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Scheme 1.
Scheme 2.
Scheme 3.
Scheme 4.
Since intermediate 9 failed to give us the desired indole
derivative, we decided to investigate the endocyclization using a
protected amino-intermediate (such an example is reported in
ref 13). Accordingly, Boc protection of 9 was effected with Boc
anhydride in tert-butanol at elevated temperature to provide
Boc protected intermediate 1114 in reasonable yield. Sub-
sequent cyclization of completely protected 11 was attempted
Table 1. Optimization of Cyclization Conditions
yield (isolated
yield)
reagents
conditions
time
Pd(PPh3)4 DMF, 120 °C
15 h
12 h
15 h
48 h
tBuOK
K2CO3
DBU
MeOH, 80 °C
DMF, 120 °C
MeOH, water, 100 °C, sealed
tube
20%
43%
28%
t
under various conditions (K2CO3, DMF, 120 °C: BuOK in
TBAF
THF, reflux
4 h
78%
methanol under heating; catalytic Pd(PPh3)4 under heating;
DBU in methanol and water under heating), wherein a very
small amount of product 12 was observed (as shown in Table
1).
Fortunately, when the cyclization was done using TBAF in
THF under reflux conditions, the substrate smoothly under-
went cyclization to provide the indole derivative 12 with
reasonable yield. Once we had the critical indole derivative 12
in hand, the only thing left was to manipulate this advanced
intermediate to the target compound 1.
This was successfully accomplished (Scheme 5) starting with
acid-catalyzed removal of the THP in 12, followed by
mesylation of the resulting alcohol 13, and subsequent
amination with anhydrous dimethyl amine solution in THF
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Scheme 5.
(prepared by bubbling of HNMe2 in THF) and finally Boc
deprotection with dilute HCl provided 1 in workable yield.
with saturated NaHCO3 solution. The organic layer was dried
over anhydrous sodium sulfate, filtered, and concentrated to get
a crude residue. The product was purified via silica gel
(neutralized with triethyl amine) column chromatography
using hexane as eluent to yield 7.7 g (70%) of 10 as colorless
oil.
CONCLUSION
■
A short and efficient synthesis of Impurity-C (1) of
antimigraine drug Rizatriptan benzoate has been described;
this study will provide an access to the reference standard of
this impurity for regulatory authorities and also help immensely
organic chemists from pharmaceutical companies currently
developing the drug.
1H NMR (CDCl3, 400 MHz, δ ppm): 4.6 (m, 1H), 3.9−3.8
(m, 2H), 3.6−3.5 (m, 2H), 2.5 (m, 2H), 2.0 (t, 1H, J = 2.7 Hz),
1.9−1.8 (m, 1H), 1.8−1.7 (m, 1H), 1.6−1.5 (m, 4H).
Preparation of 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-
(tetrahydro-2H-pyran-2-yloxy)but-1-ynyl)benzenamine
(9). To a solution of 5 (5.0 g, 17 mmol) and 10 (3.9 g, 25
mmol) in DMF (50.0 mL, LR grade) were added CuI (0.32 g,
2.0 mmol, anhydrous, purchased from Aldrich) and diisopro-
pylethylamine (1.0 mL, 7.4 mmol). The reaction mixture was
degassed with nitrogen, followed by the addition of
PdCl2(PPh3)2 (0.59 g, 0.8 mmol). The reaction mixture was
allowed to stir for 6 h at rt. After complete consumption of the
starting material, the reaction mixture was diluted with water
and extracted with ethyl acetate (3 × 50 mL). The combined
organic layer was washed with water and brine and dried over
anhydrous sodium sulfate, filtered, and evaporated to obtain a
crude residue. The product was purified via silica gel
(neutralized with triethyl amine) column chromatography
using ethyl acetate and hexane (7:3) as eluent to yield 4.9 g
(92%) of 9 as a gummy liquid.
EXPERIMENTAL SECTION
■
All materials were purchased from commercial suppliers. Unless
specified otherwise, all reagents and solvents were used as
1
supplied by manufacturers. H NMR spectra and 13C NMR
spectra were recorded on a Varian 400 MR spectrometer in
CDCl3 and DMSO-d6, and mass spectra were determined on an
API-2000LCMS mass spectrometer, Applied Biosystems.
Elemental Analysis was done in a VarioEL III instrument.
EXPERIMENTAL DETAILS
■
Preparation of 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-io-
dobenzenamine (5). To a solution of 6 (10 g, 0.06 mol) in
water (1.0 lit.) were added sodium bicarbonate (7.3 g, 0.09
mol) and iodine (14.7 g, 0.06 mol) under vigorous stirring. The
reaction mixture was stirred for 30 h. After complete conversion
of the starting material (as indicated by TLC), the reaction was
quenched by the addition of solid sodium thiosulfate (3.0 g)
followed by extraction with ethyl acetate (2 × 100 mL). The
combined organic layer was dried over anhydrous sodium
sulfate and filtered; solvent was evaporated to obtain a crude
residue. The crude product was purified via silica gel column
chromatography using methanol and dichloromethane (1:99)
as eluent to yield 15.5 g of 5 (90%) as a light brown solid.
1H NMR (CDCl3, 400 MHz, δ ppm): 8.0 (s, 1H), 8.0 (s,
1H), 7.6 (d, 1H, J = 1.8 Hz), 7.1 (dd, 1H, J = 1.8, 8.2 Hz), 6.7
(d, 1H, J = 8.2 Hz), 5.2 (s, 2H), 4.2 (bs, 2H). 13C NMR
(CDCl3, 100 MHz, δ ppm): 152.0, 147.2, 142.7, 138.8, 129.5,
125.4, 114.6, 83.7, 52.4. ESI-Mass: For C9H9N4I (M+H)/z:
301.1, Found: (M+H)/z: 301.0, (M+23)/z: 322.9. Anal. for
C9H9N4I, calcd C, 36.02; H, 3.02; N, 18.67. Found: C, 35.93;
H, 3.11; N,18.76.
1H NMR (CDCl3, 400 MHz, δ ppm): 8.0 (s, 1H), 7.9 (s,
1H), 7.2 (d, 1H, J = 2.0 Hz), 7.0 (dd, 1H, J = 2.0, 8.3 Hz), 6.7
(d, 1H, J = 8.3 Hz), 5.2 (s, 2H), 4.7 (m, 1H), 4.3 (bs, 2H), 3.9
(m, 2H), 3.6 (m, 1H), 3.5 (m, 1H), 2.7 (t, 2H, J = 6.8 Hz),
1.8−1.7 (m, 2H), 1.6−1.5 (m, 4H). 13C NMR (CDCl3, 100
MHz, δ ppm): 152.1, 148.3, 132.1, 129.3, 123.1, 114.4, 108.8,
98.8, 93.4, 77.3, 65.7, 62.3, 53.2, 30.6, 25.4, 21.1, 19.4. ESI-
Mass: For C18H22N4O2 (M+H)/z: 327.4, Found: (M+H)/z:
327.1, (M+Na)/z: 349.0. Anal. for C18H22N4O2, calcd: C,
66.24; H, 6.79; N, 17.16; Found: C, 66.19; H, 7.10; N, 17.41.
Preparation of tert-Butyl 4-((1H-1,2,4-Triazol-1-yl)-
methyl)-2-(4-(tetrahydro-2H-pyran-2-yloxy)but-1-ynyl)-
phenylcarbamate (11). To a solution of 9 (4.8 g, 15.0 mmol)
in tert-butanol (58 mL) was added Boc anhydride (6.8 mL, 30
mmol), and the reaction mixture was heated to 60 °C for 15 h.
After complete consumption of the starting material (checked
by TLC), tert-butanol was distilled off, diluted with water, and
extracted with ethyl acetate (2 × 50 mL). The combined
organic layer was washed with water and brine and dried over
anhydrous sodium sulfate, filtered, and evaporated to obtain a
crude residue. The product was purified via silica gel
(neutralized with triethyl amine) column chromatography
using ethyl acetate and hexane (3:2) as eluent to yield 5.2 g
(83%) of 11 as a gummy liquid.
Preparation of 2-(But-3-ynyloxy)tetrahydro-2H-pyran
(10). To a solution of homopropargyl alcohol (5.0 g, 71 mmol),
in dichloromethane (75 mL) were added dihydropyrane (9.7
mL, 107 mmol) and p-TSA (1.4 g, 7 mmol) at 0 °C under
nitrogen atmosphere. The reaction mixture was stirred at rt for
6 h. After complete consumption of the starting material, the
reaction mixture was diluted with dichloromethane and washed
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1H NMR (CDCl3, 400 MHz, δ ppm): 8.1 (d, 1H, J = 8.6
Hz), 8.0 (s, 1H), 8.0 (s, 1H), 7.2 (d, 1H, J = 1.8 Hz), 7.2 (dd,
1H, J = 1.8, 8.6 Hz), 5.2 (s, 2H), 4.7 (m, 1H), 3.9 (m, 2H), 3.7
(m, 1H), 3.5 (m, 1H), 2.8 (t, 2H, J = 6.8 Hz), 1.8−1.3 (m,
15H). 13C NMR (CDCl3, 100 MHz, δ ppm): 152.2, 151.9,
139.8, 131.3, 128.7, 127.8, 117.7, 112.1, 98.7, 95.1, 80.9, 76.0,
65.3, 62.1, 52.7, 30.4, 28.1, 25.2, 21.0, 19.3. ESI-Mass: For
C23H30N4O4 (M+H)/z: 427.52; Found: (M+H)/z: 427.1; (M
+Na)/z: 449.0. Anal. for C23H30N4O4: Calcd. C, 64.77; H, 7.09;
N, 13.14. Found: C, 64.90; H, 7.23; N, 12.73.
Preparation of tert-Butyl 5-((1H-1,2,4-Triazol-1-yl)-
methyl)-2-(2-tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-in-
dole-1-carboxylate (12). To a solution of 11 (3.5 g, 8.3
mmol) in THF (18.0 mL) was added TBAF (16.4 mL, 16.0
mmol, 1. 0 M solution in THF), and the reaction mixture was
heated to reflux for 4 h. After complete cyclization, the reaction
mixture was cooled to room temperature, the reaction was
quenched with saturated ammonium chloride solution (5 mL),
THF was distilled off, and the reaction mixture was diluted with
water and extracted with ethyl acetate (3 × 40 mL). The
combined organic layer was washed with water and brine, dried
over anhydrous sodium sulfate, filtered, and evaporated to
obtain a crude residue. The product was purified via silica gel
(neutralized with triethyl amine) column chromatography
using ethyl acetate and hexane (4:1) as eluent to yield 2.73 g
(78%) of 12 as a gummy liquid.
sulfonate (14). To a solution of 13 (0.36 g, 1.1 mmol) in
dichloromethane (5.0 mL) were added diisopropyl ethylamine
(0.28 mL, 1.6 mmol) and mesyl chloride (0.1 mL, 1.2 mmol) at
0 °C. The reaction mixture was allowed to stir at rt for 2 h.
After completion of the reaction (checked by TLC), the
reaction mixture was diluted with water and dichloromethane,
and it was washed with saturated sodium bicarbonate solution.
The organic layer was dried over anhydrous sodium sulfate,
filtered, and evaporated to obtain a crude residue. The crude
product (14) was used for the next reaction without any further
purification.
Preparation of tert-Butyl-5-((1H-1,2,4-triazol-1-yl)-
methyl)-2-(2-(dimethylamino)ethyl)-1H-indole-1-car-
boxylate (15). A THF solution of dimethylamine (10 mL)
was added to the crude product (obtained from the previous
step) at room temperature. The reaction mixture was heated to
60 °C in a sealed tube for 5 h. After complete consumption of
the starting material (checked by TLC), excess reagent was
evaporated, the reaction mixture was diluted with water, and
the product was extracted with ethyl acetate (3 × 20 mL). The
combined organic layer was washed with water and brine, dried
over anhydrous sodium sulfate, filtered, and evaporated to
obtain a crude residue. The product was purified via silica gel
column chromatography using ethyl acetate as eluent to yield
0.28 g (72% for two steps) of 15 as a gummy liquid.
1H NMR (CDCl3, 400 MHz, δ ppm): 8.1 (d, 1H, J = 8.6
Hz), 8.0 (s, 1H), 8.0 (s, 1H), 7.4 (s, 1H), 7.2 (dd, 1H, J = 1.3,
8.6 Hz), 6.4 (s, 1H), 5.4 (s, 2H), 3.2 (t, 2H, J = 7.3 Hz), 2.7 (t,
2H, J = 7.3 Hz), 2.4 (s, 6H), 1.7 (s, 9H). 13C NMR (CDCl3,
100 MHz, δ ppm): 152, 150.2, 142.8, 141.0, 136.4, 129.8, 128.6,
123.5, 119.8, 116.2, 107.5, 84.3, 58.5, 53.9, 45.2, 29.7, 28.2. ESI-
Mass: For C20H27N5O2 (M+H)/z: 369.47, Found: (M+H)/z:
370.1. Anal. for C20H27N5O2, Calcd. C, 65.02; H, 7.37; N,
18.96. Found: C, 65.44; H, 6.78; N, 18.76.
Preparation of 2-(5-((1H-1,2,4-Triazol-1-yl)methyl)-1H-
indole-2-yl)-N,N-dimethylethanamine (1). To a THF
solution of compound (15) (0.2 g, 0.54 mmol) was added 3
N HCl in EtOAc (3.0 mL) at room temperature, and the
reaction mixture was allowed to stir for 30 min at rt. The
reaction mixture was diluted with ethyl acetate, washed with
saturated sodium bicarbonate, and extracted with ethyl acetate.
The combined organic layer was washed with water and brine,
dried over anhydrous sodium sulfate, filtered, and evaporated to
obtain a crude residue. The product was purified via silica gel
column chromatography using methanol and dichloromethane
(3:97) as eluent to yield 120 mg (82%) of Impurity C (1) as a
gummy liquid.
1H NMR (CDCl3, 400 MHz, δ ppm): 8.1 (d, 1H, J = 8.6
Hz), 8.0 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 7.1 (dd, 1H, J = 1.5,
8.6 Hz), 6.4 (s, 1H), 5.4 (s, 2H), 4.6 (m, 1H), 4.1 (m, 1H), 3.8
(m, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.3 (t, 2H, J = 6.6 Hz),
1.8−1.7 (m, 2H), 1.7 (s, 9H), 1.6−1.5 (m, 4H). 13C NMR
(CDCl3, 100 MHz, δ ppm): 152.0, 150.2, 142.8, 140.0, 136.5,
129.8, 128.4, 123.4, 119.7, 116.1, 107.9, 98.9, 84.2, 66.0, 62.4,
53.8, 30.7, 30.6, 28.2, 25.4, 19.5. ESI-Mass: For C23H30N4O4
(M+H)/z: 427.52, Found: (M+H)/z: 427.0; (M+Na)/z:
449.1. Anal. for C23H30N4O4: Calcd. C, 64.77; H, 7.09; N,
13.14. Found: C, 64.32; H, 6.93; N, 13.40.
Preparation of tert-Butyl 5-((1H-1,2,4-Triazol-1-yl)-
methyl)-2-(2-hydroxyethyl)-1H-indole-1-carboxylate
(13). To a solution of 12 (0.7 g, 1.6 mmol) in ethanol (10.0
mL) was added p-TSA (0.16 g, 0.8 mmol), and the reaction
mixture was stirred for 15 h. After complete THP deprotection
(checked by TLC), the reaction was quenched by the addition
of 2 mL of saturated sodium bicarbonate, THF was distilled off,
and the reaction mixture was diluted with water and extracted
with ethyl acetate (3 × 20 mL). The combined organic layer
was washed with water and brine, dried over anhydrous sodium
sulfate, filtered, and evaporated to obtain a crude residue. The
product was purified via silica gel column chromatography
using methanol and dichloromethane (1:49) as eluent to yield
0.5 g (89%) of 13 as a gummy liquid.
1H NMR (CDCl3, 400 MHz, δ ppm): 10.0 (s, 1H), 7.9 (s,
2H), 7.5 (s, 1H), 7.3 (d, 1H, J = 8.3 Hz), 7.0 (dd, 1H, J = 1.6,
8.3 Hz), 6.2 (s, 1H), 5.4 (s, 2H), 3.0 (t, 2H, J = 6.1 Hz), 2.7 (t,
2H, J = 6.1 Hz), 2.4 (s, 6H). 13C NMR (CDCl3, 100 MHz, δ
ppm): 151.8, 142.7, 140.4, 135.8, 128.7, 125.0, 121.3, 120.1,
111.4, 99.3, 58.7, 54.7, 45.1, 24.9. ESI-Mass: For C15H19N5, (M
+H)/z: 269.35, found: (M+1)/z: 269.9; (M+Na)/z: 292.0.
Anal. for C15H19N5, C, 66.89; H, 7.11; N, 20.00; Found: C,
66.80; H, 6.85; N, 20.40.
1H NMR (CDCl3, 400 MHz, δ ppm): 8.0 (d, 1H, J = 8.6
Hz), 8.0 (s, 1H), 8.0 (s, 1H), 7.4 (d, 1H, J = 1.3 Hz), 7.2 (dd,
1H, J = 1.7, 8.6 Hz), 6.4 (s, 1H), 5.4 (s, 2H), 3.9 (t, 2H, J = 6.2
Hz), 3.3 (t, 2H, J = 6.2 Hz), 1.7 (s, 9 H). 13C NMR (CDCl3,
100 MHz, δ ppm): 152.0, 150.4, 142.8, 139.5, 136.6, 129.6,
128.8, 123.7, 119.8, 116.3, 108.7, 84.6, 61.6, 53.9, 33.3, 30.9,
28.2. ESI-Mass: For C18H22N4O3 (M+H)/z: 343.40, obtained:
(M+H)/z: 343.0; (M+Na)/z: 365.0. Anal. for C18H22N4O3,
Calcd. C, 63.14; H, 6.48; N, 16.36; Found: C, 62.73; H, 7.27;
N, 17.02.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data of selected intermediates and the final compound.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Preparation of 2-(1-(tert-Butoxycarbonyl)-5-((1H-
1,2,4-triazol-1-yl)methyl)-1H-indol-2-yl)ethyl Methane-
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AUTHOR INFORMATION
Corresponding Author
*Fax: +91-20-39821445. E-mail: Chinmoy.Pramanik@emcure.
co.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank Mr. Samit Mehta, our management,
and the ARD group of Emcure Pharmaceuticals Ltd. for their
willing support and constant encouragements.
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1
(10) H NMR spectral data for compound 3 (CDCl3, 400 MHz, δ
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2.0, 8.3 Hz), 6.6 (d, 1H, J = 8.3 Hz), 5.2 (s, 2H), 4.9 (t, 1H, J = 5.6
Hz), 3.6 (m, 2H), 2.6 (t, 2H, J = 6.7 Hz).
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