Synthesis of zolmitriptan and related substances

Article abstract of DOI:10.1080/00397911.2013.777742

Efficient and cost-effective synthesis of Zolmitriptan 1 employing Japp-Klingemann reaction and a new robust purification strategy is described.

Full text of DOI:10.1080/00397911.2013.777742

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Synthesis of Zolmitriptan and Related
Substances
Satish Kumar Vujjini a , Vivekananda Reddy Mothukuri a , Aminul
Islam a , Rakeshwar Bandichhor a , Mukkanti Kagga b & Golla China
Malakondaiah a
a Dr. Reddy's Laboratories, Bachupalli , Qutubullapur , India
b Department of Chemistry , Institute of Science and Technology,
J.N.T University , Hyderabad , India
Accepted author version posted online: 03 Jul 2013.
To cite this article: Satish Kumar Vujjini , Vivekananda Reddy Mothukuri , Aminul Islam , Rakeshwar
Bandichhor , Mukkanti Kagga & Golla China Malakondaiah (2013) Synthesis of Zolmitriptan and
Related Substances, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:24, 3294-3306, DOI: 10.1080/00397911.2013.777742
To link to this article: http://dx.doi.org/10.1080/00397911.2013.777742
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Synthetic Communications1, 43: 3294–3306, 2013
Copyright # Dr. Reddy’s Laboratories
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.777742
SYNTHESIS OF ZOLMITRIPTAN AND RELATED
SUBSTANCES
Satish Kumar Vujjini,1 Vivekananda Reddy Mothukuri,1
Aminul Islam,1 Rakeshwar Bandichhor,1 Mukkanti Kagga,2
and Golla China Malakondaiah1
1Dr. Reddy’s Laboratories, Bachupalli, Qutubullapur, India
2Department of Chemistry, Institute of Science and Technology, J.N.T
University, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Efficient and cost-effective synthesis of Zolmitriptan 1 employing Japp–
Klingemann reaction and a new robust purification strategy is described.
Keywords Indole derivatives; Japp–Klingemann reaction; serotonin receptor;
zolmitripton
Received November 21, 2012.
Address correspondence to Golla China Malakondaiah, Innovation Plaza, IPDO, Dr. Reddy’s
Laboratories Ltd. Bachupalli, Qutubullapur, R. R. District, Andhra Pradesh, India. E-mail:
kondaiahgcm@drreddys.com
3294

SYNTHESIS OF ZOLMITRIPTAN
3295
INTRODUCTION
Zolmitriptan 1 is a selective serotonin receptor agonist of the 1B and 1D
subtypes. It is a synthetic tryptamine variant used for the acute treatment of migraines
with or without aura in adults. Various synthetic routes are reported for the synthesis
of zolmitriptan 1. The initial synthesis of zolmitriptan 1 (Fig. 1) was reported by Glen
and coworkers[1] via seven steps, where L-4-nitrophenylalanine converts into (S)-2-
amino-3-(4-nitrophenyl)propanol via two steps followed by (S)-4-(4-nitrobenzyl)-
1,3-oxazolidin-2-one conversion, then to 1 via four steps. Whereas other groups
reported diazotization of 4-(S)-(4-aminobenzyl)-1,3-oxazolidin-2-one followed by
reduction of diazo-compound to the corresponding hydrazine intermediate, which
was directly coupled with 4,4-ethoxy-N,N-dimethylbutylamine to afford zolmitriptan
1 or after coupling of 4-(S)-(4-aminobenzyl)-1,3-oxazolidin-2-one with C-4 substi-
tuted (with a good leaving group such as chlorine or protected amine) 1-butyralde-
hyde (or its acetal)[2] by Fischer reaction, N-alkylation[3] was performed using
HCHO=NaCNBH3=AcOH. Such a process suffers from disadvantages of environ-
mentally hazardous reagents (e.g., phosgene, SnCl2, etc.), cumbersome scale-up
due to the high dilution of the reaction mass, and extraction at elevated tempera-
ture. In another approach,[4] the hydrazine intermediate was reacted with a-keto-
d-valerolactone (an uncommon chemical for industrial purposes) to furnish
hydrazone derivative, which was subsequently converted to indole derivative via
pyranoindolone intermediate. Finally, a-ester group in the indole moiety was
hydrolyzed and decarboxylated (by cuprous oxide in dry quinoline at 200 ꢀC) to
furnish zolmitriptan 1. In this process, hydrolysis and decarboxylation were
performed in two discrete steps. Hydrolysis involves strong base that may cleave
the oxazolidinone moiety. Moreover, decarboxylation process is intricate as it
involves the reagents such as cuprous oxide in dry quinoline and high temperature
of 200 ꢀC.[4] Evidently, all these processes appear to suffer from poor yields and
tedious purification procedures.
Herein, we disclose our efforts to refine the process for making an optically
pure zolmitrptan (1) in industrial scale utilizing the Japp–Klingemann[5–7] reaction
as a key step.
Figure 1. Zolmitriptan.

3296
S. K. VUJJINI ET AL.
RESULTS AND DISCUSSION
In contrast to all precedented processes, our approach involves the Japp–
Klingemann reaction followed by the Fisher reaction[8] to form the indole moiety.
Application of this well-known reaction with the intermediates 2[9] and 4[10] is a novel
and innovative approach to form 1. Diazotization of 4-(S)-(4-aminobenzyl)
oxazolidin-2-one 2 to the corresponding diazo salt 3 and simultaneous formation
of the enolate derivative 5 of alkyl 2-acetyl-5-(1,3-dioxoisoindolin-2-yl)pentanoate
Scheme 1. Synthesis of zolmitriptan 1. (Figure is provided in color online.)

SYNTHESIS OF ZOLMITRIPTAN
3297
4, followed by the coupling of 3 and 5 in the presence of mild acid via Japp–
Klingemann reaction, provided the corresponding hydrazone 6, which was cyclized
to the indole derivative 7. Deprotection of the phthalimide moiety using hydrazine
Table 1. Impurity details
Impurity profile
by HPLC
Entry
Impurity
RRT
1
0.52
Not detected
2
2.02
0.03
3
—
0.03
4
0.46
Not detected

3298
S. K. VUJJINI ET AL.
Scheme 2. Synthesis of 11. (Figure is provided in color online.)
hydrate (Ing–Manske reaction) followed by the bis-methylation of primary amine 8
furnished the corresponding N,N-dimethylated intermediate 9. Hydrolysis of the
ester functionality of indole derivative 9 using aqueous sodium carbonate solution
followed by decarboxylation under reflux condition with hydrochloric acid afforded
zolmitriptan 1 in good yield (Scheme 1).
Scheme 3. Synthesis of impurity 13. (Figure is provided in color online.)

SYNTHESIS OF ZOLMITRIPTAN
3299
Scheme 4. Synthesis of metabolite 14. (Figure is provided in color online.)
Potential Impurities in Zolmitriptan API
During the synthesis of zolmitriptan 1 various impurities were observed and it
is a decisive challenge for process chemists to control all the impurities in the pharma
stage as per regulatory guidelines (depending upon daily dosages acceptable limit
also varies). Generally known impurity level in the pharma stage should be less than
0.15% and for unknown impurity the acceptable limit is less than 0.10%. Impurity
11[11] would have possibly been generated by hydrolysis of the oxazolidinone ring
at the last stage.
Impurity 12[12] is the unreacted starting material 9 and impurity 13[13] is the
epi-zolmitriptan, whereas metabolite 14[14] is the monomethylated compound.
Relative retention time (RRT) values of all the impurities were depicted in Table 1.
All the impurities were identified, synthesized, and characterized independently.
Synthesis of 11 was accomplished by the hydrolysis of oxazolidinone ring of
zolmitriptan 1 using NaOH solution under reflux condition (Scheme 2).
Synthesis of impurity 13 (Scheme 3) was achieved using the R isomer of
4-(R)-(4-aminobenzyl)-oxazolidin-2-one as the starting material and following the
synthetic steps involved in Scheme 1 in the coupling stage.
Metabolite 14 was synthesized by treating the zolmitriptan with ethyl chloro-
formate followed by the chloro-substitution with methyl amine.
EXPERIMENTAL
Preparation of (S)-Ethyl-3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-5-[(2-
oxooxazolidin-4-yl)methyl]-1H-indole-2-carboxylate 7
Concentrated hydrochloric acid (34.0 L, 325.5 mol) was slowly added to a stir-
red solution of 4-(S)-(4-aminobenzyl)-1,3-oxazolidin-2-one 2 (25.0 kg, 130.2 mol) in a
mixture of methanol (75.0 L) and water (112.5 L) at 5–10 ꢀC. After stirring for 10 min,
a solution of sodium nitrite (11.2 kg, 162.7 mol) in water (75 L) was added slowly to
the reaction mixture at ꢁ5 to 0 ꢀC and the solution was maintained under stirring at
the same temperature for 30 min. Meanwhile, in a separate vessel, sodium acetate
(42.7 kg, 520.8 mol) was added to a stirred solution of ethyl 2-acetyl-5-(1,3-dioxo-1,3-
dihydro-2-isoindolyl) pentanoate (4) (43.3 kg, 136.6 mol) in methanol (437.5 L). After
stirring for 1 h at 25–30 ꢀC the solution was cooled to 0–5 ꢀC, and the previously pre-
pared diazotized solution was slowly added to this cooled reaction mixture and stirred
for 3 h at room temperature. After the completion of reaction (monitored by
thin-layer chromatography, TLC, using ethylacetate as mobile phase), the reaction
mass was extracted three times with dichloromethane (3 ꢂ 250 L). The combined

3300
S. K. VUJJINI ET AL.
dichloromethane layer was washed twice with water (2 ꢂ 125 L) and once with brine
(125 L). The organic layer was separated and concentrated. The crude residue (con-
taining the hydrazone intermediate) was cyclized to form the indole moiety. Methanol
(50 L) and methanolic HCl (15.0%, 150 mL) were added to the residue. and the
solution was refluxed for 6 h. The reaction mass was then cooled to room temperature
(25 ꢀC) and the obtained solid was filtered, washed with methanol (25 L), and dried to
furnish the title compound 7. Yield 46.8 kg (78%); mp 215–220 ꢀC; 1H NMR:
(DMSO-d6, 200 MHz): d 11.55 (s, 1H), 7.78 (s, 4H), 7.4 (s, 1H), 7.35 (d, 1H,
J ¼ 8.4 Hz), 7.1 (d, 1H, J ¼ 8.4 Hz), 4.25 (q, 2H, J ¼ 7.2 Hz), 4.08 (m, 1H), 3.9–3.8
(m, 4H), 3.4–3.3 (m, 2H), 2.9–2.6 (m, 2H), 1.35 (t, 3H, J ¼ 7.2 Hz); 13C NMR:
(DMSO-d6, 50 MHz): d 14.2, 23.4, 38.4, 40.9, 51.5, 53.2, 60.4, 68.2, 112.7, 118.9,
119.1, 119.9, 122.9, 123.8, 124.1, 126.7, 127.6, 127.7, 131.6, 134.3, 135.3, 158.7,
161.7, 162.1, 167.7; IR tmax cmꢁ1(KBr): 3357 (br), 2940 (br), 1759 (br), 1707, 1544,
1466, 1440, 1396, 1248, 1026 cmꢁ1; MS: m=z 462 (100%, M þ 1; Et ester).
Preparation of (S)-Ethyl 3-(2-aminoethyl)-5-((2-oxooxazolidin-
4-yl)methyl)-1H-indole-2-carboxylate Hydrochloride 8
Hydrazine hydrate (10.52 L, 10.84 kg, 216.9 mol) was added dropwise to a
stirred solution of ethyl 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-5-[(4S)-2-
oxo-oxazolidin-4-ylmethyl]-1H-indole-2-carboxylate 7 (25 kg, 54.2 mol) in methanol
(250 L) at room temperature (25–30 ꢀC) in about 20–30 min, and the reaction mixture
was maintained under stirring at 35–40 ꢀC for 2 h. After the completion of reaction
(monitored by TLC, using ethyl acetate as mobile phase), the reaction mass was
cooled to 10 ꢀC and 2 N HCl (237.5 L, 379.4 mol) was added to it in a dropwise
manner. Then the acidified reaction mixture was diluted with 137.5 L demineralized
(DM) water, the solvent was evaporated, and the misture was cooled to 10 ꢀC. The
solid residue was filtered off, and the filtrate was concentrated to 87.5–100 L volume
and stirred for 15 min at 10 ꢀC. The resulting solid was filtered and recrystallized from
a mixture of methanol (125 L) and acetone (500 L) to get the title compound 8. Yield
1
10.9 kg (61%); mp: 260–265 ꢀC. H NMR (DMSO-d6, 200 MHz): d 11.7 (s, 1H),
8.16–8.0 (br s, 2H), 7.83 (s, 1H), 7.64 (s, 1H), 7.39 (d, 1H, J ¼ 8.6 Hz), 7.18 (d, 1H,
J ¼ 8.8 Hz), 4.40–4.20 (m, 3H), 4.15–4.10 (m, 2H), 3.35 (m, 2H), 3.04–2.80 (m, 4H),
1.37 (t, 3H, J ¼ 7.0 Hz); 13C NMR (DMSO-d6, 50 MHz): d 14.4, 22.7, 40.9, 51.8,
52.9, 60.4, 68.3, 112.6, 117.6, 120.5, 124.2, 127.0, 127.4, 127.9, 135.3, 158.7, 161.6;
IR tmax cmꢁ1(KBr): 3344, 3222, 3151, 2973 (br), 2933, 1761, 1691, 1594, 1542, 1470,
1442, 1338, 1252, 1034 cmꢁ1; MS (Electronspray, þve mode): m=z 315.0 [(M þ 1)þ
for Me ester], 332.0 [(M þ 1)þ for Et ester, 100%), 663.3 [(2M þ 1)þ for Et ester].
MS (Electronspray, -ve mode): m=z 330.3 [(M ꢁ 1)ꢁ, Et ester], 366.0 [(M ꢁ 1 þ HCl)þ
for Et ester; 100%].
Preparation of 4-(S)-((3-(2-(Dimethylamino)ethyl)-1H-indol-5-yl)
methyl)-oxazolidin-2-one 1
To a stirred solution of (S)-ethyl-3-(2-aminoethyl)-5-((2-oxooxazolan-4-yl)
methyl]-1H-indole-2-carboxylate hydrochloride 8 (5.0 kg,13.6 mol) in methanol
(50 L) at room temperature, 20% sodium carbonate solution was added dropwise

SYNTHESIS OF ZOLMITRIPTAN
3301
up to pH 7. Glacial acetic acid (1.94 L, 2.04 kg, 34.01 mol) was added to the neutralized
solution at the same temperature. The reaction mass was cooled to 10–15 ꢀC, and
sodium cyanoborohydride (1.51 kg, 24.48 mol) was added pinch by pinch to the reac-
tion mass under stirring at 10–15 ꢀC. After the addition, the reaction mass was further
cooled to 0 ꢀC, and a mixture of aqueous formaldehyde solution (38%, 3.7 L, 45.5 mol)
and methanol (15 L) was added dropwise to the stirred reaction mass. The reaction
mass was stirred at the same temperature for another 60–90 min. After the completion
of the reaction (via TLC, using 30% methanol and 1.5% NH3 in dichloromethane as
the mobile phase), an aqueous solution of sodium carbonate [15 L of 20% (w=v)] was
added at 0 ꢀC, and the reaction mass was extracted twice with dichloromethane
(2 ꢂ 50 L). Combined organic layers were washed with DM water (25 L) followed
by brine (25 L), and removal of solvent furnished the crude ethyl 3-(2-dimethyl-
aminoethyl)-5-[(4S)-2-oxo-oxazolidin-4-ylmethyl]-1H-indole-2-carboxylate 9 in 4.6 kg
yield. Aqueous solution of sodium carbonate (1.36 kg, 12.8 mol in 46 L water) was
added to the crude compound and the stirred reaction mass was refluxed for
2–2.5 h. After the completion of the reaction (via TLC, using 30% methanol in dichlor-
omethane as the mobile phase), the crude reaction mass was allowed to cool to
15–18 ꢀC, and concentrated hydrochloric acid (35%, 13.8 L, 3.0 vol. with regard to
compound 9) was added dropwise to the reaction mass. The reaction mixture was
again refluxed for 4 h, and after completion of the reaction (via TLC, using 30% MeOH
and 1.5% NH3 in dichloromethane; the reaction mixture was cooled to 20–25 ꢀC and
washed with 50 L of ethyl acetate. The aqueous layer was further cooled to 15–20ꢀC,
basified with 20% sodium hydroxide solution up to pH 9.5–10 and extracted three
times with ethyl acetate (3 ꢂ 92 L) at 25–30 ꢀC. Combined ethyl acetate layers were
washed twice with water (2 ꢂ 9.2 L) and evaporated to dryness to yield 2.5 kg of solid
residue. Isopropyl alcohol (7.5 L) was added to the solid residue and slowly heated to
reflux, resulting in a clear solution. The solution was slowly cooled to 20–30ꢀC.
N-heptane (2.5 L) was added dropwise to it, stirred for 15–20 min, and then filtered.
The solid residue was washed with prechilled 50:50 mixture (2.5 L) of isopropanol
and n-heptane and finally washed with n-heptane (5.0 L) and dried at 50–55ꢀC under
50–100 mm vacuum to obtain the title compound 1 in an overall yield of 1.75 kg (45%);
mp: 138–139 ꢀC; purity: 98.55%; 1H NMR (CDCl3, 500 MHz): d 8.0 (br s, 1H), 7.4 (s,
1H), 7.35 (d, 1H, J ¼ 8.5 Hz), 7.05 (s, 1H), 6.95 (d, 1H, J ¼ 8.5 Hz), 5.0 (s, 1H), 4.5 (t,
1H, J ¼ 8.0 Hz), 4.2 (q, 1H, J ¼ 5.5 Hz and 8.5 Hz), 4.1 (q, 1H, J ¼ 5.5 Hz and 11.5 Hz),
3.05–2.90 (m, 4H), 2.62 (t, 2H, 8.0 Hz), 2.3 (s, 6H); 13C NMR (DMSO-d6, 50 MHz): d
23.1, 40.7, 45.1, 53.2, 60.0, 68.1, 111.3, 112.5, 118.8, 122.5, 122.7, 125.1, 127.6, 135.2,
158.8; IR tmax cmꢁ1(KBr): 3240, 2920, 2854, 2772, 1744, 1480, 1441, 1405, 1241, 1070,
1031 cmꢁ1; MS (electronspray): m=z 288.1 (M þ 1)þ.
2-(S)-Amino-3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-
propan-1-ol 11
Sodium hydroxide pellets (0.28 g, 0.007 mol) were added to a stirred suspension
of 4-(S)-[3-(2-dimethylaminoethyl)-1H-indol-5-ylmethyl]-oxazolidin-2-one 1 (2 g) in
water (20 mL), and reaction mass was refluxed until the TLC showed absence of start-
ing material 1. The reaction mass was cooled to room temperature (25–30 ꢀC) and
extracted three times with ethyl acetate (3 ꢂ 50 mL). Combined organic layers were

3302
S. K. VUJJINI ET AL.
washed with water (50 mL) and brine (50 mL). Removal of solvent under reduced
1
pressure furnished the product (1.5 g) in 83% yield. H NMR (200 MHz, DMSO-
d6): d 10.6 (br s, 1H), 7.27–7.20 (t, 2H, J ¼ 6.4 Hz), 7.09–7.08 (d, 1H, J ¼ 2.0 Hz),
6.92–6.87 (q, 1H, J ¼ 1.6 Hz and 8.4 Hz), 3.35–3.14 (m, 6H), 2.91–2.68 (m, 4H),
2.53–2.41 (m, 2H), 2.20 (s, 6H). MS: m=z 262 (M þ H)þ.
Preparation of Metabolite 4-(S)-[3-(2-Methylaminoethyl)-1H-indol-
5-ylmethyl]-oxazolidin-2-one 14
Ethyl chloroformate (75 mL) was added dropwise to a stirred solution of
4-(S)-[3-(2-dimethylaminoethyl)-1H-indol-5-ylmethyl]-oxazolidin-2-one 1 (25 g) in
toluene (75 mL), and the reaction mixture was refluxed for 8 h. After completion of
the reaction, the solvent was distilled off completely under reduced pressure. The same
distillation was performed twice after adding toluene (2 ꢂ 250 mL) in the residue to
remove the traces of ethyl chloroformate, and the crude product was purified by col-
umn chromatography (silica; 10% to 50% solution of ethyl acetate=petroleum ether) to
afford pure 4-(S)-[3-(2-chloroethyl)-1H-indol-5-ylmethyl]-oxazolidin-2-one 11 (5 g).
To
a
stirred solution of 4-(S)-[3-(2-chloroethyl)-1H-indol-5-ylmethyl]-
oxazolidin-2-one 11 (2.5 g) in acetonitrile (25 mL) was added 40% methyl amine
(20 mL), and the reaction mixture was heated to 55–60 ꢀC for 5 h (in a sealed tube).
After completion of the reaction, the solvent was distilled off completely under
reduced pressure, water (50 mL) was added to the residue, and the compound was
extracted twice in ethyl acetate (2 ꢂ 250 mL). The combined ethyl acetate layer was
concentrated under reduced pressure, and the crude residue was purified by column
chromatography (silica; 10% to 50% solution of MeOH=CH2Cl2) to afford pure
1
4-(S)-[3-(2-methylaminoethyl)-1H-indol-5-ylmethyl]-oxazolidin-2-one 13 (1.25 g). H
NMR (500 MHz, DMSO-d6): d 10.92 (s,1H), 8.86 (br s, 1H), 7.80 (br s, 1H), 7.45
(s, 1H), 7.30–7.28 (d, 1H, J ¼ 8.5 Hz), 7.21–7.20 (d, 1H, J ¼ 2.0 Hz), 6.98–6.96 (d,
1H, J ¼ 8.0 Hz), 4.25–4.22 (t, 1H, J ¼ 7.5 Hz), 4.09–4.01 (m, 2H), 3.14–3.13 (d, 2H,
J ¼ 7.0 Hz), 3.05–3.02 (t, 2H, J ¼ 8.5 Hz), 2.92–2.88 (q, 1H, J ¼ 4.5 Hz and 13.5 Hz),
2.80–2.76 (q, 1 h, J ¼ 7.5 Hz and 13.5 Hz), 2.57 (s, 3H). MS: m=z 274 (M þ H)þ.
(S)-Ethyl-3-(2-(dimethylamino)ethyl)-5-((2-oxazolidin-4-yl)methyl)-
1H-indole Carboxylate Hydrochloride 12
Concentrated hydrochloric acid (272 mL, 2.6 mol) was slowly added to a stirred
solution of 4-(S)-(4-aminobenzyl)-1,3-oxazolidin-2-one (2) (200 g, 1.04 mol) in a mix-
ture of methanol (600 mL) and water (900 mL) at 5–10 ꢀC. After stirring for 10 min, a
solution of sodium nitrite (90 g, 1.3 mol) in water (60 mL) was added slowly to the
reaction mixture at ꢁ5 to 0 ꢀC, and the solution was maintained under stirring at
the same temperature for 30 min. Meanwhile, in a separate vessel, sodium acetate
(340 g, 4.14 mol) was added to a stirred solution of ethyl 2-acetyl-5-(1,3-dioxo-1,3-
dihydro-2-isoindolyl) pentanoate (4) (3.6 g, 1.1 mol) in ethanol (3.4 L). After stirring
for 1 h at room temperature (25–30 ꢀC) the solution was cooled to 0–5 ꢀC, and the pre-
viously prepared diazotized solution was slowly added to this cooled reaction mixture
and stirred for 3 h at room temperature. After the completion of reaction (monitored
by TLC, using ethyl acetate as mobile phase), the reaction mass was extracted three

SYNTHESIS OF ZOLMITRIPTAN
3303
times with dichloromethane (3 ꢂ 3 L). The combined dichloromethane layer was
washed twice with water (2 ꢂ 1 L) and once with brine (1 L). The organic layer was
separated and concentrated. The crude residue (containing the hydrazone intermedi-
ate) was preceded for cyclization to form the indole moiety. Ethanolic HCl (1.2 L,
5.04 mol) was added to this residue, and the solution was refluxed for 6 h. The reac-
tion mass was then cooled to room temperature (25 ꢀC) and the obtained solid was
filtered and dried to furnish 7. To a stirred solution of ethyl 3-[2-(1,3-dioxo-1,
3-dihydro-isoindol-2-yl)-ethyl]-5-[(4S)-2-oxo-oxazolidin-4-ylmethyl]-1H-indole-2-
carboxylate (7) (200 g, 0.43 mol) in methanol (1.6 L) at room temperature (25–30 ꢀC),
hydrazine hydrate (86.8 g, 1.74 mol) was added dropwise in about 20–30 min, and the
reaction mixture was maintained under stirring at 35–40 ꢀC for 2 h. After the com-
pletion of reaction (monitored by TLC, using ethyl acetate as mobile phase), the reac-
tion mass was cooled to 10 ꢀC, and 2 N HCl (1.9 L, 3 mol) was added to it in a
dropwise manner. Then the acidified reaction mixture was diluted with 1.1 L DM
water, the solvent was evaporated, and the mixture was cooled to 10 ꢀC. The solid
residue was filtered off, and the filtrate was concentrated to 2.4 L volume and stirred
for 15 min at 10 ꢀC. The resulting solid was filtered and recrystallized from a mixture
of methanol (3.1 L) and acetone (2.1 L) to get 8. To a stirred solution of ethyl 3-(2-
aminoethyl)-5-[(4S)-2-oxo-oxazolan-4-ylmethyl]-1H-indole-2-carboxylate hydro-
chloride (8) (25 g, 0.07 mol) in methanol (250 mL) at room temperature, 20% sodium
carbonate solution was added dropwise up to pH 7. Acetic acid (10.2 g, 2.5 mol) was
added to the neutralized solution glacial at the same temperature. The reaction mass
was cooled to 10–15 ꢀC and sodium cyanoborohydride (12.65 g, 0.204 mol) was added
pinch by pinch to the reaction mass under stirring at 10–15 ꢀC. After the addition, the
reaction mass was further cooled to 0 ꢀC, and a mixture of aqueous formaldehyde
solution (39%, 52.3 mL, 0.7 mol) and methanol (75 mL) was added dropwise to the
stirred reaction mass. The reaction mass was stirred at the same temperature for
another 60–90 min. After the completion of the reaction (via TLC, using 30% meth-
anol and 1.5% NH3 in dichloromethane as the mobile phase), an aqueous solution
of sodium carbonate [72 mL of 20% (w=v)] was added at 0 ꢀC and the reaction mass
was extracted twice with dichloromethane (2 ꢂ 400 mL). The combined organic layers
were washed with DM water (2 ꢂ 350 mL) followed by brine (450 mL) and then
concentrated to 5 volumes (to a total of 125 mL) and cooled to 5–10 ꢀC. The pH
was adjusted to 5, acetone (125 ml) was added and stirred for 30 min at 5–10 ꢀC,
and the solution was filtered, washed with acetone (25 mL), and dried to get the
(S)-ethyl-3-(2-(dimethyl-amino)ethyl)-5-((2-oxooxazolidin-4-yl)methyl)-1H-indole-2-
1
carboxylate hydrochloride (12). H NMR (200 MHz, DMSO-d6): d 11.70 (s, 1H),
10.48 (br s, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.40–7.36 (d, 1H, J ¼ 8.4 Hz), 7.20–7.16
(d, 1H, J ¼ 8.6 Hz), 4.42–4.24 (m, 3H), 4.14–4.01 (m, 2H), 3.47–3.44 (d, 2H,
J ¼ 6.2 Hz), 3.24–3.21 (d, 2H, J ¼ 7.2 Hz), 2.85 (s, 6H), 2.52–2.48 (m, 2H),
1.41–1.34 (t, 3H, J ¼ 7.2 Hz). MS: m=z 360 (M þ H)þ.
Preparation of 4-(R)-((3-(2-(Dimethylamino)ethyl)-1H-indol-5-yl)
methyl)-oxazolidin-2-one 13
Concentrated hydrochloric acid (272 mL, 2.6 mol) was slowly added to a stirred
solution of 4-(R)-(4-aminobenzyl)oxazolidin-2-one (2’) (200 g, 1.04 mol) in a mixture

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S. K. VUJJINI ET AL.
of ethanol (600 mL) and water (200 mL) at 5–10 ꢀC. After stirring for 10 min, a
solution of sodium nitrite (90 g, 1.3 mol) in water (400 mL) was added slowly to the
reaction mixture at ꢁ5 to 0 ꢀC, and the solution was maintained under stirring at
the same temperature for 30 min. Meanwhile, in a separate vessel, sodium acetate
(340 g, 4.14 mol) was added to a stirred solution of ethyl 2-acetyl-5-(1,3-dioxoisoindo-
lin-2-yl)pentanoate (4) (346 g, 1.1 mol) in ethanol (2.5 L). After stirring for 1 h at room
temperature (25–30 ꢀC) the solution was cooled to 0–5 ꢀC and the previously prepared
diazotized solution was slowly added and stirred for 3 h at room temperature. After
the completion of reaction (monitored by TLC, using ethyl acetate as mobile phase),
the reaction mass was extracted three times with dichloromethane (3 ꢂ 3 L). The com-
bined dichloromethane layer was washed twice with water (2 ꢂ 1 L) and once with
brine (1 L). The organic layer was separated and concentrated. The crude residue
(containing the hydrazone intermediate) was preceded for cyclization to form the
indole moiety. To the residue was added ethanolic HCl (1.2 L, 5.04 mol), and the sol-
ution was refluxed for 6 h. The reaction mass was then cooled to room temperature
(25 ꢀC), and the obtained solid was filtered, washed with ethanol (1 L), and dried
to furnish (R)-ethyl-3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-5-[(2-oxooxazolidin-4-yl)
methyl]-1H-indole-2-carboxylate (7’). Hydrazine hydrate (86.8 g, 1.74 mol) was added
dropwise to a stirred solution 70 (200 g, 0.433 mol) in methanol (1.6 L) at room tem-
perature (25–30 ꢀC) in about 20–30 min, and the reaction mixture was maintained
under stirring at 35–40 ꢀC for 2 h. After the completion of the reaction (monitored
by TLC, using ethyl acetate as mobile phase), the reaction mass was cooled to
10 ꢀC and 2 N HCl (1.9 L, 3.03 mol) was added to it in a dropwise manner. Then
the acidified reaction mixture was diluted with 1.1 L DM water, and solvent was eva-
porated and cooled to 10 ꢀC. The solid residue was filtered off, and the filtrate was
concentrated to 750 mL volume and stirred for 15 min at 10 ꢀC. The resulting solid
was filtered and recrystallized from a mixture of methanol (3.1 L) and acetone
(2.5 L) to get (R)-ethyl 3-(2-aminoethyl)-5-((2-oxooxazolidin-4-yl)methyl)-1H-indole-
2-carboxylate hydrochloride (80). To a stirred solution 80 (25 g, 0.07 mol) in methanol
(250 mL) at room temperature 20% sodium carbonate solution was added dropwise
up to pH 7. Glacial acetic acid (10.2 g, 0.17 mol) was added to the neutralized solution
at the same temperature. The reaction mass was cooled to 10–15 ꢀC, and sodium cya-
noborohydride (12.65 g, 0.204 mol) was added pinch by pinch to the reaction mass
under stirring at 10–15 ꢀC. After the addition, the reaction mass was further cooled
to 0 ꢀC and a mixture of aqueous formaldehyde solution (38%, 20.4 g, 0.68 mol) and
methanol (75 mL) was added dropwise to the stirred reaction mass. The reaction mass
was stirred at the same temperature for another 60–90 min. After the completion of
reaction (via TLC, using 30% methanol and 1.5% NH3 in dichloromethane as the
mobile phase), an aqueous solution of sodium carbonate [72 mL of 20% (w=v)] were
added at 0 ꢀC and the reaction mass was extracted twice with dichloromethane
(2 ꢂ 150 mL). Combined organic layers were washed with DM water (250 mL),
followed by brine (250 mL) and removal of solvent furnished the crude (R)-ethyl
3-(2-(dimethylamino)ethyl)-5-((2-oxooxazolidin-4-yl)methyl)-1H-indole-2-carboxylate
hydrochloride (9). Aqueous solution of sodium carbonate (10.8 g, 0.103 mol in 108 mL
water) was added to the crude compound and the stirred reaction mass was refluxed for
2–2.5 h. After completion of the reaction (via TLC, using 30% methanol in dichloro-
methane as the mobile phase), the reaction mass was allowed to cool to 15–18 ꢀC,

SYNTHESIS OF ZOLMITRIPTAN
3305
and concentrated hydrochloric acid (32%, 77.5 mL, 0.7 mol) was added dropwise to the
reaction mass. The reaction mixture was again refluxed for 4 h, and after completion of
the reaction (via TLC, using 30% MeOH and 1.5% NH3 in dichloromethane) the reac-
tion mixture was cooled to 20–25 ꢀC and washed with 50L of ethyl acetate. The aque-
ous layer was further cooled to 15–20 ꢀC, basified with 20% sodium hydroxide solution
(160mL) up to pH 11, and extracted three times with ethyl acetate (3ꢂ 300 mL) at
25–30 ꢀC. Combined ethyl acetate layers were washed twice with water (2ꢂ 250 mL)
and evaporated to dryness to yield a solid residue. Isopropyl alcohol (37.5 mL) was
added to the solid residue and slowly heated to reflux to result in a clear solution.
The solution was slowly cooled to 20–30 ꢀC, and n-heptane (12.5 mL) was added drop-
wise to it, stirred for 15–20 min, and then filtered. The solid residue was washed with a
prechilled 50:50 mixture (25 mL) of isopropanol and n-heptane, washed with n-heptane
(50 mL), and dried at 50–55 ꢀC under a 50–100 mm vacuum to obtain 4-(R)-
1
((3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)methyl)-oxazolidin-2-one (14). H NMR
(500 MHz, DMSO-d6): d 10.92 (s,1H), 8.86 (br s, 1H), 7.80 (br s, 1H), 7.45 (s, 1H),
7.30–7.28(d, 1H, J ¼ 8.5 Hz), 7.21–7.20 (d, 1H, J ¼ 2.0 Hz), 6.98–6.96 (d, 1H,
J ¼ 8.0 Hz), 4.25–4.22 (t, 1H, J ¼ 7.5 Hz), 4.09–4.01(m, 2H), 3.14–3.13 (d, 2H,
J ¼ 7.0 Hz), 3.05–3.02 (t, 2H, J ¼ 8.5 Hz), 2.92–2.88 (q, 1H, J ¼ 4.5 Hz and 13.5 Hz),
2.80–2.76 (q, 1 h, J ¼ 7.5 Hz and 13.5 Hz), 2.57 (s, 3H); MS: m=z 274 (M þ H)þ.
Compound 9
1H NMR (DMSO-d6, 200 MHz): d 11.7 (s, 1H), 10.8–10.65 (br s, 1H), 7.9 (s,
1H), 7.7 (s, 1H), 7.40 (d, 1H, J ¼ 8.6 Hz), 7.19 (d, 1H, J ¼ 8.2 Hz), 4.42–4.21 (m,
3H), 4.19–4.0 (m, 2H), 3.45 (d, 2H, J ¼ 6.4 Hz), 3.2 (d, 2H, J ¼ 5.0 Hz), 2.70–2.95
(m, 8H), 1.39 (t, 3H, J ¼ 6.8 Hz). IR tmax cmꢁ1(KBr): 3465, 3403, 3277, 2966,
2680, 2633, 2477, 1739, 1722, 1698, 1546, 1470, 1416, 1380, 1335, 1252, 1093,
1023 cmꢁ1. MS: m=z 360 (M þ H)þ.
Intermediate Acid 10
1H NMR (DMSO-d6, 500 MHz): d 15.2–14.6 (br s, 1H), 11.0 (s, 1H), 7.8 (s,
1H), 7.45 (s, 1H), 7.3 (d, 1H, J ¼ 8.0 Hz), 7.0 (d, 1H, J ¼ 9.0 Hz), 4.25 (t, 1H,
J ¼ 7.5 Hz), 4.1–4.0 (m, 2H), 3.3–3.2 (m, 4H), 2.95 (q, 1H, J ¼ 4.0 Hz and
J ¼ 13.0 Hz), 2.80 (q, 1H, J ¼ 7.0 Hz and J ¼ 13.5 Hz), 2.55 (s, 6H). IR tmax cmꢁ1
(KBr): 3239, 3128, 2420, 1741, 1598, 1547, 1451, 1393, 1333, 1235, 1181, 1096,
1024, 941 cmꢁ1. MS: m=z 332 (M þ H)þ.
CONCLUSION
A simple, commercially viable process for the synthesis of an optically pure zol-
mitrptan 1 was accomplished on an industrial scale via the Japp–Klingemann reaction.
ACKNOWLEDGMENTS
We thank the management of Dr. Reddy’s Laboratories Ltd. for supporting
this work. Co-operation from the project colleagues of API Process Research

3306
S. K. VUJJINI ET AL.
Department, Integrated Product Development Organization, Dr. Reddy’s
Laboratories Ltd., is highly appreciated
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