Synthesis of 5-substituted indole derivatives, part II. Synthesis of sumatriptan through the Japp-Klingemann reaction

Article abstract of DOI:10.3987/COM-99-8815

Synthesis of selective 5-HT(1B/1D) receptor agonist, sumatriptan (1) was accomplished through decarboxylation of 2-carboxy-3-[2-(dimethylamino)ethyl]- N-methyl-1H-indole-5-methanesulfonamide (2) in quinoline with copper powder. The preparation of the acid (2) was effected through the Japp-Klingemann method thus avoiding the need for the formation of hydrazine from diazonium salt. Attempted decarboxylation in N,N-dimethylacetamide resulted in the formation of the β-carboline (16).

Full text of DOI:10.3987/COM-99-8815

HETEROCYCLES, Vol. 53, No. 3, 2000, pp. 665 - 673, Received, 22nd November, 1999
SYNTHESIS OF 5-SUBSTITUTED INDOLE DERIVATIVES, PART II.1
SYNTHESIS OF SUMATRIPTAN THROUGH THE JAPP-KLINGEMANN
REACTION.
Béla Petea*, István Bitterb, Kálmán Harsányic, and László Tőkeb
a
Organic Chemical Technology Research Group of the Hungarian
Academy of Sciences at the Technical University of Budapest, H-1521
Budapest, Hungary
Department of Organic Chemical Technology, Technical University of
b
Budapest, H-1521 Budapest, Hungary
Chemical Works of Gedeon Richter LTD, Research Laboratory, H-1475
c
Budapest 10, POB 27, Hungary
Abstract -Synthesis of selective 5-HT1B/1D receptor agonist, sumatriptan
(1) was accomplished through decarboxylation of 2-carboxy-3-[2-
(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide (2) in
quinoline with copper powder. The preparation of the acid (2) was
effected through the Japp-Klingemann method thus avoiding the need for
the formation of hydrazine from diazonium salt. Attempted decarboxylation
in N,N-dimethylacetamide resulted in the formation of the β-carboline (16).
The complex physiological processes of the neurotransmitter serotonin (5-HT, 5-hydroxy-
tryptamine) are becoming increasingly elucidated. In one role it acts as a vasoconstrictor in the
brain and, thereby, displays beneficial properties in the treatment of the migraine.2 Over the
past few years an extensive effort has been devoted to the development of tryptamines
showing 5-HT1D receptor agonists properties to achieve the desired activity and selectivity for
the treatment of migraine.3 Sumatriptan4 (1) is the first of this class of drugs having been
approved for this use, and its discovery initiated the synthesis of a great number of 5-
substituted tryptamines.5 Many of these works obtained tryptamines directly from Fischer
synthesis6 by the choice of appropriate starting materials. The hydrazones necessary for these
Fischer synthesis are prepared either by the condensation of a hydrazine with a 4-amino-
butyraldehyde derivative or by the reaction of a diazonium salt with a β-oxo ester. The
difficulties encountered when using hydrazine, that is, the need for tin(II) chloride to prepare
the hydrazine and the formation of byproducts during the ring closure, are treated in detail in
our previous paper on this subject.1

All these difficulties are circumvented when we carry out the synthesis of indoles by virtue of
Japp-Klingemann7 (or Abramovits-Shapiro)8 reaction (second route). In this case the hydrazo-
nes are formed directly from arenediazonium salts. No electrophilic attack is likely to occur on
the 2-carbalkoxyindole formed in the rearrangement of the hydrazone as the nucleophilicity of
the indole ring is reduced by the ester group. Then the preparation of tryptamines has been
effected by the sequence of hydrolysis and decarboxylation. We now wish to disclose our work
on the synthesis of the acid (2) and sumatriptan (1) through decarboxylation, according to
Schemes 1, 2 and 3.
NMe2
NMe2
H
H
N
N
-CO2
Me
S
Me
S
CO2H
O
O
O
O
N
H
N
H
1
2
Me
Me
O
H
HN
S
HN
N
S
Me
O
O
O
S
CO2H
O
O
O
ii
iv
iii
NH
N
+
NH
Cl
N+
R
N
N
H
O
3a R=NO2
3b R=NH2
4
5
6
i
NH2
H
N
H
v
N
NH
Me
S
Me
S
CO2H
O
O
O
O
O
N
N
H
H
8
7
Reagents: i) H2, 10% Pd/C; ii) NaNO2, 8% HCl; iii) NaOAc; iv) HCO2H, ∆; v) KOH, EtOH-H2O, ∆
Scheme 1
In Scheme 1 the Abramovits-Shapiro procedure furnishes the tryptamine (8) in 35% overall
yield from arenediazonium chloride (4) and 3-carboxy-2-piperidone (5). However, our attempts

to produce 2 from 8 by reductive methylation using formaldehyde and formic acid or
borohydride derivatives proved unsuccessful. Refluxing 8 in 15% HCl solution in order to carry
out decarboxylation prior to the reductive methylation was also unsuccessful resulting in
elimination of sulfur dioxide from the methylaminosulfonyl group. Under the conditions of
thermal decarboxylation the only product isolated was the β-carboline (7). Having failed in
methylation of tryptamine (8) we turned our attention to the dimethylamino derivative of
acetoacetate (9) as the substitute for 5. When reacting 4 and 9 in the presence of aqueous
sodium acetate, the formation of a deeply colored insoluble material was observed which we
assumed to be a diazo-coupled type of compound involving the methylaminosulfonyl group.
Attempts to render the pH so carefully as to avoid diazo-coupling reaction of 4 were
unsuccessful. So it was concluded that a protecting group must be introduced on the
sulfonamide-N of 3 prior to diazotization.
NMe2
H
N
Me
S
EtO2C
Me
4
O
O
+
N
NMe2
N
H
O
CO2Et
9
10
Scheme 2
The ethoxycarbonyl moiety as a temporary protecting group appeared to be a reasonable
choice as it can be hydrolyzed together with the 2-ethoxycarbonyl group yielding the acid (2)
(Scheme 3). The reaction of 3a with ethyl chloroformate gave quantitatively the N-protected
sulfonamide (11).1 This compound was reduced1 and then diazotized to give diazonium salt
(12) which underwent a smooth Japp-Klingemann reaction with amino ester (9) in the presence
of sodium acetate to give the hydrazone (13). Subsequent Fischer-type rearrangement of 13
furnished the indole (14) in acetic acid-gaseous HCl solution at room temperature. Finally, the
acid (2) was obtained from 14 or 15 through hydrolysis. A smooth decarboxylation took place
o
when heating 2 in quinoline with copper powder at 200 C to give the desired 1.9 The other
common procedures to effect decarboxylation, that is, boiling in hydrochloric acid or sodium
hydroxide solutions resulted in fast decomposition of the acid (2) without the formation of any
isolable product. Attempted deethoxycarbonylation10 by heating 14 in morpholine resulted in
quantitative loss of the protective group of the sulfonamide yielding 15. Heating the acid (2) in

N,N-dimethylacetamide a clean reaction took place again and a single product, the β-carboline
(16), was isolated.
CO2Et
Me
N
S
O
CO2Et
CO2Et
O
N
S
i, ii
N
S
9
NMe2
Me
Me
O
O
O
O
N
iii
O
N+
Cl
N+
O
N
N
H
12
EtO2C
11
13
NMe2
NMe2
CO2Et
H
N
iv
N
S
v
Me
Me
S
CO2Et
CO2Et
O
O
O
O
N
N
H
H
14
15
vi
vi
NMe2
H
N
H
N
NMe
O
viii
vii
Me
S
Me
S
1
CO2H
O
O
O
O
N
N
H
H
16
2
Reagents i) H2, 10% Pd/C ; ii) NaNO2, 12% HCl ; iii) NaOAc ; iv) AcOH-HCl; v) morpholine, ∆;
vi) KOH, MeOH-H2O ; vii) AcNMe2, 160 oC ; viii) quinoline, Cu, 200 oC
Scheme 3
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded at 500 MHz or 125 MHz, respectively, on a
Bruker DRX500 spectrometer. All δ values are given in ppm, TMS was used as an internal
standard. IR spectra were measured on Perkin-Elmer 1600 series FTIR spectrophotometer in
KBr discs. Low resolution chemical ionization MS were obtained on a Finnigan Automass
spectrometer in direct inlet mode using isobutane. All chemicals were reagent grade and used

without further purification. Compounds (3a,b,11 912 and 111) were prepared as described in the
literature.
Piperidine-2,3-dione 3-[4-[(N-methylaminosulfonyl)methyl]phenylhydrazone] (6).
(Z/E isomer mixture in a 1:3 ratio).
To the suspension of 3b (8.0 g, 40 mmol) in conc. HCl (30 mL) and water (60 mL) was added
o
sodium nitrite (3.0 g, 43 mmol) in water (15 mL) over a period of 30 min at -2∼0 C. Sodium 2-
piperidone-3-carboxylate (5, 6.6 g, 40 mmol) in water (30 mL) was introduced to the diazotized
solution, then aqueous sodium acetate (30%) until the pH has reached 4.5. The reaction
mixture was stirred for another 6 h at rt by that time the product separated as an oil;
crystallization could be effected by adding ethyl acetate (20 mL) to give, after filtration, 8.4 g
1
o
(68%) of 6, mp 210-212 C (decomp). H NMR (DMSO-d6) δ: 1.83, 2.60, 3.19 (m, 3x2H, CH2);
2.57 (d, 3H, J=4.0 Hz, NH-Me); 4.25 (s, 2H, CH2SO2); 6.81 (q, 1H, J=4.0 Hz, NH-Me); 7.22 (s,
4H, Ar-H); 7.88 (s, 0.75H, N-H); 8.13 (s, 0.25H, N-H); 9.68 (s, 0.75H, N-H); 13.20 (s, 0.25H, N-
13
H). C NMR (DMSO-d6 , E-isomer) δ: 21.4, 24.6, 39.9 (CH2); 28.7 (Me-NH); 55.9 (CH2SO2);
113.3, 121.6, 131.0, 135.5 (Ar); 144.7 (C=N); 161.8 (C=O). IR (cm-1): 1658.
N-Methyl-(1-oxo-1,2,3,4-tetrahydro-β-carbolin-6-yl)methanesulfonamide (7).
The mixture of hydrazone (6) (8.4 g, 27 mmol) and aqueous formic acid (70%, 40 mL) was
stirred for 1 h at reflux temperature. Water (20 mL) was added and allowed to cool to rt. The
precipitated product was filtered, washed with ethanol and recrystallized from ethanol to give
o
5.0 g (63%) of 7, mp 264-266 C (decomp). 1H NMR (DMSO-d6) δ: 2.57 (d, 3H, J=4.3 Hz, NH-
Me); 2.92 (m, 2H, CH2); 3.52 (m, 2H, CH2); 3.60 (s, 1H, N-H); 4.37 (s, 2H, CH2SO2); 6.83 (q,
1H, J=4.3 Hz, NH-Me); 7.24 (d, 1H, J=8.4 Hz, Ar-H); 7.33 (d, 1H, J=8.4 Hz, Ar-H); 7.53 (s, 1H,
Ar-H); 11.67 (s, 1H, N-H). 13C NMR (DMSO-d6 ) δ: 20.4, 41.2 (CH2); 29.0 (Me-NH); 56.2
(CH2SO2); 112.4, 118.2, 121.2, 122.5, 125.0, 126.9, 127.9, 136.8 (Ar); 161.6 (C=O). IR (cm-1):
1652, 1208. Anal. Calcd for C13H15N3O3S: C 53.23, H 5.15, N 14.32. Found: C 52.75, H 5.18, N
14.02.
3-(2-Aminoethyl)-2-carboxy-N-methyl-1H-indole-5-methanesulfonamide (8).
The mixture of β-carboline (7) (7.6 g, 26 mmol) in ethanol (100 mL) and potassium hydroxide
(10 g, 178 mmol) in water (50 mL) was refluxed for 8 h. The hot reaction mixture was treated

with activated carbon (0.5 g) and filtered. Ethanol was removed from the filtrate by rotary
evaporation and the residual aqueous solution was acidified with conc. hydrochloric acid to pH
= 4. The precipitated material was filtered off, washed with water and recrystallized from water
1
o
to give 6.6 g (82%) of 8, mp 264-268 C. H NMR (DMSO-d6) δ: 2.48 (d, 3H, J=4.3 Hz, NH-Me);
2.8-3.6 (m, 2x2H, CH2); 4.30 (m, 2H, NH2); 4.42 (s, 2H, CH2SO2); 6.90 (q, 1H, J=4.3 Hz, NH-
Me); 7.10 (d, 1H, J=8.3 Hz, Ar-H); 7.37 (d, 1H, J=8.3 Hz, Ar-H); 7.58 (s, 1H, Ar-H); 11.29 (s,
1H, N-H). 13C NMR (DMSO-d6 ) δ: 29.0 (Me-NH); 22.5, 40.9 (CH2); 57.0 (CH2SO2); 111.3,
111.8, 120.2, 121.2, 125.2, 127.8, 134.4, 134.6 (Ar); 165.9 (COOH). IR (cm-1): 3293, 1200.
Anal. Calcd for C13H17N3O4S : C 50.15, H 5.50, N 13.50. Found: C 49.78, H 5.42, N 13.93.
Ethyl 5-(dimethylamino)-2-[[4-[(N-ethoxycarbonyl-N-methylaminosulfonyl)methyl]phe-
nyl]hydrazin-2-ylidene]pentanoate (13).
To N-methyl-N-ethoxycarbonyl-(4-aminophenyl)methanesulfonamide hydrochloride1 (1.0 g,
3.24 mmol) in water (15 mL) and conc. hydrochloric acid (1 mL) was added sodium nitrite
o
(0.224 g, 3.24 mmol) in small portions over a period of 15 min at -4∼-2 C. Ethyl 2-(3-
dimethylamino-propyl)-3-oxobutanoate (9, 0.70 g, 3.25 mmol)12 was added at the same
temperature followed by sodium acetate (2 g, 24 mmol) after 5 min. The reaction mixture was
o
allowed to reach rt then warmed to 50 C and kept at this temperature for 0.5 h. During this
process the pH was kept between 3-4 by adding additional amounts of sodium acetate (ca. 0.2
g). The reaction mixture was cooled to rt, filtered and the filtrate extracted with dichloromethane
(3x30 mL). The organic layers were combined, dried (sodium sulfate) and rotary evaporated to
give 1.06 g (72%) of 13 as a brown oil which was used in the next step without further
characterization.
3-[2-(Dimethylamino)ethyl]-N,2-ethoxycarbonyl-N-methyl-1H-indole-5-methanesulfon-
amide (14).
To hydrazone (13) (1.75 g, 3.83 mmol) in glacial acetic acid (20 mL) was introduced gaseous
hydrogen chloride at rt and the mixture was allowed to stand for 24 h. White crystals started to
precipitate within 1 h. The crystals were filtered the next day, dried on air and recrystallized
o
1
from ethanol to give 1.46 g (80%) of 14, as hydrochloride, mp 220-224 C (decomp). H NMR
(DMSO-d6 ) δ: 1.29 (t, 3H, J=7 Hz, OCH2Me); 1.39 (t, 3H, J=7 Hz, OCH2Me); 2.73 (s, 3H, N-
Me); 2.84 (s, 6H, NMe2); 3.18 (m, 2H, CH2); 3.50 (m, 2H, CH2); 4.35 (q, 2H, J=7 Hz, OCH2Me);

4.40 (q, 2H, J=7 Hz, OCH2Me); 4.91 (s, 2H, CH2SO2); 7.22 (d, 1H, J=8.5 Hz, Ar-H); 7.53 (d, 1H,
J=8.5 Hz, Ar-H); 7.79 (s, 1H, Ar-H); 11.97 (s, 1H, NH). 13C NMR (DMSO-d6 ) δ: 14.1, 14.3
(CH3); 19.5, 56.3, 58.5, 60.7, 63.6 (CH2); 33.5 (N-Me); 40.0 (N-Me2); 112.9, 117.0, 119.7,
122.7, 124.7, 126.7, 127.5, 136.1 (Ar); 152.7, 161.2 (C=O). IR (cm-1): 1722, 1698. MS: m/z 440
[MH+]. Anal. Calcd for C20H29N3O6S⋅2H2O : C 50.51, H 6.99, N 8.83. Found: C 50.91, H 6.74, N
8.75.
3-[2-(Dimethylamino)ethyl]-2-ethoxycarbonyl-N-methyl-1H-indole-5-methanesulfon-
amide (15).
Ethyl indole-2-carboxylate (14) (1.0 g, 2.27 mmol) in morpholine (7 mL) was refluxed for 1.5 h.
The clear reaction mixture was evaporated to dryness, and the crystalline residue was
recrystallized from ethanol to give 0.77 g (92%) of 15, mp: 240-242 OC. 1H NMR (DMSO-d6 ) δ:
1.40 (t, 3H, J=7 Hz, OCH2Me); 2.59 (d, 3H, J=4.9 Hz, NH-Me); 2.84 (s, 6H, NMe2 ); 3.22 (m,
2H, CH2); 3.50 (m, 2H, CH2); 4.38 (s, 2H, CH2SO2); 4.40 (q, 2H, J=7 Hz, OCH2Me); 6.92 (q, 1H,
J=4.9 Hz, NH-Me); 7.31 (d, 1H, J=8.5 Hz, Ar-H); 7.44 (d, 1H, J=8.5 Hz, Ar-H); 7.80 (s, 1H, Ar-
13
H); 11.81 (s, 1H, N-H). C NMR (DMSO-d6 ) δ: 14.2 (CH3); 19.6, 56.1, 56.3, 60.6 (CH2); 28.9
(N-Me); 41.9 (N-Me2); 112.4, 117.0, 121.8, 122.4, 124.3, 126.7, 128.0, 135.9 (Ar); 161.3 (C=O).
IR (cm-1): 3176, 1698. MS: m/z 368 [MH+]. Anal. Calcd for C17H25N3O4S⋅2H2O: C 50.60, H 7.24,
N 10.41. Found: C 50.68, H 7.04, N 10.39.
2-Carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide (2).
To the ethyl indole-2-carboxylate (14) (1.0 g, 2.27 mmol) in methanol (40 mL) and water (20
mL) was added sodium hydroxide (0.8 g, 20 mmol) and allowed to stand at rt for 24 h. The pH
of the solution was adjusted to 4 (10% hydrochloric acid) and the precipitated material filtered
1
o
off and recrystallized from ethanol to give 0.695 g (90%) of 2, mp 260-265 C. H NMR (DMSO-
d6 ) δ: 2.53 (d, 3H, J=4.2 Hz, NH-Me); 2.58 (s, 6H, N-Me2); 3.03 (m, 2H, CH2); 3.26 (m, 2H,
CH2); 4.36 (s, 2H, CH2SO2); 6.80 (q, 1H, J=4.2 Hz, NH-Me); 7.16 (d, 1H, J=8.7 Hz, Ar-H); 7.36
13
(d, 1H, J=8.7 Hz, Ar-H); 7.59 (s, 1H, Ar-H); 11.18 (s, 1H, N-H). C NMR (DMSO-d6 ) δ: 20.5,
56.4, 59.8 (CH2); 28.8 (N-Me); 43.4 (N-Me2); 111.8, 120.3, 121.4, 124.5, 124.7, 125.7, 127.4,
134.6 (Ar); 164.9 (C=O). IR (cm-1): 3274, 1343, 1302. MS: m/z 340 [MH+]. Anal. Calcd for
C15H21N3O4S: C 53.08, H 6.24, N 12.38. Found: C 53.27, H 6.22, N 12.44.

N,2-Dimethyl-(1-oxo-1,2,3,4-tetrahydro-β-carbolin-6-yl)methanesulfonamide (16).
Indole-2-carboxylic acid (2) (1 g, 2.95 mmol) was dissolved in N,N-dimethylacetamide (20 mL)
o
and kept at 160 C for 1.5 h. The solution was evaporated (high vacuum) to dryeness and the
solid residue was recrystallized from ethanol to give 0.52 g (60%) of 16 as white crystals, mp
1
o
189-191 C. H NMR (DMSO-d6) δ: 2.56 (d, 3H, J=4.8 Hz, NH-Me); 2.98 (m, 2H, CH2); 2.99 (s,
3H, N-Me); 3.63 (m, 2H, CH2); 4.35 (s, 2H, CH2SO2); 6.80 (q, 1H, J=4.8 Hz, NH-Me); 7.21 (d,
13
1H, J=7.1 Hz, Ar-H); 7.39 (d, 1H, J=7.1 Hz, Ar-H); 7.54 (s, 1H, Ar-H); 11.63 (s, 1H, N-H). C
NMR (DMSO-d6 ) δ: 29.0 (Me-NH); 20.0, 33.6 (CH2); 49.5 (N-Me); 56.2 (CH2SO2); 112.3, 117.1,
121.2, 122.3, 124.8, 126.8, 127.7, 136.9 (Ar); 160.8 (C=O). IR (cm-1): 1640, 1202. Anal. Calcd
for C14H17N3O3S : C 54.71, H 5.57, N 13.67. Found: C 54.28, H 5.40, N 13.51.
3-[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide, (sumatriptan) (1).
To the indole-2-carboxylic acid (2) (1 g, 2.95 mmol) in quinoline (16 mL) was added copper
powder (80 mg) then argon gas was bubbled through the liquid for 1 h. The mixture was well
o
stirred at 190-200 C for another 1 h. The solution was filtered and the solvent evaporated in
high vacuum. The solid residue was purified on a short column of alumina, eluant: CH2Cl2-
EtOH (sat. with NH3) = 97:3, to give 0.69 g (80%) of 1, mp. 168-170 oC (ethanol), identical with
sumatriptan13 in all respect.
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