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(15) Ainsworth, C. Indazole Analogue of Tryptamine: A New Syn-
thesis of Indazoles. J . Am. Chem. Soc. 1957, 79, 5242.
(16) While the alkylation of indazole-3-carboxylic esters and of
indazole itself is known to give regiochemical mixtures of N-1
and N-2 alkylated products, the alkylation of amide 12a
predominantly gave the N-1 alkylated product. It is believed that
internal hydrogen bonding between the amide N-H and N-2 (i)
deactivates N-2 to alkylation and directs alkylation to N-1.
amino)-1-piperidinyl)ethyl)-1H-indazole-3-carboxamide (11.1 g,
26.3 mmol) in DMF (100 mL) and the reaction mixture stirred
at room temperature for 4 h. The reaction was cooled to 15
°C, 2-iodopropane (2.9 mL, 5.13 g, 29 mmol) was added
dropwise, and the reaction mixture was stirred at room
temperature for 18 h. The DMF was removed in vacuo and
the residue dissolved in EtOAc and water. The EtOAc layer
was washed sequentially with 10% sodium carbonate solution,
water and brine and evaporated to give the crude product.
Flash chromatography (5% MeOH in CH2Cl2) provided the
product as an oil (10.6 g, 87%). Crystallization of the product
as the oxalate salt provided colorless crystals, mp 149-151
°C. 1H NMR (DMSO-d6): 1.55 (d, 6H, J ) 8.0 Hz), 1.55-1.75
(m, 1H), 1.85-2.02 (m, 2H), 2.60-4.40 (m, 12H), 5.03 (s, 2H),
5.10 (septet, 1H, J ) 7.0 Hz), 7.23-7.55 (m, 7H), 7.82 (d, 1H,
J ) 9.0 Hz), 8.18 (d, 1H, J ) 9.0 Hz), 8.40-8.50 (m, 1H). MS:
463 (100). Anal. (C28H35N5O7) C,H,N.
N-[2-(4-Am in o-1-piper idin yl)eth yl)-1-isopr opylin dazole-
3-ca r boxa m id e d ioxa la te (23a ). A solution of N-(2-(4-
((benzyloxycarbonyl)amino)-1-piperidinyl)ethyl)-1-isopropylin-
dazole-3-carboxamide (8.71 g, 18.8 mmol) in EtOH (135 mL)
was hydrogenated over 5% palladium on carbon (3.0 g) at 60
psi and room temperature for 18 h. The reaction mixture was
filtered to remove the catalyst and concentrated to give an oil
(5.0 g, 81%). Crystallization of this oil as the dioxalate salt
gave colorless crystals, mp 232 °C. 1H NMR (DMSO-d6): 1.55
(d, 6H, J ) 7.0 Hz), 1.60-1.80 (m, 2H), 1.90-2.10 (m, 2H),
2.50-2.70 (m, 2H), 2.80-3.00 (m, 2H), 3.05-3.24 (m, 1H),
3.24-3.40 (m, 2H), 3.48-3.67 (m, 2H), 5.10 (septet, 1H, J )
7.0 Hz), 7.28 (t, 1H, J ) 8.0 Hz), 7.82 (d, 1H, J ) 9.0 Hz), 8.18
(d, 1H, J ) 9.0 Hz), 8.30-8.42 (m, 1H). MS: 329 (100). Anal.
(C22H31N5O9) C,H,N.
N-(2-(4-(1-Adam an tylcar boxam ido)-1-piper idin yl)eth yl)-
1-isop r op ylin d a zole-3-ca r boxa m id e Oxa la te (8). 1-Ada-
mantanecarbonyl chloride (199 mg, 1 mmol) was added to a
solution of N-(2-(4-amino-1-piperidinyl)ethyl)-1-isopropylin-
dazole-3-carboxamide (330 mg, 1.0 mmol) and triethylamine
(0.15 mL, 1.07 mmol) in THF (10 mL) at 0 °C. The reaction
mixture was allowed to warm to room temperature, stirred
for 18 h, and filtered. The filtrate was concentrated to give
an oil. Crystallization of the oxalate salt (MeOH/EtOAc) gave
the title compound as colorless crystals (267 mg, 46%), mp 228
°C. 1H NMR (DMSO-d6): 1.55 (d, 6H, J ) 8.0 Hz), 1.56-1.90
(m, 16H), 1.95 (br s, 3H), 2.80-3.05 (m, 2H), 3.05-3.20 (m,
2H), 3.30-3.55 (m, 2H), 3.55-3.70 (m, 2H), 3.70-3.90 (m, 1H),
5.10 (septet, 1H, J ) 7.0 Hz), 7.23-7.32 (m, 1H), 7.27 (t, 1H,
J ) 8.0 Hz), 7.46 (t, 1H, J ) 8.0 Hz), 7.80 (d, 1H, J ) 9.0 Hz),
8.18 (t, 1H, J ) 9.0 Hz), 8.40-8.55 (m, 1H). MS: 491 (100).
Anal. (C31H43N5O6) C,H,N.
(17) Turconi, M.; Nicola, M.; Quintero, M. G.; Maiocchi, L.; Micheletti,
R.; Giraldo, E.; Donetti, A. Synthesis of a New Class of 2,3-
Dihydro-2-oxo-1H-benzimidazole-1-carboxylic Acid Derivatives
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