726 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
Vishnu et al.
EXPERIMENTAL
General Methods
Procedure for the synthesis of 1-methyl N-endo-(9-
azabicyclo [3.3.1] non-3-yl]-1H-indazole-3- carboxamide
hydrochloride (8)
1H NMR spectra were recorded in CDCl3 & DMSO-d6
on a Mercury plus Varian 400 MHz spectrometers. Proton
chemical shifts (ꢀ) are relative to tetramethylsilane (TMS, ꢀ
0.00) as internal standard and expressed in ppm. Spin
multiplicities are given as s (singlet), d (doublet), t (triplet)
and m (multiplet). Coupling constants (J) are given in Hertz.
To
a
solution of 1-Methyl-N-endo-(9-methyl-9-
azabicyclo[3.3.1]non-3-yl)-indazole-3-carboxamide (1) (9.0
g, 28.8 mmol) in dichloromethane (270 mL) was added vinyl
chloroformate (21.1 mL, 230.7 mmol) at 25-35 °C and
stirred for 24 h. Dichloromethane was then removed, 16 %
IPA-HCl (90 mL) was added at 25 °C and stirred for 3 h at
ambient temperature. The reaction mass was concentrated,
residue was taken into isopropyl alcohol and refluxed for 1
h. The solid was filtered and dried at 50 °C under vacuum to
afford the product as a solid (3.1 g, 0.014 mol, 34.8 %
yield,).
IR (cm-1): 3271, 2943, 1637, 1534; 1H NMR (400 MHz ,
DMSO-d6): ꢀ = 9.04 (br s, 1H), 8.58 (br s, 1H), 8.34 (d, J =
8.58 Hz, 1H), 8.17 (d, J = 8.2, 1H), 7.73 (d, J = 8.5 Hz, 1H),
7.47 (m, 1H), 7.28 (t, J = 7.80 Hz, 1H), 4.48 (m, 1H), 4.14
(s, 3H), 3.77 (m, 3H), 2.5 (m, 2H), 1.73-1.93 (m, 4H), 1.52-
1.55 (m, 3H); HRMS (m/z): [M + H]+ calcd for[C17H23N4O]+
299.1872, Found: 299.1859.
Mass spectra were obtained on
a HP-5989A Mass
Spectrometer. Thin layer chromatography was performed on
silica gel plates (SRL 230-400 mesh). All solvents used are
commercially available and were distilled before use.
Procedure for the synthesis of 2-Methyl-N-endo- (9-methyl-
9-azabicyclo [3.3.1] non-3-yl)-2H- indazole -3-carboxamide
hydrochloride (7)
To a solution of indazole-3-carboxylic acid (2) (25 g,
0.15 mol), DMF (200 mL), potassium carbonate (106.4 g,
0.75 mol) was added methyl iodide (65.74 g, 0.46 mol) at 55
°C and stirred for 2 h, the reaction mixture was quenched
with water (800 mL) and extracted with ethyl acetate (500
mL x 2). Combined organic layers were washed with water
(250 mL) and concentrated under vacuum to afford the crude
compound, which was purified by column chromatography
over silica gel using Hexane-ethyl acetate 10:1 to give the
pure ester (4) (10.2 g, 0.05 mol, 35 % yield).
Procedure for the synthesis of 1-Methyl-N-exo-(9-methyl-
9-azabicyclo[3.3.1]non-3-yl)-indazole-3-carboxamide
hydrochloride (12)
To a solution of Granatoxime (9) (19 g, 0.11 mol) in n-
butanol (285 mL) was added sodium metal (21.5 g, 0.934
mmol) at 90-105 °C under nitrogen atmosphere and stirred
for 30 min at the same temperature. The reaction mixture
was cooled to ambient temperature and water (200 mL) was
added. The layers were separated, the aqueous layer was
further extracted with n-butanol (2 x 200 mL), the organic
layers were combined and concentrated at 60 °C under
vacuum to afford 18 g of exo-amine (10).
The purified ester (4) was taken into water (50 mL) and
an aqueous solution of sodium hydroxide (2.1 g, 0.0525 mol)
was added and heated to 65-70 °C for 1 h. The reaction
mixture was cooled to 35 °C and washed with ethyl acetate
(2 x 100 mL). The aqueous layer was neutralized with conc.
hydrochloric acid. The solid was filtered to afford the
product as a white crystalline solid 5. (7.93g, 0.025 mol, 85
% yield)
A mixture of 1-methyl-1H-indazole-3-carboxylic acid
(11) (9.0 g, 0.051 mol), thionyl chloride (18.2 g, 0.15 mol),
DMF (catalytic) and dichloromethane (225 mL) was
refluxed for 3 h. Excess thionyl chloride was removed at 40
°C under vacuum. To the concentrated mixture
dichloromethane (180 mL) was added. Then the mixture of
exo-amine (10) (9.5 g, 0.061 mol) in dichloromethane (45
mL) and triethyl amine (14.2 mL, 0.102 mol) was added to
the reaction mixture at 0 °C and stirred for 3 h at ambient
temperature. After completion of reaction, 5 % aq NaOH
solution (90 mL) was added to the reaction mixture, the
reaction mixture was extracted using CH2Cl2 (2 x 90 mL)
and concentrated. The residue was then stirred with IPA/HCl
(30 mL) at ambient temperature for 30 min and filtered to
afford crude product which on trituration with IPA (50 mL)
afforded the pure hydrochloride 12. (5.8 g, 0.018 mol, 32.5
% yield).
A mixture of 2-methyl-2H- indazole-3-carboxylic acid
(5) (9.0 g, 0.051 mol), thionyl chloride (18.2 g, 0.15 mol),
DMF (catalytic) and dichloromethane (225 mL) was
refluxed for 3 h. Excess thionyl chloride was removed at 40
°C under vacuum. To the concentrated mixture
dichloromethane (180 mL) was added. Then the mixture of
endo-amine (6) (9.5 g, 0.061 mol) in dichloromethane (45
mL) and triethyl amine (14.2 mL, 0.102 mol) was added to
the reaction mixture at 0 °C and stirred for 3 h at ambient
temperature. After completion of reaction, 5 % aq NaOH
solution (90 mL) was added to the reaction mixture, the
reaction mixture was extracted using CH2Cl2 (2 x 90 mL)
and concentrated. The residue was then stirred with IPA/HCl
(30 mL) at ambient temperature for 30 min and filtered to
afford crude product purified by IPA/water to afford pure
impurity-A. (10.10 g, 0.028 mol, 54.8 % yield).
1
IR (cm-1): 3489, 3332, 1643, 1533; H NMR (400 MHz,
1
IR (cm-1): 3352, 2894, 1639, 1537; H NMR (400 MHz,
CDCl3): ꢀ = 10.73 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.18 (d,
J = 8.31 Hz, 1H), 7.74 (d, J = 8.55, 1H), 7.47 (m, 1H) 7.28
(t, J = 7.33 Hz, 1H), 4.83 (d, J = 7.58, 1H), 4.15 (s, 3H), 3.53
(s, 2H), 2.9 (s, 3H), 2.25-2.5 (m, 4H), 1.71-1.94 (m, 6H);
HRMS (m/z): [M + H]+ calcd for[C18H25N4O]+ 313.2028,
Found: 313.2018.
CDCl3): ꢀ = 7.77 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.3 Hz,
1H), 7.22-7.34 (m, 2H), 5.92 (d, J = 7.8, 1H), 4.65 (m, 1H),
4.46 (s, 3H), 3.13 (d, J = 11.0, 2H), 2.6 (m, 1H), 2.51 (s,
3H), 1.96-2.00 (m, 3H), 1.55 (m, 2H), 1.35 (m, 2H);1.03-
1.06 (m, 2H); HRMS (m/z): [M + H]+ calcd for[C18H25N4O]+
313.2028, Found: 313.2020.