1622 Buchappa et al.
Asian J. Chem.
Light brown colour solid; Elemental analysis C11H16N2O4S
calcd (found) %: C 48.52 (48.22), H 5.92 (5.98), N 10.29 (10.40),
O 23.50 (23.20), S 11.77 (11.91). IR (KBr, νmax, cm-1): 3417.47-
3388.20, 3162.53-2905.33, 1716.15, 1572.53, 1529.19; 1H NMR
(400 MHz, DMSO-d6): δ 1.272-1.308 (t, 3H, -CH3), 1.508 (s,
9H, -3CH3), 4.242-4.295 (q, 2H, -CH2), 8.052 (s, 1H, ArH),
12.040 (s, 1H, -NH); 13C NMR (100 MHz, DMSO-d6): δ 164.58,
161.77, 152.99, 145.78, 121.21, 82.66, 61.24, 28.06, 14.43;
ESI-MS (m/z): 273.17 (M+1), 274.18 (M+2).
min period, raised the reaction mass temperature to 25-30 °C
and stirred the reaction mass at 25-30 °C for 24 h. After TLC
compliance distilled-off the solvent completely under plant
vacuum at the temperature not crossing 50 °C and Charge 2 N
HCl (250 mL) to the reaction mass, Stirred for 15-30 min.
Transferred the reaction mass into a Buchner funnel and flask
kept under plant vacuum. The wet cake is washed with 500
mL of water and dried the above-wet material in the dryer at
temperature 60-65 °C for 10-12 h.
2-tert-Butoxy-carbonylamino-thiazole-5-carboxylic
acid (3): Into a clean and dry 2 L 4-neck round bottom flask
connected to a mechanical stirrer, condenser, thermometer
socket is charged with 600 mL of 6N NaOH solution and slowly
add 25 g of ethyl 2-tert-butoxycarbonylamino-thiazole-5-
carboxylate (2) to the 6N NaOH solution at 25-30 °C within
30-60 min period. Maintained the reaction mass at 25-30 °C
for 24 h and after TLC compliance added 6N HCl solution
(600 mL) to the reaction mass at 25-30 °C within 60-90 min
period (pH test limit should be 0.5-1.5). Maintained the
reaction mass at 25-30 °C for 60-90 min period and trans-
ferred the reaction mass into a Buchner funnel and flask kept
under plant vacuum. Washed the wet cake with 100 mL DM
water and dried the above wet material in the dryer at 60-65
°C for 6-8 h to furnish 17 g of the title compound with purity
above 99 %.
Purification: Into a clean and dry 3.0 L 4-neck round bottom
flask connected to a mechanical stirrer, condenser, thermometer
socket is charging with 2-tert-butoxy-carbonyl-amino-N-(2-
chloro-6-methylphenyl)-5-thiazolecarboxamide crude,
methanol and isopropyl ether under stirring at 25- 30 °C. Raised
the reaction mass temperature to 60-65 °C and stirred the
reaction mass at 60-65 °C for 45-60 min. Cooled the reaction
mass temperature to 25-30 °C and transferred the reaction mass
into a Buchner funnel and flask kept under plant vacuum.
Washed the wet cake with 20.0 mL of methanol and dried the
wet material in dryer at 60-65 °C for 4-6 h to furnish 16.0 g of
the title compound with purity above 95 %.
Cream colour solid; Elemental analysis C16H18N3O3SCl
calcd (found) %: C 52.24 (52.12), H 4.93 (5.05), N 11.42 (11.31),
O 13.05 (13.25), S 8.72 (8.83). IR (KBr, νmax, cm-1): 3423.42-
3276.87, 3162.67, 2928.46, 1724.90, 1632.68-1566, 1522.80,
775.21; 1H NMR (400 MHz, DMSO-d6): δ1.504 (s, 9H, -3CH3),
2.225 (s, 3H, -CH3), 7.262-7.301 (t, 2H, ArH), 7.389-7.412
(m, 1H,ArH), 8.204 (s, 1H,ArH), 10.017 (s, 1H, -NH), 11.847
(s, 1H, -NH); 13C NMR (100 MHz, DMSO-d6):δ163.220, 159.74,
152.91, 141.27, 139.02, 133.31, 132.57, 129.34, 128.64, 127.28,
126.62, 82.33, 28.06, 18.45; ESI-MS (m/z): 368.21 (M+1),
370.18 (M+3).
Off white colour solid; Elemental analysis C9H12N2O4S
calcd (found) %: C 44.25 (44.55), H 4.95 (4.72), N 11.47 (11.31),
O 26.20 (26.07), S 13.13 (13.16). IR (KBr, νmax, cm-1): 3434.68,
1
3167.64, 2980.51, 1727.41, 1672.79, 1576.45, 1522.35; H
NMR (400 MHz, DMSO-d6): δ1.506 (s, 9H, -3CH3), 7.970 (s,
1H, ArH), 11.937 (s, 2H, -NH & -OH); 13C NMR (100 MHz,
DMSO-d6): δ 164.34, 163.09, 152.91, 145.39, 122.46, 82.40,
28.04; ESI-MS (m/z): 245.12 (M+1), 246.13 (M+2).
2-Aminothiazole-N-(2-chloro-6-methylphenyl)-5-
carboxamide (6): Into a clean and dry 2 L 4-neck round bottom
flask connected to a mechanical stirrer, condenser, thermometer
socket is charged with 2-tert-butoxy-carbonyl-amino-N-(2-
chloro-6-methylphenyl)-5-thiazolecarboxamide (50 g) and
trifluoroacetic acid (500 mL) under stirring. Maintained the
reaction mass at 25-30 °C for 3-5 h under stirring and after
TLC compliance distilled-off TFA completely under vacuum
at the temperature not crossing 50 °C. Charged 2.0 L of ethyl
acetate into reaction mass and washed the reaction mass with
5 % Aq KHCO3 (2 × 2 L) solution. Transferred the reaction
mass into a separating funnel, separated aqueous and organic
layers. Distilled-off the organic layer completely under plant
vacuum at the temperature not crossing 50 °C and cooled the
reaction mass temperature to 25-30 °C. Charged acetonitrile
(150 mL) and isopropyl ether (400 mL) to the reaction mass
and stirred for 60 min at 25-30 °C. Transferred the reaction
mass into a Buchner funnel and flask kept under plant vacuum
and washed the wet cake with 100 mL of isopropyl ether. Dried
the wet material in a dryer at 60-65 °C for 4-6 h to furnish 30 g
of the title compound with purity above 99 %.
2-tert-Butoxycarbonylamino-thiazole-5-carboxylic
acid chloride (4): Into a clean and dry 1 L 4-neck round bottom
flask connected to a mechanical stirrer, condenser, thermo-
meter socket is charged with 2-tert-butoxy-carbonylamino-
thiazole-5-carboxylic acid (3) (25.0 g), THF (1 L) and DMF
(1 mL) at 25-30 °C under stirring. Charged thionyl chloride
(22.5 mL of thionyl chloride dissolved in 125 mL of dichloro-
methane) to the mass at 25-30 °C. Maintained the reaction
mass at 25-30 °C for 4-6 h and after TLC compliance, distilled-
off solvent completely under plant vacuum at the temperature
not crossing 50 °C. Charged THF (125 mL) to the reaction
mass, stirring the mass for 10-15 min and distilled-off solvent
completely under plant vacuum at the temperature not crossing
40 °C. Charged 125 mL of dichloromethane to the reaction
mass, stirring the mass for 10-15 min and distilled-off solvent
completely under plant vacuum at the temperature not crossing
40 °C to furnish 27-28 g of crude compound.
2-tert-Butoxy-carbonyl-amino-N-(2-chloro-6-methyl-
phenyl)-5-thiazolecarboxamide (5): Into a clean and dry 3
L 4-neck round bottom flask connected to a mechanical stirrer,
condenser and thermometer socket is charged with 2-tert-
butoxycarbonylamino-thiazole-5-carboxylic acid chloride (4)
crude (27.5 g) and dichloromethane (750 mL) under stirring.
Cooled the reaction mass to 0-5 °C and add 2-chloro-6-methyl
aniline (22.2 g) to the reaction mass at 0-5 °C within 30-45 min
period. Added DiPEA to the reaction mass at 0-5 °C in 30-45
Light brown colour solid; Elemental analysis C11H10N3OSCl
calcd (found) %: C 49.35 (49.63), H 3.76 (3.54), N 15.69 (15.81),
O 5.98 (6.12), S 11.98 (12.04). IR (KBr, νmax, cm-1): 3284.01-
3378.81, 3110.16, 1627.01, 1612.25, 1538.42-1481.88, 773.58;
1H NMR (400 MHz, DMSO-d6): δ 2.206 (s, 3H, -CH3), 7.209-
7.272 (m, 2H, ArH), 7.361-7.384 (dd, 1H, ArH), 7.616 (s, 2H,