Vol. 25, No. 16 (2013)
Studies on Diastereofacial Selectivity of a Chiral tert-Butanesulfinimines 9347
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3-Methyl 1-(2-chlorophenyl)butylamine (2c): Yield:
44.4 %; 1H NMR (CDCl3): δ 7.46-7.48 (d,1H,J = 7.7Hz), 7.32-
7.34 (d,1H, J = 7.9Hz), 7.25-7.28 (t,1H, J = 7.3 Hz), 7.14-
7.18 (m,1H), 4.45-4.48 (q, 1H, J = 5.8, 8.1Hz), 2.04 (br, s,
2H), 1.52-1.83 (m, 3H), 0.93-0.97 (dd, 6H, J = 6.5,11.4, Hz);
13C NMR (CDCl3): δ 143.51, 132.66, 129.46, 127.72, 127.06,
126.99, 49.84, 46.96, 25.10, 23.16, 21.90; IR (Neat, νmax, cm-1):
2955, 2928, 2869, 1593, 1572, 1468, 1439, 1385, 1367, 1048,
1035, 754, 694; MS (m/z) = 198.3 [M + 1]+.
3-Methyl-1-o-tolyl-butylamine (2d): Yield: 37.8 %; 1H
NMR (CDCl3): δ 7.45-7.47(d,1H,J = 7.57Hz), 7.14-7.22 (m,
3H), 4.30-4.33 (t, 1H, J = 6.4 Hz), 3.95 (br, s, 2H), 2.36 (s,
3H), 1.58-1.71 (m, 3H), 0.90-0.94 (dd, 6H, J = 5.5, 10.9 Hz);
13C NMR (CDCl3): δ 141.50, 134.92, 130.45, 127.03, 126.48,
125.27, 49.08, 46.40, 24.93, 22.96, 22.16, 19.24; IR (Neat,
3-Methyl-1-phenylbutylamine (8b): Yield: 51 %; H
NMR (CDCl3): δ 7.23-7.34 (m,5H), 3.93-3.97 (t, 1H, J =
6.1Hz), 1.96 (br, s, 2H), 1.54-1.59 (m, 3H), 0.91-0.93 (m, 6H);
13C NMR (CDCl3): δ 146.68, 128.50, 126.77, 126.21, 53.98,
48.71, 24.97, 22.54, 22.42; IR (Neat, νmax, cm-1): 2955, 2927,
1655, 1602, 1492, 1466, 1453, 1384, 1366, 757, 700; MS
(m/z) = 164.2 [M + 1]+.
3-Methyl 1-(2-chlorophenyl)butylamine (8c): Yield:
61.6 %; 1H NMR (CDCl3): δ 7.45-7.47 (d,1H,J = 7.0Hz), 7.29-
7.31 (d,1H, J = 7.9Hz), 7.21-7.25 (t,1H, J = 7.3Hz), 7.08-7.19
(m, 1H), 4.43-4.47 (q, 1H, J = 5.9, 8.0Hz), 2.23 (br, s, 2H),
1.51-1.81 (m, 3H), 0.91-0.95 (dd, 6H, J = 6.45,10.75 Hz); 13C
NMR (CDCl3): δ 143.51, 132.67, 129.47, 127.73, 127.06,
126.97, 49.85, 46.96, 25.17, 23.16, 21.90; IR (Neat, νmax, cm-1):
2956, 2929, 1594, 1468, 1438, 1385, 1367, 1035, 754; MS
(m/z) = 198.3 [M + 1]+.
3-Methyl-1-o-tolyl-butylamine (8d): Yield: 40.3 %; 1H
NMR (CDCl3): δ 7.46-7.48(d,1H,J = 7.1Hz), 7.14-7.20
(m,3H), 4.80 (br, s, 2H), 4.34 (br, 1H), 2.37 (s,3H), 1.58-1.71
(m, 3H), 0.90-0.93 (7, 6H, J = 6.3 Hz); 13C NMR (CDCl3): δ
140.53, 135.03, 130.50, 127.23, 126.52, 125.37, 49.15, 45.91,
24.86, 22.84, 22.19, 19.26; IR (Neat, νmax, cm-1): 2957, 2930,
1465, 1385, 1368, 1216, 756; MS (m/z) = 178.3[M + 1]+.
3-Methyl-1-(4-piperidin-1-yl-phenyl)butylamine (8g):
ν
max, cm-1): 2955, 2927, 2868, 1600, 1464, 1384, 1367, 1049,
754, 726; MS (m/z) = 178.3 [M + 1]+.
3-Methyl-1-(4-piperidin-1-yl-phenyl)butylamine (2g):
Yield: 35.5 %; 1H NMR (CDCl3): δ 7.17-7.19 (d, 2H, J = 8.2
Hz), 6.89-6.91 (d, 2H, J = 8.2 Hz), 3.90-3.93 (t, 1H, J = 7.2
Hz), 3.13(br, 4H), 2.78 (br, s, 2H), 2.00 (s, 2H), 1.40-1.51 (m,
9H), 0.87-0.90 (t, 6H, J = 7.5 Hz); 13C NMR (CDCl3): 151.62,
131.68, 127.51(2C), 116.26(2C), 53.17, 50.31(2C), 45.53,
25.70(2C), 24.63, 24.16, 22.84, 21.88; IR (KBr, νmax, cm-1):
2632, 1614, 1577, 1521, 1401, 1238, 1130; MS (m/z) = 247.4
[M + 1]+.
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Yield: 41.5 %; H NMR (CDCl3): δ 7.19-7.21 (d, 2H, J =
8.4Hz), 6.88-6.90 (d, 2H, J = 8.5 Hz), 5.37 (br, 2H), 3.91-
3.95 (t, 1H, J = 7.45 Hz), 3.12-3.15 (t, 4H, J = 5.3Hz), 1.86 (s,
2H), 1.43-1.86 (m, 9H), 0.85-0.89 (dd, 6H, J = 6.7,9.1Hz);
13C NMR (CDCl3): 151.69, 130.70, 127.67(2C), 116.21(2C),
53.10, 50.26(2C), 44.97, 25.68(2C), 24.53, 24.16, 22.93,
21.71; IR (KBr, νmax, cm-1): 2931, 1614, 1577, 1521, 1401,
1238, 1130; MS (m/z) = 247.4 [M + 1]+; MR: 148.6-152.1 ºC.
(S)-3-Methyl-1-(2-piperidin-1-yl-phenyl)butylamine
(2a) (from 10):Yield: 58.3 %; 1H NMR (CDCl3): δ 7.33-7.35
(m, 1H), 7.09-7.22 (m, 3H), 4.47-4.50 (t, 1H, J = 6.8 Hz),
2.80-2.86 (m, 4H), 1.71-1.75 (m, 4H), 1.50-1.64 (m, 7H), 0.94-
0.97 (t, 6H, J = 6.4 Hz); 13C NMR (CDCl3): δ 152.17, 142.82,
127.02, 126.26, 124.33, 120.87, 54.86, 48.58(2C), 47.55, 26.59
(2C), 25.27, 24.21, 23.12, 22.35; IR (Neat, νmax, cm-1): 2933,
2866, 2796, 1597, 1487, 1466, 1449, 1381, 1220, 921, 752;
MS (m/z) = 247.5 [M + 1]+; SOR (C = 1 % in methanol at
20 ºC): +4.5º.
(R)-3-Methyl-1-(2-piperidin-1-yl-phenyl)butylamine
(8a) (from 10):Yield: 35.6 %; 1H NMR (CDCl3): δ 7.33-7.35
(m, 1H), 7.08-7.20 (m, 3H), 4.46-4.49 (t, 1H, J = 6.8 Hz),
2.80-2.86 (m, 4H), 1.71-1.73 (m, 4H), 1.50-1.70 (m,7H), 0.93-
0.96 (t,6H,J = 6.3Hz); 13C NMR (CDCl3): δ 152.19, 142.78,
127.03, 126.27, 124.34, 120.90, 54.86, 48.53(2C), 47.58,
26.58(2C), 25.27, 24.20, 23.10, 22.34; IR (Neat, νmax, cm-1):
2934, 2866, 2798, 1597, 1487, 1466, 1449, 1381, 1220, 921,
752; MS (m/z) = 247.5 [M + 1]+; SOR (C = 1 % in methanol
at 20°C): - 8.0º.
General procedure for the reaction of organolithium
reagents with sulfinimines: Added slowly of 1-bromo-2-
methylpropane (6 eq.) in diethyl ether to lithium metal (9.0
eq.) in diethyl ether at -10 to -15 ºC over the period of 1 h.
Stirred for 1 h to get clear solution. Cooled the mass further to
-45 to -60 ºC and added slowly sulfinimines (5a-g) (1.0 eq) in
THF at- 45 to -60 ºC. The mixture was stirred for 1 h.
The above reaction mass was quenched in to 15 % HCl
solution and stirred for 1 h at room temperature. Separated
the organic layer and washed with toluene. The aqueous layer
was basified and extracted in toluene. The organic extracts
were washed with water, concentrated and purified through
column chromatography.
Preparation of repaglinide
Synthesis of (S)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-
3-methyl-1-butyl}aminocarbonylmethyl]benzoic acid
ethyl ester (14): To a stirred solution of 2.25 g of 3-ethoxy-4-
ethoxycarbonyl phenylacetic acid (13) (8.92 mmol) and 2.5 g
of N-methyl morpholine (24.33 mmol) in 20 mL of MDC at
0-5 ºC, was added 1.12 g of pivaloyl chloride (9.32 mmol)
slowly at below 5 ºC. After 1.0 h stirring, 2.0 g amine 2a (8.11
mmol) in 10.0 mL of MDC was added slowly at 0-5 ºC.
Warmed the mass to room temperature and stirred for 15.0 h.
Quenched the reaction by adding water and separated the
organic layer. The organic later was washed with 5 % HCl
solution, 5 % NaOH solution and water. Concentrated the
organic layer gave 3.5 g of 14 was obtained in 89.6 % yield as
off white solid.
(R)-3-Methyl-1-(2-piperidin-1-yl-phenyl)butylamine
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(8a): Yield: 55.6 %; H NMR (CDCl3): δ 7.33-7.35 (m,2H),
7.09-7.21 (m, 3H), 4.46-4.50 (t,6H,J = 6.9Hz), 2.80-2.86 (m,
4H), 1.71-1.73 (m, 4H), 1.50-1.61 (m, 5H), 0.93-0.96 (t, 6H,
J = 6.3Hz); 13C NMR (CDCl3): δ 152.18, 142.86, 127.01,
126.25, 124.32, 120.87, 54.86, 48.58(2C), 47.55, 26.57(2C),
25.27, 24.20, 23.11, 22.34; IR (Neat, νmax, neat, cm-1): 2933,
2866, 2796, 1597, 1487, 1466, 1449, 1381, 1220, 922, 753;
MS (m/z) = 247.5 [M + H]+; SOR (1 % in methanol at 20 ºC):
- 4.2º.
1H NMR (CDCl3): δ 7.73-7.75(d,1H,J = 7.76Hz), 7.17-
7.26(m, 2H), 7.02-7.08(m, 2H), 6.82-6.84 (d, 1H, J = 10.0