14
A.M. Macan et al. / European Journal of Medicinal Chemistry 184 (2019) 111739
general procedure using compound 6 (250 mg; 0.656 mmol); 1 M
CuSO4 (0.2 ml); Cu (34 mg; 0.535 mmol); 3-butyne-1-ol (0.06 ml;
0.787 mmol); tert-butanol (3 ml); DMF (3 ml) and H2O (3 ml).
Compound 8p (155.3 mg; 53%; m.p. ¼105e107 ꢄC) was isolated as
white powder.
4.1.2.17.2. Method B. Compound 8p was synthesized following
general procedure using compound 4 (200 mg; 0.392 mmol); NaN3
(63.8 mg; 0.98 mmol); 1 M CuSO4 (0.12 ml); Cu (20 mg;
0.32 mmol); 3-butyne-1-ol (0.04 ml; 0.470 mmol); DMF (7 ml) and
H2O (3 ml). Compound 8p (60 mg; 34%) was isolated as white
J ¼ 8.6 Hz, 2H, Ph’), 7.61 (d, J ¼ 8.6 Hz, 2H, Ph’), 7.45e7.22 (m, 10H,
CH2Ph), 5.63 (d, J ¼ 7.1 Hz, 1H, OH), 5.21 (dd, J ¼ 22.0 Hz, 11.7 Hz, 2H,
CH2Ph), 5.03e4.91 (m, 2H, CH2Ph), 4.88 (d, J ¼ 1.1 Hz, 1H, H-4), 4.56
(dd, J ¼ 13.8 Hz, 3.9 Hz, 1H, H-6), 4.32 (dd, J ¼ 13.8 Hz, 9.3 Hz, 1H, H-
6), 4.15e4.06 (m, 1H, H-5), 4.04 (d, J ¼ 5.4 Hz, 2H, CH2NH) ppm. 13
C
NMR (75 MHz, DMSO) d 169.1 (C-1), 157.4 (C-3), 143.1 (C-8), 139.4
(Ph-q), 137.4 (Ph-q), 136.2 (Ph-q), 135.6 (Ph-q), 129.3 ꢀ 128.0 (Ph),
124.5 (C-7), 121.0 (C-2), 75.6 (C-4), 73.8 (CH2Ph), 73.0 (CH2Ph), 67.5
(C-5), 52.2 (C-6), 38.1 (CH2NH) ppm. Calcd for C29H27ClN4O7S: C,
57.00; H, 4.45; N, 9.17. Found: C, 57.16; H, 4.47; N, 9.19.
powder.
HRMS
(ESI
Q-TOF):
calcd.
For
C24H25N3O6
[MþH] ¼ 452.1822; found ¼ 452.1836. 1H NMR (300 MHz, DMSO)
4.1.2.20. Preparation of 2,3-O,O-dibenzyl-6-[(4-(2-chloro-4-
fluorobenzenesulfonamide)methyl-1,2,3-triazol-1-yl]-6-deoxy-L-
ascorbic acid (8s)
d
7.87 (s, 1H, H-7), 7.56e7.19 (m, 10H, CH2Ph), 5.64 (d, J ¼ 6.9 Hz, 1H,
OH), 5.22 (dd, J ¼ 23.3 Hz, 11.7 Hz, 2H, CH2Ph), 5.04 ꢀ 4.96 (m, 2H,
CH2Ph), 4.93 (d, J ¼ 1.3 Hz, 1H, H-4), 4.63 (t, J ¼ 5.3 Hz, 1H, OH),
4.61 ꢀ4.55 (m, 1H, H-6), 4.35 (dd, J ¼ 13.7 Hz, 9.3 Hz, 1H, H-6),
4.19e4.08 (m, 1H, H-5), 3.62 (dd, J ¼ 12.3 Hz, 6.9 Hz, 2H, H-20), 2.76
4.1.2.20.1. Method A. Compound 8s was synthesized following
general procedure using compound 6 (250 mg; 0.650 mmol); 1 M
CuSO4 (0.20 ml); Cu (34 mg; 0.530 mmol); 2-chloro-4-fluoro-N-(2-
propynyl)benzenesulfonamide (194.8 mg; 0.787 mmol); tert-
butanol (3 ml); DMF (3 ml) and H2O (3 ml). Compound 8s
(239.5 mg; 59%; m.p. ¼120e121 ꢄC) was isolated as white powder.
4.1.2.20.2. Method B. Compound 8s was synthesized following
general procedure using compound 4 (154.3 mg; 0.302 mmol);
NaN3 (49.1 mg; 0.755 mmol); 1 M CuSO4 (0.1 ml); Cu (15.7 mg;
0.247 mmol); 2-chloro-4-fluoro-N-(2-propynyl)benzenesulfona-
mide (89.9 mg; 0.363 mmol); DMF (7 ml) and H2O (3 ml). Com-
pound 8s (38.2 mg; 20%) was isolated as white powder. 1H NMR
(t, J ¼ 7.0 Hz, 2H, H-10) ppm. 13C NMR (151 MHz, DMSO)
d 169.0 (C-
1), 157.2 (C-3), 144.0 (C-8), 136.1 (Ph-q), 135.6 (Ph-q), 128.7 ꢀ 127.8
(Ph), 123.4 (C-7), 121.0 (C-2), 75.6 (C-4), 73.6 (CH2Ph), 72.8 (CH2Ph),
67.4 (C-5), 60.4 (C-20), 52.1 (C-6), 29.1 (C-10) ppm.
4.1.2.18. Preparation of 2,3-O,O-dibenzyl-6-deoxy-6-[(4-(4-
methylbenzenesulfonamide)methyl-1,2,3-triazol-1-yl]-L-ascorbic
acid (8q)
4.1.2.18.1. Method A. Compound 8q was synthesized following
general procedure using compound 6 (250 mg; 0.650 mmol); 1 M
CuSO4 (0.20 ml); Cu (34 mg; 0.530 mmol); 4-methyl-N-(2-
propynyl)benzenesulfonamide (164.6 mg; 0.790 mmol); tert-
butanol (3 ml); DMF (3 ml) and H2O (3 ml). Compound 8q (196 mg;
51%; mp ¼ 116e118 ꢄC) was isolated as white powder.
(600 MHz, DMSO)
d
8.42 (bs,1H, NH), 7.95 (dd, J ¼ 8.9 Hz, 6.0 Hz,1H,
Ph’), 7.86 (s, 1H, H-7), 7.56 (dd, J ¼ 8.7 Hz, 2.5 Hz, 1H, Ph’), 7.45e7.29
(m, 11H, CH2Ph, Ph’), 5.65 (d, J ¼ 7.1 Hz, 1H, OH), 5.22 (dd,
J ¼ 34.6 Hz,11.6 Hz, 2H, CH2Ph), 4.99 (q, J ¼ 11.2 Hz, 2H, CH2Ph), 4.87
(d, J ¼ 1.3 Hz, 1H, H-4), 4.55 (dd, J ¼ 13.8 Hz, 4.0 Hz, 1H, H-6), 4.32
(dd, J ¼ 13.8 Hz, 9.2 Hz, 1H, H-6), 4.16 (s, 2H, CH2NH), 4.10e4.04 (m,
4.1.2.18.2. Method B. Compound 8q was synthesized following
general procedure using compound 4 (250 mg; 0.490 mmol); NaN3
(79.7 mg; 1.226 mmol); 1 M CuSO4 s(0.15 ml); Cu (25.5 mg;
1H, H-5) ppm. 13C NMR (75 MHz, DMSO)
d 169.0 (C-1), 165.3; 161.9
(d, JCF ¼ 254.1 Hz, Ph-40), 157.2 (C-3), 143.0 (C-8), 136.1 (Ph-q), 135.5
(Ph-q), 134.8; 134.7 (d, JCF ¼ 3.7 Hz, Ph-10), 132.7 (d, JCF ¼ 10.0 Hz,
Ph-20), 132.6; 132.39 (d, JCF ¼ 11.5 Hz, Ph-60), 128.7 ꢀ 127.9 (Ph),
124.2 (C-7), 120.9 (C-2), 119.1; 118.8 (d, JCF ¼ 26.0 Hz, Ph’), 114.7;
114.4 (d, JCF ¼ 21.7 Hz, Ph’), 75.5 (C-4), 73.7 (CH2Ph), 72.8 (CH2Ph),
67.4 (C-5), 52.0 (C-6), 37.8 (CH2NH) ppm. Calcd for C29H26ClFN4O7S:
C, 55.37; H, 4.17; N, 8.91. Found: C, 55.48; H, 4.16; N, 8.90.
0.401 mmol);
4-methyl-N-(2-propynyl)benzenesulphonamide
(125.5 mg; 0.588 mmol); DMF (7 ml) and H2O (3 ml). Compound 8q
(52.8 mg; 18%) was isolated as white powder. 1H NMR (300 MHz,
DMSO)
d
8.01 (bs, 1H, NH), 7.86 (s, 1H, H-7), 7.67 (d, J ¼ 8.2 Hz, 2H,
Ph’), 7.48e7.19 (m, 12H, CH2Ph, Ph’), 5.65 (d, J ¼ 7.0 Hz, 1 H, OH),
5.22 (q, J ¼ 11,6 Hz, 2H, CH2Ph), 5.04e4.94 (m, 2H, CH2Ph), 4.89 (d,
J ¼ 1.3 Hz, 1H, H-4), 4.57 (dd, J ¼ 13.7 Hz, 4.0 Hz, 1H, H-6), 4.34 (dd,
J ¼ 13.8, 9.3 Hz, 1H, H-6), 4.16e4.06 (m, 1H, H-5), 4.00 (d, J ¼ 4.1 Hz,
2H, CH2NH), 2.36 (s, 3H, CH3’) ppm. 13C NMR (151 MHz, DMSO)
4.1.2.21. Preparation of 2,3-O,O-dibenzyl-6-deoxy-6-[(4-(4-
fluorobenzenesulfonamide)methyl-1,2,3-triazol-1-yl]-L-ascorbic acid
(8t)
d
169.3 (C-1), 157.4 (C-3), 143.5 (Ph-q), 143.0 (C-8), 137.5 (Ph-q),
136.2 (Ph-q),135.7 (Ph-q),129.8e126.8 (Ph),124.4 (C-7),121.1 (C-2),
75.7 (C-4), 73.9 (CH2Ph), 73.0 (CH2Ph), 67.5 (C-5), 52.3 (C-6), 38.2
(CH2NH), 21.1 (CH3’) ppm. Calcd for C30H30N4O7S: C, 61.01; H, 5.12;
N, 9.49. Found: C, 61.20; H, 5.14; N, 9.50.
4.1.2.21.1. Method A. Compound 8t was synthesized following
general procedure using compound 6 (100 mg; 0.461 mmol); 1 M
CuSO4 (0.08 ml); Cu (20 mg; 0.315 mmol); 4-fluoro-N-(2-propynyl)
benzenesulfonamide (81.9 mg; 0.384 mmol); tert-butanol (3 ml);
DMF (3 ml) and H2O (3 ml). Compound 8t (62 mg; 38%;
m.p. ¼128e130 ꢄC) was isolated as white powder.
4 .1. 2 .19 . P r e p a ra t i o n o f 2 , 3 - O , O - d i b e n z yl - 6 - [ ( 4 - ( 4 -
chlorobenzenesulfonamide)methyl-1,2,3-triazol-1-yl]-6-deoxy-L-
ascorbic acid (8r)
4.1.2.21.2. Method B. Compound 8t was synthesized following
general procedure using compound 4 (300 mg; 0.588 mmol); NaN3
(95.7 mg; 1.470 mmol); CuSO4 1 M (0.18 ml); Cu (30.56 mg;
4.1.2.19.1. Method A. Compound 8r was synthesized following
general procedure using compound 6 (190 mg; 0.500 mmol); 1 M
CuSO4 (0.20 ml); Cu (29.1 mg; 0.458 mmol); 4-chloro-N-(2-
propynyl)benzenesulfonamide (137.5 mg; 0.600 mmol); tert-
butanol (3 ml); DMF (3 ml) and H2O (3 ml). Compound 8r (154 mg;
51%; mp ¼ 123e124 ꢄC) was isolated as white powder.
0.481 mmol);
4-fluoro-N-(2-propynyl)benzenesulphonamide
(150.3 mg; 0.705 mmol); DMF (7 ml) and H2O (3 ml). Compound 8t
(115 mg; 33%) was isolated as white powder. 1H NMR (600 MHz,
DMSO)
d 8.17 (bs, 1H, NH), 7.91 (s, 1H, H-7), 7.84e7.78 (m, 2H, Ph’),
7.47e7.27 (m, 12H, CH2Ph, Ph’), 5.66 (d, J ¼ 7.1 Hz, 1H, OH),
5.34e5.13 (m, 2H, CH2Ph), 4.99 (q, J ¼ 11.1 Hz, 2H, CH2Ph), 4.90 (d,
J ¼ 1.3 Hz, 1H, H-4), 4.58 (dd, J ¼ 13.8 Hz, 3.8 Hz, 1H, H-6), 4.34 (dd,
J ¼ 13.8 Hz, 9.4 Hz, 1H, H-6), 4.10 (dd, J ¼ 10.4 Hz, 8.6 Hz, 1H, H-5),
4.1.2.19.2. Method B. Compound 8r was synthesized following
general procedure using compound 4 (250 mg; 0.490 mmol); NaN3
(79.7 mg; 1.226 mmol); 1 M CuSO4 (0.15 ml); Cu (25.5 mg;
0.401 mmol);
4-chloro-N-(2-propynyl)benzenesulfonamide
4.05 (s, 2H, CH2NH) ppm. 13C NMR (151 MHz, DMSO)
d 167.0 (C-1),
(137.7 mg; 0.601 mmol); DMF (7 ml) and H2O (3 ml). Compound 8r
164.8; 164.2 (d, JCF ¼ 250.7 Hz, Ph-40), 157.1 (C-3), 143.0 (C-8), 136.8;
136.7 (d, JCF ¼ 2.6 Hz, Ph-10), 136.1 (Ph-q), 135.5 (Ph-q),
129.6 ꢀ 127.8 (Ph), 124.2 (C-7), 120.9 (C-2), 116.2; 116.1 (d,
(70 mg; 23%) was isolated as white powder. 1H NMR (300 MHz,
DMSO)
d
8.21 (t, J ¼ 5.1 Hz, 1H, NH), 7.89 (s, 1H, H-7), 7.75 (d,