Month 2013
Synthesis of Azilsartan and Its Selected Potential Impurities
1H, Ar), 7.37 (dd, J = 7.6, 1.2 Hz, 1H, Ar), 7.35–7.31 (m, 1H, Ar),
7.31 (d, J = 8.4 Hz, 2H, Ar), 7.12 (t, J = 7.9 Hz, 1H, Ar), 7.07
(d, J = 8.4 Hz, 2H, Ar), 5.69 (s, 2H, N–CH2–Ar), 4.67 (q,
J = 7.1 Hz, 2H, OCH2CH3), 1.48 (t, J = 7.1 Hz, 3H, OCH2CH3).
13C NMR (CDCl3) d(ppm): 170.67, 158.60, 145.30, 141.72,
138.16, 136.85, 133.38, 132.87, 131.20, 129.79, 128.88,
127.48, 126.99, 123.99, 121.71, 120.95, 118.78, 117.27,
111.01, 66.78, 47.02, 14.65. IR: n(C–H) 2987, n(CꢁN) 2227,
n(C═O) 1702, n(C═C) + n(C═N) 1609, 1547, n(C–O) 1281,
1250, 1144 cmꢂ1. Anal. Calcd for C24H19N3O3: C, 72.53; H,
4.82; N, 10.57. Found: C, 72.11; H, 4.99; N, 10.33.
30 min, the insoluble portion was filtered off and washed with water
providing, after drying, 10.6 g of white precipitate containing
according to HPLC 91.5% 3a. The solid was crystallized from
2-propanol to give 8.0 g (75%) of white crystals; mp 203–206 ꢀC
(ref. [5] mp 207–209 ꢀC). HPLC purity 97.5%. HRMS for
C25H25N4O4 (M + H)+ Calcd: 445.1876, found: 445.1992. 1H NMR
(DMSO) d(ppm): 9.18 (s, 1H, OH), 7.70 (dd, J=7.9, 1.2Hz, 1H,
Ar), 7.46 (dd, J= 7.9, 1.2 Hz, 1H, Ar), 7.45–7.33 (m, 3H, Ar), 7.35
(d, J= 8.3 Hz, 2H, Ar), 7.29 (dd, J= 7.6, 1.5 Hz, 1H, Ar), 7.19 (t,
J= 7.9 Hz, 1H, Ar), 6.94 (d, J= 8.3 Hz, 2H, Ar), 5.55 (bs, 2H, NH2),
5.51 (s, 2H, N–CH2–Ar), 4.62 (q, J= 7.1 Hz, 2H, OCH2CH3), 3.71
(s, 3H, OCH3), 1.42 (t, J= 7.1 Hz, 3H, OCH2CH3). 13C NMR
(DMSO) d(ppm): 166.22, 158.33, 151.96, 141.63, 139.85, 139.74,
135.54, 133.20, 130.83, 130.02, 129.85, 128.85, 128.52, 126.90,
125.92, 122.85, 121.55, 120.81, 115.56, 66.62, 52.32, 46.29, 14.40.
Anal. Calcd for C25H24N4O4: C, 67.55; H, 5.44; N, 12.60. Found:
C, 67.27; H, 5.72; N, 12.87.
Benzyl 1-((20-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1H-benzo
[d]imidazole-7-carboxylate (3c).
A mixture of 13 (4.0 g,
10mmol), benzyl bromide (2.0g, 11.7 mmol), K2CO3 (10 g,
72mmol), and 2-butanone (100mL) was refluxed for 4 h. The
mixture was evaporated, diluted with water (150 mL), and
extracted with dichloromethane. The extract was washed with
water and dried with MgSO4. The residue after evaporation was
crystallized from acetonitrile to give 3.5g (72%) of white crystals
of 3c; mp 111–114 ꢀC. HPLC purity 99.3%. HRMS for
C31H26N3O3 (M+ H)+ Calcd: 488. 1974, found: 488.1895. 1H
NMR (DMSO) d(ppm): 7.92 (dd, J = 7.6, 1.5Hz, 1H, Ar), 7.75
(ddd, J = 7.6, 1.5 Hz, 1H, Ar), 7.72 (dd, J = 7.9, 1.2 Hz, 1H, Ar),
7.56 (ddd, J= 7.6, 1.2 Hz, 1H, Ar), 7.51 (dd, J= 7.9, 1.2 Hz, 1H,
Ar), 7.51–7.48 (m, 1H, Ar), 7.46 (d, J= 8.4 Hz, 2H, Ar), 7.38–7.27
(m, 5H, Ar), 7.20 (t, J = 7.9 Hz, 1H, Ar), 7.05 (d, J = 8.4 Hz, 2H,
Ar), 5.60 (s, 2H, N–CH2–Ar), 5.24 (s, 2H, COOCH2-Ph), 4.62
(q, J= 7.1 Hz, 2H, OCH2CH3), 1.41 (t, J= 7.1 Hz, 3H, OCH2CH3).
13C NMR (DMSO) d(ppm): 165.44, 158.31, 143.89, 141.68,
137.62, 136.67, 135.69, 133.83, 133.44, 130.95, 129.98, 128.91,
128.42, 128.17, 128.14, 128.12, 126.61, 123.01, 121.79, 120.91,
118.44, 115.38, 110.02, 66.67, 66.55, 46.32, 14.35. Anal. Calcd for
C31H25N3O3: C, 76.37; H, 5.17; N, 8.62. Found: C, 76.12; H, 5.33;
N, 8.29.
Ethyl 2-ethoxy-1-((20-(N0-hydroxycarbamimidoyl)biphenyl-4-
yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (4b). Using the
procedure described for the synthesis of 4a starting from ethyl
ester 3b, 85% yield of 4b was obtained; mp 209–211 ꢀC
(2-propanol). HPLC purity 98.0%. HRMS for C26H27N4O4
1
(M+ H)+ Calcd: 459.2032, found: 459.2189. H NMR (DMSO)
d(ppm): 9.22 (s, 1H, OH), 7.74 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.56
(dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.44–7.31 (m, 3H, Ar), 7.28 (d,
J = 8.3Hz, 2H, Ar), 7.20 (dd, J = 7.6, 1.5 Hz, 1H, Ar), 7.02 (t,
J = 7.9Hz, 1H, Ar), 6.98 (d, J = 8.3 Hz, 2H, Ar), 6.54 (bs, 2H,
NH2), 5.66 (s, 2H, N–CH2–Ar), 4.68 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.24 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.52
(t, J = 7.1 Hz, 3H, OCH2CH3), 1.27 (t, J = 7.1 Hz, 3H, OCH2CH3).
13C NMR (DMSO) d(ppm): 166.22, 158.33, 151.96, 141.63,
139.85, 139.74, 135.54, 133.20, 130.83, 130.02, 129.85, 128.85,
128.52, 126.90, 125.92, 122.85, 121.55, 120.81, 115.56, 66.62,
52.32, 46.29, 14.40, 14.10. IR: n(N–H) 3515, 3407, n(O–H)
3254, n(C–H) 2986, n(C═O) 1703, n(C═C) + n(C═N) 1634,
1611, 1545, n(C–O) 1284, 1256, 1136 cmꢂ1. Anal. Calcd for
C26H26N4O4: C, 68.11; H, 5.72; N, 12.22. Found: C, 67.78; H,
5.88; N, 12.54.
Benzhydryl 1-((20-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1H-
benzo[d]imidazole-7-carboxylate (3d).
A mixture of 13
(0.8 g, 2 mmol), benzhydryl bromide (0.55 g, 2.2 mmol), K2CO3
(2 g, 15 mmol), and 2-butanone (20 mL) was refluxed for 10 h
and then stirred without heating overnight. The mixture was
evaporated, diluted with water (50 mL), and extracted with
dichloromethane. The extract was washed with water and dried
with MgSO4. The residue after evaporation (1.25 g) was
crystallized from isopropyl acetate to give 1.05 g (93%) of white
crystals of 3d; mp 138–140 ꢀC. HPLC purity 98.7%. HRMS for
C37H30N3O3 (M + H)+ Calcd: 564.2287, found: 564.3735. 1H
NMR (DMSO) d(ppm): 7.91 (dd, J = 7.8, 1.4 Hz, 1H, Ar), 7.74
(dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.76–7.70 (m, 2H, Ar), 7.55
(dd, J = 7.6, 1.2 Hz, 1H, Ar), 7.49–7.44 (m, 4H, Ar), 7.36–7.29
(m, 7H, Ar), 7.29–23 (m, 3H, Ar), 7.02 (s, 1H, COOCHPh2),
6.96 (d, J = 8.5 Hz, 2H, Ar), 5.55 (s, 2H, N–CH2–Ar), 4.62
(q, J = 7.1 Hz, 2H, OCH2CH3), 1.41 (t, J = 7.1 Hz, 3H,
OCH2CH3). 13C NMR (DMSO) d(ppm): 164.50, 158.34,
143.79, 141.76, 140.21, 137.41, 136.62, 133.81, 133.39,
131.17, 129.94, 128.85, 128.56, 128.15, 127.81, 126.80,
126.55, 123.14, 122.09, 121.07, 118.41, 115.18, 109.93, 77.45,
66.70, 46.21, 14.35. Anal. Calcd for C37H29N3O3: C, 78.84; H,
5.19; N, 7.46. Found: C, 78.57; H, 5.39; N, 7.11.
Benzyl 2-ethoxy-1-((20-(N0-hydroxycarbamimidoyl)biphenyl-
4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (4c). Using
the procedure described for the synthesis of 4a starting from
benzyl ester 3c, 82% yield of 4c was obtained; mp
171–173 ꢀC (2-propanol). HPLC purity 96.8%. HRMS for
C31H29N4O4 (M + H)+ Calcd: 521.2189, found: 521.2157. 1H
NMR (DMSO) d(ppm): 9.19 (bs, 1H, OH), 7.69 (dd, J = 7.9,
1.2 Hz, 1H, Ar), 7.46 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.45–7.32
(m, 3H, Ar), 7.35 (d, J = 8.4 Hz, 2H, Ar), 7.27 (dd, J = 7.6, 1.5 Hz,
1H, Ar), 7.19 (t, J = 7.9Hz, 1H, Ar), 6.93 (d, J = 8.4 Hz, 2H, Ar),
5.55 (bs, 2H, NH2), 5.53 (s, 2H, N–CH2–Ar), 4.62 (q, J = 7.1 Hz,
2H, OCH2CH3), ), 4.22 (q, J = 7.1 Hz, 2H, COOCH2CH3),
1.42 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.18 (t, J = 7.1 Hz, 3H,
COOCH2CH3). 13C NMR (DMSO) d(ppm): 165.74, 158.26,
151.94, 141.59, 139.83, 139.78, 135.54, 133.18, 130.77, 130.03,
129.82, 128.86, 128.54, 126.91, 125.91, 122.84, 121.48, 120.78,
115.89, 66.62, 61.05, 46.20, 14.41, 13.93. Anal. Calcd for
C31H28N4O4: C, 71.52; H, 5.42; N, 10.76. Found: C, 71.27; H,
5.55; N, 10.93.
Methyl 2-ethoxy-1-((20-(N0-hydroxycarbamimidoyl)biphenyl-
4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (4a). A mixture
of 3a (10 g, 2.4 mmol), DMSO (75 mL), and 50% aqueous
hydroxylamine (5 mL) was stirred at 90 ꢀC for 18 h. Then the
mixture was poured into water (250 mL), the mixture was stirred for
Benzhydryl 2-ethoxy-1-((20-(N0-hydroxycarbamimidoyl)
biphe-nyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate
(4d). Using the procedure described for the synthesis of 4a
starting from benzyl ester 3d, 64% yield of 4d was obtained;
mp 234–237 ꢀC (isopropyl acetate). HPLC purity 97.3%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet