3254
M. Seki
PAPER
5.19 (d, J = 1.2 Hz, 2 H), 4.76 (s, 2 H), 3.81 (d, J = 13.6 Hz, 1 H),
3.55 (d, J = 13.6 Hz, 1 H), 3.01 (d, J = 6.0 Hz, 1 H), 1.98–1.93 (m,
1 H), 0.95–0.92 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 174.8, 154.5, 141.3, 140.0, 137.3,
135.6, 132.9, 131.4, 131.1, 130.1, 128.5, 128.4, 128.4, 128.3, 127.6,
127.5, 122.5, 66.5, 66.2, 51.7, 50.6, 31.5, 19.2, 18.4.
13C NMR (100 MHz, DMSO-d6): δ (mixture of rotomers) = 173.9,
173.8, 172.4, 167.4, 159.2, 140.9, 139.9, 139.1, 137.2, 132.2, 132.0,
131.0, 130.7, 129.7, 129.4, 129.1, 128.8, 127.4, 126.8, 126.1, 79.6,
67.9, 63.4, 49.0, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.3, 38.5, 33.0,
32.9, 30.2, 28.8, 27.5, 23.7, 22.8, 22.3, 22.1, 20.6, 19.9, 19.2, 14.3,
14.2, 11.2.
MS: m/z = 436 [M + H]+.
MS: m/z = 532 [M + H]+.
HPLC conditions: Inertsil C-18 column (5 μm × 4.6 mm × 150
mm); mobile phase: H2O–MeCN–AcOH, 500:500:1; flow rate: 1
mL/min; injection volume: 10 μL; column oven temperature: 40 °C.
HRMS: m/z [M + Na]+ calcd for C33H33N5O2Na: 554.2532; found:
554.2536.
Benzyl N-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-
yl]methyl}-N-pentanoyl-L-valinate (N-benzylvalsartan Benzyl
Ester, 1c)
1-(Cyclohexyloxycarbonyloxy)ethyl 2-Ethoxy-1-{[2′-(1H-tetra-
zol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-benzimidazole-7-car-
boxylate (Candesartan Cilexetil, 2d)
Into a 25-mL two-neck flask were sequentially added amine 8 (0.4
g, 0.75 mmol), DIPEA (0.44 mL, 2.65 mmol) and toluene (4 mL)
under nitrogen atmosphere at 25 °C. The reaction mixture was
cooled to 0–5 °C and stirred for 0.5 h. Valeroyl chloride (0.18 g, 1.5
mmol) was added dropwise and the reaction mixture was stirred for
10 min, then warmed to r.t. and stirred until completion (2 h). The
reaction mixture was cooled to –10 °C and quenched with H2O (2
mL), and then stirred for 1 h at r.t. The two layers were separated
and the organic layer was washed sequentially with H2O (2 × 10
mL), 0.2 N aq NaOH (2 × 10 mL), H2O (2 × 10 mL) and brine (10
mL). The organic layer was concentrated under reduced pressure
and the crude product was purified using column chromatography
(20–22% EtOAc in hexane) to give 1c as a viscous oil; yield: 0.38
g (83%).
Into a 5-mL one-neck flask were sequentially added 1d2d (0.1 g,
0.14 mmol), ammonium formate (0.044 g, 0.69 mmol), 5% Pd/BaSO4
(0.0152 g, 5 mol%), i-PrOH (1 mL) and H2O (0.6 mL) at 25 °C. Af-
ter completion of the reaction (14 h), EtOAc (10 mL) was added to
the mixture. The mixture was filtered through Celite®, the filtrate
was concentrated and the residue was purified by silica gel column
chromatography (hexane–EtOAc, 15:85) to give 2d as a colorless
solid; yield: 0.068 g (80%); mp 161.8 °C.
IR (KBr): 1753 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.08–8.06 (m, 1 H), 7.63–7.53 (m,
2 H), 7.53–7.48 (m, 1 H), 7.35–7.28 (m, 1 H), 7.05–6.93 (m, 2 H),
6.92–6.85 (m, 2 H), 6.72–6.70 (m, 2 H), 6.70–6.65 (m, 1 H), 5.70–
5.55 (m, 2 H), 4.45–4.40 (m, 2 H), 4.30–4.15 (m, 1 H), 1.85–1.72
(m, 2 H), 1.68–1.55 (m, 2 H), 1.49–1.14 (m, 12 H).
13C NMR (100 MHz, CDCl3): δ = 163.5, 158.2, 152.5, 140.1, 138.0,
137.0, 131.3, 131.1, 130.6, 129.4, 128.3, 125.6, 124.3, 121.2, 115.1,
92.0, 67.5, 47.0, 31.3, 31.2, 25.0, 23.5, 19.3, 14.6.
IR (KBr): 2961, 1739, 1652, 1467, 1407, 1262, 1188, 1003, 759,
665 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of rotomers) = 7.80–6.90
(m, 16 H), 6.80–6.70 (m, 2 H), 5.11 (d, J = 7.6 Hz, 0.4 H), 5.03 (s,
1 H), 4.84 (q, J = 13.2 Hz, 1.6 H), 4.64 (d, J = 7.0 Hz, 0.8 H), 4.45
(d, J = 9.8 Hz, 0.7 H), 4.27 (d, J = 10.5 Hz, 0.7 H), 2.60–2.55 (m, 1
H), 2.30–2.08 (m, 2 H), 1.54–1.39 (m, 2 H), 1.28–1.11 (m, 3 H),
0.92 (d, J = 6.5 Hz, 2 H), 0.87–0.83 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ (mixture of rotomers) = 174.3,
138.6, 137.6, 135.5, 131.5, 131.3, 130.2, 128.9, 128.8, 128.5, 128.2,
127.9, 126.8, 122.8, 77.5, 77.2, 77.0, 76.6, 66.9, 66.5, 62.7, 50.8,
48.9, 45.6, 33.4, 28.3, 27.9, 27.4, 22.4, 20.0, 18.9, 14.0, 13.8.
MS: m/z = 611 [M + H]+.
HPLC conditions: Cadenza CD-C-18 (3 μm × 4.6 mm × 180 mm);
mobile phase A: 0.03 M KH2PO4–MeCN, 95:5; mobile phase B:
MeCN–H2O, 90:10; gradient program (% B/time): 50/0, 50/5,
90/15, 90/20, 50/30, 90/35; flow rate: 1.0 mL/min; injection vol-
ume: 10 μL; column oven temperature: 40 °C.
3-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-
2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (N-Benzylirbesar-
tan, 1e)
MS: m/z = 638 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C38H41N5O3Na: 638.3107; found:
Into a 25-mL two-neck flask were sequentially added 9 (0.2 g, 0.87
mmol), bromide 3 (0.39 g, 0.95 mmol), K2CO3 (0.2 g, 1.47 mmol)
and MeCN (5.0 mL) under nitrogen atmosphere at 25 °C. The reac-
tion mixture was heated at 80–85 °C for 20 h. After reaction com-
pletion, the mixture was cooled to 25 °C, then filtered through a
sintered funnel and washed with MeCN (5 mL). The filtrate was
concentrated under reduced pressure and purified using column
chromatography (MeOH–CH2Cl2, 1:99) to give 1e as a viscous oil;
yield: 0.216 g (48%).
638.3104.
N-Pentanoyl-N-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]meth-
yl}-L-valine (Valsartan, 2c)
Into a 5-mL one-neck flask were sequentially added 1c (0.1 g, 0.16
mmol), ammonium formate (0.1 g, 1.58 mmol), 5% Pd/BaSO4
(0.035 g, 10 mol%), i-PrOH (1 mL) and H2O (0.6 mL) at 25 °C. The
reaction mixture was heated at 65 °C for 8 h. Then, the reaction
mixture was cooled to 25 °C and 5% Pd/BaSO4 (0.007 g, 2 mol%)
was added. The reaction mixture was heated at 65 °C until comple-
tion (3 h). The mixture was cooled to 25 °C then filtered through
Celite® and the Celite® was washed with i-PrOH (3 × 5 mL). The
filtrate was concentrated under reduced pressure to give a crude
product which was column chromatographed (MeOH–CH2Cl2,
5:95) to provide 2c; yield: 0.049 g (71%); mp 70–95 °C.
IR (KBr): 2957, 1723, 1347, 1216 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.6 (dt, J = 1.6, 7.6 Hz, 1 H), 7.5
(dd, J = 0.8, 7.6 Hz, 1 H), 7.4 (dt, J = 1.2, 7.6 Hz, 1 H), 7.3 (dd, J =
1.2, 7.6 Hz, 1 H), 7.2 (d, J = 7.2 Hz, 1 H), 7.16–7.13 (m, 2 H), 7.11–
7.05 (m, 4 H), 6.7 (d, J = 7.2 Hz, 2 H), 4.8 (s, 2 H), 4.6 (s, 2 H), 2.3
(t, J = 7.6 Hz, 2 H), 2.0–1.91 (m, 4 H), 1.83–1.81 (m, 4 H), 1.61–
1.53 (m, 2 H), 1.37–1.25 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H).
IR (KBr): 2961, 1738, 1649, 1457, 1219, 1003 cm–1.
13C NMR (100 MHz, CDCl3): δ = 186.7, 161.4, 154.4, 141.1, 138.3,
136.5, 133.0, 131.5, 131.2, 130.2, 129.2, 128.7, 128.6, 128.0, 127.8,
127.1, 122.7, 77.2, 76.5, 50.9, 43.1, 37.4, 29.7, 28.7, 27.7, 26.1,
22.3, 13.7.
MS: m/z = 519 [M + H]+.
HRMS: m/z [M + H]+ calcd for C32H35N6O: 519.2872; found:
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotomers) = 7.70 (d,
J = 4.0 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.47–7.36 (m, 5 H), 7.19
(dd, J = 16.8, 8.8 Hz, 4 H), 6.99 (dd, J = 9.2, 7.6 Hz, 2 H), 4.60 (s,
2 H), 4.50–4.44 (m, 2 H), 4.13 (s, 1 H), 4.08 (d, J = 10.4 Hz, 0.7 H),
2.25–2.04 (m, 4 H), 1.43 (t, J = 6.8 Hz, 1 H), 1.39–1.11 (m, 12 H),
0.91–0.72 (m, 18 H).
519.2870.
Synthesis 2014, 46, 3249–3255
© Georg Thieme Verlag Stuttgart · New York