2
989
Synthesis
M. Seki
Paper
The separated organic layer was distilled under reduced pressure and
then co-distilled with toluene (5 mL) to give an off-white solid; yield:
treated with 0.5 M aq KH PO buffer (4.0 mL), and the mixture was
2 4
stirred for 0.5 h. The pH of the mixture was adjusted to 4–5 by using
5% aq Na CO (0.4 mL). The organic layer was washed with H O (5.0
0.5 g (87%); mp 105–106 °C.
2
3
2
IR (KBr): 3436, 2929, 1718, 1614, 1511, 1467, 1032 cm–1
mL), dried (Na
2
SO
4
), filtered, and concentrated. Heptane was added
.
and the product was collected by filtration then dried under vacuum
at 45 °C for 1 h to give colorless crystals; yield: 0.154 g (98%); mp
1
H NMR (DMSO-d ): δ = 7.76–7.71 (m, 1 H), 7.63–7.55 (m, 3 H), 7.00–
6
6
.94 (m, 4 H), 6.86 (d, J = 9.0 Hz, 1 H), 6.41 (s, 1 H), 6.37 (d, J = 3.0 Hz, 1
H), 5.65 (s, 2 H), 4.76 (s, 2 H), 3.70 (s, 3 H), 3.44 (s, 3 H), 2.71 (br s, 2
H), 1.57 (s, 6 H), 1.50 (dd, J = 15.0, 6.0 Hz, 2 H), 0.85 (t, J = 6.0 Hz, 3 H).
173.6 °C.
HPLC: Column: Unisol C18 (4.6 × 150 mm; 3 μm); Buffer: NaH PO ·H O
2
4
2
(
2.76 g) in H O (1 L) + TEA (1 mL); pH adjusted to 3.3 with H PO ; Buf-
2
3
4
13
C NMR (DMSO-d ): δ = 161.1, 160.4, 157.8, 153.8, 149.9, 140.8,
6
fer–MeCN (80:20); Gradient program (% B/T): 50:0, 95:02, 95:20,
1
1
37.8, 136.5, 131.4, 131.1, 130.9, 130.1, 128.6, 127.8, 126.2, 122.6,
18.3, 113.6, 104.7, 98.2, 70.1, 55.2, 47.7, 45.6, 29.3, 27.2, 20.6, 13.4.
50:22, 50:25; Flow: 1.0 mL/min; Injection vol.: 10 μL; Column temp:
30 °C; Diluent: MeCN–H O (90:10); Sample concentration: 500 ppm;
2
MS: m/z = 597 [M + H]+.
Purity (area%): 98.1%.
HRMS: m/z [M + Na]+ calcd for C33H36N NaO : 619.2645; found:
IR (KBr): 3292, 2972, 1832, 1740, 1707 cm–1
6
5
.
619.2645.
1
H NMR (DMSO-d ): δ = 7.55–7.70 (m. 4 H), 7.04 (d, J = 8.5 Hz, 2 H),
6
6
.86 (d, J = 8.5 Hz, 2 H), 5.42 (s, 2 H), 5.21 (s, 1 H), 5.06 (s, 2 H), 2.61 (t,
J = 7.5 Hz, 2 H), 2.08 (s, 3 H), 1.54–1.63 (m, 2 H), 1.47 (s, 6 H), 0.88 (t,
J = 7.5 Hz, 3 H).
(
5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-({2′-[1-(2,4-Dimethoxy-
benzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-4-(1-hydroxy-1-
methylethyl)-2-propyl-1H-imidazole-5-carboxylate (2b)
MS: m/z = 559 [M + H]+.
An oven-dried flask was sequentially charged with carboxylic acid 9
(
5.8 g, 7.98 mmol), Na CO (1.1 g, 10.4 mmol), KI (0.0133 g, 0.08
2 3
mmol), and acetone (20.0 mL), and the mixture was stirred for 10
min. A solution of medoxomil chloride (10; 1.66 g, 11.2 mmol) in ace-
tone (9.0 mL) was added over 10 min at 25 °C, and the mixture was
heated at 45–50 °C until the reaction was complete (11 h). The mix-
ture was then cooled to 25 °C and the acetone was removed under re-
duced pressure. To the resulting mixture were added 10% aq NaCl
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378848.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
(
29.0 mL) and toluene (29.0 mL). The pH of the solution was adjusted
References
to 7–8 by using 5% aq HCl (6.3 mL), and the mixture was stirred for 10
min. The two layers were separated and the aqueous layer was ex-
tracted with toluene (2 × 15.0 mL). The organic layers were combined
and washed with 10% aq NaCl (29.0 mL). The toluene was distilled off
under reduced pressure to give a crude product that was purified by
column chromatography (silica gel, 0.4–0.5% MeOH–CH Cl ) to give a
(1) (a) The Art of Process Chemistry; Yasuda, N., Ed.; Wiley-VCH:
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2
2
colorless solid; yield: 4.19 g (74%); mp 139.8 °C.
(2) (a) Seki, M. WO 2011061996, 2010. (b) Seki, M. ACS Catal. 2011,
1
, 607. (c) Seki, M.; Nagahama, M. J. Org. Chem. 2011, 76, 10198.
IR (KBr): 3392, 2965, 2872, 2836, 1817, 1744, 1678, 1589, 1490, 1466,
–1
(d) Seki, M. Synthesis 2012, 44, 3231. (e) Seki, M. Yuki Gosei
Kagaku Kyokaishi 2012, 70, 1295. (f) Kocienski, P. Synfacts 2013,
1312, 1231, 1149, 1034, 1003, 956, 767 cm .
1
H NMR (DMSO-d ): δ = 7.74 (dt, J = 7.6, 7.2 Hz, 1 H), 7.62–7.55 (m, 3
6
9
, 0006. (g) Seki, M. In Science of Synthesis: Catalytic Transforma-
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H), 6.94 (d, J = 8 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 3 H), 6.41–6.37 (m, 2 H),
5.42 (s, 2 H), 5.21 (s, 1 H), 5.05 (s, 2 H), 4.76 (s, 2 H), 3.70 (s, 3 H), 3.45
2
(
(
1
s, 3 H), 2.62 (t, J = 7.2 Hz, 2 H), 2.07 (s, 3 H), 1.59–1.51 (m, 2 H), 1.47
s, 6 H), 0.87 (t, J = 7.2 Hz, 3 H).
(
3
C NMR (DMSO-d ): δ = 161.6, 161.1, 158.3, 157.9, 154.3, 152.1,
6
4, 4047. (m) Seki, M. Synthesis 2015, 47, 1423.
1
1
4
51.4, 141.4, 140.8, 138.1, 137.5, 133.2, 131.9, 131.5, 131.3, 130.5,
29.0, 128.2, 126.2, 123.1, 116.7, 114.1, 105.2, 98.6, 70.0, 55.7, 54.6,
8.4, 46.0, 30.1, 28.7, 21.0, 14.0, 9.1.
(
3) For selected reviews on C–H activation (arylation), see:
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42, 1074. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
MS: m/z = 709 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C38H40N NaO : 731.2805; found:
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6
8
731.2802.
8
(
2
(
90. (f) Ackermann, L. Chem. Commun. 2010, 46, 4866.
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(
5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-Hydroxy-1-methyl-
ethyl)-2-propyl-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-
H-imidazole-5-carboxylate (1; Olmesartan Medoxomil)
An oven-dried flask was sequentially charged with CH Cl (1.0 mL),
1
2
2
ester 2b (0.2 g, 0.28 mmol), and TFA (0.2 g, 1.82 mmol, 0.14 mL) at
5 °C, and the mixture was stirred at 25 °C for 6 h. When the reaction
was complete, the mixture was evaporated under reduced pressure
then co-evaporated with CH Cl (2 × 5.0 mL). CH Cl (5.0 mL) was
4
(
1
2
2
2
2
2
(4) For examples, see: (a) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.;
Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B.
III; Wells, G. J. J. Med. Chem. 1991, 34, 2525. (b) Bernhart, C. A.;
added to the residue, and the mixture was filtered through Celite,
which was washed with CH Cl (2 × 2.0 mL). The organic layer was
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2985–2990