Efficient Preparation of the Key Intermediate in Corey’s Tamiflu Synthesis
2 or 3, because the one-pot yield of 7c was reduced to
20%.
ethyl cyclohexa-1,4-dienecarboxylate 1 (15.2 g, 100
mmol) and suspended AgOCN (17.25 g, 115 mmol) in
CH2Cl2 (150 mL) was added I2 (26.65 g, 105 mmol) in
one portion at -20 ℃. The reaction mixture was
slowly raised to room temperature in 4 h and then con-
tinued until the starting material was consumed (less
than 1 h, checked by TLC). The reaction was stopped by
adding cyclohexene (2.0 g) to destroy the excessive
amount of reagents. Then 75 mL alcohol (MeOH, i-
PrOH or t-BuOH) was added to the reaction mixture,
followed by HCl in dioxane (4.0 mol/L, 15 mL). The
reaction was stirred at room temperature for 6—8 h,
then DBU (30 mL) was added slowly in 30 min. The
reaction mixture was stirred at 35 ℃ overnight, and
then filtered and concentrated. The residue-was diluted
Scheme 4 Simplified “one pot” procedure
1
with 200 mL Et2O, washed with 1.0 mol•L HCl (320
mL), saturated NaHCO3 (20 mL×3) and brine (20 mL×
3), dried with Na2SO4 and concentrated. Silic gel puri-
fication afforded oil produt 7a (16.9 g, yield 75%), 7b
(17.7 g, yield 70%), or 7c (16.0 g, yield 60%).
Reagents and conditions: (a) AgOCN, I2, CH2Cl2, -20 ℃ to r.t.,
5 h; (b) added DBU and ROH to the reaction system, 35 ℃, over-
night.
1
For 7a: H NMR (CDCl3, 500 MHz) δ: 7.04—7.06
(m, 1H), 6.17—6.20 (m, 1H), 6.10—6.13 (m, 1H), 4.76—
4.78 (m, 1H), 4.47—4.49 (m, 1H), 4.21 (q, J=7.0 Hz,
2H), 3.64 (s, 3H), 2.77—2.65 (m, 2H), 1.29 (t, J=7.0
Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 166.3, 155.5,
131.5, 131.2, 126.6, 124.7, 60.2, 51.7, 43.5, 28.4, 13.8.
HRMS calcd for C11H15NO4 248.0893 (M+Na+), found
248.0895 (M+Na+).
Experimental
General
All reagents were used as received from commercial
sources. CH2Cl2 and DMF were distilled from CaH2.
Thin layer chromatography (TLC) was performed on
pre-coated E. Merck silica gel 60 F254 plates. Flash
column chromatography was performed on silica gel
(200—300 mesh). Proton NMR spectra (1H NMR) were
recorded at 500 MHz by using a Bruker 5 mm DCH
CryoProbe. Chemical shifts are referenced to residual
protium in the NMR solvent: CDCl3, δ 7.27. Carbon
NMR (13C NMR) spectra were recorded at 125 MHz by
using the same probe, and chemical shifts (δ) are refer-
enced to the carbon signal of the solvent: CDCl3, δ 77.2.
1
For 7b: H NMR (CDCl3, 500 MHz) δ: 7.02—7.04
(m, 1H), 6.16—6.21 (m, 1H), 6.09—6.14 (m, 1H), 4.78—
4.90 (m, 2H), 4.45—4.49 (m, 1H), 4.22 (q, J=7.0 Hz,
2H), 2.77—2.65 (m, 2H), 1.31 (t, J=7.0 Hz, 3H), 1.22
(m, 6H); 13C NMR (CDCl3, 125 MHz) δ: 166.6, 155.1,
132.3, 131.5, 126.9, 124.7, 68.0, 60.4, 43.7, 28.7, 21+.9,
14.1. HRMS calcd for C11H15NO4 276.1206 (M+Na ),
found 276.1209 (M+Na+).
1
For 7c: H NMR (CDCl3, 500 MHz) δ: 7.00—7.02
Synthesis
(m, 1H), 6.10—6.20 (m, 2H), 4.58—4.62 (m, 1H), 4.38—
4.42 (m, 1H), 4.17 (q, J=7.0 Hz, 2H), 2.70—2.62 (m,
2H), 1.39 (s, 9H), 1.26 (t, J=7.0 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ: 166.7, 154.7, 132.5, 131.6, 126.9,
124.7, 79.4, 60.5, 43.4, 28.7, 28.2, 14.1.
Step 1: synthesis of ethyl cyclohexa-1,4-dienecar-
boxylate 1
Commercially available buta-1,3-diene
sealed in steel bottle was cooled to -78 ℃ and then
was dumped out (about 40 mL) directly to the precooled
(-78 ℃) high pressure glass flask, followed by adding
of ethyl propiolate (20 g), hydroquinone (2 g) and a
sitrring bar. The reaction flask was sealed and stirred for
3 d at 110 ℃ (causion: a protection pad should be used
for in case of exploration). The reastion mixture was
cooled to -78 ℃ again before opening the seal and
the residure was pruified through distillation with re-
duced pressure (b.p. 90—92 ℃/8 mm) to afford clear
oil product ethyl cyclohexa-1,4-dienecarboxylate 1 (26.4
Simplified “one pot” procedure B The first part
is the same with the “one pot” procedure A. After add-
ing the alcohol (MeOH, i-PrOH or t-BuOH), DBU (15
mL) was added in 30 min instead of HCl in dioxane.
Then the reaction was raised to 35 ℃ and stirred over-
night, filtered and concentrated. The residue -was diluted
1
with 200 mL Et2O, washed with 1.0 mol•L HCl (20
mL×3), saturated NaHCO3 (20 mL×3) and brine (20
mL×3), dried with Na2SO4 and concentrated. Silic gel
purification afforded oil produt 7a (16.9 g, yield 75%),
7b (16.5 g, yield 65%), or 7c (5.35 g, yield 20%).
1
g, 85% yield). H NMR (CDCl3, 500 MHz) δ: 6.96—
6.98 (m, 1H), 5.76—5.79 (m, 1H), 5.65—5.68 (m, 1H),
4.22 (q, J=7.0 Hz, 2H), 2.86—2.93 (m, 1H), 1.31 (t, J=
7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 167.17,
136.31, 128.02, 124.58, 122.43, 60.46, 27.17, 25.29,
14.44.
Conclusion
In conclusion, a very efficient two-step synthesis has
been developed to address the problems of practical
Step 2: “one pot” procedure A To a solution of
Chin. J. Chem. 2010, 28, 2479— 2482
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
2481