all chromatography purifications. This process has been utilized
on kilo lab scale to produce over 3 kg of 24.
solution was added 37% aqueous HCl (6 mL, catalytic amount).
The solution was heated to 105 °C for 23 h. The solution was
cooled at 40 °C and reduced to 4 volumes (4.8 L) under reduced
pressure, and n-heptane (8.4 L) was added over 1 h. The mixture
was stirred at 40 °C for 30 min and then cooled at 15 °C over
1 h; a solid was precipitated. The slurry was stirred at 15 °C
for approximately 16 h and then filtered. The solid was washed
with n-heptane (2 × 3 L) and dried in a vacuum oven at 40
°C. 1,1-Dimethylethyl-(1R,4S,6R)-2-oxo-3-azabicyclo[4.1.0]-
heptane-4-carboxylate (25) and 1,1-dimethylethyl-(1R,4R,6R)-
2-oxo-3-azabicyclo[4.1.0]heptane-4-carboxylate (33) (1.58 kg,
60%) were obtained as white solids in 67:33 ratio.
Experimental Section
All the materials were purchased from commercial suppliers
and used without further purification. All reactions were carried
out under atmosphere of nitrogen.
1,1-Dimethylethyl-(1R,4S,6R)-2-oxo-3-azabicyclo[4.1.0]hep-
tane-4-carboxylate (25) and 1,1-Dimethylethyl-(1R,4R,6R)-
2-oxo-3-azabicyclo[4.1.0]heptane-4-carboxylate (33). Sodium
iodide (2.76 kg, 18.4 mol, 1.5 equiv) was partially dissolved in
acetonitrile (12 L) after stirring at 20 °C for 10 min under
nitrogen atmosphere. TMSCl (2.3 L, 18.4 mol, 1.5 equiv) was
added over 15 min, and the resulting yellow slurry was stirred
at 20 °C for 1 h. A solution of (1R,5S)-3-oxabicyclo[3.1.0]hexan-
2-one (28, 1.2 kg, 12.2 mol, 1 equiv, > 99% ee, [R]D ) +61.5°
(c ) 1, CHCl3)) in acetonitrile (2.4 L) was added over 5 min
at 20 °C. The suspension was heated to 50 °C (internal
temperature) and then kept for 2 h at 50 °C. The mixture was
diluted with methanol (12 L) at 20 °C and concentrated to 5
volumes (6 L) under reduced pressure. Methanol (12 L) was
then added followed by TMSCl (0.72 L, 5.7 mol, 0.5 equiv).
The resulting mixture was stirred at 20 °C overnight. The
mixture was concentrated under vacuum to 5 volumes (6 L),
then 2-MeTHF was added (12 L), and the solution was
concentrated to 5 volumes (6 L). 2-MeTHF was added (12 L).
The dark-red solution was washed with aqueous 20% w/w
Na2SO3 (4.8 L) at 20 °C (solution became colourless-light
yellow). The biphasic system was separated, and the organic
layer was washed with water (4.8 L), then concentrated under
vacuum to 4 volumes (4.8 L). 2-MeTHF (12 L) was added,
and the solution was concentrated to 5 volumes (6 L), to obtain
finally the solution of methyl (1R,2S)-2-(iodomethyl)cyclopro-
panecarboxylate 27.
N-(Diphenylmethylene)glycine tert-butylester (26, 3.6 kg,
12.2 mol, 1 equiv) was suspended in dry 2-MeTHF (12 L) at
20 °C. The mixture was cooled to 0 °C, and KOtBu (1.38 kg,
12.3 mol, 1 equiv) was added in three portions. The slurry
became a yellow-orange solution and was stirred at 0 °C for
30 min. The previous solution of methyl-(1R,2S)-2-(iodometh-
yl)cyclopropanecarboxylate 27 in 2-MeTHF was slowly added
over 25 min, keeping the temperature lower than 5 °C during
the addition. The mixture was stirred at 0 °C for 2.5 h. The
mixture was quenched with buffer pH ) 7 (KH2PO4/Na2HPO4,
2.4 L) at 0 °C. The biphasic system was warmed at 20 °C. The
water phase was discharged. The organic phase was cooled to
0 °C and treated with 30% w/w citric acid (9.6 L). The biphasic
system was warmed to 20 °C and stirred overnight at 20 °C.
Cyclohexane (24 L) was added, and the phases were separated.
The water phase was washed with cyclohexane (24 L). Ethyl
acetate (24 L) was added to the aqueous phase, and then the
system was basified to pH ) 8.5 with aqueous saturated K2CO3
(6 L) and then diluted with water (3 L). The biphasic system
was separated. The aqueous layer was back extracted with ethyl
acetate (24 L). The combined organic phases were washed with
water (3.6 L) and concentrated to 10 volumes (12 L). Toluene
(24 L) was added, and the solution was concentrated to 10
volumes (12 L) and diluted again with toluene (4.8 L). To this
1
(25) H NMR (400 MHz, DMSO-d6): δ (ppm) 6.86 (br s,
1H), 3.75 (dd, J ) 11.9, 4.7 Hz, 1H), 2.20 (ddd, J ) 13.2, 4.5,
2.3 Hz, 1H), 1.74 (td, J ) 12.6, 3.4 Hz, 1H), 1.42 (s, 9H),
1.40-1.60 (m, 2H), 1.12 (q, J ) 5.3 Hz, 1H), 0.90 (ddd, J )
9.3, 7.9, 5.3 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ (ppm)
7.0, 12.5, 15.6, 24.6, 27.5, 49.7, 81.4, 170.1, 171.0. HRMS
(ESI): m/z [M + H]+ calcd for C11H17NO3: 212.1287; found
212.1288.
(33) 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.39 (d, J )
4.9 Hz, 1H), 3.87 (dddd, J ) 8.2, 5.2, 1.3, 0.7 Hz, 1H), 2.33
(d, J ) 13.9 Hz, 1H), 2.11 (ddd, J ) 14.2, 8.1, 3.2 Hz, 1H),
1.42 (s, 9H), 1.35-1.60 (m, 2H), 0.87 (m, 1H), 0.69 (td, J )
5.4, 4.4 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ (ppm)
9.0, 13.9, 15.6, 21.8, 27.5, 51.2, 81.1, 170.8, 172.7. HRMS
(ESI): m/z [M + H]+ calcd for C11H17NO3: 212.1287; found
212.1288.
1,1-Dimethylethyl-(1R,4S,6R)-4-(hydroxymethyl)-3-
azabicyclo[4.1.0]heptane-3-carboxylate (24). The mixture of
1,1-dimethylethyl (1R,4S,6R)-2-oxo-3-azabicyclo[4.1.0]heptane-
4-carboxylate (25) and 1,1-dimethylethyl-(1R,4R,6R)-2-oxo-3-
azabicyclo[4.1.0]heptane-4-carboxylate (33) (1 kg, 4.73 mol,
1 equiv) as 67:33 ratio was dissolved in toluene (3 L) and
MeOH (7 L) and stirred for 5 min at 20 °C. The mixture was
cooled to 15 °C, and powdered KOH (0.4 kg, 7.13 mol, 1.5
equiv) was added in eight portions over 1 h. The solution was
stirred at 20 °C for 3 h. The solution was cooled to 10 °C, and
TMSCl (2.4 L, 18.9 mol, 4 equiv) was added, keeping the
temperature around 10-15 °C over 45 min. White solid was
precipitated (KCl). The slurry was stirred at room temperature
overnight. NaHCO3 solid (1.4 kg) was added in three portions
to reach pH ) 5. The mixture was concentrated to 4 volumes
(4 L). THF (8 L) was added, and the volume was reduced to 4
volumes (4 L) by distillation under reduced pressure. The solid
was filtered and washed with THF (3 × 2 L). The filtrate
appeared cloudy. The solution was reduced to 2.5 volumes (2.5
L) by distillation under reduced pressure, and BF3 ·THF (3.13
L, 28.4 mol, 6 equiv) was added under stirring whilst maintain-
ing an internal temperature of 25 °C. The resulting solution
was added slowly to a solution of LiBH4 (4 M in THF, 4.8 L,
19.2 mol, 4 equiv), diluted with THF (3 L), keeping the
temperature at 25-30 °C [the line was washed with THF (0.5
L)]. The mixture was stirred at 30 °C overnight (17 h). The
mixture was slowly quenched with MeOH (4 L) at 25-30 °C
(addition time in about 1 h). The solution was stirred at 50 °C
for approximately 1 h. After this time, the solution was reduced
to 5.5 volumes (5.5 L) by distillation under reduced pressure.
1246
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Vol. 14, No. 5, 2010 / Organic Process Research & Development