the quality of intermediate 2. The use of pure, homogeneous
epoxide (using the optimised route) in the formation of 1 led
to a dramatic increase in isolated yield, suggesting that efficient
crystallisation of 1 is inhibited by impurities introduced with
this intermediate.
3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, J ) 6.6 Hz, 1H), 3.49
(2H, m), 3.73 (d, J ) 8.7 Hz, 1H), 3.98 (d, J ) 8.7 Hz, 1H).
GCMS (CI) m/z 147 (M + H), 131 (M - CH3), 89 (M + H -
C2H6O).
(S)-4-Nitro-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-
phenol (13). Toluene (142.3 kg) and NMP (73.1 kg) were added
to potassium tert-butoxide (78 kg, 2.25 mol equiv). A solution
of 12 (49.3 kg, 1.15 mol equiv) in toluene (102.3 kg) was added,
and the reaction was stirred for 50 mn at 25 °C. A solution of
11 (46.1 kg, 1.00 mol equiv) in NMP (48.6 kg) and toluene
(66.6 kg) was added. The reaction was heated at 65 °C for 1 h
30 min. The mixture was cooled to 40-50 °C, and water (235.1
kg) was added, and the two layers were separated. Acetic acid
(34.7 kg, 1.9 mol equiv) was added to the aqueous layer, and
13 was extracted into isopropyl acetate (409.3 kg). The organic
solution was washed with water (3 × 352.5 kg) to minimise
the amount of NMP carried over. The product can be isolated
by concentration to dryness in 98% yield. Alternatively, the
solution can be used directly in the next stage. 1H NMR (300
MHz, DMSO) δ 1.32 (s, 3H), 1.33 (2s, 6H), 3.74 (d, J ) 8.7
Hz, 1H), 3.92 (d, J ) 9.2 Hz, 2H), 4.00 (d, J ) 9.5 Hz, 1H),
4.03 (d, J ) 8.7 Hz, 1H), 6.47 (dd, J ) 9.2, 2.3 Hz, 1H), 6.61
(d, J ) 2.3 Hz, 1H), 7.89 (d, J ) 9.0 Hz, 1H), 10.87 (br, 1H).
LCMS (ESI) m/z 306 (MNa+), 226 (M+ - CH3COCH3).
(S)-N-[2-(2,3-Dihydroxy-2-methyl-propoxy)-4-hydroxy-
phenyl]acetamide (14). To a solution of 13 in isopropyl acetate
(16.4% w/w, 318.3 kg, 1 mol equiv) was added methanol (25.8
kg) and 5% Pd on C (57.9% w/w water, 5.3 kg, 0.005 mol
equiv). The mixture was warmed to 25 °C, and hydrogen was
charged to the reaction at 4.25 bar g. At the end of the reduction,
acetic anhydride (19.7 kg, 1.05 mol equiv) was added. The
catalyst was removed by filtration.
To the solution of 18 in isopropyl acetate/methanol was
added p-TSA monohydrate (1.43 kg, 0.045 mol equiv). The
reaction was heated at 72 °C for 40 min. The reaction was
cooled to 20 °C, and methanol was removed by distillation
under reduced pressure. Compound 14 crystallised during
distillation and was recovered by filtration in 75% yield and
95% w/w assay. 1H NMR (400 MHz, DMSO) δ 1.13 (s, 3H),
2.02 (s, 3H), 3.27 (m, 1H), 3.45 (dd, J ) 10.6, 5.5 Hz, 1H),
3.69 (d, J ) 8.6 Hz, 1H), 3.76 (d, J ) 9.0 Hz, 1H), 4.71 (t, J
) 5.6 Hz, 1H), 4.76 (s, 1H), 6.28 (dd, J ) 8.6, 2.4 Hz, 1H),
6.39 (d, J ) 2.6 Hz, 1H), 7.55 (d, J ) 8.5 Hz, 1H), 8.87 (s,
1H), 9.22 (s, 1H). LCMS (ESI) m/z 256 (M + H).
Experimental Section
2-Methyl-1,2,3-propanetriol (15). A solution of methallyl
alcohol (200 g, 2.77 mol, 1 mol equiv) and sodium tungstate
dihydrate (9.3 g, 27.7 mmol, 0.01 mol equiv) in water (400
mL) was heated to 60 °C. An aqueous solution of hydrogen
peroxide (35% w/w, 346 g, 3.60 mol, 1.3 mol equiv) was slowly
added to the reaction mixture at a rate that maintained the
internal temperature in the range 60-85 °C. Once the addition
was complete, the reaction mixture was stirred for 30 min at
70 °C to destroy most of the remaining peroxides. The reaction
mixture was then stirred for a minimum of 2 h 30 min at 100
°C to destroy all the peroxides. The reaction mixture was cooled
to 50 °C, and water was distilled off under reduced pressure.
The reaction mixture was concentrated in vacuo to afford 15
as a pale-yellow, viscous, opaque oil which was used in the
next step without purification. 1H NMR (300 MHz, DMSO) δ
0.97 (s, 3H), 3.21 (m, 4H), 4.02 (br, 1H), 4.37 (br, 2H). GCMS
m/z 107 [M + H].
Racemic (2,2,4-Trimethyl-1,3-dioxolan-4-yl)methanol (16).
The crude 15 (292 g, 2.75 mol, 1.0 mol equiv) was dissolved
in acetone (1595 g, 27.5 mol, 10 mol equiv). p-Toluenesul-
phonic acid monohydrate (52.2 g, 274 mmol, 0.10 mol equiv)
was added, and the resulting mixture was stirred at 20 °C for
2 h. The pH of the reaction solution was then set to 7-8 by
the addition of a solution of 0.6 M aqueous sodium bicarbonate,
and the acetone was removed under reduced pressure. The
aqueous mixture was extracted 5 times with TBME (400 mL).
The combined organic layers were dried by azeotropic distil-
lation at atmospheric pressure. [Racemic 16 can be isolated as
an oil by further concentration.] 1H NMR (300 MHz, CDCl3)
δ 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.92 (t, J ) 6.6 Hz,
1H), 3.49 (m, 2H), 3.73 (d, J ) 8.7 Hz, 1H), 3.98 (d, J ) 8.7
Hz, 1H). GCMS (CI) m/z 147 (M + H), 131 (M - CH3), 89
(M + H - C2H6O).
((R)-2,2,4-Trimethyl-1,3-dioxolan-4-yl)methanol (12). To
the solution of 16 in TBME was added succinic anhydride
(113.3 g, 1.13 mol, 0.41 mol equiv with respect to (wrt)
isobutenol), and the mixture was stirred at 20 °C. Lipase PS
Amano IM (12.5 g, 0.0625 wt equiv wrt isobutenol) was added
to the reaction mixture in one portion. The resulting mixture
was stirred at 20 °C for 2-6 h. The enzyme was removed by
filtration, and the filtrates were treated with a solution of aqueous
sodium carbonate (10% w/w, 792 g, 0.69 mol, 0.25 mol equiv
wrt isobutenol). The biphasic mixture was separated, and the
aqueous layer was re-extracted with TBME (470 mL). The
biphasic mixture was separated, and the combined organic layers
were washed with a solution of aqueous sodium carbonate (5%
w/w, 117 g, 55.4 mmol, 0.02 mol equiv wrt isobutenol) until
the pH of the mixture was 7.5-8.0. TBME was removed by
reduced pressure distillation to afford 12 as a pale-yellow oil.
This was purified by distillation under reduced pressure to give
12 as a clear, colourless oil in 27% yield (wrt isobutenol) and
(S)-3-(2-Methyl-oxiranylmethoxy)-4-nitro-phenol (24). To
a solution of 13 (19.6% w/w, 314 g, 217 mmol, 1 mol equiv) in
isopropyl acetate at 20 °C was added HBr in acetic acid (33%
w/w, 120 mL, 663 mmol, 3.1 mol equiv). The solution was heated
at 55 °C for 1 h. The mixture was diluted with isopropyl acetate
(620 mL) and cooled to 20 °C. The organic solution was washed
sequentially with water (620 mL) and aqueous sodium sulfite (25%
w/v, 930 mL). To the organic solution of 25 at 20 °C was added
dropwise a solution of sodium methoxide in methanol (25% w/w,
148 mL, 656 mmol, 3.0 mol equiv). After 30 min, water (620
mL) was added to the reaction, and the biphasic mixture was
separated. The aqueous solution of 28 was added dropwise to a
solution of acetic acid (12.5 mL, 218 mmol, 1 mol equiv) in water
(250 mL). Compound 24 crystallised during acidification and was
1
95% purity by GC. H NMR (300 MHz, CDCl3) δ 1.30 (s,
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