inorganic solid and washed with EtOAc (1.5 L). HCl 5-6 N
in 2-propanol (7.6 L) was added, obtaining a thick suspension.
The suspension was heated to 50-55 °C (internal temperature)
for about 1.5 h, then cooled to 20 °C, and aged overnight. The
solid was collected by filtration, washed with 2-propanol (2 ×
4.5 L), and dried under vacuum at 50 °C for several hours to
obtain compound 7 (1.93 kg) as a white solid, overall yield
97% theoretical. The process was repeated twice according to
the above-described procedure.
9.34 mol, 64%). Preparation of a second batch according to
the above-described procedure furnished 8 (1.55 kg, 9.06 mol,
62%). The filtrate of both batches (30 L) was concentrated and
acidified to pH 5.5. The brown precipitate was filtered over a
P2 glass funnel. The solids were stirred in water (5 L) for 2 h
and acetone (7 L) was added. After one hour the white
precipitate was filtered over a P2 glass funnel. The white wet
solids of the final product (1.14 kg) were dried at 45 °C (until
water content below 0.5% w/w), yielding additional compound
8 (0.605 kg, 24%). In total 3.73 kg of the final target was
prepared according to the above-described procedure.
1H NMR (600 MHz, DMSO-d6) δ 11.81 (br s, 1H), 9.9 -
11.2 (br, 2H), 9.78 (d, J ) 7.1 Hz, 1H), 8.73 (s, 1H), 8.36 (s,
1H), 4.45 (q, J ) 7.2 Hz, 2H), 4.30 (m, 1H), 3.84 (m, 2H),
3.66 (m, 2H), 2.04 (m, 2H), 1.58 (m, 2H), 1.39 (t, J ) 7.2 Hz,
3H); HPLC purity typically above 98% a/a.
1H NMR (600 MHz, DMSO-d6) δ 12.62 (br s, 1H), 3.69 (s,
2H), 2.53 (s, 3H), 2.19 (s, 3H).
13C NMR (151 MHz, DMSO-d6) δ 171.5, 162.1, 148.3,
123.0, 31.5, 18.5, 14.6; HPLC purity typically above 98% a/a.
N′-[(2,4-Dimethyl-1,3-thiazol-5-yl)acetyl]-1-ethyl-4-(tet-
rahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-
5-carbohydrazide (9). Compound 7 (1.2 kg) was charged under
nitrogen followed by dichloromethane (9.6 L) and iPr2EtN (2.76
L). The mixture was stirred at 20 °C for about 15 min.
Compound 8 (0.66 kg) was added to the suspension, and the
mixture was cooled to 5 °C (internal temperature) to add slowly,
in about 40 min, commercial T3P solution 50% w/w in EtOAc
(2.4 L), keeping the temperature below 10 °C. The suspension
was heated to 20 °C, and a solution of sodium hydroxide 2 N
(6 L) was added. A solid immediately precipitated, and the
suspension was heated to 40 °C for about 1 h, then cooled to
20 °C and aged overnight. The suspension was filtered, and
the solid washed with sodium bicarbonate 2% w/w solution
(4.8 L) and then three times with water (4.8 L). The solid was
dried in the oven at 50 °C overnight to obtain 0.826 kg of the
compound 9 as a white solid, overall yield 63% theoretical.
The process was repeated twice according to the above-
described procedure.
3-Bromolevulinic Acid (18). Levulinic acid 17 (1 kg, 8.61
mol, 0.885 L, 1 equiv) was dissolved in 37% HCl (2.5 L).
Bromine (1.45 kg, 9.10 mol, 0.4665 L, 1.05 equiv) was added
dropwise over 2 h at -5 °C, and the reaction mixture was
slowly warmed up to room temperature (using a water bath).
The dark-brown reaction mixture turned yellow at about 18 °C,
and after stirring for additional 3-4 h (at room temperature)
precipitation of a white solid was observed. After cooling to 0
°C, water (9-11 L) was added, and the white precipitate was
filtered off over a P2 glass funnel. The filtrate was extracted
twice with TBME (2 × 4 L each) and dried over Na2SO4, and
the solvent was evaporated at reduced pressure, affording crude
3-bromolevulinic acid 18 (1.23 kg, 6.31 mol, 73%, ratio 3- to
5-bromolevulinic acid 11:1). In total 11.65 kg of 3-bromole-
vulinic acid was prepared according to the above-described
procedure.
Ethyl-2-(2,4-dimethylthiazol-5-yl)acetate (15). To a solu-
tion of 3-bromolevulinic acid 18 (6.2 kg, 31.79 mol, 1 equiv)
in EtOH (40 L) was added ethanethioamide (2.6 kg, 36 mol,
1.1 equiv). The clear solution was heated to reflux for 2 h, and
after cooling to room temperature the EtOH was evaporated
under reduced pressure. The yellow semi-solid residue was
dissolved in water (10 L) and extracted with TBME (15 L).
The water layer was basified with 25% NH3 solution (2 L),
adjusting the pH to 8, and extracted with TBME (15 L). The
organic layer was washed with brine (5 L) and concentrated in
Vacuo, affording crude 15 (3.77 kg, about 60%). The material
was used in the next step without further purification.
In total 6.67 kg of crude ethyl-2-(2,4-dimethylthiazol-5-
yl)acetate was prepared according to the above-described
procedure.
(2,4-Dimethyl-1,3-thiazole-5-yl)acetic Acid (8). Crude 15
(3.77 kg, 18.57 mol, 1 equiv) and KOH (pellets; 1.16 kg, 20.71
mol, 1.1 equiv) were dissolved in MeOH (18 L). The dark-
brown reaction mixture was stirred overnight at room temper-
ature. The reaction mixture was concentrated under reduced
pressure, and water (4 L) was added with stirring (pH ) 10).
The solution was acidified with 2 N HCl (3 L) to pH ) 5.5 (a
brown precipitate was formed at pH ) 6). The solids were
filtered over a P2 glass funnel and stirred in water (2 L) for 2 h.
Subsequently acetone (3 L) was added, and the white precipitate
formed was filtered over a P2 glass funnel. The white wet solids
of the final product (3.1 kg) were dried at 45 °C (until water
content below 0.5% w/w) affording compound 8 (1.658 kg,
1H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 10.11 (s,
1H), 9.64 (d, J ) 7.4 Hz, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 4.37
(q, J ) 7.2 Hz, 2H), 4.20 (m, 1H), 3.83 (td, J ) 3.7, 11.7 Hz,
2H), 3.68 (s, 2H), 3.63 (m, 2H), 2.54 (s, 3H), 2.28 (s, 3H),
2.01 (m, 2H), 1.52 (m, 2H), 1.37 (t, J ) 7.2 Hz, 3H); HPLC
purity typically above 98% a/a.
5-{5-[(2,4-Dimethyl-1,3-thiazol-5-yl)methyl]-1,3,4-oxadia-
zol-2-yl}-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazo-
lo[3,4-b]pyridin-4-amine (1). Compound 9 (0.82 kg) was
suspended in dichloromethane (8.2 L). iPr2EtN (0.9 L) and tosyl
chloride (0.508 kg) were added, and the mixture was heated to
reflux for about 1.5 h. The mixture was cooled down to 20 °C,
and sodium hydroxide 2 N (4.1 L) was added; the layers were
separated, and the organic layer was washed with sodium
hydroxide 2N (4.1 L) and water (2 × 4.1 L). The resulting
organic layer was concentrated to about 4.9 L, dichloromethane
(1.64 L) was added, and then the solution was filtered to remove
inorganics, the filter was washed with dichloromethane (0.4 L),
and the solution was concentrated again to about 4.9 L. The
solution was seeded at 20 °C (4.1 g of 1 suspended in 82 mL
of acetone), then acetone (10.66 L) was added in about 1 h
and the slurry was aged for 2 h. The solid was collected by
filtration, washed with acetone (3 × 2.4 L) and dried under
vacuum at 50 °C for about 24 h to obtain 5-{5-[(2,4-dimethyl-
1160
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Vol. 14, No. 5, 2010 / Organic Process Research & Development