IR 3104 broad, 1660, 1595, 1462 cm-1; 1H NMR (DMSO-
d6) δ 10.96 (s, broad, 1H), 7.48 (t, J ) 8.4 Hz, 1H), 7.09 (d, J
) 8.4 Hz, 1H), 6.38 (s, broad, 2H), 2.34 (s, 3H); 13C NMR
(DMSO-d6) δ 160.7, 151.7, 151.4, 135.7, 132.1, 123.4, 121.9,
115.0, 23.2.
broad, 2H), 2.32 (s, 3H); 13C NMR (DMSO-d6) δ 160.8, 152.0,
151.8, 150.3, 149.1, 137.5, 136.2, 126.7, 126.1, 119.6, 118.3,
20.7.
2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazo-
lin-4-one Dihydrochloride, Crude (1, Dihydrochloride). In
a glass-lined reactor were added absolute ethanol (165 kg), water
(8.5 kg), and 1 (free base, 43 kg, 152 mol) under stirring.
Hydrochloric acid (33 kg, 326 mol, 36% w/w) was added, and
the mixture was stirred for 10 min. The mixture was then heated
to reflux and then immediately cooled to below 10 °C during
2.5 h. The precipitated product was isolated via centrifugation
and washed with absolute ethanol (24 kg). Drying under vacuum
(8 mbar) at 60-70 °C for 12 h gave the dihydrochloride (48
kg, 89%) as an off-white solid.
2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazo-
lin-4-one Dihydrochloride, Purified. In a glass-lined reactor
were added methanol (668 kg) and crude 1, dihydrochloride
(48.4 kg, 136 mol) under stirring. After 10 min hydrochloric
acid (8.2 kg) was added, and the mixture was heated to reflux
and maintained at this temperature for 30 min. The hot solution
was filtered through a 1 µm bag filter and then through a 0.45
µm cartridge filter. The filters were washed with methanol (20
kg), and the combined liquids were concentrated by removing
methanol (760 L) by distillation at reduced temperature. The
resulting slurry was cooled to 0 °C and kept at this temperature
overnight. The product was isolated via centrifugation and
washed with absolute ethanol (33 kg). The filter cake was
recharged together with absolute ethanol (182 kg), water (8.2
kg), and hydrochloric acid (3.1 kg, 36% w/w). The mixture
was stirred for 10 min, then heated to reflux, immediately cooled
to 0 °C, and left at this temperature overnight. The product was
collected via centrifugation and washed with absolute ethanol
(28 kg). Drying under vacuum (8 mbar) at 65 °C for 12 h gave
a solid (42 kg, 86%).
The solid (42 kg) was charged in a glass-lined reactor
together with water (523 kg) and stirred. Hydrochloric acid (12.6
kg, 36%, w/w) was added, and the mixture was stirred for 15
min. A slurry consisting of water (16.5 kg) and Carboraffin
(activated charcoal) (3.8 kg) was added, and the suspension was
stirred for 50 min. Celite 521 (3.8 kg) was added, and stirring
was continued for 10 min. The reaction mixture was passed
through a series of filters: a 10 µm bag filter, a 1 µm bag filter,
and finally a 0.5 µm cartridge filter. The filters were washed
with water (43 kg), and the combined liquids were charged in
a glass-lined reactor. Aqueous ammonium hydroxide (44 kg,
27% w/w) was added under stirring. After 35 min the precipitate
was isolated via centrifugation and washed with water (53 kg).
Drying under vacuum (8 mbar) at 65 °C for 12 h gave a solid
which was passed through a sieve to give a fine powder (32
kg, 97%). The powder (32 kg) was added to a glass-lined reactor
together with absolute ethanol (127 kg) and water (4.6 kg) under
stirring. After 10 min hydrochloric acid (31.5 kg, 36% w/w)
was added, and the mixture was stirred for another 10 min.
The mixture was heated to reflux and kept at this temperature
for 35 min. The mixture was cooled to 0 °C and kept at this
temperature overnight. The product was isolated via centrifuga-
tion and washed with absolute ethanol (42 kg). Drying under
vacuum (8 mbar) at 65 °C for 24 h gave a solid which was
2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazo-
lin-4-one (1, Free Base). A glass-lined reactor was charged
with grounded sodium hydroxide (8.56 kg, 214 mol) and
dimethylacetamide (169 kg). The mixture was stirred for 15
min after which 4-mercaptopyridine (25.5 kg, 229 mol) was
added. The mixture was stirred for 1 h at a temperature below
27 °C, and then 3 (36.0 kg, 142 mol) and copper(I) oxide (11.5
kg, 80.4 mol) were added. The mixture was heated to 80-90
°C, and the progress of the reaction was monitored with HPLC.
After 4 h the reaction was completed and the mixture was
cooled to below 30 °C over a 1 h period. A mixture of
hydrochloric acid (76 kg, 36% w/w) and water (858 kg) was
added which gave a pH just below 1. After stirring for 15 min,
the mixture was left unstirred overnight. The reaction mixture
was passed through a series of filters: a 10 µm bag filter, a 1
µm bag filter, and finally a 0.45 µm cartridge filter. The filters
were washed with water (142 kg), and the combined liquids
were stored in a polyethylene container. The content of the
container was transferred to a glass-lined reactor, and aqueous
ammonium hydroxide (67 kg, 27% w/w) was added. After
stirring for 30 min the pH was recorded to be 9.5. The
precipitated product was isolated via centrifugation and washed
with water. The wet filter cake was recharged in the reactor
together with water (558 kg). Hydrochloric acid (76 kg, 36%
w/w) was added, and the substance went into solution. Aqueous
ammonium hydroxide (67 kg, 27% w/w) was added. After
stirring for 35 min the precipitate was collected via centrifuga-
tion. The filter cake was washed with water (141 kg) and then
recharged in the reactor with water (558 kg). 2,4,6-Trimercapto-
s-triazine water solution 15% w/w (TMT-15, 14 kg) was added,
and the mixture was stirred for 1 h. Hydrochloric acid (61 kg,
36% w/w) was added, and the pH was lowered to below 1.
Compressed air was bubbled into the stirred reaction mixture
for 1 h. TMT-15 (7.5 kg) was added, and at 20-min intervales,
additional 7.5 kg portions were added (6 more additions, total
52.5 kg). The pH was kept low by addition of hydrochloric
acid (total 2.1 kg, 36% w/w). After verification of removal of
copper, Carboraffin P (activated charcoal, 4.5 kg), water (15
kg), and Celite 521 (1.5 kg) were added. The mixture was stirred
for 1 h, and then the reaction mixture was passed through a
series of filters: a 25 µm bag filter, a 1 µm bag filter, and finally
a 0.45 µm cartridge filter. The filters were washed with water
(94 kg), and the combined liquids were stored in a polyethylene
container. The solution was charged into a glass-lined reactor,
and aqueous ammonium hydroxide was added (53 kg, 27%
w/w). The precipitated product was isolated via centrifugation,
and then the filter cake was washed with water (180 kg) and
absolute ethanol (44 kg). Drying under vacuum (9 mbar) at
60-70 °C for 48 h gave the title compound (34.0 kg, 84%) as
an off-white solid. Mp 300-301 °C (lit. 301-3021); IR 3070
1
broad, 1664, 1579, 1466 cm-1; H NMR (DMSO-d6) δ 8.23
(d, J ) 5.7 Hz, 2H), 7.59 (d, J ) 8.5 Hz, 1H), 7.29 (d, J ) 8.5
Hz, 1H), 6.83 (dd, J1 ) 4.6 Hz, J2 ) 1.6 Hz, 2H), 6.42 (s,
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