1
106-109 °C; tR (HPLC8) ) 5.8 min, 99 area %; H NMR
Hz), 1.2 (m, 2H), 0.71 (m, 2H); 19F NMR δ -126 (m), -141
(m); IR (KBr) νmax 3170, 3043,1684, 1472, 1403, 1315 cm-1.
Anal. Calcd for C12H10F2N2O2: C, 57.15; H, 4.00; N, 11.11.
Found: C, 57.13; H, 3.85; N, 11.02.
(CDCl3) δ 7.8 (m, 1H), 6.6 (bs, 1H), 6.0 (bs, 1H), 2.26 (t,
3H, J ) 2 Hz); 19F NMR δ -118 (s), -130 (m), -141 (m);
IR (KBr) νmax 3523, 3510, 3171, 1704, 1603, 1434, 1383
cm-1. Anal. Calcd for C8H6F3NO: C, 50.80; H, 3.20; N,
7.41. Found: C, 50.65; H, 2.95; N, 7.32.
Preparation of 3-Amino-1-cyclopropyl-6,7-difluoro-8-
methyl-1H-quinazoline-2,4-dione, AQD Core (4). A slurry
of cyclic imide 30 (190 g, 0.754 mol) and K2CO3 (156 g,
1.13 mol, 1.5 equiv) in dioxane (2.1 L) and DMF (2.1 L)
was warmed to 72 °C for 30 min, and then O-(4-nitrophenyl)-
hydroxylamine (122 g, 0.793 mol, 1.05 equiv) was added to
the reaction mixture (an endotherm of 2 °C resulted). After
2 h at 72 °C an additional portion of aminating agent (12.3
g, 0.08 mol, 0.1 equiv) was added, and heating continued
for 20 h. The reaction mixture was allowed to cool, and the
solids that formed were filtered and washed with THF (3 ×
250 mL). The filtrate was concentrated to approximately 1/10
volume (600 mL) in vacuo. The concentrated solution was
poured into ice (1 L) and water (1.4 L) with stirring.
Precipitation of the thick syrup was initiated by adding 1 L
of TBME to the mixture with vigorous stirring for about 15
min providing a powdery beige solid. The solid was collected
and washed with water (2 × 300 mL). The crude solid was
recrystallized from hot IPA (1.5 L) and heptane (1.5 L). The
resulting solid was filtered off and dried (15 mmHg, rt) to
provide pure 4 as a light brown solid, 166 g, 83%. For 4:
mp ) 163-164 °C; tR (HPLC8) ) 14.2 min, 99 area %; 1H
NMR (DMSO-d6) δ 7.73 (t, 1H, J ) 9.3 Hz), 5.4 (s, 2H),
3.4 (m, 1H), 2.6 (t, 3H, J ) 3 Hz), 1.0 (m, 2H), 0.62 (m,
2H); 19F NMR δ -129 (m), -143 (m); IR (KBr) νmax 3333,
3244, 1716, 1637, 1474, 1410, 1308 cm-1. Anal. Calcd for
C12H11F2N3O2: C, 53.93; H, 4.15; N, 15.72. Found: C,
53.72; H, 4.10; N, 15.57.
Preparation of 1-Cyclopropyl-3-(2,4,5-trifluoro-3-me-
thylbenzoyl)urea (29). A solution of amide 28 (121 g, 0.64
mol) in (CH2Cl)2 (1.08 L) was treated at rt with (COCl)2
(72 mL, 0.82 mol, 1.3 equiv) dropwise over 30 min. The
resulting reaction mixture was then heated to and held at 55
°C for 45 min and then warmed to reflux for 17 h. The
resulting reaction mixture was allowed to cool to rt and
concentrated in vacuo to give the crude aroylisocyanate that
was used in the subsequent step without purification. The
crude aroylisocyanate was dissolved in CH2Cl2 (1 L), cooled
to 0 °C, and treated dropwise (1.25 h, -6 to 0 °C) with a
solution of cyclopropylamine (58 mL, 0.83 mol, 1.3 equiv)
in CH2Cl2 (660 mL). The solution was allowed to warm to
rt with stirring overnight (monitoring of the reaction using
TLC and LC/MS). The solvent was removed in vacuo, and
the crude resulting solid was recrystallized from hot toluene
(500 mL) and heptane (200 mL). The resulting white crystals
were collected and dried (15 mmHg, rt) to give 156 g, 90%
yield of 29. For 29: mp ) 146-149 °C; tR (HPLC9) ) 9.2
1
min, 99 area %; H NMR (CDCl3) δ 8.5 (bd, 1H, J ) 6.1
Hz), 8.4 (bs, 1H), 2.8 (m, 1H), 2.29 (t, 3H, J ) 2 Hz), 0.83
(m, 2H), 0.64 (m, 2H); 19F NMR δ -117 (s), -128 (m),
-140 (m); IR (KBr) νmax 3309, 3075, 1705, 1676, 1491,
1228 cm-1. Anal. Calcd for C12H11F3N2O2: C, 52.95; H,
4.07; N, 10.29. Found: C, 52.90; H, 3.94; N, 10.20.
Preparation of 1-Cyclopropyl-6,7-difluoro-8-methyl-
1H-quinazoline-2,4-dione (30). A slurry of NaH (60% in
oil, 112 g, 2.79 mol, 3 equiv) in toluene (2 L) was cooled to
0 °C and treated with DME (1 L). The solid cyclic urea 29
(254 g, 0.931 mol) was then added in 20-g portions over 20
min, while keeping the temperature between -9 and 0 °C.
Once the urea addition was complete, the remaining DME
was added (1 L), and the reaction was allowed to warm to
rt. The reaction vessel was then further warmed to reflux
for 46 h (monitored by TLC and LC/MS). The reaction
mixture was cooled to rt and was poured into a mixture of
HCl (2 M, 600 mL) and ice (600 mL) and this mixture was
stirred overnight, forming a precipitate. The resulting solid
was filtered (filtrate set aside) and recrystallized from THF
(550 mL), toluene (550 mL), and heptane (700 mL). Much
of what was recrystallized was not soluble and was filtered
off (119 g). This material (119 g) along with the 54 g of
crystals that crystallized proved to be pure. The filtrate
mentioned above was placed in a separatory funnel, and the
phases were separated; the aqueous phase was extracted with
THF/EtOAc (1:1, 1 × 1.5 L). The organic phases were
combined and concentrated. This material was recrystallized
(THF 120 mL, PhMe 300 mL, and heptane 200 mL; hot)
and filtered to give an additional 13 g of 30. A total of 186
g of 30 was obtained in 79% yield. For 30: mp ) 231-235
Preparation of {1(S)-[1-(3-Amino-1-cyclopropyl-6-
fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-
7-yl)pyrrolidin-3(R)-yl]ethyl}carbamic Acid tert-Butyl
Ester (31). A mixture of AQD core 4 (158 g, 0.59 mol) and
side-chain 5 (178 g, 0.83 mol, 1.4 equiv) in DMSO (600 mL)
was treated with TMG (195 mL, 1.55 mol, 2.6 equiv) and
warmed to 83 °C and held for 53 h. The reaction mixture
was allowed to cool to rt, poured into half saturated NH4Cl
(3 L), and stirred for 1 h. The resulting precipitate was fil-
tered, and the collected solid was washed with water (1 L).
The solid was dissolved in TBME/EtOAc (1:1, 3 L) and
washed sequentially with half saturated NH4Cl (1 × 1 L) and
0.5 M HCl (2 × 1.5 L). The organic phase was dried (MgSO4)
and filtered and the filtrate was concentrated in vacuo to
obtain a reddish brown foam, 255 g crude, 93%. For crude 31:
tR (HPLC6) ) 26.2 min, 90 area %; 1H NMR (CDCl3) δ 7.73
(d, 1H, J ) 12.9 Hz), 4.5 (bd, 1H, J ) 8.3 Hz), 3.7 (m, 1H),
3.6 (m, 1H), 3.4 (m, 4H), 2.4 (s, 3H), 2.3 (m, 1H), 2.1 (m,
1H), 1.7 (m, 1H), 1.4 (s, 9H), 1.2 (m, 3 H), 1.2 (d, 3H, J )
6.5 Hz), 1.1 (m, 1H), 0.60 (m, 2H); 19F NMR δ -127 (m).
Preparation of 3-Amino-7-[3(R)-(1(S)-aminoethyl)pyr-
rolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazo-
line-2,4-dione Hydrochloride (2). A solution of crude coup-
led product 31 (294 g, ca. 0.89 mol) in a solution of CH2Cl2
(2.4 L) was cooled to 5 °C, and HCl(g) was bubbled into
this solution for 3.5 h (5-15 °C). The reaction was monitored
1
°C; tR (HPLC9) ) 10.8 min, 99 area %; H NMR (CDCl3)
δ 8.5 (bs, 1H), 7.8 (m, 1H), 3.3 (m, 1H), 2.6 (d, 3H, J ) 3
448
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development