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Conclusion
4-(acetylamino)-3-bromo-2-methylphenyl acetate (13) was
lost to the aqueous acetonitrile wash to yield the product
ZD9331 Bromide (12, 56 g 62%) with HPLC purity typically
98% w/w.
Thus exploiting 19th century chemistry overcame an
inherent weakness in the first scaled synthesis, namely an
impurity that increases in concentration through subsequent
processing, always a difficult challenge, but particularly in
this case where the final API is amorphous.
1H NMR δ (DMSO-d6): 2.1 (s, 3H), 2.2 (s, 3H), 2.3 (s,
3H), 5.0 (s, 2H), 7.6 (s, 1H) 7.4 (s, 1H), 9.5 (s, 1H).
ZD9331 Nitrile (14). ZD9331 Bromide (12, 50 g, 0.167
mol), copper(I) cyanide (14.2 g, 0.159 mol), and dimethyl-
formamide (100 mL) were heated at 90 °C under an
atmosphere of nitrogen. After 6 h the mixture was cooled to
60 °C and treated portionwise with zinc powder (13.1 g, 0.2
mol), and then the slurry was reheated to 90 °C, screened
through Celite, cooled to 50 °C, and diluted with water (400
mL). On cooling to 20 °C the product was isolated by
filtration, washed with water, and dried to constant weight
at 50 °C in vacuo to yield the product ZD9331 Nitrile (14,
41.4 g 84%) with HPLC purity typically 83% w/w.
1H NMR δ (DMSO-d6): 2.1 (s, 3H), 2.25 (s, 3H), 2.5 (s,
3H), 5.3 (s, 2H), 7.6 (s, 1H), 7.9 (s, 1H), 10.3 (s, 1H).
ZD9331 Quinacetate HCl (15). Hydrogen chloride gas
(0.12 kg, 3.29 mol) was added over 60 min to a slurry of
ZD9331 Nitrile (14, 0.67 kg, 2.7 mol) in propan-2-ol (6.7
L). On cooling to 30 °C ZD9331 Quinacetate HCl (15)
crystallised out of solution. The product was isolated by
filtration, washed with propan-2-ol, and dried to constant
weight at 50 °C in vacuo to yield the product ZD9331
Quinacetate HCl (15, 0.662 kg 87%) with HPLC purity
typically 94% w/w.
Experimental Section
Reagents were purchased from standard suppliers.
NMR spectra were run at 270 MHz in d6-DMSO solution
and are reported in parts per million downfield from internal
TMS.
HPLC analyses were conducted using a HiChrome RPB
column 25 cm × 0.46 cm, solvent system acetonitrile/water/
TFA 1200/800/1 (v/v/v), flow rate 1 mL/min, and detection
at 235λ.
ZD9331 Bromide (12). Triethylamine (63 mL, 0.45 mole)
was added in one portion to a slurry of ZD9331 Alcohol
(10, 54 g, 0.3 mol equiv), in ethyl acetate (540 mL) at
ambient temperature. The slurry was heated to 50 °C, acetyl
chloride (30 mL, 0.42 mol equiv) was added over 2 h, and
after a further 30 min the mixture was cooled to 20 °C. The
slurry was extracted sequentially with water (2 × 270 mL)
and saturated brine (270 mL). The ethyl acetate extract was
solvent swapped into acetonitrile by distillation. The aceto-
nitrile solution of 4-(acetylamino)-2-methylphenyl acetate
(11) was treated with a solution of 1,3-dibromo-5,5-dimeth-
ylhydantoin (48.6 g, 0.17 mol equiv) in acetonitrile (380 mL)
at 50 °C, and after 60 min the reaction mixture was cooled
to 20 °C and poured into water (1350 mL). ZD9331 Bromide
(12) was isolated by filtration, washed with water, and dried
to constant weight at 50 °C in vacuo. The regioisomer
1H NMR δ (DMSO-d6): 2.1 (s, 3H), 2.4 (s, 3H), 2.7 (s,
3H), 5.2 (s, 2H), 7.7 (s, 1H), 8.1 (s, 1H).
Acknowledgment
We are grateful to BTG International Ltd for permission
to disclose this research.
(6) Burgess, D. A.; Rae, I. D. Aust. J. Chem. 1977, 30, 927-931.
(7) Ogata, Y.; Kawasaki, A.; Sawaki, Y.; Nakagawa, Y. Bull. Chem. Soc. Jpn.
1979, 52 (8), 2399-2401.
(8) Showell, G. A. Synth. Commun. 1980, 10 (3), 241-243.
(9) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron
2005, 61 (43), 10153-10202.
Received for review February 28, 2006.
OP060049A
(10) Shiokawa, Y.; Nagano, M.; Itani, H. EP 268989, 1987, p 59.
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