reached greater than 95:1 (w/w) by GC. The resulting slurry
was diluted with heptane (82.0 kg), cooled to -15 °C, and
mixed for 6 h. The product was isolated by filtration, rinsed
with heptane (54.7 kg), and dried in vacuo at 45 °C for 12 h to
afford 17.4 kg (96%, purity > 99% by HPLC) of 7 as a white
solid. Mp: 130–131 °C. 1H NMR [CDCl3]: δ 4.71 (s, 2H), 7.50
(dd, J ) 8.5, 1.8 Hz, 1H), 7.54 (dd, J ) 8.7, 2.0 Hz, 1H), 7.67
(d, J ) 8.6 Hz, 1H), 7.72 (d, J ) 8.5 Hz, 1H), 7.76 (s, 1H),
7.97 (d, J ) 1.9 Hz, 1H). 13C NMR [CDCl3]: δ 46.4, 120.3,
127.0, 127.1, 127.5, 129.3, 129.5, 129.5, 131.2, 133.7, 135.0.
CI-MS (NH3): m/z 254 (M + NH4+ – 18). Anal. Calcd for
C11H8BrCl: C, 51.70; H, 3.16; Br, 31.27; Cl, 13.87. Found: C,
52.11; H, 2.99; Br, 31.33 0.19; Cl, 13.60.
(6-Bromo-naphthalen-2-yl)-acetonitrile, 8. To a reaction
vessel were charged 2-bromo-6-chloromethyl-naphthalene (7)
(17.4 kg, 68.1 mol), sodium cyanide (97%, 4.5 kg, 89.0 mol),
acetonitrile (136.8 kg), and water (21.3 kg). The reaction
mixture was heated to reflux (∼80 °C), and agitated for 15 h
or until 7 was consumed by HPLC. The reaction mixture was
cooled to 30 °C and quenched with water (150.0 kg). The
mixture was distilled under reduced pressure to approximately
150 L volume and diluted with water (200 kg). The resulting
slurry was cooled to 0 °C and mixed for 5 h. The product was
collected by filtration, rinsed with water (300 kg), and purged
with nitrogen for 10 h to give 26.5 kg (loss on drying ) 39.8%,
95% yield, purity ) 97.6% by HPLC) wet cake of 8. The wet
cake was used directly in the next step. However, an analytical
sample was obtained by drying the wet cake in vacuo at 45 °C
for 20 h. Mp: 118–119 °C. 1H NMR [CDCl3]: δ 3.86 (s, 2H),
7.38 (dd, J ) 8.5, 1.8 Hz, 1H), 7.57 (dd, J ) 8.7, 1.9 Hz, 1H),
7.68 (d, J ) 8.8 Hz, 1H), 7.74 (d, J ) 8.5 Hz, 1H), 7.77 (s,
1H), 7.98 (d, J ) 1.8 Hz, 1H). 13C NMR [CDCl3]: δ 24.1, 117.3,
120.3, 126.2, 126.5, 127.4, 127.8, 129.0, 129.5, 129.9, 131.4,
133.4. CI-MS (NH3): m/z 263 (M + NH4+). Anal. Calcd for
C12H8BrN: C, 58.56; H, 3.28; Br, 32.47; N, 5.69. Found: C,
58.31; H, 3.24; Br, 32.19; N, 5.39.
slowly while maintaining a nitrogen atmosphere, and the
mixture was agitated for 0.5 h. The upper organic layer was
separated and then washed with 5% aqueous NaHCO3 (290
kg) and 25% aqueous NaCl (200 kg), respectively. The organic
solution was distilled under reduced pressure to ∼70 L volume,
and heptane (150.5 kg) was charged into the slurry. The slurry
was mixed at 25 °C for 6 h, then at -5 °C for 2 h. The product
was isolated by filtration, rinsed with heptane (27.5 kg), and
dried in vacuo at 60 °C for 20 h to afford 14.5 kg (90%, purity
) 99.1% by HPLC) of 9 as a tan solid. Mp: 104–105 °C. 1H
NMR [CDCl3]: δ 1.47 (s, 1H), 3.00 (t, J ) 6.5 Hz, 2H), 3.93
(t, J ) 6.5 Hz, 2H), 7.36 (dd, J ) 8.5, 1.8 Hz, 1H), 7.51 (dd,
J ) 8.8, 1.9 Hz, 1H), 7.63 (s, 1H), 7.64 (d, J ) 8.8 Hz, 1H),
7.68 (d, J ) 8.5 Hz, 1H), 7.95 (d, J ) 1.9 Hz, 1H). 13C NMR
[CDCl3]: δ 39.4, 63.4, 119.0, 127.0, 127.1, 128.1, 128.8, 129.1,
129.3, 131.6, 133.0, 136.3. CI-MS (NH3): m/z 268 (M + NH4+),
250 (M + NH4+ – H2O). Anal. Calcd for C12H11BrO: C, 57.39;
H, 4.42; Br, 31.82. Found: C, 57.27; H, 4.50; Br, 31.68.
2-[6-(2-Hydroxy-ethyl)-naphthalen-2-yl]-2H-pyridazin-3-
one, 4. To a reaction vessel were charged 2-(6-bromo-
naphthalen-2-yl)-ethanol 5 (14.5 kg, 57.7 mol), CuCl (286 g,
2.9 mol, 5 mol %), 8-hydroxyquinoline (420.0 g, 2.9 mol, 5
mol %), K2CO3 powder (12.0 kg, 87.0 mol), pyridazinone 12
(8.3 kg, 86.4 mol), and DMF (66.0 kg). The reaction vessel
was evacuated and backfilled with nitrogen (repeated 3 times).
The reaction vessel was then pressurized with nitrogen to 5 psi
and isolated. The mixture was heated to 140 °C and maintained
at that temperature for 18 h or until 5 was consumed by HPLC
(Caution: the internal pressure will rise, so vent as needed). The
reaction mixture was cooled to 20 °C, and ethyl acetate (270
kg), 30% aqueous NH4OH (105 kg), and 4% Na2EDTA/23%
aqueous NaCl solution (140 kg) were added. The mixture was
agitated for 0.5 h, filtered through a pad of filter aid, and then
rinsed with ethyl acetate (20 kg). The lower aqueous solution
was extracted with ethyl acetate (105 kg × 2). The combined
organics were washed with 4% Na2EDTA/23% aqueous NaCl
solution (280 kg × 3). The organic solution was assayed to
contain 13.2 kg (85% assayed yield, purity ) 92.3%) of the
product 4 and was used directly in the next step without further
purification. However, an analytical sample was obtained by
recrystallization from ethyl acetate/heptane. Mp: 139–140 °C.
1H NMR [CDCl3]: δ 1.9 (s, br, 1H), 3.00 (t, J ) 6.4 Hz, 2H),
3.89 (t, J ) 6.4 Hz, 2H), 7.03 (dd, J ) 9.5, 1.7 Hz, 1H), 7.23
(dd, J ) 9.5, 3.8 Hz, 1H), 7.36 (dd, J ) 8.5, 1.7 Hz, 1H), 7.67
(s, br, 1H), 7.66 (dd, J ) 8.5, 2.2 Hz, 1H), 7.80 (d, J ) 8.5 Hz,
1H), 7.85 (d, J ) 8.8 Hz, 1H), 7.90 (dd, J ) 3.8, 1.8 Hz, 1H),
8.06 (d, J ) 2.0 Hz, 1H). 13C NMR [DMSO-d6]: 39.5, 63,4,
123.1, 123.5, 126.9, 127.8, 127.9, 128.3, 139.8, 130.9, 131.4,
132.5, 126.5, 136.9, 138.2, 159.8. CI-MS (NH3): m/z 283 (M
+ NH4+), 267 (M + NH4+ – NH3). Anal. Calcd for: C, 72.16;
H, 5.30; N, 10.52. Found: C, 71.76; H, 5.28; N, 10.46.
(6-Bromo-naphthalen-2-yl)-acetic acid, 9. To a reaction
vessel were charged (6-bromo-naphthalen-2-yl)-acetonitrile 8
(26.5 kg, 60.2% potency, 64.8 mol), water (380.0 kg), acetic
acid (125.4 kg), and sulfuric acid (81.0 kg). The slurry was
heated to reflux (∼110 °C) and mixed for 20 h or until 8 was
consumed by HPLC. The slurry was cooled to 25 °C, diluted
with water (120.0 kg), and mixed for 4 h. The product was
isolated by filtration, rinsed with water (180 kg), and dried in
vacuo at 60 °C for 20 h to afford 17.1 kg (99%, purity ) 96.4%
1
by HPLC) of 9 as a tan solid. Mp: 178–180 °C. H NMR
[DMSO-d6]: δ 3.75 (s, 2Η), 7.48 (dd, J ) 8.5, 1.7 Hz, 1H),
7.60 (dd, J ) 8.5, 1.9 Hz, 1H), 7.80 (s, 1H), 7.83 (d, J ) 6.1,
1H), 7.85 (d, J ) 8.1 Hz, 1H), 8.05 (d, J ) 1.9 Hz, 1H), 12.41(s,
br, 1H). 13C NMR [DMSO-d6]: δ 40.7, 118.3, 126.4, 127.3,
128.5, 128.7, 128.9, 129.2, 130.9, 132.5, 133.0, 171.7. CI-MS
(NH3): m/z 282 (M + NH4+).
2-(6-Bromo-naphthalen-2-yl)-ethanol, 5. A borane–THF
complex solution (1 M in THF, d ) 0.90, 80.1 kg, 89.0 mol)
was added slowly to slurry of (6-bromo-naphthalen-2-yl)-acetic
acid (9) (17.1 kg, 64.5 mol) in toluene (285.5 kg) at <30 °C.
The solution was mixed for 1 h or until 9 was consumed by
HPLC. Citric acid 10% aqueous solution (290 kg) was added
Toluene-4-sulfonic Acid 2-[6-(6-Oxo-6H-pyridazin-1-yl)-
naphthalen-2-yl]-ethyl Ester, 11. The above organic solution
of 4 in ethyl acetate was concentrated to ∼75 L volume, and
acetonitrile (280 kg) was added. The solution was distilled to
∼75 L volume and diluted with acetonitrile (140 kg). The
solution was added to a reaction vessel containing TsCl (19.8
kg, 103.9 mol) and DMAP (635 g, 5.2 mol) and was followed
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Vol. 11, No. 6, 2007 / Organic Process Research & Development