4 h, a white crystalline solid was recovered (26.3 kg, 78.4%th).
1H NMR (400 MHz, CDCl3): δ 1.37 (s, 12 H), 5.08 (s, 2 H),
6.88 (d, 1 H), 7.09 (dd, 1 H), 7.17 (dd 1 H), 7.36 (dd, 1 H),
7.68 (d, 1 H), 7.94 (t, 1 H). 13C NMR (100 MHz, CDCl3): δ
ppm 24.9, 63.8, 83.8, 113.3, 115.6 (d, J ) 24 Hz), 123.3 (d, J
) 13 Hz), 124.3 (d, J ) 3 Hz), 126.2, 130.0 (d, J ) 5 Hz),
132.2, 133.9 (d, J ) 10 Hz), 136.4, 159.4 (d, J ) 247 Hz),
161.3. Anal. Calcd for C19H20BCl2FO3: C, 57.36; H, 5.07; B,
2.97; Cl, 17.26; F, 3.36. Found: C, 57.42; H, 4.98; B, 3.01; Cl,
17.49; F, 3.11.
Ethyl 6-(Hydroxymethyl)-2-pyrdinecarboxylate (9). To
a stirred solution of diethyl dipicolinate 8 (50 g, 1 wt, 0.226
mol) in ethanol (10 vol, 500 mL) was added sodium borohy-
dride (5 g, 0.1 wt, 0.132 mol) and the mixture stirred at ambient
temperature for 6 h. Additional sodium borohydride (1.6 g,
0.032 wt, 0.043 mol) was added and stirring continued
overnight. Water (50 mL, 1 vol) was added followed by glacial
acetic acid (10 mL, 0.2 vol) and the mixture stirred for 30 min.
The solvent was evaporated and the residue dissolved in
dichloromethane (150 mL, 3 vol) and water (100 mL, 2 vol).
The layers were separated and the aqueous phase further
extracted with dichloromethane (2 × 100 mL, 2 × 2 vol). The
combined dichloromethane solution was washed with sat. aq.
sodium bicarbonate (250 mL, 5 vol) then water (100 mL, 2
vol,) and the solvent evaporated to leave the crude product as
a white solid (29 g). The crude product was recrystallised from
toluene (150 mL, 3 vol), filtered, and dried to constant weight,
giving the product as a white crystalline solid (26.6 g, 65%th).
1H NMR (400 MHz, D2O): δ 1.43 (t, 3 H), 4.01 (t, 1 H), 4.46
(q, 2 H), 4.88 (d, 2 H), 7.55 (d, 1 H), 7.84 (t, 1 H), 8.03 (d, 1
H); MS (ES+): MH+ ) 182.
Ethyl 6-(Chloromethyl)-2-pyrdinecarboxylate (10). Thio-
nyl chloride (13.8 mL, 0.48 vol, 0.188 mol) was added to a
stirred solution of hydroxymethylpyridine 9 (28.5 g, 1 wt, 0.157
mol) in DCM (200 mL, 7 vol) at 10-15 °C and the mixture
stirred at 20-25 °C for 1 h. The solvent was evaporated and
the residue partitioned between toluene (100 mL, 3.5 vol) and
saturated sodium hydrogen carbonate (100 mL, 3.5 vol). The
layers were separated, and the organic phase was washed with
water (150 mL, 5.25 vol). The solvent was removed to leave a
pale oil which solidified on standing to a low melting beige
solid (29.5 g, 95%th). 1H NMR (400 MHz, CDCl3): δ 1.43 (t,
3 H), 4.49 (q, 2 H), 4.80 (s, 2 H), 7.72 (d, 1 H), 7.89 (t, 1 H),
8.07 (d, 1 H); MS (ES+): MH+ ) 200.
Sodium 6-[(5-Chloro-2-{[(4-chloro-2-fluorophenyl)methyl]-
oxy}phenyl)methyl]-2-pyridinecarboxylate (12). From Su-
zuki Coupling of Boronate 7 and Chloride 10. Boronate 7 (23
kg, 1 wt), chloromethylpyridine 10 (11.55 kg, 0.502 wt, 1 equiv)
and potassium carbonate (16.05 kg, 0.698 wt, 2 equiv) were
charged to the reaction vessel. Toluene (205 L, 9 vol) and EtOH
(23 L, 1 vol) were added, and the suspension was degassed by
three cycles of evacuation followed by nitrogen purge. 2-Di-
cyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (Dav-
ePhos) (0.228 kg, 0.0099 wt, 1 mol%) was added and the
reaction vessel again evacuated and purged with nitrogen before
tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3) (0.265
kg, 0.0115 wt, 0.5 mol%) was added and the vessel again
evacuated and purged with nitrogen two times. The suspension
was heated to reflux (86 °C); after 90 min further portions of
DavePhos (0.046 kg, 0.0020 wt, 0.10 mol%) and Pd2(dba)3
(0.053 kg, 0.0023 wt, 0.10 mol%) were added, and the reaction
was returned to reflux. After a further 90 min further portions
of DavePhos (0.046 kg, 0.0020 wt, 0.10 mol%) and Pd2(dba)3
(0.053 kg, 0.0023 wt, 0.10 mol%) were added, and the reaction
was returned to reflux. The reaction was cooled to 80 °C,
trimercaptotriazine (TMT) (0.62 kg, 0.027 wt, 6 equiv wrt Pd)
added, and the reaction was returned to reflux for a further 3 h,
before being cooled to ambient temperature. The solids were
removed by filtration, washing with toluene (58 L, 2.5 vol).
The filtrate was washed with water (2 × 115 L, 2 × 5 vol).
The toluene solution thus obtained was concentrated by
atmospheric pressure distillation to ∼3 vol before being cooled
to 75 °C, diluted with EtOH (250 L, 11 vol), and further
concentrated by atmospheric pressure distillation to ∼7.5 vol.
Further EtOH (250 L, 11 vol) was added and the reaction
mixture again concentrated to 7.5 vol. The reaction mixture was
heated to 70 °C and treated with aqueous sodium hydroxide
(87 L, 2 M aqueous solution, 3.8 vol), followed by heating at
reflux for a further 45 min. The reaction was cooled to 50 °C
and held at this temp for 1 h before the hot solution was filtered,
washing with 2:1 EtOH/H2O (28 L, 1.2 vol) at 50 °C. The
filtrate was heated to reflux (82 °C) before being slowly diluted
with water (173 L, 7.5 vol) at a rate to maintain the internal
temperature above 75 °C. After complete addition the transpar-
ent orange solution was cooled to 45 °C and seeded with the
product 12 (0.11 kg, 0.005 wt). The seeded solution was cooled
to room temperature over at least 1 h and stirred at this temp
for at least 2 h. The product was collected by filtration, washing
with 50% aqueous ethanol (70 L, 3 vol) followed by PhMe
(70 L, 3 vol) and dried under vacuum at 70 °C until its water
content was under 1% w/w (as determined by Karl Fischer
analysis) to yield the product as an off-white solid (19.35 kg,
1
78%th). H NMR (400 MHz, methanol-d4): δ 4.18 (s, 2 H),
5.09 (s, 2 H), 7.02 (d, 2 H, J ) 8 Hz), 7.20 (m, 3 H), 7.25 (d,
1 H, J ) 2.5 Hz), 7.30 (t, 1 H, J ) 8 Hz), 7.79 (t, 1 H, J ) 7.5
Hz), 7.96 (d 1 H, J ) 7.5 Hz); 13C NMR (100 MHz, methanol-
d4): δ 39.2, 64.7, 114.5, 116.9, 122.4, 124.2, 124.8, 125.9, 127.2,
128.7, 131.6, 132.0, 132.1, 132.2, 135.7, 138.3, 156.2, 156.3,
160.7, 173.4.
Alkylation of Hydrogenation Product 17. Phenol 17 (100 g,
1 wt) was suspended in EtOH (900 mL, 9 vol) and treated with
K2CO3 (0.95 wt, 2 equiv) followed by 4-Cl-2-F-benzyl bromide
4 (0.49 vol, 1.04 equiv). The reaction was heated to reflux for
2 h, filtered whilst hot, washing through with ethanol (100 mL,
1 vol). NaOH (510 mL, 5.1 vol of a 2 M aqueous solution, 3
equiv) was added and the reaction heated at reflux for a further
1 h. The hot reaction mixture was diluted with H2O (1 L, 10
vol) before cooling to 56 °C and seeding. The slurry was cooled
to 50 °C over 1 h then further cooled to 20 °C over 2 h. The
slurry was stirred at 20 °C for 16 h before the product was
collected by filtration, washing with 2:3 EtOH/H2O (1 L, 10
vol) followed by PhMe (1 L, 10 vol). The cake was dried
overnight at 40 °C under vacuum to furnish the desired product
as a fluffy white solid (138.4 g, 94%th). The data were in
accordance with those reported above.
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Vol. 14, No. 4, 2010 / Organic Process Research & Development