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out with 8 equiv of vinyl butyl ether and 8% Pd(OAc)2 in the
presence of DPPP at 116 °C in DMF/water, and the product
14 was isolated in 85% yield with >98% purity by HPLC. The
Pd level could be reduced16 from 1411 ppm to 8 ppm by
pretreatment of N-acetylcysteine with 3 N NaOH, followed by
addition of this solution into the suspension of the drug
substance in EtOH at 40 °C.
°C, and a 6% sodium hypochlorite aqueous solution (8.77 kg,
7.06 mol) was added at 7-10 °C over 15 min. The contents
were stirred at 7-10 °C for 8 h. Heptane (2 L), saturated
Na2SO3 solution (400 mL), and saturated Na2CO3 (150 mL)
solutions were added in sequence at 10-20 °C to quench all
unreacted sodium hypochlorite, and the pH of the mixture was
adjusted to 10. The top organic layer was washed with saturated
NaCl solution (300 mL) and concentrated at 50 °C in Vacuo to
recover methyl 3-fluoro-4-methylbenzoate (110 g) as a pale-
yellow solid. The bottom aqueous layer was acidified slowly
with conc HCl (37%) to pH 3-3.5. Isopropyl acetate (4 L)
was added to the suspension, and the mixture was stirred for 5
min. The organic layer was separated and washed with saturated
NaCl solution (500 mL) and water (200 mL). The organic layer
was concentrated at 50 °C in Vacuo to give 8 as a white solid
(67 g, 30% yield). 1H NMR (300 MHz, CD3OD) δ 3.93 (s, 3
H), 4.95 (br, 1 H), 7.76 (dd, J ) 11.1 Hz, 1.35 Hz, 1 H), 7.86
(dd, J ) 1.50, 8.1 Hz, 1 H), 8.00 (t, J ) 7.9 Hz, 1 H); 13C
NMR (300 MHz, CD3OD) δ 53.57, 119.02, 124.95, 126.2,
133.92, 137.34, 161.54, 164.97, 166.80.
Conclusions
The original synthesis of 14 from research was complicated
by a long synthetic sequence (10 + 4 steps) and unacceptable
reagents and intermediates, with a 10% overall yield. Our new
synthesis described here is short (5 + 2 steps) with an overall
yield of 35% and amenable to scale up. The drug substance 14
was obtained by treatment of compound 26 with vinyl butyl
ether in the presence of palladium acetate, DPPP, and cesium
carbonate in DMF/water at 110 °C. This one-pot operation
incorporating three chemical transformations (i.e., Heck reaction,
hydrolysis of vinyl ether, and hydrolysis of ester) was achieved
in 85% yield.
N-(4-Bromo-2-nitrophenyl)-N-ethylphenylamine, 20. A
5-L flask was charged with ethylphenylamine 21 (141.57 g,
1.17 mol) and anhydrous tetrahydrofuran (THF, 2 L). The
resulting solution was cooled to -20 °C, and 2.5 M n-BuLi in
hexane (491.4 mL, 1.228 mol) was slowly added and solution
was warmed to 10 °C. This solution was slowly added to
another flask containing 2-fluoro-5-bromonitrobenzene 22 (198
g, 0.9 mol) in THF (500 mL, anhydrous) at -60 °C. The
reaction was monitored by HPLC. After the reaction was
completed, 2 N HCl (250 mL) and water (250 mL) were added
and the product was extracted with isopropyl acetate (750 mL).
The organic phase was washed with 2 N HCl (3 × 250 mL),
water (250 mL), and brine (500 mL). The solvent was
evaporated to give the crude compound 20 as dark-red solid
(252 g) in 87% yield after recrystallization from i-PrOAc and
heptanes(1 g of compound 20/10 mL of i-PrOAc/15 mL of
Experimental Section
General. Melting points were determined on a Thomas-
Hoover melting point apparatus and are uncorrected. NMR
spectra were recorded on a Bruker AVANCE DPX-300
spectrometer (1H NMR and 13C NMR at 300 MHz). HPLC
method: Dynamax model SD-200; column: Symmetry, C18/5
µm, 4.6 mm × 250 mm; Flow rate: 1.0 mL/min; Eluents: A:B
) 90%:10%, isocratic, A is water with 0.05% TFA (v/v), B is
acetonitrile with 0.05%TFA (v/v). Retention times for com-
pounds are as follows: 20, 17.2 min; 23, 29.6 min; 8, 10.3 min;
25, 28.5 min; 26, 39.1 min; 14, 18.4 min. Reactions were carried
out under an atmosphere of nitrogen unless stated otherwise.
Preparation of Methyl 3-Fluoro-4-methylbenzoate 12. To
a suspension of 3-fluoro-4-methylbenzoic acid 15 (250 g, 97%
purity, 1.57 mol) and methanol (900 mL) was slowly added
chlorotrimethylsilane (188 g, 1.7 mol) at 20-23 °C over 30
min. The hazy contents were warmed to 47 °C and refluxed at
47-52 °C for 30 min to give a homogeneous mixture. The
reaction mixture was stirred at rt for 18 h. The mixture was
concentrated at 35 °C in Vacuo to a thick suspension. Isopropyl
acetate (1.7 L) and saturated NaHCO3 solution (420 mL) were
added, and the mixture was stirred for 10 min. The top organic
layer was washed with saturated NaCl aqueous solution (2 ×
420 mL). The organic layer was separated and dried and
concentrated at 55 °C in Vacuo to give methyl 3-fluoro-4-
methylbenzoate17 as an off-white solid (257 g, 97% yield). 1H
NMR (300 MHz, CD3OD) δ 2.32 (s, 3 H), 3.88 (s, 3 H), 7.34
(t, J ) 7.9 Hz, 1 H), 7.50-7.78, (m, 2 H).
1
heptanes). H NMR (300 MHz, CDCl3) δ 1.25 (t, J ) 7.14
Hz, 3 H), 3.76 (q, J ) 7.14 Hz, 2 H), 6.74 (d, J ) 7.7 Hz, 2
H), 6.87 (t, J ) 7.4 Hz, 1 H), 7.20 (m, 3 H), 7.23 (d, J ) 5.28
Hz, 1 H), 7.25 (s, 1 H); 13C NMR (300 MHz, CDCl3) δ 13.0,
47.3, 116.2, 117.8, 121.7, 128.9, 129.2, 129.9, 136.6, 140.2,
146.3, 146.5; m/e (M + 1) ) 322.
N-(4-Bromo-2-nitrophenyl)-ethyl-(5,5,8,8-tetramethyl-
5,6,7,8-tetrahydro-naphthalen-2-yl)-amine, 23. A flask was
charged with compound 20 (380 g, 1.18 mol), compound 2
(433.2 g, 2.37 mol, 2 equiv), and acetonitrile (700 mL). The
suspension was stirred, and the temperature was dropped from
22 to 12 °C. Three equal portions of aluminum chloride
(anhydrous, 473.3 g, 7.11 mol, 3.0 equiv) were slowly added
and the temperature was raised to 65 °C. The reaction mixture
was heated to 70 °C and maintained at this temp for 6 h. The
reaction was monitored by HPLC until compound 20 was
consumed completely. The cooled reaction mixture was slowly
added to a flask containing toluene (3.0 L) and water (4.5 L).
The phases were separated, and the organic phase was washed
with water (1000 g), saturated NaHCO3 (1.0 L), and brine (1.0
L) and was evaporated to dryness to give 465 g (91%, it
Preparation of 2-Fluoroterephthalic Acid 4-Methyl Ester
8. To a solution of methyl 3-fluoro-4-methylbenzoate 24 (200
g, 1.19 mol) in acetonitrile (1 L) were added ruthenium
trichloride hydrate (2.4 g), 2,2′-bispyridyl (3.7 g, 23.8 mmol),
tetrabutylammonium bromide (3.8 g, 11.9 mmol), and sodium
bicarbonate (300 g, 3.57 mol). The mixture was cooled to 5
(16) Garrett, C.; Prasad, K. AdV. Synth. Catal. 2003, 346, 889.
(17) Gauuan, P. F.; Trova, M. P.; Gregor-Boros, L.; Bocckino, S. B.; Crapo,
J. D.; Day, B. J. Bioorg. Med. Chem. 2002, 10 (9), 3013.
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Vol. 12, No. 6, 2008 / Organic Process Research & Development