Scheme 5. Hydrolysis of 8 to 15
mol), sodium hydroxide (16.06 g, 0.402 mol), and tetra-
hydrofuran (113 mL) is heated to reflux (67 °C) for 5 h.
The solution is diluted with another portion of tetrahydro-
furan (169 mL) and cooled to -10 °C. A 20% solution of
butyllithium in cyclohexane (122.3 g, 0.382 mol) is added
at this temperature followed by dimethyl carbonate (51.7 g,
0.573 mol). Afterwards, the solution is stirred at -10 °C
for 2 h. Concentrated hydrochloric acid (38 mL) and water
(125 mL) are added, and the organic solvents are distilled
off at reduced pressure. After addition of toluene (345 mL)
to the suspension, the pH of the water phase is adjusted to
1.5 using hydrochloric acid (34 mL). After phase separation
at 75 °C, the organic phase is washed with another portion
of water (120 mL), concentrated at reduced pressure, and
allowed to crystallize at 0 °C to yield 81.2 g of pure 5
The clean removal of the methoxycarbonyl protecting
group to 10-methoxy-iminostilbene 8 is performed in poly-
(ethylene glycol) 200/50% aqueous sodium hydroxide (4
h/100 °C). The product is isolated in 98% yield and high
purity by adding water (to dissolve all of the formed sodium
carbonate), cooling to 20 °C, filtration, washing, and drying.
The last two steps of the synthesis are combined in a one-
pot process. If compared to the synthesis of carbamazepine
3, the carbamoylation of 8 to 9 is remarkably enhanced by
the activating effect of the 10-methoxy protecting group.24
Whereas the carbamoylation of iminostilbene 2 needs
relatively drastic acidic conditions and elevated temperature
(isocyanic acid and dry HCl in ethyl acetate, 65 °C), the
carbamoylation of 8 can be performed at ambient temperature
under mild acidic conditions (sodium cyanate in acetic acid).
Crucial for a clean reaction is the complete absence of water
to avoid hydrolysis of the enol ether function.25 Once
hydrolyzed to 15 (Scheme 5), no carbamoylation of 15 to 1
takes place under the applied reaction conditions.26
1
(75%): mp 141-142 °C. H NMR (400 MHz, DMSO-d6)
δ 3.3-3.6 (m, 2H, CH2), 3.6 (s, 3H, OCH3), 7.1-7.5 (m,
9H, arom H), 12.3 (s, 1H, COOH); MS (ES-) m/z 284 (M
- H); IR (KBr) 3487, 3062, 2957, 1718, 1494, 1340, 1325,
1315, 1282, 1067 cm-1. Anal. Calcd for C16H15NO4: C,
67.36; H, 5.30; N, 4.91; O, 22.43. Found: C, 67.42; H, 5.26;
N, 4.85; O, 22.55.
2-[(Methoxycarbonyl)phenylamino]benzeneacetic Acid
(5) with Methyl Chloroformate. A mixture of 10 (80 g,
0.382 mol), sodium hydroxide (16.82 g, 0.421 mol), and
tetrahydrofuran (113 mL) is heated to reflux (67 °C) for 5
h. The solution is diluted with another portion of tetrahy-
drofuran (169 mL) and cooled to -40 °C. A 20% solution
of butyllithium in cyclohexane (122.3 g, 0.382 mol) is added
at this temperature, followed by methyl chloroformate (36.1
g, 0.382 mol). Afterwards, the solution is stirred at -40 °C
for 2 h. Concentrated hydrochloric acid (8 mL) and water
(125 mL) are added, and the organic solvents are distilled
off at reduced pressure. After addition of toluene (400 mL)
to the suspension, the pH of the water phase is adjusted to
1.7 using hydrochloric acid (30 mL). After phase separation
at 75 °C, the organic phase is washed with another portion
of water (120 mL), concentrated at reduced pressure, and
allowed to crystallize at 0 °C to yield 94.0 g of pure 5 (86%).
10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carbox-
ylic Acid Methyl Ester (6). Acid 5 (285.3 g, 1.0 mol) is
added to warm (90 °C) polyphosphoric acid (83% P2O5, 684
g, 4.0 mol) and stirred at 95 °C for 3 h. The reaction is cooled
to 80 °C, water (2500 mL) is carefully added while the
temperature is kept below 98 °C. The reaction mixture is
extracted with toluene (3 × 1000 mL), and the combined
organic phases are washed with sodium hydrogen carbonate
solution (5%, 1000 mL) and concentrated to a weight of 975
g. The solution is cooled to 0 °C and stirred at 0 °C for 3 h
to afford white crystals which are filtered and dried to give
pure 6 (194 g, 70%): mp 139-141 °C. 1H NMR (400 MHz,
CDCl3) δ 3.79 (s, 3H, COOCH3), 3.82-4.40 (AB, 2H, JAB
) 14.3 Hz), 7.2-8.1 (m, 8H, arom H); MS (ES-) m/z 266
(M - H); IR (KBr) 1714, 1674 1439, 1340,771 cm-1. Anal.
Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24; O, 17.96.
Found: C, 71.72; H, 4.88; N, 5.21; O, 17.98.
In the last chemical step, enol ether 9 is hydrolyzed with
aqueous HCl, leading to oxcarbazepine crude, which is
isolated by addition of water and filtration. After thoroughly
washing27 with water and acetone, the wet filter cake is
recrystallized from formic acid and water, and pure oxcar-
bazepine 1 is isolated by filtration, washing, and drying.
3. Summary
Starting from 1,3-dihydro-1-phenyl-2H-indol-2-one 10,
the entire new production process for oxcarbazepine has an
overall yield of around 60% and comprises only three isolated
and dried steps, namely the intermediates 5, 8, and the final
product, oxcarbazepine 1. Unlike the old production process,
no halogenated solvents are required. The efficiency of the
process is mainly based on avoiding any oxidation and
reduction steps and on using the dianion strategy for the
straightforward introduction of the methoxycarbonyl protect-
ing group in 5.
4. Experimental Section
2-[(Methoxycarbonyl)phenylamino]benzeneacetic Acid
(5) with Dimethyl Carbonate. A mixture of 10 (80 g, 0.382
(24) Under comparable reaction conditions, the carbamoylation of 8 is ca. 500
times faster than that of 2.
(25) Addition of small amounts of 2-methoxypropene, which eagerly consumes
water under the applied reaction condition, helps to suppress the hydrolysis
to 15.
(26) Carbamoylation of 15 to 1 could be achieved only by using chlorosulfonyl
isocyanate. No reaction occurs with isocyanic acid at 50 °C, and no
10,11-dihydro-10-chloro-5H-dibenz[b,f]azepine-5-carbonyl chloride is formed
if phosgene is added to 15.
(27) Washing with water is performed to eliminate sodium chloride and
acetamide; the latter is formed in a parallel reaction of acetic acid with
isocyanic acid, T. Takahashi et al. Japan Patent, JP 48020522, 1973. Washing
with acetone is performed to eliminate a drying step. The major part of
water has to be reduced from the wet filter cake to keep the amount of
formic acid small for dissolving the material in the final purification step.
10-Methoxy-5H-dibenz[b,f]azepine-5-carboxylic Acid
Methyl Ester (7). Acid 5 (285.3 g, 1.0 mol) is added to
276
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Vol. 9, No. 3, 2005 / Organic Process Research & Development