Experimental Section
C16H17N3O: C, 71.89; H, 6.41; N, 15.72. Found: C, 71.89; H,
6.40; N, 15.78.
4-[1-(Cyclopropylcarbonyl)-2-oxopropoxy]-2,6-dimethyl-
benzonitrile (4). A dried, inerted reactor was charged with
1-cyclopropylbutane-1,3-dione 1 (9 kg; 71.3 mol) and dichlo-
romethane (65 kg), and the solution was cooled to 0-5 °C.
Trimethylsilyl chloride (7.8 kg; 71.3 mol) was added, followed
by a dichloromethane line wash (3 kg), maintaining the
temperature between 0-5 °C and the mixture was aged for 30
min at 0-5 °C. A solution of N-chlorosuccinimide (9.34 kg;
69.9 mol) in dichloromethane (298 kg) was then added,
carefully controlling the temperature at 0-5 °C (addition took
65 min), followed by a dichloromethane line wash (12 kg). The
reaction was stirred for 60 min at this temperature.
The reaction mixture was warmed to 20 °C, hydrochloric
acid (2 M, 45 kg) was added, and the mixture was stirred for
5 min. The aqueous phase was discarded, and the dichlo-
romethane solution was then washed with hydrochloric acid (2
M, 45 kg), and water (2 × 45 kg). The reaction mixture was
concentrated under vacuum (at 20 °C) to approximately 22 L,
acetonitrile (36 kg) was added, and the mixture was concentrated
under vacuum to 22 L. This process was repeated to give a
solution of 2-chloro-1-cyclopropylbutane-1,3-dione 2 in aceto-
nitrile for further processing.
A solution of 4-hydroxy-2,6-dimethylbenzonitrile 3 (9.9 kg;
67.38 mol) and diisopropylethylamine (8.8 kg; 67.38 mol) in
acetonitrile (64 kg) was heated to reflux, and the previously
prepared solution of chloride 2 in acetonitrile was added over
50 min, followed by an acetonitrile line wash (2 kg). The
resulting mixture was stirred at reflux for 15 h. The reaction
mixture was concentrated to ∼25 L, and then the solvent was
exchanged to isopropanol through a series of three distill-and-
replace cycles, to give a final solution volume of ∼85 L. The
solution was cooled to 0 °C and the resulting slurry was aged
for 90 min. The solid was isolated by filtration, washed with
isopropanol (2 × 17 kg), and dried at 55 °C under vacuum to
give the title product 4 (10.88 kg; 60%) as a pale-tan solid. Mp
118 °C; 1H NMR (400 MHz, CDCl3) δ: 6.72 (s, 2H), 2.51 (s,
6H), 1.98 (s, 3H), 1.87 (m, 1H), 1.15 (m, 2H), 0.91 (m, 2H).
13C NMR (100 MHz, CDCl3) δ: 11.22, 14.03, 18.96, 21.03,
107.23, 113.70, 117.27, 130.58, 144.91, 161.13, 178.57, 194.44.
Anal. Calcd For C16H17NO3: C, 70.83; H, 6.31; N, 5.16. Found:
C, 70.74; H, 6.32; N, 5.14.
4-[(3-Cyclopropyl-5-methyl-1H-pyrazol-4-yl)oxy]-2,6-di-
methylbenzonitrile (5). Hydrazine monohydrate (2.00 kg; 40.1
mol) was added to a solution of ether 4 (10.88 kg; 40.1 mol) in
a mixture of denatured ethanol (5% methanol) (54 L) and acetic
acid (2.4 kg; 40.1 mol), carefully maintaining the temperature
below 30 °C (exothermic addition). The resulting solution was
stirred at 20 °C for 1 h. Water (54 L) was then added in one
portion, and then further water (54 L) was added over 90 min.
The resulting slurry was aged for 4 h and then filtered, washing
with water (2 × 25 L), to give the title product 5 (9.95 kg;
93%) as a white solid after drying for 30 h at 55 °C under
vacuum. Mp 122-125 °C; 1H NMR (400 MHz, CDCl3) δ: 6.66
(s, 2H), 2.48 (s, 6H), 2.10 (s, 3H), 1.69 (m, 1H), 0.81 (m, 4H).
13C NMR (100 MHz, CDCl3) δ: 6.02, 6.33, 9.59, 20.97, 106.69,
113.98, 117.49, 133.19, 144.56, 161.54. Anal. Calcd For
4-({3-Cyclopropyl-5-methyl-1-[(methylsulfanyl)methyl]-
1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile Hydrogen Sul-
fate (6a). A solution of pyrazole 5 (6.85 kg; 25.6 mol) in
anhydrous 1,2-dimethoxyethane (DME, 18.0 kg) was added to
a slurry of potassium tert-butoxide (5.75 kg; 51.2 mol) in
anhydrous DME (18.0 kg) whilst maintaining the temperature
below 20 °C. Once the addition was complete, the slurry was
aged at 22 °C for 45 min, and then a solution of chloromethyl
methyl sulfide (4.99 kg; 51.2 mol) in anhydrous DME (23.8
kg) was added over 90 min, maintaining the temperature below
30 °C throughout. The reaction was stirred at 20-25 °C for
2 h. Aqueous ammonia (4.5 M; 48 L) was then added,
maintaining the temperature between 20-25 °C. After the
mixture stirred for 20 min, isopropyl acetate (30 kg) was added,
and the phases were separated. The aqueous phase was extracted
with a second portion of isopropyl acetate (30 kg) and then
disposed to waste. The combined organic extracts were washed
successively with water (34 L), sulfuric acid (2 M, 36 L), and
water (34 L) and were then concentrated to ∼70 L by
distillation; isopropyl acetate (19 kg) was added. and the solution
was again concentrated to ∼70 L. The solution was cooled to
50 °C, and concentrated sulfuric acid (2.6 kg; 25.6 mol) was
added, followed by an isopropyl acetate line rinse (1.2 kg). The
resulting slurry was stirred at 50 °C for 2 h, then cooled to 20
°C over 4 h, and then aged at 20 °C for 6 h before the solid
was isolated by filtration, washing with isopropyl acetate (30
L) to give crude product 6a/7a (5.38 kg) as a white solid after
drying under vacuum.
The crude product 6a/7a (5.38 kg) was suspended in
acetonitrile (16.7 kg), the resulting slurry was stirred at 50 °C
for 2 h and then cooled to 20 °C over 2 h. The slurry was then
aged at 20 °C for 6 h before the solid was isolated by filtration,
washing with acetonitrile (2 × 6.2 kg) to give pure hydrogen-
sulfate salt 6a as a white solid (4.02 kg; 37%) after drying at
50 °C under vacuum. Mp 157-161 °C; 1H NMR (400 MHz,
DMSO-d6) δ: 11.57 (br. s. 2H), 6.74 (s, 2H), 5.12 (s, 2H), 2.39
(s, 6H), 2.08 (s, 3H), 2.05 (s, 3H), 1.52 (m, 1H), 0.66 (m, 4H).
13C NMR (100 MHz, DMSO-d6) δ: 4.38, 4.99, 10.37, 14.41,
20.36, 52.02, 106.00, 113.65, 117.01, 132.27, 133.72, 138.73,
144.38, 161.01. Anal. Calcd. For C18H21N3OS.H2SO4: C, 50.81;
H, 5.45; N, 9.87; S, 15.07. Found: C, 50.75; H, 5.38; N, 9.97;
S, 14.94.
4-({3-Cyclopropyl-5-methyl-1-[(methylsulfanyl)methyl]-
1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile (6): prepared
by dissolving 6a in a mixture of water and ethyl acetate,
followed by concentration of the organic phase. 1H NMR (400
MHz, CDCl3) δ: 6.64 (s, 2H), 5.02 (s, 2H), 2.48 (s, 6H), 2.17
(s, 3H), 2.13 (s, 3H), 1.60 (m, 1H), 0.78 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ: 6.71, 6.76, 8.59, 14.51, 21.00, 52.62,
106.73, 113.98, 117.47, 129.94, 134.09, 144.51, 144.86, 161.46.
4-({5-Cyclopropyl-3-methyl-1-[(methylsulfanyl)methyl]-
1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile Hydrogen Sul-
fate (7a): prepared from 7 (isolated by chromatography) and
concentrated sulfuric acid in isopropyl acetate in analogous
fashion to 6a. 1H NMR (400 MHz, DMSO-d6) δ: 11.98 (br. s,
2H), 6.69 (s, 2H), 5.21 (s, 2H), 2.39 (s, 6H), 2.17 (2, 3H), 1.86
852
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Vol. 13, No. 5, 2009 / Organic Process Research & Development