Scale-up experiments were performed in a commercial
Synthos 3000 Multiwave microwave unit. We used the con-
figuration with 16 100-mL PTFE lined tubes in ceramic cases,
allowing a maximum load of ∼70 mL per tube. Temperature
and pressure were monitored continuously in a reference tube
by an internal gas balloon thermometer; 240 °C and 40 bar are
reachable. In addition, all vials were monitored by an external
IR sensor.
Experimental Procedures for the Reactions Performed
in this Study. Preparation of 3-Oxo-3,4,4a,5,7,8-hexahydro-
2H-pyrido[4,3-c]pyridazine-6-carboxylic Acid Ethyl Ester (2)
under ConVentional Conditions. To a solution of 3-ethoxycar-
bonylmethyl-4-oxo-piperidine-1-carboxylic acid ethyl ester 1
(20 g, 78 mmol) in ethanol (60 mL) were added hydrazine
hydrate (3.9 g, 78 mmol) and acetic acid (7.8 mL, 136 mmol)
at ambient temperature. The mixture then was heated to reflux
for 4 h. After cooling to ambient temperature, the reaction
mixture was concentrated in Vacuo, and the remaining solid
was triturated in ethanol (40 mL). The product was filtered and
dried in a vacuum oven at 60 °C to yield the title compound 2
as an off-white crystalline solid (9.4 g, 54%). HPLC (tR 4.33
min, 99%); mp 166-167 °C (lit.22 167-169 °C).
Preparation of 3-Aminopyrazoles 4a-c on Large Scale in
Anton Paar Synthos 3000. In a typical procedure, p-tolylhy-
drazine hydrochloride (82 g, 517 mmol) and pivaloylacetonitrile
(71.2 g, 569 mmol) were dissolved in methanol (650 mL).
Sixteen vials were filled with 50 mL each of this solution and
placed in the rotor. The reaction mixtures were heated with
magnetic stirring to 130 °C over 5 min with 1400 W available
power, held for 20 min at 130 °C, and then cooled by air
ventilation to 50 °C over 30 min. The contents of all tubes were
combined, and solvent was evaporated in Vacuo. The remaining
solid was partly dissolved in hot DCM (100 mL) and precipi-
tated again by addition of diisopropyl ether (100 mL). The
suspension was cooled to 0 °C, stirred for 20 min, and filtered.
After filtration and drying 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-
ylamine 4a was isolated as an off-white solid (117 g, 85%).
1
HPLC (tR 3.74 min, 100%); mp 196 °C dec; H NMR (400
MHz, DMSO-d6) δ 1.29 (s, 9H), 2.38 (s, 3H), 5.67 (s, 1H),
7.36-7.50 (m, 4H).
Preparation of 5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyra-
zol-3-ylamine (4b). 3,4-Dimethyl-phenylhydrazine hydrochlo-
ride (128 g) was dissolved in methanol (700 mL), and 16 tubes
were filled with 60 mL each. The reaction mixtures were heated
to 130 °C over 5 min and held for 15 min at 130 °C. After
cooling to 50 °C, the solvent was evaporated, and the residual
oil was precipitated by addition of diethyl ether (500 mL). The
crystalline solid was filtered and dried. Compound 4b was
isolated as a white solid (178 g, 86%); HPLC (tR 3.87 min,
100%); mp 220 °C. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (s,
9H), 2.29 (s, 6H), 5.66 (s, 1H), 7.26-7.29 (m, 1H), 7.32-7.39
(m, 2H).
Preparation of 5-tert-Butyl-2-(4-cyanophenyl)-2H-pyrazol-
3-ylamine (4c). 4-Cyanophenylhydrazine hydrochloride (102 g)
was dissolved in methanol (700 mL), and 16 tubes were filled
with 50 mL each. The reaction mixtures were heated to 140
°C over 5 min and held for 25 min at 140 °C. After cooling to
50 °C, the solvent was evaporated and the residual oil solidified
upon standing. The crude material was suspended in DCM (400
mL), cooled to 0 °C, and filtered. The crystalline product was
dried, compound 4c was obtained as a white solid (128.5 g,
77%). HPLC (tR 3.97 min, 100%); mp 199-200 °C; 1H NMR
(400 MHz, DMSO-d6) δ 1.26 (s, 9H), 5.62 (s, 1H), 7.83 (d, J
) 8.6 Hz, 2H), 7.99 (d, J ) 8.6 Hz, 2H).
Preparation of 3-Oxo-3,4,4a,5,7,8-hexahydro-2H-pyrido[4,3-
c]pyridazine-6-carboxylic Acid Ethyl Ester (2) in Anton Paar
Synthos 3000. 3-Ethoxycarbonylmethyl-4-oxo-piperidine-1-car-
boxylic acid ethyl ester, 1 (130 g, 505 mmol), hydrazine hydrate
(24.6 mL, 505 mmol), and acetic acid (50.6 mL, 884 mmol)
were dissolved in ethanol (800 mL). This stock solution (∼900
mL) was charged to 16 PTFE tubes, each containing a magnetic
stirring bar, sealed in ceramic cases, and placed inside a 16-
position rotor. One tube was fitted with a gas balloon ther-
mometer; the temperature of the other vials was monitored by
an IR-sensor. The reaction mixtures were heated with magnetic
stirring to 140 °C over 12 min with 1400 W available power,
held for 20 min at 140 °C, and then cooled by air ventilation to
60 °C over 30 min. The contents of all tubes were combined,
and solvent was evaporated in Vacuo. The remaining solid was
recrystallized from ethanol (300 mL). After filtration and drying,
product 2 was isolated as a white crystalline solid (73 g, 64%).
1
HPLC (tR 4.32 min, 99%); mp 167-168 °C; H NMR (400
MHz, CD3OD) δ 1.27 (t, J ) 7 Hz, 3H), 2.50 (dt, J ) 17, 6
Hz, 4H), 2.83 (m, 1H), 3.57 (t, J ) 6 Hz, 2H), 3.65 (t, J ) 6
Hz, 2H), 4.14 (q, J ) 7 Hz, 2H).
Preparation of 5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine,
4a, and 5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-
ylamine (4b) on Small Scale under ConVentional Conditions.
In a typical procedure, p-tolylhydrazine hydrochloride (20 g,
126 mmol) and pivaloylacetonitrile (17.3 g, 139 mmol) were
mixed in methanol (200 mL) and heated to reflux. Conversion
to product was monitored by HPLC and found to be complete
after 16 h. Methanol was evaporated, and the remaining solid
was triturated in refluxing DCM (100 mL). After cooling to 0
°C, the precipitated product was filtered and dried to give
3-aminopyrazole, 4a, as colorless crystals (28.8 g, 86% as HCl
salt). HPLC (tR 3.74 min, 100%); mp 195 °C dec.
Preparation of 4,5-Diamino-6-chloropyrimidine (6). Portions
of 5-amino-4,6-dichloropyrimidine (7.5 g each, 732 mmol) were
charged to 16 PTFE tubes, and a solution of 10% ammonia in
ethanol (60 mL for each tube) was added. The tubes were
carefully sealed in ceramic cases, placed in the rotor, and heated
to 170 °C in the microwave cavity over 5 min and held for
180 min at 170 °C. After cooling to 50 °C, the content of all
tubes was combined, and the precipitated solid was filtered and
suspended again in water (750 mL) and stirred at ambient
temperature for 30 min. The precipitate was filtered, washed
with water, and dried in vacuo to give compound 6 as a yellow
solid (87.8 g, 83%); mp 248-250 °C dec (lit.24 249-250 °C).1H
NMR (400 MHz, DMSO-d6) δ 4.95 (s, 2H), 6.76 (s, 2H), 7.65
(s, 1H).
Compound 4b was obtained by a similar procedure and
isolated as an off-white solid (12.8 g, 91.5% yield). HPLC (tR
3.87 min, 100%); mp 219-220 °C.
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