Example 2
2-(Difluoromethyl)-4-(6-fluoro-3-methyl-lH-indazol-5-yl)-6-(4-fluorophenyl)-l,4-dihydropyridine- 3,5-dicarbonitrile
A mixture of 200 mg (0.569 mmol)
(2ii)-2-(4-fluorobenzoyl)-3-(6-fluoro-3-methyl-lH-indazol-5-yl)-
prop-2-enenitrile (Example 5A) and 69 mg (0.569 mmol)
3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of
acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1
(1967), ibid. 3J_, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux
for 12 h. Then, acetic acid (1.5 ml) was added, and stirring at reflux
was continued for 6 h. Upon cooling, the mixture was concentrated under
reduced pressure, and the residue was directly purified by preparative
RP-HPLC (methanol/water + 0.1 % TFA gradient, final mixture 80:20 v/v)
to yield 36 mg (15% of th.) of the racemic title compound. LC-MS (method
4): R
t = 0.97 min; MS (ESIpos): m/z = 424 (M+H)
'H-NMR (400 MHz, DMSO-dg): δ = 12.87 (br. s, 1H), 10.44 (s, 1H), 7.78 (d, 1H), 7.61 (m, 2H), 7.41-7.35 (m, 3H), 6.79 (t, 1H,
F = 51.8 Hz), 5.08 (s, 1H), 2.54 (s, 3H) ppm.
http://www.google.com/patents/WO2011069761A1?cl=en
Comparative Example B
2-(4-Fluorophenyl)-6-methyl-4-(3-methyl-lH-indazol-5-yl)-l,4-dihydropyridine-3,5-dicarbonitrile
A mixture of 200 mg (0.89 mmol)
(2i?)-2-[(3-methyl-lH-indazol-5-yl)methylidene]-3-oxobutane- nitrile
(Example 2A), 159 mg (0.98 mmol) 3-(4-fluorophenyl)-3-oxopropanenitrile
and 205 mg (2.66 mmol) ammonium acetate in ethanol/acetic acid (4: 1
v/v, 1 1 ml) was heated to reflux overnight. After cooling, the reaction
mixture was directly purified by preparative RP-HPLC
(acetonitrile/water + 0.1% TFA gradient) to afford 136 mg (41% of th.)
of the racemic title compound.
LC-MS (method 2): R
t = 1.04 min; MS (ESIpos): m/z = 370 (M+H)
+
'H-NMR (400 MHz, DMSO-dg): δ = 12.70 (br. s, 1H),
9.74 (s, 1H), 7.64-7.59 (m, 3H), 7.53 (d, 1H), 7.40-7.33 (m, 3H), 4.68
(s, 1H), 2.48 (s, 3H), 2.11 (s, 3H) ppm.
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