4-AMINO-2-CHLOROPYRIMIDINE-5-CARBONITRILE

White to yellow to brown solid

General conditions for the preparation of 2-amino-4-chloropyrimidine-5-carbonitrile:[00608] To a solution of 2, 4-dichloropyrimidine-5-carbonitrile (E-1) (2.0 g, 11.5 mmol) in 1, 4-dioxane (20 mL) at 0 °C, ammonium hydroxide (28-30percent, 4.4 mL, 34.5 mmol) is added dropwise, and the resulting mixture is stirred while warming from 0 °C to RT for 2 h. Then, the mixture is partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4 and filtered. The filtrate is mixed with silica gel and then concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0- 100percent ethyl acetate/hexanes to afford the product (E-2) (917 mg) and a mixture of (E-2) and (E-3). Additional (E-3) can be obtained from this mixture by a second column chromatographic purification.To 45.1 4-amino-2-iodopyrimidine-5-carbonitrile 4-Amino-2-chloropyrimidine-5-carbonitrile (from Alfa) (0.80 g, 5.18 mmol) is dissolved in 8 mL of acetonitrile. Iodotrimethylsilane (0.7 mL, 5.18 mmol) is added and the mixture is stirred at 80 C. for 4 hours. Ethyl acetate is added and the mixture is washed with a concentrated aqueous sodium bicarbonate solution. The organic phase is dried and concentrated under reduced pressure. Yield: 1.0 g (81% of theory) Mass spectrometry (ESI+): m/z=247 [M+H]+Step 5A: (2R)-4-(4-arnino-5-cvanopyrirnidin-2-yl)-N-[2-(l-benzylpiperidin-4- yl)ethyll-2-methylpiperazine-l -carboxamide (0311) To a solution of (2R)-N-[2-(l-benzylpiperidin-4-yl)ethyl]-2- methy lpiperazine- 1 -carboxamide 4a (0.20 g, 0.58 mmol, 1.0 eq) and 4-amino-2- chloropyrimidine-5-carbonitrile (0.90 g, 0.58 mmol, 1.0 eq) in NMP (2 mL) was added N, N-diisopropylethylamine (0.38 mL, 2.3 mmol, 4.0 eq) and the reaction mixture heated to 100 C for 1 hr. In some cases, lower temperatures or longer reaction times were used. The reaction mixture was cooled, diluted heavily with EtOAc, and washed repeatedly with brine (3x). The organic layer was dried over Na2SC>4 and concentrated. Silica gel column (24 g) was loaded using methylene chloride and run using an increasing gradient of MeOH (0-20%) in methylene chloride over 20 min to provide (2R)-4-(4-ainino-5-cyanopyrimidin-2-yl)-N-[2-(l-benzylpiperidin-4-yl)ethyl]-2- methylpiperazine-l-carboxamide 5-1 (0.14 g, 0.31 mmol, 53%) as an off-white foam.

Molecular Weight:154.56
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:154.0046238
Monoisotopic Mass:154.0046238
Topological Polar Surface Area:75.6
Heavy Atom Count:10
Complexity:162
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes