2-AMINO-5-METHYL-3-THIOPHENECARBOXAMIDE

iV-(3-hydroxyphenethyl)-2, 6-dimethylthieno[2, 3-d]pyriinidin-4- amine (Final Compound 22). a) 2-amino-5-methylthiophene-3-carboxamide; According to Scheme 5 Step 1: 2-amino5-methylthiophene-3-carbonitrile (4.0Og, 28.9mmol) in concentrated sulfuric acid (38.8ml) was stirred at r.t. for 20 hours. The mixture was poured onto ice-water (25Og) and neutralized to pH=7 with a concentrated sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4, filtered and evaporated till dryness. The residue was purified by chromatography over silica gel (Flashmart Pack: 85g/60-40um, eluent: ethyl acetate) yielding title compound (3.10g, 69percent) as a brown solid.To a DMF (100 mL) solution of cyanoacetamide (42.0 g, 0.5 mol), sulfur (16.0 g, 0.5 mol), and triethylamine (50.5 g, 0.5 mol) was slowly added dropwise an ethanol (15 mL) solution of propionaldehyde (31.9 g, 0.55 mol) at room temperature (inner temperature rose to 70°C), followed by heating under stirring at 60°C for 1.5 hours. Step A: To a stirred solution of 2-cyanoacetamide (4.2 g, 50 mmol), elemental sulfur (1.6 g, 50 mmol) and TEA (5.1 g, 50 mmol) in DMF at rt was added slowly a solution of propionaldehyde (3.2 g, 55 mmol) in EtOH. The reaction mixture was heated at 60 °C for 1.5 h, and then partitioned between water and EtOAc. The organic layer was separated, washed sequentially with water then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a mixture of DCM in MeOH to afford 2-amino-5-methylthiophene-3-carboxamide (4.1 g, 53percent). A solution of 2-Amino-5-methylthiophene-3-carboxamide (0.78 g, 5 mmol) and pyruvyl chloride (0.64 g, 6 mmol) were dissolved in dry tetrahydrofuran (5 mL), and the reaction was stirred at room temperature overnight. the precipitated solid was filtered off and washed with tetrahydrofuran. The filtrate and washings were combined, the solvent was removed by rotary evaporation, and the residue was mixed with cold methanol (30 mL) and suction filtered to give a pale yellow solid. The crude product was purified by silica gel column chromatography (eluent: petroleum / ethyl acetate = 1: 1), 0.79 g of a pale yellow solid was obtained with a yield of 70%, mp 211-215 C.

Molecular Weight:156.21
XLogP3:1.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:156.03573406
Monoisotopic Mass:156.03573406
Topological Polar Surface Area:97.4
Heavy Atom Count:10
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes