Trifluoroacetic acid → (S)-4-amino-18,20-dimethyl-12-(morpholine-4-carbonyl)-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2,4,6(22),17(21),18-hexaene-10,16-dione

Participants

Reaction Steps

5-(2-Amino-6-{2-[(S)-3-tert-butoxycarbonylamino-1-(morpholine-4-carbonyl) propylcarbamoyl]ethylsulfanyl}pyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (79 mg) obtained in Step 3 above was dissolved in dichloromethane (1.5 ml), and then trifluoroacetic acid (0.5 ml) was added thereto at room temperature. The reaction solution was stirred for two hours, and then concentrated under reduced pressure. Toluene (3 ml) was added to the obtained residue, and then concentrated under reduced pressure. The resulting pale yellow oily material was dissolved in a mixture of N,N-dimethylformamide (29 ml) and tetrahydrofuran (29 ml), and then O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (55.8 mg, 0.142 mmol) and diisopropylethylamine (0.102 ml) were added thereto at room temperature. The reaction solution was stirred for one hour. Water (20 ml) was added to the reaction solution, and concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution (30 ml) was added to the resulting residue and then extracted twice with ethyl acetate (30 ml). The ethyl acetate solution was washed twice with a saturated aqueous sodium chloride solution (20 ml) and a saturated aqueous sodium bicarbonate solution (20 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by high performance liquid chromatography (developing solvent: A, acetonitrile containing 0.05% trifluoroacetic acid; B, 0.05% aqueous trifluoroacetic acid solution; gradient condition: B, 1% (0 min)→1% (1 min)→30% (7 min)→95% (8 min)→95% (9 min)→1% (10 min); flow rate, 35 ml/min; column, Waters, SunFire PrepC18, 5 μm, 30×50 mm). A fraction containing the material of interest was neutralized with solid-supported tetraalkyl ammonium carbonate (Polymer Laboratories, PL-HCO3 MP-Resin) to yield (S)-4-amino-18,20-dimethyl-12-(morpholine-4-carbonyl)-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2,4,6(22),17(21),18-hexaene-10,16-dione (Compound 70)(37 mg) as a white solid material.

Provenance & Evidence