ibu-rG Phosphoramidite

Intermediate 15E (ARKPHARMINC, WO 02/18405 A2, 0.34 g, 0.35 mmol) was co-evaporated with dry acetonitrile several times and then dissolved in dry DCM (25 mL). Under anhydrous conditions, resin 15D (0.175 mmol) was swollen with dry acetonitrile (6 mL) twice under nitrogen. To the resin was added a solution of 1H- tetrazole (1.05 mmol) in anhydrous CLbCN (3 mL) and then the above solution of (1230) Intermediate 15E was added. The reaction mixture was stirred at room temperature for 3 h. The resin was washed with dry DCM (3x) under nitrogen, suspended in dry DCM (10 mL), and DDTT (0.52 mmol) was added. The reaction was stirred at RT for 40 min. The resin was then washed with DCM (2x), CH3CN (2x), DCM (3x) and Et^O (2x) and then dried under vacuum. The resin was then treated with a 1 : 1 AC2O/DIEA mixture (20 eq.) in DCM for 20 min, then washed with DCM (3x) and CH3CN (3x) and then treated with 3% 2, 2-dichloroacetic acid in DCM (3x, each 10 min) to remove the DMTr group. The resin was then washed with DCM, DMF, DCM, CH3CN (3x each) and then dried under vacuum. The resin was then treated with a 0.1 M solution of MSNT (2 x 4 h, 1 x 12 h). The resin was then washed with DCM, pyridine, DCM, CH3CN (2x each) and then treated with TEA/pyridine (1 : 1) (3x for 1 h). Finally, the resin was washed with DCM, DMF, DCM, ACN (3x each) and then dried.To the above solution of 2b was added the dried solution of 1b using a syringe with a bent needle (to access as much of the solution as possible). After 2 min, anhydrous tert-butyl hydroperoxide 5.5Min decane (1.1mL, 6 mmol, 3 equiv) was added. After 30 min, the solution was cooled in an ice bath, and 0.50 g of NaHSO3 dissolved in 1 mL H2O was added. The ice bath was immediately removed, the mixture was stirred for 5 min, and then concentrated to a small volume. The residual oil was dissolved in 32 mL of CH2Cl2, followed by addition of H2O (0.36 mL, 20 mmol, 10 equiv) and then 32 mL of 6% DCA (23 mmol) in CH2Cl2. After 10 min, the reaction was quenched with 20 mL of pyridine. The mixture was concentrated to a small volume, 60 mL more pyridine was added, and the solution was concentrated again, leaving 3b in40 mL.To a solution of compound 1 (20 g, 20.61 mmol, 1 eq) in CH3CN (100 mL) and H20 (742.77 mg, 41.23 mmol, 742.77 uL, 2 eq) was added pyridine;2, 2, 2-trifluoroacetic acid (5.97 g, 30.92 mmol, 1.5 eq). After 10 min, tert-butylamine (69.60 g, 951.64 mmol, 100.00 mL, 46.16 eq) was added. 10 min later the mixture was concentrated to a foam, the residue was dissolved in CH3CN (100 mL), and concentrated again to a foam. To the residue dissolved in DCM (100 mL) was added H20 (3.71 g, 206.15 mmol, 3.71 mL, 10 eq), followed by dichloroacetic acid (21.26 g, 164.92 mmol, 13.54 mL, 8 eq) in DCM (100 mL). The mixture was stirred at 20C for 10 min. TLC indicated compound 1 was consumed completely and many new spots formed. The reaction mixture was quenched by addition pyridine 10 mL at 10C, and then concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 0-50% Methanol: Ethyl acetate ether gradient 100 mL/min) to afford Compound 2 (9.7 g, 18.25 mmol, 88.52% yield) as a white solid. NMR: 400 MHz DMSO (0688) delta = 8.26 (s, 1H), 5.98 - 5.91 (m, 1H), 5.48 (br s, 1H), 4.62 - 4.53 (m, 2H), 4.12 (br s, 1H), 3.68 - 3.54 (m, 2H), 2.78 - 2.68 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H), 0.67 (s, 9H), -0.08 (s, 3H), -0.24 (s, 3H)

Molecular Weight:970.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:13
Rotatable Bond Count:22
Exact Mass:969.45854030
Monoisotopic Mass:969.45854030
Topological Polar Surface Area:180
Heavy Atom Count:68
Complexity:1690
Defined Atom Stereocenter Count:4
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes