1,1-Dimethylethyl N-[(1R)-1-methyl-2-oxoethyl]carbamate

Intermediate 322Synthesis of Compound N.1. To a cooled (-78° C. ) solution of oxalyl chloride (90 mL, 1.03 mol) in CHTo a cooled (-78° C.) solution of oxalyl chloride (90 mL, 1.03 mol) in CHExample 210; (R)-4-(l-cyclopropyl-l-hydroxypropan-2-ylamino)-6-(6-methoxypyridin-3-yl) pyrrolo -b]pyridazine-3-carboxamide, Isomer AStep 1 : (R)-tert-but l l-oxo ro an-2- l carbamate[00289] Water (2.57 ml, 143 mmol) was added dropwise to a mixture of (R)-tert- butyl (l-hydroxypropan-2-yl)carbamate (17.85 g, 102 mmol) and Dess-Martin Periodinane (60.5 g, 143 mmol) in anhydrous DCM (500 ml) at rt under a nitrogen atmosphere. The reaction was allowed to stir at rt overnight before diluting with diethyl ether and filtering. The filtrate was evaporated in vacuo and the residue diluted with diethyl ether. The organic was then washed with a 1 : 1 mixture of 10percent aq sodium thiosulfate solution: sat. sodium bicarbonate solution, followed by brine and water. The aqueous phase was then back extracted with one portion of diethyl ether, the combined organics were then dried (MgS0(A) Example 46(1-Methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester The title compound from Example 45 (3.53 g, 17.4 mmol) was dissolved in toluene (35 mL) at -78° C. and DIBAL-H (26.6 mL, 39.9 mmol) was added dropwise over 1 hour. Methanol (70 mL) was added to the reaction over 10 min. at -78° C. The reaction was moved to an ice bath and 10percent w/v citric acid in water (250 mL) was added and the reaction was allowed to stir for 1 hour. The reaction was extracted with portions of ethyl acetate and the organic extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.57 g, 85percent) as a white semi-solid.Step 1: (R)-tert-butyl 1-oxopropan-2-ylcarbamateTo a cooled solution of (R)-methyl 2-(tert-butoxycarbonylamino)propanoate (40.0 g, 98.0 mmol) in DCM (200 mL) at -78° C. was added diisobutylaluminum hydride (208 mL, 1.0 M in THF) dropwise over 30 min. The reaction mixture was stirred at -78° C. for 1.5 h then quenched with water (50 mL). After warmed to rt, the white precipitate was removed by filtration over Celite. The organic layer was then washed with brine, dried (NaEXAMPLE 49; (R)-5-Chloro-thiophene-2-carboxylic acid (1 - {3-[4-(N, N-dimethyl-carbamimidoyl)-phenyl]- isoxazol-5-yl}-ethyl)-amide; Step l :; [0553] Methyl ester 8 (4.03 g, 19.9 mmol) was diluted with 40 mL of toluene and cooled to -780C. Diisobutylaluminum hydride in toluene (26 mL, 40 mmol) was added slowly to the precooled mixture down the side of the flask. The reaction was stirred at -780C for two hours at which time it was treated slowly with ca. 5 mL of methanol precooled to -780C (vigorous reaction). The mixture was then warmed to it and partitioned with saturated sodium potassium tartrate and ethyl acetate. The layers were separated, the organic phase was extracted with ethyl acetate and the combined organic layers were dried over MgSO4. After filtration and concentration in vacuo the crude material was purified by filtration through a short plug of silica gel eluted with dichloromethane affording the aldehyde 9 as a colorless oil (2.23g, 65percent). 1H NMR (DMSO-J6, 400 MHz): δ 9.38 (s, IH), δ 7.30 (d, IH), δ 3.79 (m, IH), δ 1.31 (s, 9H), 1.06 (d, 3H).