2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylMethyl)-Morpholine-4-carboxylic acid tert-butyl ester synthesis

Yield:1308849-93-5 88%

Reaction Conditions:

in N,N-dimethyl-formamide at 110 - 115; for 16 h;

Steps:

4.B

Part B. Preparation of (R)-tert-butyl 2-((l,3-dioxoisoindolin-2- yl)methyl)morpholine-4-caPotassium phthalimide (28.4 g 0.15 mol) was added to a solution of (5)-tert-butyl 2- ((methylsulfonyloxy)methyl)morpholine-4-carboxylate (37.7 g, 0.13 mmol) in DMF (256 mL). The resulting mixture was stirred at 1 10-115°C for 16 hr, and then cooled to room temperature and poured into water (500 mL). The aqueous layer was extracted with CH₂CI₂ (3 x 250 mL). The combined organic layers were then washed with brine, dried over MgS0₄, filtered, and concentrated under reduced pressure. The residue was diluted in hexanes (200 mL) and then stirred vigorously while adding slowly Et₂0 (100 mL). The oil turned into a solid, which was filtered on a Buchner funnel. The filter cake was washed with hexanes and dried under reduced pressure. The mother liquor was concentrated, and the crude residue purified by silica gel flash chromatography (10-60% EtOAc in hexanes) to produce a second crop of solid. Both solids were combined to provide the title compound (38.9 g, 88%). ? NMR (300 MHz, CDC1₃) δ ppm 1.45 (s, 9 H), 2.68-2.82 (m, 1 H), 2.91-3.04 (m, 1 H), 3.44 (dt, J= 1 1.45, 2.81 Hz, 1 H), 3.63-3.79 (m, 3 H), 3.82-4.03 (m, 3 H), 7.70-7.78 (m, 2 H), 7.84-7.88 (m, 2 H).

References:

WO2011/62550,2011,A1 Location in patent:Page/Page column 29-30