| 91% |
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 12.00 h; |
To a mixture of commercial (4R)-4-hydroxy-L-proline (75g, 0. 57MOL) in 10percent NAOH (11) was added (Boc) 20 (186g, 0. 855mol) at 0 C with stirring. The reaction was allowed to stir at RT for 10h and then washed with petroleum ether. The aqueous layer was acidified with citric acid to pH=4 and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over NA2S04. The solvent was removed under vacuum to give crude (4R)-I-(TERT-BUTOXYCARBONYL)-4-HYDROXY-L-PROLINE (118G) as viscous liquid. Yield: 89percent To a solution of (4R)-1-(tert-butoxycarbonylo)-4-hydroxy-L-proline (100g, 0. 432MOL) in dry DMF (600ML), at 0 C was added K2CO3 (179g, 1. 3mol) followed by iodoethane (LOLG, 0. 65MOL). After stirring at RT for 12h, K2CO3 was filtered off and DMF was distilled off under reduce pressure. The residue was diluted with dichloromethane (11), washed with brine and dried. The solvent was removed under vacuum to give crude 1-1-TERT-BUTYL 2- ethyl (2S, 4R)-4-hydroxypyrrolidine-1, 2-dicarboxylate (103g) as yellow liquid. Yield: 91percent H NMR (300MHZ, CDC ) : 1.25 (t, 3H), 1.4 (d, 9H), 1.9-2. 2 (M, 2H), 2.5 (M, IH), 3.5 (M, 2H), 4.2 (M, 2H), 4.4-4. 6 (M, 2H). To a solution of 1-tert-butyl 2-ethyl (2S, 4R)-4-HYDROXYPYRROLIDINE-1, 2-dicarboxylate (100g, 0. 38MOL) in dry dichloromethane (1.51) at 25 C was added DMAP (47g, 0. 38MOL), followed by triethylamine (39g, 0. 38mol). To the above reaction mixture was added TBDMSCl (64g, 0. 42mol) dissolved in dry dichloromethane (200ML) drop-wise over a period OF 45MIN. After stirring at RT for 20H, the reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with 5percent aq. citric acid, brine and dried over NA2SO4. The solvent was removed under vacuum to give I-TERT-BUTYL 2-ethyl (2S, 4R)-4- {[TERT-BUTYL (DIMETHYL) silyl] oxy} pyrrolidine-1, 2-DICARBOXYLATE (140g) as a colorless liquid. Yield: 97percent 'H NMR (300MHz, CDC13) : 0.0 (s, 6H), 0. 8 (s, 9H), 1.2 (t, 3H), 1. 45 (d, 9H), 1. 7-1. 9 (M, 2H), 2.2 (M, 1H), 3.3-3. 5 (M, 2H), 4.2 (M, 2H), 4.5 (M, 1H). To a suspension of lithium aluminium hydride (lOg) in dry tetrahydrofuran (750ml) at- 40 C was added 1-tert-butyl 2-ethyl 1-TERT-BUTYL 2-ethyl (2S,4R)-4-{[(tert- butyl (dimethyl) silyl] oxy} pyrrolidine-1, 2-dicarboxylate (100g, 0. 289mol) drop-wise in tetrahydrofuran (250ML). After stirring AT-TO C for 5H, the reaction mixture was quenched with 10percent NAOH (40ML). Filtered off the solid residue, washed with tetrahydrofuran and the filtrate was evaporated under reduce pressure to give tert-butyl (2S, 4R)-4-{[TERT- butyl (dimethyl) silyl] OXY}-2- (HYDROXYMETHYL) PYRROLIDINE-1-CARBOXYLATE (85g) as a colorless liquid. Yield: 94percent LCMS: ESI+: 232 (M-Boc+H)+, 276 (M-tBu+H) +, 354 (M+Na) + 'H NMR (300MHZ, DMSO-d6) : 0.05 (s, 6H), 0.78 (s, 9H), 1.33 (s, 9H), 1.65-2. 00 (m, 2H), 3.20 (m, 2H), 3. 38 (m, 2H), 3.70 (m, 1H), 4.30 (m, 1H), 4. 60 (t, 1H). To a mixture of DMSO (53g, 0. 68MOL) and oxalylchloride (43G, 0. 34MOL) in dry dichloromethane (1. 51) at-78oC was added tert-butyl (2S, 4R)-4-{[tert-butyl (dimethyl) silyl] OXY}-2-(HYDROXYMETHYL) PYLROLIDINE-L-CARBOXYLATE (75g, 0. 226MOL) drop-wise. After stirring at-78oC for IH, was added triethylamine (158ml, 1. 13MOL) drop-wise and warmed the reaction mixture slowly to RT. The reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with brine and dried. The solvent was removed under vacuum to give tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl] OXY}-2-FORMYLPYRROLIDINE-L-CARBOXYLATE (70g) as pale yellow liquid. Yield: 94 percent |
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