반응 #1178445

반응 방정식

citric acid

methanesulfonyl chloride

tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate

→

tert-butyl (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate

수율 100.0%

용매

pyridine

pyridine

반응 조건

후처리

1. 1
   workup.ADDITIONare added to the residue
2. 2
   추출the acidic solution is extracted twice with 10 ml of methylene chloride each time
3. 3
   세척The combined organic phases are then washed with 10 ml of saturated sodium chloride solution
4. 4
   건조dried over sodium sulfate
5. 5
   기타Removal of the drying agent
6. 6
   여과by filtration

실험 절차

9.1 1.3 ml (16.65 mmol) of methanesulfonyl chloride are added dropwise with ice cooling to a solution of 4.5 g (11.1 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate in 20 ml of pyridine, and the reaction solution is stirred at room temperature for 12 hours. The pyridine is subsequently stripped off under reduced pressure, 10 ml of saturated citric acid solution are added to the residue, and the acidic solution is extracted twice with 10 ml of methylene chloride each time. The combined organic phases are then washed with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. Removal of the drying agent by filtration and stripping-off of the solvent gives 5.4 g (100%) of tert-butyl (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a yellow oil, ESI 484. 9.2 A mixture of 5.4 g (11.7 mmol) of tert-butyl (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate and 3.69 g (56.8 mmol) of sodium azide in 50 ml of dimethylformamide (DMF) is stirred at 60° C. for 12 hours. The insoluble matter is subsequently filtered off, and the filtrate is evaporated to dryness under reduced pressure. The residue is then dissolved in 20 ml of water, and the aqueous solution is extracted twice with 10 ml of methylene chloride each time. The combined methylene chloride extracts are finally washed once with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. Removal of the drying agent by filtration and stripping-off of the solvent gives 4.8 g (100%) of tert-butyl (2R,4S)-4-azido-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as slightly yellow crystals, ESI 431. 9.3 Analogously to Example 7, reaction of tert-butyl (2R,4S)-4-azido-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate gives the compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(8-oxomorpholin-4-yl)-phenyl]}-(2R,4S)-4-azidopyrrolidine-1,2-dicarboxamide (“A9”) as a white powder, ESI 459, m.p. 145°. 9.4 A solution of 25 mg (0.052 mmol) of “A9” and 20.46 mg (0.08 mmol) of triphenylphosphine in a mixture of 0.5 ml of tetrahydrofuran and 0.5 ml of water is stirred at room temperature for 12 hours. After the precipitated triphenylphosphine oxide has been filtered off, the filtrate is evaporated to dryness, and the residue is purified by preparative HPLC (acetonitrile/water/0.1% trifluoroacetic acid), giving 12 mg (40%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-amino-pyrrolidine-1,2-dicarboxamide (“10”) as colourless crystals, ESI 458.

출처