反应详情

A three-necked, round-bottomed flask equipped with a nitrogen inlet adapter, thermocouple, and a septum was charged with (3R,9aS)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (330 g, 840 mmol), TFA (1.65 L, 21 mol), and 3300 mL of DCM. Et3SiH (292 g, 2.52 mol, 3 equiv) was added in one portion and the reaction mixture stirred at room temperature for 24 h. The reaction mixture was concentrated and azeotroped with toluene (100 mL) to remove the TFA. The resulting material was dissolved in DCM (1.7 L) and carefully charged with 2.5 M Na2CO3 (pH should be basic). Boc2O (218 g, 1.2 equiv) was added in one portion and the reaction mixture was stirred at room temperature for 2 h. The organic layer was separated, concentrated, and purified via column chromatography (0-30% acetone-hexanes) to give a mixture of product cis/trans isomers. Chiral SFC purification (Berger MultiGram™ SFC, Mettler Toledo Co, Ltd, AD 250 mm*50 mm, 5 um column, A: supercritical CO2, B: methanol, A:B=85:15 at 150 mL/min) afforded the major trans diastereomer 17A as well as the cis diastereomer 17B.

1. customA three-necked, round-bottomed flask equipped with a nitrogen inlet adapter
2. concentrationThe reaction mixture was concentrated
3. customazeotroped with toluene (100 mL)
4. customto remove the TFA
5. dissolutionThe resulting material was dissolved in DCM (1.7 L)
6. additioncarefully charged with 2.5 M Na2CO3 (pH should be basic)
7. stirringthe reaction mixture was stirred at room temperature for 2 h
8. customThe organic layer was separated
9. concentrationconcentrated
10. custompurified via column chromatography (0-30% acetone-hexanes)
11. customto give
12. additiona mixture of product cis/trans isomers
13. customChiral SFC purification (Berger MultiGram™ SFC, Mettler Toledo Co, Ltd, AD 250 mm*50 mm, 5 um column