反应详情

温度

-75 °C

To a solution of [(R)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (5.58 g) in THF (20 mL) cooled to −75° C. was added lithium diisopropylamide (2M solution in THF, 15 mL) within 60 minutes. The reaction mixture was stirred for 5 hours at −75° C., chlorotrimethylsilane (4.6 mL) was added within 35 minutes and the reaction mixture was stirred for 15 hours at room temperature. An ice-water mixture (50 mL) was added and, after 2.5 hours stirring, EtOAc (200 mL) and brine:water 1:1 (400 mL) were added. The phases were separated, the organic phase was washed with brine:water 1:1 (300 mL) twice and the aqueous phases were extracted with EtOAc (100 mL) twice. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure until a weight of 15.8 g was obtained. The suspension obtained was filtered off and the precipitate was dried under vacuum at room temperature affording [(S)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R) -2-isopropyl-5-methyl-cyclohexyl ester (1.75 g, 31.5%), with d.e.=99.2:0.8 (HPLC), as a white powder. Heptane (132 mL) was added to the filtrate and, after 2 days at room temperature, the precipitate was filtered off affording a ca. 1:1 mixture of [(R)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester and of [(S)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester. The filtrate was concentrated under reduced pressure and dried under high vacuum affording [(R)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (3.5 g, 64% HPLC ISTD, 40%), d.e.=96.9:3.1 as a yellow oil.

1. stirringthe reaction mixture was stirred for 15 hours at room temperature
2. stirringstirring
3. customThe phases were separated
4. washthe organic phase was washed with brine:water 1:1 (300 mL) twice
5. extractionthe aqueous phases were extracted with EtOAc (100 mL) twice
6. dry with materialThe combined organic layers were dried (MgSO4)
7. concentrationconcentrated under reduced pressure until a weight of 15.8 g
8. customwas obtained
9. customThe suspension obtained
10. filtrationwas filtered off
11. customthe precipitate was dried under vacuum at room temperature