Chlorotrimethylsilane → [(1R,2S,5R)-5-methyl-2-propan-2-ylcyclohexyl] N-[(7S)-5-[(4-methoxyphenyl)methyl]-6-oxo-7H-benzo[d][1]benzazepin-7-yl]carbamate

HRID 2105896Notes

Reaction equation

[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[O:11][C:12](=[O:39])[NH:13][C@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=2[C:16]2[CH:35]=[CH:36][CH:37]=[CH:38][C:15]1=2)([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Cl-].[Na+].O.O>C1COCC1.CCOC(C)=O>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[O:11][C:12](=[O:39])[NH:13][C@@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=2[C:16]2[CH:35]=[CH:36][CH:37]=[CH:38][C:15]1=2)([CH3:2])[CH3:3]

Participants

Conditions

Temperature: -75 °C

Procedure

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.

Workup

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

Sources & evidence

ORD record: ord-52be57a905d84500a6f59fe05f2c46d1
Source dataset: uspto-grants-2009_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07579464B2

Reaction notes

Loading…