Dimethylformamide → (6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1R)-1-(3-tert-butoxyisooxazole-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamide

HRID 80585Notes

Reaction equation

HRID 80585 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16](OC2C=CC=CC=2Cl)=[O:17])[CH2:12][C:11](=[O:26])[N:10]([CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][C:31]([O:36][CH3:37])=[CH:30][C:29]=2[O:38][CH3:39])[CH2:9]1.CN(C)C=O.Cl.[C:49]([O:53][C:54]1[CH:58]=[C:57]([CH:59]([NH2:62])[CH2:60][CH3:61])[O:56][N:55]=1)([CH3:52])([CH3:51])[CH3:50].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:62][C@@H:59]([C:57]2[O:56][N:55]=[C:54]([O:53][C:49]([CH3:50])([CH3:52])[CH3:51])[CH:58]=2)[CH2:60][CH3:61])=[O:17])[CH2:12][C:11](=[O:26])[N:10]([CH2:27][C:28]2[C:29]([O:38][CH3:39])=[CH:30][C:31]([O:36][CH3:37])=[CH:32][C:33]=2[O:34][CH3:35])[CH2:9]1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 66935304(6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylateHCID 708152761-(3-Tert-butoxyisoxazol-5-yl)propylamine hydrochloride

Product 1

HCID 70815060(6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1R)-1-(3-tert-butoxyisooxazole-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamideYield 43%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolvent

Procedure

To the compound S141C described in WO 06-059801A, that is, (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxylate (395 mg) in an N,N-dimethylformamide (0.64 ml) solution, the compound S94 described in WO 06-059801A, that is, 1-(3-tert-butoxyisoxazol-5-yl)propylamine hydrochloride (150 mg), 4-dimethylaminopyridin (78 mg) and N,N-diisopropylethylamine (0.111 ml) were added at 0° C., and the mixture was stirred at that temperature for 15 hours. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was combined, successively washed with saturated aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and brine, dried over sodium sulfate, then concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=50/50 to 35/65) to obtain (6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1R)-1-(3-tert-butoxyisooxazole-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamide (189 mg) (compound S49a) and (6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1S)-1-(3-tert-butoxyisooxazol-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamide (compound S49b).

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washsuccessively washed with saturated aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=50/50 to 35/65)

Sources & evidence

ORD record
ord-89be20f1e1df46f7becb2bedadd688c9
Source dataset
uspto-grants-2014_09
Patent number
US08846660B2

Reaction notes

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