Nitrogen → (2R,5R)-4-[2-(6-Benzyl-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

HRID 1475381Notes

Reaction equation

HRID 1475381 reaction equation
N#N.[Li+].[Br-].[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][OH:19])[N:15]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29](Cl)[CH:30]=3)[C:25]([CH3:34])([CH3:33])[CH2:24]2)=[O:22])[CH2:14][C@H:13]1[CH3:35])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Br-].[CH2:37]([Zn+])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.CN1C(=O)CCC1.CO.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][OH:19])[N:15]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:30]=3)[C:25]([CH3:34])([CH3:33])[CH2:24]2)=[O:22])[CH2:14][C@H:13]1[CH3:35])=[O:11])([CH3:8])([CH3:7])[CH3:6]

Participants

9

Reactant 4

HCID 947NitrogenHCID 82050Lithium BromideHCID 86723923(2R,5R)-4-[2-(6-Chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl esterHCID 178419772HCID 178419772, compound

Product 1

HCID 86723998(2R,5R)-4-[2-(6-Benzyl-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl esterYield 12.7%

Reagents, catalysts & solvents 4

HCID 178456358HCID 178456358, compoundCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 22156051tetrahydrofuran N-methylpyrrolidinoneSolvent

Procedure

To a degassed (N2) solution of LiBr (20 mg, 0.2 mmol) and (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (1.0 mg, 0.14 mmol) in anhydrous THF/NMP (1:1, 0.48 mL) was added a solution of (2R,5R)-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (65 mg, 0.14 mmol), THF (0.1 mL) and benzylzinc bromide (575 μL, 0.30 mmol). The reaction was stirred for 18 h and diluted with MeOH then loaded onto a SCX column eluting with MeOH and then 2.0 M ammonia-MeOH to release the amine. The solvent was removed in vacuo, to give the title compound (9.0 mg, 12%) as a colourless oil. 1H NMR (Me-d3-OD): 8.03 (1H, s), 7.33-7.03 (6H, m), 6.96 (1H, d), 4.15 (1H, d), 4.10-3.93 (5H, m), 3.76 (1H, dd), 3.67 (1H, d), 3.59-3.49 (2H, m), 2.93-2.83 (2H, m), 2.65 (1H, dd), 1.48 (9H, s), 1.35 (6H, s), 1.23 (3H, d).

Workup

  1. washeluting with MeOH
  2. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-958444568ef949c68b4e19a1ee41b68f
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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