Cesium carbonate → (S)-3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 519154Notes

Reaction equation

HRID 519154 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:25])[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=1.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@@:35]([NH2:39])([CH3:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@:35]([CH3:38])([NH:39][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:25])[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86328910tert-butyl (S)-3-amino-3-methylpyrrolidine-1-carboxylateHCID 867274626-Bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one

Product 1

HCID 86727547(S)-3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 38%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Procedure

To a solution of 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one ((Preparation #1, Step E, 2.184 g, 5.12 mmol) and (S)-3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.977 g, 4.88 mmol) in toluene (5 mL) was added Pd(OAc)2 (0.110 g, 0.488 mmol) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.464 g, 0.976 mmol) followed by cesium carbonate (3.18 g, 9.76 mmol) and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give (S)-3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 38%). 1H NMR (400 MHz, CDCl3) δ 6.85 (m, 1H), 6.34-6.28 (m, 2H), 5.11 (m, 2H), 4.70-4.52 (m, 3H), 3.68 (m, 2H), 3.70-3.35 (m, 4H), 2.20 (m, 1H), 1.88 (m, 1H), 1.46 (m., 12H), 1.05 (m, 2H), 0.03 (s, 9H).

Workup

  1. temperaturethe reaction mixture was heated
  2. temperatureat reflux overnight
  3. concentrationconcentrated in vacuo
  4. customThe residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-b901afe7525f496c80665d2a13644b41
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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