Cesium carbonate → 3-Methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester

HRID 519031Notes

Reaction equation

HRID 519031 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1.[NH2:30][C:31]1([CH3:42])[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:38]([O:37][C:35]([N:33]1[CH2:34][C:31]([CH3:42])([NH:30][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=2)[CH2:32]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 56924482tert-Butyl 3-amino-3-methylazetidine-1-carboxylateHCID 867273036-Bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one

Product 1

HCID 867273933-Methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl esterYield 67.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Procedure

A mixture of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #53, Step E, 0.110 g, 0.223 mmol), tert-butyl 3-amino-3-methylazetidine-1-carboxylate (0.062 g, 0.334 mmol), Pd(OAc)2 (0.010 g, 0.045 mmol), cesium carbonate (0.109 g, 0.334 mmol) and BINAP (0.042 g, 0.067 mmol) in toluene (5 mL) was heated at reflux for 5 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.090 g, 67%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.13 (s, 1H), 5.93 (s, 1H), 5.10 (q, J=10.4 Hz, 2H), 4.62 (d, J=12.8 Hz, 1H), 4.58 (m, 1H), 4.49 (d, J=12.8 Hz, 1H), 4.37 (s, 1H), 4.00 (m, 2H), 3.95 (m, 2H), 3.66 (t, J=8.0 Hz, 2H), 1.63 (s, 3H), 1.47 (d, J=6.8 Hz, 3H) 1.45 (s, 9H), 0.99 (m, 2H), 0.00 (s, 9H).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 5 h
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated
  5. customthe residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-1f421a3de58349899683b9e5217d4825
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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