Cesium carbonate → 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 518957Notes

Reaction equation

HRID 518957 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.C[C:31]1([NH2:42])[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.C(O[Pd]OC(=O)C)(=O)C>[C:38]([O:37][C:35]([N:33]1[CH2:34][CH:31]([NH:42][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 867273063-[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 89%

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 (2.0 g, 4.05 mmol), tert-butyl 3-amino azetidine-1-carboxylate (1.39 g, 8.09 mmol), diacetoxypalladium (0.27 g, 1.21 mmol), Cs2CO3 (1.32 g, 4.05 mmol) and BINAP (1.0 g, 1.62 mmol) in toluene (10 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 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 (2.1 g, 89%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.14 (s, 1H), 5.86 (s, 1H), 5.10 (q, J=9.2 Hz, 2H), 4.63 (m, 2H), 4.51 (m, 2H), 4.33 (m, 2H), 4.18 (m, 1H), 3.77 (m, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.47 (d, J=6.4 Hz, 3H), 1.45 (s, 9H), 0.99 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).

Workup

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

Sources & evidence

ORD record
ord-5de8b81b535043679f910e168fc0876e
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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