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 519056Notes

Reaction equation

HRID 519056 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.[CH3:30][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][C:31]([CH3:30])([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 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 91%

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, 2.0 g, 4.05 mmol), tert-butyl 3-amino azetidine-1-carboxylate (0.904 g, 4.85 mmol), diacetoxypalladium (0.091 g, 0.405 mmol), Cs2CO3 (2.64 g, 8.10 mmol) and BINAP (0.252 g, 0.405 mmol) in toluene (10 mL) was heated at reflux for 10 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% 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 (2.2 g, 91%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.16 (s, 1H), 5.96 (brs, 1H), 5.13 (q, J=9.2 Hz, 2H), 4.61 (m, 1H), 4.56 (q, J=13.2 Hz, 2H), 4.41 (brs, 1H), 4.04 (m, 2H), 3.95 (d, J=12.4 Hz, 2H), 3.68 (m, 2H), 1.66 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.46 (s, 9H), 0.99 (m, 2H), 0.02 (s, 9H).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 10 h
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated in vacuo
  5. customthe residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-f1e007ae90104ecf86883b044d755ea2
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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