Tetrabutylammonium Fluoride → 3-(4(S)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester

HRID 518958Notes

Reaction equation

HRID 518958 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19](COCC[Si](C)(C)C)[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:29])([F:28])[F:30])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:40])[C:18](=[O:39])[NH:19][N:20]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:29])([F:28])[F:30])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:40])[C:18](=[O:39])[NH:19][N:20]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 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 ester

Product 2

HCID 867273043-(4(S)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl esterYield 22%HCID 867273053-(4(R)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl esterYield 21%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 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 (1.6 g, 2.73 mmol) in THF (5 mL) was added a solution of TBAF (1 M in THF, 4.1 mL, 4.1 mmol). The reaction mixture was heated at reflux for 3 days then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by chiral SFC separation (Table 2, Method 2) to give 3-(4(S)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 6), Rt=8.78 min., 0.280 g, 22%) and 3-(4(R)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 6), Rt=10.53 min., 0.260 g, 21%). 1H NMR (CDCl3, 400 MHz): δ 8.18 (s, 1H), 7.18 (s 1H), 5.91 (s, 1H), 4.68 (q, J=6.8 Hz, 1H), 4.61 (d, J=12.8 Hz, 1H), 4.52 (m, 1H), 4.51 (d, J=12.8 Hz, 1H), 4.36 (m, 2H), 4.22 (m, 1H), 3.80 (m, 2H), 1.55 (d, J=6.8 Hz, 3H), 1.49 (m, 9H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 3 days
  3. customThe solvent was removed in vacuo
  4. customthe residue was purified by chiral SFC separation (Table 2, Method 2)

Sources & evidence

ORD record
ord-349b415ffaa647e8bd437cd537e79742
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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