Trifluoroacetic acid → (R)-1-methyl-9-(methyl(3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid

HRID 519061Notes

Reaction equation

HRID 519061 reaction equation
[CH3:1][C:2]1([N:13]([CH3:42])[C:14]2[C:15]([C:38]([F:41])([F:40])[F:39])=[CH:16][C:17]3[O:36][CH2:35][C:20]4=[N:21][N:22](COCC[Si](C)(C)C)[C:23](=[O:26])[CH:24]([CH3:25])[N:19]4[C:18]=3[CH:37]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:25][C@@H:24]1[C:23](=[O:26])[NH:22][N:21]=[C:20]2[CH2:35][O:36][C:17]3[CH:16]=[C:15]([C:38]([F:40])([F:39])[F:41])[C:14]([N:13]([CH3:42])[C:2]4([CH3:1])[CH2:3][NH:4][CH2:5]4)=[CH:37][C:18]=3[N:19]12

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86727426Tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(tri methylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate

Product 1

HCID 86727427(R)-1-methyl-9-(methyl(3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acidYield 7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(tri methylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.586 g, 0.360 mmol) in DCM (4 mL) was added TFA (0.8 mL) and the mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and dioxane (1 mL) and ammonium hydroxide (25%, 1 mL) were added and the reaction mixture was stirred for 1.5 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by HPLC (Table 3, Method 19) and further separated by chiral SFC (Table 2, Method 12) to give (R)-1-methyl-9-(methyl(3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (SFC (Table 1, Method 17) Rt: 6.57 min, 0.033 g, 7%)) as a pale solid. LC/MS (Table 1, Method 5) Rt=2.319 min.; MS m/z: 384 [M+H]+.

Workup

  1. customThe solvent was removed in vacuo and dioxane (1 mL) and ammonium hydroxide (25%, 1 mL)
  2. additionwere added
  3. stirringthe reaction mixture was stirred for 1.5 h at ambient temperature
  4. customThe solvent was removed in vacuo
  5. customthe residue was purified by HPLC (Table 3, Method 19)
  6. customfurther separated by chiral SFC (Table 2, Method 12)

Sources & evidence

ORD record
ord-468a4a23a18d4b18941252ae123d4ee2
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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