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

HRID 519059Notes

Reaction equation

HRID 519059 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[C:14](=[O:15])[NH:13][N:12]=[C:11]2[CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([NH:28][C:29]4([CH3:33])[CH2:32][NH:31][CH2:30]4)=[CH:20][C:19]=3[N:10]12.C=O.[BH3-][C:37]#N.[Na+]>CO.CC(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:37][N:31]1[CH2:30][C:29]([NH:28][C:21]2[C:22]([C:24]([F:25])([F:27])[F:26])=[CH:23][C:18]3[O:17][CH2:16][C:11]4=[N:12][NH:13][C:14](=[O:15])[C@H:9]([CH3:8])[N:10]4[C:19]=3[CH:20]=2)([CH3:33])[CH2:32]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][N:31]1[CH2:30][C:29]([NH:28][C:21]2[C:22]([C:24]([F:25])([F:27])[F:26])=[CH:23][C:18]3[O:17][CH2:16][C:11]4=[N:12][NH:13][C:14](=[O:15])[C@@H:9]([CH3:8])[N:10]4[C:19]=3[CH:20]=2)([CH3:33])[CH2:32]1

Participants

7

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 867273954-Methyl-6-(3-methyl-azetidin-3-ylamino)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid

Product 2

HCID 86727423(S)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acidYield 12%HCID 86727425(R)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acidYield 12%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Procedure

To a mixture of 1-methyl-9-((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 (Example #100, Step C, 0.120 g, 0.250 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was added paraformaldehyde (neat, 0.060 g, 2 mmol). The reaction mixture was stirred at ambient temperature for 30 min then NaBH3CN (0.126 g, 2 mmol) was added and the reaction mixture was heated at 50° C. for 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 18) and further separated by chiral SFC (Table 2, Method 11) to give (S)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #101-1, Enantiomer 1, SFC (Table 1, Method 16) Rt=5.21 min, 0.019 g, 12%) and (R)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #101-2, Enantiomer 2, SFC (Table 1, Method 16) Rt=5.89 min, 0.020 g, 12%) as white solids.

Workup

  1. temperaturethe reaction mixture was heated at 50° C. for 5 h
  2. temperatureThe reaction mixture was cooled to ambient temperature
  3. customthe solvent was removed in vacuo
  4. customThe residue was purified by preparative HPLC (Table 3, Method 18)
  5. customfurther separated by chiral SFC (Table 2, Method 11)

Sources & evidence

ORD record
ord-d93b78721de8429ba0faefd57ab278ad
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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