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 519059ノート

反応式

HRID 519059 の反応式
[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

参加物

7

反応物 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

生成物 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 acid収率 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 acid収率 12%

試薬・触媒・溶媒 2

HCID 176Acetic Acid溶媒HCID 887Methanol溶媒

実験手順

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.

後処理

  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)

出典と根拠

ORDレコード
ord-d93b78721de8429ba0faefd57ab278ad
出典データセット
uspto-grants-2015_08
特許番号
US09115151B2

反応ノート

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