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 519059노트

반응식

HRID 519059 반응식
[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

참가 물질

7

반응물 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

생성물 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 acid수율 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 acid수율 12%

시약·촉매·용매 2

HCID 176Acetic Acid용매HCID 887Methanol용매

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-d93b78721de8429ba0faefd57ab278ad
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09115151B2

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