Ammonium Chloride → 5-amino-N-[5-(6-amino-4,4-difluoro-oxepan-2-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide

HRID 521952ノート

反応式

HRID 521952 の反応式
[N:1]([CH:4]1[CH2:10][O:9][CH:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:7][C:6]([F:21])([F:20])[CH2:5]1)=[N+]=[N-].[Cl-].[NH4+].[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38](O)=[O:39].CCN(C(C)C)C(C)C.CCCP(=O)=O>CCO.[Fe].O>[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38]([NH:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[CH:8]1[CH2:7][C:6]([F:21])([F:20])[CH2:5][CH:4]([NH2:1])[CH2:10][O:9]1)=[O:39]

参加物

9

反応物 5

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 16167369Propylphosphoric anhydrideHCID 594556885-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 867138835-(6-Azido-4,4-difluoro-oxepan-2-yl)-1-methyl-4-nitro-pyrazole

生成物 1

HCID 734376965-amino-N-[5-(6-amino-4,4-difluoro-oxepan-2-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide

試薬・触媒・溶媒 3

HCID 23925Iron触媒HCID 702Ethanol溶媒HCID 962Water溶媒

反応条件

温度
80 °C

実験手順

To a solution of 5-(6-azido-4,4-difluoro-oxepan-2-yl)-1-methyl-4-nitro-pyrazole (264 mg, 0.87 mmol) in EtOH (8.8 mL) was added ammonium chloride (360 mg 6.73 mmol) water (0.88 mL) and iron powder (51 mg, 0.91 mmol). The reaction mixture was heated at 80° C. for 16 hr and then cooled to room temperature. The crude slurry was filtered through Celite® washing with DCM (200 mL). The solution was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in isopropanol (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (255 mg, 0.92 mmol) and DIPEA (0.59 mL, 3.50 mmol) were added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.46 mL, 0.96 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) followed by preparative HPLC gave 122 (Diastereomer 2) as a colourless solid (24 mg, 6% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.43 and 9.39 (2s, 1H), 8.09 and 8.07 (2s, 1H), 7.32 (tt, J=8.4, 6.1 Hz, 1H), 7.06-6.96 (m, 2H), 6.19 (s, 2H), 4.92 and 4.81 (d, J=11.4 Hz, 1H), 4.27 and 4.08 (2dd, J=12.5, 5.2 Hz, 1H), 3.88 (dd, J=12.5, 6.4 Hz, 1H), 3.83 and 3.81 (2s, 3H), 3.46-3.36 (m, 1H), 2.65-2.46 (m, 1H), 2.45-2.27 (m, 2H), 1.25 (s, 3H). LCMS (ES+) m/z 485 (M+1).

後処理

  1. temperaturecooled to room temperature
  2. filtrationThe crude slurry was filtered through Celite®
  3. washwashing with DCM (200 mL)
  4. customThe solution was passed through a phase separation cartridge
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue was dissolved in isopropanol (10 mL)
  7. concentrationThe reaction mixture was concentrated under reduced pressure
  8. customPurification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM)

出典と根拠

ORDレコード
ord-3f9345f312d24e7f875c7f5e03e7e18d
出典データセット
uspto-grants-2016_05
特許番号
US09328106B2

反応ノート

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