Sulfuric Acid → 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

HRID 914247

反応式

HRID 914247 の反応式
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[C:23]([F:39])[CH:22]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:26])=[C:23]([F:39])[CH:22]=3)[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]

参加物

7

反応物 4

HCID 1118Sulfuric AcidHCID 10340Sodium CarbonateHCID 669272854-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamideHCID 866359002-Chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

生成物 1

HCID 579556334-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide収率 35.3%

試薬・触媒・溶媒 2

HCID 702Ethanol溶媒HCID 962Water溶媒2 回

反応条件

温度
100 °C

実験手順

2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.344 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg, 0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20 mmol) was added. The reaction mixture was stirred in a closed vial at 100° C. for 18 h, cooled, diluted with water (5 mL) and brought to pH=7 using solid sodium carbonate. The resulting mixture was diluted with ethanol (0.5 mL) and stirred for 5 min. The precipitate was filtered, washed with water (5 mL) and dried in air for 20-30 min. It was then suspended in ethanol (˜10 mL), treated with solid sodium bicarbonate (130 mg) and stirred vigorously for 45 min. The insoluble salts were filtered off and filtrate was concentrated in vacuo. The residue was crystallized from ethanol-water (1:7; 8 mL) and dried in vacuum to afford the title compound as a white solid (65 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.82 Hz, 6H) 1.49-1.62 (m, 2H) 1.77 (br. d., 2H) 1.95 (app. t, J=11.2 Hz, 2H) 2.15 (s, 3H) 2.73 (br. d., J=11.12 Hz, 2H) 3.33 (s, 3H) 3.71 (m, J=7.83 Hz, 1H) 3.91 (s, 3H) 4.07 (t, J=13.52 Hz, 2H) 4.90 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 7.88 (dd, J=7.33, 3.03 Hz, 1H) 7.97 (s, 1H) 8.20-8.32 (m, 2H); [M+H] calc'd for C25H32F3N7O3, 536. found 536.

後処理

  1. temperaturecooled
  2. stirringstirred for 5 min
  3. filtrationThe precipitate was filtered
  4. washwashed with water (5 mL)
  5. customdried in air for 20-30 min
  6. additiontreated with solid sodium bicarbonate (130 mg)
  7. stirringstirred vigorously for 45 min
  8. filtrationThe insoluble salts were filtered off
  9. concentrationfiltrate was concentrated in vacuo
  10. customThe residue was crystallized from ethanol-water (1:7; 8 mL)
  11. customdried in vacuum

出典と根拠

ORDレコード
ord-b46a4e79820e4523ba2fb1392400e2c3
出典データセット
uspto-grants-2011_09
特許番号
US08026234B2

関連ノート

読み込み中…