Hydrochloric Acid → Capmatinib hydrochloride anhydrous

HRID 1396532ノート

反応式

HRID 1396532 の反応式
[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[ClH:32].C(OC)(C)(C)C>CO.C(O)(C)C>[ClH:32].[ClH:32].[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]

参加物

6

反応物 3

HCID 313Hydrochloric AcidHCID 15413tert-Butyl methyl etherHCID 25145656Capmatinib

生成物 1

HCID 44513225Capmatinib hydrochloride anhydrous収率 95%

試薬・触媒・溶媒 2

HCID 887Methanol溶媒HCID 3776Isopropanol溶媒

反応条件

温度
55 °C

実験手順

A suspension of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazolo[1,2-b][1,2,4]triazin-2-yl]benzamide (15, 421.2 g, 1.021 mol) in methanol (MeOH, 6600 mL) was heated to 55° C. before a premixed solution of aqueous concentrated hydrochloric acid (conc. HCl, 37 wt. %, 12 M, 420 mL, 5.10 mol, 5.0 equiv) in isopropyl alcohol (IPA, 1510 mL) was added dropwise at 55° C. The resulting clear solution was stirred at 55° C. for 30 min before methyl tert-butyl ether (MTBE, 6750 mL) was added via an additional funnel over 30 min. The solids were slowly precipitated out after addition of methyl tert-butyl ether. The resulting mixture was stirred at 55° C. for an additional 1 h before being gradually cooled down to room temperature. The mixture was stirred at room temperature for overnight. The solids were collected by filtration, washed with methyl tert-butyl ether (MTBE, 3×500 mL), and dried in vacuum oven at 45-55° C. to constant weight. The desired 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazolo[1,2-b][1,2,4]triazin-2-yl]benzamide dihydrochloride (21, dihydrochloride, 470.7 g, 495.5 g theoretical, 95% yield) was obtained as off-white to light yellow crystalline solids. For 21 (dihydrochloride): mp (decom.) 222° C.; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 9.25 (dd, 1H, J=5.4 Hz, 1.4 Hz), 9.12 (d, 1H, J=8.3 Hz), 8.51 (m, 1H), 8.47 (d, 1H, J=0.9 Hz), 8.34 (d, 1H, J=1.3 Hz), 8.23 (s, 1H), 8.21 (dd, 1H, J=9.0 Hz, 1.8 Hz), 8.09-8.02 (m, 3H), 7.79 (dd, 1H, J=7.5 Hz, 8.3 Hz), 4.77 (s, 2H), 2.78 (s, 3H, J=4.5 Hz); 13C NMR (100 MHz, DMSO-d6) δ ppm 163.4, 159.4 (d, J=249.9 Hz), 145.8, 145.4, 144.5, 143.8, 140.4, 138.8, 136.8, 135.9, 135.7 (J=8.6 Hz), 131.2 (J=3.1 Hz), 130.7, 128.7, 128.2, 126.2 (J=14.9 Hz), 126.0, 123.1 (J=3 Hz), 122.5, 121.0, 114.9 (J=5.6 Hz), 28.4, 26.3; 19F NMR (376.3 MHz, DMSO-d6) δ ppm −113.2; C23H17FN6O (free base, MW 412.42), LCMS (EI) m/e 413.1 (M++H) and 435.0 (M++Na).

後処理

  1. additionwas added dropwise at 55° C
  2. additionwas added via an additional funnel over 30 min
  3. customThe solids were slowly precipitated out
  4. additionafter addition of methyl tert-butyl ether
  5. temperaturebefore being gradually cooled down to room temperature
  6. stirringThe mixture was stirred at room temperature for overnight
  7. filtrationThe solids were collected by filtration
  8. washwashed with methyl tert-butyl ether (MTBE, 3×500 mL)
  9. customdried in vacuum oven at 45-55° C. to constant weight

出典と根拠

ORDレコード
ord-8db16d9aa4b042529469511290c4f110
出典データセット
uspto-grants-2014_12
特許番号
US08901123B2

反応ノート

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