Hydrochloric Acid → Capmatinib hydrochloride anhydrous

HRID 1396532Notes

Reaction equation

HRID 1396532 reaction equation
[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]

Participants

6

Reactant 3

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

Product 1

HCID 44513225Capmatinib hydrochloride anhydrousYield 95%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
55 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-8db16d9aa4b042529469511290c4f110
Source dataset
uspto-grants-2014_12
Patent number
US08901123B2

Reaction notes

Loading…