Sodium Hydroxide → Cevipabulin fumarate anhydrous

HRID 1786295Notes

Reaction equation

HRID 1786295 reaction equation
Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:14]([F:15])=[CH:13][C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH3:21])=[CH:11][C:10]=2[F:22])=[C:7]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[N:6]2[N:30]=[CH:31][N:32]=[C:5]2[N:4]=1.[OH-].[Na+].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>O>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[Cl:2][C:3]1[C:8]([C:9]2[C:10]([F:22])=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH3:21])=[CH:13][C:14]=2[F:15])=[C:7]([NH:23][C@@H:24]([CH3:29])[C:25]([F:27])([F:28])[F:26])[N:6]2[N:30]=[CH:31][N:32]=[C:5]2[N:4]=1

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 444972Fumaric AcidHCID 161030185-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride

Product 1

HCID 71587814Cevipabulin fumarate anhydrousYield 75.1%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

To a slurry of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride (7.50 g, 15.0 mmol) and water (100 mL) is added sodium hydroxide solution (10 N, 2.0 mL, 20 mmol) dropwise. Then, fumaric acid (3.48 g, 30 mmol) is added. The mixture is stirred for about 15-20 min and then heated to about 65-75° C. and stirred until all of the solid dissolves. The solution is filtered and the filtrate is cooled to about 0-5° C. over about 1 h. The mixture is stirred for 1 h and then filtered and the collected solid washed with cold water and isopropanol. The solid is dried under vacuum at about 60° C./10 mmHg for about 20 h to give a white solid (6.54 g, 75%) in anhydrous form. A portion of the compound is placed in a drying dish at 80-100% relative humidity (RH) and room temperature for about 24 h. The compound absorbed 5.8% water forming a dihydrate which is stable at room temperature and at 5-100% relative humidity (RH). 1H NMR (CDCl3): δ 8.43 (s, 1H), 6.86 (d, 2H, J=10.2 Hz), 6.51 (s, 2H), 5.84 (m, 1H), 4.15 (t, 2H, J=7.9 Hz), 3.04 (t, 2H, J=7.2 Hz), 2.57 (s, 3H), 2.08 (m, 2H), 1.33 (d, J=6.7, 3H).

Workup

  1. stirringstirred until all of the solid
  2. dissolutiondissolves
  3. filtrationThe solution is filtered
  4. temperaturethe filtrate is cooled to about 0-5° C. over about 1 h
  5. stirringThe mixture is stirred for 1 h
  6. filtrationfiltered
  7. washthe collected solid washed with cold water and isopropanol
  8. customThe solid is dried under vacuum at about 60° C./10 mmHg for about 20 h

Sources & evidence

ORD record
ord-b9c8180031aa41cca7822ea0b32bd159
Source dataset
uspto-grants-2009_03
Patent number
US07507739B2

Reaction notes

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