Succinic Acid → cevipabulin succinate anhydrous

HRID 28411

Reaction equation

HRID 28411 reaction equation
[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:10][C:9]=2[F:21])=[C:6]([NH:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[N:5]2[N:29]=[CH:30][N:31]=[C:4]2[N:3]=1.[C:32]([OH:39])(=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36]>O>[C:32]([OH:39])(=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36].[Cl:1][C:2]1[C:7]([C:8]2[C:9]([F:21])=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:12][C:13]=2[F:14])=[C:6]([NH:22][C@@H:23]([CH3:28])[C:24]([F:26])([F:27])[F:25])[N:5]2[N:29]=[CH:30][N:31]=[C:4]2[N:3]=1

Participants

4

Reactant 2

HCID 1110Succinic AcidHCID 11488110Cevipabulin

Product 1

HCID 11490143cevipabulin succinate anhydrous

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

A mixture 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 (9.00 g, 19.4 mmol) and succinic acid (2.75 g, 23.3 mmol) in water (90 mL) is stirred for about 15-20 min and then heated to about 65-75° C. The solution is filtered and the filtrate is cooled to about 0-5° C. over about 1 h. The mixture is stirred for about 1 h and then filtered and the collected solid washed with cold water (2×9 mL) and cold isopropanol (9 mL). The solid is dried under vacuum at about 40° C./10 mmHg for about 20 h to give a white solid in anhydrous form (6.6 g, 73%). 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 10.2 (bs, 1H), 8.26 (s, 1H), 6.80 (d, 2H, J=10.5 Hz), 5.79 (m, 1H), 4.13 (t, 2H, J=6.3 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.57 (s, 3H), 2.35 (s, 4H), 2.07 (m, 2H), 1.27 (d, J=6.0, 3H). This compound absorbs two mole waters at 5%-100% RH to become its dihydrate, 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 succinate salt dihydrate.

Workup

  1. filtrationThe solution is filtered
  2. temperaturethe filtrate is cooled to about 0-5° C. over about 1 h
  3. stirringThe mixture is stirred for about 1 h
  4. filtrationfiltered
  5. washthe collected solid washed with cold water (2×9 mL) and cold isopropanol (9 mL)
  6. customThe solid is dried under vacuum at about 40° C./10 mmHg for about 20 h
  7. customto give a white solid in anhydrous form (6.6 g, 73%)
  8. waitA portion of the compound is placed in a drying dish at 80-100% relative humidity (RH) and room temperature for about 24 h
  9. customThe compound absorbed 5.8% water forming a dihydrate which
  10. customis stable at room temperature and at 5-100% relative humidity (RH)
  11. customThis compound absorbs two mole waters at 5%-100% RH

Sources & evidence

ORD record
ord-62f7385828cb4e94b11a167c37278db8
Source dataset
uspto-grants-2008_09
Patent number
US07419982B2

Linked notes

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