Citric Acid → 4-Fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one monocitrate

HRID 2061498Notes

Reaction equation

HRID 2061498 reaction equation
[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:24])[CH:3]=1.[C:25]([OH:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])([C:29]([OH:31])=[O:30])[OH:28]>C(#N)C>[C:25]([OH:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])([C:29]([OH:31])=[O:30])[OH:28].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:24])[CH:3]=1

Participants

4

Reactant 2

HCID 311Citric AcidHCID 16038386Gsk 1034702

Product 1

HCID 686248884-Fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one monocitrate

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
35 °C

Procedure

4-Fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one free base (1.499 mmol, 500 mg, 1 wt) was weighed into a 250 ml round bottomed flask, citric acid (1 eq, 1.499 mmol, 288 mg,) was added. Acetonitrile (95 vol. 47.5 ml) was added and a white slurry obtained, dissolution was not achieved with heating using a hot air gun. The slurry was magnetically stirred at 35° C. for four days under nitrogen. The solid was cooled and isolated by vacuum filtration and washed with acetonitrile (10 vol. 5 ml). The solid (1.0 g not dried) was recombined with the mother liquors plus acetonitrile (29 vol., 14.5 ml) and n-propanol (22 vol. 11 ml) was added. The slurry was stirred at ambient temperature overnight. The solid was isolated by vacuum filtration and washed with acetonitrile (10 vol, 5 ml). The white solid was dried under vacuum at 60° C. for 25 hours. 506 mg, 64%.

Workup

  1. customa white slurry obtained
  2. dissolutiondissolution
  3. temperaturewith heating
  4. temperatureThe solid was cooled
  5. customisolated by vacuum filtration
  6. washwashed with acetonitrile (10 vol. 5 ml)
  7. customThe solid (1.0 g not dried)
  8. additionwas added
  9. stirringThe slurry was stirred at ambient temperature overnight
  10. customThe solid was isolated by vacuum filtration
  11. washwashed with acetonitrile (10 vol, 5 ml)
  12. customThe white solid was dried under vacuum at 60° C. for 25 hours

Sources & evidence

ORD record
ord-1f7d0f7532484fe0bea2d24cd2c08ed0
Source dataset
uspto-grants-2012_10
Patent number
US08283364B2

Reaction notes

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