Methanol → 1-((3R)-6,8-Difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-1,3-dihydro-5-(2-((phenylmethyl)amino)ethyl)-2H-imidazole-2-thione

HRID 538941Notes

Reaction equation

HRID 538941 reaction equation
CO.Cl.[CH2:4]([NH:11][CH2:12][CH2:13][C:14]1[N:18]([C@@H:19]2[CH2:28][C:27]3[C:22](=[C:23]([F:30])[CH:24]=[C:25]([F:29])[CH:26]=3)[O:21][CH2:20]2)[C:17](=[S:31])[NH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[CH2:4]([NH:11][CH2:12][CH2:13][C:14]1[N:18]([C@@H:19]2[CH2:28][C:27]3[C:22](=[C:23]([F:30])[CH:24]=[C:25]([F:29])[CH:26]=3)[O:21][CH2:20]2)[C:17](=[S:31])[NH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 14798Sodium HydroxideHCID 25156755Zamicastat hydrochloride

Product 1

HCID 250526301-((3R)-6,8-Difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-1,3-dihydro-5-(2-((phenylmethyl)amino)ethyl)-2H-imidazole-2-thioneYield 96.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
67 °C

Procedure

To a mixture of Methanol (66 L) and Water (10 L) at 20° C. was added purified (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride (4.37 kg, 9.98 mol) to afford a suspension. The reaction mixture was then heated to 67° C. to affect complete dissolution, whereupon 1N Sodium hydroxide (10.48 L, 10.48 mol, 1.05 eq) was added in a single portion. The reaction mixture was adjusted back to 67° C. and held at 67° C. for 30 min. The reaction mixture was then cooled to 20° C. and aged at 20° C. for at least 30 min. The reaction was then filtered and the filter cake washed with aqueous Methanol (1:1 v/v, 20 L), sucked down for 15 min. and then dried at 45° C. under vacuum, to afford (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (3.855 kg, 96%) as a pale tan crystalline solid.

Workup

  1. additionwas added
  2. customto afford a suspension
  3. dissolutiondissolution
  4. customwas adjusted back to 67° C.
  5. temperatureThe reaction mixture was then cooled to 20° C.
  6. waitaged at 20° C. for at least 30 min
  7. filtrationThe reaction was then filtered
  8. washthe filter cake washed with aqueous Methanol (1:1 v/v, 20 L)
  9. waitsucked down for 15 min.
  10. customdried at 45° C. under vacuum

Sources & evidence

ORD record
ord-31c026185acd4b1090dfaa56d91bfb04
Source dataset
uspto-grants-2014_10
Patent number
US08865913B2

Reaction notes

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