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 526727Notes

Reaction equation

HRID 526727 reaction equation
[OH-].[K+].SCC(O)=O.[CH2:8]([N:15]([CH2:28][CH2:29][C:30]1[N:31]([C@@H:36]2[CH2:45][C:44]3[C:39](=[C:40]([F:47])[CH:41]=[C:42]([F:46])[CH:43]=3)[O:38][CH2:37]2)[C:32](=[S:35])[NH:33][CH:34]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>O.CS(C)=O>[CH2:8]([NH:15][CH2:28][CH2:29][C:30]1[N:31]([C@@H:36]2[CH2:45][C:44]3[C:39](=[C:40]([F:47])[CH:41]=[C:42]([F:46])[CH:43]=3)[O:38][CH2:37]2)[C:32](=[S:35])[NH:33][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1

Participants

7

Reactant 4

HCID 887MethanolHCID 1133Thioglycolic AcidHCID 14797Potassium Hydroxide2×HCID 71152068(R)-N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide

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%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×

Procedure

To a solution of potassium hydroxide (5M aqueous solution, 52.5 ml, 263 mmol) in water at 10° C. was added dropwise 2-mercaptoacetic acid (8.30 ml, 119 mmol). The resulting solution was stirred at room temperature for 10 minutes and a solution of (R)—N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (28 g, 47.7 mmol) in DMSO (150 ml) was added dropwise over 20 minutes. During the addition of KOH, an exothermic event was observed. The resulting slurry was stirred at 40° C. under HPLC control for 3 h. The reaction was then cooled to 20° C. and methanol (105 ml) was added followed by water (45 ml). The resulting slurry was aged for 30 minutes at 20° C. and then filtered. The beige solid was successively washed with water/MeOH (9:1) (100 ml), water (200 ml) and finally methyl tert-butyl ether (MTBE) (50 ml), dried to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (compound RY′, 18.3 g, 12.35 mmol, 96% yield).

Workup

  1. stirringThe resulting slurry was stirred at 40° C. under HPLC control for 3 h
  2. temperatureThe reaction was then cooled to 20° C.
  3. waitThe resulting slurry was aged for 30 minutes at 20° C.
  4. filtrationfiltered
  5. washThe beige solid was successively washed with water/MeOH (9:1) (100 ml), water (200 ml) and finally methyl tert-butyl ether (MTBE) (50 ml)
  6. customdried

Sources & evidence

ORD record
ord-ff42b84843fb4b818ddfa0083ff32cfe
Source dataset
uspto-grants-2016_05
Patent number
US09346751B2

Reaction notes

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