Ammonia → HCID 72705045, compound

HRID 1468088Notes

Reaction equation

HRID 1468088 reaction equation
[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][C:3]=1[F:24].[NH3:25]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:25])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][C:3]=1[F:24]

Participants

3

Reactant 2

HCID 222Ammonia2×HCID 86706701HCID 86706701, compound2×

Product 1

HCID 72705045HCID 72705045, compoundYield 74%

Conditions

Temperature
100 °C

Procedure

6′-Bromo-5′-fluoro-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 14, 0.500 g, 1.22 mmol) and ammonia (7 M in MeOH) (16.5 mL, 115 mmol) were mixed in a MW vial. The vial was sealed and the reaction was heated at 100° C. for 30 min in a MW reactor (fixed hold time). The mixture was concentrated and the residue was dissolved in new ammonia (7 M in MeOH) (16.5 mL, 115 mmol) and heated once more at 100° C. for 30 min in a MW reactor. 4 cycles of concentration, addition of ammonia and heating were performed in total. After evaporation of the solvent, the residue was partitioned between EtOAC and 2 M citric acid (10 mL). The phases were separated and the organic layer was re-extracted with 2 M citric acid (10 mL). The organic layer was discarded while the combined aqueous phases were basified to pH 12 by addition of 50% aq. NaOH and then extracted with EtOAc. The combined organic layers were dried over magnesium sulfate and concentrated, to give the title compound (0.354 g, 74% yield) as a diastereomer mixture in the ratio ˜4:1 (established by HPLC). 1H NMR (500 MHz, DMSO-d6, contains both isomers) δ ppm 0.88-0.99 (m, 1 H) 1.09-1.28 (m, 4 H) 1.32-1.52 (m, 3.8 H) 1.58-1.72 (m, 1 H) 1.81 (d, 2 H) 2.16 (s, 3.8 H) 2.88-3.07 (m, 3.7H) 3.12 (s, 0.8 H) 3.18 (s, 3 H) 6.60 (br. s., 2.6 H) 6.75 (d, 1.21 H) 7.32 (d, 1.26 H); MS (ES+) m/z 394, 396 [M+H]+.

Workup

  1. customThe vial was sealed
  2. concentrationThe mixture was concentrated
  3. temperatureheated once more at 100° C. for 30 min in a MW reactor
  4. concentration4 cycles of concentration, addition of ammonia
  5. temperatureheating
  6. customAfter evaporation of the solvent
  7. customthe residue was partitioned between EtOAC and 2 M citric acid (10 mL)
  8. customThe phases were separated
  9. extractionthe organic layer was re-extracted with 2 M citric acid (10 mL)
  10. additionwere basified to pH 12 by addition of 50% aq. NaOH
  11. extractionextracted with EtOAc
  12. dry with materialThe combined organic layers were dried over magnesium sulfate
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-23e9848b153740899894e9552c2c08e3
Source dataset
uspto-grants-2015_04
Patent number
US09000183B2

Reaction notes

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