Ammonia → 6'-Bromo-5''-methyl-3'H-dispiro[cyclobutane-1,2'-indene-1',2''-imidazol]-4''-amine

HRID 1965137Notes

Reaction equation

HRID 1965137 reaction equation
[Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[NH:15][C:14](=S)[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:20]>>[Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:20])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1

Participants

3

Reactant 2

HCID 222Ammonia2×HCID 866672806'-Bromo-5''-methyl-3'H-dispiro[cyclobutane-1,2'-indene-1',2''-imidazole]-4''(3''H)-thione

Product 1

HCID 573866666'-Bromo-5''-methyl-3'H-dispiro[cyclobutane-1,2'-indene-1',2''-imidazol]-4''-amineYield 65.1%

Conditions

Temperature
90 °C

Procedure

6′-Bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 54 Step 3, 1.62 g, 4.83 mmol) and ammonia (7M in MeOH, 15.2 mL, 106 mmol) were mixed together in a microwave vial. The vial was sealed and the reaction was heated at 90° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 15.2 mL, 106 mmol), and heated once more at 90° C. for 30 min in a microwave reactor. This cycle was repeated four more times. After evaporation of the solvent, the crude was acidified with 2 M aq. hydrochloric acid, and washed with EtOAc. The aqueous phase was treated with 2M NaOH until basic pH was reached and then it was extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated. The organic phase was then acidified with 2M citric acid. The aqueous phase was treated with 2M NaOH until basic pH was reached and then it was extracted with EtOAc. The organic phases containing the title compound were combined, dried over MgSO4 and concentrated. The residue was dissolved in EtOAc and was washed with 50% aq. NaOH The organic layer was dried over MgSO4 and concentrated to afford the title compound (1.0 g, 65% yield): NMR: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48-1.67 (m, 4 H), 1.73-1.86 (m, 1 H), 2.08-2.17 (m, 1 H), 2.19 (s, 3 H), 3.06-3.20 (m, 2 H), 6.65 (br. s., 2 H), 6.71 (d, 1 H), 7.26 (d, 1 H), 7.35 (dd, 1 H); MS (ES+) m/z 318 [M+H]+.

Workup

  1. customThe vial was sealed
  2. concentrationThe mixture was concentrated
  3. temperatureheated once more at 90° C. for 30 min in a microwave reactor
  4. customAfter evaporation of the solvent
  5. washwashed with EtOAc
  6. additionThe aqueous phase was treated with 2M NaOH until basic pH
  7. extractionit was extracted with EtOAc
  8. dry with materialThe organic phase was dried over MgSO4
  9. concentrationconcentrated
  10. additionThe aqueous phase was treated with 2M NaOH until basic pH
  11. extractionit was extracted with EtOAc
  12. additionThe organic phases containing the title compound
  13. dry with materialdried over MgSO4
  14. concentrationconcentrated
  15. dissolutionThe residue was dissolved in EtOAc
  16. washwas washed with 50% aq. NaOH The organic layer
  17. dry with materialwas dried over MgSO4
  18. concentrationconcentrated

Sources & evidence

ORD record
ord-8d8ec442340c4068ae0b18735f3c77a4
Source dataset
uspto-grants-2013_04
Patent number
US08415483B2

Reaction notes

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