Toluene → (R)-N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 250015Notes

Reaction equation

HRID 250015 reaction equation
[F:1][CH:2]([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][C:12]([N:14]3[CH:18]=[CH:17]N=C3)=S)[S:10][C:6]=2[CH:5]=1.C([N:24]([CH2:27]C)CC)C.C(N=C=NC(C)C)(C)C.[C:38]1(C)C=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C)C=[O:48]>>[F:21][CH:2]([F:1])[O:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][C:12]3[O:48][C@:17]4([CH2:18][N:14]=3)[CH:40]3[CH2:41][CH2:42][N:24]([CH2:38][CH2:39]3)[CH2:27]4)[S:10][C:6]=2[CH:5]=1

Participants

6

Reactant 5

HCID 1140TolueneHCID 6228DimethylformamideHCID 8471TriethylamineHCID 12734DiisopropylcarbodiimideHCID 58088254N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide

Product 1

HCID 58088135(R)-N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 55.5%

Conditions

Temperature
70 °C

Procedure

To a solution of N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (285 mg, 0.87 mmol) in N,N-dimethylformamide (5 mL) was added (S)-3-(aminomethyl)quinuclidin-3-ol, 2HCl (200 mg, 0.87 mmol) and triethylamine (0.4 mL, 2.87 mmol). The reaction was heated to 70° C. for 2 hours. N,N′-diisopropylcarbodiimide (0.4 mL, 2.57 mmol) was then added to the reaction mixture. The mixture was heated at 70° C. for another 3 hours. It was cooled and then poured into toluene/0.3M sodium hydroxide. The product was extracted with toluene (4×) and chloroform (3×). The organics were combined, washed with water (3×), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product. The crude material was purified via flash chromatography (2-20% [10% ammonium hydroxide/methanol]-chloroform) to afford (R)—N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (186.2mg, 0.49 mmol, 55.5% yield) as a white powder. M.P. 223-5° C. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.99 (1 H, br. s.), 7.69 (1 H, d, J=2.75 Hz), 7.61 (1 H, d, J=8.55 Hz), 7.02-7.34 (2 H, m), 3.89 (1 H, d, J=10.07 Hz), 3.64 (1 H, d, J=9.77 Hz), 3.03 (2 H, d, J=2.44 Hz), 2.73-2.86 (2 H, m), 2.62-2.70 (2 H, m), 2.07 (1 H, br. s.), 1.92 (1 H, br. s.), 1.54-1.65 (2 H, m), 1.44-1.53 (1H, m). MS (LC/MS) R.T.=1.43; [M+H]+=381.1.

Workup

  1. temperatureThe mixture was heated at 70° C. for another 3 hours
  2. temperatureIt was cooled
  3. extractionThe product was extracted with toluene (4×) and chloroform (3×)
  4. washwashed with water (3×)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto yield crude product
  9. customThe crude material was purified via flash chromatography (2-20% [10% ammonium hydroxide/methanol]-chloroform)

Sources & evidence

ORD record
ord-e93d021c82c84472bc9d6770494964b5
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

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