Triethylamine → (R)-N-(5-chloro-4-methylpyridin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 250092Notes

Reaction equation

HRID 250092 reaction equation
[Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N:8]=[C:9]=S)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([NH:8][C:9]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:6][CH:7]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 12734DiisopropylcarbodiimideHCID 574765835-Chloro-2-isothiocyanato-4-methylpyridineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58088234(R)-N-(5-chloro-4-methylpyridin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 30.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
70 °C

Procedure

To 5-chloro-2-isothiocyanato-4-methylpyridine (0.37 g, 2.0 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.7 mL, 5.0 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B of Example 17) (0.47 g, 2.0 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.94 mL, 6.0 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5-chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.19 g, 0.61 mmol, 30.3% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.79 (s, 1 H), 8.08-8.15 (m, 2 H), 6.78 (s, 1 H), 3.82 (d, J=8.55 Hz, 2 H), 3.55 (d, J=10.38 Hz, 2 H), 2.93-3.02 (m, 5 H), 2.71-2.80 (m, 5 H), 2.66 (t, J=7.63 Hz, 4 H), 2.23-2.29 (m, 7 H), 1.94-2.02 (m, 2 H), 1.92 (s, 1 H), 1.86 (s, 2 H), 1.53-1.62 (m, 5 H), 1.41-1.49 (m, J=12.55, 9.88, 7.02, 2.29 Hz, 2 H). MS (LC/MS) R.T.=0.72; [M+H]+=307.1.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. customThe crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)
  4. temperatureThe reaction was heated to 70° C. for 2 hours
  5. temperatureThe reaction was cooled to room temperature
  6. concentrationconcentrated
  7. customto yield the crude product
  8. customThe crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)

Sources & evidence

ORD record
ord-7ac876d75f8d4063a4f3e3b8dbd88297
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

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