Triethylamine → (R)-N-(5,6-dichloropyridin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 250088Notes

Reaction equation

HRID 250088 reaction equation
[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([N:9]=[C:10]=S)[N:3]=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:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]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:3][C:2]=1[Cl:1]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 12734DiisopropylcarbodiimideHCID 198833963-(Aminomethyl)-1-azabicyclo(2.2.2)octan-3-ol dihydrochlorideHCID 574765812,3-Dichloro-6-isothiocyanatopyridine

Product 1

HCID 58087959(R)-N-(5,6-dichloropyridin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 47.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
70 °C

Procedure

To 2,3-dichloro-6-isothiocyanatopyridine (0.47 g, 2.29 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.8 mL, 5.7 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.54 g, 2.34 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours, 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 (1.07 mL, 6.88 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5,6-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.36 g, 1.08 mmol, 47% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.31 (d, J=1.22 Hz, 1 H), 7.84 (s, 1 H), 6.80 (s, 1 H), 3.85 (d, J=10.07 Hz, 1 H), 3.57 (d, J=10.38 Hz, 2 H), 2.98 (s, 3 H), 2.69-2.78 (m, 3 H), 2.65 (t, J=7.78 Hz, 3 H), 2.00 (s, 2 H), 1.86 (s, 2 H), 1.58 (dd, J=7.48, 2.90 Hz, 2 H), 1.56 (s, 1 H), 1.41-1.49 (m, 2 H). MS (LC/MS) R.T.=0.81; [M+H]+=327.1.

Workup

  1. temperaturecooled 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 in vacuo
  7. customThe crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)

Sources & evidence

ORD record
ord-7228ce4cbb4340a4b4fce0707b8f153e
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

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