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

HRID 250025

Reaction equation

HRID 250025 reaction equation
[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]=[C:12]=S)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C@@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12]3[O:33][C@:25]4([CH2:24][N:23]=3)[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]4)=[N:7][NH:8]2)=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 12734DiisopropylcarbodiimideHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochlorideHCID 178505448HCID 178505448, compound

Product 1

HCID 58088057(R)-N-(6-fluoro-1H-indazol-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 64%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To 6-fluoro-3-isothiocyanato-1H-indazole (0.20 g, 1.04 mmol) in DMF (15 mL) was added triethylamine (0.43 mL, 3.11 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.26 g, 1.14 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and treated with N,N′-diisopropylcarbodiimide (0.48 mL, 3.11 mmol). The reaction was then heated to 70° C. for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude product was purified by column chromatography (85% chloroform, 14% methanol, 1% ammonium hydroxide) to afford (R)—N-(6-fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.22 g, 0.66 mmol, 64% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.16 (s, 1 H), 8.00 (s, 1 H), 7.59-7.67 (m, 1H), 7.09 (dd, J=9.77, 2.14 Hz, 1 H), 6.81-6.88 (m, 1 H), 3.81 (d, J=9.16 Hz, 1 H), 3.56 (d, J=8.85 Hz, 1 H), 3.00 (s, 2 H), 2.78 (s, 2 H), 2.67 (t, J=7.32 Hz, 2 H), 2.01 (d, J=2.44 Hz, 1 H), 1.92 (s, 1 H), 1.59 (d, J=5.80 Hz, 2 H), 1.46 (s, 1 H). MS (LC/MS) R.T.=1.44; [M+H]+=316.16.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. temperatureThe reaction was then heated to 70° C. for 2 hours
  3. temperatureThe reaction was cooled to ambient temperature
  4. concentrationconcentrated
  5. customThe crude product was purified by column chromatography (85% chloroform, 14% methanol, 1% ammonium hydroxide)

Sources & evidence

ORD record
ord-34d668b587d04c3aa8e3b031f8d70156
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Linked notes

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