3-Isocyanatobenzonitrile → (R)-1-(3-cyanophenyl)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea

HRID 588529Notes

Reaction equation

HRID 588529 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[C:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:23][C:20]2[N:18]3[N:19]=[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]

Participants

4

Reactant 2

HCID 27333153-IsocyanatobenzonitrileHCID 58334496(R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine

Product 1

HCID 45274001(R)-1-(3-cyanophenyl)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ureaYield 37%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added 3-cyanophenylisocyanate (14 mg, 0.095 mmol) in DCM (0.1 mL) drop-wise. The reaction was slowly warmed to ambient temperature and stirred for 1 hour. The reaction was diluted with DCM (2 mL), washed with water, and concentrated. The crude material was purified by reverse-phase column chromatography, eluting with 5 to 85% acetonitrile/water to yield the pure final product as a solid (3.2 mg, 37% yield). MS (apci) m/z=460.2 (M+H).

Workup

  1. washwashed with water
  2. concentrationconcentrated
  3. customThe crude material was purified by reverse-phase column chromatography
  4. washeluting with 5 to 85% acetonitrile/water

Sources & evidence

ORD record
ord-e3d7f46764d04384a31f8082849425db
Source dataset
uspto-grants-2016_01
Patent number
US09227975B2

Reaction notes

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