Water → 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile

HRID 1848254Notes

Reaction equation

HRID 1848254 reaction equation
CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][C:14]3[N:18]4[N:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][C:14]3[N:18]4[N:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 735777(1R,2R)-2-AminocyclohexanolHCID 866812283-((2-(Methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile

Product 1

HCID 866812273-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrileYield 30%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
135 °C

Procedure

A mixture of 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile (300 mg, 0.9 mmol), (1R,2R)-2-aminocyclohexanol (293 mg, 2.5 mmol) and DIEA (219 mg, 1.7 mmol) in NMP (16 mL) was stirred at 135° C. overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a brown solid (100 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (d, J=9.3 Hz, 1H), 7.87-7.84 (m, 2H), 7.70 (d, J=9.3 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.13 (dd, J=1.5, 8.1 Hz, 1H), 4.72 (d, J=5.1 Hz, 1H), 4.36 (s, 2H), 3.54-3.51 (m, 1H), 3.39-3.36 (m, 1H), 2.06-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.31-1.17 (m, 4H). LCMS (ESI) m/z 405 (M+H)+.

Workup

  1. temperatureThe mixture was cooled to rt
  2. extractionThe mixture was extracted with EtOAc (3×30 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel chromatography
  8. washeluting with 50:1 to 20:1 DCM/MeOH

Sources & evidence

ORD record
ord-20304c98f9944cbdbf1dd4eb43633f57
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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