Water → (1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

HRID 1848166Notes

Reaction equation

HRID 1848166 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:24]=[CH:23][C:16]4[N:17]=[C:18](S(C)=O)[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1.[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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:24]=[CH:23][C:16]4[N:17]=[C:18]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 735777(1R,2R)-2-AminocyclohexanolHCID 866811346-((6-Methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole

Product 1

HCID 86681135(1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolYield 33%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (320 mg, 0.89 mmol), (1R,2R)-2-amino cyclohexanol (308 mg, 2.68 mmol) and DIEA (231 mg, 1.79 mmol) in NMP (11 mL) was stirred for 1 d at 140° C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL×3). 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 10:1 DCM/MeOH, then further purified by preparative HPLC to afford (1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown solid (120 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=9.6 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.18 (d, J=9.9 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 4.72 (d, J=5.4 Hz, 1H), 4.23 (s, 2H), 3.95 (s, 3H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.28-1.14 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.

Workup

  1. temperatureThe mixture was cooled to rt
  2. extractionThe mixture was extracted with EtOAc (30 mL×3)
  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 10:1 DCM/MeOH
  9. customfurther purified by preparative HPLC

Sources & evidence

ORD record
ord-7e52edb88cb34acda6937a159f6b7fe1
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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