Sodium Iodide → Formic acid 2-[(4,4-dimethyl-1-piperidinyl)methyl]-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide

HRID 244752Notes

Reaction equation

HRID 244752 reaction equation
Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.Cl.[CH3:39][C:40]1([CH3:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CCN(C(C)C)C(C)C.[I-].[Na+].C[Si](C)(C)[O-:60].[K+]>C(#N)C.C1COCC1>[CH:8]([OH:9])=[O:60].[CH3:39][C:40]1([CH3:46])[CH2:45][CH2:44][N:43]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:21]=4[CH:22]=[CH:23][NH:24]5)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:42][CH2:41]1

Participants

8

Reactant 5

HCID 5238Sodium IodideHCID 81531DiisopropylethylamineHCID 222529024,4-Dimethylpiperidinium chlorideHCID 23668039Potassium trimethylsilanolate2×HCID 583563582-(Chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide

Product 1

HCID 67319980Formic acid 2-[(4,4-dimethyl-1-piperidinyl)methyl]-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamideYield 26.4%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
70 °C

Procedure

A solution of 2-(chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (55 mg, 0.1 mmol) in acetonitrile (0.5 ml) was added to 4,4-dimethylpiperidine hydrochloride (0.11 mmol, available from Microchemistry Ltd). DIPEA was then added (0.026 ml, 0.15 mmol), followed by sodium iodide (13 mg). The vial was capped and the stirred solution heated to 70° C. for 18 h. Potassium trimethylsilanolate (26 mg) was dissolved in THF (0.3 ml) and added to the vessel, which was then stirred at room temperature for 21 h, then heated at 50° C. for 3 h. A further equivalent of potassium trimethylsilanolate was added as a solution in THF (150 ul) and the mixture was heated at 50° C. for a further 18 h. The solution was quenched with aqueous acetonitrile (500 ul, 50:50) and neutralised. Solvent was removed by blowdown. The residue was dissolved in DMSO 0.5 mL and purified by Mass Directed AutoPrep HPLC (Method F). The solvent was removed by vacuum centrifugation to give the title compound (7 mg). LCMS (Method C) Rt=1.69 min, MH+=485.

Workup

  1. customThe vial was capped
  2. additionadded to the vessel, which
  3. temperatureheated at 50° C. for 3 h
  4. temperaturethe mixture was heated at 50° C. for a further 18 h
  5. customThe solution was quenched with aqueous acetonitrile (500 ul, 50:50)
  6. customSolvent was removed by blowdown
  7. dissolutionThe residue was dissolved in DMSO 0.5 mL
  8. custompurified by Mass Directed AutoPrep HPLC (Method F)
  9. customThe solvent was removed by vacuum centrifugation

Sources & evidence

ORD record
ord-24efc96a350d40c3a9b5ea4bc42e133c
Source dataset
uspto-grants-2014_02
Patent number
US08658635B2

Reaction notes

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