Pyridine → 2-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide

HRID 244708Notes

Reaction equation

HRID 244708 reaction equation
[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:20]=[C:21]5[CH:27]=[N:26][N:25]([S:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]5=[N:23][CH:24]=4)[CH:15]=[C:14]([NH2:37])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:44][CH2:45][C:46]1[S:47][CH:48]=[C:49]([C:51](Cl)=[O:52])[N:50]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:44][CH2:45][C:46]1[S:47][CH:48]=[C:49]([C:51]([NH:37][C:14]2[CH:15]=[C:16]([C:19]3[CH:20]=[C:21]4[CH:27]=[N:26][N:25]([S:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)(=[O:29])=[O:30])[C:22]4=[N:23][CH:24]=3)[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:52])[N:50]=1

Participants

6

Reactant 3

HCID 1049PyridineHCID 58268026HCID 58268026, compoundHCID 597024562-(Chloromethyl)-1,3-thiazole-4-carbonyl chloride3×

Product 1

HCID 583563662-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamideYield 22.4%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent5×HCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
0 °C

Procedure

1-(Phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-amine (185 mg, 0.349 mmol) was dissolved in DCM (3 ml) and pyridine (0.034 mL, 0.418 mmol) was added. The mixture was cooled to 0° C. in an ice bath and 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (77 mg, 0.349 mmol) in DCM (3 ml) was added dropwise over 5 mins. The mixture was stirred at 0° C. for 15 mins. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (38.4 mg, 0.174 mmol) in DCM (1.5 ml) was added. The mixture was stirred for 2 hours, letting the ice melt over this time. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (38.4 mg, 0.174 mmol) in DCM (1.5 ml) was added and stirring continued with monitoring by LCMS. The mixture was diluted with DCM (10 ml), saturated aqueous sodium bicarbonate (10 ml) was added and the mixture stirred vigorously for 10 mins. The organic layer was separated, washed with water (10 ml), passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in DMSO and loaded onto a 43 g C18 Reverse Phase RediSep column that was then eluted with 30-85% acetonitrile (+0.1% TFA)/H2O (+0.1% TFA) over 30 mins. The product-containing fractions were combined and concentrated in vacuo to give a cream solid which was then dried on the vacuum line for 1 hour to give the title compound (54 mg).

Workup

  1. stirringThe mixture was stirred for 2 hours
  2. stirringstirring
  3. additionwas added
  4. stirringthe mixture stirred vigorously for 10 mins
  5. customThe organic layer was separated
  6. washwashed with water (10 ml)
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in DMSO
  9. washwas then eluted with 30-85% acetonitrile (+0.1% TFA)/H2O (+0.1% TFA) over 30 mins
  10. concentrationconcentrated in vacuo
  11. customto give a cream solid which
  12. customwas then dried on the vacuum line for 1 hour

Sources & evidence

ORD record
ord-8aed7d38770b4552b06b78fcd5659348
Source dataset
uspto-grants-2014_02
Patent number
US08658635B2

Reaction notes

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