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

HRID 244713Notes

Reaction equation

HRID 244713 reaction equation
[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]5[N:25]([S:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)(=[O:30])=[O:29])[CH:26]=[CH:27][C:20]=45)[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.CCN(C(C)C)C(C)C.[Cl:47][CH2:48][C:49]1[S:50][CH:51]=[C:52]([C:54](Cl)=[O:55])[N:53]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:47][CH2:48][C:49]1[S:50][CH:51]=[C:52]([C:54]([NH:37][C:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]4[N:25]([S:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)(=[O:29])=[O:30])[CH:26]=[CH:27][C:20]=34)[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:55])[N:53]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 597024562-(Chloromethyl)-1,3-thiazole-4-carbonyl chloride3×HCID 670291711-(Phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-amine

Product 1

HCID 583563842-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamideYield 12.9%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

1-(Phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-amine (663 mg, 1.252 mmol) in chloroform (10 mL) was stirred at 0° C. DIPEA (0.437 mL, 2.504 mmol) was added into the reaction mixture, followed by 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (300 mg, 1.530 mmol) in chloroform (10 mL). The reaction mixture was stirred at 0° C. for 15 mins. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (400 mg, 1.252 mmol) was added and the reaction was monitored by LCMS. When no further conversion was apparent, a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.6 g, 1.252 mmol) was added and the reaction mixture was stirred for 18 h. The solution was treated with DCM (25 mL) and saturated aqueous sodium bicarbonate (25 mL) and stirred for 10 mins. The organic layer was separated, washed with aqueous sodium chloride (25 mL) and then passed through a hydrophobic frit. The residual solvent volume was reduced and the mixture was purified by silica column chromatography (Flashmaster II, 100 g cartridge) using a gradient of 0-100% ethylacetate/cyclohexane over 60 min to afford the title compound as a white solid (111 mg).

Workup

  1. stirringthe reaction mixture was stirred for 18 h
  2. stirringstirred for 10 mins
  3. customThe organic layer was separated
  4. washwashed with aqueous sodium chloride (25 mL)
  5. customthe mixture was purified by silica column chromatography (Flashmaster II, 100 g cartridge)
  6. customover 60 min

Sources & evidence

ORD record
ord-2e041eb580a648f5a32428b054b46b18
Source dataset
uspto-grants-2014_02
Patent number
US08658635B2

Reaction notes

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