Pyridine → 2-(Chloromethyl)-N-[6-{6-chloro-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide

HRID 1695721Notes

Reaction equation

HRID 1695721 reaction equation
[NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].N1C=CC=CC=1.[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45](Cl)=[O:46])[N:44]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([Cl:17])=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])=[O:46])[N:44]=1

Participants

6

Reactant 4

HCID 1049PyridineHCID 516892Sodium BicarbonateHCID 58255829N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methanesulfonamideHCID 597024562-(Chloromethyl)-1,3-thiazole-4-carbonyl chloride3×

Product 1

HCID 582558462-(Chloromethyl)-N-[6-{6-chloro-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamideYield 30.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent5×

Conditions

Temperature
20 °C

Procedure

N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methanesulfonamide (780 mg, 1.632 mmol) was dissolved in DCM (32 ml) and pyridine (0.198 ml, 2.448 mmol) and cooled to 0° C. To this was added 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) dropwise. The reaction was left to warm up and after final addition was stirred for a further 66 h at 20° C. Reaction was incomplete so the mixture was cooled again to 0° C. and a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) was added dropwise. The reaction was left to warm up and was stirred for a further 23 h at 20° C. Reaction still incomplete so, the mixture was cooled again to 0° C. and a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) was added dropwise. The reaction was left to warm up and was stirred for a further 23 h at 20° C. The solution was treated with DCM (25 ml) and saturated aqueous sodium bicarbonate (25 ml) and stirred vigorously for 10 mins. The organic phase was then separated, washed with dilute aqueous sodium chloride (30 ml), passed through a hydrophobic frit, and loaded directly onto a 100 g silica cartridge. This was eluted with 0-100% ethyl acetate/cyclohexane over 60 mins using the Flashmaster II. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (321 mg).

Workup

  1. waitThe reaction was left
  2. temperatureto warm up
  3. additionafter final addition
  4. customReaction
  5. temperaturewas cooled again to 0° C.
  6. waitThe reaction was left
  7. temperatureto warm up
  8. stirringwas stirred for a further 23 h at 20° C
  9. customReaction still incomplete so
  10. temperaturethe mixture was cooled again to 0° C.
  11. waitThe reaction was left
  12. temperatureto warm up
  13. stirringwas stirred for a further 23 h at 20° C
  14. stirringstirred vigorously for 10 mins
  15. customThe organic phase was then separated
  16. washwashed with dilute aqueous sodium chloride (30 ml)
  17. washThis was eluted with 0-100% ethyl acetate/cyclohexane over 60 mins
  18. customevaporated

Sources & evidence

ORD record
ord-aae6219a67e44758a1d75b32a387e7cd
Source dataset
uspto-grants-2012_04
Patent number
US08163743B2

Reaction notes

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