Ethyl chloroformate → ethyl 5-(3,5-difluorobenzyl)-3-({[4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylate

HRID 1773421Notes

Reaction equation

HRID 1773421 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[NH:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>O1CCCC1.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:10]=[C:9]2[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[NH:30][CH:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:37]

Participants

5

Reactant 2

HCID 10928Ethyl chloroformateHCID 25141092Entrectinib

Product 1

HCID 68671055ethyl 5-(3,5-difluorobenzyl)-3-({[4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylateYield 62.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22728543Water ethylacetateSolvent

Procedure

To a solution of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (200 mg, 0.356 mmol) in anhydrous tetrahydrofurane (9 mL) maintained at −50° C. under nitrogen atmosphere a 1M solution of LiHMSD in anhydrous tetrahydrofurane (0.374 mL) was added. After stirring at that temperature for 5 minutes ethyl chloroformate (0.036 mL, 0.374 mmol) was added. After 1 hour at −50° C. the reaction was completed. Reaction mixture was diluted with water/EtOAc, washed with brine, dried over sodium sulphate and evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with DCM/ethanol 100:5, affording 140 mg (62% yield) of the title compound.

Workup

  1. additionwas added
  2. additionwas added
  3. customReaction mixture
  4. washwashed with brine
  5. dry with materialdried over sodium sulphate
  6. customevaporated to dryness
  7. customThe crude was purified by flash chromatography on silica gel eluting with DCM/ethanol 100:5

Sources & evidence

ORD record
ord-0f41c496aa024a50bb4e666ae9284f82
Source dataset
uspto-grants-2016_02
Patent number
US09255087B2

Reaction notes

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