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 1526054Notes

Reaction equation

HRID 1526054 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-2ff3360210384d46bedff6640995b8fb
Source dataset
uspto-grants-2015_07
Patent number
US09085558B2

Reaction notes

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