Trifluoroacetic acid → Entrectinib

HRID 1773383Notes

Reaction equation

HRID 1773383 reaction equation
[NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:25]=[CH:26][C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[CH:28][C:2]=1[NH:1][CH:39]1[CH2:40][CH2:41][O:36][CH2:37][CH2:38]1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 121599Tetrahydro-4H-pyran-4-oneHCID 13696215Tetramethylammonium Triacetoxyborohydride (>90%)2×HCID 251758602-Amino-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Product 1

HCID 25141092EntrectinibYield 72.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (1.9 g, 3.98 mmol) in dichloromethane (80 mL) were added tetrahydro-pyran-4-one (0.55 mL, 5.98 mmol), trifluoroacetic acid (4 mL) and tetramethylammonium triacetoxyborohydride (1.57 g, 5.98 mmol). The mixture was stirred at room temperature overnight, and then more tetramethylammonium triacetoxyborohydride (1.57 g) was added. After stirring for additional 3 hours at room temperature the mixture was diluted with dichloromethane, washed with 2N sodium hydroxide and brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 96:4:0.5 as the eluant, affording 1.61 g of the title compound (72% yield).

Workup

  1. stirringAfter stirring for additional 3 hours at room temperature the mixture
  2. washwashed with 2N sodium hydroxide and brine
  3. dry with materialdried over sodium sulfate
  4. customevaporated to dryness
  5. customThe crude was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-af9f0823392345cdb5fb5b8ede114776
Source dataset
uspto-grants-2016_02
Patent number
US09255087B2

Reaction notes

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