Phthalamide → 5-(3,5-Dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester

HRID 218499

Reaction equation

HRID 218499 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31]O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:52]([NH2:63])(=[O:62])[C:53]1[C:54](=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:55](N)=[O:56]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][N:63]2[C:52](=[O:62])[C:53]3[C:54](=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:55]2=[O:56])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 6956PhthalamideHCID 11776TriphenylphosphineHCID 690419115-(3,5-Dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester

Product 1

HCID 690436475-(3,5-Dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl esterYield 16.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (0.6 g), from Synthetic Example 22, in THF (14.3 mL), under Argon, was added sequentially triphenylphosphine (1.08 g, 4.13 mmol), phthalamide (0.21 g, 1.45 mmol), followed by diisopropyl azadicarboxylate (DIAD, 0.31 g, 1.52 mmol) dropwise over 30 minutes. The mixture was stirred overnight at room temperature. The mixture was quenched with saturated sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried and concentrated. The residue was partially purified by chromatography on silica gel, followed by preparative reverse phase HPLC to give 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester (131 mg) which was used directly in the next step.

Workup

  1. customThe mixture was quenched with saturated sodium hydrogencarbonate solution
  2. extractionextracted with EtOAc
  3. washThe combined organic extracts were washed with brine
  4. customdried
  5. concentrationconcentrated
  6. customThe residue was partially purified by chromatography on silica gel

Sources & evidence

ORD record
ord-64fcf6b92af94046bcac24c5f6fcdb39
Source dataset
uspto-grants-2012_06
Patent number
US08198456B2

Linked notes

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