Trifluoroacetic acid → tert-Butyl 4-[1-({[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]amino}carbonyl)piperidin-4-yl]piperazine-1-carboxylate

HRID 2408819Notes

Reaction equation

HRID 2408819 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36](=O)[O:37]C1C=CC=CC=1)[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2].[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]2)[CH2:47][CH2:46]1.C(#N)C.O.C(O)(C(F)(F)F)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:13])=[O:14])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:52][CH2:53][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:55][CH2:56]2)[CH2:47][CH2:46]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 17750356tert-Butyl 4-(piperidin-4-yl)piperazine-1-carboxylateHCID 18373917Acetonitrile--water (1/1)HCID 86674927phenyl[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate2×

Product 1

HCID 67160388tert-Butyl 4-[1-({[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]amino}carbonyl)piperidin-4-yl]piperazine-1-carboxylateYield 43.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

100 mg (0.16 mmol) of phenyl [5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate (prepared according to Example 1, process steps 1a) to 1f)) were initially charged in 8 ml of anhydrous tetrahydrofuran (dried over molecular sieve), and 65.8 mg (0.24 mmol) of tert-butyl 4-piperidin-4-ylpiperazine-1-carboxylate were added. The mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC (silica gel, CH2Cl21MeOH 9:1) and LCMS (RP, mobile phases acetonitrile/water and 0.01% TFA). The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane and extracted with 2 N aqueous sodium hydroxide solution (1×). The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography (5 g NP-SiO2 cartridge, Chromabond) using dichloromethane/methanol in a ratio of 98:2 as mobile phase. This gave 55.3 mg (0.07 mmol, 43%) of the desired product, which was directly used in the next reaction step for Boc deprotection.

Workup

  1. customThe solvent was removed under reduced pressure
  2. extractionextracted with 2 N aqueous sodium hydroxide solution (1×)
  3. dry with materialThe combined organic phases were dried over magnesium sulphate
  4. filtrationfiltered
  5. customthe solvent was removed under reduced pressure
  6. customThe crude mixture was purified by column chromatography (5 g NP-SiO2 cartridge, Chromabond)

Sources & evidence

ORD record
ord-68858b72d01741feb4dc3ad3665a364f
Source dataset
uspto-grants-2014_08
Patent number
US08815868B2

Reaction notes

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