Triphenylphosphine → (3R*,5S*)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-[[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1698369Notes

Reaction equation

HRID 1698369 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:11][C@@H:10]([C:27](=[O:47])[N:28]([CH:44]2[CH2:46][CH2:45]2)[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:49][CH2:50][N:51]1[C:59](=[O:60])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]1=[O:61].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([CH2:49][CH2:50][N:51]2[C:52](=[O:61])[C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:59]2=[O:60])[S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:11][C@@H:10]([C:27](=[O:47])[N:28]([CH:44]2[CH2:46][CH2:45]2)[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 77499N-(2-Hydroxyethyl)phthalimideHCID 5462977Diethyl azodicarboxylateHCID 69070266(3R*,5S*)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-(2-nitro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 69071084(3R*,5S*)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-[[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of (3R*,5S*)3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-(2-nitro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.60 mmol), 2-(2-hydroxyethyl) isoindole-1,3-dione (171 mg, 0.9 mmol), and PPh3 (315 mg, 1.2 mmol) in THF is added DEAD (208 mg, 1.2 mmol) at room temperature, then the mixture is stirred at 60° C. After 13 h, the reaction mixture is quenched by H2O (20 mL) and extracted with EtOAc (50 mL). The organic phase is successively washed with 5% aqueous KHSO4, H2O, and brine, then dried over Na2SO4 and concentrated in reduced pressure. The residue is purified by silica gel column chromatography to afford the title compound as yellow amorphous material. MS: 843 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 4.41 min.

Workup

  1. customthe reaction mixture is quenched by H2O (20 mL)
  2. extractionextracted with EtOAc (50 mL)
  3. washThe organic phase is successively washed with 5% aqueous KHSO4, H2O, and brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in reduced pressure
  6. customThe residue is purified by silica gel column chromatography

Sources & evidence

ORD record
ord-a283bb612bf24fcc80196c2e83aea6f1
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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