Proton sponge → N-Desmethyl Netupitant

HRID 1017451Notes

Reaction equation

HRID 1017451 reaction equation
[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([CH3:37])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][N:33](C)[CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([CH3:37])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1

Participants

5

Reactant 3

HCID 88675Proton spongeHCID 5213051-Chloroethyl chloroformateHCID 6451149Netupitant

Product 1

HCID 9915918N-Desmethyl NetupitantYield 57.3%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 100 mg (0.173 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide (example 14 g) and 7 mg (0.035 mmol) 1,8-bis(dimethylamino)naphthalene in 1 ml 1,2-dichloroethane at 0° C. were added 26 mg (0.181 mmol) 1-chloroethyl chloroformate. After heating the reaction mixture for 1 h at 80° C. the solvent was removed in vacuo and the intermediate was purified by flash chromatography, re-dissolved in 1 ml methanol and refluxed for 3 h. Flash chromatography gave 56 mg (57%) of the title compound as white foam.

Workup

  1. customat 0° C.
  2. customwas removed in vacuo
  3. customthe intermediate was purified by flash chromatography
  4. dissolutionre-dissolved in 1 ml methanol
  5. temperaturerefluxed for 3 h

Sources & evidence

ORD record
ord-7543968332c9413f9f5a53604c4b1960
Source dataset
uspto-grants-2002_11
Patent number
US06479483B2

Reaction notes

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