Diisopropylethylamine → Netupitant

HRID 340422Notes

Reaction equation

HRID 340422 reaction equation
[CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[C:36]([C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[C:36]([C:44]([CH3:49])([CH3:48])[C:45]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 112671412-(3,5-Bis(trifluoromethyl)phenyl)-2-methylpropanoyl chlorideHCID 158874123-Pyridinamine, N-methyl-4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-

Product 1

HCID 6451149NetupitantYield 81%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
37.5 °C

Procedure

A solution of 20 g (67.5 mmol) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane, The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 31.6 g (81%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1yl)-4-(o-tolyl)pyridin-3yl)propanamide as white crystals. M.P. 155-157° C.; MS m/e (%): 579 (M+H+, 100).

Workup

  1. temperaturecooled to room temperature again
  2. customThe organic layer was separated
  3. extractionthe aqueous phase was extracted with dichloromethane
  4. dry with materialThe combined organic layers were dried (magnesium sulfate)
  5. customevaporated
  6. customThe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-8e74e7c1b9be4fedbc93dbac009bf1e0
Source dataset
uspto-grants-2014_11
Patent number
US08895586B2

Reaction notes

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