3,5-Bis(trifluoromethyl)benzoic acid → (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) 4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride

HRID 584205Notes

Reaction equation

HRID 584205 reaction equation
CN(C)CCCN=C=NCC.[ClH:12].Cl.Cl.[CH3:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]#[C:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2([CH3:37])[CH3:36])[CH2:21]1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[ClH:12].[ClH:12].[F:42][C:43]([F:57])([F:58])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:54])[F:55])[CH:52]=1)[C:47]([N:25]1[CH2:24][CH2:23][N:22]([CH2:26][C:27]#[C:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2([CH3:37])[CH3:36])[CH2:21][C@H:20]1[CH2:19][C:18]1[CH:38]=[CH:39][C:40]([CH3:41])=[C:16]([CH3:15])[CH:17]=1)=[O:48]

Participants

7

Reactant 4

HCID 128893,5-Bis(trifluoromethyl)benzoic acidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 69677662(3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine trihydrochloride

Product 1

HCID 86588519(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) 4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochlorideYield 153,486.906%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Procedure

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.22 ml) was added over 5 minutes to a mixture of (3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine trihydrochloride (0.48 g) and 3,5-bis(trifluoromethyl)benzoic acid (0.27 g), 1-hydroxybenzotriazole (0.15 g) and triethylamine (0.35 ml) in dichloromethane (10 ml). After 2 hours of stirring at room temperature, the reaction mixture was directly purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected and evaporated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate and recrystallized from a mixture of acetone and water to give colorless crystals of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine dihydrochloride (525 g).

Workup

  1. customthe reaction mixture was directly purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1)
  2. additionThe fractions containing the objective compound
  3. customwas collected
  4. customevaporated under reduced pressure
  5. additionThe residue was treated with 4N hydrogen chloride in ethyl acetate
  6. customrecrystallized from a mixture of acetone and water

Sources & evidence

ORD record
ord-bd271951e65d4c2797e0c5d1a1ca1f1f
Source dataset
uspto-grants-2005_08
Patent number
US06924278B2

Reaction notes

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