Formaldehyde → (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-isopropylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride

HRID 584194Notes

Reaction equation

HRID 584194 reaction equation
[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[CH:16])[CH2:10][C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:7].[ClH:35].[CH:36]([C@H:39]1[CH2:44][O:43][CH2:42][CH2:41][NH:40]1)([CH3:38])[CH3:37].[CH:45](NC(C)C)(C)C.C=O>O1CCOCC1.[Cu]Cl>[ClH:35].[ClH:35].[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:45][N:40]2[CH2:41][CH2:42][O:43][CH2:44][C@@H:39]2[CH:36]([CH3:38])[CH3:37])[CH2:10][C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:7]

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 7912DiisopropylamineHCID 53973560(2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-propargylpiperazineHCID 69677740(3S)-3-(propan-2-yl)morpholine hydrochloride

Product 1

HCID 86596431(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-isopropylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochlorideYield 76.6%

Reagents, catalysts & solvents 2

HCID 62652Cuprous chlorideCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-propargylpiperazine (286 mg), (3S)-3-isopropylmorpholine hydrochloride (118 mg) and N,N-diisopropylamine (92 mg) in dioxane (3 ml) was stirred at room temperature. Paraformaldehyde (22 mg) and copper(I) chloride (10 mg) were added and the whole was stirred for 30 minutes and then heated at 80° C. for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (1:1) as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-isopropylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (190 mg).

Workup

  1. stirringthe whole was stirred for 30 minutes
  2. temperatureheated at 80° C. for 4 hours
  3. filtrationThe reaction mixture was filtered
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. customThe obtained residue was purified by column chromatography on silica gel using
  6. additiona mixture of hexane and ethyl acetate (1:1) as eluent
  7. dissolutionThe obtained product was dissolved in ethyl acetate
  8. additiontreated with 4N hydrogen chloride in ethyl acetate

Sources & evidence

ORD record
ord-05cba58a22fd4a008e038b2fd3de8e97
Source dataset
uspto-grants-2005_08
Patent number
US06924278B2

Reaction notes

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