Piperazine → N-(1-(6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethyl)-2-(methylsulfonyl)-5-(piperazin-1-yl)benzenamine

HRID 1910590Notes

Reaction equation

HRID 1910590 reaction equation
ClC1C=C(C(N)C)C2OCCOC=2C=1.FC1C=C(F)C=CC=1S(C)(=O)=O.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:46]=[C:45]([CH:47]([NH:49][C:50]2[CH:55]=[C:54](F)[CH:53]=[CH:52][C:51]=2[S:57]([CH3:60])(=[O:59])=[O:58])[CH3:48])[C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1.[NH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C)C=O.C(#N)C.O>[Cl:36][C:37]1[CH:46]=[C:45]([CH:47]([NH:49][C:50]2[CH:55]=[C:54]([N:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)[CH:53]=[CH:52][C:51]=2[S:57]([CH3:60])(=[O:59])=[O:58])[CH3:48])[C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1

Participants

9

Reactant 5

HCID 4837PiperazineHCID 81531Diisopropylethylamine2×HCID 27583362,4-Difluoro-1-(methylsulfonyl)benzeneHCID 587073121-(6-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethanamineHCID 67147312N-(1-(6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine

Product 1

HCID 11633830N-(1-(6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethyl)-2-(methylsulfonyl)-5-(piperazin-1-yl)benzenamineYield 80%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Procedure

A solution of 1-(6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethanamine (130 mg, 0.61 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (116 mg, 0.61 mmol) and diisopropylethylamine (314 mg, 2.43 mmol) in N,N-dimethylformamide (2 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo to collect 53.4 mg of the desired product, which was used for the next reaction without further purification. A solution of N-(1-(6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (53.4 mg, 0.14 mmol), piperazine (239 mg, 2.76 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.38 mmol) in acetonitrile (2 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo. The crude product was purified by silica chromatography (10% ethyl acetate in hexanes) to yield 50 mg (80%) of desired product. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, 1H), 6.82 (d, 1H), 6.76 (d, 1H), 6.60 (d, 1H), 6.23 (d, 1H), 5.87 (d, 1H), 4.73 (m, 1H), 4.28 (m, 4H), 3.24 (m, 4H), 3.05 (s, 3H), 3.03 (m, 4H), 1.54 (d, 3H); MS (ESI) m/z: 452.3 (M++1).

Workup

  1. extractionextracted with diethyl ether
  2. concentrationThe solvent was concentrated in vacuo
  3. customto collect 53.4 mg of the desired product, which
  4. customwas used for the next reaction without further purification
  5. temperatureat reflux for 16 h
  6. temperatureThe reaction mixture was cooled down
  7. concentrationconcentrated under reduced pressure
  8. washwashed with water
  9. customdried
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by silica chromatography (10% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-b573f67b9c6c47cdac97f2217ba471c4
Source dataset
uspto-grants-2013_12
Patent number
US08604021B2

Reaction notes

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