N,N-Dimethylaniline → Benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(3-phenylpyrrolidine-1-carbonyloxy)phenyl]piperidine-1-carboxylate

HRID 1176580Notes

Reaction equation

HRID 1176580 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.[CH3:41][N:42](C)[C:43]1C=CC=C[CH:44]=1.[C:50](Cl)(Cl)=[O:51].[C:54]1([CH3:60])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>COC(C)(C)C>[CH3:39][O:38][CH2:37][CH2:36][CH2:35][N:31]1[C:30]2[CH:40]=[C:26]([CH2:25][O:24][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][C:50]([N:42]5[CH2:43][CH2:44][CH:60]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[CH2:41]5)=[O:51])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:10]3)[CH:27]=[CH:28][C:29]=2[O:34][CH2:33][CH2:32]1

Participants

6

Reactant 4

HCID 949N,N-DimethylanilineHCID 1140TolueneHCID 6371PhosgeneHCID 68500240benzyl 4-{4-hydroxyphenyl}-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate

Product 1

HCID 68497745Benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(3-phenylpyrrolidine-1-carbonyloxy)phenyl]piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Procedure

The stirred solution of 0.250 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 2.5 ml of toluene is admixed at 0° C. with 0.131 ml of N,N-dimethylaniline and 0.65 ml of phosgene solution (20% in toluene). The reaction mixture is stirred at room temperature over 24 hours. The resulting suspension is diluted with tert-butyl methyl ether (20 ml) and washed successively with 0.1M HCl (20 ml), 1M sodium hydrogencarbonate solution (20 ml) and water, dried over sodium sulphate, filtered and concentrated by evaporation. The residue is dissolved in 1.0 ml of ethyl acetate and added to the stirred cold mixture of 0.177 g of 3-phenylpyrrolidine, 1.80 ml of ethyl acetate and 1M sodium hydrogencarbonate solution. The mixture is stirred at 0° C. over 1 hour. The reaction mixture is poured onto brine (50 ml) and extracted with ethyl acetate (2×50 ml). The organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (1:1 EtOAc-heptane); Rt=5.87.

Workup

  1. washwashed successively with 0.1M HCl (20 ml), 1M sodium hydrogencarbonate solution (20 ml) and water
  2. dry with materialdried over sodium sulphate
  3. filtrationfiltered
  4. concentrationconcentrated by evaporation
  5. dissolutionThe residue is dissolved in 1.0 ml of ethyl acetate
  6. additionadded to the stirred cold mixture of 0.177 g of 3-phenylpyrrolidine, 1.80 ml of ethyl acetate and 1M sodium hydrogencarbonate solution
  7. stirringThe mixture is stirred at 0° C. over 1 hour
  8. additionThe reaction mixture is poured onto brine (50 ml)
  9. extractionextracted with ethyl acetate (2×50 ml)
  10. dry with materialThe organic phases are dried over sodium sulphate
  11. filtrationfiltered
  12. concentrationconcentrated by evaporation

Sources & evidence

ORD record
ord-a72563fd08384f53b42b0d309456d461
Source dataset
uspto-grants-2010_11
Patent number
US07842688B2

Reaction notes

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