Cesium carbonate → tert-Butyl (3R,4S)-3-{[[3-{[1-(cyanomethyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

HRID 1798473Notes

Reaction equation

HRID 1798473 reaction equation
[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.CS(O[CH2:57][C:58]1([CH2:61][C:62]#[N:63])[CH2:60][CH2:59]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[C:62]([CH2:61][C:58]1([CH2:57][O:51][C:42]2[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=2)[CH2:39][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:60][CH2:59]1)#[N:63]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 18353775(1-(Cyanomethyl)cyclopropyl)methyl MethanesulfonateHCID 68492454tert-Butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

Product 1

HCID 86641744tert-Butyl (3R,4S)-3-{[[3-{[1-(cyanomethyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added [1-(cyanomethyl)cyclopropyl]methyl methanesulfonate (appendage 4) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in toluene) to afford the title compound as an oil.

Workup

  1. temperatureAfter cooling to rt
  2. extractionThe organic extract
  3. washwas washed with water, brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in toluene)

Sources & evidence

ORD record
ord-dd4290b7c185453696063e89de8b3024
Source dataset
uspto-grants-2013_01
Patent number
US08343968B2

Reaction notes

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