Piperidine → (2S,4S)-4-fluoro-1-[[N-[4-[(2R)-N-(2-octyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile

HRID 227979Notes

Reaction equation

HRID 227979 reaction equation
[C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCNCC1.[NH2:55][C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH3:57]>ClCCl.O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:55][C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH3:57])=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1

Participants

8

Reactant 5

HCID 8082PiperidineHCID 11011TrichloroacetonitrileHCID 11776TriphenylphosphineHCID 27345192-Octylamine, (2R)-HCID 57634365(2S,4S)-1-[[N-(4-carboxybicyclo[2,2,2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile

Product 1

HCID 57756738(2S,4S)-4-fluoro-1-[[N-[4-[(2R)-N-(2-octyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent3×

Procedure

(2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) was suspended in dichloromethane (1 mL). To the suspension, trichloroacetonitrile (31.0 μL) and triphenylphosphine (81.1 mg) in dichloromethane (0.5 mL) were added and the mixture was stirred at room temperature for 2 hours. Subsequently, (piperidinomethyl)polystyrene (150 mg) and (2R)-2-aminooctane (57.1 μL) were sequentially added at 0° C. and the mixture was stirred at room temperature for 21 hours. This was followed by addition of (isocyanatomethyl)polystyrene (232 mg), stirring at room temperature for 1 hour, addition of water (3 mL) and dichloromethane (2 mL), and further stirring at room temperature for 50 minutes. The reaction mixture was then loaded onto an Isolute HM-N column and was extracted 5 times with 2 ml dichloromethane. The dichloromethane extracts were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column (eluant:dichloromethane:methanol=50:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[(2R)—N-(2-octyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (30.3 mg).

Workup

  1. stirringthe mixture was stirred at room temperature for 21 hours
  2. stirringstirring at room temperature for 1 hour
  3. stirringfurther stirring at room temperature for 50 minutes
  4. extractionwas extracted 5 times with 2 ml dichloromethane
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting residue was purified by silica gel column (eluant:dichloromethane:methanol=50:1)

Sources & evidence

ORD record
ord-1d0e20b7ef974728b8beedcc348b62b3
Source dataset
uspto-grants-2009_07
Patent number
US07560569B2

Reaction notes

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