Isovaleric Acid → N-{3-[3-(4-Cyanoanilino)propyl]-3-azabicyclo[3.2.1]oct-8-yl}-N,3-dimethylbutanamide

HRID 411561Notes

Reaction equation

HRID 411561 reaction equation
C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][NH:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][N:21]([CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH2:22]2.[CH3:38][CH:39]([CH3:44])[CH2:40][C:41](O)=[O:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH:23]3[CH:18]([N:17]([CH3:16])[C:41](=[O:42])[CH2:40][CH:39]([CH3:44])[CH3:38])[CH:19]([CH2:25][CH2:24]3)[CH2:20]2)=[CH:37][CH:36]=1)#[N:35]

Participants

7

Reactant 4

HCID 10430Isovaleric AcidHCID 10868DicyclohexylcarbodiimideHCID 11430Potassium CarbonateHCID 185408864-({3-[8-(Methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile

Product 1

HCID 18540954N-{3-[3-(4-Cyanoanilino)propyl]-3-azabicyclo[3.2.1]oct-8-yl}-N,3-dimethylbutanamideYield 78.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

1,3-Dicyclohexylcarbodiimide on N-methylpolystyrene (0.67 g of 2.39 mmol/g, 1.74 mmol) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Peparation G; 74.6 mg, 0.25 mmol) in DMF (3.0 mL). A solution of 3-methylbutyric acid (105.0 mg, 1.02 mmol) in DCM (1.0 mL) was added, and the mixture was stirred overnight at rt, followed by a further 72 h at 50° C. Polystyrene isocyanate (150 mg) and DCM (1.5 mL) were added, and this mixture was stirred for 1.5 h. K2CO3 (75 mg) was added and the mixture stirred for an additional 5 h. The solvents were evaporated and DCM (3 mL) was added to the resulting residue. This mixture was added to an ion-exchange solid-phase extraction plug (CBA). The plug was washed with DCM:MeCN (4:1; 10 mL). The product was then eluted with DCM:MeOH:TEA (90:5:5; 7.5 mL) to give 75 mg (70.9%) of the title compound.

Workup

  1. waitfollowed by a further 72 h at 50° C
  2. stirringthis mixture was stirred for 1.5 h
  3. stirringthe mixture stirred for an additional 5 h
  4. customThe solvents were evaporated
  5. additionDCM (3 mL) was added to the resulting residue
  6. additionThis mixture was added to an ion-exchange solid-phase extraction plug (CBA)
  7. washThe plug was washed with DCM:MeCN (4:1; 10 mL)
  8. washThe product was then eluted with DCM:MeOH:TEA (90:5:5; 7.5 mL)

Sources & evidence

ORD record
ord-b9241610fe9344899555327d45bf5e31
Source dataset
uspto-grants-2003_05
Patent number
US06559162B2

Reaction notes

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