Dimethylformamide → N-(1-azabicyclo[3.3.1]non-5-ylmethyl)-1H-indole-3-carboxamide

HRID 5381

Reaction equation

HRID 5381 reaction equation
C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C=O.[N:31]12[CH2:39][C:35]([CH2:40][NH2:41])([CH2:36][CH2:37][CH2:38]1)[CH2:34][CH2:33][CH2:32]2>O1CCCC1.CO.C(Cl)Cl>[N:31]12[CH2:39][C:35]([CH2:40][NH:41][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:2][CH:3]=3)=[O:13])([CH2:36][CH2:37][CH2:38]1)[CH2:34][CH2:33][CH2:32]2

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 682631,1'-CarbonyldiimidazoleHCID 8540401-Methylindole-3-carboxylic acidHCID 19795986{1-Azabicyclo[3.3.1]nonan-5-yl}methanamine

Product 1

HCID 9948164N-(1-azabicyclo[3.3.1]non-5-ylmethyl)-1H-indole-3-carboxamideYield 79.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of 1-methyl-1H-indole-3-carboxylic acid (1.53 g, 8.7 mmol) in anhydrous tetrahydrofuran (8 mL) under nitrogen was treated with 1.49 g (9.2 mmol) of 1,1'-carbonyldiimidazole (CDI) and stirred for 10 minutes. At this point a thick suspension formed, and anhydrous N,N-dimethylformamide (8 mL) was added. After an additional 45 minutes the solution was degassed under a stream of nitrogen over 10 minutes, then treated with a solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (1.47 g, 9.5 mmol). After 18 hours at room temperature and six hours at 55°-60° C., no acid-CDI adduct was detected by TLC (5% methanol/methylene chloride on alumina), and the mixture was concentrated in vacuo. The residue was partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing a little 2-propanol. The organic layer as separated and the aqueous solution was extracted with toluene (50 mL) containing some 2 -propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and the residue filtered through alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo and the residue triturated from ether/petroleum ethers (30°-60° ) to give a solid, which was recrystallized from tetrahydrofuran/hexane to afford 2.06 g (76%) of colorless crystals; mp 145°-147° C.

Workup

  1. customAt this point a thick suspension formed
  2. customAfter an additional 45 minutes the solution was degassed under a stream of nitrogen over 10 minutes
  3. waitAfter 18 hours at room temperature
  4. customsix hours
  5. customat 55°-60° C.
  6. concentrationthe mixture was concentrated in vacuo
  7. customThe residue was partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL)
  8. additioncontaining a little 2-propanol
  9. customThe organic layer as separated
  10. extractionthe aqueous solution was extracted with toluene (50 mL)
  11. additioncontaining some 2 -propanol
  12. dry with materialThe combined organic solution was dried (Na2SO4)
  13. concentrationconcentrated in vacuo
  14. filtrationthe residue filtered through alumina (eluted with 20% methanol/tetrahydrofuran)
  15. concentrationThe filtrate was concentrated in vacuo
  16. customthe residue triturated from ether/petroleum ethers (30°-60° )
  17. customto give a solid, which
  18. customwas recrystallized from tetrahydrofuran/hexane

Sources & evidence

ORD record
ord-5e3856e4880a45e59753efe824ac617e
Source dataset
uspto-grants-1993_09
Patent number
US05244907

Linked notes

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