Triethylamine → Bradanicline

HRID 45288Notes

Reaction equation

HRID 45288 reaction equation
[NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C@H:3]2[C@H:2]([NH:1][C:33]([C:25]3[O:24][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH:26]=3)=[O:34])[CH:7]3[CH2:6][CH2:5][N:4]2[CH2:9][CH2:8]3)[CH:12]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 10331Benzofuran-2-carboxylic acidHCID 11430Potassium CarbonateHCID 25177374(2S,3R)-2-(Pyridin-3-ylmethyl)quinuclidin-3-amine

Product 1

HCID 25147644BradaniclineYield 77%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane was transferred to a 50 L glass reaction flask equipped with a mechanical stirrer under an inert atmosphere. Dichloromethane (16.5 L), triethylamine (847 mL, 6.08 mol), benzofuran-2-carboxylic acid (948 g, 5.85 mol) and O-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate (HBTU) (2.17 kg, 5.85 mol) were added to the reaction mixture. The mixture was stirred for a minimum of 4 h at ambient temperature, and the reaction was monitored by HPLC. Upon completion of the reaction, 10% aqueous potassium carbonate (12.7 L, 17.1 mol) was added to the reaction mixture and the mixture was stirred for a minimum of 5 min. The layers were separated and the organic phase was washed with 10% brine (12.7 L). The layers were separated and the organic phase was cooled to 15° C.±10° C. 3 M Hydrochloric acid (8.0 L) was slowly added to the reaction mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 5 min, and the layers were allowed to partition for a minimum of 5 min. The solids were filtered using a table top filter. The layers of the filtrate were separated, and the aqueous phase and the solids from the funnel were transferred to the reaction flask. 3 M Sodium hydroxide (9.0 L) was slowly added to the flask in portions to adjust the pH of the mixture to pH 14. The aqueous phase was extracted with dichloromethane (2×16.5 L). The combined organic phases were dried over anhydrous sodium sulfate (1.71 kg). The mixture was filtered, and the filtrate was concentrated to give (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide (1.63 kg, 77.0% yield) as a yellow solid.

Workup

  1. customequipped with a mechanical stirrer under an inert atmosphere
  2. additionwas added to the reaction mixture
  3. stirringthe mixture was stirred for a minimum of 5 min
  4. customThe layers were separated
  5. washthe organic phase was washed with 10% brine (12.7 L)
  6. customThe layers were separated
  7. temperaturethe organic phase was cooled to 15° C.±10° C
  8. addition3 M Hydrochloric acid (8.0 L) was slowly added to the reaction mixture
  9. stirringThe mixture was then stirred for a minimum of 5 min
  10. customto partition for a minimum of 5 min
  11. filtrationThe solids were filtered
  12. customThe layers of the filtrate were separated
  13. addition3 M Sodium hydroxide (9.0 L) was slowly added to the flask in portions
  14. extractionThe aqueous phase was extracted with dichloromethane (2×16.5 L)
  15. dry with materialThe combined organic phases were dried over anhydrous sodium sulfate (1.71 kg)
  16. filtrationThe mixture was filtered
  17. concentrationthe filtrate was concentrated

Sources & evidence

ORD record
ord-2d31d08160d34388839fbe83f83c1505
Source dataset
uspto-grants-2013_09
Patent number
US08541446B2

Reaction notes

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