Oxalyl chloride → N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(phenylsulfanyl)-1,3,4-thiadiazole-2-carboxamide

HRID 2301876Notes

Reaction equation

HRID 2301876 reaction equation
[C:1]1([S:7][C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[N:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.NC1CC2CCN1CC2>C(Cl)Cl.CO>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[C@@H:23]([NH:22][C:13]([C:11]1[S:12][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][N:10]=1)=[O:15])[CH2:24]2

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 719215(3R)-1-Azabicyclo(2.2.2)octan-3-amineHCID 181809825-Phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acidHCID 189269681-Azabicyclo[2.2.2]octan-2-amine

Product 1

HCID 10132387N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(phenylsulfanyl)-1,3,4-thiadiazole-2-carboxamide

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

5-Phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acid (3.76 mmol) is placed in a flask and put under nitrogen. The acid is chilled in an ice bath. Oxalyl chloride (9 mL) that has also been cooled in an ice bath is added drop wise to the acid. The excess oxalyl chloride is removed under reduced pressure. The acid chloride is dissolved in about 5 mL CH2Cl2. The freebase of (R)-3-aminoquinuclidine (0.5 g, 2.52 mmol, 0.67 eq) is also dissolved in CH2Cl2 (5 mL), and the solution containing the acid chloride is cannulated into the flask containing the aminoquinuclidine. The reaction is stirred overnight at room temperature. The reaction mixture is diluted with MeOH, and poured through a Dowex 50AGWX2 CH+ column. The impurities are removed by washing the column with MeOH, and the product is eluted by washing the column with a solution containing 5% TEA in MeOH. The solvent is removed under reduced pressure, and the product is further purified by silica gel chromatography using a Biotage Flash 40M column (5% MeOH/CH2Cl2). This gives Example 64 (0.289.g, 22%) as a tan oil. MS (ESI) for C16H18N4OS2 m/z 347.2 (M+H)+.

Workup

  1. temperatureThe acid is chilled in an ice bath
  2. additionis added drop wise to the acid
  3. customThe excess oxalyl chloride is removed under reduced pressure
  4. dissolutionThe acid chloride is dissolved in about 5 mL CH2Cl2
  5. additionpoured through a Dowex 50AGWX2 CH+ column
  6. customThe impurities are removed
  7. washby washing the column with MeOH
  8. washthe product is eluted
  9. washby washing the column with a solution
  10. additioncontaining 5% TEA in MeOH
  11. customThe solvent is removed under reduced pressure
  12. customthe product is further purified by silica gel chromatography

Sources & evidence

ORD record
ord-e8ce54fb8fa44609b1b762163e361b2a
Source dataset
uspto-grants-2002_12
Patent number
US06500840B2

Reaction notes

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