Formaldehyde → HCID 58874500, compound

HRID 131301Notes

Reaction equation

HRID 131301 reaction equation
Cl.Cl.[NH2:3][C@@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.C([O-])(=O)C.[NH4+:16].[Br:17][C:18]1[S:22][C:21]([C:23](=O)[CH:24](O)O)=[CH:20][CH:19]=1.[CH2:28]=O.[OH-].[Na+]>O.CC(O)=O.O>[Br:17][C:18]1[S:22][C:21]([C:23]2[N:16]=[CH:28][N:3]([C@@H:4]3[CH:9]4[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]4)[CH2:5]3)[CH:24]=2)=[CH:20][CH:19]=1

Participants

8

Reactant 5

HCID 712FormaldehydeHCID 14798Sodium HydroxideHCID 517165Ammonium AcetateHCID 12494972(R)-(+)-3-Aminoquinuclidine DihydrochlorideHCID 529111971-(5-Bromothiophen-2-yl)-2,2-dihydroxyethan-1-one

Product 1

HCID 58874500HCID 58874500, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21899381Acetic acid--water (1/1)Solvent

Procedure

Five individual round-bottomed thick-walled glass vials were charged with stir bars, (R)-(+)-3-aminoquinuclidine dihydrochloride (440 mg, 2.21 mmol), ammonium acetate (195 mg, 2.53 mmol), 1-(5-bromo-thiophen-2-yl)-2,2-dihydroxyethanone (500 mg, 2.21 mmol), formaldehyde (37%, aqueous—210 μL, 2.53 mmol) and glacial AcOH/water (1:1, 3.5 mL). All vials were crimp sealed and subjected to microwave radiation for 20 minutes at 120° C. The resultant mixtures were combined, diluted with water, basified to pH˜13 with 20% NaOH (aq), and extracted with CHCl3 (5×60 mL) and EtOAc (2×40 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated by rotary evaporation to a brown gummy residue. The material was subjected to flash chromatography (SiO2—120 grams; gradient elution: 5-10% 4N NH3/MeOH—EtOAc at 90 mL/min over 48 min) to provide a ˜2:1 regio-isomeric mixture of 5- and 4-bromothienyl-imidazolyl compounds as an orange-tan gum (1.186 g, 33%) as determined by 1H NMR signal integration. The mixture was subsequently purified by SFC with 25% MeOH/CO2 with 0.5% DMEA at 50 mL/min, monitoring at 280 nm, to give (R)-3-[4-(5-bromo-thiophen-2-yl)-imidazol-1-yl]-1-azabicyclo[2.2.2]octane (Example 6) was obtained as a pale orange solid (283 mg, 8%). Mass spectrum (API+) M+1: 338 (100%); 1H NMR (300 MHz, CDCl3) δ 1.53 (m, 1H), 1.63-1.87 (m, 3H), 2.13 (app q, J=3.1 Hz, 1H), 2.81-3.04 (m, 4H), 3.14 (dd, J=14.5, 5.3 Hz, 1H), 3.48 (ddd, J=14.5, 9.7, 1.8 Hz, 1H), 4.22 (m, 1H), 6.97 (app q, J=4 Hz, 2H), 7.15 (d, J=1.3 Hz, 1H), 7.57 (d, J=1.3 Hz, 1H).

Workup

  1. customAll vials were crimp sealed
  2. customfor 20 minutes
  3. customat 120° C
  4. extractionextracted with CHCl3 (5×60 mL) and EtOAc (2×40 mL)
  5. dry with materialThe combined organic extracts were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated by rotary evaporation to a brown gummy residue
  8. washThe material was subjected to flash chromatography (SiO2—120 grams; gradient elution: 5-10% 4N NH3/MeOH—EtOAc at 90 mL/min over 48 min)
  9. customto provide
  10. customThe mixture was subsequently purified by SFC with 25% MeOH/CO2 with 0.5% DMEA at 50 mL/min

Sources & evidence

ORD record
ord-05a4bcc59ea24778966afd08333356fd
Source dataset
uspto-grants-2008_06
Patent number
US07384954B2

Reaction notes

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