Formic Acid → HCID 19097402, compound

HRID 486046Notes

Reaction equation

HRID 486046 reaction equation
[CH3:1][N:2]1[CH:7]([CH3:8])[C:6]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:3]1[C:4](C(OCC)=O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]2.C(O)=O.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[CH3:1][N:2]1[CH2:3][CH2:10][CH:9]([CH3:11])[C:6]([CH3:12])([CH2:5][CH2:4][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]1[CH3:8]

Participants

5

Reactant 4

HCID 284Formic AcidHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 19097398HCID 19097398, compound

Product 1

HCID 19097402HCID 19097402, compoundYield 36.2%

Conditions

Temperature
160 °C

Procedure

To diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate (121 g, 389 mmol) at 0° C. was added formic acid (121 mL, 3.2 mol) , followed by triethylamine (179 mL, 1.3 mol) . The mixture was slowly heated to 160° C. over a period of 2 hours and was stirred at 160° C. for 20 minutes. The mixture was cooled to room temperature, and allowed to stand under nitrogen for 24 hours. The mixture was basified by the addition of saturated NaHCO3 and was extracted with ether (3×). The organic layers were combined, washed with saturated NaHCO3 then brine and were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was taken up in 0.5 N HCl (500 mL) and washed with hexanes (3×). The aqueous layer was basified with concentrated NH4OH and extracted with ether (3×). The ether layer was dried over MgSO4 and concentrated in vacuo to afford 34 g (36%) of ethyl 1,2,3,4-tetramethyl-3-piperidinepropanoate as a yellow oil. The combined aqueous phases were concentrated in vacuo and the residue was triturated with hot ethanol (800 mL at 70° C.). The solution was filtered, triturated with additional hot ethanol (300 mL) and filtered once again. The ethanol filtrates were combined, acidified with concentrated H2SO4 and refluxed for 24 hours under nitrogen. The solution was basified with concentrated NH4OH and extracted with ether (3×) . The ether layers were combined, washed with saturated NaHCO3 (2×) and dried over MgSO4. The solvent was removed in vacuo to afford 28.5 g of additional product for a total yield of 62.5 g (67%). The product was treated with p-toluenesulfonic acid to afford ethyl 1,2,3,4-tetramethyl-3-piperidine-propanoate p-tolulenesulfonate as a white powder, m.p. 171-171.5° C.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. waitto stand under nitrogen for 24 hours
  3. extractionwas extracted with ether (3×)
  4. washwashed with saturated NaHCO3
  5. dry with materialbrine and were dried over anhydrous MgSO4
  6. customThe solvent was removed in vacuo
  7. washwashed with hexanes (3×)
  8. extractionextracted with ether (3×)
  9. dry with materialThe ether layer was dried over MgSO4
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-808c69b0c679449b87cf40c8d0fb877c
Source dataset
uspto-grants-1994_03
Patent number
US05290789

Reaction notes

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