Formaldehyde → 1-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester

HRID 390733Notes

Reaction equation

HRID 390733 reaction equation
[CH3:1][C:2]12[CH2:22][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19](O)=O)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]2.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C=O.O>C1(C)C=CC=CC=1>[CH3:30][O:29][C:25]([CH:26]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([N:7]3[CH2:8][C:2]4([CH3:1])[CH2:22][CH:6]3[CH2:5][C:4]([CH3:23])([CH3:24])[CH2:3]4)=[O:10])=[CH:16][CH:15]=2)[CH2:27]1)=[O:28]

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 962WaterHCID 7294Methyl Acrylate2×HCID 67016360[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenylamino]-acetic acid

Product 1

HCID 249502821-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-3-carboxylic acid methyl esterYield 52%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenylamino]-acetic acid (1.3 g, 3.93 mmol), methyl acrylate (275 μl, 3.03 mmol) and paraformaldehyde (636 mg, 21.18 mmol) were dissolved in toluene (180 ml) in a three necked reaction flask equipped with a water separator. The mixture was stirred at reflux temp. for 3 hrs at which time a small portion of methyl acrylate (40 μl) was added. The resulting mixture was stirred at reflux temp. for an additional 16 hrs. and evaporated. The residue was dissolved in EtOAc (50 ml) and washed with water (2×25 ml), dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using first pure heptane (300 ml) followed by a mixture of EtOAc-Heptane (1:1) as eluents. Pure fractions were collected and evaporated to dryness affording 603 mg (52%) of 1-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as an oil.

Workup

  1. temperatureat reflux temp
  2. stirringThe resulting mixture was stirred
  3. temperatureat reflux temp
  4. customand evaporated
  5. dissolutionThe residue was dissolved in EtOAc (50 ml)
  6. washwashed with water (2×25 ml)
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. customThe resulting residue was purified by column chromatography (silica gel)
  11. additionfollowed by a mixture of EtOAc-Heptane (1:1) as eluents
  12. customPure fractions were collected
  13. customevaporated to dryness

Sources & evidence

ORD record
ord-335e1499f7f74aa58f00b80ac9a05c7b
Source dataset
uspto-grants-2013_02
Patent number
US08383668B2

Reaction notes

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