(S)-(+)-2-(Aminomethyl)pyrrolidine → Adr 851

HRID 1709737Notes

Reaction equation

HRID 1709737 reaction equation
[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][C:3]=1[Cl:14].[NH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>C1COCC1>[ClH:14].[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:11]([NH:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[O:13])=[CH:4][C:3]=1[Cl:14]

Participants

4

Reactant 2

HCID 2734054(S)-(+)-2-(Aminomethyl)pyrrolidineHCID 106324014-Amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid

Product 1

HCID 130053Adr 851Yield 145.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-30 °C

Procedure

To a suspension of 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (71.1 g, 0.33 mol) in 1400 ml of anhydrous THF was added N,N'-carbonyldiimidazole (54 g, 0.33 mol) at room temperature under argon. After 6 hours, an additional 0.02 equivalent (1.08 g) of N,N'-carbonyldiimidazole was added, and the mixture stirred overnight. The TLC analysis showed the disappearance of the starting material. The temperature was lowered to -30° C. with CCl4 /dry ice bath and (S)-2-aminomethylpyrrolidine (35 g, 0.35 mol, 1.06 equivalent) in 50 ml of THF was added dropwise over a period of 1 hour while the temperature was maintained at -30° C. After stirring at -20° C. to -30° C. for another 2 hours, the reaction was completed. The solvent in the reaction mixture was evaporated and the remaining dark brown oil was diluted with 1000 ml of methylene chloride. The organic solution was washed with 1N NaOH (350 ml, 150 ml), brine (150 ml), and filtered through a pad of anhydrous MgSO4. To the organic filtrate was added 24 g of HCl (gas) in 100 ml of 2-propanol with stirring and then sonicated overnight. The resulting precipitates were collected on a filter, washed with methylene chloride to give 79.8 g of the hydrochloride of the target compound (72.8% yield) as a white solid. A total of 140 g of the hydrochloride was recrystallized by first dissolving in 300 ml of H2O and then adding 900 ml of 2-propanol to yield 102 g of pure product after drying at 60-70° C. (water bath) under pump vacuum overnight, mp 232.5-233.5° C. (dec);[β]D20 =+9.6° (C=1.0; MeOH).

Workup

  1. customThe temperature was lowered to -30° C. with CCl4 /dry ice bath
  2. stirringAfter stirring at -20° C. to -30° C. for another 2 hours
  3. customThe solvent in the reaction mixture was evaporated
  4. additionthe remaining dark brown oil was diluted with 1000 ml of methylene chloride
  5. washThe organic solution was washed with 1N NaOH (350 ml, 150 ml), brine (150 ml)
  6. filtrationfiltered through a pad of anhydrous MgSO4
  7. additionTo the organic filtrate was added 24 g of HCl (gas) in 100 ml of 2-propanol
  8. stirringwith stirring
  9. customsonicated overnight
  10. customThe resulting precipitates
  11. customwere collected on a filter
  12. washwashed with methylene chloride

Sources & evidence

ORD record
ord-728a582783a54f04baba2630aa6b2657
Source dataset
uspto-grants-1990_08
Patent number
US04950766

Reaction notes

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