Methyl chloroformate → Methyl 3-amino-1-pyrrolidinecarboxylate

HRID 736999Notes

Reaction equation

HRID 736999 reaction equation
Cl[C:2]([O:4][CH3:5])=[O:3].C(OC([NH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:16]1[CH2:17][CH2:18][CH:14]([NH2:13])[CH2:15]1)=[O:3]

Participants

5

Reactant 3

HCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 2757234tert-butyl N-(pyrrolidin-3-yl)carbamate

Product 1

HCID 18331343Methyl 3-amino-1-pyrrolidinecarboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Add methyl chloroformate (460 μL, 560 mg, 6.0 mmol, 3.0 equiv) to a solution of 3-(tert-butoxycarbonylamino)pyrrolidine (TCI; 373 mg, 2.00 mmol, 1 equiv) and triethylamine (1.1 mL, 800 mg, 7.9 mmol, 3.9 equiv) in anhydr CH2Cl2 (4 mL). Vigorous gas evolution, a slight exotherm, and precipitation can occur. After stirring 30 min, rotary evaporate the reaction mixture (60° C.). Dissolve the resultant material in MeOH to quench any residual chloroformate and rotary evaporate the solution (60° C.). Add trifluoroacetic acid (5 mL) to this material causing gas evolution. Rotary evaporate the reaction solution (40° C.; azeotroping 2× with MeOH). Resultanting in a yellow oil then dissolve in MeOH (30 mL) and add hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 9.3 g) to free-base the amine. Filter the mixture and evaporate the filtrate by rotary (40° C.; azeotroped 2× with CH2Cl2) to yield 914 mg (300%) of crude product as a light-brown oil. Mass spec indicates desired product is present. Absorb this oil to an SCX column (20 g) activated with 10% AcOH/MeOH. Push MeOH through the column to elute any non-amine material. Elute the product with 2.0 M NH3 in MeOH to yield 269 mg (93.2%) of 3-amino-pyrrolidine-1-carboxylic acid methyl ester as a yellow oil.

Workup

  1. customVigorous gas evolution, a slight exotherm, and precipitation
  2. customrotary evaporate the reaction mixture (60° C.)
  3. dissolutionDissolve the resultant material in MeOH
  4. customto quench any residual chloroformate
  5. customrotary evaporate the solution (60° C.)
  6. customRotary evaporate
  7. customthe reaction solution (40° C.; azeotroping 2× with MeOH)
  8. dissolutionResultanting in a yellow oil then dissolve in MeOH (30 mL)
  9. additionadd hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 9.3 g) to free-base the amine
  10. filtrationFilter the mixture
  11. customevaporate the filtrate
  12. customby rotary (40° C.; azeotroped 2× with CH2Cl2)
  13. customto yield 914 mg (300%) of crude product as a light-brown oil

Sources & evidence

ORD record
ord-51453af89aed4047867168f5849ee5e1
Source dataset
uspto-grants-2009_09
Patent number
US07595339B2

Reaction notes

Loading…