Carbon tetrabromide → (4S)-1-Boc-4-bromo-D-proline methyl ester

HRID 244347Notes

Reaction equation

HRID 244347 reaction equation
[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(Br)(Br)(Br)[Br:19].C(=O)=O.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CCOCC.C(O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([Br:19])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]

Participants

8

Reactant 4

HCID 11205Carbon tetrabromideHCID 11776TriphenylphosphineHCID 6951202(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esterHCID 21247280dichloromethane Drikold

Product 1

HCID 58564423(4S)-1-Boc-4-bromo-D-proline methyl esterYield 93%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (320 g, 1.30 mol) and carbon tetrabromide (540 g, 1.94 mol) in dichloromethane (3.2 L) at 0-5° C. (dry ice/dichloromethane bath) add triphenylphosphine (1.95 mol, 514 g) in portions over 30 min and stir at room temperature for 4 h. Add ethanol (3.2 L) and stir for an additional 2 h. Transfer the reaction to an 18 L carboy and add ether (8 L) until precipitation occurs. Stir the mixture overnight. Filter off the solids and concentrate the ether layer. Dissolve the oily residue in dichloromethane and filter through a silica plug eluting with dichloromethane until no more product can be detected by TLC. Concentrate the dichloromethane layer and treat with 5% ethyl acetate in hexanes (4 L) causing a white solid to form. Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes and collect only the fractions that contain the desired product. Concentrate the solution, dissolve in 5% ethyl acetate in hexanes (2 L) and purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes to obtain the title compound as a yellowish oil (372.4 g, 93%). [α]D20+53.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.33 and 1.39 (two s, 9H), 2.40 (m, 1H), 2.53 (m, 1H), 3.35 (m, 1H), 3.66 (s, 3H), 3.80 (m, 1H), 4.35 (q, 1H), 4.73 (m, 1H).

Workup

  1. customthe reaction to an 18 L carboy
  2. customuntil precipitation
  3. stirringStir the mixture overnight
  4. filtrationFilter off the solids
  5. concentrationconcentrate the ether layer
  6. dissolutionDissolve the oily residue in dichloromethane
  7. filtrationfilter through a silica plug
  8. washeluting with dichloromethane until no more product
  9. concentrationConcentrate the dichloromethane layer
  10. additiontreat with 5% ethyl acetate in hexanes (4 L)
  11. customto form
  12. washPass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes
  13. customcollect only the fractions that
  14. concentrationConcentrate the solution
  15. dissolutiondissolve in 5% ethyl acetate in hexanes (2 L)
  16. custompurify through a 1 kg silica gel pad
  17. washeluting with 5% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-4e782a8a470b4502929b15eeefdd6ef2
Source dataset
uspto-grants-2014_02
Patent number
US08658638B2

Reaction notes

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