Acetone → (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acid

HRID 2246586Notes

Reaction equation

HRID 2246586 reaction equation
[NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([OH:10])=[O:9])[C@@H:5]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:12]2=[O:27])[CH2:4][CH2:3]1.[CH3:28]N1CCOCC1.[CH3:35][C:36]([CH3:38])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClC(Cl)C.O>[CH2:20]([O:19][C:17]([NH:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:5]2[CH2:4][CH2:3][C@@H:2]([N:1]([CH:36]([CH3:38])[CH3:35])[CH3:28])[CH2:7][C@H:6]2[C:8]([OH:10])=[O:9])[C:12]1=[O:27])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1

Participants

8

Reactant 5

HCID 180AcetoneHCID 712FormaldehydeHCID 79724-MethylmorpholineHCID 5049666Sodium triacetoxyborohydride2×HCID 68567535(1R,2S,5R)-5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid

Product 1

HCID 24948561(1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acidYield 99.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 63651,1-DichloroethaneSolvent

Procedure

A stirring solution of (1R,2S,5R)-5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid (TFA salt, 35.5 g, 0.0725 mol) in dichloroethane (350 mL) was charged sequentially with N-methylmorpholine (29.3 g, 4.0 eq) and acetone (42.05 g, 10 eq). The mixture was stirred at room temperature for 10 min. and sodium triacetoxyborohydride (30.7 g, 2 eq) was added at 0° C. The mixture was stirred at room temperature for 14 h, then formaldehyde (37 wt % solution, 28.4 g, 5 eq) and sodium triacetoxyborohydride (18.4 g, 1.2 eq) were added. The mixture was stirred at room temperature for 2 h. Water (70 ml) was added and the stirring was continued for 10 minutes. The mixture was concentrated under reduced pressure to remove the organic solvents. The resulting mixture was adjusted pH to 7-8 with saturated NaHCO3 solution and then to pH˜6 with 1 N HCl. The mixture was extracted with dichloromethane (5×250 ml). The extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and the resultant solution was added dropwise to diethyl ether (1500 ml) with stirring. The solid formed was collected with filtration and washed with diethyl ether (3×50 ml). The white solid was dried in vacuo to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acid (31 g, 99%). The compound was used in the next step without further purification. LC/MS found [M+H]+=432.

Workup

  1. stirringThe mixture was stirred at room temperature for 14 h
  2. stirringThe mixture was stirred at room temperature for 2 h
  3. waitthe stirring was continued for 10 minutes
  4. concentrationThe mixture was concentrated under reduced pressure
  5. customto remove the organic solvents
  6. extractionThe mixture was extracted with dichloromethane (5×250 ml)
  7. dry with materialdried over anhydrous Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. dissolutionThe residue was dissolved in dichloromethane (100 ml)
  10. additionthe resultant solution was added dropwise to diethyl ether (1500 ml)
  11. stirringwith stirring
  12. customThe solid formed
  13. filtrationwas collected with filtration
  14. washwashed with diethyl ether (3×50 ml)
  15. customThe white solid was dried in vacuo

Sources & evidence

ORD record
ord-a2e000a4ab5f4334a781b4bd83d0705f
Source dataset
uspto-grants-2010_03
Patent number
US07687508B2

Reaction notes

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