Acetic Acid → (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid

HRID 1396924Notes

Reaction equation

HRID 1396924 reaction equation
[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([CH2:29][O:30][C:31]([N:33]2[CH2:37][CH2:36][C@@H:35]([C:38]([OH:40])=[O:39])[NH:34]2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.C(O)(=O)C>ClCCl.CC#N>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:34]2[C@H:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37][N:33]2[C:31]([O:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 68287653(S)-1-((Benzyloxy)carbonyl)pyrazolidine-3-carboxylic acidHCID 86706340(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride

Product 1

HCID 86706346(3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acidYield 62.3%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Procedure

(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (4 g, 13.01 mmol) was added into the solution of (3S)-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (3.58 g, 14.32 mmol) in dichloromethane (DCM) (52.9 ml), and followed by adding Hunig's base (6.80 ml, 39.0 mmol). The reaction mixture was stirred for 2.5 hrs at ambient temperature. The reaction was diluted with DCM (200 ml), and then acetic acid (9 ml) was added. The resulting solution was washed with aqueous NH4Cl (200 ml). The aqueous solution was extracted with DCM (2×50 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The desired product was precipitated while ethyl acetate (a few ml) was added. The desired product was filtered and washed with ethyl acetate. 3.49 g of desired product as a white solid was collected. The filtrate was purified by silica Gel chromatography (0-100% Ethyl acetate in Hexane). The solvent was removed under reduced pressure to give a solid. The solid was added about 10 ml of MeCN. The desired product (870 mg) as a white solid was collected via filtration. All desired products were combined to yield the final batch of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (4.36 g, 8.11 mmol, 62% yield). MS (ES+) m/z 538.1 (MH+).

Workup

  1. washThe resulting solution was washed with aqueous NH4Cl (200 ml)
  2. extractionThe aqueous solution was extracted with DCM (2×50 ml)
  3. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give a residue
  7. customThe desired product was precipitated while ethyl acetate (a few ml)
  8. additionwas added
  9. filtrationThe desired product was filtered
  10. washwashed with ethyl acetate
  11. custom3.49 g of desired product as a white solid was collected
  12. customThe filtrate was purified by silica Gel chromatography (0-100% Ethyl acetate in Hexane)
  13. customThe solvent was removed under reduced pressure
  14. customto give a solid
  15. filtrationThe desired product (870 mg) as a white solid was collected via filtration

Sources & evidence

ORD record
ord-7d9621df94184a3cafdaa71b5439cfd1
Source dataset
uspto-grants-2014_12
Patent number
US08901119B2

Reaction notes

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