Hydrochloric Acid → N-(2-Hydroxy-1-hydroxycarbamoyl-propyl)-4-phenylethynyl-benzamide

HRID 661795Notes

Reaction equation

HRID 661795 reaction equation
C[O:2][C:3](=O)[CH:4]([NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH:5]([OH:7])[CH3:6].Cl.[NH2:27][OH:28].C[O-].[Na+].Cl>CO.C(Cl)Cl.CCOC(C)=O>[OH:7][CH:5]([CH3:6])[CH:4]([NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:3](=[O:2])[NH:27][OH:28]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 443297Hydroxyamine hydrochlorideHCID 10942334Sodium Methoxide5×HCID 666772683-Hydroxy-2-(4-phenylethynyl-benzoylamino)-butyric acid methyl ester

Product 1

HCID 75599898N-(2-Hydroxy-1-hydroxycarbamoyl-propyl)-4-phenylethynyl-benzamideYield 55%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of tolanoic-Thr methyl ester (4) (2.34 g, 7.0 mmol) in MeOH (20 ml) and DCM (30 ml) was added to a cooled (−10° C. bath) suspension of hydroxylamine HCl salt (4.81 g, 70.0 mmol) and NaOMe (4.16 g, 77.0 mmol) in MeOH (30 ml). Follow reaction by LCMS. After stirring for 2 hours, the reaction seems to stall at 50% completion. Add an additional 1 equivalent of NaOMe (0.416 g). After 3 hours, the reaction was 75% complete. Add an additional 0.5 equivalent of NaOMe (0.21 g). After 4 hours, the reaction was 90% complete. Add an additional 0.15 equivalent of NaOMe (0.064 g) for a total of 12.65 equivalents of NaOMe. The pH of the reaction was between 11-12 and had reacted about 95% completion. The reaction was diluted with EtOAc (500 ml) and washed with sat aq. NaHCO3 (2×60 ml), 50% diluted brine (60 ml), sat brine (60 ml), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in minimal DMA. The product was purified by prep. HPLC using a reverse phase Ultro 120 C18 column running a 2% gradient (AcCN/water, 0.1% TFA). The purified fractions were lyophilized to dryness. The product as the TFA salt was dissolved in AcCN/water (50:50) (80 ml), 1N aq. HCl (13 equivalent) and lyophilized again to give 1.3 g of white powder in 55% yield and >97% purity.

Workup

  1. temperaturea cooled
  2. customreaction by LCMS
  3. waitAfter 3 hours
  4. waitAfter 4 hours
  5. customhad reacted about 95% completion
  6. washwashed
  7. dry with materialdried with Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. dissolutionThe residue was dissolved in minimal DMA
  11. customThe product was purified by prep
  12. dissolutionThe product as the TFA salt was dissolved in AcCN/water (50:50) (80 ml)

Sources & evidence

ORD record
ord-105f3bbc248a45f080c844edef685cd4
Source dataset
uspto-grants-2011_12
Patent number
US08084615B2

Reaction notes

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