Hydrochloric Acid → N-Boc-O-TBDMS-D-threonine

HRID 1056117Notes

Reaction equation

HRID 1056117 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=O)=O.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([O:15][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 79372,6-LutidineHCID 10340Sodium CarbonateHCID 123564tert-Butyldimethylsilyl trifluoromethanesulphonateHCID 6992541(2R,3S)-2-(((tert-butoxy)carbonyl)amino)-3-hydroxybutanoic acid

Product 1

HCID 25232732N-Boc-O-TBDMS-D-threonineYield 96%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 57417360Sodium chloride; waterSolvent

Procedure

A solution of (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-hydroxybutanoic acid (Frontier Scientific, Utah) (9.94 g, 45.3 mmol) in DCM (100 mL) was treated with 2,6-dimethylpyridine (Fluka) (15.79 mL, 136 mmol). A solution of tert-butyldimethylsilyl trifluoromethanesulfonate (Fluka) (22.9 mL, 100 mmol) in DCM (50 mL) was added dropwise over 1 h. The mixture was stirred for an additional 2 h, after which time the reaction was complete by LC-MS analysis. The mixture was diluted with saturated brine (100 mL) and acidified with a slight excess of 1.0 M aq. HCl. The mixture was stirred for 30 min, the layers were separated, and the aq. layer was extracted with DCM (100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give crude product as a white semi-solid (26 g). The crude product was dissolved in MeOH (25 mL) and a solution of anhydrous Na2CO3 (4.80 g, 45.3 mmol) in water (25 mL) was added dropwise. The solution was stirred for 15 min and then concentrated to remove the MeOH. The resulting oily solution was diluted with water (175 mL) and hexane (200 mL) and stirred for 15 min. The aq. layer was separated and washed with a further 200 mL of hexane. The aq. layer was separated, diluted with DCM (200 mL), and 1.0 M aq. HCl was added dropwise to the stirred mixture. The mixture was separated and the aq. layer extracted with DCM (100 mL). The combined organic layers were dried (MgSO4) and concentrated to give (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoic acid (615a) (14.52 g, 43.5 mmol, 96% yield) as a colorless viscous oil. LC-MS m/z 356.1 [M+Na]1.

Workup

  1. stirringThe mixture was stirred for 30 min
  2. customthe layers were separated
  3. extractionthe aq. layer was extracted with DCM (100 mL)
  4. dry with materialThe combined organic extracts were dried (MgSO4)
  5. concentrationconcentrated
  6. customto give crude product as a white semi-solid (26 g)
  7. stirringThe solution was stirred for 15 min
  8. concentrationconcentrated
  9. customto remove the MeOH
  10. additionThe resulting oily solution was diluted with water (175 mL) and hexane (200 mL)
  11. stirringstirred for 15 min
  12. customThe aq. layer was separated
  13. washwashed with a further 200 mL of hexane
  14. customThe aq. layer was separated
  15. additiondiluted with DCM (200 mL), and 1.0 M aq. HCl
  16. additionwas added dropwise to the stirred mixture
  17. customThe mixture was separated
  18. extractionthe aq. layer extracted with DCM (100 mL)
  19. dry with materialThe combined organic layers were dried (MgSO4)
  20. concentrationconcentrated

Sources & evidence

ORD record
ord-e1e5222a9e554dfebb86a4b768ca9005
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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