N-BOC-(S)-2-AMINO-3-HYDROXY-3-METHYLBUTANOIC ACID Chemical Properties

Melting point:

116-118℃

Boiling point:

391.1±37.0 °C(Predicted)

Density 

1.175±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

DMSO (Slightly), Methanol (Slightly)

form 

Solid

pka

3.62±0.10(Predicted)

color 

White to Off-White

Safety Information

Risk Statements 

36/37/38

Safety Statements 

26-36/37/39

HazardClass 

IRRITANT

HS Code 

29225090

N-BOC-(S)-2-AMINO-3-HYDROXY-3-METHYLBUTANOIC ACID Usage And Synthesis

Chemical Properties

White powder

Uses

N-Boc-3-hydroxy-L-valine is used as a reagent in the synthesis of metabolites of PPI-2458, which is a selective, irreversible inhibitor of methionine aminopeptidase-2 (MetAP2). N-Boc-3-hydroxy-L-valine is also used in the preparation of Boceprevir (B674500); an NS3 serine protease inhibitor of hepatitis C virus for the treatment of HCV infection.

Synthesis

The general procedure for the synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid from tert-butyl (R)-(1,3-dihydroxy-3-methylbutan-2-yl)carbamate was as follows: 2,2,6,6-tetramethylpiperidinium 1-yloxy (TEMPO, 2.3 g, 15 mmol) was added to (R)-(1,3-dihydroxy-3-methyl tert-butyl (33.0 g, 150 mmol) carbamate in acetonitrile (750 mL) and sodium phosphate buffer (600 mL, 0.7 M, pH 6-7) and heated to 35 °C. Subsequently, sodium chlorite solution (34.2 g, dissolved in 150 mL of water) and dilute sodium hypochlorite solution (3 mL of commercial solution diluted in 100 mL of water, 60 drops total) were added dropwise simultaneously to the reaction mixture. The reaction mixture was stirred at 35°C overnight, cooled to room temperature, then the pH was adjusted to 3 with citric acid (~15 g), saturated with sodium chloride, and extracted with ethyl acetate (3 x 2 L). The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in 1.5 L of 2 M sodium carbonate solution and washed with ethyl acetate (2 x 2 L). The aqueous layer was cooled to 0°C, the pH was adjusted to 3.0 with 2M phosphoric acid solution and saturated again with sodium chloride. Extracted with ethyl acetate (3×2L), the organic phases were combined, dried, filtered and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid (28.4 g, 81% yield) as a colorless solid. NMR (400 MHz, DMSO-d6): δ= 1.15 (s, 3H), 1.17 (s, 3H), 1.39 (s, 9H), 3.86 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H).

References

[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 5, p. 1168 - 1170
[2] Journal of Organic Chemistry, 2018, vol. 83, # 13, p. 6977 - 6994
[3] Patent: WO2013/110643, 2013, A1. Location in patent: Paragraph 00108; 00109
[4] Chemical Communications, 2017, vol. 53, # 40, p. 5549 - 5552
[5] Nature Chemistry, 2010, vol. 2, # 4, p. 280 - 285

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