Fmoc-6-chloro L-Tryptophan Chemical Properties

Melting point:

>115°C (dec.)

Boiling point:

732.6±60.0 °C(Predicted)

Density 

1.406±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

DMSO (Slightly), Methanol (Slightly)

pka

3.72±0.10(Predicted)

form 

Solid

color 

White to Off-White

Fmoc-6-chloro L-Tryptophan Usage And Synthesis

Uses

Fmoc-6-chloro L-Tryptophan is used for preparation of acyltryptophanols as FSH antagonists.

Synthesis

The general procedure for the synthesis of Fmoc-6-chloro-L-tryptophan from 9-fluorenylmethyl-N-succinimidyl carbonate and (S)-2-amino-3-(6-chloro-1H-indol-3-yl)propionic acid was as follows: first, 6-chloroindole (500 mg, 3.31 mmol, 1 eq.) was dissolved in acetic acid (10 mL), L-serine (695 mg. 6.62 mmol, 2 eq.) and acetic anhydride (3.1 mL, 33.1 mmol, 10 eq.). The mixture was stirred at 73 °C for 4 hours under argon protection. Upon completion of the reaction, the mixture was concentrated to half the original volume, diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and evaporated to give the crude product N-acetyl-6-chloro-D,L-tryptophan 686 mg in 74% yield. Next, N-acetyl-6-chloro-D,L-tryptophan (686 mg, 1.45 mmol) was dissolved in pH 8.0 phosphate buffer (50 mL) containing 1 mM CoCl2-6H2O. Acylase I (500 mg) was added and stirred at 37 °C for 24 h, during which time the pH was adjusted with LiOH to 8.0. The reaction mixture was heated to 60 °C and kept at 60 °C for 5 min, cooled to room temperature and then filtered through diatomaceous earth. The filtrate was acidified with HCl to pH about 3 and extracted with ethyl acetate. The aqueous layer was lyophilized as the crude product for the next step of the reaction in an estimated yield of 43% (based on the theoretical yield of the L-enantiomer) to give 125.4 mg. Finally, 6-chloro-L-tryptophan (125.4 mg, 0.527 mmol, 1 eq.) was dissolved in a mixed solvent of water/acetone (1:1, v/v) and NaHCO3 (88.5 mg, 1.05 mmol, 2 eq.) was added. Fmoc-OSu (195.6 mg, 0.58 mmol, 1.1 eq.) was dissolved in acetone and added to the reaction mixture in batches over 3 hours. After completion of the reaction, the acetone was evaporated and the aqueous layer was acidified with acetic acid to pH about 3 and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and evaporated. The crude product was purified by fast column chromatography using hexane:ethyl acetate:acetic acid (10:9:1) as solvent system to give 237 mg of pure Fmoc-6-chloro-L-tryptophan in 98% yield.

References

[1] Patent: WO2015/153761, 2015, A2. Location in patent: Paragraph 00256
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 5, p. 2038 - 2046