(1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester Chemical Properties

Boiling point:

388.9±21.0 °C(Predicted)

Density 

1.228

storage temp. 

2-8°C

pka

16.00±0.20(Predicted)

Appearance

White to off-white Solid

InChI

InChI=1S/C11H18N2O3/c1-11(2,3)16-10(15)13-7-4-6(7)5-8(13)9(12)14/h6-8H,4-5H2,1-3H3,(H2,12,14)/t6-,7-,8-/m0/s1

InChIKey

VLAGXRRGXCNITB-FXQIFTODSA-N

SMILES

[C@@]12([H])[C@@]([H])(C1)C[C@@H](C(N)=O)N2C(OC(C)(C)C)=O

(1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester Usage And Synthesis

Uses

N-Boc-L-cis-4,5-Methanoprolineamide is an intermediate used to prepare methanoprolinenitrile-contg. dipeptide mimetics as DPP-IV inhibitors and as antidiabetic agents.

Synthesis

At -15°C, (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (1.2 g) was dissolved in THF (20 ml) and 4-methylmorpholine (710 μl) was added. Subsequently, isobutyl chloroformate (780 μl) was added slowly over a period of 5 min and stirring was continued at this temperature for 30 min. The reaction system was cooled to -30°C and aqueous ammonia solution (25 ml, 0.5 M) dissolved in dioxane was slowly added. The reaction mixture was stirred at -30 °C for 30 min and then gradually warmed to room temperature and continued stirring overnight. After completion of the reaction, the pH was adjusted to 4.5 with 10% aqueous citric acid solution and extracted with ether (3 x 50 ml). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (eluent: cyclohexane/ethyl acetate, 1:10) afforded the target product (1S,3S,5S)-tert-butyl (1.0 g, 84% yield, MNa+ = 248) of (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

References

[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 10, p. 2587 - 2598
[2] Patent: WO2006/116157, 2006, A2. Location in patent: Page/Page column 114-116
[3] Patent: EP2272825, 2015, B1. Location in patent: Paragraph 0182; 0183
[4] Patent: CN106928124, 2017, A. Location in patent: Paragraph 0037; 0095-0100

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