(R)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate

Uses

(R)-tert-Butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate is a useful reagent in the preparation of oxadiazoles as sphingosine 1 phosphate receptor modulators useful in the treatment of S1P1-associated diseases.

Synthesis

At 0 °C, (R)-1-amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride (INT-50, 11.6 g, 59.6 mmol) was dissolved in dichloromethane (DCM, 100 mL) and triethylamine (TEA, 12.0 mL, 131.0 mmol) was added. Subsequently, a solution of di-tert-butyl dicarbonate (Boc anhydride, 14.3 g, 65.6 mmol) in DCM (30 mL) was slowly added to the reaction system. The reaction mixture was stirred at room temperature for 1.5 hours. Upon completion of the reaction, the reaction mixture was washed with brine and the organic layer was dried over anhydrous magnesium sulfate (MgSO4) and filtered. Additional DCM was added to the filtrate to a total volume of 250 mL and activated carbon (Norit, 4.5 g) was added. The mixture was refluxed for 15 minutes and then filtered through a diatomaceous earth/silica pad while hot. The filtrate was concentrated and recrystallized by ethyl acetate (EA, 50 mL) and hexane (150 mL) to afford 12.93 g (84% yield) of tert-butyl (R)-(4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate (INT-52) as an off-white solid.Calculated values for LCMS-ESI (m/z): C15H18N2O2 were 258.3; measured value was 281.1 [M+Na]+, retention time (tR) = 3.45 min. Elemental analysis results (C15H18N2O2): calculated C=69.74%, H=7.02%, N=10.84%; measured C=69.98%, H=7.14%, N=10.89%.1H NMR (400MHz, CDCl3) δ: 7.64-7.49 (m, 2H), 7.34 (dt, J=7.7, 3.8Hz, 1H). 3.8 Hz, 1H), 5.36-5.20 (m, 1H), 4.78 (d, J=6.8 Hz, 1H), 3.20 (ddd, J=16.9,8.9,3.3 Hz, 1H), 3.02 (dt, J=25.4,8.4 Hz, 1H), 2.82-2.53 (m, 1H), 1.88 (dq, J=13.2 ,8.6Hz, 1H), 1.55-1.44 (m, 9H).13C NMR (101MHz, DMSO) δ: 155.52, 146.68, 146.32, 130.89, 128.70, 127.63, 117.51, 107.76, 77.98, 55.09, 31.88, 29.11. 28.19. Chiral HPLC analysis: tert-butyl (R)-4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate showed an enantiomeric excess (ee) of >99.9% and a retention time (tR) = 19.36 min, using a hexane solution of 2.5% ethanol as eluent.

References

[1] Patent: WO2011/60389, 2011, A1. Location in patent: Page/Page column 92-93
[2] Patent: WO2015/66515, 2015, A1. Location in patent: Page/Page column 78-79
[3] Patent: WO2018/64356, 2018, A1. Location in patent: Page/Page column 57