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ChemicalBook CAS DataBase List (R)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate
1306763-30-3

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

5synthesis methods
Di-tert-butyl dicarbonate

24424-99-5

(R)-1-amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride

1306763-29-0

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

1306763-30-3

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.

24424-99-5 Synthesis
Di-tert-butyl dicarbonate

24424-99-5
867 suppliers
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(R)-1-amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride

1306763-29-0
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(R)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate

1306763-30-3
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Yield: 84%

Reaction Conditions:

with triethylamine in dichloromethane at 0 - 20; for 2 h;

Steps:

52
[0458] (R )-tert-butyl 4-cyano-2, 3-dihydro-lH-inden-l-ylcarbamate (INT-52)[0459] To (R)-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile HC1 INT-50 (11.6 g, 59.6 mmol) in DCM (100 mL) at 0°C was added TEA (12.0 mL, 131.0 mmol). To the resulting solution was added a solution of Boc anhydride (14.3 g, 65.6 mmol) in DCM (30 mL) and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was washed with brine, and the organic layers were dried over MgS04 and filtered. Additional DCM was added to a total volume of 250 mL and Norit (4.5 g) was added. The product was refluxed for 15 mins and the hot mixture filtered through a pad of celite / silica. The filtrate was concentrated and recrystallized from EA (50 mL) and hexane (150 mL) to produce 12.93 g (84%) of (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate INT-52 as an off-white solid. LCMS-ESI (m z) calculated for Ci5H18N202: 258.3; found 281.1 [M+Na]+, tR = 3.45 min. Elemental Analysis determined for Ci5H18N202; C calculated = 69.74%; found = 69.98%. H calculated = 7.02%; found = 7.14%. N calculated = 10.84%; found = 10.89%. NMR (400 MHz, CDC13) 6 7.64 - 7.49 (m, 2H), 7.34 (dt, J = 7.7, 3.8, 1H), 5.36 - 5.20 (m, 1H), 4.78 (d, J = 6.8, 1H), 3.20 (ddd, J = 16.9, 8.9, 3.3, lH), 3.02 (dt, J = 25.4, 8.4, 1H), 2.82 - 2.53 (m, 1H), 1.88 (dq, J = 13.2, 8.6, 1H), 1.55 - 1.44 (m, 9H). 13C NMR (101 MHz, 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: (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l- ylcarbamate was eluted using 2.5% EtOH in hexanes: >99.9% ee, tR = 19.36 min.

References:

RECEPTOS, INC.;MARTINBOROUGH, Esther;BOEHM, Marcus, F.;YEAGER, Adam, Richard;TAMIYA, Junko;HUANG, Liming;BRAHMACHARY, Enugurthi;MOORJANI, Manisha WO2011/60389, 2011, A1 Location in patent:Page/Page column 92-93

60899-34-5 Synthesis
2,3-dihydro-1-oxo-1H-indene-4-carbonitrile

60899-34-5
213 suppliers
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(R)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate

1306763-30-3
52 suppliers
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