Hydrazine hydrate (1:1) → (1R,2S)-N1-(tert-Butoxycarbonyl)-1,2-cyclohexanediamine

Temperature

80 °C

Crude cis-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)cyclohexylcarbamate (3.90 g) was dissolved in toluene (20 mL) and charged to a round bottom flask. Hydrazine hydrate (0.70 mL) was added and the mixture was heated to 80° C. for 2 h whereupon TLC analysis indicated the reaction was complete. The reaction was cooled to RT and the solids were filtered and washed with toluene (2×5 mL). The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated. The aqueous phase was extracted with toluene (2×5 mL) and the combined organic extracts were washed with 10% HOAc aq (2×10 mL). The combined aqueous washes were basified with 2 N NaOH aq (13 mL). The product was extracted with IPAc (2×10 mL) and the combined organic extracts were washed with water (5 mL). The organic phase was concentrated to dryness to give 0.78 g of crude product. The oil was re-dissolved in IPAc (12 mL), heated to about 75° C., and maleic acid (423 mg) was added. Precipitation of solids occurred immediately and the thick mixture was diluted with IPAc (5 mL). The slurry was cooled to RT and allowed to stand for 20 min. The solids were filtered, washed with IPAc (10 mL), and dried to give a maleic acid salt of the title compound as white crystalline solid (730 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34-1.42 (m, 2H), 1.50 (s, 9H), 1.50-1.64 (m, 6H), 3.22 (m, 1H), 3.83 (br s, 1H), 6.02 (s, 2H), 6.86 (d, J=7.5 Hz, 1H), 7.68 (br s, 3H).

1. additioncharged to a round bottom flask
2. temperatureThe reaction was cooled to RT
3. filtrationthe solids were filtered
4. washwashed with toluene (2×5 mL)
5. washThe filtrates were washed with 2 N NaOH aq (10 mL) and phase
6. customseparated
7. extractionThe aqueous phase was extracted with toluene (2×5 mL)
8. washthe combined organic extracts were washed with 10% HOAc aq (2×10 mL)
9. extractionThe product was extracted with IPAc (2×10 mL)
10. washthe combined organic extracts were washed with water (5 mL)
11. concentrationThe organic phase was concentrated to dryness
12. customto give 0.78 g of crude product
13. dissolutionThe oil was re-dissolved in IPAc (12 mL)
14. temperatureheated to about 75° C.
15. customPrecipitation of solids
16. additionthe thick mixture was diluted with IPAc (5 mL)
17. temperatureThe slurry was cooled to RT
18. filtrationThe solids were filtered
19. washwashed with IPAc (10 mL)
20. customdried

ORD record

ord-c8a42614cffa4b12a25f5a667084b633

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09181255B2