反应详情

Alternate Synthesis of Compound 8: Cyclohexanone (Acros, 19.6 g, 200 mmol) and tert-butylcarbazate (Acros, 26.4 g, 200 mmol) were combined in 350 mL dry hexane and stirred under argon for ½ hour. The mixture was then subjected to reflux temperature for 1.5 hours and permitted to cool to room temperature. A white solid formed on cooling which was removed by filtration and dried in vacuo—40.31 g (95%): mp 147-149° C.; MS (ES+ calculated: 212.29; found: 235.05 M+Na). 1H NMR (400 MHz, DMSO-d6) δ 9.47 (br s, 1H), 2.27 (m, 2H), 2.16 (m, 2H), 1.52 (m, 2H), 1.59 (m, 4H), 1.42 (s, 9H). t-Butylcarboxycyclohexanone hydrazone generated above (40.02 g, 189 mmol) was dissolved in a mixture of 175 mL tetrahydrofuran and 225 mL anhydrous methanol. Sodium cyanoborohydride (Acros, 14.3 g, 227 mmol) was added in portions over ten minutes and the mixture was stirred under argon overnight at room temperature. 135 mL of 6N hydrochloric acid were then added dropwise and the mixture was refluxed for one hour. The reaction was permitted to cool to room temperature and a white solid was removed by filtration. The mother liquor was concentrated and residual water was removed by azeotroping with ethanol on a rotary evaporator (3×100 mL). The mixture was concentrated to dryness and was taken up into hot isopropanol (˜300 mL). The solid that was present was removed by filtration and the mother liquor was concentrated to ½ volume at which point an equal volume of ethyl ether was added. This caused cyclohexylhydrazine hydrochloride to precipitate as a white solid. Yield (20.0 g, 93%). To cyclohexylhydrazine hydrochloride (7.52 g, 50 mmol) generated above in 500 mL absolute ethanol was added sodium methoxide (Aldrich, 2.7 g, 50 mmol). The mixture was stirred briefly and ethoxymethylmalononitrile (Acros, 6.11 g, 50 mmol) was added in small portions over twenty minutes. The reaction mixture was then heated at 70° C. under argon overnight. On cooling, the reaction was concentrated and subjected to flash chromatography on silica gel (1:1 hexane: ethyl acetate) affording 6.3 g (66%) of a light brown solid. Compound 8: mp 99-103° C.; MS (ES+ calculated: 190.25; found: 191.15 M+H). HPLC (97% purity, retention time 11.135 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 6.49 (br s, 2H), 4.02 (m, 1H), 1.80-1.10 (m, 10 H).

1. temperatureto reflux temperature for 1.5 hours
2. customA white solid formed
3. temperatureon cooling which
4. customwas removed by filtration
5. customdried in vacuo—40.31 g (95%)
6. dissolutionwas dissolved in a mixture of 175 mL tetrahydrofuran and 225 mL anhydrous methanol
7. stirringthe mixture was stirred under argon overnight at room temperature
8. temperaturethe mixture was refluxed for one hour
9. temperatureto cool to room temperature
10. customa white solid was removed by filtration
11. concentrationThe mother liquor was concentrated
12. customresidual water was removed
13. customby azeotroping with ethanol on a rotary evaporator (3×100 mL)
14. concentrationThe mixture was concentrated to dryness
15. customThe solid that was present was removed by filtration
16. concentrationthe mother liquor was concentrated
17. additionwas added
18. customThis caused cyclohexylhydrazine hydrochloride to precipitate as a white solid
19. customYield (20.0 g, 93%)
20. stirringThe mixture was stirred briefly
21. temperatureThe reaction mixture was then heated at 70° C. under argon overnight
22. temperatureOn cooling
23. concentrationthe reaction was concentrated