反应详情

A mixture of 37 g, (160 mmoles) of 2-butyl-1,3-diazaspiro [4.4]nonan-4-one, hydrochloride, 1.7 mL of a 75% aqueous solution of methyl tributylammonium chloride, 125 mL of a 33% (10 N) aqueous solution of sodium hydroxide and 125 mL of methylene chloride was vigorously stirred at room temperature for five minutes. To this vigorously stirred mixture was added a solution of 44.34 g (163.6 mmoles as determined quantitatively by HPLC) of 4'-(bromomethyl) [1,1'-biphenyl]-2-carbonitrile in 400 mL of methylene chloride over a period of 40 to 60 minutes. After that, the phases were separated and the organic phase was washed twice with 100 mL of water. Then the organic phase was evaporated under reduced pressure to give an oily residue. The oily residue was dissolved in 250 mL of methyl-tertiarybutyl ether and the resulting solution was treated with 110 mL of concentrated HCl at a temperature below 40° C. Then the biphasic mixture was stirred for 10 minutes, allowed to settle and the phases separated. The aqueous acidic phase was washed once with 150 mL of methyl-tertiarybutyl ether. Then the aqueous acidic phase was divided into two equal portions and one portion was used for crystallization. To one stirred portion were added 25 mL of DMF and 25 mL of methyl-tertiarybutyl ether and 55 mL of 33% aqueous sodium hydroxide over a period of two to three hours. The slurry was allowed to stir overnight and then a total of 50 mL of water was added to the slurry and the slurry additionally stirred for 45 minutes. After that the slurry was cooled to 0° C. in an ice bath for 35 minutes and filtered. The wet cake remaining on the filter paper was washed once with a mixture of 90 mL/10 mL of water and methyl-tertiarybutyl ether. Then the cake was dried in a vacuum oven at 40° C. and at pressure of 2.3 mm Hg to give 23.3 g (yield 75.4%) of the title compound having a laboratory HPLC of HI of 99.8.

1. additionTo this vigorously stirred mixture was added a solution of 44.34 g (163.6 mmoles
2. customof 40 to 60 minutes
3. customAfter that, the phases were separated
4. washthe organic phase was washed twice with 100 mL of water
5. customThen the organic phase was evaporated under reduced pressure
6. customto give an oily residue
7. stirringThen the biphasic mixture was stirred for 10 minutes
8. customthe phases separated
9. washThe aqueous acidic phase was washed once with 150 mL of methyl-tertiarybutyl ether
10. customwas used for crystallization
11. additionTo one stirred portion were added 25 mL of DMF and 25 mL of methyl-tertiarybutyl ether and 55 mL of 33% aqueous sodium hydroxide over a period of two to three hours
12. stirringto stir overnight
13. additiona total of 50 mL of water was added to the slurry
14. stirringthe slurry additionally stirred for 45 minutes
15. temperatureAfter that the slurry was cooled to 0° C. in an ice bath for 35 minutes
16. filtrationfiltered
17. washwas washed once with a mixture of 90 mL/10 mL of water and methyl-tertiarybutyl ether
18. customThen the cake was dried in a vacuum oven at 40° C. and at pressure of 2.3 mm Hg