反应详情

33.0 mg of a mixture of tert-butyl 1-(3-amino-4-chloro-2-fluorobenzyl)cyclopropanecarboxylate and tert-butyl 1-(3-amino-6-chloro-2-fluorobenzyl)cyclopropanecarboxylate (Example 24A/25A, ratio about 1.5:1) were dissolved in 0.16 ml of abs. THF, the solution was cooled to −10° C. and a solution of 38 mg (0.132 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl chloride in about 0.1 ml of abs. THF was added dropwise. After the addition had ended, the mixture was slowly warmed to RT, and after 2 h, water was added. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The product mixture obtained was separated by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 23.2 mg (38% of theory) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 186A) and 18.7 mg (31% of theory) of tert-butyl 1-(6-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 187A).

1. additionAfter the addition
2. extractionThe mixture was extracted three times with ethyl acetate
3. washthe combined organic phases were washed with 1 N hydrochloric acid and saturated sodium chloride solution
4. dry with materialdried over magnesium sulphate
5. concentrationconcentrated under reduced pressure
6. customThe product mixture obtained
7. customwas separated by preparative RP-HPLC (mobile phase acetonitrile/water)