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ClinicaltrialsforCrizotinibpowder
Entry Acyl Donor (1 eq) Conv. (%) e.e.prod (%) E
1 Isopropenyl acetate 44 2 Ethyl acetate 3 Vinyl acetate 32 26 99 >200 99 >200 95 54
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Reaction conditions: 1-(2,6-dichloro-3-fluorophenyl)-ethanol (2) (0.048 mmol, 10mg), isopropenyl acetate or vinyl acetate or ethyl acetate (1eqv) as acyl donor, and 60mg (20%w/v) of CAL B Novozym 435 (N435) in cyclohexane (3 mL) for 10 days at 60 °C, measured by GC-FID method and enantioselectivity was measured based on (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the corresponding ester retention times.
4.ApprovalsandindicationsforCrizotinibpowder
On August 26, 2011, the U.S. Food and Drug Administration approved Crizotinib powder (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene. Approval required a companion molecular test for the EML4-ALK fusion. In March 2016, the U.S. Food and Drug Administration approved Crizotinib powder in ROS1-positive non-small cell lung cancer.
As expected, isopropenyl acetate lead to the best results on the kinetic resolution of 1-(2,6-dichloro-3-fluorophenyl)ethanol (2), arriving on the desired acetylated R-enantiomer in good conversions and high selectivity (Table 1, entry 1). Vinyl acetate was probably too reactive under the designed reaction conditions, leading to a decrease of enantiomeric ratio. A blank experiment was performed in order to evaluate the uncatalyzed reaction and small amounts of acetylated alcohol could be obtained (<10%). Regarding ethyl acetate, surprisingly, it presented interesting selectivity with moderate conversion (Table 1, entries 3 and 2 respectively). Despite the fact that Table 1 present the results for the kinetic resolution after 10 days, the reactions were monitored in the first 3 days every 12 h and after the 3rd day, every 24 h. What could be seen is the conversion
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