3-(Trifluoromethyl)aniline (I) was protected as the tert-butyl carbamate (II) by treatment with Boc2O at 80 C. Lithiation of (II) with sec-butyllithium at -78 C, followed by condensation with diethyl oxalate afforded keto ester (III). Subsequent acid hydrolysis of the Boc group of (III) with concomitant cyclization gave rise to 6-(trifluoromethyl)isatin (IV). Addition of Grignard reagent (V) to (IV) produced the 3-hydroxy-3-aryloxindole (VI). Conversion of (VI) to the corresponding 3-fluoro oxindole was then effected by treatment with diethylaminosulfur trifluoride at low temperature. Finally, optical resolution by means of chiral HPLC furnished the title (S)-enantiomer.

A chiral process for the synthesis of the title compound was later reported. Chlorination of 2-methoxyphenylacetic acid (VII) with sulfuryl chloride gave (VIII), which was further converted to the corresponding methyl ester (IX) by treatment with dimethyl sulfate and K2CO3. Conversion of (IX) to the lithium enolate with lithium hexamethyldisilazide, followed by condensation with aryl fluoride (X) yielded the diarylacetic ester (XI). This was reacted with N-fluoro-bis(phenylsulfonyl)amine to provide fluoro ester (XII). Basic hydrolysis afforded the racemic carboxylic acid (XIII), which was resolved via conversion to the diastereoisomeric salts with (S)-alpha-methylbenzylamine. Reduction of the nitro group from the desired (S)-enantiomer (XIV), and subsequent acidic treatment then produced the title oxindole derivative.

3-(Trifluoromethyl)aniline (I) was protected as the tert-butyl carbamate (II) by treatment with Boc2O at 80 C. Lithiation of (II) with sec-butyllithium at -78 C, followed by condensation with diethyl oxalate afforded keto ester (III). Subsequent acid hydrolysis of the Boc group of (III) with concomitant cyclization gave rise to 6-(trifluoromethyl)isatin (IV). Addition of Grignard reagent (V) to (IV) produced the 3-hydroxy-3-aryloxindole (VI). Conversion of (VI) to the corresponding 3-fluoro oxindole was then effected by treatment with diethylaminosulfur trifluoride at low temperature. Finally, optical resolution by means of chiral HPLC furnished the title (S)-enantiomer.

3-(Trifluoromethyl)aniline (I) was protected as the tert-butyl carbamate (II) by treatment with Boc2O at 80 C. Lithiation of (II) with sec-butyllithium at -78 C, followed by condensation with diethyl oxalate afforded keto ester (III). Subsequent acid hydrolysis of the Boc group of (III) with concomitant cyclization gave rise to 6-(trifluoromethyl)isatin (IV). Addition of Grignard reagent (V) to (IV) produced the 3-hydroxy-3-aryloxindole (VI). Conversion of (VI) to the corresponding 3-fluoro oxindole was then effected by treatment with diethylaminosulfur trifluoride at low temperature. Finally, optical resolution by means of chiral HPLC furnished the title (S)-enantiomer.

A chiral process for the synthesis of the title compound was later reported. Chlorination of 2-methoxyphenylacetic acid (VII) with sulfuryl chloride gave (VIII), which was further converted to the corresponding methyl ester (IX) by treatment with dimethyl sulfate and K2CO3. Conversion of (IX) to the lithium enolate with lithium hexamethyldisilazide, followed by condensation with aryl fluoride (X) yielded the diarylacetic ester (XI). This was reacted with N-fluoro-bis(phenylsulfonyl)amine to provide fluoro ester (XII). Basic hydrolysis afforded the racemic carboxylic acid (XIII), which was resolved via conversion to the diastereoisomeric salts with (S)-alpha-methylbenzylamine. Reduction of the nitro group from the desired (S)-enantiomer (XIV), and subsequent acidic treatment then produced the title oxindole derivative.

3-(Trifluoromethyl)aniline (I) was protected as the tert-butyl carbamate (II) by treatment with Boc2O at 80 C. Lithiation of (II) with sec-butyllithium at -78 C, followed by condensation with diethyl oxalate afforded keto ester (III). Subsequent acid hydrolysis of the Boc group of (III) with concomitant cyclization gave rise to 6-(trifluoromethyl)isatin (IV). Addition of Grignard reagent (V) to (IV) produced the 3-hydroxy-3-aryloxindole (VI). Conversion of (VI) to the corresponding 3-fluoro oxindole was then effected by treatment with diethylaminosulfur trifluoride at low temperature. Finally, optical resolution by means of chiral HPLC furnished the title (S)-enantiomer.

A chiral process for the synthesis of the title compound was later reported. Chlorination of 2-methoxyphenylacetic acid (VII) with sulfuryl chloride gave (VIII), which was further converted to the corresponding methyl ester (IX) by treatment with dimethyl sulfate and K2CO3. Conversion of (IX) to the lithium enolate with lithium hexamethyldisilazide, followed by condensation with aryl fluoride (X) yielded the diarylacetic ester (XI). This was reacted with N-fluoro-bis(phenylsulfonyl)amine to provide fluoro ester (XII). Basic hydrolysis afforded the racemic carboxylic acid (XIII), which was resolved via conversion to the diastereoisomeric salts with (S)-alpha-methylbenzylamine. Reduction of the nitro group from the desired (S)-enantiomer (XIV), and subsequent acidic treatment then produced the title oxindole derivative.

The reaction of 3-(trifluoromethyl)aniline (I) with Boc2O gives the carbamate (II), which is condensed with 14C labeled diethyl oxalate (III) by means of BuLi to yield the ketoester (IV). The cyclization of (IV) by means of refluxing aq. HCl affords the labeled 6-(trifluoromethyl)isatin (V), which is condensed with 5-chloro-2-methoxyphenylmagnesium bromide (VI) to provide the hydroxyketone (VII). The fluorination of (VII) with DAST gives the target compound as a racemic mixture (VIII), which is finally submitted to optical resolution by chiral HPLC.

The methylation of the phenolic OH of indanone (I) with tritium labeled methyl iodide and Cs2CO3 gives the methyl ether (II). The fluorination of the remaining OH of (II) with DAST yields the target compound as a racemic mixture, that is optically resolved by chiral HPLC.