3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a preferred embodiment, (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid is prepared by reaction of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile with acid. (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanenitrile can be prepared by reacting 1,1,1-trifluoroacetone with sodium cyanide in the presence of hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile. The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile is then reacted with an acid chloride such as butyryl chloride to form the ester. The racemic ester is reacted with a lipase enzyme such as crude porcine pancreatic lipase that selectively cleaves the ester group from the (R) enantiomer leaving the ester of the (S) enantiomer. The ester group of the (S) enantiomer is then removed using standard procedures to provide (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile, which is in turn treated with acid such as sulfuric acid or hydrochloric acid to form (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Scheme 2 shows the preparation of (S)-(-)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide wherein the (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid intermediate is prepared by selective crystallization with a resolving agent rather than by an enzymatic process. As shown in Scheme 2, 1,1,1-trifluoroacetone (1) is reacted with a cyanide such as sodium cyanide in the presence of an acid such as hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2). The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2) is then hydrolyzed with, for example, hydrochloric acid or sulfuric acid to provide racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3). Racemic (3) is then selectively crystallized with a resolving agent such as (1R,2S)-norephedrine (4) to form a salt (5) which may be recrystallized to diastereomeric purity. The purified salt (6) contains (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7). (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (7) after liberation from the salt is reacted with 4-aminobenzophenone (8) and SOCl2 using an organic base such as triethylamine or Hunig's base to form (S)-(-)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (9), which can then be purified by recrystallization. is prepared by selective crystallization with a resolving agent rather than by an enzymatic process

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a particular aspect of the invention, (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid is prepared by reaction of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile with acid. (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanenitrile can be prepared by reacting 1,1,1-trifluoroacetone with sodium cyanide in the presence of hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile. The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile is then reacted with an acid chloride such as butyryl chloride to form the ester. The racemic ester is reacted with a lipase enzyme such as crude porcine pancreatic lipase that selectively cleaves the ester group from the (R) enantiomer leaving the ester of the (S) enantiomer. The ester group of the (S) enantiomer is then removed using standard procedures to provide (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile, which is in turn treated with acid such as sulfuric acid or hydrochloric acid to form (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In Scheme 2, 1,1,1-trifluoroacetone (1) is reacted with a cyanide such as sodium cyanide in the presence of an acid such as hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2). The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2) is then hydrolyzed with, for example, hydrochloric acid or sulfuric acid to provide racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3). Racemic (3) is then selectively crystallized with a resolving agent such as (lR,2S)-norephedrine (4) to form a salt (5) which may be recrystallized to diastereomeric purity. The purified salt (6) contains (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7). (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (7) after liberation from the salt is reacted with 4-aminobenzophenone (8) and SOCl2 using an organic base such as triethylamine or Hunig's base to form (S)-(−)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (9), which can then be purified by recrystallization.