Hydrochloric Acid → 3,3,3-Trifluoro-2-hydroxy-2-methylpropanenitrile
Reaction equation
C(C1C=CC([NH:15][C:16](=O)[C@@:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])=CC=1)(=O)C1C=CC=CC=1.FC(F)(F)[C@](O)(C)C(O)=O.FC(F)(F)C(C)=O.[C-]#N.[C-]#N.[Na+].Cl>>[F:19][C:18]([F:21])([F:20])[C:17]([OH:23])([CH3:22])[C:16]#[N:15]Participants
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.
Workup
- customis prepared by selective crystallization with a resolving agent rather than by an enzymatic process
Sources & evidence
- ORD record
- ord-406ba2ee39f646d68555ba83ab0b5a67
- Source dataset
- uspto-grants-2000_08
- Patent number
- US06110729
Reaction notes
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