Process for the synthesis of an antiviral compound

A process for isolation of a first enantiomer of an optically active organic acid compound in high optical purity from a composition comprising a first enantiomer and a second enantiomer of the compound, the process comprising:

• (a) providing a first mother liquor comprising a first and a second optically active enantiomer in acid form dissolved in a polar, aprotic solvent;
• (b) contacting the first mother liquor with a first resolving agent which forms with said second enantiomer a precipitate which is not more than sparingly soluble in said first mother liquor, said resolving agent further characterized in that it does not form with said first enantiomer any substantial amount of a precipitate from said first mother liquor;
• (c) forming a first precipitate comprising said first resolving agent and said second enantiomer;
• (d) separating from said first mother liquor substantially all of said first precipitate;
• (e) subsequent to step (d), forming a second mother liquor by replacing said polar, aprotic solvent in said first mother liquor with a non-polar, aprotic solvent;
• (f) contacting said second mother liquor with an aqueous acid solution;
• (g) forming a third mother liquor by replacing said non-polar, aprotic solvent of said second mother liquor with a polar, aprotic solvent;
• (h) contacting said third mother liquor with a second resolving agent which forms with said first enantiomer a precipitate which is not more than sparingly soluble in said third mother liquor;
• (i) forming a second precipitate comprising said first enantiomer and said second resolving agent;
• and
• (j) separating substantially all of said second precipitate from said third mother liquor.

A process for separation of (R) 3-hydroxy-3-(2-phenylethyl)-hexanoic acid from a mixture comprising (R) 3-hydroxy-3-(2-phenylethyl)-hexanoic acid and (S) 3-hydroxy-3-(2-phenylethyl)-hexanoic acid comprising:

• (a) contacting a first mother liquor comprising a mixture of (R) and (S) 3-hydroxy-3-(2-phenylethyl)-hexanoic acid in acid form dissolved in acetonitrile with (D)(+)-norephedrine;
• (b) forming a first precipitate comprising (S) 3-hydroxy-3-(2-phenylethyl)-hexanoic acid and (D)(+)-norephedrine;
• (c) separating said first mother liquor from substantially all of said first precipitate;
• (d) forming a second mother liquor by substantially replacing said acetonitrile in said first mother liquor with toluene;
• (e) contacting said second mother liquor with aqueous HCl;
• (f) subsequent to step (e), forming a third mother liquor by substantially replacing said toluene in said second mother liquor with acetonitrile;
• (g) contacting said third mother liquor with with (L)(−)-norephedrine;
• and
• (h) forming a second precipitate comprising (R) 3-hydroxy-3-(2-phenylethyl)-hexanoic acid and (L)(−)-norephedrine.

A process for synthesizing [R—(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide comprising the steps of:

• (a) providing a racemic mixture of 3-hydroxy-3-(2-phenylethyl)-hexanoate ethyl acetate by reacting 1-phenyl-hexan-3-one with ethylbromoacetate under Reformatsky conditions;
• (b) isolating (R)-3-hydroxy-3-(2-phenylethyl)-hexanoic acid in enantiomeric excess by saponification and reverse resolution of the racemate of step (a) to produce a resolved product;
• (c) isolating the free acid from the resolved product of step (b);
• (d) synthesizing a keto-ester comprising (R)-ethyl-5-hydroxy-3-oxo-5-phenyethyl-octanoate by reaction of said (R)-3-hydroxy-3-(2-phenylethyl)-hexanoic acid from step (c) with monoethyl malonate magnesium salt in the presence of 1,1′-carbonyldiimidazole;
• (e) converting the keto-ester of step (d) to a hydroxy-lactone intermediate comprising (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenylethyl)]-6-propyl-2H-pyran-2-one;
• (f) converting the hydroxy-lactone intermediate of step (e) to the nitro-propenyl compound comprising [3α(R),6(R)]-5,6-dihydro-4-hydroxy-3-[(Z)-1-(3-nitrophenyl)-propenyl]-6-[1-(2-phenylethyl)]-6-propyl-2H-pyran-2-one and its enantiomer by condensing the hydroxy-lactone intermediate with m-nitropropiophenone in the presence of titanium tetrachloride and pyridine;
• (g) stereospecifically reducing said nitro-propenyl compound from step (f) to the nitro-propyl compound comprising [3α(R),6(R)]-5,6-dihydro-4-hydroxy-3-[1-(3-nitrophenyl)-propyl]-6-[1-(2-phenylethyl)]-6-propyl-2H-pyran-2-one by contact with [(1,5-cyclooctadiene)rhodium(I)-1,2-bis-(2R,5R)-dimethyl-phospholano)benzene]tetrafluoroborate in the presence of hydrogen;
• (h) reducing the nitro-propyl compound of step (f) to the amino-propyl compound comprising [3α(R),6(R)]3-[1-(3-aminophenyl)-propyl]-5,6-dihydro-4-hydroxy-6-[1-(2-phenylethyl)]-6-propyl-2H-pyran-2-one by contact with a palladium catalyst in the presence of hydrogen;
• and
• (i) reacting the amino propyl compound of step (g) with 5-(trifluoromethyl)-2-pyridinesulfonyl chloride in the presence of pyridine followed by acidification of the mixture, thus providing [R—(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide.