Improved processes for the preparation of linezolid using novel intermediates

A process for the preparation of Linezolid of formula I:

• or an enantiomeric form or a mixture of enantiomeric forms thereof,
• which comprises:
• a) acetylating (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• with an acetylating agent, optionally in the presence of a base, to produce an (R)-phthalimido-2-acetyloxypropyl-carbamate compound of formula III:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is as defined in formula IV, and ‘Ac’ represents an acetyl group;
• and
• b) reacting the (R)-phthalimido-2-acetyloxypropyl-carbamate compound of formula III with a suitable reagent, optionally in the presence of a base, to produce the Linezolid of formula I.

A process for the preparation of (R)-phthalimido-2-acetyloxypropyl-carbamate compound of formula III:

• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• and ‘Ac’ represents an acetyl group;
• comprising acetylating (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is as defined above;
• with an acetylating agent optionally in the presence of a base to produce an (R)-phthalimido-2-acetyloxypropyl-carbamate compound of formula III or an enantiomeric form or a mixture of enantiomeric forms thereof.

A process for the preparation of Linezolid of formula I, or an enantiomeric form or a mixture of enantiomeric forms thereof, which comprises:

• a) reacting (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• with a reagent, optionally in the presence of a base, to produce (S)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl-methyl amine of formula II:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof and
• b) acetylating the amine compound of formula II with an acetylating agent to produce the Linezolid of formula I.

A process for the preparation of (S)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl-methyl amine of formula II:

• or an enantiomeric form or a mixture of enantiomeric faints thereof, or a salt thereof;
• comprising reacting (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• with a reagent, optionally in the presence of a base, to produce the aminomethyl compound of formula II, or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.

A process for the preparation of (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:

• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• comprising reacting N-[3-phthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline of formula XIII:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof;
• with an activating agent, optionally in the presence of a base, wherein the activating agent is a carbonate compound of formula XIVa, or a chloroformate compound of formula XiVb:
• wherein the radical R1 is as defined in Formula IV;
• to produce the (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV or an enantiomeric form or a mixture of enantiomeric forms thereof.

A process for the preparation of (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:

• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• which comprises:
• a) reacting a (R)-2-hydroxypropyl-aniline compound of formula XV or N-[2(R)-2,3-epoxypropyl]-3-fluoro-4-(4-morpholinyl)aniline of formula X:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein Y is a leaving group selected from a halogen or a sulfonyloxy group;
• with an activating agent, optionally in the presence of a base, wherein the activating agent is a carbonate compound of formula XIVa, or a chloroformate compound of formula XIVb:
• wherein the radical R1 is as defined in Formula IV;
• to produce an (R)-2-hydroxypropyl-carbamate compound of formula VII or an (R)-2,3-epoxypropyl-carbamate compound of formula IX:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 and Y are as defined above;
• and
• b) reacting the (R)-2-hydroxypropyl-carbamate compound of formula VII or the (R)-2,3-epoxypropyl-carbamate compound of formula IX obtained in step-(a) with potassium phthalimide, optionally in the presence of a base, to produce the (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV or an enantiomeric form or a mixture of enantiomeric forms thereof.

A process for the preparation of (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:

• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• comprising reacting the (R)-2-hydroxypropyl-carbamate compound of formula VII or the (R)-2,3-epoxypropyl-carbamate compound of formula IX:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is as defined in formula IV, and Y is a leaving group selected from a halogen or a sulfonyloxy group;
• with potassium phthalimide, optionally in the presence of a base, to produce the (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV or an enantiomeric form or a mixture of enantiomeric forms thereof.

A process for the preparation of (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV:

• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• which comprises:
• a) reacting a (R)-2-hydroxypropyl-aniline compound of formula XV or N-[2(R)-2,3-epoxypropyl]-3-fluoro-4-(4-morpholinyl)aniline of formula X:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein Y is a leaving group selected from a halogen or a sulfonyloxy group;
• with potassium phthalimide, optionally in the presence of a base, to produce N-[3-phthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline of formula XIII:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof;
• and
• b) reacting the N-[3-phthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline of formula XIII or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof;
• with an activating agent, optionally in the presence of a base, wherein the activating agent is a carbonate compound of formula XIVa, or a chloroformate compound of formula XIVb:
• wherein the radical R1 is as defined in Formula IV;
• to produce the (R)-phthalimido-2-hydroxypropyl-carbamate compound of formula IV or an enantiomeric form or a mixture of enantiomeric forms thereof.

A compound selected from:

• i) (R)-2-Hydroxypropyl-carbamate compound of formula VII:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• and Y is a leaving group selected from a halogen or a sulfonyloxy group;
• ii) (R)-2-Acetyloxypropyl-carbamate compound of formula VIII:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• Y is a leaving group selected from a halogen or a sulfonyloxy group, and ‘Ac’ represents an acetyl group;
• iii) (R)-2,3-Epoxypropyl-carbamate compound of formula IX:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• N-[2(R)-2,3-Epoxypropyl]-3-fluoro-4-(4-morpholinyl)aniline of formula X:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof;
• v) (R)-Acetamido-2-hydroxypropyl-carbamate compound of formula XI:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• and
• vi) (R)-acetamido-2-acetyloxypropyl-carbamate compound of formula XII:
• or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R1 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
• and ‘Ac’ represents an acetyl group.