Mallinckrodt, Inc.

Mallinckrodt Specialty Chemicals Company

Narayanasamy Gurusamy

Jerry R Patton

Tao Jiang

Peter Xianqi Wang

John F Lang

Catherine K Jung

The present invention provides processes for the preparation of saturated ketone morphinan compounds. In particular, the invention provides processes for the conversion of a morphinan comprising an allyl alcohol ring moiety into a morphinan comprising a saturated ketone ring moiety by an isomerization reaction catalyzed by an inorganic salt of a late transition metal.

Preparation of saturated ketone morphinan compounds

Bromobiphenyls (such as 2-fluoro-4-bromobiphenyl) are synthesized by reacting together a phenylboronic acid (such as phenylboronic acid) and a bromoiodobenzene (such as 2-fluoro-4-bromoiodobenzene). The reaction generally takes place with the aid of a catalyst (such as palladium in a zero valance state) and an inert solvent (such as fluorobenzene). Control of temperature is very important to obtain both an acceptable reaction rate and an acceptable level of terphenyl byproduct.

Synthesis of bromobiphenyls

Aromatic amine compounds are halogenated in the presence of a quaternary ammonium halide.

Halogenation of aromatic amine compounds

A process for the production of 2,4-dihaloaniline, especially 4-bromo-2-fluoroaniline, via the halogenation (bromination) of 2-haloaniline (2-fluoroaniline) in the presence of quaternary ammonium halide (bromide) catalyst in an inert solvent. The yield and selectivity are very high and the inventive method includes continuous processing with recycle of the catalyst/solvent mixture.

Catalytic bromination of 2-fluoroaniline

The present invention comprises compounds of the formulas: ##STR1## wherein X is Cl or Br. These compounds are useful as intermediaries for the production of 2,4,5-trifluorobenzoic acid and 2,4,5-trifluorobenzoyl fluoride.

Novel intermediates for the production of 2,4,5-trifluorobenzoyl fluoride

Disclosed is a practical and efficient process for preparing 6-substituted 4-chromanones from phenolic acrylate ester compounds derivable from para-substituted phenolic or thiophenolic compounds and beta-unsubstituted acrylic acid compounds which are esterifiable therewith. The process includes effecting rearrangement of a phenolic or thiophenolic acrylate ester in the presence of a rearrangement effective amount of hydrogen fluoride to the corresponding hydroxy--or mercapto (vinyl ketone) wherein the carbonyl carbon atom of the vinyl carboxy group is directly attached to the benzene ring ortho to the hydroxy or mercapto group. Thereafter, the vinyl ketone is cyclized to the corresponding 6-substituted 4-chromanone in the presence of a cyclization-effective amount of hydrogen fluoride. The 6-substituted 4-chromanones prepared by the process are useful as intermediates for preparing pharmaceutical agents.

Preparation of 6-substituted 4-chromanones

Disclosed is a practical and efficient process for preparing 6-substituted 4-chromanones from phenolic acrylate ester compounds derivable from para-substituted phenolic or thiophenolic compounds and beta-unsubstituted acrylic acid compounds which are esterifiable therewith. The process includes effecting rearrangement of a phenolic or thiophenolic acrylate ester in the presence of a rearrangement effective amount of hydrogen fluoride to the corresponding hydroxy - or mercapto (vinyl ketone) wherein the carbonyl carbon atom of the vinyl carboxy group is directly attached to the benzene ring ortho to the hydroxy or mercapto group. Thereafter, the vinyl ketone is cyclized to the corresponding 6-substituted 4-chromanone in the presence of a cyclization-effective amount of hydrogen fluoride. The 6-substituted 4-chromanones prepared by the process are useful as intermediates for preparing pharmaceutical agents.

Growing community of inventors

Ballwin, MO, United States of America

Narayanasamy Gurusamy