Arylation method for the functionalization of O-allyl erythromycin derivatives

A method for preparing an O-alkenylaryl erythromycin A derivative comprising the steps of:

• reacting the hydroxyl of a hydroxyl containing erythromycin A derivative with an allylating agent to form an allylic erythromycin A derivative;
• reacting the allyl group of said allylic erythromycin A derivative with an arylating agent in the presence of an inorganic base, a phase transfer catalyst and less than six mole percent of a palladium catalyst in an organic solvent, without addition of a phosphine, at a temperature of from about 90° C. to about 120° C. to form an O-alkenylarylerythromycin A derivative;
• and then,
• optionally isolating said O-alkenylarylerythromycin A derivative.

A method of preparing a 2′,4″-hydroxyl protected 6-O-alkenylarylerythromycin A derivative comprising the steps of:

• protecting the 2′-hydroxyl and 4″-hydroxyl groups of a 6-hydroxyl, 2′-hydroxyl, 4″-hydroxyl erythromycin A derivative with at least one hydroxyl-protecting agent to form a 6-hydroxyl, 2′,4″-hydroxyl protected erythromycin A derivative;
• allylating the C-6 hydroxyl of said 6-hydroxyl, 2′,4″-hydroxyl protected erythromycin A derivative with an allylating agent to form a 6-O-allyl, 2′,4″-hydroxyl protected erythromycin A derivative;
• arylating said 6-O-allyl, 2′,4″-hydroxyl protected erythromycin A derivative with an arylating agent in the presence of an inorganic base, a phase transfer catalyst and less than six mole percent of a palladium catalyst in an organic solvent, without addition of a phosphine, at a temperature of from about 90° C. to about 120° C. to form a 2′,4″-hydroxyl protected 6-O-alkenylarylerythromycin A derivative;
• and then,
• optionally isolating said 2′,4″-hydroxyl protected 6-O-alkenylaryl erythromycin A derivative.

A method for a single pot allylation and arylation of erythromycin A comprising the steps of:

• reacting the 6-hydroxyl of erythromycin A with allyl t-butyl carbonate and a palladium catalyst to form 6-O-propenyl erythromycin A;
• reacting the allyl group of 6-O-propenyl erythromycin A with 3-bromoquinoline in the presence of sodium bicarbonate, tetrabutyl ammonium chloride and less than six mole percent of Pd(OAc)2 catalyst in N,N-dimethylformamide, without addition of a phosphine, at a temperature of from about 90° C. to about 120° C. to form 6-O-(3-(3-quinolyl)-2-propen-1-yl) erythromycin A;
• and then,
• optionally isolating 6-O-(3-(3-quinolyl)-2-propen-1-yl) erythromycin A.

A method of preparing 6-O-(3-(3-quinolyl)-2-propen-1-yl) erythromycin A-2′,4″-dibenzoate comprising the steps of:

• protecting the 2′-hydroxyl and 4″-hydroxyl groups of erythromycin A with benzoic anhydride to form erythromycin A 2′,4″-dibenzoate;
• allylating the C-6 hydroxyl of erythromycin A 2′,4″-dibenzoate with allyl t-butyl carbonate and a palladium catalyst to form 6-O-propenyl erythromycin A 2′,4″-dibenzoate;
• arylating 6-O-propenyl erythromycin A 2′,4″-dibenzoate with 3-bromoquinoline in the presence of sodium bicarbonate, tetrabutyl ammonium chloride and less than six mole percent of Pd(OAc)2 catalyst in N,N-dimethylformamide, without addition of a phosphine, at a temperature of from about 90° C. to about 120° C. to form 6-O-(3-(3-quinolyl)-2-propen-1-yl) erythromycin A-2′,4″-dibenzoate;
• and then,
• optionally isolating 6-O-(3-(3-quinolyl)-2-propen-1-yl) erythromycin A-2′,4″-dibenzoate.