Methods for synthesizing substituted tetracycline compounds

Abstract

Methods of synthesizing substituted tetracycline compounds are provided.

1 - 20 . (canceled) 
     
     
         21 . A method for synthesizing a 9-substituted tetracycline compound, the method comprising:
 a) reacting a 9-halogenated tetracycline compound with carbon monoxide, a first palladium catalyst, a silane and a base to generate a 9-carboxaldehyde substituted tetracycline compound; and   b) reacting said 9-carboxaldehyde substituted tetracycline compound with a primary or secondary amine under hydrogenolysis or reductive amination conditions to generate said 9-substituted tetracycline compound, or a pharmaceutically acceptable salt or ester thereof.   
     
     
         22 . The method of  claim 21 , wherein said 9-halogenated tetracycline compound is 9-halogenated minocycline. 
     
     
         23 . The method of  claim 22 , wherein said 9-halogenated minocycline is a 9-iodine substituted minocycline, a 9-chlorine substituted minocycline, or a 9-bromine substituted minocycline. 
     
     
         24 . The method of  claim 23 , wherein said 9-halogenated minocycline is a 9-iodine substituted minocycline. 
     
     
         25 . The method of  claim 21 , wherein said hydrogenolysis conditions comprise a second palladium catalyst, an ammonium compound and one or more solvents; and wherein said reductive amination conditions comprise a reducing agent and a solvent. 
     
     
         26 . The method of  claim 21 , wherein said first palladium catalyst is Pd(OAc) 2 , PdCl(tBu 2 PhP) 2  [dichlorobis(di-tert-butylphenylphosphine palladium (II)] or PdCl 2 (DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride]. 
     
     
         27 . The method of  claim 26 , wherein said first palladium catalyst is Pd(OAc) 2  or PdCl 2 (tBu 2 PhP) 2 . 
     
     
         28 . The method of  claim 21 , wherein the silane is a compound represented by the chemical formula R 2 SiH 2  or R 3 SiH, wherein each R is independently C 1 -C 10  branched or straight chain alkyl or C 5 -C 14  aryl. 
     
     
         29 . The method of  claim 28 , wherein the silane is selected from the group consisting of tripropylsilane (Pr 3 SiH), triisopropylsilane (iPr 3 SiH), benzyldimethylsilane, di-tert-butylsilane (tBu 2 SiH 2 ), triethylsilane (Et 3 SiH), cyclohexyldimethylsilane, dimethylphenylsilane, diethylisopropylsilane, methylphenylsilane, dimethylisopropylsilane, diethylmethylsilane, dimethylethylsilane, diethylsilane (Et 2 SiH 2 ), trioctylsilane, dimethyloctadecylsilane, trihexylsilane, triphenylsilane (Ph 3 SiH), diisopropyloctylsilane, methyldiphenylsilane, triisobutylsilane (iBu 3 SiH), tributylsilane (Bu 3 SiH), diphenylsilane (Ph 2 SiH 2 ) and dimethylphenethylsilane. 
     
     
         30 . The method of  claim 29 , wherein the silane is Et 3 SiH. 
     
     
         31 . The method of  claim 21 , wherein the base is a carbonate base. 
     
     
         32 . The method of  claim 31 , wherein the carbonate base is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate and lanthanum carbonate. 
     
     
         33 . The method of  claim 32 , wherein the base is sodium carbonate. 
     
     
         34 . The method of  claim 21 , wherein the base is a trialkylamine. 
     
     
         35 . The method of  claim 34 , wherein the base is selected from the group consisting of trimethylamine, triethylamine, tributylamine, triisopropylamine, dimethylethylamine, diisopropylethylamine, diethylmethylamine, dimethylisopropylamine and dimethylbutylamine. 
     
     
         36 . The method of  claim 32 , wherein the base is diisopropylethylamine. 
     
     
         37 . The method of  claim 21 , wherein the reaction in step a) comprises a Lewis acid. 
     
     
         38 . The method of  claim 37 , wherein the Lewis acid is InCl 3 .