Patent ID: 7317100

Claim:
A process for the preparation of an epothilone of formula I, wherein A represents O or NR 7 ; R 1 is hydrogen or lower alkyl which is unsubstituted or substituted by hydroxy, lower acyloxy, lower alkoxy, halogen, amino, lower alkyl amino, di-lower alkyl amino or lower acyl amino; R 2 is unsubstituted or substituted heteroaryl having at least one nitrogen atom; R 3 represents hydrogen or lower alkyl; R 5 and R 6 are hydrogen; and R 7 is hydrogen or lower alkyl; and Z is O or a bond; or a pharmaceutically acceptable sale thereof; comprising the steps of: (a) reacting an aldehyde of formula II wherein R 1 , R 2 and Z have the meanings as provided above for a compound of formula I and R 4 is a protecting group, with an ethylketone of formula III, wherein R 5 is H or a protecting group different or identical to R 4 and R3 has the meaning as provided above for a compound of formula I, to provide the aldol of formula IV, wherein R 1 , R 2 , R 3 and Z have the meanings as provided above for a compound of formula I, R 4 a protecting group, R 5 is H or a protecting group different or identical to R 4 and R 6 is hydrogen (b) reacting the aldol of formula IV with a reagent capable to introduce a protecting group which is different or identical to R 4 furnishing a carboxylic acid of formula IV, wherein R 1 , R 2 , R 3 and Z have the meanings as provided above for a compound of formula I, R 4 a protecting group and R 5 is H or R 5 and R 6 are protecting groups different or identical to R 4 ; (c) reacting the carboxylic acid of formula IV with a reagent capable to remove the protecting group R 4 under conditions which do not result in the removal of the protecting groups R 5 and R 6 providing a carboxylic acid of formula IV, wherein R 1 , R 2 , R 3 and Z have the meanings as provided above for a compound of formula I, R 4 is hydrogen and R 5 is H or R 5 is H or R 5 and R 6 are protecting groups, (d) macrolactonizing the carboxylic acid of formula IV providing the epothilone of formula I, wherein R 1 , R 2 , R 5 and Z have the meanings as provided above for a compound of formula I, A is O and R 5 is H or R 5 and R 6 are protecting groups; (e) reacting the epothilone of formula I with a reagent capable of removing the protecting groups R 5 and R 6 furnishing an epothilone of formula I, wherein R 1 , R 2 , R 3 , R 5 , R 6 and Z have the meanings as provided above for a compound of formula I and A is O; and (f) optionally reacting the epothilone of formula I into an epothilone of formula I wherein R 1 , R 2 , R 3 , R 5 , R 6 and Z have the meanings as provided above for a compound of formula I and A is NR 7 , wherein R 7 is hydrogen or lower alkyl.