Processes for the preparation of O-[5-(4-amino-thiazol-2-yl)-pyridin-2-ylmethyl]-hydroxylamine

#The present invention relates generally to the processes and intermediates useful in the preparation O-[5-(4-Amino-thiazol-2-yl)-pyridin-2-ylmethyl]-hydroxylamine which is a reagent in the synthesis of certain bridged erythromycin and ketolide derivatives described in U.S. Pat. No. 6,878,691, U.S. Patent Pub. No. 2005037982 and PCT Application WO 03/097659 A1.

#Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms). The macrolide antibiotic family (14-, 15- and 16-membered ring derivatives) shows a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin, clarithromycin, and azithromycin. Macrolides possessing a 3-oxo moiety in place of the 3-cladinose sugar are known as ketolides and have shown enhanced activity towards gram-negative bacteria and macrolide resistant gram-positive bacteria. The search for macrolide compounds which are active against MLSB-resistant strains (MLSB=Macrolides-Lincosamides-type B Streptogramines) has become a major goal, together with retaining the overall profile of the macrolides in terms of stability, tolerance and pharmacokinetics.

#Recently PCT Application WO 03/095466 A1, published Nov. 20, 2003 and PCT Application WO 03/097659 A1, published Nov. 27, 2003 disclose a series of bicyclic erythromycin derivatives.

#In a first embodiment, the present invention provides a process for the preparation of compounds of formulae (I);

#wherein R1, R2, R3 and R4 are each independently selected from: (a) hydrogen; or (b) NH2; or one of R1/R2 and/or one of R3/R4 is a hydrogen and the other of R1/R2 and/or the other of R3/R4 is selected from: (a) C(O)R5, where R5 is C1-C6 alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl; (b) C(O)OR5, where R5 is as previously defined; alternatively, R1,R2 and/or R3,R4 are taken together with the nitrogen atom to which they are attached to form (a)

#wherein A and B are each independently hydrogen, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alicyclic group, or a substituted or unsubstituted heteroaryl group; or A and B taken together with the carbon to which they are attached form a cyclic moiety selected from: aryl, substituted aryl, heterocyclic, substituted heterocyclic, alicyclic, or substituted alicyclic; b) N═C(R6)(R7), where R6 and R7 are each independently selected from a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alicyclic group, or a substituted or unsubstituted heteroaryl group; said process comprising one or more of the following steps: (1) halogenating 6-hydroxymethyl-nicotinic acid methyl ester (III) with a chlorinating reagent to form compounds of formulae (IV):