New syntheses of levofloxacin

Abstract

In our studies on a new synthesis of levofloxacin (1c), a few highly enantioselective synthetic methods have been developed. At first, the benzoyl acrylates 22 (a, b, c, and d), which are useful intermediates for the synthesis of levofloxacin (1c), were prepared from the benzoyl chlorides 14 (a and b) and the acrylates 25 (a and b). The new acrylates 25 (a and b) were prepared from the reaction of its precursor 24, which was derived from (S)-2-amino-1-propanol and ethyl propiolate, with a TBDMSCl and an acetyl chloride as protecting groups in quantitative yields, respectively. In the synthesis of the precursor (S)-21 of levofloxacin (1c) from 22 (a, b, c, and d), four reactions composed of cyclization to form a quinolone ring, deprotection, cyclization to form a benzoxazine ring, and hydrolysis occurred in one pot and in good yield. Alternatively, another useful intermediate (R)-28 was prepared from (S)-11 by using several methods such as the Mitsunobu reaction, catalytic reduction, and mild hydrolysis with quantitative yields. The optically pure compound (S)-11 was synthesized from 10 using the baker``s yeast reduction. The precursor (S)-21 was efficiently obtained from the key intermediate (R)-28 by general procedures including the Gould-Jacobs reaction sequence and the Mitsunobu inversion cyclization. Also, a new enantioselective intramolecular cyclization for the primary aromatic amine was established to synthesize levofloxacin (1c) from (R)-28 by the modified Mitsunobu conditions in the presence of excess zinc chloride. Under the conditions of $Ph_3P$, DEAD, and $ZnCl_2$ in MeCN at reflux for 1 hr, (R)-28 was efficiently converted to (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-1,4-benzoxazine(5), a key intermediate of levofloxacin (1c) in 76% yield in ≥ 99 %$ ee. (R)-28 was also converted to (S)-5 in 52 % yield in ≥ 99 %$ ee within 10 min under the conditions of $Ph_3P,$CCl_4$, and $ZnCl_2$ in MeCN at reflux.