Methods of elaborating erythromycin fragments into amine-containing fragments of azalide antibiotics

A method of synthesizing amine product compounds of the formula ##STR33## wherein R.sup.1 is hydrogen, methyl, C.sub.1-10 alkoxycarbonyl or phenylsulfonyl;

• one of R.sup.2 and R.sup.3 is hydrogen and the other is NHR, NMeR or OR where R is hydrogen, methyl C1-10 alkoxycarbonyl or phenylsulfonyl;
• R.sup.4 is hydrogen or C.sub.1-10 alkyl
• R.sup.5 is hydrogen or C.sub.1-3 alkyl
• one of R.sup.6 and R.sup.7 is hydrogen and the other is methyl when R.sup.5 is C.sub.1-3 alkyl
• R.sup.6 is methyl and R.sup.7 is hydrogen when R.sup.5 is hydrogen;
• said method comprising the steps of
• (1) cleaving an erythromycin-like compound of the formula ##STR34## where R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined before, to produce compounds of the formula ##STR35## where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are as defined above, R.sup.5 is hydrogen or C.sub.1-3 alkyl when R.sup.8 is oxo, R.sup.5 is a covalent bond to the C-9 carbon atom when R.sup.8 is hydroxyl, R.sup.8 is oxo when R.sup.5 is hydrogen or alkyl and R.sup.8 is hydroxyl of either stereochemical orientation when R.sup.5 is a covalent bond to the C-9 carbon atom;
• (2) converting the product of step (1) into an oxime of the formula ##STR36## where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined above;
• and
• (3) reducing the oxime product of step (2) to said amine product compound, which is as defined above.

A method of synthesizing amine product compounds of the formula ##STR37## wherein R.sup.5 is hydrogen or methyl;

• one of R.sup.6 and R.sup.7 is hydrogen and the other is methyl when R.sup.5 is methyl;
• R.sup.6 is methyl and R.sup.7 is hydrogen when R.sup.5 is hydrogen;
• said method comprising the steps of
• (1) cleaving an erythromycin-like compound of the formula ##STR38## where R.sup.5 is as defined before, to produce compounds of the formula ##STR39## where R.sup.6 and R.sup.7 are as defined above, R.sup.5 is hydrogen or methyl when R.sup.8 is oxo, R.sup.5 is a covalent bond to the C-9 carbon atom when R.sup.8 is hydroxyl, R.sup.8 is oxo when R.sup.5 is hydrogen or methyl and R.sup.8 is hydroxyl of either sterochemical orientation when R.sup.5 is a covalent bond to the C-9 carbon atom;
• (2) converting the product of step (1) into an oxime of the formula ##STR40## where R.sup.5 is hydrogen or methyl and R.sup.6 and R.sup.7 are as defined above and
• (3) reducing the oxime product of step (2) to said amine product compound, which is as defined above.

A method of synthesizing amine product compounds of the formulae IIIe and IIIf ##STR41## wherein R.sup.1 is hydrogen, methyl, C.sub.1 -10 alkoxycarbonyl or phenylsulfonyl,

• one of R.sup.2 and R.sup.3 is hydrogen and the other is OR, NHR or NMeR where R is hydrogen, C.sub.1 -10 alkyl or phenalkyl,
• R.sup.4 is hydrogen, C.sub.1 -10 alkyl or phenalkyl;
• said method comprising the steps of
• (1) cleaving an erythromycin-like compound of the formula ##STR42## where R.sup.1, R.sup.2 and R.sup.3 are as defined above, to produce compounds of the formulae IIe and IIf ##STR43## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, (2) converting the products of step (1) into an oxime of the formula Ve ##STR44## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above;
• (3) converting the oxime product of step (2) to iminoethers VIe and VIIe of the formulae ##STR45## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above;
• (4) reducing the iminoether products of step (3) to aminals IXe and Xe, respectively, of the formula ##STR46## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above;
• and (5) hydrolyzing the aminal products of step (4) to amine products IIIe and IIIf respectively, as defined above.