合成路线1

1) Condensation of minocycline (I) with N-(hydroxymethyl)phthalimide (II) by means of trifluoromethanesulfonic acid and trifluoromethanesulfonic anhydride gives the 2-N,9-bis(phthalimidomethyl) derivative (III) along with minor amounts of the tris(phthalimidomethyl) compound (IV), which are deprotected with methylamine in EtOH, yielding a mixture of primary amines (V) and (VI). Finally, amines (V)/(VI) are reductively alkylated with pivalaldehyde (VII), with concomitant de-aminomethylation of (VI) in the presence of H2 and Pd/C (1) or NaBH(OAc)3 (2). Scheme 1.
2) Reaction of neopentylamine (VIII) with paraformaldehyde in hot hexane gives the triazine derivative (IX), which upon treatment with chloroacetic anhydride (X) in CH2Cl2 gives the N-(acyloxymethyl)amide (XI). Subsequent Tscherniac–Einhorn reaction of (XI) with minocycline (I) in the presence of trifluoromethanesulfonic acid yields the protected compound (XII), which is submitted to acidic hydrolysis of the chloroacetyl and hydroxymethyl groups in 3 N HCl at 70 °C, followed by reequilibration of the partly epimerized C4 center with NaOH or ethanolamine (3). Scheme 1.

合成路线2

3) Iodination of minocycline (I) by treatment with N-iodosuccinimide in methanesulfonic acid gives compound (XIII) (4), which is converted to aldehyde (XIV) by palladium-catalyzed carbonylation with carbon monoxide gas in the presence of phosphine ligands and triethylsilane. Finally, aldehyde (XIV) is reductively aminated with neopentylamine (VIII) under catalytic hydrogenation conditions (5). Scheme 2.

合成路线3

合成路线4