Process for the preparation of 5-(halocetyl)-8-(substituted oxy)-(1h)-quinolin-2-ones

A process for preparing 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolinone-2-one salts comprising:

• (a) reacting
• (i) 8-hydroxy-(1H)-quinolin-2-one with an acylating agent and a Lewis acid to form 5-acetyl-8-hydroxy-(1H)-quinolin-2-one;
• or
• (ii) 8-hydroxy-(1H)-quinolin-2-one with an acylating agent to form 8-acetoxy-(1H)-quinolin-2-one, and treating, in-situ, the 8-acetoxy-(1H)-quinolin-2-one with a Lewis acid to form 5-acetyl-8-hydroxy-(1H)-quinolin-2-one;
• or
• (iii) 8-acetoxy-(1H)-quinolin-2-one with a Lewis acid to form 5-acetyl-8-hydroxy-(1H)-quinolin-2-one;
• (b) reacting the 5-acetyl-8-hydroxy-(1H)-quinolin-2-one prepared in Step (i) with a compound having the Formula RL in the presence of a base and a solvent to form 5-acetyl-8-substituted oxy-(1H)-quinolin-2-one, wherein R is a protecting group and L is a leaving group;
• (c) reacting the 5-acetyl-8-substituted oxy-(1H)-quinolin-2-one with a halogenating agent in the presence of a solvent to form a 5-(α-haloacetyl)-8-substituted oxy-(1H)-quinolin-2-one;
• (d) reacting an 5-α-haloacetyl)-8-substituted oxy-(1H)-quinolin-2-one with a reducing agent in the presence of a chiral catalyst to form 8-(substituted oxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one;
• (e) treating the 8-(substituted oxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one with a base in the presence of a solvent to form 8-(substituted oxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one;
• (f) reacting the 8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one having Formula (I)
• with 2-amino-(5-6-diethyl)-indan to form a reaction mixture containing compounds having Formulae (II), (Ill) and (IV)
• wherein R is a protecting group;
• (g) treating the reaction mixture prepared in Step (i) with an acid in the presence of a solvent to form a corresponding salt;
• (h) isolating and crystallizing a salt having Formula (V)
• wherein R is a protecting group and A— is an anion;
• (i) removing the protecting group from the salt having Formula (V) in the presence of a solvent to form a salt having Formula (VI):
• wherein A— is an anion;
• and
• (j) treating the salt having Formula (VI) with an acid in the presence of a solvent to form 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one salt having Formula (VII)
• wherein X— is an anion.