Substituted heterocycle fused gamma-carbolines synthesis

A method for preparing (A) a compound of Formula 1I or (B) a compound of Formula 1J, as provided below:

• wherein:
• R is methyl;
• and
• Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl;
• each in free or salt form, comprising the steps of:
• (a) reacting a compound of Formula 1E:
• in free or salt form, wherein (i) A is Br;
• (ii) R is methyl;
• and (iii) B is an acyl protecting group;
• with (i) a transition metal catalyst selected from the group consisting of CuI, CuBr, CuCl, Cu(OAc)2, Cu2Cl2, CuBr2, CuSO4, Cu2SO4, and Cu2O, (ii) a carbonate base, (iii) optionally an alkali metal iodide, and (iv) the ligand DBU, in a solvent selected from toluene, xylene, and chlorobenzene, to form an intermediate of Formula 1F:
• in free or salt form, wherein (i) R is methyl;
• and (ii) B is an acyl protecting group;
• (b) reducing the amide carbonyl of the compound of Formula 1F to yield an intermediate of Formula 1H,
• in free or salt form, wherein (i) R is methyl;
• and (ii) B is an acyl protecting group;
• and
• (c) deprotecting the piperidine nitrogen of the compound of Formula 1H to yield the compound of Formula 1I,
• in free or salt form, wherein (i) R is methyl;
• and when the product of the method is the compound of Formula 1J, the method further comprising the steps of:
• (d) alkylating the piperidine nitrogen of the compound of Formula 1I with a suitable alkylating agent to yield the compound of Formula 1J, in free or salt form;
• and optionally
• (e) converting the compound of Formula 1J in free form to a compound of Formula 1J in salt form.