NK
A compound having the general structure shown in Formula I: or pharmaceutically acceptable salts and/or solvates thereof are useful in treating diseases or conditions mediated by NK 1 receptors, for example various physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough.
1. A process for making a compound of formula 42
comprising,
reacting a compound of formula 42d
with HMDS/TMSCl/LiI to form the compound of formula 42, or, alternatively, reacting a compound of formula 42g
with TMSI or Pd(OH)/H2 to form compound 42.
2. A process for producing a compound of formula 42d
comprising the steps of:
reacting ketone 1:
with sodium cyanide, ammonium chloride and ammonia to form compounds 42b and 42c:
purifying compounds 42b and 42c to form isolated 42b;
reacting compound 42b with phosgene (COCL2) in CH2Cl2 and NaHCO3 solution and then treating the formed residue with NH2NHC(O)H/pyridine to form compound 42d.
3. A process for making a compound of formula 42g:
comprising the steps of,
oxidizing a compound of formula 23h to form a compound of formula 42e:
reacting the compound of formula 42e with hydroxylamine hydrochloride and sodium acetate to form a compound 42f:
reacting compound 42f with 1,1-oxalyldiimidazole to form compound 42g:
4. A process for making a compound of formula 23h
comprising the steps of,
(a) reacting compound 23a with NaBH4 to form compound 23b:
(b) reacting compound 23b with paraformaldehyde to form compounds 23c and 23d:
(c) purifying compound 23c and reacting compound 23c with Zn dust in acetic acid to form compound 23e:
(d) benzylating compound 23e to form compound 23f:
(e) reacting compound 23f with N-ethoxymethylene-hydrazine carboxylic acid methyl ester (31c) to form the compound 23 g:
(f) Reacting compound 23g with BCl3 to form compound 23h:
5. A process for making a compound of formula 42
comprising the steps of:
(a) reacting compound 23a with NaBH4 to form compound 23b:
(b) reacting compound 23b with paraformaldehyde to form compounds 23c and 23d:
(c) purifying compound 23c and reacting compound 23c with Zn dust in acetic acid to form compound 23e:
(d) benzylating compound 23e to form compound 23f:
(e) reacting compound 23f with N-ethoxymethylene-hydrazine carboxylic acid methyl ester (31c) to form the compound 23 g:
(f) reacting compound 23g with BCl3 to form compound 23h:
(g) oxidizing a compound of formula 23h to form a compound of formula 42e:
(h) reacting the compound of formula 42e with hydroxylamine hydrochloride and sodium acetate to form a compound 42f:
(i) reacting compound 42f with 1,1-oxalyldiimidazole to form compound 42g:
(j) reacting a compound of formula 42g
with TMSI or Pd(OH)/H2 to form compound 42.
6. A process for making a compound of formula 42
comprising the steps of:
reacting ketone 1:
with sodium cyanide, ammonium chloride and ammonia to form compounds 42b and 42c:
purifying compounds 42b and 42c to form isolated 42b;
reacting compound 42b with phosgene (COCL2) in CH2Cl2 and NaHCO3 solution and then treating the formed residue with NH2NHC(O)H/pyridine to form compound 42d;
reacting a compound of formula 42d with HMDS/TMSCl/LiI to form the compound of formula 42.