Process and intermediates for the synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds
This application discloses a novel process to synthesize 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds, which may be used, for example, as NK-1 inhibitor compounds in pharmaceutical preparations, intermediates useful in said process, and processes for preparing said intermediates; also disclosed is a process for removal of metals from N-heterocyclic carbine metal complexes.
1. A process for preparing compound VIII:
the process comprising treating compound I:
with hydrochloric acid;
wherein compound I is prepared from compound VII or VIIb:
wherein “salt 3” represents at least one proton bonded to a base functional group in the compound VII.
2. The process of claim 1 , wherein the compound I is prepared by treating compound VII:
with a reagent suitable to reduce compound VII,
wherein “salt 3” represents at least one proton bonded to a base functional group in the compound VII.
3. The process of claim 1 , wherein the compound I is prepared by treating compound VIIb
with a reagent suitable to reduce compound VIIb.
4. The process of claim 3 , wherein the compound VIIb is prepared by treating compound VII:
with a hydroxide base of Formula M-OH,
wherein
“salt 3” represents at least one proton bonded to a base functional group in the compound VII; and
“M” is an alkaline metal or alkali earth metal to provide the compound VIIb.
5. The process of claim 2 or claim 4 , wherein the compound VII is prepared by treating compound VIa:
with a ring-closing metathesis catalyst,
wherein “salt 2” represents at least one proton bonded to a base functional group in the compound VIa.
6. The process of claim 5 , wherein the compound VIa is prepared by treating compound VI:
with an acid.
7. The process of claim 6 , wherein the compound VI is prepared by treating compound V:
with a reagent suitable to reduce compound V.
8. The process of claim 7 , wherein compound V is prepared by combining compounds III and IV to form a mixture:
wherein the mixture is heated.
9. The process of claim 1 , wherein the compound VIII is recrystallized to provide compound Ia:
10. The process of claim 2 , wherein the reagent suitable to reduce compound VII is a source of hydrogen.
11. The process of claim 10 , wherein, in addition to the source of hydrogen, the compound VII is treated with a catalyst selected from: palladium on carbon, palladium oxide, platinum on carbon, Wilkinson's catalyst (chlorotris(triphenylphosphine)rhodium(I)), and any combination thereof.
12. The process of claim 3 , wherein the reagent suitable to reduce compound VIIb is a source of hydrogen.
13. The process of claim 12 , wherein, in addition to the source of hydrogen, the compound VIIb is treated with a catalyst selected from: palladium on carbon, palladium oxide, platinum on carbon, Wilkinson's catalyst (chlorotris(triphenylphosphine)rhodium(I)), and any combination thereof.
14. The process of claim 4 , wherein the hydroxide base is NaOH.
15. The process of claim 2 , wherein salt 3 is an HCl salt.
16. The process of claim 3 , wherein salt 3 is an HCl salt.
17. The process of claim 5 , wherein salt 2 is the same or different as salt 3.
18. The process of claim 5 , wherein salt 2 is a TsOH salt.
19. The process of claim 6 , wherein the acid is selected from: p-toluene sulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, HCI, HBr, and sulfuric acid.
20. The process of claim 7 , wherein the reagent suitable to reduce compound V is selected from: sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.