Process for the synthesis of quaternary amine compounds

1. A process for the synthesis of a compound of Formula IIA by quaternization of a compound of Formula II:

wherein,

s is 0, 1, 2 or 3;

Y— is a pharmaceutically acceptable counterion;

each R 1 , R 2 , R 3 , R 4 , R 7 and R 8 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

R 5 , and R 6 together with the atoms they are attached form one additional optionally substituted ring;

alternatively R 2 and R 3 together with the carbon they are attached to form a C═X group;

wherein each R 20 and R 21 is independently selected from hydrogen, halogen, —OH, —SH, —NH 2 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OH, —C(O)NH 2 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl;

X is S, O or C(R 20 )(R 21 ); and,

Q is aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

wherein the quaternization process comprises the step of reacting a compound of Formula II with Q-LG in the presence of a base and a solvent, wherein LG is a leaving group;

wherein said compound of Formula IIA is insoluble in said solvent.

2. A process for the synthesis of a compound of Formula IIIA by quaternization of a compound of Formula III:

wherein;

s is 0, 1, 2 or 3;

Y— is a pharmaceutically acceptable counterion;

each R 1 , R 2 , R 3 , R 4 , R 7 and R 8 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

Alternatively R 2 and R 3 together with the carbon they are attached to form a C═X group;

Wherein each R 20 and R 21 is independently selected from hydrogen, halogen, —OH, —SH, —NH 2 , —CF 3 , —CN, —NO 2 , —N 3 —C(O)OH, —C(O)NH 2 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl;

t is 0, 1, 2, 3, 4, 5, 6, or 7;

each R 9 , R 10 and R 11 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

alternatively two R 10 groups together with the carbon they are attached to form a C═X group; wherein the quaternization process comprises the step of reacting a compound of Formula III with Q-LG in the presence of a base and a solvent, wherein LG is a leaving group; wherein said compound of Formula IIIA is insoluble in said solvent.

3. The process according to claim 1 , wherein said quaternization process is selected from methylation of a tertiary amine from Processes 1 and 11-18:

4. The process according to claim 1 , wherein said base is selected from: triethyl amine, dimethyl amine, tert-butyl amine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.

5. The process according to claim 1 , wherein Q-LG is an alkyl halide.

6. The process according to claim 1 , wherein Q-LG is CH 3 -LG, and LG is selected from bromide, chloride, iodide, alkyl sulfonate or aryl sulfonate, preferably mesylate or tosylate.

7. The process according to claim 1 , wherein Q-LG is CH 3 CH 2 -LG, and LG is selected from bromide, chloride, iodide, alkyl sulfonate or aryl sulfonate, preferably mesylate or tosylate.

8. The process according to claim 1 , wherein Y— is a halogen, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl.

9. The process according to claim 1 , wherein said solvent is a polar aprotic solvent or a non-polar solvent.

10. The process according to claim 9 wherein said polar aprotic solvent is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile, sulfolane, dimethylacetamide, N-methylpyrrolidine-2-one, isopropyl acetate, dimethylsulfoxide, nitromethane and mixtures thereof.

11. The process according to claim 1 , wherein said solvent is acetonitrile.

12. The process according to claim 2 , wherein said solvent is acetonitrile.

13. The process according to claim 3 , wherein said solvent is acetonitrile.