IP Library › Patent Application 16205525
Patent Application
App. No. 16/205,525

METHODS OF MANUFACTURING BENZOQUINOLINE COMPOUNDS

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Quick Facts
Patent No.
US None
App. No.
16/205,525
Abstract

The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.

Claims (32)

1 . A process of preparing a compound of Formula IV:

or a salt thereof, comprising:

a step of reacting a compound of Formula II or a salt thereof with a compound of Formula III:

in the presence of a base;

wherein:

R 7 -R 12 and R 15 are independently selected from the group consisting of hydrogen and deuterium; and

Y 1 is selected from the group consisting of acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and aryloxy, any of which may be optionally substituted.

2 . The process of claim 1 wherein Y 1 is C 1 -C 4 alkoxy.

3 . The process of claim 2 wherein Y 1 is ethoxy.

4 . The process of claim 1 wherein Y 1 is acetoxy.

5 . The process of claim 1 wherein Y 1 is selected from the group consisting of fluorine, chlorine, and bromine.

6 . The process of claim 1 wherein said base is selected from the group consisting of alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, alkali metal carbonates, and trialkylamines.

7 . The process of claim 6 wherein said base is an alkali metal alkoxide.

8 . The process of claim 7 wherein said base is sodium tert-butoxide.

9 . A process of preparing a compound of Formula VI:

comprising:

a step of reacting a compound of Formula IV or a salt thereof with a compound of Formula V:

in a solvent and in the presence of a base;

wherein:

R 1 -R 12 and R 15 are independently selected from the group consisting of hydrogen and deuterium; and

Y 2 is selected from the group consisting of halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted.

10 . The process of claim 9 wherein Y 2 is iodide or methylsulfate.

11 . The process of claim 10 wherein Y 2 is iodide.

12 . The process of claim 9 wherein said base is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, and trialkylamines.

13 . The process of claim 12 wherein said base is an alkali metal carbonate.

14 . The process of claim 13 wherein said base is potassium carbonate.

15 . The process of claim 9 wherein said solvent is selected from the group consisting of acetone, acetonitrile, dimethyl formamide, 2-methyltetrahydrofuran, and tetrahydrofuran.

16 . The process of claim 15 wherein said solvent is acetone.

17 . The process of claim 15 wherein the volume of said solvent is between about 5 to about 15 times the mass of the compound of Formula IV.

18 . The process of claim 15 wherein the volume of said solvent is about 8 times the mass of the compound of Formula IV.

19 . The process of claim 9 wherein said reaction step is carried out in the presence of a phase transfer catalyst that is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium iodide, and 18-crown-6.

20 . The process of claim 19 wherein said phase transfer catalyst is tetrabutylammonium bromide.