Compounds and compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-10927124-B2
Application number	US-201816214985-A
Country	US
Kind code	B2
Filing date	Dec 10, 2018
Priority date	Jul 29, 2016
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

Disclosed are compounds of formula (I):

and pharmaceutical compositions containing such compounds. Methods of treating neurological or psychiatric disease and disorders in a subject in need are also disclosed.

First claim

The invention claimed is:

1. A process for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, having the structure:

or a pharmaceutically acceptable salt thereof, comprising deprotecting tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate, having the structure:

2. The process of claim 1 , wherein the deprotecting comprises treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid.

3. The process of claim 2 , wherein the treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid is carried out in the presence of ethyl acetate.

4. The process of claim 2 , wherein the treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid is carried out at ambient temperature.

5. The process of claim 2 , wherein the treating tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with hydrochloric acid is carried out for about 16 h.

6. The process of claim 1 , further comprising separating (S)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine and (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine.

7. The process of claim 6 , wherein the separating is performed by chiral HPLC.

8. The process of claim 1 , wherein tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate is prepared by a process comprising converting tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate, having the structure:

to tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate.

9. The process of claim 8 , wherein the converting tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate to tert-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate comprises treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under an H 2 atmosphere.

10. The process of claim 9 , wherein the treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under an H 2 atmosphere is carried out in the presence of methanol.

11. The process of claim 9 , wherein the treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under H 2 atmosphere is carried out at ambient temperature.

12. The process of claim 9 , wherein the treating tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate with Pd/C under H 2 atmosphere is carried out for about 4 h.

13. The process of claim 8 , wherein tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate is prepared by a process comprising protecting 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine, having the structure:

14. The process of claim 13 , wherein the protecting 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine comprises treating 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine with di-tert-butyl dicarbonate.

15. The process of claim 14 , wherein the treating 1-(5-bromo-8-fluoroisochroman-1-y1)-N-methylmethanamine with di-tert-butyl dicarbonate is carried out in the presence of water.

16. The process of claim 14 , wherein the treating 1-(5-bromo-8-fluoroisochroman-1-y1)-N-methylmethanamine with di-tert-butyl dicarbonate is carried out at ambient temperature.

17. The process of claim 14 , wherein the treating 1-(5-bromo-8-fluoroisochroman-1-y1)-N-methylmethanamine with di-tert-butyl dicarbonate is carried out for about 3 h.

18. The process of claim 13 , wherein 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine is prepared by a process comprising reacting 2-(2-bromo-5-fluorophenyl) ethanol, having the structure:

with 2,2-dimethoxy-N-methylethanamine, having the structure:

in the presence of an acid.

19. The process of claim 18 , wherein the acid is trifluoromethanesulfonic acid.

20. The process of claim 18 , wherein the acid is trimethylsilyl trifluoromethanesulfonate.

21. The process of claim 18 , wherein the reacting of 2-(2-bromo-5-fluorophenyl) ethanol with 2,2-dimethoxy-N-methylethanamine is carried out in the presence of dichloromethane.

22. The process of claim 18 , wherein the reacting of 2-(2-bromo-5-fluorophenyl) ethanol with 2,2-dimethoxy-N-methylethanamine is carried out at about 0° C.

23. The process of claim 18 , wherein the reacting of 2-(2-bromo-5-fluorophenyl) ethanol with 2,2-dimethoxy-N-methylethanamine is carried out for about 16 h.

24. A process for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, having the structure:

or a pharmaceutically acceptable salt thereof, comprising:
a) reacting 2-(2-bromo-5-fluorophenyl) ethanol, having the structure:

with 2,2-dimethoxy-N-methylethanamine, having the structure:

in the presence of an acid to provide 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine, having the structure:

b) protecting 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine to provide tert-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate, having the structure:

c) converting tent-butyl ((5-bromo-8-fluoroisochroman-1-yl)methyl)(methyl)carbamate to tent-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate having the structure:

and
d) deprotecting tent-butyl ((8-fluoroisochroman-1-yl)methyl)(methyl)carbamate to provide (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, or a pharmaceutically acceptable salt thereof.

25. A compound, which is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, or a pharmaceutically acceptable salt thereof, prepared by the process of claim 1 .

26. A compound, which is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine, or a pharmaceutically acceptable salt thereof, prepared by the process of claim 24 .

Assignees

• Pgi Drug Discovery Llc
• Sunovion Pharmaceuticals Inc

Inventors

• Xie Linghong
• Heffernan Michele L R
• Jones Philip Glyn
• Hanania Taleen G

Classifications

• A61P25/14

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• C07D493/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/353

  3,4-Dihydrobenzopyrans, e.g. chroman, catechin · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D307/87

  Benzo [c] furans; Hydrogenated benzo [c] furans · CPC title