Compounds and compositions and uses thereof
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.
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 .