Processes for preparation of 4-aminoindane compounds and related aminoindane amides
A process for preparation of 4-aminoindane derivatives of a first formula, salts and enantiomers thereof comprising the steps of: a) hydrogenating a 1,2-dihydroquinoline of a second formula to give a corresponding tetrahydroquinoline of a third formula; b) acylating the tetrahydroquinoline of the third formula with a carboxylic acid derivative of a fourth formula to obtain a corresponding acyl derivative compound of a fifth formula; c) rearranging the acyl derivative compound of the fifth formula under acidic conditions so as to give an acyl indane compound of a sixth formula; and d) hydrolysing the acyl group of the acyl indane compound of the sixth formula so as to obtain the 4-aminoindane derivatives of the first formula.
1. A process for preparation of 4-aminoindane compounds of Formula (I), salts and enantiomers thereof
comprising the steps of:
a) hydrogenating a 1,2-dihydroquinoline of Formula (IV)
to give a corresponding tetrahydroquinoline of Formula (V)
b) acylating the tetrahydroquinoline of Formula (V) with a carboxylic acid derivative of Formula RC(O)LG to obtain a corresponding acyl derivative compound of Formula (VI) in a reaction mixture
c) rearranging the acyl derivative compound of Formula (VI) under acidic conditions so as to give an acyl indane compound of Formula (VII) or an addition salt thereof
and
d) hydrolyzing the acyl group of the acyl indane compound of Formula (VII) so as to obtain the 4-aminoindane compounds of Formula (I), salts and enantiomers thereof;
wherein in the formulae:
n is an integer selected within the range from 0 to 3, inclusive;
R is a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group, these groups being optionally substituted with one or more of: C 1 -C 6 alkyl groups or halogen atoms; and
LG is a leaving group selected from: (i) a hydroxy group; (ii) a halogen atom; (iii) a C 1 -C 6 alkylsulfonyloxy group; (iv) a C 6 -C 10 arylsulfonyloxy group; or (v) a R a COO group wherein R a is a C 1 -C 6 alkyl group, the groups (iii)-(v) being optionally substituted with one or more halogen atoms; and
the process further comprising:
adding an organic solvent to the reaction mixture obtained at the completion of step (b); and
prior to step (c), distilling the organic solvent from the reaction mixture to remove any excess of the carboxylic acid derivative of Formula RC(O)LG and to form a slurry comprising the acyl derivative compound of Formula (VI).
2. The process of claim 1 , wherein the slurry comprising the acyl derivative compound of Formula (VI) is fed to step (c).
3. A process for preparation of 4-aminoindane compounds of Formula (I), salts and enantiomers thereof
comprising the steps of:
a) hydrogenating a 1,2-dihydroquinoline of Formula (IV)
to give a corresponding tetrahydroquinoline of Formula (V)
b) acylating the tetrahydroquinoline of Formula (V) with a carboxylic acid derivative of Formula RC(O)LG to obtain a corresponding acyl derivative compound of Formula (VI)
c) rearranging the acyl derivative compound of Formula (VI) under acidic conditions so as to give an acyl indane compound of Formula (VII) or an addition salt thereof
and
d) hydrolyzing the acyl group of the acyl indane compound of Formula (VII) so as to obtain the 4-aminoindane compounds of Formula (I), salts and enantiomers thereof;
wherein in the formulae:
n is an integer selected within the range from 0 to 3, inclusive;
R is a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group, these groups being optionally substituted with one or more of: C 1 -C 6 alkyl groups or halogen atoms; and
LG is a leaving group selected from: (i) a hydroxy group; (ii) a halogen atom; (iii) a C 1 -C 6 alkylsulfonyloxy group; (iv) a C 6 -C 10 arylsulfonyloxy group; or (v) a R a aCOO group wherein R a is a C 1 -C 6 alkyl group, the groups (iii)-(v) being optionally substituted with one or more halogen atoms; and
wherein step (c) comprises suspending the acyl derivative compound of Formula (VI) in an organic solvent and contacting the thus obtained suspension with an organic acid or an inorganic acid so as to obtain the acyl indane compound of Formula (VII) in a form of an addition salt.
4. The process of claim 3 , further comprising:
forming a slurry comprising the acyl indane compound of Formula (VII) in the form of the addition salt;
wherein the slurry comprising the acyl indane compound of Formula (VII) in the form of the addition salt is fed to step (d).
5. The process of claim 3 , wherein the acyl indane compound of Formula (VII) in the form of the addition salt is contacted with an alkaline aqueous solution so as to obtain the 4-aminoindane compounds of Formula (I), salts and enantiomers thereof.
6. A process for preparation of 4-aminoindane compounds of Formula (I), salts and enantiomers thereof
comprising the steps of:
a) hydrogenating a 1,2-dihydroquinoline of Formula (IV)
to give a corresponding tetrahydroquinoline of Formula (V)
b) acylating the tetrahydroquinoline of Formula (V) with a carboxylic acid derivative of Formula RC(O)LG to obtain a corresponding acyl derivative compound of Formula (VI)
c) rearranging the acyl derivative compound of Formula (VI) under acidic conditions so as to give an acyl indane compound of Formula (VII) or an addition salt thereof
and
d) hydrolyzing the acyl group of the acyl indane compound of Formula (VII) so as to obtain the 4-aminoindane compounds of Formula (I), salts and enantiomers thereof;
wherein in the formulae:
n is an integer selected within the range from 0 to 3, inclusive;
R is a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group, these groups being optionally substituted with one or more of: C 1 -C 6 alkyl groups or halogen atoms; and
LG is a leaving group selected from: (i) a hydroxy group; (ii) a halogen atom; (iii) a C 1 -C 6 alkylsulfonyloxy group; (iv) a C 6 -C 10 arylsulfonyloxy group; or (v) a R a COO group wherein R a is a C 1 -C 6 alkyl group, the groups (iii)-(v) being optionally substituted with one or more halogen atoms; and
wherein step (c) comprises suspending the acyl derivative compound of Formula (VI) in an organic solvent and contacting the thus obtained suspension with sulfuric acid or orthophosphoric acid so as to obtain the acyl indane compound of Formula (VII) in a form of an addition salt.
7. The process of claim 1 , wherein the organic solvent is selected from: aliphatic or cycloaliphatic hydrocarbons, chlorinated hydrocarbons, aromatic hydrocarbons, alcohols, glycols, esters, or mixtures thereof.
8. The process of claim 1 , wherein the organic solvent is selected from: hexane, heptane, methylene chloride, dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate, or mixtures thereof.
9. The process of claim 3 , wherein the organic solvent is selected from: aliphatic or cycloaliphatic hydrocarbons, chlorinated hydrocarbons, aromatic hydrocarbons, alcohols, glycols, esters, or mixtures thereof.
10. The process of claim 3 , wherein the organic solvent is selected from: hexane, heptane, methylene chloride, dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate, or mixtures thereof.
11. The process of claim 1 , wherein step (a) comprises:
dissolving the 1,2-dihydroquinoline of Formula (IV) in an organic solvent; and
contacting the 1,2-dihydroquinoline of Formula (IV) dissolved in the organic solvent with gaseous hydrogen in the presence of a hydrogenation catalyst so as to obtain the tetrahydroquinoline of Formula (V).
12. The process of claim 1 , wherein step (a) comprises:
dissolving the 1,2-dihydroquinoline of Formula (IV) in a polar solvent; and
contacting the 1,2-dihydroquinoline of Formula (IV) dissolved in the polar solvent with gaseous hydrogen in the presence of a hydrogenation catalyst so as to obtain the tetrahydroquinoline of Formula (V).
13. The process of claim 1 , wherein step (b) is carried out in the absence of added solvent.
14. The process of claim 3 , wherein step (a) comprises:
dissolving the 1,2-dihydroquinoline of Formula (IV) in an organic solvent; and
contacting the 1,2-dihydroquinoline of Formula (IV) dissolved in the organic solvent with gaseous hydrogen in the presence of a hydrogenation catalyst so as to obtain the tetrahydroquinoline of Formula (V).
15. The process of claim 3 , wherein step (a) comprises:
dissolving the 1,2-dihydroquinoline of Formula (IV) in a polar solvent; and
contacting the 1,2-dihydroquinoline of Formula (IV) dissolved in the polar solvent with gaseous hydrogen in the presence of a hydrogenation catalyst so as to obtain the tetrahydroquinoline of Formula (V).
16. The process of claim 3 , wherein step (b) is carried out in the absence of added solvent.
17. The process of claim 3 , wherein the inorganic acid is sulfuric acid.
18. The process of claim 6 , wherein step (a) comprises:
dissolving the 1,2-dihydroquinoline of Formula (IV) in an organic solvent; and
contacting the 1,2-dihydroquinoline of Formula (IV) dissolved in the organic solvent with gaseous hydrogen in the presence of a hydrogenation catalyst so as to obtain the tetrahydroquinoline of Formula (V).
19. The process of claim 6 , wherein step (a) comprises:
dissolving the 1,2-dihydroquinoline of Formula (IV) in a polar solvent; and
contacting the 1,2-dihydroquinoline of Formula (IV) dissolved in the polar solvent with gaseous hydrogen in the presence of a hydrogenation catalyst so as to obtain the tetrahydroquinoline of Formula (V).
20. The process of claim 6 , wherein step (b) is carried out in the absence of added solvent.