TETRAHYDROISOQUINOLINES AND INTERMEDIATES THEREFOR
Disclosed are processes for preparing tetrahydroisoquinolines, intermediates useful in the preparation of tetrahydroisoquinolines, processes for preparing such intermediates, and a crystalline form of 6-[(4S)-2-methyl-4-(naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine. Also disclosed are pharmaceutical compositions comprising tetrahydroisoquinolines, methods of using tetrahydroisoquinolines in the treatment of depression and other conditions and methods for obtaining the crystalline form.
1 . A compound having the following formula:
where R 1 is selected from the group consisting of Br and H 3 CO.
2 . A compound of claim 1 having the following formula:
3 . A compound having the following formula:
where R 1 is selected from the group consisting of Br and H 3 CO.
4 . A compound of claim 3 having the following formula:
5 . A compound having the following formula:
where R 2 is selected from the group consisting of Br, H 3 CO and HO.
6 . A compound of claim 5 having the following formula:
7 . A compound having the following formula:
where R 3 is selected from the group consisting of
where R 4 is C 1 -C 4 alky, aryl or phenyl, and n is 1 or 2.
8 . A compound of claim 7 having the following formula
9 . A compound having the following formula:
Where each R 5 is independently selected from the group consisting of hydrogen t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3 and COCF 3 .
10 . A compound of claim 9 having the following formula:
11 . A compound having the following formula:
Where each R 5 is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3 and COCF 3 .
12 . A compound of claim 11 having the following formula:
13 . A compound having the following formula:
where each R 5 is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3 and COCF 3 .
14 . A compound of claim 13 having the following formula:
15 . A compound having the following formula:
Where each R 5 is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3 and COCF 3 , and X is selected from the group consisting of Cl, Br, I and trifluoromethanesulfonyloxy.
16 . A compound of claim 15 having the following formula:
17 . A process of making a compound having the formula:
where R 2 is selected from the group consisting of Br, H 3 CO and HO, comprising reacting a compound having the formula:
where R 1 is selected from Br or H 3 CO, under conditions effective to promote the formation of Compound 17R.
18 . A process of making a compound having the formula:
comprising reacting a compound having the formula:
under conditions effective to promote the formation of compound 6.
19 . A process of making a compound having the formula:
comprising reacting a compound having the formula;
where R 2 is selected from the group consisting of Br, H 3 CO and HO,
under conditions effective to promote the formation of a compound having the formula;
where R 3 is selected from
where R 4 is C 1 -C 4 alky, aryl or phenyl, and n is 1 or 2, and reacting Compound 18R under conditions effective to promote the formation of compound rac-1.
20 . A process of making a compound having the formula:
comprising reacting a compound having the formula;
under conditions effective to promote the formation of a compound having the formula
and reacting compound 8 under conditions effective to promote the formation of Compound 2.
21 . A process of making a compound having the formula:
comprising reacting a compound having the formula;
under conditions effective to promote the formation of Compound 28.
22 . A process of making a compound having the formula:
comprising reacting a compound having the formula;
under conditions effective to promote the formation of compound rac-1.
23 . A process of making a compound having the formula:
comprising reacting a compound having the formula;
under conditions effective to promote the formation of Compound 29.
24 . A process of making a compound having the formula:
comprising reacting a compound having the formula;
under conditions effective to promote the formation of compound rac-1.
25 . A process of making a compound having the formula:
comprising reacting a compound having the formula
where each R 5 is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3 and COCF 3 , under conditions effective to promote the formation of Compound 2.
26 . A process of making a compound having the formula:
comprising reacting a compound having the formula
where R 3 is selected from the group consisting of
where R 4 is C 1 -C 4 alky, aryl or phenyl, and n is 1 or 2, under conditions effective to promote the formation of compound rac-1.
27 . A process of making a compound having the formula:
where R 6 is selected from the group consisting of C 1 -C 4 alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl,
comprising reacting a compound of formula
under conditions effective to promote the formation of compound 7R.
28 . A process of making a compound having the formula:
where R 6 is selected from the group consisting of C 1 -C 4 alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl,
comprising reacting a compound of formula
under conditions effective to promote the formation of compound 7R.
29 . A compound having the following formula:
where R 6 is selected from the group consisting of C 1 -C 4 alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl.
30 . A compound according to claim 5 , wherein R 6 is CH 3 .
31 . A process of making a compound having the formula:
where R 6 is selected from the group consisting of C 1 -C 4 alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl,
comprising reacting a compound of formula
under conditions effective to promote the formation of Compound 22R.
32 . A compound having the following formula:
where each R 5 is independently selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3 and COCF 3 .
33 . A compound of claim 32 having the following formula: