Process for preparing indane-like compounds

Details Process for preparing indane-like compounds Process for preparing indane-like compounds

1999-06-10

2001-04-03

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C546S205000, C548S578000, C564S207000, C564S252000, C564S271000, C564S428000

Reexamination Certificate

active

06211364

ABSTRACT:

The present invention relates an improved process and intermediates for preparing novel indane-like compounds.
The novel indane-like compounds prepared using the presently claimed process and intermediates have useful muscarinic receptor activity. Thus, the compounds prepared using the process and intermediates of this invention can be useful for the treatment of conditions associated with the modulation of a muscarinic receptor. For example, such conditions include, but are not limited to psychosis, Alzheimer's Disease, glaucoma, pain, bladder dysfunction, irritable bowel syndrome, and Parkinsonism.
The previous processes for preparing such indane-like compounds are tedious and do not provide an efficient mechanism for rapid synthesis. The presently claimed invention addresses this need for a more efficient process for preparing novel indane-like compounds.
The present invention provides a process for preparing a compound of the Formula I:
R
1
is selected from the group consisting of hydrogen, —OR
4
, —SR
5
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S (O)
m2
, —COR
4b′
, and —OC(O)—R
15
;
m2 is from 0 to 2;
R
2
is selected from the group consisting of C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, substituted C
2
-C
10
alkenyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
R
4
is hydrogen, C
1
-C
3
alkyl;
R
5
is hydrogen, C
1
-C
3
alkyl;
R
10
is selected from the group consisting of hydrogen, carbonyl, halo, and C
1
-C
3
alkyl;
R
11
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
12
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl;
R
13
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl; or
R
12
and R
13
together with the nitrogen to which they are attached form a group of the formula II:
or
II′ wherein the III group is a group of Formula II which is unsaturated; or
R
11
and R
12
together with the nitrogen and carbon to which they are bound can join to form a three to six membered ring;
R
14
is selected from the group consisting of H, halo, C
1
-C
3
alkyl, S(O)
m3
and —OR
16
;
R
15
is C
1
-C
3
alkyl or aryl;
R
16
is C
1
-C
3
alkyl;
R
17
is independently selected from the group consisting of hydrogen, —OR
4′
, —SR
5′
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2′
, —COR
4b
, and —OC(O)—R
15′
;
R
4b
and R
4b′
are each independently selected from hydrogen and C
1
-C
3
alkyl;
R
15′
is C
1
-C
3
alkyl or aryl;
m2′ is 0 to 2;
R
4′
is hydrogen, C
1
-C
3
alkyl;
R
5′
is hydrogen, C
1
-C
3
alkyl;
m2 is 0 to 2;
X is selected from the group consisting of C, O, S, N, carbonyl, and a bond;
n′ is 0 to 2;
m′ is 0 to 2;
m3 is 0 to 2;
n is 0 to 3; or
a pharmaceutically acceptable salt or solvate thereof; comprising coupling a compound of the formula
with a compound of the formula
R
21
and R
22
are selected from H and O;
R
20
is selected from amine protecting groups;
R
1′
is selected from the group consisting of —OR
4
, —SR
5
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2
, —COR
4b′
, and —OC(O)—R
15
;
m2 is 0 to 2;
R
4
and R
4b′
are each independently selected from hydrogen and C
1
-C
3
alkyl;
R
5
is selected from hydrogen and C
1
-C
3
alkyl; R
15
is C
1
-C
3
alkyl or aryl.
A further embodiment of this invention is the a process comprising catalytic hydrogenation of a compound of the formula
wherein both R
21
and R
22
are each O; to form a compound wherein both R
21
and R
22
are each H;
R
21
and R
22
are selected from H and O;
R
20
is selected from amine protecting groups;
R
1′
is selected from the group consisting of —OR
4
, —SR
5
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2
, —COR
4b′
, and —OC(O)—R
15
;
m2 is 0 to 2;
R
4
and R
4b′
are each independently selected from hydrogen and C
1
-C
3
alkyl;
R
5
is selected from hydrogen and C
1
-C
3
alkyl; R
15
is C
1
-C
3
alkyl or aryl.
Additionally, this invention provides a process for preparing a compound of the Formula I′
R
1
is selected from the group consisting of hydrogen, —OR
4
, —SR
5
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2
, —COR
4b′
, and —OC(O)—R
15
;
m2 is from 0 to 2;
R
2
is selected from the group consisting of C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, substituted C
2
-C
10
alkenyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
R
4
is hydrogen, C
1
-C
3
alkyl;
R
5
is hydrogen, C
1
-C
3
alkyl;
R
10
is selected from the group consisting of hydrogen, carbonyl, halo, and C
1
-C
3
alkyl;
R
11
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
12
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl;
R
13
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl; and
R
12
and R
13
together with the nitrogen to which they are attached form a group of the formula II:
R
14
is selected from the group consisting of H, halo, C
1
-C
3
alkyl, S(O)
m3
and —OR
16
;
R
15
is C
1
-C
3
alkyl or aryl;
R
16
is C
1
-C
3
alkyl;
R
17
is independently selected from the group consisting of hydrogen, —OR
4′
, —SR
5′
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2′
, COR
4b
, and —OC(O)—R
15′
;
R
4b
and R
4b′
are each independently selected from hydrogen and C
1
-C
3
alkyl;
R
15′
is C
1
-C
3
alkyl or aryl;
m2′ is 0 to 2;
R
4′
is hydrogen, C
1
-C
3
alkyl;
R
5′
is hydrogen, C
1
-C
3
alkyl;
m2 is 0 to 2;
X is selected from the group consisting of C, O, S, N, carbonyl, and a bond;
n′ is 0 to 2;
m′ is 0 to 2;
m3 is 0 to 2;
n is 0 to 3;
comprising contacting a neat amine with a catalytic acid to provide the desired compounds of Formula I′.
The present invention provides compounds of the Formula III′
.R
1
is selected from the group consisting of hydrogen, —OR
4
, —SR
5
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2
, —COR
4b′
, and —OC(O)—R
15
;
m2 is from 0 to 2;
R
4
is hydrogen, C
1
-C
3
alkyl;
R
5
is hydrogen, C
1
-C
3
alkyl;
R
10
is selected from the group consisting of hydrogen, carbonyl, halo, and C
1
-C
3
alkyl;
R
11
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
12
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl;
R
13
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl; or
R
12
and R
13
together with the nitrogen to which they are attached form a group of the formula II:
or
II′ wherein the II′ group is a group of Formula II which is unsaturated; or
R
11
and R
12
together with the nitrogen and carbon to which they are bound can join to form a three to six membered ring;
R
14
is selected from the group consisting of H, halo, C
1
-C
3
alkyl, S(O)
m3
and —OR
16
;
R
15
is C
1
-C
3
alkyl or aryl;
R
16
is C
1
-C
3
alkyl;
R
17
is independently selected from the group consisting of hydrogen, —OR
4′
, —SR
5′
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2′
, —COR
4b
, and —OC(O)—R
15′
;
R
4b
and R
4b′
are each independently selected from hydrogen and C
1
-C
3
alkyl;
R
15′
is C
1
-C
3
alkyl or aryl;
m2′ is 0 to 2;
R
4′
is hydrogen, C
1
-C
3
alkyl;
R
5′
is hydrogen, C
1
-C
3
alkyl;
m2 is 0 to 2;
X is selected from the group consisting of C, O, S, N, carbonyl, and a bond;
n′ is 0 to 2;
m′ is 0 to 2;
m3 is 0 to 2;
n is 0 to 3;
R
20
is selected from amine protecting groups; or
a pharmaceutically acceptable salt or solvate thereof.
Additionally, this invention provides a formulation comprising a compound of Formula III′

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