Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-01-07
2001-07-31
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S402000, C562S491000, C568S327000
Reexamination Certificate
active
06268535
ABSTRACT:
BACKGROUND OF THE INVENTION
Biogenic amines derived from the amino acid tyrosine (dopamine, norepinephrine, and epinephrine) and tryptophan (serotonin) are neurotransmitters that have been shown to be involved in disorders such as psychosis, depression, and Parkinson's disease. Chemicals that modulate the activity of one or more of these neurotransmitters can be used to treat the symptoms of these disorders. Trans-3-aryl-1-indanamines have been shown to be potent inhibitors of dopamine, norepinephrine and epinephrine uptake, while cis-3-aryl-1-indanamines have been shown to selectively inhibit the uptake of serotonin (Bogeso, et al,
J. Med. Chem.,
(1985), 28:1817).
Current synthetic routes to 3-aryl-1-indanamines produce a mixture of the regioisomers which must be separated. These methods typically are costly and time consuming.
SUMMARY OF THE INVENTION
The present invention is a method of preparing a 3-aryl-1-indanamine sented by structural formula I:
and physiologically acceptable salts thereof.
In structural formula I, phenyl ring A can be unsubstituted or substituted with 1-4 substitutents.
R
1
is an aromatic group which can be substituted or unsubstituted.
R
2
and R
3
are each, independently, hydrogen, an aliphantic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, an aralkyl group, or a substituted aralkyl group. Alternatively, R
2
and R
3
, taken together with the nitrogen substitutent on the indan ring, form a non-aromatic ring system having 1-2 heteroatoms such as nitrogen, oxygen or sulfur.
The method of preparing a 3-aryl-1-indanamine represented by structural formula I comprises a first step of reacting, in the presence of a Friedel-Crafts catalyst and a proton source, a substituted or unsubstituted benzene, having at least two consecutive unsubstituted aromatic carbons, with a 3-aryl-1-prop-2-enoic acid to form a 3-aryl-3-phenyl-1-propanoic acid. 3-Aryl-1-prop-2-enoic acid and 3-aryl-3-phenyl-1-propanoic acid can be represented by structural formulas II and III, respectively:
The method further comprises a second step in which the 3-aryl-3-phenyl-1-propanoic acid (III) formed in step 1 is treated with a second Friedel-Crafts catalyst to form a 3-arylindan-1 -one represented by structural formula IV:
The method further comprises a third step in which the 3-arylindan-1-one (IV) formed in step 2 is reacted with a reducing agent to form a 3-arylindan-1-o1 represented by structural formula V:
The method further comprises a fourth step in which the 3-arylindan-1-o1(V) formed in step 3 is reacted with an activating agent in the presence of a base to form an activated 3-arylindan-1-o1.
The method further comprises a fifth step in which the activated 3-arylindan-1-o1 formed in step 4 is reacted with an amine compound represented by structural formula VI:
to form a 3-aryl-1-indanamine.
Another embodiment of the present invention is a method of forming a 3-phenyl-1-indanamine represented by structural formula VII:
and physiologically acceptable salts thereof
Rings A and B are each, independently, substituted or unsubstituted. Ring A can be unsubstituted or can have 1-4 substitutents, and ring B can be unsubstituted or can have 1-5 substitutents.
R
2
and R
3
are defined as above.
The method of preparing a 3-phenyl-1-indanamine represented by structural formula VII comprises a first step of reacting, in the presence of sulfuric acid, a substituted or unsubstituted benzene, having at least two consecutive unsubstituted aromatic carbons, with a 3-phenyl-1-prop-2-enoic acid to form a 3,3-diphenyl-1-propanoic acid. 3-Phenyl-l-prop-2-enoic acid and 3,3-diphenyl-1-propanoic acid can be represented by structural formulas VIII and IX, respectively:
The method further comprises a second step of treating the 3,3-diphenyl-1-propanoic acid (IX) formed in step 1 with chlorosulfonic acid to form a 3-phenylindan-1-one represented by structural formula X:
The method further comprises a third step of reacting the 3-phenylindan-1-one (X) formed in step 2 with sodium borohydride to form a 3-phenylindan-1-o1 represented by structural formula XI:
The method further comprises a fourth step in which the 3-phenylindan-1-o1 (XI) formed in step 3 is reacted with an aliphatic or aromatic sulfonyl chloride in the presence of a base to form a 3-phenylindan-1-sulfonate ester represented by structural formula XII:
wherein R
4
is a substituted or unsubstituted aliphatic or aromatic group.
The method further comprises a fifth step in which the 3-phenylindan-1-sulfonate ester (XII) formed in step 4 is reacted with an amine compound represented by structural formula VI to form the 3-phenyl-1-indanamine (VII).
Another embodiment of the present invention is a method of preparing a 3-phenyl indan-1 -one represented by structural formula X. The method comprises a first step of reacting, in the presence of a first Friedel-Crafts catalyst and a proton source, a compound represented by structural formula VIII with a substituted or unsubstituted benzene having at least two consecutive unsubstituted aromatic carbons to form a 3,3-diphenyl-1-propanoic acid (IX), and a second step in which the 3,3-diphenyl-1-propanoic acid (IX) is converted to a 3-phenylindan-1-one (X) by treatment with a second Friedel-Crafts catalyst.
Another embodiment of the present invention is a method of preparing a 3-phenyl indan-1-o1 represented by structural formula XI. The method comprises three reaction steps. In the first step, a compound represented by structural formula VIII is reacted, in the presence of a first Friedel-Crafts catalyst and a proton source, with a substituted or unsubstituted benzene having at least two consecutive unsubstituted aromatic carbons to form a 3,3-diphenyl-1-propanoic acid (IX). In the second step, the 3,3-diphenyl-1-propanoic acid (IX) is converted to a 3-phenylindan-1-one (X) by treatment with a second Friedel-Crafts catalyst. In the third step, the 3-phenyl indan-1-one (X) is reacted with a reducing agent to form a 3-phenylindan-1-o1 (XI).
Another embodiment of the present invention is a method of preparing a 3-phenylindan-1-one represented by structural formula X. The method comprises the step of treating a 3,3-diphenyl-1-propanoic acid (IX) with a Friedel-Crafts catalyst.
Another embodiment of the present invention is a method of preparing a 3-phenyl-1-indanamine represented by structural formula VII. The method comprises a first step in which a 3-phenylindan-1-o1 (XI) is reacted with an activating agent in the presence of a base to form an activated 3-phenyl-1-indanamine, and a second step in which the activated 3-phenyl-1-indanamine is reacted with an amine compound represented by structural formula VI to form the 3-phenyl 1-indanamine (VII).
3-Aryl-1 -indanamines are potent inhibitors of dopamine, norepinephrine, epinephrine and serotonin uptake, and therefore, expected to be useful in treating disorders such as psychosis, depression and Parkinson'disease. The method described herein allows 3-aryl-1-indanamines to be synthesized in high yields with fewer reaction steps than previously described methods. In addition, trans-3-aryl-1-indanamines can be selectively prepared by the method of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The features and other details of the method on the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.
A schematic representation of the method of preparing a 3-aryl-1-indanamine can be seen in Scheme I. The first step is a Friedel-Crafts alkylation in which a benzene adds to a double bond. Dialkylation is minimized by using excess benzene. A proton source is necessary for the reaction, therefore protonic Friedel-Crafts catalysts are pre
Haider Reem
Jurayj Jurjus
Moussa Adel M.
Suh HaeSuk
Taft Heather
Hamilton Brook Smith & Reynolds P.C.
Killos Paul J.
Pharm-Eco Laboratories, Inc.
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