Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-14
2004-02-17
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S080000
Reexamination Certificate
active
06693197
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel process of producing derivatives of 2,3-dihydro-1,4-dioxino [2,3-f]quinoline in a highly convergent and efficient manner, as well as intermediates thereof. Compounds of the present invention are SSRI/5-HT
1A
antagonists useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems such as depression, including childhood depression, obsessive compulsive disorders, panic disorder, generalized anxiety disorder, social anxiety disorders, sexual dysfunction, eating disorders such as bulimia, obesity, addictive disorders caused by ethanol or cocaine abuse and dysthymia as described in copending application Ser. No. 60/275,564 filed Mar. 14, 2001.
SUMMARY OF THE INVENTION
In accordance with the present invention is provided methods of making compounds of Formula I:
wherein
R
1
is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R
2
, R
3
, R
4
, and R
6
are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms
R
5
is hydrogen or alkyl of 1 to 6 carbon atoms;
A dotted line represents an optional double bond;
A and D are selected from carbon, substituted by R
1
, and nitrogen, provided that at least one of A and D is nitrogen;
E and G are carbon, substituted by R
1
; and
Z is N or CR
6
;
or pharmaceutically acceptable salts thereof, comprising the steps of:
a) halogenating a compound of the formula:
wherein R′ is alkyl of 1-6 carbon atoms;
with a halogenating reagent to afford a compound of the formula:
wherein X is Br, Cl, or I;
b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
c) alkylating the compound of Formula 4 with R″ protected glycidyl ethers
wherein R″ is benzyl or substituted benzyl to afford compound of the formula:
d) cyclizing the compound of Formula 5 with palladium or copper catalyst to afford a compound of the formula:
e) debenzylating the compound of Formula 6 to afford the compound of the formula:
f) activating the hydroxy moiety of the compound of Formula 7 with a sulfonating reagent to afford a compound of the formula:
wherein R′″ is an aryl-, or alkyl-sulfonate and
g) coupling the compound of Formula 8 with the appropriate azaheterocycle of Formula 9
in the presence of base to provide a compound of Formula I.
In alternative embodiments of the present invention the hydroxy moiety of compounds of Formula 7 may be activated to halide to afford a compound of the formula:
wherein X is I, Br, or Cl and
the compound of Formula 10 may be coupled with the appropriate azaheterocycle of Formula 9
in the presence of base to provide a compound of Formula I.
In other embodiments of the present invention are provided methods of making compounds of Formula I
comprising the steps of:
a) halogenating a compound of the formula:
wherein R′ is alkyl of 1-6 carbon atoms;
with a halogenating reagent in a solvent to afford a compound of the formula:
wherein X is Br, Cl, or I;
b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
c) alkylating the compound of Formula 4 with R″ protected glycidyl ethers
wherein R″ is benzyl or substituted benzyl to afford compound of the formula:
d) cyclizing the compound of Formula 5 with palladium or copper catalyst to afford a compound of the formula:
e) debenzylating the compound of Formula 6 to afford the compound of the formula:
f) activating the hydroxy moiety of the compound of Formula 7 with a sulfonating reagent to afford a compound of the formula:
wherein R′″ is an aryl- or alkyl-sulfonate; and
g) coupling the compound of Formula 8 with the appropriate azaheterocycle of Formula 9
in the presence of base to provide a compound of Formula I.
In alternative embodiments of the present invention the hydroxy moiety of compounds of Formula 7 may be activated to halide to afford a compound of the formula:
wherein X is I, Br, or Cl and
the compound of Formula 10 may be coupled with the appropriate azaheterocycle of Formula 9
in the presence of base to provide a compound of Formula I.
In some embodiments of the present invention is provided a method of making a compound of Formula Ia
comprising the steps:
a) halogenating a compound of the formula:
wherein R′ is alkyl of 1-6 carbon atoms;
with a halogenating reagent to afford a compound of the formula:
wherein X is Br, Cl, or I;
b) dealkylating the compound of Formula 3a in an acid to afford a compound of the formula:
c) alkylating the compound of Formula 4a with R″ protected glycidyl ethers
wherein R″ is benzyl or substituted benzyl; to afford a compound of the formula:
d) cyclizing the compound of Formula 5a with palladium or copper catalyst to afford a compound of the formula:
e) debenzylating the compound of Formula 6a to afford a compound of the formula:
f) activating the hydroxy moiety of the compound of Formula 7a with a sulfonating reagent to afford a compound of the formula:
wherein R′″ is an aryl- or alkyl-sulfonate; and
g) coupling the compound of Formula 8a with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula Ia.
Alternatively, the hydroxy moiety of compounds of Formula 7a may be activated to halide to afford a compound of Formula 10a
wherein X is I, Br, or Cl and
the compound of Formula 10a may be coupled with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula Ia.
In accordance with other aspects of the invention is provided a method of preparing compounds of Formula 5:
wherein A, D, E, G, X and R″ are as defined for Formula I and R″ is benzyl or substituted benzyl, comprising alkylating the compound of Formula 4
with R″ protected glycidyl ethers
wherein R″ is benzyl or substituted benzyl. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the present invention is provided a method of preparing compound of Formula 6
where A, D, E and G are as defined for Formula I, and R″ is benzyl or substituted benzyl, comprising the step of cyclizing a compound of Formula 5
with palladium or copper catalyst. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the invention is provided a method of preparing compound of Formula 8
wherein A, D, E and G are defined as for Formula I and R′″ is an aryl- or alkyl-sulfonate; comprising activating the hydroxy moiety of the compound of Formula 7
with a sulfonating reagent. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the invention is provided a method of preparing compound of Formula 10
wherein A, D, E and G are as defined for Formula I, and X is I, Cl or Br, comprising activating compound of Formula 7
to halide with halophosphorous such as phosphorous triiodide, phosphorous tribromide or phosphorous pentachloride, or with thionyl halide or any standard halogenating reagent.
Further in accordance with the present invention is provided a method of preparing compound of Formula 7
wherein A, D, E and G are as defined Formula I, comprising debenzylating a compound of Formula 6
where R″ is benzyl or substituted benzyl.
In some embodi
Chan Anita W.
Chew Warren
Curran Timothy T.
Ding Zhixian
Feigelson Gregg
Aulakh Charanjit S.
Woodcock & Washburn LLP
Wyeth
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