Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-05-31
2003-01-28
Fan, Jane (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06512125
ABSTRACT:
The synthesis of memory enhancing, analgetic, and antidepressant N-alkyl-N-pyridinyl-1H-indol-1-amines 1, involving arylation of a compound of formula 2:
by a halopyridine of formula 3:
to provide an N-pyridinyl-1H-indol-1-amine of formula 4:
followed by alkylation of 4 by a compound of formula 5:
R
2
Z 5
to yield an ultimate N-alkyl-N-pyridinyl-1H-indol-1-amine of formula 1:
wherein R is hydrogen, loweralkyl or loweralkoxy; R
1
is hydrogen or loweralkyl; R
2
is loweralkyl; R
3
is hydrogen, loweralkyl or loweralkoxy; and m is 1 has been described. See, for example, U.S. Pat. No. 4,880,822 granted Nov. 14, 1989.
Applicants have now found that by starting with a 3-haloindole of formula 6:
wherein R is as above and in addition is trifluoromethyl, R
1
is as above and m is as above and in addition is 2, prepared by halogenation of an indole of formula 7:
wherein R (including trifluoromethyl), R
1
and m (including 2) are as above with a halosuccinimide of formula 8:
wherein X is bromo, chloro or iodo, aminating a 3-haloindole 6 to a 1-amino-3-haloindole 9:
wherein R (including trifluoromethyl), R
1
, X and m (including 2) are as above, arylating a 1-aminoindole 9, so obtained, with a halopyridine 3 wherein Y is a halogen to a 3-halo-N-pyridinylaminoindole 10:
wherein R (including trifluoromethyl), R
1
, R
3
, X and m (including 2) are as above, alkylating an N-pyridinylaminoindole 10, so obtained, to an N-alkyl-3-halo-N-pyridinylaminoindole 11:
wherein R (including trifluoromethyl), R
1
, R
2
, R
3
, X and m (including 2) are as above, and finally dehalogenating an N-alkyl-3-halo-N-pyridinylaminoindole 11 so obtained, an ultimate N-alkyl-N-pyridinyl-1H-indol-1-amine 1 wherein R (including trifluoromethyl), R
1
, R
2
, R
3
and m (including 2) are as above is obtained in high overall yield, even though a halo group is introduced in the first step of the sequence and removed in the last step to form the final product. In addition, costly, time consuming, yield reducing chromatographic separations and purifications are avoided in the present process to prepare the desired pharmacological product.
Thus, the present invention relates to a process for the preparation of memory enhancing, analgetic and antidepressant N-alkyl-N-pyridinyl-1H-indole-1-amines. More particularly, the present invention relates to a process for the preparation of memory enhancing, analgetic and antidepressant N-alkyl-N-pyridinyl-1H-indol-1-amines of formula 1 involving the steps of halogenating a commercially available or readily preparable indole 7 to a 3-haloindole 6 aminating a 3-haloindole 6 to a 1-amino-3-haloindole 9, arylating a 1-amino-3-haloindole 9 to a 3-halo-N-pyridinyl-aminoindole 10, alkylating a 3-halo-N-pyridinylaminoindole 10 to an N-alkyl-3-halo-N-pyridinylaminoindole 11 and dehalogenating an N-alkyl-3-halo-N-pyridinylaminoindole 11 to an N-alkyl-N-pyridinylaminoindole 1, wherein R, R
1
, R
2
, X and M are as described immediately above.
The present process is most particularly useful for the preparation of N-alkyl-N-pyridinyl-1H-indole amines 1 wherein R is hydrogen; R
1
is hydrogen, R
2
is loweralkyl, R
3
is hydrogen and m is 1, and still most particularly wherein R
2
is n-propyl.
The halogenation of an indole 7 to a 3-haloindole 6 is accomplished by methods known in the art, for example, by the use of an N-halosuccinimide 8 such as N-chlorosuccinamide in an aprotic dipolar solvent, such as dimethylformamide at a reaction temperature of about 10° to 18° C.
The amination is achieved by contacting a 3-haloindole 7 with hydroxylamine-O-sulfonic acid in a dipolar aprotic solvent in the presence of a base or bases. Among dipolar aprotic solvents, there may be mentioned dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide and hexamethylphosphoramide, dimethylformamide being preferred. Among bases, there may be mentioned, alkali metal hydroxides and alkali metal carbonates, such as lithium, sodium and potassium hydroxides and lithium, sodium and potassium carbonates, respectively. Potassium hydroxide is the preferred base. A mixture of potassium hydroxide and potassium carbonate is the preferred mixture of bases. The amination reaction temperature is not narrowly critical; the reaction proceeds at a satisfactory rate at a reduced temperature of about −10° to about 20° C., an amination temperature of about 0° to about 10° being preferred.
The arylation is effected by contacting a 1-amino-3-haloindole 9 with a halopyridine 3, as the free base or hydrohalide salt, preferably a hydrochloride salt, in a dipolar aprotic solvent such as, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethyl phosphoramide, and N-methyl-2-pyrrolidinone, N-methyl-2-pyrrolidinone being preferred. The arylation proceeds at a reasonable rate at a reaction temperature within the range of about 60° to 120° C., an arylation temperature of about 80° C. being preferred.
A 3-halo-N-pyridinylindolamine 10, is isolated as a benzoate salt, preferably the salicylate salt, prepared by treating a 3-halo-N-pyridinylindolamine 10, with a benzoic acid, preferably salicylic acid, in an alkyl alkanoate, preferably ethyl acetate, at ambient temperature.
The alkylation is achieved by reacting a 3-halo-N-pyridinylindolamine 10, with an alkyl halide 5, preferably an alkyl bromide, in a dipolar aprotic solvent (e.g., dimethylacetamide, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or N-methyl-2-pyrrolidinone) in the presence of a base (e.g., an alkali metal alkoxide, such as a lithium, sodium or potassium alkoxide). Dimethylformamide is the preferred solvent. Potassium tert-butoxide is the preferred base.
The alkylation is preferably performed at reduced temperatures within the range of about −10° to about 0° C. Alkylation temperatures within the range of about −20° to about 20° may be employed to effect the conversion.
When a benzoate salt of a 3-halo-N-pyridinylindolamine 10 is used in the alkylation step, the salt, preferably the salicylate salt, is converted to the free base by treatment with an alkali metal hydroxide, such as sodium hydroxide, in an aromatic solvent, such as toluene, by ordinary methods.
An N-alkyl-3-halopyridinylindolamine 11 is isolated as a hydrohalide salt, preferably the hydrochloride salt, prepared by treating an N-alkyl-3-halopyridinylindolamine 11 with a hydrogen halide, preferably hydrogen chloride, in an ethereal solvent, preferably diethyl ether.
The final step of the sequence, the dehalogenation of an N-alkyl-3-halo-N-pyridinylindolamine 11 to a pharmacologically active N-alkyl-N-pyridinylindolamine 1 is accomplished by contacting an N-alkyl-3-halo-N-pyridinylindolamine 11 with formic acid in the presence of a metal catalyst in an alkanol. Among alkanols, included are methanol, ethanol, 1- and 2-propanols, 1,1-dimethylethanol and the like. 2-Propanol is preferred. Included among metal catalysts are palladium-on-carbon, Raney nickel, tetrakistriphenylphosphine palladium (0) and palladium acetate. Palladium-on-carbon is preferred.
The dehalogenation is carried out at elevated temperature, preferably the reflux temperature of the reaction medium, although it proceeds at a reasonable rate at lower temperatures.
The dehalogenation may also be carried out on a hydrohalide salt, preferably the hydrochloride, of an N-alkyl-3-halo-N-pyridinylindolamine 11. When a hydrohalide salt is used, a tertiary anine (e.g., triethylamine, pyridine, picoline, lutidine, s-collidine, and the like) is employed to convert the salt to the free base.
An N-alkyl-N-pyridinylindolainine 11 is characterized as a hydrohalide salt, preferably the hydrochloride salt, prepared by treating an indolamine 11 with a hydrohalic acid in an alkanol/ether, preferably methaniol/methyl tert-butyl ether, under ordinary conditions.
As used throughout the specification and appended claims, the term “alkyl” refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 8 carbon atoms such as methyl, ethyl, 1-
Goehring Keith E.
Lee Thomas B.
Aventis Pharmaceuticals Inc.
Fan Jane
Gupta Balaram
LandOfFree
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