The present invention relates to a process for the preparation of 3-amino-4-(isobutylamino)quinoline compound. This compound serves as an intermediate for the preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine; an immune response modifier.
1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine is an immune response modifier, indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults.
US patent 4,689,338 (hereinafter refers as '338 patent) to John F. Gerster discloses 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine and process thereof. Its chemical structure is as provided below-
(Formula Removed)Several methods are known in the prior art for making 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine.
The '338 patent describes the preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine in many steps comprising the nitration of 4-hydroxyquinoline (I) to get 4-hydroxy-3-nitroquinoline (II) which on chlorination provides 4-chloro-3-nitroquinoline (III). The compound (III) is then treated with an amine to get compound of formula (IV) which on catalytic reduction using platinum catalyst such as platinum on charcoal provides compound of formula (V). The compound of formula (V) is then cyclized to get compound (VI), which is then converted to
the compound of formula (VII). The compound of formula (VII) is finally converted to 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine (IX) via formation of intermediate compound (VIII). [Scheme-1]
(Scheme Removed) [Scheme 1: Preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine]
Reported prior art describe various methods for the preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine (IX) wherein the introduction of amino function in the 4-position is described in three ways. Nucleophilic substitution of a leaving group e.g. Cl, triflate etc., with ammonia, dibenzylamine or an azido group is the first method. The second is by reacting above compound of formula (VII) with ammonium hydroxide or its salts in presence of tosyl chloride
at 0-5°C. The third reported method is by reacting compound of formula (VII) with benzoyl isocyanate.
WO Publications W02004009593, W09206093; US patents 5,395,937; 5, 756,747; 4,988,815; 5,602,256; 5,578,727; 4,698,348; 4,689,388; European patents EP 145340, EP 0385630, EP 310950 and JP 04193866 and examples therein, describe nucleophilic substitution reactions.
WO 9748704 discloses the preparation of some tetrazole derivatives. The chemistry for preparation is essentially similar to as shown in scheme-1. In this patent application, the nitro group of analogous compound to above formula (IV) is reduced with platinum on carbon or palladium on carbon to the corresponding amino group.
U.S. patent 5,756,747 discloses the preparation of quinoline derivatives comprising the conversion of compound of formula (IV) to compound of formula (V) with the help of platinum on charcoal.
The process of converting 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline (VI) to compound of formula (VII) has been disclosed in WO 2004/11462, WO 2004/009593 using peracetic acid in toluene as a solvent. This conversion is also reported in WO 9215581, WO 9206093 and US 5,175,296 using a combination of formic acid and peracetic acid. During the process, while converting above compound of formula (IV) to compound (V), the patents/applications make use of platinum or palladium on carbon.
In all the foregoing references, reduction of 4-isobutylamino-3-nitroquinoline (IV) to 3-amino-4-(isobutylamino)quinoline (V) is performed by the use of platinum or palladium on charcoal/carbon in the presence of toluene. The solubility of 3-amino-4-(isobutylamino)quinoline (V) in toluene is very poor and therefore it is difficult to isolate compound (V) in good yields. Because of the low solubility of compound (V) in toluene, the procedure needs heating or other techniques in
order to isolate the compound (V) in good yields thus making the overall process tedious and expensive. The catalysts used in prior art processes are also very costly.
In order to overcome the difficulties associated with the prior art processes, the inventors of the present invention develop a simple process to prepare 3-amino-4-(isobutylamino)quinoline (V) which reduces the overall manufacturing cost for the preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine (IX).
The present invention provides a process for the preparation of 3-amino-4-(isobutylamino)quinoline (V) which comprises reduction of 4-isobutylamino-3-nitroquinoline (IV) by the use of raney nickel in presence of methanol. The resultant product serves as an intermediate for the preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine of formula (IX); an immune response modifier.
The aspects provided below describe the nature of the invention in detail.
A first aspect of the present invention provides a process for the preparation of 3-amino-4-(isobutylamino)quinoline (V),
(Formula Removed)which comprises
a) reducing 4-isobutylamino-3-nitroquinoline (IV) with raney nickel in presence of organic solvent
(Formula Removed)


b) isolating the compound of formula (V) from the solution of step a) and
c) crystallizing the compound of formula (V) of step b) with organic
solvent.
A mixture of 4-isobutylamino-3-nitroquinoline (IV) and raney nickel in organic solvent is hydrogenated on a Parr apparatus at 3-4 kg hydrogen pressure for 2-3 hours. Crude 3-amino-4-(isobutylamino)quinoline of formula (V) is isolated from the mixture by filtering it through celite bed and concentrating the filtrate. This crude product is finally recrystallized from organic solvent to achieve highly pure compound of formula (V).
Organic solvent as hereinabove mentioned in the first aspect of the invention is any solvent which is capable of dissolving 3-amino-4-(isobutylamino)quinoline of formula (V). A skilled artisan can easily select the organic solvent on the basis of boiling point, polarity and solubility nature (or dielectric constant) of the solvent. By way to define first aspect of the invention, present inventors like to specify some of the organic solvents, mentioned below, but these are not intended to limit the scope of the invention. These includes alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 2-pentanol, denatured spirit and n-octanol; esters such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and tert-butyl acetate; chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and ethylene chloride; aromatic hydrocarbons such as xylene, toluene, benzene, substituted benzene, substituted toluene, substituted xylenes and substituted benzyl; aliphatic

hydrocarbons such as hexane, heptane and petroleum ether; cycloalkyl hydrocarbons such as cyclopentane, cyclohexane, cycloheptane, substituted cyclohexane and substituted cycloheptane; ether such as tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether and methyl tert-butyl ether; nitriles such as acetonitrile, propionitrile; polar aprotic solvents such as dimethylacetamide, dimethylformamide and dimethylsulphoxide or mixtures thereof. Preferably, the alcoholic solvents are used at the process step a) and etheral solvents are used for crystallization purpose.
The compound of formula (V) obtained by following this aspect of invention is highly pure in nature.
A second aspect of the invention provides a process for preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine of formula (IX) comprising

(Formula Removed)a) reducing 4-isobutylamino-3-nitroquinoline (IV) with raney nickel in presence of organic solvent

(Formula Removed)b) isolating the compound of formula (V) from the solution of step a)
c) (Formula Removed)crystallizing the compound of formula (V) of step b) with organic solvent
d) converting the compound of formula (V) of step c) to 1-(2-methylpropyl)-
1H-imidazo [4,5-c]quinoline-4-amine of formula (IX) by conventional
methods.
4-isobutylamino-3-nitroquinoline compound of formula (IV) can be prepared by following any conventional method (e.g. scheme-1). The present inventors essentially follow the method of US '338 to prepare the compound (IV).
The preparation, isolation and crystallization of compound of formula (V) are the same as described in first aspect of the invention.
The organic solvent used in this aspect is described in foregoing aspect of the invention.
The compound of formula (V) can be converted to compound of formula (IX) by following US '338 patent. The present inventors follow essentially the same procedure as described in the '338 patent for this conversion.
The compound of formula (IX) produced by following this aspect of the invention is highly pure.
A third aspect of the invention provides a process for the preparation of 3-amino-4-(isobutylamino)quinoline (V),
(Formula Removed)which comprises
a) reducing 4-isobutylamino-3-nitroquinoline (IV) with presence of methanol(Formula Removed)

raney nickel in

b) isolating the compound of formula (V) from the solution of step a) and
c) crystallizing the compound of formula (V) of step b) with isopropyl ether.
The preparation, isolation and crystallization of compound of formula (V) are the same as described in first aspect of the invention.
The compound of formula (V) obtained by this aspect of invention is highly pure.
A fourth aspect of the invention provides a process for preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine of formula (IX) comprising

(Formula Removed)a) reducing 4-isobutylamino-3-nitroquinoline (IV) with raney nickel in presence of methanol(Formula Removed)
(Formula Removed)crystallizing the compound of formula (V) of step b) with isopropyl ether
c) converting the compound of formula (V) of step c) to 1-(2-methylpropyl)-
1H-imidazo [4,5-c]quinoline-4-amine of formula (IX) by conventional
methods
4-isobutylamino-3-nitroquinoline compound of formula (IV) can be prepared by following any conventional method (e.g. scheme-1). The present inventors essentially follow the method of US '338 to prepare the compound (IV).
The preparation, isolation and crystallization of compound of formula (V) are the same as described in first aspect of the invention.
The compound of formula (V) can be converted to compound of formula (IX) by following US '338 patent. The present inventors follow essentially the same procedure as described in the '338 patent for this conversion.
The compound of formula (IX) produced by following this aspect of the invention is highly pure.
The present invention is further illustrated by the following example, which is not intended to limit the scope of this invention in any way.
EXAMPLE 1
Preparation of 3-amino-4-(isobutvlamino)quinoline
4-lsobutylamino-3-nitroquinoline (100 g, 0.407 moles) and Raney nickel (20 g wet) in methanol (1 Lt) were mixed together and then hydrogenated on a Parr apparatus at 3.5 Kg hydrogen pressure for 2.5 hrs. The mixture was filtered through celite bed and the solvent was removed from filtrate to provide 95 g of crude 3-amino-4-(isobutylamino)quinoline. It was recrystallized from isopropyl ether to obtain titled product (60 g).
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative example and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present aspects and example be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

WE CLAIM:
1. A process for the preparation of 3-amino-4-(isobutylamino)quinoline (V),
(Formula Removed)which comprises
a) reducing 4-isobutylamino-3-nitroquinoline (IV) with raney nickel in presence of organic solvent
(Formula Removed)isolating the compound of formula (V) from the solution of step a) and
b) crystallizing the compound of formula (V) of step b) with organic
solvent.
2. A process for the preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine of formula (IX)
(Formula Removed)which comprises
a) reducing 4-isobutylamino-3-nitroquinoline (IV) with raney nickel in presence of organic solvent(Formula Removed)


c) crystallizing the compound of formula (V) of step b) with organic
solvent
d) converting the compound of formula (V) of step c) to 1-(2-
methylpropyi)-1H-imidazo [4,5-c]quinoline-4-amine of formula (IX) by
conventional methods.

3. The process of claim 1 or 2 wherein organic solvent comprises any
solvent capable of dissolving 3-amino-4-(isobutylamino)quinoline
compound.
4. The process of claim 1 or 2 wherein in step a) organic solvent is selected
from alcoholic solvents.
5. The process of claim 1 or 2 wherein in step c) organic solvent is selected
from etheral solvents.
6. The process of claim 1 or 2 wherein isolation comprises filtering and
removing the solvent from filtrate.
7. A process for the preparation of 3-amino-4-(isobutylamino)quinoline (V),
(Formula Removed)which comprises
a) reducing 4-isobutylamino-3-nitroquinoline (IV) with raney nickel in presence of methanol(Formula Removed)
b) isolating the compound of formula (V) from the solution of step a) and
c) crystallizing the compound of formula (V) of step b) with isopropyl
ether
8. A process for preparation of 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine of formula (IX) comprising

(Formula Removed)a) reducing 4-isobutylamino-3-nitroquinoline (IV) with raney nickel in presence of methanol
(Formula Removed)(Formula Removed)crystallizing the compound of formula (V) of step b) with isopropyl ether
c) converting the compound of formula (V) of step c) to 1-(2-
methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine of formula (IX) by
conventional methods.
9. The process of claim 7 or 8 wherein isolation comprises filtering and removing the solvent from filtrate.
10. 3-amino-4-(isobutylamino)quinoline compound of high purity.
11. 1-(2-methylpropyl)-1H-imidazo [4,5-c]quinoline-4-amine compound
substantially free from impurities.