WO2008023333A2

WO2008023333A2 - Process for the preparation of 4-(isobutylamino)-3-amino-quinoline

Info

Publication number: WO2008023333A2
Application number: PCT/IB2007/053334
Authority: WO
Inventors: Suresh Babu Jayachandra; Jigar Bhaskarbhai Shah; Sailu Chiguru; Chandra Has Khanduri
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2006-08-22
Filing date: 2007-08-21
Publication date: 2008-02-28
Also published as: WO2008023333A3

Abstract

The invention relates to a process for the preparation of 4-isobutylamino-3- aminoquinoline. This compound is a useful pharmaceutical intermediate for the preparation of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-4-amine - a compound known generically as imiquimod, an immune response modifier.

Description

PROCESS FOR THE PREPARATION OF 4-(ISOBUTYLAMINO)-3-

AMINO-QUINOLINE

Field of the Invention

The invention relates to a process for the preparation of 4-isobutylamino-3- aminoquinoline. This compound is a useful pharmaceutical intermediate for the preparation of l-(2-methylpropyl)-lH-imidazo[4,5-c]quinoline-4-amine - a compound known generically as imiquimod, an immune response modifier.

Background of the Invention

Imiquimod is an immune response modifier, known to be useful for topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults.

US patent 4,689,338 (the '338 patent') discloses l-(2-methylpropyl)-lH- imidazo[4,5-c]quinolme-4-amine (imiquimod) and processes for its preparation. Imiquimod is chemically depicted as follows-

(l-a)

Several methods are known in the prior art for making imiquimod. The '338 patent describes the preparation of l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolme-4-amine (imiquimod) in many steps as shown in Scheme I 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) by the use of peracids. The compound of formula (VII) is finally converted to 1 -(2- methylpropyl)-lH-imidazo [4,5-c]quinoline-4-amine (imiquimod) of formula (I-a) via formation of intermediate compound (VIII).

Scheme 1: Preparation of l-(2-methylpropyl)-lH-imidazo [4,5-c]quinoline-4-amine

Reported prior art describe various methods for the preparation of imiquimod wherein the introduction of amino function at 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 0-5⁰C. The third reported method is by reacting compound of formula (VII) with benzoyl isocyanate.

Gerster et. al. (J. Med. Chem, 2005, 48, 3481-3491) describe the preparation of imiquimod and related compounds in which the reduction of aforementioned compound of formula (IV) to get compound of formula (V) is carried out with the help of platinum catalyst. U.S. patent 5,756,747 discloses the preparation of quinoline derivatives comprising reducing the compound of formula (IV) to the compound of formula (V) with the help of platinum on charcoal.

The methods of preparing quinoline compounds, particularly imiquimod, are described in many references, e.g., PCT applications WO2004/11462, WO2004/009593, WO92/15581, WO92/06093 and US patent 5,175,296. During the preparation methods, while converting the compound of formula (IV) to compound (V), the patents/applications make use of platinum or palladium on carbon. hi all the foregoing references, reduction of 4-isobutylamino-3-nitroquinoline (FV) to 4-isobutylamino-3-aminoquinoline (V) is performed by the use of platinum or palladium on charcoal/carbon in the presence of toluene. The solubility of 4-isobutylamino-3- aminoquinoline (V) in toluene is very poor and therefore it is difficult to isolate compound (V) in good yields. In order to isolate the said compound (V) in good yields, the procedure requires additional step(s) of heating or other expensive technique(s), thus making the overall preparation method tedious and complex. The catalysts used in prior art processes are also very costly.

Summary of the invention

In order to overcome the difficulties associated with the prior art processes, the inventors have come up with a simple and cost effective process to prepare A- isobutylamino-3-aminoquinoline (V), which further reduces the overall manufacturing cost for the preparation of imiquimod.

The present invention provides a process for the preparation of 4-isobutylamino-3- aminoquinoline (V) which comprises reduction of 4-isobutylamino-3-nitroquinoline (IV) by the use of raney nickel in presence of methanol. The resultant compound (V) can be used for the preparation of imiquimod.

Detailed Description of the Invention

The nature of the present invention is described in detail by way of the following aspects. A first aspect of the present invention provides a process for the preparation of 4- isobutylamino-3-aminoquinoline of formula (V),

which comprises reducing 4-isobutylamino-3-nitroquinoline of formula (IV)

with raney nickel.

In an embodiment of this aspect, the aforementioned reduction can be performed in the presence of an organic solvent. In further embodiment of this aspect, the compound of formula (V) can be isolated and crystallized with an organic solvent,

A mixture of 4-isobutylamino-3-nitroquinoline (IV) and raney nickel in an organic solvent is hydrogenated on a Parr apparatus at 3-4 kg hydrogen pressure for 2-3 hours. Crude 4-isobutylamino-3-aminoquinoline 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 an organic solvent to achieve highly pure compound of formula (V).

The term Organic solvent' as used hereinabove is any solvent which is capable of dissolving 4-isobutylamino-3-aminoquinoline of formula (V). These include 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 and substituted xylenes; aliphatic hydrocarbons such as hexane, heptane and petroleum ether; cycloalkyl hydrocarbons such as cyclopentane, cyclohexane, cycloheptane, substituted cyclohexane and substituted cycloheptane; ethers 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; and mixtures thereof. Preferably, the alcoholic solvents can be used at the reduction stage and ether solvents can be used for the crystallization purpose.

In further embodiment of this aspect, the aforementioned reduction can be performed in the presence of methanol. In further embodiment of this aspect, the crystallization of formula (V) can be performed from isopropyl ether.

Thus, a mixture of 4-isobutylamino-3-nitroquinoline (IV) and raney nickel in methanol is hydrogenated on a Parr apparatus at 3-4 kg hydrogen pressure for 2-3 hours. Crude 4-isobutylaraino-3-aminoquinoline 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 isopropyl ether to achieve highly pure compound of formula (V). hi a further aspect of the invention, the compound of formula (V) can be converted to imiquimod by following conventional methods e.g. the method described in US '338 patent. 4-isobutylamino-3-nitroquinoline compound of formula (FV) can be prepared by following any conventional method, for example, scheme-1, the method of US '338.

High yield of imiquimod can be achieved by following the process of this the invention.

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 4-isobutylamino-3-aminoquinoline

4-isobutylamino-3-nitroquinoline (100 g, 0.407 moles) and raney nickel (20 g wet) in methanol (1 Lt) were mixed together and then hydrogenation carried out 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 4-isobutylamino-3- aminoquinoline. It was recrystallized from isopropyl ether to obtain title compound (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.

Claims

We Claim: 1. A process for the preparation of 4-isobutylamino-3-aminoquinoline of formula (V),

which comprises reducing 4-isobutylamino-3-nitroquinoline of formula (IV)

with raney nickel.

2. The process of claim 1, wherein reduction takes place in presence of an organic solvent.

3. The process of claim 1 , wherein the compound of formula (V) is isolated from the organic solvent.

4. The process of claim 2, wherein organic solvent is an alcohol.

5. The process of claim 4, wherein the alcohol is methanol.

6. The process of claim 2, wherein the compound of formula (V) is further crystallized from an organic solvent,

7. The process of claim 6, wherein the organic solvent is an ether.

8. The process of claim 7, wherein the ether is isopropyl ether.

9. Use of the process of claim 1 for the preparation of imiquimod.

10. A process for the preparation of imiquimod which comprises the step of obtaining 4- isobutylamino-3-aminoquinoline of formula (V)

by reducing 4-isobutylamino-3-nitroquinoline of formula (IV)

with raney nickel and further converting the compound of formula (V) to imiquimod by conventional methods.