4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline, also known as Imiquimod, is an immune response modifier, useful for treating genital warts. The drug is marketed as a 5% cream under the trade name Aldara® and has the following structural formula (I):

The synthesis of Imiquimod was described in several patents, for example in U.S. Pat. Nos. 4,689,338 and 4,929,624 (to Minnesota Mining and Manufacturing Co. Inc.). The final step of the processes described therein involves an ammonolysis reaction carried out by heating the compound 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline of formula (II) in the presence of ammonium hydroxide or ammonia in methanol under high pressure (e.g. in a steel bomb) at 150° C. to afford Imiquimod of formula (I), as depicted in Scheme 1.

U.S. Pat. No. 4,988,815 describes a different process for preparing Imiquimod, however the said final step also involves the same ammonolysis of the compound 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline.
Another process is disclosed in U.S. Pat. No. 5,175,296, wherein the compound 1H-imidazo[4,5-c]quinoline 5N-oxide is reacted with benzoyl isocyanate and the product is hydrolyzed to obtain Imiquimod.
U.S. Pat. No. 5,367,076 discloses another process of preparing Imiquimod, wherein the compound 1H-imidazo[4,5-c]quinoline 5N-oxide is reacted with an acylating agent and the product is aminated to obtain Imiquimod.
US Patent Application Publication No. 2005/0085500 discloses yet another process for preparing Imiquimod, wherein the compound 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline is converted to Imiquimod in three steps. In the first step the compound 4-(N-benzylamino)-1-isobutyl-1H-imidazo[4,5-c]quinoline is obtained by reacting 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline with benzylamine. In the second step the acid addition salt of 4-(N-benzylamino)-1-isobutyl-1H-imidazo[4,5-c]quinoline is prepared, and in the third step Imiquimod is obtained from the said acid addition salt by reaction with NaOH.
The disadvantage of the above process is that it is lengthy. The processes using ammonolysis like U.S. Pat. Nos. 4,689,338 and 4,929,624, are also disadvantageous because the reaction is conducted at high temperature and under pressure, which is undesirable with respect to industrial safety measures.
Using benzoyl isocyanate, as taught in U.S. Pat. No. 5,175,296, is also disadvantageous because the compound is toxic and may react with water or acid to produce very toxic hydrogen cyanide gas, hence its usage in industrial processes is limited.
Thus, there is still a need in the art for an improved one-step process of preparing highly pure Imiquimod starting from 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline. The process should be more suitable for industrial use in comparison to the present processes for preparing Imiquimod and should enable preparing highly pure Imiquimod in a shorter synthetic preparation and more industrially feasible conditions, for example by using lower reaction temperature and/or by converting the compound of formula (II) to Imiquimod without application of high pressure.
Ammonolysis in relatively milder conditions is documented in the literature. However, in the examples found, the reaction conditions are not optimal. Thus for example in “Organic Syntheses: Collective Volume 2”, Ed. by A. H. Blatt, 1943, 2,4-dinitroaniline is prepared by reacting 2,4-dinitrochlorobenzene with ammonia in the presence of ammonium acetate at 170° C. without application of pressure. An alternative example is reported by Kym in Ber. 1899, 32, 3539 for preparing 2,4-dinitroaniline by hydrolysis of the 2,4-dinitroacetanilide obtained when 2,4-dinitrochlorobenzene and acetamide are heated at 200-210° C. Another option is using the example reported by Bredereck et al. in Chem. Ber. 1954, 87, 537, wherein 2,4-dinitroaniline is obtained by heating under reflux (210° C.) a solution of 2,4-dinitrochlorobenzene in formamide. Ammonolysis of chloronitrobenzenes with ammonia in formamide was carried out at high temperature without application of pressure by Rondestvedt as reported in J. Org. Chem. 1977, 42 (19), 3118 and by Niclas et al. as reported in Zeits. fuer Chem. 1985, 24(4), 137.
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