MX2008007810A - Preparation of 1h-imidazo[4,5-c]quinolin-4-amines via 1h-imidazo[4,5-c]quinolin-4-phthalimide intermediates - Google Patents

Abstract

The present invention provides process for the preparation of 4-amino-1H-imidazo[4,5-c]quinolines comprising the step of reacting a 1H-imidazo[4,5-c]quinolin-4-phthalimide with an amine selected from the group consisting of:alkylamine, aralkylamine, alkyldiamine, and aralkyldiamine.

Description

PREPARATION OF IH-IMIDAZO [, 5-c] QUINOLIN-4-AMINAS THROUGH INTERMEDIATES OF IH-IMIDAZO [4, 5-c] QUINOLIN-4-FTALIMIDA Field of the Invention The present invention relates to a process for the synthesis of lH-imidazo [, 5-c] quinolin-4-amines. More particularly, the present invention relates to a process for the presparation of Imiquimod through 1H-imidazo [4, 5-c] quinolin-4-phthalimide.

Background of the Invention Imiquimod, 4-amino-1-isobutyl-1H-imidazo [4, 5-c] quinoline of following structure: it is a modifier of the immune response, useful for treating viral infections, such as genital warts. Imiquimod developed by 3M Pharmaceuticals is marketed as a cream, under the trade name ALDARA®.

One of the ways to prepare Imiquimod is disclosed in WO Patent Application No. 2004/009593, and is illustrated with the following structure: wherein a phthalimide group is introduced in the first stage, and then removed using hydrated hydrazine in a mixture of water and methanol solvents.

Carbohydrate Research, 1993, 243, 139-164 discloses the elmination of a phthalimide group from trisaccharides, which represent very different chemical structures of lH-imidazo [4, 5-c] quinolines disclosed herein. This method uses a large excess of an amine in place of the hydrazine. The method disclosed in this publication uses 400-600 equivalents of amine for the elimination of a phthalimide group.

Extract of the invention In one embodiment, the present invention provides a process for preparing a 4-amino-1H-imidazo [4, 5-c] quinoline of the formula I (ID comprising reacting lH-imidazo [4, 5-c] quinolin-4-phthalimide of formula II and an amine selected from the group consisting of: alkylamine, aralkylamine, alkyldiamine, and aralkyldiamine, wherein Ri and R2 are selected independently of the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon and phenyl-substituted aromatic hydrocarbon, wherein R is selected from the group consisting of: alkoxy, alkyl, and halogen; and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.

In the preceding embodiments: Preferably, the alkylamine is an alkylamine of Ci-6.

Preferably, the alkyldiamine is an alkyldiamine of Ci_e.

Preferably, the aralkyldiamine is an aralkyldiamine of Ce-s- Preferably, the alkyl is a straight or branched chain alkyl of Ci-i0; more preferably straight or branched chain alkyl of Ci-e; even more preferably Ci_ straight or branched chain alkyl.

Preferably, the alkoxy is C1-4 alkoxy.

Preferably, the halogen is F, Cl, Br or I; more preferably F.

Preferably, the aromatic hydrocarbon is a C6-12 aromatic hydrocarbon In another embodiment, the present invention provides a process for preparing a 4-amino-1H-imidazo [4, 5-c] quinoline of the formula I (I) from a lH-imidazo [4, 5-c] quinoline-N-oxide of the formula III (III) which comprises reacting lH-imidazo [4, 5-c] quinolin-N-oxide of the formula III, with phthalimide to obtain an IH-imidazo [4, 5-c] quinolin-4-phthalimide of the formula II, and reacting the lH-imidazo [, 5-c] quinolin-4-phthalimide of the formula II and a amine selected from the group consisting of: alkylamine, aralkylamine, alkyldiamine, and aralkyldiamine; wherein Ri and R2 are independently selected from the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon and phenyl substituted aromatic hydrocarbon; wherein R is selected from the group consisting of: alkoxy, alkyl, and halogen; and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.

Detailed description of the invention The present invention relates to a process for preparing 1H-imidazo [5-c] quinolin-4-amines of the formula I, in particular 4-amino-1-isobutyl-1H-imidazo [4, 5-c] quinoline , Imiquimod, using a non-carcinogenic, economic and efficient agent to eliminate the phthalimide group.

The process can be done according to the following scheme: ( wherein Ri and 6 R2 are independently selected from the group consisting of hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon, and phenyl substituted aromatic hydrocarbon, wherein R is selected from the group consisting of alkoxy, alkyl and halogen; and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.

Preferably for Rx and R2, the straight or branched chain alkyl is Ci_io straight or branched chain alkyl, more preferably Ci_8 straight or branched chain alkyl; even more preferably straight or branched chain alkyl of Ci_7; and more preferably straight or branched chain alkyl of Ci_4. Preferably, the straight or branched chain alkyl of Ci_ 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tere-butyl; more preferably, isobutyl. Preferably, the aromatic hydrocarbon is a C6-i2 aromatic hydrocarbon more preferably C6-s aromatic hydrocarbon; more preferably phenyl, tolyl, or xylyl; more preferably phenyl. Preferably, the phenyl-substituted aromatic hydrocarbon contains one or two substituents on the benzene ring. Preferably, the substituents for the R group are selected from the group consisting of: a C 1-4 alkyl group, a C 1-4 alkoxy group and halogen with the proviso that when the benzene ring of the compound of the formulas (I), (II) or (III) is substituted with the groups, the total number of carbon atoms on the substituents is no more than 6. Preferably, the Ci_4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, or tere-butyl, more preferably, methyl. Preferably, the Ci_4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, more preferably methoxy. Preferably, the halogen is F, Cl, Br, or I; more preferably, F. More preferably, Ri is isobutyl. More preferably, R2 is hydrogen. More preferably, R is hydrogen.

Preferably, when Ri is isobutyl, R 2 is hydrogen and n is 0, said compound of the formula I refers to 4-amino-1-isobutyl-1H-imidazo [5-c] quinoline (called Imiquimod) of the following formula: said formula II corresponds to 1-isobutyl-lH-imidazo [4, 5-c] quinolin-4-phthalimide of the following formula, and said compound of formula III corresponds to 1-isobutyl-imidazo [4, 5-c] quinolin-N-oxide of the following formula.

IH-imidazo [4, 5-c] quinoline-N-oxide of the formula III can be prepared, for example, according to the process disclosed in WO 2004/009593.

The compound of formula II can be obtained, for example, in accordance with the process disclosed in patent publication WO 2004/009593 or in Example I hereof. The process comprises reacting the lH-imidazo [4,5-c] quinolin-N-oxide of the formula III with a phthalimide, wherein Ri, R2, R and n are as described above.

The compound of the formula II can react with the amine according to the preceding scheme without being recovered before the reaction, that is, a reaction of a container. Preferably, the compound of the formula II is recovered before the reaction with the amine.

The lH-imidazo [, 5-c] quinolin-4-phthalimide of formula II (II) is then converted to the 4-amino-lH-imidazo [, 5-c] quinoline of the formula I (I) by a process comprising reacting 1H-imidazo [4, 5-c] quinolin-4-phthalimide of formula II and an amine selected from the group consisting of: alkylamine, aralkylamine, alkyldiamine, and aralkyldiamine; wherein R and R2 are independently selected from the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon and substituted aromatic hydrocarbon; wherein R is selected from the group consisting of: alkoxy, alkyl, and halogen; and n is a number integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.

Preferably, R, Ri, R2 and n are as described above.

The reaction between the compound of the formula II and the amine is carried out in a solvent selected from the group consisting of: water, alcohol; linear, branched and cyclic ether; aliphatic hydrocarbon, aromatic hydrocarbon, nitroalkene, alkyl cyanide, and mixtures thereof.

Preferably, the alcohol is Ci_4 alcohol, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or tert-butanol; more preferably methanol. Preferably, the linear, branched or cyclic ester is linear, branched or cyclic C2-8 ether. Preferably, the linear, reamified or cyclic C2-s ether is diethyl ether, diisopropyl ether, or tetrahydrofuran; more preferably, tetrahydrofuran. Preferably, the aliphatic hydrocarbon is C5-e aliphatic hydrocarbon; more preferably p-pentane, n-hexane, cyclohexane, n-heptane, or n-octane, more preferably n-hexane. Preferably, the nitroalkane is C 1-4 nitroalkane, more preferably nitromethane, nitroethane, nitropropane or nitrobutane; more preferably, nitromethane. Preferably, the cyanide of alkyl is C1-4 alkyl cyanide, more preferably acetonitrile, propionitrile, or butoronitrile, more preferably acetonitrile. Preferably, the aromatic hydrocarbon is a C6-8 aromatic hydrocarbon most preferably benzene, toluene or xylene, more preferably toluene. The most preferred solvent is water.

Preferably, the alkylamine is C 1-6 alkylamine. Preferably, Ci-6 alkylamine is primary amine; more preferably, methylamine, ethylamine, propylamine, butylamine, pentylamine, or hexylamine, more preferably methylamine. Preferably, aralkylamine is a C6-8 aralkylamine, more preferably, benzylamine or A -methylbenzylamine, more preferably benzylamine. Preferably, the alkyldiamine is C 1-6 alkyldiamine, more preferably, ethylenediamine (1,2-diaminoethane), diaminopropane, diaminobutane, diaminopetane or diaminohexane; more preferably ethylenediamine. The alkyldiamines are preferably end amines, that is to say they have the general formula: H2N (CH2) mNH2. Preferably, the aralkyldiamine is C6-8 aralkyldiamine, more preferably xylylenediamine or amino ethylaniline more preferably xylylenediamine. The most preferred amine is ethylene diamine. Preferably, the amine is present in an amount of 1 to 10 molar equivalents for each molar equivalent of the compound of formula II, more preferably from 1.5 to 5 molar equivalents and more preferably from 1.5 to 2 molar equivalents for each molar equivalent of the compound of formula II. In one embodiment, the molar ratio is from 1.5 to 2.5 molar equivalents.

Preferably, the amine is added to a suspension or solution of the compound of the formula II in the solvent, depending on the type of the solvent. Preferably, the aggregate is made dropwise. Preferably, the aggregate is carried out for a period of 1 minute to 60 minutes; more preferably for 5 to 30 minutes. Preferably, the aggregate is made at a temperature of 40 ° C to 90 ° C; more preferably from 60 ° C to 80 ° C.

Preferably, a mixture is obtained after the aggregate. Preferably, the mixture is heated to a temperature of 40 ° C to 100 ° C; more preferably from 90 ° C to 95 ° C. Preferably the heating is carried out for 2 to 12 hours, more preferably for 3 to 6 hours. The conversion of the compound of the Formula II in Formula I can be monitored by TLC, preferably using a mixture of dichloromethane and methanol in a ratio of 8 to 2 as an eluent.

The reaction of the compound of formula II and the amine may also comprise a recovery process. Recovery can be accomplished by any method known to those skilled in the art. Preferably, the recovery process may include cooling the heated mixture; adding an alcohol solvent such as methanol, ethanol or propanol; keep the mixture at a temperature of 50 ° C to 90 ° C; more preferably from 60 ° C to 65 ° C; cool the mixture; and filter the product. Preferably, the heated mixture is cooled to a temperature of 65 ° C to 20 ° C; more preferably from 60 ° C to 40 ° C. Preferably, the mixture is maintained for 5 to 60 minutes; more preferably for 10 to 30 minutes. Preferably, the cooling step before filtering the compound product of formula I is carried out at a temperature of 45 ° C to 5 ° C; more preferably from 20 ° C to 25 ° C.

The quality and yield of the crude compound of the formula I, in particular Imiquimod, are influenced by the process of eliminating the phthalimide group. The recovered Imiquimod can be obtained by the above process with a purity of 99.0% to 99.5% by HPLC and with yields of 75% to 85% by weight. Preferably, it may contain less than 0.1%, preferably less than 0.05% -0.15% and more preferably less than 0.08% at O, 12% area by HPLC of Imiquimod-OH of the following formula: More preferably, it may contain 0.1% area by HPLC to 0.01% area by HPLC of the above Imiquimod-OH.

To increase the level of purity, the compound of the formula I can be purified by reacting it with an acid to obtain the salt of the compound of the formula I and reacting it with a base, to obtain the compound of formula I, as described, for example, in Example 7.

The present invention is illustrated in more detail with reference to the following non-exhaustive examples.

EXAMPLES Example 1: Preparation of 1-isobutyl-lH-imidazo [4, 5-c] quinolin-4-f alimide To a stirred suspension of 1-isobutyl-1H-imidazo [4, 5-c] quinoline-N-oxide (700 g, 2900 mmol) in ethyl acetate (3500 ml), tributylamine (1750 ml, 2.5 ml) was added. equivalents) and phthalimide (490 g, 1.2 equivalent). The suspension was cooled to 0 ° C-5 ° C and then, within 1.5-2 hours, benzoyl chloride (480 ml, 1.4 equivalent) was added in portions (the temperature was maintained between 0 ° C). 5 ° C). The suspension was heated to a temperature of 20 ° C-25 ° C and stirred for another 2 hours (conversion was monitored by TLC using 10: 1 DCM-MeOH as an eluent). The reaction mixture was filtered and the cake was washed with ethyl acetate (4 × 500 ml) and then with methanol (2 × 500 ml). The wet solid was suspended in methanol (6 L) and stirred for 5 hours at a temperature of 40 ° C-45 ° C and then cooled to a temperature of 20 ° C-25 ° C. The suspension was filtered and the cake was washed with methanol (3x600 ml). The wet material was dried under vacuum at 50 ° C for 12 hours and 1-isobutyl-1H-imidazo [5-c] quinolin-4-phthalimide (910 g, 84.6%) was removed. HPLC: 98.63% of 1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-phthalimide and 0.19% area of Imiquimod-OH.

Example 2: Preparation of Imiquimod To a stirred suspension of 1-alkyl-lH-inidazo [4,5-c] quinoline-N-oxide (290 mol) in ethyl acetate (350 ml) is added tributylamine (175 ml, 2.5 equivalents) and phthalimide (49 g, 1.2 equivalent). The suspension is cooled to a temperature of 0 ° C-5 ° C and then within 1.5-2 hours benzoyl chloride (48 ml, 1.4 equivalent) is added in portions (the temperature is maintained between 0 ° C -5 ° C). The suspension is heated to a temperature of 20 ° C-25 ° C and stirred for another 22 hours (conversion is monitored by TLC using 10: 1 DCM-MeOH as an eluent). The reaction mixture is filtered and the cake is washed with ethyl acetate (4 × 100 ml) and then with methanol (2 × 100 ml). The wet solid is suspended in methanol (0.6 L) and stirred for 5 hours at 40 ° C-45 ° C and then cooled to a temperature of 20 ° C-25 ° C. The suspension is filtered and the cake washed with methanol (2x120 ml) and water (2x120 ml). The wet material is suspended in water (350 ml) and ethylenediamine (32 ml, 2 equivalents) is added dropwise at 70 ° C. The mixture is heated to a temperature of 90 ° C-95 ° C and stirred for 4 hours (conversion is monitored by TLC using 8: 2 DCM-MeOH as an eluent).

After cooling to 60 ° C, methanol (870 ml) is added and the reaction mixture is stirred at reflux temperature for 15 minutes. minutes After cooling to a temperature of 20 ° C-25 ° C the mixture is filtered and the cake is washed with aqueous methanol (MeOH: H20 = 3: 5: 1 v / v, 2x120 ml) and water (2x120 ml). The wet solid material is suspended in water (870 ml) and the stirred suspension is treated with 37% HC1 (22 ml, 1.1 equivalent), then heated to a temperature of 90 ° C-93 ° C. and this suspension is maintained for 30 minutes. The hot solution is treated with sodium dithionite (Na2S204, 0.6 g, 1%) and carbon (3 g, 5%). After 30 minutes the mixture is filtered and the cake washed with water (2x60 ml). The filtrate is cooled to a temperature of 70 ° C-75 ° C and the pH is adjusted to 11.4-11.6 by adding 30% aqueous NaOH (40 ml). The stirred mixture is cooled to a temperature of 20 ° C-25 ° C and 1 hour later the solid material is filtered. The cake is washed with water (3c90 ml) and the wet solid is suspended in a mixture of water (265 ml) and n-butanol (117 ml). The stirred suspension is treated with 37% HC1 (21 ml, 1.1 equivalent) and then heated to a temperature of 60 ° C-65 ° C until complete dissolution occurs. The solution is cooled to a temperature of 20 ° C-25 ° C and the precipitated hydrochloride salt is filtered and then washed with n-butanol (53 ml). The wetted hydrochloride salt is dissolved in water (580 ml) at a temperature of 85 ° C-90 ° C and the solution is filtered and the filtered solid is washed with hot water (27 ml). The filtrate is treated with sodium dithionite (Na2S204, 0.1 g, 0.2%), cooled to a temperature of 70 ° C-75 ° C and the pH is adjusted to 9.6 tt 9.8 adding 30% aqueous NaOH (20 ml). The stirred mixture is cooled to a temperature of 20 ° C-25 ° C and the solid material is filtered. The cake is washed with water (4x80 ml) and methanol (2x50 ml) and then dried under vacuum at 50 ° C for 7-8 hours and gives crystallized 1-alkyl-5,4-imidazo [4,5-c] quinoline (60% -65%).

Example 3: Preparation of crude Imiquimod To a stirred suspension of 1-isobutyl-1H-imidazo [4, 5-c] quinoline-4-phthalimide (740 g, 2 mol) in water (3000 ml), ethylenediamine (270 ml, 2 g) was added dropwise. equivalents) at 70 ° C. The mixture was heated to a temperature of 90 ° C-95 ° C and stirred for 4 hours (conversion was monitored by TLC using 8:22 DCM-MeOH as an eluent). After cooling to 60 ° C, methanol (7400 ml) was added and the reaction mixture was stirred at reflux temperature for 15 minutes. After cooling to a temperature of 20 ° C-25 ° C, the mixture was filtered and the cake was washed with aqueous methanol (MeOH: HO = 3.5: 1 v / v, 3x620 ml). The wet solid material was dried under vacuum at 50 ° C for 7-8 hours and crude Imiquimod was obtained (441 g, 91.8%). HPLC: 99.40% area and 0.09% area of Imiquimod-OH.

Example 4: Purification of crude Imiquimod The dried crude Imiquimod (440 g) was suspended in water (7400 ml) and the stirred suspension was treated with 37% HC1 (180 ml) and then heated to a temperature of 90 ° C-93 ° C and this temperature was maintained for 30 minutes. The hot solution was treated with sodium dithionite (Na2S204, 5 g, 1%) and carbon (24 g, 5%). After 30 minutes, the mixture was filtered and the cake was washed with water (2x500 ml). The filtrate was cooled to 70 ° C-75 ° C and the pH was adjusted to 11.4-11.6 by adding 30% aqueous NaOH. The stirred mixture was cooled to a temperature of 20 ° C-25 ° C and after 1 hour the solid material was filtered. The cake was washed with water (3x500 ml) and methanol (90 ml), then dried under vacuum at 50 ° C for 7-8 hours, and purified Imiquimod gave 421 g, 95.7%). HPLC: 99.77% area of Imiquimod and 0.07% area of Imiquimod-OH.

Example 5: Crystallization of purified Imiquimod The dried purified Imiquimod (400 g, 1.66 mol) was suspended in a mixture of water (2000 ml) and n-butanol (900 ml) and the stirred suspension was treated with 37% HC1 (150 ml, 1.1 equivalent). ) and then heated to a temperature of 60 ° C-65 ° C until complete dissolution occurred. The solution was cooled to a temperature of 20 ° C-25 ° C and the Imiquimod hydrochloride which precipitated was filtered and it was then washed with n-butanol (400 ml). The wet hydrochloride salt * was dissolved in water (4500 ml) at a temperature of 85 ° C-90 ° C, the solution was filtered and the filtered solid was washed with hot water (200 ml). The filtrate was treated with sodium dithionite (Na2S204, 0.9 g, 0.2%), cooled to a temperature of 70 ° C-75 ° C and the pH adjusted to 9.6-9.8 by adding 30 g. % aqueous NaOH (160 ml). The stirred mixture was cooled to a temperature of 20 ° C-25 ° C and the solid material was filtered. The cake was washed with water (3x200 ml) and methanol (2x200 ml) and then dried under vacuum at 50 ° C for 7-8 hours and gave the crystallized Imiquimod (351 g, 87.8%). HPLC: 99.97% area of Imiquimod and 0.03% area of Imiquimod-OH. * If necessary, the wet hydrochloride salt can be dried at 50 ° C.

Example 6: Preparation of lH-imidazo [4, 5-c] quinolin-N-oxide according to WO 2004/009593 The oxidation of 1-isobutyl-1H-imnidazo [4, 5-c] quinoline (which can be produced as in Example 3 of WO 2004/009593) is carried out in toluene at a temperature of 40 ° C-45 ° C using peracetic acid as an oxidant to produce 1-isobutyl-1H-imidazo [4, 5-c] quinoline N-oxide. The product is isolated by filtration after adding a solution of sodium sulfate and ammonium hydroxide.

Example 7: Purification of Imiquimod in accordance with WO 2004/009593 53.55 ml of water, 23.62 ml of butyl alcohol, 10.57 of crude Imiquimod and 4.77 g of 37% of HC1 are loaded in a 100 ml reactor. The mixture is heated to a temperature of 55 ° C-60 ° C and a solution is obtained. The solution is cooled to room temperature and a white crystal precipitates. The solid is filtered and washed twice with 5 ml of alcohol. 13.63 g of wet Imiquimod hydrochloride are obtained.

HPLC analysis shows that 99.89% of Imiquimod and 0.01% of phthalhydrazide are present. 120 ml of water 13.63 g of wet Imiquimod hydrochloride are charged to a 250 ml reactor and heated to a temperature of 85 ° C-90 ° C. The hot solution is filtered and the cake is washed with 5 ml of hot water. Then 0.024 g of Na2S204 is added. The colorless solution is cooled to a temperature of 70 ° C-75 ° C and 5.3 g of 30% NaOH are added to provide a pH of 9.7, at which point a solid precipitates. The suspension is cooled to 20 ° C and filtered. The cake is washed 3 times with 5 ml of water and twice with 5 ml of methanol. During the washings, chloride with silver nitrate is not detected. The solid is dried under vacuum at 50 ° C for 8 hours. 8.98 g of Imiquimod (whitish color) are obtained. The HPLC shows that the purity is 99.94% and that the yield is 63.3% based on the initial material isobutyl-1H-imidazo [4, 5-c] quinoline N-oxide).

Claims (24)

1. CLAIMS A process for preparing a 4-amino-1H-imidazo [4,5-Iquinoline of the formula I (I) which comprises reacting lH-imidazo [4, 5-c] quinolin-4-phthalimide of formula II (II) and an amine selected from the group consisting of: alkylamine, aralkylamine, alkyldiamine, and aralkyldiamine; wherein R x and R 2 are independently selected from the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon and phenyl substituted aromatic hydrocarbon; wherein R is selected from the group consisting of: ackoxi, alkyl, and halogen; and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.
2. 2. The process according to claim 1, wherein Ri and R are independently selected from the group consisting of: hydrogen, straight or branched chain aluqyl of Ci_i0, a C6-i2 aromatic hydrocarbon, an aromatic hydrocarbon substituted with alkyl phenyl of Ci_4, aromatic hydrocarbon substituted with phenyl of Ci_4 alkoxy group and aromatic hydrocarbon substituted with halogen phenyl.
3. 3. The process according to claim 1 or claim 2, wherein Rx and R2 are independently selected from the group consisting of: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, phenyl, tolyl, xylyl, aromatic hydrocarbon substituted with methyl phenyl, aromatic hydrocarbon substituted with ethyl phenyl, aromatic hydrocarbon substituted with n-propyl phenyl, aromatic hydrocarbon substituted with isopropyl phenyl, aromatic hydrocarbon substituted with n-butyl phenyl, aromatic hydrocarbon substituted with isobutyl phenyl, aromatic hydrocarbon substituted with tert-butyl phenyl, aromatic hydrocarbon substituted with methoxy phenyl, hydrocarbon aromatic substituted with ethoxy phenyl, aromatic hydrocarbon substituted with n-propoxy phenyl, aromatic hydrocarbon substituted with isopropoxy phenyl, aromatic hydrocarbon substituted with n-butoxy phenyl, aromatic hydrocarbon substituted with isobutoxy phenyl, aromatic hydrocarbon substituted with tert-butoxy phenyl, substituted aromatic hydrocarbon with F phenyl, aromatic hydrocarbon substituted with Cl phenyl, aromatic hydrocarbon substituted with Br phenyl, and aromatic hydrocarbon substituted with phenyl.
4. 4. The process according to any of the preceding claims, wherein R2 is hydrogen.
5. 5. The process according to any of the preceding claims, wherein Ri is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl; phenyl, tolyl, xylyl, and preferably isobutyl.
6. 6. The process according to any of the preceding claims, wherein R is H, Rx is isobutyl, R2 is hydrogen and n is 0.
7. 7. The process according to any of the preceding claims, wherein the reaction of the compound of the formula II and the amine is carried out in a solvent selected from the group consisting of: water, alcohol, linear, branched and cyclic ether, aliphatic hydrocarbon, aromatic hydrocarbon, nitroalkane, alkyl cyanide and mixtures thereof.
8. 8. The process according to claim 7, wherein the solvent is selected from the group consisting of: Ci_4 alcohol, linear, branched or cyclic C2-8 ether, C5-8 aliphatic hydrocarbon, nitroalkane, Ci_4 alkyl cyanide, Ces aromatic hydrocarbon, water and mixtures thereof.
9. 9. The process according to claim 8, wherein the solvent is a C6-s-10 aromatic hydrocarbon.
10. The process according to claim 9, wherein the solvent is benzene, toluene or xylene.
11. 11. The process according to claim 10, wherein the solvent is toluene.
12. 12. The process according to claim 8, wherein the solvent is selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, r-butanol, isobutanol, tert-butanol, diethyl ether, diisopropyl ether, tetrahydrofuran, n -pentano, n- hexane, cyclohexane, n-heptane, n-octane, nitromethane, nitroethane, nitropropane, nitrobutane, acetonitrile, propionitrile, butyronitrile, benzene, toluene or xylene, water and mixtures thereof.
13. 13. The process according to claim 8, wherein the solvent is water.
14. 14. The process according to any of the preceding claims, wherein the alkylamine is an Ci-6 alkylamine, the aralkylamine is an aralkylamine of eg, the alkyldiamine is an alkyldiamine of i- e, the aralkyldiamine is a C6-8 aralkyldiamine. ·
15. 15. The process according to claim 14, wherein the Ci_6 alkylamine is methylamine, ethylamine, propylamine, butylamine, pentylamine or hexylamine; aralkylamine is is benzylamine or 4-methylbenzylamine; the Ci-6 alkyldiamine is ethylene diamine (1,2-diaminoethane), diaminopropane, diaminobutane, diaminopentane, or diaminohexane; and the aralkyldiamine of C6_8 is xylylenediamine or aminoethylaniline.
16. 16. The process according to claim 15, wherein the amine is ethylenediamine.
17. 17. The process according to any of the preceding claims, wherein the amine is present in an amount of 1 to 10 mole equivalents for each mole equivalent of the compound of Formula II.
18. 18. The process according to claim 17, wherein the amine is present in an amount of 1.5 to 5 molar equivalents of the compound of the formula II.
19. 19. The process according to claim 18, wherein the amine is present in an amount of 1.5 to 2.5 molar equivalents for each molar equivalent of the compound of the formula II.
20. 20. The process according to any of the preceding claims, wherein the amine is added to a suspension or a solution of the compound of the formula II in the solvent, and provides a mixture.
21. 21. The process according to claim 20, wherein the mixture is heated to a temperature of 40 ° C to 100 ° C.
22. 22. The process according to any of the preceding claims, which also comprises the recovery of the compound of the formula I.
23. 23. The process according to any of the preceding claims, wherein the compound of the formula II is obtained by a process comprising reacting a 1H-imidazo [4,5-c] quinolin-N-oxide of the formula III (III) with phthalimide.
24. 24. The process according to claim 23, wherein the compound of the formula II obtained is not isolated before its conversion into the compound of the formula I.