Patent Grant
8106202
The present invention concerns a method for manufacturing 1-substituted 1H-imidazo[4,5-c]quinolin-4-amine compounds, particularly 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, through their corresponding formamides. The invention also concerns new formamide intermediates.
Imiquimod, 1-isobutyl-1H-imidazo[4,5]quinolin-4-amine, is an immune response modifier, useful for treating viral infections, such as genital warts.
Imiquimod was firstly disclosed in EP 145340 and has the following structural formula:
Some different methods have been disclosed for the preparation of imiquimod and other 1-substituted-1H-imidazo[4,5-c]quinolin-4-amines. Certain methods, such as those disclosed in U.S. Pat. No. 4,988,815, U.S. Pat. No. 5,578,727, U.S. Pat. No. 5,602,256, U.S. Pat. No. 4,698,348, U.S. Pat. No. 4,689,338 and U.S. Pat. No. 4,929,624, use the corresponding 4-chloro precursors and their conversion to 4-amino final products implies very energetic conditions comprising heating under pressure in the presence of ammonium hydroxide or ammonia in hermetically sealed reactors for long periods of time. Such required pressures are extremely high, thus forcing to use special manufacturing facilities. Moreover, said processes afford 4-amino final products with moderate yields.
The present invention provides a method for manufacturing a compound of formula (I):
wherein
R1 is selected from the group consisting of straight-chain or branched-chain alkyl containing one to ten carbon atoms and substituted straight-chain or branched-chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight-chain or branched-chain alkyl containing one to four carbon atoms; straight-chain or branched-chain alkenyl containing two to ten carbon atoms and substituted straight-chain or branched-chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight-chain or branched-chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, with the proviso that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms;
R2 is selected from the group consisting of hydrogen; straight-chain or branched-chain alkyl containing one to eight carbon atoms; benzyl; (phenyl)ethyl; and phenyl; the benzyl, (phenyl)ethyl, or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, and
wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and Z is selected from the group consisting of alkoxy containing one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, and thioalkyl of one to four carbon atoms;
R is selected from the group consisting of lower alkoxy, halogen, and lower alkyl;
and n is zero or one,
or a pharmaceutically acid addition salt thereof.
The present invention shows important advantages over the prior art because high-pressure conditions are not required to conduct the transformation at gentle reaction temperature conditions, thus enabling to perform the process in conventional facilities. Contrary to prior art, reaction times are short and compounds (I) can be isolated almost quantitatively.
The present invention comprises:
(i) Reacting a 4-halo-1H-imidazo[4,5]quinoline (II):
wherein R, R1, R2 and n are as defined above, and X is a halogen selected from the group consisting of chlorine and bromine, with formamide, thus providing the compound of formula (III):
wherein R, R1, R2 and n are as defined above, and
(ii) Converting (III) to final compound (I) by thermal treatment or by acid or basic hydrolysis.
The intermediates of general formula (II) wherein X is chlorine can be obtained by known methods, such as those disclosed in U.S. Pat. No. 4,988,815, U.S. Pat. No. 5,578,727, U.S. Pat. No. 5,602,256, U.S. Pat. No. 4,698,348, U.S. Pat. No. 4,689,338 and U.S. Pat. No. 4,929,624. When X is bromine, intermediates of general formula (II) can be prepared, for instance, from the corresponding N-oxides by reaction with phosphorus oxybromide.
According to the present invention, 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines of general formula (I) can be prepared as shown in Scheme 1:
In another embodiment, the 1-substituted 1H-imidazo[4,5-c]quinoline-4-formamide (III) intermediates are prepared by reacting 4-halo-1H-imidazo[4,5-c]quinolines (II) with formamide in solvolytic conditions or with formamide in another solvent medium, in the presence of a base, in a wide range of temperatures, preferably from about 25 to about 150° C., and more preferably from about 70 to about 110° C.
In another embodiment, said solvent medium can be selected from the group of aprotic polar solvents such as dimethylsulfoxide, dimethylacetamide, N-methylpiperidone, N-methylpyrrolidone, dimethylformamide and 1,3-dimethyl-2-imidazolidinone, or mixtures thereof, preferably dimethylsulfoxide.
In another embodiment, when aprotic polar solvents are used, addition of a phase-transfer catalyst is optional. The phase-transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate. Tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate are preferred.
In another embodiment, the bases are selected from the group consisting of alkaline or alkaline earth metal hydroxydes, alkaline or alkaline earth metal carbonates, alkaline or alkaline earth metal bicarbonates, alkaline or alkaline earth metal alkoxides or alkaline or alkaline earth metal hydrides. Alkoxides and more specifically potassium tert-butoxide are preferred.
Intermediate formamides (III) can be isolated from the reaction medium or alternatively it is possible to force their complete conversion to corresponding final compounds (I). When compounds (III) are isolated, then they can be hydrolyzed by known methods of Organic Chemistry. The inventors have preferred not to isolate said intermediates in order to simplify the process.
In another embodiment, intermediate formamides (III) are not isolated.
In another embodiment, the present invention comprises the compounds of formula (III).
In a more preferred embodiment, the present invention comprises the compound of formula (III) which is 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-formamide.
Advantageously, the method of the present invention does not require special manufacturing facilities because high pressure is not required and operation temperatures are gentle. Moreover, when the intermediate formamides are not isolated, the final corresponding products are afforded in a unique step with an almost quantitative yield.
The various aspects of the present invention are described more in details in the non-limitative examples presented hereinafter.
Potassium tert-butoxide (4.32 g, 0.038 mole), 4.5 mL of dimethylacetamide and 1.53 mL (0.038 mole) of formamide were added in a 50-mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-chloro-1H-imidazo[4,5-c]quinoline (1 g, 3.8 mmoles), the mixture was heated at 120° C., followed by stirring for 1 hour and then cooled to room temperature. The reaction mixture was filtered followed by washing with abundant water and dried to give 0.4 g of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine. Yield 39%.
The mother waters were concentrated under vacuum and precipitated with methylene dichloride to give 0.5 g of 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-formamide. Yield 54%.
Mp 225-226° C.
IR: 3469, 3177, 3127, 2954, 1687, 1582 cm−1.
1HNMR (CDCl3): 9.98 (d, J=10.4 Hz, 1H, CHO), 9.66 (d, J=10.8 Hz, 1H, NH), 8.13 (s, 1H, NCH═N), 8.04 (m, 2H, aromatic), 7.64 (m, 1H, aromatic), 7.52 (m, 1H, aromatic), 4.36 (d, J=7.2 Hz, 2H, CH2), 2.37 (m, 1H, (CH3)2CH), 1.05 (d, J=6.8 Hz, 6H, 2CH3).
13CRMN (CDCl3): 162.8 (CO), 144.27 (NCHN), 143.86 (NCNH), 133.98 (C ar), 129.25 (CH ar), 128.22 (CH ar), 127.83 (CH ar), 124.87 (CH ar), 120.03 (CH ar), 116.82 (Car), 109.97 (CH ar), 55.19 (CH2), 28.81 ((CH3)2CH), 19.78 (CH3).
Potassium tert-butoxide (2.16 g, 0.019 mole), 4.5 mL of dimethylsulfoxide and 0.76 mL (0.019 mole) of formamide were added in a 50-mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-chloro-1H-imidazo[4,5-c]quinoline (1 g, 3.8 mmoles), the mixture was heated at 105° C., followed by stirring for 2 hours and then cooled to room temperature.
Then 10 mL of water and 6N HCl were sequentially added until pH 8. The reaction mixture was filtered followed by washing with abundant water and dried to give 0.91 g of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine. Yield 98%.
Potassium tert-butoxide (3.69 g, 0.033 mole), 5 mL of dimethylacetamide and 1.31 mL (0.033 mole) of formamide were added in a 50 mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-bromo-1H-imidazo[4,5-c]quinoline (1 g, 3.3 mmoles), the mixture was heated at 140° C., followed by stirring for 2 hours and then cooled to room temperature. Then 10 mL of water were added and the reaction mixture was filtered followed by washing with abundant water and dried to give 0.75 g of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine. Yield 75.4%.
| Number | Date | Country | Kind |
|---|---|---|---|
| 05102229 | Mar 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/060887 | 3/20/2006 | WO | 00 | 1/14/2008 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2006/100226 | 9/28/2006 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 4689338 | Gerster | Aug 1987 | A |
| 5741908 | Gerster et al. | Apr 1998 | A |
| 7323568 | Naddaka et al. | Jan 2008 | B2 |
| Number | Date | Country | |
|---|---|---|---|
| 20090005566 A1 | Jan 2009 | US |
