KR20070102652A - A process for preparation of 4-amino-1-isobutyl-1h-imidazo[4,5-c]-quinoline (imiquimod) - Google Patents

Abstract

A process for preparation of imiquimod comprising oxidation of 1-Isobutyl-1H-imidazo quinoline quinoline (II) afforded 1-Isobutyl-lH-imidazo-[4,5-c]-quinoline-5-N-oxide (III) which is isolated in pure form as its hydrochloride salt (IV) followed by conversion to 4-chloro derivative(V) and conversion to corresponding 4-iodo derivative (VI) which is a new intermediate. This new intermediate is convened to imiquimod (VIII) and purified via its novel maleate salt.

Description

A process for preparation of 4-Amino-1-isobutyl-1 H-imidazo [4, 4-amino-1-isobutyl-1Η-imidazo [4,5-c] -quinoline (imquimod) 5-c] -quinoline (Imiquimod)}

The present invention relates to a process for the synthesis of 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinoline. The present invention also relates to a novel purification process via a novel maleate salt.

Imiquimod, or 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline, is an immune response modifier and is a virus such as genital warts. It is useful for treating infections. Imiquimod is disclosed in US Pat. Nos. 4,689,338 and 5,238,944 and has the following structure.

Several methods for making imiquimod are known in the art.

1-isobutyl-1H-imadazo- [4,5-c] -quinoline (II) to 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide (III ) Is disclosed in WO2004 / 0011462A1, WO2004 / 009593A1, using peracetic acid in toluene as solvent. This transformation is also disclosed in WO92 / 15581, WO92 / 06093 and US Pat. No. 5,175,296, using a combination of formic acid and peracetic acid. However, since the yield is inferior and the reaction is incomplete, it is necessary to develop an oxidation method under milder conditions.

Known prior art discloses various methods of preparing 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinoline, i.e., imiquimod, and provides amino functionality at the 4-position. Three ways of introducing are disclosed. The first method is nucleophilic substitution of a leaving group such as Cl or triflate with ammonia, dibenzylamine or azido groups. The second is 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide (III) with ammonium hydroxide or its salt at 0-5 ° C. in the presence of tosyl chloride. To react. A third known method is the reaction of 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide with benzoyl isocyanate.

Patents WO2004 / 009593, WO92 / 06093 and US Pat. No. 5,395,937; 5,756,747; 5,756,747; 4,988,815; 4,988,815; 5,602,256; 5,602,256; 5,578,727; 5,578,727; No. 4,698,348; European Patents EP145340, EP0385630, EP310950 and JP04193866 and examples thereof, as well as 4,689,388, disclose nucleophilic substitution reactions.

WO97 / 48704 introduces amino groups by reacting 4-chloro derivatives with sodium azide to obtain tetrazole moieties. Treatment of the tetrazole moiety with triphenyl phosphine gives a 4-amino derivative.

In US Pat. No. 5,395,937, 4-triplate derivatives react with dibenzylamine to form 4-dibenzylamino derivatives. Catalytic reduction then yields the amino function at the desired 4-position.

U.S. Pat.No. 5,756,747 discloses isomerization of 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide (III) with 4-hydroxy derivatives and subsequently with POCl ₃ Nucleophilic substitution with ammonia on the corresponding 4-chloro derivatives prepared by the reaction is disclosed. Several patents disclose nucleophilic substitution of 4-chloro-1-isobutyl-1H-imidazo- [4,5-c] -quinoline (V) with ammonia at high temperatures and pressures. These are US 4,988,815; US5,602,256; US5,578,727; US4,698,348; US4,689,388; EP145340; EP0385630; EP310950 and JP04193866.

Patents WO2004 / 009593, US2004138459 introduce amino groups at the 4-position via 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-4-phthalimide intermediates (ie phthalimido protecting groups) The method for producing 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline (ie, imiquimod) is disclosed.

WO92 / 06093 is prepared by reacting 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide (III) with ammonium hydroxide or ammonium salt at 0-5 ° C. in the presence of tosyl chloride. A method of making imiquimod is disclosed.

WO92 / 15581 discloses 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide (III) with benzoyl isocyanate, followed by hydrolysis to remove imiquimod. To generate.

Purification of imiquimod is disclosed in WO2004 / 009593, US Pat. No. 4,689,338, through the formation of pharmaceutical salts, ie using HCl, H ₂ SO ₄ , H ₃ PO ₄ , HNO ₃ and methane sulfonic acid. There is still a need to produce 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline, i.e., imiquimod, in high yield and high purity.

Purpose of the Invention

It is an object of the present invention to develop a simple method of making imiquimod.

Another object of the present invention is to provide a purification method that is simple and performed on a large scale.

Another object of the present invention is to produce high purity imiquimod.

Summary of the Invention

The present invention provides a process for preparing 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline comprising the following steps:

1) 1-isobutyl-1H-imidazo- [4,5-c] -quinoline (II) is reacted with peracid, preferably meta-chloro perbenzoic acid, in an organic solvent to give a purer 1-isobutyl-1H Substantially yielding imidazo- [4,5-c] -quinoline-5-N-oxide (III). It is further purified with its hydrochloric salt (IV).

2) converting 5-N-oxide hydrochloride (IV) to 4-chloro derivative (V) by treatment with phosphorus oxychloride.

3) In another aspect of the invention, a 4-chloro-1H-imidazo- [4,5-c] -quinoline (V) compound is reacted with an alkali halide, preferably sodium iodide, to correspond to the corresponding 4-iodo derivative The present invention relates to a method for producing 4-amino-1H-imidazo- [4,5-c] quinoline (IV), which is produced and treated with ammonia to convert to (iii).

4) separating the product VII into a pharmaceutically acceptable maleate salt.

5) finally converting the imiquimod malate salt into imiquimod having a purity of at least 99.5% by HPLC in methanolic ammonia.

These and other aspects of the invention will be described in more detail with reference to the following detailed description of the invention.

Detailed description of the invention

The present invention relates to a process for producing imiquimod, i.e., 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline. However, the process of the present invention is described in US Pat. No. 5,756,747, which is incorporated by reference in its entirety; 5,395,937; 5,395,937; 4,689,338; 4,689,338; EP385630, WO97 / 48704; It can also be used for the preparation of any compound within the scope of its derivatives, including those disclosed in WO92 / 06093 and WO92 / 15581.

Cyclization of 3-amino-4- (isobutylamino) -quinoline (I) by treating it with formic acid to obtain 1-isobutyl-1H-imidazo- [4,5-c] -quinoline (II) Is achieved. Satisfactory yields by any method known in the art, including those disclosed in patents WO92 / 06093 and US Pat. No. 5,175,296, which are incorporated by reference in their entirety.

4-iodo-1-isobutyl-1H-imidazo- [4,5-c] -quinoline, ie (VI), is 4-chloro-1-isobutyl-1H-imidazo- [4,5-c ] -Quinoline (V) is prepared by reacting with an alkali halide such as sodium iodide.

1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide of formula (III) is described in US Pat. No. 5,756,747, which is incorporated by reference in its entirety; It can be obtained by any method known in the art, including those disclosed in WO92 / 06093 and WO92 / 15581. In the present invention, it is achieved using meta-chloroperbenzoic acid. Preferred solvents are aliphatic alkyl esters and their carbon chains may preferably be C ₁ -C ₄ . Preferably ethyl acetate is used as the solvent. The reaction is preferably carried out at a temperature in the range from 20 to 80 ° C., more preferably in the range from 40 to 80 ° C. and most preferably at about 70 ° C. The meta-chloroperbenzoic acid is preferably added over a period of about 1 to 3 hours, more preferably about 1 to 2 hours, most preferably 1 hour and 30 minutes. The reaction is complete when 1-isobutyl-1H-imidazo- [4,5-c] -quinoline (II) is not detected by TLC. When the reaction was completed, excess m-chloro benzoic acid was filtered off, and the organic layer containing the 1H-imidazo- [4,5-c] quinoline-5-N-oxide (III) compound was washed with ethyl acetate. And further concentrated. The reaction is very pure and shows a higher yield compared to the known references disclosed in patents WO2004 / 011462A1, WO2004 / 009593A1, WO92 / 15581, WO92 / 06093, US Pat. No. 5,175,296.

The 1-isobutyl-1H-imidazo- [4,5-c] -quinoline-5-N-oxide (III) is purified by preparing its hydrochloride salt (IV) in 8% alcoholic hydrochloride solution. Preferred alcohols are C ₁ -C ₄ aliphatic alcohols. Most preferably ethanol is used.

The formation of the hydrochloride is carried out at a temperature in the range of 5 to 20 ° C, more preferably in the range of 10 to 20 ° C and most preferably in the range of 10 to 15 ° C. When the hydrochloride formation is complete, the product (IV) is filtered off and washed with ethyl alcohol.

The 4-chloro-1H-imidazo- [4,5-c] -quinoline, which is an intermediate of formula (V), is the 1H-imidazo- [4,5-c] -quinoline-5-N of formula (IV). Phosphoric oxychloride in an aprotic solvent, ie dimethylformamide, by any method known in the art, including -oxide hydrochloride, as disclosed in US Pat. No. 4,689,338, which is incorporated by reference in its entirety. It is obtained by reacting with.

The novel intermediate, 4-iodo-1H-imidazo- [4,5-c] -quinoline (VI), is 4-chloro-1H-imidazo- [4,5-c] -quinoline- (V). Is prepared by reaction via a halogen exchange reaction in an aliphatic ketone, preferably an alkali halide. The reaction is preferably carried out in the presence of sodium iodide. The reaction is accomplished in acetone as a solvent. The reaction is preferably carried out over a period of about 8-10 hours at a temperature in the range from 25 to 35 ° C. The novel compounds are characterized by MP, ¹ H NMR and mass spectroscopy.

In the second stage at the end, 4-iodo-1H-imidazo- [4,5-c] -quinoline (VI) is converted to crude imiquimod, which converts its maleate salt It refine | purifies through and it becomes the compound of the formula of this invention. The reaction is carried out in the presence of ammonium hydroxide or preferably ammonia.

The crude imiquimod is then converted into its pharmaceutically acceptable maleate salt in water-soluble alcohol. The reaction is carried out in aliphatic alcohol, most preferably methanol. The alcohol: water ratio is 2: 1. The formation of the salts is preferably carried out at 60 to 90 ° C.

Formation of the malate is completed within 2 to 3 hours, after which the reaction mass is slowly cooled to 25 to 35 ° C., at which point the imiquimod malate is crystallized out. The product is separated by filtration. Imiquimod malate is obtained in good yield (˜90%) and purity (99% by HPLC). Imiquimod malate salt is preferably taken in a mixture of water, methanol and solution ammonia. The reaction mass is preferably heated to 60-80 ° C., more preferably 70 ° C. for neutralization of the salt. Light white imiquimod precipitates out at alkaline pH (-9-11). The reaction mass is first cooled to 25-30 ° C. and finally cooled to 8-10 ° C. to precipitate pure imiquimod. The purity of the product is improved to 99-99.5% by HPLC.

Example  1.1-isobutyl-1H- Imidazo Preparation of-[4,5-c] -quinoline (II)

3-amino-4-isobutyl amino quinoline (215 g, 1.0 mole) was dissolved in formic acid (1,000 mL), and the reaction mass was then refluxed at 110-115 ° C. Reflux was maintained for 8-10 hours. After the reaction was completed, excess formic acid was removed under reduced pressure and 3.5 L of water was added to the concentrated mass. This diluted mass was then basified to pH (10-11) with 30% NaOH at 20 ° C. The reaction mass was further cooled to 10 ° C. and stirred for a further 3 hours to give a solid. The solid was filtered, washed with water and dried to give the title compound as a white solid (221 g, 98%).

M.P. 91 to 94 ° C

MS- (m / z) M ⁺ 226

¹ H NMR (200 MHz, DMSO D ₆ )

δ value Proton 0.95 (6H, d, CH ₃ × 2) 2.1-2.2 (1H, m, -CH) 4.5 (2H, d, CH ₂ ) 7.7 (2H, m, Ar) 8.2-8.3 (2H, m, Ar) 8.4

9.25

Example  2. 1-isobutyl-1H- Imidazo -[4,5-c] -quinoline-5-N- Oxide · HCl (IV) Preparation

The compound of Example 1 (220 g, 0.978 moles) was added to ethyl acetate (1,760 mL). The reaction mass was heated to 60-65 ° C. for dissolution. Meta-chloroperbenzoic acid (485 g, 70%, 1.377 moles) was added in lots at 60-65 ° C. over 2-3 hours and the temperature was maintained for 6-8 hours. After the reaction was completed, the upper aqueous layer was separated. The lower organic layer was then concentrated in vacuo. To the concentrated mass 8% ethanol hydrochloride (450 mL) was added at 10-15 ° C. The hydrochloride salt was precipitated, filtered, washed with ethyl acetate and dried to give the title product (255 g, 94%).

M.P. 200 to 204 ℃

MS- (m / z) M ⁺ 241

¹ H NMR (200 MHz, DMSO D ₆ )

δ value Proton 0.95 (6H, d, CH ₃ × 2) 2.2-2.5 (1H, m, -CH) 4.6 (2H, d, CH ₂ ) 8.0-8.1 (2H, m, Ar) 8.5-8.7 (2H, m, Ar) 8.85

10.0

Example  3. 4- Chloro -1-isobutyl--1H- Imidazo Preparation of-[4,5-c] -quinoline (V)

Next, the compound of Example 2 (100 g, 0.3604 mole) and phosphorus oxychloride (157 g) were added to N, N-dimethylformamide (600 mL) at 20 ° C. The resulting solution was stirred at 20 ° C. for 30 minutes and then heated at 80 ° C. for 2 hours. The resulting suspension was immersed in 3.0 L cooling water and the pH was alkalized to 9-10 with 30% sodium hydroxide solution. The precipitated solid was filtered, washed with water and dried to give the title product (70 g, 74%).

M.P. 134 to 136 ° C

MS- (m / z) M ⁺ 261

¹ H NMR (200 MHz, DMSO D ₆ )

δ value Proton 0.95 (6H, d, CH ₃ × 2) 2.17-2.2 (1H, m, -CH) 4.5 (2H, d, CH ₂ ) 7.7-7.8 (2H, m, Ar) 8.0-8.3 (2H, m, Ar) 8.5

Example  4. 4-iodo-1-isobutyl-1H- Imidazo Preparation of-[4,5-c] -quinoline (VI)

The compound of Example 3 (50 g, 0.19 mol) was added to acetone (200 mL). Thereafter, separately prepared sodium iodide solution in acetone (ie, 28 g in 200 mL acetone) was added dropwise to the reaction mass and maintained at 25-30 ° C. for 8 hours. Precipitated sodium chloride was filtered off and the acetone was concentrated in vacuo to afford the title product.

M.P. 125 to 127 ° C

MS- (m / z) M ⁺ 351

¹ H NMR (200 MHz, DMSO D ₆ )

δ value Proton 0.93 (6H, d, CH ₃ × 2) 2.1-2.7 (1H, m, -CH) 4.53-4.57 (2H, d, NCH ₂ ) 7.75-7.8 (2H, m, Ar) 8.08-8.11 (1H, m, Ar) 8.33-8.38 (1H, m, Ar) 8.5

Example  5. Joe Imiquimodal  Produce

The compound of Example 4 (67 g, 0.1903 moles) was added to 750 mL of 15% methanolic ammonia solution in a pressurized reactor (ie autoclave) and heated to 150-155 ° C. (˜20 kg pressure). The reaction mass was then kept at this temperature and all product precipitated out. The precipitated solid was filtered off and washed with 50 ml of methanol. The product was dried at 55-60 ° C. for 8 hours to give the title product (40 g, 86%).

part  A. 4-amino-1-isobutyl-1H- Imidazo -[4,5-c] -quinoline Maleate (Iii) manufacturing

The compound of Example 5 (35 g, 0.145 mol) was added to a mixture of 350 ml methanol and 175 ml water. Subsequently, one lot of 35 g (0.3017 mol) of maleic acid was added and the reaction mass was heated to 74 ° C. at reflux. The reaction mass was charcoalized and maintained for 0.5 h. The hyflo bed was washed with 20 ml of hot methanol and the hot reaction mass was filtered through hyflo. Thereafter, the filtrate was slowly cooled to room temperature and again cooled to 8-10 ° C in 1 hour. The precipitated product was filtered off and washed with 20 ml of methanol. The product was dried at 55-60 ° C. (47.2 g, 91%).

M.P. 190 to 192 ° C

MS- (m / z) M ⁺ 241

¹ H NMR (200 MHz, DMSO D ₆ )

δ value Proton 0.95 (6H, d, CH ₃ × 2) 2.1-2.3 (1H, m, -CH) 4.5 (2H, d, NCH ₂ ) 6.09 (2H, s, maleic acid = C-H) 7.5-7.8 (3H, m, Ar) 8.1 (1H, d, Ar) 8.5

8.8 (2H, brs, -NH ₂ ) D ₂ O exchangeable

part  B. 4-Amino-1-isobutyl-1 H- Imidazo Preparation of-[4,5-c] -quinoline

Example 6 (47.2 g, 0.132 mole) of the compound was added to a mixture of 350 ml methanol and 175 ml water. The reaction mass was heated to 75 ° C. and 3.5 g of charcoal was added and held for 0.5 h. The hot reaction mass was filtered through hyflo and then 25% ammonia solution (40 mL) was added until alkaline pH. The precipitated product was filtered off, washed with water and dried to give the title product (31.4 g, 89.7%).

M.P. 292-294 ° C

MS- (m / z) M ⁺ 241

¹ H NMR (200 MHz, DMSO D ₆ )

δ value Proton 0.97 (6H, d, CH ₃ × 2) 2.18-2.25 (1H, m, CH) 4.5 (2H, d, CH ₂ ) 7.5-7.72 (2H, m, Ar) 7.8-7.9 (2H, m, Ar) 8.5

8.8 (1H, s, NH ₂ ) D ₂ O exchangeable

Claims (21)

a) 1-isobutyl-1H-imidazo- [4,5-c] -quinoline (II) is oxidized with peracid in an organic solvent to 1-isobutyl-1H-imidazo- [4,5-c] -Yielding quinoline-5-N-oxide (III); b) purification with its hydrochloric salt (IV); c) converting 5-N-oxide hydrochloride (IV) to 4-chloro derivative (V) using a chlorinating agent; d) reacting 4-chloro-1H-imidazo- [4,5-c] -quinoline (V) with an alkali halide in a solvent medium to obtain the corresponding 4-iodo derivative (VI); e) converting the 4-iodo derivative (VI) to (iii) by alcoholic ammonia treatment; f) separating the product VII into a pharmaceutically acceptable maleate salt; And g) a process for preparing 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline comprising the step of converting imiquimod malate to imiquimod . The method of claim 1, Wherein said peracid used for oxidation is meta-chloroperbenzoic acid. The method according to claim 1 and 2, Wherein said organic solvent used for oxidation is ethyl acetate. The method according to claim 1, 2 and 3, The oxidation is carried out at about 60 ° C to 70 ° C. The method according to claim 1, 2 to 4, The oxidation reaction is completed in about 6-10 hours. The method of claim 1, Wherein said 5-N-oxide (III) is purified by preparation of its hydrochloride salt (IV) in ethanol hydrochloric acid. The method of claim 1, The chlorinating agent used to convert 5-N-oxide hydrochloride (IV) to 4-chloro derivative (V) is phosphorus oxychloride. The method of claim 1, Said alkali halide is preferably sodium iodide. The method according to claim 1 and 8, The reaction is carried out in acetone. The method of claim 1, Conversion of said 4-iodo derivative to imiquimod is achieved in methanolic ammonia. The method according to claim 1 and 10, The reaction is carried out at 140 ° C.-155 ° C. and a pressure of 15-20 kg. The method according to claim 1, 10 and 11, The reaction is completed within about 8 hours. The method of claim 1, The preparation of 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinoline maleate is achieved in aqueous methanol. The method according to claim 1 and 13, The reaction temperature is about 70 ° C-80 ° C. The method according to claim 1, 13, 14, The product is separated at 8-10 ° C. The method according to claim 1, 13 to 15, The product obtained is at least 99% pure. The method of claim 1, 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline maleate is replaced by 4-amino-1-isobutyl-1H-imidazo- [4,5-c] Conversion to quinoline is carried out in aqueous methanol. The method according to claim 1 and 17, The product obtained is at least 99.5% pure. 4-iodo-1-isobutyl-1H-imidazo- [4,5-c] -quinoline (VI) compound specified by ¹ H NMR, mass and MP. 4-Amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline maleate compound specified by ¹ H NMR, mass and MP. Process for the preparation of 4-amino-1-isobutyl-1H-imidazo- [4,5-c] -quinoline substantially disclosed herein with reference to Examples 1-5 described above .