WO2006070408A2 - A process for the preparation of substantially pure 4-amino-1-isobutyl-1h-imidazo[4,5-c]-quinoline (imiquimod) - Google Patents

A process for the preparation of substantially pure 4-amino-1-isobutyl-1h-imidazo[4,5-c]-quinoline (imiquimod) Download PDF

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WO2006070408A2
WO2006070408A2 PCT/IN2005/000433 IN2005000433W WO2006070408A2 WO 2006070408 A2 WO2006070408 A2 WO 2006070408A2 IN 2005000433 W IN2005000433 W IN 2005000433W WO 2006070408 A2 WO2006070408 A2 WO 2006070408A2
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imiquimod
imidazo
quinoline
isobutyl
solvent
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PCT/IN2005/000433
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French (fr)
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WO2006070408B1 (en
WO2006070408A3 (en
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Venkatasubramanian Radhakrishnan Tarur
Suresh Mahadev Kadam
Anil Purushottam Joshi
Sachin Baban Gavhane
Dhananjay Govind Sathe
Kamlesh Digambar Sawant
Tushar Anil Naik
Gurmeet Chandramohan Wadhawa
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Usv Limited
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Priority to EP05850947A priority Critical patent/EP1831219A2/en
Priority to AU2005320890A priority patent/AU2005320890A1/en
Priority to JP2007548976A priority patent/JP2008525521A/en
Publication of WO2006070408A2 publication Critical patent/WO2006070408A2/en
Publication of WO2006070408A3 publication Critical patent/WO2006070408A3/en
Publication of WO2006070408B1 publication Critical patent/WO2006070408B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for synthesis of substantially pure 4- Amino- 1-isobutyl-lH-imidazo [4,5-cJ-quinoline.
  • the invention also relates to a novel purification method via novel organic salts.
  • Imiquimod 4-Amino-l -isobutyl-l H- imidazo-[4,5-c]-quinoline (VIII) is an immune response modifier, useful for treating viral infections such as genital warts.
  • Imiquimod is disclosed in US patents 4,689,338 and 5,238,944 and has the structure (VIII).
  • VIII Several methods are known in the prior art for making Imiquimod (VIII). Reported prior art describe various methods for the preparation of 4-Amino-l- isobutyl-lH-imidazo [4,5-c] quinoline (VIII) i.e. Imiquimod wherein the introduction of amino function in the 4-position is described in three ways. Nucleophilic substitution of a leaving group e.g. Cl or triflate with ammonia, dibenzylamine or an azido group is the first method.
  • a leaving group e.g. Cl or triflate with ammonia, dibenzylamine or an azido group
  • the second is by reacting 1-Isobutyl- lH-imidazo- [4,5-c]-quinoline-5-N-oxide (III) with ammonium hydroxide or its salts in presence of tosyl chloride at 0 - 5°C.
  • the third reported method is by reacting 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline-5-N-o ⁇ ide with benzoyl isocyanate.
  • WO9748704 the amino group is introduced by reaction of a 4-Chloro derivative with sodium azide to obtain a tetrazole moiety. Treatment of the tetrazole moiety with triphenyl phosphine gives the 4-amino derivative.
  • U.S. patent 5,756,747 discloses the nucleophilic substitution with ammonia on the corresponding 4-chloro derivative, which is prepared by isomerization of 1- Isobutyl-IH- imidazo-[4,5-c]-quinoline-5-N ⁇ oxide (III) via the 4-hydroxy derivative followed by reaction with POCl 3 .
  • Several patents disclose nucleophilic substitution of 4-Chloro-l-isobutyl-lH- imidazo-[4,5-c]-quinoline (V) with ammonia at high temperature and high pressure.
  • Isobutyl-1H- imidazo-[4,5-c]-quinoline-5-N-oxide (III) has been disclosed in WO2004/0011462 Al, WO 2004/009593 Al using peracetic acid in toluene as a solvent. This conversion is also reported in WO9215581, WO9206093 and US 5175296 using a combination of formic acid and peracetic acid. However, since the yields are poor and reaction is incomplete, there is a need to develop an oxidation process with milder conditions.
  • Imiquimod by introducing an amino group in the 4-position via 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline-4-phthalimide intermediate (i.e. phthalimido protecting group).
  • WO 9206093 discloses reaction of l-Isobutyl-lH-imidazo-[4,5-c]-quinoline-5- N-oxide (III) with ammonium hydroxide or ammonium salts in the presence of tosyl chloride at 0 - 5°C to give Imiquimod.
  • WO 9215581 relates to reaction of l-Isobutyl-lH-imidazo-[4,5-c]-quinoline-5- N-oxide (III) with benzoyl isocyanate which on subsequent hydrolysis yields Imiquimod (VIII).
  • Imiquimod Purification of Imiquimod has been described via formation of pharmaceutical salts in WO 2004009593, US 4,689,338 i.e. using HCl, H 2 SO 4 , H 3 PO 4 , HNO 3 and methane sulfonic acid. There is still a need for preparation of 4-Amino-l-isobutyl-lH- imidazo-[4,5-c]-quinoline (VIII) namely Imiquimod in high yield and purity.
  • the use of organic acid in place of inorganic acid gives corresponding organic salt with better yield and thus improves the yield of pure imiquimod. Obj ects of the invention
  • An object of the present invention is to develop a simple process for the preparation of Imiquimod.
  • Another object of the present invention is to provide a purification process, which is simple and implemented on a large scale.
  • a further object of the present invention is to produce Imiquimod (VIII) of substantial high purity.
  • Imiquimod maleate, Imiquimod fumarate and Imiquimod oxalate salts Imiquimod maleate, Imiquimod fumarate and Imiquimod oxalate salts.
  • the present invention provides a process for the preparation of substantially pure 4-Amino-l-isobutyl-lH-imidazo-[4,5-c]-quinoline (VIII) comprising: i. treating 3-Amino-4-(isobutylamino)-quinoline (I) with formic acid to obtain 1- isobutyl- 1 H-imidazo- [4 , 5 -c] -quinoline (II) ; ii.
  • Fig. 1 shows X Ray Powder diffraction pattern of pure Imiquimod.
  • Fig. 2 shows X Ray Powder diffraction pattern of Imiquimod Maleate Form I
  • Fig. 3 shows FT-IR spectrum of Imiquimod Maleate Form I
  • Fig. 4 shows X Ray Powder diffraction pattern of Imiquimod Fumarate Form I
  • Fig. 5 shows FT-IR spectrum of Imiquimod Fumarate Form
  • Fig. 6 shows X Ray Powder diffraction pattern of Imiquimod Fumarate Fo ⁇ n II
  • Fig. 7 shows FT-IR spectrum of Imiquimod Fumarate Form II
  • Fig. 8 shows X Ray Powder diffraction pattern of Imiquimod Fumarate Form III
  • Fig. 9 shows FT-IR spectrum of Imiquimod Fumarate Form III
  • Fig. 10 shows X Ray Powder diffraction pattern of Imiquimod Oxalate Form I
  • Fig. 11 shows FT-IR spectrum of Imiquimod Oxalate Form I
  • Fig. 12 shows X Ray Powder diffraction pattern of Imiquimod Oxalate Form II
  • Fig. 13 shows FT-IR spectrum of Imiquimod Oxalate Fo ⁇ n II
  • Fig. 14 shows X Ray Powder diffraction pattern of Imiquimod Oxalate III
  • Fig. 15 shows FT-IR spectrum of Imiquimod Oxalate Form III
  • the Fourier-transform infrared (FT-IR) spectrum of Form I was obtained on a FT-IR 8300 Shimadzu instrument, in the range of 400-4000 cm “1 with a resolution of 4 cm " .
  • the present invention relates to a process for preparing Imiquimod, 4-Amino-
  • the 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline ⁇ 5-N-oxide of formula (III) can be obtained by any method known in the art including those in U.S. patent 5,756,747; WO 9206093 and WO 9215581 all of which are incorporated by reference in their entirety. In the present invention it has been achieved using meta-chloroperbenzoic acid.
  • a preferred solvent is an aliphatic alkyl ester where in carbon chain may be preferably Ci-C 4 .
  • Ethyl acetate is used as solvent.
  • the reaction is preferably carried out at a temperature of between 20 - 8O 0 C more preferably between 40 - 80°C.
  • the meta-chloroperbenzoic acid is preferably added over a period of about 1 to 3 h more preferably from about 1 - 2 h.
  • the reaction is complete when no 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline (II) is detected by TLC.
  • this excess of m-chloro benzoic acid is filtered, washed with ethyl acetate and the organic layer containing the IH- Imidazo-[4,5-c]-quinoline-5-N-oxide (III) compound is further concentrated.
  • the l-Isobutyl-lH-imidazo-[4,5-c]-quinoline-5-N-oxide (III) is purified by preparing its hydrochloride salt (IV) in 8 % alcoholic hydrochloride solution.
  • a preferred alcohol is from C1-C4 aliphatic alcohol.
  • the hydrochloride formation is carried out at a temperature between 5 - 20 0 C, more preferably between 10 - 20 0 C. When the hydrochloride formation is complete the product (IV) is filtered and washed with ethyl alcohol.
  • the 4-Chloro-lH- imidazo-[4,5-c]-quinoline an inte ⁇ nediate of formula (V) is obtained by reaction of IH- imidazo-[4,5-c]-quinoline-5-N-oxide hydrochloride of fo ⁇ nula (IV) with phosphorous oxychloride in an aprotic solvent i.e. dimethylformamide by any method known in the art including those disclosed in US patent US 4,689,338 all of which are incorporated by reference in their entirety herein.
  • the 4-Iodo-lH- imidazo-[4,5-c]-quinoline (VI), a novel inte ⁇ nediate is prepared by reacting 4-Chloro-lH- imidazo-[4,5-c]-quinoline- (V) in an aliphatic ketone preferably with alkali halide via the halogen exchange reaction.
  • the reaction is preferably carried out in the presence of sodium iodide.
  • the reaction is achieved in acetone as a solvent.
  • the reaction is preferably carried out at temperatures between 25 - 35 0 C over a period of about 8 - 10 h.
  • This novel compound is characterized by its MJP. , 1 HNMR and mass spectroscopy.
  • Imiquimod (Crude) is subsequently converted to its pharmaceutically acceptable organic salt (VII) in aqueous alcohol or in dipolar aprotic solvents.
  • the reaction is carried out in aliphatic alcohol and most preferably in methanol.
  • the proportion of alcohol: water is 2: 1.
  • the salt fo ⁇ nation is preferably done at 60 - 90°C,
  • Imiquimod salt (VII) Salt formation is completed in 2 -3 h and then reaction mass is cooled slowly to 25-35 0 C, when Imiquimod salt (VII) crystallizes out.
  • the product is isolated by filtration.
  • Imiquimod salt (VII) is obtained in good yield (-90 %) and purity (99 % by HPLC).
  • Imiquimod salt (VII) is taken preferably in a mixture of water, methanol and liquor ammonia.
  • the reaction mass is preferably heated to 60 - 80 °C more preferably at 70 °C for neutralization of salt. At an alkaline pH -9-11 pale white pure Imiquimod (VIII) precipitates out.
  • the reaction mass is cooled initially to 25-30 °C and finally cooled to 8 -10 °C wherein pure Imiquimod precipitates out.
  • the purity of product is enhanced from 99 to >99.5 % by HPLC.
  • the pure Imiquimod thus prepared shows characteristic peaks in the XRPD at
  • Imiquimod maleate (Vila) Form I crystals.
  • Imiquimod maleate (Vila) prepared by the process described in the experimental session result in to polymorphic crystalline Form I.
  • Imiquimod maleate Form I is also prepared by using polar aprotic solvents like acetone, acetonitrile, DMF and 1,4-Dioxane as dissolving solvents and polar protic solvents like water, Cj-C 4 alcohols, chlorinated hydrocarbons like chloroform and MDC as antisolvents.
  • the Imiquimod maleate Form I thus prepared shows characteristic peaks in the
  • the Imiquimod maleate Form I thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3298, 3129.3, 3089.8, 1676, 1608.5, 1494.1 1467, 1448, 1407, 1361.7, 1213.1, 1083.9, 948.9, 867.9, 776.3, 754.1, 692.4, 673.1, 661.5, 640.3, 590.2, 563.2 cm “1 (Fig. 3).
  • One more embodiment of the present invention provides a process for preparation of Imiquimod fumarale (VIIb) and its three polymorphic crystalline forms viz. Form I, Form II and Form III.
  • Imiquimod fumarate Form I is prepared by using polar aprotic solvents like 1,4-Dioxane and DMF as dissolving solvents and polar protic solvents like water, C]-
  • the Imiquimod fumarate Form I thus prepared shows characteristic peaks in the XRPD at 2 ⁇ value 6.86, 8.87, 10.74, 13.57, 14.63, 18.34, 20.30, 20.87, 21.51, 22.33, 22.85, 22.98, 25.48, 26.43, 27.03, 27.85, 29.71, 30.08, 31.21, 33.91, 35.28 (Fig. 4).
  • the Imiquimod fumarate Form I thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3489.0, 3093.6, 2970.21695.3, 1527.5, 1379, 1124.4, 1103.2, 985, 754.1, 682.8, 563.2 cm “1 (Fig. 5).
  • Imiquimod fumarate Form II is prepared by crystallizing it from polar aprotic solvents like 1,4-Dioxane or by using polar aprotic solvents like DMF and DMSO solvents as dissolving solvent and polar protic solvents like C)-C 4 alcohols or aromatic hydrocarbons like toluene or aliphatic ethers like diethyl ether, diisopropyl ether or acetone or acetonitrile as antisolvents.
  • the Imiquimod fumarate Form II thus prepared shows characteristic peaks in the XRPD at 2 ⁇ value 10.87, 11.44, 12.43, 14.36, 15.46, 18.39, 19.25, 21.62, 22.03, 22.18, 24.55, 31.91 (Fig. 6).
  • the Imiquimod fumarate Form II thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3311.5, 3178, 2958.6, 1645.2, 1614.3, 1527.5, 1469.7, 1396.4, 1371.3, 1251.7, 1097,4, 991.3, 873.7, 848.6, 821.6, 759.9, 640.3, 607.5 cm '1 (Fig. 7).
  • Imiquimod fumarate Form III is prepared by crystallizing it from polar protic solvents like Ci-C 4 alcohols preferably methanol, isopropyl alcohol.
  • the Imiquimod fumarate Fomi III thus prepared shows characteristic peaks in the XRPD at 2 ⁇ value 9.10, 1 1.47, 16.48, 17.34, 18.00, 19.24, 19.60.21.38, 22.80, ' 23.50, 24.98, 25.99, 26.79, 27.32, 28.69, 29.51 , 30.76, 37.36 (Fig. 8).
  • the Imiquimod fumarate Form III thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3477, 3234/4, 3093.6, 2758, 2362.6, 1693, 1606.6, 1531.4, 1375.2, 756.0, 684.7, 569 cm -1 (Fig. 9).
  • Another embodiment of the present invention further provides a process for preparation of Imiquimod oxalate (VIIc) and its three crystalline polymorphic forms viz. Form I, Form II and Form III.
  • Imiquimod oxalate Form I is prepared by crystallizing it from polar protic solvents like water or by using polar aprotic like 1 ,4-Dioxane and protic solvents like
  • Ci -C 4 alcohols as dissolving solvents and polar protic solvents like water, methanol or chlorinated hydrocarbons like chloroform, MDC or Ci -C 4 aliphatic ethers as antisolvents.
  • the Imiquimod oxalate Form I thus prepared shows characteristic peaks in the XRPD at 2 ⁇ value 10.83, 11.43, 14.39, 15.44, 18.36, 19.10, 19.24, 21.63, 22.17, 24.56, 31.88 (Fig. 10).
  • Imiquimod oxalate Form I thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3419.6, 3217, 3062.7, 2962.5, 2360.7, 1701, 1541 1309, 756, 769,715,688, 669, 567 cm “1 (Fig. 11).
  • Imiquimod oxalate Form IT is prepared by crystallizing it from polar aprotic solvents like DMF and DMSO.
  • the Imiquimod oxalate Form II thus prepared shows characteristic peaks in the XRPD at 2 ⁇ value 7.92, 15.56, 15.91, 16.60, 16.76, 17.74, 18.03, 23.25, 25.01, 27.92, 31.48 (Fig. 12).
  • the Imiquimod oxalate Form II thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3315, 3182, 2958,1647, ' 1614, 1529, 1583, 1465, 1475, 1253, 1095, 873, 848, 761, 665 cm "1 (Fig. 13).
  • Imiquimod oxalate Form III is prepared by suspending under stirring Form I or Form II in a mixture of polar protic solvent like Ci-C 4 alcohols preferably methanol and chlorinated hydrocarbon solvent like Chloroform, MDC
  • the Imiquimod oxalate Form III thus prepared shows characteristic peaks in the XRPD at 2 ⁇ value 6.96, 7.42, 9.99, 10.31, 10.45, 12.41 , 13.31 , 13.79, 16.16, 19.21, 21.12, 23.74, 24.90, 25.62, 25.94, 26.60 (Fig. 14).
  • the Imiquimod oxalate Form III thus prepared shows characteristic absorption at in FT-IR spectrum and they are at 3101, 2962, 1685, 1218, 1099, 948, 748,713, 690, 657, 632, 590 cm "1 (Fig. 15).
  • Example No: (v-c) Part A Preparation of 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoline oxalate salt (VIIc) Add the compound from Example v (50 gm, 0.20 mole) to a mixture of 350 ml of DMF and 175 ml water. Subsequently, add 49 gm (0.41 mole) oxalic acid in one lot and reflux the reaction mass at a temperature of 160 0 C. Charcoalise and maintain the reaction mass for 0.5 lir, wash the hyflo bed with 20 ml hot water and filter the hot reaction mass through hyflo.
  • Example 7 Dissolve 0.5 g of Imiquimod maleate in 15 ml of DMF at 60 0 C. Allow the hot solution to cool to 25 0 C following it by addition of 25 ml of MDC. Further cool the solution and maintain at 5 0 C for one hour. Filter the separated solid and dry at 55 0 C to get Form I crystals
  • Example 8 Dissolve 0.5 g of Imiquimod maleate in 15 ml of DMF at 60 0 C. Allow the hot solution to cool to 25 0 C for 1 hr, Filter the separated solid and dry at 55 0 C to get Form I crystals
  • Example 24 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0 C. Allow the hot solution to cool to 70 °C following it by addition of 40 ml of diisopropyl ether. Cool the hot solution to 10 0 C for one hour. Filter the separated solid and dry at 55 0 C to get
  • Example 25 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0 C. Allow the hot solution to cool to 70 0 C following it by addition of 40 ml of methanol. Cool the hot solution to 10 0 C for one hour. Filter the separated solid and dry at 55 °C to get Form
  • Example 26 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0 C. Allow the hot solution to cool to 70 0 C following it by addition of 40 ml of toluene. Cool the hot solution to 10 0 C for one hour. Filter the separated solid and dry at 55 0 C to get Form
  • Example 27 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0 C. Allow the hot solution to cool to 70 °C following it by addition of 40 ml of isopropyl alcohol. Cool the hot solution to 10 0 C for one hour. Filter the separated solid and dry at 55 0 C to get
  • Example 28 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMF at 105 0 C. Allow the hot solution to cool to 70 0 C following it by addition of 40 ml of acetone. Cool the hot solution to 10 0 C for one hour. Filter the separated solid and dry at 55 0 C to get Form
  • Example 29 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMF at 105 0 C. Allow the hot solution to cool to 70 0 C following it by addition of 40 ml of acetonitrile. Cool the hot solution to 10 0 C for one hour. Filter the separated solid and dry at 55 0 C to get Form
  • the present invention provides Imiquimod in substantially pure form.
  • the product is having purity greater than 99 %.
  • the present invention provides Imiquimod with 88% yield.

Abstract

A process for preparation of Imiquimod comprising oxidation of 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline (II) afforded 1-Isobutyl-1H- 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 novel intermediate. This novel intermediate is converted to imiquimod (VIII) and purified via its organic salt. The invention also relates to crystalline polymorphic forms of Imiquimod Maleate, Fumarate and Oxalate.

Description

A process for the preparation of substantially pure 4-Amino-l- isobutyl-lH-imidazo[4,5-c]-quinoline (Imiquimod)
Field of the invention
The present invention relates to a process for synthesis of substantially pure 4- Amino- 1-isobutyl-lH-imidazo [4,5-cJ-quinoline. The invention also relates to a novel purification method via novel organic salts.
Background of the invention
Imiquimod, 4-Amino-l -isobutyl-l H- imidazo-[4,5-c]-quinoline (VIII) is an immune response modifier, useful for treating viral infections such as genital warts. Imiquimod is disclosed in US patents 4,689,338 and 5,238,944 and has the structure (VIII).
Figure imgf000002_0001
(VIII) Several methods are known in the prior art for making Imiquimod (VIII). Reported prior art describe various methods for the preparation of 4-Amino-l- isobutyl-lH-imidazo [4,5-c] quinoline (VIII) i.e. Imiquimod wherein the introduction of amino function in the 4-position is described in three ways. Nucleophilic substitution of a leaving group e.g. Cl or triflate with ammonia, dibenzylamine or an azido group is the first method. The second, is by reacting 1-Isobutyl- lH-imidazo- [4,5-c]-quinoline-5-N-oxide (III) with ammonium hydroxide or its salts in presence of tosyl chloride at 0 - 5°C. The third reported method is by reacting 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline-5-N-oχide with benzoyl isocyanate.
WO Publications WO2004009593, WO9206093; US patents 5,395,937; 5,756,747; 4,988,815; 5,602256; 5,578,727; 4,698,348; 4,689,388; European patents EP 145340, EP 0385630, EP 310950 and JP 04193866 and examples therein, describe nucleophillic substitution reactions. In WO9748704 the amino group is introduced by reaction of a 4-Chloro derivative with sodium azide to obtain a tetrazole moiety. Treatment of the tetrazole moiety with triphenyl phosphine gives the 4-amino derivative.
In US patent 5,395,937 a 4-trifiate derivative reacts with dibenzylamine to give 4-dibenzylamino derivative. Subsequent catalytic reduction gives the desired amino function in 4-position.
U.S. patent 5,756,747 discloses the nucleophilic substitution with ammonia on the corresponding 4-chloro derivative, which is prepared by isomerization of 1- Isobutyl-IH- imidazo-[4,5-c]-quinoline-5-N~oxide (III) via the 4-hydroxy derivative followed by reaction with POCl3. Several patents disclose nucleophilic substitution of 4-Chloro-l-isobutyl-lH- imidazo-[4,5-c]-quinoline (V) with ammonia at high temperature and high pressure. These include US 4,988,815; US 5,602,256; US 5,578,727; US 4,698,348; US 4,689,388; EP 145340; EP 0385630; EP 310950 and JP 04193866. The process of converting 1-Isobutyl-l H- imidazo-[4,5-c]-quinoline (II) to 1-
Isobutyl-1H- imidazo-[4,5-c]-quinoline-5-N-oxide (III) has been disclosed in WO2004/0011462 Al, WO 2004/009593 Al using peracetic acid in toluene as a solvent. This conversion is also reported in WO9215581, WO9206093 and US 5175296 using a combination of formic acid and peracetic acid. However, since the yields are poor and reaction is incomplete, there is a need to develop an oxidation process with milder conditions.
The patents WO 2004/009593, US2004138459, disclose a process for the preparation of 4-Amino-l-isobutyl-lH- imidazo-[4,5-c]-quinoline (VIII) (i.e.
Imiquimod) by introducing an amino group in the 4-position via 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline-4-phthalimide intermediate (i.e. phthalimido protecting group).
WO 9206093 discloses reaction of l-Isobutyl-lH-imidazo-[4,5-c]-quinoline-5- N-oxide (III) with ammonium hydroxide or ammonium salts in the presence of tosyl chloride at 0 - 5°C to give Imiquimod. WO 9215581 relates to reaction of l-Isobutyl-lH-imidazo-[4,5-c]-quinoline-5- N-oxide (III) with benzoyl isocyanate which on subsequent hydrolysis yields Imiquimod (VIII).
Purification of Imiquimod has been described via formation of pharmaceutical salts in WO 2004009593, US 4,689,338 i.e. using HCl, H2SO4, H3PO4, HNO3 and methane sulfonic acid. There is still a need for preparation of 4-Amino-l-isobutyl-lH- imidazo-[4,5-c]-quinoline (VIII) namely Imiquimod in high yield and purity. The use of organic acid in place of inorganic acid gives corresponding organic salt with better yield and thus improves the yield of pure imiquimod. Obj ects of the invention
An object of the present invention is to develop a simple process for the preparation of Imiquimod.
Another object of the present invention is to provide a purification process, which is simple and implemented on a large scale. A further object of the present invention is to produce Imiquimod (VIII) of substantial high purity.
Another object of the present invention is to provide a process for the preparation of Imiquimod Maleate crystals, Imiquimod Fumarate crystals and Imiquimod oxalate crystals. Yet another object of the present invention is to provide polymorphic forms of
Imiquimod maleate, Imiquimod fumarate and Imiquimod oxalate salts.
Summary of the Invention
Accordingly the present invention provides a process for the preparation of substantially pure 4-Amino-l-isobutyl-lH-imidazo-[4,5-c]-quinoline (VIII) comprising: i. treating 3-Amino-4-(isobutylamino)-quinoline (I) with formic acid to obtain 1- isobutyl- 1 H-imidazo- [4 , 5 -c] -quinoline (II) ; ii. reacting l-Isobutyl-lH-imidazo-[4,5-c] -quinoline (II) with per acid preferably meta-chloro perbenzoic acid in organic solvent to yield 1-Isobutyl-lH- imidazo-[4,5:c]-quinoline-5-N-oxide (III). This is further converted to its hydrochloride salt (IV); iii. converting 5-N-oxide hydrochloride (IV) to 4-Chloro-lH- imidazo-[4,5-c]- quinoline (V) by treating with phosphorous oxychloride; iv. reacting compound 4-Chloro-lH- iniidazo-[4,5-c]-quinoline (V) with an alkali halide preferably sodium iodide to produce the corresponding 4-iodo derivative (VI) which is treated with ammonia to obtain crude (VIII); v. treating the crude (VIII) to obtain a pharmaceutically acceptable salt of an organic acid selected from a group consisting of Imiquimod Maleate (Vila), Fumarate (VIIb) and Oxalate (VIIc); and vi. finally converting the pharmaceutically acceptable salt of above step to highly pure Imiquimod (VIII) in methanolic ammonia.
These and other aspects of the present invention are described in more detail with reference to the following detailed description of the invention.
Detailed Description of Figures
Fig. 1 shows X Ray Powder diffraction pattern of pure Imiquimod. Fig. 2 shows X Ray Powder diffraction pattern of Imiquimod Maleate Form I Fig. 3 shows FT-IR spectrum of Imiquimod Maleate Form I Fig. 4 shows X Ray Powder diffraction pattern of Imiquimod Fumarate Form I Fig. 5 shows FT-IR spectrum of Imiquimod Fumarate Form I Fig. 6 shows X Ray Powder diffraction pattern of Imiquimod Fumarate Foπn II Fig. 7 shows FT-IR spectrum of Imiquimod Fumarate Form II
Fig. 8 shows X Ray Powder diffraction pattern of Imiquimod Fumarate Form III Fig. 9 shows FT-IR spectrum of Imiquimod Fumarate Form III Fig. 10 shows X Ray Powder diffraction pattern of Imiquimod Oxalate Form I Fig. 11 shows FT-IR spectrum of Imiquimod Oxalate Form I Fig. 12 shows X Ray Powder diffraction pattern of Imiquimod Oxalate Form II Fig. 13 shows FT-IR spectrum of Imiquimod Oxalate Foπn II Fig. 14 shows X Ray Powder diffraction pattern of Imiquimod Oxalate III Fig. 15 shows FT-IR spectrum of Imiquimod Oxalate Form III
X-ray powder diffraction pattern has been obtained on PANalytical X'PertPRO diffractometer equipped with accelerator detector using Copper Ka (λ = 1.5406 A) radiation with scanning range between 2-50 θ at scanning speed of 27min. The Fourier-transform infrared (FT-IR) spectrum of Form I was obtained on a FT-IR 8300 Shimadzu instrument, in the range of 400-4000 cm"1 with a resolution of 4 cm" .
Detailed description of invention The present invention relates to a process for preparing Imiquimod, 4-Amino-
1-isobutyl-lH- imidazo-[4,5-c]-quinoline of formula (VIII). However, the inventive process can be used to prepare any compound within the scope of formula (VIII) and its derivative including those disclosed in US patents 5,756,747; 5,395,937; 4,689,338; EP 385630, WO 9748704; WO 9206093 and WO 9215581 all of which are incorporated by reference in their entirety.
The cyclisation of 3-Amino-4-(isobutylamino)-quinoline (I) is accomplished by treating it with formic acid to obtain 1-isobutyl-lH- imidazo-[4,5-c]-quinoline (II).
Satisfactory yield by any method known in the art including those disclosed in patents
WO 92 06093 and US 5,175,296 all of which are incorporated by reference in their entirety.
The 1-Isobutyl-lH- imidazo-[4,5-c]-quinolineτ5-N-oxide of formula (III) can be obtained by any method known in the art including those in U.S. patent 5,756,747; WO 9206093 and WO 9215581 all of which are incorporated by reference in their entirety. In the present invention it has been achieved using meta-chloroperbenzoic acid. A preferred solvent is an aliphatic alkyl ester where in carbon chain may be preferably Ci-C4. Preferably Ethyl acetate is used as solvent. The reaction is preferably carried out at a temperature of between 20 - 8O0C more preferably between 40 - 80°C. The meta-chloroperbenzoic acid is preferably added over a period of about 1 to 3 h more preferably from about 1 - 2 h. The reaction is complete when no 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline (II) is detected by TLC. When the reaction is complete this excess of m-chloro benzoic acid is filtered, washed with ethyl acetate and the organic layer containing the IH- Imidazo-[4,5-c]-quinoline-5-N-oxide (III) compound is further concentrated. This is more efficient with respect to yield and purity in comparison to reported reference disclosed in patent WO 2004/01 1462, WO 2004/009593, WO.9215581, WO 9206093, US 5175296. The l-Isobutyl-lH-imidazo-[4,5-c]-quinoline-5-N-oxide (III) is purified by preparing its hydrochloride salt (IV) in 8 % alcoholic hydrochloride solution. A preferred alcohol is from C1-C4 aliphatic alcohol. The hydrochloride formation is carried out at a temperature between 5 - 20 0C, more preferably between 10 - 200C. When the hydrochloride formation is complete the product (IV) is filtered and washed with ethyl alcohol.
The 4-Chloro-lH- imidazo-[4,5-c]-quinoline an inteπnediate of formula (V) is obtained by reaction of IH- imidazo-[4,5-c]-quinoline-5-N-oxide hydrochloride of foπnula (IV) with phosphorous oxychloride in an aprotic solvent i.e. dimethylformamide by any method known in the art including those disclosed in US patent US 4,689,338 all of which are incorporated by reference in their entirety herein.
The 4-Iodo-lH- imidazo-[4,5-c]-quinoline (VI), a novel inteπnediate is prepared by reacting 4-Chloro-lH- imidazo-[4,5-c]-quinoline- (V) in an aliphatic ketone preferably with alkali halide via the halogen exchange reaction. The reaction is preferably carried out in the presence of sodium iodide. The reaction is achieved in acetone as a solvent. The reaction is preferably carried out at temperatures between 25 - 35 0C over a period of about 8 - 10 h. This novel compound is characterized by its MJP. , 1HNMR and mass spectroscopy.
In the penultimate stage, 4-Iodo-lH- imidazo-[4,5-c]-quinoline (VI) is converted to Imiquimod (Crude) by ammonolysis in a lower aliphatic alcohol. The reaction is carried out in the presence of ammonium hydroxide or ammonium carbonate or ammonia, preferably ammonia.
Imiquimod (Crude) is subsequently converted to its pharmaceutically acceptable organic salt (VII) in aqueous alcohol or in dipolar aprotic solvents. The reaction is carried out in aliphatic alcohol and most preferably in methanol. The proportion of alcohol: water is 2: 1. The salt foπnation is preferably done at 60 - 90°C,
' more preferably about 50 - 80 0C in alcohol or at 150 - 180 0C, more preferably about
150-160 0C in dipolar aprotic solvents. Scheme I
MCPBA/Clliyl iccc Uc
Figure imgf000008_0001
-Amino-4-(isobuty]ammo)-qumoline (I) l-Isobιιtyl-I H-Imidazol-[4,5-c]-quinolme (II)
POCI. /DM r
Figure imgf000008_0002
l-Isobutyl-lH-Imidazo-[4,S-c]-quinoIine-5-N-oxide l -Isobutyl-l H-Imidazo-^S-cJ-qumoline-S-N-oxide Hydiochlii ide (IV)
Ndl/Acctonc
Mcthanolic immoni i
Figure imgf000008_0003
Figure imgf000008_0004
-Chloιo-l-isobutyl-lH-Imidazo-[4,5-c]-quinolιne (V) 4-Iodo-I -isobutyl-l I I-Imidazo-[4,5-c]-quino!me (VI)
Figure imgf000008_0005
Q tide Imquimαd (VIII) Pure Imiquimod (VIII)
Figure imgf000008_0006
αi Oλahc acic ^ '
Salt formation is completed in 2 -3 h and then reaction mass is cooled slowly to 25-35 0C, when Imiquimod salt (VII) crystallizes out. The product is isolated by filtration. Imiquimod salt (VII) is obtained in good yield (-90 %) and purity (99 % by HPLC). Imiquimod salt (VII) is taken preferably in a mixture of water, methanol and liquor ammonia. The reaction mass is preferably heated to 60 - 80 °C more preferably at 70 °C for neutralization of salt. At an alkaline pH -9-11 pale white pure Imiquimod (VIII) precipitates out. The reaction mass is cooled initially to 25-30 °C and finally cooled to 8 -10 °C wherein pure Imiquimod precipitates out. The purity of product is enhanced from 99 to >99.5 % by HPLC. The pure Imiquimod thus prepared shows characteristic peaks in the XRPD at
2Θ values: 10.81, 11.26, 11.3963, 15.38, 19.16, 20.22, 21.56, 22.13, 24.48, 26.42, 30.25, and 31.86 (Fig. 1).
Another embodiment of the present invention relates to the process of preparation of Imiquimod maleate (Vila) Form I crystals. Imiquimod maleate (Vila) prepared by the process described in the experimental session result in to polymorphic crystalline Form I. Imiquimod maleate Form I is also prepared by using polar aprotic solvents like acetone, acetonitrile, DMF and 1,4-Dioxane as dissolving solvents and polar protic solvents like water, Cj-C4 alcohols, chlorinated hydrocarbons like chloroform and MDC as antisolvents. The Imiquimod maleate Form I thus prepared shows characteristic peaks in the
XRPD at 2Θ value 9.50, 9.95, 17.13, 19.15, 19.93, 21.63, 24.37, 24.71, 27.09 (Fig. 2).
The Imiquimod maleate Form I thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3298, 3129.3, 3089.8, 1676, 1608.5, 1494.1 1467, 1448, 1407, 1361.7, 1213.1, 1083.9, 948.9, 867.9, 776.3, 754.1, 692.4, 673.1, 661.5, 640.3, 590.2, 563.2 cm"1 (Fig. 3).
One more embodiment of the present invention provides a process for preparation of Imiquimod fumarale (VIIb) and its three polymorphic crystalline forms viz. Form I, Form II and Form III.
Imiquimod fumarate Form I is prepared by using polar aprotic solvents like 1,4-Dioxane and DMF as dissolving solvents and polar protic solvents like water, C]-
C4 alcohols or aromatic hydrocarbon like toluene, chlorinated hydrocarbons like chloroform, MDC or aliphatic ethers like diethyl ether, diisopropyl ether as antisolvents.
The Imiquimod fumarate Form I thus prepared shows characteristic peaks in the XRPD at 2Θ value 6.86, 8.87, 10.74, 13.57, 14.63, 18.34, 20.30, 20.87, 21.51, 22.33, 22.85, 22.98, 25.48, 26.43, 27.03, 27.85, 29.71, 30.08, 31.21, 33.91, 35.28 (Fig. 4).
The Imiquimod fumarate Form I thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3489.0, 3093.6, 2970.21695.3, 1527.5, 1379, 1124.4, 1103.2, 985, 754.1, 682.8, 563.2 cm"1 (Fig. 5). Imiquimod fumarate Form II is prepared by crystallizing it from polar aprotic solvents like 1,4-Dioxane or by using polar aprotic solvents like DMF and DMSO solvents as dissolving solvent and polar protic solvents like C)-C4 alcohols or aromatic hydrocarbons like toluene or aliphatic ethers like diethyl ether, diisopropyl ether or acetone or acetonitrile as antisolvents. The Imiquimod fumarate Form II thus prepared shows characteristic peaks in the XRPD at 2Θ value 10.87, 11.44, 12.43, 14.36, 15.46, 18.39, 19.25, 21.62, 22.03, 22.18, 24.55, 31.91 (Fig. 6).
The Imiquimod fumarate Form II thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3311.5, 3178, 2958.6, 1645.2, 1614.3, 1527.5, 1469.7, 1396.4, 1371.3, 1251.7, 1097,4, 991.3, 873.7, 848.6, 821.6, 759.9, 640.3, 607.5 cm'1 (Fig. 7).
Imiquimod fumarate Form III is prepared by crystallizing it from polar protic solvents like Ci-C4 alcohols preferably methanol, isopropyl alcohol.
The Imiquimod fumarate Fomi III thus prepared shows characteristic peaks in the XRPD at 2Θ value 9.10, 1 1.47, 16.48, 17.34, 18.00, 19.24, 19.60.21.38, 22.80, ' 23.50, 24.98, 25.99, 26.79, 27.32, 28.69, 29.51 , 30.76, 37.36 (Fig. 8).
The Imiquimod fumarate Form III thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3477, 3234/4, 3093.6, 2758, 2362.6, 1693, 1606.6, 1531.4, 1375.2, 756.0, 684.7, 569 cm-1 (Fig. 9). Another embodiment of the present invention further provides a process for preparation of Imiquimod oxalate (VIIc) and its three crystalline polymorphic forms viz. Form I, Form II and Form III.
Imiquimod oxalate Form I is prepared by crystallizing it from polar protic solvents like water or by using polar aprotic like 1 ,4-Dioxane and protic solvents like
Ci -C4 alcohols as dissolving solvents and polar protic solvents like water, methanol or chlorinated hydrocarbons like chloroform, MDC or Ci -C4 aliphatic ethers as antisolvents.
The Imiquimod oxalate Form I thus prepared shows characteristic peaks in the XRPD at 2Θ value 10.83, 11.43, 14.39, 15.44, 18.36, 19.10, 19.24, 21.63, 22.17, 24.56, 31.88 (Fig. 10).
The Imiquimod oxalate Form I thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3419.6, 3217, 3062.7, 2962.5, 2360.7, 1701, 1541 1309, 756, 769,715,688, 669, 567 cm"1 (Fig. 11). Imiquimod oxalate Form IT is prepared by crystallizing it from polar aprotic solvents like DMF and DMSO.
The Imiquimod oxalate Form II thus prepared shows characteristic peaks in the XRPD at 2Θ value 7.92, 15.56, 15.91, 16.60, 16.76, 17.74, 18.03, 23.25, 25.01, 27.92, 31.48 (Fig. 12). The Imiquimod oxalate Form II thus prepared shows characteristic absorption peaks in FT-IR spectrum at 3315, 3182, 2958,1647,'1614, 1529, 1583, 1465, 1475, 1253, 1095, 873, 848, 761, 665 cm"1 (Fig. 13).
Imiquimod oxalate Form III is prepared by suspending under stirring Form I or Form II in a mixture of polar protic solvent like Ci-C4 alcohols preferably methanol and chlorinated hydrocarbon solvent like Chloroform, MDC
The Imiquimod oxalate Form III thus prepared shows characteristic peaks in the XRPD at 2Θ value 6.96, 7.42, 9.99, 10.31, 10.45, 12.41 , 13.31 , 13.79, 16.16, 19.21, 21.12, 23.74, 24.90, 25.62, 25.94, 26.60 (Fig. 14). The Imiquimod oxalate Form III thus prepared shows characteristic absorption at in FT-IR spectrum and they are at 3101, 2962, 1685, 1218, 1099, 948, 748,713, 690, 657, 632, 590 cm"1 (Fig. 15).
Experimental data
Example No. (i) Preparation of 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline (H)
Dissolve 3-Amino~4-isobutyl amino quinoline (215 gm, 1.0 mole) in formic acid (1.0 L) and reflux the reaction mass to 110-115 0C. Maintain refluxing for 8-10 h. On completion of reaction remove excess formic acid under reduced pressure and add 3.5 L of water to the concentrated mass. Basify this diluted mass with 30 % NaOH to pH 10-11 at 20 0C. Cool the reaction mass to 10 °C and stir for further 3 h to obtain solid product. Filter the solid, wash with water and dry to get the title compound as a white solid.
M.P. 91 to 940C
MS - (m/z) M+ 226
1HNMR (200 MHz, DMSO D6)
Yield: 221 gm, 98 %
δ values Proton
0,95 (6H, d, CH3 x 2)
2.1-2.2 (IH, m, -CH2)
4.5 (2H. d, CH2)
7,7 (2H, m, Ar)
8.2-8,3 (2H, m, Ar)
8.4 (IH, s, >N-CH=N-)
9.25 (IH, s, -N-CH=N-)
Example No. (ii)
Preparation of 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline-5-N-oxide.HCl (IV)
Add compound from Example (i) (220 gm, 0.97 mole) to ethyl acetate (1.7 L). Heat the reaction mass to 60 to 65 0C for dissolution. Add meta-chloroperbenzoic acid (485 gm, 70 %, 1.37 mole) in lots at 60-65 0C over a period of 2-3 h and maintain the temperature for 6-8 h. On completion of reaction, separate the upper aqueous layer. Concentrate the lower organic layer under vacuum. To this concentrated mass, add 8 % ethanolic hydrochloride (450 ml) at 10-15 0C. Filter the precipitated hydrochloride salt, wash with ethyl acetate and dry to obtain the title product
M.P. 200 to 204 0C MS - (m/z) M+ 241
1HNMR (200 MHz, DMSO D6) Yield: 255 gm, 94 %
δ values Proton
0,95 (6H, d, CH3 x 2)
2.2-2.5 (IH, m, -CH)
4.6 (2H, d, CH2)
8.0-8.1 (2H, ni, Ai-)
8.5-8.7 (2H, m, Ai-)
8.85 (IH, s, -CH=N-) (IH, S; -CH=N-) 10.0
O
Example No. (iii)
Preparation of 4-Chloro-l-isobutyl-lH- imidazo-[4,5-c|-quinoIine (V)
Take the compound from Example (ii) (100 gm, 0.36 mole) and phosphorous oxychloride (157 gm) in N,N-Dimethylformamide (600 ml) at 20 0C. Stir the resulting solution for 30 minutes at 20 0C and subsequently heat to 80 0C for 2 h. Drown the resulting suspension in 3.0 L cold water and basify to pH 9-10 with 30 % sodium hydroxide solution. Filter the precipitated solid, wash with water and dry to obtain the title product.
M.P. 134 to 1360C
MS - (m/z) M+ 261
1HNMR (200 MHz, DMSO D6)
Yield: 70 gm, 74 %
δ values Proton
0.95 (6H, d, CH3 x 2)
2.17-2.2 (IH, m, -CH)
4.5 (2H, d, CH2)
Figure imgf000013_0001
8.0-8.3 (2H, m, Ar)
8.5 (IH, s, -CH=N-)
Example No. (iv)
Preparation of 4-Iodo-l-isobutyl-lH- Imidazo-[4,5-c|-qιiinoline (VI) Add the compound from Example (iii) (50 gm, 0.19 mole) to acetone (200 ml). Then add dropwise separately prepared solution of sodium iodide in acetone (i.e. 28 gm in 200 ml acetone) to the reaction mass and maintain at 25 - 30 0C for 8 h. Filter the precipitated sodium chloride and concentrate the acetone under vacuum to obtain the title product.
M.P. 125 to l27°C MS - (m/z) M+ 351
1HNMR (200 MHz, DMSO D6) Yield: 55 gm, 82 %
δ values Proton
0,93 (6H, d, CH3 x 2)
2.1-2.7 (IH, m, -CH)
4.53-4.57 (2H, d, NCH2)
7.75-7.8 (2H, m, Ar)
8.08-8.11 (IH, m, Ar)
8.33-8.38 (IH, m, Ai-)
8,5 (IH, s, -CH=N-)
Example No. (v)
Preparation of Imiquimod (Crude)
Add the compound from Example (iv) (67 gm, 0,19 mole) to 750 ml of 15 % methanolic ammonia solution in a pressure reactor (i,e. autoclave) and heat to 150 — 155 0C (~ 20 Kg pressure), Maintain the reaction mass at this temperature, till the product precipitates out. Filter the precipitated solid, wash with 50 ml methanol. Dry at 55 to 60 0C for 8 h to obtain the title product. Yield: 40 gm, 86 %, Purity: 95 %. Example No: (v-a)
Part A
Preparation of 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoIine maleate salt (Vila)
Add the compound from Example (v) (35 gm, 0.14 mole) to a mixture of 350 ml of methanol and 175 ml water. Subsequently, add 35 gm (0.30 mole) maleic acid in one lot and heat the reaction mass to reflux temperature of 74 0C. Charcoalise and maintain the reaction mass for 0.5 hr, wash the hyflo bed with 20 ml hot methanol and filter the hot reaction mass through hyflo. The filtrate is then slowly cooled to RT and then to 8-
10 0C in 1 hr. Filter the precipitated product, wash with 20 ml methanol. Dry at 55-60 0C. Yield: 47.2 gm, 91 %; Purity: 99.9 %.
M.P. 190 to l 92°C
MS - (m/z) M+ 241
1HNMR (200 MHz, DMSO D6)
δ values Proton
0.93 (6H, d, CH3 x 2)
2.1-2.3 (IH, m, -CH)
4.5 (2H, ,d, NCH2)
6.09 (2H, s, =C-H of maleic acid)
7.5-7.8 (3H, ra, Ai-)
8.1 (IH, d, Ar)
8.5 (IH, s, -CH=N-)
8.8 (2H, brs , -NH2) D2O exchangeable
Part B
Preparation of 4-Amino-l-isobutyMH- Imidazo-[4,5-c]-quinoline (VIII) Add 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoline maleate salt (Vila) (47.2 gm, 0.13 mole) to a mixture of 350 ml methanol and 175 ml water. Heat the reaction mass to 75 0C and further add 3.5 gm charcoal, maintaining the reaction for 0.5 hr. Filter the hot reaction mass through hyflo and subsequently add 25 % ammonia solution (40 ml) till alkaline pH. Filter the precipitated product, wash with water. Dry to obtain the title product. Yield: 31.4 gm, 89.7 %; Purity: 99.9 %.
M.P. 292 to 294°C
MS - (m/z) M+ 241 1HNMR (200 MHz, DMSO D6)
δ values Proton
0.97 (6H, d, CH3 x 2)
2.1-2.25 (IH, m, -CH)
4.5 (2H, d, CH2)
Figure imgf000016_0001
7.8-7.9 (2H, m, Ar)
8.5 (IH, s, -CH=N-)
8.8 (IH, s, -NH2) P2O exchangeable
Example No: (v-b) Part A
Preparation of 4-Amino-l-isobutyl-lH- lmidazo-[4,5-c]-quinoline fumarate salt (VIIb)
Add the compound from Example (v) (50 gm, 0.20 mole) to a mixture of 350 ml of DMF and 175 ml water. Subsequently, add 48 gm (0.41 mole) fumaric acid in one lot and reflux the reaction mass temperature of 160 0C. Charcoalise and maintain the reaction mass for 0.5 hr, wash the hyflo bed with 20 ml hot water and filter the hot reaction mass through hyflo. Cool the filtrate slowly to RT and then to 8 - 10 °C in 1 hr. Filter the precipitated product, wash with 20 ml of water. Dry the product at 55 - 60 0C. Yield: 66.4 gm, 89 %; Purity: 99.9 %.
Part B
Preparation of 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoline (VIII)
Add 4-Amino-l-isobutyl-lH- lmidazo-[4,5-c]-quinoline fumarate salt (VIIb) ( 66.49 gm, 0.18 mole) to a mixture of 350 ml methanol and 175 ml water. Heat the reaction mass to 75 0C and further add 3.5 gm of charcoal, maintaining the reaction for 0.5 hr. Filter the hot reaction mass through hyflo and subsequently add 25 % ammonia solution (40 ml) till alkaline pH. Filter the precipitated product, wash with water. Dry to obtain the title product. Yield: 40.9 gm, 90 %; Purity: 99.92 %.
Example No: (v-c) Part A Preparation of 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoline oxalate salt (VIIc) Add the compound from Example v (50 gm, 0.20 mole) to a mixture of 350 ml of DMF and 175 ml water. Subsequently, add 49 gm (0.41 mole) oxalic acid in one lot and reflux the reaction mass at a temperature of 160 0C. Charcoalise and maintain the reaction mass for 0.5 lir, wash the hyflo bed with 20 ml hot water and filter the hot reaction mass through hyflo. Slowly cool the filtrate to RT and then to 8 - 10 0C in 1 hr. Filter the precipitated product, wash with 20 ml of water. Dry the product at 55 - 60 0C. Yield: 61.8 gm, 90 %; Purity: 99.9 %.
Part B Preparation of 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoline (VIII)
Add 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoline oxalate salt (VIIc) (61.8 gm, 0.18 mole) to a mixture of 350 ml methanol and 175 ml water. Heat the reaction mass to 75 0C and further add 3.5 gm of charcoal, maintaining the reaction for 0.5 hr. Filter the hot reaction mass through hyflo and subsequently add 25 % ammonia solution (40 ml) till alkaline pH. Filter the precipitated product, wash with water. Dry to obtain the title product. Yield: 38.4 gm, 88 %; Purity: 99.91 %.
PROCESS OF OBTAINING IMIQUIMOD MALEATE (Vila) CRYSTALS
Example 1
Dissolve 0.5 g of Imiquimod maleate in 25 ml of acetonirile at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml water. Maintain the solution at 25 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals.
Example 2
Dissolve 0.5 g of Imiquimod maleate in 25 ml of acetone at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml water. Further cool the solution to 5 0C and maintain for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals.
Example 3
Dissolve 0.5 g of Imiquimod maleate in 75 ml of methylene dichloride at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml hexane. Further cool the solution to 5 0C and maintain for one hour. Filter the separated solid and diy at 55 0C to get Form I crystals. Example 4
Dissolve 0.5 g of Imiquimod maleate in 75 ml of water at 100 0C. Allow the hot solution to cool to 25 0C. Further cool the solution to 5 0C and maintain for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals Example 5
Dissolve 0.5 g of Imiquimod maleate in 15 ml of DMF at 60 0C. Allow the hot solution to cool to 25 0C following it by addition qf 25 ml of IPA. Maintain the solution at 25 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals Example 6
Disperse 1 g of Imiquimod Maleate in 50 ml IPA at 30 0C. Maintain the solution at 300C under stirring for 16 h. Filter the dispersed solid and dry at 55 0C to get Form I crystals
Example 7 Dissolve 0.5 g of Imiquimod maleate in 15 ml of DMF at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml of MDC. Further cool the solution and maintain at 5 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals
Example 8 Dissolve 0.5 g of Imiquimod maleate in 15 ml of DMF at 60 0C. Allow the hot solution to cool to 25 0C for 1 hr, Filter the separated solid and dry at 55 0C to get Form I crystals
Example 9
Dissolve 0.5 g of Imiqμimod maleate in 15 ml of DMF at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml of DIPE. Maintain the solution at 25 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals
Example 10
Dissolve 0.5 g of Imiquimod maleate in 15 ml of I)MF at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml of acetone. Maintain the solution at 25 0C for one hour. Filter the separated solid and diy at 55 °C to get Form I crystals Example 11
Dissolve 0.5 g of Imiquimod maleate in 5 ml of acetonirile at 60 °C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml of ethyl acetate. Maintain the solution at 25 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals
Example 12
Dissolve 0.5 g of Imiquimod Maleate in 40 ml of 1 , 4-Dioxane at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml water. Maintain the solution at 25 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals Example 13
Dissolve 0.5 g of Imiquimod Maleate in 25 ml of methanol at 60 0C. Allow the hot solution to cool to 25 0C following it by addition of 25 ml of DIPE and 5 ml water. Maintain the solution at 25 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals. PROCESS OF PREPARING IMIQUIMOD FUMARATE (VIIb) CRYSTALS
A) Imiquimod Fumarate Form I Example 14
Dissolve 0.5 g of Imiquimod fumarate in 20 ml of 1 , 4-Dioxane at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of toluene. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals
Example 15
Dissolve 0.5 g of Imiquimod fumarate in 20 ml of 1, 4-Dioxane at 105 0C. Allow the hot solution to cool to 70 °C following it by addition of 40 ml water. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 °C to get Foπn I crystals.
Example 16
Dissolve 0.5 g of Imiquimod fumarate in 20 ml of 1 , 4-Dioxane at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of diisopropyl ether. Cool the hot solution to 10 °C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals. Example 17
Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMF at 160 0C. Allow the hot solution to cool to 30 °C, further cooling it to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals. Example 18
Dissolve 0.5 g of Imiquimod ftimarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of chloroform. Cool the hot solution to 10 0C for one hour, Filter the separated solid and dry at 55 0C to get Form I crystals. Example 19
Dissolve 0.5 g of Imiquimod ftimarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of toluene. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals. Example 20
Dissolve 0.5 g of Imiquimod ftimarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of water. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals. Example 21
Dissolve 0.5 g of Imiquimod ftimarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of methanol. Cool the hot solution to 10 0C for one hour, Filter the separated solid and dry at 55 0C to get Form I crystals. Example 22
Dissolve 0.5 g of Imiquimod ftimarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of ethanol. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Foπn I crystals. Example 23
Dissolve 0.5 g of Imiquimod ftimarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of isopropyl alcohol. Cool the hot solution to 10 °C for one hour. Filter the separated solid and dry at 55 0C to get Foπn I crystals.
B) Imiquimod Fumarate Form II
Example 24 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0C. Allow the hot solution to cool to 70 °C following it by addition of 40 ml of diisopropyl ether. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get
Form II crystals.
Example 25 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of methanol. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 °C to get Form
II crystals.
Example 26 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of toluene. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form
II crystals.
Example 27 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMSO at 105 0C. Allow the hot solution to cool to 70 °C following it by addition of 40 ml of isopropyl alcohol. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get
Form II crystals.
Example 28 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of acetone. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form
II crystals.
Example 29 Dissolve 0.5 g of Imiquimod fumarate in 20 ml of DMF at 105 0C. Allow the hot solution to cool to 70 0C following it by addition of 40 ml of acetonitrile. Cool the hot solution to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form
II crystals. C) Imiquimod Fumarate Form III
Example 30
Dissolve 0.5 g of Imiquimod Fumarate in 20 ml of methanol at 70 0C. Allow the hot solution to cool to 30 0C, further cooling to 10 0C for one hour. Filter the separated solid and dry at 55 0C to get Form III crystals.
PROCESS OF PREPARING IMIQUIMOD OXALATE (VIIc) CRYSTALS A) Imiquimod oxalate Form I Example 31 Dissolve 0.5 g of Imiquimod oxalate in 40 ml of water at 100 0C. Allow the hot solution to cool to 30 0C, further cooling to 5 0C for one hour. Filter the separated solid and dry at 55 0C to get Form 1 crystals.
Example 32
Dissolve 0.5 g of Imiquimod oxalate in 10 ml of methanol at 60 0C. Allow the hot solution to cool to 30 0C following it by addition of 40 ml chloroform. Cool the solution to 5 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals.
Example 33
Dissolve 0.5 g of Imiquimod oxalate in 10 ml of dioxane at 60 0C. Allow the hot solution to cool to 30 0C following it by addition of 20 ml methanol. Cool the solution to 5 0C for one hour. Filter the separated solid and dry at 55 0C to get Form I crystals.
Example 34
Dissolve 0.5 g of Imiquimod oxalate in 20 ml of methanol at 60 0C. Allow the hot solution to cool to 30 0C following it by addition of 40 ml water. Cool the solution to 5 0C for one hour. Filter the separated solid and dry at 55 0C to get Foπn I crystals.
Example 35
Dissolve 0.5 g of Imiquimod oxalate in 20 ml of methanol at 60 0C. Allow the hot solution to cool to 30 0C following it by addition of 40 ml diisopropyl ether. Cool the solution to 5 0C for one hour. Filter the separated solid and diy at 55 0C to get Form I crystals.
Example 36
Dissolve 0.5 g of Imiquimod oxalate in 10 ml of isopropyl alcohol at 60 0C. Allow the hot solution to cool to 30 0C following it by addition of 20 ml water. Cool the solution to 5 0C for one hour. Filter the separated solid and dry at 55 °C to get Foπn I crystals. B) Imiquimod oxalate Form II
Example 37
Dissolve 0.5 g of Imiquimod oxalate in 20 ml of DMF at 160 0C. Allow the hot solution to cool to 30 0C following it by cooling the solution to 5 0C for one hour. Filter the separated solid and dry at 55 0C to get Form II crystals.
Example 38
Dissolve 0.5 g of Imiquimod oxalate in 10 ml of DMSO at 170 0C. Allow the hot solution to cool to 30 0C, further cooling the solution to 5°C for one hour. Filter the separated solid and dry at 55 °C to get Form II crystals, C) Imiquimod oxalate Form III
Example 39
Suspend 0.5 g of Imiquimod oxalate Form I crystals in 20 ml methanol and 40 ml chloroform. Stir the resultant suspension at 25 0C for 12 h. Filter the solid and dry at
55 0C to get Form III It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as described. The present embodiments are, therefore, to be considered in all , respects as illustrative and not restrictive. ADVANTAGES OF THE PRESENT INVENTION
The present invention provides Imiquimod in substantially pure form. The product is having purity greater than 99 %.
The present invention provides Imiquimod with 88% yield.

Claims

We Claim,
1. A process for preparation of substantially pure 4-Amino-l-isobutyl-lH- imidazo-[4,5-c]-quinoline (VIII), said process comprising of: a. cyclizing 3-Amino-4-(isobutylamino)-quinoline (I) with formic acid to obtain 1-isobutyl-lH- imidazo-[4,5-c]-quinoline (II);
Figure imgf000024_0001
b. oxidizing l-Isobutyl-lH-imidazo-[4,5-d]-quinoline (II) with per acid in an organic solvent affording 1-isobutyl-lH- imidazo-[4,5-c]-quinoline- 5-N-oxide (III ); .
Figure imgf000024_0002
treating 1-Isobutyl-lH- imidazo-[4,5-c]-quinoline-5-N-oxide (III) with alcoholic hydrochloric acid to form its hydrochloride salt (IV);
Figure imgf000024_0003
IV reacting hydrochloride salt (IV) with a chlorinating agent to form A- Chloro-1H- imidazo-[4,5-c]-quinolme (V);
Figure imgf000025_0001
V e. reacting 4-Chloro-lH- imidazo-[4,5-c]-quinoline (V) with an alkali halide in a dipolar aprotic solvent medium to obtain the corresponding 4-iodo derivative (VI);
Figure imgf000025_0002
Vl f. ammonolysing the said 4-iodo derivative (VI) to obtain crude product Imiquimod (VIII) in ammonia solution; g. converting the crude product Imiquimod (VIII) into a pharmaceutically acceptable organic salt (VII) by reacting the crude (VIII) with an organic acid, in a suitable solvent medium; and
Figure imgf000025_0003
(VII) h. obtaining pure Imiquimod (VIII) from Imiquimod salt (VII) by treating it with ammonia.
Figure imgf000025_0004
V I I I 2. The process as claimed in claim 1 wherein in step (b) the peracid used is preferably meta-chloroperbenzoic acid.
3. The process as claimed in claim 1 , wherein in step (b) the organic solvent used in oxidation is ethyl acetate. 4. The process as claimed in claim 1, wherein in step (b) oxidation is performed at about 60-70 °C.
5. The process as claimed in claim 1, wherein in step (b) the oxidation reaction is completed in about 6-10 h.
6. The process as claimed in claim 1, wherein in step (c) the alcoholic hydrochloric acid is preferably ethanolic hydrochloric acid.
7. The process as claimed in claim 1 wherein in step (d) the chlorinating agent used to convert 5-N-oxide hydrochloride (IV) to 4-chloro derivative (V) is phosphorous oxychloride, ;
8. The process as claimed in claim 1, wherein in step (e) the alkali halide is preferably sodium iodide.
9. The process as claimed in claim 1 wherein in step (e) the dipolar aprotic solvent is acetone.
10. The process as claimed in claim 1 wherein in step (f) the ammonia solution is preferably methanolic ammonia. 11. The process as claimed in claim 1, wherein in step (f) the ammonolysis is performed at 140-155 0C and at 15 - 20 Kg pressure.
12. The process as claimed in claims 10 and 1 1 , wherein in step (f) the product is dried for about 8 h.
13. The process as claimed in claim 1, wherein in step (g) the acid used to prepare the organic salts is carboxylic acid.
14. The process as claimed in claim 1, wherein! in step (g) in the acid used is preferably dicarboxylic acids selected from a group consisting of maleic acid, fumaric acid and oxalic acid
15. The process as claimed in claim 1, wherein in step (g), the solvent used is selected from a group consisting of water, methanol, DMF and mixture thereof. 16. The process as claimed in claim 1, wherein in step (g) the preparation of A- amino-l-isobutyl-lH-imidazo[4,5-c] quinoline maleate (Vila) is achieved in aqueous methanol at a temperature in the range of about 70-800C.
17. The process as claimed in claim 1, wherein in step (g) the preparation of A- amino-l-isobutyl-lH-imidazo[4,5-c] quinoline fumarate (VIIb) is achieved in
DMF at a temperature in the range of about 150-1700C.
18. The process as claimed in claim 1, wherein in step (g) the preparation of 4- amino-l-isobutyl-lH-imidazo[4,5-c] quinoline oxalate (VIIc) is achieved in DMF at a temperature in the range of about 150-1700C. 19. The process as claimed in claim 1, wherein in step (g) the product (VII) is isolated at 8 - 10°C for about 1 hour.
20. The process as claimed in claim 1, wherein in step (g) the product obtained is having purity greater than 99 %.
21. The process according to claim 1, wherein }n step (h) the conversion of 4- amino-l-isobutyl-lH-imidazo[4,5-c] quinoline maleate (Vila) to 4-Amino-l- isobutyl-lH- imidazo-[4,5-c]-quinoline (VIII) pure, is performed in aqueous methanol. .
22. The process according to claim 1 wherein in step (h) the product obtained is having purity greater than 99.5 %. 23. The process according to claim 1 wherein in step (h) the product shows peaks in XRPD at 2Θ values: 10.81, 11.26, 11.3963, 15.38, 19.16, 20.22, 21.56, 22.13, 24.48, 26.42, 30.25, 31.86.
24. The process as claimed in claim 1 wherein in step (h) the said compound pure Imiquimod (VIII) formation is earned out in mixture of water and polar protic or aprotic solvent.
25. The process as claimed in claim 24, wherein in step (h) the ratio of water to solvent is in the ratio of 1 : 2.
26. The process as claimed in claim 24, wherein the polar protic solvent used is Ci-C4 alcohols, preferably methanol. 27. The process as claimed in claim 24, where in polar aprotic solvents used is selected from a group consisting of Dimethyl formamide and Dimethyl sulfoxide, preferably Dimethyl formamide (D]VlF). 28. A process to prepare crystalline polymorphic form I of imiquimod Maleate, said process comprising dissolving Imiquimod maleate in suitable polar aprotic solvent and optionally adding polar protic solvent as antisolvent.
29. The process claimed in claim 28, wherein the polar aprotic solvent is selected from acetone, acetonitrile, DMF and 1,4-Dioxane.
30. The process claimed in claim 28 wherein the polar protic solvents is selected from water, Ci-C4 alcohols preferably IPA1 chlorinated hydrocarbons like chloroform, MDC, preferably MDC.
31. A process to prepare crystalline polymorphic forms of Imiquimod fumarate vzz. Form I, Form II and Form III.
32. The process for the preparation of imiquimod fumarate form I crystals as claimed in claim 31, by dissolving imiquimod fumarate in polar aprotic solvent and optionally adding an antisolvent selected from a group consisting of polar protic solvent, polar aprotic solvent, aromatic hydrocarbon, chlorinated hydrocarbon and aliphatic ether to crystallize.
33. The process as claimed in claim 32, wherein the polar aprotic solvent is either 1,4-Dioxane or DMF.
34. The process as claimed in claim 32 the antisolvent is selected from a group consisting of water, Ci-C4 alcohols, toluene, Chloroform, MDC and diisopropyl ether.
35. The process for the preparation of Imiquimod fumarate Form II crystals as claimed in claim 31, by dissolving in polar aprotic solvent and adding an antisolvent selected from group consisting ■ of polar protic solvent, polar aprotic solvent, aromatic hydrocarbon and aliphatic ether. 36. The process as claimed in claim 35 wherein the polar aprotic solvent used is either DMF or DMSO.
37. The process as claimed in claim 35 wherein1 the antisolvent used is selected from, polar protic solvent selected from Ci-C4 alcohols such as methanol and IPA, polar aprotic solvent such as acetone and acetonitrle aromatic hydrocarbon solvent such as toluene, and ethers selected from C1-C4 aliphatic ether such as diisopropyl ether.
38. The process as claimed in claim 35 when the polar aprotic solvent used is DMF, the antisolvent used is selected either acetone or acetonitrile. 39. The process as claimed in claim 35 when the polar aprotic solvent used is •DMSO, the antisolvent used is selected from a group consisting of Ci-C4 alcohols preferably methanol or IPA, aromatic hydrocarbon solvent preferably toluene, and ethers selected from Ci-C4 aliphatic ether preferably diisopropyl ether.
40. The process for the preparation of Imiquimod fumarate Form III crystals as claimed in claim 31 by dissolving Imiquimod fumarate in a polar protic solvent.
41. The process as claimed in claim 40, wherein the polar protic solvent used is selected from the group of Ci -C4 alcohols preferably methanol or isopropyl alcohol.
42. A process to prepare crystalline polymorphic forms of Imiquimod oxalate viz. Form I, Form II and Form III.
43. The process for preparation of Imiquimod oxalate Form I crystals as claimed in claim 42, by dissolving Imiquimod oxalate! in a solvent selected from polar protic solvent and aprotic solvent, and optionally adding an antisolvent which is selected from polar protic solvent, chlorinated hydrocarbon and aliphatic ether.
44. The process as claimed in claim 43, the polar protic solvent used is water. 45. The process as claimed in claim 43, wherein the solvent for dissolving is selected from a group consisting of methanol, isopropyl alcohol and 1 ,4- Dioxane
46. The process as claimed in claim 43 wherein the solvent used as antisolvent is selected from a group consisting of water, methanol, Chloroform, MDC and diisopropyl ether
47. The process for preparation of Imiquimod oxalate Form II crystals as claimed in claim 42, by dissolving Imiquimod oxalate in a polar aprotic solvent
48. The process as claimed in claim 47, wherein the polar aprotic solvent used is either DMF or DMSO. . ' 49. The process for preparation of Imiquimod oxalate Foπn III crystals as claimed in claim 42, by suspending Imiquimod oxalate Form I or Imiquimod oxalate Form II in a mixture of polar protic solvent and chlorinated hydrocarbon solvent. 50. The process as claimed in claim 49, wherein the polar protic solvent used is selected from the group Of Ci-C4 alcohol and chlorinated hydrocarbon.
51. The process as claimed in claim 49, wherein the polar protic solvent used is methanol, chloroform and MDC. 52. A compound 4-Iodo-l-isobutyl-lH- Imidazo<-[4,5-c]-quinoline (VI).
Figure imgf000030_0001
53. A compound 4-amino-l~isobutyl-lH-imidazo[4,5-c] quinoline maleate(VIIa) and its polymorphic form thereof.
COOH
Figure imgf000030_0002
54. A substantially pure 4-amino-l-isobutyl-lH-imidazo[4,5-c] quinoline maleate (Vila) in the form of crystalline polymorph' form I, being characterized by peaks at below shown diffraction angles in XRPD and absorption peaks in FTIR spectra:
Form I: Characteristic peaks in XRPD at 26 values 9.50, 9.95, 17.13, 19.15, 19.93, 21.63, 24.37, 24.71, 27.09 and wave numbers (cm-1) in FT-IR spectrum at 3298, 3129.3, 3089.8, 1676, 1608.5, 1494.1 1467, 1448, 1407, 1361.7, 1213.1,1083,9, 948.9, 867.9, 776.3, 754.1, 692.4, 673.1, 661.5, 640.3, 590.2, 563.2.
55. A compound 4-amino-l-isobutyl-lH-imidazo[4,5-c] quinoline fumarate( VIIb). H
Figure imgf000031_0001
56. A substantially pure 4-amino-l -isobutyl-lH-imidazo[4,5-c] quinoline fumarate (VIIb) in the form of crystalline polymorphs selected from a group consisting of I, II and III, each polymorph being characterized by peaks at below shown diffraction angles in XRPD and absorption peaks in FTIR spectra: a. Form I. Characteristic peaks in XRPD at 2Θ values 6.86, 8.87, 10.74, 13.57, 14.63, 18,34, 20.30, 20.87, 21.51 , 22.33, 22.85, 22.98, 25.48, 26.43, 27.03, 27.85, 29.71, 30.08, 31.21, 33.91, 35.28 and wave numbers (cm"1) in the FT-IR spectra , 3489.0, 3093.6, 2970.21695.3,
1527.5, 1379, 1124.4, 1103.2, 985, 754.1 , 682.8, 563.2. b. Form II. Characteristic peaks in XRPD at 2Θ values 10.87, 11.44, 12.43, 14.36, 15.46, 18.39, 19.25, 21.62, 22.03, 22.18, 24.55, 31.91 and wave numbers (cm'1) in the FT-IR spectra 3311.5, 3178, 2958.6, 1645.2, 1614.3, 1527.5, 1469.7, 1396.4, 1371.3, 1251.7, 1097.4, 991.3,
873.7, 848.6, 821.6, 759.9, 640.3, 607.5. c. Form III. Characteristic peaks in XRPD at 2Θ values 9.10, 11.47, 16.48, 17.34, 18.00, 19.24, 19.60.21.38, 22.80, 23.50, 24.98, 25.99, 26.79, 27.32, 28.69, 29.51, 30.76, 37.36 and wave numbers (cm"1) in the FT-IR spectra 3477, 3234.4, 3093.6, 2758, 2362.6, 1693, 1606.6,
1531.4, 1375.2, 756.0, 684.7, 569.
57. A compound 4-amino-l-isobutyl-lH-imidazo[4,5-c] quinoline oxalate( VIIc).
H H
Figure imgf000031_0002
58. A substantially pure 4-amino-l -isobutyl-lH-imidazo[4,5-c] quinoline oxalate (VIIc) in the form of crystalline polymorphs selected from a group consisting of I, II and III, each polymorph being characterized by peaks at below shown diffraction angles in XRPD and absorption peaks in FTIR spectra: a. Form I. Characteristic peaks in XRPD at 2Θ values 10.83, 11.43, 14.39, 15.44, 18.36, 19.10, 19.24, 21.63, 22,17, 24.56, 31.88 and wave numbers (cm"1) in the FT-IR spectra 3419.6, 3217, 3062.7, 2962.5, 2360.7, 1701, 1541 1309, 756, 769,715;688, 669, 567. b. Form II. Characteristic peaks in XRPD at 2Θ values 7.92, 15.56, 15.91,
16.60, 16.76, 17.74, 18.03, 23.25, 25.01, 27.92, 31.48 and wave numbers (cm'1) in the FT-IR spectra 3315, 3182, 2958,1647,1614, 1529, 1583, 1465, 1475, 1253, 1095, 873, 848, 761, 665. c. Form III. Characteristic peaks in XRPD at 2Θ values 6.96, 7.42, 9.99, 10.31, 10.45, 12.41, 13.31 , 13.79, 16,16, 19.21, 21.12, 23.74, 24.90,
25.62, 25.94, 26,60 and wave numbers (cm"1) in the FT-IR spectra 3101, 2962, 1685, 1218, 1099, 948, 748,713, 690, 657, 632, 590.
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