Title of Invention

"A 1H-IMIDAZO[4,5-C] QUINOLINE 4-PHTHALIMIDE COMPOUND OF FORMULA (II) AND PROCESS FOR PREPARING THE SAME"

Abstract The invention provides a lH-imidazo[4,5-C] quinolin-4-phthalimide intermediates useful in the synthesis of IH-imidazo[4,5-C] quinoline-4-amines, particularly Imiquimod. The invenitno further provides a method for making the intermediates and a method for making l-H-imidazo(4,5-C)quinoline-4-amines via the intermediates.
Full Text The present invention relates to a lH-imidazo[4,5-c] quinoline 4-phthalimide compound of formula (II) and process for preparing the same.
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of provisional application Serial No. 60/397,607, filed .July 23,2002, the contents of which is incorporated herein.
FIELD OF THE INVENTION
The present invention relates to a process for the synthesis of IH-imidazo [4,5-c] quinoline 4-phthalijroide intermediates useful in preparing IH-imidazo [4,5-C] quinoline 4-amines, a process for preparing IH-imidazo [4,5-C] quinoline 4-amines using such intermediates; and, to the lH-Emidazo[4,5-c] quinoHne 4-phthaliinide intermediates. More particularly, the present invention relates to a novel process for the preparation of 1-isobutyl-lI-I-imidazo [4,5-C] quinoline 4-ainine (Imdquimod) by introducing an amino group in the 4 position of 1-isobutyl-lH-imidazo [4,5~CI quinoIin-4-amine via a l-isobutyl-lH-imidazo[4,5-c] quinoline 4-phtb;aIimide intermediate, and to the 1-isobutyl- lH-imidazo[4,5-c] quinoline 4-phthalimide intermediate.
BACKGROUND OF THE INVENTION
Imiquiinod, 1-isobutyl-IH-imidazo [4,5-C] quinolin-4-amine, is an immune response modifier, useful for treating viral infections, such as genital warts. Jmiquiraod is disclosed in U.S. patents 4,689,338 and 5^38,944 and has the structure:
(Structure Removed)
Several methods are kown in the art for making IH-imidazo [4,5-c]quinoline 4-ainines, including Imiquimod. The amino group in the 4 position has been introduced in essentially three
ways: The first is by nucleophilic sabstitution of a leaving group, e.g CI, triflate, etc., with ammoma, dibenzylaminc or an azido group; the second is by reacting 1-isobutyl-lH-imidazo [4,5-c} quinoline-N-oxide with axmnoniwn hydroxide or anmaoninm salts in the presaice of tosyl chloride at 0-5°C; and the third is by reacting l-isobutyl-lH-inidazo[4,5-c]qainolinc-N-oxide with bttizoyl isocyanate.
Nucleophilic substitution reactions are disclosed in, for examle, WO 97/48704, WO 92/06093, VS. patents 5395^7.5,756,747,4,988,815,5,602256,5,578,727,4,698,348, 4,689388, European patents EP 145340, EP 0385630, EP 310950 and JP 04193866. Specificaily, in WO 97/48704 the amino group is iaitroduccd by reaction of a 4-chloro derivative with sodium azide to obtain a tetrazoie nooiety. Reaction of the tettazole moiety with triphenylphosphine gives the 4-amino derivative. In US. patent 5395937, a 4~triflate derivative is reacted with dibenzylaminc. The catalytic reduction of the 4-dibcnzylaniino derivative places an annuo group in the 4-postion. U.S. patent 5,756,474, ducloses a nucleophilic substitotion Willi ammonia on a 4-chloro derivative, obtained by isomerization of 1-isobutyl-lH-imidazo[4,5-c]quino}ine-N-oxidc to the 4-hydroxy derivative, followed by reaction with POCI3. The following patents all disclose a nucleophilic sobstitution of l-isobutyl-IH-inudazo[4,5-c] quinoline-4-chloro with axmonia at high temperature and pressure: 4,988,815,5,602256, 5,578,727,4,698348,4,689388, EP 145340, JP 04193866, EP 0385630, and EP 310950.
WO 92/06093 disdoses reacting l-isobutyl-lH-inaidazo [4,5-c] quinoline-N-oxide with amamonium hydnxdde or ammoniam salts in the presence of to tosyl chloride at 0-3 °C.
WO 92/15581 discloses reacting l-isobuiyHH-imidazo[4,5-c]quinoline-N-oxide with benzoyl isocyanate.
However, a need exists in the art formaking IH-inudazo [4,5-0] quinoline 4-amines, especially Imiqmmod, in high purity and high yidd and which does not require high temperature or pressure.

SUMMARY OF THE INVENTION
In aspect, the present invention is directed to a compound of formula

(Formula Removed)
wherein
R1 is selected from the group consisting of: hydrogen; a straight or branched diain alkyl of one to about 10 carbon atoms, optionally substituted with a substituent selected from the group consisting of lower alkyl, cycloalkyl of 3 to about 6 carbon atoms, wherein said cycloalkyl is optionally substituted with a lower- alkyl group; straight or branched cham aDccnyl of 2 to about 10 carbon atoms, whoein tb,e olefinic unsataraticm in the alkenyl group is at least one carbon atom removed firom the l-nxtrogen, and wherein tiic straight or branched chain alkyl is optionally substituted with a substituwit selected from the groiq) consisting of lower alkyl, cycloalkyl of 3 to about 6 carbon atoms, wherein said igrcloa;lcyl is optioiially substituted with alower allcyl group; hydroxyalkcyl of one to about six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to sixnat Sour caibor atoms erbeoz^loxy aad the afi^ mojety contains one to about ax carbon atoms; ben2yl; (phaiyl)ethjd; and phenyl, wherdba said bcaizyl, (phcnyl)ethyl and phenyl substituaits are optionally substituted on the benzene ring by one or two moieties indepedeotly selected from the group consisting of lower allcyl, lower alkcoxy, and halogai, with fee proviso that when the benzene ring is substituted by two such moieties, then the moieties togetha: contain more than 6 carbon atoms;
R2 is selected from the group consisting of: hydrogen; straight or branched chain alkyl containing one to about eight carbon atoms; benzyl; (phenyl)cthyl; and phenyl, wherein said benzyl, (phenyl)cthyl and phenyl substituents are optionally substituted on the benzene ring by one or two mcneties independently selected from the group consisting of lower alkyl, lower
alkoxy, and halogen, with i the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain more than 6 carbon atoms;
R is independently selected from the group consisting of: aDcoxy of one to about four carbon atoms; alkyl of one to about foxir carbon atoms; and halogen; and
n is an integex from 0 to 2, with the proviso that if n is 2, then said groops together contain no more than 6 carbon atoms.
hi a preferred embodiment, R1 is isobutyl, R2 is hydrogen, n is 0.
In another aspect, the jaresent inverstion is directed to a process for prqaaring a IH-iimdazo[4,5-c] qoinoline 4-phthalim2dc of formula.(II) comprising reacting a compound of formula (III) with phthaHmide in a suitable organic solvent, wherein R, R1, R2 and n are defined above.
(Formula Removed)
In another aspect, the present invention is direded to a. process for prreparing a compound of formuula (I):
(Formula Removed)
comprising reacting a compound of fomula (II) with hydrazine hydrate in a suitable solvent, wh«Bin R, R1, R2 and n are defined above.
These and other aspects of the present invention will now be described in more detail
with reference to the following detailed desciption of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention is directed to a process for preparing IH-imidazo [4,5-c]qiunoline-4~amines of formula (I). The preferred lH-imidazo[4,5-c]quinoline-4-amine is imiquimod. However, the inventive process can be used to prepare any compound within the scope of formula (I), including those disclosed in U.S. patets 5,156,1 Al, 5,395,937, 4,689.338, EP 385630, WO 97/48704, WO 92/06093 and WO 92/15581, all of which are incorporated by rrfexence in their entirety herein.
The invention is also directed to novel lH-imidazo[4,5-c] quinohne 4-phthaIicnide intermediates of formula (II), whidi arc usrful in preparing lH-inudazo[4,5-c]quinoline-4-amines of formula (I), and to a process for preparing the intermediates of fonnula (IT).
The lH-imidazo[4,5-c] quinoline4-phthalisiide intermediates of fonnula (H) are prepared by reacting a lH-imida2»[4,5-c] quinoline N-oxide of fonnula (HI) with phthalimide. The leactioo is canied out in a solvent and a base. Preferred solvents include methyloie chlohde and etfaylacetate. Preferred bases include txi-n-butjdamine, tricthylamine and tmsobutylamine. The most piefored mixture is ethylacctate and tri-n-butylaminc. The reaction is preferably carried out in tas presence of benzoyl chloride. The reaction is preferably canied out at a temperature of between about 0-10 °C, over a period of about one hour.
The lH-imidazo[4,5-c] quinoUne N-oxides of formula (III) can be obtained by any method known in the art, including those disclosed in: U.S. patent 5,756,747, WO 92/06093 and WO 92/15581, all of which axe incorporated by reference in their entirety herein.
The lH-imidazo[4,5-c] quinoline 4-phdialimide intermediates of formula (II) are then reacted with hydrazine hydrate in a suitable solvent to form lH-imidazo[4,5-c]quinoline-4-amincs of formula (I). Water is a preferred solvent. Pref^arably, isooctyl alcohol is added to avoid foam formation. The reaction is preferably canied out at a temperature of between about 94-95 °C, over a period of about 4-5 hours.
One reaction scheme that may be used to make lH-'iznidazo[4,5-c]quznoline-4-amincs of formula (I) is shown below:

(Formula Removed)
The present invention is illustxated in furthcr detail with reference to the following non-limiting axamples.
Example 1 Preparation of 4-isobutyl-3-nitro quinoline 4-chloro-3-nJtro-qoinoliae is reacted with isobutyl amine in the presence of triethylanune (TEA) at between -10 and +15 °C in toluene, -while excluding tnoisture. After washing and phase seiKKcation, the organic solution is ready for the next step.
Example 2
Preparation of 4-isobutyl-3-'anuno quinoiine The nitcoxide group on the 4-isobutyl-3-nitro quinoiine produced in Example 1 is reduce by catalytic reduction using tohieie as solvent, Pd/C 5% (50% wet) as catalyst, at 40-45 X and atmospheric pressure to produce 4-isobutyi 3-aznino quinoiine. The rate of reaction depends on efficiency of stiiring. After catalyst filtration the solution is ready for the next step.
Preparation of l-isobutyl-lH-inridazo[4,5-c3quinoline The cylization of 4-isobutyl 3-aniino quinoline-isroduced in Example 2 is carried out in toluene at 102-110 °C using TEOF(tiicftyl orthofonnate) and 20% moles of formic acid to increase the rate of reaction, to produce l-isobutyl-lH-imkl3zo[4^-i;}quinolinfi. Befois addition of TEOF, in order to preveat its hydrolysis, it is necessary to ranove water formed during the catalytic rcducdon by azeotropic distillation. A mixtute of cthanol and toluene is distiUed during the reaction to maintain the internal temperature at 102-110 °C.
Example 4
Preparatian of l-isobutyl-lH-imidazo[4,5-c]qainoline N-oxide The oxidation of l-isobutyl-lH-imidazo[4,5-c]quinoline produced in Example 3 is carried out in toluene at 40-45 °C 'oamg peracetic acid as oxidant to produce l~isobutyi-lH-imidazo[4,5-c3quinoline N-oxide, The product is isolated by filtration after additicm of a sodium sulfate solution and ammonixun hydroxide.
Example 5
Preparation of 1-isobxityl-lH-imidazo[4,5-c]quinoline-4-phthaIiimde 93 ml of mefliyienc chloride and 15 g of l-isobutyi-lH-imidazo[4,5-c]qiiinoiineN-oxide CHPLC= 95%) are loaded into a 250 ml three necked round flask. Then 24.55 g of tri n-butylamine (98%) and 10.06 g of phthalimide (99%) are added to the flask imder nitrogen and stirring. THE suspension formed is cooled to 0 °C and the following solution is dropped into the suspension over 1 houn 12.7 g of benzoyl chloride (98%) in 13 ml of methylraie chloride, as the tempexature is kept between 0-10 °C. The mixture is stirred at room temperature for about 30 nsinutes and a $anq>]e is taken. HPLC anaiy»s shows that there is 0.32% of the starting material, 87.72% of the target product, and 0.43% of ^ 4-hydroxy derivative. The solution is filtered and the filter cake is washed 3 times with 10 ml of metibi}4ene chloride. The wet filter cake is resuspoided at 25 °C for at least 7 hours in 100 ml of methanoL After resuspension the solution is filtered and the filter cake is washed 2 times witb 10 ml of me&anoL Prior to the second filtration, IB?LC shows that there is Ppreparation of l-isolontyl-lH-iniidazo[4,5-c}quinoline-4-amine 72 mi water and 18 g l-isobutyd-lH-imida2o[4,5-c]quinoItne-4-phthalimide (HPLO=98.98%) are heated to 70 °C in a 250 ml reactor. 4.8 g hydraziae hydrate is dropped into the reat^r while stining aiui then 2 ml iso-octyl alcohol is added to the reactor. The reactiom mixture is heated at 94-95 "C for 4 hours and a sample is taken. HPLC analysis shows that there is 6.16% starting material and 94 % target material. To obtain a complete conversion of starting matorial the reaction is allowed to proceed for another hour. The reaction mixture is cooled at 60*C and 180 ml of methanol is added. The mixture is warmed at reflux for 15 minutes, fbea cooled at rocm teiiiperatnre. The solution is filtered and &e cake is washed 3 time with 15 ml of a 3.5:1 mixture of methanol and water. The wet solid obtained weighs 22.4 g. HPLC analysis shows that its purity is 98.23% (no phthalhydrazide integration). The wet
sofid is treated with 180 ml of water and 5.2 g of 37% HCl at 90-93 "C for 30 minutes. The hot suspension is filtered and ibe cake is washed 3 limes with 15 ml of water. The solid is phfljalhydraaade weighing 4.5 g. The hot solution is treated at 90-93 °C with 0.115 g Na2S2O4 and 0.576 g charcoal. After 30 minutes the diarcoal is filtered off and the cake is washed two times with 10 ml water. The soluticm is cooled at 70-75°C and 10 g of 30% NaOH is added to pH 11.54, at whicb time a solid predpitErtcs. The mixture is cooled to room temperature and after 1 hour the solid is filtered and tiie cake is washed 3 times with 10 ml water. 15.1 g of crude wet Imiquimod (pale pink color) is obtained. The Imiquimod is dried to a weight of 10.S7 g. BDPLC shows the purity to be 98.12%. There is 1.55% phthalhydrazide present.
Example 7
Purification of l-is6buQd-lH-imidazo[4,5-c]quinoliiie-4-amine 53.55 ml water, 23.62 ml butjd alcohol, 10.57 crude Imiquimod and 4.77 g of 37% HCl are loaded into a 100 ml reactor. The mixture is heated to 55-60"C to obtain a solution. The solution is cooled to room temperature and a white crystal prec^itates. The solid is filtered and washed 2 times with 5 ml butyl alcohol. 13.63 g of wet Xmiquimod chloridtate is obtained. HPLC analysis shows that there is 99.S9% Imiquimod and 0.01% phthalhydrazide. 120 ml water and 13.63 g of wet imiquimod cbloridate arc loaded into a 250 ml reactor and heated to 85-90°C. The hot solutxon is filtered and the cake is washed 5 ml of hot water. Then 0.024 g of Na2S2O4 is added. The coloriess solution is cooled to 70-75 °C and 5.3 g of 30% NaOH is added to provide a pH of 9-7, at which point a solid precipitates. The suspension is ojoled to 20°C and filtaed. The cake is washed 3 times with 5 ml water and twice with 5 ml methanol. During the washes no chloride was detected by silvs-nitiate. The solid is dried under vacuum at 50°C for 8 hours. 8.98 g of Imiquimod (off-white color) is obtained. HPLC shows the purity to be 99.94% and the yield to be 63.3% based on the startii^ material (1-isobutyi-lH-iinidazo[4,5-c]qunoline N-oxide).
Having thus described tbe inventicm with reference to particular preferred embodiments and illustrated it with cxaxaples, &ose of skill in the art msy ^predate modifications to the inveation as desoibed and illustrated that do not dqpart j6tom the spirit and scope of the invention
as disclosed in the specification.





WE CLAIM:
1. A lH-imidazo[4,5-c] quinoline 4-phthalimide compound of formula (II):
(Formula Removed)
wherein
Ri is selected from the group consisting of: hydrogen; a straight or branched chain alkyl of one to 10 carbon atoms, optionally substituted with a substituent selected from the group consisting of lower alkyl, cycloalkyl of 3 to 6 carbon atoms, wherein said cycloalkyl is optionally substituted with a lower alkyl group; straight or branched chain alkenyl of 2 to 10 carbon atoms, wherein the olefinic unsaturation in the alkenyl group is at least one carbon atom removed from the 1-nitrogen, and wherein the straight or branched chain alkyl is optionally substituted with a substituent selected from the group consisting of lower alkyl, cycloalkyl of 3 to 6 carbon atoms, wherein said cycloalkyl is optionally substituted with a lower alkyl group; hydroxyalkyl of 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, wherein said benzyl, (phenyl)ethyl and phenyl substituents are optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of lower alkyl, lower alkoxy, and halogen, with the
proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain more than 6 carbon atoms;
R2 is selected from the group consisting of: hydrogen; straight or branched chain alkyl containing one to eight carbon atoms; benzyl; (phenyl)ethyl; and phenyl, wherein said benzyl, (phenyl)ethyl and phenyl substituents are optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of lower alkyl, lower alkoxy, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain more than 6 carbon atoms;
R is independently selected from the group consisting of alkoxy of one to four carbon atoms; alkyl of one to four carbon atoms; and halogen; and
n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.
2. A compound as claimed in claim 1, wherein Ri is isobutyl, R2 is hydrogen, and n is 0.
A process for preparing a lH-imidazo[4,5-c] quinoline 4-phthalimide of formula (II):
(Formula Removed)
comprising reacting a compound of formula III:

(Formula Removed)
with phthalimide, wherein R1 is selected from the group consisting of: hydrogen; a straight or branched chain alky of one to 10 carbon atoms, optionally substituted with a substituent selected from the group consisting of lower alkyl, cycloalkyl of 3 to 6 carbon atoms, wherein said cycloalkyl is optionally substituted with a lower alkyl group; straight or branched chain alkenyl of 2 to 10 carbon atoms, wherein the olefinic unsaturation in the alkenyl group is at least one carbon atom removed from the 1-nitrogen, and wherein the straight or branched chain alkyl is optionally substituted with a substituent selected from the group consisting of lower alkyl, cycloalkyl of 3 to 6 carbon atoms, wherein said cycloalkyl is optionally substituted with a lower alkyl group, hydroxyalkyl of 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, wherein said benzyl, (phenyl)ethyl and phenyl substituents are optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of lower alkyl, lower alkoxy, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain more than 6 carbon atoms; R2 is selected from the group consisting of: hydrogen; straight or branched chain alkyl containing one to eight carbon atoms; benzyl; (phenyl)ethyl; and phenyl, wherein said benzyl, (phenyl)ethyl and phenyl substituents are optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of lower alkyl, lower alkoxy, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain more than 6 carbon atoms;
R is independently selected from the group consisting of: alkoxy of one to four carbon atoms; alkyl of one to four carbon atoms; and halogen; and
n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.
4. The process as claimed in claim 3, wherein Ri is isobutyl, Ra is hydrogen, and n is 0.
5. The process as claimed in claim 3 or claim 4, wherein the reaction takes place in the presence of a base and a solvent.The process as claimed in claim 5, wherein the solvent is selected from the group consisting of methylene chloride and ethylacetate and the base is selected from the group consisting of tri-n-butylamine, triethylamine, and triisobutylamine.
6. The process as claimed in claim 6, wherein the solvent is ethylacetate and the base is tri-n-butylamine.
8. The process as claimed in claim 5, wherein the reaction further takes place in the presence of an organic acid halide.
9. The process as claimed in claim 8, wherein the organic acid halide is benzoyl chloride.
10. The process as claimed in claim 3 or claim 4, wherein the reaction takes place at a temperature of between 0 to 10° C.
11. The process as claimed in claim 3 or claim 4, wherein the compound of formula (III) and phthalimide are reacted over a period of 1 hour.
12. A compound as claimed in claim 1, produced by the process of claim 3.

Documents:

182-delnp-2005-abstract.pdf

182-delnp-2005-assignment.pdf

182-delnp-2005-claims.pdf

182-delnp-2005-complete specification (as file).pdf

182-delnp-2005-complete specification (granted).pdf

182-delnp-2005-correspondence-others.pdf

182-delnp-2005-correspondence-po.pdf

182-delnp-2005-description (complete).pdf

182-delnp-2005-form-1.pdf

182-delnp-2005-form-13.pdf

182-delnp-2005-form-18.pdf

182-delnp-2005-form-2.pdf

182-delnp-2005-form-3.pdf

182-delnp-2005-form-5.pdf

182-delnp-2005-gpa.pdf

182-delnp-2005-pct-101.pdf

182-delnp-2005-pct-210.pdf

182-delnp-2005-pct-220.pdf

182-delnp-2005-pct-304.pdf

182-delnp-2005-pct-306.pdf

182-delnp-2005-pct-308.pdf

182-delnp-2005-petition-137.pdf

182-delnp-2005-petition-138.pdf


Patent Number 243957
Indian Patent Application Number 182/DELNP/2005
PG Journal Number 47/2010
Publication Date 19-Nov-2010
Grant Date 11-Nov-2010
Date of Filing 18-Jan-2005
Name of Patentee TEVA PHARMACEUTICAL WORKS PRIVATE LIMITED COMPANY
Applicant Address PALLAGI 13, H-4042 DEBRECEN, HUNGARY.
Inventors:
# Inventor's Name Inventor's Address
1 SILVIA MANTOVANI VIA S. MARIA NUOVA 11/1, 45026 LENDINARA, ITALY.
2 STEFANO BIANCHI VIA RONCHETTO N 20, 22100 BRECCIA COMO, 22100, ITALY.
3 VALERIANO MERLI VIA CESARE BATTISTI N21, 23894 CREMELLA LECCO, ITALY.
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/US2003/023153
PCT International Filing date 2003-07-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/397,607 2002-07-23 U.S.A.