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WO2008048683A2 - Préparation de 1h-imidazo[4,5-c]quinoléin-4-amines via des intermédiaires de 1h-imidazo[4,5-c]quinoléin-4-phtalimide - Google Patents

Préparation de 1h-imidazo[4,5-c]quinoléin-4-amines via des intermédiaires de 1h-imidazo[4,5-c]quinoléin-4-phtalimide Download PDF

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Publication number
WO2008048683A2
WO2008048683A2 PCT/US2007/022321 US2007022321W WO2008048683A2 WO 2008048683 A2 WO2008048683 A2 WO 2008048683A2 US 2007022321 W US2007022321 W US 2007022321W WO 2008048683 A2 WO2008048683 A2 WO 2008048683A2
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WIPO (PCT)
Prior art keywords
aromatic hydrocarbon
phenyl substituted
substituted aromatic
formula
group
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PCT/US2007/022321
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WO2008048683A3 (fr
Inventor
Janos Hajko
Csaba Szabo
Piroska Kovacs
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Works PLC
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
Original Assignee
Teva Pharmaceutical Works PLC
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Priority to BRPI0706205-2A priority Critical patent/BRPI0706205A2/pt
Priority to EP07852861A priority patent/EP1966205A2/fr
Publication of WO2008048683A2 publication Critical patent/WO2008048683A2/fr
Publication of WO2008048683A3 publication Critical patent/WO2008048683A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 the synthesis of lH-imidazo[4,5- c]quinolin-4-amines. More particularly, the present invention relates to a process for the preparation Imiquimod via lH-imidazo[4,5-c]quinolin-4-phthalimide.
  • Imiquimod developed by 3M Pharmaceuticals is marketed as a cream, under the trade name ALD ARA®.
  • a phthalimide group is introduced in the first stage, and then removed using hydrazine hydrate in a solvent mixture of water and methanol.
  • the present invention provides a process for preparing a 4-amino- lH-imidazo[4,5-c]quinoline of formula I
  • (H) comprising reacting the lH-imidazo[4,5-c]quinolin-4-phthalimide of formula II and an amine selected from the group consisting of: alkylamine, aralkylamine, alkyldiamine, and aralkyldiamine; wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon, and phenyl substituted aromatic hydrocarbon, wherein R is selected from the group consisting of: alkoxy, alkyl, and halogen; and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.
  • R 1 and R 2 are independently selected from the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon, and phenyl substituted aromatic hydrocarbon, wherein R is selected from the group consisting of: alkoxy, alkyl, and halogen; and n
  • the alkylamine is a C 1-6 alkylamine.
  • the alkyldiamine is a Ci -6 alkyldiamine.
  • the aralkyldiamine is C 6-8 aralkyldiamine.
  • the alkyl is Ci-io straight or branched chain alkyl; more preferably Ci -8 straight or branched chain alkyl; even more preferably C 1-7 straight or branched chain alkyl.
  • the alkoxy is C 1-4 alkoxy.
  • the halogen is F, Cl, Br, or I; more preferably F.
  • the aromatic hydrocarbon is C 6-I2 aromatic hydrocarbon.
  • the present invention provides a process for preparing a 4- amino- lH-imidazo[4,5-c]quino line of formula I
  • (III) comprising reacting the lH-imidazo[4,5-c]quinolin-N-oxide of formula III, with phthalimide to obtain a lH-imidazo[4,5-c]quinolin-4-phthalimide of formula II, and reacting the lH-imidazo[4,5-c]quinolin-4-phthalimide of formula II and an amine selected from the group consisting of: alkylamine, aralkylamine, alkyldiamine, and aralkyldiamine; wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon, and phenyl substituted aromatic hydrocarbon; wherein R is selected from the group consisting of: alkoxy, alkyl, and halogen; and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.
  • the present invention is directed to a process for preparing lH-imidazo[4,5- c]quinolin-4-amines of formula I, in particular 4-amino-l-isobutyl-lH-imidazo[4,5- cjquinoline, Imiquimod, using a non-carcinogenic, cheap and efficient agent for removing the phthalimide group.
  • the process may be done according to the following scheme:
  • R 1 and R 2 are independently selected from the group consisting of: hydrogen, a straight or branched chain alkyl, aromatic hydrocarbon, and phenyl substituted aromatic hydrocarbon wherein R is selected from the group consisting of: alkoxy, alkyl, and halogen; and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms.
  • the straight or branched chain alkyl is C 1-I o straight or branched chain alkyl; more preferably C 1-8 straight or branched chain alkyl; even more preferably Ci -7 straight or branched chain alkyl; and most preferably Ci -4 straight or branched chain alkyl.
  • the C M straight or branched chain alkyl is methyl, ethyl, «-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; more preferably isobutyl.
  • the aromatic hydrocarbon is C 6-I2 aromatic hydrocarbon; more preferably C 6-8 aromatic hydrocarbon; most preferably phenyl, tolyl, or xylyl; most preferably phenyl.
  • the phenyl substituted aromatic hydrocarbon contains one or two substituents on the benzene ring.
  • the substituents for the group R are selected from the group consisting of: a Ci -4 alkyl group Ci -4 alkoxy group, and halogen with the proviso that when the benzene ring of the compound of Formulae (I), (II) or (III) is subsituted by two groups, the total number of carbon atoms on the substituents is no more than 6.
  • the C] -4 alkyl group is methyl, ethyl, M-propyl, isopropyl, rt-butyl, isobutyl, or tert-butyl; more preferably methyl.
  • the Ci -4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, w-butoxy, isobutoxy, or tert-butoxy; more preferably methoxy.
  • the halogen is F, Cl, Br, or I; more preferably F.
  • R] is isobutyl.
  • R 2 is hydrogen.
  • R is hydrogen.
  • said compound of formula I refers to 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline (referred to as Imiquimod) of the following formula,
  • lH-imidazo[4,5-c]quinolin-N-oxide of formula III can be prepared, for example, according to the process disclosed in WO 2004/009593.
  • the compound of formula II can be obtained, for example, according to the process disclosed in WO patent application 2004/009593 or in Example 1 herein.
  • the process comprises reacting the lH-imidazo[4,5-c]quinolin-N-oxide of formula III with phthalimide, wherein R 1 , R 2 , R and n are as described above.
  • the compound of formula II may react with the amine according to the above scheme without being recovered prior to the reaction, i.e., one-pot reaction.
  • the compound of formula II is recovered prior to reacting with the amine.
  • R, Ri, R 2 and n are as described above.
  • the reaction between the compound of formula II and the amine is carried out in a solvent selected from the group consisting of: water; alcohol; linear, branched, and cyclic ether; aliphatic hydrocarbon, aromatic hydrocarbon; nitroalkane; alkylcyanide; and mixtures thereof.
  • the alcohol is Ci -4 alcohol, methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, or tert-butanol; more preferably methanol.
  • the linear, branched or cyclic ether is linear, branched, or cyclic C 2-8 ether.
  • the linear, branched, or cyclic C 2-8 ether is diethyl ether, diisopropyl ether, or tetrahydrofuran; more preferably tetrahydrofuran.
  • the aliphatic hydrocarbon is Cs -8 aliphatic hydrocarbon; more preferably w-pentane, n-hexane, cyclohexane, n-heptane, or w-octane; most preferably n-hexane.
  • the nitroalkane is Ci -4 nitroalkane; more preferably nitromethane, nitroethane, nitropropane, or nitrobutane; most preferably nitromethane.
  • the alkylcyanide is Ci -4 alkylcyanide; more preferably acetonitrile, propionitrile, or butyronitrile; most preferably acetonitrile.
  • the aromatic hydrocarbon is a C 6-8 aromatic hydrocarbon, more preferably benzene, toluene or xylene, most preferably toluene.
  • the most preferred solvent is water.
  • the alkylamine is Ci -6 alkylamine.
  • the Ci -6 alkylamine is primary amine; more preferably methylamine, ethylamine, propylamine, butylamine, pentylamine, or hexylamine; most preferably methylamine.
  • the aralkylamine is C 6- 8 aralkylamine; more preferably benzylamine or 4-methylbenzylamine; most preferably benzylamine.
  • the alkyldiamine is Ci -6 alkyldiamine; more preferably ethylenediamine (1,2-diaminoethane), diaminopropane, diaminobutane, diaminopentane, or diaminohexane; most preferably ethylenediamine.
  • the alkyldiamines are preferably terminal amines - i.e. amines having general formula: H 2 N(CH 2 ) m NH 2 .
  • the aralkyldiamine is C 6-8 aralkyldiamine; more preferably xylylenediamine or aminoethylaniline most preferably xylylenediamine.
  • the most preferred amine is ethylenediamine.
  • the amine is present in an amount of about 1 to about 10 mole equivalents per mole equivalent of compound of formula II; more preferably about 1.5 to about 5 mole equivalents; and most preferably about 1.5 to about 2 mole equivalents per mole equivalent of compound of formula II. In one embodiment, the molar ratio is about 1.5 to about 2.5 mole equivalents.
  • the amine is added to a suspension or solution of the compound of formula II in the solvent, depending on the kind of the solvent.
  • the addition is done drop- wise.
  • the addition is done over a period of about 1 minute to about 60 minutes; more preferably for about 5 to about 30 minutes.
  • the addition is done at a temperature of about 4O 0 C to about 9O 0 C; more preferably at about 6O 0 C to about 8O 0 C.
  • a mixture is obtained after the addition.
  • the mixture is heated to a temperature of about 4O 0 C to about 100 0 C; more preferably about 9O 0 C to about 95 0 C.
  • the heating is done for about 2 to about 12 hours; more preferably for about 3 to about 6 hours.
  • the conversion of the compound of Formula II to Formula I can be monitored by TLC, preferably using a mixture of dichloromethane and methanol in a ratio of 8 to 2 as an eluent.
  • reaction of compound of formula II and the amine may further comprise a recovery process.
  • the recovery may be done by any method known to the skilled artisan.
  • the recovery process may include cooling the heated mixture; adding an alcoholic solvent such as methanol, ethanol, or propanol; maintaining the mixture at a temperature of about 5O 0 C to about 9O 0 C; more preferably about 6O 0 C to about 65 0 C; cooling the mixture; and filtering the product.
  • the heated mixture is cooled to a temperature of about 65 0 C to about 2O 0 C; more preferably to about 6O 0 C to about 4O 0 C.
  • the mixture is maintained for about 5 to about 60 minutes; more preferably for about 10 to about 30 minutes.
  • the cooling step prior to filtering the product compound of formula I is done to a temperature of about 45 0 C to about 5 0 C; more preferably to about 2O 0 C to about 25 0 C.
  • the quality and yield of the crude compound of formula I, in particular of Imiquimod are influenced by the process of removing the phthalimide group.
  • the recovered Imiquimod may be obtained by the above process in a purity of about 99.0% to about 99.5% by HPLC and in yields of about 75% to about 85% by weight. Preferably, it may contain less than about 0.1%, preferably less than about 0.05-0.15%, and more preferably less than about 0.08 to about 0.12% area by HPLC of Imiquimod-OH of the following formula:
  • it may contain about 0.1% area by HPLC to about 0.01% area by HPLC of the above Imiquimod-OH.
  • the compound of formula I may be purified by reacting it with an acid to obtain the salt of the compound of formula I,
  • Example 1 Preparation of l-isobutyl-lH-imidazo[4.5-clquinolin-4-phthalimide
  • l-isobutyl-lH-imidazo[4.5-c]quinolin-N-oxide 700 g, 2900 mmol
  • tributylamine 1750 ml, 2.5 equiv
  • phthalimide 490 g, 1.2 equiv
  • the suspension was cooled to 0-5°C and then, within 1.5-2 hours, benzoyl chloride (480 ml, 1.4 equiv) was added portion-wise (temperature was kept between 0-5°C).
  • the suspension was heated to 20-25°C and stirred for an additional 2 hours (conversion was monitored by TLC using 10:1 DCM-MeOH as an eluent).
  • the reaction mixture was filtered and the cake was washed with ethyl acetate (4x500 ml) and then with methanol (2x500 ml).
  • the wet solid was suspended in methanol (6 L) and stirred for 5 hours at 40-45 0 C, and then cooled to 20-25°C.
  • the suspension was filtered and the cake was washed with methanol (3x600 ml).
  • Example 2 Preparation of Imiquimod To a stirred suspension of l-alkyl-lH-imidazo[4.5-c]quinolin-N-oxide (290 mmol) in ethyl acetate (350 ml) is added tributylamine (175 ml, 2.5 equiv) and phthalimide (49 g, 1.2 equiv). The suspension is cooled to 0-5 0 C and then within 1.5-2 hours benzoyl chloride (48 ml, 1.4 equiv) is added portion-wise (temperature is kept between 0-5 0 C).
  • the suspension is heated to 20-25 0 C and stirred for additional 2 hours (conversion is monitored by TLC using 10:1 DCM-MeOH as an eluent).
  • the reaction mixture is filtered and the cake is washed with ethyl acetate (4x100 ml) and then with methanol (2 ⁇ 100 ml).
  • the wet solid is suspended in methanol (0.6 L) and stirred for 5 hours at 40-45 0 C, and then cooled to 20-25 0 C.
  • the suspension is filtered and the cake was washed with methanol (2x120 ml) and water (2x120 ml).
  • the wet material is suspended in water (350 ml) and ethylenediamine_(32 ml, 2 equiv) was added drop-wise at 70°C. The mixture is heated to 90-95 0 C and stirred for 4 hours (conversion is monitored by TLC using 8:2 DCM-MeOH as an eluent).
  • the hot solution is treated with sodium dithionite (Na 2 S 2 O 4 , 0.6 g, ca 1%) and charcoal (3 g, ca 5%). After 30 min the mixture is filtered and the cake is washed with water (2 ⁇ 60 ml). The filtrate is cooled to 70-75 0 C and the pH is adjusted to 11.4-11.6 by the addition of aqueous 30% NaOH (ca 40 ml). The stirred mixture is cooled to 20-25 0 C and after 1 hour the solid material is filtered off. The cake is washed with water (3x90 ml) and the wet solid is suspended in a mixture of water (265 ml) and «-butanol (117 ml).
  • the stirred suspension is treated with 37% HCl (21 ml, 1.1 equiv) and then heated to 60-65 0 C until complete dissolution occurred.
  • the solution is cooled to 20-25 0 C and the precipitated hydrochloride salt is filtered and then washed with n-butanol (53 ml).
  • the wet hydrochloride salt is dissolved in water (580 ml) at 85-90 0 C and the solution is filtered and the filtered solid is washed with hot water (27 ml).
  • the filtrate is treated with sodium dithionite (Na 2 S 2 O 4 , 0.1 g, ca 0.2%), cooled to 70-75°C, and the pH is adjusted to 9.6-9.8 by the addition of aqueous 30% NaOH (ca 20 ml).
  • the stirred mixture is cooled to 20-25°C and the solid material is filtered off.
  • the cake is washed with water (4> ⁇ 80 ml) and methanol (2> ⁇ 50 ml), then dried under vacuum at 5O 0 C for 7-8 hours to give crystallized l-alkyl-4-amino-lH-imidazo[4,5-c]quinoline (60-65%).
  • the dried crude Imiquimod (440 g) was suspended in water (7400 ml) and the stirred suspension was treated with 37% HCl (180 ml) and then heated to 90-93 0 C, and this temperature was maintained for 30 min.
  • the hot solution was treated with sodium dithionite (Na 2 S 2 O 4 , 5 g, ca 1%) and charcoal (24 g, ca 5%).
  • the mixture was filtered and the cake was washed with water (2x500 ml).
  • the filtrate was cooled to 70-75 0 C and the pH was adjusted to 11.4-11.6 by the addition of aqueous 30% NaOH .
  • the stirred mixture was cooled to 20-25 0 C and after 1 hour the solid material was filtered off.
  • the dried purified Imiquimod (400 g, 1.66 mol) was suspended in a mixture of water (2000 ml) and w-butanol (900 ml) and the stirred suspension was treated with 37% HCl (150 ml, 1.1 equiv), and then heated to 60-65 0 C until complete dissolution occurred.
  • the solution was cooled to 20-25 0 C and the precipitated Imiquimod hydrochloride was filtered and then washed with w-butanol (400 ml).
  • the wet hydrochloride salt* was dissolved in water (4500 ml) at 85-90°C, the solution was filtered, and the filtered solid was washed with hot water (200 ml).
  • oxidation of l-isobutyl-lH-imidazo[4,5-c]quinoline (which may be produced as in Example 3 of WO 2004/009593) is carried out in toluene at 40-45°C using peracetic acid as oxidant to produce l-isobutyl-lH-imidazo[4,5-c]quinoline N-oxide.
  • the product is isolated by filtration after addition of a sodium sulfate solution and ammonium hydroxide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé permettant la préparation de 4-amino-1H-imidazo [4,5-c]quinoléines qui comprend l'étape consistant à faire réagir un 1H-imidazo[4,5-c]quinoléin-4-phtalimide avec une amine sélectionnée parmi le groupe constitué par une alkylamine, une aralkylamine, une alkyldiamine et une aralkyldiamine.
PCT/US2007/022321 2006-10-16 2007-10-16 Préparation de 1h-imidazo[4,5-c]quinoléin-4-amines via des intermédiaires de 1h-imidazo[4,5-c]quinoléin-4-phtalimide Ceased WO2008048683A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BRPI0706205-2A BRPI0706205A2 (pt) 2006-10-16 2007-10-16 preaparo de 1h imidazo [4,5-c] quinolin-4-aminas via intermediários 1h-imidazo [4,5-c] quinolin-4-ftalimide
EP07852861A EP1966205A2 (fr) 2006-10-16 2007-10-16 Préparation de 1h-imidazo[4,5-c]quinoléin-4-amines via des intermédiaires de 1h-imidazo[4,5-c]quinoléin-4-phtalimide

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US85215306P 2006-10-16 2006-10-16
US60/852,153 2006-10-16
US89997407P 2007-02-06 2007-02-06
US60/899,974 2007-02-06
US92034907P 2007-03-26 2007-03-26
US60/920,349 2007-03-26

Publications (2)

Publication Number Publication Date
WO2008048683A2 true WO2008048683A2 (fr) 2008-04-24
WO2008048683A3 WO2008048683A3 (fr) 2008-06-05

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CN1315828C (zh) * 2002-07-23 2007-05-16 特瓦药厂私人有限公司 通过1h－咪唑并[4,5－c]喹啉－4－邻苯二甲酰亚胺类中间体制备1h－咪唑并[4,5－c]喹啉－4－胺类化合物

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EP1966205A2 (fr) 2008-09-10
WO2008048683A3 (fr) 2008-06-05

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