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[ CAS No. 99011-02-6 ] {[proInfo.proName]}

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Chemical Structure| 99011-02-6
Chemical Structure| 99011-02-6
Structure of 99011-02-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 99011-02-6 ]

CAS No. :99011-02-6 MDL No. :MFCD00866946
Formula : C14H16N4 Boiling Point : -
Linear Structure Formula :- InChI Key :DOUYETYNHWVLEO-UHFFFAOYSA-N
M.W : 240.30 Pubchem ID :57469
Synonyms :
R 837;S-26308;Beselna.;Vyloma;Zyclara;Imiquimod Brand name: Aldara;TMX 101

Calculated chemistry of [ 99011-02-6 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 13
Fraction Csp3 : 0.29
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 75.12
TPSA : 56.73 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.91 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.14
Log Po/w (XLOGP3) : 2.62
Log Po/w (WLOGP) : 2.83
Log Po/w (MLOGP) : 2.06
Log Po/w (SILICOS-IT) : 2.05
Consensus Log Po/w : 2.34

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.38
Solubility : 0.0995 mg/ml ; 0.000414 mol/l
Class : Soluble
Log S (Ali) : -3.46
Solubility : 0.0831 mg/ml ; 0.000346 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.26
Solubility : 0.0131 mg/ml ; 0.0000545 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.2

Safety of [ 99011-02-6 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P501-P270-P264-P280-P337+P313-P301+P310+P330 UN#:2811
Hazard Statements:H300-H315-H319 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 99011-02-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 99011-02-6 ]

[ 99011-02-6 ] Synthesis Path-Downstream   1~73

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  • [ 177212-77-0 ]
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  • [ 99010-63-6 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
76% With ammonia; chloroformic acid ethyl ester; In dichloromethane; water; at 0 - 20℃; for 1h;Cooling with methanol-ice bath; (c) The intermediate 1-isobutyl-1H-imidazo[4,5-c]quinoline-5-oxide prepared from the above reaction (64.6 g, 268 mmol) was dissolved in dichloromethane (640 mL) and cooled to about 10 C. in a methanol ice-bath. Ammonium hydroxide (100 mL was added. The two-phase system was then treated with a solution of ethyl chloroformate (36 mL, 400 mmol) in dichloromethane (75 mL). The solution was added at a rate to keep the temperature below 0 C. After the addition was complete, the thick suspension was allowed to warm to room temperature for one hour. This thick slurry was filtered through a D-sized sintered glass frit. The solid recovered from the frit was washed with water (2*200 mL), methanol (3*150 mL) and air dried to yield about 100 g. The solid was recrystallized from dimethylformamide (DMF) (1300 mL) at 140 C. and washed with ethanol. Imiquimod (1-isobutyl-1H-[4,5-c]quinolin-4-ylamine) was isolated as a white solid, 48.6 g, 76% yield, HPLC: 99.6. The Imiquimod from the above reaction was combined with another batch, the combination having a total weight about 66 g, and was dissolved in acidic ethanol (300 mL 1M HCl and 400 mL EtOH) at 55 C. To this solution was added conc. ammonium hydroxide (75 mL) and water (200 mL). A thick white precipitate formed immediately upon addition. The mixture was cooled to room temperature, filtered and washed with ethanol (200 mL), water (200 mL) and ethanol (200 mL), The white solid was air-dried, then placed in a vacuum oven overnight to yield 66.06 g.
  • 3
  • [ 99010-64-7 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
85.7% With ammonia; In dimethyl sulfoxide; at 20 - 150℃; under 1875.19 - 3750.38 Torr; for 6 - 12h;Product distribution / selectivity; This example demonstrates the preparation of imiquimod by reaction of compound II with ammonia in DMSO at 140-150 C. under a pressure of about 5 bar.A 250 glass reactor ?Miniclave? was charged with 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline (II) (20 g, 0.0733 mol) and DMSO (50 ml). Ammonia gas (2 g, 0.118 mol, 1.6 equiv.) was added into the closed reactor and the mixture was heated under stirring to 145-150 C. to obtain a pressure sustaining a glass reactor of about 5 bars. After heating at 140-150 C. for 10 hours the pressure was reduced to atmospheric pressure and the reaction mixture was cooled to ambient temperature. A sample was withdrawn and injected to an HPLC system. According to the HPLC chromatogram the product contained 51 % of imiquimod and 49% of the compound II in the reaction mixture.Then, a second portion of ammonia gas (2 g) was added into the closed reactor at ambient temperature followed by heating the reaction mixture to 145 C. to obtain a pressure of about 5 bar. The heating was continued for 12 hours during which time the pressure was reduced to 2.5 bar. The reaction mixture was cooled to ambient temperature and a sample was withdrawn and injected to an HPLC system. According to the HPLC chromatogram the product contained 99.93% of imiquimod and 0.07% of compound II in the reaction mixture; This example demonstrates the preparation of imiquimod by reaction of compound II with ammonia in DMSO at 140-150 C. under a pressure of about 5 bar.A 250 glass reactor ?Miniclave? was charged with 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline (II) (20 g, 0.0733 mol) and DMSO (50 ml). Ammonia gas (2 g, 0.118 mol, 1.6 equiv.) was added into the closed reactor and the mixture was heated under stirring to 145-150 C. to obtain a pressure sustaining a glass reactor of about 5 bars. After heating at 140-150 C. for 10 hours the pressure was reduced to atmospheric pressure and the reaction mixture was cooled to ambient temperature.Then, a second portion of ammonia gas (2 g) was added into the closed reactor at ambient temperature followed by heating the reaction mixture to 145 C. to obtain a pressure of about 5 bar. The heating was continued for 6 hours during which time the pressure was reduced to 2.5 bar. The reaction mixture was cooled to ambient temperature and a sample was withdrawn and injected to an HPLC system. According to the HPLC chromatogram the product contained about 92% of imiquimod and 8% of compound II in the reaction mixture.A colorless precipitate was collected by filtration and washed with water (3×50 ml). The wet product was treated with water (80 ml) under stirring at 70-80 C. for 1 hour. Then, the hot suspension was filtered and the precipitate was washed with hot water (40 ml) and methanol (40 ml) and dried at 80 C. under reduced pressure to yield 16.0 g of crude imiquimod in 85.7% yield; having a purity of 99.9% (by HPLC).
78.0 - 80.2% With ammonia; formamide; at 145℃; for 20 - 25h;Product distribution / selectivity; Example 5; Preparing Imiquimod (I) by Reacting Compound (II) with Formamide in the Presence of Ammonia (Bubbling During the Whole Course of the Reaction); A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (100.0 g, 0.385 mole) and formamide (250 ml, 6.27 mole, 16.3 equiv.) was heated to 145 C. under nitrogen atmosphere. Then, ammonia (gas) (92 g, 5.29 mole, 14 equiv.) was bubbled (4-5 g per hour) into the reaction mixture at this temperature during a period of 20 hours. Then, the reaction mixture was cooled to ambient temperature and stirred at this temperature for 3 hours. A colorless solid was collected by filtration, washed with methanol (3×100 ml), water (3×100 ml) and again with methanol (3×50 ml) and dried at 50 C. under reduced pressure overnight to give a crude Imiquimod (74.1 g, 80.2% yield, purity by HPLC: 99.3%). The crude compound (74.1 g) was slurried in a boiling mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 6 ml) for 4 hours. The hot mixture was filtered and the thus obtained cake was washed with methanol (3×40 ml), water (3×50 ml) and again with methanol (3×40 ml) and dried at 50 C. under reduced pressure to yield 72.2 g of Imiquimod in 77.9% yield, having a purity of 99.85% (by HPLC); Example 6; Preparation of Imiguimod (I) by Reacting the Compound of Formula (II) with Formamide in the Presence of Ammonia (Bubbling During 15 Minutes of Each Hour); A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (400.0 g, 1.54 mole) and formamide (1000 ml, 25.08 mole, 16.3 equiv.) was heated to 145 C. under nitrogen atmosphere. Then, ammonia (gas) (60 g, 3.53 mole, 2.3 equiv.) was bubbled (2-2.5 g during 15 minutes of each hour) into the reaction mixture at this temperature during 25 hours. Then, the reaction mixture was cooled to ambient temperature and stirred at this temperature for 3 hours. A colorless solid was collected by filtration, washed with methanol (3×400 ml), water (3×400 ml) and again with methanol (3×200 ml) and dried at 50 C. under reduced pressure overnight to give 288.3 g, of crude Imiquimod in 78.0% yield, having a purity of 99.6% (by HPLC).
74.4 - 77.7% EXAMPLE 1; This example illustrates an exemplary process for preparing imiquimod by reaction of compound II with 10 equivalents of urea in DMSO at 135-140 C.A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (3 g, 0.0116 mol), urea (6.9 g, 0.116 mol, 10 equiv.) and DMSO (20 ml) was heated under stirring at 140 C. for 35 hours. Then, the reaction mixture was cooled to 80 C. and water (30 ml) and 46% aqueous NaOH solution were added to produce a pH of 10-11. The mixture was stirred at ambient temperature for 1 hour and a precipitate was collected by filtration. The wet compound was treated with water (20 ml) at 70-80 C. under stirring for 1 hour. A solid was collected by filtration from the hot mixture, washed with water (3×20 ml) and methanol (20 ml) and dried at 80 C. under reduced pressure overnight to yield 2.4 g of crude Imiquimod in 87.6% yield, having 99.0% purity (by HPLC, containing 1.0% of compound II).A mixture of the crude product (2.4 g) and DMSO (45 ml) was heated under stirring at 140 C. to obtain a solution. 46% aqueous NaOH solution was added drop-wise to the solution to produce a pH of 10-11. The mixture was stirred at 140 C. for 1 hour. A sample was withdrawn and injected to an HPLC system. According to the HPLC chromatogram the product contained 0.07% of compound II. The hot solution was filtered and the filtrate was cooled to ambient temperature and kept at 20-25 C. for 8 hours. A precipitate was collected by filtration, washed with water (3×20 ml) and methanol (2×10 ml) and dried at 80 C. overnight to obtain 2.1 g of imiquimod in 87.8% yield; total yield: 77.0%, having a purity of 99.94% (by HPLC).; EXAMPLE 2; This example illustrates an exemplary process for preparing imiquimod by reaction of compound II with 20 equivalents of urea in DMSO at 155-160 C.A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (3 g, 0.0116 mol), urea (13.8 g, 0.232 mol, 20 equiv.) and DMSO (25 ml) was heated under stirring at 155-160 C. for 12 hours. Then, the reaction mixture was cooled to 80 C. and water (30 ml) and 46% aqueous NaOH solution were added to produce a pH of 10-11. The mixture was stirred at ambient temperature for 1 hour and a precipitate was collected by filtration. The wet compound was treated with water (20 ml) at 70-80 C. under stirring for 1 hour. A solid was collected by filtration from the hot mixture, washed with water (3×20 ml) and methanol (20 ml) and dried at 80 C. under reduced pressure overnight to yield 2.45 g of crude imiquimod in 88.5% yield, having a purity of 99.0% (by HPLC, containing 1.0% of the compound II). The crude imiquimod was purified by the method presented in Example 1 to obtain 2.15 g of imiquimod in 87.8% yield; total yield: 77.7%; having a purity of 99-93% (by HPLC).; EXAMPLE 3; This example illustrates an exemplary process for preparing imiquimod by reaction of compound II with 20 equivalents of urea in DMSO at 145-150 C.A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (4 g, 0.0154 mol), urea (18.5 g, 0.308 mol, 20 equiv.) and DMSO (26 ml) was heated under stirring at 145-150+C for 24 hours. Then, the reaction mixture was cooled to 80 C. and water (52 ml) and 46% aqueous NaOH solution were added to produce a pH of 10-11. The mixture was stirred at ambient temperature for 1 hour and a precipitate was collected by filtration. The wet compound was treated with water (25 ml) at 70-80 C. under stirring for 1 hour. A solid was collected by filtration from the hot mixture, washed with water (3×20 ml) and methanol (20 ml) and dried at 80 C. under reduced pressure overnight to yield 3.13 g of crude imiquimod in 84.8% yield, having a purity of 99.4% by HPLC, (containing 0.6% of the compound II). The crude imiquimod was purified by the method presented in Example 1 to obtain 2.75 g of imiquimod in 87.8% yield; total yield: 74.4%; having a purity of 99.93% (by HPLC).
70% With ammonia; In methanol; EXAMPLE 10 1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine A mixture of 4-chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (66 g), methanol (266 mL) and ammonia (46.2 g) was placed in a steel bomb and heated at 150 C. for 8 h. The resulting mixture was filtered, and the solid was washed with water and dried to afford the product 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine in 70% yield.
52% With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; for 12h;Heating / reflux;Product distribution / selectivity; Example 4: Synthesis of Imiquimod A round-bottom three-necked flask equipped with condenser, magnetic stirrer, thermometer, is loaded with 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (5.0 g, 0.019 mol), hydroxylamine hydrochloride (2.6 g, 0.038 mol), sodium acetate (3.1 g, 0.038 mol), an ethanol/water 2:1 v/v mixture (60 ml). The reaction mixture is refluxed for 12 hours then left to cool at room temperature. The precipitated solid (3 g, 0.010 mol) is filtered with suction and dried under vacuum at 50C to constant weight. The resulting solid is then dissolved in water (6 ml) and added with sodium acetate (1 g, 0.012 mol). The precipitated product is filtered and dried under vacuum in a static dryer at 50C. Weight = 2.4 g, Yield 52%.
47.6% Example 1; Preparation of Imiguimod (I) by Reacting Compound (II) with Formamide; A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]-quinoline (50.0 g, 0.192 mol) and formamide (125 ml, 3.136 mole, 16.3 equiv.) was heated at about 140 C. under nitrogen atmosphere for 26 hours. Then, the reaction mixture was cooled to 95 C. and water (10 ml) was added. The reaction mixture was heated at this temperature for 2 hours. Water (250 ml) and 47% aqueous sodium hydroxide solution were then added to produce a pH of about 9 and the mixture was stirred at ambient temperature for 2 hours. A solid was collected by filtration, washed with water (3×50 ml) and methanol (3×50 ml) and dried at 50 C. under reduced pressure overnight to give crude 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (Imiquimod) (39.0 g). The crude compound (39.0 g) was slurried in a mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 33.0 ml) under reflux for 6 hours. The mixture was cooled to ambient temperature and a colorless solid was collected by filtration, washed with methanol (3×20 ml), water (3×20 ml) and methanol (3×20 ml) and dried at 50 C. under reduced pressure overnight to yield 22.0 g of Imiquimod in 47.6% yield, having a purity of 98.2% (by HPLC). The product was crystallized from N,N-dimethylformamide to afford colorless Imiquimod having a purity of 99.9% (by HPLC).
35.7 - 46% Examples 2-4; The data obtained by reacting the compound of formula (II) with formamide at different reaction temperatures for different reaction times is summarized in Table 1.
With ammonia; In methanol; EXAMPLE 6 1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine A solution of 4-chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (0.86 g) in 7 g of a methanol solution containing 20% by weight of ammonia was placed in a steel bomb for 20 h at 150 C. After cooling to 20 C., the solid formed was collected by filtration and washed with methanol. The crude product 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was recystallized from N,N-dimethylformamide.

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  • [ 144660-62-8 ]
  • [ 99011-02-6 ]
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  • [ 99011-02-6 ]
  • [ 723281-26-3 ]
YieldReaction ConditionsOperation in experiment
To a solution of 1-ISOBUTYL-LH-IMIDAZO [4,5-c] quinolin-4-amine (10.0 g, 41.6 mmol) in acetic acid (150 ML) was added Br2 (10.0 g, 62.6 mmol), and after 24 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in a saturated aqueous solution OF NAHS03, after which it was again collected and stirred with a 2 M solution of NA2C03 for 18 h. The solid was collected by filtration, washed with H2O, and azeotropically dried with toluene on a rotary evaporator. Purification on silica gel (7%-10% methanol in CH2C12 gradient) afforded 3.4 g of 8-BROMO-1-ISOBUTYL-LH- imidazo [4,5-c] quinolin-4-amine. 1H NMR (400 MHz, CDCl3) 8 8.00 (d, J = 2.2 Hz, 1H), 7.79 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 8.8, 2.2 Hz, 1H), 5.60 (s, 2H), 4.26 (d, J = 7.4 Hz, 2H), 2.37-2. 27 (m, 1H), 1.05 (d, J = 6.6 Hz, 6H).
With N-Bromosuccinimide; In chloroform; at 20 - 50℃; for 1.83333h;Heating / reflux; A solution of 1- (2-METHYLPROPYL)-LH-IMIDAZO [4,5-c] quinolin-4-amine (30.0 g, 125 mmol) in chloroform (620 mL) was heated to 50 C, and N bromosuccinimide (28.8 g, 162 mmol) was added in five portions over a period of five minutes. The resulting dark red solution was heated at reflux for 45 minutes, allowed to cool to ambient temperature, and stirred for one hour. A precipitate formed, was isolated by filtration, and was washed with water and diethyl ether to provide 9.0 g of 8-bromo-1-(2-methylpropyl)-lH-imidazo [4,5- C]-QUINOLIN-4-AMINE as a solid.
  • 6
  • [ 99011-02-6 ]
  • [ 723283-87-2 ]
YieldReaction ConditionsOperation in experiment
A solution of 1-(2-methylpropyl)-1H-imidazo [4,5-c] quinolin-4-amine (28.3 g, 0.118 mol) in concentrated sulfuric acid (150 ML) was cooled to 5 C. A solution of 70% nitric acid (8.4 mL, 0.130 mol) in sulfuric acid (30 ML) was added in portions over a period of one hour. The reaction temperature was maintained below 10 C. The solution was allowed to warm to ambient temperature, stirred for two hours, and then poured into 500 g of ice. The resulting solution was made basic with the addition of ammonium hydroxide while keeping the solution cold. A precipitate formed, was isolated by filtration, washed with water, and dried to provide 1- (2-METHYLPROPYL)-8-NITRO-LH- imidazo [4,5-c] QUINOLIN-4-AMINE as a yellow solid.
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  • [ 133860-75-0 ]
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  • [ 15151-57-2 ]
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  • [ 132521-66-5 ]
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  • [ 99011-02-6 ]
  • 8-chloro-1-isobutyl-1<i>H</i>-imidazo[4,5-<i>c</i>]quinolin-4-ylamine [ No CAS ]
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  • [ 99011-02-6 ]
  • [ 723283-88-3 ]
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  • [ 610-94-6 ]
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  • [ 16245-89-9 ]
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  • [ 177212-59-8 ]
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  • [ 177212-60-1 ]
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  • [ 177212-74-7 ]
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  • [ 177212-75-8 ]
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  • 1-Isobutyl-2-methylsulfanyl-5-tributylstannanyl-1H-imidazole [ No CAS ]
  • [ 99011-02-6 ]
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  • [ 1026888-62-9 ]
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  • [ 177212-63-4 ]
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  • [ 177212-71-4 ]
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  • imiquimod hydrochloride [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
80.5% 100 ml water and 10 g crude Imiquimod [HC1] are loaded into a 250 ml reactor. The mixture is heated to [85-90C] to obtain a solution. 0.2 g sodium hydrosulfite is added and the solution turns from orange to yellow. 1 g of charcoal is added and after 10 minutes at [90-95 C] the charcoal is filtered off and the cake is washed with 10 ml of hot water. To the pale yellow solution obtained, 1 g of charcoal is added and stirred for 10 minutes at [90-95 C.] The charcoal is filtered off and the cake is washed with 10 ml hot water. To the colorless solution obtained, 3 g [NH40H] (NH3 26%) is added at [80 C.] The white suspension obtained is cooled to [20 C] and filtered. The cake is washed three times with 10 ml water. No chloride should be detected by silver nitrate during the washes. The solid is dried under vacuum at [50C] for 10 hours. A 7 g solid is obtained and the yield is 80. 5 %.
With sodium hydroxide; In water; at 20℃; for 0.5h;Product distribution / selectivity; Step 3 : Preparation of 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (45-C) QUINOLINE (COMPOUND of formula (1)) The isolated acid addition salt was suspended IN-22% NAOH solution (100 mL) at room temperature for 30 minutes. The mixture was filtered and the collected solids were washed with water and dried, providing 10.9 grams of 4-AMINO-1-ISOBUTYL-1H- imidazo (4,5-c) quinoline (85% yield from 4-(N-benzylamino)-1-isobutyl-lH-imidazo (4,5- c) quinoline).
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  • N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-phthalimide [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
91.8% With ethylenediamine; In water; at 70 - 95℃; for 4h; Example 3 Preparation of Crude Imiquimod To a stirred suspension of 1-isobutyl-1H-imidazo[4.5-c]quinolin-4-phthalimide (740 g, 2 mol) in water (3000 ml), was added drop-wise ethylenediamine (270 ml, 2 equiv) at 70 C. The mixture was heated to 90-95 C. and stirred for 4 hours (conversion was monitored by TLC using 8:2 DCM-MeOH as an eluent). After cooling to 60 C., methanol was added (7400 ml) and the reaction mixture was stirred at reflux temperature for 15 min. After cooling to 20-25 C., the mixture was filtered and the cake was washed with aqueous methanol (MeOH:H2O=3.5:1 v/v, 3*620 ml). The wet solid material was dried under vacuum at 50 C. for 7-8 hours to obtain crude Imiquimod (441 g, 91.8%). HPLC: 99.40 a % of Imiquimod and 0.09 a % of Imiquimod-OH
63.3% 72 ml water and 18 g [1-ISOBUTYL-LH-IMIDAZO] [4,5-c] quinoline-4-phthalimide (HPLC=98. [98%)] are heated to [70 C] in a 250 ml reactor. 4.8 g hydrazine hydrate is dropped into the reactor while stirring and then 2 ml iso-octyl alcohol is added to the reactor. The reaction 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 material the reaction is allowed to proceed for another hour. The reaction mixture is cooled at [60C] and 180 ml of methanol is added. The mixture is warmed at reflux for 15 minutes, then cooled at room temperature. The solution is filtered and the cake is washed 3 times 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 solid is treated with 180 ml of water and 5.2 g of [37%] [HC1] at [90-93 C] for 30 minutes. The hot suspension is filtered and the cake is washed 3 times with 15 ml of water. The solid is phthalhydrazide weighing 4.5 g. The hot solution is treated at [90-93 C] with 0.115 g [NA2S204] and 0.576 g charcoal. After 30 minutes the charcoal is filtered off and the cake is washed two times with 10 ml water. The solution is cooled at [70-75 C] and 10 g of 30% [NAOH] is added to pH 11.54, at which time a solid precipitates. The mixture is cooled to room temperature and after 1 hour the solid is filtered and the 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 10.57 g. HPLC shows the purity to be 98.12%. There is 1.55% phthalhydrazide present.
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  • [ 87386-81-0 ]
  • [ 99011-02-6 ]
  • [ 847453-14-9 ]
YieldReaction ConditionsOperation in experiment
23% With triethylamine; In chloroform; at 40℃; for 60h; To a suspension of 1-Isobutyl-1H-imidazo[4,5-c]quinolin-4-ylamine 31 (0.15 g, 0.62 mmol, prepared according to the procedure given in WO94/17043) in CHCl3 (5 mL) was added NEt3 (0.09 mL, 0.65 mmol) and dipentyl pyrocarbonate (0.231 g, 0.94 mmol). The mixture was stirred at 40 C. for 60 h. The reaction mixture was washed with aqueous NaHCO3, brine and dried over MgSO4. The filtrate was concentrated and purified by flash chromatography using a 10% to 70% gradient of ethyl acetate in hexanes to give 50.5 mg of 34 (23%) as a white solid: 1H NMR (400 MHz, CDCl3)delta 8.31 (br s, 1H), 8.15 (t, J=8.0 Hz, 2H), 7.85 (t, J=7.2 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 4.43 (d, J=7.6 Hz, 2H), 4.36 (t, J=7.2 Hz, 2H), 2.31 (m, 11H), 1.75 (t, J=6.8 Hz, 2H), 1.36 (m, 4H), 1.06 (d, J=6.4 Hz, 6H), 0.89 (t, J=6.8 Hz, 2H); MS (+)-ES [M+H]+355.3 m/z.
  • 37
  • 4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline sulfate [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In water; for 0.25 - 1h;pH 8 - 12;Product distribution / selectivity; Step 3: Preparation of 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (45-C) QUINOLINE (COMPOUND of formula (1)) The flask was cooled in an ice bath, and an aqueous solution of about 10% sodium hydroxide was slowly added to the mixture from step (b) until a pH of about 12 was achieved. The suspension was stirred for 15 minutes. The mixture was filtered, and the collected solids were washed with water. The solid was dried at 85C, providing 0.63 gram of 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (4,5-c) quinoline (85% yield from 4- (N- benzylamino)-1-isobutyl-1H-imidazo (4,5-c) quinoline).; Step 3: Preparation of 4-AMINO-1-ISOBUTEL-LH-IMIDAZO (4, 5-C) QUINOLINE (compound of formula (1)) The acid addition salt (compound of formula (5) ) was slurried in 30 mL of water at room temperature for 15 minutes, and then 20 mL of an aqueous solution of 20% NAOH was added. The slurry was stirred for 1 hour, while ensuring that the pH was at least about 8. The mixture was filtered, and the collected solids were washed with water. The solid was dried, providing 11.9 grams OF 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (4,5- c) quinoline (82% yield from 4-(N-benzylamino)-1-isobutyl-lH-imidazo (4,5-c) quinoline).
  • 38
  • 4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline trifluoroacetate [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In water;pH 12;Product distribution / selectivity; Step 3: Preparation of 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (4, 5-c) quinoline (compound of formula (1)) Acid addition salt (compound of formula (5) ) is suspended in 10 mL of water followed by the slow addition of 10% sodium hydroxide until a pH of about 12 is achieved. The suspension is filtered, and the collected solids are washed with water and dried, providing 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (4,5-c) quinoline (imiquimod).
  • 39
  • [ 415726-68-0 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogen; triethylamine;palladium(II) hydroxide/carbon; In ethanol; at 40℃; under 760.051 Torr;Product distribution / selectivity; Step 2: Preparation of 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (4, 5-C) quinoline 1.0 gram OF 4- (N-BENZYLAMINO)-1-ISOBUTYL-LH-IMIDAZO (4,5-c) quinoline is added to 10 mL of ethanol, followed by the addition of 0.03 gram triethylamine and 0.2 gram of Pearlman's catalyst (20% Pd (OH) 2/C). The mixture is stirred at 40C under 1 atm hydrogen until completion. The mixture is then filtered through Celite and the filtrate, containing 4-AMINO-1-ISOBUTYL-LH-IMIDAZO (4,5-c) quinoline (imiquimod), is concentrated in vacuo.
  • 40
  • [ 201030-96-8 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogenchloride; sodium formate;palladium 10% on activated carbon; In water; for 84h;Heating / reflux;Product distribution / selectivity; Example 6: Synthesis of Imiquimod starting from N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-hydrazine A round-bottom three-necked flask equipped with condenser, magnetic stirrer, thermometer, is loaded with N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-hydrazine (4.5 g, 0.018 mol), water (40 ml) 37% hydrochloric acid (1.8 g, 0.018 mol), 10% Pd-C (humid, 50% of water) (3.8 g, 0.0018 mol) and sodium formate (4.9 g 0.072 mol). The mixture is refluxed for 84 hours then left to cool at room temperature, diluted with 10 ml of a 5% HCl solution to pH<2; filtered through Celite and alkalinised with an ammonia aqueous solution to pH>8. The precipitated solid is filtered with suction and dried under vacuum in a static dryer at 50C, thereby obtaining 4.3 g in 98% molar yield.
98% A round-bottom three-necked flask equipped with condenser, magnetic stirrer, thermometer, is loaded with N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-hydrazine (4.5 g, 0.018 mol), water (40 ml) 37% hydrochloric acid (1.8 g, 0.018 mol), 10% Pd-C (humid, 50% of water) (3.8 g, 0.0018 mol) and sodium formate (4.9 g 0.072 mol). The mixture is refluxed for 84 hours then left to cool at room temperature, diluted with 10 ml of a 5% HCl solution to pH<2; filtered through Celite and alkalinised with an ammonia aqueous solution to pH>8. The precipitated solid is filtered with suction and dried under vacuum in a static dryer at 50 C., thereby obtaining 4.3 g in 98% molar yield.
  • 41
  • N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-O-methyl-hydroxylamine [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
70% With hydrogenchloride; zinc; In ethanol; water; at 20℃; for 1h;Product distribution / selectivity; Example 3: Synthesis of Imiquimod starting from N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-O-methyl-hydroxylamine A round-bottom three-necked flask equipped with condenser, magnetic stirrer, thermometer, is loaded with N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-O-methyl-hydroxylamine (0.2 g, 0.74 mmol) and ethanol (15 ml). 37% HCl (1 ml) and zinc powder (48 mg, 0.74 mmol) are added under stirring. After stirring for one hour at room temperature the reaction is completed. The mixture is concentrated to half the volume, alkalinised with 50% w/w NaOH to pH 9-10 and left under stirring for 30 minutes. The resulting solid is filtered and dried under vacuum in a static dryer at 50C. (0.12 g, yield 70%). 1H-NMR (300 M Hz, DMSO-d6): delta (ppm): 8.16 (s,1H), 8.0 (d,1H, J = 8.2 Hz), 7.61 (d,1H, J = 8.2 Hz), 7.42 (t,1H, J = 8.2 Hz), 7.26 (t,1H, J = 8.2 Hz), 6.54 (bs, 2H), 4.39(d, 2H, J = 7.5 Hz), 2.18 (m,1H), 0.91(d, 6H, J = 7.5 Hz).
70% A round-bottom three-necked flask equipped with condenser, magnetic stirrer, thermometer, is loaded with N-(1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)-O-methyl-hydroxylamine (0.2 g, 0.74 mmol) and ethanol (15 ml). 37% HCl (1 ml) and zinc powder (48 mg, 0.74 mmol) are added under stirring. After stirring for one hour at room temperature the reaction is completed. The mixture is concentrated to half the volume, alkalinised with 50% w/w NaOH to pH 9-10 and left under stirring for 30 minutes. The resulting solid is filtered and dried under vacuum in a static dryer at 50 C. (0.12 g, yield 70%). 1HNMR (300 M Hz, DMSO-d6): delta (ppm): 8.16 (s, 1H), 8.0 (d, 1H, J=8.2 Hz), 7.61 (d, 1H, J=8.2 Hz), 7.42 (t, 1H, J=8.2 Hz), 7.26 (t, 1H, J=8.2 Hz), 6.54 (bs, 2H), 4.39 (d, 2H, J=7.5 Hz), 2.18 (m, 1H), 0.91 (d, 6H, J=7.5 Hz).
  • 42
  • [ 110-16-7 ]
  • [ 99011-02-6 ]
  • 4-amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% In methanol; water; at 74℃;Heating / reflux; 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 %.
  • 43
  • [ 110-17-8 ]
  • [ 99011-02-6 ]
  • 4-amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline fumarate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In water; N,N-dimethyl-formamide; at 160℃; for 0.5h; 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 %.
  • 44
  • [ 144-62-7 ]
  • [ 99011-02-6 ]
  • 4-amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline oxalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% In water; N,N-dimethyl-formamide; at 160℃; for 0.5h; 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 %.
  • 45
  • [ 99011-02-6 ]
  • 4-amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With maleic acid; In methanol; water; at 74℃; for 0.5h; Part A Preparation of 4-Amino-l-isobutyMH- Imidazo-[4,5-c]-quinoline maleate salt(VII)The compound from Example 5 (35 gm, 0.145 mole) was added to mixture of 350 ml of methanol and 175 ml water. Subsequently, 35 gm (0.3017 mole) maleic acid was added in one lot and the reaction mass was heated to reflux temperature 740C. Charcoalised and maintained the reaction mass for 0.5 hr. Washed the hyflo bed with 20 ml hot methanol and filtered the hot reaction mass through hyflo. The filtrate was then slowly cooled to RT and then to 8 - 100C in 1 hr. The precipitated product was filtered and washed with 20 ml of methanol. The product was dried at 55 - 600C (47.2 gm, 91%).M.P. 190 to 192CMS - (m/z) M+ 2411HNMR (200 MHz, DMSO D6)(values in table)
  • 46
  • [ 896106-15-3 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
86% With ammonia; In methanol; at 150 - 155℃;Autoclave (ca. 20 kg pressure); Example No. 5 Preparation of Imiquimod (Crude)The compound from Example 4 (67 gm, 0.1903 mole) was added to 750 ml of 15% methanoHc ammonia solution in a pressure reactor (i.e. autoclave) and heated to 150 - 1550C (~ 20 Kg pressure). The reaction mass was then maintained at this temperature, when all the product precipitates out. The precipitated solid was filtered EPO <DP n="12"/>and washed with 50ml methanol. The product was dried at 55 to 600C for 8 hrs to obtain the title product (40gm, 86%).
86% With ammonia; In methanol; at 150 - 155℃; under 14711.4 Torr;Autoclave;Product distribution / selectivity; 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 %.
  • 47
  • 4-amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline maleate [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
89.7% Part B Preparation of 4-Amino-l-isobutyl-lH- Imidazo-[4,5-c]-quinoline (VIII)The compound from Example 6 (47.2 gm, 0.132 mole) was added to a mixture of 350 ml methanol and 175 ml water. The reaction mass was heated to 75C and 3.5 gm charcoal was further added and maintained for 0.5 hr. Filtered the hot reaction mass through hyflo and subsequently added 25% ammonia solution (40 ml) till EPO <DP n="13"/>alkaline pH. Product precipitated out was filtered, washed with water and dried to obtain the title product (31.4 gm, 89.7%).M.P. 292 to 294CMS - (m/z) M+ 2411HNMR (200 MHz, DMSO D6)(values in table)
89.7% With ammonia; water; In methanol;Product distribution / selectivity; 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 294CMS - (m/z) M+ 241 EPO <DP n="16"/>1HNMR (200 MHz, DMSO D6)delta values Proton0.97 (6H, d, CH3 x 2)2.1-2.25 (IH, m, -CH)4.5 (2H, d, CH2) 7.8-7.9 (2H, m, Ar)8.5 (IH, s, -CH=N-)8.8 (IH, s, -NH2) P2O exchangeable
  • 48
  • 4-amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline fumarate [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
90% With ammonia; water; In methanol;Product distribution / selectivity; 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 %.
  • 49
  • 4-amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline oxalate [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
88% With ammonia; water; In methanol;Product distribution / selectivity; 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 %.
YieldReaction ConditionsOperation in experiment
95% In methanol; for 4h;Heating / reflux;Purification / work up; This example demonstrates the purification of imiquimod by slurrying crude imiquimod, containing 8% of 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline, in methanol.A suspension of crude imiquimod (2 g, containing 8% of 4-chloro-1-isobutyl-1H-imidazo [4,5-c] quinoline) in methanol (14 ml) was stirred under reflux for 4 hours. The hot mixture was then filtered off and the obtained solid was washed with methanol and dried at 60 C. overnight to afford 1.9 g of pure imiquimod in 95% yield, having 99.89% purity (by HPLC).
95% In toluene; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
95.7% Example 5 Crystallization of Purified Imiquimod The dried purified Imiquimod (400 g, 1.66 mol) was suspended in a mixture of water (2000 ml) and n-butanol (900 ml) and the stirred suspension was treated with 37% HCl (150 ml, 1.1 equiv), and then heated to 60-65 C. until complete dissolution occurred. The solution was cooled to 20-25 C. and the precipitated Imiquimod hydrochloride was filtered and then washed with n-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). The filtrate was treated with sodium dithionite (Na2S2O4, 0.9 g, ca 0.2%), cooled to 70-75 C., and the pH was adjusted to 9.6-9.8 by the addition of aqueous 30% NaOH (ca 160 ml). The stirred mixture was cooled to 20-25 C. and the solid material was filtered off. The cake was washed with water (3*200 ml) and methanol (2*200 ml) and then dried under vacuum at 50 C. for 7-8 hours to give crystallized Imiquimod (351 g, 87.8%) HPLC: 99.97 a % of Imiquimod and 0.03 a % of Imiquimod-OH *If necessary wet hydrochloride salt can be dried at 50 C. Example 7; Purification of Imiquimod according to WO 2004/009593; 53.55 ml water, 23.62 ml butyl 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 precipitates. The solid is filtered and washed 2 times with 5 ml butyl alcohol. 13.63 g of wet Imiquimod hydrochloride is obtained. HPLC analysis shows that there is 99.89% Imiquimod and 0.01% phthalhydrazide. 120 ml water and 13.63 g of wet Imiquimod hydrochloride are loaded into a 250 ml reactor and heated to 85-90 C. The hot solution is filtered and the cake is washed with 5 ml of hot water. Then 0.024 g of Na2S2O4 is added. The colorless 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 cooled to 20 C. and filtered. The cake is washed 3 times with 5 ml water and twice with 5 ml methanol. During the washes no chloride was detected by silver nitrate. 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 starting material (1-isobutyl-1H-imidazo[4,5-c]quinoline N-oxide).
94.3% In isopropyl alcohol; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
93.5% In tetrahydrofuran; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
91% In 2-methyltetrahydrofuran; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
90% In ethyl acetate; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
90% In acetonitrile; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
90% In acetone; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
80% In propan-1-ol; for 4h;Heating / reflux;Purification / work up; These examples demonstrate the purity of imiquimod obtained by slurrying crude imiquimod (having about 92% purity, by HPLC) in various organic solvents in a similar procedure to the one detailed in example 3. The results are listed in Table 1.
75.5% In dimethyl sulfoxide; at 20 - 140℃; for 5h;Purification / work up; Example 7; Crystallization of Crude Imiguimod from Dimethyl Sulfoxide; Crude Imiquimod (288.3 g) was dissolved in dimethyl sulfoxide (5700 ml) at 140 C. and the hot solution was filtered. The filtrate was cooled to about 20 C. and the suspension was stirred at this temperature for 5 hours. The colorless crystals were collected by filtration, washed with methanol (3×400 ml) and dried at 50 C. under reduced pressure overnight to yield 279.8 g of Imiquimod in 75.5% yield, having a purity of 99.91% (by HPLC).
claim 30 wherein the IRM is 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N'-cyclohexylurea, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine, 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, 2-methylthiazolo[4,5-c]quinolin-4-amine, 2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, 2-ethylthiazolo[4,5-c]quinolin-4-amine, 4-amino-2-butyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c][1,5]naphthyridine-1-ethanol, 1-{2-[3-(3-pyridyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine, ...
COMPARATIVE EXAMPLE 1 Production of ointment containing 2% Imiquimod 0.5 g of Imiquimod synthesised by the method described in U.S. Pat. No. 4,988,815 was added to 5 g of isostearic acid maintained at 80 C. and dissolved by stirring. 19.5 g of white petrolatum separately melted by heating (80 C.) was added thereto and the mixture was cooled to room temperature with stirring.
EXAMPLE 5 1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine Palladium hydroxide on carbon, Pearlman's catalyst, (0.25 g) was added to a solution containing N,N-bis(phenylmethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 0.95 mmole, Example 4) in formic acid (20 mL). The reaction was heated at reflux for about 16 hours at which time more catalyst (0.2 g) was added and heating was continued until the reaction was complete as indicated by thin layer chromatography (silica gel; 5% methanol in methylene chloride). The reaction mixture was diluted with water (20 mL), methylene chloride (40 mL) and methanol (10 mL) then filtered. The filtrate layers were separated and the organic layer was concentrated under vacuum. The residue was recrystallized from dimethyl formamide then suspended in methanol and stirred before being isolated by filtration and dried to provide 0.1 g of a solid. The melting point and spectral properties of this material matched those of an authentic sample.
EXAMPLE 12 1-(2-Methylpropyl)-1H-imidazo [4,5-c]quinolin-4-amine 1-(2-Methylpropyl)-N-triphenylphosphinyl-1H-imidazo [4,5-c]quinolin-4-amine (100 mg, Example 10) was suspended in a mixture of methanol (3 mL) and hydrochloric acid (10 mL of 0.5N). The mixture was heated on a steam bath for 2 hours then allowed to stand at ambient temperature overnight. The reaction mixture was filtered. The filtrate was made basic with 10% sodium hydroxide. The resulting precipitate was isolated by filtration then dried to provide 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. The spectral properties of this material matched those of an authentic sample.
Part E N-Benzoyl-1-(2-methylpropyl)-1H-imidazol[4,5-c]quinolin-4-amine (5.0 g, 0.0145 mol) and sodium methoxide (10 drops of a 25% by weight solution in methanol) were mixed in methanol (50 mL) and the mixture was heated at reflux for 75 minutes. The mixture was cooled to room temperature, and a solid formed. The solid was filtered from the mixture, washed sequentially with water and methanol, and dried. A crude yield of colorless product of 3.3 g (94.3%) was obtained. Spectral properties of the product corresponded to those of an authentic sample.
EXAMPLE 137 Alternative Preparation of a Compound of Formula I A mixture of 6.0 g (0.023 mole) of 4-chloro-1-isobuty-I-1H-imidazo[4,5-c]quinoline (from Example 77) and 30 ml of 20% ammonia in methanol was heated in a steel bomb for 18 hours at 150 C. The bomb was cooled, and the solid was separated by filtration, washed with methanol and recrystallized from N,N-dimethylformamide to provide 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 292-294 C. Analysis: Calculated for C14 H16 N4: % C, 70.0; H, 6.7; % N, 23.3; Found: % C, 69.9; % H, 6.7; % N, 23.6.
More preferably, it is a compound defined by formula VI. Particularly preferred is when the 1H-imidazo[4,5-c]quinolin-4-amine derivative is a compound of formula VI selected from the group consisting of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; 1-(2-hydroxy-2-methylpropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine; 1-(2,hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; 1-(2-hydroxy-2-methylpropyl)-2-ethoxymethyl-1-H-imidazo[4,5-c]quinolin-4amine
Example 4; Purification of Crude Imiquimod; 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 C., and this temperature was maintained for 30 min. The hot solution was treated with sodium dithionite (Na2S2O4, 5 g, ca 1%) and charcoal (24 g, ca 5%). After 30 min, the mixture was filtered and the cake was washed with water (2×500 ml). The filtrate was cooled to 70-75 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 C. and after 1 hour the solid material was filtered off. The cake was washed with water (3×500 ml) and methanol (90 ml), then dried under vacuum at 50 C. for 7-8 hours to give purified Imiquimod (421 g, 95.7%). HPLC: 99.77 a % of Imiquimod and 0.07 a % of Imiquimod-OH

  • 51
  • [ 132206-92-9 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
98% Potassium tert-butoxide (2.16 g, 0.019 mole), 4.5 mL of dimethylsulfoxide and 0.76 mL (0.019 mole) of formamide were added in a 50-mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-chloro-lfl-imidazo [4, 5-c] quinoline (I g, 3.8 mmoles) , the mixture was heated at 1050C, followed by stirring for 2 hours and then cooled to room temperature.Then 10 mL of water and 6N HCl were sequentially added until pH 8. The reaction mixture was filtered followed by washing with abundant water and dried to give 0.91 g of1-isobutyl-lfl-imidazo [4, 5-c] quinolin-4-amine. Yield 98%.
  • 52
  • [ 132206-92-9 ]
  • 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-formamide [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
54%; 39% Potassium tert-butoxide (4.32 g, 0.038 mole), 4.5 mL of dimethylacetamide and 1.53 mL (0.038 mole) of formamide were added in a 50-mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-chloro-li-imidazo [4, 5-c] quinoline (I g, 3.8 EPO <DP n="9"/>mmoles) , the mixture was heated at 1200C, followed by stirring for 1 hour and then cooled to room temperature. The reaction mixture was filtered followed by washing with abundant water and dried to give 0.4 g of 1- isobutyl-1-ff-imidazo [4, 5-c] quinolin-4-amine. Yield 39%.The mother waters were concentrated under vacuum and precipitated with methylene dichloride to give 0.5 g of l-isobutyl-lfl-imidazo [4, 5-c] quinoline-4-formamide . Yield 54%. Mp 225-226C.IR: 3469, 3177, 3127, 2954, 1687, 1582 cm"1.1HNMR (CDCl3): 9.98 (d, J=IO.4 Hz, IH, CHO), 9.66 (d, J=IO.8 Hz, IH, NH), 8.13 (s, IH, NCH=N), 8.04 (m, 2H, aromatic), 7.64 (m, IH, aromatic), 7.52 (m, IH, aromatic), 4.36 (d, J=7.2 Hz, 2H, CH2), 2.37 (m, IH, (CHs)2CH), 1.05 (d, J=6.8 Hz, 6H, 2CH3).13CRMN (CDCl3): 162.8 (CO), 144.27 (NCHN), 143.86 (NCNH), 133.98 (C ar) , 129.25 (CH ar) , 128.22 (CH ar) , 127.83 (CH ar) , 124.87 (CH ar) , 120.03 (CH ar) , 116.82 (Car), 109.97 (CH ar) , 55.19 (CH2), 28.81 ( (CH3) 2CH) , 19.78 (CH3)
  • 53
  • 4-bromo-1H-imidazo[4,5-c]quinoline [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
75.4% Potassium tert-butoxide (3.69 g, 0.033 mole), 5 mL of dimethylacetamide and 1.31 mL (0.033 mole) of formamide were added in a 50 mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-bromo-li-imidazo [4, 5-c] quinoline (1 g, 3.3 mmoles) , the mixture was heated at 1400C, followed by stirring for 2 hours and then cooled to room temperature. Then 10 mL of water were added and the reaction mixture was filtered followed by washing with abundant water and dried to give 0.75 g of 1-isobutyl-lfl-imidazo [4, 5- c] quinolin-4-amine. Yield 75.4%.
  • 54
  • [ 99010-09-0 ]
  • [ 99010-64-7 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
With ammonia; In methanol; Step (E) A mixture of 6.0 g (0.0231 mole) of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline from Step (D) above and 30 ml of 20% ammonia in methanol was heated in a steel bomb for about 8 hours at about 145 C. The bomb was allowed to stand overnight at room temperature. The bomb was then cooled in an ice bath, and the solid therein was filtered, washed with methanol, and dried. Recrystallization from N,N-dimethylformamide provided 4.1 g of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 288-291 C.
  • 55
  • [ 99010-64-7 ]
  • [ 1336-21-6 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 99 Preparation of a Compound of Formula I A mixture of 4.0 g (0.0154 mole) of 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline (from Example 77) and 25 cc of concentrated ammonium hydroxide was placed in a metal bomb and heated at 150 C. for about 16 hours. After cooling the solid was separated by filtration, washed with water and recrystallized from ethanol to provide white crystals of 1-isobutyl-1H-imidazo [4,5-c]quinolin-4-amine, m.p. 288-291 C. Recrystallization from N,N-dimethylformamide is preferred. Analysis: Calculated for C14 H16 N4: % C, 70.0; H, 6.7; % H, 23.3; Found: % C, 69.3; % H, 6.6; % N, 23.2.
  • 56
  • [ 64-18-6 ]
  • [ 99011-02-6 ]
  • 4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline formate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; at 0℃;Heating / reflux; EXAMPLE 1. Preparation of imiquimod formate salt A 1 L 4-necked round-bottom flask, equipped with mechanical stirrer, reflux condenser and thermometer, is loaded with 127 g of imiquimod free base, 127 g of 99% formic acid and 1270 ml of methanol. The dispersion is refluxed and subsequently hot filtered through Celite (25 g) to remove insolubles. After washing the celite cake with 150 ml of hot methanol, mother liquors and washings are combined and concentrated to a weight of 270 g. The resulting concentrate is cooled at a temperature of 0C, after 20 minutes the resulting solid is filtered with suction, washed with methanol at 5C (2 x 70 ml) and dried in a static dryer under vacuum at a temperature of 60C to constant weight, thereby obtaining 102 g of imiquimod formate as yellow crystals, having an XRPD spectrum substantially as illustrated in Figure 1, wherein the most intense diffraction peaks fall at 5.72; 11.15; 11.54; 17.42; 21.38; 24.95 in 2theta. By proceeding analogously the imiquimod salt with acetic, propionic, oxalic, citric, tartaric, malic, fumaric, malonic and maleic acid is obtained.
  • 57
  • 4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline formate [ No CAS ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In water; at 20℃;pH 11;Heating / reflux; EXAMPLE 2. Preparation of imiquimod free base A 500 ml 4-necked round-bottom flask, equipped with mechanical stirrer, reflux condenser and thermometer, is loaded with 41 g of imiquimod salt formate and 300 ml of water. The dispersion is refluxed, added with 4 g of active charcoal, then hot filtered through Celite. The cake is thoroughly washed with 50 ml of hot water. Mother liquors and washings are combined and alkalinized to pH 11 with 50% NaOH, then cooled to room temperature to precipitate a white solid. This is filtered with suction, washed with water (1 x 30 ml) and methanol (1 x 30 ml), then dried to constant weight in a static dryer under vacuum at a temperature of 60C, thereby obtaining 19 g of imiquimod free base as a white crystalline product, having HPLC purity higher than 99.5%, potentiometric titre ranging from 99 to 101%, water content according to Karl-Fischer equivalent to or lower than 0.05%, an XRPD spectrum substantially as illustrated in Figure 2, wherein the most intense diffraction peaks fall at 11.04; 17.97; 18.81; 21.24; 21.78; 24.18 in 2theta, and D[4,3] diameter mean of approx. 20 mum.
  • 58
  • [ 99010-64-7 ]
  • [ 593-85-1 ]
  • [ 1040136-68-2 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 5; This example illustrates an exemplary process for preparing imiquimod by reaction of compound II with 2 molar equivalents of guanidine carbonate in DMSO at 140-150 C.A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (6.0 g, 0.0232 mol), guanidine carbonate (8.4 g, 0.0466 mol, 2.0 molar equiv.) and DMSO (50 ml) was heated under stirring at 140-150 C. for 1 hour. A sample was withdrawal and injected to an HPLC system. According to the HPLC chromatogram the product contained 5.76% of imiquimod, 93.58% of the compound III and 0.66% of the compound II in the reaction mixture. Stirring was continued at 140-150 C. for Her 9 hours, after which time a sample was withdrawn and injected to an HPLC system. According to the HPLC chromatogram the product contained 99.4% of imiquimod and 0.6% of compound III. Then, the reaction mixture was cooled to ambient temperature and a precipitate was collected by filtration, washed with water (3×40 ml) and methanol (35 ml) and dried at 80 C. under reduced pressure overnight to yield 4.5 g of crude Imiquimod in 81.2% yield, having a purity of 99.85% (by HPLC).The crude imiquimod (4.5 g) was dissolved in DMSO (80 ml) at 140 C. The hot solution was filtered off and the filtrate was kept at 20 C. overnight. A precipitate was collected by filtration, washed with water (3×20 ml) and methanol (3×10 ml) and dried at 80 C. under reduced pressure overnight to obtain 4.0 g of pure imiquimod in 87.8% yield, overall yield: 71.3%; having a purity of 99.93% (by HPLC).
  • 59
  • [ 1040136-68-2 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
70% EXAMPLE 6; This example illustrates an exemplary process for producing imiquimod by reaction of a compound III with sulfuric acid in DMSO at 140 C.A mixture of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-guanidine (III) (10.0 g, 0.0357 mol), 95-98% sulfuric acid (0.5 ml), water (2 ml) and DMSO (50 ml) was heated under stirring at 140 C. for 20 hours. Then, the reaction mixture was cooled to 60 C. and water (100 ml) was added followed by addition of 46% aqueous NaOH solution drop-wise to produce a pH of 10-11. The mixture was stirred at ambient temperature for 2 hours and a precipitate was collected by filtration, washed with water (3×40 ml) and methanol (35 ml) and dried at 80 C. under reduced pressure overnight to yield 6 g, of crude compound I, in 70% yield.
EXAMPLE 5; This example illustrates an exemplary process for preparing imiquimod by reaction of compound II with 2 molar equivalents of guanidine carbonate in DMSO at 140-150 C.A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (6.0 g, 0.0232 mol), guanidine carbonate (8.4 g, 0.0466 mol, 2.0 molar equiv.) and DMSO (50 ml) was heated under stirring at 140-150 C. for 1 hour. A sample was withdrawal and injected to an HPLC system. According to the HPLC chromatogram the product contained 5.76% of imiquimod, 93.58% of the compound III and 0.66% of the compound II in the reaction mixture. Stirring was continued at 140-150 C. for Her 9 hours, after which time a sample was withdrawn and injected to an HPLC system. According to the HPLC chromatogram the product contained 99.4% of imiquimod and 0.6% of compound III. Then, the reaction mixture was cooled to ambient temperature and a precipitate was collected by filtration, washed with water (3×40 ml) and methanol (35 ml) and dried at 80 C. under reduced pressure overnight to yield 4.5 g of crude Imiquimod in 81.2% yield, having a purity of 99.85% (by HPLC).The crude imiquimod (4.5 g) was dissolved in DMSO (80 ml) at 140 C. The hot solution was filtered off and the filtrate was kept at 20 C. overnight. A precipitate was collected by filtration, washed with water (3×20 ml) and methanol (3×10 ml) and dried at 80 C. under reduced pressure overnight to obtain 4.0 g of pure imiquimod in 87.8% yield, overall yield: 71.3%; having a purity of 99.93% (by HPLC).
  • 60
  • [ 960254-02-8 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
90 - 96% With sodium amide; In toluene; at 20 - 100℃; for 2h; Step (d) 4-Amino-1-(2-methylpropyl)-imidazo-[4,5-c]quinoline (Imiquimod) (4). To compound 3, (1.20, 5 mmol), suspended in 20 mL of anhydrous toluene, was added under N2 at room temperature (0.2 g, 5 mmol) NaNH2. The mixture was stirred at 90-100C. Monitoring of the reaction by thin layer chromatography showed complete conversion in less than 2h. After cooling below 5C 2 mL of ice water were added dropwise and the mixture was evaporated until dryness. Imiquimod was isolated upon trituration of the residue with 5 mL cold water. Yield: 90-96% Mp > 260C. 1H-NMR (400 MHz, CDCl3) 1.02(d, 6H, 2 CH3); 2.35(non, 1H, CH); 4.30(d, 2H, CH2); 5.50(s, 2H, NH2); 7.32(t, 1H, 8-H), 7.55(t, 1H, 7-H); 7.80(s, 1H, 2-H); 7.82(d, 1H, 6-H); 7.92(d, 1H, 9-H).
  • 61
  • [ 179691-31-7 ]
  • [ 99011-02-6 ]
  • C24H25N5O4 [ No CAS ]
  • 62
  • [ 1188307-60-9 ]
  • [ 99011-02-6 ]
  • C36H39N5O14 [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% <strong>[99011-02-6]Imiquimod</strong> (90 mg, 0.33 mmol, 1.9 eq)and Huenig?s base (0.075 mE, 0.43 mmol, 2.5 eq) were dissolved in 2 mE of EtOAc that was dried overnight prior to use. The mixture was stirred for 20 mm in a microwave reaction vessel before addition of compound 4 (0.11 g, 0.17 mmol, 1.0 eq) dissolved in 2 mE of dry EtOAc. The reaction was placed in a Biotage Initiator+ microwave reactor (87 C., 75 W average) and irradiated for 45 mm. Solvent was evaporated from the resulting crude reaction mixture in vacuo before purification via column chromatography (1% MeOH in DCM for 20 CVs, 1% to 10% over 10 CVs). Product fractions were collected, solvent evaporated, and lyophilized from benzene to yield compound 5 as a white powder (52 mg, 0.07 mmol, 40% yield); Rf (100% EtOAc) =0.40; 1H NMR (400 MHz, [D6]DMSO, 25 C.): oe=10.10 (s, 1H), 8.35 (s, 1H), 8.24 (d, J(H,H)=8.0 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J(H,H)=8.0 Hz, 1H), 7.80 (d, J(H,H)=8.4 Hz, 1H), 7.66 (t, J(H,H)=7.6 Hz, 1H), 7.61 (t, J(H,H)=6.8 Hz, 1H), 7.43 (d, J(H,H)=10.8 Hz, 1H), 5.60 (d, J(H,H)=6.8 Hz, 1H), 5.36 (d, J(H,H)=3.0 Hz, 1H), 5.30-5.22 (m, 4H),4.51-4.47 (m, 3H), 4.18-4.10 (m, 2H), 2.22-2.17 (m, 1H),2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.95 (s, 3H), 0.92 (d, J=6.4, 6H) ppm; 13C (100 MHz, [D6]DMSO, 25 C.):oe=169.9, 169.8, 169.5, 168.9, 152.7, 147.8, 144.7, 144.4, 142.9, 140.2, 133.4, 133.2, 132.4, 131.1, 128.9, 127.3,125.4, 123.7, 120.8, 117.7, 116.7, 98.6, 70.8, 69.9, 67.7,67.1, 64.3, 61.2, 53.5, 28.4, 20.49, 20.38, 20.32, 20.30, 19.3 ppm. IR(ATR): v=2963, 1750, 1601, 1582, 1534, 1480, 1371, 1235, 1073 cm-i; UV/Vis (methanol): 2. max(c)=284nm. MS mlz calculated for C36H40N5014 [M+H]+ 766. 25718; Observed 766.25488 Da.
  • 63
  • [ 99011-02-6 ]
  • sarcosine 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amide hydrochloride [ No CAS ]
  • 64
  • [ 70533-97-0 ]
  • [ 99011-02-6 ]
  • tert-butoxycarbonyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-sarcosine [ No CAS ]
YieldReaction ConditionsOperation in experiment
87.5% With triethylamine; for 8h;Reflux; 32.2 g (0.1 mol) of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine was suspended in 500 ml of ethyl acetate. 72 g (0.2 mol) of N-t-Butyloxycarbonyl-N-methylglycine anhydride [(Boc-N-Me-Gly)2O] and 30 ml of triethylamine were added into the reaction mixture. The mixture was refluxed for 8 h. The solution was washed with water (1×100 ml), 10% citric acid (1×100 ml), water (1×100 ml), 5% sodium bicarbonate (1×100 ml), and water (3×100 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. The ethyl acetate solution was evaporated to dryness. After drying, it yielded 36 g of the desired product (87.5%). Elementary analysis: C22H29N5O3; MW: 411.50; calculated % C, 64.21; H, 7.10; N, 17.02; O, 11.66. found C, 64.17; H, 7.15; N, 16.97; O, 11.71.
87.5% With triethylamine; In ethyl acetate; for 2h;Reflux; 32.2 g (0.1 mol) of1-isobutyl-1H-imidazo [4,5-c] quinolin-4-amineDissolved in 500Ml of ethyl acetate. To the reaction mixture was added 36 g (0.1 mol)N-t-butoxycarbonyl-N-methylglycine anhydride [(Boc-N-Me-Gly) 2O] and 20 ml of triethylamine.The mixture was refluxed for 2 hours. The solution was washed once with water, 100 ml each time, 10% citric acid was washed once,Each 100 ml, washed 1 times, each 100 ml, 5% sodium bicarbonate solution wash 1,Each 100 ml, then washed three times, each 100 ml. The ethyl acetate layer was dried over anhydrous sodium sulfate.Evaporated to dry ethyl acetate solvent. After drying, 36 g of the desired product was obtained (yield 87.5%).
  • 65
  • [ 99011-02-6 ]
  • 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-sarcosine hydrochloride [ No CAS ]
  • 66
  • C28H28N2O17 [ No CAS ]
  • [ 99011-02-6 ]
  • C36H39N5O14 [ No CAS ]
YieldReaction ConditionsOperation in experiment
19% With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 87℃; for 0.75h;Microwave irradiation; To a 5 mE microwave reactor vial with stir vane was added compound (10) (0.15 g, 0.23 mmol, 1.0 eq) dissolved in dry ethyl acetate (6 mE). Next, <strong>[99011-02-6]Imiquimod</strong> (0.10 g, 0.42 mmol, 1.9 eq) and Hunig?s base (98 tE, 0.56 mmol, 2.5 eq) were added to the vial. The vial was sealed, placed in a microwave reactor and irradiated for 45 mm (87 C., 90 W, pre-stirring: 30 s). Afier the solution had cooled to room temperature, the insoluble material was filtered oil and the filtrate concentrated in vacuo. The crude material was submitted to flash chromatography (isocratic, 100% EtOAc, rf=0.96) and the desired fractions were collected, solvent evaporated, and the material lyophilized from benzene to obtain compound (11) (0.032 g, 0.042 mmol, 19% yield) asa white solid. ?H NMR (400 MHz, DMSO-d6, 25 C.):oe=10.09 (s, 1H; CONH), 8.35 (s, 1H; ArCH), 8.21 (d,J(H,H)=8.0 Hz, 1H; ArCH), 8.13 (d, J(H,H)=2.0 Hz, 1H;ArCH), 7.97 (d, J(H,H)=8.0 Hz, 1H; ArCH), 7.81 (dd,J(H,H)=8.6, 2.0 Hz, 1H; ArCH), 7.68-7.54 (m, 3H; ArCH),6.05 (d, J(H,H)=1.2 Hz, 1H; CH), 5.39 (dd, J(H,H)=3.4, 1.8Hz, 1H; CH), 5.33 (dd, J(H,H)=10, 3.4 Hz, 1H; CH),5.24-5.19 (m, 3H; CH2, CH), 4.49 (d, J(H,H)=7.6 Hz, 2H;CH2), 4.15 (dd, J(H,H)=12, 5.4 Hz, 1H; CH2), 4.06 (qd,J(H,H)=9.8, 5.4, 2.0 Hz, 1H; CH), 3.97 (dd, J(H,H)=12, 2.0Hz, 1H), 2.23-2.16 (m, 4H; CH, CH3), 2.05 (s, 3H; CH3),1.97 (s, 3H; CH3), 1.89 (s, 3H; CH3), 0.92 (d, J(H,H)=6.8Hz, 6H, (CH3)2); ?3C NMR (100 MHz, DMSO-d6, 25 C.)oe=169.80, 169.51, 169.50, 169.42, 152.65, 146.82, 144.71,144.34, 142.94, 139.70, 133.70, 133.37, 131.93, 131.13,128.86, 127.34, 125.34, 124.53, 120.79, 117.77, 116.70,95.31, 69.47, 68.22, 67.86, 64.81, 64.34, 61.51, 53.50,28.42, 20.56, 20.44, 20.40, 20.36, 19.29 ppm; UV/VIS(Methanol): XMCX(c)=246 nm (71000); IR (ATR): v=2962,1746, 1581, 1531, 1477, 1427, 1367, 1213, 1132, 1055, 972,759 cm?; HRMS (Expected for [C35H38N4O,5+Na]: 766.2572, Observed 766.25757, (A=0.5 ppm))
  • 67
  • C42H76N2O15 [ No CAS ]
  • [ 99011-02-6 ]
  • C56H90N6O14 [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% With HATU; In dichloromethane; at 20℃; General procedure: E-27 (1.2 mmol) and Quinoline-amine (1 eq) was taken up in DCM (5 mL). To this was added HATU (1.2 eq) neat. The reaction was stirred overnight at room temperature. Reaction was very sluggish an additional 0.5 eq of HATU was added. Reaction was stirred for 2 days or disappearance of starting material was observed (TLC or MS). Reaction solution was removed in vacuo and the crude material directly purified by chromatography to get the desired product.
  • 68
  • [ 1353016-71-3 ]
  • [ 99011-02-6 ]
  • C33H29N5O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; In chloroform; N,N-dimethyl-formamide; at 20 - 35℃; for 37h;Inert atmosphere; Weighing 0.03 g (0.075 mmol) of dibenzocyclooctene-succinimide ester,<strong>[99011-02-6]Imiquimod</strong> 0.036g (0.15mmol) was dissolved in a 25mL single-neck round bottom flask containing magnets, dissolved in 10mL chloroform:DMF=20:1 mixed solvent, then added to 1mL refined under argon protection. The dimethyl chloride 4-DMA-pyridine (DMAP) 0.003g, stirred at room temperature for 1h, transferred to 35 C for 36h, after the reaction is completed, the column is separated by silica gel column to obtain diphenylcyclooctyne functional group <strong>[99011-02-6]Imiquimod</strong>. Its structural characterization is shown in Figure 5 of the NMR spectrum.
  • 69
  • [ 66826-78-6 ]
  • [ 99011-02-6 ]
  • C22H22N4O [ No CAS ]
  • 70
  • [ 99011-02-6 ]
  • [ 100-51-6 ]
  • [ 415726-68-0 ]
  • 71
  • [ 25637-18-7 ]
  • [ 99011-02-6 ]
  • [ 2723501-28-6 ]
YieldReaction ConditionsOperation in experiment
98% With tributyl-amine; trimethylsilyl(cumyl) peroxide; N,N,N′,N′-tetramethyl-N″-tert-butylguanidine; copper(l) chloride In N,N-dimethyl-formamide; <i>tert</i>-butyl alcohol at 20℃; for 1h; Sealed tube; Inert atmosphere; General procedure for the amination of alkyl iodides. General procedure: An oven-dry tube equipped with a stirring bar was charged with the alkyl iodide (0.20 mmol, 1.0 equiv.), the N-nucleophile (0.30 mmol, 1.5 equiv.) and [Cu(MeCN)4]PF6 (7.5 mg, 0.020 mmol, 10 mol%). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl) and evacuated and refilled with N2 (three times). Dry and degassed CH3CN (1.0 ml), t-BuOH (1.0 ml), (n-Bu)3N (238 μl, 1.0 mmol, 5.0 equiv.), BTMG (80 μl, 0.40 mmol, 2.0 equiv.) were sequentially added. The resulting solution was treated with cumOOTMS (224 mg, 238 μl, 1.00 mmol, 5.0 equiv.) dropwise under vigorous stirring. After 1 h the tube was opened and the mixture diluted with brine (2 ml) and EtOAc (2 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (5 ml × 2). The combined organic layers were dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography on silica gel.
  • 72
  • [ 2758621-41-7 ]
  • [ 99011-02-6 ]
YieldReaction ConditionsOperation in experiment
100% With ethanolamine In ethanol at 80℃; General Procedure B: Synthesis of 2-Aminopyridines from Pyridine N-Oxides; General procedure: To a stirred solution of pyridine N-oxide and pyridine (5.0 equiv.) in CH2Cl2 or CH3CN (0.1-0.2 M) was added trifluoroacetic anhydride (2.0-3.0 equiv.) at 0 °C. The resulting mixture wasstirred at room temperature, and reaction progress was monitored by LCMS. Upon completion,the reaction mixture was concentrated, dissolved in a minimal amount of CH2Cl2, and trituratedfrom rapidly stirring Et2O. The crude pyridinium salt was isolated by filtration and washedwith Et2O. When solid pyridinium salts were not formed, the crude mixture was purified bychromatography on silica gel (MeOH/CH2Cl2) or reversed-phase C18 (CH3CN/H2O). Thepyridinium salt was dissolved in EtOH (0.1-0.2 M) and treated with hydrazine monohydrate or2-aminoethanol (5.0-10.0 equiv.). The reaction mixture was either heated to 80 oC or stirred atroom temperature overnight. Upon completion by LCMS, the reaction was worked upaccordingly, and the product was isolated after silica gel column chromatography.
  • 73
  • [ CAS Unavailable ]
  • [ 99011-02-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
44.5% Stage #1: imiqimod With 2,6-dimethylpyridine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: mcValCit-OH With benzotriazol-1-ol; HATU at 20℃; for 12h; 5 LP1: Preparation of 6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-(1-(1-isobutyl- 1H-pyrrolo[3,2-c]quinolin-4-ylamino)-1-oxo-5-ureidopentan-2-ylamino)-3-methyl-1- oxobutan-2-yl)hexanamide [mcValCit-Imiquimod] Imiquimod (10 mg, 42 µmol) and 2,6-dimethylpyridine (15 µL, 0.13 mmol) in DMF (2 mL) were stirred together for 15 min at rt before adding HOBt (8.3 mg, 54 µmol), HATU (19 mg, 50 µmol) and mcValCit-OH (21 mg, 46 µmol). The reaction mixture was further stirred for 12 h at rt. The crude reaction mixture was purified by reverse phase preparative HPLC using (10% to 95% ACN in water containing 0.05% TFA). Fractions containing the desired compound were dried under high vacuum to give 12.9 mg (44.5%) of title compound as a yellow oily substance. LC-MS (Protocol A): m/z 690.4 [M+1]+; Retention time = 2.32 min. 1H NMR (400 MHz, DMSO) δH/ppm 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 6.5 Hz, 1H), 8.43 (d, J = 8.4 Hz, 2H), 7.86 (ddd, J = 14.1, 12.0, 5.7 Hz, 4H), 6.99 (s, 2H), 4.89 (s, 1H), 4.61 (d, J = 7.5 Hz, 2H), 4.50 (d, J = 7.5 Hz, 1H), 4.29 - 4.22 (m, 1H), 3.37 (t, J = 7.0 Hz, 3H), 3.04 (dd, J = 10.9, 6.8 Hz, 2H), 2.94 (s, 1H), 2.23 - 2.08 (m, 5H), 1.53 - 1.40 (m, 10H), 1.18 (dd, J = 13.8, 9.4 Hz, 4H), 0.95 (t, J = 6.5 Hz, 9H), 0.90 (d, J = 6.8 Hz, 4H), 0.87 - 0.81 (m, 8H). [0220] LP2: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-isobutyl-1H-pyrrolo[3,2- c]quinolin-4-yl)hexanamide [mc-Imiquimod]
44.5 % Stage #1: imiqimod With 2,6-dimethylpyridine In N,N-dimethyl-formamide at 20℃; Stage #2: mcValCit-OH With benzotriazol-1-ol; HATU at 20℃; 5 LP1: Preparation of 6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-(1-(1-isobutyl- 1H-pyrrolo[3,2-c]quinolin-4-ylamino)-1-oxo-5-ureidopentan-2-ylamino)-3-methyl-1- oxobutan-2-yl)hexanamide [mcValCit-Imiquimod] Imiquimod (10 mg, 42 µmol) and 2,6-dimethylpyridine (15 µL, 0.13 mmol) in DMF (2 mL) were stirred together for 15 min at rt before adding HOBt (8.3 mg, 54 µmol), HATU (19 mg, 50 µmol) and mcValCit-OH (21 mg, 46 µmol). The reaction mixture was further stirred for 12 h at rt. The crude reaction mixture was purified by reverse phase preparative HPLC using (10% to 95% ACN in water containing 0.05% TFA). Fractions containing the desired compound were dried under high vacuum to give 12.9 mg (44.5%) of title compound as a yellow oily substance. LC-MS (Protocol A): m/z 690.4 [M+1]+; Retention time = 2.32 min. 1H NMR (400 MHz, DMSO) δH/ppm 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 6.5 Hz, 1H), 8.43 (d, J = 8.4 Hz, 2H), 7.86 (ddd, J = 14.1, 12.0, 5.7 Hz, 4H), 6.99 (s, 2H), 4.89 (s, 1H), 4.61 (d, J = 7.5 Hz, 2H), 4.50 (d, J = 7.5 Hz, 1H), 4.29 - 4.22 (m, 1H), 3.37 (t, J = 7.0 Hz, 3H), 3.04 (dd, J = 10.9, 6.8 Hz, 2H), 2.94 (s, 1H), 2.23 - 2.08 (m, 5H), 1.53 - 1.40 (m, 10H), 1.18 (dd, J = 13.8, 9.4 Hz, 4H), 0.95 (t, J = 6.5 Hz, 9H), 0.90 (d, J = 6.8 Hz, 4H), 0.87 - 0.81 (m, 8H). [0220] LP2: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-isobutyl-1H-pyrrolo[3,2- c]quinolin-4-yl)hexanamide [mc-Imiquimod]
44.5 % Stage #1: imiqimod With 2,6-dimethylpyridine In N,N-dimethyl-formamide at 20℃; Stage #2: mcValCit-OH With benzotriazol-1-ol; HATU at 20℃; 5 LP1: Preparation of 6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-(1-(1-isobutyl- 1H-pyrrolo[3,2-c]quinolin-4-ylamino)-1-oxo-5-ureidopentan-2-ylamino)-3-methyl-1- oxobutan-2-yl)hexanamide [mcValCit-Imiquimod] Imiquimod (10 mg, 42 µmol) and 2,6-dimethylpyridine (15 µL, 0.13 mmol) in DMF (2 mL) were stirred together for 15 min at rt before adding HOBt (8.3 mg, 54 µmol), HATU (19 mg, 50 µmol) and mcValCit-OH (21 mg, 46 µmol). The reaction mixture was further stirred for 12 h at rt. The crude reaction mixture was purified by reverse phase preparative HPLC using (10% to 95% ACN in water containing 0.05% TFA). Fractions containing the desired compound were dried under high vacuum to give 12.9 mg (44.5%) of title compound as a yellow oily substance. LC-MS (Protocol A): m/z 690.4 [M+1]+; Retention time = 2.32 min. 1H NMR (400 MHz, DMSO) δH/ppm 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 6.5 Hz, 1H), 8.43 (d, J = 8.4 Hz, 2H), 7.86 (ddd, J = 14.1, 12.0, 5.7 Hz, 4H), 6.99 (s, 2H), 4.89 (s, 1H), 4.61 (d, J = 7.5 Hz, 2H), 4.50 (d, J = 7.5 Hz, 1H), 4.29 - 4.22 (m, 1H), 3.37 (t, J = 7.0 Hz, 3H), 3.04 (dd, J = 10.9, 6.8 Hz, 2H), 2.94 (s, 1H), 2.23 - 2.08 (m, 5H), 1.53 - 1.40 (m, 10H), 1.18 (dd, J = 13.8, 9.4 Hz, 4H), 0.95 (t, J = 6.5 Hz, 9H), 0.90 (d, J = 6.8 Hz, 4H), 0.87 - 0.81 (m, 8H). [0220] LP2: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-isobutyl-1H-pyrrolo[3,2- c]quinolin-4-yl)hexanamide [mc-Imiquimod]
44.5 % Stage #1: imiqimod With 2,6-dimethylpyridine In N,N-dimethyl-formamide at 20℃; Stage #2: mcValCit-OH With benzotriazol-1-ol; HATU at 20℃; 5 LP1: Preparation of 6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-(1-(1-isobutyl- 1H-pyrrolo[3,2-c]quinolin-4-ylamino)-1-oxo-5-ureidopentan-2-ylamino)-3-methyl-1- oxobutan-2-yl)hexanamide [mcValCit-Imiquimod] Imiquimod (10 mg, 42 µmol) and 2,6-dimethylpyridine (15 µL, 0.13 mmol) in DMF (2 mL) were stirred together for 15 min at rt before adding HOBt (8.3 mg, 54 µmol), HATU (19 mg, 50 µmol) and mcValCit-OH (21 mg, 46 µmol). The reaction mixture was further stirred for 12 h at rt. The crude reaction mixture was purified by reverse phase preparative HPLC using (10% to 95% ACN in water containing 0.05% TFA). Fractions containing the desired compound were dried under high vacuum to give 12.9 mg (44.5%) of title compound as a yellow oily substance. LC-MS (Protocol A): m/z 690.4 [M+1]+; Retention time = 2.32 min. 1H NMR (400 MHz, DMSO) δH/ppm 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 6.5 Hz, 1H), 8.43 (d, J = 8.4 Hz, 2H), 7.86 (ddd, J = 14.1, 12.0, 5.7 Hz, 4H), 6.99 (s, 2H), 4.89 (s, 1H), 4.61 (d, J = 7.5 Hz, 2H), 4.50 (d, J = 7.5 Hz, 1H), 4.29 - 4.22 (m, 1H), 3.37 (t, J = 7.0 Hz, 3H), 3.04 (dd, J = 10.9, 6.8 Hz, 2H), 2.94 (s, 1H), 2.23 - 2.08 (m, 5H), 1.53 - 1.40 (m, 10H), 1.18 (dd, J = 13.8, 9.4 Hz, 4H), 0.95 (t, J = 6.5 Hz, 9H), 0.90 (d, J = 6.8 Hz, 4H), 0.87 - 0.81 (m, 8H). [0220] LP2: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(1-isobutyl-1H-pyrrolo[3,2- c]quinolin-4-yl)hexanamide [mc-Imiquimod]

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