CN104402878A - Preparation method of imiquimod - Google Patents

Abstract

The invention relates to a preparation method of an antiviral drug imiquimod, wherein the preparation method comprises the steps: (1) with 4-hydroxyquinoline as a starting material, nitrifying to obtain 3-nitro-4-hydroxyquinoline; (2) carrying out chlorination and amination on 3-nitro-4-hydroxyquinoline to obtain 3-nitro-4-isobutyl amine quinoline; (3) carrying out hydrogenation on 3-nitro-4-isobutyl amine quinoline to obtain 3-amino-4-isobutyl amine quinoline, and separating in a formate mode; (4) carrying out cyclization, oxidation and ammoniation on 3-amino-4-isobutyl amine quinoline, carrying out a reaction in a same reactor, and thus obtaining an imiquimod crude product; and (5) preparing a hydrochloride of imiquimod from the imiquimod crude product, purifying, and carrying out alkaline hydrolysis to obtain the high-purity imiquimod. In the method, the imiquimod is prepared from 4-hydroxyquinoline as the starting material, and the total yield can reach 55%; the method has the advantages of high yield, less reaction steps, less discharge of three wastes, mild and more complete reaction conditions, and simple and convenient operation, is suitable for industrialized production, and has relatively high practical value. The obtained product is more stable in quality, and the purity can reach more than 99.7%.

Description

A kind of preparation method of Imiquimod

Technical field

The present invention relates to a kind of preparation method of Imiquimod, particularly relate to a kind of preparation method of high purity Imiquimod.

Background technology

Imiquimod (Imiquimod), chemical name 4-amino-1-isobutyl--1H-imidazoles [4,5-c]-quinoline, is the antiviral with immunoregulation effect of 3M drugmaker of U.S. exploitation, is used for the treatment of adult's pointed condyloma.Imiquimod is disclosed in United States Patent (USP) 4689338 and 5238944, has structure (VII)

The synthetic route of known Imiquimod is more in the prior art, be summed up mainly contain following several: (1) with 3-nitro-4-hydroxyquinoline for Material synthesis; (2) with 3-nitro-2,4-dihydroxyl quinoline for Material synthesis; (3) with 3-nitro-4-hydroxyquinoline-2-ketone for Material synthesis; (4) with 2,4,5-tribromoimidazole for Material synthesis; (5) with 2-bromo-benzoic acid for Material synthesis.

Wherein the 4th, 5 article of route will use some reagent that are expensive, that not easily buy, and some severe reaction conditions, trivial operations, yield is low, and cost is high, is difficult to carry out large-scale industrial production.And the 2nd, 3 article of route all need by intermediate 3-nitro-2,4 dichloroquinolines carry out amine substitution reaction, but the selective control condition that this intermediate carries out amine replacement is more difficult, selectivity is not high, thus cause productive rate lower, and will carry out high temperature or reaction under high pressure time prepared by crude product, operation is complicated, and large-scale industrial production is more difficult.

Route 1 commercial routes is reasonable in design, and reaction conditions is conventional, and simple to operate, stable yield is the route of more satisfactory applicable suitability for industrialized production.This route is as follows:

This route be Genster JF report in 1987 with 3-nitro-4-hydroxyquinoline for raw material is through chlorination, amination, reduction, cyclization, oxidation, chlorination and condensation seven step synthesis Imiquimod, Genster JF improved the last two steps reaction in 1992.Namely, when there being N → O key in quinoline structure, 2 one hydrogen of this structure can be replaced by amino under Tosyl chloride participates in, and doing so avoids necessary condition of high voltage in the substitution reaction of former ammonia.

In prior art, the processing condition Problems existing of this route 1 is:

1) when preparing starting raw material 3-nitro-4-hydroxyquinoline, nitration reaction is multiplex makees nitrating agent to nitrosonitric acid, but nitrosonitric acid potential safety hazard is large aborning, and price is more expensive, is not suitable for suitability for industrialized production;

2) when preparing intermediate 3-nitro-4-isobutyl amine quinoline, the chlorination reaction of the first step is that 3-nitro-4-hydroxyquinoline is first used phosphorus oxychloride chlorination, through a series of process, obtain intermediate 3-nitro-4-chlorine-quinoline, itself and isobutylamine are carried out amine substitution reaction and obtain 3-nitro-4-isobutyl amine quinoline by second step amination reaction again, and above two step operations also make production cost increase;

3) when preparing intermediate 3-amino-4-isobutyl amine quinoline, amino due to this intermediate is exposed in air oxidizable, the operations such as conventional distillation and concentration all can cause 3-amino-4-isobutyl amine quinoline Quality Down, thus reduce yield and the quality of product.

Summary of the invention

Based on the defect existed in above-mentioned prior art, the object of this invention is to provide a kind of preparation method of Imiquimod of optimization, obtain the Imiquimod product of high-purity high-yield.

Another object of the present invention is by simplifying reactions steps, reduces discharging of waste liquid, thus provides low cost, high-environmental, is applicable to the preparation method of the Imiquimod of industrialization scale operation.

For achieving the above object, the preparation method of Imiquimod of the present invention, with 4-hydroxyquinoline for raw material, the primitive reaction through nitrated, chlorination, amination, hydrogenation, cyclization, oxidation and ammonification carrys out obtained highly purified Imiquimod.

Synthetic route is as follows:

The inventive method step comprises:

(1) be added to by nitrating agent in the organic solvent of 4-hydroxyquinoline and carry out nitration reaction, suction filtration obtains 3-nitro 4-hydroxyquinoline (I),

Wherein, described organic solvent is propionic acid, nitrating agent is nitric acid, preferably, the consumption of propionic acid is 5-15 times of 4-hydroxyquinoline quality, is more preferably 10 times, preferably, the consumption of nitric acid is 0.9 times of 4-hydroxyquinoline quality, preferably, the speed that adds of nitric acid is add complete in 1-2 hour, more preferably, adding speed is add complete in 1.5 hours, preferably, described nitrating agent adds at 90-125 DEG C, preferably adds at 100-120 DEG C, be more preferably 105-115 DEG C, be more preferably 110 DEG C.

Wherein, the mother liquor after suction filtration is applied mechanically through distillation process Posterior circle, and carry out air distillation by nitrated mother liquor, distillation temperature is 140 DEG C, and filter cake is applied mechanically after weighing, and insufficient section supplements new propionic acid.

Compared with the nitrifying method of published this area, the nitration reaction of the inventive method adds speed and temperature of reaction by what control nitric acid, improve reaction efficiency, and reclaimed by reaction mother liquor recycled and filter cake, improve productive rate, Recycling Mother Solution applies mechanically reaction 8 times, yield can reach close to 95%, mother liquor filter cake is reclaimed and also reduces cost, decrease the discharge of waste acid water, be beneficial to environmental protection.

(2) 3-nitro 4-hydroxyquinoline is through sulfur oxychloride chlorination, obtain 3-nitro-4-chlorine-quinoline intermediate reaction liquid, in reaction solution, directly add isobutylamine after being adjusted to weakly alkaline with triethylamine carry out amination reaction and obtain 3-nitro-4-isobutyl amine quinoline (III).

Wherein, above-mentioned chlorination reaction is carried out in organic solvent, and preferably organic solvent is methylene dichloride, ethylene dichloride, toluene etc., is more preferably ethylene dichloride.Wherein, chlorination reaction is carried out under back flow reaction, and the reaction times is 1-5 hour, is preferably 3 hours, and when TLC (membrane chromatographic) can't detect 3-nitro 4-hydroxyquinoline (I), reaction completes.

Wherein, intermediate reaction liquid is cooled to less than 0 DEG C and adds triethylamine adjust pH to 7-8, then be cooled to the mixing solutions that less than-5 DEG C add triethylamine and isobutylamine, preferably, added in 1-3 hour, more preferably, add in 2 hours.Add back flow reaction 30 minutes, three times are washed with sodium hydroxide solution after reaction, merge aqueous phase, use solvent stripping twice again, preferably, described solvent is methylene dichloride, merges organic phase, organic phase is distilled to obtain solid product, filters after adding ethanol stirring and obtain 3-nitro-4-isobutyl amine quinoline (III).

With disclosed Measures compare, when the inventive method prepares 3-nitro-4-isobutyl amine quinoline (III), chlorination, amination reaction are carried out in a reactor.Do not need separation of intermediates product 3-nitro-4-chloroquinoline (II) after chlorination reaction, thus decrease single stepping, be more suitable for industrial operation, product yield brings up to 98.5%, and by organic solvent recycled in the inventive method, reduce the discharge of waste liquid, environmental protection more.

(3) 3-nitro-4-isobutyl amine quinoline (III) is under catalyst action, hydrogenation is carried out in organic solvent with hydrogen, drip formic acid adjust pH crystallization again, after solid-liquid separation, obtain intermediate 3-amino-4-isobutyl amine quinolinecarboxylic acid salt (IV).

Wherein, described catalyzer is active nickel, and described organic solvent is methyl alcohol, ethanol, ethyl acetate, toluene etc., is preferably ethyl acetate.

Wherein, the temperature of reaction of described hydrogenation is 30-100 DEG C, is preferably 50-70 DEG C, is more preferably 60 DEG C.Reaction pressure is 0.2-0.8Mpa, is preferably 0.4-0.6Mpa, is more preferably 0.5Mpa.

Wherein, the time for adding of formaldehyde is 10-60 minute, is preferably 30 minutes, and dropping temperature is less than 50 DEG C, is preferably less than 20 DEG C, is more preferably less than 0 DEG C, and formic acid consumption is and 3-nitro-4-isobutyl amine quinoline equimolar amount.

In the prior art, the treatment process after known report hydrogenation has following several: 1. by filtrate concentrated solution to small volume crystallization; 2. direct for filtrate evaporate to dryness is obtained solid or solubilizing agent dispersion; 3. hydrochloride is made into ethanol solution hydrochloride.First two method all will through pyrogenic distillation solvent, those skilled in the art know, the amino generated after nitro hydro-reduction is exposed to as easy as rolling off a log oxidation in air, especially under the condition of high temperature, need carry out in the absence of oxygen during distillation, otherwise product is oxidized blackening very soon, generates a large amount of impurity, subsequent reactions efficiency is reduced, and yield does not reach 90%.And the productive rate of the third method products therefrom is lower, only 70%, and if need first to carry out alkaline hydrolysis process, complicated operation before carrying out next step reaction, be unfavorable for industrial production.

And the inventive method is by generating formate by the product 3-amino-4-isobutyl amine quinoline after hydrogenation, thus solve above-mentioned three kinds of method Problems existing well, 3-amino-4-isobutyl amine quinolinecarboxylic acid the salt that the inventive method generates is stablized, not easily oxidized, its purity can reach more than 99%, directly can carry out follow-up ring-closure reaction with it, improve the reaction efficiency of ring-closure reaction.Mother liquor distillation and concentration reclaims the 3-amino-4-isobutyl amine quinolinecarboxylic acid salt that non-crystallization goes out, make yield reach 99%, the solvent distilled out carries out recovery recycled, and catalyzer also carries out recycled, not only make production cost greatly reduce, and realize producing without discharging of waste liquid.

(4) formate (IV) of 3-amino-4-isobutyl amine quinoline is through high temperature cyclization, obtain reactant 1-isobutyl--1H-imidazo [4,5-C] quinoline (V), reactant (V) after cyclization and Peracetic Acid are carried out oxidizing reaction in organic solvent under the effect of catalyzer, again by oxidation reaction product (VI) according to method disclosed in WO92/06093, under the existence of Tosyl chloride, be obtained by reacting Imiquimod crude product (VII) with ammoniacal liquor.

Wherein, 3-amino-4-isobutyl amine quinolinecarboxylic acid salt (IV) carries out high temperature ring-closure reaction, after TLC (thin-layer chromatography) detection reaction is complete, steams solvent, obtains reactant (V).

Wherein, the organic solvent in described oxidizing reaction is methyl alcohol, ethanol, ethyl acetate, methylene dichloride etc., is more preferably ethanol.Described catalyzer is diacetyl oxide.Catalyzed reaction temperature is 40-60 DEG C, is preferably 50 DEG C.The consumption of catalyzer is 0.2-0.4 times of 3-amino-4-isobutyl amine quinolinecarboxylic acid salt quality, is preferably 0.4 times.HPLC monitors reaction, and after detecting that unreacted reactant 1-isobutyl--1H-imidazo [4,5-C] quinoline (V) content is less than 5%, evaporated under reduced pressure obtains 1-isobutyl--1H-imidazo [4,5-C] quinoline-5N oxide compound (VI).

Wherein, according to published method (WO92/06093), methylene dichloride joined in oxidation reaction product (VI), add ammoniacal liquor again, remain on 0-5 DEG C, drip the dichloromethane solution containing Tosyl chloride.Suction filtration, and wash with water with 95% ethanol filter wash cake colourless to washings successively, wherein methylene dichloride can reclaim use, dries filter cake and obtains Imiquimod (VII) crude product.

In above-mentioned cyclization oxidizing reaction, the oxygenant that the known oxidation reaction method of prior art adopts has hydrogen peroxide, Peracetic Acid, m-chlorine peroxybenzoic acid etc., but report all can not well react completely.Applicant surprisingly finds, when the inventive method uses Peracetic Acid to be oxidized, under the effect of catalyst acetic acid acid anhydride, oxidizing reaction can well be carried out, and turnover ratio can improve a lot.

(5) Imiquimod (VII) crude product and hydrochloric acid effect generate Imiquimod hydrochloride, then carry out Basic fluxing raction with ammoniacal liquor, obtain as Imiquimod, have purity be greater than 99.7% through HPLC analysis.

Wherein, Imiquimod crude product (VII) is converted into Imiquimod hydrochloride in purified water solvent, purified water consumption is 5-20 times of Imiquimod crude product quality, be preferably 10 times, reaction is preferably carried out at 85-95 DEG C, and drip concentrated hydrochloric acid until Imiquimod crude product all dissolves, crystallization filtering separation obtains Imiquimod hydrochloride, HPLC measures purity and is greater than 99%, productive rate 80%.

Wherein, be dissolved in purified water by the Imiquimod hydrochloride obtained, purified water consumption is 5-20 times of Imiquimod hydrochloride quality, is preferably 10 times, decolouring, filters, and filtrate cools, with ammoniacal liquor adjust pH to 9-10, filtering-depositing obtains Imiquimod, and HPLC measures purity can reach more than 99.5%.

Compare with disclosed patent CN 101048404A, the inventive method prepares Imiquimod fine work, and to have cost low, the feature of cleanliness without any pollution.Also have report to adopt DMF to refine, but the method needs quantity of solvent up to 50 times, decolours at a reflux temperature, no matter from the angle of cost and safety, be not a good process for purification, and highly purified Imiquimod can not be obtained.

Embodiment

Hereafter set forth the present invention further in conjunction with specific embodiments, the reagent adopted in embodiment is other reagent of technical grade.

embodiment one

Preparation 3-nitro 4-hydroxyquinoline (I)

Stirring joins in 100kg propionic acid by 10kg 4-hydroxyquinoline, warming while stirring extremely about 50 DEG C, dissolution of solid, continue slowly to be warming up to 105 DEG C, starting to drip mass concentration is 68% nitric acid 9kg, and the process that drips to keep in retort about 105 DEG C, within about 1.5 hours, dropwises.

By reaction solution back flow reaction 30 minutes again after dripping off, be cooled to about 20 DEG C, suction filtration, obtain mother liquor and be about 89kg, continue to employ, obtain solid filter cake simultaneously, filter cake is washed till pH value 5-6, after being filtered dry with large water gaging, filter cake is dried at about 90 DEG C, obtain faint yellow solid and 3-nitro 4-hydroxyquinoline (I) 12.1kg, yield: 92.4%

M.p > 300 DEG C of document m.p 325 DEG C

HPLC measures purity 99.2%.

embodiment two

Recycling Mother Solution uses preparation 3-nitro 4-hydroxyquinoline (I)

By in above-mentioned suction filtration gained 89kg mother liquor suction retort (model), heat up and carry out air distillation, stop distillation when distillation temperature is increased to 140 DEG C, obtain product of distillation 15.7kg, slightly add 27kg propionic acid after cooling, thus mother liquor is reclaimed.

Then recovery mother liquor is used to carry out next round reaction.In recovery mother liquor, 10kg 4-hydroxyquinoline is again added below 100 DEG C, warming while stirring to 105 DEG C, start to drip the nitric acid 9kg that mass concentration is 68%, dropping process to keep in retort about 115 DEG C, within about 1.5 hours, dropwise, back flow reaction 30 minutes again after dripping off, be cooled to 30 DEG C, suction filtration obtains mother liquor and is about 90kg, (carrying out above-mentioned recycling Posterior circle to use), by the filter cake massive laundering that obtains to pH value 5-6, after being filtered dry, filter cake is dried at 70-90 DEG C, obtain faint yellow solid and 3-nitro 4-hydroxyquinoline (I) 12.3kg, yield: 93.9%.

HPLC measures purity 99.1%.

M.p > 300 DEG C of document m.p 325 DEG C

Repeat above step, after Recycling Mother Solution uses and reacts for 8 times, recording yield is 95%.

embodiment three

Preparation 3-nitro-4-isobutyl amine quinoline (III)

Successively 100kg methylene dichloride, 5kg dimethyl formamide are joined in the retort of dried and clean, start stirring and add 10kg itrated compound, 8.5kg sulfur oxychloride, start heating, back flow reaction 3 hours, TLC detects (membrane chromatographic), when can't detect 3-nitro 4-hydroxyquinoline, reacts completely.

Stop heating, icy salt solution is lowered the temperature, and is cooled to less than 0 DEG C maintenance, and drips triethylamine adjust pH to 7-8, continues to keep temperature in less than-5 DEG C, directly drips the mixing solutions of 4.5kg isobutylamine and 7.3kg triethylamine, within 2 hours, dropwises.

Drip off after nature is warming up to room temperature, heating reflux reaction 30 minutes, adds 50kg water, stir after 10 minutes, stratification, water layer is continued to employ, and organic layer washes three times with the aqueous sodium hydroxide solution that 50kg mass concentration is 0.5% again, merge aqueous phase, with 25kg dichloromethane extraction twice, aqueous phase discards, and merges organic phase, filter and remove insolubles, filtrate air distillation obtains solid product.In gained solid, add 20kg ethanol, stir 30 minutes, suction filtration, a small amount of ethanol rinse of filter cake, gained solid, 60-70 DEG C of oven dry, obtains golden yellow 3-nitro-4-isobutyl amine quinoline (III) 12.7kg, yield 98.5%.

Comparative example

Bibliographical information (Zhang Yan, Cheng Wenxiang etc., the synthesis of Imiquimod, Chinese pharmacists, 13rd volume the 2nd phase in 2010,209-211) with 3-nitro 4-hydroxyquinoline for raw material, phosphorus oxychloride is chlorizating agent, and DMF is that solvent carries out chlorination reaction, filter and first obtain intermediate product 3-nitro-4-chlorine-quinoline, then intermediate product and isobutylamine are carried out next step and be obtained by reacting 3-nitro-4-isobutyl amine quinoline.Two step yields are only 85%.

HPLC measures purity 99.1%

DEG C document m.p114 ~ 118 DEG C, m.p115 ~ 117.

embodiment four

Preparation 3-amino-4-isobutyl amine quinolinecarboxylic acid salt (IV)

Add in the autoclave of dried and clean by 100kg ethyl acetate, 10kg 3-nitro-4-isobutyl amine quinoline (III), 1kg active nickel, airtight kettle cover, is evacuated to-0.09MPa, is filled with to 0.3Mpa in nitrogen to still, emptying.Be filled with nitrogen again and discharge nitrogen again to 0.3Mpa, be evacuated to-0.09MPa, then be filled with hydrogen in the lower 60 DEG C of reactions of 0.5MPa, to no longer consuming hydrogen, react complete.

Discharge hydrogen, be evacuated to 0.09MPa, emptying, be cooled to 20-30 DEG C.Filter out catalyzer, filtrate is added formic acid 1.88kg at about 0 DEG C, adjust pH is to 6-7, separate out faint yellow solid, stir 30 minutes, suction filtration, filter cake with a small amount of ethyl acetate drip washing once, filter cake drying at 60-70 DEG C is obtained 3-amino-4-isobutyl amine quinolinecarboxylic acid salt (IV) 9.9kg, yield 93.0%.

Filtrate washing lotion is distilled in the lump, again obtains 0.64kg3-amino-4-isobutyl amine quinolinecarboxylic acid salt, merges yield 99%.

The hydrogenated products 3-amino-4-isobutyl amine quinolinecarboxylic acid salt that aforesaid method obtains, stable, not easily oxidized under normal temperature, and purity is high, the ring-closure reaction after being directly used in.

The above-mentioned solvent distilled out, catalysts all can recycled, reduces discharging of waste liquid, and increases operation rate, reduce production cost.

Bibliographical information (Zhang Yiwei, Chen Haiquan etc., the improvement of Synthesis Procedure of Imiquimod, South China Science & Engineering University's journal, 35th volume the 7th phase, 78-81) with 3-nitro-4-isobutyl amine quinoline for raw material is through reduced iron powder hydrogenation, gained 3-amino-4-isobutyl amine quinoline hydrochloride yield only 76%.

Bibliographical information (Zhang Yan, Cheng Wenxiang etc., the synthesis of Imiquimod, Chinese pharmacists, 13rd volume the 2nd phase in 2010,209-211) with 3-nitro-4-isobutyl amine quinoline for raw material, with palladium carbon for catalyzer carries out hydrogenation, gained 3-amino-4-isobutyl amine quinoline yield only 81%.

HPLC measures purity 99.4%

mp 124～126℃

Ultimate analysis C14H19N3O2

Calculated value: C64.3% H7.3% N16.1% O12.3%

Measured value: C64.2% H7.4% N16.0% O12.4%

embodiment five

Prepare Imiquimod (VII) crude product

Slowly joined in 50kg anhydrous formic acid by 10kg 3-amino-4-isobutyl amine quinolinecarboxylic acid salt (IV), be heated with stirring to back flow reaction 10 hours, TLC detection reaction is complete, and underpressure distillation formic acid, to not going out, obtains reactant (V).

30kg dehydrated alcohol is added in reactant (V), add the Peracetic Acid that 18Kg mass concentration is 16%, diacetyl oxide 4kg is added below 45 DEG C, again in 48 ~ 50 DEG C of reactions 24 hours, HPLC detects unreacted reactant 1-isobutyl--1H-imidazo [4,5-C] quinoline (V) is 4.5% (massfraction) (being less than 5%), remove solvent under reduced pressure and obtain product 1-isobutyl--1H-imidazo [4,5-C] quinoline-5N oxide compound (VI).

In product (VI), add 40kg methylene dichloride, icy salt solution is cooled to 0 DEG C, and at 0 ~ 10 DEG C, drip ammoniacal liquor (35kg), keeps 0 ~ 5 DEG C, adds 9kg Tosyl chloride in batches, 15 ~ 30 DEG C of stirring reactions 2 hours after adding.Suction filtration, washes with water, 95% washing with alcohol filter cake successively, substantially colourless to washings, from filtrate, reclaim methylene dichloride.Filter cake, in 70 DEG C ~ 80 DEG C oven dry, obtains off-white color Imiquimod crude product 7.8kg.Yield: 84.8%.

Document CN 10104840A reports, with 3-amino-4-isobutyl amine quinoline for starting raw material: through formic acid cyclisation, metachloroperbenzoic acid is oxidized, gained oxide compound alcohol hydrochloric acid salify, chlorination is carried out again with phosphorus oxychloride, carry out iodate with sodium iodide, gained iodide react with methanol ammonia again prepares Imiquimod crude product.Its yield is: 58.9%.

embodiment six

Refining of Imiquimod

Stirring is slow down to add in 100kg purified water by 10kg Imiquimod crude product (VII), heat up, keep 85-95 DEG C to drip concentrated hydrochloric acid, stop dripping after material is entirely molten, add activated carbon, 85 DEG C decolour 30 minutes, filtered while hot, appropriate hot water wash, in the crystallizer that the suction of filtrate washing lotion is clean, stirring is cooled to 0 ~ 5 DEG C, crystallization 2 hours.Filter, 10kg cold wash filter cake, filter cake, in 70 DEG C of drying under reduced pressure, obtains Imiquimod hydrochloride 10.5kg.

Stirring is slow down to be joined in 105kg purified water by 10.5kg Imiquimod hydrochloride, stirs and is warming up to 90 DEG C, after material is entirely molten, add gac, more than 80 DEG C decolour 30 minutes, filter, filtrate is cooled to 25 DEG C, drips ammoniacal liquor (massfraction) adjust pH to 9.5 of 25%, filters, the abundant filter wash cake of purified water, after inspection by sampling muriate is qualified, then use ethanol filter wash cake, filter cake is in 75 DEG C of decompression dryings, obtain Imiquimod 9.1kg, yield: 91%.Document (CN 101048404A) yield: 89.7%.

m.p 293～295；HPLC：99.8％。

Ultimate analysis (C14H16N4):

Theoretical value (%): C69.97, H6.71, N23.32;

Measured value: C69.95, H6.8, N23.57

1HNMR structural identification

INSTRUMENT MODEL, condition determination

Instrument 1NOVA-500; Solvent DMSO-d6

Hydrogen nuclear magnetic resonance modal data is in table 1

Table 1 proton nmr spectra (1H NMR) is composed

Claims (9)

1. a preparation method for Imiquimod, comprises the following steps:

(1) be added to by nitrating agent in the organic solvent of 4-hydroxyquinoline and carry out nitration reaction and obtain 3-nitro 4-hydroxyquinoline, mother liquor is applied mechanically through distillation process Posterior circle;

(2) 3-nitro-4-hydroxyquinoline is through sulfur oxychloride chlorination reaction, the intermediate 3-nitro-4-chlorine-quinoline reaction solution obtained, the mixture directly adding triethylamine and isobutylamine after being adjusted to weakly alkaline with triethylamine again in reaction solution carries out amination reaction, obtains 3-nitro-4-isobutyl amine quinoline;

(3) 3-nitro-4-isobutyl amine quinoline is under catalyst action, carries out hydrogenation in organic solvent, make crystallization with formic acid adjust pH to 5-7 with hydrogen, obtains the formate of intermediate 3-amino-4-isobutyl amine quinoline after solid-liquid separation;

(4) formate of 3-amino-4-isobutyl amine quinoline is through high temperature cyclization, obtain the reactant 1-isobutyl--1H-imidazo [4 after cyclization, 5-C] quinoline, again itself and Peracetic Acid are carried out oxidizing reaction under the effect of catalyzer, oxidation reaction product is reacted to obtain Imiquimod crude product with ammoniacal liquor under Tosyl chloride exists;

(5) Imiquimod crude product is to generate Imiquimod hydrochloride with hydrochloric acid effect, then carries out Basic fluxing raction with ammoniacal liquor, obtains Imiquimod.

2. the preparation method of Imiquimod according to claim 1, it is characterized in that, nitrating agent described in step (1) is nitric acid, the consumption of nitric acid is 0.9 times of 4-hydroxyquinoline quality, described organic solvent is propionic acid, the consumption of propionic acid is 5-15 times of 4-hydroxyquinoline quality, is more preferably 10 times.

3. the preparation method of Imiquimod according to claim 1, it is characterized in that, nitric acid described in step (1), adding speed is add complete in 1-2 hour, preferably, adding speed is add complete in 1.5 hours, preferably, nitrating agent adds at 90-125 DEG C, preferably adds at 100-120 DEG C, be more preferably 105-115 DEG C, be more preferably 110 DEG C.

4. the preparation method of Imiquimod according to claim 1, is characterized in that, described in step (1), mother liquor is through air distillation, and distillation temperature is 140 DEG C, and debris is applied mechanically after weighing, and insufficient section supplements new propionic acid.

5. the preparation method of Imiquimod according to claim 1, it is characterized in that, described in step (2), chlorination reaction is carried out in organic solvent, preferably, organic solvent is methylene dichloride, ethylene dichloride, toluene, and be more preferably ethylene dichloride, described chlorination reaction is carried out under back flow reaction, reaction times is 1-5 hour, is preferably 3 hours.

6. the preparation method of Imiquimod according to claim 1, it is characterized in that, in step (2) after chlorination reaction, not treatedly directly carry out amination reaction, the mixture of described triethylamine and isobutylamine, below-5 DEG C, added, preferably in 1-3 hour, add in 2 hours, add back flow reaction 30 minutes.

7. the preparation method of Imiquimod according to claim 1, is characterized in that, the catalyzer described in step (3) is active nickel, and described organic solvent is methyl alcohol, ethanol, ethyl acetate, toluene, is preferably ethyl acetate,

Wherein, the temperature of reaction of described hydrogenation is 30-100 DEG C, is preferably 50-70 DEG C, and be more preferably 60 DEG C, reaction pressure is 0.2-0.8Mpa, is preferably 0.4-0.6Mpa, is more preferably 0.5Mpa.

Wherein, the joining day of formic acid is 10-60 minute, is preferably 30 minutes, and dropping temperature is less than 50 DEG C, is preferably less than 20 DEG C, is more preferably less than 0 DEG C, and formic acid consumption is and 3-nitro-4-isobutyl amine quinoline equimolar amount.

8. the preparation method of Imiquimod according to claim 1, is characterized in that, the described oxidizing reaction in step (4) is carried out in organic solvent, and organic solvent is methyl alcohol, ethanol, ethyl acetate, methylene dichloride, is preferably ethanol,

Wherein, described catalyzer is diacetyl oxide, and catalyzed reaction temperature is 40-60 DEG C, is preferably 50 DEG C, and the consumption of catalyzer is 0.2-0.4 times of 3-amino-4-isobutyl amine quinolinecarboxylic acid salt quality, is preferably 0.4 times.

9. the preparation method of Imiquimod according to claim 1, is characterized in that, step is converted into Imiquimod hydrochloride in (5) in purified water solvent, purified water consumption is 5-20 times of Imiquimod crude product quality, be preferably 10 times, reaction is preferably carried out at 85-95 DEG C

Wherein, described Basic fluxing raction is first dissolved in purified water by Imiquimod hydrochloride, and purified water consumption is 5-20 times of Imiquimod hydrochloride quality, be preferably 10 times, then decolour, filter, filtrate cools, and with ammoniacal liquor adjust pH to 9-10, filtering-depositing obtains Imiquimod.