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WO2011039782A1 - Procédés de préparation d'imatinib et de ses sels pharmaceutiquement acceptables - Google Patents

Procédés de préparation d'imatinib et de ses sels pharmaceutiquement acceptables Download PDF

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Publication number
WO2011039782A1
WO2011039782A1 PCT/IN2010/000649 IN2010000649W WO2011039782A1 WO 2011039782 A1 WO2011039782 A1 WO 2011039782A1 IN 2010000649 W IN2010000649 W IN 2010000649W WO 2011039782 A1 WO2011039782 A1 WO 2011039782A1
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Prior art keywords
formula
solvent
imatinib
process according
mixture
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Inventor
Ashvin Kumar Aggarwal
Anshul Kumar Jain
Shekhar Bhaskar Bhirud
Lalit Wadhwa
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IND-SWIFT LABORATORIES Ltd
Ind Swift Laboratories Ltd
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IND-SWIFT LABORATORIES Ltd
Ind Swift Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to an improved process for the preparation of imatinib of formula I,
  • the present invention also relates to processes for the preparation of ⁇ -crystalline form of imatinib mesylate.
  • Imatinib of formula I is chemically known as N- ⁇ 5-[4-(4-methyl-piperazinomethyl)-benzoylamido]-2- methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine
  • Imatinib chronic myeloid leukemia (CML), Philadelphia chromosome positive leukemia, for patients in chronic phase and in blast crisis, accelerated phase and also for malignant gastrointestinal stromal tumors. It selectively inhibits activation of target proteins involved in cellular proliferation. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. Imatinib is sold in the U.S. by Novartis as Gleevec I M capsules containing imatinib mesylate equivalent to 100 or 400 mg of imatinib free base.
  • imatinib is prepared by the reaction of 2-amino-4-nitrotoluene with 65% nitric acid to form its nitrate salt which is condensed with aqueous solution of cyanamide to give guanidine nitrate intermediate followed by condensation with the 3-dimethylamino-l -(3-pyridyl)-2-propen-l -one in the presence of sodium hydroxide solution in isopropanol to form a nitro pyrimi ne, intermediate.
  • US patent 6,894,05 1 discloses the crystalline forms of imatinib mesylate namely a- and ⁇ forms.
  • the process for the generation of ⁇ -crystalline form of imatinib mesylate involves the reaction of imatinib base in alcoholic solvent with methane sulfonic acid. The process requires the seeding of the reaction mixture with the desired crystalline form.
  • Use of alcoholic solvents makes the process unsuitable as this result in the formation of sulfonic esters of alcohols, which are known to be genotoxic in mammalian cell system.
  • US patent application 2004/0248918 discloses the preparation of amino pyrimidine intermediate which can be further converted to imatinib.
  • the preparation of amino pyrimidine intermediate involves the reaction of 2-methyl-5-nitroaniline with an aqueous solution of cyanamide in the presence of concentrated nitric acid in ethanol to form guanidine nitrate which is then condensed with 3-dimethylamino-l-(3-pyridyl)-2-propene- 1 -one in presence of isopropanol and sodium hydroxide to give nitro pyrimidine derivative.
  • the nitro pyrimidine intermediate is then reduced using stannous chloride and approximately 9 volumes of solvent followed by condensation to give amine pyrimidine intermediate.
  • the process described here involves the guanidine nitrate intermediate for the further reaction.
  • PCT publication WO 2004/108699 discloses a process for the preparation of imatinib and its analogues by the reaction of 2-methyl-5-nitroaniline with nitric acid in n-butanol to form its nitrate salt and then reaction with an aqueous solution of cyanamide followed by washing with methanol and ether to give guanidine nitrate.
  • the guanidine nitrate then undergoes condensation with 3-dimethylamino- l-(3-pyridyl)-2-propen-l - one to form nitro pyrimidine intermediate which is then reduced in the presence of hydrochloric acid and stannous chloride to give corresponding amino compound.
  • the amino intermediate is then condensed with the 4-chloromethylbenzoyl chloride in the presence of triethylamine and chloroform to give benzamide intermediate, which is reacted with N-methylpiperazine to give imatinib.
  • the yield of the nitro pyrimidine intermediate is reported around 88%, and purity is reported only by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • This nitro pyrimidine intermediate is found to be contaminated with some inorganic salt impurities, which may be the reason for such a high yield.
  • the contamination of the nitro intermediate with inorganic salt impurities is also reflected during the reduction of nitro intermediate, as it yields amine intermediate in low yield i.e. 61 .5% due to presence of inorganic salt impurities which are washed out during the workup of amine intermediate.
  • US patent application 2006/0149061 discloses the synthesis of imatinib starting from 2-chloro-4-(3- pyridy])-pyrimidine which is reacted with 2-amino-4-nitrotoluene in presence of catalyst to give N-(2- methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine which is purified by slurrying in a suitable solvent.
  • the nitro pyrimidine intermediate is then reduced using catalyst in a solvent to give corresponding amine intermediate which is then condensed with 4-(4-methyl-piperazin- l-ylmethyl)-benzoyl chloride in the presence of organic solvent to give imatinib.
  • the obtained product is then purified with a suitable solvent.
  • the reduction reaction requires approximately 15 times solvent with respect to nitro pyrimidine intermediate, which makes the process unattractive.
  • US patent application 2006/173 182 discloses the preparation of imatinib by the reduction of nitro pyrimidine intermediate in the presence of stannous chloride to form the corresponding amino compound which undergoes coupling reaction with 4-(4-methyl-piperazin- l -ylmethyl)-benzoyl chloride dihydrochloride in presence of dimethylformamide as a solvent to give imatinib trihydrochloride monohydrate, which is converted to imatinib base.
  • Imatinib thus prepared is suspended in isopropanol followed by reaction with methane sulfonic acid to give imatinib mesylate.
  • Coupling reaction described in this patent application produces the hydrohalide salt of imatinib, which has to be treated with a base in order to afford the imatinib base, thus an extra step is required which makes the process unattractive on commercial scale.
  • US patent application 2008/0194819 discloses a process for the preparation of imatinib by the reaction of 2- methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to give guanidine hydrochloride intermediate which is then converted to its nitrate salt and then condensed with 3-dimethylamino-l -(3- pyridyl)-2-propene-l -one to give nitro pyrimidine derivative.
  • the nitro pyrimidine intermediate is then reduced with Raney nickel using hydrazine hydrate, followed by condensation with 4-chloromethy (benzoyl chloride in the presence of inorganic base and finally with N-methylpiperazine to give imatinib.
  • the process discloses the synthesis of guanidine intermediate, which is two-step reaction; firstly the hydrochloride salt is prepared which is then converted to nitrate salt.
  • the reaction involves 99% cyanamide for the generation of guanidine nitrate, which is very difficult to handle 99% and highly toxic. Cyanamide of this much purity is also difficult to procure commercially.
  • the condensation reaction yields nitro intermediate of low purity which on reduction with Raney nickel also requires more volume of solvent even in the presence of hydrazine hydrate. All the above shortcomings of the process make it unattractive and economically inefficient at the industrial level.
  • PCT publication WO 2008/ 1 17298 discloses a process for the preparation of imatinib by the reduction of N- (2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine using sodium disulfide or sodium polysulfide in ethanol to give corresponding amine intermediate which is then condensed with 4-(4-methyl-piperazin- l - ylmethyl)-benzoyl chloride in presence of potassium carbonate in alcoholic solvent to give imatinib.
  • PCT publication WO 2008/136010 discloses a process for the preparation of imatinib base by the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine with 4-(4-methyl- piperazin- l -ylmethyl)-benzoyl chloride in the presence of potassium hydroxide in chloroform to give imatinib which is further purified by converting to maleic acid salt, this requires the conversion of imatinib maleate in to the imatinib base of very high purity.
  • the process adds an extra step for the preparation of imatinib mesylate.
  • chloroform which is carcinogenic and not suitable to use for the commercial production as the national toxicology programmer's report on carcinogens implicates that chloroform is reasonably anticipated to be a human carcinogen. Therefore, use of chloroform makes the process unviable.
  • Alcohols such as methanol, ethanol, isopropanol, butanol and their esters results in the formation of genotoxic impurities like methyl mesylate, ethyl mesylate, isopropyl mesylate, butyl mesylate and the like.
  • genotoxic impurities like methyl mesylate, ethyl mesylate, isopropyl mesylate, butyl mesylate and the like.
  • the presence of these impurities in final API makes it not suitable for use as a drug substance.
  • present invention aims to solve the problems associated with the prior art.
  • present invention provides an efficient, industrially feasible and cost effective process for the preparation of imatinib which improves the economics by providing the intermediate as well as final product in high yield as well as purity and also free from the genotoxic impurities.
  • the process of present invention is convenient to operate on a commercial scale and gives the desired product in good yield and quality.
  • the process of the present invention avoids the use of alcoholic solvent during the synthesis of imatinib mesylate from imatinib free base.
  • the principal and foremost object of the present invention is to provide an improved process for the preparation of imatinib and pharmaceutically acceptable salts thereof in good yield and quality, which is efficient, industrially advantageous and convenient to operate on industrial scale.
  • Another object of the present invention is to provide an improved process for the preparation of imatinib wherein isolated free base of guanidine intermediate is used in place of nitrate salt of guanidine intermediate to remove the inorganic salts and other undesirable impurities prior to the reduction.
  • Another object of the present invention is to provide an improved process for the preparation of imatinib wherein the use of large volume of solvent during the reduction reaction and use of pyridine as a solvent at the penultimate stage is avoided.
  • Another object of the present invention is to provide a process for the preparation of ⁇ -crystalline form of imatinib mesylate using non-alcoholic solvent to avoid the formation of genotoxic impurities.
  • present invention provides an improved process for the preparation of imatinib of formula I,
  • present invention provides a process for the preparation of ⁇ -crystalline form of imatinib mesylate, comprises the steps of:
  • present invention provides a process for the preparation of ⁇ -crystalline form of imatinib mesylate, comprises the steps of:
  • the present invention provides an efficient, industrially advantageous process for the preparation of imatinib of formula I,
  • the process involves the reaction of cyanamide with compound of formula I I in presence of nitric acid and suitable solvent to form guanidine nitrate intermediate of formula III, FORMULA III
  • the reaction takes place at a temperature of 30 °C to reflux temperature of the solvent for 1 -20 hours. Preferably, the reaction takes place at reflux temperature for 1 to 5 hours. It is preferable to use aqueous solution of cyanamide instead of pure cyanamide as used in prior art processes, as it is very easy to handle aqueous solution of cyanamide as compared to highly toxic pure cyanamide. It is highly advantageous to use aqueous solution of cyanamide due to commercial non-availability of the pure cyanamide i.e. about 99% pure.
  • Suitable solvent employed for the reaction includes alcohol such as methanol, ethanol, isopropanol, n-butanol and the like or mixture thereof.
  • methanol, ethanol or isopropanol can be employed as a solvent.
  • the reaction mixture was cooled to 20 °C to -25 °C.
  • the guanidine nitrate intermediate of formula III may optionally be isolated from the reaction mixture by suitable techniques such as filtration, centrifugation.
  • the isolated product may be washed with a suitable solvent which includes alcohol such as methanol, ethanol; halogenated solvent such as dichloromethane and the like or mixture thereof.
  • the guanidine nitrate intermediate of formula 111 in situ, or after isolation can be then neutralized with a suitable base at a temperature of 0 to 50 °C to form guanidine intermediate of formula IV, FORMULA IV
  • Suitable base can be organic or inorganic base.
  • Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof, preferably the base is selected from sodium hydroxide or potassium hydroxide and the like.
  • the base employed in the reaction can be used as such or their aqueous solution.
  • the guanidine intermediate of formula IV is then isolated from the reaction mixture using suitable techniques like filtration. It is highly beneficial to proceed further reaction with guanidine intermediate of IV as during workup of the intermediate inorganic salt impurities, generated during the hydrolysis of the guanidine nitrate intermediate of formula III with an inorganic base, along with some other undesired impurities are removed from the reaction mixture.
  • the intermediate of formula IV can be synthesized directly from starting material of formula II without the isolation of the guanidine nitrate intermediate of formula III.
  • the guanidine intermediate of formula IV thus prepared is found to be obtained in overall high yield and purity.
  • the guanidine intermediate of formula IV thus obtained may have purity more than 95% by HPLC, more preferably having purity 98 % by HPLC.
  • the yield of the compound is found to be more than 65%, preferably more than 73 %, even after using the aqueous solution of the cyanamide, which is an added advantage.
  • compound of formula IV may contain isomeric analogues as impurity, which will result in the formation of isomeric analogue of imatinib by the subsequent reaction steps same for the imatinib. Therefore to control, the formation of isomeric analogues of imatinib, the guanidine intermediate of formula IV has been prepared free from all isomeric analogues of following formula,
  • the guanidine intermediate of formula IV undergoes condensation reaction with the enaminoketone of formula V, FORMULA V in the presence of an organic solvent to form nitro pyrimidine intermediate of formula VI.
  • the enaminoketone of formula V can be prepared by the methods already known in the art or by the method as described here for reference Specifically, the preparation of enaminoketone of formula V involves the reaction of 3-acetylpyridine with NN-dimethylformamide dimethyl acetal in the presence of a suitable acid at a temperature of 25 to 1 10 °C for 1 -3 hours, preferably till the completion of the reaction.
  • Suitable acid employed for the reaction includes carboxylic acid such as acetic acid and the like. It is preferable to remove the methanol from the reaction mixture, as methanol may form as by product in the reaction, so it is advantageous to perform the reaction under the condition favorable for the removal of methanol formed as by product. After the completion of the reaction, the solvent can be removed from the reaction mixture by suitable techniques like distillation, evaporation.
  • the enaminoketone of formula V is optionally isolated from the reaction mass or it can be used as such for further reaction.
  • enaminoketone of formula V can be extracted from the reaction mixture using a suitable solvent followed by recovery of the product from the resulting solution by solvent removal.
  • suitable solvent employed for the extraction includes halogenated solvent such as dichlo omethane; aliphatic or aromatic hydrocarbon such as toluene, benzene and the like or mixture thereof.
  • the enaminoketone of formula V, thus obtained can optionally be purified using a suitable methods like crystallization, slurry wash and the like.
  • resulting product can be crystallized from a suitable solvent which includes but not limited to aliphatic hydrocarbon such as cyclohexane, n-hexane, n-heptane and the like or mixture thereof.
  • the enaminoketone of formula V or the reaction mass (as obtained above) can be then reacted with guanidine intermediate of formula IV in the presence of an organic solvent at a temperature of about 50°C to reflux temperature of the solvent till the completion of the reaction.
  • an organic solvent at a temperature of about 50°C to reflux temperature of the solvent till the completion of the reaction.
  • the reaction mixture is heated to reflux for 4- 16 hours.
  • Suitable solvent includes ketones such as methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof.
  • desired product can be isolated from the reaction mixture by suitable techniques like filtration or centrifugation.
  • the isolated nitro pyrimidine intermediate of formula VI if desired can be purified with a suitable solvent which includes, but not limited to ketone such as methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof. It is highly advantageous to perform the condensation reaction by employing free base of guanidine intermediate of formula IV, instead of guanidine nitrate intermediate of formula III, with enaminoketone compound of formula V, as guanidine intermediate of formula IV is free from the inorganic impurities.
  • the nitro pyrimidine intermediate thus obtained is found to be of good quality and may have purity more than 97%, preferably more than 98% by HPLC with comparable yields.
  • the process of reduction of nitro pyrimidine intermediate is accomplished by catalytical transfer hydrogenation.
  • the reduction is carried out by hydrogenation over a suitable catalyst in the presence of hydrogen donor.
  • Suitable catalyst includes palladium, ruthenium or platinum with or without support (carbon), and the like.
  • Suitable hydrogen donor includes for example hydrazine hydrate or sodium hypophosphite and the like.
  • Solvent includes alcohol such as methanol, ethanol, isopropanol; esters such as ethyl acetate and the like or mixture thereof.
  • the reduction is carried out by hydrogenation over a noble metal catalyst in particular, palladium with or without support (carbon), in the presence of hydrazine hydrate.
  • the reaction can be carried out at temperature of 25°C to reflux temperature.
  • the reduction can be carried out by hydrogenation over a noble metal catalyst in particular, palladium on carbon, in the presence of hydrazine hydrate in methanol at 20°C to reflux temperature.
  • the use of hydrazine hydrate in the present reaction is highly efficient as its presence reduces the amount of solvent required for the reaction.
  • the solvent used for the reaction is 3 to 12 times to the nitro pyrimidine intermediate as compared prior art where in 50 volumes of solvent has been used.
  • solvent used is 5 to 10 times.
  • Base can be organic or inorganic base.
  • Organic base includes amines such as triethylamine, trimethylmaine, diisopropylamine, diisopropylethylamine and the like.
  • Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof such as potassium carbonate, sodium carbonate and the like.
  • Solvent employed for the reaction includes alcohol such as methanol, isopropanol; amide solvent such as N,N-dimethylfotmamide, dimethylacetamide, N-methyl pyrrolidone; nitrile solvent such as acetonitrile; halogenated solvent such as dichloromethane; ketone such as acetone; ether such as tertrahydrofuran; aprotic solvents such as dimethylsulfoxide; sulfolane; hexamethylphosphoramide and the like or mixture thereof.
  • imatinib can be isolated from the reaction mixture by suitable methods known in the art.
  • imatinib can be isolated either by precipitating the imatinib in the reaction mixture by the addition of water followed by filtration or reaction mixture may be quenched by suitable quenching agent that includes a suitable acid selected from hydrochloric acid, oxalic acid and the like along with a suitable solvent, if required, followed by layer separation. Acid employed can be used as such or in solution with water. After quenching of the reaction, aqueous layer may be optionally diluted with suitable solvent, which includes ester such as ethyl acetate, butyl acetate; ketone such as acetone, methyl ethyl ketone; ether such as tetrahydrofuran and the like or mixture thereof.
  • suitable solvent which includes ester such as ethyl acetate, butyl acetate; ketone such as acetone, methyl ethyl ketone; ether such as tetrahydrofuran and the like or mixture thereof.
  • Suitable base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate and the like.
  • aqueous solution of sodium hydroxide can be employed.
  • the imatinib free base can optionally be purified by the conventional methods such as precipitation, crystallization or slurrying, washing in a solvent, solvent employed for the purification includes water, ester such as ethyl acetate, n-propyl acetate; ether such as diethyl ether, tetrahydrofuran, diisopropyl ether, methyl tertiary butyl ether; alcohol such as methanol, isopropanol, ethanol; ketone such as acetone, methyl isobutyl ketone; hydrocarbon such as n-hexane, toluene, xylene, halogenated solvent such as chlorobenzene; nitrile solvent such as acetonitrile, and the like or mixture thereof.
  • the solid product can be recovered by suitable techniques such as decantation, filtration by gravity or by suction, centrifugation and the like.
  • Imatinib free base may be converted to pharmaceutically acceptable salts of imatinib by methods already known in the art.
  • Pharmaceutically acceptable acids used for the salt formation includes inorganic acid such as hydrochloric acid, hydrobromic acid; organic acid includes acetic acid, tartaric acid, formic acid, citric acid, oxalic acid, methansulfonic acid and the like.
  • imatinib mesylate is prepared.
  • Imatinib can be converted to imatinib mesylate by any method known in the art. Specifically, present invention avoids the use of alcoholic solvent to circumvent the possibility of formation of even low levels of alkyl sulfonate in imatinib mesylate.
  • the present invention employes the use of non-alcoholic solvents that includes ketone such as acetone, methyl isobutyl ketone, nitrile such as acetonitrile, ether such as t- butylmethyl ether and tetrahydrofuran, amide such as N,N-dimethylformamide, N.N-dimethylacetamide, and others like N-methyl pyrrolidone, 1 ,4-dioxane; hydrocarbon such as toluene, heptane; either alone or in admixture thereof so that may not generate any sulfonic acid esters of alkyl or aryl sulfonic acids.
  • ketone such as acetone, methyl isobutyl ketone
  • nitrile such as acetonitrile
  • ether such as t- butylmethyl ether and tetrahydrofuran
  • amide such as N,N-dimethylformamide, N.N
  • present invention provides a process for the preparation of ⁇ -crystalline form of imatinib mesylate.
  • mesylate can be prepared by the reaction of imatinib base in a first solvent with methansulfonic acid. The reaction takes place at a temperature of 0°C to reflux temperature of the solvent till the formation of imatinib mesylate.
  • First solvent is selected from the solvent in which imatinib mesylate has high solubility. It is highly advantageous to add a solvent to the reaction mixture like water in which imatinib mesylate has high solubility, so that clear solution can be obtained and resulting solution can be charcoal ised.
  • First solvent includes aprotic solvents, mixture of water with suitable solvent selected from nitriles, ketones, ether, and the like.
  • first solvent is selected from water: acetonitrile, water: acetone, water: tetrahydrofuran, NN-dimethylformamide and the like.
  • Second solvent can be selected from the solvent in which imatinib mesylate has no solubility or very less solubility, that includes but limited to nitriles, ethers, ketones and the like or mixture thereof.
  • second solvent that can induce precipitation are selected from methyl tertiary butyl ether, acetone, acetonitrile, tetrahydrofuran or mixture thereof.
  • the imatinib mesylate can be isolated from the reaction mixture by the suitable techniques such as filtration, centrifugation and the like. According to another aspect, present invention provides a process for the preparation of ⁇ -crystalline form of imatinib mesylate using a suitable carboxylic acid.
  • the process involves the treatment of imatinib free base in solvent with a suitable carboxylic acid at a temperature of 0° to reflux temperature of the solvent for few minutes to several hours.
  • reaction is carried out at a temperature of 0°C to 80°C.
  • Suitable solvent includes esters such as ethyl acetate; ketone; ethers such as tetrahydrofuran and the like or mixture thereof.
  • methansulfonic acid was added at a temperature of 0° to reflux temperature.
  • the suitable carboxylic acid employed for the reaction is one that can be further replaced by methane sulfonic acid, preferably selected from acetic acid, formic acid and the like.
  • the ⁇ -form of imatinib mesylate can be isolated from the reaction mixture by suitable methods such as cooling followed by filtration.
  • the imatinib mesylate can be prepared by the reaction of imatinib base in a suitable solvent with methansulfonic acid at temperature of 0 °C to reflux temperature of solvent for few minutes to several hours.
  • Suitable solvent includes ketones such as methyl ethyl ketone, methyl isobutyl ketone; and the like or mixture thereof. After the completion of the reaction, water was added to the reaction mixture and imatinib mesylate was isolated from the reaction mixture by suitable techniques like filtration, centrifugation.
  • Imatinib mesylate salt thus obtained by the present invention is highly pure.
  • the product is having purity more than 98%, preferably more than 99%, preferably purity 99.8%.
  • the starting material of formula VIII can be acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester. It can be prepared by the methods already known in the art. Specifically, it is prepared by the reaction of the corresponding acid derivative with a suitable activating agent which includes oxalyl chloride, phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halide like acetyl chloride, pivaolyl chloride, alkyl or aryl chloroformates, Lewis acid like boric acid, and the like.
  • a suitable activating agent which includes oxalyl chloride, phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halide like acetyl chloride, pivaolyl chloride, alkyl or aryl chloroformates, Lewis acid like boric acid, and the like.
  • Major advantages of the present invention lies in high purity of imatinib and as well as of imatinib mesylate.
  • the process involves condensation of isolated guanidine free base intermediate of formula IV and with enaminoketone of formula V, which removes the inorganic salts and other impurities prior to reduction and hence over all purity and yields are improved.
  • the process of the present invention minimizes the use of the solvent for the reduction process by employing the use of hydrazine hydrate in combination with catalyst.
  • the present invention also avoids the formation of genotoxic impurities by employing non-alcoholic solvents during the conversion of imatinib in to its mesylate.
  • the last but not the least advantage of the process is to avoid the use of pyridine which eliminate the requirement of removal of residue of pyridine from the final product.
  • Method B 3-Acetylpyridine ( l OOg, 0.82mol), N,N-dimethylformamide dimethyl acetal ( 148g, 1.24mol) and acetic acid ( 10ml) were heated at 90-95 °C tor 2 hours with continuous removal of methanol. After completion of reaction, excess of methanol formed in the reaction was distilled out under vacuum. The resulting residue was diluted with toluene (1400ml) and stirred with silica gel (25g) for 30 minutes at 25-30 °C, filtered and washed with toluene. The solvent was distilled out completely under vacuum to give a residue which was crystallized with cyclohexane (200 ml), filtered and washed to give 128g (86.5%) of the title compound having purity 98.4 % by HPLC.
  • Method A A solution of N-(2-methyl-5-nitrophenyl) guanidine (88g, 0.45mol) and 3-dimethyl pyridin-3- yl-propenone (68.6g, 0.39mol as prepared above) in methyl isobutylketone (880 ml) was refluxed for 12 hours. After completion of reaction, the reaction mass was cooled and filtered. The resulting solid was washed and purified with methyl isobutylketone to give 96.8g (70%) of the title compound as yellow solid having purity 98.3% by HPLC.
  • Method B A solution of 3-acetylpyridine (25g, 0.20mol) and N,N-dimethylformamide dimethylacetal (37g, 0.3 1 mol) in acetic acid (2.5 ml) was heated at 90-95 °C for 2 hours with continuous removal of methanol. After completion of reaction, the reaction mixture was concentrated under vacuum. The resulting residue was diluted with methylisobutylketone (250 ml). N-(2-Methyl-5-nitrophenyl)guanidine (46g) was added to the reaction mixture and refluxed for 12 hours. After completion of reaction, the reaction mass was cooled, filtered and purified with methyl isobutylketone to give 50g (79%) of the title compound having purity 98.1% by HPLC.
  • Method A A mixture of 4-(4-methylpiperzin- l-ylmethyl)benzoic acid dihydrochloride hemihydrate (6.45g, 0.02mo.), thionyl chloride (25.8ml) and NN-dimethylformamide (1.61 ml) was refluxed for 20 hours. After completion of reaction, reaction mixture was distilled out completely under vacuum to give residue which was diluted with acetone (20 ml). The precipitated solid was filtered and washed with acetone to give 4-(4-methylpiperzin-l -ylmethyl)benzoyl chloride dihydrochloride.
  • Method B A mixture of 4-(4-methylpiperzin- l -ylmethyl)benzoic acid dihydrochloride hemihydrate (6.45g, 0.02mol), thionyl chloride (25.8ml) and N.N-dimethylformamide ( 1.61 ml) was refluxed for 20 hours. After completion of reaction, the reaction mixture was distilled out completely under vacuum to give residue which was diluted with acetone (20 ml). The precipitated solid was filtered and washed with acetone ( 13 ml) to give 4-(4-methylpiperzin- i ylmethyl)benzoyl chloride dihydrochloride.
  • Method C A mixture of 4-(4-methylpiperzin-l-ylmethyl)benzoic acid dihydrochloride hemihydrate ( 1 l g, 0.03mol), thionyl chloride (44 ml) and N,N-dimethylformamide (3ml) was refluxed for 2 hours. After completion of reaction, reaction mixture was distilled out completely under vacuum. The resulting residue was diluted with toluene (33 ml). The solid thus precipitated was filtered and washed to give 4-(4- methylpiperzin-l-ylmethyl)benzoyl chloride dihydrochloride.
  • Method E A mixture of 4-(4-methylpiperzin- l -ylmethyl)benzoic acid dihydrochloride hemihydrate (45.6g, 0.14mol), thionyl chloride ( 182.4ml) and NN-dimethylformamide ( 10.5ml) was refluxed for 20 hours. After completion of reaction, the reaction mixture was distilled out completely under vacuum to give residue which was diluted with acetone ( 137 ml). The solid thus precipitated was filtered and washed with acetone (92 ml) to give 4-(4-methylpiperzin-l -ylmethyl)benzpyl chloride dihydrochloride.
  • Method F A mixture of 4-(4-methylpiperzin-l-ylmethyI)benzoic acid dihydrochloride hemihydrate ( 182g, 0.57mol), thionyl chloride (728ml) and N,N-dimethylformamide (45.5ml) was refluxed for 20 hours. After completion of reaction, the reaction mixture was distilled out completely under vacuum to give residue which was diluted with dichloromethane (455 ml). The solid thus precipitated was filtered and washed to give 4-(4-methylpiperzin- l -ylmethyl)benzoyl chloride dihydrochloride.
  • Method A Acetic acid (0.82ml) was added in a suspension of imatinib (3g, 6mmol) in ethyl acetate ( 120ml) at 50-55°C, stirred for 30 minutes. The reaction mixture was charcoalised and filtered. To the resulting filtrate, methanesulfonic acid (0.6 g, 6mmol) was added at 50-55°C and stirred for 30 minutes. The resulting mass was cooled to 25-30°C, filtered, washed with ethyl acetate and dried under vacuum to give 3g (84%) of the title compound having purity 99.3% by HPLC.
  • Method B Formic acid (0.82ml) was added to a suspension of imatinib (3g, 6mmol) in ethyl acetate ( 120ml) at 50-55°C, and stirred for 30 minutes The reaction mixture was charcoalised and filtered. To the resulting filtrate, methanesulfonic acid (0.6g, 0 nmol)was added at 50-55°C and stirred for 30 minutes. The resulting mass was cooled to 25-30°C, filtered washed with ethyl acetate and dried under vacuum to give 3g (84%) of the title compound having purity ' ) .3% by HPLC.
  • Method C Acetic acid (1.66ml) was added ⁇ > a suspension of imatinib (5g, l Ommol) in tetrahydrofuran (50ml) and refluxed for 30 minutes. etha; sulfonic acid (0.97g, l Ommol) was added to the reaction mixture and stirred for 30 minutes at 50-55°C. The resulting mixture was cooled to 25-30°C, filtered, washed and dried under vacuum to give 4.3g (72%) of the title compound having purity 99.5% by HPLC.
  • Method D To a stirred suspension of imatinib (5g, l Ommol) in N,N-dimethylformamide ( 15ml), methanesulphonic acid (0.97g, l Ommol) was added to get clear solution. Reaction mixture was filtered to remove any undissolved solid. t-Butylmethyl ether (75ml) was added and stirred at 60°C. to precipitate the product. The resulting mixture was stirred at 25-30°C for 1 hour, filtered, washed with t-butylmethyl ether and dried to give 5g (84%) of the title compound.
  • Method E To a stirred suspension of imatinib (5g, l Ommol) in acetonitrile (20ml) and water (10ml), methanesulphonic acid (0.97g, l Ommol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Acetonitrile (75ml) was added to the reaction mixture at 25- 30°C. The resulting mixture was filtered, washed with t-butylmethyl ether and dried to give 5 g (84%) of the title compound having purity 99.94 % by HPLC.
  • Method F To a stirred suspension of imatinib (5g, l Ommol) in tetrahydrofuran (20ml) and water ( 10ml), methanesulphonic acid (0.97g, lOmmol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Tetrahydrofuran (75ml) was added slowly to the reaction mixture at 25-30°C. The resulting mixture was filtered, washed with t-butylmethyl ether and dried to give 5. lg (86%) of the title compound having purity 99.71 % by HPLC.
  • Method G To a stirred suspension of imatinib (5g, l Ommol) in methyl isobutylketone (100ml), methanesulphonic acid (l g, l Ommol) was added and reaction mixture was stirred at 50-55°C. Water (2 ml) was added to the reaction mixture, stirred and filtered. The filtered solid was washed with methyl isobutylketone and dried under vacuum to give 5.1 g (84%) of the title compound having 99.9% by HPLC.
  • Method H To a stirred suspension of imatinib (5g, l Ommol) in methyl ethyl ketone ( 100ml), methanesulphonic acid (l g, l Ommol) was added and reaction mixture was stirred at 50-55°C. Water (2 ml) was added to the reaction mixture, stirred and filtered. The filtered solid was washed with methyl ethyl ketone and dried under vacuum to give 4.7 g (79%) of the title compound having purity 99.95% by HPLC.
  • Method I To a stirred suspension of imatinib ( l Og, 20.2mmol) in a mixture of acetonitrile (20ml) and demineralized water ( 10ml), methansulfonic acid (2g, 20.2mmol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Acetonitrile (200ml) was added to the reaction mixture at 25-30°C. The resulting mixture was filtered, washed with acetonitrile and dried to give l Og (84%) of the title compound having purity 99.8% by HPLC.
  • Method J To a stirred suspension of imatinib (20g, 40mmol) in a mixture of acetone (40ml) and water (20ml), methanesulphonic acid (3.92g, 40mmol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Acetone (340ml) was added to the reaction mixture at 25-30°C. The resulting mixture was filtered, washed with t-butylmethyl ether and dried to give 20.2g (85%) of the title compound having purity 99.9% by HPLC.
  • Method K To a mixture of imatinib (25g, 50mmol) in water and acetonitrile, methanesulphonic acid (3.3ml, 34mmol) was added at 25-30°C, and stirred for 30 minutes. The reaction mixture was charcoalised and filtered. Filtrate was evaporated under vacuum completely and toluene ( 150 ml) was added to the resulting residue and distilled to remove water completely. Acetonitrile ( 125ml) was added to the reaction, refluxed, cooled to 25-30°C and filtered. The filtered solid was washed with acetonitrile and dried under vacuum to give 28g (94%) of the title compound having purity 99.8% by HPLC.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation d'imatinib de formule (I) et de ses sels pharmaceutiquement acceptables, plus spécifiquement le mésylate d'imatinib.
PCT/IN2010/000649 2009-09-29 2010-09-28 Procédés de préparation d'imatinib et de ses sels pharmaceutiquement acceptables Ceased WO2011039782A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157450A1 (fr) 2010-06-18 2011-12-22 Krka, D. D., Novo Mesto Nouvelle forme polymorphique d'imatinib base et préparation de ses sels
WO2012131711A1 (fr) * 2011-03-31 2012-10-04 Ind-Swift Laboratories Limited Procédé amélioré pour la préparation d'imatinib et de son sel de mésylate
WO2013035102A1 (fr) * 2011-09-05 2013-03-14 Natco Pharma Limited Procédés pour la préparation d'imatinib sous forme de base et leurs intermédiaires
CN103694145A (zh) * 2013-11-28 2014-04-02 山东鑫泉医药有限公司 （2-甲基-5-硝基苯基）胍硫酸盐的合成方法
EP2927223A1 (fr) * 2014-04-04 2015-10-07 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé de préparation de l'imatinib et de ses sels, exempt d'impureté génotoxique f
US11229650B2 (en) 2019-05-16 2022-01-25 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
US11464776B2 (en) 2019-05-16 2022-10-11 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
US11980689B2 (en) 2013-07-31 2024-05-14 Avalyn Pharma Inc. Inhaled imatinib for treatment of pulmonary arterial hypertension (PAH)
CN119490479A (zh) * 2024-11-15 2025-02-21 广州科锐特药业有限公司 一种甲磺酸伊马替尼的制备方法

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US5521184A (en) * 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
WO1999003854A1 (fr) * 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
US20090012296A1 (en) * 2007-05-29 2009-01-08 Alexandr Jegorov Processes for the preparation of crystalline form beta of imatinib mesylate

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US5521184A (en) * 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
WO1999003854A1 (fr) * 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
US20090012296A1 (en) * 2007-05-29 2009-01-08 Alexandr Jegorov Processes for the preparation of crystalline form beta of imatinib mesylate

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157450A1 (fr) 2010-06-18 2011-12-22 Krka, D. D., Novo Mesto Nouvelle forme polymorphique d'imatinib base et préparation de ses sels
WO2012131711A1 (fr) * 2011-03-31 2012-10-04 Ind-Swift Laboratories Limited Procédé amélioré pour la préparation d'imatinib et de son sel de mésylate
US8912325B2 (en) 2011-03-31 2014-12-16 Ind-Swift Laboratories Limited Process for preparation of imatinib and its mesylate salt
WO2013035102A1 (fr) * 2011-09-05 2013-03-14 Natco Pharma Limited Procédés pour la préparation d'imatinib sous forme de base et leurs intermédiaires
US11980689B2 (en) 2013-07-31 2024-05-14 Avalyn Pharma Inc. Inhaled imatinib for treatment of pulmonary arterial hypertension (PAH)
CN103694145A (zh) * 2013-11-28 2014-04-02 山东鑫泉医药有限公司 （2-甲基-5-硝基苯基）胍硫酸盐的合成方法
EP2927223A1 (fr) * 2014-04-04 2015-10-07 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé de préparation de l'imatinib et de ses sels, exempt d'impureté génotoxique f
US11229650B2 (en) 2019-05-16 2022-01-25 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
US11413289B2 (en) 2019-05-16 2022-08-16 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
US11464776B2 (en) 2019-05-16 2022-10-11 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
US11806349B2 (en) 2019-05-16 2023-11-07 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
US11813263B2 (en) 2019-05-16 2023-11-14 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
US11298355B2 (en) 2019-05-16 2022-04-12 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
CN119490479A (zh) * 2024-11-15 2025-02-21 广州科锐特药业有限公司 一种甲磺酸伊马替尼的制备方法

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