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WO2021140425A1 - Procédé de préparation d'imatinib en utilisant un réactif de vilsmeier - Google Patents

Procédé de préparation d'imatinib en utilisant un réactif de vilsmeier Download PDF

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Publication number
WO2021140425A1
WO2021140425A1 PCT/IB2021/050010 IB2021050010W WO2021140425A1 WO 2021140425 A1 WO2021140425 A1 WO 2021140425A1 IB 2021050010 W IB2021050010 W IB 2021050010W WO 2021140425 A1 WO2021140425 A1 WO 2021140425A1
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Prior art keywords
imatinib
process according
reaction
formula
vilsmeier reagent
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Ceased
Application number
PCT/IB2021/050010
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English (en)
Inventor
Guruprasad Ramchandra VADER
Aarsh Sanjaybhai SHAH
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Sakar Healthcare Ltd
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Sakar Healthcare Ltd
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Publication of WO2021140425A1 publication Critical patent/WO2021140425A1/fr
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C07D295/116—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring

Definitions

  • the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib (formula 1) in presence of Vilsmeier reagent (formula 9) preferably in the presence of base solvent.
  • Imatinib also known as 4-[(4-Methyl-l-piperazinyl)methyl]-N-[4 methyl-3-[[4-(3-pyridinyl)- 2- pyrimidinyl]amino]-phenyl]benzamide, is commercially available as mesylate salt.
  • Imatinib is protein-tyrosine kinase inhibitor or BCR-ABL tyrosine kinase inhibitor used for the treatment of different type of Leukemia and Gastrointestinal Stromal Tumors. Imatinib is usually administered orally in the form of tablets or capsules. Imatinib can be represented by structural Formula I. 1
  • Loiseleur et al in W02003066613A1 described the preparation of Imatinib base (Scheme - 2) where in condensation of 4-(3-pyridinyl)-2-pyrimedinamine(5) with N-(3-bromo-4- methylphenyl)-4-(4-methyl piperazine)- lyl-methyl)-benzamide(4)is described.
  • the process involved the use of highly expensive Pd 2 (dba)3 CHCh catalyst and rac-BINAP as ligand. This method also involves use of special sonication equipment and further tedious purification of the product using flash chromatography and column chromatography which renders the process not suitable for commercial production.
  • Loiseleur et al in W02003066613A1 described the process where in the condensation 4- methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)benzene-l,3-diamine(2)with 4-chloromethyl- benzoyl chloride(6) is effected to obtained benzamide derivative (7) followed by its reaction with N-methyl piperazine(8) to obtain Imatinib.
  • the yield of this process is less and the process is cumbersome to operate.
  • Scheme - 4 Kompella et al in W02004108699A1 described a kilogram scale process(Scheme-4) where in 4-(4-N-Methyl-piperazine-l-yl) benzoic acid(8) is reacted with large amount of thionyl chloride to obtain the acid chloride(3) and then acid chloride was condensed with amine (2) to obtain Imatinib base.
  • the usage of large volume of toxic thionyl chloride and long reaction time renders this process ecologically not suitable and the procedure is cumbersome. Further, the base is obtained by taking the purification where in there is loss of yield.
  • the work-up involves distillation of excess thionyl chloride under vacuum and further work up and filtration of the toxic intermediate for product isolation.
  • the operations are cumbersome and have safety and environmental issues, and very difficult to adopt on commercial level.
  • the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent preferably in the presence of base solvent.
  • Vilsmeier reagent in the present invention is prepared by reaction of chlorinating agent and catalyst.
  • chlorinating agent is thionyl chloride and catalyst is dimethyl formamide.
  • the present invention relates to a process for preparing Imatinib of formula- 1 by reacting N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-l-pyramidine amine of formula 2 with a 4-[(4-methyl)-l-piperazinyl)methyl]benzoyl chloride of formula 3
  • the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent.
  • the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent and wherein said Vilsmeier reagent is prepared by reaction of chlorinating agent and catalyst.
  • the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent and wherein said Vilsmeier reagent is prepared by reaction of thionyl chloride and dimethylformamide.
  • the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent and wherein said according to present invention is carried out is prepared by reaction of thionyl chloride and dimethylformamide, and wherein thionyl chloride is in the amount of at least one (1) mole per mole of benzoic acid intermediate (formula 8) and dimethylformamide is in the amount of at least three (3) mole per mole of benzoic acid intermediate (formula 8).
  • a process of preparation of Imatinib according to present invention is carried out in the presence of base solvent at the pH range of 7 to 11.
  • a process of preparation of Imatinib according to present invention is carried out without isolation of Vilsmeier reagent before preparation of Imatinib.
  • the invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent, wherein said Vilsmeier reagent is formed in situ.
  • the invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent, wherein chlorinating agent is added into reaction mixture at temperature below 5°C.
  • the invention relates to a process for preparing Imatinib of formula- 1, wherein said process comprises step of a) Suspending benzoic acid intermediate formula (8) in base solvent, b) Adding catalyst to the mixture of step (a), c) Optionally, cooling reaction mass to less than 5°C, d) Adding chlorinating agent to the mixture of step (c), e) Slowly increasing temperature of reaction mass to 50°C, f) Optionally, adding base solvent to get thin slurry, g) Adding N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-l-pyramidine amine(2) in base solvent to mixture of step (f), h) Extracting Imatinib base, i) Optionally further converting into suitable salt.
  • Imatinib refers to 4-[(4-Methyl-l-piperazinyl)methyl]-N-[4 methyl-3-[[4-(3- pyridinyl)-2- pyrimidinyl]amino]-phenyl]benzamide, represented by structural Formula I. 1
  • benzoic acid intermediate refers to benzoic acid intermediate of formula 8 as below.
  • Vilsmeier reagent is a versatile organic reagent useful in the synthesis of a wide variety of organic molecules.
  • Weike Su et. al. The new General for Organic synthesis; 2010; 42:6,503- 555) reported several applications of Vilsmeier reagent.
  • Vilsmeier Reaction refers to process of preparation of carboxylic acid chloride by reaction of a chlorinating agent such as phosgene, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, thionyl chloride or the like with a carboxylic acid.
  • a chlorinating agent such as phosgene, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, thionyl chloride or the like
  • the chlorinating agent reacts with the amide to form a Vilsmeier reagent (chloroiminium salt).
  • Vilsmeier reagent refers to a reagent suitable for performing the Vilsmeier reaction (also known as Vilsmeier-Haack formylation), usually formed by a reaction between an amide (typically a N,N-disubstituted amide) and an acid chloride. Formation of the Vilsmeier reagent may be performed prior to conducting the formylation reaction or may be performed in situ as part of the reaction. Alternatively, a commercially available Vilsmeier reagent may be used.
  • in situ refers to reagent or compound being formed in the reaction vessel.
  • the amount of the Vilsmeier reagent to be used in this reaction is aboutl to 2 mole per mole of benzoic acid intermediate (formula 8).
  • the process involve the preparation of acid chloride (3) in presence of minimum amount of base such as di-isopropylethylamine, pyridine, pecoline, triethylamine, n- methyl pyrolidone etc. and reacting the acid (8) with optimum use of thionyl chloride and optimum amount of Vilsmeier reagent. Further the acid chloride (3) prepared is reacted with amine(2) in the presence of the Vilsmeier reagent as catalyst to obtain Imatinib(l) in good yield.
  • base such as di-isopropylethylamine, pyridine, pecoline, triethylamine, n- methyl pyrolidone etc.
  • the reaction converting acid (8) into acid chloride (3) is accomplished by the reacting the reactant in minimum amount of base as solvent as well as acid acceptor, and using Vilsmeier catalyst (9) prepared in situ by reacting dimethyl formamide and thionyl chloride
  • the Imatinib base obtained by this method is further converted into its pharmaceutically accepted salt namely Imatinib Mesylate
  • the present invention relates to use of Vilsmeier reagent (9) formed in situ during the reaction for the activation of -carboxylic group in the intermediate ⁇ ) to transform it in to acid chloride(3) derivative by the reaction of optimum quantity of thionyl chloride (SOC12) in the presence of suitable base.
  • the Vilsmeier reagent(9) is formed in situ during the reaction by the addition of dimethyl formamide (DMF) in the presence of suitable base and reacting it with thionyl chloride to obtain(9) which is not isolated.
  • DMF dimethyl formamide
  • the acid chloride(3) so formed is further reacted with the base (2) without isolating acid chloride(3) and the Vilsmeier reagent (9) from the reaction mixture.
  • Imatinib(l) is formed in the reaction mixture.
  • the product is isolated, purified and further converted in to Imatinib mesylate(lM) salt in high yield and purity by reacting Imatinib with methane sulphonic acid(10) in suitable solvent.
  • the present invention relates to process of preparation of Imatinib using bare minimum quantity of thionyl chloride and minimum quantity of DMF to obtain complete conversion into Vilsmeier Reagent, which is not isolated and used upto condensation stage to obtain Imatinib in much lesser time.
  • chlorinating agent examples include phosgene, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, thionyl chloride and so on.
  • Oxalyl chloride and thionyl chloride are preferably usedon an industrial scale since they can be easily removed from a reaction system along with by-product.
  • Preferred Chlorinating agent as per present invention is thionyl chloride.
  • the amount of the chlorinating agent to be used in this reaction is at least one (1) mole per mole of benzoic acid intermediate (formula 8). When the lesser amount used, a reaction does not progress sufficiently.
  • chlorinating agent is added into reaction mixture at temperature below 5°C.
  • Examples of catalyst used in the invention for reacting the chlorinating agent with the benzoic acid intermediate is not particularly limited, as far as it can react with the chlorinating agent to form the Vilsmeier reagent, and includes amide type compounds such as N,N- dimethylformamide (DMF), N-methyl formanilide, N-methyl formamide, N-formylpiperidine and N-formylindoline, unsubstituted formamide, N, N-dimethyl acetamide, N-methyl acetamide, N, N-dimethyl benzamide, pentamethyl acetamide and so on.
  • DMF is particularly preferable from a viewpoint of availability, cost and reactivity of the Vilsmeier reagent.
  • the amount of the catalyst used in this reaction is not particularly limited and is in the amount of at least one mole to three (3) mole per mole of benzoic acid intermediate (formula 8). When the amount used is less than the range, a reaction rate is low and thereby it takes longer time to complete the reaction.
  • Examples of basic solvent such as di-isopropylethylamine, pyridine, pecoline, triethylamine, n- methyl pyrolidone or mixture thereof.
  • the pH of the reaction mixture during the process may be between 7 to 11.
  • reaction mass diluted with 100ml of water and pH was adjusted to 7.5 by adding of ammonia solution and stirred for 20min methylenechloride(MDC) 100ml was added, stirred and layers separated. Two more extracts of 60ml each of MDC where given to the aqueous phase. The combined organic phase washed with water followed by saturated solution of sodium chloride and then the Organic layer distilled under vacuum to obtain a residue. Ethyl acetatelOOml was added to the residue and heated to reflux for half an hour and cooling applied to the slurry to obtain 10-15°C, Slurry was filtered and solids washed with ethyl acetate.. On drying under vacuum. The output of Imatinib 8.8g, HPLC purity 99.2%.
  • Isopropanol 50ml was added to a reaction flask and 5g of Imatinib base (I) obtained from above examples was charged to it to obtain the thin slurry. Slowly rise the temp to 50°C and 0.75ml of methane sulphonic acid was added to it. The reaction mass was reflux for 1 hr and then slowly cooled and then chilled to Oto 5°C. It was stirred at this temperature for 2hrs and then filtered and washed with chilled IPA. The solid was dried under vacuum at 60° to obtain Imatinib mesylate 4.9gm. HPLC purity 99.5%, XRD analysis proves that this is alpha polymorphic form.

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

Abstract

La présente invention concerne un procédé de préparation d'imatinib, ledit procédé comprenant une ou plusieurs étapes de conversion d'un intermédiaire d'acide benzoïque (formule 8) en imatinib en présence d'un réactif de Vilsmeier de préférence dans des conditions basiques. Le réactif de Vilsmeier selon la présente invention est préparé par réaction d'un agent de chloration et d'un catalyseur. Dans un mode de réalisation préféré, l'agent de chloration est le chlorure de thionyle et le catalyseur est le diméthyl formamide.
PCT/IB2021/050010 2020-01-12 2021-01-04 Procédé de préparation d'imatinib en utilisant un réactif de vilsmeier Ceased WO2021140425A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202021001347 2020-01-12
IN202021001347 2020-01-12

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WO2021140425A1 true WO2021140425A1 (fr) 2021-07-15

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080366A1 (fr) * 2007-12-22 2009-07-02 Synthon B.V. Procédé de fabrication d'imatinib
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080366A1 (fr) * 2007-12-22 2009-07-02 Synthon B.V. Procédé de fabrication d'imatinib
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

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