WO2012017443A1 - Procédé pour la préparation de pemetrexed dialkylé de haute pureté - Google Patents

Procédé pour la préparation de pemetrexed dialkylé de haute pureté Download PDF

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Publication number
WO2012017443A1
WO2012017443A1 PCT/IN2010/000700 IN2010000700W WO2012017443A1 WO 2012017443 A1 WO2012017443 A1 WO 2012017443A1 IN 2010000700 W IN2010000700 W IN 2010000700W WO 2012017443 A1 WO2012017443 A1 WO 2012017443A1
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WO
WIPO (PCT)
Prior art keywords
pemetrexed
formula
dialkyl
purification
solvent
Prior art date
Application number
PCT/IN2010/000700
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English (en)
Inventor
Mahesh Bhagoji Dalvi
Rajesh Shashikant Kenny
Pradeep Kisan Tarade
Original Assignee
Neon Laboratories Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neon Laboratories Ltd. filed Critical Neon Laboratories Ltd.
Priority to RU2013109299/04A priority Critical patent/RU2552519C2/ru
Priority to UAA201302744A priority patent/UA105580C2/uk
Publication of WO2012017443A1 publication Critical patent/WO2012017443A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel process for preparation of highly pure dialkyl pemetrexed of formula (I) using substituted triphenyl phosphate reagent of formula (IV), which is a mild, safe, inexpensive, non-oxidative and easy to handle reagent.
  • X is electron withdrawing group
  • Y and Z are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or Y and Z when placed ortho to each other form benzene ring
  • R3 and R4 are independently hydrogen, alky] containing 1 to 7 carbon atoms, or R3 and R4 together with nitrogen form 3 to 7 members heterocyclic ring.
  • the invention also relates to a process for purification of dialkyl pemetrexed of formula (I) by crystallization or trituration, and its conversion to highly pure pemetrexed or its disodium salt.
  • Dialkyl pemetrexed of formula (I) is an intermediate of pemetrexed which is chemically N ⁇ 4-[2(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)ethyl]benzoyl ⁇ -L-glutamic acid.
  • Pemetrexed is known to have antifolate activity.
  • Pemetrexed disodium is a multitargeted antifolate agent approved as a single agent for the treatment of non-small cell lung cancer, and in combination with cisplastin for the treatment of patients with malignant pleural mesothelioma, under the trade name Alimta ®.
  • the European patent EP0334636 discloses preparation of pyrrolopyrimidineglutamate by condensation of pyrrolopyrimidinylalkylbenzoic acid with glutamic acid or its diester using carbodiimide, diphenylphosphoryl azide or phosphorocyanidate as condensing agents which are toxic and hazardous.
  • the quantity of the reagent required is 1 to 20 equivalents.
  • the preferred reagent used in this patent is dicyclohexylcarbodiimide (DCC), which is a potent allergen and a sensitizer, often causes skin rashes.
  • DCC dicyclohexylcarbodiimide
  • EP0334636 also discloses preparation of pyrrolopyrimidineglutamate by condensation of reactive derivatives of pyrrolopyrimidinylalkylbenzoic acid with glutamic acid or its diester.
  • the reactive derivatives include acid halides, acid anhydrides, mixed acid anhydride with monoalkyl carbonic esters, active esters, acid azide, mixed acid anhydride with phosphoric acid diesters, mixed acid anhydride with phosphorous acid diesters of the pyrrolopyrimidinylalkylbenzoic acid.
  • EP0334636 does not specifically disclose the process for preparation of diethyl pemetrexed and its conversion to pemetrexed or its pharmaceutically acceptable salts. Pemetrexed and its preparation have been described for the first time in the US patent US5344932. The synthesis of dialkyl pemetrexed disclosed in this patent is not suitable for industrial production due to the number of process steps and the poor overall yield.
  • the US patents US6013828 and US6066732 disclose preparation of pemetrexed disodium by condensation of 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3- yl)ethylbenzoic acid with diethyl L-glutamate using 4-chloro-2,6-dimethoxytriazine (CDMT) as a condensing agent.
  • CDMT 4-chloro-2,6-dimethoxytriazine
  • This process is not suitable for industrial application as CDMT is hazardous as well as expensive reagent which is not easily available.
  • Use of CDMT causes irritation to eyes, respiratory system and skin. It is found that the products obtained by using triazene reagents are not colourless but has bluish to grey colour and need column chromatography to get colourless products.
  • pyrrolopyrimidineglutamates can contain extraneous compounds or impurities that can come from any source.
  • the impurities can be in the form of unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products.
  • the pyrrolopyrimidineglutamates containing impurities can lead to impure pemetrexed or its salts. Impurities in pemetrexed or its salts are undesired and might even be harmful to a patient being treated with a dosage form containing the same.
  • dialkyl pemetrexed The known methods for purification of dialkyl pemetrexed are column chromatography and purification by salt formation (e.g. tosylate salt). Purification by column chromatography is not industrially applicable.
  • WOOl I4379 discloses purification of diethyl pemetrexed via tosylate salt formation which may affect the yield of pemetrexed. Purification of diethyl pemetrexed via tosylate salt formation does not result into more than 99% purity.
  • US6066732 discloses purification of diethyl pemetrexed via column chromatography and hence not suitable for industrial application.
  • an object of the invention is to overcome or ameliorate atleast one disadvantage of the prior art or to provide a useful alternative.
  • Another object of the invention is to provide a process for preparation of highly pure dialkyl pemetrexed by using safe, mild, inexpensive, non-oxidative and easy to handle reagent.
  • Another object of the invention is to provide an economic and industrially applicable process for preparation of highly pure dialkyl pemetrexed.
  • Yet another object of the invention is to provide a concise and industrially applicable process for purification of dialkyl pemetrexed to provide the product with more than 99% purity when measured by HPLC.
  • Yet another object of the invention is to convert dialkyl pemetrexed which are obtained by the present method, into highly pure pemetrexed and its disodium salt. Summary of the invention:
  • the present invention provides concise, economic and industrially feasible process for the preparation of highly pure dialkyl pemetrexed using safe, mild, inexpensive, non-oxidative and easy to handle reagent.
  • the present invention provides a process for preparation of dialkyl pemetrexed comprising reacting 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3- yl)ethylbenzoic acid with glutamic acid diester or its salt in presence of a substituted triphenyl phosphate .
  • the present invention provides a method for purification of pyrrolopyrimidineglutamic acid derivatives via crystallization or trituration in a suitable solvent.
  • any of the words 'having', 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitations' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose illustration rather than limitation of the invention as set forth the appended claims. Accordingly, the present invention provides a process to prepare highly pure dialkyl pemetrexed comprising the following steps:
  • X is electron withdrawing group
  • Y and Z are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or Y and Z when placed ortho to each other form benzene ring
  • R3 and R4 are independently hydrogen, alkyl containing 1 to 7 carbon atoms, or R3 and R4 together with nitrogen form 3 to 7 members heterocyclic ring.
  • Rl and R2 are carboxyl protecting groups.
  • R l and R2 are independently alkyl group containing 1 to 7 carbon atoms. More preferably Rl and R2 are independently methyl or ethyl group.
  • the process of the present invention is advantageously carried by reacting the carboxyl ic acid of formula (II) with diethyl L-glutamate using tris(para-nitrophenyl)phosphate, tris(ortho-nitrophenyl)phosphate or tris(para-cyanophenyl)phosphate as a reagent.
  • The. reagents are mild, safe, inexpensive, non-oxidative and easy to handle.
  • the preferred reagent is tris(para-nitrophenyl)phosphate or tris(ortho-nitrophenyl)phosphate.
  • triphenylphosphate of formula (IV) used for the synthesis is 1 to 4 equivalent of 2-(4- hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)ethylbenzoic acid, more preferably 1.2 to 3.5 equivalents.
  • the most preferred quantity of the reagent is 1 .5 to 1 .7 equivalents.
  • the process of the present invention is carried out in the presence of a base and a suitable solvent.
  • the base which may be used in the present invention is organic or inorganic.
  • organic base include tertiary amines such as trialkyl amine.
  • inorganic base include alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate and mixture thereof.
  • alkali metal carbonate include sodium carbonate and potassium carbonate.
  • alkali metal bicarbonate include sodium bicarbonate and potassium bicarbonate.
  • alkaline earth metal carbonate include calcium carbonate and magnesium carbonate.
  • alkaline earth metal bicarbonate include calcium bicarbonate and magnesium bicarbonate.
  • the preferred base is triethyl amine or sodium carbonate.
  • the base is conveniently used in an amount, relative to 2-(4-hydroxy-6-aminopyrrolo(2,3- d)pyrimidin-3-yl)ethylbenzoic acid, preferably in a range between 1 to 6 equivalents, more preferably 2 to 5 equivalents.
  • the most preferred quantity of the base is 4 equivalents.
  • the solvent may be selected from any polar solvent.
  • the preferred solvent is acetonitrile or dimethyl formamide.
  • the process of the present invention may be carried out at suitable temperature.
  • the reaction is carried out at 25 to 60°C, more preferably at 35 to 55°C.
  • the most preferred reaction temperature is 45 to 50°C.
  • the reaction normally completes in a span of 2 to 24 hours, more preferably 10 to 18 hours, most preferably 12 to 13 hours.
  • pemetrexed diester can be recovered from the reaction mass in a convenient manner.
  • the workup of the reaction involves quenching of the reaction mixture in water followed by extracting the mixture using a water insoluble organic solvent.
  • the water insoluble organic solvent is selected from a group of halogenated or a non-halogenated solvent.
  • the most preferred solvent is ethyl acetate, chloroform, dichloromethane, dichloroethane or mixture thereof.
  • the organic solvent containing diethyl pemetrexed is made free of substituted diphenyl hydrophosphates and substituted phenols by washing with aqueous alkali carbonate solution.
  • the alkali metal carbonates are selected from the group of lithium, sodium or potassium carbonate, most preferably sodium carbonate.
  • the process further involves evaporation of the organic solvent containing pemetrexed diester till dryness.
  • the solvent evaporation is carried out by distillation of the solvent at its boiling point.
  • the solvent evaporation is carried out under reduced pressure and the crude pemetrexed diester is isolated with the HPLC purity of at least 98%.
  • the isolated pemetrexed diester is purified by crystallization or trituration in a suitable solvent.
  • the solvent used for crystallization or trituration is selected from a class of halogenated or non-halogenated solvent or a mixture thereof.
  • the solvent used for purification of dialkyl pemetrexed is selected from ethyl acetate, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dimethyl acetamide or mixture thereof.
  • the most preferred solvent used for purification of pemetrexed diester is a mixture of dimethyl formamide and acetone in the ratio of 1 :3 to 1 :8 vol/vol, more preferably 1 :4 to 1 :7 vol/vol or most preferably 1 :5 to 1 :6 vol/vol.
  • the purified diakyl pemetrexed has the purity of greater than 99%.
  • the purified pemetrexed diester is subjected to hydrolysis to obtain pemetrexed disodium either by methods known in the art or the process disclosed herein.
  • the pemetrexed diester is hydrolyzed using sodium hydroxide to provide pemetrexed disodium salt.
  • the hydrolysis may be carried out at a room temperature.
  • the substituted triphenyl phosphate of formula (IV) can be easily prepared by methods known in the prior art or the process disclosed herein. In a typical procedure a substituted phenol is reacted with phosphorous oxychloride in presence of a base and a solvent to yield substituted triphenyl phosphate of formula (IV).
  • the solvent used for the preparation of the substituted triphenyl phosphate of formula (IV) is an aprotic solvent selected from not limited to dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, toluene acetonitrile and dimethyl sulfoxide.
  • the preferred solvent used for preparing the triaryl phosphate is toluene.
  • the base used for the preparation of the triaryl phosphate is preferably pyridine.
  • the pure pemetrexed disodium obtained by the process of the invention may be formulated into a dosage form by combining with one or more pharmaceutically acceptable excipients using known techniques. Further the dosage form may be immediate release or extended release. Further details of the process of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
  • Tris(para-nitrophenyl)phosphate (15.4 gm, 0.0334 moles) was added to the reaction mixture. The reaction mixture was maintained for one hour at 30 to 35 °C.
  • diethyl-L-glutamate hydrochloride (17.4 gm, 0.0726 moles) was dissolved in dimethylformamide (30 ml) and triethyl amine (7.92 gm, 0.078 moles). The reaction mixture was stirred for 5 minutes and filtered.
  • the filtrate was added in the reaction mixture in the flask (A), and stirred for 1 1 hours at 40 to 45°C.
  • the reaction mixture was cooled to 20 °C, quenched into distilled water (600 ml) at 20 to 25°C, extracted with dichloromethane (3 X 150 ml).
  • Dichloromethane layers were collected and washed with 5% sodium carbonate solution (3 X 300 ml).
  • Dichloromethane layer was separated, washed with distilled water (300 ml), dried over sodium sulfate, and concentrated.
  • Acetone (400 ml) was charged into the concentrated reaction mixture and stirred at 30 to 35°C for i hour.
  • the solid was filtered, washed with acetone (2 X 50 ml) to yield crude diethyl pemetrexed (yield 20 gm, 98.12% HPLC purity).
  • Diethyl pemetrexed obtained in the example 4 was purified as per the example 6 to obtained purified product with 99.01 % HPLC purity.
  • Diethyl pemetrexed obtained in the example 5 was purified as per the example 6 to obtained purified product with 99.5% HPLC purity.
  • Pemetrexed disodium heptahydrate (3 gm) obtained in the example 9 was dissolved in water (60 ml). Acetic acid (4 ml) was added to the reaction mixture and heated at 70°C for 3 hours. The reaction mixture was cooled tb room temperature, stirred for one hour, filtered and washed with distilled water to obtain pemetrexed (2.5 gm, 99.42% HPLC purity). The HPLC of pemetrexed was compared with the standard sample.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention divulgue un procédé pour la préparation de pemetrexed dialkylé de haute pureté par la réaction d'un acide 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)éthylbenzoïque avec un diester de l'acide glutamique ou son sel en présence d'un réactif sûr, doux, bon marché, non oxydant et facile à manipuler tel que le phosphate de triphényle substitué. L'invention divulgue en outre la purification du pemetrexed dialkylé par cristallisation ou trituration, et la conversion du pemetrexed dialkylé purifié en pemetrexed ou en son sel disodique.
PCT/IN2010/000700 2010-08-02 2010-10-27 Procédé pour la préparation de pemetrexed dialkylé de haute pureté WO2012017443A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
RU2013109299/04A RU2552519C2 (ru) 2010-08-02 2010-10-27 Способ получения высокочистого диалкилпеметрекседа
UAA201302744A UA105580C2 (uk) 2010-08-02 2010-10-27 Спосіб одержання діалкілпеметрекседу високої чистоти

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IN2194/MUM/2010 2010-08-02
IN2194MU2010 2010-08-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120245349A1 (en) * 2011-03-23 2012-09-27 Scinopharm Taiwan, Ltd. Process for the production of a pemetrexed salt

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0334636A2 (fr) 1988-03-24 1989-09-27 Takeda Chemical Industries, Ltd. Dérivés de la pyrrolo pyrimidine, leur préparation et utilisation
US5344932A (en) 1989-12-11 1994-09-06 Trustees Of Princeton University N-(pyrrolo(2,3-d)pyrimidin-3-ylacyl)-glutamic acid derivatives
US6013828A (en) 1997-09-26 2000-01-11 Eli Lilly And Company Processes and intermediates useful to make antifolates
WO2000011004A1 (fr) * 1998-08-21 2000-03-02 The Trustees Of Princeton University Procede de preparation de pyrrolo[2,3-d]pyrimidines
WO2001014379A2 (fr) * 1999-08-23 2001-03-01 Eli Lilly And Company Nouvelle forme cristalline de disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-l- sel d'acide glutamique et procedes de preparation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0334636A2 (fr) 1988-03-24 1989-09-27 Takeda Chemical Industries, Ltd. Dérivés de la pyrrolo pyrimidine, leur préparation et utilisation
US5344932A (en) 1989-12-11 1994-09-06 Trustees Of Princeton University N-(pyrrolo(2,3-d)pyrimidin-3-ylacyl)-glutamic acid derivatives
US6013828A (en) 1997-09-26 2000-01-11 Eli Lilly And Company Processes and intermediates useful to make antifolates
WO2000011004A1 (fr) * 1998-08-21 2000-03-02 The Trustees Of Princeton University Procede de preparation de pyrrolo[2,3-d]pyrimidines
US6066732A (en) 1998-08-21 2000-05-23 The Trustees Of Princeton University Process for the preparation of pyrrolo[2,3-d]pyrimidines
WO2001014379A2 (fr) * 1999-08-23 2001-03-01 Eli Lilly And Company Nouvelle forme cristalline de disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-l- sel d'acide glutamique et procedes de preparation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D.P. KJELL ET AL.: "Determination of the source of N-methyl impurity in the synthesis of pemetrexed disodium heptahydrate", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 9, no. 6, 2005, pages 738 - 742, XP002634585 *
GREEN CHEMISTRY, vol. 7, 2005, pages 217
ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 9, 2005, pages 738 - 742

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120245349A1 (en) * 2011-03-23 2012-09-27 Scinopharm Taiwan, Ltd. Process for the production of a pemetrexed salt
US9051322B2 (en) * 2011-03-23 2015-06-09 Scinopharm Taiwan, Ltd. Process for the production of a pemetrexed salt

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Publication number Publication date
UA105580C2 (uk) 2014-05-26
RU2013109299A (ru) 2014-09-10
RU2552519C2 (ru) 2015-06-10

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