WO2014060953A1 - Process for preparing pemetrexed di potassium and its hydrates - Google Patents
Process for preparing pemetrexed di potassium and its hydrates Download PDFInfo
- Publication number
- WO2014060953A1 WO2014060953A1 PCT/IB2013/059378 IB2013059378W WO2014060953A1 WO 2014060953 A1 WO2014060953 A1 WO 2014060953A1 IB 2013059378 W IB2013059378 W IB 2013059378W WO 2014060953 A1 WO2014060953 A1 WO 2014060953A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- potassium
- formula
- ethyl
- pyrrolo
- dihydro
- Prior art date
Links
- 0 *OC(CC[C@@](C(O*)=O)NC(c1ccc(CCc2c[n]c(N=C(N)N3)c2C3=O)cc1)=O)=O Chemical compound *OC(CC[C@@](C(O*)=O)NC(c1ccc(CCc2c[n]c(N=C(N)N3)c2C3=O)cc1)=O)=O 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Pemetrexed's chemical name is (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic acid and has the following chemical structure:
- Pemetrexed disodium has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7- dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)- ethyl]benzoyl]-, disodium salt.
- Pemetrexed disodium heptahydrate is the active ingredient of Eli Lilly and Company's ALIMTA® injectable composition.
- Pemetrexed disodium heptahydrate has the following chemical structure:
- Pemetrexed disodium is a multi-targeted antifolate that strongly inhibits various folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolatereductase (DHFR) and glycinamideribonucleotideformyltransferase (GARFT).
- TS thymidylate synthase
- DHFR dihydrofolatereductase
- GARFT glycinamideribonucleotideformyltransferase
- Pemetrexed disodium has been proved effective on a wide variety of solid tumors in clinical trials.
- pemetrexed disodium is commercial available in USA, European Union, Canada, Japan and China etc.
- pemetrexed disodium is a unique chemotherapeutic agent in the market currently.
- pemetrexed disodium has a comparative efficacy and reduced toxicities compared with the standard drug Docetaxel.
- the clinical studies of pemetrexed disodium in the treatment of breast, bowel, pancreatic, head and neck, gastric and bladder cancers are still ongoing.
- Pemetrexed being an important anticancer therapeutic agent
- additional and improved ways of preparing pemetrexed pharmaceutically acceptable salt may be of immense value to pharmaceutical science and the healthcare of cancer patients.
- new salt in stableform and economically viable process, which may be industrially amenable to scalable up, economically viable, safer for handling, less time consuming and with better and consistent quality parameters.
- This application also relates to the process for preparation of Pemetrexed di potassium (I) and its hydrates, which is substantially free from process related impurities.
- Pemetrexed di potassium (I) and its hydrates obtained by the process according to the present invention are useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment of cancer. Different aspects of the present application are summarized herein below individually.
- the present invention provides Di potassium (S)-2-(4-(2- (2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido) pentanedioate (I) and its hydrates. 0 " K +
- compound of Formula (A) i.e. starting material for the preparation of compound of Formula (I) is selected from N-[4-[2-(2-amino-4,7-dihydro-4- oxo-1 H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic disodium salt or N-[4-[2-(2- amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic di-acid or N-[4-[2-(2-amino-4,7-dihydro-4-oxo- lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L- glutamic dimethyl ester.
- the compound of formula (I) according to the present invention is isolated as dipotassium salt of pemetrexed having purity greater than 99% w/w and total impurities are not more than 0.7% w/w.
- Said compound of formula (I) and its hydrates are useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment of cancer.
- embodiments of the present invention provide Pemetrexed di potassium (I) and its hydrates and process for preparation thereof. Individual embodiments of the present invention are detailed herein below separately.
- This application relates to process for preparation of Pemetrexed di potassium (I) and its hydrates, which is substantially free from process related impurities.
- Pemetrexed di potassium (I) and its hydrates obtained by the process according to the present invention are useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment of cancer.
- Different embodiments of the present application are detailed herein below individually.
- Dipotassium (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5- l)ethyl)benzamido) pentanedioate (I) is highly pure compound,wherein potassium content ranges between 14.5% to 16.5% w/w on anhydrous basis.
- Said Di potassium salt of pemetrexed having purity greater than 99% w/w and total impurities are not more than 0.7% w/w.
- Compound of Formula (A) i.e. starting material for the preparation of compound of Formula (I) is selected from N-[4-[2-(2-amino-4,7-dihydro-4-oxo-l H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic disodium salt or N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic di-acid or N-[4-[2-(2-amino-4,7-dihydro-4-oxo- 1H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl] -L-glutamic dimethyl ester.
- the process necessarily involves the use of alcohol solvent, which
- Scheme-I provides summary of the process encompassed according to the present invention. The process is based on the choice of individual key starting materials; however, itcan also be understood based on the non-limiting examples given later.
- step j) optionally repeating the steps a) to g) at room temperature, by isolating the solid material from step i).
- step c) wherein aqueous solution of KOH is added under stirring at 0-15°C, it is necessary to ensure the temperature range to be at lower level, since addition of aqueous KOH done at temperature above 15°C may result in large number of degradation impurities formation leading to recovery of an impure material, which is difficult to purify in the subsequent steps.
- the process for preparing compound of formula (I) involves use of alcoholin step i), wherein alcohol is selected from CI to C5 alcohol. In one of the particular embodiment, it involved the use of ethanol.
- Water soluble potassium saltused in step g) is preferably potassium acetate.
- isolation of the solid title product comprise steps of- i. filtering the solid
- the drying is performed between temperatures ranging between 35-50°C under high vacuum conditions (550 to 700 mmHg) to recover the desired stable hydrated material.
- group 'R' of Formula (A) is Na or H
- compound of Formula (A) is provided as solution in water solvent optionally containing hydrochloric acid
- 'R' is CH 3 compound of Formula (A) is provided as solution in a water immiscible organic solvent selected from dichloromethane, toluene, hexane and heptane.
- the processfor preparing compound of formula (I) starting from pemetrexed dimethyl ester optionally involves the recovery of water immiscible organic solvent layer, re-addition of water immiscible organic solvent, stirring and separation of aqueous layer.
- Pemetrexed dimethyl ester, used in this reaction may be used in an already isolated form or in- situ form if prepared fresh from its starting materials.
- KOH is utilized up to more than 2.2 Moles but less than 4 moles with respect to starting material i.e. compound of Formula (A). In some of the embodiment's amount of KOH used may vary from range of 2.2-4 moles depending upon the method of preparation of the starting materials of Formula (A).
- the compound of formula (I) according to the present invention is isolated as dipotassium salt of pemetrexed having purity greater than 99% w/w and total impurities not more than 0.7% w/w.Said compound of formula (I) and its hydrates are useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment of cancer.
- Pemetrexed di potassium and its hydrates can be isolated by conventional processes, which are not limited to scrapping, breaking, triturating and if required conventional drying.
- the Pemetrexed di potassium and its hydrates obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules useful in the treatment or prevention of cancer.
- Pemetrexed di potassium and its hydrates of the present invention may have one or more advantageous and desirable properties compared to the known Pemetrexed di sodium, which are not limited to better stability, solubility and quality parameter leading to improved storage and distribution.
- the Pemetrexed di potassium and its hydrates described herein were characterized by NMR ( Jeol 400 MHz)/ IR (Make - Perkin Elmer, model- spectrum 100) and HPLC (Waters Alliance using Empower software). While determining purity by HPLC, following analytical chromatographic conditions were used to determine the purity of the material along with impurity profile wherever required. Certain conditions may vary to some extent as per system suitability as well as person skilled in the art to perform the sample preparation and executing the analysis, however, following method of purity according to the one of the merits of invention provides robust, consistent and reliable information.
- the Pemetrexed di potassium and its hydrates obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
- the active product is mixed with one or more pharmaceutically acceptable excipients.
- the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
- compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
- a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
- These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
- the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
- compositions comprising Pemetrexed di potassium and its hydrates of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like.
- diluents such as starch, pregelatinized starch
- compositions derived from Pemetrexed di potassium and its hydrates of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
- the process for preparing pemetrexed dipotassium salt comprise of following sequence of operations-
- reaction mixture was stirred for 90 mins and then 103.0 g solution ofL-glutamic acid dimethylester hydrochloride in 200 ml of dimethylformamide was added drop-wise in 1.5 - 2 hrs under stirring. Further stirredthe reaction mass for 1 hr. Cooling was removed andthe reaction was allowed to come to 25-30°C wherein stirring is performed for ⁇ 3 hrs. After completion of the reaction as monitored by HPLC the reaction mixture was poured into 2000 ml of DM Water under stirring.pH of the reaction mixture was adjusted to 7.5 to 8.0 by adding 40.0 g solid potassium bicarbonate slowly. 2000 ml of dichloromethane was added and stirring was done for 15 minutes. Then the different solvent layers were allowed to settle and separate. DCM layer was washed with 2 x 2000 ml of DM Water and the DCM layer was taken in RB flask and cooled to 15-20°C under stirring.
- reaction mass was filtered and suck dried for 30 minutes, followed by washing with 164 ml of ethanol.
- the wet material obtained was suck dried for 30 minutes, followed by further drying in vacuum tray drier (VTD) at 40-45°C for 8-10 hrs under vacuum of 650 mmHg, to obtain the title compound (47g, 90.38%) with purity of 99.66%.
- VTD vacuum tray drier
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ705994A NZ705994A (en) | 2012-10-17 | 2013-10-16 | Process for preparing pemetrexed di potassium and its hydrates |
AU2013333497A AU2013333497A1 (en) | 2012-10-17 | 2013-10-16 | Process for preparing pemetrexed di potassium and its hydrates |
EP13846436.7A EP2909208A4 (en) | 2012-10-17 | 2013-10-16 | Process for preparing pemetrexed di potassium and its hydrates |
CA2888611A CA2888611A1 (en) | 2012-10-17 | 2013-10-16 | Process for preparing pemetrexed dipotassium and its hydrates |
US14/426,765 US20150259348A1 (en) | 2012-10-17 | 2013-10-16 | Process for preparing pemetrexed di potassium and its hydrates |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN4322/CHE/2012 | 2012-10-17 | ||
IN4322CH2012 | 2012-10-17 |
Publications (1)
Publication Number | Publication Date |
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WO2014060953A1 true WO2014060953A1 (en) | 2014-04-24 |
Family
ID=50487631
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IB2013/059378 WO2014060953A1 (en) | 2012-10-17 | 2013-10-16 | Process for preparing pemetrexed di potassium and its hydrates |
Country Status (6)
Country | Link |
---|---|
US (1) | US20150259348A1 (en) |
EP (1) | EP2909208A4 (en) |
AU (1) | AU2013333497A1 (en) |
CA (1) | CA2888611A1 (en) |
NZ (1) | NZ705994A (en) |
WO (1) | WO2014060953A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016001792A1 (en) * | 2014-06-30 | 2016-01-07 | Shilpa Medicare Limited | Pemetrexed dipotassium formulations |
EP3074015A1 (en) * | 2013-11-25 | 2016-10-05 | Shilpa Medicare Limited | Process for crystalline pemetrexed dipotassium salt |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1840530A (en) * | 2005-03-28 | 2006-10-04 | 齐鲁制药有限公司 | Process for preparing pemetrexed |
CN101417998A (en) * | 2007-10-24 | 2009-04-29 | 重庆医药工业研究院有限责任公司 | Purification method of pemetrexed salt |
WO2012134392A1 (en) * | 2011-03-25 | 2012-10-04 | Scinopharm Taiwan Ltd | Process for the production of a pemetrexed salt |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6890800A (en) * | 1999-08-23 | 2001-03-19 | Eli Lilly And Company | A novel crystalline form of disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-D]- pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid salt and processes therefor |
ATE492547T1 (en) * | 2006-08-14 | 2011-01-15 | Sicor Inc | METHOD FOR PRODUCING LIPOPHILIC PHARMACEUTICALLY ACCEPTABLE SALTS FROM PEMETREXED DISACID |
CN101684121B (en) * | 2008-09-22 | 2013-04-03 | 重庆医药工业研究院有限责任公司 | New crystal form of pemetrexed diacid and method for preparing same |
-
2013
- 2013-10-16 AU AU2013333497A patent/AU2013333497A1/en not_active Abandoned
- 2013-10-16 NZ NZ705994A patent/NZ705994A/en not_active IP Right Cessation
- 2013-10-16 WO PCT/IB2013/059378 patent/WO2014060953A1/en active Application Filing
- 2013-10-16 US US14/426,765 patent/US20150259348A1/en not_active Abandoned
- 2013-10-16 CA CA2888611A patent/CA2888611A1/en not_active Abandoned
- 2013-10-16 EP EP13846436.7A patent/EP2909208A4/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1840530A (en) * | 2005-03-28 | 2006-10-04 | 齐鲁制药有限公司 | Process for preparing pemetrexed |
CN101417998A (en) * | 2007-10-24 | 2009-04-29 | 重庆医药工业研究院有限责任公司 | Purification method of pemetrexed salt |
WO2012134392A1 (en) * | 2011-03-25 | 2012-10-04 | Scinopharm Taiwan Ltd | Process for the production of a pemetrexed salt |
Non-Patent Citations (1)
Title |
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See also references of EP2909208A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3074015A1 (en) * | 2013-11-25 | 2016-10-05 | Shilpa Medicare Limited | Process for crystalline pemetrexed dipotassium salt |
EP3074015A4 (en) * | 2013-11-25 | 2017-05-03 | Shilpa Medicare Limited | Process for crystalline pemetrexed dipotassium salt |
WO2016001792A1 (en) * | 2014-06-30 | 2016-01-07 | Shilpa Medicare Limited | Pemetrexed dipotassium formulations |
US9789113B2 (en) | 2014-06-30 | 2017-10-17 | Shilpa Medicare Limited | Pemetrexed dipotassium formulations |
Also Published As
Publication number | Publication date |
---|---|
US20150259348A1 (en) | 2015-09-17 |
NZ705994A (en) | 2015-08-28 |
EP2909208A1 (en) | 2015-08-26 |
AU2013333497A1 (en) | 2015-04-02 |
EP2909208A4 (en) | 2016-07-13 |
CA2888611A1 (en) | 2014-04-24 |
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