WO2015034293A1 - 고순도 페메트렉세드 제조를 위한 향상된 중간체 제조 방법 및 이를 사용하여 고순도 페메트렉세드를 제조하는 방법 - Google Patents

고순도 페메트렉세드 제조를 위한 향상된 중간체 제조 방법 및 이를 사용하여 고순도 페메트렉세드를 제조하는 방법 Download PDF

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Publication number
WO2015034293A1
WO2015034293A1 PCT/KR2014/008331 KR2014008331W WO2015034293A1 WO 2015034293 A1 WO2015034293 A1 WO 2015034293A1 KR 2014008331 W KR2014008331 W KR 2014008331W WO 2015034293 A1 WO2015034293 A1 WO 2015034293A1
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WIPO (PCT)
Prior art keywords
formula
pemetrexed
acid
diethyl ester
salt
Prior art date
Application number
PCT/KR2014/008331
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English (en)
French (fr)
Korean (ko)
Inventor
김영민
김문숙
김성호
조진숙
Original Assignee
주식회사 삼양바이오팜
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Application filed by 주식회사 삼양바이오팜 filed Critical 주식회사 삼양바이오팜
Priority to CN201480049311.5A priority Critical patent/CN105531276A/zh
Priority to US14/916,303 priority patent/US20160214987A1/en
Priority to EP14841740.5A priority patent/EP3042904A4/en
Priority to JP2016540811A priority patent/JP2016531925A/ja
Publication of WO2015034293A1 publication Critical patent/WO2015034293A1/ko

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an improved method for preparing intermediates for the production of high purity pemetrexed, and to a method for producing high purity pemetrexed using the same, and more particularly, to pemetrexed diethyl ester which is an intermediate for the production of pemetrexed or A novel process for the preparation of salts thereof in high purity and a process for the preparation of pemetrexed disodium salts in high purity using intermediates thereof.
  • Pemetrexed is N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl ] Benzoyl) -L-glutamic acid ⁇ N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrroro [2,3-d] pyrimidin-5-yl) ethyl] benzoyl ) -L-glutamic acid ⁇ , the disodium salt has the structure of formula (1).
  • peme track Said disodium salt heptahydrate intravenous administration of a sterile lyophilized powder for active ingredient
  • peme track Said anti folate represents the activity, Eli Lilly (Eli Lilly and Company), trade name alrimta (Alimta) TM by four It is marketed as a treatment for lung cancer and pleural mesothelioma.
  • Pemetrexed disodium salt can be prepared by the following Scheme 1, as described in Republic of Korea Patent Publication No. 0162654, more specific preparation method is described in C.J. Barnett, et al., "A Practical Synthesis of Multitargeted Antifolate LY231514," Organic Process Research & Development, 3 (3): 184-188 (1999).
  • pemetrexed disodium salt is prepared by the following steps:
  • the pemetrexed diethyl ester (Compound 4 compound) prepared by the method of Scheme 1 had a low purity of 90% or less of HPLC purity, and was prepared with PTSA salt for purification (Compound 3 compound) ) HPLC purity was only 95% or less.
  • the amount of by-products generated in the relative purity time (RRT) of about 1.01 to 1.03 in HPLC purity analysis was 5-6% at maximum, and remained over 0.5% after purification.
  • the method for preparing pemetrexed disodium salt according to Scheme 1 has serious problems in the generation of low purity and by-products in the preparation of intermediates, and these problems are allowed even if modifications such as lowering the reaction temperature and performing further purification are performed. It is not improved to the extent possible. Therefore, for the preparation of high-purity pemetrexed disodium salt, a method of producing a fundamentally new intermediate different from the method of Scheme 1 is required.
  • the present invention is to solve the problems of the prior art as described above, using a novel method for producing a high-purity pemetrexed diethyl ester or a salt thereof for the preparation of pemetrexed, and the intermediate product of the pemex It is a technical object of the present invention to provide a method for producing trexed disodium salt in high purity and high yield.
  • the present invention (1) a step of desalting L- glutamic acid diethyl ester hydrochloride of the formula (5) with a basic aqueous solution, using an organic solvent; And (2) to the desalted L-glutamic acid diethyl ester obtained in step (1), dimethylformamide, a compound of formula (6), N-methylmorpholine and 2-chloro-4,6-dimethoxy-1
  • a method for producing a pemetrexed diethyl ester of formula (4) or a salt thereof comprising the step of adding, reacting, and reacting 3,5-triazine in this order:
  • the method for producing the pemetrexed diethyl ester or a salt thereof water and an organic solvent are added to the resultant mixture of step (2), the organic layer is extracted, and ethanol and acid are added thereto. The addition is further provided to obtain the final product as an acid salt of pemetrexed diethyl ester.
  • pemetrexed diethyl ester or its salt useful as an intermediate for the preparation of pemetrexed disodium salt can be prepared in high purity, and the high purity pemetrexed diethyl ester or its preparation
  • the use of salts makes it highly industrially feasible to produce high purity pemetrexed diacids and high purity pemetrexed disodium salts with high efficiency without further purification.
  • the basic aqueous solution used for the desalting of L-glutamic acid diethyl ester hydrochloride is not particularly limited, and preferably one selected from potassium hydrogen carbonate, potassium carbonate, ammonia water, N-methylmorpholine, calcium chloride and calcium carbonate
  • the above base may be used, and more preferably a saturated aqueous solution of sodium hydrogen carbonate (NaHCO 3 ) may be used.
  • organic solvent used for extraction for example, chlorine-based dichloromethane (DCM), carbon tetrachloride, chloroform, etc., ether-based diethyl ether, methyl t- butyl ether (MTBE), Aromatics include toluene, xylene and benzene, and alcohols having 4 or more carbon atoms include butyl alcohol and pentyl alcohol, and hydrocarbons having 4 or more carbon atoms include butane, pentane, hexane and heptane, and esters. Ethyl acetate, and the like, or a combination of two or more thereof may be used.
  • Desalting of L-glutamic acid diethyl ester hydrochloride may be performed under conventional desalting conditions, such as 10 minutes to 2 hours at room temperature, but is not limited thereto.
  • additional DMF solvent is added without further dehydration and concentrated in vacuo to remove 80% or more of the extraction organic solvent (eg, DCM), which is then used in subsequent steps.
  • step (2) dimethylformamide (DMF) as a reaction solvent, the compound of formula 6, N-methylmorpholine (NMM) and 2-chloro-4 , 6-Dimethoxy-1,3,5-triazine (CDMT) is continuously added and reacted in this order (step (2)).
  • DMF dimethylformamide
  • NMM N-methylmorpholine
  • CDMT 6-Dimethoxy-1,3,5-triazine
  • the compound of Chemical Formula 6 is preferably prepared from the compound of Chemical Formula 7, and thus the method for preparing pemetrexed diethyl ester or salt thereof according to the present invention may include preparing a compound of Chemical Formula 6 from the compound of Chemical Formula 7 It may further include:
  • the equivalent (eq.) Number of the reagent used in the step (2) is based on 1 equivalent of the compound of the formula (6), the NMM is preferably 1.2 to 3.1 equivalents, more preferably 1.5 to 3.0 equivalents, most preferably 2.9 to 3.0 equivalents; CDMT is preferably 1.0 to 1.4 equivalents, more preferably 1.1 to 1.3 equivalents, most preferably 1.15 to 1.25 equivalents; LGA is preferably 1.0 to 1.4 equivalents, more preferably 1.1 to 1.3 equivalents, most preferably 1.15 to 1.25 equivalents.
  • the input temperature of the reagents may be 0 to 20 ° C, preferably 0 to 15 ° C, and more preferably 0 to 10 ° C.
  • the reaction temperature after the reagent addition may be 0 to 27 ° C, preferably 0 to 20 ° C, more preferably 0 to 15 ° C, and even more preferably 5 to 15 ° C.
  • the reaction time may be 5 minutes to 3 hours, preferably 10 minutes to 1 hour, and more preferably 30 minutes to 1 hour.
  • step (2) water (eg, purified water) and an organic solvent are added to the resultant mixture of step (2), the organic layer is extracted, and ethanol (EtOH) and an acid are added thereto, and the final result is pemetrexe. Further included is a step of obtaining with an acid salt of ced diethyl ester.
  • Dichloromethane is preferable as a solvent used for extraction of the organic layer, and sulfuric acid, hydrochloric acid, tartaric acid, or p-toluenesulfonic acid (PTSA) is used as an acid added to obtain an acid salt of pemetrexed diethyl ester.
  • PTSA p-toluenesulfonic acid
  • the reaction of the pemetrexed diethyl ester with an acid is preferably carried out in a mixed solvent of dichloromethane (DCM), dimethylformamide (DMF) and ethanol (EtOH), and is a temperature above room temperature (eg, 40 to 60 ° C). ), For example, for 30 minutes to 3 hours.
  • Sulfonates can be obtained with high purity of at least 99.0% HPLC purity.
  • the reaction rate is faster, the purity of the target product can be significantly increased compared to the prior art (HPLC purity: 99.0% or more, more preferably 99.5% or more), and at the same time, the generation of by-products can be significantly reduced (RRT weakness in HPLC purity analysis). Amount of individual analogues occurring at 1.01 to 1.03: 0.15% or less, more preferably 0.1% or less).
  • the method comprising the steps of: (a) reacting the pemetrexed diethyl ester or salt thereof prepared by the method with sodium hydroxide; (b) adding an acid to the resultant of step (a) to prepare a pemetrexed diacid of Chemical Formula 2; And (c) reacting the pemetrexed diacid prepared in step (b) with sodium hydroxide.
  • the method for preparing pemetrexed disodium salt of Chemical Formula 1 is provided.
  • sodium hydroxide is preferably provided in the form of an aqueous solution (eg, 1N aqueous solution), the reaction of pemetrexed diethyl ester or its salt and sodium hydroxide is preferably at 5 to 20 °C, more Preferably it may be carried out at 5 to 15 °C, for example for 30 minutes to 3 hours, more preferably for 1 hour to 2 hours.
  • aqueous solution eg, 1N aqueous solution
  • the reaction of pemetrexed diethyl ester or its salt and sodium hydroxide is preferably at 5 to 20 °C, more Preferably it may be carried out at 5 to 15 °C, for example for 30 minutes to 3 hours, more preferably for 1 hour to 2 hours.
  • the acid used is preferably hydrochloric acid, the amount of the acid, the amount of adjusting the pH of the resulting solution after the addition of the acid is preferably 2.8 to 3.2, the reaction temperature of step (b) is 5 -25 degreeC is preferable and 5-15 degreeC is more preferable.
  • the pemetrexed diacid prepared in step (b) is filtered and used in subsequent steps.
  • sodium hydroxide is preferably provided in the form of an aqueous solution (eg 1N aqueous solution), the reaction of pemetrexed diacid and sodium hydroxide is preferably at 5 to 25 °C, more preferably 5 to At 15 ° C., for example, for 30 minutes to 3 hours, more preferably for 30 minutes to 1 hour.
  • the pH can be adjusted to 7.5 to 8.5 by addition of acid (eg hydrochloric acid).
  • the pemetrexed disodium salt prepared in step (c) thereafter, for example, crystallization (50 ⁇ 60 °C, in EtOH), cooling, filtration, washing and vacuum drying
  • the post-treatment process may be performed, and as a result, high purity pemetrexed disodium salt having an HPLC purity of 99.9% or more and an individual softener content of 0.05% or less may be obtained.
  • the method for preparing pemetrexed disodium salt of formula (1) comprises the steps of: (i) desalting L-glutamic acid diethyl ester hydrochloride of Formula 5 into a basic aqueous solution and extracting using an organic solvent ; (ii) to the dechlorinated L-glutamic acid diethyl ester obtained in step (i), dimethylformamide, the compound of formula 6, N-methylmorpholine and 2-chloro-4,6-dimethoxy-1, Adding 3,5-triazine in this order and reacting to prepare pemetrexed diethyl ester or a salt thereof; (iii) reacting the pemetrexed diethyl ester or salt thereof prepared in step (ii) with sodium hydroxide; (iv) adding an acid to the result of step (iii) to prepare a pemetrexed diacid of Chemical Formula 2; And (v) reacting the pemetrexed diacid prepared in step (i
  • HPLC high performance liquid chromatography
  • Solution A 0.2% trifluoroacetic acid (TFA) in 100% water
  • Solution B 0.2% trifluoroacetic acid (TFA) in 100% acetonitrile (ACN)
  • Diluent A Approximately 4.0 g of anhydrous sodium phosphate dibasic anhydrous (Na 2 HPO 4 ) is added and dissolved in 1 L of ultrapure water (pH 8.5-9.5).
  • Solution A 0.2% TFA in 100% water
  • Diluent A Approximately 4.0 g of anhydrous sodium phosphate dibasic (Na 2 HPO 4 ) is weighed and dissolved in 1 L of ultrapure water (pH 8.5-9.5).
  • Diluent of pemetrexed disodium salt ultrapure water

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/KR2014/008331 2013-09-05 2014-09-04 고순도 페메트렉세드 제조를 위한 향상된 중간체 제조 방법 및 이를 사용하여 고순도 페메트렉세드를 제조하는 방법 WO2015034293A1 (ko)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201480049311.5A CN105531276A (zh) 2013-09-05 2014-09-04 用于制备高纯度培美曲塞的得到提高的中间体的制备方法及利用其来制备高纯度培美曲塞的方法
US14/916,303 US20160214987A1 (en) 2013-09-05 2014-09-04 Method for preparing an intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using the intermediate
EP14841740.5A EP3042904A4 (en) 2013-09-05 2014-09-04 Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate
JP2016540811A JP2016531925A (ja) 2013-09-05 2014-09-04 ペメトレキセド製造のための中間体製造方法及びこれを用いて高純度ペメトレキセドを製造する方法

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KR1020130106497A KR101578093B1 (ko) 2013-09-05 2013-09-05 고순도 페메트렉세드 제조를 위한 향상된 중간체 제조 방법 및 이를 사용하여 고순도 페메트렉세드를 제조하는 방법
KR10-2013-0106497 2013-09-05

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EP (1) EP3042904A4 (und)
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Cited By (1)

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CN115925549A (zh) * 2022-12-19 2023-04-07 浦拉司科技（上海）有限责任公司 一种1,3-丙酮二羧酸二甲酯的提纯方法

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WO2019244965A1 (ja) * 2018-06-20 2019-12-26 日本化薬株式会社 ペメトレキセドナトリウム注射用溶液製剤、並びにその製造方法
CN109912605B (zh) * 2019-04-11 2020-09-04 重庆迈德凯医药有限公司 一种培美曲塞中间体的纯化方法
CN110031567A (zh) * 2019-05-15 2019-07-19 南京制药厂有限公司 培美曲塞二钠中间体二乙酯的分析方法
CN112521405A (zh) * 2019-09-17 2021-03-19 鲁南制药集团股份有限公司 一种培美曲塞二钠杂质化合物
KR102638538B1 (ko) * 2021-12-28 2024-02-20 주식회사 한서켐 우라피딜 제조 중간체의 제조방법

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DOUGLAS P. KJELL ET AL.: "Determination of the Source of the N-Methyl Impurity in the Synthesis of Pemetrexed Disodium Heptahydrate", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 9, no. 6, 2005, pages 738 - 742, XP002634585 *
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Publication number Priority date Publication date Assignee Title
CN115925549A (zh) * 2022-12-19 2023-04-07 浦拉司科技（上海）有限责任公司 一种1,3-丙酮二羧酸二甲酯的提纯方法

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US20160214987A1 (en) 2016-07-28
JP2016531925A (ja) 2016-10-13
EP3042904A4 (en) 2017-02-22
EP3042904A1 (en) 2016-07-13
KR20150027986A (ko) 2015-03-13
KR101578093B1 (ko) 2015-12-16

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