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WO2018168643A1 - Procédé de fabrication d'ioflupane - Google Patents

Procédé de fabrication d'ioflupane Download PDF

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Publication number
WO2018168643A1
WO2018168643A1 PCT/JP2018/008984 JP2018008984W WO2018168643A1 WO 2018168643 A1 WO2018168643 A1 WO 2018168643A1 JP 2018008984 W JP2018008984 W JP 2018008984W WO 2018168643 A1 WO2018168643 A1 WO 2018168643A1
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WO
WIPO (PCT)
Prior art keywords
radioactive
labeled
aqueous solution
iodine
radioactive iodine
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2018/008984
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English (en)
Japanese (ja)
Inventor
正人 外山
恵美 梅原
友博 木野
森田　武
伸介 大畑
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nihon Medi Physics Co Ltd
Original Assignee
Nihon Medi Physics Co 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 Nihon Medi Physics Co Ltd filed Critical Nihon Medi Physics Co Ltd
Priority to JP2019505938A priority Critical patent/JP7241013B2/ja
Priority to CN201880027329.3A priority patent/CN110582494A/zh
Publication of WO2018168643A1 publication Critical patent/WO2018168643A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se

Definitions

  • the present invention relates to a method for producing ioflupan.
  • [ 123 I] ioflupan ( 123 I) has a high affinity for the dopamine transporter (DAT) in the synapse of striatal dopaminergic neurons, and therefore, a line of ataxia disorder in which nigrostriatal dopamine neurons degenerate.
  • DAT dopamine transporter
  • the DAT distribution density in the striatum can be visualized by single photon emission tomography (SPECT), and is used for the diagnosis of Parkinson's disease and other Parkinson's syndrome, which are the above-mentioned ataxia, and dementia with Lewy bodies.
  • SPECT single photon emission tomography
  • the tropane compound described in Patent Document 1 is known as a tropane compound that is a similar compound to [ 123 I] ioflupan.
  • the synthesis time is shortened and the prescription time is simplified. Therefore, after the radioactive iodine labeling reaction, it has been reported that the reaction solution is purified by HPLC using a compact column and an aqueous ethanol solution with a retention time of 5 to 6 minutes (Non-patent Document 3).
  • Non-Patent Documents 1 and 2 have a problem in that methanol having low safety is used in consideration of application to humans. Therefore, by adopting a method that uses safer ethanol as an eluent, it has been approved as a pharmaceutical in 34 countries or regions (as of July 2013), and it has been filed in Japan since 2014. It is sold by people.
  • Non-Patent Document 3 and Patent Document 1 do not disclose or suggest any problems relating to the mass production of [ 123I ] ioflupan.
  • the present invention has been made in view of the above circumstances, without reducing the quality, and to provide a process for producing a large amount [123 I] Iofurupan.
  • the present inventors obtained [ 123 I] ioflupan by using a high-performance liquid chromatography (HPLC) method using a reaction column obtained by radiolabeling reaction with a column having a large diameter.
  • HPLC high-performance liquid chromatography
  • the radioactive iodide ion used in the step (a) has a radioactivity of 200 GBq or more at the start of the step (a)
  • the method (b) provides a method for producing radioiodine-labeled ioflupan, wherein a reverse phase column having a diameter of 7 mm or more is used and an aqueous ethanol solution is used as an eluent.
  • R is a trialkylstannyl substituent having 1 to 6 carbon atoms in the alkyl chain or a triphenylstannyl substituent.
  • X is a radioactive isotope of iodine.
  • the reaction solution obtained by the radiolabeling reaction is purified by HPLC using a column having a large diameter, the concentration of radioactivity in the column is suppressed and the productivity is improved. Can do.
  • the term “ioflupan” refers to methyl (1R, 2S, 3S, 5S) -8- (3-fluorophenyl) -3- (4-iodophenyl) -8-azabicyclo [3. 2.1] A compound called octane-2-carboxylate or N- ⁇ -fluoropropyl-2 ⁇ -carbomethoxy-3 ⁇ - (4-iodophenyl) nortropane.
  • Radioiodination step In the radioiodination step (a) of the present invention, the labeling precursor compound represented by the general formula (1) is reacted with a radioiodide ion to perform a radioiodination reaction, whereby the general formula (2) To obtain a radioactive iodine-labeled compound represented by the formula:
  • R is preferably a trialkylstannyl substituent having 1 to 6 carbon atoms in the alkyl chain, and is a trimethylstannyl substituent or triethylstannyl substituent. More preferred are groups, tripropylstannyl groups and tributylstannyl groups.
  • the labeling precursor compound can be synthesized using, for example, the methods described in Non-Patent Documents 1 and 2 above.
  • the reaction between the labeled precursor compound and the radioactive iodide ion is preferably performed in a suitable solvent in the presence of an oxidizing agent.
  • radioactive iodide ions include ions such as 123 I, 124 I, 125 I, and 131 I. Of these, 123 I is preferable.
  • the radioiodide ion has a radioactivity of 200 GBq or more at the start of the radioiodination step (a), but the method of the present invention provides high yield even when the radioiodination step (a) is started at 400 GBq or more. Radioiodine labeled ioflupan can be produced at a high rate.
  • the upper limit of the radioactivity amount of radioactive iodide ions is not particularly limited, for example, it is 3500 GBq or less, and 2000 GBq or less is practical.
  • the radioactive iodide ion may be a salt having a counter ion.
  • the counter ion include an alkali metal ion and an alkaline earth metal.
  • the salt containing an iodide ion include sodium iodide (NaI), potassium iodide (KI), and ammonium iodide (NH 4 I ), Iodates of amines such as cesium iodide (CsI), lithium iodide (LiI), triethylamine hydroiodide (Et 3 N HI), quaternary such as tetrabutylammonium iodide (Bu 4 NI)
  • An ammonium salt can be exemplified, and among these, radioactive sodium iodide is preferable.
  • any solvent conventionally used for radioiodination reaction may be used.
  • Acidic solutions such as hydrochloric acid, trifluoroacetic acid, sulfuric acid and acetic acid, alcohol solvents such as ethanol; ether solvents such as tetrahydrofuran (THF); Examples include polar solvents selected from acetonitrile and the like, halogen solvents such as methylene chloride, and nonpolar solvents selected from toluene and the like.
  • These acidic liquids, polar solvents and nonpolar solvents can be used singly or in combination of two or more. When using a polar solvent and a nonpolar solvent, it is preferable to add and use the acidic liquid illustrated above, and the acidic buffer of phosphoric acid and phosphoric acid.
  • oxidizing agent examples include N-chlorosuccinimide and hydrogen peroxide.
  • the concentration of the labeled precursor compound in the solvent is not particularly limited, but is preferably 0.3 mg / mL or more from the viewpoint of improving the yield of radioactive iodine-labeled ioflupan, 0.3 to 0.8 mg / mL It is more preferable that
  • the reaction between the labeled precursor compound and radioactive iodide ions is preferably performed in the presence of non-radioactive iodide ions.
  • the concentration of non-radioactive iodide ions is not limited, but from the viewpoint of improving the yield of radioactive iodine-labeled ioflupan, it is preferably 0.015 mg / mL or more, and 0.015-0.04 mg / mL. It is more preferable that
  • the amount of the reaction solution in the radioiodination reaction is not particularly limited, but is, for example, 1 to 5 mL.
  • the temperature at the time of the reaction between the labeling precursor compound and iodide ion is not particularly limited, but is preferably 10 to 120 ° C, more preferably 15 to 40 ° C.
  • the reaction time between the labeling precursor compound and the radioactive iodide ion is not particularly limited, but is preferably 5 to 30 minutes.
  • reaction vessel for performing the radioactive iodine labeling reaction a glass vessel or a plastic vessel resistant to a solvent can be used.
  • a heater For example, a block heater and an air heater are used.
  • the purification step (b) of the present invention is a step of purifying the radioactive iodine-labeled compound represented by the general formula (2) from the reaction solution obtained in the step (a) by the HPLC (high performance liquid chromatography) method. Specifically, the reaction solution is packed in a reverse-phase column with an appropriate eluent and then eluted from the reverse-phase column, and the eluate having a retention time at which the radioactive iodine-labeled compound is eluted is collected. And isolating the radioactive iodine-labeled compound.
  • the present invention uses a reverse phase column having a diameter of 7 mm or more as the column and an ethanol aqueous solution as the eluent, thereby eluting the radioactive iodine-labeled compound with a retention time of 12 minutes or less. It is characterized in that it makes it possible.
  • the column temperature during HPLC is preferably 10 to 30 ° C.
  • a reverse phase column having an inner diameter of 7 mm or more is used as the reverse phase column, and a reverse phase column having an inner diameter of 7 to 30 mm is more preferably used.
  • the length of the reverse phase column is preferably 50 to 200 mm, more preferably 60 to 170 mm from the viewpoint of shortening the holding time and reducing the pressure loss.
  • the silyl group is selected from n-ethyl group, n-butyl group, n-octyl group, n-octadecylsilyl group, phenyl group, cyanopropyl group, trimethylsilyl group, and triacontyl group.
  • Such reverse phase columns are commercially available from, for example, Waters, Phenomenex, Nomura Chemical, Tosoh, Shiseido, YMC.
  • One column may be used alone, or two or more columns may be linked and used.
  • the first column is shorter than the subsequent columns, and after removing non-radioactive inorganic substances from the reaction solution and concentrating, eluting and purifying You may make it function as a pretreatment column for introducing into a column.
  • the length of the pretreatment column is preferably 10 to 50 mm, more preferably 10 to 20 mm, from the viewpoint of efficiency of concentration.
  • the second column preferably functions as a purification column and is longer than the pretreatment column.
  • the length of the purification column is preferably 50 to 150 mm, more preferably 100 to 150 mm.
  • the eluent used in the present invention contains ethanol and water, and a mixture of ethanol and a buffered aqueous solution or an aqueous solution of an alkali metal salt of a weak acid is preferable.
  • a buffer aqueous solution phosphate buffer, acetate buffer, citrate buffer, tartaric acid buffer, borate buffer and the like can be used, and among these, acetate buffer is preferable.
  • These buffers can be prepared from a conjugate acid and a conjugate base.
  • an acetate buffer can be prepared from an aqueous solution in which acetic acid and sodium acetate are mixed.
  • aqueous solution of the alkali metal salt of the weak acid an aqueous solution of an alkali metal salt of a weak acid such as phosphoric acid, acetic acid, citric acid, tartaric acid, boric acid (for example, sodium salt or potassium salt) is used.
  • a sodium acetate aqueous solution is preferred.
  • the pH of the buffered aqueous solution or the aqueous solution of the alkali metal salt of the weak acid is preferably set so that the elution peak of the radioactive iodine-labeled ioflupan is shortened and the reproducibility is improved.
  • the degree of separation between iodine-labeled ioflupan and impurities is improved. Moreover, since it can reduce the damage of a reverse phase column by setting it as pH12 or less, it is more preferable. More preferably, the pH is 4.5 to 8.6.
  • the ethanol concentration in the eluent is preferably 30 to 75% by volume, more preferably 50 to 70% by volume, based on 100% by volume of ethanol and the buffered aqueous solution.
  • a solution containing ethanol from the viewpoint of further reducing the radiolysis of radioiodine labeled ioflupan. More preferably, by preparing the ethanol concentration to be 20% by volume or less and performing HPLC, radiolysis of radioactive iodine-labeled ioflupan can be suppressed without affecting the separation conditions.
  • the eluate eluted in the step (b) is usually a high concentration as it is, from the viewpoint of further reducing the radiolysis of radioactive iodine-labeled ioflupan, an appropriate concentration can be obtained with an appropriate diluent at the time of recovery to the recovery container. It is preferable to dilute to a concentration of 10 GBq / mL or less at the time of elution.
  • the diluent include a diluent containing ethanol and / or a buffered aqueous solution. As this buffer aqueous solution, what was mentioned above as what can be used for an eluent can be used.
  • the diluent is preferably a mixed solution of ethanol and acetate buffer, and more preferably the same as the eluent. Dilution may be performed by directly storing the eluate containing the iodine-labeled compound eluted from the reverse phase column in a collection container in which the dilute solution is previously stored.
  • the radioiodine labeled ioflupan obtained in the present invention is finally prepared in various dosage forms such as injections and provided as a preparation.
  • a preparation is generally provided in the form of an aqueous solution containing the radioiodine-labeled compound of the above general formula (2), and the aqueous solution diluted with the diluent may be further diluted as necessary, physiologically or pharmaceutically
  • additives that are chemically or chemically acceptable.
  • additives examples of additives that can be included include stabilizers, pH adjusters, physiological saline, and solubilizers. Such an additive may be added in advance to the diluent.
  • the pH range generally used is pH 2 to 10, preferably pH 4 to 8, particularly preferably pH 4 to 6.
  • the radioiodine labeled ioflupan obtained in the present invention can be used as an imaging agent used for various diagnoses in the brain, specifically, in ataxia diseases in which striatal dopamine neurons degenerate. It can be suitably used as an imaging agent for diagnosis by SPECT such as certain Parkinson's disease and other Parkinson's syndrome and dementia with Lewy bodies.
  • an absolute ethanol solution of N- ⁇ -fluoropropyl-2 ⁇ -carbomethoxy-3 ⁇ - (4-trimethylstannylphenyl) nortropane (hereinafter SnFP-CT), 50% of 30% hydrogen peroxide, 40 ⁇ L of 25% sulfuric acid, and After adding 50 ⁇ L of 0.2 mol / L sodium acetate aqueous solution and stirring at room temperature for 10 minutes or more, 150 ⁇ L of 30% sodium pyrosulfite aqueous solution and 250 ⁇ L of 0.2 mol / L sodium acetate aqueous solution were added to quench the reaction. In Examples 4 to 6, ethanol was added so that the ethanol concentration was 18% by volume.
  • Examples 1 to 6 were subjected to high performance liquid chromatography under conditions A below and Comparative Example 1 was under conditions B below to separate and purify ioflupan ( 123 I).
  • Examples 1 to 3 In Comparative Example 1, a recovery container containing 5 mL of acetic acid / sodium acetate buffer solution, and in Examples 4 to 6, 75 mL of acetic acid / sodium acetate buffer solution and 5 mL of ethanol were maintained so as to be maintained at 10 GBq / mL or less at the time of elution. was eluted into a collection container containing ioflupan to obtain an ioflupan ( 123 I) fraction.
  • Iofurupan (123 I) and Iofurupan standard solution 1 Take appropriate amount of mixed sample solution in 1, ethyl acetate / acetone / triethylamine mixture (57: 43: 1) as the developing solvent, to about the lower end of the thin layer plate
  • the general test method for the drug base was tested by thin layer chromatography, developed about 10 cm from the original line, and then the radioactivity on the thin layer was measured using a chromatogram scanner. It was measured.
  • the thin layer plate was prepared using silica gel for thin layer chromatography (with fluorescent agent).
  • SOS is the production start time of Ioflupan ( 123 I).
  • the production start time is the time when the preparation of [ 123 I] iodide ion was completed in the above (a) labeling step and the concentration was started at 120 ° C. Further, the yield is obtained by attenuation correction.
  • the expiration date is 34 to 35 hours after the start of the production. ND indicates that data is not acquired.

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  • Optics & Photonics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention fournit un procédé permettant de fabriquer un ioflupane ［１２３Ｉ］ en grande quantité, sans baisse de qualité. Plus précisément, l'invention concerne un procédé de fabrication d'ioflupane marqué à l'iode radioactif qui inclut : (a) une étape au cours de laquelle un composé de précurseur marqué et des ions d'iodure radioactif sont mis en réaction, et un composé marqué à l'iode radioactif est ainsi obtenu ; et (b) une étape au cours de laquelle le composé marqué à l'iode radioactif obtenu au cours de l'étape (a) est purifié selon un procédé de chromatographie liquide à haute performance (CLHP). La quantité de radioactivité des ions d'iodure radioactif mis en œuvre à l'étape (a) est supérieure ou égale à 200GBq au début de l'étape (a). L'étape (b) met en œuvre une colonne à phase inversée de diamètre supérieur ou égal à 7mm, et est effectuée à l'aide d'une solution aqueuse d'éthanol en tant qu'éluant.
PCT/JP2018/008984 2017-03-17 2018-03-08 Procédé de fabrication d'ioflupane Ceased WO2018168643A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2019505938A JP7241013B2 (ja) 2017-03-17 2018-03-08 イオフルパンの製造方法
CN201880027329.3A CN110582494A (zh) 2017-03-17 2018-03-08 碘氟潘的制造方法

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JP2017-052700 2017-03-17
JP2017052700 2017-03-17

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WO2018168643A1 true WO2018168643A1 (fr) 2018-09-20

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CN114487184A (zh) * 2022-01-21 2022-05-13 江苏省原子医学研究所 一种测定2β-甲酯基-3β-(4-氯苯基)托品烷及其有关物质的方法
CN116399984A (zh) * 2023-06-09 2023-07-07 天津辰欣药物研究有限公司 一种利用液相-质谱联用法测定wxtj0262原料药中四丁基碘化铵残留量的方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114487184A (zh) * 2022-01-21 2022-05-13 江苏省原子医学研究所 一种测定2β-甲酯基-3β-(4-氯苯基)托品烷及其有关物质的方法
CN114487184B (zh) * 2022-01-21 2023-09-22 江苏省原子医学研究所 一种测定2β-甲酯基-3β-(4-氯苯基)托品烷及其有关物质的方法
CN116399984A (zh) * 2023-06-09 2023-07-07 天津辰欣药物研究有限公司 一种利用液相-质谱联用法测定wxtj0262原料药中四丁基碘化铵残留量的方法
CN116399984B (zh) * 2023-06-09 2023-08-15 天津辰欣药物研究有限公司 一种利用液相-质谱联用法测定wxtj0262原料药中四丁基碘化铵残留量的方法

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JPWO2018168643A1 (ja) 2020-01-16
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