Method of producing radioactive fluorine-labelled organic compound

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a radioactive fluorine-labelled organic compound of formula (3). The method involves a step for splitting an ester of formula (1), where R1 is a straight or branched C1-C10 alkyl and R2 is a protecting group selected from straight or branched C2-C7 alkyloxycarbonyl groups, passed through and held in a reverse phase column containing filler with a structure in which C2-C18 alkyl groups are attached to a substrate by silicon. In order to split said ester, alkali solution is fed into the column, after which alkaline solution is discharged from the column to obtain a compound of formula (2), where X is sodium or potassium and R2 is a protecting group selected from straight or branched C2-C7 alkyloxycarbonyl groups. At the next step, the protecting group R2 of the compound of formula (2), obtained at the ester splitting step, is removed to obtain a compound of formula (3).

EFFECT: method enables to reduce the amount of nonradioactive impurities and obtain a compound of formula (3) with good output.

2 cl, 3 dwg, 5 tbl, 2 ex

 

The technical field

The present invention relates to a method for producing a radioactive fluorine-labeled organic compounds. More specifically, the invention relates to a method for producing a radioactive fluorine-organic compounds suitable for the detection of tumors positron emission tomography.

Prior art

The study of nuclear medicine, presents positron emission tomography (hereafter in this document referred to as PET) and single photon emission computed tomography (hereinafter referred to in this document referred to as SPECT), is effective in diagnosing a variety of diseases, including heart disease and cancer. These methods include the introduction of an agent that belongs to a particular radioisotope (hereinafter referred to in this document referred to as the radiopharmaceutical agent), the patient with subsequent detection of γ-rays emitted directly or indirectly from the agent. The study of nuclear medicine is characterized by the fact that it not only has high specificity and sensitivity to diseases, but also the advantage of providing information about the functional properties of damage comparable to other methods of research.

For example, [18F] 2-fluoro-deoxy-D-glucose (hereinafter in this document is those denoted as "[ 18F]-FDG"), one of radiopharmaceutical funds used for PET studies may concentrate in areas where glucose metabolism is enhanced, making it possible, therefore, specifically to determine the tumor, in which glucose metabolism is increased.

The study of nuclear medicine performed by measuring the radioactive distribution introduced radiopharmaceutical means, and the data obtained in the survey vary depending on the nature of the radiopharmaceutical funds. Thus, a variety of radiopharmaceuticals remedies for various diseases and some of them are put into clinical use. For example, have developed a variety of diagnostic agents for tumors, diagnostic agents blood flow and receptor Charterhouse agents.

In recent years, a series of radioactive halogen-labeled amino acid compounds, including [18F] 1-amino-3-fertilisation acid (hereafter in this document referred to as [18F]FACBC), were conceived as a new radiopharmaceutical products and their clinical application is in the study (patent document 1 and non-patent documents 1 and 2). [18F]FACBC is effective as a diagnostic agent for vysokopolie is positive tumors, because it has the ability to be specifically absorbed amino acid carrier.

As methods of obtaining [18F]FACBC disclosed methods, which include the provision of ester 1-(N-(t-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1 carboxylic acid as the labeled precursor, substitution triflate group in position 3 of the predecessor radioactive fluorine and execution of the reactions of elimination of the ester group and Boc group by means of exposure to the compounds obtained in the form of a solution acidic conditions (patent document 1 and non-patent documents 1 and 2).

To obtain a [18F]-FDG disclosed the method of synthesis, where the stage of removing the protective group is performed in the solid phase, which makes it possible to reduce the time of synthesis, reduced the number of reagents and reduced the number of components in the receiving apparatus (patent document 2).

Patent document 1: published Japanese patent application No. 2000-500442.

Patent document 2: published Japanese patent application No. 11-508923.

Non-patent document 1: Jonathan McConathy and others, “Improved synthesis of anti-[18F]FACBC: improved preparation of labeling precursor and automated radiosynthesis.”, Applied Radiation and Isotopes, (Netherlands), 2003, 58, p. 657-666.

Non-patent document 2: Timothy M. Shoup and others, “Synthesis and Evaluation of [18F]1-Amino-3-fluorocyclobutane-1-carboxylic Acid to Image Brain Tumors.”, The Journal of Nclear Medicine, 1999, 40, p. 331-338.

Disclosure of invention

Problems to be solved by the invention of

Thus, long-disclosed methods of obtaining [18F]FACBC was achieved outputs product from 12 to 24% (J. McConathy and others, Applied Radiation and Isotopes, 2003, 58, p. 657-666), which cannot be considered as being quite high from the viewpoint of industrial production. That is, with the purpose of industrial production [18F]FACBC is desirable to use a method of obtaining or conditions that can consistently provide higher output.

Getting [18F]FACBC mainly includes a step radiotolerance, which is added to the radioactive fluorine-labeled for predecessor; and the stage of cleavage of ester and removal of the protection of the intermediate compound obtained in stage radiotolerance, is subjected to the cleavage of ester and remove the protection. The authors of the present invention have conducted research under radiotolerance to improve product yield and widely known way, whereby the output stage fluorination can be improved to 73,79%, which was 24,16% according to traditional methods. As a result, the inventors have made it possible to improve the yield of [18F]FACBC to 54.8 ± 4,8% (N = 15). However, a detailed study conducted by the inventors revealed that the resulting aqueous [8 F]FACBC solution contained a large amount of non-radioactive impurities (see comparative examples described below). The amount of impurities in pharmaceuticals should be kept to a certain level or below. Thus, if after completion of the reaction impurities are present at a certain level or higher, the impurities must be removed at a later stage. However, the addition of the subsequent stage filter to reduce impurities causes a lengthening of the time required for the stages of receipt, followed by labeling with radioactive fluorine. Due to the fact that the half-life of the radioactive fluorine is short - approximately 110 minutes is not preferable to lengthen the time required for stages after labeling with radioactive fluorine, from the viewpoint of industrial production labeled with radioactive fluorine compounds.

The present invention was made in view of the above circumstances and aims at providing a method of obtaining [18F]FACBC, which can reduce the resulting number of non-radioactive impurities.

Solutions to problems

As a result of research by the inventors, it was found that the amount of impurities in the target product can be easily and effectively reduced the execution stage of cleavage of the ester group of ester, which the traveler is a protected carboxyl group in the reversed phase column for solid phase extraction and thus, completed the present invention. Solid-phase method of removing the protective groups have traditionally been used mainly for the purpose of reducing the time of receipt (see, for example, published Japanese patent No. 11-508923). The authors of the present invention it has been found that the use of solid-phase method of removing the protective group can be achieved reducing the amount of impurities introduced in the target product, and applied this discovery.

In accordance with the present invention provide a method of obtaining a radioactive fluorine-labeled organic compounds containing phase cleavage of ester, held in the column with reversed phase, compounds represented by the following formula (1):

where R1is1-C10linear or branched alkyl chain or aromatic Deputy; and R2is a protective group;

download column of the alkali solution for cleavage of ester of the above-mentioned compounds and the subsequent discharge of the alkaline solution from the column to obtain a compound represented by a following formula (2):

where X is sodium or potassium; and R2is a protective group; and

the stage of removing the protective group aminosidine group connection is which obtained at the stage of cleavage of ester to obtain a compound represented by a following formula (3):

In the formulas shown above, R1is1-C10linear or branched alkyl chain or aromatic substituent and, preferably, is a Deputy chosen from methyl, ethyl, t-butyl and phenyl groups.

In the formulas shown above, R2is a protective group is not particularly limited, provided that it can prevent the reaction between the radioactive fluorine and amino group. In particular, can be used protective group selected from the group consisting of various urethane substituents, various amide substituents, various imenik deputies and various amine substituents. Preferably, there can be used a protective group selected from the group consisting of linear or branched C2-C7allyloxycarbonyl deputies; linear or branched C3-C7alkenylacyl deputies;7-C12benzyloxycarbonyl substituents, which may be modified group; C2-C7alkylglycerol deputies; linear or branched C1-C6alkylamine deputies; Lina is different or branched C 2-C6alkenylamine deputies;6-C11benzamidine substituents, which may be modified group; C4-C10cyclic imenik deputies;6-C11aromatic imine substituents, which may have a Deputy; a linear or branched C1-C6alkylamine deputies; linear or branched C2-C6alkenylamine substituents; and (C6-C11benzylamine substituents, which may be modified group. More preferably, can be used protecting group selected from t-butoxycarbonyl group, allyloxycarbonyl group, phthalimide group and N-benzyladenine Deputy; and, most preferably, may be used t-butoxycarbonyl group or talimena group.

In the formulas shown above, X is a cation contained in the alkali used at the stage of cleavage of ester and is selected according to the type of alkali. For example, with sodium hydroxide X is sodium, potassium hydroxide X is potassium.

At the stage of cleavage of ester as a column with reversed phase can be used in different column filler,whose functional groups are hydrophobic groups, such as the dryer is l, cyclohexyl, and alkyl groups. Preferably, use columns with reversed phase with a filler having a structure in which2-C8alkyl chain attached to the substrate through the silicon. Example of a column with reversed phase column includes having as functional groups octadecylsilane group.

The retention of the compounds of the above formula (1) in the column with reversed phase can be done in different ways. In particular, there may be used a method in which a solution of the compound of the above formula (1)obtained a stage of radiotolerance, diluted with water and passed through a column of reversed phase. Water for cultivation can be used in a quantity suitable for binding of the compounds above-mentioned formula (1) in the column with reversed phase.

As the alkaline solution can be used in many different solutions, but the use of sodium hydroxide solution is preferred. The amount of alkaline solution for use, preferably, is equal to or greater than the filling capacity of the column for solid phase extraction. The concentration of the alkaline solution is not limited, provided that the alkali may be introduced into the column in a quantity sufficient to perform the splitting of the false air; however, you must pay attention, because if its amount is too large, it will be necessary to use more acid in the subsequent stage of removing the protective group. At the stage of cleavage of ester column with reversed phase was incubated for a certain period of retention time compounds the above formula (1), while pour the alkaline solution. The time at which a column of reversed phase withstand flooding the alkaline solution is not particularly limited, provided that it is sufficient to perform the cleavage reaction of ester.

When the alkaline solution is drained from the column, the connection represented by the above formula (2), merge together with the alkaline solution. At this time, through the column can be optionally skipped the water after draining the alkaline solution to wash off any remaining connection (2). This flushing operation can further improve the yield of the compound (2).

The stage of removing the protective group can be performed using known methods, for example by the method described in the literature “J. McConathy and others, Applied Radiation and Isotopes, 2003, 58, p. 657-666”; and, in particular, the way in which acidic conditions to give a reaction solution after completion of the cleavage of ester.

Stage is adaptirovani can be performed by application of a known method or a combination of this method with the terms and conditions I installed the authors of the present invention. In particular, the connection represented by a following formula (4):

and the inert organic solvent is added to the mixture containing the phase transfer catalyst with18F ions and potassium ions, so as to obtain a reaction solution, and the reaction solution in the mixing process is used, the reaction conditions, such as heating.

In formula (4), R1and R2are as defined above; R3is an element selected from the group consisting of linear or branched C1-C10halogenated sulfonic acid substituents; a linear or branched C1-C10alkyl sulfonic acid substituents; persulfonic acid substituents and an aromatic sulfonic acid substituents. Preferably used may be a Deputy chosen from methanesulfonic acid, toluensulfonate acid, nitrobenzenesulfonic acid, benzosulfimide acid, triftormetilfullerenov acid, persulfonic acid and performancelevel acid.

Under radiotolerance can be used in a variety of inert organic solvents, but should be used amphiphilic organic solvent. In particular, the can is to be used the solvent, selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acetone, dimethylformamide, dimethyl sulfoxide and acetonitrile, the acetonitrile is preferable. The amount of inert organic solvent for use, preferably, is adjusted so that the concentration of the labeled precursor into the reaction solution under the reaction conditions of radiotolerance was 40 mmol/l or more, to significantly improve the yield in the reaction of radiotolerance.

As the reaction conditions for stage radiotolerance can be used in different conditions, for example, can be used in a condition in which the reaction solution is heated in the mixing process. In this case, the heating temperature should not be higher than the boiling point of the inert organic solvent is added to the reaction solution, for example, when the inert organic solvent used acetonitrile, the heating temperature may be from 70 to 90°C.

The effects of the invention

The method of obtaining of the present invention can reduce the number of non-radioactive impurities, obtained upon receipt of a radioactive fluorine-labeled amino acid compounds, such as [18F]FACBC and is also suitable as a method of cleaning such radioacti the data fluorine-labeled amino acid compounds.

The best option of carrying out the invention

Hereinafter in this description to describe in detail a method of obtaining a radioactive fluorine-labeled amino acid according to the invention.

In the most preferred implementation of the method of obtaining of the present invention involves the following stages: (1) reaction of the labeled precursor with a mixture containing the catalyst phase transition,18F ions and potassium ions for tagging labeled predecessor radioactive fluorine, thereby obtaining an ester of a radioactive fluorine-labeled precursor (stage radiotolerance); (2) the stage of cleavage of ester radioactive fluorine-labeled precursor in the column for solid phase extraction (stage cleavage of ester); and (3) removing the protective group aminosidine group of the compound obtained at the stage of cleavage of ester (stage removing the protective group).

Radioactive fluorine can be obtained in a known manner, for example the way in which H218About enriched water is used as target and subjected to proton irradiation. In this example, the radioactive fluorine exists in H218Oh, enriched water used as a target. H218Oh, enriched water containing radioactive fluorine, allow to pass through anyoneeven the th column to radioactive fluorine was adsorbiroval and was going on the column, thus separating from the H218O-enriched water. Accordingly, a solution of potassium carbonate to pass through the column for elution of radioactive fluorine and the eluate complement the phase transfer catalyst and evaporated to dryness to obtain a mixture containing the phase transfer catalyst as well as18F ions and potassium ions.

The amount of potassium carbonate for use as a potassium ion may be equal to or greater than the number of labeled precursor used in the subsequent stage of radiotolerance; however, excess potassium carbonate is not preferable, because the reaction product may decompose under the influence of carbonate ions. In the most preferred implementation of the concentration and quantity of the potassium carbonate solution is adjusted to make the amount of potassium ion is approximately equivalent to the amount of labeled precursor.

As the phase transfer catalyst may be used various compounds having a property to form a clathrate with18F ion. In particular, there can be used various compounds used for producing radioactive fluorine-labeled organic compounds, can b the th used 18-crown-ether and various other aminopolyamide. In the preferred implementation can be used 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8] hexacosane.

A greater amount of the phase transfer catalyst will be more output, but an excessive amount is not preferred because the removal of the excessively added phase transfer catalyst will often be insufficient. In the preferred implementation the total number of catalyst interfacial transition can be 0.2 mol or less, for example, when the number of labeled precursor for use is 80 mol, the molar ratio of catalyst interfacial transition to a labeled precursor is 2.5 or less.

After the mixture containing the catalyst phase transition, and18F ions and potassium ions, perform radiotolerans reaction labeled predecessor and18F ions. For stage radiotolerance can be used in different ways, for example, may be used a method in which ethyl ester 1-(N-(t-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1-carboxylic acid and an inert organic solvent added to the above mixture to obtain a reaction solution and then allow the reaction solution such reaction conditions as to heat the tion under stirring to obtain the ethyl ester of [ 18F]1-(N-(t-butoxycarbonyl)amino)-3-forceclosure-1-carboxylic acid (hereinafter in this description referred to as "[18F]Boc-FACBC"). In the most preferred implementation of the labeled precursor, ethyl ester 1-(N-(t-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1-carboxylic acid can be dissolved in an inert organic solvent before it is added to the mixture.

As the inert organic solvent used at the stage of radiotolerance are used in various solvents, which do not have the ability to enter into chemical reaction with [18F] fluoride ion as a catalyst, the interfacial transition, potassium ion and a substance labeled precursor; and, preferably, may be used a solvent selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acetone, dimethylformamide, dimethyl sulfoxide and acetonitrile, with acetonitrile being most preferred. The amount of inert organic solvent for use, preferably, is adjusted so that the concentration of the labeled precursor in the reaction solution in the reaction of radiotolerance was 40 mmol/l or more to significantly improve the yield in the reaction of radiotolerance.

As the reaction conditions for the study is radiotolerance can be used in different conditions, for example, there may be used a condition in which the reaction solution is heated in the mixing process. The heating temperature in this case, preferably, not higher than the boiling point of the inert organic solvent is added to the reaction solution, for example, when the inert organic solvent used acetonitrile, the heating temperature may be from 70 to 90°C. the Reaction time depends on the reaction temperature, for example, when the reaction temperature is 83°C., a sufficient reaction time is 3 minutes or more. Longer reaction involves the addition, the reaction of radioactive fluorine-labeling, but must take into account the fact that at the same time runs the splitting of radioactive fluorine.

After stage radiotolerance was completed, perform a stage of cleavage of ester to obtain a [18F]1-(N-(t-butoxycarbonyl)amino)-3-forceclosure-1-carboxylic acid (hereinafter in this description referred to as "[18F]DE-Boc-FACBC"). The present invention is characterized by the fact that the reaction mechanism of ester at this stage, perform in a column for solid phase extraction. In the most preferred implementation example for cleavage of ester, namely [18F]DE-Boc-FACBC catch on column DL is solid-phase extraction dilution of the reaction solution, contains [18F]Boc-FACBC obtained under radiotolerance, water and passing the resulting solution as the sample through the column for solid phase extraction. Dilution of the reaction solution is performed to prevent [18F]Boc-FACBC from the extract from the adsorbent without being caught on the column when the sample is passed through the column for solid phase extraction. For this reason, the water used for cultivation, can be used in a quantity sufficient to capture [18F]Boc-FACBC on the filler column for solid phase extraction, when the solvent of the reaction solution is acetonitrile, a sufficient amount of water equal to five times the amount of solvent.

Column for solid phase extraction used at the stage of cleavage of ester should be a column for solid phase extraction, filled with the filler with reversed phase. Preferably, the filler of the column is filled with a hydrophobic functional group, such as phenyl, cyclohexyl, and alkyl groups, and, more preferably, the filler having a structure with a substrate, in which a2-C18alkyl groups attached through silicon. In the preferred implementation can be used column filled with napolnitel is m, having as functional groups octadecylsilyl group. In addition, it is preferable to use a filler column, has a structure which is difficult to separate the functional groups from the substrate when water reaction conditions and in the course of long-cleavage reaction of ester.

After the specimen was captured on the column for solid phase extraction, column load alkaline solution. In the most preferred implementation of the alkaline solution download direct introduction of the alkaline solution into the column, stopping the supply of the alkaline solution after confirming that the alkaline solution began to flow through the outlet of the column. Examples of the alkali used herein include sodium hydroxide and potassium hydroxide, with sodium hydroxide, which is preferably covered with the purpose of obtaining of the invention, used as the input sample.

In the most preferred implementation, the volume of the alkaline solution is approximately equal to that of the column. In this example, should be taken into account that, if the volume of the alkaline solution for use is excessive, the sample previously split of ester can be unloaded together with sbresny solution, thus causing an increase in output.

the concentration of the used alkaline solution is not limited, provided the alkali may be introduced into the column in a quantity sufficient to perform the cleavage of ester. The concentration of the alkaline solution is determined in consideration of the usable volume of the alkaline solution and the required amount of alkali. In this example, it is necessary to take into account that if used an excessive amount of alkali, it will be necessary to use more acid to neutralize at a later stage of removing the protective groups.

Once in a column for solid phase extraction was loaded alkaline solution, the column can withstand inactive for a certain period of time with the intent to cleave ester in the column. In this example, the temperature of the column does not have to be specifically controlled, but steps can be performed at room temperature. The duration in which the column stand dormant, can be a period of time sufficient to allow cleavage of ester. The long duration of additional cleavage reaction of ester will continue, but you must pay attention to the fact that at the same time runs the splitting of radioactive fluorine. For example, when [18F]Boc-FACBC keep in ODS column containing 400 mg of tar and 0.8 ml of 4 mol/l solution of sodium hydroxide is leading in column for complete cleavage of ester, sufficient is the period of time from 1 to 5 minutes.

After cleavage of ester open the outlet of the column, thus causing unloading of [18F]DE-Boc-FACBC, obtained by cleavage of ester, together with an alkaline solution. After the alkaline solution was unloaded, the alkaline solution may be further added to the column, followed by repeating the same operations as described above, so that [18F]Boc-FACBC remaining in the column with reversed phase, could be more thoroughly subjected to cleavage of ester, thereby improving the yield. It is preferred that after unloading the column then washed with water so as to unload the remainder of [18F]DE-Boc-FACBC from the column, thus additionally improving the output.

After the stage of cleavage of ester perform stage of removing the protective groups for removing the amino-protective group, thereby producing [18F]FACBC, which is the target product of the present invention. The stage of removing the protective group can be performed according to known methods, for example, by a method described in the literature "J. McConathy and others, Applied Radiation and Isotopes, 2003, 58, p. 657-666". In the preferred implementation stage of removing the protective group can be performed by providing the acidic conditions in the reaction rastv the re, contains [18F]DE-Boc-FACBC. Acidic conditions can be ensured in various ways, for example the way in which the acid is added to a solution containing [18F]DE-Boc-FACBC. The acid for use here is not particularly limited, but preferably includes an acid selected from inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids, such as perfluoroalkyl carboxylic acid (for example, triperoxonane acid). The amount of acid added should be sufficient to bring the pH of the solution containing [18F]DE-Boc-FACBC, to 1 or less. In particular, the amount of acid should be such as to neutralize the alkali in [18F]DE-Boc-FACBC solution obtained at the stage of cleavage of ester, and bring sufficient acidic conditions in the sample solution. For example, when [18F]Boc-FACBC is subjected to cleavage of ester, repeated twice with 0.8 ml of 4 mol/l solution of sodium hydroxide, can be added to 2.2 ml of 6 mol/l hydrochloric acid extracted from the adsorbent of the reaction solution. At the stage of removing the protective group, the reaction solution preferably is heated to allow the reaction to proceed more quickly. The reaction time depends on the reaction temperature or other conditions, but when Rea is the operation of removing the protective group under the above conditions perform at 60°C, sufficient reaction time is 5 minutes. [18F]FACBC solution obtained at the stage of removing the protective group may be optionally purified using ion-exchange column, the column of aluminum oxide column with reversed phase.

Examples

Hereinafter in the description of the present invention will be described in more detail by way of examples and comparative examples; however, the invention is not limited to these examples.

Reference example 1

Synthesis of ethyl ester SYN-1-(N-(t-butoxycarbonyl)amino)-3--[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1-carboxylic acid

Hydrolysis of sin-as (Fig. 1, stage 1)

250 ml of a saturated aqueous solution of barium hydroxide was added to x 6.15 g (25 mmol) of SYN-5-(3-benzyloxyresorufin)as and the mixture was heated in a flask under reflux on an oil bath at 114°C for 24 hours or more. Then did the TLC analysis, using as mobile solvent two types of systems, namely chloroform:methanol = 5:1 (Rf value of sin-as equals, approximately, 0,3), and confirmed the completion of reaction (based on staining with UV and phosphomolybdenum acid).

After confirming that the reaction was completed, the resulting reaction solution was cooled to room temperature and added approximately 24 ml of 1 moll sulfuric acid to neutralize the reaction solution. After neutralizing the reaction solution was further stirred at room temperature for 5 minutes and the resulting precipitate was filtered. Then the filtrate was collected with getting 5,67 g of SYN-1-amino-3-benzyloxycarbonyl-1-carboxylic acid as colorless crystals.

The formation of complex ethyl ester (Fig. 1, stage 2)

5.6 g of SYN-1-amino-benzyloxyresorufin-1-carboxylic acid, which completely dried to remove water, was dissolved in 200 ml of ethanol. To this solution was added to 9.5 ml (respectively, 75 mmol) of triethylamine and the mixture was cooled to -78°C for 20 min, followed by the addition there of 4.6 ml (respectively, 62.5 mmol) of thionyl chloride. The reaction solution was stirred at 0°C for 1 hour and at room temperature for 1 hour, followed by heating in a flask under reflux on an oil bath at 95°C during the night. Then the completion of the reaction was confirmed by TLC analysis, which was performed, using as mobile solvent two types of systems, namely chloroform:methanol = 95:1 (Rf value of the target product is approximately 0,6) (in which the confirmation was based on staining with UV and phosphomolybdenum acid). After confirming that the reaction was completed, the resulting reaction solution was collected under reduced pressure to get to 7.64 g these the new ester SYN-1-amino-3-benzyloxycarbonyl-1-carboxylic acid as colorless crystals.

Adding Boc (Fig. 1, stage 3)

of 7.64 g of ethyl ester SYN-1-amino-3-benzyloxycarbonyl-1-carboxylic acid was dissolved in 250 ml of a mixed solution of ethanol:triethylamine = 9:1. The resulting solution was cooled in an ice bath for 15 minutes, then there was added 8.6 ml (respectively, 37.5 mmol) di-tert-butyl dicarbonate and the mixture was left overnight under stirring. Then the completion of the reaction was confirmed by TLC analysis, which was performed using as mobile solvent hexane:ethyl acetate = 1:1 (Rf value of the target product is approximately 0,6) (in which the confirmation was based on staining with UV and phosphomolybdenum acid). After confirming that the reaction was completed, the resulting reaction solution was collected under reduced pressure to obtain a residue in the form of colorless crystals. To the residue was added 150 ml of cold ethyl acetate and 150 ml of 0.5 mol/l of cold hydrochloric acid, the mixture was stirred at room temperature for 5 minutes and stood for separation. The organic layer was extracted and washed twice with 150 ml water, 150 ml of saturated aqueous sodium hydrogen carbonate solution, 150 ml of water twice, and 150 ml of saturated brine twice in this order, the extract was dried with anhydrous sodium sulfate and then was collected under reduced pressure to give a yellow oil is a substance. Separate the aqueous layer was extracted and washed twice with 150 ml of ethyl acetate twice 150 ml of water and 150 ml of saturated brine in this order, and the extract was dried with anhydrous sodium sulfate and then was collected under reduced pressure, thus gathered a small amount of a yellow oily substance. The series of operations gave 8,82 g of light yellow oily substance. The residue was separated and purified by chromatography on a column of silica gel (hexane:ethyl acetate = 1:1) obtaining of 8.04 g (respectively, 23 mmol) ethyl ester SYN-1-(N-(t-butoxycarbonyl)amino)-3-benzyloxy-CYCLOBUTANE-1-carboxylic acid as colorless crystals.

Dibenzylamine (Fig. 2, stage 4)

150 ml of ethanol was added to 8,04 g (respectively, 23 mmol) ethyl ester SYN-1-(N-(t-butoxycarbonyl)amino)-3-benzyloxy-CYCLOBUTANE-1-carboxylic acid, and then there was added 960 mg of palladium on charcoal (10% palladium), purged with hydrogen, and the mixture was left to stir at room temperature overnight. After the reaction palladium on charcoal was filtered using Celite, and the obtained filtrate was collected under reduced pressure to give 5,74 g residue in the form of colorless crystals. The reaction was monitored by TLC analysis, using as mobile solvent hexane:ethyl acetate = 1:1 (Rf value of the target reaction etc the product is, approximately 0,2)(the proof was based on the staining with UV and ninhydrin) to confirm completion of the reaction. Then the residue was separated and purified by chromatography on a column of silica gel (hexane:ethyl acetate = 1:1, hexane:ethyl acetate = 4:1) to obtain are 5.36 g (respectively, of 20.7 mmol) ethyl ester SYN-1-(N-(t-butoxycarbonyl)amino)-3-hydroxy-CYCLOBUTANE-1-carboxylic acid as colorless crystals.

The introduction of the triflate (Fig. 3, stage 5)

2,07 g (8 mmol) of ethyl ether SYN-1-(N-(t-butoxycarbonyl)amino)-3-hydroxy-CYCLOBUTANE-1-carboxylic acid was dissolved in 26 ml of pyridine and the solution was stirred in an ice bath for 20 minutes. There was added 2.0 ml (respectively, 12 mmol) of anhydrous triftoratsetata and the mixture was stirred as it is for 30 minutes. The reaction was monitored by TLC analysis, using as mobile solvent hexane:diethyl ether = 1:1 (Rf value of the target reaction product is approximately 0,6) (the proof was based on the staining with ninhydrin) to confirm completion of the reaction. To confirm that the reaction was completed, the reaction solution was added 100 ml of water and 100 ml of ether, the mixture was extracted and washed with 100 ml of 1 mol/l hydrochloric acid, twice with 100 ml of water twice, and 100 ml saturated brine twice in this order. Recip is to cancel the extract was dried with anhydrous sodium sulfate and then was collected under reduced pressure, to give 2,78 g of light yellow crystals. The reaction mixture was separated and purified by chromatography on a column of silica gel (hexane:diethyl ether = 3:1) to obtain white crystals and the resulting white crystals were again precrystallization using pentane:diethyl ether to obtain 1.84 g (respectively, 4.7 mmol) ethyl ester SYN-1-(N-(t-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1-carboxylic acid.

Comparative example

H218Oh, contain [18F] fluoride ions (13 to 182 GBq)was passed through anion exchange column so that [18F] fluoride ions were adsorbed and trapped on the column. Then passed through the column a solution of potassium carbonate to extract from the adsorbent [18F] fluorine, then the column was rinsed with water and the aqueous solution was mixed with the eluate. In the resulting solution was added to the solution in acetonitrile 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (trade name: Kryptofix 222, manufactured by Merck) and the mixture was heated and evaporated to dryness.

To the dried mixture was added a solution obtained by dissolving 32 mg ethyl ester SYN-1-(N-(t-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1-carboxylic acid in 1 ml of acetonitrile, and the resulting mixture was stirred for 3 minutes at 83°C. to allow the reaction RA is oftolerance continue. Then the mixture was cooled at room temperature for 5 minutes and to it was added 4 ml of diethyl ether. The resulting mixture was passed through a Silica Sep-Pak (registered trademark Waters Investments Limited or trade name, available from Nihon Waters K. K.)to obtain acetonitrile/diethyl ether solution of [18F]BOC-FACBC.

In the resulting solution of acetonitrile/diethyl ether [18F]BOC-FACBC was added to 1.5 ml of 4 mol/l hydrochloric acid and the mixture was heated at 120°C for 15 minutes to remove the protective groups. The resulting solution was further purified by passing through an ion exchange column (trade name: AG11A8 manufactured by Bio-Rad Laboratories Japan, Inc.), a column of aluminum oxide (trade name: Sep-Pak (registered trademark, produced Waters Investments Limited) light ALUMN, produced by Nihon Waters K. K.) and a column of reversed phase (trade name: Oasis HLB Plus EXTRACTION Cartridge Column manufactured by Nihon Waters K. K.) in this order to obtain a solution of [18F]FACBC. Output [18F]FACBC solution was from 9.4 to 13.4 ml Obtained [18F]FACBC was subjected to TLC analysis under the following conditions and radiochemical purity was confirmed according to the next equation (1).

The terms of the TLC analysis:

Mobile phase: acetonitrile/methanol/water/acetic acid = 20/5/5/1.

TLC plate: Silica Gel 60F254 (trade name, film thickness: 0.25 mm, manufactured by Merck)

P is havlaga length: 10 cm

The analyzer TLC: Rita Star (produced Raytesr)

(1)

In addition the number of non-radioactive impurities in the target product were compared with values obtained by introducing amendments in accordance with the following equation (2), the peak area of each impurity, confirmed by HPLC analysis of the subsequent conditions (hereinafter in this description are marked as "corrected value"). The sample solution is subjected to HPLC analysis, sufficiently diluted, using physiological saline solution (dilute factor equal to from 2.1 to 9.9).

(2)

HPLC measurement conditions:

Column: CAPCELLPAK C18 MG (trade name, produced by Shiseido Co., Ltd, size: 5 µm, 4.6 mm I.D. × 250 mm)

The column temperature: room temperature (approximately 25°C)

Mobile phase: used 5 mmol/l sodium octanesulfonate containing phosphate buffer (pH 2,1)as solution a and acetonitrile as a solution, the control of the concentration gradient was performed by varying the ratio of components of the mixture of solutions a and b as shown in Table 1.

Table 1
The mobile phase in HPLC analysis
Time (min) after administration The mobile phase A (%)The mobile phase(%)
0-1095 → 905 → 10
10-409010
40-4190 → 9510 → 5

The volume flow of mobile phase (1.0 ml/min

The amount of the sample:10 l

Conditions poslegarantijnogo obtain derivatives:

The reaction solution: 0.3 mol/l boric acid buffer (pH 10,4), 6 mmol/l o-phthalic aldehyde and 6 mmol/l N-acetyl-L-cysteine.

The volume flow of the reaction flow rate: 1.0 ml/min

Reaction temperature: 50°C

Detector: fluorescence detector (type: Waters 2475 model, manufactured by Nihon Waters K. K.); stimulating wavelength: 330 nm; fluorescence wavelength: 430 nm)

The experience of Comparative Example 1 was repeated 19 times.

Radiochemical purity of the obtained [18F]FACBC was 98,8 ± 0,4%. Peaks of impurities, confirmed by HPLC chromatograms were identified, as shown in Table 2. The adjusted value of the peak area of each impurity shown in Table 3.

Table 2
The name of each impurity
Relative retention time (average) (min)Name impurities
8,0And
8,9B
9,8C
14,7D
23,8E
30,3F
30,8G
35,9H

Table 3
The adjusted value of the area of each impurity
The adjusted area value/108
ABCDEFGHTotal
515,663,040,21,6226,326,6 44,140,7968,8

Examples 1 and 2

H218Oh, contain [18F] fluoride ions (7-36 GBq)was passed through anion exchange column so that [18F] fluoride was adsorbiroval and was located on the column. Then passed through the column to extract from the adsorbent [18F] fluorine, potassium carbonate solution and the column was rinsed with water and the washing solution was mixed with the eluate. In the resulting solution was added to the solution in acetonitrile 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (trade name: Kryptofix 222, manufactured by Merck) and the mixture was heated and evaporated to dryness.

In the dried mixture was added a solution obtained by dissolving 32 mg of ethyl ester 1-(N-(t-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1-carboxylic acid in 1 ml of acetonitrile, and the resulting mixture was heated at 83°C. under stirring for 3 minutes.

The resulting reaction solution was cooled at room temperature for 5 minutes and then was diluted with 14 ml of water and the resulting solution was passed through each Sep-Pak (registered trademark, Waters Investments Limited) cartridge (manufactured by Nihon Waters K. K.), shown in Table 4, and then the column was further washed with 10 ml water.

Table 4
Column for solid phase extraction used in each Example
Column for solid phase extraction (product name)
Example 1tC2
Example 2tC18

A column for solid phase extraction was dried by passing air through it and then the column was loaded 0.8 ml/l to 4 mol/l solution of sodium hydroxide with subsequent clogging of the outlet of the column. After the expiration of 3 minutes the outlet of the column was opened to extract from the adsorbent of the alkaline solution from the column for the solid-phase extraction and the eluate collected in the vial. In the column was additionally loaded to 0.8 ml of 4 mol/l sodium hydroxide solution and repeating the same procedure as described above. A column for solid phase extraction then washed with 3 ml of water and the washing solution was mixed with the previously collected alkaline solution.

In the above-mentioned collected solution was added 2.2 ml of 6 mol/l hydrochloric acid, and carried out the reaction of removing the protective group at 60°C for 5 minutes. The resulting product was further purified by passing through an ion exchange column (trade name: AG11A8 produced Bio-Rad Laboratories Japan, Inc.), a column of aluminum oxide is I (trade name: Sep-Pak (registered trademark, Waters Investments Limited) light ALUMN, manufactured by Nihon Waters K. K.) and a column of reversed phase (trade name: Oasis HLB Plus EXTRACTION Cartridge Column, manufactured by Nihon Waters K. K.) in this order to obtain a [18F]FACBC solution. Output [18F]FACBC solutions ranged from 11.9 to 17,0 ml.

Obtained [18F]FACBC solution was evaluated on the radiochemical purity of [18F]FACBC and the adjusted value of the area of each impurity under the same conditions as in the Comparative Example. The sample solution subjected to HPLC analysis, suitably diluted using physiological saline solution (dilution ratio is 3.0 to 4.7).

Radiochemical purity of [18F]FACBC obtained in Examples 1 and 2 were 99.4 and 99.3%, respectively. Table 5 shows the adjusted value of the area of peaks of each impurity. As shown in Table 5, in each of Example 1 and 2 the number of all non-radioactive impurities, except for impurities D, is reduced compared with the sample obtained according to conventional method (Comparative Example 1) and the total adjusted value of the field is reduced to less than half. These results confirmed that the number of non-radioactive impurities can be reduced way to obtain [18F]FACBC in accordance with the present invention.

Table 5
The adjusted value of the area of each impurity
The adjusted area value/108
ABCDEFGHTotal
Example 1203,56,24,019,79,30,5a 4.93,2257,7
Example 2218,7of 5.48,338,25,22,04,41,6292,6

Industrial applicability

A method of obtaining a radioactive fluorine-labeled organic compounds according to the invention can be used in the production of radiopharmaceuticals funds.

Brief description of the tion drawings

Figure 1 is a scheme of synthesis of ethyl ether SYN-1-(N-(t-butoxycarbonyl)amino)-3-benzyloxy-CYCLOBUTANE-1-carboxylic acid.

Figure 2 is a scheme of synthesis of ethyl ether SYN-1-(N-(t-butoxycarbonyl)amino)-3-hydroxy-CYCLOBUTANE-1-carboxylic acid.

Figure 3 is a scheme of synthesis of ethyl ether SYN-1-(N-(t-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]-CYCLOBUTANE-1-carboxylic acid.

1. A method of obtaining a radioactive fluorine-labeled organic compound of the formula (3):

which includes:
stage cleavage of ester represented by the following formula (1):

where R1is a linear or branched C1-C10the alkyl, and R2is a protective group selected from linear or branched C2-C7allyloxycarbonyl groups, noise and held in the column with reversed phase containing a filler having a structure in which C2-C18alkyl groups attached to the substrate through silicon via download in the column of alkali solution for cleavage of ester of the above compounds and the subsequent discharge of the alkaline solution from the column with obtaining compounds represented by the following formula (2):

2is a protective group selected from linear or branched C2-C7allyloxycarbonyl groups; and
the stage of removing the protective group R2the compounds of formula (2)obtained at the stage of cleavage of ester, to obtain the compound represented by formula (3).

2. A method of obtaining a radioactive fluorine-labeled organic compound according to claim 1 in which the alkaline solution used at the stage of cleavage of ester is an aqueous solution of sodium hydroxide.



 

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26 cl, 17 ex, 1 tbl

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3 cl, 3 dwg, 2 tbl, 2 ex

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1 ex

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11 cl, 10 ex, 2 tbl

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SUBSTANCE: invention relates to a method of producing compounds of formula

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, where R1-R3, R9, defined above, are precursors of compounds of formula (I), as well as to a radiopharmaceutical set and a cartridge for use in positron emission tomography, which contain said precursors.

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11 cl, 1 tbl, 6 ex

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4 cl, 14 ex, 2 tbl

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