Method for producing compound for pet probe and method for producing intermediate thereof

Abstract

The present invention realizes a method for stably producing a raw material of a compound for a PET probe. The present invention is a method for producing a compound represented by formula (VI). [In formula (VI), R1 is a halogen group, an alkyl group, -CN, -N3 or -NO2, n denotes the number of R1 moieties and is an integer of 1-4, Z is a C1-C4 hydrocarbyl group, X is a group comprising a linear carbon chain having 1-4 carbon atoms, and R2 is a group derived from an organic tin compound.]

Description

Method for producing a compound for a PET probe and a method for producing an intermediate thereof

[0001] The present invention relates to a method for producing a compound for a PET probe, and a method for producing an intermediate thereof.

[0002] As a PET probe targeting synaptic vesicle glycoprotein 2A (SV2A), for example, １１ C-UCB-J is being used in clinical research. SV2A is expressed in synaptic terminals throughout the brain and has the function of facilitating the action potential-dependent synaptic secretion of neurotransmitters, and is involved in various neurological disorders such as epilepsy and Alzheimer's disease. １１ C-UCB-J is capable of imaging and quantifying SV2A in the human brain and is used in many PET facilities as a PET probe (for example, non-patent documents 1 to 5).

[0003] Non-patent documents 1, 2, and 4 have １１ When synthesizing C-UCB-J, BF ３ -Dm-UCB-J is disclosed.

[0004] Nabulsi NB., et al., J Nucl Med. 2016;57:777-784.Rokka J., et al., EJNMMI Radiopharm Chem. 2019;4:30.Finnema SJ., et al., Epilepsia. 2020;61:2183-2193.Milicevic Sephton S., et al., J Labelled Comp Radiopharm. 2020;63:151-158.Finnema SJ., et al. Sci Transl Med. 2016. 8. 348-396.

[0005] However, in the conventional method, BF ３ In order to prepare BF-Dm-UCB-J, complicated operations under severe conditions were required. ３ -Dm-UCB-J is １１ CH ３ It has low reactivity with I, １１There was a problem that the yield of C-UCB-J was unstable. １１ There has been a demand for providing raw materials that enable stable production of probes such as C-UCB-J.

[0006] One aspect of the present invention is １１ The present invention aims to realize a method for stably producing an intermediate of a compound for a PET probe having C.

[0007] In order to solve the above-mentioned problems, a method for producing a compound according to one aspect of the present invention is a method for producing a compound represented by the following formula (VI): A step A of treating a compound represented by the following formula (II) and a compound represented by the following formula (IV) with a second reducing agent, and then treating them with a condensing agent to obtain a compound represented by the following formula (V); Step B: treating a compound represented by the following formula (V) with an organotin compound to convert it into a compound represented by the following formula (VI); [wherein R １ is a halogen group, alkyl group, -CN, -N ３ , or -NO ２ and n is R １ Z is an integer of 1 to 4 representing the number of １ -C ４ is a hydrocarbyl group, X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms, Q is a halogen group, or -Li, -CH=O, -N=NH, -NH ２ and R ２ is a group derived from the organotin compound.

[0008] According to one aspect of the present invention, １１ It is possible to realize a method for stably producing an intermediate of a compound for a PET probe having C.

[0009] 1 shows the results of HPLC analysis of Compound 6 and its racemate prepared in Example 1. １１ 1 shows the synthesis procedure of C-UCB-J. １１1 shows a separation chart of C-UCB-J synthesized in Example 2. １１ 1 shows the analytical chart (chiral) of C-UCB-J synthesized in Example 2. １１ 1 is a diagram showing an analysis chart of C-UCB-J in Example 3. １１ 1 shows the synthesis procedure of C-UCB-J. １１ 1 shows a separation chart of C-UCB-J synthesized in Example 3. １１ 1 shows the analytical chart (chiral) of C-UCB-J synthesized in Example 3. １１ FIG. 1 is a diagram showing an analysis chart of C-UCB-J.

[0010] [Method for producing compound (VI)] Hereinafter, one embodiment of the present invention will be described in detail. The production method according to this embodiment is a method for producing a compound represented by the following formula (VI). Hereinafter, the compound represented by formula (VI) will be referred to as compound (VI). The same applies to compounds represented by other formulas.

[0011]

[0012] Compound (VI) is an intermediate used in the synthesis of a compound for a PET probe. Compound (VI) will be described below.

[0013] R １ is a group bonded to the phenyl group. １ is a halogen group, an alkyl group, —CN, —N3, or —NO2. １ is preferably a halogen group. From the viewpoint of realizing favorable probe performance, R １ It is particularly preferred that is —F.

[0014] n is R １ n is an integer of 1 to 4, representing the number of groups. n is preferably 2 or 3, and particularly preferably 3. When n is 2 or more, R １ may be different groups or may be the same group. １ The binding position of R is not particularly limited as long as it can achieve probe performance. １is preferably bonded to at least the second position of the phenyl group. When n is 3, R １ is preferably substituted at the 2-, 3-, and 4-positions of the phenyl group.

[0015] X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms. X is preferably a group consisting of a linear carbon chain having 1 to 2 carbon atoms, and particularly preferably a group having 1 carbon atom. The group consisting of a carbon chain is preferably a saturated hydrocarbon group (however, when the group has 1 carbon atom, it is not particularly limited to CH ２ That is, in formula (VI), X is —CH ２ It is preferable that −.

[0016] R ２ is a group derived from the organotin compound used in step B. More specifically, R ２ is a tin-containing organic group derived from an organotin compound. ２ may be a monovalent group in which one to three alkyl groups or a hydrogen atom are bonded to a tin atom, and is particularly preferably a monovalent group in which three alkyl groups are bonded. For example, R ２ -Sn(C1H3) ３ , -Sn(C2H5) ３ , -Sn(C ３ H ７ ) ３ , -Sn(C ４ H ９ ) ３ , -Sn(CH 11 ) ３ , -Sn(C ６ H 1３ ) ３ , or -Sn(C ７ H 1５ ) ３ It is preferable that R ２ Preferably, R has a linear alkyl group. ２ is -Sn(n-C ４ H ９ ) ３ It is particularly preferred that:

[0017] R in the pyridine group ２The binding position of R can be appropriately designed depending on the probe performance of compound (VII) described below. ２ is particularly preferably bonded to the 3-position of the pyridine group.

[0018] The above definitions also apply to compounds represented by other formulas below.

[0019] Compound (VI) is preferably Sn-UCB-J represented by the following formula: In this specification, when simply written as Sn-UCB-J, it means (R)-Sn-UCB-J.

[0020]

[0021] Compound (VI) is a tin-labeled compound, wherein: １１ BF, which was previously used in the production of C-UCB-J ３ -Dm-UCB-J is １１ CH ３ It has low reactivity with I, １１ There was a problem that the yield of C-UCB-J was unstable. ３ -Dm-UCB-J has been used in various ways and various studies have been carried out. １１ There was no significant improvement in the yield or amount of C-UCB-J. １１ CH ３ Highly reactive with I １１ A production method that stabilizes the yield of C-UCB-J can be realized.

[0022] The method for producing compound (VI) will be described in detail below. Each of the steps shown below can be carried out under mild reaction conditions. Therefore, the method for producing compound (VI) including each of the steps below is as follows: １１ This is preferred as a method for stably producing an intermediate of a compound for a PET probe having C.

[0023] (Step A) Step A is a step for obtaining compound (V) from compound (II) and compound (IV). In step A, compound (II) and compound (IV) are treated with a second reducing agent, and then treated with a condensing agent to obtain a compound represented by compound (V). The scheme of step A is shown below.

[0024]

[0025] In formula (II), Z is C １ -C ４ Z is a hydrocarbyl group. １ -C ４ It is preferably an alkyl group, and C １ -C ２ An alkyl group is particularly preferred.

[0026] In formula (IV) and formula (V), X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms. X is preferably a group consisting of a linear carbon chain having 1 to 2 carbon atoms, and particularly preferably a group having 1 carbon atom. The carbon chain is preferably a saturated hydrocarbon structure (however, when the carbon atom is 1, it is CH in formula (IV) and CH in formula (V)). ２ In this case, compound (IV) has an aldehyde group at the end of X. That is, in formula (IV), -X=O is preferably -CH=O. In formula (V), X is preferably -CH ２ It is preferable that −.

[0027] In formula (V), Q is a halogen group, —Li, —CH═O, —N═NH, or —NH ２ Q is preferably a halogen group, and Q is particularly preferably -I. When Q is -I, step B described below can be carried out under mild conditions, and this is particularly preferred from the viewpoint of stably producing compound (VI) while maintaining the R-configuration.

[0028] In step A, compound (II) and compound (IV) are reacted with each other by reacting the —NH ２The group undergoes dehydration condensation with the carbonyl group of compound (IV) in the presence of a second reducing agent, resulting in an imine. The imine is reduced to an amine by the action of the second reducing agent. Subsequent treatment with a condensing agent results in a ring-closing reaction via intramolecular condensation of the amine, yielding compound (V).

[0029] The second reducing agent is preferably a reducing agent that reduces imines to amines, such as sodium cyanoborohydride, lithium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, potassium borohydride, zinc borohydride, or lithium aluminum hydride.

[0030] The condensing agent is not particularly limited as long as it enables intramolecular condensation of the ring-opening compound. For example, the condensing agent is preferably a strong base. For example, the condensing agent is preferably sodium methoxide, sodium ethoxide, sodium butoxide, or potassium t-butoxide.

[0031] Step A is preferably carried out at a temperature of −10° C. or higher and 25° C. or lower. For example, step A may be carried out at a temperature of −5° C. or higher and 5° C. or lower. Such temperature conditions are mild reaction conditions, and are preferred from the viewpoint of maintaining the R-configuration of compound (II) and stably producing compound (V).

[0032] Step A may be carried out in the presence of a base. The base is not particularly limited, but may be a tertiary amine from the viewpoint of carrying out the reaction suitably. The base in Step A is preferably, for example, trimethylamine, triethylamine, tripropylamine, tributylamine, trioctylamine, or diisopropylethylamine. The tertiary amine is particularly preferably triethylamine.

[0033] Any solvent may be used in Step A. The solvent in Step A may be an organic solvent capable of reacting with compounds (II) and (IV). For example, ethanol or methanol is preferred.

[0034] In step A, compounds (II) and (IV) may be compounds obtained by any method. On the other hand, it is preferable to produce compounds (II) and (IV) based on the production method for compound (II) and the production method for compound (IV) described below, from the viewpoint of carrying out the reaction under mild conditions and maintaining the structure of the optical isomers.

[0035] (Step B) Step B is a step for treating compound (V) with an organotin compound to obtain compound (VI). The scheme of step B is shown below.

[0036]

[0037] In step B, Q of compound (V) is converted to R derived from an organotin compound. ２ The type of organotin compound is selected from R ２ There is no particular limitation as long as it can introduce the group. For example, the organotin compound may be a compound in which one to three alkyl groups are bonded to a tin atom, and a compound in which three alkyl groups are bonded is preferred. In particular, the organotin compound is -Sn(C １ H ３ ) ３ , -Sn(C ２ H ５ ) ３ , -Sn(C ３ H ７ ) ３ , or -Sn(C ４ H ９ ) ３ It is particularly preferred that the compound is a compound for introducing the following formula: and such a compound is preferably bis(trimethyltin), bis(triethyltin), bis(tripropyltin), bis(tributyltin), or tributyltin chloride.

[0038] Step B is preferably carried out in the presence of a first catalyst. The first catalyst used in step B may be any catalyst. For example, the first catalyst may be a palladium catalyst or a metal catalyst. The palladium catalyst may be, for example, Pd(t-Bu ３ P) ２ , or Pd(PPh３ ) ４ The metal catalyst is preferably magnesium or butyllithium.

[0039] Step B may be carried out at a temperature of 80° C. or higher, and is preferably carried out at a temperature of 90° C. or higher from the viewpoint of reactivity.

[0040] [Method for producing compound (II)] Step C is a step of treating compound (I) in a lower alcohol with an acylating agent under acidic conditions to obtain a compound represented by formula (II). The scheme of step C is shown below.

[0041]

[0042] The lower alcohol used in step C refers to a saturated or unsaturated alcohol having 1 to 4 carbon atoms, and is preferably a saturated alcohol having 1 to 4 carbon atoms, such as ethanol or methanol. In compound (II), Z is derived from a lower alcohol.

[0043] In step C, the acylating agent is not particularly limited as long as it allows step C to proceed. For example, the acylating agent is preferably thionyl chloride or oxalyl chloride.

[0044] In step C, the method for creating an acidic condition is not particularly limited. For example, the solvent may be made acidic by bubbling any acidic gas through the solvent, or by adding any acidic solution to the solvent. When any acidic gas is bubbled, the acidic gas may be, for example, hydrogen chloride gas or acetic acid gas. Furthermore, the any acidic solution may be, for example, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, or p-toluenesulfonic acid.

[0045] Other reaction conditions for step C can be set appropriately. For example, step C is preferably carried out under strongly acidic conditions of pH 4 or less. The temperature conditions for step C are preferably −10° C. or higher and 25° C. or lower, and more preferably −5° C. or higher and 5° C. or lower. These temperature conditions are mild reaction conditions, and are preferred from the viewpoint of maintaining the R-isomer structure of compound (I) and stably producing compound (II).

[0046] [Preparation of Compound (IV)] Step D is a step of reducing compound (III) with a first reducing agent to obtain compound (IV). The scheme of Step D is shown below.

[0047]

[0048] In formula (III), X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms. The carbon chain is preferably a saturated hydrocarbon chain (however, when the carbon chain has 1 carbon atom, it is a carbon atom). Compound (III) has an ester group at the end of X. X is preferably a group consisting of a linear carbon chain having 1 to 2 carbon atoms, and particularly preferably a group having 1 carbon atom. That is, in formula (III), -X(=O)O- is preferably -C(=O)O-.

[0049] The first reducing agent is not particularly limited as long as it has the effect of reducing the ester to an aldehyde in step D. For example, it may be diisobutylaluminum hydride or lithium aluminum hydride.

[0050] There are no particular limitations on the conditions for step D. For example, step D may be carried out at a temperature of −60° C. or lower.

[0051] [Other Steps] Steps other than those described above may be included as appropriate. For example, after steps A to D, an optional extraction step and purification step may be included.

[0052] [Method for producing compound (VII)] Another embodiment of the present invention will be described below. The method for producing a compound represented by formula (VII) is as follows.

[0053]

[0054] In formula (VII), １１ By C is intended the radioactive isotope carbon. １１ CH ３ The binding position can be designed depending on the probe performance. １１ CH ３ is particularly preferably bonded to the 3-position of the pyridine group.

[0055] The method for producing compound (VII) includes step E. Step E is a step of treating compound (VI) with a catalyst composition to obtain compound (VII). The scheme of step E is shown below.

[0056]

[0057] The catalyst composition comprises １１ CH ３ I, a second catalyst, a phosphine ligand, and a copper halide.

[0058] The second catalyst is R in compound (VI). ２ of １１ CH ３ The second catalyst is not particularly limited as long as it can catalyze the substitution reaction of the compound with the group 1. For example, the second catalyst may be at least one of a palladium catalyst and a metal catalyst. In particular, a palladium catalyst is preferred. The palladium catalyst is not particularly limited, but examples thereof include Pd ２ (dba) ３ , and Pd(PPh ３ ) ４ Examples include:

[0059] Examples of the phosphine ligand include tri(o-tolyl)phosphine, triphenylphosphine, and triethylphosphine.

[0060] Preferably, the copper halide (CuCl or CuBr) is a cuprous halide.

[0061] The components contained in the catalyst composition in step E can be appropriately set. For example, it is preferable that the catalyst composition further contains at least one of a carbonate and an alkali metal salt of an alkali metal fluoride.

[0062] Carbonates include potassium carbonate, sodium carbonate, and cesium carbonate.

[0063] Alkali metal fluorides include CsF and KF.

[0064] The catalyst composition preferably contains a carbonate. In particular, the catalyst composition particularly preferably contains potassium carbonate. Inclusion of a carbonate in the catalyst composition is preferred from the viewpoints of simplifying the step E and improving the final yield.

[0065] The catalyst composition may contain other optional components. In step E, compound (VI) may be prepared by any method.

[0066] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

[0067] [Summary] A production method according to aspect 1 of the present invention is a method for producing a compound represented by the following formula (VI): A step A of treating a compound represented by the following formula (II) and a compound represented by the following formula (IV) with a second reducing agent, and then treating them with a condensing agent to obtain a compound represented by the following formula (V); Step B: treating a compound represented by the following formula (V) with an organotin compound to convert it into a compound represented by the following formula (VI); [wherein in the above formulae (II), (IV), (V), and (VI), R １ is a halogen group, alkyl group, -CN, -N ３ , or -NO ２ and n is R １ Z is an integer of 1 to 4 representing the number of １ -C ４ is a hydrocarbyl group, X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms, Q is a halogen group, -Li, -CH=O, -N=NH, or -NH ２ and R ２ is a group derived from the organotin compound.

[0068] The production method according to Aspect 2 of the present invention may be a method according to Aspect 1 described above, which includes a step C of treating the compound represented by formula (I) in a lower alcohol with an acylating agent under acidic conditions to obtain the compound represented by formula (II). [In the above formula (I), R １ is a halogen group, alkyl group, -CN, -N ３ , or -NO ２ It is.]

[0069] The production method according to Aspect 3 of the present invention may be a method according to Aspect 1 or 2, which includes a step D of reducing a compound represented by formula (III) with a first reducing agent to obtain a compound represented by formula (IV). [In the above formula (III), X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms.]

[0070] The production method according to Aspect 4 of the present invention is the same as that according to any one of Aspects 1 to 3, wherein R ２ is -Sn(C １ H ３ ) ３ , -Sn(C ２ H ５ ) ３ , -Sn(C ３ H ７ ) ３ , -Sn(C ４ H ９ ) ３ , -Sn(C ５ H １１ ) ３ , -Sn(C ６ H １３ ) ３ , or -Sn(C ７ H １５ ) ３ The method may be:

[0071] The production method according to Aspect 5 of the present invention is the same as that according to any one of Aspects 1 to 4, wherein R ２ is -Sn(n-C ４ H ９ ) ３ The method may be:

[0072] The production method according to Aspect 6 of the present invention is the same as that according to any one of Aspects 1 to 5, except that in the above formulae (I) to (VI), R １ is -F, n is 3, and Z is C １ -C ４ X is a group consisting of a linear carbon chain having 1 or 2 carbon atoms; Q is -I; and m is 1.

[0073] A production method according to Aspect 7 of the present invention may be a method in which, in any one of Aspects 1 to 6 described above, in Step A, the second reducing agent is sodium cyanoborohydride or lithium aluminum hydride, the condensing agent is sodium methoxide, sodium ethoxide, sodium butoxide, or potassium t-butoxide, and Step A is carried out in the presence of a base at a temperature of −10° C. or higher and 25° C. or lower.

[0074] A production method according to an eighth aspect of the present invention is the method according to any one of the first to seventh aspects, wherein the step B is carried out in the presence of a first catalyst, and the catalyst is Pd(t-Bu ３ P) ２ , or Pd(PPh ３ ) ４ The method may be:

[0075] A method according to a ninth aspect of the present invention may be a method according to the second aspect, wherein in the step C, the lower alcohol is ethanol or methanol, and the acylating agent is thionyl chloride or oxalyl chloride.

[0076] A production method according to Aspect 10 of the present invention may be a method in which, in the above-mentioned Aspect 3, in Step D, the first reducing agent is isobutylaluminum hydride or lithium aluminum hydride, and Step D is carried out at a temperature of −60° C. or lower.

[0077] A production method according to an eleventh aspect of the present invention is a production method for a compound represented by formula (VII) in any one of the above-mentioned aspects 1 to 10, comprising the steps of: １１ CH ３and a step E of treating the compound I with a catalyst composition comprising a second catalyst, a phosphine ligand, and a copper halide to convert the compound I to a compound of formula (VII).

[0078] A twelfth aspect of the present invention is a production method according to the eleventh aspect, wherein the catalyst composition contains a carbonate.

[0079] An embodiment of the present invention will now be described.

[0080] In Example 1, Sn-UCB-J was synthesized according to the following synthesis scheme. Here, Sn-UCB-J is an example of the above-mentioned compound (IV). Hereinafter, steps 1 to 4 correspond to the above-mentioned steps C, D, A, and B, respectively.

[0081]

[0082] (Step 1) Under an argon atmosphere, anhydrous ethanol (89 mL) was added to compound 1 (4.0 g, 18.59 mmol), and the mixture was ice-cooled and stirred for 1 hour while bubbling hydrogen chloride gas. After bubbling was stopped, the mixture was refluxed for 20 hours. Since raw materials remained, the reaction mixture was ice-cooled and stirred again for 30 minutes while bubbling hydrogen chloride gas. After bubbling was stopped, the mixture was refluxed for 6 hours. After ice-cooling the reaction mixture, thionyl chloride (13.6 mL, 186 mmol) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, azeotroped twice with ethanol (20 mL), and dried to obtain compound 2 (5.1 g, 92% yield) as a brown oil.

[0083] Step 1 is shown in the diagram below.

[0084]

[0085] (Step 2) Under an argon atmosphere, compound 3 (3.0 g, 11.4 mmol) was dissolved in dehydrated toluene (54 mL) and cooled to an external temperature of -80°C. Diisobutylaluminum hydride (1 M in toluene, 20.5 mL, 20.5 mol) was added dropwise over 2 hours, and the mixture was stirred at that temperature for 30 minutes. Methanol (60 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled, and 5N hydrochloric acid (22.8 mL) was added dropwise, followed by stirring at room temperature for 15 minutes.

[0086] A saturated aqueous solution of potassium carbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The aqueous layer was subjected to suction filtration to remove insoluble matter, and the filtrate was extracted with ethyl acetate (50 mL). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (SiO ２ The crude product was purified with a solvent (hexane / ethyl acetate = 70 / 30 to 50 / 50) to give compound 4 (1.98 g, 75% yield) as a pale yellow solid.

[0087]

[0088] (Step 3) Under an argon atmosphere, anhydrous ethanol (38.1 mL) was added to compound 2 (2.56 g, 8.58 mmol) and compound 4 (2.0 g, 8.58 mmol), and triethylamine (1.8 mL, 12.9 mmol) was added over 5 minutes, followed by stirring at room temperature for 2 hours. The reaction solution was ice-cooled, and sodium cyanoborohydride (0.66 g, 10.5 mmol) was added in two portions every 30 minutes, followed by stirring at room temperature for 1 hour. The mixture was ice-cooled again, and sodium methoxide (1.16 g, 21.5 mmol) dissolved in anhydrous ethanol (8.6 mL) was added, followed by stirring at the same temperature for 2 hours.

[0089] The reaction mixture was returned to room temperature, saturated aqueous ammonium chloride solution (40 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 2). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The extract was purified by silica gel column chromatography (SiO ２The mixture was purified with a solvent mixture containing 100 ml of hexane / ethyl acetate / triethylamine (70 / 30 / 0.5 to 30 / 70 / 0.5) to give compound 5 (2.39 g, 64% yield) as a yellow oil.

[0090]

[0091] (Step 4) Under argon atmosphere, compound 5 (0.2 g, 0.463 mmol), Pd(t-Bu ３ P) ２ To the resulting solution (0.01 g, 0.023 mmol), dehydrated N,N-dimethylformamide (3.58 mL) and bis(tributyltin) (0.702 mL, 1.39 mmol) were added, and the mixture was stirred at 100° C. for 3 hours.

[0092] The reaction mixture was returned to room temperature, added to water (5 mL), and extracted with ethyl acetate (20 mL) and heptane (10 mL). The organic layer was washed with water (20 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column chromatography (SiO ２ The residue was purified with a solvent (hexane / ethyl acetate = 90 / 10 to 50 / 50) to give (R)-Sn-UCB-J (0.156 g, 56% yield) as a pale purple oil.

[0093]

[0094] (Measurement) The obtained Sn-UCB-J and a racemic mixture of Sn-UCB-J prepared for comparison were subjected to HPLC analysis under the following conditions.

[0095] Equipment used: Shimadz LC-2010A Column: CHIRALPAC IC, 150×4.6 mm, S-3 μm Mobile phase: hexane / 2-propanol = 50 / 50 Flow rate: 1.0 ml / min Detection: 254 nm Column temperature: 40 °C

[0096] Figure 1(a) shows the results of measuring Sn-UCB-J produced by the method of Example 1, and Figure 1(b) shows the results of measuring the comparative racemate. As a result of subjecting the compound produced by the method of Example 1 to measurement, only one peak was detected at a retention time of approximately 5.6 to 6.6 seconds, and the peak at a retention time of approximately 7.4 to 8.6 seconds that was detected in the racemate of Sn-UCB-J prepared for comparison was not detected. Therefore, it was confirmed that the compound produced by the method of Example 1 was (R)-Sn-UCB-J.

[0097] [Example 2] In Example 2, the compound was synthesized according to the following synthesis scheme. １１ C-UCB-J was synthesized, where: １１ C-UCB-J is an example of the above-mentioned compound (IV). The outline of the procedure shown below is shown in Figure 2. The following step corresponds to the above-mentioned step E.

[0098]

[0099] In a V vial, CsF (2.3 mg), CuCl (1.6 mg), Pd ２ (dba) ３ (1.3 mg), each in a separate sample tube (o-tol) ３ P (1.6 mg, A) and Sn-UCB-J (2.2 mg, B) were weighed out and placed under a nitrogen atmosphere.

[0100] Anhydrous DMF (150 μL) was added to A (o-tol) ３ P was dissolved and added to a V vial and stirred at room temperature for 3 to 5 minutes. Sn-UCB-J(B) dissolved in anhydrous DMF (100 μL) was then added to the V vial (reaction mixture) and stirred at room temperature for 1 minute. This prepared raw material mixture was transferred to a reaction vessel. １１ CH ３ I was collected at low temperature and reacted at 80°C for 5 minutes. Then, HPLC solvent was added to stop the reaction. Purification was performed using Radio-HPLC, and fractions with a retention time of approximately 8 minutes were collected. The collected fractions were concentrated and redissolved in saline (3-10 mL) and a mixture (200-300 μL) of aqueous sodium ascorbate and Tween 80 (85:15). １１C-UCB-J was obtained with a total process time of 30 minutes, a radiochemical yield (EOB) of 39±6% (end of synthesis, n = >20), and a radiochemical purity of 99% or more.

[0101] (Measurement) Obtained １１ C-UCB-J was subjected to HPLC analysis under the following conditions.

[0102] Measurement condition 1: Equipment used: JASCO PU-2080 Plus, UV-970 (detection: UV-254 nm) Column: CAPCELL PAK C18 UG80 (10 x 250 mm) Mobile phase: CH3CN-50 mM ammonium acetate = 45-55 Flow rate: 5.0 mL / min

[0103] Measurement conditions 2 Equipment used: JASCO PU-2089 Plus, UV-2075 (detection: UV-254 nm) Column: CHIRALPAK AS-RH (4.6×150 mm) Mobile phase: CH3CN-H2O=40-60 Flow rate: 1.0 mL / min

[0104] Measurement condition 3: Equipment: JASCO PU-2089 Plus, UV-2075 (detection: UV-254 nm) Column: CAPCELL PAK C18 UG80 (4.6 x 250 mm) Mobile phase: CH3CN-50 mM ammonium acetate = 45-55 Flow rate: 1.0 mL / min

[0105] According to measurement condition 1 １１ The separation chart of C-UCB-J is shown in Figure 3. １１ The analytical chart (chiral) of C-UCB-J is shown in Figure 4. １１ The analytical chart of C-UCB-J is shown in Figure 5. The radiochemical yield (EOB) of the production method according to Example 2 was 39±6%.

[0106] [Example 3] In Example 3, according to the following synthesis scheme １１ C-UCB-J was synthesized, where: １１C-UCB-J is an example of the above-mentioned compound (IV). The outline of the procedure shown below is shown in Figure 6. The following step corresponds to the above-mentioned step E.

[0107]

[0108] V vial with K ２ CO ３ (1.1mg), CuCl (0.9mg), Pd ２ (dba) ３ (2.0mg), (o-tol) ３ P (2.7 mg) and Sn-UCB-J (2 mg) were weighed into a separate sample tube, and the tube was placed under a nitrogen atmosphere.

[0109] One to two minutes before the end of irradiation, Sn-UCB-J dissolved in anhydrous DMF (300 μL) was added to the V vial (reaction mixture) and stirred at room temperature for about 30 seconds. This prepared raw material mixture was transferred to a reaction vessel. １１ CH ３ I was collected at low temperature and reacted at 80°C for 5 minutes. １１ CH ３ After about 10 minutes (until capture), HPLC solvent was added to stop the reaction. Purification was performed using Radio-HPLC, and fractions with a retention time of approximately 8 minutes were collected. The collected fractions were concentrated and redissolved in physiological saline (3-10 mL) and a mixture (200-300 μL) of aqueous sodium ascorbate and Tween 80 (85:15). １１ C-UCB-J was obtained. The total process time was 35 minutes, the radiochemical yield (EOB) was 56±10% (at the end of synthesis, n=3), and the radiochemical purity was 99% or more.

[0110] The synthesized compounds were measured in the same manner as in Example 2. The measurement results are shown in Figures 7 to 9. １１ The radiochemical yield (EOB) of C-UCB-J was 56±15%. Furthermore, the production method of Example 3 enabled the preparation of the catalyst composition in a single step. Furthermore, the reaction time after adding the raw materials to the catalyst composition was approximately 30 seconds at room temperature, shortening the process.

[0111] Comparative Example 1 In Comparative Example 1, a compound was synthesized according to the following synthesis scheme:１１ C-UCB-J was synthesized.

[0112]

[0113] BF ３ The synthesis was carried out using -Dm-UCB-J as an intermediate and the same catalyst composition as in Example 3. １１ The EOB yield of C-UCB-J was below 10%.

[0114] The present invention can be used to provide a PET probe.

Claims

1. A method for producing a compound represented by the following formula (VI): A step A of treating a compound represented by the following formula (II) and a compound represented by the following formula (IV) with a second reducing agent, and then treating them with a condensing agent to obtain a compound represented by the following formula (V); Step B: treating a compound represented by the following formula (V) with an organotin compound to convert it into a compound represented by the following formula (VI); [wherein R １ is a halogen group, alkyl group, -CN, -N ３ , or -NO ２ and n is R １ Z is an integer of 1 to 4 representing the number of １ -C ４ is a hydrocarbyl group, X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms, Q is a halogen group, -Li, -CH=O, -N=NH, or -NH ２ and R ２ is a group derived from the organotin compound.

2. The process according to claim 1, comprising step C of treating the compound of formula (I) in a lower alcohol with an acylating agent under acidic conditions to obtain the compound of formula (II). [In the above formula (I), R １ is a halogen group, alkyl group, -CN, -N ３ , or -NO ２ It is.] 3. The method according to claim 2, comprising a step D of reducing the compound represented by formula (III) with a first reducing agent to obtain the compound represented by formula (IV). [In the above formula (III), X is a group consisting of a linear carbon chain having 1 to 4 carbon atoms.] 4. In the above formula (VI), R ２ is -Sn(C １ H ３ ) ３ , -Sn(C ２ H ５ ) ３ , -Sn(C ３ H ７ ) ３ , -Sn(C ４ H ９ ) ３ , -Sn(C ５ H １１ ) ３ , -Sn(C ６ H １３ ) ３ , or -Sn(C ７ H １５ ) ３ The method according to claim 1, wherein 5. In the above formula (VI), R ２ is -Sn(n-C ４ H ９ ) ３ The method according to claim 1, wherein 6. In the above formulas (I) to (VI), R １ is -F, n is 3, and Z is C １ -C ４ The method according to claim 3 , wherein X is an alkyl group, X is a group consisting of a linear carbon chain having 1 or 2 carbon atoms, Q is -I, and m is 1.

7. The method according to claim 1, wherein in step A, the second reducing agent is sodium cyanoborohydride or lithium aluminum hydride, the condensing agent is sodium methoxide, sodium ethoxide, sodium butoxide or potassium t-butoxide, and step A is carried out in the presence of a base at a temperature of -10°C or higher and 25°C or lower.

8. Step B is carried out in the presence of a first catalyst, the catalyst being Pd(t-Bu ３ P) ２ , or Pd(PPh ３ ) ４ The method according to claim 1, wherein 9. The method according to claim 2, wherein in step C, the lower alcohol is ethanol or methanol, and the acylating agent is thionyl chloride or oxalyl chloride.

10. The method according to claim 3, wherein in step D, the first reducing agent is isobutylaluminum hydride or lithium aluminum hydride, and step D is carried out at a temperature of -60°C or lower.

11. A method for producing a compound represented by formula (VII), comprising: １１ CH ３ and step E of treating I with a catalyst composition comprising a second catalyst, a phosphine ligand, and a copper halide to convert I to a compound of formula (VII).

12. The method of claim 11, wherein the catalyst composition further comprises a carbonate salt.

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