Fluorine-containing compounds and contrast agents

Abstract

Provided is a fluorine-containing compound represented by formula (1) (in formula (1), R1, R2, R3, and R4 represent a C1-10 alkyl group that is unsubstituted or substituted by a fluorine-atom-free substituent. X is any of formulas (2-1), (2-2), and (2-3).)

Description

[Technical Field]

[0001] The present invention relates to a fluorine-containing compound and a contrast agent. This application claims priority based on Japanese Patent Application No. 2021-043725 filed in Japan on March 17, 2021, and Japanese Patent Application No. 2021-177507 filed in Japan on October 29, 2021, the contents of which are incorporated herein by reference. [Background technology]

[0002] Magnetic resonance imaging (hereinafter sometimes referred to as "MRI") diagnosis is one of the imaging diagnostic methods, along with X-ray diagnosis and ultrasound (US) diagnosis, and is widely used in the medical field in both basic research and clinical applications.

[0003] Currently, medical MRI uses proton ( 1 H) is used as the detection nucleus. 1 H-MRI is used. 1 H-MRI captures and images the magnetic environment of water molecules present in the body. There is a difference in the magnetic environment of protons between diseased tissue and normal tissue in the body. This is 1 This appears as a difference in H-MRI and provides diagnostic information. Water molecules are present almost everywhere in the body. 1 H-MRI can be used for whole-body imaging.

[0004] Nuclides that can be detected by MRI include: 1 In addition to H, 19 F, 23 Na, 31 P, 15 N, 13 C, etc. In MRI, which uses these elements as detection nuclei, 1 It provides different information than H-MRI. Among these, the detection nuclei are 19 MRI using F 1 It is expected to be used in the next generation of diagnostic methods following H-MRI diagnosis. Fluorine is an inexpensive element with a natural abundance of 100%, 19The detection sensitivity of F 1 High at 83% of H. 19 Since the gyromagnetic ratio of F is close to that of the proton, 1 This is because it can be imaged using an H-MRI device.

[0005] Also, MRI detectable 19 F is hardly present in the body. Therefore, by using a compound containing a fluorine atom as a contrast agent, 19 F was used as a tracer 19 F-MRI diagnosis is possible. For example, by using a fluorine compound as a contrast agent that recognizes and accumulates in the tissue due to disease, 19 F-MRI provides location information of the lesion, which is useful for diagnosing lesions that do not cause morphological changes and cannot be detected by conventional imaging diagnostic methods.

[0006] Currently, nuclear medicine techniques are used to obtain imaging information specific to lesions. Nuclear medicine techniques use radiopharmaceuticals that utilize radioisotopes. Specifically, nuclear medicine techniques include Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). However, nuclear medicine techniques have problems such as the large scale equipment required to synthesize radioisotopes and the risk of radiation exposure.

[0007] 19 F-MRI diagnosis does not have the above problems that occur with nuclear medicine techniques. 19 In F-MRI diagnosis, by extracting information such as chemical shift, diffusion, and relaxation time, not only the location of the lesion but also many other diagnostic information can be obtained. 19 F-MRI and 1 By simultaneously capturing 1H-MRI images and superimposing the images, it is possible to obtain useful diagnostic information that combines anatomical and functional information.

[0008] Contrast agents for MRI diagnosis that use fluorine as a detection nucleus include those described in Patent Documents 1 and 2, for example. Patent Document 1 describes polylactic acid-co-glycolic acid (PLGA) particles containing perfluorocrown ether and a gadolinium complex, while Patent Document 2 describes a fluorine-containing porphyrin complex and a contrast agent compound that can be used in MRI using fluorine as a detection nucleus. However, the contrast agents described in Patent Documents 1 and 2 contain metal ions, which raises concerns about their safety in vivo.

[0009] Furthermore, Patent Document 3 describes a compound having a nitroxide covalently bonded to a fluorine-containing compound. However, the fluorine-containing compound described in Patent Document 3 is easily reduced by a reducing agent such as ascorbic acid (see, for example, Non-Patent Document 1), and therefore has a problem with stability in vivo. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Japan Special Publication No. 2015-534549 (A) [Patent Document 2] Japanese Patent Application Publication No. 11-217385 (A) [Patent Document 3] US Patent No. 5362477 (B) [Non-patent literature]

[0011] [Non-Patent Document 1] ACS Central Science,2017,3,800-811. Summary of the Invention [Problem to be solved by the invention]

[0012] Conventional MRI contrast agents that use fluorine as a detection nucleus were not able to provide highly sensitive MRI images and were not stable in vivo. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a fluorine-containing compound that can be used as a material for a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, thereby providing highly sensitive magnetic resonance images and having high stability in vivo. Another object of the present invention is to provide a contrast agent for magnetic resonance imaging diagnosis that contains the fluorine-containing compound of the present invention, has high stability in vivo, and can provide highly sensitive images, and uses fluorine as a detection nucleus. [Means for solving the problem]

[0013] [1] A fluorine-containing compound represented by the following general formula (1):

[0014] [ka] (In general formula (1), R 1 , R 2 , R 3 , R 4 are each independently an alkyl group having 1 to 10 carbon atoms, which is unsubstituted or substituted with a substituent not containing a fluorine atom. X is a substituent represented by any one of general formulas (2-1), (2-2), and (2-3). (In the general formula (2-1), L 1 is either a chain hydrocarbon group having 1 to 16 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom, or a linking group containing an aryl group having 6 to 12 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom. m is an integer of 1 to 5. (In the general formula (2-2), L 3 is either a chain hydrocarbon group having 1 to 16 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom, or a linking group containing an aryl group having 6 to 12 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom. p is an integer of 1 to 5. (In the general formula (2-3), L 4is either a chain hydrocarbon group having 1 to 16 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom, or a linking group containing an aryl group having 6 to 12 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom. q is an integer of 1 to 5.

[0015] [2] R in the general formula (1) 1 , R 2 , R 3 , R 4 and each independently represent an alkyl group having 1 to 5 carbon atoms which is unsubstituted or substituted with a substituent not containing a fluorine atom. [3] L in general formula (2-1) 1 , L in general formula (2-2) 3 , L in general formula (2-3) 4 is a chain hydrocarbon group having 1 to 10 carbon atoms which is unsubstituted or substituted with a substituent not containing a fluorine atom. [4] L in general formula (2-1) 1 , L in general formula (2-2) 3 , L in general formula (2-3) 4 is a linking group containing a phenyl group.

[0016] [5] The fluorine-containing compound according to any one of [1] to [4], wherein m in the general formula (2-1) is an integer of 1 to 3, p in the general formula (2-2) and q in the general formula (2-3) are each 1 or 2.

[0017] [6] The fluorine-containing compound according to any one of [1] to [5], which is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus.

[0018] [7] A contrast agent for magnetic resonance imaging using fluorine as a detection nucleus. A contrast agent containing the fluorine-containing compound according to any one of [1] to [6]. [Effects of the Invention]

[0019] The fluorine-containing compound of the present invention is a compound represented by the above general formula (1). Therefore, it has high stability in vivo. Furthermore, when the fluorine-containing compound of the present invention is used as a material for a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, highly sensitive magnetic resonance images can be obtained. The contrast agent of the present invention contains the fluorine-containing compound of the present invention. Therefore, the contrast agent of the present invention has high stability in vivo. Furthermore, when the contrast agent of the present invention is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, highly sensitive magnetic resonance images can be obtained. [Brief explanation of the drawings]

[0020] [Figure 1] 19F-MRI 19F spin-lattice relaxation time (T1) weighted image of Example 1 (Compound 11). [Figure 2] 19F-MRI 19F spin-lattice relaxation time (T1) weighted image of Comparative Example 1 (Compound A1). DETAILED DESCRIPTION OF THE INVENTION

[0021] The fluorine-containing compound and contrast agent of the present invention will be described in detail below. [Fluorine-containing compounds] The fluorine-containing compound of the present embodiment is represented by the following general formula (1).

[0022] [ka] (In general formula (1), R 1 , R 2 , R 3 , R 4 are each independently an alkyl group having 1 to 10 carbon atoms, which is unsubstituted or substituted with a substituent not containing a fluorine atom. X is a substituent represented by any one of general formulas (2-1), (2-2), and (2-3). (In the general formula (2-1), L 1is either a chain hydrocarbon group having 1 to 16 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom, or a linking group containing an aryl group having 6 to 12 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom. m is an integer of 1 to 5. (In the general formula (2-2), L 3 is either a chain hydrocarbon group having 1 to 16 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom, or a linking group containing an aryl group having 6 to 12 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom. p is an integer of 1 to 5. (In the general formula (2-3), L 4 is either a chain hydrocarbon group having 1 to 16 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom, or a linking group containing an aryl group having 6 to 12 carbon atoms which is substituted or unsubstituted with a substituent not containing a fluorine atom. q is an integer of 1 to 5.

[0023] Here, the reason why a contrast agent containing the fluorine-containing compound of this embodiment is highly stable in vivo and can provide highly sensitive magnetic resonance images (MRI) when used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus will be explained.

[0024] High sensitivity 19 In order to obtain F-MRI, the fluorine-containing compounds contained in the contrast agent are 19 It is preferable to use a compound having a short F spin-lattice relaxation time (T1). The shorter the T1 of the fluorine-containing compound, the shorter the repetition time can be set. This is because the amount of signal obtained per unit time increases, and a highly sensitive image can be obtained. On the other hand, 19 If the F spin-spin relaxation time (T2) is too short, the signal intensity will decrease.

[0025] Fluorine-containing compounds 19 F spin-lattice relaxation time (T1) and 19The F spin-spin relaxation time (T2) is affected by the paramagnetic relaxation enhancement (PRE) effect, which is a phenomenon in which the unpaired electron spins of a paramagnetic material shorten the T1 and T2 of MRI observation nuclei near the unpaired electron spins.

[0026] The PRE effect is inversely proportional to the sixth power of the distance between the paramagnetic substance and the MRI observation nucleus (in this embodiment, a fluorine atom) that relaxes to the paramagnetic substance. Therefore, in the fluorine-containing compound represented by formula (1) of this embodiment, the shorter the distance between the nitroxide radical, which is a paramagnetic substance, and the fluorine atom, the shorter T1 and T2 become. In the fluorine-containing compound represented by formula (1), a substituent having a fluorine atom attached to its terminal (X in formula (1)) is bonded to the carbon at the 4-position of the piperidine ring via an oxygen atom. Therefore, the distance between the nitroxide radical and the fluorine atom is appropriate, and T1 is sufficiently short and T2 can be sufficiently ensured. Therefore, by using the fluorine-containing compound represented by formula (1) as a contrast agent for MRI diagnosis using fluorine as the detection nucleus, highly sensitive magnetic resonance images can be obtained.

[0027] Furthermore, unlike closed-shell species, organic radicals have a half-occupied molecular orbital (SOMO) with an unpaired electron between their highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The oxidation-reduction process of organic radicals corresponds to the process of electron transfer at the SOMO. The reduction reaction of organic radicals by reducing agents such as ascorbic acid is more likely to occur when the energy difference between the HOMO of the reducing agent and the SOMO of the organic radical is smaller. Therefore, the lower the energy level of the SOMO of an organic radical, the more easily it is reduced.

[0028] In the fluorine-containing compound represented by formula (1) of this embodiment, three carbon atoms are located between the nitrogen atom of the piperidine ring and the substituent represented by X in formula (1), and two or more carbon atoms are located between the oxygen atom bonded to the substituent represented by X and the fluorine atom. As a result, in the fluorine-containing compound represented by formula (1), the nitroxide radical and the fluorine atom are located at positions sufficiently distant from each other, making the nitroxide radical less susceptible to electronic influence from the fluorine atom. Therefore, in the fluorine-containing compound represented by formula (1), there is no decrease in the energy level of the SOMO of the nitroxide radical due to the fluorine atom, which is an electron-withdrawing group. Therefore, the SOMO of the nitroxide radical in the fluorine-containing compound of this embodiment has a sufficiently large energy difference from the HOMO of a reducing agent such as ascorbic acid. Therefore, the fluorine-containing compound represented by formula (1) is less likely to be reduced in vivo and is highly stable in vivo.

[0029] Furthermore, the fluorine-containing compound of this embodiment represented by formula (1) is a non-metallic compound that does not contain metals, and therefore is safer in vivo than contrast agents containing metal ions. Therefore, the fluorine-containing compound of this embodiment is suitable as a material for contrast agents for magnetic resonance imaging diagnosis that use fluorine as a detection nucleus. Furthermore, the fluorine-containing compound represented by formula (1) of this embodiment is a compound having a piperidine ring and has a structure similar to 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPOL), which is highly safe in vivo. Therefore, the fluorine-containing compound represented by formula (1) of this embodiment is presumed to be more stable in vivo than, for example, fluorine-containing compounds having a pyrrolidine ring.

[0030] In the fluorine-containing compound represented by formula (1) of this embodiment, R 1 , R 2 , R 3 , R 4are each independently an alkyl group having 1 to 10 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom, and preferably an alkyl group having 1 to 5 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom. 1 , R 2 , R 3 , R 4 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, the synthesis of the fluorine-containing compound represented by formula (1) is easy. 1 , R 2 , R 3 , R 4 When is a substituted or unsubstituted alkyl group having 2 to 10 carbon atoms, the alkyl group becomes suitably bulky and can prevent a reducing agent from approaching the nitroxide radical. When the alkyl group has 5 or less carbon atoms, the synthesis of the fluorine-containing compound represented by formula (1) becomes easier, which is preferable.

[0031] R contained in the fluorine-containing compound represented by formula (1) 1 , R 2 , R 3 , R 4 When has a substituent that does not contain a fluorine atom, the substituent can be, for example, a methyl group or an ethyl group. R in the fluorine-containing compound represented by formula (1) of this embodiment 1 , R 2 , R 3 , R 4 Specifically, is preferably a methyl group or an ethyl group, and is more preferably a methyl group because of ease of synthesis.

[0032] In the fluorine-containing compound represented by formula (1) of this embodiment, X is a substituent represented by any one of formulas (2-1), (2-2), and (2-3). Therefore, the fluorine-containing compound represented by formula (1) has an appropriate distance between the nitroxide radical and the fluorine atom, and T1 is sufficiently short and T2 is sufficiently ensured. Therefore, by using the fluorine-containing compound represented by formula (1) as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, highly sensitive images can be obtained. Furthermore, because the distance between the nitroxide radical and the fluorine atom is appropriate, the nitroxide radical is less susceptible to electronic influence from the fluorine atom. Moreover, because the substituents represented by formulas (2-1), (2-2), and (2-3) are all bulky, the approach of a reducing agent to the nitroxide radical is sterically shielded and prevented. Therefore, the fluorine-containing compound represented by formula (1) is less likely to be reduced in vivo and is highly stable in vivo.

[0033] In the substituent represented by formula (2-1) contained in the fluorine-containing compound represented by formula (1), L 1 is either a chain hydrocarbon group having 1 to 16 carbon atoms which is unsubstituted or substituted with a substituent that does not contain a fluorine atom, or a linking group which contains an aryl group having 6 to 12 carbon atoms which is unsubstituted or substituted with a substituent that does not contain a fluorine atom. L 1 When L is a chain hydrocarbon group having 1 to 16 carbon atoms that is unsubstituted or substituted with a substituent that does not contain a fluorine atom, the distance between the nitroxide radical and the fluorine atom is appropriate. 1 is a chain hydrocarbon group having 1 to 16 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom, it is preferably a chain hydrocarbon group having 1 to 10 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom, and more preferably a chain hydrocarbon group having 1 to 5 carbon atoms. When the chain hydrocarbon group has 16 or fewer carbon atoms, the distance between the nitroxide radical and the fluorine atom does not become too great, and T1 becomes sufficiently short. When the chain hydrocarbon group has 10 or fewer carbon atoms, T1 becomes even shorter, which is preferable.

[0034] L 1When the chain hydrocarbon group having 1 to 16 carbon atoms, which is substituted or unsubstituted with a substituent not containing a fluorine atom and represented by the formula (I) has a substituent, the substituent not containing a fluorine atom can be, for example, a methyl group, an ethyl group, or a phenyl group. L 1 When is a chain hydrocarbon group having 1 to 16 carbon atoms, substituted or unsubstituted with a substituent not containing a fluorine atom, it is more preferably any one selected from -CH2-, -(CH2)2-, -(CH2)3-, and -(CH2)4-, and particularly preferably any one selected from -(CH2)2-, -(CH2)3-, and -(CH2)4-. In this case, the distance between the nitroxide radical and the fluorine atom becomes more suitable. As a result, the nitroxide radical is less susceptible to electronic influence from the fluorine atom, resulting in a fluorine-containing compound with higher in vivo stability. Furthermore, since this fluorine-containing compound has a shorter T1, when used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, it can provide images with higher sensitivity.

[0035] L 1 When L is a linking group containing an aryl group having 6 to 12 carbon atoms, which is substituted or unsubstituted with a substituent that does not contain a fluorine atom, the distance between the nitroxide radical and the fluorine atom becomes appropriate. 1 When L is a linking group containing an aryl group having 6 to 12 carbon atoms, which is substituted or unsubstituted with a substituent that does not contain a fluorine atom, it is preferably a linking group containing a phenyl group. When the aryl group has 12 or less carbon atoms, the distance between the nitroxide radical and the fluorine atom does not become too large, and T1 becomes sufficiently short. 1 When is a linking group containing a phenyl group, the synthesis of the fluorine-containing compound represented by formula (1) becomes easy, which is preferable.

[0036] L 1 When the linking group containing an aryl group having 6 to 12 carbon atoms, which is substituted or unsubstituted with a substituent not containing a fluorine atom, represented by the formula (I) has a substituent, the substituent not containing a fluorine atom can be, for example, a p-phenylene group, an m-phenylene group, an o-phenylene group, a biphenylene group, or a benzylene group. L1 When L is a linking group containing an aryl group having 6 to 12 carbon atoms, which is substituted or unsubstituted with a substituent not containing a fluorine atom, it is preferably any one selected from a p-phenylene group, an m-phenylene group, and an o-phenylene group. In this case, the distance between the nitroxide radical and the fluorine atom becomes more suitable, and L 1 becomes bulky. As a result, the nitroxide radical is less susceptible to electronic influence from fluorine atoms, resulting in a fluorine-containing compound with higher stability in vivo. Furthermore, since this fluorine-containing compound has a sufficiently short T1, when used as an MRI contrast agent using fluorine as a detection nucleus, images with higher sensitivity can be obtained.

[0037] In the substituent represented by formula (2-1) contained in the fluorine-containing compound represented by formula (1), m is an integer of 1-5. In the substituent represented by formula (2-1), L 1 When L is a chain hydrocarbon group having 1 to 16 carbon atoms which is unsubstituted or substituted with a substituent not containing a fluorine atom, m is preferably an integer of 1 to 3. 1 is a chain hydrocarbon group having 1 to 16 carbon atoms, which is substituted or unsubstituted with a substituent not containing a fluorine atom, and m is an integer of 1 to 3, when used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, 19 This allows for high-quality imaging with suppressed chemical shift artifacts. 19 F-MRI is also obtained for fluorine-containing compounds where m is 3, compared with fluorine-containing compounds where m is 1 or 2. 19 This is preferable because it has a large number of fluorine atoms that show F-MRI peaks and can provide strong signal intensity.

[0038] L 1 When L is a linking group containing an aryl group having 6 to 12 carbon atoms which is substituted or unsubstituted with a substituent that does not contain a fluorine atom, m is an integer of 1 to 5, and is preferably 1 or 2. 1is a linking group containing an aryl group having 6 to 12 carbon atoms, which is substituted or unsubstituted with a substituent not containing a fluorine atom, and m is 1 or 2, when used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, 19 This allows for high-quality imaging with suppressed chemical shift artifacts. 19 F-MRI is also obtained for fluorine-containing compounds where m is 2, compared with fluorine-containing compounds where m is 1. 19 The number of fluorine atoms that show the F-MRI peak is large, resulting in strong signal intensity.

[0039] L in formula (2-2) contained in the fluorine-containing compound represented by formula (1) 3 , L in general formula (2-3) 4 is L in formula (2-1) 1 Similarly, each independently represents either a chain hydrocarbon group having 1 to 16 carbon atoms and being unsubstituted or substituted with a substituent not containing a fluorine atom, or a linking group containing an aryl group having 6 to 12 carbon atoms and being unsubstituted or substituted with a substituent not containing a fluorine atom.

[0040] L in formula (2-2) 3 , L in general formula (2-3) 4 is L in formula (2-1) 1 Similarly, in the case of a chain hydrocarbon group having 1 to 16 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom, the chain hydrocarbon group is preferably a chain hydrocarbon group having 1 to 10 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom, more preferably a chain hydrocarbon group having 1 to 5 carbon atoms, and even more preferably any one selected from -CH2-, -(CH2)2-, -(CH2)3-, and -(CH2)4-. L in formula (2-2) 3 , L in general formula (2-3) 4 is L in formula (2-1) 1Similarly, in the case of a linking group containing an aryl group having 6 to 12 carbon atoms that is unsubstituted or substituted with a substituent that does not contain a fluorine atom, the linking group is preferably a phenyl group, and more preferably any one selected from a p-phenylene group, an m-phenylene group, and an o-phenylene group.

[0041] p in formula (2-2) and q in formula (2-3) contained in the fluorine-containing compound represented by formula (1) each independently represent an integer of 1 to 5, and are preferably 1 or 2 for ease of synthesis, and most preferably 1. When a fluorine-containing compound in which p and q are each independently 1 or 2 is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, a single 19 This allows for high-quality imaging with suppressed chemical shift artifacts. 19 Furthermore, fluorine-containing compounds with p and q equal to 2 have a single F-MRI compared to fluorine-containing compounds with p and q equal to 1. 19 The number of fluorine atoms that show the F-MRI peak is large, resulting in strong signal intensity.

[0042] Specifically, the fluorine-containing compound represented by formula (1) is preferably any one of the fluorine-containing compounds represented by the following formulae (11) to (29).

[0043] [ka]

[0044] [ka]

[0045] [Method of producing fluorine-containing compounds] Next, the method for producing the fluorine-containing compound of the present embodiment represented by formula (1) will be described with reference to an example. The method for producing the fluorine-containing compound of the present embodiment is not particularly limited, and the compound can be produced using a conventionally known production method.

[0046] The fluorine-containing compound of the present embodiment represented by formula (1) can be produced, for example, by the production method shown below. First, the 2- and 6-positions of the piperidine ring are each provided with R 1 , R 2 , R 3 , R 4 A 4-piperidone with a hydroxyl group bonded to the 4-position of the piperidine ring is prepared. This compound is then reacted with di-tert-butyl dicarbonate to bond a tertiary butoxycarbonyl (t-Boc) protecting group to the nitrogen atom of the piperidine ring, forming the first intermediate compound. The first intermediate compound is then reduced using sodium borohydride to form the second intermediate compound with a hydroxyl group bonded to the 4-position of the piperidine ring.

[0047] Next, a compound having a group corresponding to X in the fluorine-containing compound represented by formula (1) is reacted with the second intermediate compound to produce a third intermediate compound in which a group corresponding to X is bonded to the oxygen atom bonded to the 4-position of the piperidine ring. Thereafter, using dichloromethane and trifluoroacetic acid, the tertiary-butoxycarbonyl protecting group is removed from the nitrogen atom forming the piperidine ring of the third intermediate compound, converting it into a nitroxide radical. By the above method, the fluorine-containing compound represented by formula (1) can be obtained.

[0048] "Contrast agent" The contrast agent of this embodiment contains the fluorine-containing compound of this embodiment. The contrast agent of this embodiment is a contrast agent for magnetic resonance imaging diagnosis, which uses fluorine as a detection nucleus. The contrast agent of this embodiment can be produced by formulating the fluorine-containing compound of this embodiment into a form such as a solid formulation, powder formulation, or liquid formulation using a known formulation technique. The contrast agent of the present embodiment may contain, in addition to the fluorine-containing compound of the present embodiment, one or more additives used in known pharmaceutical preparations, such as excipients, stabilizers, surfactants, buffers, and electrolytes, as necessary. Since the contrast agent of the present embodiment contains the fluorine-containing compound of the present invention, it has high stability in vivo. Further, by using the contrast agent of the present embodiment as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, a high-sensitivity magnetic resonance image can be obtained.

[0049] As described above, the embodiments of the present invention have been described in detail. However, each configuration and their combinations in each embodiment are examples, and additions, omissions, substitutions, and other changes of the configuration are possible within the scope not departing from the gist of the present invention.

Example

[0050] 「Example 1」 (Synthesis of Compound 11) (Synthesis of tert-Butyl 2,2,6,6-Tetramethyl-4-oxopiperidine-1-carboxylate (1-1)) 7.762 g (50.0 mmol) of 2,2,6,6-tetramethylpiperidin-4-one was dissolved in 50 ml of tetrahydrofuran (THF) and cooled in an ice bath. A solution of 14.6 ml (105 mmol) of triethylamine (Et3N) and 7.364 g (52.5 mmol) of di-tert-butyl dicarbonate (Boc2O) in 50 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hours to cause a reaction.

[0051] The reaction solution was concentrated under reduced pressure, and hexane was added. After filtering off the obtained solid and washing it with hexane, tert-butyl 2,2,6,6-tetramethyl-4-oxopiperidine-1-carboxylate represented by the following formula (1-1), which is the target product having a tert-butoxycarbonyl group (t-Boc group), a protecting group, bonded to the nitrogen atom of the piperidine ring, was obtained (yield 11.491 g, yield 90%).

[0052] (Synthesis of tert-Butyl 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-carboxylate (1-2)) Under an argon atmosphere, 11.491 g (45.0 mmol) of tert-butyl-2,2,6,6-tetramethyl-4-oxopiperidine-1-carboxylate (1-1) synthesized by the above reaction was dissolved in 30 ml of ethanol (EtOH) and cooled in an ice bath. 0.875 g (23.0 mmol) of sodium borohydride was slowly added, and the mixture was stirred at room temperature for 6 hours to react.

[0053] Saturated brine was added to the reaction solution, which was then extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the target product, tert-butyl-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-carboxylate represented by formula (1-2) (yield: 9.844 g, 85%).

[0054] <Synthesis of compound (1-3)> Under an argon atmosphere, 10 ml of tetrahydrofuran (THF) was added to 2.007 g (46.0 mmol) of 55% sodium hydride and cooled in an ice bath. 50 ml of a tetrahydrofuran solution of 9.844 g (38.3 mmol) of tert-butyl-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-carboxylate (1-2) synthesized by the above reaction was added over 20 minutes, and the mixture was stirred for 30 minutes to allow the reaction to proceed.

[0055] To the reaction solution, 30 ml of a tetrahydrofuran solution of 17.018 g (46.0 mmol) of 1-bromo-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butane was added over 10 minutes, and the mixture was stirred at room temperature for 12 hours to allow the reaction to proceed. Water was added to the reaction solution, and the mixture was extracted with diethyl ether and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 4:1) to obtain the target compound represented by formula (1-3) (yield 10.485 g, 50%).

[0056] Synthesis of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetramethylpiperidine (1-4) 10.485 g (19.2 mmol) of compound (1-3) synthesized by the above reaction was dissolved in 60 ml of dichloromethane, and 11.5 ml (150 mmol) of trifluoroacetic acid (TFA) was added. The mixture was stirred at room temperature for 18 hours to remove the protecting group, tert-butoxycarbonyl. The reaction solution was concentrated under reduced pressure, water was added, and the organic layer was neutralized with aqueous sodium bicarbonate solution. After extraction with diethyl ether, the organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain the target compound, 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetramethylpiperidine represented by formula (1-4) (yield: 7.989 g, 93%).

[0057] Synthesis of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (11) 7.989 g (17.9 mmol) of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetramethylpiperidine (1-4) synthesized by the above reaction, 0.660 g (2.00 mmol) of sodium tungstate dihydrate, and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 15 ml (143 mmol) of 30% hydrogen peroxide solution was slowly added, and the mixture was stirred at room temperature for 24 hours. Potassium carbonate was added to the reaction solution, and the mixture was extracted with chloroform and dried over magnesium sulfate.

[0058] After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound, 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (11) represented by formula (11) (yield: 5.046 g, 61%).

[0059] Mass spectrometry of the obtained compound revealed m / z=462 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (11). Furthermore, the purity of the compound represented by formula (11) was confirmed to be 97.3% by high performance liquid chromatography (HPLC).

[0060] [ka]

[0061] "Example 2" (Synthesis of Compound 12) The target compound represented by formula (12) was synthesized in the same manner as in Example 1, except that 2-(2-bromoethoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane was used instead of 1-bromo-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butane. Mass spectrometry of the obtained compound revealed m / z=434 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (12). Furthermore, the purity of the compound represented by formula (12) was confirmed to be 97.0% by high performance liquid chromatography (HPLC).

[0062] "Example 3" (Synthesis of Compound 13) The target compound represented by formula (13) was synthesized in the same manner as in Example 1, except that 3,3,3-trifluoro-1-iodopropane was used instead of 1-bromo-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butane. Mass spectrometry of the obtained compound revealed m / z=268 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (13). Furthermore, the purity of the compound represented by formula (13) was confirmed to be 96.5% by high performance liquid chromatography (HPLC).

[0063] Example 4 (Synthesis of Compound 14) The target compound represented by formula (14) was synthesized in the same manner as in Example 1, except that 4,4,4-trifluoro-1-iodobutane was used instead of 1-bromo-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butane. Mass spectrometry of the obtained compound revealed m / z=282 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (14). Furthermore, the purity of the compound represented by formula (14) was confirmed to be 96.9% by high performance liquid chromatography (HPLC).

[0064] "Example 5" (Synthesis of Compound 15) <Synthesis of Compound (1-5)> Under an argon atmosphere, 2.572 g (10.0 mmol) of tert-butyl-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-carboxylate (1-2) synthesized by the above reaction, 2.08 mL (15.0 mmol) of nonafluoro-tert-butanol, 3.934 g (15.0 mmol) of triphenylphosphine (PPh), and 40 mL of tetrahydrofuran (THF) were mixed and cooled in an ice bath. 2.92 mL (15.0 mmol) of diisopropyl azodicarboxylate (iPrOCNNCOiPr) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 24 hours to allow the reaction to proceed.

[0065] The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 4:1) to obtain the target compound represented by formula (1-5) (yield: 2.471 g, 52%).

[0066] Synthesis of 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetramethylpiperidine (1-6) 2.471 g (5.20 mmol) of the compound represented by formula (1-5) synthesized by the above reaction was dissolved in 15 ml of dichloromethane, 3.1 ml (40.0 mmol) of trifluoroacetic acid (TFA) was added, and the reaction was stirred at room temperature for 18 hours to remove the protecting group, tert-butoxycarbonyl. The reaction solution was concentrated under reduced pressure, water was added, and the organic layer was neutralized with aqueous sodium bicarbonate solution. After extraction with diethyl ether, the organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain the target product, 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetramethylpiperidine represented by formula (1-6) (yield 1.853 g, 95%).

[0067] Synthesis of 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (15) 1.853 g (4.94 mmol) of 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetramethylpiperidine (1-6) synthesized by the above reaction, 0.165 g (0.50 mmol) of sodium tungstate dihydrate, and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 15 ml (143 mmol) of 30% hydrogen peroxide solution was slowly added, and the mixture was stirred at room temperature for 24 hours to allow the reaction to proceed. Potassium carbonate was added to the reaction solution, and the mixture was extracted with chloroform and dried over magnesium sulfate.

[0068] After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound, 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl represented by formula (15) (yield: 1.118 g, 58%).

[0069] Mass spectrometry of the obtained compound revealed m / z=390 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (15). Furthermore, the purity of the compound represented by formula (15) was confirmed to be 95.6% by high performance liquid chromatography (HPLC).

[0070] [ka]

[0071] "Example 6" (Synthesis of Compound 16) The target compound represented by formula (16) was synthesized in the same manner as in Example 5, except that 1,1,1,3,3,3-hexafluoro-2-propanol was used instead of nonafluoro-tert-butanol. Mass spectrometry of the obtained compound revealed m / z=322 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (16). Furthermore, the purity of the compound represented by formula (16) was confirmed to be 97.5% by high performance liquid chromatography (HPLC).

[0072] "Example 7" (Synthesis of Compound 17) The target compound represented by formula (17) was synthesized in the same manner as in Example 5, except that 2,2,2-trifluoroethanol was used instead of nonafluoro-tert-butanol. Mass spectrometry of the obtained compound revealed m / z=254 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (17). Furthermore, the purity of the compound represented by formula (17) was confirmed to be 96.9% by high performance liquid chromatography (HPLC).

[0073] "Example 8" (Synthesis of Compound 18) The target compound represented by formula (18) was synthesized in the same manner as in Example 5, except that 2-hydroxybenzotrifluoride was used instead of nonafluoro-tert-butanol. Mass spectrometry of the obtained compound revealed m / z=316 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (18). Furthermore, the purity of the compound represented by formula (18) was confirmed to be 95.2% by high performance liquid chromatography (HPLC).

[0074] "Example 9" (Synthesis of Compound 19) The target compound represented by formula (19) was synthesized in the same manner as in Example 5, except that 3-hydroxybenzotrifluoride was used instead of nonafluoro-tert-butanol. Mass spectrometry of the obtained compound revealed m / z=316 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (19). Furthermore, the purity of the compound represented by formula (19) was confirmed to be 95.7% by high performance liquid chromatography (HPLC).

[0075] "Example 10" (Synthesis of Compound 20) The target compound represented by formula (20) was synthesized in the same manner as in Example 5, except that 3,5-bis(trifluoro)phenol was used instead of nonafluoro-tert-butanol. Mass spectrometry of the obtained compound revealed m / z=384 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (20). Furthermore, the purity of the compound represented by formula (20) was confirmed to be 95.0% by high performance liquid chromatography (HPLC).

[0076] "Example 11" (Synthesis of Compound 21) The target compound represented by formula (21) was synthesized in the same manner as in Example 5, except that 4-hydroxybenzotrifluoride was used instead of nonafluoro-tert-butanol. Mass spectrometry of the obtained compound revealed m / z=316 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (21). Furthermore, the purity of the compound represented by formula (21) was confirmed to be 97.0% by high performance liquid chromatography (HPLC).

[0077] "Example 12" (Synthesis of Compound 22) <Synthesis of 1,2,2,6,6 - pentamethyl - 4 - piperidone (1 - 7)> Under an argon stream, 15.524 g (100 mmol) of 2,2,6,6 - tetramethylpiperidin - 4 - one, 23.288 g (150 mmol) of paraformaldehyde, and 100 ml of toluene were mixed and heated to 90 °C. 5.70 ml (150 mmol) of formic acid was added dropwise over 30 minutes, and the mixture was heated at 100 °C for 12 hours to react.

[0078] The reaction solution was cooled to room temperature, 2.000 g (50 mmol) of sodium hydroxide was added, and after stirring for one hour, suction filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained concentrate was subjected to vacuum distillation (70 - 72 °C / 2 mmHg) to obtain 1,2,2,6,6 - pentamethyl - 4 - piperidone represented by formula (1 - 7) as the target product (yield 13.532 g, yield 80%).

[0079] <Synthesis of 2,2,6,6 - tetraethyl - 4 - piperidone (1 - 8)> Under an argon stream, 13.532 g (80.0 mmol) of 1,2,2,6,6 - pentamethyl - 4 - piperidone (1 - 7) synthesized by the above reaction and 25.3 ml (240 mmol) of 3 - pentanone were dissolved in 100 ml of dimethyl sulfoxide (DMSO), and 25.675 g (480 mmol) of ammonium chloride was added over 30 minutes. The reaction mixture was stirred at 60 °C for 5 hours, cooled to room temperature, water was added, and it was neutralized with 1N - hydrochloric acid. After extraction with diethyl ether, the aqueous layer was adjusted to pH 9 with 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain 2,2,6,6 - tetraethyl - 4 - piperidone represented by formula (1 - 8) as the target product (yield 6.758 g, yield 40%).

[0080] <Synthesis of tert - butyl 2,2,6,6 - tetraethyl - 4 - oxopiperidine - 1 - carboxylate (1 - 9)> 6.758 g (32.0 mmol) of 2,2,6,6-tetraethyl-4-piperidone (1-8) synthesized by the above reaction was dissolved in 30 ml of tetrahydrofuran (THF) and cooled in an ice bath. A solution of 9.34 ml (67.2 mmol) of triethylamine (Et3N) and 4.713 g (33.6 mmol) of di-tert-butyl dicarbonate (Boc2O) in 30 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hours to effect the reaction.

[0081] The reaction solution was concentrated under reduced pressure, and hexane was added. The resulting solid was filtered off and washed with hexane to obtain tert-butyl 2,2,6,6-tetraethyl-4-oxopiperidine-1-carboxylate represented by formula (1-9), which is the target product having a tert-butoxycarbonyl group (t-Boc group), a protecting group, bonded to the nitrogen atom of the piperidine ring (yield 7.769 g, yield 78%).

[0082] <Synthesis of tert-butyl 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-carboxylate (1-10)> Under an argon stream, 7.769 g (25.0 mmol) of tert-butyl 2,2,6,6-tetraethyl-4-oxopiperidine-1-carboxylate (1-9) synthesized by the above reaction was dissolved in 15 ml of ethanol (EtOH) and cooled in an ice bath. 0.495 g (13.0 mmol) of sodium borohydride was slowly added, and the mixture was stirred at room temperature for 6 hours to effect the reaction.

[0083] Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. It was concentrated under reduced pressure to obtain tert-butyl 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-carboxylate represented by formula (1-10), which is the target product (yield 6.735 g, yield 86%).

[0084] <Synthesis of compound (1-11)> Under an argon atmosphere, 1.126 g (25.8 mmol) of 55% sodium hydride was added to 10 mL of tetrahydrofuran (THF) and cooled in an ice bath. A 30 mL tetrahydrofuran solution of 6.735 g (21.5 mmol) of tert-butyl-4-hydroxy-2,2,6,6-tetraethylpiperidine-1-carboxylate (1-10) synthesized by the above reaction was added over 20 minutes and stirred for 30 minutes. A 20 mL tetrahydrofuran solution of 9.572 g (25.8 mmol) of 1-bromo-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butane was added over 10 minutes and stirred at room temperature for 12 hours.

[0085] Water was added to the reaction solution, extracted with diethyl ether, and dried over magnesium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 4:1) to obtain the target compound represented by formula (1-11) (yield: 6.070 g, 47%).

[0086] Synthesis of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetraethylpiperidine (1-12) 6.070 g (10.1 mmol) of compound (1-11) synthesized by the above reaction was dissolved in 30 ml of dichloromethane, 5.37 ml (70 mmol) of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 18 hours to react and remove the tert-butoxycarbonyl protecting group.

[0087] The reaction solution was concentrated under reduced pressure, water was added, and the organic layer was neutralized with aqueous sodium bicarbonate solution. After extraction with diethyl ether, the organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain the target compound, 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetraethylpiperidine represented by formula (1-12) (yield: 4.574 g, 90%).

[0088] Synthesis of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (22) 4.574 g (9.09 mmol) of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetraethylpiperidine (1-12) synthesized by the above reaction, 0.330 g (1.00 mmol) of sodium tungstate dihydrate, and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 10 ml (95.3 mmol) of 30% hydrogen peroxide solution was slowly added, and the mixture was stirred at room temperature for 24 hours. Potassium carbonate was added to the reaction solution, and the mixture was extracted with chloroform and dried over magnesium sulfate.

[0089] After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound, 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl represented by formula (22) (yield: 2.968 g, 63%).

[0090] Mass spectrometry of the obtained compound revealed m / z=518 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (22). Furthermore, the purity of the compound represented by formula (22) was confirmed to be 95.4% by high performance liquid chromatography (HPLC).

[0091] [ka]

[0092] "Example 13" (Synthesis of Compound 23) The target compound represented by formula (23) was synthesized in the same manner as in Example 12, except that 2-(2-bromoethoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane was used instead of 1-bromo-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butane. Mass spectrometry of the obtained compound revealed m / z=490 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (23). Furthermore, the purity of the compound represented by formula (23) was confirmed to be 96.6% by high performance liquid chromatography (HPLC).

[0093] "Example 14" (Synthesis of Compound 24) <Synthesis of compound (1-13)> Under an argon atmosphere, 3.133 g (10.0 mmol) of tert-butyl-4-hydroxy-2,2,6,6-tetraethylpiperidine-1-carboxylate (1-10) synthesized by the above reaction, 2.08 mL (15.0 mmol) of nonafluoro-tert-butanol, 3.934 g (15.0 mmol) of triphenylphosphine (PPh), and 40 mL of tetrahydrofuran (THF) were mixed and cooled in an ice bath. 2.92 mL (15.0 mmol) of diisopropyl azodicarboxylate (iPrOCNNCOiPr) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 24 hours.

[0094] The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 4:1) to obtain the target compound represented by formula (1-13) (yield: 2.327 g, 45%).

[0095] Synthesis of 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetraethylpiperidine (1-14) 2.327 g (4.50 mmol) of compound (1-13) synthesized by the above reaction was dissolved in 15 ml of dichloromethane, 3.1 ml (40.0 mmol) of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 18 hours to remove the protecting group, tert-butoxycarbonyl. The reaction solution was concentrated under reduced pressure, water was added, and the organic layer was neutralized with aqueous sodium bicarbonate solution. After extraction with diethyl ether, the organic layer was washed with saturated saline and dried over magnesium sulfate.

[0096] Concentration under reduced pressure gave the target product, 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetraethylpiperidine represented by formula (1-14) (yield 1.746 g, 90%).

[0097] Synthesis of 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (22) 1.746 g (4.05 mmol) of 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetraethylpiperidine (1-14) synthesized by the above reaction, 0.132 g (0.40 mmol) of sodium tungstate dihydrate, and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 15 ml (143 mmol) of 30% hydrogen peroxide solution was slowly added, and the mixture was stirred at room temperature for 24 hours to allow the reaction to proceed. Potassium carbonate was added to the reaction solution, and the mixture was extracted with chloroform and dried over magnesium sulfate.

[0098] After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound, 4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2,6,6-tetraethylpiperidine-1-oxyl represented by formula (22) (yield: 0.891 g, 51%).

[0099] Mass spectrometry of the obtained compound was performed, and a peak was confirmed at m / z = 431 (M + ). From this, it was confirmed that the synthesized compound was the compound represented by formula (24). Also, the purity of the compound represented by formula (24) confirmed by high performance liquid chromatography (HPLC) was 96.2%.

[0100]

Chemical formula

[0101] "Example 15" (Synthesis of Compound 25) (Synthesis of 2,2 - diethyl - 6,6 - dimethyl - 4 - piperidone (1 - 15)) Under an argon stream, 13.532 g (40.0 mmol) of 1,2,2,6,6 - pentamethyl - 4 - piperidone (1 - 7) synthesized in the same manner as in Example 12 and 25.3 ml (60.0 mmol) of 3 - pentanone were dissolved in 50 ml of dimethyl sulfoxide (DMSO), and 25.675 g (240 mmol) of ammonium chloride was added over 30 minutes. The reaction mixture was stirred at 60°C for 5 hours, cooled to room temperature, water was added, and it was neutralized with 1N - hydrochloric acid. After extraction with diethyl ether, the aqueous layer was adjusted to pH 9 with a 10% aqueous potassium carbonate solution and extracted with ethyl acetate.

[0102] The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain 2,2 - diethyl - 6,6 - dimethyl - 4 - piperidone represented by formula (l - 15) as the target product (yield 1.100 g, yield 15%).

[0103] (Synthesis of tert - butyl 2,2 - diethyl - 6,6 - dimethyl - 4 - oxopiperidine - 1 - carboxylate (1 - 16)) 1.100 g (6.00 mmol) of 2,2 - diethyl - 6,6 - dimethyl - 4 - piperidone (1 - 15) synthesized by the above reaction was dissolved in 10 ml of tetrahydrofuran (THF) and cooled in an ice bath. 10 ml of a tetrahydrofuran solution of 1.76 ml (12.6 mmol) of triethylamine (Et3N) and 1.440 g (6.60 mmol) of di - tert - butyl dicarbonate (Boc2O) was added, and the mixture was stirred at room temperature for 2 hours to effect the reaction.

[0104] The reaction solution was concentrated under reduced pressure, and hexane was added. The resulting solid was filtered off and washed with hexane to obtain tert - butyl - 2,2 - diethyl - 6,6 - dimethyl - 4 - oxopiperidine - 1 - carboxylate represented by formula (1 - 16), which is the target product having a tert - butoxycarbonyl group (t - Boc group) bonded to the nitrogen atom of the piperidine ring (yield 1.394 g, yield 82%).

[0105] <Synthesis of tert - butyl - 4 - hydroxy - 2,2 - diethyl - 6,6 - dimethylpiperidine - 1 - carboxylate (1 - 17)> Under an argon stream, 1.394 g (4.92 mmol) of tert - butyl - 2,2 - diethyl - 6,6 - dimethyl - 4 - oxopiperidine - 1 - carboxylate (1 - 16) synthesized by the above reaction was dissolved in 5 ml of ethanol (EtOH) and cooled in an ice bath. 0.095 g (2.50 mmol) of sodium borohydride was slowly added, and the mixture was stirred at room temperature for 6 hours to effect the reaction.

[0106] Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. It was concentrated under reduced pressure to obtain tert - butyl - 4 - hydroxy - 2,2 - diethyl - 6,6 - dimethylpiperidine - 1 - carboxylate represented by formula (1 - 17), which is the target product (yield 1.208 g, yield 86%). <The synthesis of compound (1 - 18)>

[0107] Under an argon atmosphere, 5 ml of tetrahydrofuran (THF) was added to 0.222 g (5.08 mmol) of 55% sodium hydride and cooled in an ice bath. 5 ml of a tetrahydrofuran solution of 1.208 g (4.23 mmol) of tert-butyl-4-hydroxy-2,2-diethyl-6,6-dimethylpiperidine-1-carboxylate (1-17) synthesized by the above reaction was added over 20 minutes, and the mixture was stirred for 30 minutes.

[0108] A solution of 1.885 g (5.08 mmol) of 1-bromo-4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butane in 5 ml of tetrahydrofuran was added over 10 minutes, and the mixture was stirred at room temperature for 12 hours to allow the reaction to proceed. Water was added to the reaction solution, extracted with diethyl ether, and dried over magnesium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 4:1) to obtain the target compound represented by formula (1-18) (yield: 1.217 g, 50%).

[0109] Synthesis of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2-diethyl-6,6-dimethylpiperidine (1-19) 1.217 g (2.12 mmol) of compound (1-18) synthesized by the above reaction was dissolved in 5 ml of dichloromethane, 1.1 ml (14.0 mmol) of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 18 hours to react and remove the tert-butoxycarbonyl protecting group.

[0110] The reaction solution was concentrated under reduced pressure, water was added, and the organic layer was neutralized with aqueous sodium bicarbonate solution. After extraction with diethyl ether, the organic layer was washed with saturated brine and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain the target compound, 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2-diethyl-6,6-dimethylpiperidine represented by formula (1-19) (yield: 0.907 g, 90%).

[0111] Synthesis of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2-diethyl-6,6-dimethylpiperidine-1-oxyl (25) 0.907 g (1.91 mmol) of 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2-diethyl-6,6-dimethylpiperidine (1-19) synthesized by the above reaction, 0.066 g (0.200 mmol) of sodium tungstate dihydrate, and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 2 ml (19 mmol) of 30% hydrogen peroxide solution was slowly added, and the mixture was stirred at room temperature for 24 hours to allow the reaction to proceed. Potassium carbonate was added to the reaction solution, and the mixture was extracted with chloroform and dried over magnesium sulfate.

[0112] After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound, 4-(4-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)butoxy)-2,2-diethyl-6,6-dimethylpiperidine-1-oxyl represented by formula (25) (yield: 0.562 g, 60%).

[0113] Mass spectrometry of the obtained compound confirmed a peak at m / z = 490 (M+). From this, it was confirmed that the synthesized compound was the compound represented by formula (25). Furthermore, the purity of the compound represented by formula (25) confirmed by high performance liquid chromatography (HPLC) was 95.0%.

[0114] [ka]

[0115] "Example 16" (Synthesis of Compound 26) Synthesis of 4-(4-((1,1,1,3,3,3-hexafluoro)propan-2-yl)oxy)butoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (26) The target compound represented by formula (26) was synthesized in the same manner as in Example 1, except that 1-bromo-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)butane was used instead of 1-bromo-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)butane.

[0116] Mass spectrometry of the obtained compound revealed m / z=394 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (26). Furthermore, the purity of the compound represented by formula (26) was confirmed to be 96.5% by high performance liquid chromatography (HPLC).

[0117] [ka]

[0118] "Example 17" (Synthesis of Compound 27) <Synthesis of 4-((8-bromooctyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-20)> Under an argon atmosphere, 1.047 g (24.0 mmol) of 55% sodium hydride (NaH) was added to 15 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. 30 ml of a dimethylformamide solution of 3.445 g (20.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes and stirred at room temperature for 3 hours. 5.55 ml (30.0 mmol) of 1,8-dibromooctane was added to the stirred solution in an ice bath and stirred at room temperature for 20 hours to allow the reaction to proceed. Water was added to the reaction solution, which was then extracted with diethyl ether and washed with water. The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound, 4-((8-bromooctyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-20) (yield: 2.091 g, 29%).

[0119] Synthesis of 4-((8-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)octyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (27) Under an argon stream, 2.091 g (5.75 mmol) of 4-((8-bromooctyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-20) obtained by the above reaction and 2.225 g (8.63 mmol) of sodium-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-2-propanolate were dissolved in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 16 hours and then at 65°C for 9 hours to allow the reaction to proceed. Water was added to the reaction solution, and the mixture was extracted with diethyl ether, washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain the target compound, 4-((8-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)octyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (27) (yield: 2.391 g, 80%).

[0120] Mass spectrometry of the obtained compound revealed m / z=519 (M + A peak was confirmed at 1000 kJ / cm2 (H). This confirmed that the synthesized compound was the compound represented by formula (27). Furthermore, the purity of the compound represented by formula (27) was confirmed to be 95.9% by high performance liquid chromatography (HPLC).

[0121] [ka]

[0122] "Example 18" (Synthesis of Compound 28) The target compound represented by the above formula (28) was synthesized in the same manner as in Example 17, except that 1,12-dibromododecane was used instead of 1,8-dibromooctane. Mass spectrometry of the obtained compound revealed m / z=574 (M + ) was confirmed. This confirmed that the synthesized compound was the compound represented by formula (28). Furthermore, the purity of the compound represented by formula (28) was confirmed to be 93.5% by high performance liquid chromatography (HPLC).

[0123] "Example 19" (Synthesis of Compound 29) The target compound represented by the above formula (29) was synthesized in the same manner as in Example 17, except that 1,16-dibromooctadecane was used instead of 1,8-dibromooctane. Mass spectrometry of the obtained compound revealed m / z=630 (M + ) was confirmed. This confirmed that the synthesized compound was the compound represented by formula (29). Furthermore, the purity of the compound represented by formula (29) was confirmed to be 95.0% by high performance liquid chromatography (HPLC).

[0124] "Comparative Example 1" Trifluoromethylbenzene represented by the following formula (A1) was prepared. "Comparative Example 2" (Synthesis of Compound A2) Trifluoromethylbenzene represented by formula (A1) and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPOL) (manufactured by Tokyo Chemical Industry Co., Ltd.) represented by the following formula (A2) were mixed in a molar ratio ((A1):(A2)) of 1:1 to obtain the compound of Comparative Example 2.

[0125] [ka]

[0126] The compounds of Examples 1 to 19, Comparative Examples 1 and 2 thus obtained were each purified by the following methods. 19 The F spin-lattice relaxation time (T1) was measured, and the results are shown in Table 1.

[0127] ( 19 F spin-lattice relaxation time (T1) The compound was dissolved in a 50 mM concentration of deuterated chloroform solution and analyzed by the repeated rotation method using a 500 MHz NMR apparatus under the following conditions: 19 The longitudinal relaxation time (T1) of F nuclei was measured. (Measurement conditions) NMR device: JNM-ECA500 (manufactured by JOEL) Measurement temperature: 36℃ Pulse sequence: double_pulse relaxation_delay:10[s] tau_interval:4,3,2,1,0.8,0.6,0.4,0.2,0.1[s],80,60,40,20,10,8,6,4,2[ms] Accumulation count: 16 times

[0128] The half-occupied molecular orbital (SOMO) energy levels of the compounds of Examples 1 to 19 and the compound of Comparative Example 3 represented by formula (A3) were calculated by the method shown below. The results are shown in Table 1.

[0129] (Calculation of SOMO energy levels) Molecular orbital calculations for the compounds were performed using Gaussian09 manufactured by Gaussian Inc., USA. The energy levels of half-occupied molecular orbitals (SOMO) were calculated by geometry optimization calculations using density functional theory (DFT) with B3LYP as the functional and 6-31+G(d,p) as the basis set.

[0130] [Table 1]

[0131] As shown in Table 1, the compounds of Examples 1 to 19 have the following properties compared to the compounds of Comparative Examples 1 and 2: 19 The F spin-lattice relaxation time (T1) was short. Furthermore, the compounds of Examples 1 to 19 had higher half-occupied molecular orbitals (SOMO) energy levels than the compound of Comparative Example 3.

[0132] This is because in Comparative Example 3 (Compound A3), there is only one carbon atom between the fluorine atom and the carbons at the 2- and 5-positions of the pyrrolidine ring, and the distance between the nitroxide radical and the fluorine atom is shorter than in the compounds of Examples 1 to 19. As a result, it is presumed that the nitroxide radical contained in Comparative Example 3 (Compound A3) is susceptible to electronic influence from the fluorine atom, and the effect of the fluorine atom as an electron-withdrawing group lowers the energy level of the SOMO.

[0133] Furthermore, 5 mM and 10 mM deuterated chloroform solutions were prepared for the compounds of Example 1 and Comparative Example 1, respectively, and T1 weighted images (phantom images) were obtained under the following imaging conditions. (imaging conditions) Imaging device: MRI BioSpec117 / 11 (manufactured by Burker) Pulse Sequence: RAREVTR Repeat time: TR=1500ms Echo time: TE = 12 ms Accumulation count: 36 times Total shooting time: 16 minutes 33 seconds

[0134] FIG. 1 shows the structure of Example 1 (Compound 11). 19 2 is a T1 weighted F-MRI image of Comparative Example 1 (Compound A1). 19 This is a T1-weighted F-MRI image. The image of Example 1 (Compound 1) shown in FIG. 1 was brighter than the image of Comparative Example 1 (Compound A1) shown in FIG. 2, whether it was a 5 mM deuterated chloroform solution or a 10 mM deuterated chloroform solution. Furthermore, it was confirmed from FIG. 1 that by using Example 1 (Compound 1) as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, highly sensitive images that are sufficiently clinically applicable can be obtained. [Industrial Applicability]

[0135] It is possible to provide a contrast agent that is highly stable in vivo, and to obtain highly sensitive magnetic resonance images.

Claims

1. A fluorine-containing compound represented by the following general formula (1): 【Chemical 1】 (In general formula (1), R １ , R ２ , R ３ , R ４ are each independently an alkyl group having 1 to 10 carbon atoms, which is unsubstituted or substituted with a substituent not containing a fluorine atom. X is a substituent represented by any one of general formulas (2-1), (2-2), and (2-3). (In the general formula (2-1), L １ is either an unsubstituted chain hydrocarbon group having 1 to 16 carbon atoms or an unsubstituted aryl group having 6 carbon atoms. m is an integer of 1 to 5. (In the general formula (2-2), L ３ is either an unsubstituted chain hydrocarbon group having 1 to 16 carbon atoms or an unsubstituted aryl group having 6 carbon atoms. p is an integer of 1 to 5. (In the general formula (2-3), L ４ is either an unsubstituted chain hydrocarbon group having 1 to 16 carbon atoms or an unsubstituted aryl group having 6 carbon atoms. q is an integer of 1 to 5.

2. R in the general formula (1) １ , R ２ , R ３ , R ４ and each independently represent an alkyl group having 1 to 5 carbon atoms which is unsubstituted or substituted with a substituent not containing a fluorine atom.

3. L in general formula (2-1) １ , L in general formula (2-2) ３ , L in general formula (2-3) ４ The fluorine-containing compound according to claim 1 or 2, wherein is an unsubstituted chain hydrocarbon group having 1 to 10 carbon atoms.

4. L in general formula (2-1) １ , L in general formula (2-2) ３ , L in general formula (2-3) ４ The fluorine-containing compound according to claim 1 or 2, wherein is a phenyl group.

5. 5. The fluorine-containing compound according to claim 1, wherein m in the general formula (2-1) is an integer of 1 to 3, p in the general formula (2-2) and q in the general formula (2-3) are 1 or 2.

6. 6. The fluorine-containing compound according to claim 1, which is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus.

7. It is a contrast agent for magnetic resonance imaging diagnosis that uses fluorine as a detection nucleus. A contrast agent comprising the fluorine-containing compound according to any one of claims 1 to 6.

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