Fluorine-containing compound and contrast agent

Abstract

To provide a fluorinated compound that can give a high-sensitivity magnetic resonance image and can be easily dispersed in aqueous medium.SOLUTION: The present invention provides a fluorinated compound represented by the formula (1) (R1, R2, R3, R4 each represent a C1-10 alkyl group. R11 represents -CH2-O-C(CF3)rH3-r (r represents an integer of 1-3) or -O-CH2-C[CH2-O-C(CF3)sH3-s]p(CH3)3-p (s, p each represent an integer of 1-3). R12 represents -CH2-O-C(CF3)tH3-t (t represents an integer of 0-3) or -CH3. R13 represents -CH2-O(CH2CH2O)nY (Y represents -CH3 or -H. n represents an integer of 6-45). X represents -(CH2)m-O-CH2- (m represents an integer of 1-12) or -CH2-).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a fluorine-containing compound and a contrast agent.

Background Art

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

[0003] Currently, for medical MRI, 1 1H-MRI using proton 1 1H as a detection nucleus is used. 1 1H-MRI images the magnetic environment of water molecules present in the living body. There are differences in the magnetic environment of protons between diseased tissues and normal tissues in the living body. This 1 appears as the difference in 1H-MRI and becomes diagnostic information. In addition, water molecules are present in almost the entire living body. Therefore, 1 1H-MRI can be used for whole-body imaging.

[0004] Nuclides detectable by MRI include, 1 in addition to 1H, 19 19F, 23 23Na, 31 31P, 15 14N, 13 13C, etc. In MRI using these elements as detection nuclei, different 1 information from 1H-MRI can be obtained. Among these, MRI using 19 19F as a detection nucleus is 1 expected to be used as the next-generation diagnostic method following 1H-MRI diagnosis. That is because fluorine is an inexpensive element with a natural abundance ratio of 100%, 19 the detection sensitivity of 19F is 1 as high as 83% of 1H, and 19 since the magnetic gyromagnetic ratio of 19F is close to that of protons, it can be imaged with a conventional 1 1H-MRI device.

[0005] In addition, 19 F hardly exists in the living body. Therefore, by using a compound containing a fluorine atom as a contrast agent, 19 F-MRI diagnosis using 19 F as a tracer is possible. For example, by using a fluorine compound that recognizes and accumulates due to internal changes caused by a disease as a contrast agent, 19 positional information of the lesion can be obtained from

[0006] 19 F-MRI. This method is useful for diagnosing lesions that do not cause morphological changes that could not be detected by conventional imaging diagnostic methods. 19 In 1 F-MRI diagnosis, by extracting information such as chemical shift, diffusion, and relaxation time, not only positional information of the lesion but also more diagnostic information can be obtained. Also, in a single diagnosis,

[0007] As a fluorine-containing compound used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, for example, Patent Document 1 describes a compound having a nitroxide covalently bonded to a fluorine-containing compound.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0009] Conventional contrast agents used in MRI diagnosis with fluorine as the detection nucleus did not provide high-sensitivity MRI. As a material for a contrast agent that can provide high-sensitivity MRI, it is conceivable to use a fluorine-containing compound having a large number of fluorine atoms. In three-dimensional (3D) MRI (in two-dimensional (2D) MRI, in a pixel), the larger the number of fluorine atoms in a voxel, the larger the amount of signal obtained, and it becomes easier to obtain a high-sensitivity image.

[0010] However, fluorine-containing compounds containing a large number of fluorine atoms have low water solubility and are difficult to disperse in an aqueous medium. Therefore, when using a fluorine-containing compound containing a large number of fluorine atoms as a contrast agent for MRI diagnosis, it was necessary to use a surfactant to make an emulsion of the fluorine-containing compound so that it could be dispersed in the aqueous medium in the living body.

[0011] The present invention has been made in view of the above circumstances, and an object thereof is to provide a fluorine-containing compound that can be used as a material for a contrast agent for magnetic resonance imaging diagnosis with fluorine as the detection nucleus, can obtain a high-sensitivity magnetic resonance image, and is easily dispersed in an aqueous medium. Another object of the present invention is to provide a contrast agent for magnetic resonance imaging diagnosis with fluorine as the detection nucleus, which contains the fluorine-containing compound of the present invention, has good dispersibility in an aqueous medium, and can obtain a high-sensitivity image.

Means for Solving the Problems

[0012] [1] A fluorine-containing compound characterized by being represented by the following general formula (1).

[0013]

Chemical formula

[0014] -CH2-O-C(CF3) r H 3-r ···(1-1) (In formula (1-1), r is an integer from 1 to 3.) -O-CH2-C[CH2-O-C(CF3) s H 3-s p (CH3) 3-p ···(1-2) (In formula (1-2), s and p are each independently an integer from 1 to 3.) -CH2-O-C(CF3) t H 3-t ···(1-3) (In formula (1-3), t is an integer from 0 to 3.) -CH2-O(CH2CH2O) n Y ···(1-4) (In formula (1-4), Y is -CH3 or -H. n is an integer from 6 to 45.) -(CH2) m -O-CH2- ···(1-5) (In formula (1-5), m is an integer from 1 to 12. -(CH2) m - in formula (1-5) is bonded to the oxygen atom bonded to the carbon at the 4-position of the piperidine ring.)

[0015] [2] R in the general formula (1) 11 is represented by the formula (1-1), r in the formula (1-1) is 3, and R 12 is represented by the formula (1-3), and t in the formula (1-3) is 3. The fluorine-containing compound according to [1]. [3] R in the general formula (1) 11 ​The fluorine-containing compound according to [1], which is represented by the formula (1-2) and in which s and p in the formula (1-2) are 3.

[0016] [4] The fluorine-containing compound according to any one of [1] to [3], wherein Y in the formula (1-4) is -CH3. [5] The fluorine-containing compound according to any one of [1] to [4], wherein n in the formula (1-4) is an integer of 15 or more. [6] R in the general formula (1) 1 , R 2 , R 3 , R 4 are each independently a methyl group or an ethyl group, and the fluorine-containing compound according to any one of [1] to [5].

[0017] [7] The fluorine-containing compound according to any one of [1] to [6], which is used as a contrast agent for magnetic resonance imaging using fluorine as a detection nucleus. [8] 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 [7].

Advantages of the Invention

[0018] The fluorine-containing compound of the present invention is a compound represented by the above general formula (1). Therefore, it can be dispersed in an aqueous medium. Moreover, by using the fluorine-containing compound of the present invention as a material for a contrast agent for magnetic resonance imaging using fluorine as a detection nucleus, a high-sensitivity magnetic resonance image 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 good dispersibility in an aqueous medium. Further, by using the contrast agent of the present invention as a contrast agent for magnetic resonance imaging using fluorine as a detection nucleus, a high-sensitivity magnetic resonance image can be obtained.

Brief Description of the Drawings

[0019]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0020] Hereinafter, the fluorine-containing compound and the contrast agent of the present invention will be described in detail. [Fluorine-Containing Compound] The fluorine-containing compound of the present embodiment is represented by the following general formula (1).

[0021]

Chemical formula

[0022] -CH2-O-C(CF3) r H 3-r ···(1-1) (In formula (1-1), r is an integer of 1 to 3.) -O-CH2-C[CH2-O-C(CF3) s H 3-s p (CH3)​3-p ···(1-2) (In formula (1-2), s and p are each independently an integer from 1 to 3.) -CH2-O-C(CF3) t H 3-t ···(1-3) (In formula (1-3), t is an integer from 0 to 3.) -CH2-O(CH2CH2O) n Y ···(1-4) (In formula (1-4), Y is -CH3 or -H. n is an integer from 6 to 45.) -(CH2) m -O-CH2- ···(1-5) (In formula (1-5), m is an integer from 1 to 12. The -(CH2) in formula (1-5) m - is bonded to the oxygen atom bonded to the carbon at the 4-position of the piperidine ring.)

[0023] Here, when the contrast agent containing the fluorine-containing compound of the present embodiment is used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, the reason why the dispersibility in an aqueous medium is good and a high-sensitivity magnetic resonance image (MRI) can be obtained will be explained.

[0024] High-sensitivity 19 To obtain a high-sensitivity 19 F-MRI, it is preferable to use a fluorine-containing compound having a short 19 F spin-lattice relaxation time (T1) as the fluorine-containing compound contained in the contrast agent. The shorter the T1 of the fluorine-containing compound, the shorter the repetition time can be set. For this reason, the amount of signal obtained per unit time increases, and a high-sensitivity image can be obtained. On the other hand, if the

[0025] F spin-spin relaxation time (T2) of the fluorine-containing compound is too short, the signal intensity decreases. 19 F spin-lattice relaxation time (T1) and 19The F spin-spin relaxation time (T2) is affected by the paramagnetic relaxation enhancement (PRE) effect. The PRE effect is a phenomenon in which the T1 and T2 of MRI-observed nuclei near the unpaired electron spin are shortened by the unpaired electron spin of a paramagnetic substance.

[0026] The PRE effect is inversely proportional to the sixth power of the distance between the paramagnetic substance and the MRI-observed nucleus (fluorine atom in this embodiment) to be relaxed by the paramagnetic substance. Therefore, in the fluorine-containing compound represented by formula (1) of this embodiment, the closer the distance between the nitroxide radical as the paramagnetic substance and the fluorine atom, the shorter the T1 and T2. In the fluorine-containing compound represented by formula (1), a terminal group containing one or more trifluoromethyl groups (-CF3) (R in formula (1) 11 and R 12 , or R 11 ) having one or two is ether-bonded (-O-) via a linking group (formula (1-5) or -CH2-) represented by X in formula (1). For this reason, the distance between the nitroxide radical and the fluorine atom is appropriate, 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 a detection nucleus, a highly sensitive magnetic resonance image can be obtained.

[0027] Also, in order to obtain a highly sensitive 19 F-MRI, it is preferable to use a fluorine compound contained in the contrast agent having a large number of structurally equivalent fluorine atoms. The fluorine-containing compound represented by formula (1) of this embodiment has a terminal group containing one or more trifluoromethyl groups (-CF3) (R in formula (1) 11 and R 12 , or R 11) has one or more. The trifluoromethyl group (-CF3) contains three structurally equivalent fluorine atoms. Therefore, the fluorine-containing compound represented by formula (1) has three or more structurally equivalent fluorine atoms in the molecule. Thus, the fluorine-containing compound represented by formula (1) has a sufficiently large number of structurally equivalent fluorine atoms in the molecule, and when used as a contrast agent for MRI diagnosis using fluorine as the detected nucleus, a strong signal intensity can be obtained, and a high-sensitivity image can be obtained.

[0028] Generally, fluorine-containing compounds containing a large number of fluorine atoms have low water solubility and are difficult to disperse in an aqueous medium. However, the fluorine-containing compound represented by formula (1) of the present embodiment has R 13 represented by formula (1-4). Formula (1-4) has 6 to 45 ethylene glycol chains represented by -(CH2CH2O) n . As a result, the fluorine-containing compound represented by formula (1) can be dispersed in an aqueous medium despite having three or more structurally equivalent fluorine atoms.

[0029] In addition, in the fluorine-containing compound represented by formula (1), since the ethylene glycol chain is contained in R 13 , it can be easily synthesized, and while appropriately maintaining the distance between the fluorine atom and the nitroxide radical, it has good dispersibility in an aqueous medium. On the other hand, for example, compounds in which an ethylene glycol chain is introduced into R 1 , R 2 , R 3 , R 4 in formula (1) are technically difficult to synthesize.

[0030] In this specification, "a fluorine-containing compound is not dispersed in an aqueous medium" means that the fluorine-containing compound placed in the aqueous medium is separated in the aqueous medium. "A fluorine-containing compound is dispersed in an aqueous medium" means a state in which the fluorine-containing compound exists without being separated in the aqueous medium. The aqueous medium in which the fluorine-containing compound is dispersed may be transparent or opaque when placed in a 2-ml vial and visually observed. "A fluorine-containing compound is dissolved in an aqueous medium" means a state of "a fluorine-containing compound is dispersed in an aqueous medium" and is transparent when placed in a 2-ml vial and visually observed.

[0031] In the fluorine-containing compound represented by the formula (1) of the present embodiment, R 1 , R 2 , R 3 , R 4 is each independently an alkyl group having 1 to 10 carbon atoms which may be substituted or unsubstituted with a substituent containing no fluorine atom, and is preferably an alkyl group having 1 to 5 carbon atoms which may be substituted or unsubstituted with a substituent containing no fluorine atom. Since R 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 the formula (1) is easy. Further, when R 1 , R 2 , R 3 , R 4 is a substituted or unsubstituted alkyl group having 2 to 10 carbon atoms, it becomes moderately bulky and can prevent the approach of the reducing agent to the nitroxide radical. When the number of carbon atoms of the above alkyl group is 5 or less, the synthesis of the fluorine-containing compound represented by the formula (1) becomes even easier, which is preferable. Further, in the fluorine-containing compound represented by the formula (1), since R 1 , R 2 , R 3 , R 4 does not contain a fluorine atom, the distance between the nitroxide radical and the fluorine atom is not too close, and the signal intensity is not insufficient.

[0032] R contained in the fluorine-containing compound represented by the formula (1)1 , R 2 , R 3 , R 4 When R, R, R, and R have substituents that do not contain a fluorine atom, examples of the substituents that can be used include a methyl group and an ethyl group. In the fluorine-containing compound represented by formula (1) of the present embodiment, R, R, R, R, and R 1 , R 2 , R 3 , R 4 are each preferably independently a methyl group or an ethyl group. When R, R, R, and R are methyl groups, the fluorinated compound has fewer manufacturing steps and is superior in productivity compared to the case where they are ethyl groups, which is preferable. 1 , R 2 , R 3 , R 4 When R, R, R, and R are methyl groups, the fluorinated compound has fewer manufacturing steps and is superior in productivity compared to the case where they are ethyl groups, which is preferable.

[0033] R, R, R, R, and R contained in the fluorine-containing compound represented by formula (1) 1 , R 2 , R 3 , R 4 may be different from each other, or some or all of them may be the same. When R, R, R, and R are all the same, the synthesis of the fluorine-containing compound represented by formula (1) becomes easy, which is preferable. 1 , R 2 , R 3 , R 4 When R, R, R, and R are all the same, the synthesis of the fluorine-containing compound represented by formula (1) becomes easy, which is preferable.

[0034] In the fluorine-containing compound represented by formula (1) of the present embodiment, R 11 is represented by formula (1-1) or formula (1-2). R 12 is represented by formula (1-3) when R 11 is formula (1-1), and is -CH3 when R 11 is formula (1-2). Therefore, the fluorine-containing compound represented by formula (1) of the present embodiment has one or more trifluoromethyl groups (-CF3) and has three or more structurally equivalent fluorine atoms in the molecule. For this reason, the fluorine-containing compound represented by formula (1) 19When the number of fluorine atoms indicating the F-MRI peak is sufficiently large and it is used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, a strong signal intensity can be obtained and a highly sensitive image can be obtained.

[0035] In the present embodiment, r in formula (1-1) is an integer of 1 to 3. The larger the number of trifluoromethyl groups (-CF3) in formula (1-1), the larger the number of structurally equivalent fluorine atoms, and the more likely it is to obtain a more highly sensitive image. Therefore, r is preferably 2 or 3, and most preferably 3.

[0036] In the present embodiment, s and p in formula (1-2) are each independently an integer of 1 to 3. The larger the number of trifluoromethyl groups (-CF3) in formula (1-2), the larger the number of structurally equivalent fluorine atoms, and the more likely it is to obtain a more highly sensitive image. Therefore, s and p are each independently preferably 2 or 3, and most preferably both s and p are 3.

[0037] In the fluorine-containing compound represented by formula (1), R 11 is formula (1-1), and R 12 is formula (1-3), when R 11 is formula (1-2), and R 12 is -CH3, compared with the case, it is a fluorine-containing compound that requires fewer manufacturing steps and has excellent productivity, which is preferable.

[0038] In the present embodiment, t in formula (1-3) is an integer of 0 to 3. The larger the number of trifluoromethyl groups (-CF3) in formula (1-3), the larger the number of structurally equivalent fluorine atoms, and the more likely it is to obtain a more highly sensitive image. Therefore, t is preferably an integer of 1 to 3, more preferably 2 or 3, and most preferably 3.

[0039] The number of trifluoromethyl groups (-CF3) contained in the fluorine-containing compound represented by formula (1) may be one or more. Moreover, since it becomes easier to obtain a higher-sensitivity image, it is preferably 3 or more, and preferably 6 to 9. The number of trifluoromethyl groups is preferably 6 or 9 because it is a fluorinated compound with fewer manufacturing steps and excellent productivity, and particularly preferably 6.

[0040] In the fluorine-containing compound represented by formula (1), R 13 is represented by formula (1-4). The ethylene glycol chain represented by (CH2CH2O) in formula (1-4) contributes to the water solubility of the fluorine-containing compound represented by formula (1). n in formula (1-4) is an integer from 6 to 45. Since n is an integer of 6 or more, the fluorine-containing compound represented by formula (1) can be dispersed in an aqueous medium even though it has 3 or more structurally equivalent fluorine atoms. n in formula (1-4) is preferably an integer of 15 or more because even a fluorine-containing compound having 18 or more structurally equivalent fluorine atoms can be dissolved in an aqueous medium. Further, since n in formula (1-4) is an integer of 45 or less, it can be easily and efficiently manufactured and has excellent productivity. Also, when n in formula (1-4) is an integer of 45 or less, the purification of the synthesized fluorine-containing compound is easy, which is preferable.

[0041] Y in formula (1-4) is -CH3 or -H. When Y is -CH3, compared with the case where Y is -H, it is a fluorinated compound with fewer manufacturing steps and excellent productivity, which is preferable. Also, when Y is -H, it binds to the oxygen atom of the ethylene glycol chain represented by (CH2CH2O) arranged on the most terminal side of formula (1-4) to form a hydroxyl group (-OH). Therefore, when Y is -H, it becomes an even more fluorine-containing compound that is easily dispersed in an aqueous medium, which is preferable.

[0042] In the fluorine-containing compound represented by the formula (1) of the present embodiment, X is the formula (1-5) or -CH2-, and m in the formula (1-5) is an integer of 1 to 12. Therefore, in the fluorine-containing compound represented by the formula (1), the distance between the nitroxide radical and the fluorine atom is appropriate, T1 is sufficiently short, and T2 can be sufficiently ensured. Therefore, by using the fluorine-containing compound represented by the formula (1) as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, a high-sensitivity image can be obtained. m in the formula (1-5) is preferably an integer of 1 to 6, and more preferably an integer of 1 to 3, because the distance between the nitroxide radical and the fluorine atom does not become too long and T1 becomes shorter.

[0043] In particular, when R 11 is the formula (1-2), in order to prevent the distance between the nitroxide radical and the fluorine atom from becoming too long, X is preferably -CH2- or m in the formula (1-5) is an integer of 1 to 3, and more preferably -CH2- or m in the formula (1-5) is 1 or 2. In particular, since it is a fluorinated compound that requires fewer manufacturing steps and has excellent productivity, when R 11 is the formula (1-2), X is preferably -CH2-.

[0044] Further, in the fluorine-containing compound represented by the formula (1), when X is the formula (1-5), -(CH2) m - in the formula (1-5) is bonded to the oxygen atom bonded to the carbon at the 4-position of the piperidine ring, and thus it can be easily produced using the production method described later.

[0045] The fluorine-containing compound represented by the general formula (1) has R 1 , R 2 , R 3 , R 4 all being methyl groups, R 11 being the formula (1-1) with r being 3, and R 12In the formula (1-3), it is preferable that t is 3, Y in the formula (1-4) is -CH3, and X is -CH2-. That is, the fluorine-containing compound represented by the general formula (1) is preferably a fluorine-containing compound represented by the following general formula (2). Since the fluorine-containing compound represented by the general formula (2) has six trifluoromethyl groups and 18 structurally equivalent fluorine atoms, a higher-sensitivity image can be more easily obtained. In addition, the fluorine-containing compound represented by the general formula (2) can be easily and efficiently produced and is excellent in productivity.

[0046]

Chemical formula

[0047] -(CH2) m -O-CH2- ···(1-5) (In the formula (1-5), m is an integer from 1 to 12. In the formula (1-5), -(CH2) m - is bonded to the oxygen atom bonded to the carbon at the 4th position of the piperidine ring.)

[0048] Specifically, the fluorine-containing compound represented by the formula (1) is preferably any of the fluorine-containing compounds represented by the following formulas (11) to (28). The compounds represented by the formulas (11) to (28) all have good dispersibility in an aqueous medium, and moreover, when used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, a high-sensitivity image can be obtained. The compounds represented by the formulas (11) to (16) are fluorine-containing compounds represented by the formula (2). The compounds represented by the formulas (17) and (18) are R 1 、R 2 、R 3 、R 4 are all ethyl groups, R 11 is the formula (1-1) where r is 3, R 12 is the formula (1-3) where t is 3, R 13It is a fluorine-containing compound in which Y is -CH3 and X is -CH2- in the formula (1-4).

[0049] The compounds represented by the formulas (19) to (21) are fluorine-containing compounds represented by the formula (2), and X is the formula (1-5). In the formula (19), m is 3, in the formula (20), m is 6, and in the formula (21), m is 12. The compound represented by the formula (22) is R 1 、R 2 、R 3 、R 4 are all ethyl groups, R 11 is the formula (1-1) where r is 3, R 12 is the formula (1-3) where t is 3, R 13 is a fluorine-containing compound in which Y is -CH3 and X is the formula (1-5) where m is 3 in the formula (1-4).

[0050] The compound represented by the formula (23) is R 1 、R 2 、R 3 、R 4 are all methyl groups, and R 11 is the formula (1-1) where r is 3, R 12 is the formula (1-3) where t is 3, R 13 is a fluorine-containing compound in which Y is -H and X is -CH2- in the formula (1-4). The compounds represented by the formulas (24) to (27) are such that R 11 is the formula (1-2) where both s and p are 3, R 12 is -CH3, R 13 is a fluorine-containing compound in which Y is -CH3 and X is -CH2- in the formula (1-4). The compound represented by the formula (28) is such that R 11 is the formula (1-2) where both s and p are 3, R 12 is -CH3, R 13 is a fluorine-containing compound in which Y is -CH3 and X is the formula (1-5) where m is 3 in the formula (1-4).

[0051]

Chemical formula

[0052]

Chem.

[0053] [Method for Producing Fluorine-Containing Compound] Next, the method for producing the fluorine-containing compound of the present embodiment represented by the general formula (1) will be described with examples. The method for producing the fluorine-containing compound of the present embodiment is not particularly limited and can be produced using a conventionally known production method. The fluorine-containing compound of the present embodiment represented by the general formula (1) can be produced, for example, using the production methods shown below.

[0054] [First Production Method] <R in the fluorine-containing compound represented by the general formula (1) 11 is the formula (1-1), R 12 is the formula (1-3), R 13 is the formula (1-4) and Y is -CH3 and X is -CH2- First, at the 2-position and 6-position of the piperidine ring, R in the fluorine-containing compound represented by the general formula (1) 1 , R 2 , R 3 , R 4 are bonded, and a compound having a hydroxyl group bonded to the 4-position and a nitroxide radical is prepared. This compound may be synthesized or a commercially available one may be used. When synthesizing, for example, 2,2,6,6-tetramethyl-4-piperidone can be used as a raw material and a method of synthesizing by a known method can be used.

[0055] Also, R in the fluorine-containing compound represented by the general formula (1) 11 , R 12Prepare a halogen compound having a group corresponding to and two halogenated alkyl groups. Specifically, prepare a halogen compound having a group represented by formula (1-1), a group represented by formula (1-3), and two groups represented by u-(CH2)- (where u is a halogeno group). This halogen compound can be produced by a known method. For example, R 11 is represented by formula (1-1) and r is 3, and R 12 is represented by formula (1-3) and t is 3, it can be produced by a method such as reacting a compound having two hydroxymethyl groups (-CH2OH) and a halogenated alkyl group with nonafluoro-tert-butanol.

[0056] Subsequently, react one of the two halogeno groups of the above halogen compound with the hydroxyl group of the compound having the above nitroxide radical. As a result, a terminal group corresponding to R 11 (group represented by formula (1-1)) and a terminal group corresponding to R 12 (group represented by formula (1-3)) and a group having a halogenated alkyl group are ether-bonded (-O-) via -CH2- to form a first intermediate compound.

[0057] Subsequently, react the halogenated alkyl group of the first intermediate compound with the hydroxyl group of ethylene glycol monomethyl ether having an ethylene glycol chain corresponding to the number n of ethylene glycol chains in R 13 . By the above method, a fluorine-containing compound represented by general formula (1) is obtained, where R 11 is formula (1-1), R 12 is formula (1-3), R 13 is formula (1-4), Y is -CH3, and X is -CH2-.

[0058] (Second production method) <In the fluorine-containing compound represented by general formula (1), R 11 is formula (1-1), R 12 is formula (1-3), R 13When Y is -CH3 in formula (1-4) and X is formula (1-5)> In the same manner as in the first production method, R in the fluorine-containing compound represented by formula (1) is bonded to the 2-position and 6-position of the piperidine ring, respectively. 1 R 2 R 3 R 4 A compound having a nitroxide radical in which R is bonded to the 4-position and a hydroxyl group is bonded to the 4-position is prepared.

[0059] Next, a tetrahydropyranyl ether containing a group corresponding to -(CH2) in formula (1-5) is prepared. Specifically, a compound having a group represented by u-(CH2)-O- (where u is a halogeno group and m is the same as in formula (1-5)) at the 2-position of tetrahydropyran is prepared. This compound can be produced by a known method. m Next, a tetrahydropyranyl ether containing a group corresponding to -(CH2) in formula (1-5) is prepared. Specifically, a compound having a group represented by u-(CH2)-O- (where u is a halogeno group and m is the same as in formula (1-5)) at the 2-position of tetrahydropyran is prepared. This compound can be produced by a known method. m Next, a tetrahydropyranyl ether containing a group corresponding to -(CH2) in formula (1-5) is prepared. Specifically, a compound having a group represented by u-(CH2)-O- (where u is a halogeno group and m is the same as in formula (1-5)) at the 2-position of tetrahydropyran is prepared. This compound can be produced by a known method. Next, the halogeno group of the tetrahydropyranyl ether is reacted with the hydroxyl group of the compound having the nitroxide radical to obtain a first intermediate compound. Then, tetrahydropyran is removed from the first intermediate compound by a known method. As a result, a second intermediate compound in which a group represented by -(CH2)-OH (where m is the same as in formula (1-5)) is bonded to the oxygen atom bonded to the 4-position of the piperidine ring is obtained. Protection and deprotection of the hydroxyl group using a tetrahydropyranyl group can be carried out using a known method. m Next, the halogeno group of the tetrahydropyranyl ether is reacted with the hydroxyl group of the compound having the nitroxide radical to obtain a first intermediate compound. Then, tetrahydropyran is removed from the first intermediate compound by a known method. As a result, a second intermediate compound in which a group represented by -(CH2)-OH (where m is the same as in formula (1-5)) is bonded to the oxygen atom bonded to the 4-position of the piperidine ring is obtained. Protection and deprotection of the hydroxyl group using a tetrahydropyranyl group can be carried out using a known method.

[0060] Next, in the same manner as in the first production method, a halogen compound having a group represented by formula (1-1), a group represented by formula (1-3), and two groups represented by u-(CH2)- (where u is a halogeno group) is prepared. Then, one of the two halogeno groups of the halogen compound is reacted with the hydroxyl group of the second intermediate compound. As a result, a terminal group (group represented by formula (1-1)) corresponding to R and R 11 corresponding to R 12A third intermediate compound in which a group having a terminal group corresponding thereto (a group represented by the formula (1-3)) and a halogenated alkyl group are ether-bonded (-O-) via a linking group represented by the formula (1-5) is produced.

[0061] Subsequently, the halogenated alkyl group of the third intermediate compound is reacted with the hydroxyl group of ethylene glycol monomethyl ether having an ethylene glycol chain corresponding to the number n of ethylene glycol chains in R 13 . By the above method, when R 11 is the formula (1-1), R 12 is the formula (1-3), and R 13 is the formula (1-4) with Y being -CH3 and X being the formula (1-5), a fluorine-containing compound represented by the general formula (1) is obtained.

[0062] (The third production method) <When R 11 in the general formula (1) is the formula (1-2), R 12 is -CH3, and R 13 is the formula (1-4) with Y being -CH3 and X being -CH2-> In the same manner as in the first production method, a compound having a nitroxide radical in which R 1 , R 2 , R 3 , R 4 in the fluorine-containing compound represented by the formula (1) are bonded to the 2-position and 6-position of the piperidine ring, respectively, and a hydroxyl group is bonded to the 4-position is prepared.

[0063] Also, a halogen compound having a hydroxyl group, a methyl group, and two halogenated methyl groups is prepared. This halogen compound can be produced by a known method. The hydroxyl group of the halogen compound is protected using a tetrahydropyranyl group, and R 1 , R 2 , R 3 , R 4It is combined and reacted with the hydroxyl group of a compound having a nitroxide radical with a hydroxyl group bonded to the 4-position, and then the tetrahydropyranyl group is deprotected. As a result, a methyl halide group, a hydroxyl group, and a group in which a methyl group is bonded to a carbon atom are ether-bonded via a methylene group (-CH2-) to the 4-position of the piperidine ring of the compound having the nitroxide radical to form a fourth intermediate compound. The protection and deprotection of the hydroxyl group using the tetrahydropyranyl group can be carried out using known methods.

[0064] Also, -C[CH2-O-C(CF3) in formula (1-2) s H 3-s p (CH3) 3-p (where s and p in the formula are the same as those in formula (1-2).) A halogen compound having a group represented by and a methyl halide group is prepared. This halogen compound can be produced by a known method. For example, when both s and p in formula (1-2) are 3, it can be produced by a method such as reacting 2-(bromomethyl)-2-(hydroxymethyl)-1,3-propanediol with nonafluoro-tert-butanol.

[0065] Then, the halogeno group of the halogen compound is reacted with the hydroxyl group of the fourth intermediate compound. As a result, at the carbon at the 4-position of the piperidine ring of the compound having the nitroxide radical, a terminal group corresponding to R 11 (a group represented by formula (1-2)) and R 12 (a methyl group) and a group having an alkyl halide group are ether-bonded (-O-) via -CH2- to form a fifth intermediate compound.

[0066] Subsequently, the halogeno group of the fifth intermediate compound is reacted with the hydroxyl group of ethylene glycol monomethyl ether having an ethylene glycol chain corresponding to the number n of ethylene glycol chains in R 13 . By the above method, R 11 is formula (1-2), R 12 is -CH3, and R 13 ​A fluorine-containing compound represented by the general formula (1) in which Y is -CH3 and X is -CH2 in the formula (1-4) is obtained.

[0067] R 11 is the formula (1-2), and R 12 is -CH3, and R 13 When producing a fluorine-containing compound represented by the general formula (1) in which Y is -CH3 and X is the formula (1-5) in the formula (1-4), in the third production method, the following compound may be used as the raw material of the fourth intermediate compound. That is, in the 2-position and 6-position of the piperidine ring, R in the fluorine-containing compound represented by the formula (1) 1 、R 2 、R 3 、R 4 is bonded, and instead of the compound having a nitroxide radical with a hydroxyl group bonded to the 4-position, an oxygen atom bonded to the 4-position of the piperidine ring of the compound having the nitroxide radical produced in the second production method is -(CH2) m -OH (m in the formula is the same as in the formula (1-5).) A second intermediate compound to which a group represented by is bonded is used.

[0068] (Fourth production method) <R in the general formula (1) 13 When Y is -H in the formula (1-4)> R 13 Prepare polyethylene glycol having an ethylene glycol chain corresponding to the number n of ethylene glycol chains in. Protect one of the two hydroxyl groups of the polyethylene glycol with a tetrahydropyranyl group. Then, react with either the halogeno group of the first intermediate compound in the first production method, the halogeno group of the third intermediate compound in the second production method, or the halogeno group of the fifth intermediate compound in the third production method of the hydroxyl group not protected by the tetrahydropyranyl group, and perform deprotection of the tetrahydropyranyl group. By the above method, a fluorine-containing compound represented by the general formula (1) in which R 13 is the formula (1-4) and Y is -H is obtained.

[0069] "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 using fluorine as a detection nucleus. The contrast agent of this embodiment can be produced by formulating the fluorine-containing compound of this embodiment into forms such as solid preparations, powder preparations, liquid preparations, etc. using known formulation techniques. Since the fluorine-containing compound of this embodiment has good dispersibility in an aqueous medium, it is suitable when in the form of a solvent. In addition to the fluorine-containing compound of this embodiment, the contrast agent of this embodiment may contain one or more additives used in known preparations such as excipients, stabilizers, surfactants, buffers, electrolytes, etc. as necessary. Since the contrast agent of this embodiment contains the fluorine-containing compound of the present invention, it has good dispersibility in an aqueous medium. Further, by using the contrast agent of this 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.

[0070] 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.

Examples

[0071] "Example 1" (Synthesis of Compound 11)

[0072]

Chemical formula

[0073]

Chemical formula

[0074] <Synthesis of 2-(3-bromo-2-(bromomethyl)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1)> Under an argon stream, 11.096 g (42.4 mmol) of 2,2-bis(bromomethyl)-1,3-propanediol, 27.777 g (105.9 mmol) of triphenylphosphine (PPh3), 10.000 g of molecular sieves (MS) 4A, and 150 ml of tetrahydrofuran (THF) were mixed and cooled in an ice bath. 20.6 ml (105.9 mmol) of diisopropyl azodicarboxylate (DIAD) was added dropwise over 10 minutes and stirred for 20 minutes. 25.000 g (105.9 mmol) of nonafluoro-tert-butanol was added all at once and stirred at 45 °C for 72 hours.

[0075] After filtering the reaction solution, it was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the target compound 2-(3-bromo-2-(bromomethyl)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) (yield 25.052 g, yield 85%).

[0076] <Synthesis of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-2)> Under an argon stream, 10 ml of dimethylformamide (DMF) was added to 0.786 g (18.0 mmol) of 55% sodium hydride (NaH) and stirred at room temperature for 10 minutes. A 20 ml dimethylformamide solution of 2.584 g (15.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl was added dropwise over 10 minutes and stirred at room temperature for 3 hours.

[0077] Under an ice bath, 40 mL of a dimethylformamide solution containing 12.595 g (18.0 mmol) of 2-(3-bromo-2-(bromomethyl)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0078] 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, purification was performed by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) to obtain the target 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-2) (yield 7.730 g, yield 65%).

[0079] <Synthesis of Compound (11)> Under an argon stream, 3 mL of dimethylformamide (DMF) was added to 0.142 g (3.25 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. 7 mL of a dimethylformamide solution containing 0.963 g (3.25 mmol) of hexaethylene glycol monomethyl ether was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. Under an ice bath, 10 mL of a dimethylformamide solution containing 1.973 g (2.50 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 11 hours.

[0080] Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. The organic layer was concentrated under reduced pressure and then purified by silica gel column chromatography (ethyl acetate) to obtain the target compound (11) (yield 1.942 g, yield 77%).

[0081] Mass spectrometry of the obtained compound showed that a peak was confirmed at m / z = 1005 (M + ). From this, it was confirmed that the synthesized compound was the compound represented by formula (11). Also, the purity of the compound represented by formula (11) confirmed by high performance liquid chromatography (HPLC) was 99.5%.

[0082] "Example 2" (Synthesis of Compound 12)

[0083] [Chemical formula]

[0084] Under an argon stream, 3 ml of dimethylformamide (DMF) was added to 0.199 g (4.56 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 7 ml dimethylformamide solution of 1.753 g (4.56 mmol) of octaethylene glycol monomethyl ether was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 7 ml of a dimethylformamide solution containing 2.400 g (3.04 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 16 hours.

[0085] Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with water and dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 99:1) to obtain the target compound (12) (yield 2.063 g, yield 62%).

[0086] Mass spectrometry of the obtained compound was carried out, and a peak was confirmed at m / z = 1091 (M + ). From this, it was confirmed that the synthesized compound was the compound represented by formula (12). Also, the purity of the compound represented by formula (12) confirmed by high performance liquid chromatography (HPLC) was 99.0%.

[0087] "Example 3" (Synthesis of Compound 13)

[0088] [Chemical formula]

[0089] Under an argon stream, 2 ml of dimethylformamide (DMF) was added to 0.078 g (1.78 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. An 8 ml dimethylformamide solution of 1.000 g (1.78 mmol) of dodecaethylene glycol monomethyl ether was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 10 ml of a dimethylformamide solution containing 1.263 g (1.60 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 18 hours.

[0090] Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 97:3) to obtain the target compound (13) (yield 1.060 g, yield 52%).

[0091] Mass spectrometry of the obtained compound was carried out, and a peak was confirmed at m / z = 1269 (M +) A peak was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by the formula (13). Also, the purity of the compound represented by the formula (13) confirmed by high performance liquid chromatography (HPLC) was 98.8%.

[0092] "Example 4" (Synthesis of Compound 14)

[0093] [Chemical formula]

[0094] Under an argon stream, 3 ml of dimethylformamide (DMF) was added to 0.262 g (6.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. 7 ml of a dimethylformamide solution of 4.500 g (6.00 mmol) of polyethylene glycol monomethyl ether 750 (average molecular weight 750) (Me-PEG-750) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. Under an ice bath, 10 ml of a dimethylformamide solution containing 2.315 g (2.93 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0095] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 9:1) to obtain the target compound (14) (yield 1.951 g, yield 47%).

[0096] When the mass spectrometry of the obtained compound was performed, m / z = 1401 (M +) A peak was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by the formula (14). Also, the purity of the compound represented by the formula (14) confirmed by high performance liquid chromatography (HPLC) was 99.0%.

[0097] "Example 5" (Synthesis of Compound 15)

[0098]

Chemical formula

[0099] Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.349 g (8.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 ml dimethylformamide solution of 8.040 g (8.00 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 10 ml of a dimethylformamide solution containing 1.579 g (2.00 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0100] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (15) (yield 1.476 g, yield 43%).

[0101] When mass spectrometry of the obtained compound was performed, m / z = 1709 (M +) A peak was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by the formula (15). Also, the purity of the compound represented by the formula (15) confirmed by high performance liquid chromatography (HPLC) was 99.0%.

[0102] "Example 6" (Synthesis of Compound 16)

[0103] [Chemical formula]

[0104] Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.393 g (9.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 ml dimethylformamide solution of 18.000 g (8.00 mmol) of polyethylene glycol monomethyl ether 2000 (average molecular weight 2000) (Me-PEG-2000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 1 hour. Under an ice bath, 20 ml of a dimethylformamide solution containing 2.398 g (3.00 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 5 hours.

[0105] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, purification was performed by silica gel column chromatography (ethyl acetate:methanol = 2:1) to obtain the target compound (16) (yield 6.169 g, yield 76%).

[0106] When mass spectrometry of the obtained compound was performed, m / z = 2722 (M +) A peak was confirmed at this position. From this, it was confirmed that the synthesized compound was the compound represented by the formula (16). Further, the purity of the compound represented by the formula (16) confirmed by high performance liquid chromatography (HPLC) was 99.2%.

[0107] "Example 7" (Synthesis of Compound 17)

[0108]

Chemical Structure

[0109] (Synthesis of 1,2,2,6,6 - pentamethyl - 4 - piperidone (1 - 3)) Under an argon stream, 15.524 g (100 mmol) of 2,2,6,6 - tetramethyl - 4 - piperidone, 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. After cooling to room temperature, 2.000 g (50 mmol) of sodium hydroxide was added and stirred for one hour. Then, suction filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained concentrate was distilled under reduced pressure (70 - 72 °C / 2 mmHg) to obtain the desired 1,2,2,6,6 - pentamethyl - 4 - piperidone (1 - 3) (yield 13.532 g, yield 80%).

[0110] (Synthesis of 7 - aza - 3,11 - dithiadispiro[5.1.5.3]hexadecane - 15 - one (1 - 4)) Under an argon stream, 12.373 g (73.1 mmol) of 1,2,2,6,6 - pentamethyl - 4 - piperidone (1 - 3) synthesized by the above reaction and 25.000 g (215.2 mmol) of 4 - oxothiane were dissolved in 100 ml of dimethyl sulfoxide (DMSO). 23.001 g (430.0 mmol) of ammonium chloride was added, and then 14 ml of a 40% aqueous solution of benzyltrimethylammonium hydroxide (Triron B) was added, and the mixture was stirred at 50 °C for 10 hours.

[0111] Water was added to the reaction solution, and the pH was adjusted to 1 with 5% hydrochloric acid, followed by washing 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 aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. After purification by silica gel column chromatography (hexane:ethyl acetate = 3:1 to 1:1), reprecipitation was carried out with hexane-ethyl acetate to obtain the target 7-aza-3,11-dithiadispiro[5.1.5.3]hexadecane-15-one (1-4) (yield 5.771 g, yield 29%).

[0112] <Synthesis of 4-hydroxy-2,2,6,6-tetraethylpiperidine (1-5)> Under an argon stream, 320 ml of ethanol (EtOH) was added to 5.500 g (20.3 mmol) of 7-aza-3,11-dithiadispiro[5.1.5.3]hexadecane-15-one (1-4) synthesized by the above reaction. 50.00 g of Raney-Ni (aqueous suspension, Ni>92.5%, Al<6.5%) was added while washing it in with 60 ml of ethanol, and the mixture was stirred at 65 °C for 72 hours.

[0113] The reaction solution was filtered through celite and concentrated under reduced pressure. After adjusting the pH to 12 with saturated aqueous potassium carbonate solution, it was extracted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Then, it was concentrated under reduced pressure, 7% hydrochloric acid was added, and it was washed with diethyl ether. After adjusting the pH to 12 with 5M aqueous potassium hydroxide solution, it was extracted with ethyl acetate and washed with saturated aqueous sodium chloride solution. After washing, it was dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane:ethyl acetate = 5:1) gave the target 4-hydroxy-2,2,6,6-tetraethylpiperidine (1-5) (yield 2.599 g, yield 60%).

[0114] <Synthesis of 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-6)> Under an argon stream, 2.599 g (12.2 mmol) of 4-hydroxy-2,2,6,6-tetraethylpiperidine (1-5) synthesized by the above reaction was dissolved in 400 ml of dichloromethane and cooled in an ice bath. 80 ml of a dichloromethane solution containing 24.4 mmol of meta-chloroperbenzoic acid (mCPBA) was added dropwise over 45 minutes, and the mixture was stirred at room temperature for 3 hours.

[0115] After concentrating the reaction solution under reduced pressure, the obtained crude product was dissolved in diethyl ether. After washing with saturated aqueous sodium carbonate and then saturated aqueous sodium chloride, it was dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to obtain the target 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-6) (yield 1.811 g, yield 65%).

[0116] <Synthesis of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-7)> Under an argon stream, 10 ml of dimethylformamide (DMF) was added to 0.786 g (18.0 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution of 3.425 g (15.0 mmol) of 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-6) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0117] Under an ice bath, 40 ml of a dimethylformamide solution containing 12.595 g (18.0 mmol) of 2-(3-bromo-2-(bromomethyl)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0118] 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, purification was performed by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) to obtain the target 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-7) (yield 7.355 g, yield 58%).

[0119] <Synthesis of Compound (17)> Under an argon stream, 3 ml of dimethylformamide (DMF) was added to 0.262 g (6.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 7 ml dimethylformamide solution of 4.500 g (6.00 mmol) of polyethylene glycol monomethyl ether 750 (average molecular weight 750) (Me-PEG-750) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. Under an ice bath, 10 ml of a dimethylformamide solution containing 2.536 g (3.00 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-7) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0120] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After the organic layer was concentrated under reduced pressure, purification was performed by silica gel column chromatography (ethyl acetate:methanol = 9:1) to obtain the target compound (17) (yield 1.951 g, yield 47%).

[0121] When mass spectrometry of the obtained compound was performed, m / z = 1457 (M +) A peak was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (17). Also, the purity of the compound represented by formula (17) confirmed by high performance liquid chromatography (HPLC) was 98.8%.

[0122] "Example 8" (Synthesis of Compound 18)

[0123] [Chemical formula]

[0124] Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.392 g (9.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 ml dimethylformamide solution of 9.045 g (9.00 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 10 ml of a dimethylformamide solution containing 2.536 g (3.00 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-7) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0125] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (18) (yield 2.654 g, yield 50%).

[0126] When mass spectrometry of the obtained compound was performed, m / z = 1765 (M +) A peak was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by the formula (18). Also, the purity of the compound represented by the formula (18) confirmed by high performance liquid chromatography (HPLC) was 99.0%.

[0127] "Example 9" (Synthesis of Compound 19)

[0128]

Chemical formula

[0129]

Chemical formula

[0130] (Synthesis of 2-(2-Bromopropoxy)tetrahydro-2H-pyran (1-8)) Under an argon stream, 4.170 g (30.0 mmol) of 3-bromo-1-propanol was dissolved in 150 ml of dichloromethane, and 3.30 ml (36.0 mmol) of 3,4-dihydro-2H-pyran and 1.508 g (6.00 mmol) of pyridinium p-toluenesulfonate (PPTS) were added in this order, and the mixture was stirred at room temperature for 18 hours.

[0131] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the target 2-(2-bromopropoxy)tetrahydro-2H-pyran (1-8) (yield 5.555 g, yield 83%).

[0132] (Synthesis of 2,2,6,6-Tetramethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidin-1-oxyl (1-9)) Under an argon stream, 10 mL of dimethylformamide (DMF) was added to 1.091 g (25.0 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 20 mL 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 the mixture was stirred at room temperature for 3 hours. Under an ice bath, 10 mL of a dimethylformamide solution containing 5.555 g (24.9 mmol) of 2-(2-bromopropoxy)tetrahydro-2H-pyran (1-8) synthesized by the above reaction was added, and the mixture was stirred at room temperature for 10 hours.

[0133] Water was added to the reaction solution, and after extraction with diethyl ether, the mixture was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, purification was performed by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 2,2,6,6-tetramethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-9) (yield 5.089 g, yield 65%).

[0134] <Synthesis of 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-10)> 5.089 g (16.2 mmol) of 2,2,6,6-tetramethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-9) synthesized by the above reaction and 0.407 g (1.62 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 mL of ethanol (EtOH), and the mixture was stirred at 78 °C for 3 hours.

[0135] The reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-10) (yield 3.358 g, yield 90%).

[0136] <Synthesis of Compound (1-11)> Under an argon stream, 10 mL of dimethylformamide (DMF) was added to 0.873 g (20.0 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 20 mL dimethylformamide solution of 3.358 g (14.6 mmol) of 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-10) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0137] Under an ice bath, 40 mL of a dimethylformamide solution containing 13.960 g (18.0 mmol) of 2-(3-bromo-2-(bromomethyl)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0138] 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, purification by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) gave the target compound (1-11) (yield 7.423 g, yield 60%).

[0139] <Synthesis of compound (19)> Under an argon stream, 5 mL of dimethylformamide (DMF) was added to 0.393 g (9.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 mL dimethylformamide solution of 9.045 g (9.00 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 10 mL of a dimethylformamide solution containing 2.542 g (3.00 mmol) of compound (1-11) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0140] 1 mL of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. The organic layer was concentrated under reduced pressure and then purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (19) (yield 2.444 g, yield 46%).

[0141] Mass spectrometry of the obtained compound showed that a peak was confirmed at m / z = 1771 (M + ). From this, it was confirmed that the synthesized compound was the compound represented by formula (19). Also, the purity of the compound represented by formula (19) confirmed by high performance liquid chromatography (HPLC) was 98.4%.

[0142] "Example 10" (Synthesis of Compound 20)

[0143] [Chemical formula]

[0144] [Chemical formula]

[0145] (Synthesis of 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (1-12)) Under an argon stream, 2.72 mL (20.0 mmol) of 6-bromo-1-hexanol was dissolved in 100 mL of dichloromethane, and 2.019 g (24.0 mmol) of 3,4-dihydro-2H-pyran and 1.005 g (4.00 mmol) of pyridinium p-toluenesulfonate (PPTS) were added in this order, and the mixture was stirred at room temperature for 18 hours.

[0146] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the target 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (1-12) (yield 4.667 g, yield 88%).

[0147] <Synthesis of 2,2,6,6 - tetramethyl - 4-(2 - (((tetrahydro - 2H - pyran - 2 - yl)oxy)hexyl)oxy)piperidine - 1 - oxyl (1 - 13)> Under an argon stream, 10 mL of dimethylformamide (DMF) was added to 0.768 g (17.6 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 20 - mL dimethylformamide solution of 2.756 g (16.0 mmol) of 4 - hydroxy - 2,2,6,6 - tetramethylpiperidine - 1 - oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Under an ice bath, 10 mL of a dimethylformamide solution containing 4.667 g (17.6 mmol) of 2 - ((6 - bromohexyl)oxy)tetrahydro - 2H - pyran (1 - 12) synthesized by the above reaction was added, and the mixture was stirred at room temperature for 10 hours.

[0148] Water was added to the reaction solution, and after extraction with diethyl ether, the mixture was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, purification was performed by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 2,2,6,6 - tetramethyl - 4-(2 - (((tetrahydro - 2H - pyran - 2 - yl)oxy)hexyl)oxy)piperidine - 1 - oxyl (1 - 13) (yield 4.267 g, yield 68%).

[0149] <Synthesis of 4-(6 - (hydroxyhexyl)oxy)-2,2,6,6 - tetramethylpiperidine - 1 - oxyl (1 - 14)> 4.267 g (11.6 mmol) of 2,2,6,6 - tetramethyl - 4-(2 - (((tetrahydro - 2H - pyran - 2 - yl)oxy)hexyl)oxy)piperidine - 1 - oxyl (1 - 13) synthesized by the above reaction and 0.292 g (1.16 mmol) of pyridinium p - toluenesulfonate (PPTS) were dissolved in 200 mL of ethanol (EtOH), and the mixture was stirred at 78 °C for 3 hours.

[0150] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(6-(hydroxyhexyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-14) (yield 2.672 g, yield 85%).

[0151] <Synthesis of Compound (1-15)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.480 g (11.0 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10 ml dimethylformamide solution of 2.672 g (9.81 mmol) of 4-(6-(hydroxyhexyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-14) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0152] Under an ice bath, 20 ml of a dimethylformamide solution containing 7.678 g (11.0 mmol) of 2-(3-bromo-2-(bromomethyl)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0153] Water was added to the reaction solution, and after extraction with diethyl ether, it was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) to obtain the target compound (1-15) (yield 5.846 g, yield 67%).

[0154] <Synthesis of Compound (20)> Under an argon stream, 5 mL of dimethylformamide (DMF) was added to 0.393 g (9.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 mL dimethylformamide solution of 9.045 g (9.00 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 10 mL of a dimethylformamide solution containing 2.668 g (3.00 mmol) of the compound (1-15) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0155] 1 mL of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After the organic layer was concentrated under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (20) (yield 2.284 g, yield 42%).

[0156] When the mass spectrometry of the obtained compound was performed, a peak was confirmed at m / z = 1813 (M + +). From this, it was confirmed that the synthesized compound was the compound represented by the formula (20). Also, the purity of the compound represented by the formula (20) confirmed by high performance liquid chromatography (HPLC) was 98.8%.

[0157] "Example 11" (Synthesis of Compound 21)

[0158]

Chemical formula

[0159]

Chemical formula

[0160] (Synthesis of 2-((6-bromododecyl)oxy)tetrahydro-2H-pyran (1-16)) Under an argon stream, 5.000 g (18.9 mmol) of 12-bromo-1-dodecanol was dissolved in 100 ml of dichloromethane, 2.019 g (24.0 mmol) of 3,4-dihydro-2H-pyran and 1.005 g (4.00 mmol) of pyridinium p-toluenesulfonate (PPTS) were added in this order, and the mixture was stirred at room temperature for 18 hours.

[0161] After the reaction solution was concentrated under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the target 2-((6-bromododecyl)oxy)tetrahydro-2H-pyran (1-16) (yield 5.282 g, yield 80%).

[0162] <Synthesis of 2,2,6,6-tetramethyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)dodecyl)oxy)piperidine-1-oxyl (1-17)> Under an argon stream, 10 ml of dimethylformamide (DMF) was added to 0.659 g (15.1 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 20-ml dimethylformamide solution of 2.360 g (13.7 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Under an ice bath, 10 ml of a dimethylformamide solution containing 5.282 g (15.1 mmol) of 1-bromo-12-(methoxymethyl)dodecane (1-16) synthesized by the above reaction was added, and the mixture was stirred at room temperature for 10 hours.

[0163] 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, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 2,2,6,6-tetramethyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)dodecyl)oxy)piperidine-1-oxyl (1-17) (yield 3.743 g, yield 62%).

[0164] <Synthesis of 4-(12-(Hydroxydodecyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-18)> 3.743 g (8.49 mmol) of 2,2,6,6-tetramethyl-4-(2-(((tetrahydro-2H-pyran-2-yl)oxy)dodecyl)oxy)piperidine-1-oxyl (1-17) synthesized by the above reaction and 0.214 g (0.85 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 ml of ethanol (EtOH) and stirred at 78 °C for 3 hours.

[0165] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(12-(hydroxydodecyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-18) (yield 2.513 g, yield 83%).

[0166] <Synthesis of Compound (1-19)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.371 g (8.50 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10 ml dimethylformamide solution of 2.513 g (7.05 mmol) of 4-(12-(hydroxydodecyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-18) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0167] Under an ice bath, 20 ml of a dimethylformamide solution containing 5.933 g (8.50 mmol) of 2-(3-bromo-2-(bromomethyl)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0168] 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, it was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) to obtain the target compound (1-19) (yield 3.981 g, yield 58%).

[0169] <Synthesis of Compound (21)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.393 g (9.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 ml dimethylformamide solution of 9.045 g (9.00 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 20 ml of a dimethylformamide solution containing 2.921 g (3.00 mmol) of the compound (1-19) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0170] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (21) (yield 2.846 g, yield 50%).

[0171] When the mass spectrometry of the obtained compound was performed, a peak was confirmed at m / z = 1898 (M + +). From this, it was confirmed that the synthesized compound was the compound represented by formula (21). Also, the purity of the compound represented by formula (21) confirmed by high performance liquid chromatography (HPLC) was 99.0%.

[0172] 「Example 12」 (Synthesis of Compound 22)

[0173]

Chemical formula

[0174]

Chem.

[0175] <Synthesis of 2,2,6,6 - tetraethyl - 4-(2 - ((tetrahydro - 2H - pyran - 2 - yl)oxy)propoxy)piperidine - 1 - oxyl (1 - 21)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.524 g (12.0 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10 - ml dimethylformamide solution containing 2.284 g (10.0 mmol) of 4 - hydroxy - 2,2,6,6 - tetraethylpiperidine - 1 - oxyl (1 - 6) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Under an ice bath, 10 ml of a dimethylformamide solution containing 2.677 g (12.0 mmol) of 2-(2 - bromopropoxy)tetrahydro - 2H - pyran (1 - 8) synthesized by the above reaction was added, and the mixture was stirred at room temperature for 10 hours.

[0176] Water was added to the reaction solution, and after extraction with diethyl ether, it was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 2,2,6,6 - tetraethyl - 4-(2 - ((tetrahydro - 2H - pyran - 2 - yl)oxy)propoxy)piperidine - 1 - oxyl (1 - 21) (yield 2.149 g, yield 58%).

[0177] <Synthesis of 4-(3 - hydroxypropoxy)-2,2,6,6 - tetraethylpiperidine - 1 - oxyl (1 - 22)> 2,2,6,6 - Tetraethyl - 4-(2 - ((tetrahydro - 2H - pyran - 2 - yl)oxy)propoxy)piperidine - 1 - oxyl (1 - 21) 2.149 g (5.80 mmol) synthesized by the above reaction and pyridinium p - toluenesulfonate (PPTS) 0.146 g (0.58 mmol) were dissolved in 200 ml of ethanol (EtOH) and stirred at 78 °C for 3 hours.

[0178] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(3 - hydroxypropoxy)-2,2,6,6 - tetraethylpiperidine - 1 - oxyl (1 - 22) (yield 1.495 g, yield 90%).

[0179] <Synthesis of compound (1 - 23)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.275 g (6.30 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10 - ml dimethylformamide solution of 1.495 g (5.22 mmol) of 4-(3 - hydroxypropoxy)-2,2,6,6 - tetraethylpiperidine - 1 - oxyl (1 - 22) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0180] Under an ice bath, 20 ml of a dimethylformamide solution containing 4.397 g (6.30 mmol) of 2-(3 - bromo - 2-(bromomethyl)-2 - (((1,1,1,3,3,3 - hexafluoro - 2 - (trifluoromethyl)propan - 2 - yl)oxy)methyl)propoxy)-1,1,1,3,3,3 - hexafluoro - 2 - (trifluoromethyl)propane (1 - 1) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0181] 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, it was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 - 9:1) to obtain the target compound (1 - 23) (yield 2.924 g, yield 62%).

[0182] <Synthesis of Compound (22)> Under an argon stream, 5 mL of dimethylformamide (DMF) was added to 0.393 g (9.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 mL dimethylformamide solution of 9.045 g (9.00 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 10 mL of a dimethylformamide solution containing 2.924 g (3.24 mmol) of the compound (1-23) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0183] 1 mL of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (22) (yield 2.960 g, yield 50%).

[0184] When mass spectrometry of the obtained compound was performed, a peak was confirmed at m / z = 1827 (M + +). From this, it was confirmed that the synthesized compound was the compound represented by formula (22). Also, the purity of the compound represented by formula (22) confirmed by high performance liquid chromatography (HPLC) was 98.9%.

[0185] "Example 13" (Synthesis of Compound 23)

[0186]

Chemical formula

[0187] <Synthesis of Compound (1-24)> Under an argon stream, 20.000 g (20.0 mmol) of polyethylene glycol 1000 (average molecular weight 1000) was dissolved in 100 ml of dichloromethane. 2.019 g (24.0 mmol) of 3,4-dihydro-2H-pyran and 1.005 g (4.00 mmol) of pyridinium p-toluenesulfonate (PPTS) were added in this order, and the mixture was stirred at room temperature for 18 hours.

[0188] The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the target compound (1-24) (yield 13.008 g, yield 60%).

[0189] <Synthesis of compound (1-25)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.393 g (9.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 30 ml dimethylformamide solution of 9.756 g (9.00 mmol) of the compound (1-24) synthesized by the above reaction was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 1 hour.

[0190] Under an ice bath, 20 ml of a dimethylformamide solution containing 2.398 g (3.00 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 5 hours.

[0191] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off by distillation under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After the organic layer was concentrated under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (1-25) (yield 2.404 g, yield 45%).

[0192] <Synthesis of compound (23)> 2.404 g (1.35 mmol) of the compound (1-25) synthesized by the above reaction was dissolved in 50 ml of methanol (MeOH) and 50 ml of tetrahydrofuran (THF). 10 ml of 37% hydrochloric acid was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After concentration under reduced pressure, purification was carried out by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target compound (23) (yield 1.038 g, yield 75%).

[0193] Mass spectrometry of the obtained compound showed a peak at m / z = 1695 (M + ). From this, it was confirmed that the synthesized compound was the compound represented by formula (23). Also, the purity of the compound represented by formula (23) confirmed by high performance liquid chromatography (HPLC) was 98.0%.

[0194] "Example 14" (Synthesis of Compound 24)

[0195]

Chemical formula

[0196]

Chemical formula

[0197] Synthesis of <1,3-dibromo-2-methyl-2-propanol (1-26) Under an argon stream, 2.000 g (15.0 mmol) of 3-bromo-2-methyl-1-propene was dissolved in 90 ml of dimethyl sulfoxide (DMSO) and 5 ml of water, and the solution was cooled to -10 °C. 5.270 g (30.0 mmol) of N-bromosuccinimide (NBS) was added little by little over 15 minutes, and the mixture was stirred for 3 hours.

[0198] Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was distilled under reduced pressure to obtain the target 1,3-dibromo-2-methyl-2-propanol (1-26) (yield 1.565 g, yield 45%).

[0199] <Synthesis of 2-((1,3-dibromo-2-methylpropan-2-yl)oxy)tetrahydro-2H-pyran (1-27)> Under an argon stream, 1.565 g (6.75 mmol) of 1,3-dibromo-2-methyl-2-propanol (1-26) synthesized by the above reaction was dissolved in 100 ml of dichloromethane, and 0.681 g (8.10 mmol) of 3,4-dihydro-2H-pyran and 0.339 g (1.35 mmol) of pyridinium p-toluenesulfonate (PPTS) were added in this order, and the mixture was stirred at room temperature for 18 hours.

[0200] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain 2-((1,3-dibromo-2-methylpropan-2-yl)oxy)tetrahydro-2H-pyran (1-27) (yield 1.707 g, yield 80%).

[0201] <Synthesis of 4-(3-bromo-2-methyl-2-((2-(tetrahydro-2H-pyranyl)oxy)propoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-28)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.236 g (5.40 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10 ml dimethylformamide solution of 0.775 g (4.50 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Under an ice bath, 10 ml of a dimethylformamide solution containing 1.707 g (5.40 mmol) of 2-((1,3-dibromo-2-methylpropan-2-yl)oxy)tetrahydro-2H-pyran (1-27) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 10 hours.

[0202] Water was added to the reaction solution, and after extraction with diethyl ether, it was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(3-bromo-2-methyl-2-((2-(tetrahydro-2H-pyranyl)oxy)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-28) (yield 1.283 g, yield 70%).

[0203] <Synthesis of 4-(3-bromo-2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-29)> 1.283 g (3.15 mmol) of 4-(3-bromo-2-methyl-2-((2-(tetrahydro-2H-pyranyl)oxy)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-28) synthesized by the above reaction and 0.080 g (0.32 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 ml of ethanol (EtOH) and stirred at 78 °C for 3 hours.

[0204] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(3-bromo-2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-29) (yield 0.916 g, yield 90%).

[0205] <Synthesis of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-30)> Under an argon stream, 5.000 g (25.1 mmol) of 2-(bromomethyl)-2-(hydroxymethyl)-1,3-propanediol, 27.777 g (105.9 mmol) of triphenylphosphine (PPh3), 10.000 g of molecular sieves (MS) 4A, and 130 ml of tetrahydrofuran (THF) were mixed and cooled in an ice bath. 20.6 ml (105.9 mmol) of diisopropyl azodicarboxylate (DIAD) was added dropwise over 10 minutes and stirred for 20 minutes. 25.000 g (105.9 mmol) of nonafluoro-tert-butanol was added all at once, and the mixture was stirred at 45 °C for 72 hours.

[0206] After filtering the reaction solution, it was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain the target compound 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-30) (yield 16.055 g, yield 75%).

[0207] <Compound (1-31) synthesis> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.149 g (3.40 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10 ml dimethylformamide solution of 0.916 g (2.84 mmol) of 4-(3-bromo-2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-29) synthesized by the above reaction was added dropwise over 10 minutes and stirred at room temperature for 3 hours.

[0208] Under an ice bath, 30 mL of a dimethylformamide solution containing 2.133 g (2.50 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-30) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0209] Water was added to the reaction solution, and after extraction with diethyl ether, the mixture was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, purification was performed by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) to obtain the target compound (1-31) (yield 1.588 g, yield 58%).

[0210] <Synthesis of Compound (24)> Under an argon stream, 5 mL of dimethylformamide (DMF) was added to 0.218 g (5.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 mL dimethylformamide solution of 3.750 g (5.00 mmol) of polyethylene glycol monomethyl ether 750 (average molecular weight 750) (Me-PEG-750) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 20 mL of a dimethylformamide solution containing 1.588 g (1.45 mmol) of compound (1-31) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0211] 1 mL of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and after extraction with ethyl acetate, the mixture was dried over magnesium sulfate. After concentration of the organic layer under reduced pressure, purification was performed by silica gel column chromatography (ethyl acetate:methanol = 9:1) to obtain the target compound (24) (yield 1.330 g, yield 52%).

[0212] Mass spectrometry of the obtained compound showed that m / z = 1723 (M +) A peak was confirmed at this position. 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 99.0%.

[0213] "Example 15" (Synthesis of Compound 25)

[0214]

Chemical Structure

[0215] Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.262 g (6.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 ml dimethylformamide solution of 6.030 g (6.00 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 20 ml of a dimethylformamide solution containing 2.191 g (2.00 mmol) of the compound (1-31) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0216] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After concentrating the organic layer under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (25) (yield 1.898 g, yield 47%).

[0217] When mass spectrometry of the obtained compound was performed, a peak was confirmed at m / z = 2015 (M + ) at this position. From this, it was confirmed that the synthesized compound was the compound represented by formula (25). Also, the purity of the compound represented by formula (25) confirmed by high performance liquid chromatography (HPLC) was 98.5%.

[0218] "Example 16" (Synthesis of Compound 26)

[0219]

Chem.

[0220] Under an argon stream, 5 mL of dimethylformamide (DMF) was added to 0.262 g (6.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15 mL dimethylformamide solution of 12.000 g (6.00 mmol) of polyethylene glycol monomethyl ether 2000 (average molecular weight 2000) (Me-PEG-2000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 20 mL of a dimethylformamide solution containing 2.191 g (2.00 mmol) of the compound (1-31) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0221] 1 mL of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After the organic layer was concentrated under reduced pressure, it was purified by silica gel column chromatography (ethyl acetate:methanol = 2:1) to obtain the target compound (26) (yield 3.677 g, yield 61%).

[0222] When mass spectrometry of the obtained compound was performed, a peak was confirmed at m / z = 3017 (M + +). From this, it was confirmed that the synthesized compound was the compound represented by formula (26). Also, the purity of the compound represented by formula (26) confirmed by high performance liquid chromatography (HPLC) was 98.1%.

[0223] "Example 17" (Synthesis of Compound 27)

[0224]

Chem.

[0225] [Chemical]

[0226] <Synthesis of 4-(3-bromo-2-methyl-2-((2-(tetrahydro-2H-pyranyl)oxy)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-32)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.524 g (12.0 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. Then, 10 ml of a dimethylformamide solution containing 2.284 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-6) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Under an ice bath, 10 ml of a dimethylformamide solution containing 3.792 g (12.0 mmol) of 2-((1,3-dibromo-2-methylpropan-2-yl)oxy)tetrahydro-2H-pyran (1-27) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 10 hours.

[0227] Water was added to the reaction solution, and after extraction with diethyl ether, it was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(3-bromo-2-methyl-2-((2-(tetrahydro-2H-pyranyl)oxy)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-32) (yield 2.735 g, yield 59%).

[0228] <Synthesis of 4-(3-bromo-2-hydroxy-2-methylpropoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-33)> 4-(3-Bromo-2-methyl-2-((2-(tetrahydro-2H-pyranyl)oxy)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-32) 2.735 g (5.90 mmol) synthesized by the above reaction and pyridinium p-toluenesulfonate (PPTS) 0.148 g (0.59 mmol) were dissolved in 200 ml of ethanol (EtOH) and stirred at 78 °C for 3 hours.

[0229] After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target 4-(3-bromo-2-hydroxy-2-methylpropoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-33) (yield 1.947 g, yield 87%).

[0230] <Synthesis of Compound (1-34)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.262 g (6.00 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10 ml dimethylformamide solution of 1.947 g (5.13 mmol) of 4-(3-bromo-2-hydroxy-2-methylpropoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-33) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0231] Under an ice bath, 30 ml of a dimethylformamide solution containing 3.412 g (4.00 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-30) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0232] 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, purification was carried out by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) to obtain the target compound (1-34) (yield 2.533 g, yield 55%).

[0233] <Synthesis of Compound (27)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.288 g (6.60 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15-ml dimethylformamide solution of 6.633 g (6.60 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 20 ml of a dimethylformamide solution containing 2.533 g (2.20 mmol) of the compound (1-34) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0234] 1 ml of water was added to the reaction solution, and dimethylformamide was distilled off under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and then dried over magnesium sulfate. After the organic layer was concentrated under reduced pressure, purification was carried out by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (27) (yield 2.009 g, yield 44%).

[0235] When mass spectrometry of the obtained compound was performed, a peak was confirmed at m / z = 2071 (M + +). From this, it was confirmed that the synthesized compound was the compound represented by formula (27). Also, the purity of the compound represented by formula (27) confirmed by high performance liquid chromatography (HPLC) was 98.1%.

[0236] 「Example 18」 (Synthesis of Compound 28)

[0237]

Chemical formula

[0238] [Chemistry]

[0239] [Synthesis of Compounds (1 - 35)] Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.524 g (12.0 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. Then, 10 ml of a dimethylformamide solution containing 2.303 g (10.0 mmol) of 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-10) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0240] Under an ice bath, 10 ml of a dimethylformamide solution containing 3.792 g (12.0 mmol) of 2-((1,3-dibromo-2-methylpropan-2-yl)oxy)tetrahydro-2H-pyran (1-27) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 10 hours. Water was added to the reaction solution, and after extraction with diethyl ether, it was washed with water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target compound (1-35) (yield 2.560 g, yield 55%).

[0241] [Synthesis of Compounds (1 - 36)] 2.560 g (5.50 mmol) of the compound (1-35) synthesized by the above reaction and 0.138 g (0.55 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 ml of ethanol (EtOH), and the mixture was stirred at 78 °C for 3 hours. After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the target compound (1-36) (yield 1.867 g, yield 89%).

[0242] [Synthesis of Compounds (1 - 37)] Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.240 g (5.50 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 10-ml dimethylformamide solution of 1.867 g (4.89 mmol) of the compound (1-36) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours.

[0243] Under an ice bath, 30 ml of a dimethylformamide solution containing 3.412 g (4.00 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-30) synthesized by the above reaction was added, and the mixture was stirred at 60 °C for 10 hours.

[0244] 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, purification was performed by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 9:1) to obtain the target compound (1-37) (yield 2.399 g, yield 52%).

[0245] <Synthesis of Compound (28)> Under an argon stream, 5 ml of dimethylformamide (DMF) was added to 0.272 g (6.24 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 15-ml dimethylformamide solution of 6.271 g (6.24 mmol) of polyethylene glycol monomethyl ether 1000 (average molecular weight 1005) (Me-PEG-1000) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 40 minutes. Under an ice bath, 20 ml of a dimethylformamide solution containing 2.399 g (2.08 mmol) of the compound (1-37) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 4 hours.

[0246] 1 mL of water was added to the reaction solution, and dimethylformamide was distilled off by distillation under reduced pressure. Water was added to the concentrate, and after extraction with ethyl acetate, it was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure and then purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to obtain the target compound (28) (yield 1.901 g, yield 44%).

[0247] Mass spectrometry of the obtained compound showed a peak at m / z = 2073 (M + ). From this, it was confirmed that the synthesized compound was the compound represented by formula (28). Also, the purity of the compound represented by formula (28) confirmed by high performance liquid chromatography (HPLC) was 98.4%.

[0248] "Comparative Example 1" (Synthesis of Compound A1)

[0249]

Chemical formula

[0250] Under an argon stream, 3 mL of dimethylformamide (DMF) was added to 0.154 g (3.52 mmol) of 55% sodium hydride (NaH), and the mixture was stirred at room temperature for 10 minutes. A 5 mL dimethylformamide solution of 0.69 mL (3.52 mmol) of tetraethylene glycol monomethyl ether was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. Under an ice bath, 7 mL of a dimethylformamide solution containing 1.851 g (2.35 mmol) of 4-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidin-1-oxyl (1-2) synthesized by the above reaction was added, and the mixture was stirred at 50 °C for 14 hours.

[0251] Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 to 1:2) to obtain the target compound (A1) (yield 1.513 g, yield 70%).

[0252] Mass spectrometry of the obtained compound showed a peak at m / z = 917 (M + ). From this, it was confirmed that the synthesized compound was the compound represented by formula (A1). Also, the purity of the compound represented by formula (A1) confirmed by high performance liquid chromatography (HPLC) was 99.7%.

[0253] "Comparative Example 2" 1,3-Bis(2,2,2-trifluoro-1,1-bis(trifluoromethyl(ethoxy)-2,2-bis((2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxy)methyl)propane (PERFECTA, manufactured by Aldrich) represented by the following formula (A2) was prepared.

[0254] [Chemical formula]

[0255] For the compounds of Examples 1 to 18, Comparative Example 1 and Comparative Example 2 thus obtained, a water solubility test was performed by the methods shown below. The results are shown in Table 1.

[0256] (Water solubility test) 1 mL of water and the compound were placed in a 2 mL vial so that the concentration of the compound in the solution would be 5 mmol / L or 50 mmol / L. Then, it was stirred for 1 minute using a vortex mixer (trade name: VTX-3000L, manufactured by LMS) at a temperature of 50°C to 60°C. Thereafter, it was mixed for 5 minutes using an ultrasonic cleaner (trade name: MCD-10, manufactured by AS ONE) at a temperature of 30°C. Stirring with the vortex mixer and mixing with the ultrasonic cleaner were each repeated 3 to 5 times. Thereafter, the vial was allowed to stand and cooled to room temperature, the mixing state was visually confirmed, and evaluation was performed based on the following criteria. The results are shown in Table 1.

[0257] <Criterion> Dissolution; The compound placed in water exists without separating in the solution, and the solution is transparent. Dispersion; The compound placed in water exists without separating in the solution, and the solution is opaque. No dispersion; The compound placed in water is separated in the solution.

[0258] [Table 1]

[0259] As shown in Table 1, for the compounds (11) to (13) of Examples 1 to 3 in which the number of ethylene glycol chains n in the fluorine-containing compound represented by the general formula (1) is 6 to 12, even when the concentration of the compound was 5 mmol / L or 50 mmol / L, they were uniformly dispersed in water. Also, for the compounds (14) to (28) of Examples 4 to 18 in which the number of ethylene glycol chains n in 13 R is 17 to 45, even when the concentration of the compound was 5 mmol / L or 50 mmol / L, they were dissolved in water. 13 On the other hand, the compound (A1) of Comparative Example 1 in which the number of ethylene glycol chains n in R when applied to the general formula (1) is 4, and the compound (A2) of Comparative Example 2 having no ethylene glycol chain did not mix with water even when the concentration of the compound was 5 mmol / L. 13

[0260] ​​ Also, for the compounds of Examples 1 to 18, Comparative Example 1 and Comparative Example 2, by the methods shown below, 19 the F spin-lattice relaxation time (T1) was measured. The results are shown in Table 2.

[0261] ( 19 (Measurement of F spin-lattice relaxation time (T1)) The compound was dissolved in deuterated chloroform at a concentration of 5 mM, and using a 500 MHz NMR apparatus, by the iterative rotation method, under the conditions shown below 19 the longitudinal relaxation time (T1) of the F nucleus was measured. (Measurement conditions) NMR apparatus: JNM-ECA500 (manufactured by JEOL Ltd.) Measurement temperature: 36 °C Pulse width: 90° 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] Number of integrations: 128 times

[0262] [Table 2]

[0263] As shown in Table 1, the compounds (11) to (28) of Examples 1 to 18 having a nitroxide radical, compared with the compound (A2) of Comparative Example 2 having no nitroxide radical, 19 had a very short F spin-lattice relaxation time (T1). Therefore, the compounds of Examples 1 to 18 can increase the signal amount per unit time compared with the compound of Comparative Example 2, and high-sensitivity images can be obtained.

[0264] Also, for the compounds of Example 5 (Compound 15), Example 15 (Compound 25) and Comparative Example 2 (Compound A2), 5 mM chloroform solutions were prepared respectively, and under the following imaging conditions19 The T1-weighted image (phantom image) of F-MRI was obtained. (Imaging conditions) Device: MRI BioSpec117 / 11 manufactured by Burker Pulse sequence: RAREVTR Repetition time TR = 300 ms Echo time TE = 6 ms Number of phase encodings = 64 Number of echo trains = 1 Flip angle = 180° Number of acquisitions = 16 times Total imaging time: 5.1 minutes

[0265] Figure 1 shows the 19 F-MRI 19 F spin-lattice relaxation time (T1)-weighted image. Figure 2 is a photograph showing the positions of Example 5 (Compound 15), Example 15 (Compound 25), and Comparative Example 2 (Compound A2) on the image shown in Figure 1. 19 F-MRI 19 F spin-lattice relaxation time (T1)-weighted image, and is a photograph showing the positions of Example 5, 15 and Comparative Example 2 on the image shown in Figure 1.

[0266] Also, using image processing software (ImageJ), the SNR (signal-to-noise ratio) of Example 5, 15 and Comparative Example 2 was calculated from the gray values at the positions of Example 5, 15 and Comparative Example 2 in the (T1)-weighted image shown in Figure 1. The results are shown in Table 3.

[0267] [Table 3]

[0268] As shown in Figures 1 and 2, the images of Example 5 (Compound 15) and Example 15 (Compound 25) were of higher brightness compared to the image of Comparative Example 2 (Compound A2). Also, as shown in Table 3, it was confirmed that Example 5 (Compound 15) and Example 15 (Compound 25) could obtain a large SNR even with an imaging time as short as about 5 minutes when compared with Comparative Example 2 (Compound A2). From these results, it was shown that by using Example 5 (Compound 15) and Example 15 (Compound 25) as contrast agents for MRI diagnosis using fluorine as the detection nucleus, images that are sufficiently applicable to clinical practice can be obtained.

[0269] From the results of the above examples, it was confirmed that the fluorine-containing compound of the present invention can obtain highly sensitive magnetic resonance images and is easily dispersed in an aqueous medium.

Claims

1. A fluorine-containing compound characterized by being 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 unsubstituted alkyl group having 1 to 5 carbon atoms. R １１ is represented by the following formula (1-1) or the following formula (1-2). R １２ is represented by the following formula (1-3) when R １１ is the following formula (1-1), and is -CH １１ when R ３ is the following formula (1-2). R １３ is represented by the following formula (1-4). X is the following formula (1-5) or -CH ２ -. ) -CH ２ -O-C(CF ３ ) ｒ H ３－ｒ ...(1-1) (In formula (1-1), r is an integer of 1 to 3.) -O-CH ２ -C[CH ２ -O-C(CF ３ ) ｓ H ３－ｓ ｐ (CH ３ ) ３－ｐ ...(1-2)​ (In formula (1-2), s and p are each independently an integer of 1 to 3.) -CH ２ -O-C(CF ３ ) ｔ H ３－ｔ ...(1-3) (In formula (1-3), t is an integer of 0 to 3.) -CH ２ -O(CH ２ CH ２ O) ｎ Y ··· (1 - 4) (In formula (1-4), Y is -CH ３ or -H. n is an integer from 6 to 45.) -(CH ２ ) ｍ -O-CH ２ -...(1 - 5) (In formula (1-5), m is an integer from 1 to 12. In formula (1-5), -(CH ２ )) ｍ - is bonded to the oxygen atom bonded to the carbon at the 4-position of the piperidine ring.)

2. R in the general formula (1) １１ is represented by the formula (1-1), r in the formula (1-1) is 3, and R １２ is represented by the formula (1-3), and t in the formula (1-3) is 3. The fluorine-containing compound according to claim 1.

3. R in the general formula (1) １１ is represented by the formula (1-2), and s and p in the formula (1-2) are 3. The fluorine-containing compound according to claim 1.

4. In the formula (1-4), Y is -CH ３ The fluorine-containing compound according to any one of claims 1 to 3, wherein it is

5. The fluorine-containing compound according to any one of Claims 1 to 4, wherein n in the formula (1-4) is an integer of 15 or more.

6. R in the general formula (1) １ 、R ２ 、R ３ 、R ４ is each independently a methyl group or an ethyl group, and the fluorine-containing compound according to any one of claims 1 to 5.

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

8. A contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, which contains the fluorine-containing compound according to any one of Claims 1 to 7.

Images