Compounds and derivatives reagents, and methods of synthesis of compounds

Abstract

Compound and derivative reagent, and method for synthesizing compound. [Problem] To provide a compound capable of further improving the detection sensitivity of a compound having a diene (particularly, a vitamin D metabolite) can be cited. [Solution] A compound represented by the following general formula (100) is provided. (In the general formula (100), n is an integer of 2 or more.)

Description

Technical Field

[0001] This invention relates to compounds and derivative reagents, as well as methods for synthesizing compounds. Background Technology

[0002] The quantification of vitamin D metabolites is now widely conducted using liquid chromatography-tandem mass spectrometry (LC / MS / MS), which incorporates a tandem mass spectrometer. Furthermore, it is known that derivatization with a derivatizing reagent can improve ionization efficiency and chromatographic separation. The derivatizing reagent used here has a 1,2,4-triazolline-3,5-dione structure.

[0003] Regarding the derivatization of vitamin D metabolites, for example, 4-[4-dimethylaminophenyl]-1,2,4-triazolline-3,5-dione (DAPTAD) has been proposed (see Non-Patent Literature 1). The derivatization of vitamin D metabolites is carried out by subjecting the diene moiety of a vitamin D metabolite (optionally containing vitamin D) to a Diels-Alder reaction to form a derivative of the vitamin D metabolite.

[0004] Existing technical documents

[0005] Non-patent literature

[0006] Non-patent literature 1: Rapid Commun. Mass Spectrum. 2013, 27, 2453-2460 Summary of the Invention

[0007] The problem the invention aims to solve

[0008] However, there are concerns that the technology proposed in Non-Patent Literature 1 may not be able to further improve the detection sensitivity of vitamin D metabolites.

[0009] Therefore, the present invention has been made in view of this situation, and the first object is to provide: a compound capable of further improving the detection sensitivity of vitamin D metabolites, a derivative reagent containing the compound for derivativeizing vitamin D metabolites, and a method for synthesizing the compound.

[0010] Furthermore, in this invention, the scope of the analyte is not limited to vitamin D metabolites, but can be expanded to include compounds containing dienes. Therefore, a second object of this invention is to provide: a compound capable of further improving the detection sensitivity of compounds containing dienes, a derivatization reagent containing the compound for derivatizing compounds containing dienes, and a method for synthesizing the compound.

[0011] Solution for solving the problem

[0012] In order to solve the above-mentioned objectives, the inventors conducted in-depth research and surprisingly, successfully developed a compound that can further improve the detection sensitivity of compounds containing dienes (especially vitamin D metabolites), a derivatization reagent containing the compound for derivatizing compounds containing dienes (especially vitamin D metabolites), and a method for synthesizing the compound, thus completing the present invention.

[0013] That is, in this invention, as a first aspect, a compound represented by the following general formula (100) is provided.

[0014]

[0015] In the above general formula (100), n is an integer greater than or equal to 2.

[0016] In the compounds of the first aspect of the present invention, the compounds represented by the aforementioned general formula (100) can be compounds represented by the following formula (I).

[0017]

[0018] Furthermore, as a second aspect of the present invention, a derivative reagent is provided for derivativeizing a compound having a diene, which contains a compound represented by the following general formula (100).

[0019]

[0020] In the above general formula (100), n is an integer greater than or equal to 2.

[0021] In the derivative reagent of the second aspect of the present invention, the compound represented by the aforementioned general formula (100) can be the compound represented by the following formula (I).

[0022]

[0023] Furthermore, as a third aspect of the present invention, a method for synthesizing a compound represented by the following general formula (100) is provided, comprising: a nucleophilic substitution reaction of an aryl halogen with a saturated heterocyclic amine compound.

[0024]

[0025] In the above general formula (100), n is an integer greater than or equal to 2.

[0026] Furthermore, in the synthesis method of the third aspect of the present invention, the compound represented by the aforementioned general formula (100) can be the compound represented by the following formula (I).

[0027] The aforementioned saturated heterocyclic amine compound can be piperidine.

[0028]

[0029] The effects of the invention

[0030] According to the present invention, the detection sensitivity of compounds containing dienes (especially vitamin D metabolites) can be further improved. It should be noted that the effects described herein are not necessarily limited to those described herein, and any effect described in this specification may be applicable. Attached Figure Description

[0031] Figure 1 A graph showing the analytical results of PIPTAD derivatives and DAPTAD derivatives of vitamin D metabolites.

[0032] Figure 2 The figure shows the NMR spectral data of 1,2,4-triazolidine-3,5-dione (VIII). Detailed Implementation

[0033] The following describes a suitable mode for implementing this technology. The embodiments described below illustrate an example of a representative implementation of this technology and are not intended to be interpreted narrowly as limiting the scope of this technology.

[0034] It should be noted that the explanations are presented in the following order.

[0035] 1. Summary of the Invention

[0036] 2. First Embodiment (Example 1 of the Compound)

[0037] 3. Second Embodiment (Example of Derivatization Reagent)

[0038] 4. Third Embodiment (Example of a method for synthesizing a compound)

[0039] 5. Fourth Embodiment (Example 2 of the Compound)

[0040] 6. Example

[0041] 6-1. Example 1

[0042] 6-2. Example 2

[0043] 6-3. Analysis Results

[0044] <1. Summary of the Invention>

[0045] First, a summary of the present invention will be given. The present invention relates to: compounds and derivative-derivating agents for derivativeizing compounds having dienes (especially vitamin D metabolites), and methods for synthesizing such compounds.

[0046] In existing technologies, the detection and quantification of trace amounts of active vitamin D (e.g., 1,25-dihydroxyvitamin D3, 1,25(OH)2D3) present in organisms requires the use of antibody column concentration (e.g., see non-patent literature Clinica Chimica Acta 2017, 473, 173-179). However, the sensitivity of the derivative reagent DAPTAD is not sufficient, and for more accurate quantification, it is desirable to develop derivative reagents with higher sensitivity than DAPTAD. For example, 1,25(OH)2D3 is an important metabolite central to the physiological function of vitamin D; therefore, there is a significant need for its accurate quantification.

[0047] This invention was made in view of the above circumstances. This invention is for the high-sensitivity detection of vitamin D metabolites in clinical testing using mass spectrometry, and can be used regardless of the manufacturer of the mass spectrometer. Subsequently, the quantification of vitamin D metabolites based on mass spectrometry has become widespread in the field of clinical testing. Therefore, it is necessary to obtain the same values ​​anytime, anywhere using devices from any manufacturer. This invention compensates for the differences in device types among manufacturers by improving detection sensitivity, thereby facilitating widespread adoption.

[0048] The following describes in detail suitable methods for carrying out the present invention. The embodiments described below illustrate an example of a representative embodiment of the present invention and are not intended to be interpreted narrowly as limiting the scope of the invention.

[0049] <2. First Embodiment (Example 1 of the Compound)>

[0050] The compound of the first embodiment of the present invention (Example 1 of the compound) is the compound shown in the following general formula (100) (4-cycloalkylaminophenyl-1,2,4-triazolline-3,5-dione).

[0051]

[0052] In the general formula (100), n is an integer greater than or equal to 2.

[0053] The compound represented by general formula (100) is preferably the compound represented by formula (I) below. The compound represented by formula (I) is the compound represented by general formula (100) in which n = 5 (a saturated heterocycle of a 6-membered ring), and is 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolline-3,5-dione (PIPTAD).

[0054]

[0055] <3. Second Embodiment (Example of Derivatization Reagent)>

[0056] The derivative reagent in the second embodiment of the present invention (example of a derivative reagent) is a derivative reagent for derivativeizing a compound having a diene, and contains a compound represented by the following general formula (100). Moreover, the derivative reagent containing the compound represented by the following general formula (100) is a Cooksen-type derivative reagent.

[0057]

[0058] In the general formula (100), n is an integer greater than or equal to 2.

[0059] The derivative reagent of the second embodiment of the present invention is for quantitative analysis based on a tandem mass spectrometer (LC-MS / MS) connected to a liquid chromatograph. It is used to derivative compounds containing dienes, particularly vitamin D metabolites in biological samples such as blood, serum, plasma, urine, saliva, cerebrospinal fluid, and fingernails / toenails, for high-sensitivity detection. Thus, the derivative reagent provided according to the present invention can be used to derivative compounds containing dienes contained in biological samples. The aforementioned biological samples are not limited to those listed above and can be liquid or solid components contained in organisms (particularly mammals, and more particularly humans).

[0060] Furthermore, compounds containing dienes can be quantitatively reacted and derivatized with compounds of general formula (100) contained in the derivatization reagent of the second embodiment of the present invention via a Diels-Alder reaction. For example, in quantitative analysis based on LC / ESI (electrospray ionization)-MS / MS, compounds containing dienes (e.g., vitamin D metabolites) can be detected with high sensitivity and high selectivity.

[0061] The compound represented by general formula (100) is preferably the compound represented by formula (I) below. The compound represented by formula (I) is a compound in which n = 5 (a saturated heterocyclic structure of a 6-membered ring) in the compound represented by general formula (100), and is 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolline-3,5-dione (PIPTAD).

[0062]

[0063] The following describes in detail the diene-containing compounds that are the targets of derivativeization.

[0064] Examples of compounds containing dienes include compounds containing s-cis-dienes and compounds containing s-trans-dienes. It should be noted that when a compound containing s-trans-dienes is derivatized using a derivatizing agent containing a compound of the aforementioned general formula (100) (e.g., PIPTAD) or a derivatizing agent containing a compound of the following general formula (100-1), as a preheating treatment, it is necessary to isomerize the compound containing s-trans-dienes into a compound containing s-cis-dienes.

[0065] Next, specific examples of compounds having s-cis-diene will be described. There are no particular limitations on the compounds having s-cis-diene; for example, steroidal compounds, vitamin D, or vitamin D metabolites can be cited.

[0066] Among compounds containing s-cis-diene, there are no particular limitations on steroidal compounds. They are not limited to naturally occurring compounds, but can also be synthetic compounds or analogues. Examples include 7-dehydrocholesterol, ergosterol, conjugated linoleic acid, and vitamin A.

[0067] Among compounds containing s-cis-diene, vitamin D, in a broad classification, belongs to open-ring steroidal compounds. It is a collective term for vitamin D2 derived from plant-based foods and vitamin D3 derived from animal-based foods and skin. Both are considered to be homologous compounds differing only in their side-chain structures, metabolized similarly in the human body, and possessing equivalent physiological activities. Therefore, in this specification, the two are sometimes referred to simply as vitamin D. Additionally, in this specification, vitamin D and vitamin D metabolites are sometimes also referred to simply as vitamin D. These refer to any molecular type related to vitamin D generated through the conversion of vitamin D, whether naturally occurring or synthetically produced, or from intermediates and products of vitamin D metabolism.

[0068] There are no particular limitations on the molecular types of vitamin D (vitamin D metabolites), but examples include: 25-hydroxyvitamin D3 (25(OH)D3), 25-hydroxyvitamin D2 (25(OH)D2), 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), 1α,25-dihydroxyvitamin D2 (1,25(OH)2D2), 23,25-dihydroxyvitamin D3 (23,25(OH)2D3), 25 Vitamin D molecules can be 26-dihydroxyvitamin D3 (25,26(OH)2D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), 4β,25-dihydroxyvitamin D3 (4β,25(OH)2D3), 25-hydroxyvitamin D3-23,26-lactone (25(OH)D3Lactone), 1α,25-dihydroxyvitamin D3-23,26-lactone (1,25(OH)2D3Lactone), etc. Vitamin D molecules can be isomers of the aforementioned molecules; for example, 3-epio-25-hydroxyvitamin D3 (3-epio-25(OH)D3) can be included. In addition, these vitamin D molecules can also be sulfates, such as 25-hydroxyvitamin D3-3β-sulfate (25(OH)D3S) and 25-hydroxyvitamin D3-3β-glucuronic acid (25(OH)D3Gluc). It should be noted that the quantitative analysis of vitamin D can include multiple molecular types of these vitamin D (vitamin D metabolites).

[0069] For example, the reaction formula for the derivative reaction of 25(OH)D3 with PIPTAD is as follows.

[0070]

[0071] In process S200, PIPTAD(I) is added to the s-cis-diene moiety of 25(OH)D3(1) to form 25(OH)D3-PIPTAD derivative (2). Due to the electron-donating effect of the alkyl group, the electron density of the nitrogen atom in 25(OH)D3-PIPTAD derivative (2) is increased, thus making it easier for protons to be added and ionized.

[0072] <4. Third Embodiment (Example of a method for synthesizing a compound)>

[0073] The method for synthesizing the compound in the third embodiment of the present invention (example of a method for synthesizing a compound) is a method for synthesizing a compound represented by the following general formula (100), which includes: a nucleophilic substitution reaction of an aryl halogen with a saturated heterocyclic amine compound.

[0074]

[0075] In the general formula (100), n is an integer greater than or equal to 2.

[0076] The compound represented by general formula (100) is preferably the compound represented by formula (I) below. The compound represented by formula (I) is a compound in which n = 5 (a saturated heterocycle of a 6-membered ring) in the compound represented by general formula (100), and is 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolline-3,5-dione (PIPTAD).

[0077] In the nucleophilic substitution reaction of the synthetic method of the compound shown in Formula (I), piperidine is used as the saturated heterocyclic amine compound. Furthermore, in the nucleophilic substitution reaction of the synthetic method of the compound shown in Formula (I), methyl p-fluorobenzoate is suitable as the aryl halogen.

[0078]

[0079] <5. Fourth Embodiment (Example 2 of the Compound)>

[0080] The compound of the fourth embodiment of the present invention (Example 2 of the compound) is the compound shown in the following general formula (100-1).

[0081]

[0082] In general formula (100-1), X is a N (nitrogen) atom, a P (phosphorus) atom, an O (oxygen) atom, or a S (sulfur) atom. In general formula (100-1), n ​​is an integer greater than or equal to 1, and n1 is an integer greater than or equal to 1.

[0083] The reagent containing the compound shown in general formula (100-1) can, in the same manner as the compound of the first embodiment of the present invention (Example 1 of the compound), be used to derivatize the compound having a diene. Specific examples of compounds having a diene are described above.

[0084] The synthesis method of the compound represented by general formula (100-1) can also include, in the same way as the synthesis method of the compound represented by general formula (100) above, a nucleophilic substitution reaction of an aryl halogen with a saturated heterocyclic amine compound.

[0085] <6. Examples>

[0086] The following examples illustrate the effects of the present invention. It should be noted that the scope of the present invention is not limited to these examples.

[0087] <6-1. Example 1>

[0088] Synthesis of 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolline-3,5-dione (PIPTAD(I))]

[0089] Based on the following reaction scheme, 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolline-3,5-dione (PIPTAD(I)) was synthesized.

[0090]

[0091] Synthesis of methyl 1,4-(1-piperidinyl)benzoate (III) [Step S1]

[0092] Methyl p-fluorobenzoate (II) (256 μL, 2 mmol) was dissolved in toluene (5 mL), and potassium carbonate (140 mg, 1.0 mmol) and piperidine (311 μL, 6.0 mmol) were added. The mixture was heated under reflux for 12 hours. The reaction solution was diluted with ethyl acetate (25 mL) and washed with brine (25 mL × 2). The organic layer was dried over magnesium sulfate (MgSO4), and the solvent was removed under reduced pressure to give methyl 4-(1-piperidinyl)benzoate (III) as a colorless solid (403 mg, 1.8 mmol).

[0093] Synthesis of 2,4-(1-piperidinyl)benzoic acid (IV) [Step S2]

[0094] Methyl 4-(1-piperidinyl)benzoate (III) (360 mg, 1.6 mmol) was mixed with sodium hydroxide (100 mg, 2.5 mmol) in 10 mL of 50% methanol aqueous solution and stirred overnight at 100 °C. The solvent was removed under reduced pressure, and the residue was dissolved in 2 mL of water. The solution was then chilled and acidified with 10% hydrochloric acid. The precipitated colorless powder of 4-(1-piperidinyl)benzoic acid (IV) was recovered by vacuum filtration while thoroughly washing it in cold water (290 mg, 1.4 mmol).

[0095] Synthesis of 3,4-(1-piperidinyl)benzoic acid azide (V) [Step S3]

[0096] Dissolve 4-(1-piperidinyl)benzoic acid (IV) (205 mg, 1.0 mmol) in DMF (1 mL), add DPPA (265 μL, 1.2 mmol) and triethylamine (500 μL) dropwise, and stir at ice temperature for 1.5 hours. Dilute the reaction solution with ethyl acetate (25 mL) and wash with saline (25 mL × 3). Dry the organic layer on magnesium sulfate (MgSO4), remove the solvent by vacuum distillation, and feed the residue into a Wakogel-filled container. (R)(Registered Trademark) Silica gel column chromatography (150 × 12 mm id) using 60N (particle size 63–212 μm). The hexane-ethyl acetate (9:1, v / v) elution fraction was collected, and the solvent was removed under reduced pressure to give 4-(1-piperidinyl)benzoic acid azide (V) as a colorless solid (170 mg, 0.74 mmol).

[0097] Synthesis of 4,4-(1-piperidinyl)phenylaminourea (VII) [Steps S4 and S5]

[0098] 4-(1-piperidinyl)benzoic acid azide (V) (170 mg, 0.74 mmol) was dissolved in toluene (2 mL) and refluxed for 20 minutes to convert to compound (VI) [Step S4]. Without separating compound (VI), a benzene solution of ethyl carbamate (110 mg, 1.1 mmol) (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, followed by reflux for another 1 hour. After natural cooling, the resulting precipitate was washed with cold toluene while being filtered to give 4-(1-piperidinyl)phenylaminourea (VII) as a colorless solid (210 mg, 0.69 mmol).

[0099] Synthesis of 5,4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolidine-3,5-dione (VIII) [Step S6]

[0100] Add 5 mL of an aqueous solution of potassium carbonate (90 mg, 0.64 mmol) to 4-(1-piperidinyl)phenylaminourea (VII) (100 mg, 0.32 mmol) and stir at 90 °C for 3 hours. While confirming the pH using Universal pH paper, add acetic acid to the reaction solution to adjust the pH to approximately 6. After removing the solvent under reduced pressure, feed the residue into a container filled with Wakogel. (R) ODS column chromatography (300×10mm id) of (registered trademark) 100C18 (particle size 63~212μm). The elution fraction of MeOH-water (3:7, v / v) was collected, the solvent was removed under reduced pressure, and the fraction was recrystallized with water to give a colorless solid (48mg, 0.18mmol) of 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolidine-3,5-dione (VIII).

[0101] 1 H-NMR(CD3OD)δ7.24(d,J=9.0Hz,2H),7.04(d,J=9.0Hz,2H),3.20(m,4H),1.70(m,4H),1.61(m,2H)( Figure 2 ).

[0102] Synthesis of 6,4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolline-3,5-dione (PIPTAD)(I) [Step S7]

[0103] Suspend 2 mg of 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolidine-3,5-dione (VIII) in 10 mL of ethyl acetate, add 3 mg of iodophenyl diacetate, and stir at room temperature for 3 hours. Centrifuge the reaction mixture (1000 g, 10 min), and store the supernatant as an ethyl acetate solution (2 μg / 10 μL) of 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolidine-3,5-dione (PIPTAD) (I). Note that this solution should be stored at -18 °C.

[0104] <6-2. Example 2>

[0105] [4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolline-3,5-dione (PIPTAD(I)) (Analysis of Vitamin D Metabolites Based on PIPTAD(I))]

[0106] For each of the five concentrated and dried vitamin D metabolites (25(OH)D3, 3-epi(epi)-25(OH)D3, 25(OH)D2, 24,25(OH)2D3, and 1,25(OH)2D3), 100 μL of an ethyl acetate solution of PIPTAD(I) (2 μg / 10 μL) was added, and the mixture was allowed to stand at room temperature for 30 minutes. After the reaction was stopped by adding 20 μL of ethanol, the mixture was purged with nitrogen and dried. The solutions were then redissolved in 100 μL of 50% acetonitrile solution, and 10 μL was analyzed by LC-MS / MS.

[0107] It should be noted that, as a comparative example, for the five vitamin D metabolites (25(OH)D3, 3-epi(epi)-25(OH)D3, 25(OH)D2, 24,25(OH)2D3, 1,25(OH)2D3), respectively, an ethyl acetate solution (2 μg / 10 μL) of DAPTAD(3) (4-[4-dimethylaminophenyl]-1,2,4-triazolline-3,5-dione) was used.

[0108] For example, the reaction formula for the derivative reaction of 25(OH)D3 with DAPTAD is as follows.

[0109]

[0110] In process S500, DAPTAD (3) is added to the s-cis-diene portion of 25(OH)D3 (1) to form a 25(OH)D3-DAPTAD derivative (4).

[0111] The LC / MS / MS was performed on a Xevo TQ-XS triple quadrupole mass spectrometer connected to a Japan Waters Corp. ACQUITY UPLC I-Class system.

[0112] (LC analysis conditions)

[0113] The analytical column is C18. The LC analysis conditions for the analytes 25(OH)D3, 3-epi(table)-25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 are shown in Table 1 below. The LC analysis conditions for the analytes 1,25(OH)2D3 are shown in Table 2 below.

[0114] (MS / MS analysis conditions)

[0115] The ionization conditions were ESI (electrospray ionization) positive electrode. The analytes (PIPTAD derivatives of the vitamin D metabolites of the above 5 components and DAPTAD derivatives of the vitamin D metabolites of the above 5 components) and MRM parameters are shown in Table 3 below.

[0116] It should be noted that the data parsing uses QuanLinx, the automated processing system within Waters (registered trademark) MassLinx 4.1 software.

[0117] [Table 1]

[0118]

[0119] [Table 2]

[0120]

[0121] [Table 3]

[0122]

[0123] <6-3. Analysis Results>

[0124] The analysis results are shown below. Figure 1 . Figure 1The horizontal axis, from left to right, represents the derivatives of 25(OH)D3-PIPTAD, 25(OH)D3-DAPTAD, 3-epi(epi)-25(OH)D3-PIPTAD, 3-epi(epi)-25(OH)D3-DAPTAD, 25(OH)D2-PIPTAD, 25(OH)D2-DAPTAD, 24,25(OH)2D3-PIPTAD, 24,25(OH)2D3-DAPTAD, 1,25(OH)2D3-PIPTAD, and 1,25(OH)2D3-DAPTAD. The vertical axis represents ionic strength.

[0125] Figure 1 The results of a comparison of the ionic strength (Area Comparison) of PIPTAD-based and DAPTAD-based derivatives for the five vitamin D metabolites (25(OH)D3, 3-epi(epi)-25(OH)D3, 25(OH)D2, 24,25(OH)2D3, 1,25(OH)2D3) are shown.

[0126] like Figure 1 As shown, the ionic strength of the 25(OH)D3-PIPTAD derivative is 83494, and the ionic strength of the 25(OH)D3-DAPTAD derivative is 50386. That is, for 25(OH)D3, PIPTAD achieves approximately 1.7 times the sensitivity improvement compared to DAPTAD.

[0127] like Figure 1 As shown, the ionic strength of the 3-epi(epi)-25(OH)D3-PIPTAD derivative is 10887, which is equal to the ionic strength of the 3-epi(epi)-25(OH)D3-DAPTAD derivative, which is 6480. That is, for 3-epi(epi)-25(OH)D3, PIPTAD achieves approximately 1.7 times the sensitivity improvement compared to DAPTAD.

[0128] like Figure 1 As shown, the ionic strength of the 25(OH)D2-PIPTAD derivative is 13786, and the ionic strength of the 25(OH)D2-DAPTAD derivative is 5868. That is, for 25(OH)D2, PIPTAD achieves approximately 2.3 times the sensitivity improvement compared to DAPTAD.

[0129] like Figure 1As shown, the ionic strength of the 24,25(OH)2D3-PIPTAD derivative is 8586, and the ionic strength of the 24,25(OH)2D3-DAPTAD derivative is 6445. That is, for 24,25(OH)2D3, PIPTAD achieves approximately 1.3 times the sensitivity improvement compared to DAPTAD.

[0130] like Figure 1 As shown, the ionic strength of the 1,25(OH)₂D₃-PIPTAD derivative is 6376.3, and the ionic strength of the 1,25(OH)₂D₃-DAPTAD derivative is 2871. That is, for 1,25(OH)₂D₃, PIPTAD achieves approximately 2.2 times the sensitivity improvement compared to DAPTAD.

[0131] However, the present invention is not limited to the above-described embodiments and examples, and various modifications can be made without departing from the spirit of the present invention.

[0132] Furthermore, the effects described in this manual are merely examples and are not limited; other effects may also be possible.

[0133] Alternatively, the present invention may also take the following configuration. [1]

[0135] A compound represented by the following general formula (100).

[0136]

[0137] (In this general formula (100), n is an integer greater than or equal to 2.) [2]

[0139] According to the compound described in [1], wherein the compound represented by the aforementioned general formula (100) is the compound represented by the following formula (I).

[0140] [3]

[0142] A derivativeling agent for derivativeling a compound having a diene, comprising a compound represented by the general formula (100) below.

[0143]

[0144] (In this general formula (100), n is an integer greater than or equal to 2.) [4]

[0146] According to the derivative reagent described in [3], wherein the compound represented by the aforementioned general formula (100) is the compound represented by the following formula (I).

[0147] [5]

[0149] A method for synthesizing a compound represented by the following general formula (100) comprises: a nucleophilic substitution reaction of an aryl halogen with a saturated heterocyclic amine compound.

[0150]

[0151] (In this general formula (100), n is an integer greater than or equal to 2.) [6]

[0153] According to the synthetic method described in [5], wherein the compound represented by the aforementioned general formula (100) is the compound represented by the following formula (I),

[0154] The aforementioned heterocyclic amine compound is piperidine.

[0155]

Claims

1. A compound represented by formula (I) below, 2. A derivativeizing agent for derivativeizing a compound having a diene, comprising a compound represented by formula (I) below.

3. A method for synthesizing a compound represented by formula (I) below, comprising: Nucleophilic substitution reactions of aryl halides with saturated heterocyclic amine compounds.

Images