JP7328657B2 - Compounds and derivatization reagents, and methods for synthesizing compounds - Google Patents

Description

The present invention relates to compounds and derivatizing reagents, and methods of synthesizing compounds.

In quantifying vitamin D metabolites, a liquid chromatography tandem mass spectrometer (hereinafter sometimes referred to as "LC/MS/MS") equipped with a tandem mass spectrometer (hereinafter also referred to as "MS/MS") ) is widely used. It is known that ionization efficiency and chromatographic separation are improved by derivatization with a derivatization reagent. The derivatizing reagents used herein have a 1,2,4-triazoline-3,5-dione structure.

As a derivatization method for vitamin D metabolites, for example, 4-[4-dimethylaminophenyl]-1,2,4-triazoline-3,5-dione (DAPTAD) has been proposed (see Non-Patent Document 1). reference). A method of derivatizing a vitamin D metabolite is to subject the diene moiety of the vitamin D metabolite (which may include vitamin D) to a Diels-Alder reaction to form a derivative of the vitamin D metabolite.

Rapid Commun. Mass Spectrum. 2013, 27, 2453-2460

However, the technique proposed in Non-Patent Document 1 may not be able to further improve the detection sensitivity of vitamin D metabolites.

Therefore, the present invention has been made in view of such circumstances, and provides compounds capable of further improving the detection sensitivity of vitamin D metabolites, and vitamin D metabolites containing the compounds. A first object is to provide a derivatization reagent for derivatization and a method for synthesizing the compound.

In addition, in the present invention, the range of analysis targets is not limited to vitamin D metabolites, and the range of analysis targets can be expanded to include diene-containing compounds. Therefore, the present invention provides a compound capable of further improving the detection sensitivity of a diene-containing compound, a derivatization reagent for derivatizing a diene-containing compound containing the compound, and a synthesis of the compound. A second object is to provide a method.

The present inventors have conducted intensive studies to solve the above-mentioned objects, and surprisingly, further improvement in detection sensitivity of compounds having a diene (in particular, vitamin D metabolites are included). To develop a derivatization reagent for derivatizing a compound having a diene (particularly vitamin D metabolites) containing the compound and the compound, and a method for synthesizing the compound It succeeded and came to complete this invention.

That is, the present invention provides, as a first aspect, a compound represented by the following general formula (100).

In the above general formula (100), n is an integer of 2 or more.

In the compound according to the first aspect of the present invention, the compound represented by the general formula (100) may be a compound represented by the following formula (I).

As a second aspect, the present invention provides a derivatization reagent for derivatizing a compound having a diene, which contains a compound represented by the following general formula (100).

In the above general formula (100), n is an integer of 2 or more.

In the derivatization reagent of the second aspect of the present invention, the compound represented by the general formula (100) may be a compound represented by the following formula (I).

Furthermore, the present invention provides, as a third aspect, a method for synthesizing a compound represented by the following general formula (100), comprising a nucleophilic substitution reaction between an aryl halide and a saturated heterocyclic amine compound. do.

In the above general formula (100), n is an integer of 2 or more.

Furthermore, in the synthesis method of the third aspect of the present invention, the compound represented by the general formula (100) may be a compound represented by the following formula (I),
The saturated heterocyclic amine compound may be piperidine.
In addition, the present invention
A method for synthesizing a compound represented by the formula (I), comprising a nucleophilic substitution reaction between an aryl halide and a saturated heterocyclic amine compound,
the heterocyclic amine compound is piperidine,
wherein the aryl halide is methyl p-fluorobenzoate;
The synthetic method is also provided.

ADVANTAGE OF THE INVENTION According to this invention, the further improvement of the detection sensitivity of the compound (especially vitamin D metabolites is mentioned) which has a diene can be implement|achieved. Note that the effects described here are not necessarily limited, and may be any of the effects described in this specification.

FIG. 1 is a diagram showing the analysis results of a PIPTAD derivative of vitamin D metabolites and a DAPTAD derivative of vitamin D metabolites. FIG. 2 shows NMR spectrum data of 1,2,4-triazolidine-3,5-dione (VIII).

A preferred embodiment for implementing the present technology will be described below. The embodiments described below are examples of representative embodiments of the present technology, and the scope of the present technology should not be interpreted narrowly.

The description will be given in the following order.
1. Outline of the present invention 2 . First Embodiment (Compound Example 1)
3. Second embodiment (example of derivatization reagent)
4. Third Embodiment (Example of Compound Synthesis Method)
5. Fourth Embodiment (Compound Example 2)
6. Example 6-1. Example 1
6-2. Example 2
6-3. result of analysis

<1. Outline of the present invention>
First, the outline of the present invention will be explained. The present invention relates to compounds and derivatization reagents for derivatizing compounds with dienes, particularly vitamin D metabolites, and methods of synthesizing the compounds.

Conventional technology requires concentration using an antibody column to detect and quantify trace amounts of active vitamin D (e.g., 1,25-dihydroxyvitamin D ₃ and 1,25(OH) ₂ D ₃ ) in vivo. (See, for example, Non-Patent Document Clinica Chimica Acta 2017, 473, 173-179.). However, the derivatization reagent DAPTAD is not sufficiently sensitive, and for more accurate quantification, the development of a derivatization reagent with higher sensitivity than DAPTAD is desired. For example, 1,25(OH) _2D3 is an important metabolite that is central to the physiological action of vitamin D _, so its accurate quantification is in great demand.

The present invention has been made in view of the above circumstances. INDUSTRIAL APPLICABILITY The present invention is directed to the field of clinical testing, particularly the highly sensitive detection of vitamin D metabolites using mass spectrometry, and can be used regardless of the manufacturer of the mass spectrometer. In the future, in order to widely spread the quantification of vitamin D metabolites by mass spectrometry in the field of clinical testing, it is essential that the same value can be obtained anytime, anywhere with any manufacturer's equipment. It supports the popularization by filling the difference between models.

Preferred embodiments for carrying out the present invention will be described in detail below. The embodiments described below are examples of representative embodiments of the present invention, and the scope of the present invention should not be construed narrowly.

<2. First Embodiment (Compound Example 1)>
The compound of the first embodiment (Compound Example 1) according to the present invention is a compound represented by the following general formula (100) (4-cycloalkylaminophenyl-1,2,4-triazoline-3,5 -dione).

In general formula (100), n is an integer of 2 or more.

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

<3. Second Embodiment (Example of Derivatization Reagent)>
The derivatization reagent of the second embodiment (example of derivatization reagent) according to the present invention is a derivatization agent for derivatizing a compound having a diene, which contains a compound represented by the following general formula (100): Reagent. A derivatization reagent containing a compound represented by the following general formula (100) is a Cookson-type derivatization reagent.

In general formula (100), n is an integer of 2 or more.

The derivatization reagent of the second embodiment of the present invention is a diene-containing compound, particularly blood, for quantitative analysis by a tandem mass spectrometer (LC-MS/MS) connected to liquid chromatography. A reagent for derivatizing and sensitively detecting vitamin D metabolites in biological specimens such as serum, plasma, urine, saliva, cerebrospinal fluid, and nails. Thus, the derivatizing reagents provided by the present invention may be used to derivatize diene-containing compounds contained in biological specimens. The biological sample is not limited to those listed above, and may be a liquid component or a solid component contained in living organisms (especially mammals, more particularly humans).

Then, the compound having a diene is quantitatively reacted with the compound represented by the general formula (100) contained in the derivatization reagent of the second embodiment according to the present invention by a Diels-Alder reaction to be derivatized, For example, in quantitative analysis by LC/ESI (electrospray ionization)-MS/MS, diene-containing compounds (eg, vitamin D metabolites) can be detected with high sensitivity and high selectivity.

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

A compound having a diene to be derivatized is specifically described in detail below.

Examples of diene-containing compounds include s-cis-diene-containing compounds and s-trans-diene-containing compounds. The compound having s-trans-diene is a derivatization reagent containing the compound represented by the general formula (100) (for example, PIPTAD) or a compound represented by the general formula (100-1) described later. When derivatization is performed with a derivatization reagent containing , a preheat treatment is required to isomerize the compound with the s-trans-diene to the compound with the s-cis-diene.

Next, specific examples of compounds having s-cis-diene are described. Compounds having s-cis-diene include, but are not limited to, steroids, vitamin D or vitamin D metabolites, and the like.

Among compounds having s-cis-diene, steroids are not particularly limited, but are not limited to naturally occurring compounds, and may be synthetic compounds or analogues thereof, such as 7-dehydrocholesterol and ergosterol. , conjugated linoleic acid, vitamin A and the like.

Among compounds with s-cis-diene, vitamin D belongs to secosteroids in a broad sense, and is a general term for vitamin _D2 derived from plant foods and vitamin _D3 derived from animal foods and skin production. . Both are homologues differing only in side chain structure, are metabolized in the same manner in the human body, and are considered to have equivalent physiological activities. Therefore, in the present specification, the two are sometimes simply referred to as vitamin D without distinguishing between them. In addition, in this specification, vitamin D and vitamin D metabolites may be simply referred to as vitamin D. These refer to any molecular species related to vitamin D produced by conversion of vitamin D, such as naturally or synthetically obtained vitamin D or intermediates and products of vitamin D metabolism.

The molecular species of such vitamin D (vitamin D metabolite) is not particularly limited, but examples include 25-hydroxyvitamin D ₃ (25(OH)D ₃ ), 25-hydroxyvitamin D ₂ (25(OH) D ₂ ), 1α,25-dihydroxyvitamin D ₃ (1,25(OH) ₂ D ₃ ), 1α,25-dihydroxyvitamin D ₂ (1,25(OH) ₂ D ₂ ), 23,25-dihydroxyvitamin D ₃ (23,25(OH) ₂ D ₃ ), 25,26-dihydroxyvitamin D ₃ (25,26(OH) ₂ D ₃ ), 24,25-dihydroxyvitamin D ₃ (24,25(OH) ₂ D ₃ ), 4β,25-dihydroxyvitamin D ₃ (4β,25(OH) ₂ D ₃ ), 25-hydroxyvitamin D ₃ -23,26-lactone (25(OH)D ₃ Lactone), 1α,25- dihydroxyvitamin D ₃ -23,26-lactone (1,25(OH) ₂ D ₃ Lactone) and the like. The molecular species of vitamin D may be isomers of the aforementioned molecular species, such as 3-epi-25-hydroxyvitamin D ₃ (3-epi-25(OH)D ₃ ). Further, these molecular species of vitamin D may be sulfates, such as 25-hydroxyvitamin D ₃ -3β-sulfate (25(OH)D ₃ S) and 25-hydroxyvitamin D ₃ -3β- glucuronic acid (25(OH) _D3Gluc ) and the like. In quantitative analysis of vitamin D, a plurality of molecular species of these vitamin D (vitamin D metabolites) may be included.

For example, the reaction formula for the derivatization reaction between 25(OH) _D3 and PIPTAD is as follows.

In step S200, PIPTAD (I) is added to the s-cis-diene moiety of 25(OH)D ₃ (1) to form 25(OH)D ₃ -PIPTAD derivative (2). In the 25(OH)D ₃ -PIPTAD derivative (2), the electron-donating effect of the alkyl group increases the electron density of the nitrogen atom, making it easier to add protons and ionize.

<4. Third Embodiment (Example of Method for Synthesizing Compound)>
A method for synthesizing a compound according to the third embodiment (an example of a method for synthesizing a compound) according to the present invention includes a nucleophilic substitution reaction between an aryl halide and a saturated heterocyclic amine compound, represented by the following general formula ( 100) is a method for synthesizing the compound represented by

In general formula (100), n is an integer of 2 or more.

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

Piperidine is used as the saturated heterocyclic amine compound in the nucleophilic substitution reaction in the method for synthesizing the compound represented by formula (I). In the nucleophilic substitution reaction in the method for synthesizing the compound represented by formula (I), methyl p-fluorobenzoate is preferably used as the aryl halide.

<5. Fourth Embodiment (Compound Example 2)>
The compound of the fourth embodiment (compound example 2) according to the present invention is a compound represented by the following general formula (100-1).

In general formula (100-1), X is an N (nitrogen) atom, P (phosphorus) atom, O (oxygen) atom or S (sulfur) atom, and n is 1 in general formula (100-1) n1 is an integer of 1 or more.

A reagent containing a compound represented by the general formula (100-1) can derivatize a compound having a diene, like the compound of the first embodiment (compound example 1) of the present invention. . Specific examples of diene-containing compounds are as described above.

The method for synthesizing the compound represented by the general formula (100-1) is the same as the method for synthesizing the compound represented by the general formula (100) described above, using an aryl halide and a saturated heterocyclic amine compound. can include nucleophilic substitution reactions of

<6. Example>
EXAMPLES The effects of the present invention will be specifically described below with reference to examples. In addition, the scope of the present invention is not limited to the examples.

<6-1. Example 1>
[Synthesis of 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazoline-3,5-dione (PIPTAD(I))]
Based on the scheme below, 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazoline-3,5-dione (PIPTAD(I)) was synthesized.

1. Synthesis of methyl 4-(1-piperidinyl)benzoate (III) [Step S1]
Methyl p-fluorobenzoate (II) (256 μL, 2 mmol) was dissolved in toluene (5 mL), potassium carbonate (140 mg, 1.0 mmol) and piperidine (311 μL, 6.0 mmol) were added, and the mixture was heated under reflux for 12 hours. let me The reaction solution was diluted with ethyl acetate (25 mL) and washed with saturated brine (25 mL×2). The organic layer was dried over magnesium sulfate (MgSO ₄ ) and the solvent was distilled off under reduced pressure to give methyl 4-(1-piperidinyl)benzoate (III) as a colorless solid (403 mg, 1.8 mmol).

2. Synthesis of 4-(1-piperidinyl)benzoic acid (IV) [Step S2]
4-(1-Piperidinyl)methyl benzoate (III) (360 mg, 1.6 mmol) and sodium hydroxide (100 mg, 2.5 mmol) were mixed with 10 mL of 50% aqueous methanol solution and heated at 100°C. Stir overnight. The solvent was distilled off under reduced pressure and the residue was dissolved in 2 mL of water. The solution was then ice-cooled and acidified by adding 10% hydrochloric acid. The precipitated colorless powder of 4-(1-piperidinyl)benzoic acid (IV) was washed well with cold water and collected by suction filtration (290 mg, 1.4 mmol).

3. Synthesis of 4-(1-piperidinyl)benzoic acid azide (V) [Step S3]
4-(1-piperidinyl)benzoic acid (IV) (205 mg, 1.0 mmol) was dissolved in DMF (1 mL), DPPA (265 μL, 1.2 mmol), and triethylamine (500 μL) were added dropwise, and the mixture was cooled with ice. Stirred for 1.5 hours. The reaction solution was diluted with ethyl acetate (25 mL) and washed with saturated brine (25 mL×3). The organic layer was dried over magnesium sulfate (MgSO ₄ ), the solvent was distilled off ^under reduced pressure, and the residue was subjected to silica gel column chromatography (150 × 12 mm i.d.). Hexane-ethyl acetate (9:1, v/v) elution fractions were collected, the solvent was distilled off under reduced pressure, and 4-(1-piperidinyl)benzoic acid azide (V) was obtained as a colorless solid (170 mg, 0.74 mmol). Obtained.

4. Synthesis of 4-(1-piperidinyl)phenyl semicarbazide (VII) [Step S4 and Step S5]
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]. A benzene solution (1 mL) of ethyl carbazate (110 mg, 1.1 mmol) was added to the reaction solution without isolating compound (VI), and the mixture was stirred at room temperature for 1 hour and then refluxed for an additional hour. After allowing to cool, the resulting precipitate was washed with cold toluene and suction filtered to obtain 4-(1-piperidinyl)phenyl semicarbazide (VII) as a colorless solid (210 mg, 0.69 mmol).

5. Synthesis of 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolidine-3,5-dione (VIII) [Step S6]
An aqueous solution (5 mL) of potassium carbonate (90 mg, 0.64 mmol) was added to 4-(1-piperidinyl)phenyl semicarbazide (VII) (100 mg, 0.32 mmol), and the mixture was stirred at 90° C. for 3 hours. Acetic acid was added to the reaction solution to adjust the pH to about 6 while checking with a universal pH test paper. After the solvent was distilled off under reduced pressure, the residue was subjected to ODS column chromatography (300×10 mm id) packed with ^Wakogel® 100C18 (particle size 63-212 μm). MeOH-water (3:7, v/v) Eluted fractions were collected, the solvent was distilled off under reduced pressure, recrystallization was performed with water, and 4-[4-(1-piperidinyl)phenyl]-
A colorless solid of 1,2,4-triazolidine-3,5-dione (VIII) (48 mg, 0.18 mmol) was obtained.
¹ H-NMR (CD ₃ OD) δ 7.24 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 3.20 (m, 4H), 1.70 (m, 4H), 1.61 ( m, 2H) (Fig. 2).

6. Synthesis of 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazoline-3,5-dione (PIPTAD) (I) [Step S7]
4-[4-(1-piperidinyl)phenyl]-1,2,4-triazolidine-3,5-dione (VIII) (2 mg) was suspended in ethyl acetate (10 mL) and iodobenzene diacetate (3 mg). was added and stirred at room temperature for 3 hours. The reaction mixture was centrifuged (1000 g, 10 min), and the supernatant was treated with 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazoline-3,5-dione (PIPTAD) (I) in acetic acid. Stored as an ethyl solution (2 μg/10 μL). This solution was stored at -18°C.

<6-2. Example 2>
[Analysis of vitamin D metabolites by 4-[4-(1-piperidinyl)phenyl]-1,2,4-triazoline-3,5-dione (PIPTAD(I)) (PIPTAD(I))]
Concentrated to dryness, the five vitamin D metabolites (25(OH)D ₃ , 3-epi-25(OH)D ₃ , 25(OH)D ₂ , 24,25(OH) ₂ D ₃ , 1,25(OH) ₂ D ₃ ), 100 μL of a solution of PIPTAD(I) in ethyl acetate (2 μg/10 μL) was added and allowed to stand at room temperature for 30 minutes. After stopping the reaction by adding 20 μL of ethanol, the mixture was dried by blowing nitrogen gas. After redissolving with 100 μL of 50% acetonitrile solution, 10 μL was analyzed using LC-MS/MS.

As comparative examples, five vitamin D metabolites (25(OH)D ₃ , 3-epi (epi)-25(OH)D ₃ , 25(OH)D ₂ , 24,25(OH) ₂ D ₃ , 1,25(OH) ₂ D ₃ ), DAPTAD (3) (4-[4-dimethylaminophenyl]-1,2,4-triazoline-3,5-dione) in ethyl acetate A solution (2 μg/10 μL) was used.

For example, the reaction formula for the derivatization reaction between 25(OH) _D3 and DAPTAD is as follows.

In step S500, DAPTAD (3) is added to the s-cis-diene moiety of 25(OH)D ₃ (1) to form 25(OH)D ₃ -DAPTAD derivative (4).

LC/MS/MS was used by connecting a Xevo TQ-XS triple quadrupole mass spectrometer to an ACQUITY UPLC I-Class system manufactured by Nippon Waters Co., Ltd.

(LC analysis conditions)
The analytical column is a C18 series, and the analytes are 25(OH)D ₃ , 3-epi(epi)-25(OH)D ₃ , 25(OH)D ₂ , 24,25(OH) _{2D 3} The LC analysis conditions for one case are as shown in Table 1 below, and the LC analysis conditions for the case where the analyte is 1,25(OH) _{2 D3} are shown in Table 2 below. It is as it was.

(MS/MS analysis conditions)
The ionization conditions were ESI (electrospray ionization) positive, the analytes (the PIPTAD derivative of the five vitamin D metabolites above and the DAPTAD derivative of the five vitamin D metabolites above), and the MRM parameters were: As shown in Table 3.

For data analysis, QuanLinx, an automated processing system within Waters (registered trademark) MassLinx 4.1 software, was used.

<6-3. Analysis Results>
The analysis results are shown in FIG. The horizontal axis of FIG. 1 represents, from the left, 25(OH)D ₃ -PIPTAD derivative, 25(OH)D ₃ -DAPTAD derivative, 3-epi(epi)-25(OH)D ₃ -PIPTAD derivative, 3- epi(epi)-25(OH)D ₃ -DAPTAD derivative, 25(OH)D ₂ -PIPTAD derivative, 25(OH)D ₂ -DAPTAD derivative, 24, 25(OH) ₂ D ₃ -PIPTAD derivative, 24, 25(OH) ₂ D ₃ -DAPTAD derivative, 1,25(OH) ₂ D ₃ -PIPTAD derivative and 1,25(OH) ₂ D ₃ -DAPTAD derivative, and the vertical axis is the ionic strength.

FIG. 1 shows the five vitamin D metabolites (25(OH)D ₃ , 3-epi-25(OH)D ₃ , 25(OH)D ₂ , 24,25(OH) ₂ D ₃ , 1,25(OH) ₂ D ₃ ), showing the results of comparison of ionic strength (Area comparison) of derivatives with PIPTAD and derivatives with DAPTAD.

As shown in FIG. 1, the ionic strength of the 25(OH)D ₃ -PIPTAD derivative was 83494 and the ionic strength of the 25(OH)D ₃ -DAPTAD derivative was 50386. That is, for 25(OH) _D3 , PIPTAD achieved about 1.7-fold sensitivity improvement over DAPTAD.

As shown in FIG. 1, the ionic strength of the 3-epi(epi)-25(OH)D ₃ -PIPTAD derivative is 10887, and the ionic strength of the 3-epi(epi)-25(OH)D ₃ -DAPTAD derivative is The intensity was 6480. That is, for 3-epi(epi)-25(OH) _D3 , PIPTAD achieved about 1.7-fold sensitivity improvement over DAPTAD.

As shown in FIG. 1, the ionic strength of the 25(OH)D ₂ -PIPTAD derivative was 13786 and the ionic strength of the 25(OH)D ₂ -DAPTAD derivative was 5868. That is, for 25(OH) _D2 , PIPTAD achieved about 2.3-fold sensitivity improvement over DAPTAD.

As shown in FIG. 1, the ionic strength of the 24,25(OH) ₂ D ₃ -PIPTAD derivative was 8586 and the ionic strength of the 24,25(OH) ₂ D ₃ -DAPTAD derivative was 6445. That is, for 24,25(OH) ₂ D ₃ , PIPTAD achieved about 1.3-fold sensitivity enhancement compared to DAPTAD.

As shown in FIG. 1, the ionic strength of the 1,25(OH) ₂ D ₃ -PIPTAD derivative was 6376.3 and the ionic strength of the 1,25(OH) ₂ D ₃ -DAPTAD derivative was 2871. . That is, for 1,25(OH) ₂ D ₃ , PIPTAD achieved about 2.2-fold sensitivity enhancement compared to DAPTAD.

By the way, the present invention is not limited to the above-described embodiments and examples, and various modifications can be made without departing from the scope of the present invention.

Moreover, the effects described in this specification are only examples and are not limited, and other effects may also occur.

Moreover, the present invention can also take the following configurations.
[1]
A compound represented by the following general formula (100).
(In the general formula (100), n is an integer of 2 or more.)
[2]
The compound according to [1], wherein the compound represented by the general formula (100) is a compound represented by the following formula (I).
[3]
A derivatization reagent for derivatizing a compound having a diene, containing a compound represented by the following general formula (100).
(In the general formula (100), n is an integer of 2 or more.)
[4]
The derivatization reagent according to [3], wherein the compound represented by the general formula (100) is a compound represented by the following formula (I).
[5]
A method for synthesizing a compound represented by the following general formula (100), comprising a nucleophilic substitution reaction between an aryl halide and a saturated heterocyclic amine compound.
(In the general formula (100), n is an integer of 2 or more.)
[6]
The compound represented by the general formula (100) is a compound represented by the following formula (I),
The synthetic method according to [5], wherein the heterocyclic amine compound is piperidine.

Claims (5)

A compound represented by the following general formula (100).
(In the general formula (100), n is an integer of 2 or more.) The compound represented by the general formula (100) is a compound represented by the following formula (I),
A compound according to claim 1 .
A derivatization reagent for derivatizing a compound having a diene, containing a compound represented by the following general formula (100).
(In the general formula (100), n is an integer of 2 or more.) The compound represented by the general formula (100) is a compound represented by the following formula (I),
4. The derivatization reagent according to claim 3.
A method for synthesizing a compound represented by formula (I) below comprising a nucleophilic substitution reaction between an aryl halide and a saturated heterocyclic amine compound,
the heterocyclic amine compound is piperidine,
wherein the aryl halide is methyl p-fluorobenzoate;
The synthetic method.