Encapsulation of BCP and Novel Synthesis Method of Propellane

Abstract

To provide a method for readily preparing a [1.1.1]propellane solution.SOLUTION: An inclusion complex contains a bicyclo[1.1.1]pentane derivative represented by formula (1), and cyclodextrin or a cyclodextrin derivative. X-BCP-Y (1).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an inclusion complex encapsulating a bicyclo[1.1.1]pentane (BCP) derivative. The present invention also relates to a novel method for synthesizing [1.1.1]propellane using a BCP derivative.

Background Art

[0002] [1.1.1]Bicyclopentane skeleton (hereinafter also referred to as "BCP") is known as a bioisostere of the benzene ring and has a rigid structure, so it has attracted great attention in the fields of medical and agricultural drugs and functional materials (see Fig. 1). By introducing BCP, it is possible to increase metabolic stability, water solubility, and membrane permeability in the pharmaceutical field (Non-Patent Documents 1 and 2). Therefore, BCP has emerged as a promising substituent in drug evaluation.

[0003] However, synthetic methods for introducing BCP into various molecular skeletons have not yet been fully developed. Currently, the most promising approach for constructing the BCP skeleton depends on the use of [1.1.1]propellane (Non-Patent Document 3, etc.), which utilizes the specific reaction of a remarkable "inverted" central σ bond (see Fig. 2).

[0004] In recent years, many protocols for derivatizing BCP have been developed based on reactions driven by the release of ring strain of [1.1.1]propellane (Non-Patent Document 4, etc.). Therefore, at present, for introducing the BCP skeleton, it is necessary to prepare [1.1.1]propellane, but the preparation method of this compound has hardly progressed since the first practical synthesis by Szeimies and co-workers in 1985 (Non-Patent Document 5).

[0005] The pioneering method by Szeimies et al. has problems such as the following. (1) The first lithium-bromine exchange of the tetrahalide (compound 1 in Figure 2) requires the use of 2 equivalents of MeLi and results in the formation of 2 equivalents of MeBr (boiling point: 4 °C). This is difficult to separate from [1.1.1]propellane (boiling point: about 30 °C) by distillation. Also, due to the use of organolithium reagents, safety precautions are necessary. (2) The distilled and purified [1.1.1]propellane is obtained as an ether solution (generally in Et2O), which can be a problem when subsequent reactions require different solvents. Furthermore, (3) [1.1.1]propellane is thermally and chemically unstable, so it is desirable to prepare it before use.

[0006] Thus, the conventional synthetic method of [1.1.1]propellane has problems in that it is time-consuming and needs to be stored at low temperatures in a low-concentration organic solvent solution, making it unsuitable for storage.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Disclosure of the Invention

Problems to be Solved by the Invention

[0008] An object of the present invention is to provide a method for easily preparing a [1.1.1]propellane solution.

Means for Solving the Problems

[0009] To solve the above problems, as a result of intensive studies, the present inventors have found a method for easily preparing [1.1.1]propellane as a solution in various organic solvents using 1,3-dihalogenated BCP such as 1,3-diiodo BCP as a raw material. In addition, the present inventors have found a novel complex in which 1,3-diiodo BCP and other BCP derivatives are included in cyclodextrin. It has also been found that BCP derivatives can be easily taken out from this novel complex.

[0010] That is, the present invention provides [1] An inclusion complex comprising a bicyclo[1.1.1]pentane derivative represented by formula (1) and cyclodextrin or a cyclodextrin derivative. X-BCP-Y (1) (In the formula, BCP represents bicyclo[1.1.1]pentane, X and Y may be the same or different, and each independently is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylamino group, an alkylaminocarbonyl group, an amino group, a carboxyl group, and a carboxamide group.) [2] The inclusion complex according to [1], comprising the bicyclo[1.1.1]pentane derivative and cyclodextrin or a cyclodextrin derivative at a molar ratio of 1:2. [3] The inclusion complex according to [1] or [2], wherein the bicyclo[1.1.1]pentane derivative represented by formula (1) is incorporated into the cavity of a dimer of cyclodextrin or a cyclodextrin derivative. [4] A composition comprising the inclusion complex according to any one of [1] to [3] and water. [5] A method for preparing a cyclodextrin-bicyclo[1.1.1]pentane derivative inclusion complex, comprising: (1) A step of preparing a formulation containing water, cyclodextrin or a cyclodextrin derivative, and a bicyclo[1.1.1]pentane derivative; (2) A step of mixing the formulation; (3) A step of recovering the generated inclusion complex: The preparation method comprising the above steps. [6] A method for recovering a bicyclo[1.1.1]pentane derivative from a cyclodextrin-bicyclo[1.1.1]pentane derivative inclusion complex, comprising: (a) A step of preparing a formulation containing the inclusion complex according to any one of claims 1 to 3, water, and at least one organic solvent; (b) A step of mixing the formulation: (c) A step of separating the organic layer, evaporating it, and recovering the bicyclo[1.1.1]pentane derivative; The method comprising the above steps. [7](1) A step of preparing a mixture containing a bicyclo[1.1.1]pentane derivative represented by formula (2), a base, and a solvent; (2) A step of stirring the mixture and irradiating it with UV light; A method for preparing [1.1.1]propellane, which comprises X’-BCP-Y’ (2) (wherein BCP represents bicyclo[1.1.1]pentane, X’ and Y’ may be the same or different and each independently is selected from fluorine, chlorine, bromine or iodine.) [8] The preparation method according to [7], wherein the base is hydrazine anhydride (NH2NH2), hydrazine hydrate (NH2NH2·H2O), a hydrazine derivative, or diisopropylamine (i-Pr2NH). [9] The preparation method according to [7] or [8], further comprising a step of filtering the obtained mixture using alumina after irradiating with UV light.

[10] (1) A step of preparing a formulation containing a bicyclo[1.1.1]pentane derivative represented by formula (2), a base, and a solvent; (2) A step of adding a nucleophile to the formulation and stirring the reaction mixture; comprising, wherein the nucleophile is Non-shared a phosphorus-containing compound or a nitrogen-containing compound having an electron pair, a method for preparing [1.1.1]propellane. X’-BCP-Y’ (2) (wherein BCP represents bicyclo[1.1.1]pentane, X’ and Y’ may be the same or different and each independently is selected from fluorine, chlorine, bromine or iodine.)

[11] The preparation method according to

[10] , wherein the nucleophile is selected from the group consisting of trialkylphosphine (PR3), triarylphosphine (PAr3), alkyl(aryl)phosphine (PR n Ar 3-n )(n is an integer of 1 or 2), tris(dialkylamino)phosphine (P(NR2)3), tetraalkylammonium iodide (R4NI) (R represents an alkyl group having 1 to 6 carbon atoms, Ar represents an aryl group).

[12] The preparation method according to

[10] or

[11] , wherein the base is hydrazine anhydride (NH2NH2), hydrazine hydrate (NH2NH2·H2O), or a hydrazine derivative.

[13] The preparation method according to any one of

[10] to

[12] , wherein the solvent is a polar solvent.

[14] The preparation method according to any one of

[10] to

[13] , further comprising a step of distilling the reaction mixture under reduced pressure and filtering the obtained fraction using alumina. which is provided.

Advantages of the Invention

[0011] According to the present invention, a [1.1.1] propellane solution can be easily prepared. In addition, [1.1.1] propellane solutions in various solvents that could not be prepared heretofore can be synthesized.

[0012] Furthermore, according to the present invention, by complexing 1,3-diiodo BCP, the light resistance is improved and it becomes possible to handle more stably. Also, various complexes incorporating other BCP derivatives were found to have sublimation resistance and light resistance. The BCP derivative can be easily taken out from these inclusion complexes of the present invention, and the conversion from the complex → 1,3-diiodo BCP → propellane can be smoothly carried out.

Brief Description of the Drawings

[0013]

Figure 1

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Figure 10

Figure 11

Figure 12

Mode for Carrying Out the Invention

[0014] 1. Inclusion complex One embodiment of the present invention is an inclusion complex comprising a bicyclo[1.1.1]pentane derivative represented by formula (1) and a cyclodextrin or a cyclodextrin derivative (hereinafter also referred to as "the inclusion complex of the present invention"). X-BCP-Y (1)

[0015] In formula (1), BCP represents bicyclo[1.1.1]pentane and can also be represented by the following structural formula. TIFF0007694948000001.tif29147

[0016] X and Y may be the same or different, and each independently is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylamino group, an alkylaminocarbonyl group, an amino group, a carboxyl group, and a carboxamide group.

[0017] Examples of the halogen atom include fluorine, chlorine, bromine, and iodine. Preferably, it is bromine or iodine, and particularly preferably iodine.

[0018] The alkyl group having 1 to 4 carbon atoms may be a linear or branched alkyl group, preferably a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, and more preferably a methyl group.

[0019] The alkoxy group is preferably an alkoxy group having 1 to 4 carbon atoms, and particularly preferably a methoxy group, an ethoxy group, an isopropoxy group, or a tert-butoxy group.

[0020] The alkylcarbonyl group preferably has an alkyl group having 1 to 4 carbon atoms, more preferably an acetyl group, an ethylcarbonyl group, or a tert-butylcarbonyl group, and among them, the acetyl group (Ac) is particularly preferred.

[0021] The alkylcarbonyloxy group preferably has an alkyl group having 1 to 4 carbon atoms, more preferably an acetyloxy group, an ethylcarbonyloxy group, or a tert-butylcarbonyloxy group, and particularly preferably an acetyloxy group.

[0022] The alkoxycarbonyl group preferably has an alkoxy group having 1 to 4 carbon atoms, and particularly preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a tert-butoxycarbonyl group.

[0023] The alkylamino group includes a monoalkylamino group having 1 to 4 carbon atoms and a dialkylamino group having 1 to 4 carbon atoms. Examples thereof include a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, an isopropylamino group, a diisopropylamino group, a tert-butylamino group, and the like.

[0024] The alkylaminocarbonyl group preferably has an alkyl group having 1 to 4 carbon atoms. Particularly, a methylaminocarbonyl group, a dimethylaminocarbonyl group, an ethylaminocarbonyl group, a diethylaminocarbonyl group, a propylaminocarbonyl group, and a tert-butylaminocarbonyl group are preferred.

[0025] X-BCP-Y of formula (1) can also be represented by the following structural formula. TIFF0007694948000002.tif32129

[0026] Cyclodextrin and cyclodextrin derivatives specifically include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, triacetyl-β-cyclodextrin, and trimethyl-β-cyclodextrin, and preferably α-cyclodextrin.

[0027] The inclusion complex of the present invention preferably contains a bicyclo[1.1.1]pentane derivative and a cyclodextrin or a cyclodextrin derivative in a molar ratio of 1:2.

[0028] In one aspect of the inclusion complex of the present invention, the bicyclo[1.1.1]pentane derivative represented by formula (1) is incorporated into the cavity of a dimer of cyclodextrin or a cyclodextrin derivative. Cyclodextrin (CD) can contain various hydrophobic compounds through host-guest complex formation. According to a detailed structural analysis by the present inventors, it has been found that CD such as α-CD and X-BCP-Y form a head-to-head (facing the secondary rim) type supramolecular nanocapsule structure having a host-guest stoichiometric ratio of 2:1.

[0029] An exemplary structure of the inclusion complex of the present invention is shown in FIG. 3. In the inclusion complex of the present invention, by complexing the BCP derivative, the sublimation resistance and light resistance are improved, and it becomes possible to handle more stably.

[0030] Specific examples of the inclusion complex of the present invention are shown below, but are not limited thereto. Supramolecular complex (5a) represented by (α-CD)2⊃I-BCP-I, where X and Y in formula (1) are I. Here, it is shown that in the complex of 5a, I-BCP-I is incorporated into the cavity of the dimer of α-cyclodextrin to form a supramolecular nanocapsule structure. The same applies hereinafter. Supramolecular complex (5b) represented by (α-CD)2⊃I-BCP-Br, where X in formula (1) is I and Y is Br. Supramolecular complex (5c) represented by (α-CD)2⊃I-BCP-Cl, where X in formula (1) is I and Y is Cl. Supramolecular complex (5d) represented by (α-CD)2⊃I-BCP-Me, where X in formula (1) is I and Y is a methyl group (Me). Supramolecular complex (5e) represented by (α-CD)2⊃Br-BCP-Br, where X and Y in formula (1) are Br. Supramolecular complex (5f) represented by (α-CD)2⊃Ac-BCP-Ac, where X and Y in formula (1) are acetyl groups (Ac).

[0031] One aspect of the present invention is a composition containing the inclusion complex of the present invention and water.

[0032] Another embodiment of the present invention is a method for preparing a cyclodextrin-bicyclo[1.1.1]pentane derivative inclusion complex, comprising: (1) a step of preparing a formulation containing water, cyclodextrin or a cyclodextrin derivative, and a bicyclo[1.1.1]pentane derivative; (2) a step of mixing the formulation; (3) a step of recovering the generated inclusion complex: The preparation method including this (hereinafter also referred to as "the preparation method of the inclusion complex of the present invention").

[0033] In the preparation method of the inclusion complex of the present invention, it is preferable to add cyclodextrin or a cyclodextrin derivative and a bicyclo[1.1.1]pentane derivative at a ratio of 2:1 (molar ratio).

[0034] The concentration of cyclodextrin or a cyclodextrin derivative in the above-mentioned formulation is preferably 0.01 to 0.18 mol / L.

[0035] The step of preparing the formulation and the step of mixing the formulation are usually carried out near room temperature. In addition, the generated inclusion complex can usually be recovered by filtering the inclusion complex and drying it under vacuum to obtain the inclusion complex.

[0036] Another aspect of the present invention is a method for recovering a bicyclo[1.1.1]pentane derivative from a cyclodextrin-bicyclo[1.1.1]pentane derivative inclusion complex, comprising: (a) A step of preparing a formulation containing the inclusion complex of the present invention, water, and at least one organic solvent; (b) A step of mixing the formulation; (c) A step of separating the organic layer, evaporating it, and recovering the solid. The method including this.

[0037] As the organic solvent, toluene, hexane, THF, diethyl ether, xylene, chloroform, acetonitrile, pivalonitrile, ethyl acetate, etc. can be preferably used.

[0038] The concentration of the inclusion complex in the formulation is preferably 0.001 to 0.180 mol / L.

[0039] The step of mixing the formulation is usually carried out near room temperature. In addition, the separated organic layer is usually evaporated under reduced pressure.

[0040] 2. Synthesis of [1.1.1]propellane Another embodiment of the present invention is a method for synthesizing [1.1.1]propellane from a bicyclo[1.1.1]pentane derivative. The methods for synthesizing [1.1.1]propellane are roughly classified into a method using ultraviolet light (UV irradiation method) and a method using a nucleophile (nucleophile method).

[0041] (A) UV irradiation method One embodiment of the present invention is (1) A step of preparing a mixture containing a bicyclo[1.1.1]pentane derivative represented by formula (2), a base, and a solvent; (2) A step of stirring the mixture and irradiating it with ultraviolet light (UV light); A method for preparing [1.1.1]propellane, which includes (hereinafter also referred to as "the UV irradiation method of the present invention").

[0042] X’-BCP-Y’ (2) In formula (2), BCP represents bicyclo[1.1.1]pentane.

[0043] X’ and Y’ may be the same or different, and each independently is a halogen selected from fluorine, chlorine, bromine, or iodine, preferably bromine or iodine. More preferably, both X’ and Y’ are bromine or iodine, and even more preferably iodine.

[0044] As the base, when X’ and Y’ are the same halogen, for example, when X’ and Y’ are iodine, if it has a reducing action that can selectively capture I2 generated in the reaction and rapidly convert it to I - it can be preferably used. Examples of such bases include hydrazine anhydride (NH2NH2), hydrazine hydrate (NH2NH2·H2O), hydrazine derivatives, and diisopropylamine (iPr2NH). Hydrazine derivatives specifically include alkylhydrazine, 1,2-dialkylhydrazine, arylhydrazine, 1,2-diarylhydrazine, and more specifically, hydrazine having an alkyl or aryl group with 1 to 6 carbon atoms. Preferred specific examples are methylhydrazine, 1,2-dimethylhydrazine, phenylhydrazine, and 1,2-diphenylhydrazine. Among the above bases, anhydrous hydrazine, hydrazine hydrate, and methylhydrazine are particularly preferred.

[0045] The amount of the base used is usually 2 to 1000 molar amounts, preferably 2 to 100 molar amounts, more preferably 2 to 50 molar amounts, and particularly preferably 2 to 8 molar amounts with respect to the BCP compound.

[0046] As the solvent used in the UV irradiation method of the present invention, any solvent that is not decomposed by ultraviolet light can be used, and polar solvents, non-polar solvents, or ether solvents can be preferably used. Examples of polar solvents include methanol, ethanol, chloroform, dichloromethane, acetonitrile, pivalonitrile, etc. Examples of non-polar solvents include hexane, toluene, heptane, xylene, pentane, etc., and preferably hexane or toluene. Examples of ether solvents include tert-butyl methyl ether (t-BuOMe), cyclopentyl methyl ether (CPME), THF, 2-methyl THF, diethyl ether etc and preferably t-BuOMe or CPME.

[0047] The wavelength, intensity, and irradiation time of ultraviolet light can be appropriately determined according to the reaction scale, raw materials used, etc. For example, the wavelength is preferably 250 to 800 nm. Also, it can be carried out for 1 minute to 24 hours at an irradiation intensity of 300 to 450 mW / cm 2 Moreover, a medium-pressure mercury lamp can be used as the ultraviolet lamp to be used. The step of preparing the above mixture and the step of irradiating with ultraviolet light are usually carried out near room temperature.

[0048] The UV irradiation method of the present invention preferably further includes a step of filtering the obtained mixture using alumina after irradiating with UV light. Thereby, residual bases such as hydrazine can be dramatically reduced to the ppm level. As the alumina, an alumina pad or the like can be used. Further, the filtration is preferably carried out at 0°C to 25°C.

[0049] (B) Nucleophilic reagent method Another aspect of the present invention is (1) A step of preparing a formulation containing a bicyclo[1.1.1]pentane derivative represented by formula (2), a base, and a solvent; (2) A step of adding a nucleophilic reagent to the formulation and stirring the reaction mixture; including, wherein the nucleophilic reagent is Non-shared a phosphorus-containing compound or a nitrogen-containing compound having an electron pair, a method for preparing [1.1.1]propellane (hereinafter also referred to as "the nucleophilic reagent method of the present invention").

[0050] X’-BCP-Y’ (2) In formula (2), BCP, X’, and Y’ are the same as BCP, X’, and Y’ described in the UV irradiation method of the present invention.

[0051] Of the nucleophilic reagent Non-shared Examples of the phosphorus-containing compound having an electron pair include trialkylphosphine (PR3), triarylphosphine (PAr3), alkyl(aryl)phosphine (PR n Ar 3-n(wherein n is an integer of 1 or 2), tris(dialkylamino)phosphine (P(NR2)3) can be mentioned. Here, R represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and Ar represents an aryl group. Among the above, preferred specific examples include triethylphosphine (PEt3), tributylphosphine (PBu3), triphenylphosphine (PPh3), tris(dimethylamino)phosphine (P(NMe2)3), tri-tert-butylphosphine (P(t-Bu)3), tricyclohexylphosphine (PCy3).

[0052] As the nucleophilic reagent Non-shared Examples of the nitrogen-containing compound having an electron pair include tetraalkylammonium iodide (R4NI) etc. (R is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms), preferably tetraethylammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide, and more preferably tetrabutylammonium iodide.

[0053] The amount of the nucleophilic reagent used is usually 1 to 10 molar amounts, preferably 1 to 3 molar amounts, relative to 1 molar amount of the BCP compound.

[0054] Examples of the base include anhydrous hydrazine (NH2NH2), hydrazine hydrate (NH2NH2·H2O), or hydrazine derivatives etc. The hydrazine derivative specifically represents alkylhydrazine, 1,2-dialkylhydrazine, arylhydrazine, 1,2-diarylhydrazine, and more specifically represents hydrazine having an alkyl or aryl group having 1 to 6 carbon atoms. Preferred specific examples include methylhydrazine, 1,2-dimethylhydrazine, phenylhydrazine, 1,2-diphenylhydrazine. Among the above, particularly preferred are anhydrous hydrazine, hydrazine hydrate, and methylhydrazine.

[0055] The concentration of the base is usually from 1 molar amount to 100 molar amounts, preferably from 1 molar amount to 10 molar amounts, and more preferably from 1 molar amount to 5 molar amounts.

[0056] As the solvent, it is preferable to use a polar solvent. The polar solvent is selected from the group consisting of THF, MeOH, CHCl3 and MeCN, pivalonitrile, 2-methyl THF, and dichloromethane, and preferably THF, MeOH, CHCl3, MeCN, and dichloromethane.

[0057] The nucleophilic reagent method of the present invention preferably further includes a step of distilling the reaction mixture under reduced pressure and filtering the obtained fraction using alumina. Thereby, residual bases such as residual hydrazine can be dramatically reduced to the ppm level. As the alumina, an alumina pad or the like can be used. Further, the filtration is preferably carried out at 0 to 25°C.

[0058] Schematic diagrams of non-limiting examples of the UV irradiation method and the nucleophilic reagent method of the present invention are shown in FIG. 5.

[0059] Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto.

Examples

[0060] 1. General procedure (1) Apparatus The NMR spectra were obtained with a BRUKER AVANCE III HD 500 spectrometer. The chemical shifts were recorded in ppm on the δ scale relative to tetramethylsilane ( 1 δ = 0.00 in 1H NMR) and the remaining non-deuterated solvent (HDO: δ = 4.79, CHD2SOCD3: δ = 2.50). The following abbreviations were used: s = singlet, d = doublet, t = triplet, m = multiplet (indicating a complex pattern), and dt = doublet of a triplet signal.

[0061] The melting point was measured using a Yanaco micro melting point measuring device or an SRS MPA 100 OptiMelt automatic melting point system. The ESI mass spectrum was measured with a Bruker micrOTF-II spectrometer. The IR spectrum was obtained with a JASCO FT / IR-4700 spectrometer.

[0062] The reaction under UV irradiation was carried out in a Schlenk tube using a 430 mW / cm medium-pressure mercury lamp (YMC-P-0066) equipped with a cooling fan. 2

[0063] (2) Reagents Unless otherwise specified, they were purchased from Aldrich Co., Ltd., Fujifilm Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co., Ltd., etc., and were properly purified before use. 1,1-Dibromo-2,2-bis(chloromethyl)cyclopropane (1) was purchased from WuXi LabNetwork (Wuhan) Chemical Technology Co., Ltd. and Tokyo Chemical Industry Co., Ltd., respectively. The handling of air- and moisture-sensitive compounds was carried out using standard Schlenk techniques under an argon atmosphere. The p-(dimethylamino)benzaldehyde visual colorimetric method was used as a quantitative method for hydrazine, and its simple test product was purchased from Kyoritsu Chemical-Check Lab Co., Ltd. The bicyclo[1.1.1]pentane derivatives (3a - 3g) were prepared according to the procedures reported in References 1 - 8.

[0064] 2. Encapsulation of α-CD and bicyclo[1.1.1]pentane derivatives General procedure α-Cyclodextrin (4) (100 mg, 0.10 mmol, 2.0 equiv) was charged into a flask equipped with a stir bar, and water (0.9 mL) was added to prepare an α-cyclodextrin solution. The bicyclo[1.1.1]pentane derivative (3) (0.05 mmol) was added to the solution at room temperature in air and stirred for 3 h. The resulting highly viscous slurry-like reaction mixture was filtered, washed with water, and dried under reduced pressure to obtain the product (5). Examples of encapsulation using each bicyclo[1.1.1]pentane derivative are described below. An overview of the results is shown in Fig. 4.

[0065] [Synthesis Example 1] Preparation of (α-CD)2⊃I-BCP-I complex (5a) Using I-BCP-I (3a), the title compound was isolated as a white solid in a yield of 95% (108 mg) using a general procedure. 1 H NMR (500 MHz, DMSO-d6): δ 2.71 (s, 6H, CH2 of I-BCP-I), 3.28 (dt, 12H, H 4 of α-CD), 3.39 (t, 12H, H 2 of α-CD), 3.57 - 3.69 (m, 36H, H 5 and H 6a,b of α-CD), 3.77 (dt,12H, H 3 of α-CD), 4.46 (t, 12H, OH Z of α-CD), 4.80 (d, 12H, H 1 of α-CD), 5.43 (d, 12H,OH Y of α-CD), 5.50 (d, 12H, OH X of α-CD). ATR-FTIR (neat): 3334, 2921, 1325, 1194, 1152, 1029, 948, 844, 697, 649, 576, 528,505 cm -1 . m.p.: 132 - 143 °C (dec). HRMS (ESI (+)): m / z: calcd for C 77 H 126 I2NaO 60 + [M + Na + : 2287.4795. Found: 2287.4879.

[0066] [Synthesis Example 2] (Preparation of (α-CD)2⊃I-BCP-Br complex (5b)) Using I-BCP-Br (3b), the title compound was isolated as a white solid in 81% yield (89.9 mg) using a general procedure. 1 H NMR (500 MHz, DMSO-d6): δ 2.66 (s, 6H, CH2 of I-BCP-Br), 3.26 - 3.31 (m, 12H, H 4 of α-CD), 3.39 (t, 12H, H 2 of α-CD), 3.57 - 3.67 (m, 36H, H 5 and H 6a,b of α-CD), 3.77 (dt, 12H, H 3 of α-CD), 4.46 (t, 12H, OH Z of α-CD), 4.80 (d, 12H, H 1 of α-CD), 5.43 (d,12H, OH Y of α-CD), 5.50 (d, 12H, OH X of α-CD). ATR-FTIR (neat): 3324, 2920, 1375, 1196, 1151, 1028, 947, 856, 753, 705, 648, 611, 576, 525 cm -1 . m.p.: 140 - 147 °C (dec). HRMS (ESI (+)): m / z: calcd for C 77 H 126 BrINaO 60 + [M + Na + : 2239.4934. Found: 2239.4689.

[0067] [Synthesis Example 3] (Preparation of (α-CD)2⊃I-BCP-Cl complex (5c)) Using I-BCP-Cl (3c), the title compound was isolated as a white solid in 86% yield (93.5 mg) using a general procedure. 1 1H NMR (500 MHz, DMSO-d6): δ 2.60 (s, 6H, CH2 of I-BCP-Cl), 3.26 - 3.30 (dt, 12H, H 4 of α-CD), 3.39 (t, 12H, H 2 of α-CD), 3.57 - 3.69 (m, 36H, H 5 and H 6a,b of α-CD), 3.77(dt, 12H, H 3 of α-CD), 4.46 (t, 12H, OH Z of α-CD), 4.80 (d, 12H, H 1 of α-CD), 5.43 (d,12H, OH Y of α-CD), 5.50 (d, 12H, OH X of α-CD). ATR-FTIR (neat): 3336, 2932, 1360, 1200, 1148, 1019, 944, 871, 753, 699, 648, 573, 530 cm -1 . m.p.: 160 - 165 °C (dec). HRMS (ESI(+)): m / z: calcd for C 77 H 126 C lI O 60 + [M + Na + : 2195.5439. Found: 2196.5341.

[0068] [Synthesis Example 4] Preparation of (α-CD)2⊃I-BCP-Me complex (5d) Using I-BCP-Me (3d), the title compound was isolated as a white solid in 91% yield (97.9 mg) using the general procedure. 11H NMR (500 MHz, DMSO-d6): δ 1.19 (s, 3H, CH3 of I-BCP-Me), 2.21 (s, 6H, CH2 of I-BCP-Me), 3.29 - 3.40 (m, 24H, H 2 and H 4 of α-CD), 3.57 - 3.67 (m, 36H, H 5 and H 6a,b of α-CD), 3.77 (t, 12H, H 3 of α-CD), 4.48 (s, 12H, OH Z of α-CD), 4.80 (d, 12H, H 1 of α-CD), 5.43 (s, 12H, OH Y of α-CD), 5.51 (d, 12H, OH X of α-CD). ATR-FTIR (neat): 3324, 2925, 1338, 1148, 1030, 947, 835, 750, 705, 651, 608, 573, 527 cm -1 . m.p.: 132 - 149 °C (dec). HRMS (ESI(+)): m / z: calcd for C 78 H 129 INaO 60 + [M + Na + : 2175.5985. Found: 2175.5772.

[0069] [Synthesis Example 5] Preparation of (α-CD)2⊃Br-BCP-Br complex (5e) Using Br-BCP-Br (3e) and following the general procedure, the title compound was isolated as a white solid in 95% yield (103 mg). 1 1H NMR (500 MHz, DMSO-d6): δ 2.65 (s, 6H, CH2 of Br-BCP-Br), 3.26 - 3.30 (m, 12H, H 4 of α-CD), 3.39 (t, 12H, H2 of α-CD), 3.57 - 3.69 (m, 36H, H 5 and H 6a,b of α-CD), 3.77 (dt, 12H, H 3 of α-CD), 4.46 (t, 12H, OH Z of α-CD), 4.80 (d, J = 3.5 Hz, 12H, H 1 of α-CD), 5.43 (d, 12H, OH Y of α-CD), 5.50 (d, 12H, OH X of α-CD). ATR - FTIR (neat): 3288, 2923, 1326, 1148, 1030, 947, 865, 753, 696, 645, 608, 572 cm -1 . m.p.: 169 - 178 °C (dec). HRMS (ESI(+)): m / z: calcd for C 77 H 126 Br2NaO 60 + [M + Na + : 2191.5073. Found: 2191.4867.

[0070] [Synthesis Example 6] Preparation of (α - CD)2⊃Ac - BCP - Ac complex (5f) Using Ac - BCP - Ac (3f), the title compound was isolated as a white solid in 89% yield (93.5 mg) using the general procedure. 1 H NMR (500 MHz, DMSO - d6): δ 2.09 (s, 6H, CH3 of Ac - BCP - Ac), 2.15 (s, 6H, CH2 of Ac - BCP - Ac), 3.25 - 3.29 (m, 12H, H 4 of α - CD), 3.40 - 3.41 (m, 12H, H 2 of α - CD), 3.56 - 3.68 (m, 36H, H 5 and H 6a,bof α-CD), 3.76 (dt, 12H, H 3 of α-CD), 4.49 (t, 12H,OH Z of α-CD), 4.79 (d, 12H, H 1 of α-CD), 5.44 (d, 12H, OH Y of α-CD), 5.51 (d, 12H,OH X of α-CD). ATR-FTIR (neat): 3312, 2929, 1707, 1647, 1366, 1193, 1151, 1031, 950, 856, 750, 704,651, 608, 573, 527 cm -1 . m.p.: 248 - 260 °C (dec). HRMS (ESI(+)): m / z: calcd for C 81 H 132 NaO 62 + [M + Na + : 2119.7074 Found: 2119.6993.

[0071] [Synthesis Example 6 (Comparative Example)] Preparation of (α-CD)2⊃Bpin - BCP - Me2PhSi complex (5 g) Attempted preparation of Bpin - BCP - Me2PhSi complex (5 g) using Bpin - BCP - Me2PhSi (3 g) (pin = pinacolato) according to the general procedure, but Bpin - BCP - Me2PhSi did not form an inclusion complex with α - CD.

[0072] [Example 1] α-Cyclodextrin (4) (100 mg, 0.10 mmol, 1.0 equiv) was charged into a flask equipped with a stirring bar, and bicyclo[1.1.1]pentane derivative (3a) (0.1 mmol) was added to the α-cyclodextrin solution prepared by adding water (0.9 mL) at room temperature in air and stirred for 3 h. The resulting highly viscous slurry-like reaction mixture was filtered, washed with water, and dried under reduced pressure to obtain only the product (5a). From these results, it was found that an inclusion complex containing the bicyclo[1.1.1]pentane derivative and cyclodextrin or a cyclodextrin derivative in a 1:2 (molar ratio) can be obtained even when the mixing ratio of cyclodextrin and the bicyclo[1.1.1]pentane derivative is changed.

[0073] [Example 2] (1) Measurement of solution NMR NMR measurements were performed on the D2O solutions of the water-insoluble precipitates obtained in Synthesis Examples 1 to 6. The results are shown in Fig. 6.

[0074] Fig. 6 shows the ROESY NMR spectra of (α-CD)2⊃I-BCP-I (5a) and (α-CD)2⊃Ac-BCP-Ac (5f) in D2O solution. NOEs between the CH2 of the BCP skeleton and the internal H 3 protons of the α-CD ring were clearly observed in both complexes. In (α-CD)2⊃Ac-BCP-Ac (5f), NOEs 5 between the internal H protons of the α-CD ring and Ac were also observed. These data indicate the formation of an inclusion complex in which X-BCP-Y (3) is accommodated in the cavity of the dimeric α-CD capsule and its substituents are present in the vicinity of the internal protons of α-CD.

[0075] [Example 3] (α-CD)2⊃Ac-BCP-Ac complex (5f) single crystal X-ray structure Single crystal X-ray structure analysis was performed on complex 5f. The crystal structure data after refinement of 5f are shown in Table 1, and the X-ray crystal structure of 5f is shown in Fig. 7.

[0076]

Table 1

[0077] As shown in Fig. 7, single-crystal X-ray diffraction analysis clearly showed that 1 equivalent of Ac-BCP-Ac (3f) was completely incorporated into the head-to-head dimeric α-CD capsule. It was found that the cavity of the α-CD capsule has a high affinity for the BCP skeleton and that the dimeric encapsulation is induced by the BCP-guest.

[0078] [Example 4] (α-CD)2⊃BCP Derivative and Sublimation Experiment of BCP Derivative Supramolecular encapsulation can change the intrinsic physicochemical properties of guest molecules. In fact, the volatile liquid compound 3d (I-BCP-Me, b.p. 37 °C, 8 Torr) was encapsulated in α-CD, and (α-CD)2⊃I-BCP-Me (5d) was obtained as white microcrystals, facilitating handling. Next, a test was conducted to compare the sublimation properties of the (α-CD)2⊃BCP derivative and the BCP derivative. The sample in the Petri dish was left at room temperature and weighed at any time point. The measured weight was expressed as the weight retention rate, and the initial weight was 100%.

[0079] Fig. 8(a) shows the sublimation properties of complex 5e and compound 3e. The supramolecular complex (α-CD)2⊃Br-BCP-Br (5e) can be stored at 25 °C without decomposition or sublimation for at least 7 days, while Br-BCP-Br (3e) itself sublimated and completely disappeared within 3 hours under the same conditions. Also, Fig. 8(b) shows the sublimation properties of complex 5d and compound 3d, and Fig. 8(c) shows the sublimation properties of complex 5f and compound 3f. In Figs. 8(b) and (c) as well, the same tendency as in Fig. 8(a) was obtained.

[0080] [Example 5] (α-CD)2⊃BCP Derivative and Photostability Test of BCP Derivative It is known that supramolecular encapsulation can also greatly improve the light stability of guest molecules. Therefore, the photostability of the (α-CD)2⊃BCP derivative and the BCP derivative was investigated. The test was carried out by putting the sample into a screw vial and leaving it at room temperature under irradiation with fluorescence (19 W, total luminous flux: 170 lm). The sample weight was measured at any time, and dichloromethane was used as the internal standard. 1 The sample content was calculated from the 1H NMR analysis. From these values, the molar amount was calculated for the weight retention rate with the initial molar amount taken as 100%.

[0081] Figure 9(a) shows the photostabilities of complex 5a and compound 3a. I-BCP-I(5a) did not decompose after 65 days, in contrast to the case of I-BCP-I(3a) alone (100% decomposition after about 65 days). Similar stabilization by encapsulation was also observed for Ac-BCP-Ac(3f) (Figure 9(b)).

[0082] [Example 6] Decapsulation of the (α-CD)2⊃I-BCP-I complex (5a) Currently, the most important precursor for introducing the BCP group is [1.1.1]propellane. Therefore, it was investigated whether the α-CD capsule containing the I-BCP-I complex (5a) of the present invention could be used as a precursor of [1.1.1]propellane.

[0083] (α-CD)2⊃I-BCP-I complex (5a, 113 mg, 0.05 mmol), water (5.0 mL), THF (5.0 mL) and toluene (3.5 mL) were placed in a flask using a stir bar. The mixture was stirred in air at room temperature for 10 minutes. The organic layer was separated and evaporated under reduced pressure to obtain I-BCP-I(3a, 16 mg, 100%) as a white solid.

[0084] Thus, I-BCP-I(3a) could be recovered in 100% yield simply by stirring the α-CD inclusion capsule in toluene-THF-water and then extracting 3a with toluene (Figure 12).

[0085] 3. Preparation of [1.1.1]propellane [Example 7] (1) Examination of the UV irradiation method Next, it was investigated whether I-BCP-I could be converted to [1.1.1]propellane. First, the photoinduced decomposition of I-BCP-I into [1.1.1]propellane and I2 was investigated. Here, the reverse reaction to regenerate I-BCP-I is known to be rapid and have no activation barrier (Reference 12), and in fact, this reaction has been used to titrate [1.1.1]propellane (Reference 13). Therefore, the inventors considered that a possible solution to this problem is to remove I2 from the reaction system by using a base having an appropriate reducing action that can rapidly convert I2 to I - so as not to react with [1.1.1]propellane, and extensive screening was carried out using various reagents. As a result, it was found that anhydrous hydrazine is an excellent base for this purpose. Furthermore, research on the optimization of the UV irradiation method was carried out based on the following general procedure.

[0086] General procedure for the optimization study of the UV irradiation method 1,3-Diiodobicyclo[1.1.1]pentane (3a, 300 mg, 1.0 mmol), a base, and a solvent (2.0 mL) were charged into a dry Schlenk tube equipped with a stir bar at room temperature under an argon atmosphere. The reaction mixture was stirred at the same temperature and irradiated with a medium-pressure Hg lamp of 430 mW / cm 2 for 1 hour. The yield was calculated from the 1H NMR analysis results using dichloromethane as an internal standard substance. 1

[0087] The results of the study on the optimization of the UV irradiation method conditions are shown in Table 2 below.

[0088]

Table 2

[0089] From Table 2, it can be seen that when hydrazine anhydride is used as the base, [1.1.1]propellane is obtained in high yield in hexane. Also, the generation of [1.1.1]propellane under UV irradiation was completed promptly. In contrast, the reaction was slow under visible light (blue LED) or fluorescent lamp irradiation at room temperature. In particular, the solvent for this reaction is not limited to hexane, and [1.1.1]propellane solutions can be obtained in other solvents such as toluene, THF, and Et2O with equivalent yields, and a [1.1.1]propellane solution was also obtained in CHCl3.

[0090] (2) Investigation of the nucleophilic reagent method Next, using the following general procedure, an appropriate nucleophilic reagent to promote the deiodination reaction of I-BCP-I was screened.

[0091] General procedure for the optimization study of the nucleophilic reagent method 1,3-Diiodobicyclo[1.1.1]pentane (3a, 16 mg, 0.05 mmol), and deuterated chloroform (2.0 mL) were charged into a dry flask containing a stir bar. A base was added to this solution at 0 °C. After the addition of the base, the reaction mixture was stirred at room temperature, 1 and it was confirmed by 1H NMR analysis that 3a had disappeared. The yield was calculated from the 1H NMR analysis results using dichloromethane as the internal standard substance. 1

[0092] The results of the investigation on the optimization of the nucleophilic reagent method conditions are shown in Table 3 below.

[0093]

Table 3

[0094] As shown in Table 3, it was found that the combination of tributylphosphine (PBu3) and hydrazine anhydride promotes the elimination of I2 from I-BCP-I without the need for UV irradiation. Also, other nucleophilic reagents such as pyridine and ammonium iodide salts did not improve the reaction results. Also, in the absence of hydrazine, no [1.1.1]propellane was obtained at all.

[0095] (3) Preparation of [1.1.1]propellane in various solvents Next, using the optimized conditions of the above-described UV irradiation method and nucleophile method, the preparation protocol of [1.1.1]propellane in various solvents was optimized. First, a method for removing hydrazine from the [1.1.1]propellane solution was investigated, and it was found that simple filtration through alumina dramatically reduced the residual hydrazine to the ppm level. Typical procedures under the optimized conditions for the UV irradiation method and nucleophile method are shown below.

[0096] Typical procedure for the optimization conditions under UV irradiation in a nonpolar or ether solvent 1,3-Diiodobicyclo[1.1.1]pentane (3a, 513 mg, 1.6 mmol), anhydrous hydrazine (309 mg, 9.6 mmol, 6.0 eq), and a solvent (5 mL) were charged into a dry Schlenk tube equipped with a stir bar under an argon atmosphere at room temperature. The reaction mixture was stirred at the same temperature and irradiated with a medium-pressure Hg lamp of 430 mW / cm 2 for 1 hour. The reaction yield was calculated from 1 1H NMR analysis using dichloromethane as an internal standard. After irradiation, the mixture was filtered through an alumina pad at 0 °C to obtain a solution of [1.1.1]propellane (2). The isolated yield was calculated from the 1 1H NMR analysis results using dichloromethane as an internal standard substance.

[0097] PBu in a polar solvent 3 Typical procedure for the optimization conditions by 1,3-Diiodobicyclo[1.1.1]pentane (3a, 300 mg, 1.0 mmol), hydrazine anhydrous (88 mg, 2.8 mmol, 2.8 eq.), and a solvent (3.0 mL) were placed in a dry flask equipped with a stir bar. To this solution, PBu3 (223 mg, 1.1 mmol, 1.1 eq.) was added dropwise at 0 °C in air. After the nucleophile was added, the reaction mixture was stirred at room temperature for 1 h. The reaction yield was calculated from GC analysis using anisole as an internal standard. After completion of the reaction, the mixture was gradually concentrated under reduced pressure and distilled at 70 - 100 mmHg at room temperature. During distillation, the receiver flask was cooled to -78 °C (when acetonitrile was used as the solvent, the receiver flask was cooled to -40 °C). The resulting fraction was filtered through an alumina (600 mg) pad at 0 °C to obtain a solution of [1.1.1]propellane (2). Dichloromethane was used as an internal standard substance. 1 The isolated yield was calculated from the 1H NMR analysis results.

[0098] The results obtained are summarized in Table 4 below.

[0099]

Table 4

[0100] In conclusion, nonpolar (hexane, toluene) or ether (t-BuOMe, cyclopentylmethyl ether (CPME)) solutions of [1.1.1]propellane could be prepared by the UV method followed by simple filtration over alumina. On the other hand, for polar or other solvents such as THF, MeOH, CHCl3, and MeCN, the PBu3 method was effective, and high-purity solutions of [1.1.1]propellane could be obtained by distillation (to remove PBu3) and alumina filtration (to remove hydrazine). To the best of the inventors' knowledge, this method is the first method enabling the preparation of [1.1.1]propellane in various solvents.

[0101] [Example 8] Synthesis of Ac-BCP-Ac (3f) with [1.1.1]propellane (2) Next, to demonstrate the utility of the inventors' method, 1,3-diacetyl BCP (Ac-BCP-Ac; 3f), an important intermediate in the synthesis of a wide range of BCP derivatives, was prepared (Figure 13). Michl et al. developed a synthetic protocol for 3f by radical addition of diacetyl to [1.1.1]propellane in Et2O under UV irradiation. However, since ethereal solvents are disadvantageous for radical reactions, the yield is moderate. On the other hand, a toluene solution of [1.1.1]propellane prepared by the UV method of the present invention was subjected to the same diacetylation conditions, and 3f was obtained from (α-CD)2⊃Ac-BCP-Ac (5f) in 94% yield. The significant improvement in yield is considered to be the result of suppressing unwanted side reactions by changing the solvent to toluene. The synthetic protocol is shown below.

[0102] Synthesis of Ac-BCP-Ac (3f) with [1.1.1]propellane (2) in toluene A toluene solution of diacetyl (103 mg, 1.2 mmol, 1.2 eq.) and [1.1.1]propellane (2, 4.26 g, 1.0 mmol, 1.55 wt%) was charged into a dry Schlenk tube equipped with a stir bar at 0 °C under an argon atmosphere. The reaction mixture was stirred at the same temperature and irradiated with a medium-pressure Hg lamp of 430 mW / cm 2 for 30 minutes. After irradiation, volatile substances were evaporated, and the residue was distilled on a Kugelrohr apparatus to obtain the pure product (3f, 143 mg, 94% yield).

[0103] As described above, the α-CD encapsulation technique offers many important advantages. In particular, (1) it avoids the problems of the inherent volatility, sublimability, and low boiling point of BCP derivatives, and (2) it provides excellent chemical, thermal, photo, and air stability. Encapsulated BCP can be easily generated simply by mixing BCP and α-CD in water, and the product is storable and easy to handle. This technique provides a platform for the general synthesis of BCP derivatives. In addition, a new protocol for the deiodination reaction of 1,3-diiodo BCP (I-BCP-I) to obtain [1.1.1]propellane was developed. The combination of these technologies enables the facile preparation of [1.1.1]propellane in various solvents (protic / aprotic / polar / nonpolar) that could not be prepared heretofore (Figure 14). This is considered to be useful for opening up new fields in chemistry and materials science.

[0104] Literature 1. K. B. Wiberg, S. T. Waddell, J. Am. Chem. Soc. 1990, 112, 2194. 2. P. Kaszynski, A. C. Friedli, J. Michl, J. Am. Chem. Soc. 1992, 114, 601. 3. M. Messner, S. I. Kozhushkov, A. de. Meijere, Eur. J. Org. Chem. 2000, 1137. 4. I. R. Milne, D. K. Taylor, J. Org. Chem. 1998, 63, 3769. 5. P. Kaszynski, J. Michl, J. Org. Chem. 1988, 53, 4593. 6. K. B. Wiberg, F. H. Walker, J. Am. Chem. Soc. 1982, 104, 5240. 7. M. Kondo, J. Kanazawa, T. Ichikawa, T. Shimokawa, Y. Nagashima, K. Miyamoto, M. Uchiyama, Angew. Chem. Int. Ed. 2020, 59, 1970. 8. K. B. Wiberg, N. McMurdie, J. Am. Chem. Soc. 1994, 116, 11990. 9.Y. Nishiyama, Solid State Nucl. Magn. Reson. 2016, 78, 24. 10.S.P. Brown, Prog. Nucl. Magn. Reson. Spectrosc. 2007, 50, 199. 11.N. T. Duong, F. Rossi, M. Makrinich, A. Goldbourt, M. R. Chierotti, R. Gobetto, Y. Nishiyama, J. Magn. Reson. 2019, 308, 106559.

Claims

1. An inclusion complex comprising a bicyclo[1.1.1]pentane derivative represented by formula (1) and a cyclodextrin or a cyclodextrin derivative. X-BCP-Y (1) (In the formula, BCP represents bicyclo[1.1.1]pentane, X and Y may be the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylamino group, an alkylaminocarbonyl group, an amino group, a carboxyl group, and a carboxamide group.)

2. The inclusion complex according to claim 1, comprising the bicyclo[1.1.1]pentane derivative and the cyclodextrin or the cyclodextrin derivative in a molar ratio of 1:

2.

3. The inclusion complex according to claim 1 or 2, wherein the bicyclo[1.1.1]pentane derivative represented by formula (1) is incorporated into the cavity of a dimer of the cyclodextrin or the cyclodextrin derivative.

4. A composition comprising the inclusion complex according to any one of claims 1 to 3 and water.

5. A method for preparing a cyclodextrin-bicyclo[1.1.1]pentane derivative inclusion complex, comprising: (1) preparing a formulation comprising water, a cyclodextrin or a cyclodextrin derivative, and a bicyclo[1.1.1]pentane derivative; (2) mixing the formulation; (3) recovering the generated inclusion complex: The preparation method comprising the above steps.

6. A method for recovering a bicyclo[1.1.1]pentane derivative from a cyclodextrin-bicyclo[1.1.1]pentane derivative inclusion complex, comprising: Step of preparing a formulation comprising the inclusion complex according to any one of claims 1 to 3, water, and at least one organic solvent; Step of mixing the formulation; Step of separating the organic layer and evaporating to recover the bicyclo[1.1.1]pentane derivative; The method comprising the above steps.

7. Step of preparing a mixture comprising a bicyclo[1.1.1]pentane derivative represented by formula (2), a base, and a solvent; Step of stirring the mixture and irradiating with UV light; Method for preparing [1.1.1]propellane comprising the above steps. X'-BCP-Y' (2) (In the formula, BCP represents bicyclo[1.1.1]pentane, X' and Y' may be the same or different and are each independently selected from fluorine, chlorine, bromine, or iodine.)

8. The base is hydrazine anhydride (NH ２ NH ２ ), hydrazine hydrate (NH ２ NH ２ ·H ２ O), a hydrazine derivative, or diisopropylamine (i-Pr ２ NH), and the preparation method according to claim 7.

9. The preparation method according to claim 7 or 8, further comprising a step of filtering the obtained mixture using alumina after irradiating with UV light.

10. Step of preparing a formulation comprising a bicyclo[1.1.1]pentane derivative represented by formula (2), a base, and a solvent; Step of adding a nucleophile to the formulation and stirring the reaction mixture; A method for preparing [1.1.1]propellane comprising the above steps, wherein the nucleophile is a phosphorus-containing compound or a nitrogen-containing compound having a lone pair of electrons, The method, wherein the base is a base having a reducing action. X'-BCP-Y' (2) (In the formula, BCP represents bicyclo[1.1.1]pentane, X' and Y' may be the same or different and are each independently selected from fluorine, chlorine, bromine or iodine.)

11. The nucleophilic reagent is trialkylphosphine (PR ３ ), triarylphosphine (PAr ３ ), alkyl(aryl)phosphine (PR ｎ Ar ３－ｎ )(n is an integer of 1 or 2), tris(dialkylamino)phosphine (P(NR ２ )) ３ ), tetraalkylammonium iodide (R ４ NI), and is selected from the group consisting of (R represents an alkyl group having 1 to 6 carbon atoms, and Ar represents an aryl group), and the preparation method according to claim 10.

12. The base is hydrazine anhydride (NH ２ NH ２ ), hydrazine hydrate (NH ２ NH ２ ·H ２ O), or a hydrazine derivative, and the preparation method according to claim 10 or 11.

13. The solvent is a polar solvent, and the preparation method according to any one of claims 10 to 12.

14. The preparation method according to any one of claims 10 to 13, further comprising a step of distilling the reaction mixture under reduced pressure and filtering the obtained fraction using alumina.

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