Process for the production of 1,3-disubstituted bicyclo[1.1.1]pentanes based on photoreactions

Abstract

A method for producing 1,3-disubstituted bicyclo[1.1.1]pentane, comprising the step of: allowing [1.1.1]spirobicycloalkane to react with a 1,2-diketone compound in a solvent containing a noncyclic ether solvent having 5 or more carbon atoms to obtain 1,3-disubstituted bicyclo[1.1.1]pentane, while allowing a cyclic ether compound to coexist in the reaction solution.

Description

Technical Field

[0001] This invention relates to a method for producing 1,3-disubstituted bicyclo[1.1.1]pentane based on a photoreaction. Background Technology

[0002] Bicyclic [1.1.1]pentane (BCP) compounds have attracted attention as biologically active compounds. The BCP motif possesses biofunctionality equivalent to para-substituted phenyl, alkynyl, and tert-butyl groups, exhibits high three-dimensionality, and demonstrates high biocompatibility, thus holding promise for drug delivery applications. In the synthesis of pharmaceutical candidate compounds, 1,3-disubstituted BCP derivatives are actually being introduced as building blocks.

[0003] Methods for obtaining 1,3-disubstituted BCP by photoreaction of [1.1.1]spiroline and 1,2-dione compounds are known. For example, as a method for synthesizing 1,3-diacetyl BCP, Patent Document 1 describes a method for photoreaction of [1.1.1]spiroline and 2,3-butanedione. Furthermore, Patent Document 2 describes a method for obtaining 1,3-disubstituted BCP by photoreaction of [1.1.1]spiroline and glyoxylic acid compounds.

[0004] Previous technical documents

[0005] Patent documents

[0006] Patent Document 1: Japanese Patent Publication No. 2020-533330

[0007] Patent Document 2: Japanese Patent Publication No. 2019-510012 Summary of the Invention

[0008] The technical problem to be solved by the invention

[0009] The objective of this invention is to provide a method for producing 1,3-disubstituted BCP that can promote the photoreaction and efficiently obtain the target 1,3-disubstituted BCP when performing a photoreaction on [1.1.1]spiroalkane and a 1,2-dione compound to obtain 1,3-disubstituted BCP.

[0010] means for solving technical problems

[0011] The problem of the present invention is solved by the following solution.

[0012] [1]

[0013] A method for producing 1,3-disubstituted bicyclo[1.1.1]pentane includes the following steps: when [1.1.1]spiroline is photo-reacted with a 1,2-dione compound in a solvent containing a non-cyclic ether solvent with 5 or more carbon atoms to obtain 1,3-disubstituted bicyclo[1.1.1]pentane, the cyclic ether compound is coexisting in the reaction solution.

[0014] [2]

[0015] According to the method for producing 1,3-disubstituted bicyclo[1.1.1]pentane described in [1], wherein,

[0016] The number of carbon atoms in the above-mentioned non-cyclic ether solvents is 5 to 10.

[0017] [3]

[0018] According to the method for producing 1,3-disubstituted bicyclo[1.1.1]pentane described in [1] or [2], wherein,

[0019] The above-mentioned non-cyclic ether solvents have 5 or 6 carbon atoms.

[0020] [4]

[0021] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [3], wherein,

[0022] The above-mentioned 1,2-dione compounds are diacetyl compounds or glyoxylic acid compounds.

[0023] [5]

[0024] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [4], wherein,

[0025] The above-mentioned cyclic ether compounds are tetrahydrofuran compounds.

[0026] [6]

[0027] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [5], wherein,

[0028] The above photoreaction is carried out by irradiating light with a wavelength of 200–600 nm.

[0029] [7]

[0030] The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of [1] to [6], wherein,

[0031] The reaction temperature of the above photoreaction is set to -50 to 50℃.

[0032] In this invention or specification, the numerical range indicated by “~” refers to the range encompassed by the values ​​recorded before and after “~” as the lower and upper limits.

[0033] Invention Effects

[0034] According to the method for manufacturing 1,3-disubstituted BCP of the present invention, the photoreaction of [1.1.1]spiroalkyl with 1,2-dione compound can be promoted, and the target 1,3-disubstituted BCP can be obtained with high efficiency through photoreaction. Attached Figure Description

[0035] Figure 1 This is a schematic diagram of the flow reaction system used in the embodiments. Detailed Implementation

[0036] In the method for producing 1,3-disubstituted BCP of the present invention (hereinafter also referred to as the manufacturing method of the present invention), [1.1.1]spiroline is photo-reacted with a 1,2-dione compound in a solvent containing a non-cyclic ether solvent having 5 or more carbon atoms. In the manufacturing method of the present invention, the cyclic ether compound coexists in the reaction solution during this photo-reaction, thereby enabling the efficient acquisition of the target 1,3-disubstituted BCP. In this reaction system, the cyclic ether acts as an additive to promote the reaction.

[0037] [Acyclic ether solvents with 5 or more carbon atoms]

[0038] The noncyclic ether solvent with 5 or more carbon atoms used in the manufacturing method of the present invention preferably has 5 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, even more preferably 5 to 7 carbon atoms, and even more preferably 5 or 6 carbon atoms.

[0039] By using noncyclic ether solvents with 5 or more carbon atoms, the reaction-promoting effect based on the addition of cyclic ethers can be effectively demonstrated.

[0040] The noncyclic ether solvent with 5 or more carbon atoms is more preferably at least one of cyclopentylmethyl ether and methyl tert-butyl ether.

[0041] The solvent used in the manufacturing method of the present invention may include solvents other than noncyclic ethers with 5 or more carbon atoms (solvents other than "noncyclic ethers with 5 or more carbon atoms") (excluding cyclic ether compounds). Solvents other than noncyclic ether solvents with 5 or more carbon atoms are not particularly limited and can be used appropriately without impairing the effects of the present invention. As a preferred example of a solvent other than a noncyclic ether solvent with 5 or more carbon atoms, hydrocarbon solvents can be cited, among which aliphatic hydrocarbon solvents (e.g., hexane, cyclohexane, pentane, heptane, etc.) are preferred. When noncyclic ethers with 5 or more carbon atoms and other solvents are included, their mass ratio is preferably [noncyclic ether solvent with 5 or more carbon atoms] / [solvent other than noncyclic ethers with 5 or more carbon atoms] is 1 / 10 or more, more preferably 1 / 5 or more, further preferably 1 / 2 or more, and even more preferably 1 / 1 or more. That is, the proportion of noncyclic ether solvent with 5 or more carbon atoms in the solvent is preferably 50% by mass or more, more preferably 60% by mass or more, and more preferably 65% ​​by mass or more.

[0042] [[1.1.1]Propellane]

[0043] [1.1.1] Propellane can generally be obtained by reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with organometallic reagents.

[0044] As organometallic compounds, alkyllithium, aryllithium, etc., can be widely used.

[0045] The reaction of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent to obtain [1.1.1]spiropropane is well known, for example, see Chem. Commun., 2021, Vol. 57, pp. 2871-2874.

[0046] [1,2-Diketone compounds]

[0047] 1,2-Diketone compounds are compounds with a "*-C(=O)-C(=O)-*" structure. * indicates the linking site. 1,2-Diketone compounds readily undergo photocatalytic cleavage between the two carbonyl groups, reacting with [1.1.1]spiroalkyl to generate 1,3-disubstituted BCPs.

[0048] Examples of 1,2-diketone compounds include diacetyl compounds (2,3-butanedione compounds) and glyoxylic acid compounds. In this invention, the term "~compound" refers to a "compound having a ~ skeleton." For example, "diacetyl compound" refers to a compound in which at least a portion of the hydrogen atoms of diacetyl are substituted, in addition to diacetyl itself (2,3-butanedione itself). Specifically, the substitution of at least a portion of the hydrogen atoms of diacetyl includes a configuration where the -CH3 group of diacetyl is replaced with an unsaturated bond, such as -CH=CH2 or -CN. Furthermore, in configurations where two or three hydrogen atoms of the -CH3 group of diacetyl are substituted with substituents, there are also configurations where two or three substituents are linked together to form a ring.

[0049] Preferred examples of the above-described diacetyl compounds are shown below. In the table below, D represents deuterium.

[0050] [Chemical Formula 1]

[0051]

[0052] The following are specific examples of preferred glyoxylic acid compounds.

[0053] [Chemical Formula 2]

[0054]

[0055] [Cyclic ether compounds]

[0056] In this invention, the cyclic ether compound does not function as a solvent, but is added in small amounts and acts as a reaction promoter. That is, in the manufacturing method of this invention, a non-cyclic ether solvent with 5 or more carbon atoms is used as the solvent, and the cyclic ether compound is incorporated as an additive different from the solvent. By adding the cyclic ether compound, the reaction rate of the photoreaction specified in this invention can be significantly promoted, and the yield of the target 1,3-disubstituted BCP can be effectively increased. While the reason is unclear, one possible reason is that the active species between the two carbonyl groups of the 1,2-diketone compound, which are photo-cleaved, becomes stable due to the cyclic ether compound, and the recombination of the active species is inhibited. As shown in the examples described later, even when various compounds other than the cyclic ether compound are added, no reaction-promoting effect is observed. That is, in the photoreaction specified in this invention, the reaction-promoting effect of the cyclic ether compound is not observed in other compounds; this is a unique effect of the cyclic ether compound.

[0057] Preferred examples of cyclic ether compounds include tetrahydrofuran (THF) compounds (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methylTHF), 2,5-dihydrofuran, tetrahydrofuran-d8 (deuterated tetrahydrofuran), 3-methyltetrahydrofuran, 2-hydroxytetrahydrofuran, 2-chlorotetrahydrofuran, etc.), tetrahydropyran, 4-methyltetrahydropyran, furan, 1,4-dioxane, etc. Among these, THF compounds are preferred, and at least one of THF and 2-methylTHF is more preferred.

[0058] In the photoreaction, the content of cyclic ether compounds in the reaction solution (the solution in which the photoreaction is carried out, also known as the reaction matrix solution) is preferably 1-50% by mass, more preferably 2-40% by mass, even more preferably 4-35% by mass, even more preferably 6-30% by mass, even more preferably 10-25% by mass, even more preferably 12-23% by mass, and even more preferably 15-22% by mass.

[0059] [Light Reaction]

[0060] In this invention, the photoreaction is a reaction in which [1.1.1]spiroalkyl reacts with a 1,2-dione compound under light irradiation to produce a 1,3-disubstituted BCP. The reaction diagram is shown below. R represents a hydrogen atom or a substituent.

[0061] [Chemical Formula 3]

[0062]

[0063] In this invention, as described above, the photoreaction is carried out by adding a cyclic ether compound as a reaction promoter to a solvent containing a non-cyclic ether solvent with 5 or more carbon atoms.

[0064] The photoreaction is preferably carried out by irradiating light with a wavelength of 300–500 nm, more preferably by irradiating light with a wavelength of 320–450 nm, and even more preferably by irradiating light with a wavelength of 340–430 nm. As a light source, light-emitting diode (LED) lamps, ultraviolet (UV) lamps, incandescent lamps (e.g., tungsten lamps) can be used without particular limitations.

[0065] This photoreaction can be carried out either in a batch process or in a flow process. From the viewpoint of light absorption efficiency, a flow process is preferred.

[0066] The photoreaction in a flow reaction can be carried out using a photoreactor. A photoreactor can be constructed, for example, by winding a transparent reaction tube around a light source cooling tube. A light source is disposed inside the light source cooling tube and is cooled by water or other solvents. To suppress light loss, the photoreactor is preferably covered with a reflective material such as aluminum foil. Examples of materials for the transparent reaction tube include tetrafluoroethylene / hexafluoropropylene copolymer (FEP) tubes, tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA) tubes, and polytetrafluoroethylene (PTFE) tubes, but are not limited to these; various materials can be used for the reaction tube without impairing the effects of the present invention.

[0067] A flow-through reaction can be configured, for example, as follows: a solution is prepared in which [1.1.1]spiroalkane, 1,2-dione compound and cyclic ether compound coexist in a solvent containing a noncyclic ether solvent with 5 or more carbon atoms, and the solution is pumped into a reaction tube to allow it to flow through the reaction tube.

[0068] Furthermore, it is also possible to configure the process as follows: a solution obtained by dissolving [1.1.1]spiroline in a solvent containing a non-cyclic ether solvent with 5 or more carbon atoms and a solution obtained by dissolving a 1,2-diketone compound in a solvent containing a non-cyclic ether solvent with 5 or more carbon atoms are flowed separately in different flow paths, and then merged, and a photoreaction is generated through a photoreactor as the merged liquid flows downstream. In this reaction, the cyclic ether compound is added as a reaction promoter no later than before the photoreaction. For example, the cyclic ether compound can be contained in the [1.1.1]spiroline solution, or in the 1,2-diketone compound solution, or the solutions containing the cyclic ether can be merged before the photoreaction.

[0069] In the foregoing, preferred reaction modes have been described, but the present invention is not limited to the modes described above, except as specified herein. For example, using a batch reaction mode is also a preferred embodiment of the present invention.

[0070] Next, the preferred reaction conditions for the photoreaction will be explained.

[0071] The reaction temperature of the photoreaction can be set to -50 to 50°C, but from the viewpoint of improving the yield, it is preferable to set it to -30 to 30°C, more preferably to set it to -20 to 20°C, and also preferably to set it to -10 to 10°C.

[0072] Furthermore, the reaction time of the light reaction is not particularly limited and can be set appropriately. For example, it can be set to 0.001 to 7000 minutes, 0.01 to 5000 minutes, or 0.1 to 700 minutes.

[0073] In the above reaction, the molar ratio of [1.1.1]spiroalkyl to the 1,2-dione compound can be appropriately adjusted considering stoichiometry, etc. For example, the ratio of [[1.1.1]spiroalkyl] / [1,2-dione compound] can be set to 1 / 0.5 to 1 / 10, preferably 1 / 1 to 1 / 5, and more preferably 1 / 1 to 1 / 2.

[0074] The concentrations of [1.1.1]spiroline and 1,2-dione compounds in the reaction solution (the solution for carrying out the photoreaction) can be appropriately set according to the purpose and taking into account the above-mentioned reaction molar ratio. For example, the concentration of [1.1.1]spiroline in the reaction solution can be set to 0.01 to 3 mol / L, and is preferably set to 0.1 to 0.5 mol / L.

[0075] The yield in the manufacturing method of the present invention (the yield of 1,3-disubstituted BCP in the reaction of [1.1.1]spiroline with a 1,2-dione compound to obtain 1,3-disubstituted BCP, i.e., [molar amount of 1,3-disubstituted BCP generated] / [molar amount of [1.1.1]spiroline as starting material]) is preferably 80% or more, more preferably 85% or more, further preferably 90% or more, and also preferably 92% or more. Such a high yield can be achieved by adding a cyclic ether compound as a reaction promoter.

[0076] In the manufacturing method of the present invention, the 1,3-disubstituted BCP generated by the photoreaction can be further separated and purified. General methods can be appropriately applied as this separation or purification method. For example, column chromatography, recrystallization, reprecipitation, sublimation, etc., can be used alone or in combination.

[0077] The invention will be described in further detail with reference to the embodiments, but the invention is not limited to these embodiments.

[0078] Example

[0079] [Example 1]

[0080] 1,3-Diacetyl BCP was obtained according to the following diagram.

[0081] [Chemical Formula 4]

[0082]

[0083] <[1.1.1] Preparation of Propellane>

[0084] 100 mL of cyclopentylmethyl ether (CPME) and 10 g of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane were placed in a 500 mL three-necked flask and cooled to -78 °C under a nitrogen atmosphere. 42 mL of a solution of n-butyllithium dissolved in n-hexane at a concentration of 1.6 M was added, and the mixture was stirred for 10 minutes to allow the reaction to proceed. The temperature was then raised to 0 °C, and the mixture was stirred for another 30 minutes. Thus, [1.1.1]spiropyran was obtained in the solvent. 30 mL of water was added, and the mixture was heated to room temperature (25 °C), followed by separation to obtain an organic layer. The organic layer was cooled to 0 °C, and a distillation apparatus was connected. The receiving flask was cooled to -78 °C and distilled, transferring the [1.1.1]spiropyran to the receiving flask. Thus, a CPME / n-hexane (3.6 / 1, mass ratio) solution containing [1.1.1]spiroline at a concentration of 0.15 M was obtained. The yield of [1.1.1]spiroline was 62%. The yield of [1.1.1]spiroline was confirmed based on the following data.

[0085] based on 1 The chemical shift σ (ppm) of the 1H-NMR (400MHz, solvent: DMSO-d6, internal standard: tetramethylfuran (TMS)) was 2.04 (6H, s).

[0086] <Preparation of 1,3-Diaacetyl BCP>

[0087] 1,3-Diacetyl BCP was prepared via a flow-rate reaction. A summary of the flow-rate reaction system used is as follows: Figure 1 As shown. In this flow reaction system, a stainless steel (SUS316) tube 3 with an inner diameter of 1.0 mm and a length of 1.0 m is placed in a thermostatic bath 2 set at 0°C. A PFA tube 4 with an inner diameter of 1.6 mm and a length of 3.0 m is connected downstream of the tube. The PFA tube 4 is wound around a light source cooling tube 5. A 100W LED lamp with a wavelength of 385 nm is placed inside the light source cooling tube 5 as the light source. The temperature of the light source cooling tube 5 (equivalent to the reaction temperature of the photoreaction) is set to 0°C. The reaction matrix solution 1 is delivered by a syringe pump.

[0088] The CPME / n-hexane solution containing [1.1.1]spiroline at a concentration of 0.15 M, obtained in the preparation of [1.1.1]spiroline, and 2,3-butanedione at a molar equivalent (twice the molar amount of [1.1.1]spiroline) relative to [1.1.1]spiroline, were further mixed with THF at the concentrations shown in the table below. This mixture was cooled to 5°C and bubbled under nitrogen for 5 minutes, serving as the reaction matrix solution (the reaction solution before the photoreaction). This reaction matrix solution was fed into the flow path of the aforementioned flow reaction system at a flow rate of 1.2 mL / min, where 1,3-diacetyl BCP was generated via photoreaction. The reaction time of this photoreaction (the flow time within the PFA tube wound around the light source cooling tube 5) was 5 minutes. Using the resulting reaction solution, the yield of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroline with 2,3-butanedione was calculated by nuclear magnetic resonance (internal standard: biphenyl). The results are shown in the table below. The following data confirmed the yield of 1,3-diacetyl BCP [alias: 1,1'-(bicyclo[1.1.1]pentane-1,3-diyl)bis(ethyl-1-one)].

[0089] based on 1 The chemical shifts σ (ppm) of H-NMR (400MHz, solvent: DMSO-d6, internal standard: tetramethylfuran (TMS)) were 2.16 (6H, s) and 2.10 (6H, s).

[0090] [Examples 2-4]

[0091] In Example 1, the THF concentration in the reaction matrix solution was varied as shown in the table below, otherwise 1,3-diacetyl BCP was obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0092] [Example 5]

[0093] In Example 1, the CPME used in <[1.1.1]Preparation of Propellane> was changed to methyl tert-butyl ether (MTBE). Otherwise, an MTBE / n-hexane solution containing [1.1.1]propellane at a concentration of 0.15 M was obtained in the same manner as in <[1.1.1]Preparation of Propellane> in Example 1.

[0094] Then, instead of the 0.15 M MTBE / n-hexane solution containing [1.1.1]spiroline, the 1,3-diacetyl BCP was obtained in the same manner as in Example 1, <Preparation of 1,3-diacetyl BCP>. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroline with 2,3-butanedione are shown in the table below.

[0095] [Examples 6-8]

[0096] In Example 5, the THF concentration in the reaction matrix solution was varied as shown in the table below, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 5. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0097] [Example 9]

[0098] In Example 1, 2-methylTHF was used instead of THF, and otherwise 1,3-diacetyl BCP was obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroline with 2,3-butanedione are shown in the table below.

[0099] [Examples 10-12]

[0100] In Example 9, the concentration of 2-methyl THF in the reaction matrix solution was varied as shown in the table below, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 9. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0101] [Example 13]

[0102] In Example 9, the MTBE / n-hexane solution containing [1.1.1]spiroline at a concentration of 0.15 M was used instead of the CPME / n-hexane solution containing [1.1.1]spiroline at a concentration of 0.15 M, as in Example 5. Otherwise, 1,3-diacetyl BCP was obtained in the same manner as in Example 9. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroline with 2,3-butanedione are shown in the table below.

[0103] [Examples 14-16]

[0104] In Example 13, the concentration of 2-methylTHF in the reaction matrix solution was varied as shown in the table below, otherwise 1,3-diacetyl BCP was obtained in the same manner as in Example 13. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0105] [Example 17]

[0106] As the light source configured in the light source cooling tube of the flow reaction system, a 100W LED with a wavelength of 405nm was used instead of a 100W LED with a wavelength of 385nm. Otherwise, 1,3-diacetyl BCP was obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0107] [Example 18]

[0108] In Example 17, the THF concentration in the reaction matrix solution was varied as shown in the table below, but otherwise 1,3-diacetyl BCP was obtained in the same manner as in Example 17. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0109] [Example 19]

[0110] In Example 17, the MTBE / hexane solution containing [1.1.1]spiroline at a concentration of 0.15 M was used instead of the CPME / hexane solution containing [1.1.1]spiroline at a concentration of 0.15 M, as in Example 5. Otherwise, 1,3-diacetyl BCP was obtained in the same manner as in Example 17. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroline with 2,3-butanedione are shown in the table below.

[0111] [Example 20]

[0112] In Example 19, the THF concentration in the reaction matrix solution was varied as shown in the table below, but otherwise 1,3-diacetyl BCP was obtained in the same manner as in Example 19. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0113] [Example 21]

[0114] As the light source configured in the light source cooling tube of the flow reaction system, a 100W LED with a wavelength of 365nm was used instead of a 100W LED with a wavelength of 385nm. Otherwise, 1,3-diacetyl BCP was obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0115] [Example 22]

[0116] In Example 21, the THF concentration in the reaction matrix solution was varied as shown in the table below, but otherwise 1,3-diacetyl BCP was obtained in the same manner as in Example 21. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0117] [Example 23]

[0118] In Example 21, the MTBE / hexane solution containing [1.1.1]spiroline at a concentration of 0.15 M was used instead of the CPME / hexane solution containing [1.1.1]spiroline at a concentration of 0.15 M, as in Example 5. Otherwise, 1,3-diacetyl BCP was obtained in the same manner as in Example 21. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroline with 2,3-butanedione are shown in the table below.

[0119] [Example 24]

[0120] In Example 23, the THF concentration in the reaction matrix solution was varied as shown in the table below, but otherwise 1,3-diacetyl BCP was obtained in the same manner as in Example 23. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0121] [Comparative Example 1]

[0122] In Example 1, THF was not incorporated into the reaction matrix solution, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0123] [Comparative Example 2]

[0124] In Example 5, THF was not incorporated into the reaction matrix solution, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 5. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0125] [Comparative Example 3]

[0126] In Example 1, ethyl acetate (EtOAc) was incorporated into the reaction matrix solution instead of THF, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0127] [Comparative Example 4]

[0128] In Comparative Example 3, the concentration of ethyl acetate in the reaction matrix solution was changed as shown in the table below, and 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 3. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0129] [Comparative Example 5]

[0130] In Example 1, toluene was incorporated into the reaction matrix solution instead of THF, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0131] [Comparative Example 6]

[0132] In Comparative Example 5, the concentration of toluene in the reaction matrix solution was changed as shown in the table below, and 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 5. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0133] [Comparative Example 7]

[0134] In Example 1, acetonitrile was incorporated into the reaction matrix solution instead of THF, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0135] [Comparative Example 8]

[0136] In Comparative Example 7, the concentration of acetonitrile in the reaction matrix solution was changed as shown in the table below, but otherwise 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 7. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0137] [Comparative Example 9]

[0138] In Example 1, acetone was incorporated into the reaction matrix solution instead of THF, and 1,3-diacetyl BCP was otherwise obtained in the same manner as in Example 1. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0139] [Comparative Example 10]

[0140] In Comparative Example 9, the concentration of acetone in the reaction matrix solution was changed as shown in the table below, but otherwise 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 9. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0141] [Comparative Example 11]

[0142] In Comparative Example 2, a 100W LED with a wavelength of 405nm was used instead of a 100W LED with a wavelength of 385nm as the light source in the light source cooling tube of the flow reaction system. Otherwise, 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 2. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0143] [Comparative Example 12]

[0144] In Comparative Example 2, a 100W LED with a wavelength of 365nm was used instead of a 100W LED with a wavelength of 385nm as the light source in the light source cooling tube of the flow reaction system. Otherwise, 1,3-diacetyl BCP was obtained in the same manner as in Comparative Example 2. The yields of 1,3-diacetyl BCP based on the photoreaction of [1.1.1]spiroalkyl with 2,3-butanedione are shown in the table below.

[0145] [Table 1]

[0146]

[0147] As shown in the table above, it can be seen that if tetrahydrofuran compounds that form cyclic ethers are incorporated into the reaction matrix solution, the yield increases dramatically compared to the unincorporated case (comparison of Comparative Example 1 with Examples 1-4 and Examples 9-12, Comparative Example 2 with Examples 5-8 and Examples 13-16, Comparative Example 11 with Examples 19 and 20, Comparative Example 12 with Examples 23 and 24).

[0148] Furthermore, when compounds other than cyclic ether compounds were tried as reaction promoters, no increase in yield was observed (Comparative Examples 3-10). Based on these results, it can be concluded that cyclic ether compounds exhibit a prominent role as reaction promoters in the photoreaction of the present invention.

[0149] The invention has been described together with its embodiments, but unless otherwise specified, no detail in the description is intended to limit our invention, and it is thought that it should be interpreted broadly without departing from the spirit and scope of the invention as shown in the appended claims.

[0150] This application claims priority based on Japanese Patent Application No. 2021-148842, filed on September 13, 2021, the contents of which are incorporated herein by reference as part of the description.

[0151] Symbol Explanation

[0152] 1-Reaction matrix solution (injection pump), 2-Thermostatic bath, 3-SUS tube, 4-PFA tube, 5-Light source cooling tube.

Claims

1. A method for producing 1,3-disubstituted bicyclo[1.1.1]pentane, comprising the following: When [1.1.1]spiroline, as a reactant, is photo-reacted with a 1,2-dione compound in a solvent containing a non-cyclic ether solvent with 5 or 6 carbon atoms to obtain 1,3-disubstituted bicyclic [1.1.1]pentane, a cyclic ether compound is added to the reaction solution in addition to the solvent of the reactant. The cyclic ether compound is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, 2,5-dihydrofuran, tetrahydrofuran-d8, 3-methyltetrahydrofuran, 2-hydroxytetrahydrofuran, 2-chlorotetrahydrofuran, tetrahydropyran, 4-methyltetrahydropyran, furan, and 1,4-dioxane. The content of the cyclic ether compound in the reaction solution is 10% to 50% by mass.

2. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to claim 1, wherein, The solvent of the reaction raw materials does not contain cyclic ether compounds.

3. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to claim 1, wherein, The non-cyclic ether solvent has 5 carbon atoms.

4. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of claims 1 to 3, wherein, The 1,2-dione compound is a diacetyl compound or a glyoxylic acid compound.

5. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of claims 1 to 3, wherein, The cyclic ether compound is a tetrahydrofuran compound.

6. The method for producing 1,3-disubstituted bicyclo[1.1.1]pentane according to any one of claims 1 to 3, wherein, The photoreaction is carried out by irradiating light with a wavelength of 200–600 nm.

7. The 1,3-disubstituted bicyclic ring according to any one of claims 1 to 3 [ 1.1.1] A method for producing pentane, wherein, The reaction temperature of the photoreaction is set to -50 to 50°C.

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