Process for producing halogenobicyclo[1.1.1]pentane

Abstract

A method for producing a halogenobicyclo[1.1.1]pentane comprising: a step (a) in which [1.1.1]propellane is obtained by causing a reaction between 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and an organometallic reagent in a solvent containing a non-cyclic ether having five or more carbon atoms; and a step (b) in which a halogenobicyclo[1.1.1]pentane is obtained by reacting the obtained [1.1.1]propellane with a halogen in a state in which light having a wavelength of 400 nm or less is blocked.

Description

Technical Field

[0001] The present invention relates to a method for producing halogenobicyclo[1.1.1]pentane.

Background Art

[0002] Bicyclo[1.1.1]pentane (BCP) compounds have attracted attention as biologically active compounds. The BCP motif has biocompatibility equivalent to that of para-substituted phenyl groups, alkynyl groups, tert-butyl groups, etc., while having high three-dimensionality and high biosafety, and thus is expected to be applied to drug delivery. In addition, halides of BCP (halogeno BCP) are useful compounds as building blocks, and among them, 1,3-diiodo BCP is actually being introduced in the synthesis of pharmaceutical candidate compounds. Several methods for synthesizing 1,3-diiodo BCP have been proposed. For example, Non-Patent Document 1 describes that [1.1.1]propellane is obtained by reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with methyllithium in a diethyl ether solvent, and then reacting this [1.1.1]propellane with iodine to obtain 1,3-diiodo BCP.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The synthesis of halogeno BCP useful as a building block involves reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with methyllithium using diethyl ether as a solvent as described above in the synthesis of the intermediate [1.1.1]propellane. However, there are restrictions on its application to industrial production, such as diethyl ether being a special flammable substance. In addition, as the inventors further investigated, when [1.1.1]propellane was obtained using 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane as a starting material and then halogenated to obtain halogeno BCP, it was speculated that the yield of the resulting halogeno BCP was low and there were some restrictions on improving the yield.

[0005] An object of the present invention is to provide a new method for producing halogeno BCP that is suitable for industrial production and can effectively increase the yield.

Means for Solving the Problems

[0006] The problems of the present invention have been solved by the following means.

[0007] 〔1〕 Step (a) of reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent in a solvent containing an acyclic ether solvent having 5 or more carbon atoms to obtain [1.1.1]propellane, and step (b) of reacting the obtained [1.1.1]propellane with a halogen in a solvent containing an acyclic ether solvent having 5 or more carbon atoms in a state where light having a wavelength of 400 nm or less is blocked to obtain halogenobicyclo[1.1.1]pentane A method for producing halogenobicyclo[1.1.1]pentane comprising. 〔2〕 The method for producing halogenobicyclo[1.1.1]pentane according to [1], wherein the organometallic reagent contains at least one of alkyllithium and aryllithium. 〔3〕 The method for producing a halogenobicyclo[1.1.1]pentane according to [2], wherein the alkyl lithium has 2 to 10 carbon atoms. [4] The method for producing a halogenobicyclo[1.1.1]pentane according to [2] or [3], wherein the aryl lithium is phenyl lithium. [5] The method for producing a halogenobicyclo[1.1.1]pentane according to any one of [2] to [4], wherein the alkyl lithium is butyl lithium. [6] The method for producing a halogenobicyclo[1.1.1]pentane according to any one of [1] to [5], wherein the reaction temperature in the above step (a) is 0°C or lower. [7] The method for producing a halogenobicyclo[1.1.1]pentane according to any one of [1] to [6], wherein in the above steps (a) and (b), the acyclic ether solvent has 5 to 10 carbon atoms. [8] The method for producing a halogenobicyclo[1.1.1]pentane according to [7], wherein in the above steps (a) and (b), the acyclic ether solvent has 5 or 6 carbon atoms. [9] The method for producing a halogenobicyclo[1.1.1]pentane according to any one of [1] to [8], wherein the halogen is iodine.

[10] The method for producing a halogenobicyclo[1.1.1]pentane according to any one of [1] to [9], wherein the halogenobicyclo[1.1.1]pentane is diiodobicyclo[1.1.1]pentane.

[11] The method for producing a halogenobicyclo[1.1.1]pentane according to any one of [1] to

[10] , which does not have the step of distilling the above [1.1.1]propellane.

[0008] In the present invention or the specification, the numerical range represented by using "~" means a range including the numerical values described before and after "~" as the lower limit value and the upper limit value. [Advantages of the Invention]

[0009] The method for producing a halogenated BCP of the present invention is suitable for industrial production and can effectively increase the yield of the obtained halogenated BCP.

Embodiments for Carrying Out the Invention

[0010] The method for producing a halogenated BCP of the present invention (hereinafter, also referred to as the production method of the present invention) includes a step (a) of reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent in a solvent containing an acyclic ether having 5 or more carbon atoms to obtain [1.1.1]propellane, and a step (b) of reacting the obtained [1.1.1]propellane with a halogen in a solvent containing an acyclic ether solvent having 5 or more carbon atoms in a state where light having a wavelength of 400 nm or less is blocked to obtain a halogenated BCP.

[0011] [Step (a)] <Acyclic ether solvent having 5 or more carbon atoms> The acyclic ether solvent having 5 or more carbon atoms used in the production method of the present invention preferably has 5 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, still more preferably 5 to 7 carbon atoms, and still more preferably 5 or 6 carbon atoms. Conventionally, in the step of reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent to obtain [1.1.1]propellane, diethyl ether has been frequently used to dissolve organometallic reagents such as methyllithium. However, diethyl ether is a special flammable substance, and certain restrictions occur in its use in industrial production. In the present invention, an acyclic ether solvent having 5 or more carbon atoms is used instead of diethyl ether. Even when such a solvent is used, a sufficiently high reaction efficiency can be achieved as in the case of using diethyl ether. When a cyclic ether, an aromatic compound, or the like is used as the solvent, the yield of the obtained [1.1.1]propellane is poor. That is, in the balance between the target reaction and the side reaction, it is considered that the solvent effect of the acyclic ether having 5 or more carbon atoms effectively acts on the progress of the target reaction. The acyclic ether solvent having 5 or more carbon atoms is more preferably at least one of cyclopentyl methyl ether and methyl tert-butyl ether.

[0012] The solvent used in step (a) may contain a solvent other than the acyclic ether solvent having 5 or more carbon atoms (that is, it may be a mixed solvent). The solvent other than the acyclic ether solvent having 5 or more carbon atoms is not particularly limited and can be appropriately used as long as the effects of the present invention are not impaired. Preferable examples of the solvent other than the acyclic ether solvent having 5 or more carbon atoms include aliphatic hydrocarbon solvents (such as hexane, cyclohexane, pentane, heptane, etc.). When the solvent used in step (a) is a mixed solvent containing an acyclic ether solvent having 5 or more carbon atoms and another solvent, the mass ratio of these amounts is preferably [acyclic ether solvent having 5 or more carbon atoms] / [solvent other than acyclic ether solvent having 5 or more carbon atoms] of 1 / 10 or more, more preferably 1 / 5 or more, further preferably 1 / 2 or more, and still further preferably 1 / 1 or more. That is, the proportion of the acyclic ether solvent having 5 or more carbon atoms in the solvent is preferably 50% by mass or more, preferably 60% by mass or more, and preferably 65% by mass or more.

[0013] <Organometallic reagent> The organometallic reagent used in the present invention is not particularly limited as long as it reacts with 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane to produce [1.1.1]propellane. For example, alkyllithium, aryllithium, etc. can be widely used. The alkyl group of alkyllithium may be linear or branched, and is preferably linear. The carbon number of alkyllithium is preferably 2 to 10, more preferably 3 to 8, further preferably 3 to 6, and still further preferably 3 to 5. Alkyllithium is preferably butyllithium, and particularly preferably n-butyllithium. When methyl lithium is used, bromomethane, which is designated as an ozone-depleting substance, is by-produced. From this viewpoint as well, the carbon number of alkyllithium is preferably 2 or more. The aryl group of aryllithium preferably has 6 to 30 carbon atoms, more preferably 6 to 20 carbon atoms, still more preferably 6 to 15 carbon atoms, still more preferably 6 to 12 carbon atoms, and still more preferably 6 to 10 carbon atoms. The aryllithium is preferably at least one of phenyllithium, tolyllithium, methoxyphenyllithium, chlorophenyllithium, and naphthyllithium, and among them, phenyllithium is preferred. Moreover, it is also preferable to use the above alkyl lithium as an organometallic reagent and use it together with bromobenzene. In this case, phenyllithium is generated in the reaction system. By adopting such a form, there is an advantage that it can be used in the reaction without reducing the activity of phenyllithium.

[0014] <Reaction conditions of step (a)> Step (a) may be a batch reaction or a flow reaction. In the case of a batch reaction, for example, a solvent containing an acyclic ether solvent having 5 or more carbon atoms and 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane are placed in a container, and preferably under an atmosphere of an inert gas (such as nitrogen gas or noble gas), the temperature can be controlled to, for example, a temperature range of -100 to 20°C. From the viewpoint of improving the yield, the temperature is preferably 10°C or lower, more preferably 0°C or lower, still more preferably -10°C or lower, still more preferably -20°C or lower, still more preferably -30°C or lower, still more preferably -40°C or lower, still more preferably -45°C or lower. When the above temperature is shown as a preferable range by specifying the upper and lower limit values, -100 to 10°C is preferable, -100 to 0°C is more preferable, -100 to -10°C is still more preferable, -100 to -20°C is still more preferable, -100 to -30°C is still more preferable, -100 to -40°C is still more preferable, -100 to -45°C is still more preferable. This solution and a solution obtained by dissolving an organometallic reagent are mixed and reacted at the above temperature. This reaction time is not particularly limited as long as the target reaction can be sufficiently carried out. For example, it can be 30 seconds or longer, preferably 1 minute or longer, preferably 5 minutes or longer, and preferably 10 minutes or longer. This reaction time is usually 3 hours or shorter, may be 2 hours or shorter, may be 1 hour or shorter, and is preferably 30 minutes or shorter. When the above reaction time is shown as a preferable range by specifying the upper and lower limit values, 30 seconds or longer and 3 hours or shorter is preferable, 1 minute or longer and 2 hours or shorter is also preferable, 5 minutes or longer and 1 hour or shorter is also preferable, and 10 minutes or longer and 30 minutes or shorter is also preferable. During this reaction, the temperature may be increased or decreased within the above temperature range. Further, from the viewpoint of more surely suppressing the remaining of the raw materials, for example, after sufficiently reacting with the initial temperature control at -100 to -30°C, the temperature can be further raised to -10 to 0°C and held for a certain period of time. The above reaction conditions can be appropriately set while confirming the yield of the obtained BCP. In the case of a flow-type reaction, for example, a solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and a solution of an organometallic reagent are each passed through different flow paths, the two solutions are merged, and the reaction is carried out while flowing downstream. The liquid temperature can be controlled to a temperature of, for example, -100 to 20 °C as described above. Also, the reaction time can be controlled by the flow time of the merged liquid. The reaction time can be, for example, 5 minutes or more as described above. As such a form of flow-type reaction, for example, reference can be made to Chem. Commun., 2021, Vol. 57, p. 2871-2874.

[0015] The reaction conditions in step (a) can apply the preferred reaction temperature, reaction time, etc. described in the above batch-type reaction regardless of the reaction format such as batch-type reaction or flow-type reaction.

[0016] In the above reaction, regardless of the reaction format such as batch-type reaction and flow-type reaction, the reaction molar ratio of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane to the organometallic reagent is preferably [1,1-dibromo-2,2-bis(chloromethyl)cyclopropane] / [organometallic reagent] of 1 / 1.5 to 1 / 3, more preferably 1 / 1.9 to 1 / 2.3, and even more preferably 1 / 2 to 1 / 2.2. Also, the respective concentrations of the solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and the solution of the organometallic reagent are appropriately set according to the purpose. For example, the concentration of the solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane can be 0.1 to 30% by mass, and it is also preferable to be 1 to 20% by mass. Also, the concentration of the solution of the organometallic reagent can be 0.1 to 40% by mass, and it is also preferable to be 10 to 30% by mass. In step (a), after the reaction, [1.1.1]propellane may be distilled, or it can also be directly used as a reaction raw material for the next step (b) without distilling [1.1.1]propellane. From the perspective of working efficiency, it is preferable that step (a) does not have a step of distilling [1.1.1]propellane.

[0017] [Step (b)] In step (b), [1.1.1]propellane obtained in step (a) and a halogen are reacted in a solvent containing an acyclic ether solvent having 5 or more carbon atoms in a state where light having a wavelength of 400 nm or less is blocked to obtain halogeno BCP. The halogeno BCP is preferably dihalogeno BCP, and more preferably 1,3-dihalogeno BCP. Examples of the halogen include fluorine, chlorine, bromine, and iodine, and iodine is preferred. That is, the halogeno BCP is more preferably diiodo BCP, and even more preferably 1,3-diiodo BCP. The acyclic ether solvent having 5 or more carbon atoms used in step (b) is the same as the acyclic ether solvent having 5 or more carbon atoms described in step (a), and the preferred forms are also the same. Further, when the solvent used in step (b) contains a solvent other than the acyclic ether solvent having 5 or more carbon atoms, the form of such a mixed solvent is also the same as that described in step (a), and the preferred forms are also the same. Note that the solvent composition used in step (a) and the solvent composition used in step (b) may be the same or different.

[0018] Step (b) may be a batch reaction or a flow reaction. In the case of a batch reaction, for example, a solution obtained by dissolving a halogen in a solution obtained by dissolving [1.1.1]propellane obtained in step (a) in a solvent is dropped and mixed to obtain a halide of BCP. This reaction can be carried out, for example, with temperature control at -100°C to 20°C. This reaction temperature is preferably 10°C or lower, more preferably 5°C or lower. Also, this reaction temperature is preferably -50°C or higher, preferably -30°C or higher, preferably -20°C or higher, and preferably -10°C or higher. When the above reaction temperature is shown as a preferred range by specifying the upper and lower limit values, -500 to 10°C is preferred, -30 to 5°C is more preferred, -20 to 5°C is even more preferred, and -10 to 5°C is even more preferred. Further, the reaction time (including the dropping time) is preferably 0.001 to 600 minutes, more preferably 0.01 to 300 minutes, and even more preferably 0.1 to 60 minutes. In a flow-type reaction, the solution of [1.1.1]propane obtained in step (a) and the solution containing halogen may be made to flow through different flow paths, the two solutions are merged, and the reaction is carried out while flowing downstream. The reaction temperature, reaction time, etc. can adopt the forms described in the above batch-type reaction. As a form of flow-type reaction, for example, reference can be made to Chem. Commun., 2021, Vol. 57, p. 2871-2874.

[0019] In the above reaction, regardless of the reaction form such as batch-type reaction and flow-type reaction, the reaction molar ratio of [1.1.1]propane to halogen is preferably [[1.1.1]propane] / [halogen] = 1 / 0.5 to 1 / 5, more preferably 1 / 0.9 to 1 / 2, and even more preferably 1 / 1 to 1 / 1.5.

[0020] The concentrations of the solution of [1.1.1]propane and the solution of halogen are appropriately set according to the purpose. For example, the concentration of the solution of [1.1.1]propane can be 0.01 to 50% by mass, and it is also preferably 0.1 to 10% by mass. Also, the concentration of the solution of halogen can be 0.1 to 80% by mass, and it is also preferably 10 to 30% by mass.

[0021] The reaction in step (b) is carried out in a state where light with a wavelength of 400 nm or less is blocked. Thereby, the yield of the obtained halogeno BCP can be greatly increased. The reason for this is not clear, but it is considered that one of the reasons is that halogeno BCP is vulnerable to light of a specific wavelength, and by blocking light with a wavelength of 400 nm or less, the decomposition of the generated halogeno BCP can be effectively reduced. The method of light shielding is not particularly limited, and examples include using a yellow LED as the light source for illumination, using a light source for illumination with a cut filter, or using a reactor with a reflective material. Note that if light with a wavelength of 400 nm or less is blocked, it is not necessary to block light with a wavelength longer than 400 nm. Also, after blocking light with a wavelength of 400 nm or less, part or all of the light with a wavelength longer than 400 nm may be blocked. Further, it is preferable that the light with a wavelength of 400 nm or less is completely blocked.

[0022] The yield in step (b) (the yield in the reaction of halogenating [1.1.1]propellane to obtain halogeno BCP, that is, [molar amount of the produced halogeno BCP] / [molar amount of [1.1.1]propellane as the starting material]) is preferably 65% or more, more preferably 70% or more, still more preferably 80% or more, even more preferably 85% or more, further preferably 90% or more, and also preferably 92% or more. Such a high yield can be achieved by blocking light with a wavelength of 400 nm or less.

[0023] The halogeno BCP produced in step (b) can also be separated and purified. As this separation or purification method, general methods can be appropriately applied. For example, column chromatography, recrystallization, reprecipitation, sublimation, etc. can be applied alone or in combination.

[0024] The present invention will be described in more detail based on examples, but the present invention is not limited by these examples.

Examples

[0025] [Example 1] 1,3-Diiodo BCP was obtained according to the following scheme.

[0026]

Chemical formula

[0027] <Step (a)> 100 mL of cyclopentyl methyl 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. A solution of n-butyllithium dissolved in n-hexane at a concentration of 1.6 M was added thereto in an amount of 42 mL, and the mixture was stirred at -78 °C for 10 minutes to cause a reaction. Then, the temperature was raised to 0 °C and stirring was continued for another 30 minutes. Thus, [1.1.1]propellane was obtained in the solvent (CPME / n-hexane). A portion of the obtained [1.1.1]propellane solution was sampled, treated with water, and separated by liquid-liquid extraction. The 1 The yield of [1.1.1]propellane was calculated from the 1H-NMR analysis. Biphenyl was used as the internal standard. The presence of [1.1.1]propellane was confirmed from the following data. 1 1H-NMR (400 MHz, solvent: DMSO-d6, internal reference substance: tetramethylsilane (TMS)) chemical shift σ (ppm) = 2.04 (6H, s)

[0028] <Step (b)> An environment was created in which light with a wavelength of 400 nm or less was completely blocked by using a yellow fluorescent lamp as the light source for illumination. A solution of 9.0 g of iodine dissolved in 50 mL of CPME was added dropwise to the [1.1.1]propellane solution (0 °C) obtained in the above step (a) over 5 minutes, and the mixture was stirred at 0 °C. Then, 30 mL of a 14 mass% aqueous sodium thiosulfate solution was added dropwise over 3 minutes, followed by liquid-liquid extraction, and the obtained organic phase was concentrated. The obtained concentrated organic phase was transferred to a flask, 10 mL of an 80 volume% methanol (MeOH) aqueous solution was added, and the mixture was stirred at 5 °C and then filtered to obtain a crude product of 1,3-diiodo BCP. The obtained crude product was transferred to a flask, 7 mL of MeOH was added, and the mixture was stirred at 5 °C and then filtered to obtain 1,3-diiodo BCP. The presence of 1,3-diiodo BCP was confirmed from the following data. 1 1H-NMR (400 MHz, solvent: DMSO-d6, internal reference substance: tetramethylsilane (TMS)) chemical shift σ (ppm) = 2.71 (6H, s)

[0029] The yields in each of steps (a) and (b) are shown in the table below.

[0030] [Examples 2 - 9] In Example 1, except that the CPME used in step (a) and the reaction temperature of -78°C in step (a) were as described in "Solvent type in step (a)" and "Temperature in step (a)" in the table below, and the solvent of the iodine solution used in step (b) was the same as that in "Solvent type in step (a)" in the table below, 1,3 - diiodo - BCP was obtained in the same manner as in Example 1. For each example, the yields in each of steps (a) and (b) are shown in the table below. In the table below, MTBE is methyl tert - butyl ether, and Bu 2 O is dibutyl ether.

[0031] [Comparative Examples 1 - 9] In Example 1, except that the CPME used in step (a) and the reaction temperature of -78°C in step (a) were as described in "Solvent type in step (a)" and "Temperature in step (a)" in the table below, the solvent of the iodine solution used in step (b) was the same as that in "Solvent type in step (a)" in the table below, and the reaction in step (b) was carried out without blocking light with a wavelength of 400 nm or less (a white fluorescent lamp was used as the illumination light source), 1,3 - diiodo - BCP was obtained in the same manner as in Example 1. For each comparative example, the yields in each of steps (a) and (b) are shown in the table below.

[0032] [Table 1]

[0033] As shown in the above table, it was found that when step (b) was carried out with light having a wavelength of 400 nm or less blocked, the yield in step (b) was increased by 10% or more compared to the case where it was not blocked. Note that even if the non-cyclic ether solvent having 5 or 6 carbon atoms (MTBE or CPME) is not included as the solvent species in step (b), the effects of the present invention (improvement in the yield of step (b) due to light shielding) can be enjoyed (comparison between Example 9 and Comparative Example 8). However, it was also found that the yield in step (b) is lower compared to the case where a non-cyclic ether solvent having 5 or 6 carbon atoms is used (comparison between Examples 3 and 8 and Example 9). Regarding step (a), it can be seen that the lower the reaction temperature, the more the yield tends to increase.

[0034] [Example 10] 1,3-Diiodo BCP was obtained according to the following scheme.

[0035] [Chemical formula]

[0036] [Step (a)] 40 mL of MTBE and 10.8 g of bromobenzene were placed in a 200 mL flask and cooled to 0 °C under a nitrogen atmosphere. 43 mL of a solution of n-butyllithium dissolved in n-hexane at a concentration of 1.6 M was added thereto, and the mixture was stirred for 1 hour. The resulting solution was added dropwise over 40 minutes to a 500 mL three-necked flask containing 60 mL of MTBE and 10 g of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane cooled to -40 °C under a nitrogen atmosphere, and then stirred at -40 °C for 10 minutes to cause a reaction. Then, the temperature was raised to 0 °C and further stirred for 30 minutes. Thus, [1.1.1]propellane was obtained in the solvent (MTBE / n-hexane). The yield was calculated in the same manner as in Example 1.

[0037] [Step (b)] An environment in which light with a wavelength of 400 nm or less was completely blocked was created by using a yellow fluorescent lamp as the light source for illumination. A solution prepared by dissolving 9.0 g of iodine in 50 mL of MTBE was added dropwise over 5 minutes to the [1.1.1]propellane solution (at 0 °C) obtained in the above step (a), and the mixture was stirred at 0 °C. Then, 30 mL of a 14 mass% aqueous sodium thiosulfate solution was added dropwise over 3 minutes, followed by liquid separation, and the resulting organic phase was concentrated. The obtained concentrated organic phase was transferred to a flask, 10 mL of an 80 volume% aqueous MeOH solution was added, the mixture was stirred at 5 °C, and then filtered to obtain a crude product of 1,3-diiodo BCP. The obtained crude product was transferred to a flask, 7 mL of MeOH was added, the mixture was stirred at 5 °C, and then filtered to obtain 1,3-diiodo BCP. The presence of 1,3-diiodo BCP was confirmed in the same manner as in Example 1 1 by 1H-NMR.

[0038] The yields in each step of step (a) and step (b) are shown in the following table.

[0039] [Comparative Example 10] 1,3-Diiodo BCP was obtained in the same manner as in Example 10, except that in Example 10, the reaction in step (b) was carried out without blocking light with a wavelength of 400 nm or less (using a white fluorescent lamp as the light source for illumination). The yields in each step of step (a) and step (b) are shown in the following table.

[0040]

Table 2

[0041] In Example 10 and Comparative Example 10, phenyl lithium is produced in the reaction system by co-existing bromobenzene and n-butyllithium in step (a). It can be seen that even in this reaction system, the yield is significantly increased by carrying out step (b) while blocking light with a wavelength of 400 nm or less as defined in the present invention.

[0042] [Example 11] In Example 3, after obtaining [1.1.1]propellane in a solvent in step (a), the organic phase obtained by treating the [1.1.1]propellane solution with water and separating the layers was used as the [1.1.1]propellane solution (0 °C) in step (b), and 1,3-diiodo BCP was obtained in the same manner as in Example 3 except for this. The yields in each step of step (a) and step (b) are shown in the table below.

[0043] [Comparative Example 11] In Example 11, 1,3-diiodo BCP was obtained in the same manner as in Example 11 except that the reaction in step (b) was carried out without blocking light having a wavelength of 400 nm or less (a white fluorescent lamp was used as the illumination light source). The yields in each step of step (a) and step (b) are shown in the table below.

[0044]

Table 3

[0045] In Example 11 and Comparative Example 11, the [1.1.1]propellane obtained in step (a) is purified and used in step (b). Even in this reaction system, as defined in the present invention, it can be seen that the yield is effectively increased by carrying out step (b) while blocking light of 400 nm or less.

[0046] Although the present invention has been described with its embodiments, we do not intend to limit our invention in any detail of the description unless otherwise specified, and we believe that it should be interpreted broadly without departing from the spirit and scope of the invention shown in the appended claims.

[0047] This application claims priority based on Japanese Patent Application No. 2021-148840 filed in Japan on September 13, 2021, the contents of which are incorporated herein by reference as part of the description of this specification.

Claims

1. (a) reacting 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent containing at least one of an alkyllithium and an aryllithium in a solvent containing an acyclic ether solvent having 5 to 10 carbon atoms to obtain [1.1.1]propellane; a step (b) of reacting the obtained [1.1.1]propellane with iodine in a solvent containing an acyclic ether solvent having 5 to 10 carbon atoms while blocking light having a wavelength of 400 nm or less to obtain diiodobicyclo[1.1.1]pentane; A method for producing diiodobicyclo[1.1.1]pentane, comprising:

2. The method for producing diiodobicyclo[1.1.1]pentane according to claim 1, wherein the alkyllithium has 2 to 10 carbon atoms and the aryllithium is phenyllithium.

3. The method for producing diiodobicyclo[1.1.1]pentane according to claim 2, wherein the alkyllithium is butyllithium.

4. The method for producing diiodobicyclo[1.1.1]pentane according to any one of claims 1 to 3, wherein the reaction temperature in the step (a) is 0°C or lower.

5. The method for producing diiodobicyclo[1.1.1]pentane according to any one of claims 1 to 3, wherein in the steps (a) and (b), the acyclic ether solvent has 5 or 6 carbon atoms.

6. The method for producing diiodobicyclo[1.1.1]pentane according to any one of claims 1 to 3, which does not include a step of distilling the [1.1.1]propellane.

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