Alkyl group-containing phosphine compound and production method therefor

Abstract

Provided is a production method that has excellent yield and is for producing a novel alkyl group-containing phosphine compound that is useful as a ligand. Specifically, provided is a production method for an alkyl group-containing phosphine compound represented by formula (1), said method comprising a reaction step for synthesizing an alkyl group-containing phosphine compound represented by formula (1) by reacting a compound represented by formula (4) and a phosphine compound represented by formula (5) in the presence of a hydrocarbon lithium compound.

Description

Alkyl-containing phosphine compound and method for producing same REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority based on Japanese Patent Application No. 2024-133403 filed on August 8, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a method for producing a novel alkyl group-containing phosphine compound (hereinafter also referred to as a compound represented by formula (1)).

[0003] Numerous phosphines have been designed and synthesized and used in various catalytic reactions. Phosphines play a major role in improving activity and controlling chemoselectivity or stereoselectivity. In particular, the structural design of trisubstituted alkylphosphines is important for controlling the activity of homogeneous transition metal catalysts.

[0004] In recent years, it has been reported that trisubstituted phosphines bearing bulky substituents at remote positions exhibit high activity in cross-coupling reactions. For example, the CyTyrranoPhos ligand has bulky substituents at the 3,5-positions of the phenyl group on phosphorus, giving it the steric characteristic of occupying a remote space rather than near the metal (Non-Patent Document 1). This allows for high catalytic reaction efficiency in Suzuki-Miyaura (SM) coupling. On the other hand, Non-Patent Document 2 describes how N-heterocyclic carbene ligands achieve high catalytic activity by imparting flexibility to the bulky substituents of the aryl group linked to the imidazole ring (Non-Patent Document 2). Based on the above findings, introducing flexible and bulky substituents into remote positions in phosphine ligands may be one method for dramatically improving catalytic activity.

[0005] Newman-Stonebraker, SH et al., Science 2021, 374, pp.301-308Altenhoff, G. et al., J. Am. Chem. Soc. 2004, 126, pp.15195-15201

[0006] However, no examples of phosphines having flexible and bulky substituents at remote positions as described above have been known, and there is a demand for such phosphines.

[0007] The present inventors have found that although the novel alkyl group-containing phosphine compound of the present invention can be obtained by reacting a compound represented by the following formula (4) with a phosphine compound represented by the following formula (5), the yield of the novel alkyl group-containing phosphine compound is low.

[0008] As a result of extensive investigations aimed at solving the above problems, the present inventors have found that the yield of the novel alkyl group-containing phosphine compound of the present invention can be improved by further making a specific base present in a step of reacting a compound represented by the following formula (4) with a phosphine compound represented by the following formula (5) in order to synthesize the novel alkyl group-containing phosphine compound of the present invention, and have thus completed the present invention.

[0009] Therefore, an object of the present invention is to provide a method for producing novel alkyl group-containing phosphine compounds useful as ligands, with excellent yield.

[0010] That is, according to the present invention, the following inventions are provided: [1] An alkyl group-containing phosphine compound represented by the following formula (1): (In formula (1), A represents the following formulas (2) and (3): (In formula (2), the wavy line indicates a bond to P.) (In formula (3), the wavy line indicates a bond to P.) In formula (1), R １ , R ２ are each independently an optionally substituted hydrocarbon group or an optionally substituted pyridyl group, and in formula (1), n1 and n2 are each independently an integer of 0 to 2, and the sum of n1 and n2 is 0 to 2. In addition, P in formula (1) is a phosphorus atom. (In formula (4), R ３represents one halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom. (In formula (5), R １ , R ２ , n1 and n2 have the same meanings as in formula (1). In formula (5), P represents a phosphorus atom. A method for producing an alkyl group-containing phosphine compound includes a reaction step of reacting a phosphine compound represented by formula (5) with a phosphine compound represented by formula (5) in the presence of a hydrocarbon-based lithium compound to synthesize an alkyl group-containing phosphine compound represented by formula (1). [2] R １ , R ２ are each independently selected from the group consisting of an optionally substituted alkyl group, an optionally substituted phenyl group, and an optionally substituted adamantyl group. [3] The method according to [1] or [2], wherein the reaction temperature in the reaction step is -80 to 120°C. [4] The method according to any one of [1] to [3], wherein a non-aqueous solvent is further present in the reaction step. [5] The method according to any one of [1] to [4], wherein the reaction time in the reaction step is 0.1 to 5 hours. [6] The method according to any one of [1] to [5], wherein the amount of hydrocarbon-based lithium compound used in the reaction step is an amount such that the counter anion in the hydrocarbon-based lithium compound is 0.5 to 5 equivalents per equivalent of the halogeno group in the compound represented by formula (4). [7] The method according to formula (4): (In formula (4), R ３ represents one halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom. [8] A compound represented by the following formula (4): (In formula (4), R ３ represents one halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom, comprising reacting a compound represented by the following formula (6): and compounds represented by the following formulas (7) to (9): (In formula (7), R ３ is the same as formula (4). (In formula (8), R ３is the same as formula (4). (In formula (9), R ３ is synonymous with formula (4). [9] A method for producing a compound according to [8], wherein in the reaction step, when the halogen-containing compound is a compound represented by formula (7), triphenylphosphine is further present, when the halogen-containing compound is a compound represented by formula (8), pyridine is further present, and when the halogen-containing compound is a compound represented by formula (9), iodine is further present.

[0011] According to the present invention, a novel method for producing an alkyl group-containing phosphine compound with excellent yield can be provided. Such a novel alkyl group-containing phosphine compound is useful as a ligand. Furthermore, the production method of the present invention is advantageous in that it can reduce the production of by-products that are difficult to separate from the target alkyl group-containing phosphine compound. Furthermore, the production method of the present invention is advantageous in that it can eliminate the need for a liquid separation operation.

[0012] The compound represented by formula (6) obtained in Example 1 １ 1H-NMR spectrum of the compound represented by formula (6) obtained in Example 1. １３ 1 is a C-NMR spectrum of the compound represented by formula (4-1) obtained in Example 2-1. １ 1H-NMR spectrum of the compound represented by formula (4-1) obtained in Example 2-1. １３ 1 is a C-NMR spectrum of the alkyl group-containing phosphine compound obtained in Example 4-1. １ 1H-NMR spectrum of the alkyl group-containing phosphine compound obtained in Example 4-1. １３ 1 is a C-NMR spectrum of the alkyl group-containing phosphine compound obtained in Example 4-1. ３１ 1 is a P-NMR spectrum of the alkyl group-containing phosphine compound obtained in Example 5-1. １ 1H-NMR spectrum of the alkyl group-containing phosphine compound obtained in Example 5-1. １３1 is a C-NMR spectrum of the alkyl group-containing phosphine compound obtained in Example 5-1. ３１ P-NMR spectrum.

[0013] [Alkyl Group-Containing Phosphine Compound] The alkyl group-containing phosphine compound of the present invention is represented by the following formula (1): It is expressed as:

[0014] In formula (1), A represents the following formulas (2) and (3): is an alkyl group represented by a chemical formula selected from the group consisting of:

[0015] As used herein, the term "triisobutylene (hereinafter also referred to as TIB) group" refers to an isobutylene trimer structure (having 12 carbon atoms). Specific examples of the TIB group include TIB groups derived from the structures of the following formulas (2-1), (2-2), and (10-1), with the TIB group derived from the structure of formula (2-1) being preferred.

[0016] Examples of the TIB group derived from the structure of the following formula (2-1) (2,2,6,6-tetramethyl-4-methyleneheptane) include the TIB group represented by the following formula (2) and the TIB group represented by the following formula (3), with the TIB group represented by the following formula (2) being preferred. Also, examples of the TIB group derived from the structure of the following formula (2-2) (2,2,4,6,6-pentamethyl-3-heptene) include the TIB group represented by the following formula (3):

[0017] An example of the TIB group derived from the structure of the following formula (10-1) (2,4,4,6,6-pentamethylhept-1-ene) is the TIB group represented by the following formula (10).

[0018] R in formula (1) １ , R ２are each independently an optionally substituted hydrocarbon group, an alkoxy group, an amide group, or an optionally substituted pyridyl group. １ If there are two R １ may be the same or different, and are preferably the same. ２ If there are two R ２ may be the same or different, and are preferably the same. １ and R ２ The number of carbon atoms in the hydrocarbon group represented by is not particularly limited, but may be 1 to 36, preferably 2 to 30, and more preferably 3 to 10. Examples of the hydrocarbon group include alkyl groups, alicyclic hydrocarbon groups, aromatic hydrocarbon groups, and groups formed by combining these.

[0019] R １ and R ２ The number of carbon atoms in the alkyl group represented by is not particularly limited, but examples thereof include those having 1 to 20 carbon atoms, preferably 1 to 12, and more preferably 1 to 8. The alkyl group may be either a linear or branched alkyl group, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, a 2-ethylhexyl group, a saturated hydrocarbon group having 8 carbon atoms (for example, a linear octyl group or a branched octyl group), a nonyl group, a decyl group, an undecyl group, a saturated hydrocarbon group having 12 carbon atoms (for example, a linear dodecyl group or a branched dodecyl group), and a TIB (triisobutylene) group, and preferred are a tert-butyl group, a branched octyl group, a branched dodecyl group, and a TIB group.

[0020] R １ and R ２ The alkyl group represented by may be substituted, and the substituents include halogen atoms, -P(TIB) ２ groups and alkoxy groups, and preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, -P(TIB) ２ a straight or branched chain C group such as a methoxy group or an ethoxy group １－４It is referred to as an alkoxy group.

[0021] R １ and R ２ The number of carbon atoms in the alicyclic hydrocarbon group represented by is not particularly limited, but examples include 3 to 36 carbon atoms, preferably 5 to 30 carbon atoms, and more preferably 6 to 20 carbon atoms. The alicyclic hydrocarbon group may be either a saturated or unsaturated alicyclic hydrocarbon group. The alicyclic hydrocarbon group may be either a monocyclic or polycyclic group, and examples of monocyclic alicyclic hydrocarbon groups include cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl groups, with cyclopentyl and cyclohexyl groups being preferred. Examples of polycyclic alicyclic hydrocarbon groups include decahydronaphthyl, adamantyl, 2-alkyladamantan-2-yl, 1-(adamantan-1-yl)alkan-1-yl, norbornyl, methylnorbornyl, and isobornyl groups, with adamantyl being preferred.

[0022] R １ and R ２ The alicyclic hydrocarbon group represented by the formula (I) may be substituted, and examples of the substituent include a halogen atom and an alkoxy group, and preferably a linear or branched C C group such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, or an ethoxy group. １－４ It is referred to as an alkoxy group.

[0023] According to a preferred embodiment of the present invention, R １ and R ２ The adamantyl group represented by the formula (I) may be substituted, and examples of the substituent include a halogen atom and an alkoxy group, and preferably a linear or branched C C group such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, or an ethoxy group. １－４ It is referred to as an alkoxy group.

[0024] R １ and R ２The aromatic hydrocarbon group represented by the formula (I) is not particularly limited in the number of carbon atoms, but may have 3 to 36 carbon atoms, preferably 5 to 30, and more preferably 6 to 20. Examples of the aromatic hydrocarbon group include a phenyl group and a naphthyl group, and preferably a phenyl group.

[0025] R １ and R ２ The aromatic hydrocarbon group represented by may be substituted, and the substituents include halogen atoms, -P(TIB) ２ , a 2-furyl group, a 2-thienyl group, a cyclopentadienyl group and an alkoxy group, and preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, -P(TIB) ２ , a linear or branched chain C such as a methoxy group, an ethoxy group, etc. １－４ It is referred to as an alkoxy group.

[0026] According to a preferred embodiment of the present invention, R １ and R ２ The aromatic hydrocarbon group (preferably a phenyl group) represented by may be substituted, and the substituent may be a straight-chain or branched C １－４ Alkyl group; straight-chain or branched-chain C such as methoxy group (OMe) and tert-butoxy group (O-tert-Bu) １－４ Alkoxy group; dimethylamino group (NMe ２ ), -P(TIB) ２ groups, substituted phenyl groups, and halogen atoms are more preferred. １ and R ２Examples of the optionally substituted phenyl group represented by the formula (I) include tolyl groups such as o-tolyl, m-tolyl, and p-tolyl; xylyl groups such as 2,4-xylyl, 2,5-xylyl, and 3,5-xylyl; tert-butylphenyl groups such as p-tert-butylphenyl; di-tert-butoxyphenyl groups such as 3,5-di-tert-butylphenyl; di-tert-butylphenyl; methoxyphenyl groups such as p-methoxyphenyl and o-methoxyphenyl; tert-butoxyphenyl groups such as p-tert-butoxyphenyl; pentafluorophenyl; (2,4,6-triisopropylphenyl)phenyl; and o-(TIB) ２ -p-phenyl group, p-(TIB) ２ -P-phenyl group, m-(TIB) ２ (TIB) such as -P-phenyl group ２ A —P-phenyl group is an example.

[0027] R １ and R ２ The pyridyl group represented by the formula (I) may be substituted, and the substituents thereof include a halogen atom, -P(TIB) ２ and an alkoxy group, and preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, -P(TIB) ２ , a linear or branched chain C such as a methoxy group, an ethoxy group, etc. １－４ It is referred to as an alkoxy group.

[0028] In formula (1), n1 and n2 are each independently an integer of 0 to 2, and the sum of n1 and n2 is 0 to 2.

[0029] When A in formula (1) is 2 or more, each A independently represents an alkyl group represented by a chemical formula selected from the above formulas (2) and (3). Here, when there is 2 or more A (specifically, when the sum of n1 and n2 is 0 or 1 and there are 2 or 3 A), A is an alkyl group represented by a chemical formula selected from the following formulas (2) and (3), and each A may be the same or different, and is preferably the same.

[0030] The wavy line in formula (2) indicates a bond to P.

[0031] The wavy line in formula (3) indicates a bond to P.

[0032] In formula (1), A, R １ , R ２ According to a preferred embodiment of the combination of n1 and n2, A is an alkyl group represented by the chemical formula (2) or (3), more preferably an alkyl group represented by the chemical formula (2), n1 is 2, n2 is 0, and R １ are both groups selected from the group consisting of an optionally substituted alkyl group, an optionally substituted phenyl group, and an optionally substituted alicyclic hydrocarbon group (preferably an optionally substituted cyclohexyl group or an optionally substituted adamantyl group), and R ２ In formula (1), A, R １ , R ２ According to another preferred embodiment of the combination of n1 and n2, A is an alkyl group represented by the chemical formula (2) or (3), more preferably an alkyl group represented by the chemical formula (2), n1 is 1, n2 is 0, and R １ represents a group selected from the group consisting of an optionally substituted alkyl group, an optionally substituted phenyl group, and an optionally substituted alicyclic hydrocarbon group (preferably an optionally substituted cyclohexyl group or an optionally substituted adamantyl group), and R ２ In formula (1), A, R １ , R ２ According to another preferred embodiment of the combination of n1 and n2, A is an alkyl group represented by the chemical formula (2) or (3), more preferably an alkyl group represented by the chemical formula (2), n1 is 0, n2 is 0, and R １ and R ２ does not exist.

[0033] Preferred embodiments of the alkyl group-containing phosphine compound represented by the above formula (1) include the following compounds: In the following formula, tBu represents a tertiary butyl group, TIB represents a triisobutylene skeleton group, and iPr represents an isopropyl group.

[0034] The ligand composed of the alkyl group-containing phosphine compound represented by the above formula (1) has two or more bulky tert-butyl groups at positions distant from the phosphorus atom, and it is believed that the tert-butyl groups can flexibly stabilize the active metal center and improve catalytic activity.

[0035] [Method for producing alkyl group-containing phosphine compound] The method for producing the alkyl group-containing phosphine compound represented by the formula (1) is not particularly limited, but includes, for example, a reaction step of reacting a compound represented by the formula (4) with a phosphine compound represented by the formula (5) in the presence of a hydrocarbon-based lithium compound to synthesize the alkyl group-containing phosphine compound represented by the formula (1). The reaction step will be described in detail below.

[0036] (Halogenated triisobutylene compound) The compound represented by the following formula (4): (In formula (4), R ３ represents one halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom.) A compound represented by the formula (I) is also called a halogenated triisobutylene compound.

[0037] In formula (4), R ３ is preferably a bromine atom or a chlorine atom, and more preferably a bromine atom. ３ A halogenated triisobutylene compound (a compound represented by formula (4-1) described below) in which is a bromine atom is 1-bromo-2-(2,2-dimethylpropyl)-4,4-dimethylpentane, which will hereinafter also be referred to as a brominated triisobutylene compound or a TIB-Br compound. A method for producing a halogenated triisobutylene compound will be described later.

[0038] (Phosphine Compound) The phosphine compound used in the present invention is represented by the following formula (5): In formula (5), R １ , R２ , n1 and n2 have the same meanings as in formula (1), and preferred embodiments are also the same.

[0039] Preferred embodiments of the phosphine compound represented by the above formula (5) include the following compounds.

[0040] The amount of the phosphine compound represented by formula (5) used is not particularly limited as long as it does not impair the effects of the present invention, but is an amount such that the reactive group (hydrogen group) contained in the phosphine compound is, for example, 0.1 to 2.0 equivalents, preferably 0.2 to 1.5 equivalents, relative to 1 equivalent of the halogeno group contained in the halogenated triisobutylene compound represented by formula (4). According to another embodiment of the present invention, the amount of the phosphine compound represented by formula (5) used is, for example, 0.1 to 2.0 times the molar amount, preferably 0.2 to 1.5 times the molar amount, relative to 1 mole of the halogenated triisobutylene compound represented by formula (4).

[0041] The hydrocarbon-based lithium compound used in the present invention is not particularly limited as long as it does not impair the effects of the present invention. Examples include alkyl lithiums such as methyl lithium (MeLi), n-butyl lithium (n-BuLi), sec-butyl lithium (sec-BuLi), and tert-butyl lithium (tert-BuLi), and aromatic lithiums such as phenyl lithium (PhLi), with n-butyl lithium being preferred.

[0042] (Solvent) The solvent used in the reaction step is not particularly limited, but from the viewpoint of maintaining the oxidation resistance of the tri-substituted phosphine compound, which is the target of synthesis, a non-aqueous solvent is preferred. For example, amide solvents such as N,N-dimethylformamide (DMF) and dimethylacetamide; ether solvents such as tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), dioxane, diethyl ether, glyme, and diglyme; halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and o-dichlorobenzene; aromatic hydrocarbon solvents such as toluene, benzene, o-, m-, and p-xylene and mesitylene; aliphatic hydrocarbon solvents such as pentane, normal hexane, and cyclohexane; fluorine-containing organic solvents such as hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, and dichloropentafluoropropane can be used. Among these, DMF, THF, and mixtures thereof are preferred from the viewpoint of improving the affinity of the added base.

[0043] By using a non-aqueous solvent as the solvent in the reaction step, for example, non-aqueous post-treatment (e.g., Na ２ SO ４ -10H ２ O) can be carried out to obtain an alkyl group-containing phosphine compound represented by formula (1). Here, in organic synthesis, if water and an organic solvent are mixed in the reaction system, a liquid separation operation is required, which may cause an increase in time cost and a decrease in yield. Therefore, by using a non-aqueous solvent as the solvent and then performing a non-aqueous post-treatment, the liquid separation operation becomes unnecessary, and the experimental operation can be simplified.

[0044] The amount of the solvent used is not particularly limited, but may be, for example, 1 to 10,000 parts by mass, and preferably 10 to 4,000 parts by mass, relative to 100 parts by mass of the total of the halogenated triisobutylene compound and the phosphine compound represented by formula (5).

[0045] (Reaction Conditions) The atmosphere in which the halogenated triisobutylene compound and the phosphine compound represented by the above formula (5) are brought into contact with each other is not particularly limited. From the viewpoint of maintaining the oxidation resistance of the tri-substituted phosphine compound, which is the synthesis target, an inert gas atmosphere is preferred, and a nitrogen or argon atmosphere is more preferred.

[0046] The temperature in the reaction step of the halogenated triisobutylene compound with the phosphine compound represented by the formula (5) is not particularly limited, but is, for example, −80 to 120° C., and from the viewpoint of shortening the reaction time, is preferably 0 to 110° C., and more preferably room temperature to 105° C. Here, room temperature is 20 to 30° C.

[0047] The reaction time for the reaction step of the halogenated triisobutylene compound with the phosphine compound represented by the above formula (5) is not particularly limited, but is, for example, 0.1 hours or more, and from the viewpoint of shortening the reaction time, is preferably 0.1 hours to 5 hours, and more preferably 0.5 hours to 4 hours.

[0048] The amount of the hydrocarbon-based lithium compound used is not particularly limited as long as it does not impair the effects of the present invention, but is preferably an amount such that the counter anion in the hydrocarbon-based lithium compound (which may be referred to as a counter anion derived from the hydrocarbon-based lithium compound) is, for example, 0.5 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to 1 equivalent of the halogeno group contained in the halogenated triisobutylene compound represented by formula (4). Here, when the hydrocarbon-based lithium compound is n-butyllithium, the counter anion is nBu. － According to another embodiment of the present invention, the amount of the hydrocarbon-based lithium compound used is, for example, 0.5 to 5.0 times by mole, and preferably 1.0 to 2.0 times by mole, per mole of the halogenated triisobutylene compound represented by formula (4).

[0049] PHPh ２ and PHCy ２It is known that phosphine compounds represented by formula (5) such as (I) are unstable in air and quickly undergo oxidative degradation to be converted to phosphine oxide. Furthermore, when phosphine oxide is present in the reaction system, by-products that are difficult to separate from the alkyl group-containing phosphine compound represented by formula (1) are generated. Therefore, in order to obtain the alkyl group-containing phosphine compound represented by formula (1) in a pure form, it is important to prevent the generation of by-products derived from this phosphine oxide. Here, by including a reaction step in which the compound represented by formula (4) and the phosphine compound represented by formula (5) are reacted in the presence of a hydrocarbon-based lithium compound to synthesize the alkyl group-containing phosphine compound represented by formula (1), the generation of by-products that are difficult to separate from the alkyl group-containing phosphine compound represented by formula (1) can be reduced, and preferably, is advantageous in that they are not generated at all.

[0050] [Method for Purifying Alkyl Group-Containing Phosphine Compound] According to one embodiment of the present invention, the method for producing an alkyl group-containing phosphine compound of the present invention may further include a step of purifying the alkyl group-containing phosphine compound synthesized above. The purification method is not particularly limited, and a conventionally known purification method can be applied. Examples of the purification method include solvent distillation under reduced pressure, filtration (e.g., silica gel filtration), preparative chromatography, vacuum filtration, recrystallization, liquid separation, washing with a solvent, and ultrasonic washing, and preparative chromatography, recrystallization, and solvent distillation under reduced pressure are preferred.

[0051] According to a preferred embodiment of the present invention, when the alkyl group-containing phosphine compound obtained in the reaction step is oily, its purification method is preparative chromatography. The column used in the chromatography is not particularly limited, but a normal phase column is preferred. The conditions for preparative chromatography include, for example, the following: Developing solvent: hexane / CH ２ Cl ２ = 10 / 1 Column: normal phase silica gel (Universal column L size (Yamazen Co., Ltd.)) Instrument: Smart Flash AKROS (Yamazen Co., Ltd.) Temperature: room temperature Detection wavelength: 254 nm

[0052] According to another preferred embodiment of the present invention, when the alkyl group-containing phosphine compound obtained in the above reaction step is in the form of crystals, the purification method is recrystallization.

[0053] According to one embodiment of the present invention, when a non-aqueous solvent is used as the solvent in the reaction step, a non-aqueous post-treatment (e.g., Na ２ SO ４ -10H ２ It is preferable to carry out the addition of O.

[0054] [Method for Producing Halogenated Triisobutylene Compound] The method for producing the halogenated triisobutylene compound represented by formula (4) of the present invention is not particularly limited, but may include, for example, a step of synthesizing the halogenated triisobutylene compound represented by formula (4) by reacting a TIB-OH compound represented by formula (6) with a halogen-containing compound represented by a chemical formula selected from the group consisting of formulas (7) to (9). The production method is described in detail below.

[0055] (Compound Represented by Formula (6)) The compound represented by the following formula (6) is 2-(2,2-dimethylpropyl)-4,4-dimethyl-1-pentanol, and hereinafter may also be referred to as a triisobutylene hydroxide compound or a TIB-OH compound. The compound represented by the above formula (6) is not particularly limited, but can be synthesized, for example, in accordance with the method described in International Publication No. 2020 / 017141 (Patent Document 1).

[0056] (Halogen-containing compound) The halogen-containing compound used in the present invention is represented by the following formulas (7) to (9): The compound is represented by a chemical formula selected from the group consisting of:

[0057] R in the above formulas (7), (8), and (9) ３ has the same meaning as formula (4), and preferred embodiments are also the same.

[0058] Preferred embodiments of the halogen-containing compound include the compound represented by the above formula (7) or the compound represented by the above formula (8), and more preferably the compound represented by the above formula (7).

[0059] The amount of the halogen-containing compound used is not particularly limited as long as it does not impair the effects of the present invention, but may be, for example, 0.5 to 2.0 times by mole, and preferably 1.0 to 1.8 times by mole, per mole of the TIB-OH compound.

[0060] (Solvent) The solvent used in the reaction step is not particularly limited, but examples thereof include halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and o-dichlorobenzene; aromatic hydrocarbon solvents such as toluene, benzene, o-, m-, and p-xylene and mesitylene; aliphatic hydrocarbon solvents such as hexane and cyclohexane; ether solvents such as cyclopentyl methyl ether (hereinafter also referred to as CPME), tetrahydrofuran (hereinafter also referred to as THF), dioxane, diethyl ether, glyme, and diglyme; and fluorinated organic solvents such as hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, and dichloropentafluoropropane. Among these, from the viewpoints of shortening the reaction time, improving the purification efficiency, and improving the yield, dichloromethane, toluene, CPME, and mixtures thereof are preferred, and dichloromethane is more preferred. As a preferred embodiment of the halogen-containing compound and solvent of the present invention, when the halogen-containing compound is a compound represented by the chemical formula (7), the solvent may be dichloromethane or chloroform, more preferably dichloromethane, and when the halogen-containing compound is a compound represented by the chemical formula (8), the solvent may be toluene or CPME, more preferably toluene.

[0061] The amount of the solvent used is not particularly limited, but may be, for example, 0.01 to 10,000 parts by mass, preferably 0.03 to 6,000 parts by mass, per 100 parts by mass of the TIB-OH compound and the halogen-containing compound combined. According to one embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (7), the amount of the solvent used is preferably 100 to 10,000 parts by mass, more preferably 400 to 6,000 parts by mass, and even more preferably 300 to 1,200 parts by mass or 4,000 to 6,000 parts by mass, per 100 parts by mass of the TIB-OH compound and the halogen-containing compound combined. According to another embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (8), the amount of the solvent used is preferably 0.1 to 200 parts by mass, more preferably 1 to 70 parts by mass, per 100 parts by mass of the TIB-OH compound and the halogen-containing compound combined.

[0062] (Reaction Conditions) The temperature at which the TIB-OH compound and the halogen-containing compound are reacted is not particularly limited, but is, for example, −30° C. or higher, and from the viewpoint of shortening the reaction time, is preferably −30 to 150° C. According to one embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (7), the temperature at which the TIB-OH compound and the halogen-containing compound are reacted is preferably −30 to 100° C., more preferably −20 to 50° C., and even more preferably room temperature or 35 to 50° C. Here, room temperature is 20 to 30° C. According to another embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (8), the temperature at which the TIB-OH compound and the halogen-containing compound are reacted is preferably 80 to 150° C., more preferably 90 to 100° C.

[0063] The time for reacting the TIB-OH compound with the halogen-containing compound is not particularly limited, but is, for example, 0.1 hour or more. From the viewpoint of shortening the reaction time, it is preferably 0.5 hours to 3 days, more preferably 1 hour to 2 days. According to one embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (7), the temperature for reacting the TIB-OH compound with the halogen-containing compound is preferably 0.1 hours to 3 days, more preferably 1 hour to 2 days, and even more preferably 0.5 to 4 hours or 1 day to 2 days. According to another embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (8), the temperature for reacting the TIB-OH compound with the halogen-containing compound is preferably 0.5 hours to 4 hours, more preferably 1 hour to 3 hours.

[0064] According to a preferred embodiment of the present invention, in the method for producing a halogenated triisobutylene compound represented by formula (4) of the present invention, when the halogen-containing compound is a compound represented by formula (7), the solvent used in the reaction step is dichloromethane or chloroform, preferably dichloromethane, and the reaction temperature of the TIB-OH compound and the halogen-containing compound is 35 to 50°C, the reaction time is 0.5 to 4 hours, and the amount of the solvent used is 300 to 1200 parts by mass per 100 parts by mass of the total of the TIB-OH compound and the halogen-containing compound. In particular, when the reaction temperature is within the above range, it is possible to reduce the amount of solvent and shorten the reaction time.

[0065] According to one embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (7), it is preferable to further add triphenylphosphine when reacting the TIB-OH compound with the halogen-containing compound. The amount of triphenylphosphine used is not particularly limited as long as it does not impair the effects of the present invention, but it is, for example, 0.5 to 2.0 times by mole, and preferably 1.0 to 1.8 times by mole, per mole of the TIB-OH compound.

[0066] According to another embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (8), pyridine is preferably further present when reacting the TIB-OH compound with the halogen-containing compound. The amount of pyridine used is not particularly limited as long as it does not impair the effects of the present invention, but may be, for example, 0.5 to 2.0 times by mole, and preferably 1.0 to 1.8 times by mole, per mole of the TIB-OH compound.

[0067] According to another embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (9), it is preferable to further add iodine to the reaction of the TIB-OH compound with the halogen-containing compound. The amount of iodine used is not particularly limited as long as it does not impair the effects of the present invention, but may be, for example, 0.5 to 2.0 times by mole, and preferably 1.0 to 1.8 times by mole, per mole of the TIB-OH compound.

[0068] [Method for Purifying a Halogenated Triisobutylene Compound] According to one embodiment of the present invention, the method for producing a halogenated triisobutylene compound of the present invention may further include a step of purifying the halogenated triisobutylene compound synthesized above. The purification method is not particularly limited, and conventionally known purification methods can be applied. Examples of purification methods include filtration (e.g., silica gel filtration), preparative chromatography, vacuum filtration, recrystallization, liquid separation, solvent distillation, washing with a solvent, and ultrasonic washing, and preferably filtration (e.g., silica gel filtration) or preparative chromatography.

[0069] The column used in the above-mentioned chromatography is not particularly limited, but a normal phase column is preferred. Examples of conditions for preparative chromatography include the following: Developing solvent: a mixed solvent of ethyl acetate / hexane = 10 / 90 (volume %) Column: normal phase silica gel (preferably Universal Column L size (manufactured by Yamazen Co., Ltd.)) Instrument: Smart Flash AKROS (manufactured by Yamazen Co., Ltd.) Temperature: room temperature Detection wavelength: 254 nm

[0070] According to one embodiment of the invention, when the halogen-containing compound is a compound represented by formula (7), filtration (e.g., silica gel filtration) is preferred as a method for purifying the halogenated triisobutylene compound synthesized above. For example, by distilling off the polar solvent, such as dichloromethane, used in the reaction step after completion of the reaction and adding a nonpolar solvent, such as hexane, it becomes possible to utilize the difference in solubility between the target halogenated triisobutylene compound and the by-product. By using a nonpolar solvent, by-products that are insoluble in the nonpolar solvent can be removed by silica gel filtration alone, and the target halogenated triisobutylene compound can be isolated.

[0071] According to another embodiment of the present invention, when the halogen-containing compound is a compound represented by formula (8), the halogenated triisobutylene compound synthesized above is preferably purified by preparative chromatography.

[0072] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.

[0073] The compound represented by formula (1) obtained by the following method was structurally analyzed under the following conditions: １ H-NMR measurement, １３ C-NMR measurement, and ３１ P-NMR measurement was carried out. １ H-NMR conditions] NMR measurement device: spectrometer AVANCE NEO, magnet Ascend 600 (manufactured by BRUKER JAPAN) １ H-NMR measurement conditions: frequency 600.03MHz, CD ２ Cl ２ Solvent / measurement time: about 30 minutes １３ C-NMR conditions] NMR measurement device: spectrometer AVANCE NEO, magnet Ascend 600 (manufactured by BRUKER JAPAN) １３ C-NMR measurement conditions: frequency 150.89 MHz, CD ２ Cl ２ Solvent / measurement time: approx. 60 minutes ３１ P-NMR conditions] NMR measurement device: spectrometer AVANCE NEO, magnet Ascend 600 (manufactured by BRUKER JAPAN)３１ P-NMR measurement conditions: frequency 242.97MHz, CD ２ Cl ２ Solvent / measurement time: about 30 minutes

[0074] The compounds represented by formula (4-1) and (6) obtained by the following method were structurally analyzed under the following conditions: １ H-NMR measurement and １３ C-NMR measurement was carried out. １ H-NMR conditions] NMR measurement device: spectrometer AVANCE NEO, magnet Ascend 600 (manufactured by BRUKER JAPAN) １ H-NMR measurement conditions: frequency 600.03 MHz, CDCl ３ Solvent / measurement time: about 30 minutes １３ C-NMR conditions] NMR measurement device: spectrometer AVANCE NEO, magnet Ascend 600 (manufactured by BRUKER JAPAN) １３ C-NMR measurement conditions: frequency 150.89 MHz, CDCl ３ Solvent / measurement time: Approximately 60 minutes

[0075] Example 1 Production of Compound Represented by Formula (6) (TIB-OH Compound) A compound represented by formula (6) was synthesized with reference to the description of Synthesis Example 1 in WO 2020 / 017141.

[0076] Specifically, the reaction was carried out by the following method. In a reaction vessel under a nitrogen stream, 60 mL of dehydrated THF was added to 10.00 g (59.4 mmol) of a triisobutylene raw material (manufactured by TCI) containing a compound represented by the following formula (11-1) (sometimes abbreviated as "compound (11-1)") and a compound represented by the following formula (11-2) (sometimes abbreviated as "compound (11-2)"), and the mixture was stirred. 9-Borabicyclo[3.3.1]nonane (9-BBN) (89.1 mmol) was added dropwise to the mixture at 0°C under ice cooling, and the mixture was heated to 35°C after 30 minutes (Reaction Scheme I).

[0077] The reaction mixture was cooled again on ice, and 79 mL (238 mmol) of 3M NaOH aq was added dropwise. ２ O ２The solution (80 mL) was added dropwise and allowed to react overnight (Reaction Scheme II).

[0078] After separating the organic and aqueous layers, the organic layer was added with K ２ CO ３ The water remaining in the organic solvent was separated by adding MgSO. After separating the aqueous layer, the same procedure was repeated two more times. The aqueous layers were combined and extracted three times with ethyl acetate. Finally, the organic layers were combined and extracted with MgSO. ４ The drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain 18.22 g of a colorless, transparent, oily crude product. Note that the unreacted internal olefin structure was removed during the distillation under reduced pressure.

[0079] The crude product was roughly purified by vacuum distillation (bath temperature: 100°C, top temperature: 45°C, vacuum level: 1.3 kPa), and then purified on a silica gel column (Silicagel: 92.8 g, eluent: Heptane / Ethyl acetate = 7 / 1) to obtain a white solid TIB-OH compound. The yield was 2.74 g (14.7 mmol), 25%.

[0080] <Compound represented by formula (6) (TIB-OH compound) １ H-NMR measurement and １３ C-NMR measurement of the obtained TIB-OH compound １ H-NMR measurement and １３ C-NMR measurement was carried out. １ The H-NMR spectrum is shown in FIG. １３ The C-NMR spectrum is shown in Figure 2. １ H-NMR spectral data and １３ C-NMR spectrum data was obtained. Spectral analysis confirmed that the compound was the compound represented by formula (6). 1 H-NMR(600.03MHz,CDCl3): δ 0.93(s,18H), 1.14-1.39(d,4H), 1.23 (s, 1H), 1.64(m,1H), 3.52(t,2H) 13 C-NMR(150.89MHz,CDCl3): δ 67.9, 47.5, 33.9, 31.2, 30.3

[0081] <Production of Compound Represented by Formula (4-1) (TIB-Br Compound)-1> [Example 2] [Example 2-1] The compound represented by formula (6) (TIB-OH compound) (1.24 g, 6.65 mmol) obtained in Example 1 and 120 mL of dichloromethane were placed in a 100 mL recovery flask and stirred while cooling with ice water. ３ ) (2.61 g, 9.98 mmol) was added and dissolved by stirring. N-bromosuccinimide (NBS) (1.72 g, 9.98 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for 2 days to allow the reaction to proceed (Reaction Formula III). After the reaction, the solvent was distilled off, and the product was extracted with hexane and then purified by filtration using silica gel. After distilling off the solvent, 1.40 g (85%) of the target TIB-Br compound was obtained (Table 1).

[0082]

[0083] The chemical structure of the isolated TIB-Br compound was determined by NMR measurement. １ The H-NMR spectrum is shown in FIG. １３ The C-NMR spectrum is shown in Figure 4. １ H-NMR spectral data and １３ C-NMR spectrum data was obtained. Spectral analysis confirmed that the compound was the compound represented by formula (4-1). 1 H-NMR(600.03MHz,CDCl3): δ 0.94(s,18H),1.21-1.44 (dd,4H),1.85(m,1H),3.47(d,2H) 13 C-NMR(150.89MHz,CDCl3): δ 49.1, 44.1, 33.2, 31.1, 30.2

[0084] [Examples 2-2 to 2-3] In Examples 2-2 and 2-3, TIB-Br compounds were synthesized in the same manner as in Example 2-1, except that the amounts of TIB-OH compound, dichloromethane, triphenylphosphine, and N-bromosuccinimide used were the amounts shown in Table 1. The yields of the TIB-Br compounds obtained in Examples 2-2 and 2-3 are shown in Table 1.

[0085] [Example 2-4] The compound represented by formula (6) (TIB-OH compound) (1.24 g, 6.65 mmol) obtained in Example 1 and 13.3 mL of dichloromethane were placed in a 25 mL Schlenk flask and stirred while cooling with ice water. ３ ) (2.61 g, 9.98 mmol) was added and then stirred to dissolve. N-bromosuccinimide (NBS) (1.72 g, 9.98 mmol) was added to the resulting solution, and the mixture was stirred at 40°C (under solvent reflux) for 3 hours to allow the reaction to proceed (Reaction Formula III). After the reaction, the dichloromethane solvent was distilled off, and hexane was added, followed by filtration and purification using a small amount of silica gel. After the hexane solvent was distilled off, 1.40 g (85%) of the target TIB-Br compound was isolated. The results are shown in Table 2.

[0086]

[0087] The yield (85%) of the TIB-Br compound in Example 2-4 was similar to that in Example 2-1. Meanwhile, the amount of solvent used in Example 2-4 was significantly reduced from that in Example 2-1, and the reaction time in Example 2-4 was also significantly shortened from that in Example 2-1. Therefore, the production method in Example 2-4 can reduce the production cost of the TIB-Br compound. Furthermore, the production cost of the TIB-Br compound can be reduced by avoiding expensive column fractionation as a purification method and employing an inexpensive silica gel filtration method.

[0088] <Production of Compound Represented by Formula (4-1) (TIB-Br Compound)-2> [Example 3] [Example 3-1] A 25 mL Schlenk flask was charged with a TIB-OH compound (a compound represented by formula (6)) (2.79 g, 15 mmol) and 4 mL of CPME as a solvent, and the resulting mixture was cooled to -10°C and stirred. ３ (4.47 g, 16.5 mmol) was added and dissolved with stirring. After stirring at room temperature for 30 minutes, the mixture was heated to 100°C and reacted for 2 hours. After that, the reaction solution was cooled to -10°C, and water was gradually added. After that, the organic layer was recovered by extraction and separation, and the solvent was distilled off to obtain a crude product. Next, the obtained crude product was purified by preparative chromatography (column: normal phase silica gel (Universal Column L size (Yamazen Corporation)), equipment: Smart Flash AKROS (Yamazen Corporation), temperature: room temperature, detection wavelength: 254 nm). As the developing solution for preparative chromatography, a mixed solution of ethyl acetate / hexane was used, and the ethyl acetate concentration was gradually changed to 5% by volume and 10% by volume. As a result, when the ethyl acetate concentration of the chromatographic developing solution (ethyl acetate / hexane) was 10% by volume, the target substance (TIB-Br compound) was isolated (yield: 36%). The chemical structure of the TIB-Br compound isolated in Example 3-1 was assigned by NMR measurement, and it was confirmed to be the same as that of Example 2-1, and to be the compound represented by formula (4-1).

[0089] [Example 3-2] A TIB-Br compound was synthesized in the same manner as in Example 3-1, except that the solvent used in Example 3-2 was changed from CPME to toluene. As a result, the yield was 49%.

[0090] <Compound represented by formula (1) (alkyl-containing phosphine compound; TIB-PPh ２ Example 4-1: Preparation of a compound under an inert gas atmosphere (specifically, N ２ Diphenylphosphine (PHPh) was added to a vial in a glove box under atmospheric pressure. ２A phosphine compound represented by formula (5) (70 μL, 0.441 mmol, 1.1 eq) and THF (4 mL) were added and stirred at 0°C, and then n-butyllithium (n-BuLi) (1.6 M in hexane) (0.501 mL, 0.802 mmol, 2.0 eq) was added dropwise at 0°C to obtain a reaction solution (color development of the solution was confirmed). Subsequently, a TIB-Br compound (a compound represented by formula (4-1)) (100 mg, 0.401 mmol) was added dropwise to the reaction solution, and the mixture was stirred in the air at room temperature for 3.5 hours to cause a reaction (Reaction Scheme IV). TLC (developing solvent: hexane / CH ２ Cl ２ After confirming the disappearance of the TIB-Br compound using a 10 / 1 ratio, water was added to the reaction solution until the color of the solution disappeared. After that, the solution was extracted with dichloromethane (10 mL x 3), washed with saturated brine (10 mL x 1), and then washed with Na ２ SO ４ -10H ２ O drying was performed. ２ SO ４ -10H ２ The crude product was purified by column chromatography (column: normal phase silica gel (Universal Column L size (Yamazen Co., Ltd.)), equipment: Smart Flash AKROS (Yamazen Co., Ltd.)), temperature: room temperature, detection wavelength: 254 nm, developing solvent: hexane / CH ２ Cl ２ = 10 / 1), and the solvent was removed to obtain the target TIB-PPh ２ A compound (compound represented by formula (1-1)) was obtained (0.1140 g, yield 80%, colorless oil). The results are shown in Table 3.

[0091] Isolated TIB-PPh ２ The chemical structure of the compound was determined by NMR measurement. ２ Compound １ The H-NMR spectrum is shown in FIG. １３ The C-NMR spectrum is shown in FIG. ３１ The P-NMR spectrum is shown in Figure 7. １ H-NMR spectral data, １３C-NMR spectral data and ３１ P-NMR spectrum data was obtained. Spectral analysis confirmed that the compound was the compound represented by formula (1-1). 1 H-NMR(600.03MHz,CD2Cl2): δ 0.82(s,18H),1.2-1.5(m,4H),2.07(d,2H), 7.30-7.44 (m,10H) 13 C-NMR(150.89MHz,CD2Cl2): δ 139.7, 133.1, 128.3, 128.2, 51.5, 38.5, 31.3, 30.3, 28.2 31 P-NMR(242.97MHz,CD2Cl2): δ -19.5

[0092] [Example 4-2] In Example 4-2, the stirring time at room temperature after the TIB-Br compound was added dropwise to the reaction solution was changed to 30 minutes, and the substance added to the reaction solution as a post-treatment was changed from water to Na ２ SO ４ -10H ２ 0, and then extracted with dichloromethane, washed with saturated saline, and ２ SO ４ -10H ２ TIB-PPh was prepared in the same manner as in Example 4-1, except that drying was not performed. ２ The compound was synthesized. ２ The amount of the compound obtained was 0.109 g, and the yield was 77.1%. The results are shown in Table 3.

[0093] Reference Example 4-3: Under an inert gas atmosphere (specifically, N ２ In a glove box under atmospheric pressure, diphenylphosphine (PHPh) was added to a 20 mL Schlenk flask. ２(a phosphine compound represented by formula (5)) (70 μL, 0.441 mmol, 1.1 eq) and potassium tert-butoxide (tBuOK) (49 mg, 0.441 mmol, 1.1 eq) were added, and DMF (4 mL) solvent was added and stirred at room temperature for 20 minutes. Thereafter, TIB-Br compound (a compound represented by formula (4-1)) (100 mg, 0.401 mmol, 1.0 eq) was added, and the reaction was carried out by stirring at 100°C for 24 hours (Reaction Formula IV). After the reaction, as a post-treatment, the DMF solvent was distilled off and the reaction product was extracted with diethyl ether, and the extract was washed with pure water and saturated saline. After this washing, the diethyl ether layer was recovered and dehydrated and dried, and the solvent was distilled off, resulting in the target TIB-PPh. ２ A compound (compound represented by formula (1-1)) was obtained (61 mg, yield 43%, colorless oil). The results are shown in Table 3.

[0094]

[0095] In the above Examples 4-1 to 4-2 and Reference 4-3, TIB-PPh in the reaction system ２ The suppression of oxidative degradation of the compound was also investigated. Specifically, the investigation was carried out under the following conditions. First, TLC (developing solvent: hexane / CH ２ Cl ２ One spot that was detected by the chromatographic method (chromatographic separation of hexane / CH2Cl2 = 10 / 1) and was believed to be the target product was isolated by column chromatography (column: normal phase silica gel (Universal Column L size (Yamazen Co., Ltd.)), equipment: Smart Flash AKROS (Yamazen Co., Ltd.), temperature: room temperature, detection wavelength: 254 nm, developing solvent (or mobile phase): hexane / CH2Cl2 = 10 / 1). ３１ P-NMR measurement confirmed that the peak was not that of a single compound, i.e., the presence of impurity peaks. In other words, the formation of by-products that are difficult to separate was confirmed. As a result, as shown in Table 3, by adding n-BuLi, the reaction was completed in a shorter time and the by-products were not formed.

[0096] Furthermore, in Example 4-2, non-aqueous post-treatment (Na ２ SO ４ -10H２ By performing O), TIB-PPh ２ The non-aqueous post-treatment eliminated the need for separation procedures, simplifying the experimental procedures.

[0097] <Compound represented by formula (1) (alkyl-containing phosphine compound; TIB-PCy ２ Example 5-1: Preparation of a compound under an inert gas atmosphere (specifically, N ２ Dicyclohexylphosphine (PHCy) was added to a vial in a glove box under atmospheric pressure. ２ A phosphine compound represented by formula (5) (89 μL, 0.441 mmol, 1.1 eq) and THF (4 mL) were added and stirred at 0° C., and then n-BuLi (1.6 M in hexane) (0.501 mL, 0.802 mmol, 2.0 eq) was added dropwise at 0° C. to obtain a reaction solution (color development of the solution was confirmed). Then, a TIB-Br compound (a compound represented by formula (4-1)) (100 mg, 0.401 mmol) was added dropwise to the reaction solution, and N ２ The mixture was stirred at room temperature for 30 minutes under atmospheric pressure to cause a reaction (Reaction Formula V). ２ Cl ２ After confirming the disappearance of the TIB-Br compound, Na ２ SO ４ -10H ２ O was added until the color of the solution disappeared. ２ SO ４ -10H ２ The O was removed by filtration, and the solvent was removed to obtain a crystalline crude product. The crude product was recrystallized (solvent: hexane / CH ２ Cl ２ = 10 / 1) and washed with methanol to obtain the target TIB-PCy ２ A compound (compound represented by formula (1-2)) was obtained (0.1378 g, yield 94%, colorless crystals). The results are shown in Table 4.

[0098] Isolated TIB-PCy ２ The chemical structure of the compound was determined by NMR measurement. ２ Compound１ The H-NMR spectrum is shown in FIG. １３ The C-NMR spectrum is shown in FIG. ３１ The P-NMR spectrum is shown in Figure 10. １ H-NMR spectral data, １３ C-NMR spectral data and ３１ P-NMR spectrum data was obtained. Spectral analysis confirmed that the compound was the compound represented by formula (1-2). 1 H-NMR(600.03MHz,CD2Cl2): δ 0.8-1.0(m), 1.2-1.6(m), 1.79(m) 13 C-NMR(150.89MHz,CD2Cl2): δ 51.8, 33.6, 32.0, 31.3, 30.6, 30.0, 29.6, 27.4, 26.7 31 P-NMR(242.97MHz,CD2Cl2): δ -10.2

[0099] Reference Example 5-2: Under an inert gas atmosphere (specifically, N ２ In a glove box under atmospheric pressure, dicyclohexylphosphine (PHCy) was placed in a 20 mL Schlenk flask. ２ (a phosphine compound represented by formula (5)) (0.12 mL, 0.60 mmol, 1.0 eq) and potassium carbonate (K ２ CO ３ ) (0.82 g, 6.0 mmol, 10 eq) was added, and DMF (6 mL) solvent was added and stirred at room temperature for 20 minutes. Thereafter, TIB-Br compound (compound represented by formula (4-1)) (450 mg, 1.8 mmol, 3.0 eq) was added, and the mixture was stirred at 100°C for 48 hours to react (Reaction Formula V). After the reaction, as a post-treatment, the DMF solvent was distilled off, and the reaction product was extracted with dichloromethane, and the extract was washed with methanol. As a result of distilling off the solvent, the target TIB-PCy ２ A compound (compound represented by formula (1-2)) was obtained (15 mg, yield 7%, colorless crystals). The results are shown in Table 4.

[0100]

[0101] In the above Example 5-1 and Reference 5-2, as in Example 4-1, TIB-PCy in the reaction system ２ The suppression of oxidative degradation of the compound was also investigated, and as a result, as shown in Table 4, the addition of n-BuLi completed the reaction in a short time and did not produce the by-products.

[0102] Furthermore, in Example 5-1, non-aqueous post-treatment (Na ２ SO ４ -10H ２ By performing O), TIB-PPh ２ The compound was obtained. The non-aqueous post-treatment described above can simplify the experimental procedure.

Claims

1. An alkyl group-containing phosphine compound represented by the following formula (1): (In formula (1), A represents the following formulas (2) and (3): (In formula (2), the wavy line indicates a bond to P.) (In formula (3), the wavy line indicates a bond to P.) In formula (1), R １ , R ２ are each independently an optionally substituted hydrocarbon group or an optionally substituted pyridyl group, and in formula (1), n1 and n2 are each independently an integer of 0 to 2, and the sum of n1 and n2 is 0 to 2. (In formula (4), R ３ represents one halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom. (In formula (5), R １ , R ２ , n1 and n2 are defined as in formula (1), in the presence of a hydrocarbon-based lithium compound, to thereby synthesize the alkyl group-containing phosphine compound represented by formula (1).

2. R １ , R ２ are each independently a group selected from the group consisting of an optionally substituted alkyl group, an optionally substituted phenyl group, and an optionally substituted adamantyl group.

3. The method according to claim 1 or 2, wherein the reaction temperature in the reaction step is -80 to 120°C.

4. The method according to claim 1 or 2, wherein a non-aqueous solvent is further present in the reaction step.

5. The method according to claim 1 or 2, wherein the reaction time of the reaction step is 0.1 to 5 hours.

6. The method according to claim 1 or 2, wherein the amount of the hydrocarbon-based lithium compound used in the reaction step is such that the amount of counter anion in the hydrocarbon-based lithium compound is 0.5 to 5 equivalents per equivalent of the halogeno group in the compound represented by formula (4).

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