JP2024091067A - Method for producing intermediate compound, method for producing ligand, and method for producing quaternary asymmetric carbon-containing compound - Google Patents

Abstract

To provide a method for producing an intermediate compound capable of reducing production cost.SOLUTION: The production method includes: a first reaction step of reacting a hydrogen halide with formaldehyde at 20°C or higher and 100°C or lower in the presence of an acid catalyst by using, for example, methyl 5-methylsalicylate as a first raw material compound to synthesize a second raw material compound; and a second reaction step of reacting the synthesized second raw material compound with a third raw material compound at 20°C or higher and 150°C or lower to synthesize a fourth raw material compound (intermediate compound).SELECTED DRAWING: Figure 1

Description

The present invention relates to a method for producing an intermediate compound. The present invention also relates to a method for producing a ligand for a catalyst using the intermediate compound. Furthermore, the present invention also relates to a method for producing a quaternary asymmetric carbon-containing compound using a catalyst having the ligand.

Conventionally, optically active compounds have had to be synthesized as chiral compounds that do not contain optical isomers, because only one of the enantiomers may be useful or harmful. One method of synthesis is asymmetric synthesis using a catalyst, and various catalysts have been investigated.

In addition, to obtain the desired compound containing a quaternary asymmetric carbon, it is necessary to proceed with the reaction process while maintaining the optical state of the compound. For example, Non-Patent Document 1 discloses a reaction method in which diethyl malonate raw material is partially reduced with a lithium tri-tert-butoxyaluminum catalyst, but it is reported that when one of the esters is reduced to an alcohol, the desired optical state cannot be maintained and a racemic state results.

Tetrahedron Letters (1999), 40(30), 5467

Therefore, there is a need for a method for efficiently producing catalytic ligands and intermediate compounds that can be used in the synthesis of compounds containing quaternary asymmetric carbon.

As a result of intensive research conducted by the inventors to solve the above problems, they discovered that compounds containing quaternary asymmetric carbon can be selectively and efficiently synthesized by an asymmetric synthesis reaction using a catalyst with a specific compound as a ligand. They also discovered an efficient method for producing the ligand and its intermediate compound. Based on these findings, the inventors have completed the present invention.

That is, according to the present invention, the following inventions are provided.
[1] The following formula (1):
(In formula (1), R ¹ represents an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a hydroxy group, an amino group, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms;
^R2 represents an alkyl group having 1 to 6 carbon atoms.
reacting a first raw material compound represented by the formula:
The following formula (2):
In formula (2), R ¹ and R ² are the same as those in formula (1),
X represents a halogen atom.
A first reaction step of synthesizing a second raw material compound represented by
The second raw material compound and a compound represented by the following formula (3):
(In formula (3), R ³ and R ⁴ each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted.)
and a third raw material compound represented by the formula:
The following formula (4):
(In formula (4), ^R1 and ^R2 are the same as those in formula (1), and ^R3 and ^R4 are the same as those in formula (3).)
A second reaction step of synthesizing a fourth raw material compound represented by
A method for producing an intermediate compound, comprising:
[2] The method for producing the intermediate compound according to [1], wherein the yield of the by-product in the second reaction step is 20% or less.
[3] The fourth raw material compound is reacted with an organic halogen compound in the presence of an organolithium compound,
The following formula (5):
In formula (5), R ³ and R ⁴ are the same as those in formula (3),
^R5 and ^R6 each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted.
A third reaction step of synthesizing a compound represented by
A method for producing a ligand comprising the steps of:
[4] In the formula (5), R ³ and R ⁴ each independently represent an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted;
R ⁵ and R ⁶ each independently represent an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted.
[5] The method for producing a ligand according to [3] or [4], wherein the ligand is for a zinc catalyst.
[6] The method for producing a ligand according to any one of [3] to [5], wherein the organolithium compound is butyllithium.
[7] The following formula (6):
In formula (6), R ¹¹ and R ¹² each independently represent an alkyl group having 1 to 6 carbon atoms.
R ¹³ and R ¹⁴ each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted, provided that R ¹³ and R ¹⁴ are not the same functional group.
in the presence of a zinc catalyst having a compound represented by formula (5) according to claim 3 as a ligand and a reducing agent,
The following formula (7):
(In formula (7), R ¹¹ , R ¹³ and R ¹⁴ are the same as those in formula (6).)
A method for producing a quaternary asymmetric carbon-containing compound, comprising a reaction step of synthesizing a quaternary asymmetric carbon-containing compound represented by the following formula:
[8] The method for producing a quaternary asymmetric carbon-containing compound according to [7], wherein the reducing agent is a metal hydride.
[9] The method for producing a quaternary asymmetric carbon-containing compound according to [7] or [8], wherein the metal hydride is at least one selected from the group consisting of trialkoxysilane, sodium borohydride, and tributyltin hydride.
[10] The method for producing a quaternary asymmetric carbon-containing compound according to any one of [7] to [9], wherein the optical purity of the quaternary asymmetric carbon-containing compound is 80% ee or more.

According to the present invention, it is possible to provide a method for efficiently producing a catalytic ligand and an intermediate compound thereof that can be used in a synthesis reaction of a compound containing a quaternary asymmetric carbon. Furthermore, according to the present invention, it is possible to efficiently and selectively produce a compound containing a quaternary asymmetric carbon using a catalyst having the ligand.

1 is a ¹ H-NMR spectrum of the intermediate compound obtained in Example 1. 1 is a ¹ H-NMR spectrum of the ligand obtained in Example 1. 1 is a ¹ H-NMR spectrum of the quaternary asymmetric carbon-containing compound obtained in Example 2. 1 is a ¹³ C-NMR spectrum of the quaternary asymmetric carbon-containing compound obtained in Example 2.

[Method for producing intermediate compounds]
The method for producing an intermediate compound according to the present invention includes a first reaction step and a second reaction step. The method for producing an intermediate compound according to the present invention may further include a purification step after the first reaction step. Each step will be described in detail below.

(First reaction step)
In the first reaction step, the following formula (1):
(In formula (1), R ¹ represents an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a hydroxy group, an amino group, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms;
^R2 represents an alkyl group having 1 to 6 carbon atoms.
A first raw material compound represented by the following formula (2):
In formula (2), R ¹ and R ² are the same as those in formula (1),
X represents a halogen atom.
A second raw material compound represented by the following formula is synthesized.

In the above formula (1), R ¹ preferably represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, an amino group, or an amino group substituted with an alkyl group having 1 to 4 carbon atoms. R ² preferably represents an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 2 carbon atoms.

Preferred embodiments of the first raw material compound represented by the above formula (1) include the following compounds. In the following formula, Me represents a methyl group, Et represents an ethyl group, and tBu represents a tertiary butyl group (the same applies to the descriptions of other chemical formulas below). The first raw material compound may be used alone or in combination of two or more kinds.

Examples of hydrogen halides used in the first reaction step include hydrogen bromide, hydrogen chloride, and hydrogen iodide. Among these, it is preferable to use hydrogen bromide.

Examples of acid catalysts used in the first reaction step include sulfuric acid and hydrochloric acid. Among these, it is preferable to use sulfuric acid.

The first reaction step may be carried out under an inert gas (nitrogen; a rare gas such as helium or argon, etc.) atmosphere.
The reaction temperature is preferably 20°C or higher and 100°C or lower, more preferably 30°C or higher and 90°C or lower, and further preferably 50°C or higher and 80°C or lower.
The reaction time is not particularly limited, but is preferably from 1 hour to 48 hours, more preferably from 2 hours to 36 hours, even more preferably from 3 hours to 24 hours, and even more preferably from 4 hours to 12 hours.

In the above formula (2), preferred embodiments of R ¹ and R ² are the same as those in the above formula (1).
X may be a bromine atom, a chlorine atom, or an iodine atom. Of these, a bromine atom is preferred.

Preferred embodiments of the second raw material compound represented by the above formula (2) include the following compounds.

(Refining process)
The purification step is a step of purifying the reaction solution containing the second raw material compound represented by the above formula (2) obtained in the above first reaction step and an acid catalyst, etc., to isolate the second raw material compound. The purification means in the purification step is not particularly limited, and any conventionally known purification means can be used. Examples of the purification means include reduced pressure filtration, recrystallization, liquid separation, column chromatography purification, and solvent distillation.

(Second reaction step)
In the second reaction step, the second raw material compound represented by the above formula (2) obtained in the first reaction step is reacted with a compound represented by the following formula (3):
(In formula (3), R ³ and R ⁴ each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted.)
and a third raw material compound represented by the formula:
The following formula (4):
(In formula (4), ^R1 and ^R2 are the same as those in formula (1), and ^R3 and ^R4 are the same as those in formula (3).)
A fourth raw material compound represented by the following formula is synthesized.

In the above formula (3), R ³ and R ⁴ each independently represent an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted, more preferably an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with an alkoxy group having 1 to 4 carbon atoms, and even more preferably an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with an alkoxy group having 1 to 2 carbon atoms. Examples of the aromatic hydrocarbon group include aryl groups and aralkyl groups. The aryl group includes not only monocyclic aromatic hydrocarbon groups but also polycyclic aromatic hydrocarbon groups.

Preferred embodiments of the third raw material compound represented by the above formula (3) include the following compounds. The third raw material compound may be used alone or in combination of two or more kinds.

In the second reaction step, a carbonate may be added as a catalyst to promote the reaction. Examples of reaction catalysts include potassium carbonate and sodium carbonate. Among these, it is preferable to use potassium carbonate.

In the second reaction step, the molar ratio of the second raw material compound to the third raw material compound is preferably 1:1 to 1:10, more preferably 1:1.5 to 1:5.0, even more preferably 1:1.7 to 1:3.0, and most preferably 1:2.0 to 1:2.5. By adjusting the molar ratio of the second raw material compound to the third raw material compound, the reaction efficiency of the second reaction step can be improved.

The second reaction step may be carried out under an inert gas (nitrogen; rare gases such as helium and argon, etc.) atmosphere.
The reaction temperature is preferably 20°C or higher and 150°C or lower, more preferably 20°C or higher and 100°C or lower, and further preferably 20°C or higher and 80°C or lower.
The reaction time is not particularly limited, but is preferably from 1 hour to 48 hours, more preferably from 2 hours to 36 hours, even more preferably from 3 hours to 24 hours, and even more preferably from 4 hours to 12 hours.

In the above formula (4), preferred embodiments of ^R1 and ^R2 are the same as those in the above formula (1), and preferred embodiments of ^R3 and ^R4 are the same as those in the above formula (3).

上記式中、Ａｒは上記式（３）と同様である。 Preferred embodiments of the fourth raw material compound (intermediate compound) represented by the above formula (4) include the following compounds.

In the above formula, Ar is the same as in formula (3).

In the second reaction step, the type of the second raw material compound, the type of the third raw material compound, and the ratio of the amounts of substances thereof can be adjusted to improve the reaction efficiency and suppress the yield of by-products. In the second reaction step, the yield of the fourth raw material compound (intermediate compound) is preferably 80% or more, more preferably 85% or more. In addition, the yield of by-products in the second reaction step is preferably 20% or less, more preferably 15% or less, and even more preferably 10% or less. In the second reaction step, the yield of the raw material compound (intermediate compound) can be improved while suppressing the yield of by-products, and the purification step after the second reaction step can be simplified or omitted.

[Method for producing the ligand]
The method for producing a ligand according to the present invention includes a third reaction step. The method for producing a ligand according to the present invention may further include a purification step after the third reaction step. Each step will be described in detail below.

(Third reaction step)
In the third reaction step, the fourth raw material compound (intermediate compound) represented by the above formula (4) obtained in the second reaction step is reacted with an organic halogen compound in the presence of an organolithium compound,
The following formula (5):
In formula (5), R ³ and R ⁴ are the same as those in formula (3),
^R5 and ^R6 each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted.
A compound represented by the following formula is synthesized.

The organic halogen compound used in the third reaction step includes organic bromides, organic chlorides, organic iodides, etc. The structure of the organic substance is not particularly limited as long as it can provide the chemical structures of ^R5 and ^R6 in the above formula (5).

As the organolithium compound used in the third reaction step, it is preferable to use an alkyllithium. The number of carbon atoms in the alkyl group of the alkyllithium is preferably 1 to 6, more preferably 1 to 4. The alkyl group may be either linear or branched. Examples of alkyllithium include methyllithium and butyllithium (n-butyllithium, sec-butyllithium, tert-butyllithium). Among butyllithiums, it is preferable to use n-butyllithium from the viewpoint of reactivity.

The third reaction step may be carried out under an inert gas (nitrogen; rare gases such as helium and argon, etc.) atmosphere.
The reaction temperature is preferably from -100°C to 100°C, more preferably from -80°C to 90°C, and further preferably from 0°C to 80°C.
The reaction time is not particularly limited, but is preferably from 10 minutes to 12 hours, more preferably from 20 minutes to 6 hours, and even more preferably from 30 minutes to 3 hours.

In the above formula (5), preferred embodiments of ^R3 and ^R4 are the same as those in the above formula (3).
^R5 and ^R6 each independently represent an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted, more preferably an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with an alkoxy group having 1 to 4 carbon atoms, and even more preferably an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with an alkoxy group having 1 to 2 carbon atoms. Examples of the aromatic hydrocarbon group include aryl groups and aralkyl groups. The aryl group includes not only monocyclic aromatic hydrocarbon groups but also polycyclic aromatic hydrocarbon groups.

上記式中、Ａｒは上記式（３）と同様である。
上記式中、Ａｒ^２は下記式で表される。
Preferred embodiments of the ligand represented by the above formula (5) include the following compounds: The first raw material compound may be used alone or in combination of two or more kinds.

In the above formula, Ar is the same as in formula (3).
In the above formula, ^Ar2 is represented by the following formula:

In the third reaction step, the yield of the compound (ligand) represented by the above formula (5) is preferably 80% or more, more preferably 85% or more. In the third reaction step, the yield can be improved by appropriately adjusting the reaction conditions.

(Refining process)
In the purification step, the reaction solution containing the second raw material compound represented by the above formula (2) obtained in the third reaction step and an acid catalyst, etc., is purified to isolate the second raw material compound. The purification means in the purification step is not particularly limited, and any conventionally known purification means can be used. Examples of the purification means include reduced pressure filtration, recrystallization, liquid separation, column chromatography purification, and solvent distillation.

The ligand obtained by the manufacturing method of the present invention is suitable for use as a catalyst, and is particularly suitable for use as a zinc catalyst.

[Method of producing a compound containing a quaternary asymmetric carbon]
The method for producing a compound containing a quaternary asymmetric carbon according to the present invention includes a reaction step of synthesizing an alcohol containing a quaternary asymmetric carbon by partial reduction reaction of an ester containing a quaternary asymmetric carbon while maintaining the optical state. The method for producing a compound containing a quaternary asymmetric carbon according to the present invention may further include a purification step after the partial reduction reaction step. Each step will be described in detail below.

(Partial reduction reaction step)
In the partial reduction reaction step, the following formula (6):
In formula (6), R ¹¹ and R ¹² each independently represent an alkyl group having 1 to 6 carbon atoms.
R ¹³ and R ¹⁴ each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted, provided that R ¹³ and R ¹⁴ are not the same functional group.
in the presence of a zinc catalyst having a compound represented by formula (5) as a ligand and a reducing agent,
The following formula (7):
(In formula (7), R ¹¹ , R ¹³ and R ¹⁴ are the same as those in formula (6).)
A quaternary asymmetric carbon-containing compound represented by the following formula is synthesized.

In the above formula (6), R ¹¹ and R ¹² each independently represent an alkyl group having preferably 1 to 4 carbon atoms, and more preferably an alkyl group having 1 to 2 carbon atoms.
R ¹³ and R ¹⁴ each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an ester group. Examples of the hydrocarbon group include an alkyl group having 1 to 4 carbon atoms and an aromatic hydrocarbon group having 6 to 12 carbon atoms. Examples of the aromatic hydrocarbon group include an aryl group and an aralkyl group. The aryl group includes not only monocyclic aromatic hydrocarbon groups such as a phenyl group, but also polycyclic aromatic hydrocarbon groups such as a naphthyl group.
A preferred embodiment of the present invention includes, for example, a compound in which, in the above formula (6), R ¹³ represents an alkyl group having 1 to 4 carbon atoms, and R ¹⁴ represents an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an ester group.

Preferred embodiments of the compound represented by the above formula (6) include the following compounds. These compounds may be used alone or in combination of two or more.

Examples of zinc catalysts used in the partial reduction reaction include dimethylzinc and diethylzinc. Among these, diethylzinc is preferred as the zinc catalyst.

The zinc catalyst used in the partial reduction reaction has a molar ratio of zinc to ligand of preferably 1:1 to 3:1, more preferably 1.5:1 to 2.5:1, and even more preferably 1.9:1 to 2.1:1. By adjusting the molar ratio of zinc to ligand, the optical purity of the product (quaternary asymmetric carbon-containing compound) can be improved.

The reducing agent used in the partial reduction reaction is preferably a metal hydride. Examples of the metal hydride include trialkoxysilane, sodium borohydride, and tributyltin hydride. Examples of the trialkoxysilane include trimethoxysilane and triethoxysilane.

In the above formula (7), the preferred embodiments of R ¹¹ , R ¹³ and R ¹⁴ are the same as those in the above formula (6).

Preferred embodiments of the quaternary asymmetric carbon-containing compound represented by the above formula (7) include the following compounds.

In the partial reduction reaction, the yield of the quaternary asymmetric carbon-containing compound represented by the above formula (7) is preferably 80% or more, more preferably 85% or more. In the partial reduction reaction, the yield can be improved by appropriately adjusting the reaction conditions.

The optical purity (% ee) of the quaternary asymmetric carbon-containing compound represented by formula (7) obtained by the partial reduction reaction is preferably 80% ee or more, more preferably 85% ee or more, and even more preferably 90% ee or more.
The optical purity (% ee) of a compound containing a quaternary asymmetric carbon can be calculated by the following formula.
(A _S −A _R )/(A _S +A _R )×100
(In the formula, A _S and A _R are the mole fractions of the enantiomers (S and R), respectively.)

(Refining process)
In the purification step, the reaction solution containing the quaternary asymmetric carbon-containing compound represented by the formula (7) obtained in the partial reduction reaction step and the zinc medium is purified to isolate the quaternary asymmetric carbon-containing compound. The purification means in the purification step is not particularly limited, and any conventionally known purification means can be used. Examples of the purification means include reduced pressure filtration, recrystallization, liquid separation, column chromatography purification, and solvent distillation.

(solvent)
In the above-mentioned reaction steps in the present invention, the reaction may be carried out in the presence of a solvent inert to the reaction. The solvent is not particularly limited, and a conventional organic solvent can be used. Examples of the organic solvent that can be used include aromatic hydrocarbon solvents such as benzene, toluene, o-, m-, p-xylene, and mesitylene; aliphatic hydrocarbon solvents such as hexane and cyclohexane; halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and o-dichlorobenzene; ether-based solvents such as tetrahydrofuran, dioxane, diethyl ether, glyme, and diglyme; and fluorine-containing organic solvents such as hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, and dichloropentafluoropropane. Among these, benzene, toluene, o-, m-, and p-xylene, mesitylene, dichloromethane, chloroform, chlorobenzene, o-dichlorobenzene, diethyl ether, dioxane, THF (tetrahydrofuran), hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, and the like, and mixtures thereof are preferred.

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

<Analysis Condition 1>
The structures of the intermediate compounds and ligands obtained below were analyzed by the following methods.
(1) The structures of the intermediate compounds and the ligands were analyzed by ¹ H-NMR under the conditions described below.
( ^1H -NMR conditions)
NMR measurement device: BRUKER JAPAN ^1H -NMR measurement conditions: Frequency 400MHz, CDCl ₃ solvent Detection peaks of intermediate compounds (TMS internal standard): δ 10.88 (s, 1H), 7.58 (d, 2H), 7.50 (m, 1H), 7.42 (d, 2H), 7.06 (s, 1H), 6.79 (m, 4H), 5.29 (s, 1H), 3.92 (m, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.33 (m, 2H), 2.88 (m, 1H), 2.43 (m, 1H), 1.92-1.47 (m, 4H)
Ligand detection peaks (TMS internal standard): δ 8.70 (d, 0.6H), 8.64 (d, 0.4H), 8.37 (m, 1H), 7.86 (m, 4H), 7.38 (m, 7H), 7.32 (m, 2H), 7.10 (m, 1H), 6.78 (s, 0.4H), 6.67 (m, 4H), 6.63 (m, 2H), 6.59 (s, 0.6H), 6.06 (s, 1H), 3.83 (m, 1H), 3.73 (m, 6H), 3.68 (s, 0.4H), 3.55 (d, 0.6H), 3.32 (m, 1H), 3.12 (s, 0.4H), 2.85 (m, 0.6H), 2.43 (m, 1H), 2.04 (m, 1H), 1.99-1.35 (m, 4H)

<Analysis Condition 2>
The structures and optical purities (% ee) of the quaternary asymmetric carbon-containing compounds obtained below were analyzed by the following methods.
(1) The structure of the compound containing a quaternary asymmetric carbon was analyzed by ¹ H-NMR and ¹³ C-NMR under the conditions described below.
( ^1H NMR conditions)
NMR measurement device: BRUKER JAPAN ^1H -NMR measurement conditions (TMS internal standard): Frequency 400MHz, CDCl ₃ solvent Detected peaks of quaternary asymmetric carbon-containing compounds: δ 7.34 (m, 2H), 7.29 (m, 3H), 4.20 (m, 2H), 4.05 (dd, 1H), 3.62 (dd, 1H), 2.53 (m, 1H), 1.65 (s, 3H), 1.22 (t, 3H)
( ^13C -NMR conditions)
NMR measurement device: BRUKER JAPAN ^13C -NMR measurement conditions: Frequency 100 MHz, CDCl ₃ solvent Detection peaks of quaternary asymmetric carbon-containing compounds (TMS internal standard): δ 176.1, 140.6, 128.6, 127.3, 126.2, 69.8, 61.1, 52.6, 20.0, 14.0
(2) The optical purity (% ee) of the compound containing a quaternary asymmetric carbon was measured by optical HPLC under the conditions described below.
(HPLC conditions)
HPLC device: Agilent Corporation, model number HP1260
Column: CHIRALPAK ID-3 column manufactured by Daicel Corporation Flow rate: 1.0 mL/min Mobile phase: 10% isopropanol/90% hexane Temperature: 35° C.
Detection: UV 230 nm

[Example 1]
<Synthesis of intermediate compounds>
Into a recovery flask were added 4.105 g (1 equivalent) of methyl 5-methylsalicylate (first raw material compound), 1.113 g (1.5 equivalents) of paraformaldehyde, and 30.813 g (7.4 equivalents) of 48% hydrogen bromide solution, and the following reaction was carried out at 70° C. for 8 hours while adding special grade sulfuric acid dropwise (first reaction step, reaction formula I).

Then, the resulting reaction solution was cooled to room temperature to precipitate crystals. The crystals were washed with water while filtering under reduced pressure to obtain the product (second raw material compound). The yield of the second raw material compound was 44%.

Next, 0.259 g (2.1 equivalents) of the second raw material compound obtained above, 0.313 g (1 equivalent) of a third raw material compound represented by the following formula, 0.552 g (4 equivalents) of potassium carbonate, and 4 mL of N,N-dimethylformamide as a solvent were added to a recovery flask, and the following reaction was carried out at room temperature (25° C.) for 9 hours (second reaction step, reaction formula II).

Subsequently, an aqueous solution of ammonium chloride was added to the obtained reaction solution to inactivate the reaction. Thereafter, solvent extraction was performed using methylene chloride, followed by drying and distillation of the solvent to obtain a product (fourth raw material compound). The obtained product was subjected to ¹ H-NMR measurement under the above-mentioned analysis condition 1, and the ¹ H-NMR spectrum shown in FIG. 1 was obtained. As a result of the spectrum analysis, it was confirmed that the product was the fourth raw material compound (intermediate compound) of the above formula. The yield of the fourth raw material compound (intermediate compound) was 88%.

<Synthesis of Ligand>
Into a recovery flask were added 0.360 g (1 equivalent) of the fourth raw material compound obtained above, 1.213 g (8 equivalents) of 1-bromonaphthalene, 2.502 g (8 equivalents) of a 15% n-butyllithium/hexane solution, and 15 mL of tetrahydrofuran as a solvent, and the temperature was raised from −78° C. to room temperature (25)° C., and then the following reaction was carried out at 65° C. for 1 hour (third reaction step, reaction formula III).

Subsequently, an aqueous solution of ammonium chloride was added to the obtained reaction solution to inactivate the reaction. Thereafter, solvent extraction was performed using ethyl acetate, followed by drying and distillation of the solvent to obtain a product (ligand). The obtained product was subjected to ¹ H-NMR measurement under the above-mentioned analysis condition 1, and the ¹ H-NMR spectrum shown in FIG. 2 was obtained. As a result of the spectrum analysis, it was confirmed that the product was the ligand of the above formula. The yield of the intermediate compound was 89%.

[Example 2]
<Synthesis of diaryl compounds containing quaternary asymmetric carbon>
First, 21.6 mg (0.1 equivalents) of the ligand obtained above, 72.6 mg (0.2 equivalents) of diethylzinc, and dehydrated toluene were mixed together to prepare a catalyst solution.
Next, 75.0 mg (1 equivalent) of diethyl malonate, 110.0 mg (3 equivalents) of trimethoxysilane, and dehydrated toluene were added to the flask and mixed. After that, the catalyst solution prepared above was added to the flask at 0° C., and the following asymmetric synthesis reaction was carried out at 0° C. for 7 hours. Ligand represents the ligand obtained above.

Subsequently, triethylamine-hydrogen trifluoride was added to the obtained reaction solution to inactivate the reaction. Thereafter, the reaction mixture was diluted with diethyl ether solvent and then filtered under reduced pressure. The filtrate was concentrated and then purified by column chromatography (developing solution was a mixture of hexane/ethyl acetate = 2/1) to obtain a product (quaternary asymmetric carbon-containing compound). The obtained product was subjected to ¹ H-NMR measurement and ¹³ C-NMR measurement under the above analysis condition 2, and ^{the 1} H-NMR spectrum shown in Figure 3 and ^{the 13} C-NMR spectrum shown in Figure 4 were obtained. As a result of the spectrum analysis, it was confirmed that the compound was a quaternary asymmetric carbon-containing compound of the above formula. The yield of the quaternary asymmetric carbon-containing compound was 88%.

Furthermore, the optical purity of the resulting quaternary asymmetric carbon-containing compound was 92% ee when analyzed by optical HPLC under the above analytical condition 2.

[Comparative Example 1]
The reaction was carried out in the same manner as in Example 2, except that an aluminum catalyst (lithium tri-tert-butoxyaluminum) was added instead of the catalyst solution containing a zinc catalyst, and the synthesis was carried out in THF solvent.

The resulting quaternary asymmetric carbon-containing compound was analyzed in the same manner as in Example 2, and the optical purity was found to be 0% ee.

Claims (10)

The following formula (1):
(In formula (1), R ¹ represents an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a hydroxy group, an amino group, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms;
^R2 represents an alkyl group having 1 to 6 carbon atoms.
reacting a first raw material compound represented by the formula:
The following formula (2):
In formula (2), R ¹ and R ² are the same as those in formula (1),
X represents a halogen atom.
A first reaction step of synthesizing a second raw material compound represented by
The second raw material compound and a compound represented by the following formula (3):
(In formula (3), R ³ and R ⁴ each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted.)
and a third raw material compound represented by the formula:
The following formula (4):
(In formula (4), ^R1 and ^R2 are the same as those in formula (1), and ^R3 and ^R4 are the same as those in formula (3).)
A second reaction step of synthesizing a fourth raw material compound represented by
A method for producing an intermediate compound, comprising: The method for producing the intermediate compound according to claim 1, wherein the yield of the by-product in the second reaction step is 20% or less. reacting the fourth raw material compound with an organic halogen compound in the presence of an organolithium compound;
The following formula (5):
In formula (5), R ³ and R ⁴ are the same as those in formula (3),
^R5 and ^R6 each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted.
A third reaction step of synthesizing a compound represented by
A method for producing a ligand comprising the steps of: In the formula (5), R ³ and R ⁴ each independently represent an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted,
The method for producing a ligand according to claim 3, wherein R ⁵ and R ⁶ each independently represent an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted. The method for producing the ligand according to claim 3, wherein the ligand is for use in a zinc catalyst. The method for producing the ligand according to claim 3, wherein the organolithium compound is butyllithium. The following formula (6):
In formula (6), R ¹¹ and R ¹² each independently represent an alkyl group having 1 to 6 carbon atoms.
R ¹³ and R ¹⁴ each independently represent a hydrocarbon group having 1 to 12 carbon atoms which may be substituted, provided that R ¹³ and R ¹⁴ are not the same functional group.
in the presence of a zinc catalyst having a compound represented by formula (5) according to claim 3 as a ligand and a reducing agent,
The following formula (7):
(In formula (7), R ¹¹ , R ¹³ and R ¹⁴ are the same as those in formula (6).)
A method for producing a quaternary asymmetric carbon-containing compound, comprising a reaction step of synthesizing a quaternary asymmetric carbon-containing compound represented by the following formula: The method for producing a quaternary asymmetric carbon-containing compound according to claim 7, wherein the reducing agent is a metal hydride. The method for producing a quaternary asymmetric carbon-containing compound according to claim 8, wherein the metal hydride is at least one selected from the group consisting of trialkoxysilane, sodium borohydride, and tributyltin hydride. The method for producing a quaternary asymmetric carbon-containing compound according to claim 7, wherein the optical purity of the quaternary asymmetric carbon-containing compound is 80% ee or more.