HK1249498B - Method for producing optically active 2- (2-fluorobiphenyl-4-yl)propanoic acid - Google Patents

Description

Preparation method of optically active 2-(2-fluorobiphenyl-4-yl)propionic acid

Technical Field

The present invention relates to a novel preparation method of optically active 2-(2-fluorobiphenyl-4-yl)propionic acid.

Background Art

2-(2-fluorobiphenyl-4-yl) propionic acid or its pharmaceutically acceptable salt is known to have anti-inflammatory effect, analgesic effect etc. as medicament, is widely used.As the preparation method of this 2-(2-fluorobiphenyl-4-yl) propionic acid, report has for example the method (patent documentation 1) obtained by using the metal salt of 2-(2-fluorobiphenyl-4-yl) magnesium bromide and 2-bromopropionic acid, the method (patent documentation 2) obtained by using 2-(2-fluorobiphenyl-4-yl) magnesium bromide, 2-bromopropionic acid ester and nickel catalyst by the form of ester intermediate.However, these are all synthetic methods of the form of optically active body, in order to obtain optically active 2-(2-fluorobiphenyl-4-yl) propionic acid, need to carry out optical resolution again thereafter. As an optical resolution method, a method has been reported in which a salt of one optical isomer is preferentially crystallized by forming a salt with an optically active amine. However, obtaining 2-(2-fluorobiphenyl-4-yl)propionic acid of high optical purity requires multiple recrystallization steps, and the recovery rate is as low as approximately 60% (Patent Document 3). In addition, as an asymmetric synthesis method, asymmetric hydrogenation of 2-(2-fluorobiphenyl-4-yl)acrylic acid has been reported (Non-Patent Document 1). However, due to the large number of steps and the use of a toxic rhodium catalyst in the final step, it is not practical.

On the other hand, as a method for stereoselectively constructing a carbon-carbon bond at the α-position of a carbonyl group, Non-Patent Document 2 reports an asymmetric Kumada reaction using a nickel catalyst and an optically active bisoxazoline ligand with an α-haloketone as a substrate. Furthermore, Non-Patent Document 3 reports an asymmetric Negishi reaction with an α-haloamide as a substrate, and Non-Patent Document 4 reports an asymmetric Negishi reaction with an α-haloketone as a substrate. However, the asymmetric Kumada reaction requires a low reaction temperature of -60 to -40°C, and both reactions use 6.5 to 13% of an optically active bisoxazoline ligand obtained through a multi-step synthesis, making them unsuitable as industrial production methods. Furthermore, there are no reports of the synthesis of profens, nor of the synthesis of α-haloesters that can be easily derived into profens. In addition, as reports on the construction of the lofen structure, Patent Document 4, Patent Document 5, and Non-Patent Document 5 report an asymmetric Kumada reaction using a cobalt catalyst and an optically active bisoxazoline ligand, and Non-Patent Document 6 reports an asymmetric Kumada reaction using an iron catalyst and an optically active bisoxazoline ligand. However, the asymmetric Kumada reaction using a cobalt catalyst requires an extremely low reaction temperature of -80°C, and in each reaction, 6 to 12% of the optically active bisoxazoline ligand is used, making it unsuitable as an industrial production method.

Therefore, a method for producing optically active 2-(2-fluorobiphenyl-4-yl)propionic acid that is suitable as an industrial production method has been sought.

Prior art literature

Patent Literature

Patent Document 1: US3959364A

Patent Document 2: Japanese Patent Application Laid-Open No. 2004-339085

Patent Document 3: Japanese Patent Application Laid-Open No. 2000-143580

Patent Document 4: CN103755554

Patent Document 5: CN103755566

Non-patent literature

Non-patent literature 1: Org. Chem. Front., 2014, 1, 155.

Non-patent document 2: J. Am. Chem. Soc., 2010, 132, 1264.

Non-patent document 3: J. Am. Chem. Soc., 2005, 127, 4594.

Non-patent document 4: Angew. Chem. Int. Ed., 2009, 48, 154.

Non-patent document 5: J. Am. Chem. Soc., 2014, 136, 17662.

Non-patent literature 6: J. Am. Chem. Soc., 2015, 137, 7128.

Summary of the Invention

Problems to be solved by the invention

The object of the present invention is to provide a novel method for preparing optically active 2-(2-fluorobiphenyl-4-yl)propionic acid.

Means for solving problems

The present inventors have conducted intensive studies to achieve the above-mentioned objectives and have found that, as shown in Scheme 1, optically active 2-(2-fluorobiphenyl-4-yl)propionic acid can be prepared by reacting a compound represented by formula [1] (hereinafter sometimes referred to as compound [1]) with magnesium and, if necessary, with a zinc compound, and reacting the resulting organometallic reagent with a compound represented by formula [2] (hereinafter sometimes referred to as compound [2]) in the presence of a catalytic amount of a nickel compound and a catalytic amount of an optically active compound represented by formula [3] (hereinafter sometimes referred to as compound [3]), and converting the resulting compound represented by formula [4] (hereinafter sometimes referred to as compound [4]) into a compound represented by formula [5] (hereinafter sometimes referred to as compound [5]) or a pharmaceutically acceptable salt thereof.

Solution 1

[Chemistry 1]

Furthermore, the present inventors have discovered that, by the above-mentioned preparation method, the compound represented by formula [2] can be reacted with the prepared organometallic reagent in the presence of a smaller catalytic amount of a nickel compound and an even smaller catalytic amount of an optically active compound represented by formula [3] than in conventional methods, to prepare the compound represented by formula [4].

Furthermore, the present inventors have found that, by the above-mentioned preparation method, the compound represented by formula [4] can be prepared by reacting the compound represented by formula [2] with the prepared organometallic reagent in the presence of a catalytic amount of a nickel compound and a catalytic amount of an optically active compound represented by formula [3] at a higher reaction temperature than in conventional methods.

That is, the present invention is as follows.

(1) A method for preparing optically active 2-(2-fluorobiphenyl-4-yl)propionic acid or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps (a) to (c):

(a) a step of preparing an organometallic reagent, which comprises reacting a compound represented by formula [1] with magnesium;

[Chemistry 2]

(b) reacting the compound represented by formula [2] with the organometallic reagent prepared in step (a) in the presence of a catalytic amount of a nickel compound and a catalytic amount of an optically active compound represented by formula [3] to obtain a compound represented by formula [4]; and

[Chemistry 3]

(c) a step of converting the obtained compound represented by formula [4] into a compound represented by formula [5] or a pharmaceutically acceptable salt thereof;

[Chemistry 4]

It should be noted that in the above steps (a) to (c), among the compounds represented by the above formulas [1] to [5],

^X1 represents a halogen atom,

^X2 represents a halogen atom,

^R1 represents tert-butyldiphenylsilyl, _C1-6 alkyl, _C2-6 alkenyl, _C3-8 cycloalkyl, phenyl, or benzyl optionally substituted with 1 to 2 groups selected from Substituent Group A1,

^R2 and ^R3 independently represent _C1-6 alkyl,

or R ² , R ³ , and the carbon atom adjacent to the substituent may together form a C _3-6 cycloalkane,

^R4 and ^R5 independently represent a _C1-6 alkyl group, a benzyl group, a phenethyl group, or a phenyl group optionally substituted with 1 to 2 groups selected from Substituent Group A2,

Here, the substituent group A1 represents a group consisting of a C _1-6 alkyl group and a phenyl group,

Substituent Group A2 represents the group consisting of a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, and a phenyl group.

(2) The preparation method described in (1), wherein in step (a), the compound represented by formula [1] is reacted with magnesium and then reacted with zinc chloride or zinc bromide to prepare an organometallic reagent.

(3) The preparation method described in (1) or (2), wherein, in the compound represented by formula [2] in step (b), R ¹ is a C _1-6 alkyl group.

(4) The preparation method described in (3), wherein, in the compound represented by formula [2] in step (b), R ¹ is tert-butyl.

(5) The preparation method described in any one of (2) to (4), wherein in step (b), the catalytic amount of the nickel compound used is 0.03 to 1.00 mol% relative to the compound represented by formula [2], and the catalytic amount of the optically active compound represented by formula [3] used is 0.036 to 1.20 mol%.

(6) The preparation method described in (1), (3) or (4), wherein in step (b), the catalytic amount of the nickel compound used is 0.50-1.00 mol% relative to the compound represented by formula [2], and the catalytic amount of the optically active compound represented by formula [3] used is 0.60-1.20 mol%.

(7) The preparation method according to any one of (2) to (5), wherein in step (b), the reaction temperature is 0 to 25°C.

(8) The preparation method described in (1), (3), (4) or (6), wherein in step (b), the reaction temperature is -20 to 0°C.

(9) The preparation method according to any one of (1) to (8), wherein in step (c), the step of converting the compound represented by formula [4] into the compound represented by formula [5] is carried out under acidic conditions.

(10) The preparation method according to any one of (1) to (9), wherein, in step (b), the optically active compound represented by formula [3] is

^R2 and ^R3 are both methyl,

^R4 and ^R5 are both phenyl groups.

(11) The preparation method according to any one of (2) to (5) and (7) to (9), wherein in step (a), the compound represented by formula [1] is reacted with magnesium to prepare an organomagnesium reagent, and the molar ratio of the organomagnesium reagent to the zinc chloride or zinc bromide to be reacted is 2:1 to 3:1.

(12) The preparation method described in (2), wherein in step (b), the catalytic amount of the nickel compound used is 0.10 mol% or less, and the catalytic amount of the optically active compound represented by formula [3] used is 0.12 mol% or less, relative to the compound represented by formula [2].

(13) The preparation method described in (1), wherein in step (b), the catalytic amount of the nickel compound used is 1.00 mol% or less, and the catalytic amount of the optically active compound represented by formula [3] used is 1.20 mol% or less, relative to the compound represented by formula [2].

(14) The preparation method described in (9), wherein, in step (c), the acid used for conversion to the compound represented by formula [5] under acidic conditions is an acid selected from hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid.

(15) The preparation method described in (2), wherein in step (b), the catalytic amount of the nickel compound used is 1.00 mol% or less, and the catalytic amount of the optically active compound represented by formula [3] used is 1.20 mol% or less, relative to the compound represented by formula [2].

(16) The preparation method described in (15), wherein in step (b), the reaction temperature is above 0°C.

(17) A method for preparing optically active 2-(2-fluorobiphenyl-4-yl)propionic acid, characterized in that the method comprises:

(a) a step of reacting the compound represented by formula [1] with magnesium, and then reacting with zinc chloride or zinc bromide as appropriate, thereby preparing an organometallic reagent;

[Chemistry 5]

(b) reacting the compound represented by formula [2] with the organometallic reagent prepared in step (a) in the presence of a catalytic amount of a nickel compound and a catalytic amount of an optically active compound represented by formula [3] to obtain a compound represented by formula [4]; and

[Chemistry 6]

(c) a step of converting the obtained compound represented by formula [4] into a compound represented by formula [5] or a pharmaceutically acceptable salt thereof;

[Chemistry 7]

Here,

In the above formulas [1] to [5],

^X1 represents a halogen atom,

^X2 represents a halogen atom,

^R1 represents tert-butyldiphenylsilyl, _C1-6 alkyl, _C2-6 alkenyl, _C3-8 cycloalkyl, phenyl, or benzyl optionally substituted with 1 to 2 groups selected from Substituent Group A1,

^R2 and ^R3 independently represent _C1-6 alkyl,

or R ² , R ³ , and the carbon atom adjacent to the substituent may together form a C _3-6 cycloalkane,

^R4 and ^R5 independently represent a _C1-6 alkyl group, a benzyl group, a phenethyl group, or a phenyl group optionally substituted with 1 to 2 groups selected from Substituent Group A2,

Here, the substituent group A1 represents a group consisting of a C _1-6 alkyl group and a phenyl group,

Substituent Group A2 represents the group consisting of a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, and a phenyl group.

(18) The preparation method described in (17), wherein in step (a), the compound represented by formula [1] is reacted with magnesium and then reacted with zinc chloride or zinc bromide.

(19) The preparation method described in (17), wherein in step (a), the compound represented by formula [1] is reacted with magnesium and then is not reacted with zinc chloride or zinc bromide.

(20) The preparation method described in (17), wherein, with respect to the compound represented by formula [2] in step (b), R ¹ is a C _1-6 alkyl group.

(21) The preparation method described in (17), wherein in step (b), the catalytic amount of the nickel compound used is 1.00 mol% or less relative to the compound represented by formula [2], and the catalytic amount of the optically active compound represented by formula [3] used is 1.20 mol% or less.

(22) The preparation method described in (21), wherein in step (b), the reaction temperature is above 0°C.

(23) The preparation method described in (17), wherein in step (c), the step of converting the compound represented by formula [4] into the compound represented by formula [5] is carried out under acidic conditions.

(24) The preparation method according to (17), wherein, in step (b), the optically active compound represented by formula [3] is

^R2 and ^R3 are both methyl,

^R4 and ^R5 are both phenyl groups.

(25) The preparation method described in (20), wherein, regarding the compound represented by formula [2] in step (b),

^R1 is tert-butyl.

(26) The preparation method described in (18), wherein in step (a), the compound represented by formula [1] is reacted with magnesium to prepare an organomagnesium reagent, and the molar ratio of the organomagnesium reagent to the zinc chloride or zinc bromide to be reacted is 2:1 to 3:1.

(27) The preparation method described in (18), wherein in step (b), the catalytic amount of the nickel compound used is 0.10 mol% or less relative to the compound represented by formula [2], and the catalytic amount of the optically active compound represented by formula [3] used is 0.12 mol% or less.

(28) The preparation method described in (27), wherein in step (b), the catalytic amount of the nickel compound used is 0.03~0.10mol% relative to the compound represented by formula [2], and the catalytic amount of the optically active compound represented by formula [3] used is 0.036~0.12mol%.

(29) The preparation method described in (19), wherein in step (b), the catalytic amount of the nickel compound used is 1.00 mol% or less relative to the compound represented by formula [2], and the catalytic amount of the optically active compound represented by formula [3] used is 1.20 mol% or less.

(30) The preparation method described in (29), wherein in step (b), the catalytic amount of the nickel compound used is 0.50~1.00mol% relative to the compound represented by formula [2], and the catalytic amount of the optically active compound represented by formula [3] used is 0.60~1.20mol% or less.

(31) The preparation method described in (22), wherein in step (b), the reaction temperature is 0~25℃.

(32) The preparation method described in (23), wherein, in step (c), the acid used for conversion to the compound represented by formula [5] under acidic conditions is an acid selected from hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid.

Effects of the Invention

According to the present invention, 2-(2-fluorobiphenyl-4-yl)propionic acid can be produced with high optical purity. In addition, according to the present invention, compared with conventional methods, the compound represented by formula [4] can be produced by using a smaller catalytic amount of nickel compound and a smaller catalytic amount of optically active compound represented by formula [3]. Furthermore, according to the present invention, compared with conventional methods, the compound represented by formula [4] can be produced at a higher reaction temperature.

The present invention can provide a method useful as an industrial method for producing optically active 2-(2-fluorobiphenyl-4-yl)propionic acid, which is a drug having anti-inflammatory and analgesic effects.

DETAILED DESCRIPTION

The present invention is described in detail below.

Optically active 2-(2-fluorobiphenyl-4-yl)propionic acid that can be prepared by the present invention has the structure shown below.

[Chemistry 8]

In this specification, unless otherwise specified, the “optically active compound” represented by formula [4] and [5] represents either the (S) isoform or the (R) isoform in terms of absolute configuration.

In the present invention, "n" refers to positive, "i" refers to iso, "s" and "sec" refer to secondary, "t" and "tert" refer to tertiary, "c" refers to ring, "o" refers to pro, "m" refers to meta, and "p" refers to para.

The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C _1-6 alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, tert-pentyl, n-hexyl, and isohexyl.

"Halo-substituted C _1-6 alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. The preferred number of halogen atoms is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropane-2-yl, 1,1-difluoro-2-methylpropane-2-yl, 1-fluoropentyl, and 1-fluorohexyl.

" _C2-6 alkenyl" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms. Examples thereof include vinyl, (E)-prop-1-en-1-yl, (Z)-prop-1-en-1-yl, prop-2-en-1-yl, but-3-en-1-yl, pent-4-en-1-yl, and hex-5-en-1-yl.

"C _1-6 alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, n-hexyloxy, and isohexyloxy.

"Halo-substituted C _1-6 alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom. The preferred number of halogen atoms is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 1,3-difluoropropan-2-yloxy, 2-fluoro-2-methylpropoxy, 2,2-difluoropropoxy, 1-fluoro-2-methylpropan-2-yloxy, 1,1-difluoro-2-methylpropan-2-yloxy, and 4,4,4-trifluorobutoxy.

"C _3-6 cycloalkane" refers to a cyclic alkane having 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

"C _3-8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms, and is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

An "organometallic reagent" is a reagent prepared by reacting an organic compound with a metal reagent. This includes reagents prepared by further reacting the resulting organometallic reagent with another metal reagent. In the present invention, an organozinc-containing reagent (hereinafter referred to as an "organozinc reagent") prepared by reacting an organic compound with magnesium (hereinafter sometimes referred to as a Grignard reagent) is prepared by further reacting the organomagnesium reagent (hereinafter referred to as a Grignard reagent) with a "zinc compound" to form an organozinc.

The term "zinc compound" refers to a compound that can be prepared as an organozinc reagent when reacting with an organomagnesium reagent, and examples thereof include zinc halides. Specifically, zinc chloride, zinc bromide, or zinc iodide can be mentioned.

"Nickel compound" refers to a halogen-containing nickel compound or nickel complex, and examples thereof include nickel (II) chloride, nickel (II) bromide, nickel (II) iodide, nickel (II) chloride/DME complex (DME: 1,2-dimethoxyethane), nickel (II) acetylacetonate, and bis(triphenylphosphine) nickel (II) chloride.

Examples of the “ether-based solvent” include tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, diethyl ether, dimethoxyethane, and cyclopentyl methyl ether.

Examples of the “benzene-based solvent” include benzene, toluene, and xylene.

Examples of the “hydrocarbon solvent” include toluene, xylene, benzene, heptane, and hexane.

Examples of the “alcohol-based solvent” include methanol, ethanol, 1-propanol, 2-propanol, and tert-butyl alcohol.

An example of the “ester-based solvent” is ethyl acetate.

Examples of the “pharmaceutically acceptable salt” include amino acid salts such as glycine salts, lysine salts, arginine salts, histidine salts, ornithine salts, glutamate salts, and aspartate salts; inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts; and salts with organic bases such as ammonium salts, triethylamine salts, diisopropylamine salts, and cyclohexylamine salts.

It should be noted that salts include hydrated salts.

The optically active compound represented by formula [3] is described below.

[Chemistry 9]

In the preparation method of the present invention, a catalytic amount of an optically active compound represented by formula [3] is used to react the compound represented by formula [2] with the organometallic reagent prepared in step (a) in the presence of a catalytic amount of a nickel compound, thereby preparing an optically active compound represented by formula [4].

Here, when an optically active compound represented by formula [3] having an absolute configuration of (R,R) is used, a compound represented by formula [4] having an absolute configuration of (S) can be prepared. Furthermore, conversely, when an optically active compound represented by formula [3] having an absolute configuration of (S,S) is used, a compound represented by formula [4] having an absolute configuration of (R) can be prepared.

The optically active compound represented by formula [3] can be obtained by commercially available products or by known methods described in literature (eg, J. Am. Chem. Soc., 2014, 136, 17662).

In this specification, (R) and (S) represent the stereo configuration of a chiral molecule having a chiral center. In this specification, (Z) and (E) represent stereochemistry: in a planar portion of a molecule connected by a double bond, among groups bonded to atoms forming the double bond, groups with a preferred order are counted as (E) when located on opposite sides, and as (Z) when located on the same side.

A "catalyst" is a substance that does not change itself but acts as an intermediary in the chemical reaction of other substances, accelerating or slowing down the reaction rate. Generally speaking, the amount of the catalyst used is an equal amount or less relative to the other substances (substrates) to be reacted. In the present invention, "catalytic amount" means, for example, when the compound represented by formula [2] is reacted with an organomagnesium reagent, the amount of the nickel compound used is 10 mol% or less, preferably 1.00 mol% or less, more preferably in the range of 0.50 to 1.00 mol% relative to the compound represented by formula [2], and the amount of the optically active compound represented by formula [3] used is 12 mol% or less, preferably 1.20 mol% or less, more preferably in the range of 0.60 to 1.20 mol%. Furthermore, when the compound represented by formula [2] is reacted with an organozinc reagent, the amount of the nickel compound used is 10 mol% or less, preferably 1.00 mol% or less, more preferably in the range of 0.03 to 1.00 mol%, further preferably 0.10 mol% or less, particularly preferably in the range of 0.03 to 0.10 mol%, relative to the compound represented by formula [2], and the amount of the optically active compound represented by formula [3] used is 12 mol% or less, preferably in the range of 0.036 to 1.20 mol%, further preferably 0.12 mol% or less, particularly preferably in the range of 0.036 to 0.12 mol%.

There is no particular upper limit on the amount of the compound [3] used. As long as it is used in excess relative to the nickel compound, the reaction can proceed smoothly.

When compound [3] is used as a catalyst, its amount is 12 mol% or less relative to compound [2]. When the compound represented by formula [2] is reacted with an organomagnesium reagent, it is more preferably 1.20 mol% or less, and further preferably 0.60 to 1.20 mol%. When the compound represented by formula [2] is reacted with an organozinc reagent, it is more preferably 0.12 mol% or less, and further preferably 0.036 to 0.12 mol%.

The upper limit of the amount of the nickel compound is not particularly limited.

When a nickel compound is used as a catalyst, its amount is 10 mol% or less relative to compound [2]. When the compound represented by formula [2] is reacted with an organomagnesium reagent, it is more preferably 1.00 mol% or less, and further preferably 0.50 to 1.00 mol%. When the compound represented by formula [2] is reacted with an organozinc reagent, it is more preferably 0.10 mol% or less, and further preferably 0.03 to 0.10 mol%.

Preferred embodiments of the present invention are as follows.

Preferably, X ¹ is a chlorine atom, a bromine atom, or an iodine atom, and more preferably, X ¹ is a bromine atom.

Preferably, X ² is a chlorine atom, a bromine atom, or an iodine atom, and more preferably, X ² is a chlorine atom or a bromine atom.

Preferably, ^R1 is tert-butyldiphenylsilyl, _C1-6 alkyl, _C2-6 alkenyl, _C3-8 cycloalkyl, phenyl, or benzyl optionally substituted by 1 to 2 groups selected from Substituent Group A1. More preferably, ^R1 is tert-butyldiphenylsilyl, _C1-6 alkyl, _C3-8 cycloalkyl, or benzyl optionally substituted by 1 to 2 groups selected from Substituent Group A1. Further preferably, ^R1 is tert-butyldiphenylsilyl, tert-butyl, neopentyl, tert-pentyl, cyclohexyl, 1-methyl-1-phenylethyl, or benzhydryl. Particularly preferably, ^R1 is tert-butyl.

Preferably, R ² is a C _1-6 alkyl group, more preferably, R ² is a methyl group or an ethyl group, and further preferably, R ² is a methyl group.

Preferably, R ³ is a C _1-6 alkyl group, more preferably, R ³ is a methyl group or an ethyl group, and further preferably, R ³ is a methyl group.

Furthermore, a preferred C _3-6 cycloalkane formed by R ² , R ³ , and the carbon atom adjacent to the substituent is cyclopropane.

Preferably, R ⁴ is a C _1-6 alkyl group or a phenyl group optionally substituted with 1 to 2 groups selected from Substituent Group A2, and more preferably, R ⁴ is a phenyl group.

Preferably, R ⁵ is a C _1-6 alkyl group or a phenyl group optionally substituted by 1 to 2 groups selected from the substituent group A2, and more preferably, R ⁵ is a phenyl group.

The zinc compound to be reacted with the organomagnesium reagent (Grignard reagent) obtained by reacting the compound represented by formula [1] with magnesium is preferably zinc chloride or zinc bromide, depending on the circumstances.

Preferred nickel compounds are nickel(II) chloride, nickel(II) iodide, nickel(II) chloride·DME complex, nickel(II) acetylacetonate, or bis(triphenylphosphine)nickel(II) chloride.

In the present invention, a preferred method for preparing the compound represented by formula [4] is the preparation method shown in the following Scheme 2.

Option 2

[Chemistry 10]

Here, preferred embodiments of X ¹ , X ² , R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as described above.

At this time, the more preferred method is as follows:

^X1 is a bromine atom,

^X2 is a chlorine atom or a bromine atom,

^R1 is tert-butyl,

^R2 and ^R3 are both methyl,

^R4 and ^R5 are both phenyl groups.

In the present invention, another preferred method for preparing the compound represented by formula [4] is the preparation method shown in the following Scheme 3.

Option 3

[Chemistry 11]

Here, preferred embodiments of X ¹ , X ² , R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as described above. In addition, the zinc compound represents zinc chloride or zinc bromide.

At this time, a more preferred method is the following:

^X1 is a bromine atom,

^X2 is a bromine atom,

^R1 is tert-butyldiphenylsilyl, tert-butyl, neopentyl, tert-pentyl, cyclohexyl, 1-methyl-1-phenylethyl, or diphenylmethyl,

^R2 and ^R3 are both methyl or ethyl,

or, R ² , R ³ , and the carbon atom adjacent to the substituent together form a C _3-6 cycloalkane is cyclopropane,

^R4 and ^R5 are both phenyl,

The zinc compound is zinc bromide.

At this time, a further preferred embodiment is the following:

^R2 and ^R3 are both methyl groups.

At this time, another more preferred embodiment is the following:

^R1 is tert-butyl.

Another more preferred embodiment is the following:

^X1 is a bromine atom,

^X2 is a bromine atom,

^R1 is tert-butyl, tert-amyl, 1-methyl-1-phenylethyl, or diphenylmethyl,

^R2 and ^R3 are both methyl or ethyl,

or, R ² , R ³ , and the carbon atom adjacent to the substituent together form a C _3-6 cycloalkane is cyclopropane,

^R4 and ^R5 are both phenyl,

The zinc compound is zinc bromide.

At this time, a further preferred embodiment is the following:

^R2 and ^R3 are both methyl groups.

At this time, another more preferred embodiment is the following:

^R1 is tert-butyl.

In the preparation method shown in the following Scheme 4 for converting the obtained compound represented by formula [4] into the compound represented by formula [5], a preferred method is the conversion under acidic conditions.

Option 4

[Chemistry 12]

Here, preferred embodiments of R ¹ are as described above.

In this case, a more preferred embodiment is when R ¹ is a tert-butyl group.

In this case, the acid used for conversion to the compound represented by formula [5] is preferably an acid selected from hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and formic acid is more preferred.

Next, each step in the preparation method of the present invention is described in detail.

1. Step (a), preparation method of organomagnesium reagent [6]

Option 5

[Chemistry 13]

Here, ^X1 is as defined above.

In this step, as compound [1], compound [1] in which X ¹ is a halogen atom can be used. Here, compound [1] in which X ¹ is a chlorine atom, a bromine atom, or an iodine atom is preferably used, and compound [1] in which X ¹ is a bromine atom is more preferably used.

The amount of magnesium used is theoretically equimolar to compound [1], but can be about 1.0 to 1.3 equivalents.

The solvent that can be used in this step is any solvent that does not inhibit the reaction. Preferably, the solvent is an ether solvent, more preferably tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, or diethyl ether, and even more preferably tetrahydrofuran.

The reaction temperature is preferably adjusted to 0 to 60° C., and cooling or heating may be performed as needed. In addition, additives such as iodine and 1,2-dibromoethane may be used in the preparation of the Grignard reagent.

The reaction time can be determined by checking the residual amount of the raw material compound [1], and is usually 0.5 hours to 10 hours from the addition of the compound [1]. Preferably, it is 2 to 3 hours.

2. Step (b), a method for preparing a compound represented by formula [4] from an organomagnesium reagent [6]

Option 6

[Chemistry 14]

Here, X ² , R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined above.

In this step, as compound [2], a compound in which ^X2 is a halogen atom can be used. Here, compound [2] in which ^X2 is a chlorine atom or a bromine atom is preferably used, and compound [2] in which X2 is a bromine atom is more preferably used. In addition, compound [2] in which ^R1 is a _C1-6 alkyl group can be used. Here, compound [2] in which ^R1 is a tert-butyl group is preferably used.

The Grignard reagent to be reacted with the compound [2] is preferably used in an amount of 1.0 to 1.5 equivalents of the raw material compound [1] relative to the compound [2].

In this step, as compound [3], a compound [3] in which R ² and R ³ are independently C _1-6 alkyl can be used. Here, a compound [3] in which both R ² and R ³ are methyl is preferably used.

In addition, as compound [3], a compound [3 ^] in which ^R4 and R5 are independently _C1-6 alkyl, benzyl, phenethyl, or phenyl optionally substituted with 1 to 2 groups selected from substituent group A2 can be used. In this case, compound [3] in which ^R4 and ^R5 are both phenyl is preferably used.

There is no particular upper limit on the amount of the compound [3] used, and it may be used in excess relative to the nickel compound so that the reaction can proceed smoothly.

When compound [3] is used as a catalyst, its amount is 12 mol% or less, more preferably 1.20 mol% or less, and even more preferably 0.60 to 1.20 mol% relative to compound [2].

The upper limit of the amount of the nickel compound is not particularly limited, but it may be 0.5 mol % or more relative to the compound [2], so that the reaction can proceed smoothly.

When a nickel compound is used as a catalyst, its amount is 10 mol% or less, more preferably 1.00 mol% or less, and even more preferably 0.50 to 1.00 mol% relative to compound [2].

Examples of the nickel compound used generally include known nickel catalysts such as nickel(II) chloride·DME complex, nickel(II) chloride, bis(triphenylphosphine)nickel(II) chloride, nickel(II) iodide, and nickel(II) acetylacetonate. More preferred are nickel(II) chloride·DME complex and nickel(II) acetylacetonate, and even more preferred is nickel(II) acetylacetonate.

The solvent that can be used in this step is any solvent that does not inhibit the reaction, preferably an ether-based or benzene-based solvent, and more preferably tetrahydrofuran.

The solvent may be used alone or in combination. The amount used is generally affected by the physical properties of the compound and reagent used in the reaction and can therefore be arbitrarily set according to the type of compound. The concentration of compound [2] is preferably 0.05 to 1 M, more preferably 0.1 to 0.5 M.

The reaction temperature can be any temperature between -78°C and the boiling point of the reaction solvent, preferably -20°C to room temperature, more preferably -20°C to 0°C, and even more preferably at 0°C.

The reaction time can be determined while confirming the residual amount of the compound [2], and can usually be set to 0.5 hours or more and 24 hours or less from the addition of the organomagnesium reagent [6].

The (S)-form compound [4] obtained by the "coupling reaction" of the organomagnesium reagent [6] with the compound [2] can be obtained as a mixture with the (R)-form compound [4].

Compound [4] is dissolved in a predetermined organic solvent by heating, and then allowed to cool to precipitate crystals. The precipitated crystals are separated from the solvent by filtration, centrifugation, etc., and then dried to obtain crystals of compound [4]. It should be noted that recrystallization may be repeated two or more times, but is usually repeated only once.

The cooling time is not particularly limited, but is usually 10 minutes to 24 hours, preferably 1 to 5 hours.

Solvents that can be used for recrystallization of compound [4] include alcoholic solvents and water. Preferred solvents are methanol, ethanol, 2-propanol, and water, and more preferred solvents are ethanol and water.

Furthermore, during crystallization, seed crystals of the compound [4] may be used as necessary.

Seed crystals can be obtained by methods well known to those skilled in the art, such as scraping the wall of a container into which the solution for crystallization is added with a spatula.

The crystallization temperature is within the range of -20°C to 60°C unless otherwise specified.

By performing recrystallization in this step, compound [4] with high optical purity and in the (S) form can be obtained. Alternatively, compound [5] with high optical purity and in the (S) form can be obtained by converting the compound into compound [5] or a pharmaceutically acceptable salt thereof without performing recrystallization in this step and then performing recrystallization.

3. Step (a), preparation method of organozinc reagent [7]

Option 7

[Chemistry 15]

Here, ^X1 and the zinc compound are as defined above.

In this step, as compound [1], compound [1] in which X ¹ is a halogen atom can be used. Here, compound [1] in which X ¹ is a chlorine atom, a bromine atom, or an iodine atom is preferably used, and compound [1] in which X ¹ is a bromine atom is more preferably used.

The amount of magnesium used can theoretically be equimolar, but can be about 1.0 to 1.3 equivalents relative to compound [1]. As the zinc compound, zinc bromide or zinc chloride can be used, but zinc bromide is preferred. In addition, the amount of the zinc compound used can be 0.3 to 1.0 equivalents relative to compound [1], preferably 0.3 to 0.5 equivalents, and more preferably 0.5 equivalents.

The solvent that can be used in this step is any solvent that does not inhibit the reaction. Preferably, the solvent is an ether solvent, more preferably tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, or diethyl ether, and even more preferably tetrahydrofuran.

The solvent may be used alone or in combination. The amount used is generally affected by the physical properties of the compound and reagent used in the reaction and can therefore be arbitrarily set according to the type of compound. The concentration of compound [2] is preferably 0.05 to 1 M, more preferably 0.1 to 0.5 M.

The reaction temperature is preferably adjusted to 0 to 60° C., and cooling or heating may be performed as needed. In addition, additives such as iodine and 1,2-dibromoethane may be used in the preparation of the Grignard reagent.

Regarding the reaction time, for the preparation of the Grignard reagent, it can be determined while confirming the residual amount of the raw material compound [1], and can generally be set to 0.5 hours or more and 10 hours or less from the addition of the compound [1]. Preferably, it is 2 to 3 hours. For the preparation of the organozinc reagent, it is preferably 10 minutes to 1 hour from the addition of zinc bromide or zinc chloride to the Grignard reagent.

4. Step (b), preparation method of the compound represented by formula [4] from the organozinc reagent [7]

Option 8

[Chemistry 16]

Here, X ² , R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined above.

In this step, as compound [2], a compound wherein X ² is a halogen atom can be used. Here, compound [2] wherein X ² is a bromine atom is preferably used. In addition, compound [2] wherein R ¹ is tert-butyldiphenylsilyl, C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl, phenyl, or a benzyl group optionally substituted by 1 to 2 groups selected from substituent group A1 can be used. Here, compound [2] wherein R ¹ is tert-butyldiphenylsilyl, C _1-6 alkyl, C _3-8 cycloalkyl, or a benzyl group optionally substituted by 1 to 2 groups selected from substituent group A1 is preferably used, more preferably compound [2] wherein R ¹ is tert-butyldiphenylsilyl, tert-butyl, neopentyl, tert-pentyl, cyclohexyl, 1-methyl-1-phenylethyl, or diphenylmethyl is used, and further preferably compound [2] wherein R ¹ is tert-butyl.

In the organic zinc reagent reacted with compound [2], the amount of compound [1] as a raw material is preferably used in an amount of 1.0 to 1.5 equivalents relative to compound [2].

In this step, as compound [3], a compound [3] in which R ² and R ³ are independently C _1-6 alkyl can be used. Here, compound [3] in which R ² and R ³ are both methyl or ethyl is preferably used, and compound [3] in which both are methyl is more preferably used.

In addition, as compound [3], a compound [3] in which R ² , R ³ , and the carbon atom adjacent to the substituent together form a C _3-6 cycloalkane can also be used. Here, a compound [3] in which R ² , R ³ , and the carbon atom adjacent to the substituent together form a cyclopropane is preferably used.

In addition, as compound [3], a compound [3 ^] in which ^R4 and R5 are independently _C1-6 alkyl, benzyl, phenethyl, or phenyl optionally substituted with 1 to 2 groups selected from substituent group A2 can be used. In this case, compound [3] in which ^R4 and ^R5 are both phenyl is preferably used.

There is no particular upper limit on the amount of the compound [3] used, and it may be used in excess relative to the nickel compound so that the reaction can proceed smoothly.

When compound [3] is used as a catalyst, its amount is 12 mol% or less relative to compound [2], preferably in the range of 0.036 to 1.20 mol%, more preferably 0.12 mol% or less, and even more preferably 0.036 to 0.12 mol%.

The upper limit of the amount of the nickel compound is not particularly limited.

When a nickel compound is used as a catalyst, its amount is 10 mol% or less, preferably in the range of 0.03 to 1.00 mol%, more preferably 0.10 mol% or less, and even more preferably 0.03 to 0.10 mol%, relative to compound [2].

Examples of the nickel compound used include well-known nickel catalysts such as nickel(II) chloride·DME complex, nickel(II) chloride, bis(triphenylphosphine)nickel(II) chloride, nickel(II) iodide, and nickel(II) acetylacetonate.

The solvent that can be used in this step is any solvent that does not inhibit the reaction. Preferred solvents are ether-based, benzene-based, and ester-based solvents, more preferred solvents are tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, and ethyl acetate, and even more preferred solvent is tetrahydrofuran.

The solvent may be used alone or in combination. The amount used is generally affected by the physical properties of the compound and reagent used in the reaction and can therefore be arbitrarily set according to the type of compound. The concentration of compound [2] is preferably 0.05 to 1 M, more preferably 0.1 to 0.5 M.

When additives are used, they may be used alone or in combination. The amount of the additives used can be arbitrarily set according to the type of compound used in the reaction, and is generally 0.1 to 50 equivalents, preferably 0.5 to 20 equivalents, and more preferably 1 to 5 equivalents relative to compound [1].

The reaction temperature can be any temperature between -78°C and the boiling point of the reaction solvent, but is preferably between -20°C and 25°C, and more preferably between 0 and 25°C.

The reaction time can be determined by checking the residual amount of the raw material compound, and can usually be set to 0.5 hours or more and 24 hours or less from the addition of the organomagnesium reagent [7].

The (S)-form compound [4] obtained by the "coupling reaction" of the organozinc reagent [7] with the compound [2] can be obtained as a mixture with the (R)-form compound [4].

As mentioned above, by performing recrystallization in this step, compound [4] with high optical purity and in the (S) form can be obtained. Alternatively, by converting the compound [5] or a pharmaceutically acceptable salt thereof without performing recrystallization in this step and then performing recrystallization, compound [5] with high optical purity and in the (S) form can also be obtained.

5. Step (c), preparation method of the compound represented by formula [5]

Option 9

[Chemistry 17]

Here, ^R1 is as defined above.

Preferably, R ¹ is as described above, and more preferably, R ¹ is tert-butyl.

For the deprotection step, generally known conditions can be used (see Theodora W. Greene, Peter G. M. Wuts, "Greene's Protective Groups in Organic Synthesis, Forth Edition"; Wiley Interscience).

In this step, the conversion to compound [5] can be carried out under acidic conditions.

As the acid used, hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, or p-toluenesulfonic acid can be used. Preferably, hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid is used, and more preferably, formic acid is used.

The solvent used in this step may be any solvent that does not inhibit the reaction, and preferred solvents include heptane, toluene, acetic acid, and 1,4-dioxane.

The reaction temperature can be any temperature between room temperature and the boiling point of the reaction solvent, and is preferably between room temperature and 80°C.

The reaction time can be determined while confirming the residual amount of compound [4], and can usually be set to 0.5 hours or more and 40 hours or less.

Compound [5] is dissolved in a predetermined organic solvent by heating, and then allowed to cool to precipitate crystals. The precipitated crystals are separated from the solvent by filtration, centrifugation, etc., and then dried to obtain crystals of compound [5]. It should be noted that recrystallization may be repeated two or more times, but is usually repeated only once.

The cooling time is not particularly limited, but is usually 10 minutes to 24 hours, preferably 1 to 5 hours.

Solvents that can be used for recrystallization of compound [5] include benzene-based solvents, hydrocarbon-based solvents, alcohol-based solvents, and water. Preferred solvents are toluene, heptane, methanol, ethanol, 2-propanol, and water, and more preferred solvents are toluene and heptane.

The solvent used for the recrystallization may be used alone or as a mixture of two or more solvents.

In addition, during crystallization, seed crystals of compound [5] may be used as needed. Seed crystals can be obtained by methods well known to those skilled in the art, such as scraping the wall of a container into which the solution for crystallization is placed with a spatula.

Seed crystals of compound [5] can also be obtained by the method described in Example 9-1 below, for example.

The crystallization temperature is within the range of -20°C to 80°C unless otherwise specified.

The compound obtained by the above-mentioned production method can be purified by known means such as recrystallization, various chromatography methods, and the like to obtain the target product.

Example

The present invention is explained in more detail by the following examples, but they are not intended to limit the present invention and may be varied without departing from the scope of the present invention.

In the following Examples, packed columns (Reveleris (registered trademark) Flash Cartridges Silica manufactured by Graes Co., Ltd. and Biotage (registered trademark) SNAP Cartridge HP-Sphere manufactured by Biotage Co., Ltd.) were used for silica gel column chromatography.

ISOLUTE (registered trademark) Phase Separator manufactured by Biotage Co., Ltd. was used as the phase separator in the following Examples.

Nuclear magnetic resonance (NMR) spectra were measured at room temperature at 600 MHz (JNM-ECA600, JEOL Ltd.) and 400 MHz (AVANCE III-HD400, BRUKER). Chemical shift values in this specification are expressed in parts per million (δ) relative to an internal standard substance (tetramethylsilane).

Mass spectra were measured using a Shimadzu LCMS-IT-TOF mass spectrometer (ESI: electron spray ionization/APCI: atmospheric pressure ionization dual).

The optical purity was measured by high performance liquid chromatography (HPLC) using Agilent 1100 manufactured by Agilent Technologies and by supercritical fluid chromatography (SFC) using Acquity UPC2 manufactured by Worldwide Corporation.

The optical rotation was measured using an AUTOPOLV polarimeter manufactured by Ludlow Lisachi Analitic KK.

Each abbreviation used in this specification has the following meanings.

s ： singlet

d ： doublet

t ： triplet

q ： broad peak (quartet)

m: Multiplet (multiplet)

J: coupling constant

Hz ： Hertz

Chloroform-d, CDCl ₃ : Deuterated chloroform

NMR: Nuclear Magnetic Resonance

MS: Mass spectrometry

ee: enantiomeric excess

HPLC: High Performance Liquid Chromatography

Et: ethyl

Me：methyl

Ph: phenyl

MsOH: mesylic acid, methanesulfonic acid

TsOH: tosylic acid, p-toluenesulfonic acid

TFA: trifluoroacetic acid

acac: acetylacetone

PPh ₃ : triphenylphosphine

TBDPS: tert-butyldiphenylsilane

THF: Tetrahydrofuran

DME: 1,2-dimethoxyethane

MgSO ₄ : anhydrous magnesium sulfate

rt: room temperature

Compound naming is sometimes performed using software such as ACD/Name (ACD/Labs 12.01, Advanced Chemistry Development Inc.).

In this specification, room temperature refers to 20 to 30°C.

Ice cooling refers to 0~5℃.

Example 1-1

Preparation method of (S)-2-(2-fluorobiphenyl-4-yl)propionic acid tert-butyl ester

[Chemistry 18]

(1) Under an argon atmosphere, a THF solution (1.99 mL) of 4-bromo-2-fluorobiphenyl (1.00 g, 3.98 mmol) was added to a magnesium flake (116 mg, 4.78 mmol) and stirred at room temperature for 2 hours to prepare a Grignard reagent. A THF solution (3.98 mL) of zinc bromide (448 mg, 1.99 mmol) was added to the mixture and stirred at room temperature for 30 minutes to prepare an organozinc reagent.

(2) Under argon atmosphere, a THF (5 mL) solution of nickel (II) chloride·DME complex (11 mg, 0.0501 mmol) and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (20 mg, 0.0598 mmol) was prepared. 0.306 mL (0.0031 mmol of nickel (II) chloride·DME complex, 0.0037 mmol of (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline); 0.1 mol% of nickel (II) chloride·DME complex, 0.12 mol% of (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) relative to tert-butyl 2-bromopropionate) was added at 0°C. -2,2'-isopropylidenebis(4-phenyl-2-oxazoline)) was added with a THF solution (3.92 mL) of tert-butyl 2-bromopropionate (640 mg, 3.06 mmol), and stirred at the same temperature for 5 minutes. Furthermore, the total amount of the organozinc reagent prepared in (1) above was added dropwise at 0°C, and stirred at the same temperature for 20 hours. After adding a saturated aqueous ammonium chloride solution, the mixture was extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. Methanol was added to the residue, and after stirring at room temperature for 30 minutes, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 98:2~85:15), and the fractions containing the target title compound were collected. The solvent was distilled off under reduced pressure to obtain the title compound (770 mg) as a colorless solid.

The yields of the obtained compounds are described below.

Chemical yield: 84%

¹ H NMR and MS of the obtained compound are described below.

The optical purity of the obtained compound and the HPLC analysis conditions using a chiral column are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: R-form = 4.19 minutes, S-form = 4.60 minutes

Optical purity: 93%ee(S).

The absolute stereo configuration was determined by derivatizing the obtained compound to 2-(2-fluorobiphenyl-4-yl)propionic acid using the method described in Example 9-6 below and then determining the specific rotation with reference to the description in patent literature and CN1356304 ([α] ²⁰ _D = +45.1 (c=1, EtOH)).

The results of ¹ H NMR, MS, and specific rotation of the obtained 2-(2-fluorobiphenyl-4-yl)propionic acid are described below.

The HPLC analysis conditions using a chiral column for the obtained compound are described below.

Column name: DAICEL CHIRALPAK AY-H/SFC (4.6mmΦ x 250mmL)

Eluent: methanol: carbon dioxide = 10:90

Flow rate: 3.0 mL/min

Column temperature: 40°C

Retention time: R-form = 2.37 minutes, S-form = 3.13 minutes

Optical purity: 97%ee(S).

Example 2-1

[Chemistry 19]

The reaction was carried out using tert-butyl 2-bromopropionate (640 mg, 3.06 mmol), nickel(II) chloride/DME complex (0.0031 mmol, 0.1 mol% relative to tert-butyl 2-bromopropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.0037 mmol, 0.12 mol% relative to tert-butyl 2-bromopropionate) under the same conditions as Example 1-1, except that zinc bromide was replaced with zinc chloride. The compounds used, their amounts, yields, and optical purities are shown in Table 1-1.

Example 2-2

The reaction was carried out under the same conditions as in Example 1-1, except that the amount of zinc bromide was changed, using tert-butyl 2-bromopropionate (641 mg, 3.07 mmol), nickel(II) chloride/DME complex (0.031 mmol, 1.0 mol% relative to tert-butyl 2-bromopropionate), (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.037 mmol, 1.2 mol% relative to tert-butyl 2-bromopropionate), and magnesium flakes (101 mg, 4.14 mmol) instead of magnesium flakes (116 mg, 4.78 mmol). The compounds used, their amounts, yields, and optical purities are shown in Table 1-1.

[Table 1-1]

Example No. Zinc compounds Amount of zinc compound [mmol] Grignard reagent amount [mmol] Yield [%] Optical yield [%ee]/absolute configuration 2-1 zinc chloride 1.99 3.98 76 92/(S) 2-2 Zinc bromide 1.34 3.99 56 94/(S)

Example 3-1 and Example 3-2

[Chemistry 20]

The reaction was carried out using 4-bromo-2-fluorobiphenyl (1.007 g, 3.99 mmol), tert-butyl 2-bromopropionate (641 mg, 3.07 mmol), and zinc bromide (1.99 mmol) under the same conditions as in Example 1-1, except for the reaction temperature. The compounds used, their amounts, yields, and optical purities are shown in Table 2-1.

Example 3-3 and Example 3-4

The reaction was carried out using 4-bromo-2-fluorobiphenyl (1.007 g, 3.99 mmol), tert-butyl 2-bromopropionate (641 mg, 3.07 mmol), and zinc bromide (1.99 mmol) under the same conditions as in Example 1-1, except that the amounts of nickel(II) chloride/DME complex and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (represented as compound [3-1] in Table 2-1) were varied (each expressed as mol % relative to tert-butyl 2-bromopropionate). The compounds used, their amounts, yields, and optical purities are shown in Table 2-1.

[Table 2-1]

Example 4-1 to Example 4-10

[Chemistry 21]

The reaction was carried out under the same conditions as in Example 1-1, except that tert-butyl 2-bromopropionate was used as the compound. (0.1 mol% of nickel(II) chloride/DME complex and 0.12 mol% of (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) were used relative to 2-bromopropionate (represented as compound [2-1] in Table 3-1). The compounds used, yields, and optical purities are shown in Table 3-1.

[Table 3-1]

¹ H NMR and MS of the compound obtained in Example 4-1 are described below.

The HPLC analysis conditions using a chiral column for the compound obtained in Example 4-1 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: R form = 5.50 minutes, S form = 6.18 minutes.

¹ H NMR and MS of the compound obtained in Example 4-2 are described below.

The HPLC analysis conditions using a chiral column for the compound obtained in Example 4-2 are described below.

Column name: DAICEL CHIRALPAK AD-3 x 2 (4.6mmΦ x 150mmL x 2)

Eluent: Hexane: Ethanol = 96:4

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: R form = 4.44 minutes, S form = 5.54 minutes.

¹ H NMR and MS of the compound obtained in Example 4-3 are described below.

The HPLC analysis conditions using a chiral column for the compound obtained in Example 4-3 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: R form = 4.02 minutes, S form = 4.31 minutes.

¹ H NMR and MS of the compound obtained in Example 4-4 are described below.

The HPLC analysis conditions using a chiral column for the compound obtained in Example 4-4 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: R form = 6.18 minutes, S form = 6.91 minutes.

¹ H NMR and MS of the compound obtained in Example 4-5 are described below.

The HPLC analysis conditions using a chiral column for the compound obtained in Example 4-5 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: R form = 4.61 minutes, S form = 5.15 minutes.

¹ H NMR and MS of the compounds obtained in Examples 4-6 are described below.

The HPLC analysis conditions using a chiral column for the compounds obtained in Examples 4-6 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: R form = 22.7 minutes, S form = 26.9 minutes.

¹ H NMR and MS of the compounds obtained in Examples 4-7 are described below.

The HPLC analysis conditions using a chiral column for the compounds obtained in Examples 4-7 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: S form = 10.5 minutes, R form = 12.4 minutes.

¹ H NMR and MS of the compounds obtained in Examples 4-8 are described below.

The HPLC analysis conditions using a chiral column for the compounds obtained in Example 4-8 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: S form = 8.23 minutes, R form = 9.19 minutes.

¹ H NMR and MS of the compounds obtained in Examples 4-9 are described below.

The HPLC analysis conditions using a chiral column for the compounds obtained in Example 4-9 are described below.

Column name: DAICEL CHIRALPAK OJ-3 (4.6mmΦ x 250mmL)

Eluent: hexane: ethanol = 84:16

Flow rate: 1.0 mL/min

Column temperature: 40°C

Retention time: S form = 16.2 minutes, R form = 17.7 minutes.

¹ H NMR and MS of the compounds obtained in Examples 4-10 are described below.

The absolute stereo configuration of the obtained compound was determined by HPLC analysis using a chiral column as described in Example 1-1, after the obtained compound was derivatized to 2-(2-fluorobiphenyl-4-yl)propionic acid using the method of Example 9-6 described later for Examples 4-1 to 4-6 and the method described below for Examples 4-7 to 4-10. The results confirmed that the compound was S-isomer.

The compound obtained in Example 4-7 (100 mg) was dissolved in methanol (3 mL), and 10% palladium/activated carbon (20 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite (Celite, registered trademark) to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 85:15). Fractions containing the title compound were collected and the solvent was distilled off under reduced pressure to obtain 2-(2-fluorobiphenyl-4-yl)propanoic acid (66 mg) as a colorless solid.

The optical purity of the obtained compound was measured by HPLC analysis using a chiral column in the same manner as in Example 1-1.

Optical purity: 84%ee(S)

The compound obtained in Example 4-8 (50 mg) was dissolved in chloroform (0.3 mL), TFA (0.106 mL) was added, and the reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution and extracted twice with chloroform. The organic layer was separated using a phase separator and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 88:12~10:90), and the fractions containing the target title compound were collected. The solvent was distilled off under reduced pressure to obtain 2-(2-fluorobiphenyl-4-yl)propionic acid (29 mg) as a colorless solid.

The optical purity of the obtained compound was measured by HPLC analysis using a chiral column in the same manner as in Example 1-1.

Optical purity: 95%ee(S)

The compound obtained in Example 4-9 (57 mg) was dissolved in chloroform (0.3 mL), TFA (0.106 mL) was added, and the reaction solution was stirred at room temperature for 3 hours and at 60°C for 3 hours. Water was added to the reaction solution and extracted twice with chloroform. The organic layer was separated using a phase separator and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 88:12~10:90), and the fractions containing the target title compound were collected. The solvent was distilled off under reduced pressure to obtain 2-(2-fluorobiphenyl-4-yl)propionic acid (34 mg) as a colorless solid.

The optical purity of the obtained compound was measured by HPLC analysis using a chiral column in the same manner as in Example 1-1.

Optical purity: 89%ee(S)

The compound obtained in Example 4-10 (30 mg) was dissolved in tetrahydrofuran, and a 1M tetrabutylammonium fluoride solution in tetrahydrofuran (0.124 mL) was added. The mixture was stirred at room temperature for 8 hours. Water and 1M hydrochloric acid were added to the reaction mixture to adjust the pH to 3-4, followed by extraction twice with chloroform. The organic layer was separated using a phase separator, and the solvent was evaporated under reduced pressure to obtain 2-(2-fluorobiphenyl-4-yl)propanoic acid (30 mg) as a colorless solid.

The optical purity of the obtained compound was measured by HPLC analysis using a chiral column in the same manner as in Example 1-1.

Optical purity: 91%ee(S).

Example 5-1 to Example 5-4

[Chemistry 22]

The reaction was carried out under the same conditions as in Example 1-1 using 6.0 mL (1.36 mmol, 0.90 equivalents relative to tert-butyl 2-bromopropionate) of a THF solution of an organozinc reagent and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (represented as compound [3-1] in Table 4-1, with the amount used shown in Table 4-1 as mol % relative to tert-butyl 2-bromopropionate). The nickel(II) chloride/DME complex and its amount (expressed as mol % relative to tert-butyl 2-bromopropionate) were used as the compound used. The compounds used, their amounts, yields, and optical purities are shown in Table 4-1.

In this example, nickel(II) chloride·DME complex and compound [3-2] were prepared in advance in THF solutions in the same manner as in Example 1-1, and the amounts required for the reaction were measured and used.

[Table 4-1]

Example 6-1 and Example 6-2

[Chemistry 23]

The reaction was conducted using 4-bromo-2-fluorobiphenyl (999 mg, 3.98 mmol), tert-butyl 2-bromopropionate (640 mg, 3.06 mmol), zinc bromide (2.9 mmol), and nickel(II) chloride/DME complex (0.0031 mmol, 0.1 mol% relative to tert-butyl 2-bromopropionate) under the same conditions as Example 1-1, except that (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) was used as the compound. Table 5-1 shows the compound used (represented as compound [3-2] in Table 5-1), its amount (expressed as mol% relative to tert-butyl 2-bromopropionate), yield, and optical purity.

In this example, nickel(II) chloride·DME complex and compound [3-2] were prepared in advance in THF solutions in the same manner as in Example 1-1, and the amounts required for the reaction were measured and used.

[Table 5-1]

Example 7-1 to Example 7-5

[Chemistry 24]

The reaction was carried out under the same conditions as in Example 1-1, using 209 mg (1.0 mmol) of tert-butyl 2-bromopropionate, 1.5 ml (0.341 mmol, 0.68 equivalents relative to tert-butyl 2-bromopropionate) of an organozinc reagent (compound [7-1]) in THF, nickel(II) chloride/DME complex (0.0010 mmol, 0.1 mol% relative to tert-butyl 2-bromopropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.0012 mmol, 0.12 mol% relative to tert-butyl 2-bromopropionate). The solvents used, yields, and optical purities are shown in Table 6-1.

As described above, compound [7-1] was prepared using 0.5 equivalents of zinc chloride relative to the prepared organomagnesium reagent.

[Table 6-1]

Example 8-1

[Chemistry 25]

In the above scheme, the "additive" is ethyl acetate or lithium bromide.

Under the same conditions as in Example 1-1, after preparing the organozinc reagent, ethyl acetate (20 times the amount relative to 4-bromo-2-fluorobiphenyl) was added to form a mixed solvent with THF, and a coupling reaction with tert-butyl 2-bromopropionate was carried out for 3 hours. Purification by silica gel column chromatography was not performed, and purification by recrystallization was performed using a mixed solvent of ethanol and water (3:1).

The yields of the obtained compounds are described below.

Chemical yield: 75%

The optical purity of the obtained compound is described below.

Optical purity: 99%ee(S).

Example 8-2

Under the same conditions as in Example 1-1, after preparing the organozinc reagent, lithium bromide (1 equivalent relative to tert-butyl 2-bromopropionate) was added to carry out a coupling reaction with tert-butyl 2-bromopropionate for 2 hours.

The yields of the obtained compounds are described below.

Chemical yield: 55%

The optical purity of the obtained compound is described below.

Optical purity: 89%ee(S).

Example 9-1

Preparation method of (S)-2-(2-fluorobiphenyl-4-yl)propionic acid

[Chemistry 26]

To (S) -2- (2-fluorobiphenyl -4- base) propionic acid tert-butyl ester (37.0g, 123mmol) was added heptane (111mL) and formic acid (111mL), and the mixture was stirred at room temperature for 20 hours. Toluene (74mL) and water (111mL) were added, and the mixture was stirred at an internal temperature of 50°C for 1 hour. After separation of the organic layer, it was washed with water (111mL, 50°C). Heptane (333mL) was added to the organic layer, and the internal temperature was raised to 70°C and dissolved. Stirring was allowed to cool, and the seed crystals obtained below were added at 60°C, stirred at room temperature for 1 hour, and stirred under ice cooling for 1 hour. The precipitated solid was filtered and washed with heptane (148mL, 5°C). The obtained solid was dried under reduced pressure to obtain the title compound (25.5g) as a colorless powder. The yield and optical purity are shown in Table 7-1.

¹ H NMR and MS of the obtained compound are described below.

The HPLC analysis conditions using a chiral column for the obtained compound are described below.

Column name: DAICEL CHIRALPAK AY-H/SFC (4.6mmΦ x 250mmL)

Eluent: methanol: carbon dioxide = 10:90

Flow rate: 3.0 mL/min

Column temperature: 40℃.

Here, the seed crystals used in Example 9-1 were obtained by the following method.

(S)-2-(2-fluorobiphenyl-4-yl)propionic acid tert-butyl ester (4.88 g, 16.2 mmol) was reacted in the same manner as in Example 9-1, and post-treatment was performed. The resulting organic layer was concentrated under reduced pressure. The resulting residue was dissolved in toluene (4.9 mL) and heptane (49 mL) at an internal temperature of 90°C, stirred and allowed to cool, stirred at room temperature for 1 hour, and stirred under ice cooling for 1 hour. The precipitated solid was filtered and washed with heptane (19.5 mL, 5°C). The resulting solid was dried under reduced pressure to obtain (S)-2-(2-fluorobiphenyl-4-yl)propionic acid (3.51 g, optical purity 99% ee (S)) as a colorless powder. 1 g of the resulting powder was dissolved in toluene (2 mL) and heptane (12 mL) at an internal temperature of 70°C, stirred and allowed to cool, stirred at room temperature for 1 hour, and stirred under ice cooling for 1 hour. The precipitated solid was filtered and washed with heptane (4 mL, 5°C). The obtained solid was dried under reduced pressure to obtain (S)-2-(2-fluorobiphenyl-4-yl)propanoic acid (950 mg) as a colorless powder, which was used as a seed crystal.

Example 9-2 to Example 9-9

The reaction was carried out under the same conditions as in Example 9-1, except for the reaction temperature, reaction time, acid and solvent used. The compounds used, yields and optical purities are shown in Table 7-1.

[Table 7-1]

Example 10-1

A Grignard reagent was prepared under the same conditions as in Example 1-1(1), except that zinc bromide was not added and an organozinc reagent was used instead. A coupling reaction was carried out using the prepared Grignard reagent (47.8 mmol), tert-butyl 2-bromopropionate (10 g, 47.8 mmol), nickel(II) chloride/DME complex (0.478 mmol, 1 mol% relative to tert-butyl 2-bromopropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.574 mmol, 1.2 mol% relative to tert-butyl 2-bromopropionate) under the same conditions as in Example 1-1(2), at a reaction temperature of -20°C and a reaction time of 24 hours.

The yields of the obtained compounds are described below.

Chemical yield: 72%

The optical purity of the obtained compound is described below.

Optical purity: 86%ee(S).

Example 10-2

A Grignard reagent was prepared under the same conditions as in Example 1-1(1), except that zinc bromide was not added and an organozinc reagent was used instead. A coupling reaction was carried out using the prepared Grignard reagent (12 mmol), tert-butyl 2-bromopropionate (2.09 g, 10 mmol), nickel(II) chloride·DME complex (0.1 mmol, 1 mol% relative to tert-butyl 2-bromopropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.12 mmol, 1.2 mol% relative to tert-butyl 2-bromopropionate) under the same conditions as in Example 1-1(2), at a reaction temperature of -20°C and a reaction time of 24 hours.

The yields of the obtained compounds are described below.

Chemical yield: 89%

The optical purity of the obtained compound is described below.

Optical purity: 87%ee(S).

Example 10-3

A Grignard reagent was prepared under the same conditions as in Example 1-1(1), except that zinc bromide was not added and an organozinc reagent was used instead. A coupling reaction was carried out under the same conditions as in Example 1-1(2) at a reaction temperature of -10°C and a reaction time of 3 hours using the prepared Grignard reagent (10 mmol), tert-butyl 2-bromopropionate (2.09 g, 10 mmol), nickel(II) chloride·DME complex (0.05 mmol, 0.5 mol% relative to tert-butyl 2-bromopropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.06 mmol, 0.6 mol% relative to tert-butyl 2-bromopropionate).

The yields of the obtained compounds are described below.

Chemical yield: 72%

The optical purity of the obtained compound is described below.

Optical purity: 87%ee(S).

Example 10-4

A Grignard reagent was prepared under the same conditions as in Example 1-1(1), except that zinc bromide was not added and an organozinc reagent was used instead. A coupling reaction was carried out using the prepared Grignard reagent (10 mmol), tert-butyl 2-bromopropionate (2.09 g, 10 mmol), nickel(II) chloride·DME complex (0.1 mmol, 1 mol% relative to tert-butyl 2-bromopropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.12 mmol, 1.2 mol% relative to tert-butyl 2-bromopropionate) under the same conditions as in Example 1-1(2), at a reaction temperature of -10°C and a reaction time of 3 hours.

The yields of the obtained compounds are described below.

Chemical yield: 73%

The optical purity of the obtained compound is described below.

Optical purity: 89%ee(S).

Example 10-5

A Grignard reagent was prepared under the same conditions as in Example 1-1(1), except that zinc bromide was not added and an organozinc reagent was used instead. A coupling reaction was carried out under the same conditions as in Example 1-1(2) for 3 hours using the prepared Grignard reagent (10 mmol), tert-butyl 2-bromopropionate (2.09 g, 10 mmol), nickel(II) chloride·DME complex (0.1 mmol, 1 mol% relative to tert-butyl 2-bromopropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.12 mmol, 1.2 mol% relative to tert-butyl 2-bromopropionate).

The yields of the obtained compounds are described below.

Chemical yield: 72%

The optical purity of the obtained compound is described below.

Optical purity: 86%ee(S).

Example 10-6

A Grignard reagent was prepared under the same conditions as in Example 1-1(1), except that zinc bromide was not added and an organozinc reagent was used instead. A coupling reaction was carried out using the prepared Grignard reagent (10 mmol), nickel(II) chloride·DME complex (0.1 mmol, 1 mol% relative to tert-butyl 2-chloropropionate), and (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.12 mmol, 1.2 mol% relative to tert-butyl 2-chloropropionate) under the same conditions as in Example 1-1(2), except that tert-butyl 2-chloropropionate (1.65 g, 10 mmol) was used instead of tert-butyl 2-bromopropionate. The reaction time was 24 hours.

Chemical yield: 60%

The optical purity of the obtained compound is described below.

Optical purity: 94%ee(S).

Example 10-7

A Grignard reagent was prepared under the same conditions as in Example 1-1(1), except that zinc bromide was not added and an organozinc reagent was used instead. A coupling reaction was carried out using the prepared Grignard reagent (10 mmol), nickel(II) chloride·DME complex (0.1 mmol, 1 mol% of tert-butyl 2-chloropropionate), (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (0.12 mmol, 1.2 mol% of tert-butyl 2-chloropropionate), and ethyl 2-chloropropionate (1.37 g, 10 mmol) was used instead of tert-butyl 2-bromopropionate under the same conditions as in Example 1-1(2) for 24 hours.

The yields of the obtained compounds are described below.

Chemical yield: 79%

The optical purity of the obtained compound is described below.

Optical purity: 85%ee(S).

Example 10-8

A Grignard reagent was prepared under the same conditions as in Example 1-1(1) except that zinc bromide was not added and an organozinc reagent was used instead. The prepared Grignard reagent (2.0 mmol), tert-butyl 2-bromopropionate (0.42 g, 2.0 mmol), and nickel(II) chloride/DME complex (0.1 mmol, 5 mol% relative to tert-butyl 2-bromopropionate) were used. Under the same conditions as in Example 1-1(2), (R,R)-2,2'-(pentane-3,3-diyl)bis(4-phenyl-2-oxazoline) (0.12 mmol, 6 mol% relative to tert-butyl 2-bromopropionate) was used instead of (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) to carry out a coupling reaction with tert-butyl 2-bromopropionate at a reaction temperature of -20°C and a reaction time of 3 hours.

The yields of the obtained compounds are described below.

Chemical yield: 53%

The optical purity of the obtained compound is described below.

Optical purity: 90%ee(S).

Industrial Applicability

According to the present invention, optically active 2-(2-fluorobiphenyl-4-yl)propionic acid, which is useful as a pharmaceutical, can be produced with high optical purity.

Claims (20)

1. A method for preparing the compound shown in formula [4], characterized in that it comprises the following steps (a) to (b): (a) The step of preparing an organometallic reagent, which includes reacting the compound of formula [1] with magnesium; (b) In the presence of a catalytic amount of a nickel compound and a catalytic amount of an optically active compound of formula [3], the compound of formula [2] is reacted with the organometallic reagent prepared in step (a) to obtain the compound of formula [4]; and Furthermore, in steps (a) to (b) above, in equations [1] to [4] above, ^X1 represents a halogen atom. X ² represents a halogen atom. R ¹ represents tert-butyldiphenylsilyl, _C1-6 alkyl, _C2-6 alkenyl, _C3-8 cycloalkyl, phenyl, or benzyl, optionally substituted with 1-2 groups selected from substituent group A1. ^R2 and ^R3 independently represent _C1-6 alkyl groups. Alternatively, ^R2 , ^R3 , and the carbon atom adjacent to the substituent can together form a _C3-6 cycloalkanes. ^R4 and ^R5 independently represent _C1-6 alkyl, benzyl, phenethyl, or phenyl groups optionally substituted with 1-2 groups selected from substituent group A2. Here, substituent group A1 represents the group consisting of _C1-6 alkyl and phenyl groups. Substituent group A2 represents the group consisting of halogen atoms, _C1-6 alkyl groups, halo _-C1-6 alkyl groups, _C1-6 alkoxy groups, halo- _C1-6 alkoxy groups, and phenyl groups. 2. The preparation method according to claim 1, wherein in step (a), the compound shown in formula [1] is reacted with magnesium and then reacted with zinc chloride or zinc bromide to prepare an organometallic reagent. 3. The preparation method according to claim 1, further comprising (c) converting the resulting compound of formula [4] into the compound of formula [5] or a pharmaceutically permissible salt thereof, . 4. The preparation method according to claim 3, wherein in step (a), the compound shown in formula [1] is reacted with magnesium and then reacted with zinc chloride or zinc bromide to prepare an organometallic reagent. 5. The preparation method according to any one of claims 1 to 4, wherein, with respect to the compound represented by formula [2] in step (b), ^R1 is a _C1-6 alkyl group. 6. The preparation method according to any one of claims 1 to 4, wherein, with respect to the compound represented by formula [2] in step (b), R ¹ is tert-butyl. 7. The preparation method according to claim 1, wherein in step (b), the amount of nickel compound catalyst used is less than 10 mol% relative to the compound shown in formula [2]. 8. The preparation method according to claim 1, wherein, in step (b), the amount of the optically active compound of formula [3] used as a catalyst is 12 mol% or less relative to the compound of formula [2]. 9. The preparation method according to claim 2, wherein in step (b), the amount of nickel compound catalyst used is 0.03 to 1.00 mol% relative to the compound shown in formula [2], and the amount of optically active compound catalyst used is 0.036 to 1.20 mol%. 10. The preparation method according to claim 4, wherein in step (b), the amount of nickel compound catalyst used is 0.03 to 1.00 mol% relative to the compound shown in formula [2], and the amount of optically active compound catalyst used is 0.036 to 1.20 mol%. 11. The preparation method according to claim 1, wherein in step (b), the amount of nickel compound catalyst used is 0.50 to 1.00 mol% relative to the compound shown in formula [2], and the amount of optically active compound catalyst used is 0.60 to 1.20 mol%. 12. The preparation method according to claim 3, wherein in step (b), the amount of nickel compound catalyst used is 0.50 to 1.00 mol% relative to the compound shown in formula [2], and the amount of optically active compound catalyst used is 0.60 to 1.20 mol%. 13. The preparation method according to claim 1, wherein in step (b), the reaction temperature is -78°C to the boiling point of the reaction solvent. 14. The preparation method according to claim 1, wherein in step (b), the reaction temperature is -20℃ to 25℃. 15. The preparation method according to claim 2, wherein in step (b), the reaction temperature is 0~25℃. 16. The preparation method according to claim 4, wherein in step (b), the reaction temperature is 0~25℃. 17. The preparation method according to claim 1, wherein in step (b), the reaction temperature is -20~0℃. 18. The preparation method according to claim 3, wherein in step (b), the reaction temperature is -20~0℃. 19. The preparation method according to claim 3, wherein, in step (c), the step of converting the compound shown in formula [4] into the compound shown in formula [5] is a conversion under acidic conditions. 20. The preparation method according to claim 4, wherein step (c) of converting the compound represented by formula [4] into the compound represented by formula [5] is a conversion under acidic conditions.