WO2006049211A1

WO2006049211A1 - 2-aryl-2-fluoroalkanoic acid, ester thereof, and processes for producing these

Info

Publication number: WO2006049211A1
Application number: PCT/JP2005/020217
Authority: WO
Inventors: Yoshio Takeuchi; Hidehito Fujisawa
Original assignee: National University Corporation University Of Toyama
Priority date: 2004-11-02
Filing date: 2005-11-02
Publication date: 2006-05-11
Also published as: JPWO2006049211A1

Abstract

A process shown by the following scheme which is for producing a 2-aryl-2-fluoroalkanoic acid ester in a high yield through a small number of steps; and a novel 2-aryl-2-fluoroalkanoic acid compound produced by the process. The compound produced, which has a fluorine atom introduced into the chiral center, heightens the pharmacological activity of an antipyretic/analgesic/anti-inflammatory agent, reduces the side effects of the agent, and is useful as a novel optical resolver, a raw material for a liquid crystal, etc. (In the formula (1), Ar means optionally substituted aryl, etc.; Ra means a carboxy-protecting group; and R1 means optionally substituted alkyl.).

Description

Specification

2-Aryl _ 2_Fluoroalkanoic acid and its ester and production method thereof

Technical field

[0001] The present invention relates to a novel 2-aryl-2 fluoroalkanoic acid, its optically active substance and an ester thereof, 2-aryl 2-fluoroalkanoic acid ester, and a method for producing the optically active substance.

Background art

[0002] There are two types of optical isomers in 2-arylpropionic acids (ibuprofen, naproxen, flurbiprofen, fenoprofen, etc.) that are used as non-steroidal anti-inflammatory drugs. However, since these may be isomerized in vivo [Non-patent Document 1], the pharmacological activity and pharmacokinetics as an optically active substance cannot be strictly investigated. In contrast, attempts have been made to investigate pharmacological activity and pharmacokinetics as optically active substances by preventing in vivo isomerism by using compounds in which 2-position hydrogen of 2-arylpropionic acids is substituted with a fluorine atom. [Non-patent document 2, Non-patent document 3].

On the other hand, perchloryl fluoride is used when a fluorine atom is introduced into a compound, and for example, there is a production of fluorosalidomide [Patent Document 1]. Examples of the use of perchloryl fluoride to produce fluoralkanoic acids include a-fluoro 1-nitro 1-phenol substituted alkanoic acid esters, specifically a-fluoro-a-tro 13- There is a synthesis of ferrule ethyl pionate [Patent Document 2]. This use example can be applied only to compounds in which a specific substituent such as a -tro group is bonded to the carbon at the α-position of the carboxylic acid.

[0004] Further, the present inventors derived phenylethyl acetate to the corresponding enol silyl ether form, and then reacted the enol silyl ether form with perchloryl fluoride gas in the presence of t-butylamine as a base. It has been reported that α-fluorophenyl acetate can be obtained with a yield of at least% [Non-patent Document 4].

[0005] Patent Document 1: JP 2000-159761

Patent Document 2: JP-A 63-79854 Non-Patent Document 1: J. Pharm. Pharmacol, 693, 35, 1983

Non-Patent Document 2: Tetrahedron, 52 (24), 8257-8262, 1996

Non-Patent Document 3: Tetrahedron, 52 (39), 12761-12774, 1996

Non-Patent Document 4: Summary of the 25th Fluorination Discussion Meeting, 258-260,2001

Disclosure of the invention

Problems to be solved by the invention

[0006] The photoactive form of the 2-position fluorine-substituted product of 2-aryl alkanoic acids such as 2-aryl propionic acid does not undergo racemization. Therefore, it is a useful compound for investigating the difference in biological activity among stereoisomers and the effect of introduction of fluorine atoms. First, the necessary 2-aryl-fluoroalkanoic acids are selectively synthesized. It was necessary to establish a method.

Means for solving the problem

[0007] As a result of diligent research, the present inventors have found that fluorination using perchloryl fluoride is a useful method for direct fluorination of the 2-position carbon of 2-arylalkanoic acids, Furthermore, the obtained fluorinated product was successfully optically resolved, and the present invention was completed.

That is, the present invention provides a general formula

[Chemical 1]

(Wherein Ar is an optionally substituted formula

[Chemical 2]

(Z ring is absent, or represents a benzene ring or a bicyclic heterocyclic ring); R ^a represents ^a carboxyl protecting group; R ¹ represents an optionally substituted alkyl group. , Each means. ) Wherein 2-aryl alkanoic acid ester is reacted with perchloryl fluoride in the presence of a base.

[Chemical 3]

(In the formula, Ar, R ^a and R ¹ are as defined above.)

Wherein Ar is a phenyl group that may be substituted, a naphthyl group that may be substituted, or a formula that may be substituted

[Chemical 4]

zN,

Or a group represented by the formula:

[Chemical 5]

It is preferable that the group represented by

The present invention also provides a general formula

[Chemical 6]

R

(Wherein Ar ^a is phenyl, phenol, halogen and phenol, oxocyclopentylmethyl, alkenylamino, or 2_phenyl-1,3-dioxolane. A phenyl group substituted with 2-yl

[Chemical 7]

R represents a hydrogen atom or a carboxyl protecting group; IT represents an alkyl group which may be substituted, or

Ar ^a represents a phenyl group; R represents a hydrogen atom or a carboxyl protecting group; R ¹ represents a branched alkyl group or an aralkyl group, respectively. )

2-aryl 2-fluoroalkanoic acid represented by the following formula: The invention's effect

[0010] According to the production method of the present invention, a chiral compound in which a fluorine atom is introduced into a structurally important asymmetric center of 2-arylalkanoic acid can be synthesized in a short process. Furthermore, the novel 2-aryl 2-fluoroalkanoic acids produced by the method of the present invention can be expected to enhance the pharmacological action of antipyretic “analgesic” anti-inflammatory drugs and reduce side effects.

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] In the present specification, an aryl group refers to phenol and naphthyl; an aryloxy group refers to funoxy and naphthoxy; and an aryl hydrocarbon group refers to full carbon and naphthyl carbonate. A heteroaryl group is an aromatic cyclic group containing a heteroatom such as pyridyl, fulleryl, chenyl, pyrrolyl, imidazolyl, oxazolyl, pyrazil, pyridazyl, pyrimidinyl; The group is an oxy group to which a heteroaryl group is bonded; the heteroarylcarbonyl group is a bond to a heteroaryl group. An alkyl group is a C alkyl group such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; an alkoxy group is methoxy

1-6

, Ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy and other C alkyloxy groups; alkellyl groups are bur (etul), allyl (2-probe)

1-6

), 1-probe, 1-methylvinyl, 1-butur, 2-butyl, 3-butur, etc .; C alkyl groups; such as alkyl groups are ethur, 1-propiel, 2-pro

2-6

C alkyl group such as pinyl and butynyl; alkylamino group means methylamino,

2-6

Mono- or di-C alkylamino groups such as tyramino and methylethylamino;

1-6

-Luamino group means mono C alk eramino such as arylamine, isopropylamine, etc.

2-6

Group; halogen atom means fluorine atom, chlorine atom, bromine atom, iodine atom;

V and alkyl groups are branched C-alkyl such as iso-propyl, iso-butyl, tert-butyl, etc.

Aralkyl refers to an aryl-C alkyl group such as benzyl, phenethyl, diphenylmethyl, or trityl.

1-6

[0012] The scheme of the production method of the present invention is as follows.

[Chemical 9]

Scheme 1

(Wherein Ar is an optionally substituted formula

[Chemical 10]

(Z ring is absent, or represents a benzene ring or a bicyclic heterocyclic ring); R ^a represents ^a carboxyl protecting group; R ¹ represents an optionally substituted alkyl group. , Each means. )

[0013] Ar substituents in the general formulas [2] and [3] include alkyl groups, alkenyl groups, Lucinyl, alkoxyl, aryl, aroxy, aryl carbonate

, Heteroaryl group, heteroaryloxy group, heteroaryl carboxyl group, nitro group

, Alkylamino group, alkenylamino group, and halogen atomic energy, including one or more selected groups, alkyl group, aryl group, aryloxy group, arylcarbonyl group, alkellamino group, and one or more selected groups It is preferable that Examples of the carboxyl protecting group for R ^a include C such as methyl group, ethyl group, and t-butyl group.

1 Alkyl group; aralkyl groups such as benzyl group, diphenylmethyl group, and trityl group

6

It is done. In the general formulas [2] and [3] and the general formula [1] (described later), the substituent represented by R ¹ includes an alkyl group, an alkyl group, an alkyl group, an alkoxyl group, an aryl group. And one or more groups selected from an aryloxy group, an arylcarbonyl group, a heteroaryl group, a heteroaryloxy group, a heteroarylcarbonyl group, a nitro group, and a halogen atom, and an aryl group (particularly a phenol group). I prefer that.

[0014] The 2-aryl alkanoic acid ester of the general formula [2] is mixed with a base as a solvent in an ether such as tetrahydrofuran (THF) at a low temperature, for example, 20 ° C or lower, preferably 40 ° C to 78 ° C. For example, a metal amide such as lithium dialkylamide (LDA), sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc. (the metal amide may be formed in the reaction solution), and then fluorinated. Perchloryl (FCIO), preferably fluorinated perchlor

Three

By reacting ril gas, a 2-aryl 2-fluoroalkanoate of the general formula [3] can be produced.

[0015] Further, in the present production method, when the 2-aryl alkanoic acid ester as a raw material has a ketone portion, for example, a method of fluorinating the ketone portion after ketal protection is more preferred and may be mentioned as a method. .

[0016] Examples of the 2-aryl 2-fluoroalkanoic acid ester produced in Scheme 1 are those shown in Tables 1 and 2.

[0017] [Table 1]

.TZ0Z0 / S00Zdf / X3d L 6tO / 900Z OAV [Table 2]

Ar R ¹ R ^£

The 2-aryl-2-fluoroalkanoic acid ester of general formula [3] can be hydrolyzed to the corresponding 2-aryl 2-fluoroalkanoic acid. Next, 2-aryl 2 fluoroalkanoic acid is condensed with power rangeol (compound [5]) to give two corresponding diastereomers, which are separated by silica gel chromatography and then hydrolyzed. Then, an optically active substance can be obtained. Skip these steps 2

[0020] [Chemical 11]

Scheme 2

Ar 'ヽ COCI

[3] [4]

[1 B] (one body)

[1 B] (+) body

[0021] The compound of the present invention has the following general formula [1]

[Chemical 12]

(Wherein Ar ^a is phenyl / reoxy, phenol, halogen and phenyl, oxocyclopentylmethyl, alkenylamino, or 2_phenyl-1,3-dioxan-2-yl. Or a group substituted with

[Chemical 13] Y. ^

Group or formula represented by

[Chemical 14]

R represents a hydrogen atom or a carboxyl protecting group; R ¹ represents an optionally substituted alkyl group, respectively, or

2-aryl-2-fluoroalkanoic acid and esters thereof, and optically active substances thereof. These can be obtained by the production method of the present invention described above. A compound in which R ¹ is an aralkyl group can also be produced by using N-fluorobenzenesulfonimide instead of perchloryl fluoride. Specific examples of the compounds are shown in Tables 3 and 4.

[Table 3]

_Ar VaZ, c ○ OR

O

CH. H [0023] [Table 4]

Example

[0024] Hereinafter, the present invention will be described with reference to examples. The present invention is not limited to these examples! /

(zH8 = f 'Ρ'

HZ) QZ'L

'b' HT) 0Z "S '(s' HS) Z9"S' P 'HZ) WZ'

Awakening H _T

0 to ui. W— ^ Rinse ci l (/ é ^:-)-S ·

. 00 ^ Stop 翁 HS [00] (ω 'HS) SS'Z— IS'Z' (ω ') WL-ZZ'L' (ω Ή2) 9ΓΖ-60 "Ζ

. ¾¾ (% 66) 0 · ΐ [J ^ Rinse ci l (/ ΰ ΰ /-ε- /--

^ c ^^ c ^. : Mw ^ grace ^ wm ^ ^^^ ^ ^ ^ m

/ 邈 4S Marquis ¾. _n 爵一, つ, α ψ 工 ^ Dij¾ 继缀氺マ (H

. · Η stops. ο¾τ " _{Μ /} -^;], stop

Πωθε / — ^ §000 · ΐ 邈 be ci l (/ ΰ ΰ /-ε-/---S (I) [9200]

[ιε]

εmale + γ

^ ([n

[S200] ίΙΖ0Ζ0 / ζ00Ζάΐ / 13ά 6tO / 900Z OAV Colorless crystals

Melting point: 85-87 ° C

IR (KBr) cm ^_1 : 1740

1H NMR (CDC1) δ: 1.57 (3H, d, J = 7Hz), 3.66 (3H, s), 3.85 (1H, q, J = 7Hz), 3.89 (3H,

Three

s), 7.10-7.15 (2H, m), 7.39 (1H, dd, J = 2, 8Hz), 7.65 (1H, d, J = 2Hz), 7.68 (1H, s), 7.71 (1H, s)

[0029] · 2- (3-Phenoxyphenyl) methyl propanoate

Colorless oil

IR (Neat) cm— 1739

^J H NMR (CDC1) δ: 1.48 (3Η, d, J = 7 Hz), 3.66 (3H, s), 3.70 (1H, q, J = 7 Hz), 6.85—

Three

6.89 (1H, m), 6.97—7.13 (5H, m), 7.24-7.37 (3H, m)

[0030] · 2- (3-Benzylphenol) methyl propanoate

Colorless oil

IR (Neat) cm " ¹ : 1660, 1738

^J H NMR (CDC1) δ: 1.54 (3Η, d, J = 7 Hz), 3.68 (3H, s), 3.81 (1H, q, J = 7 Hz), 7.41—

Three

7.83 (9H, m)

[0031] (2) -40 ° C, lithium diisopropylamide (LDA) 1.5 eq. In tetrahydrofuran 15 mL, 2- (4-phenyl-3-fluorophenyl) propanoic acid methyl [2f] lg Tetrahydrofuran solution 5 mL was added. The mixture was stirred for about 10 minutes, and perchloryl fluoride (FC10) was introduced for 1 hour. The water

Three

In addition, the solvent was distilled off. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solution was concentrated. Insoluble material was removed by Celite filtration. Silica gel column chromatography (hexane: ethyl acetate = 2: 1, W / W) to remove impurities, 2-fluoro-2- (

841 mg of methyl 4-phenyl-3-fluorophenol) propanoate [3f] was obtained.

Colorless needle

Melting point: 67-70 ° C

IR (KBr) cm " ¹ : 1748

^J H NMR (CD OD) δ: 1.96 (3H, dd, J = 2, 22 Hz), 3.81 (3H, s), 7.30-7.56 (8H, m)

Three

[0032] Similarly, the following compounds were obtained (see Examples 3 and 4 described below). • Methyl 2-fluoro-2- (4-isobutylphenol) propanoate [3a]

Colorless oil

IR (Neat) cm " ¹ : 1743

1H NMR (CDCl) δ: 0.90 (6Η, d, J = 7 Hz), 1.81-1.91 (IH, m), 1.93 (3H, d, J = 22 Hz

Three

), 2.47 (2H, d, J = 7 Hz), 3.77 (3H, s), 7.16 (2H, d, J = 8 Hz), 7.39 (2H, d, J = 8 Hz) [0033] 2- Fluoro-2- (6-methoxy-2-naphthyl) propanoic acid methyl ester [3d]

Colorless solid

Melting point: 94-96 ° C

IR (KBr) cm " ¹ : 1743

^J H NMR (CDCl) δ: 2.03 (3H, d, J = 22 Hz), 3.77 (3H, s), 3.92 (3H, s), 7.13 (IH, d,

Three

J = 2 Hz), 7.17 (IH, dd, J = 2, 9 Hz), 7.55 (IH, dd, J = 2, 9 Hz), 7.74 (IH, s), 7.77 (IH, d, J = l Hz), 7.89 (IH, d, J = l Hz)

[0034] · 2-Fluoro-2- (3-phenoxyphenol) methyl propanoate [3b]

Yellow oil

IR (Neat) cm " ¹ : 1744

^J H NMR (CDCl) δ: 1.91 (3Η, d, J = 22 Hz), 3.77 (3H, s), 6.93—7.03 (3H, m), 7.09—

Three

7.26 (3H, m), 7.30—7.38 (3H, m)

[0035] (3) Methyl 2-fluoro-2- (4-phenol-3-fluorophenyl) propanoate [3f] 389 mg was dissolved in 20 mL of methanol and stirred with 4% hydroxide at room temperature. 5 mL of an aqueous potassium solution was added dropwise. After 3.5 hours, the solvent was distilled off, 10% hydrochloric acid was added, and the mixture was extracted with ethyl acetate and concentrated. The obtained solid was washed with black mouth form and dried to obtain 349 mg of colorless solid 2-fluoro-2- (4-phenol-3-fluorophenol) propanoic acid [If].

Melting point: 97-100 ° C

IR (KBr) cm " ¹ : 1618, 3406

^J H NMR (CD OD) δ: 1.86 (3H, d, J = 22 Hz), 7.32-7.44 (6H, m), 7.47-7.54 (2H, m

Three

)

[0036] The following compounds were obtained in the same manner.

• 2-Fluoro-2- (4-isobutylphenol) propanoic acid [la]

[9ΐ ^]

(zH2 = f ^ 'Ηΐ) 66

'(ω' Η) WL-9L'L '(ω' Η) WL-WL ^ ΗΖΖ = ί 'Ρ Ήε) 00: 9 (OQD) Awakening Η _τ

990S '8ε ΐ' 099ΐ: _τ _ωο-) HI

Ρΐ] 邈 be ΰ 1 (/ é /: be: ^-ε)-ΰ /-[6S00] (ω Ή6) ZS "Z-0Z" 9 '(zHS2 = f' Ρ Ήε) Ζ6 HN _{τ τ}

'es i: G () I

One. 99- Whip

'P' Ηΐ) Z6'L '(s' Ηΐ) 9Z "Z '(s'HI) ZL'L' PP Ή ΐ) zs'z '(ω Ή2) 8ΓΖ-ΪΓΖ' (s Ήε) ΐ6 · ε zz = ['p Ήε) wz: 9 (\ DQDWH H _T

ff £ '6SZT: _τ _ωο (-iel) HI

One. ^ ΐ-6ΐΐ: Whip

[Ρΐ] 邈 be ci l (^--9)-ci /-[ζεοο]

'P' ΗΖ) fVL 'P' ΗΖ) LYZ

'( ^z H22 = f' P Ήε) Ζ8 · ΐ '(ω' Ηΐ) ΐ6 · ΐ— ε8 · ΐ '( ^Ζ ΗΖ = Γ' Ρ 'Η9) 68: 9 (\ DQDWH Η _Τ

S £ f £ '3ΐΖΐ: _τ _ωο () HI

One. (-89: Whip

.TZ0Z0 / S00Zdf / X3d 91 6tO / 900Z OAV Scheme 4

[1f] (+) body

[0041] (1) 2-Fluoro-2- (4-phenol-3-fluorophenol) propanoic acid [If] 337 mg is dissolved in tetrahydrofuran lOmL, and dimethylformamide 10 / z L is added, At room temperature, 0.22 mL of oxalyl chloride ((COC1)) was added dropwise. After stirring for 4 hours, the solvent and the like are distilled off, and the muddy compound [4f]

2

Obtained.

[0042] (2) Force range ol [5] was dissolved in 20 mL of tetrahydrofuran, and 221 mg of compound [4f], 0.4 mL of triethylamine (Et N), and 10 mg of dimethylaminopyridine (DMAP) were sequentially added. 15 hours later

Three

The insoluble material was removed by Celite filtration, and the solvent was distilled off. Purification by silica gel column chromatography (1) (chloroform form: ethyl acetate = 95: 5, W / W) gave compound [6] (177 mg, 191 mg of two diastereomers and 46 mg of a mixture thereof). The lower polarity was taken as compound [6L] and the higher polarity was taken as compound [6M].

[0043] (3) Compound [6L] 177 mg was dissolved in 5 mL of methanol, and 5 mL of a 4% aqueous solution of sodium hydroxide power was added dropwise at room temperature with stirring. After 50 minutes, the solvent was distilled off, 10% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. When acetone is passed through silica gel column chromatography as a solvent, Eluted. Subsequently, when methanol: acetone = 1: 1 (W / W) was passed, 2-fluoro-2- (4-phenol-3-fluorophenol) propanoic acid [If] was eluted. did. After filtration with cotton plug with ethanol: ethyl acetate = 1: 1 (W / W), the solution was concentrated and colorless solid 2-fluoro-2- (4-phenyl-3-fluorophenyl) propanoic acid [ If] (one) body 65mg was obtained.

[α] ²⁵ -33.8 (c = 1.0 in MeOH)

D

Melting point 111-113 ° C

IR (KBr) cm " ¹ : 1619, 3423

^J H NMR (CD OD) δ: 1.86 (3H, d, J = 22 Hz) 7.32-7.44 (6H, m), 7.47-7.54 (2H, m)

Three

Similarly, 191 mg of compound [6M] was dissolved in 5 mL of methanol, and 5 mL of 4% aqueous potassium hydroxide solution was added dropwise at room temperature with stirring. After 50 minutes, the solvent was distilled off, and 10% hydrochloric acid was extracted with ketyl acetate. When acetone was passed through silica gel column chromatography as a solvent, calendole was eluted. Subsequently, when methanol: acetone = 1: 1 (W / W) was passed, 2-fluoro-2- (4-phenol-3-fluorophenol) propanoic acid [If] (+) form was eluted. did. After filtration with a cotton plug with ethanol: ethyl acetate = 1: 1 (W / W), the solution was concentrated and colorless solid 2-fluoro-2- (4-phenyl-3-fluorophenyl) propanoic acid [If] (+) body 87mg was obtained.

[α] ²⁶ +33.9 (c = 1.0 in MeOH)

D

Melting point: 112-115 ° C

IR (KBr) cm " ¹ : 1619, 3410

^J H NMR (CD OD) δ: 1.86 (3H, d, J = 22 Hz), 7.32-7.44 (6H, m), 7.47-7.54 (2H, m)

Three

[0045] The following compounds were obtained in the same manner as in the above (1) to (3).

• 2-Fluoro-2- (4-isobutylphenol) propanoic acid [la] (one)

Colorless solid

Melting point: 164-165 ° C

[α] ²⁷ -27.1 (c = ll, EtOH)

D

IR (KBr) cm " ¹ : 1716, 3421

1H NMR (CDCl) δ: 0.89 (6H, d, J = 7 Hz), 1.87 (3H, d, J = 22 Hz), 1.83-1.91 (1H, m

Three

), 2.47 (2H, d, J = 7 Hz), 7.14 (2H, d, J = 8 Hz), 7.38 (2H, d, J = 8 Hz)

• (+) form of 2-fluoro-2- (4-isobutylphenol) propanoic acid [la] Colorless solid

Melting point: 159-163 ° C

[α] ²⁵ +30.6 (c = 1.0, EtOH)

D

IR (KBr) cm " ¹ : 1716, 3419

1H NMR (CDCl) δ: 0.89 (6H, d, J = 7 Hz), 1.87 (3H, d, J = 22 Hz), 1.83-1.91 (IH, m

Three

), 2.47 (2H, d, J = 7 Hz), 7.14 (2H, d, J = 8 Hz), 7.38 (2H, d, J = 8 Hz)

[0046] · (1) Form of 2-Fluoro-2- (6-methoxy 2-naphthyl) propanoic acid [Id]

Colorless crystals

Melting point: 113-115 ° C

[α] ²⁶ -46.9 (c = 1.0, MeOH)

D

IR (KBr) cm " ¹ : 1739, 3442

^J H NMR (CDCl) δ: 2.04 (3H, d, J = 22 Hz), 3.91 (3H, s), 7.11-7.18 (2H, m), 7.57 (

Three

IH, dd, J = 2, 9 Hz), 7.73 (IH, s), 7.76 (IH, s), 7.92 (IH, d, J = l Hz)

• (+) form of 2-Fluoro-2- (6-methoxy 2-naphthyl) propanoic acid [Id]

Colorless crystals

Melting point: 112-115 ° C

[α] ²⁶ +46.5 (c = 1.0, MeOH)

D

IR (KBr) cm " ¹ : 1737, 3447

Three

IH, dd, J = 2, 9 Hz), 7.73 (IH, s), 7.76 (IH, s), 7.92 (IH, d, J = l Hz)

[0047] · 2-Fluoro-2- (3-phenoxyphenol) propanoic acid [lb] (one)

Yellow oil

[α] ²⁵ -3.1 (c = 1.2, CHC1)

D 3

IR (Neat) cm " ¹ : 1729, 2990

1H NMR (CDCl) δ: 1.92 (3H, d, J = 23 Hz), 6.70-7.37 (9H, m)

Three

• 2-Fluoro-2- (3-phenoxyphenol) propanoic acid [lb] (+) form

Yellow oil

[α] ²⁶ +3.2 (c = 1.4, CHC1) IR (Neat) cm: 1731, 2989

1H NMR (CDCl) δ: 1.92 (3H, d, J = 23 Hz), 6.70-7.37 (9H, m)

Three

[0048] · (1) isomer of 2-fluoro-2- (3-benzoylphenol) propanoic acid [lc]

Yellow oil

[α] ²⁵ -4.9 (c = 0.9, CHC1)

D 3

IR (Neat) cm " ¹ : 1660, 1740, 2990

^J H NMR (CDCl) δ: 2.00 (3H, d, J = 22 Hz), 7.45-7.64 (4H, m), 7.76-7.81 (4H, m), 7.

Three

99 (1H, t, J = 2 Hz)

• (+) form of 2-fluoro-2- (3-benzoylphenol) propanoic acid [lc]

Yellow oil

[α] ²⁸ +4.9 (c = 0.7, CHC1)

D 3

IR (neat) cm " ¹ : 1660, 1734, 3066

Three

99 (1H, t, J = 2 Hz)

[0049] Example 3: Synthesis of methyl ester of fluoroibuprofen [methyl 2-fluoro-2- (4-isobutylphenol) propanoate]

Add 0.05 mL of diisopropylamine and 0.24 mL of 1.6 M n-butyllithium to 5 mL of tetrahydrofuran at 40 ° C, and stir. After 10 minutes, add 55 mg of methyl 2- (4-isobutylphenol) propanoate and continue stirring. After 10 minutes, dilute perchloryl fluoride (FC10) gas for 1 hour

Three

Introduced. Hexane was added and polar substances were removed with a short column. When purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1.W / W), it was a colorless oily methyl 2-fluoro-2- (4-isobutylphenol) propanoate [3a] 52 mg (93%) was obtained.

Example 4: Methyl ester of fluoronaproxen [methyl 2-fluoro-2- (3-phenoxyphenol) propanoate] and methyl ester of fluorophenoprofen [2-Fluoro-2- (3 Of -Phenoxyphenyl) methyl propanoate]

In the same manner as in Example 3, methyl 2- (6-methoxy-2-naphthyl) propanoate to methyl 2-fluoro-2- (6-methoxy-2-naphthyl) propanoate [3d] (96%), 2 -(3-Phenoxyphenol) methyl methyl 2-panfluorate-2-methyl (3-phenoxyphenyl) propanoate [3b] (97%) Got.

[0051] Example 5: Synthesis of methyl ester of fluoroketoprofen [methyl 2-fluoro-2,2- (3-benzoylphenyl) propanoate]

Synthesis of methyl ester of fluoroketoprofen (3c) was performed as shown in Scheme 5.

[Chemical 17]

Scheme 5

[3k] [3c]

[0052] (1) Methyl 2- (3-benzoylphenol) propanoate [2c] 1.0 g, ethylene glycol 0.85 mL, p-toluenesulfonic acid monohydrate 70 mg and toluene 20 mL heated for 18 hours I returned it. To the reaction mixture was added 10 mL of saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solution was concentrated. It was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, W / W), and colorless oily 2- [3- (2-phenol-1,3-dioxolane-2-y (L) phenol] methyl propanoate [2k] was obtained (yield 62%).

IR (Neat) cm " ¹ : 1737

^J H NMR (CDC1) δ: 1.48 (3Η, d, J = 7 Hz), 3.63 (3H, s), 3.71 (1H, q, J = 7 Hz), 4.05

Three

(4H, s), 7.21-7.39 (6H, m), 7.45-7.52 (3H, m)

[0053] (2) Example 1 In the same manner as in (2), methyl 2- [3- (2-phenol-1,3-dioxan-2-yl) phenol] propanoate [2k] In the presence of lithium diisopropylamide (LDA) in tetrahydrofuran with THF (THF) to give 2-fluoro-2- [3- (2-phenyl-1,3- Dioxolan-2-yl) phenyl] methyl propanoate [3k] was obtained (yield 79%).

Colorless oil

IR (Neat) cm " ¹ : 1742

1H NMR (CDCl) δ: 1.91 (3Η, d, J = 22 Hz), 3.74 (3H, s), 4.06 (4H, s), 7.24-7.37 (4

Three

H, m), 7.40-7.52 (4H, m), 7.71 (1H, t, J = 2Hz)

[0054] (3) 2-Fluoro 2- [3- (2-Fel-1,3-dioxolan-2-yl) phenol] methyl propanoate [3k] To 5 mL of a methanol solution of 562 mg, 5 mL of 10% hydrochloric acid was added and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and methanol was distilled off. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / l, W / W) to give colorless oily methyl 2-fluoro-2- (3-benzoylphenol) propanoate [ 3c] was obtained (yield 93%).

IR (Neat) cm " ¹ : 1661, 1744

^J H NMR (CDCl) δ: 1.97 (3Η, d, J = 22 Hz), 3.78 (3H, s), 7.46-7.66 (4H, m), 7.73-

Three

7.81 (4H, m), 7.96 (1H, d, J = 2 Hz)

[0055] Example 6: Fluorination of loxoprofen derivative

[Chemical 18]

Scheme 6

[31]

[0056] (1) 2- [4- (2-oxocyclopentylmethyl) phenol] propanoic acid 'sodium salt dihydrate [2gg] lg was dissolved in 10 mL of 10% hydrochloric acid and extracted with ethyl acetate The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated. Stir 20 mL of methanol. 1 mL of thionyl chloride was added dropwise and stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was added for neutralization, and methanol was distilled off. Extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated. By purifying with silica gel column chromatography (hexane / ethyl acetate = 4 / l, W / W), yellow oily methyl 2- [4_ (2_oxocyclopentylmethyl) phenol] propanoate [2g] 812 mg (95%) was obtained.

[0057] (2) At room temperature, 704 μL of ethylene glycol is stirred in methyl 2- [4- (2-oxocyclopentylmethyl) phenol] propanoate [2 g]. Ethyl orthoformate 570 μL, Bu NBr 1

4 3

5 mg was added sequentially. After 80 minutes, the reaction solution was poured into 10 mL of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solution was concentrated. Shrinked. Impurities were removed by silica gel column chromatography (hexane: ethyl acetate = 4: 1, W / W) to obtain 948 mg of a yellow oily compound [21].

[0058] (3) To a solution of lithium diisopropylamide (LDA) in 15 mL of tetrahydrofuran (THF) at 40 ° C, a solution of 948 mg of compound [21] in 5 mL of tetrahydrofuran was added. The mixture was stirred for 10 minutes, and perchloryl fluoride (FC10) was introduced for 1 hour. An aqueous salt ammonium solution was added and the solvent was distilled off.

Three

The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solution was concentrated. Insoluble material was removed by Celite filtration. The impurities were removed by silica gel column chromatography (chloroform: ethyl acetate = 95: 5, W / W) to obtain 550 mg of yellow oily compound [31] (diastereomer mixture).

[0059] Example 7

(1) 5 g of 2-phenylbutanoic acid was dissolved in 10 mL of methanol, and 3.4 mL of chlorochloride was added dropwise under ice cooling. After 5 minutes, the temperature was raised to room temperature. After stirring for 3 hours, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and the solvent was distilled off. Extraction with ethyl acetate, washing with saturated aqueous sodium hydrogen carbonate solution and saturated brine, drying over sodium sulfate and concentration yielded 4.543 g of colorless oily methyl 2-phenylbutanoate.

IR (Neat) cm " ¹ : 1736

'H-NMR (CDCl) δ: 0.89 (t, J = 14.7 Hz, 3H), 1.76—1.84 (m, 1H), 2.03—2.11 (m, 1H

Three

), 3.45 (t, J = 7.7 Hz, 1H), 3.65 (s, 3H), 7.24-7.32 (m, 5H)

[0060] Similarly, the following compound was obtained.

• Methyl 3-methyl-2-phenylbutanoate

Colorless oil

IR (Neat) cm— ¹ : 1738

^J H-NMR (CDCl) δ: 0.71 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 2.34 (qqd, J =

Three

6.5, 6.7, 10.6 Hz, 1H), 3.15 (d, J = 10.6 Hz, 1H), 3.65 (s, 3H), 7.25-7.34 (m, 5H) [0061] (2) Methyl 2-phenylbutanoate 1.13 g was dissolved in 20 mL of tetrahydrofuran, 2 mol of lithium diisopropylamide was added at 40, and 10 minutes later, perchloryl fluoride was introduced for about 50 minutes. The insoluble material was filtered through celite, and the solvent was distilled off. Impurities were removed by silica gel column chromatography (hexane: ethyl acetate = 4: 1, W / W), and yellow oily 2-fluoro-2-2-sulfate was removed. 1.02 g of methyl butanoate was obtained.

IR (neat) cm " ¹ : 1741

1H-NMR (CDC1) δ: 0.97 (t, J = 7.4 Hz, 3H), 2.06—2.51 (m, 2H), 3.78 (s, 3H), 7.16—

Three

7.53 (m, 5H)

In the same manner, the following compound was obtained.

• 2-Fluoro-3-methyl-2-phenylbutanoate

Pale yellow oil

IR (Neat) cm " ¹ : 1739

^J H-NMR (CDC1) δ: 0.75 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 2.68 (sepd, J =

Three

6.8, 31.1 Hz, 1H), 3.76 (s, 3H), 7.31-7.54 (m, 5H)

[0063] (3) Methyl 2-fluoro-2-phenylbutanoate (300 mg) was dissolved in 20 mL of methanol, and 3 mL of 1N aqueous potassium hydroxide solution was added dropwise with stirring. After 22 hours, the solvent was distilled off, washed with methylene chloride, and the aqueous layer was adjusted to pH 1 with hydrochloric acid. Extraction with methylene chloride, drying over sodium sulfate, and concentration yielded 260 mg of 2-fluoro-2-phenolbutanoic acid as a pale yellow solid.

Melting point: 38-43 ° C

IR (KBr) cm " ¹ : 1696, 2978

^J H-NMR (CDC1) δ: 0.98 (t, J = 7.4 Hz, 3H), 2.13—2.51 (m, 2H), 7.32-7.55 (m, 5H)

Three

[0064] Similarly, the following compound was obtained.

• 2-Fluoromouth-3-methyl-2-phenylbutanoic acid

Pale yellow solid

Melting point: 67-74 ° C

IR (KBr) cm " ¹ : 1701, 2977

1H-NMR (CDC1) δ: 0.77 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H), 2.67 (sepd, J =

Three

6.9, 31.6 Hz, 1H), 7.31-7.55 (m, 5H)

(0065) 2-Fluoro-2-phenylbutanoic acid lg was dissolved in 20 mL of anhydrous methylene chloride, and 1 drop of dimethylformamide was added. Under ice-cooling, 1 mL of salt oxalyl was added dropwise and stirred for 19 hours. The solvent was distilled off, and power range ol 935 mg, dimethylaminopyridine 10 mg, anhydrous methyl chloride 20 mL, and triethylamine 2 mL were sequentially added. After stirring for 23 hours, insoluble by Celite filtration Ηΐ 'ω) Ζ · ΐ— S9'I' (Ηΐ 'ω) ε · ΐ ΐ' (HS 's) 82 "ΐ' (HS '^ Η 8 · 9 = f' Ρ) ZVl '(HS 8

6 · 0 '(HS' s) Ζ6 '(HS' ΖΗ 6 · 9 = f 'Ρ) 9Ζ ΗΖ' ω) ΖΖ -Ζ9: 9 (OQD) Ν Ν-Η _Τ

(¾¾ ^) [ϊ9] ί¾? ^ · (HS 'ω) WL-QZ'L' (Ηΐ 'ΖΗ 6 · 6' S'Z

= ['ΡΡ) ·' (Ηΐ 'ΖΗ Vfl' S'Z = ['ΡΡ) VZ' (Ηΐ '^ Η · ΐ' 6 · 6 = f 'ΡΡ) Ζ6 "ΐ' (Ηΐ

'ω) 09 · ΐ' (HS 's) 92 "ΐ' (HS 'ΖΗ 9 · 9 = f' Ρ) ΐΓΐ '(Ηΐ' ω) 9ΐ · ΐ— SO'I '(HS' s) 6

6 · 0 '(HS' s) Ζ6 '(HS' ^ Η 6 · 9 = f 'Ρ) 08' {HZ WO— S9'0: 9 (OQD) H NH _T

(W¾) [li9] i¾? ^-Ss i: G -) HI

(D9] i¾? ^ »/ D / — ^ ^ pe o) 邈 be ^: / é-^-ε-ΰ /-s ·

.呦 ^ etsu) 翁 ^ [Z900] {HZ ' ^Ζ Η · 8' 8 · ΐ = ί "'ΡΡ) OS'Z' (HS OVL-Z ^ L '(Η ΐ' ^Ζ Η 6 · 6 '9 "Ζ = Γ 'ΡΡ) 63 ^' (Η2 'ω) WZ-L ^ Z' (Ηΐ '^ Η' W 'S'Z = f' ΡΡ) WZ '(Ηΐ' ζ

Η L-fl '6 · 6 = ί "' ΡΡ) 66 · ΐ '(Ηΐ' ω) SZ'I— 9 · ΐ '(Ηΐ' ω) εε · ΐ- 6ΐ · ΐ '(HS ΐ' (HS 'ζ

Η ί = ί 66 '(HS' s) 66 '(HS Ζ6 ΗΖ' ω) ΖΖ -99: 9 (OQD) Η Ν-Η _Τ

('爾掣) 呦 ^ ；] · (HS' ZH S'8 '8 · ΐ = ί "' ΡΡ) WL '(Η ε' ω)

'ΡΡ) 9VZ' (HI 'Ζ

Η L-fi 'ε · 6 = ί "' ΡΡ) 6" ΐ '(ΗΪ ΐζ · ΐ— 6s'i' (ΗΪ εε · ΐ— '(HS' s) IZ'l '(HS' ζ

Η Γ8 = Γ ') 00 · ΐ' (HS 's) 00 · ΐ' (HS 's) Ζ 6' (Ηΐ 'ω) ΖΖ -99: 9 ODOD) Η Ν-Η _Τ

6SZT: G -) HI

° (Su¾SS: [腳

, ^Su ¾SS: [T19] 呦 ^^ fi fi ¾—mu; ^ C) T ^ (/ 'S: S6 = /

^ 4S: Ma 4m ΰΗ /,. ^Su ¾ (W9) 呦 ^

, ^! ¾ 呦 ίΙΖ0Ζ0 / ζ00Ζάΐ / 13ά 93 6tO / 900Z OAV ), 1.95-2.13 (m, 2H), 2.59—2.81 (m, IH), 4.58 (dd, J = 7.5, 9.9 Hz, IH), 7.30-7.53 (m, 5H)

[0068] (5) Compound [6hL] (235 mg) was dissolved in methanol Z water Z tetrahydrofuran (5 mL / 5 mL / l mL), 0.3 g of potassium hydroxide was added, and the mixture was stirred for 2 hours. The solvent was distilled off, washed with methylene chloride and acidified with hydrochloric acid. Extraction with methylene chloride, drying over sodium sulfate, and concentration gave 127 mg of (+)-2-fluoro-2-phenolbutanoic acid as a yellow oil.

[α] ²² + 3.5, c = 1.0, CHCl

D 3

[0069] Similarly, the following compound was obtained.

• (+)-2-Fluoro-3-methyl-2-phenolbutanoic acid

Yellow oil

[α] ²³ + 6.2, c = 0.12, CHCl

D 3

[0070] (6) Compound [6hM] (252 mg) was dissolved in methanol Z water Z tetrahydrofuran (5 mL / 5 mL / l mL), 0.3 g potassium hydroxide was added, and the mixture was stirred for 2 hours. The solvent was distilled off, washed with methylene chloride and acidified with hydrochloric acid. Extraction with methylene chloride, drying over sodium sulfate, and concentration yielded 137 mg of yellow oil (I) -2-fluoro-2-phenolbutanoic acid.

[α] ²² + 4.5, c = 1.0, CHCl

D 3

Similarly, the following compound was obtained.

• (-)-2-Fluoro-3-methyl-2-phenolbutanoic acid

Yellow oil

[α] ²³ -6.2, c = 0.10, CHCl

D 3

[0072] Example 8

(1) 3 g of 2,3-diphenylpropanoic acid was dissolved in 30 mL of methanol, and 2 mL of titanium chloride was added dropwise under ice cooling. After 5 minutes, the temperature was raised to room temperature. After stirring for 3 hours, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and the solvent was distilled off. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated to give 3.2 g of colorless oily methyl 2,3-diphenylpropanoate.

'H-NMR (CDC1) δ: 0.64-0.75 (m, 2H), 0.95 (s, 3H), 0.95 (s, 3H), 1.11 (s, 3H), 1.

Three

24-1.28 (m, IH), 1.55—1.60 (m, IH), 1.86—2.05 (m, 2H), 3.40 (dd, J = 14.4, 17.0 Hz, IH), 3.65 (dd, J = 14.4, 33.8 Hz, IH), 4.49 (dd, J = 2.3, 7.7 Hz, IH), 7.2-7.7 (m, 10H) [0073] (2) 2,3-Diphe -Methyl lupropanoate lg was dissolved in 20 mL of tetrahydrofuran. Next, 3.2 mL of lithium diisopropylamide solution (2M) was added at -78 ° C. Ten minutes later, 1.4 g of N-fluorobenzenesulfonimide dissolved in 10 mL of tetrahydrofuran was obtained. After stirring for 23 hours (by raising the temperature naturally to room temperature), hexane was added and the mixture was filtered through Celite. Impurities were removed by silica gel column chromatography (hexane Z ethyl acetate = 4Zl, W / W) to obtain 0.9 g of light yellow oily methyl 2-fluoro-2,3-diphenylpropanoate.

IR (Neat) cm- 1: 1739

'H-NMR (CDCl) δ: 3.39 (dd, J = 14.5, 19.8 Hz, IH), 3.65 (dd, J = 14.5, 30.9 Hz,

Three

IH), 3.69 (s, 3H), 7.18-7.58 (m, 10H)

[0074] (3) Dissolve 2.29 g of methyl 2-fluoro-2,3-diphenylpropanoate in water, Z-methanol, Z-tetrahydrofuran (lOmL / lOmL / lOmL) and add 2.3 g of potassium hydroxide under stirring. I was frightened. After stirring for 22 hours, the solvent was distilled off, washed with methylene chloride, and the aqueous layer was adjusted to pH 1 with hydrochloric acid. Extraction with methylene chloride, drying over sodium sulfate, and concentration yielded 1.7 g of 2-fluoro-2,3-diphenylpropanoic acid as a pale yellow solid.

Melting point; 98-103 ° C

IR (KBr) cm " ¹ : 1707, 3031

'H-NMR (CDCl) δ: 3.41 (dd, J = 14.5, 19.7 Hz, IH), 3.67 (dd, J = 14.5, 30.8 Hz,

Three

IH), 7.20-7.59 (m, 10H)

(4) 1.7 g of 2-fluoro-2,3-diphenylpropanoic acid was dissolved in 40 mL of anhydrous methylene chloride, and 1 drop of dimethylformamide was prepared. Under ice cooling, 1.2 mL of salt oxalil was added dropwise. After stirring for 4 hours, the solvent was distilled off, and 1.19 mg of power range ol, 10 mg of dimethylaminopyridine, 40 mL of anhydrous methylene chloride and 2 mL of triethylamine were sequentially added. After stirring for 24 hours, insoluble materials were removed by Celite filtration, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, W / W) to obtain a colorless oily compound [6j] (914 mg). In addition, diastereomers were resolved (compound 6jL and compound 6jM) by silica gel chromatography (black mouth form Z ethyl acetate = 95Z5).

[0076], compounds [6j] IR (Neat) cm " ¹ : 1746

'Compound [6jL] (low polarity)

1H-NMR (CDC1) δ: 0.64-0.75 (m, 2H), 0.95 (s, 3H), 0.95 (s, 3H), 1.11 (s, 3H), 1.

Three

24-1.28 (m, 1H), 1.55—1.60 (m, 1H), 1.86— 2.05 (m, 2H), 3.40 (dd, J = 14.4, 17.0 H z, 1H), 3.65 (dd, J = 14.4, 33.8 Hz, 1H), 4.49 (dd, J = 2.3, 7.7 Hz, 1H), 7.2-7.7 (m, 10H)

• Compound [6jM] (High polarity)

^J H-NMR (CDC1) δ: 0.64—0.75 (m, 2H), 0.95 (s, 3H), 0.95 (s, 3H), 1.17 (s, 3H), 1.

Three

2-1.3 (m, 1H), 1.3-1.5 (m, 1H), 1.8— 2.1 (m, 2H), 3.44 (dd, J = 14.8, 20.0 Hz, 1H), 3.65 (dd, J = 14.8, 31.0 Hz, 1H), 4.50 (dd, J = 7.7, 9.9 Hz, 1H), 7.2-7.7 (m, 10H) [0077] (5) Compound [6jL] 63 mg in methanol Z water Z tetrahydrofuran (3 mL / 3 mL / 1 mL), 0.2 g of potassium hydroxide was added, and the mixture was stirred for 2 hours. The solvent was distilled off, washed with methylene chloride and acidified with hydrochloric acid. Extraction with methylene chloride, drying over sodium sulfate, and concentration yielded 34 mg of (+) isomer of pale yellow 2-fluoro-2,3-diphenylpropanoic acid.

[α] ²² + 14, c = 0.5, CHC1

D 3

[0078] (6) Compound [6jM] 60 mg was dissolved in methanol Z water Z tetrahydrofuran (3 mL / 3 mL / l mL), 0.2 g of potassium hydroxide was added, and the mixture was stirred for 2 hours. The solvent was distilled off, washed with methylene chloride and acidified with hydrochloric acid. Extraction with methylene chloride, drying over sodium sulfate, and concentration were performed to obtain 33 mg of (one) form of 2-fluoro-2,3-diphenylpropanoic acid as a pale yellow solid.

[α] ²² — 14, c = 0.5, CHC1

D 3

Industrial applicability

[0079] In the production method of the present invention, fluorination of the asymmetric central site of 2-arylalkanoic acids can be performed in a short process. In addition, compounds in which a fluorine atom is introduced at the chiral center have uses such as antipyretic, analgesic and anti-inflammatory drugs, enhanced side effects, reduced side effects, new optical resolution agents, and liquid crystal raw materials.

Claims

Claim [1] General formula

[Chemical 1]

(Wherein Ar is an optionally substituted formula

[Chemical 2]

Wherein 2-aryl alkanoic acid ester is reacted with perchloryl fluoride in the presence of a base.

[Chemical 3]

(In the formula, Ar, R ^a and R ¹ are as defined above.)

A method for producing a 2-aryl 2-fluoroalkanoic acid ester represented by the formula:

[2] Ar-substituted phenyl group, optionally substituted naphthyl group, optionally substituted formula

[Chemical 4]

Or a group represented by the formula:

[Chemical 5]

The method for producing a 2-aryl 2-fluoroalkanoic acid ester according to claim 1, which is a group represented by the formula:

General formula

[Chemical 6]

(Wherein Ar ^a is substituted with phenyl, phenyl carboyl, halogen and phenyl, oxocyclopentylmethyl, alkenylamino or 2_phenyl-1,3-dioxan-2-yl. Or the formula

[Chemical 7]

Group or formula represented by

[Chemical 8]

R represents a hydrogen atom or a carboxyl protecting group; R ¹ represents an optionally substituted alkyl group, or

Ar ^a is a fuel group; R is a hydrogen atom or a carboxyl protecting group; R ¹ is a branched It means an alkyl group or an aralkyl group, respectively. )

2-aryl 2-fluoroalkanoic acid or its ester represented by: