JPH07133251A - New halomethylene compound or its salt - Google Patents

Abstract

PURPOSE:To obtain a new halomethylene compound useful as an important synthetic intermediate for a triazole derivative having excellent antifungal activity and its salt. CONSTITUTION:A compound of formula I [R<1> is an (substituted)aryl or a heterocyclic group bonding to the compound through a carbon atom in a ring; R<2> is H, an (substituted)alkyl, an acyl or a heterocyclic group; R<3> is OH, an alkoxy, formula II (R<4> and R<5> are H or an (substituted)alkyl) or R<2> and R<3> together form a bonding; X is a halogen; Y is H, a halogen or an (substituted)alkyl] or its salt, e.g. ethyl-4-acetoxy-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxybutylate. Among the compounds of formula I, a compound expressed by formula Ia (R<2a> is same as R<2> but excluding H; R<3> is an alkoxy) is obtained by reacting a compound of formula III with a compound of formula IV (Z is a halogen; R<6> is an alkyl) and zinc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The invention of this application has the general formula [1].

[Chemical 3] "Wherein R ¹ is an optionally substituted aryl or a heterocyclic group bonded through a carbon atom in the ring;
² is a hydrogen atom or an optionally substituted alkyl,
An acyl or heterocyclic group, R ³ is a hydroxyl group, an alkoxy group or a formula

[Chemical 4] (In the formula, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group.), Or R ² and R ³ together form a bond. X is a halogen atom; Y is a hydrogen atom, a halogen atom or an optionally substituted alkyl group. And a salt thereof.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 5-213906 discloses, for example, a general formula [2]

[Chemical 5] [Wherein R ⁷ represents an optionally substituted aryl or a heterocyclic group bonded through a carbon atom in the ring;
⁸ is a hydrogen atom, a fluorine atom or an optionally substituted alkyl group; R ⁹ is a group represented by the formula:

[Chemical 6] [Wherein R ¹⁰ is a hydroxyl group or

[Chemical 7] (In the formula, R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group.)]
Represents a group represented by. A compound represented by "or a salt thereof and the like are disclosed.

[0003]

However, it is desired to develop a method which is more excellent than the method described in JP-A-5-213906, and particularly to develop an excellent synthetic method for an optically active compound. It was

[0004]

Under these circumstances, the inventors of the present application have conducted diligent research and found that the general formula

[Chemical 8] "Wherein R ¹ is an optionally substituted aryl or a heterocyclic group bonded through a carbon atom in the ring;
² is a hydrogen atom or an optionally substituted alkyl,
An acyl or heterocyclic group, R ³ is a hydroxyl group, an alkoxy group or a formula

[Chemical 9] (In the formula, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group.), Or R ² and R ³ together form a bond. X is a halogen atom; Y is a hydrogen atom, a halogen atom or an optionally substituted alkyl group. Found that the novel halomethylene compound represented by the formula or a salt thereof is, for example, a compound of the general formula [2] or a salt thereof, particularly a useful intermediate of an optically active form thereof, and completes the invention of this application. Came to.
Hereinafter, the compound of the present invention will be described in detail.

Unless otherwise specified in this specification, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and the alkyl group means, for example,
A linear or branched C _1-10 alkyl group such as methyl, ethyl, n-propyl, isopropyl and n-butyl; an alkoxy group includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy and a linear or branched C _1-10 alkoxy group such as n-butoxy;
Acyl groups include, for example, formyl groups, C _2-10 alkanoyl groups such as acetyl and ethylcarbonyl, and aroyl groups such as benzoyl and naphthoyl; aryl groups include, for example, phenyl and naphthyl groups; and heterocyclic groups. And, for example, tetrahydropyran-
It means an oxygen-containing heterocyclic group bonded via a carbon atom such as 2-yl and tetrahydrofuran-2-yl, respectively.

The heterocyclic group of the heterocyclic group bonded via the carbon atom in the ring in R ¹ is a 5- or 6-membered heterocyclic group containing at least one oxygen, sulfur or nitrogen atom, For example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2H-pyran-3-yl, pyrrol-3-yl, imidazol-2-yl, thiazole-2.
-Yl, thiazol-4-yl, isothiazol-3-
Yl, isoxazol-3-yl, pyridin-2-yl, pyridin-3-yl, 1-oxide-pyridin-3
-Yl, pyrazin-2-yl, pyrimidin-2-yl,
Pyrrolidin-2-yl, pyrrolidin-3-yl, 2-pyrrolin-3-yl, imidazolidin-2-yl, 2-imidazolidin-4-yl, piperidin-2-yl, morpholin-3-yl and the like can be mentioned. To be

Heterocyclic groups attached via an aryl group in R ¹ and a carbon atom in the ring; alkyl groups in R ² , acyl groups, heterocyclic groups; alkyl groups in R ⁴ and R ⁵ ; and in Y Examples of the substituent of the alkyl group include a halogen atom, an alkoxy group, and an aryl group which may be substituted with a halogen atom. Each group of R ¹ , R ² , R ⁴ , R ⁵ and Y may be substituted with one or more of the above-mentioned substituents.

Examples of the salt of the compound of the general formula [1] include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid,
Salts with carboxylic acids such as citric acid, oxalic acid and aspartic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; and salts with alkali metals such as sodium and potassium. .

When isomers such as optical isomers, geometric isomers and tautomers are present in the compound of the present invention, the compound of the present invention includes all the isomers and hydrates. , Solvates and all crystalline forms.

The novel halomethylene compound of the general formula [1] or a salt thereof can be produced, for example, by the following production methods 1 to 5.

[0011]

[Chemical 10] Wherein Z is a halogen atom; R ^2a is an optionally substituted alkyl, acyl or heterocyclic group; R ⁶
Represents an alkyl group; R ¹ , X and Y each have the same meaning as described above. "

[0012]

[Chemical 11] "In the formula, R ^2b represents an optionally substituted acyl group; R ¹ , R ⁶ , X and Y each have the same meaning as described above."

[0013]

[Chemical 12] "In the formula, R ¹ , R ^2b , R ⁴ , R ⁵ , R ⁶ , X and Y each have the same meaning as described above."

[0014]

[Chemical 13] "In the formula, R ^2c represents an optionally substituted alkyl or heterocyclic group; R ¹ , R ⁴ , R ⁵ , R ⁶ , X and Y
Have the same meanings as described above. "

[0015]

[Chemical 14] "In the formula, R ¹ , R ⁴ , R ⁵ , X and Y each have the same meaning as described above."

Next, the method for producing the novel halomethylene compound of the general formula [1] or a salt thereof will be described in more detail according to the above-mentioned production methods 1 to 5.

Production Method 1 The compound of the general formula [3] can be produced by a method known per se or a method analogous thereto. In addition, the compound of the general formula [1a] is, for example, tetrahedron letters (Tetrahedron Lett.) Vol. 25, p. 2301 (1984).
, Vol. 29, p. 1803 (1988) or Chemistry Letters (Chem. Lett.) P. 1165 (1984). [4]] and zinc.

Process 2 The compound of general formula [1c] can be obtained by subjecting the compound of general formula [1b] to an ordinary hydrolysis reaction. Furthermore, the compound of general formula [1c] easily undergoes dehydration ring closure to produce a compound of general formula [1d].

Process 3 The compound of general formula [1e] can be obtained by reacting the compound of general formula [1b] with the compound of general formula [5] in the presence or absence of a solvent.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane; methanol and ethanol, etc. Alcohols; N, N
-Amides such as dimethylformamide; dimethylsulfoxide; and water, and these solvents may be used alone or in combination of two or more.

The amount of the compound of the general formula [5] used may be equimolar or more to the compound of the general formula [1b].
This reaction may be carried out at 0-100 ° C for 0.1-24 hours.

Process 4 The compound of the general formula [1f] is reacted with the compound of the general formula [5] according to the process 3 to prepare the compound of the general formula [1].
g] can be obtained.

Process 5 The compound of general formula [1e] can be obtained by reacting the compound of general formula [1d] with the compound of general formula [5] in the presence or absence of a solvent. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, for example, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane; alcohols such as methanol and ethanol. Amides such as N, N-dimethylformamide; dimethylsulfoxide; and water. These solvents may be used alone or in admixture of two or more.

The amount of the compound of the general formula [5] used may be equimolar or more with respect to the compound of the general formula [1d].
This reaction may be carried out usually at 0 to 100 ° C. for 0.1 to 24 hours.

The general formula [1] thus obtained
The compound ([1a] to [1g]) or a salt thereof can be isolated and purified by a conventional method such as extraction, crystallization, distillation and column chromatography. In addition, the general formula [1]
Or a salt thereof, for example, an alkylation reaction,
Other desired compounds of the general formula [1] or salts thereof can be obtained by appropriately combining methods known per se such as acylation reaction, cyclization reaction, substitution reaction, hydrolysis reaction, oxidation reaction, reduction reaction and deprotection. Can be guided to.
Furthermore, in the above-described method for producing the compound of the present invention, in the compounds of the general formulas [1] and [3] to [5] or salts thereof, isomers such as optically active isomers, geometric isomers and tautomers. , Etc., those isomers can also be used.

The compound of the general formula [1] or a salt thereof thus obtained has two diastereomers when it has two asymmetric carbon atoms in its molecule. One of the diastereomers can be easily isolated from the mixture of diastereomers by a conventional method such as crystallization or column chromatography. From this intermediate, for example,
General formula [2]

[Chemical 15] An optically active form of the compound represented by "wherein R ⁷ , R ⁸ and R ⁹ have the same meanings as described above" can be obtained.

[0027]

EXAMPLES Next, the invention of the present application will be described with reference to examples and reference examples, but the invention of the present application is not limited thereto. The mixing ratios of the mixed solvent and the eluent are all volume ratios. Further, silica gel 60 (manufactured by Merck) was used as a carrier in column chromatography. In the table, A following the example number indicates a mixture of diastereomers; and the following abbreviations have the following meanings. Ac: acetyl Bn: benzyl Et: ethyl MOM: methoxymethyl Ph: phenyl THP: tetrahydropyran-2-yl

Example 1 To a suspension of 200 ml of tetrahydrofuran containing 9.16 g of zinc, 2.66 g of titanium tetrachloride was added dropwise at 5-10 ° C. After stirring for 30 minutes at 25-30 ° C, 2-acetoxy-1- (2.4
20.0 g of -difluorophenyl) ethanone are added, and then 26.5 g of ethyl bromodifluoroacetate are added dropwise at the same temperature. After reacting at 20-25 ° C for 4 hours, the reaction mixture was introduced into a mixed solvent of 400 ml of ethyl acetate and 400 ml of water,
Adjust to pH 0.5 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography [eluent; n-hexane: ethyl acetate = 9: 1].
If purified with, oily ethyl-4-acetoxy-3-
(2,4-difluorophenyl) -2,2-difluoro-
20.6 g of 3-hydroxybutyrate are obtained. IR (neat) cm ^-1 : 3445,2990,1760,1615,1505

Examples 2 to 5 In the same manner as in Example 1, the compounds in Table 1 are obtained. In addition, R ¹ and R ² in Table 1 are respectively expressed by the following equations.

[Chemical 16] The substituents of the compound represented by

[0030]

[Table 1]

Example 6 2-acetoxy-1- (2,4-difluorophenyl)
5.0 g of ethanone and 2.3 g of zinc were suspended in a mixed solvent of 35 ml of methylene chloride and 10 ml of dimethoxyethane, and the mixture was refluxed.
5 ml of a methylene chloride solution containing 6.0 g of ethyl bromofluoroacetate is added dropwise over 30 minutes. Then, after refluxing for 20 minutes, the reaction mixture was mixed with 100 ml of ethyl acetate and 5 ml of water.
It is introduced into 0 ml of a mixed solvent and adjusted to pH 1.0 with 6N hydrochloric acid.
The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: n-hexane: ethyl acetate = 10: 1] to give oily ethyl-4-acetoxy-3- (2,4-difluorophenyl) -2- 5.6 g of fluoro-3-hydroxybutyrate (mixture of diastereomers) are obtained. IR (neat) cm ^-1 : 3450,1750,1620,1500,1240

Example 7 To a 25 ml suspension of tetrahydrofuran containing 2.29 g of zinc, 443 mg of titanium tetrachloride was added dropwise at 5-10 ° C. After stirring for 30 minutes at 25-30 ° C, 2-acetoxy-1- (2.4
Add 5.00 g of -difluorophenyl) ethanone, then add 7.11 g of ethyl bromodifluoroacetate dropwise at the same temperature. After reacting for 4 hours at 20-25 ° C, the reaction mixture was introduced into a mixed solvent of 50 ml of ethyl acetate and 50 ml of water,
Adjust to pH 0.5 with N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was dissolved in 58 ml of ethanol, and then 58 ml of 2N sodium hydroxide aqueous solution was added to 10-
Add at 15 ℃ and incubate at the same temperature for 30 minutes. Then, the reaction mixture is introduced into a mixed solvent of 100 ml of ethyl acetate and 100 ml of water. After separating the aqueous layer and adding 100 ml of ethyl acetate,
Adjust to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3- (2,4-difluorophenyl) -2,2-difluoro-3, A mixture of 4-dihydroxybutyric acid and 3- (2,4-difluorophenyl) -2,2-difluoro-3-hydroxy-4-butanolide is obtained. Then, after dissolving this mixture in 50 ml of toluene, using a Dean-Stark water separator, water was distilled off under reflux, and the solvent was distilled off under reduced pressure.
4.50 g of 3- (2,4-difluorophenyl) -2,2-difluoro-3-hydroxy-4-butanolide having a melting point of 68.5-70.5 ° C. are obtained. IR (KBr) cm ^-1 : 3445,1810,1620,1510,1405

Example 8 The same as Example 7, showing a melting point of 103.0 to 105.5 ° C.
(2-Chloro-4-fluorophenyl) -2,2-difluoro-3-hydroxy-4-butanolide is obtained. IR (KBr) cm ^-1 : 3455,1810,1605,1500,1400

Example 9 168 g of 3- (2,4-difluorophenyl) -2,2-difluoro-3-hydroxy-4-butanolide was dissolved in ethanol.
It is dissolved in 500 ml, 89.6 g of R-(+)-1-phenylethylamine is added at 5 to 10 ° C., and the mixture is reacted at the same temperature for 30 minutes. Then, the solvent was distilled off under reduced pressure, ethyl acetate (500 ml) and water (300 ml) were added to the obtained residue, and the pH was adjusted to 1 with 6N hydrochloric acid.
Adjust to 0. The organic layer was separated and washed with saturated saline,
It is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of n-hexane and diisopropyl ether to give a melting point of 79.5-8
(R, R) -3- (2,4-difluorophenyl) -2,2-difluoro-3,4-dihydroxy-N showing 1.0 ° C
-(1-phenylethyl) butanamide and (S,
202 g of a mixture of R) -3- (2,4-difluorophenyl) -2,2-difluoro-3,4-dihydroxy-N- (1-phenylethyl) butanamide are obtained. IR (KBr) cm ^-1 : 3365,3215,1695,1665,1500

Examples 10 to 14 In the same manner as in Example 9, the compounds in Table 2 are obtained. In addition, R ¹ and R ³ in Table 2 are respectively represented by the following equations.

[Chemical 17] The substituents of the compound represented by

[0036]

[Table 2]

Example 15 5.2 g of ethyl-4-acetoxy-3- (2,4-difluorophenyl) -2-fluoro-3-hydroxybutyrate (mixture of diastereomers) in 100 ml of 4.2N ammonia-ethanol solution. Dissolve and react at 20-25 ° C for 15 hours. Then, the solvent is distilled off under reduced pressure, and the obtained residue is introduced into a mixed solvent of 100 ml of ethyl acetate and 30 ml of water. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; n-hexane: ethyl acetate = 1: 1],
3- (2,4-difluorophenyl) -2-fluoro-
1.6 g of 3,4-dihydroxybutanamide (one of the diastereomers) are obtained. IR (KBr) cm ^-1 : 3445,3300,1685,1505,1070 Further eluting with ethyl acetate, the other diastereomer, 3- (2,4-difluorophenyl)-
0.8 g of 2-fluoro-3,4-dihydrobutanamide is obtained. IR (KBr) cm ^-1 : 3445,3335,1715,1500,1125

Example 16 200 g of the mixture of diastereomers obtained in Example 9 is dissolved in 1000 ml of methylene chloride and 46.9 g of pyridine at 5-10 ° C.
Add. Then, 108 g of trichloroacetyl chloride is added dropwise at the same temperature, and the mixture is reacted at 10 to 15 ° C for 30 minutes. Water (500 ml) is added to the reaction mixture, the organic layer is separated, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was washed with a mixed solvent of n-hexane and diisopropyl ether and then recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to give a melting point of 147.5 to 149.0 ° C (R, R) -3-
(2,4-difluorophenyl) -2,2-difluoro-
3-hydroxy-N- (1-phenylethyl) -4-trichloroacetoxybutanamide or (S, R) -3
-(2,4-Difluorophenyl) -2,2-difluoro-3-hydroxy-N- (1-phenylethyl) -4-
114g of either trichloroacetoxybutanamide
To get IR (KBr) cm ^-1 : 3240,1765,1685,1505,1240 Optical rotation [α] _D = + 64.4 ° (C = 1.05, EtOH, 25 ° C)

Example 17 41.40 g of N-benzyl-3- (2-chloro-4-fluorophenyl) -2,2-difluoro-3,4-dihydroxybutanamide was dissolved in 207 ml of methylene chloride to give 5-10
At 52 ° C. 10.52 g of pyridine are added. Then S-at the same temperature
42 ml of a methylene chloride solution of S-(+)-2-phenylpropionyl chloride prepared from 19.2 g of (+)-2-phenylpropionic acid and 16.88 g of oxalyl chloride is added dropwise, and the mixture is reacted at 15 to 25 ° C for 1 hour. Water to the reaction mixture 25
Add 0 ml and adjust to pH 1.5 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of n-hexane and diisopropyl ether to give N-benzyl-mol.
3- (2-chloro-4-fluorophenyl) -2,2-
10.48 g of difluoro-3-hydroxy-4-[(S) -2-phenylpropionyloxy] butanamide (one of the diastereomers) are obtained. IR (KBr) cm ^-1 : 3385,1735,1680,1595,1155 Optical rotation [α] _D = + 29.6 ° (C = 1.00, CHCl ₃ , 25 ° C)

Example 18 113 g of one of the diastereomers obtained in Example 16
Add to a mixed solvent of 800 ml of ethanol and 73 ml of concentrated sulfuric acid,
Reflux for 3 hours. Then, 500 ml of water was added, ethanol was distilled off under reduced pressure, and 500 m of ethyl acetate was added to the obtained residue.
add l The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was dissolved in 250 ml of ethanol and added to 4.7
Add 140 ml of N-ammonia-ethanol solution at 15-20 ° C.
Incubate for 30 minutes. The solvent is distilled off under reduced pressure, 230 ml of ethyl acetate and 230 ml of water are added to the obtained residue, and the pH is adjusted to 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to give (+)-3- (2,4-difluorophenyl) -2,2-difluoro-3, having a melting point of 142.5-144.5 ° C. 44.2 g of 4-dihydroxybutanamide are obtained. IR (KBr) cm ^-1 : 3485,3420,1705,1600,1505 Optical rotation [α] _D = + 18.8 ° (C = 1.03, EtOH, 25 ° C)

Reference Example 1 (+)-3- (2,4-difluorophenyl) -2,2-
43.0 g of difluoro-3,4-dihydroxybutanamide are dissolved in 215 ml of methylene chloride and 27.7 g of methanesulfonyl chloride are added at 5-10 ° C. Then, 24.4 g of triethylamine is added dropwise at the same temperature and the reaction is carried out at 10 to 15 ° C for 1 hour. Water (215 ml) is added to the reaction mixture, and the pH is adjusted to 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
The obtained residue is dissolved in 550 ml of N, N-dimethylformamide, 21.3 g of 1,2,4-triazole and 66.7 g of potassium carbonate are added, and the mixture is reacted at 50-60 ° C for 7 hours. Then, the insoluble matter is filtered off, and the solvent is distilled off under reduced pressure.
To the obtained residue, 430 ml of ethyl acetate and 215 ml of water are added, and the pH is adjusted to 1.5 with 6N hydrochloric acid. The organic layer is separated and the aqueous layer is extracted 5 times with 120 ml of ethyl acetate. The organic layers are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography [eluent; chloroform: methanol = 25: 1] to give amorphous (−)-3-
(2,4-difluorophenyl) -2,2-difluoro-
28.1 g of 3-hydroxy-4- (1H-1,2,4-triazol-1-yl) butanamide are obtained. The compound was then dissolved in 240 ml of ethyl acetate and 2.86 at 20-25 ° C.
37 ml of N hydrochloric acid-ethyl acetate solution is added dropwise. After stirring at the same temperature for 2 hours and then filtering, (-)-3- (2,4-difluorophenyl) -2, which shows a melting point of 189 to 202 ° C (decomposition).
2-difluoro-3-hydroxy-4- (1H-1,2,
4-triazol-1-yl) butanamide hydrochloride 26.2
get g. IR (KBr) cm ^-1 : 3480,1715,1610,1505,1430 Optical rotation [α] _D = -67.1 ℃ (C = 1.00, EtOH, 25 ℃)

Claims (1)

[Claims] 1. A general formula: "Wherein R ¹ is an optionally substituted aryl or a heterocyclic group bonded through a carbon atom in the ring;
² is a hydrogen atom or an optionally substituted alkyl,
An acyl or heterocyclic group, R ³ is a hydroxyl group, an alkoxy group or a group of the formula (In the formula, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group.), Or R ² and R ³ together form a bond. X is a halogen atom; Y is a hydrogen atom, a halogen atom or an optionally substituted alkyl group. Or a salt thereof.