JP2000086645A - Epoxy derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an intermediate for pharmaceuticals such as an intermediate for retinol. SOLUTION: This compound is represented by formula I (R1 is H or a protective group for hydroxy group) such as 8-iodo-7-hydroxy-3,7-dimethyl-2,5-octadienyl acetate. The compound is obtained by following steps; a trien derivative represented by formula II is subjected to a halohydrination reaction using an alkali metal salt of periodic acid and an aqueous hydrogensulfite solution in a solvent such as tetrahydrofuran and at a reaction temperature between -78 deg.C and the boiling point of the solvent so as to obtain a halohydrin derivative represented by formula III (X is a halogene), and then the resultant product is reacted with a base such as sodium hydroxide in a solvent such as tetrahydrofuran at a reaction temperature between -78 deg.C and the boiling point of the solvent and usually for 10 min to 48 h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an epoxy derivative useful as a pharmaceutical intermediate, for example, an intermediate of retinol, and a method for producing the same.

[0002]

2. Description of the Related Art An epoxy derivative represented by the following general formula (1) has not been known. An object of the present invention is to provide an advantageous method for producing an epoxy derivative represented by the general formula (1).

[0003]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have reached the present invention. That is, the present invention relates to general formula (1) (Wherein R ¹ represents a hydrogen atom or a hydroxyl-protecting group) and a method for producing the same.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

[0005] The epoxy derivative represented by the general formula (1) of the present invention can be prepared by the following method: (Wherein R ¹ has the same meaning as described above), which is subjected to a halohydrination reaction to give a general formula (3) (Wherein, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and X represents a halogen atom.) A halohydrin derivative represented by the following formula is obtained, followed by reaction with a base.

The triene derivative represented by the general formula (2), which is a raw material compound used in the present invention, can be produced from geraniol, and may be any of the geometric isomers of E or Z, or a mixture thereof. Furthermore, it may be racemic or optically active.

In the triene derivative represented by the general formula (2) used in the present invention, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group. Examples of the hydroxyl-protecting group include formyl, acetyl, ethoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl,
Bromoacetyl, dibromoacetyl, tribromoacetyl, propionyl, 2-chloropropionyl, 3-chloropropionyl, butyryl, 2-chlorobutyryl, 3-
Chlorobutyryl, 4-chlorobutyryl, 2-methylbutyryl, 2-ethylbutyryl, valeryl, 2-methylvaleryl, 4-methylvaleryl, hexanoyl, isobutyryl, isovaleryl, pivaloyl, benzoyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o Acyl groups such as -hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxybenzoyl, o-acetoxybenzoyl, o-methoxybenzoyl, m-methoxybenzoyl, p-methoxybenzoyl, p-nitrobenzoyl, trimethylsilyl, triethylsilyl, t- Butyldimethylsilyl, silyl groups such as t-butyldiphenylsilyl, tetrahydropyranyl,
Alkoxymethyl groups such as methoxymethyl, methoxyethoxymethyl and 1-ethoxyethyl, benzyl groups, p-
Methoxybenzyl group, t-butyl group, trityl group, methyl group, 2,2,2-trichloroethoxycarbonyl group,
An allyloxycarbonyl group and the like.

In the halohydrin derivative represented by the general formula (3), examples of the halogen atom for X include a chlorine atom, a bromine atom and an iodine atom. General formula (3)
Can be obtained by subjecting the triene derivative of the general formula (2) to a halohydrination reaction. As the halohydrination reaction, for example, N
-A method using a halosuccinimide and water, a method using a halogen and water, a method using a perhalogenated acid or a halogenated acid or a salt thereof and a bisulfite aqueous solution. As a method using N-halosuccinimide and water, N-bromosuccinimide in a mixed solvent of water and tetrahydrofuran is used at 0 ° C. for 3 hours and then at room temperature for 12 hours.
Time reaction (Bull. Chem. Soc. Jpn., (1985),
58 (5), 1607-1608), as a method using halogen and water, a method of reacting at room temperature for 2 hours using an aqueous bromine solution with water as a solvent (Synth. Commun., (1989), 19 (17), 2977) -
2985), a method using a perhalogenated acid or a halogenated acid or a salt thereof and an aqueous solution of bisulfite includes a mixture of periodic acid dihydrate or sodium periodate or sodium bromate and sulfurous acid in a mixed solvent of water and acetonitrile. A method of reacting at 25 ° C. for 2 hours using an aqueous sodium hydrogen solution (J. Org. Chem., (1994), 59 (19), 5553)
-5555). In these methods, the general formula (3)
1,2-adduct represented by the general formula (4) (Wherein, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and X represents a halogen atom). In many cases, the mixture is a mixture of 1,4-adducts. In the method using the agent, the 1,2-adduct of the general formula (3) can be selectively obtained. In the synthesis of the epoxy derivative (1), the 1,2-adduct may be separated from the mixture of the 1,2-adduct and the 1,4-adduct, or the mixture may be used as it is. Examples of the alkali metal periodate used in the above reaction include sodium periodate and potassium periodate. Other perhalogenated acids or halogenated acids or salts thereof include periodic acid, iodic acid, sodium iodate, potassium iodate, bromate, sodium bromate, potassium bromate, perchloric acid, perchloric acid Examples include sodium, potassium perchlorate, chloric acid, sodium chlorate, potassium chlorate and the like. The amount of use is usually about 0.5 to 5 times, preferably about 0.8 to 1.2 times the molar amount of the triene derivative represented by the general formula (2). Examples of the reducing agent include sodium bisulfite, sodium sulfite, sodium thiosulfate and the like. The amount thereof is usually about 1 to 10 times, preferably 1.6 to 2.0 times the amount of the triene derivative represented by the general formula (2).
The range is about 4 mole times. In the above reaction, examples of the method using N-halosuccinimide and water include N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide and the like as N-halosuccinimide. The amount of use is usually about 0.5 to 5 times, preferably about 0.8 to 1.2 times the molar amount of the triene derivative represented by the general formula (2). In the above reaction, examples of the method using halogen and water include iodine, bromine, and chlorine as the halogen. The amount used is based on the triene derivative represented by the general formula (2).
Usually about 0.5 to 5 mole times, preferably 0.8 to 1.2 times.
The range is about mole times. In the above reaction, a solvent may be used together with water.Examples of such a solvent include hydrocarbon solvents such as n-hexane, cyclohexane, n-pentane, toluene, and xylene, diethyl ether, tetrahydrofuran, dimethoxyethane, and anisole. Ether solvents, halogen solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, o-dichlorobenzene, alcohol solvents such as methanol, ethanol, isopropanol, or acetonitrile;
An aprotic polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, N, N-dimethylacetamide, hexamethylphosphoric triamide and the like can be mentioned. Preferably, a hydrophilic solvent is used, such as tetrahydrofuran and acetonitrile. These may be used in a mixture of two or more. The reaction temperature is usually from -78 ° C to the boiling point of the solvent, preferably from about 0 to 30 ° C. The reaction time varies depending on the reaction temperature, but is usually in the range of 10 minutes to 48 hours.

The epoxy derivative represented by the general formula (1) can be produced by reacting a halohydrin derivative of the general formula (3) with a base. As the base used in the above reaction, an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal bicarbonate, an alkali metal or alkaline earth metal hydride, Alkoxides of alkali metals and the like, specifically, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride , Calcium hydride, sodium methoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide and the like. As a solid material, a fine powder material is preferably used. Further, pyridine, dimethylaminopyridine, 3-ethyl-4-methylpyridine, 5-
Ethyl-2-methylpyridine, imidazole, 2-methylimidazole, 3-methylimidazole, 2-ethyl-4-methylimidazole, DBN, DBU, trimethylamine, triethylamine, dimethylethylamine,
Methyl diethylamine, diisopropylethylamine,
t-butyldimethylamine and the like. The use amount thereof is usually about 1 to 20 times, preferably about 1 to 5 times the mole of the halohydrin derivative represented by the general formula (3).

[0010] In the above reaction, a solvent may be used. Examples of such a solvent include n-hexane, cyclohexane and n-hexane.
Hydrocarbon solvents such as pentane, toluene and xylene; ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane and anisole; alcohol solvents such as methanol, ethanol and isopropanol; or acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide , N, N-dimethylacetamide,
An aprotic polar solvent such as hexamethylphosphoric triamide is exemplified. Among them, a hydrophilic solvent is preferably used. More preferably tetrahydrofuran,
Acetonitrile is used. These may be used in a mixture of two or more.

The reaction temperature is usually in the range of -78 ° C to the boiling point of the solvent, preferably about 0 to 30 ° C. The reaction time varies depending on the reaction temperature, but is usually in the range of 10 minutes to 48 hours. After completion of the reaction, water is added to the obtained reaction mixture, extracted, and then the organic layer is concentrated to obtain the epoxy derivative represented by the general formula (1).

[0012]

Industrial Applicability The present invention can provide an epoxy derivative represented by the general formula (1), which is useful as an intermediate of a drug or the like, for example, an intermediate of retinol, and an advantageous production method thereof.

[0013]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

(Example 1) 3,7-dimethyl acetic acid
2,5,7-octatrienyl (500 mg, 2.57
mmol) was dissolved in 10 ml of water and 5 ml of acetonitrile, and sodium periodate (550 mg, 2.58 mmol) was added.
l) was added at room temperature, and then 5.4 ml of a 1 M aqueous NaHSO3 solution was added dropwise at room temperature over 1 hour. 5 at room temperature
After stirring for an hour, it was confirmed by TLC that the raw materials had disappeared, water was added, and the mixture was extracted with ether. The organic layer is Na
_The extract was washed with an aqueous solution of ₂ SO _3, dried over anhydrous magnesium sulfate, and evaporated to remove acetic acid 8-iodo-7.
-Hydroxy-3,7-dimethyl-2,5-octadienyl (870 mg, 2.57 mmol) was obtained in 100% yield.

Example 2 3,7-Dimethyl acetic acid
2,5,7-octatrienyl (500 mg, 2.57
mmol) was dissolved in 6 ml of water and 10 ml of acetonitrile, and periodic acid dihydrate (710 mg, 3.09 mm
ol) at room temperature, followed by the dropwise addition of 5.4 ml of a 1 M aqueous NaHSO 3 solution at 0 ° C. over 1 hour. After stirring at room temperature for 2 hours, it was confirmed by TLC that the raw materials had disappeared, and water was added, followed by extraction with ether. The organic layer is Na
_The extract was washed with an aqueous solution of ₂ SO _3, dried over anhydrous magnesium sulfate, and evaporated to remove acetic acid 8-iodo-7.
A mixture of about 3: 2 of -hydroxy-3,7-dimethyl-2,5-octadienyl and 8-iodo-5-hydroxy-3,7-dimethyl-2,5-octadienyl acetate (800 mg, 2.36 mmol) was prepared. Obtained in 92% yield.

Example 3 3,7-Dimethyl acetic acid
2,5,7-octatrienyl (1.0 g, 5.15 m
mol) was dissolved in 20 ml of water and 10 ml of acetonitrile, and sodium bromate (0.93 g, 6.18 mmol) was dissolved.
At room temperature followed by 1M aqueous NaHSO3 1
2.4 ml was added dropwise over 1 hour at room temperature. After stirring at room temperature for 5 hours, TLC confirmed that the raw materials had disappeared.
Water was poured in and extracted with ether. The organic layer is Na2S
The mixture was washed with an aqueous solution of O3, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 8-bromo-7-acetic acid.
About 7: 3 mixture of hydroxy-3,7-dimethyl-2,5-octadienyl and 8-bromo-5-hydroxy-3,7-dimethyl-2,6-octadienyl acetate (1.4 g, 4.89 mmol) Was obtained in a yield of 95%. These could be separated by column chromatography.

Example 4 3,7-Dimethyl acetic acid
2,5,7-octatrienyl (5.16 g, 26.6
mmol) and water (0.48 g, 26.6 mmol)
Was cooled to 10 ° C., and N-bromosuccinimide (4.78 g, 26.6 mmol) was added thereto. The reaction vessel was taken out of the refrigerant and stirred at room temperature for 40 minutes. After confirming the disappearance of the raw materials by gas chromatography, water was added. Ethyl acetate was added thereto, followed by liquid separation, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were sequentially washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give 8-bromo-7-hydroxy-3,7-dimethyl acetate.
An approximately 4: 1 mixture (6.11 g, 21.0 mmol) of 2,5-octadienyl and 8-bromo-5-hydroxy-3,7-dimethyl-2,6-octadienyl acetate was added to 7
Obtained in 9% yield. These could be separated by column chromatography.

Example 5 8-Bromo-7-hydroxy-3,7-dimethyl-2,5-octadienyl acetate (950 mg, 3.26 mmol) was dissolved in 10 ml of THF, and powdered NaOH (154 mg, 3.85 mmol) was dissolved.
l) and stirred at 20 ° C for 1 hour.
Add aOH (163 mg, 4.08 mmol) and add 20 ° C
For 3 hours. After adding water and extracting three times with ether, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and use acetic acid as light yellow oil
7,8-Epoxy-3,7-dimethyl-2,5-octadienyl (670 mg, 3.19 mmol) was obtained in 98% yield. ¹ H NMR δ (270 MHz, CDCl ₃ ) 1.47
(S, 3H), 1.71 (s, 3H), 2.07 (s,
3H), 2.73-2.83 (m, 4H), 4.63.
(D, J = 6.9 Hz, 2H), 5.30-5.41
(M, 2H), 5.72~5.83 ( m, 1H) 13 C-NMR δ (67.8MHz, CDCl 3) 16.
3, 19.4, 20.8, 42.0,
55.1, 55.5, 61.0, 119.
3, 130.0, 133.2, 140.1
, 170.8 FD-MS 210 [M] ⁺

Example 6 8-Iodo-7-hydroxy-3,7-dimethyl-2,5-octadienyl acetate (500 mg, 1.48 mm)
ol) was dissolved in 10 ml of THF and powdered NaOH (70
mg, 1.78 mmol) and stirred at 20 ° C. for 2 hours. After adding water and extracting three times with ether, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
It was concentrated under reduced pressure, and as a pale yellow oil, 7,8-epoxy-3,
7-dimethyl-2,5-octadienyl (311 mg,
1.48 mmol) in 100% yield.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Shinzo Seko 2-10-1 Tsukahara, Takatsuki-shi, Osaka Sumitomo Kagaku Kogyo Co., Ltd. F-term (reference) 4C048 AA01 BB07 BB12 CC01 UU01 UU03 XX02 XX04

Claims (4)

[Claims] 1. The general formula (1) (Wherein, R ¹ represents a hydrogen atom or a hydroxyl-protecting group). 2. The epoxy derivative according to claim 1, wherein R ¹ is an acetyl group. 3. The general formula (2) (Wherein R ¹ has the same meaning as described above), which is subjected to a halohydrination reaction to give a general formula (3) (Wherein, R ¹ represents a protecting group for a hydrogen atom or a hydroxyl group, and X represents a halogen atom). After obtaining a halohydrin derivative represented by the following formula, it is reacted with a base. Method for producing epoxy derivatives. 4. The production method according to claim 3, wherein an alkali metal periodate and an aqueous solution of bisulfite are used for the halohydrination reaction.