JP2003176263A - Hydroxysulfone derivative and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a hydroxysulfone derivative and provide a method for producing the same. <P>SOLUTION: The hydroxysulfone derivative is expressed by general formula (1) (wherein Ar expresses an aryl which may be substituted; R<SP>1</SP>expresses H or an OH-protecting group; a wave line expresses either one of E/Z geometrical isomers or a mixture thereof). The method for producing the hydroxysulfone derivative is to react a sulfone expressed by general formula (2) with an aldehyde expressed by general formula (3) in the presence of a base. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hydroxysulfone derivative useful as an intermediate for medicines, feed additives and food additives, for example, an intermediate for retinol derivatives and a method for producing the same.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION Conventionally, the sulfone derivative of the present invention has not been known. In addition, the inventors of the present invention have proposed a novel intermediate which is an important intermediate of vitamin A through a coupling reaction of sulfones represented by the general formula (2) and allyl halides derived from C10 alcohols (geraniol etc.). A sulfone derivative (Japanese Patent Laid-Open No. 11-222479) has been found, but as a result of further diligent studies to develop a separate production method, the present invention was completed.

[0003]

That is, the present invention is based on the general formula (1) (In the formula, Ar represents an aryl group which may have a substituent, R ¹ represents a hydrogen atom or a hydroxyl-protecting group, and the wavy line represents one of E / Z geometric isomers or a mixture thereof. A hydroxysulfone derivative represented by the general formula (2) (In the formula, Ar has the same meaning as described above.) And a sulfone represented by the general formula (3). (In the formula, R represents a hydroxyl-protecting group, and the wavy line has the same meaning as described above.) A method for producing a hydroxysulfone derivative represented by the general formula (1), which comprises reacting with an aldehyde represented by the formula (1). Is provided.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. R ¹ in the general formula (1) represents a hydrogen atom or a hydroxyl protecting group, and R in the general formula (3) represents a hydroxyl protecting group. Examples of the protective group for the hydroxyl group include formyl, acetyl, ethoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl, propionyl, 2-chloro. Propionyl,
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-hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxybenzoyl, o
-Acetoxybenzoyl, o-methoxybenzoyl,
m-methoxybenzoyl, p-methoxybenzoyl, p
-Acyl group such as nitrobenzoyl, trimethylsilyl,
A silyl group such as triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl, 1
An alkoxymethyl group such as ethoxyethyl, a benzyl group, a p-methoxybenzyl group, a t-butyl group, a trityl group, a 2,2,2-trichloroethoxycarbonyl group, an allyloxycarbonyl group and the like, and usually an acetyl group. Is preferably used.

Ar in the general formulas (1) and (2) represents an aryl group which may have a substituent, and examples of the aryl group include a phenyl group and a naphthyl group. Examples thereof include a C5 straight chain or branched alkyl group, a C1 to C5 straight chain or branched alkoxy group, a halogen atom, and a nitro group. Substituent A
Specific examples of r include phenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl,
m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodo Phenyl, o-fluorophenyl, m-
Examples thereof include fluorophenyl, p-fluorophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl and the like.

Sulfones (2), which are the raw material compounds of the present invention, are prepared by the method described in Chem. Lett. 479 (1975), and aldehydes (3) are prepared by J. Org. Chem., 44 ,
It can be produced by the method described in 9451 (1979).

Examples of the base used in the production method of the present invention include alkyllithium, alkali metal alkoxide, Grignard reagent, and the like. Specifically, for example, n-butyllithium, s-butyllithium, t-butyl. Examples thereof include lithium, sodium methoxide, potassium methoxide, potassium t-butoxide, sodium t-butoxide, ethyl magnesium bromide, ethyl magnesium chloride, methyl magnesium bromide, methyl magnesium chloride, isopropyl magnesium bromide and isopropyl magnesium chloride. The amount of such a base used is usually about 0.5 to 3 mol times the sulfone (2).

The above reaction is usually carried out in an organic solvent, and the solvent used is acetonitrile, N, N-
Aprotic polar solvents such as dimethylformamide, hexamethylphosphoric triamide, sulfolane, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, diethyl ether, tetrahydrofuran, 1,4-dioxane, Examples thereof include ether solvents such as dimethoxyethane and anisole, and hydrocarbon solvents such as n-hexane, cyclohexane, n-pentane, benzene, toluene and xylene. These may be used alone or as a mixed solvent of two or more kinds.

The reaction temperature can usually be arbitrarily selected within the range from -78 ° C to the boiling point of the solvent, but is preferably -60.
It is in the range of about 60 ° C. The reaction time varies depending on the type of base used and the reaction temperature, but is usually in the range of about 0.5 hours to 10 hours. After the reaction, the hydroxysulfone derivative (1) can be produced by a usual post-treatment such as washing with water, extraction, crystallization and various chromatographies.

Hydroxysulfone derivative of the present invention (1)
(When R ¹ is a hydrogen atom, a protecting group is introduced) can be introduced into the vitamin A intermediate according to the scheme below. That is, hydroxysulfone derivative (1)
Reductive elimination reaction (Tetrahedron Letters 4833 (197
It can be converted to compound (4) by 3)). Compound (4)
Can be further induced to vitamin A and the like by the method described in Pure & Appl. Chem., 66 , 1509 (1994) and the like.

[0011]

EFFECTS OF THE INVENTION According to the production method of the present invention, a coupling reaction of an aldehyde (3) with a sulfone (2), which can be easily produced from isoprene in 3 steps, and has a low boiling point and is relatively easy to purify. The hydroxysulfone derivative (1), which can be a useful intermediate of the retinol derivative, can be produced by subjecting the product to

[0012]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

(Example 1) 0.29 g (1.0 mm) of sulfone (I)
ol) is dissolved in 2 ml of tetrahydrofuran (THF), -60 ℃
Cooled to. Then 1.6M n-BuLi in hexane 0.63m
l (1.0 mmol) was added dropwise and the mixture was kept at the same temperature for 1 hour. Then, a solution of 0.15 g (1.0 mmol) of aldehyde (II) dissolved in 2 ml of THF was added dropwise at the same temperature and stirred for 3 hours. After the reaction
It was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product as a pale yellow solid. The resulting crude product was quantified by high performance liquid chromatography to find that hydroxysulfone (II
The yield of I) was 51.5%. Hydroxysulfone (III) ¹ H-NMR δ (CDCl ₃ ) 0.68 (3H, s), 0.87 (3H, s), 1.31
-1.58 (4H, m), 1.59 (3H, s), 1.63 (3H, s), 2.03 (3H, s),
2.11-2.15 (2H, m), 2.44 (3H, m), 3.86 (1H, d, J = 4Hz),
3.99 (1H, d, J = 7Hz), 4.55 (2H, d, J = 6Hz), 5.09 (1H, d
d, J = 4Hz, 8Hz), 5.53 (1H, t, J = 6Hz), 7.33 (2H, d, J = 8
Hz), 7.89 (2H, d, J = 8Hz)

(Example 2) 0.29 g (1 mmo of sulfone (I)
l) in 2 ml of THF and then 1M EtMgBr in THF.
1 ml (1 mmol) was charged and kept at 50 ° C. for 3 hours. afterwards,-
After cooling to 30 ° C, 0.15 g (1.0 mmol) of aldehyde (II) was added.
A solution dissolved in 2 ml of THF was added dropwise at the same temperature and stirred for 3 hours. After the reaction, the mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product as a pale yellow solid. When the obtained crude product was quantified by high performance liquid chromatography, the yield of hydroxysulfone (III) was 20.9%.

The structural formulas of the compounds of the examples are shown below. However, Ts represents a p-tolylsulfonyl group.

Claims (5)

[Claims] 1. A general formula (1) (In the formula, Ar represents an aryl group which may have a substituent, R ¹ represents a hydrogen atom or a hydroxyl-protecting group, and the wavy line represents one of E / Z geometric isomers or a mixture thereof. A hydroxysulfone derivative represented by the formula (1). 2. General formula (2) (In the formula, Ar has the same meaning as described above.) And a sulfone represented by the general formula (3). (In the formula, R represents a hydroxyl-protecting group, and the wavy line has the same meaning as described above.) The aldehyde represented by the general formula (1) is reacted in the presence of a base. (Wherein Ar, R ¹ and the wavy line have the same meanings as described above). 3. The method according to claim 2, wherein the base is an alkyllithium, an alkali metal alkoxide, or a Grignard reagent. 4. The production method according to claim 3, wherein the alkali metal alkoxide is sodium t-butoxide or potassium t-butoxide. 5. The method according to claim 2, wherein R is acetyl.
The manufacturing method described in.