JP2000198770A - Production and intermediate of retinol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as an intermediate for producing retinol used in such fields as medicaments, feed additives and food additives. SOLUTION: This new compound is a compound of formula I [Ar is a (substituted) aryl; X is a halogen], e.g. 1-hydroxy-5-chloro-3,7-dimethyl-9-(2,6,6- trimethylcyclohexen-1-yl)-9-(4-methylphenylsulfonyl)-nona-2,6-diene. The compound of formula I is obtained by reaction of a compound of formula II [e.g. 1,5- dihydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)-9-(4-methylp henylsulfonyl)- nona-2,6-diene] with a group IV transition metal halide such as titanium tetrachloride pref. in the presence of an ether compound such as dimethoxyethane pref. at 20-60 deg.C normally for 1-24 h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing retinol useful in the fields of medicines, feed additives, and food additives, and intermediates thereof.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a retinol derivative, a method of enriching a side chain using a C13 carbonyl compound (β-ionone) as a key intermediate (for example, Pure & Appl.
Chem. Vol. 66, p. 1509-1518 (1994)) or a method of coupling a C10 sulfonyl compound (cyclogeranyl sulfone) with a C10 aldehyde derivative as a key intermediate (for example, Japanese Patent Publication No. 5-61265) Etc.) have been reported. However, in the former method, the key intermediate β-ionone requires a multi-step process for its synthesis and is a very expensive raw material. In the latter method, the aldehyde derivative of C10 An oxidizing agent that is difficult to obtain is required for synthesis (Japanese Patent Publication No. 7-17555)
However, these methods are not necessarily industrially superior. Under these circumstances, the present inventors have obtained that a diol compound represented by the following general formula (2) can be obtained by a coupling reaction between a C10 sulfonyl compound and a C10 allyl halide derivative which can be derived using inexpensive raw materials. (EP-9
00785 A2). However, in the next halogenation step, in order to halogenate only the secondary hydroxyl group of a compound in which primary and secondary hydroxyl groups coexist in the molecule such as the diol compound (2), generally, the primary hydroxyl group is generally used. Protection was required and required a multi-step process.

[0003]

SUMMARY OF THE INVENTION
The present inventors have prepared a diol compound (2) that can be easily synthesized from linalool or geraniol, which are relatively inexpensive raw materials, without using the above-mentioned β-ionone of C13 or an aldehyde derivative of C10, in a short process. We studied diligently to develop a method to guide the students. As a result, by using a specific halogenating agent, the 2-hydroxyl compound of the diol compound (2) can be protected without protecting the coexisting primary hydroxyl group.
It has been found that only a high-grade hydroxyl group can be selectively halogenated, leading to the present invention.

[0004]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein, Ar represents an aryl group which may have a substituent, and X represents a halogen atom), a method for producing the same, and a method for producing retinol. .

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The halogenated sulfone derivative represented by the general formula (1) is represented by the general formula (2) (In the formula, Ar represents an aryl group which may have a substituent.) A diol compound represented by the formula (1) is reacted with a halide of a Group 4 transition metal. In this reaction, protection of the primary hydroxyl group is not necessary, and only the secondary hydroxyl group can be selectively halogenated.

The halogenated sulfone derivative (1) of the present invention
And the substituent Ar in the diol compound (2) represents an aryl group which may have a substituent, and examples of the aryl group include a phenyl group and a naphthyl group, and the substituent includes C1 to C5. Alkyl group, C1 to C5
And an alkoxy group, a halogen atom and a nitro group. Specifically, 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
-Iodophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl and the like. The substituent X in the halogenated sulfone derivative (1) represents a halogen atom, and specifically includes a chlorine atom, a bromine atom and an iodine atom.

The halides of the Group 4 transition metals used in the above reaction include titanium tetrachloride, titanium tetrabromide, titanium tetraiodide, dichlorotitanium diisopropoxide, chlorotitanium triisopropoxide, and zirconium tetrachloride. , Zirconium tetrabromide, hafnium tetrachloride and the like. Among them, titanium chloride is preferable,
Particularly, titanium tetrachloride is preferable.

[0008] The amount of the halide of the Group 4 transition metal is usually about 0.1 to 5 times, preferably about 0.2 to 3 times the mole of the diol compound (2).

In the above reaction, an organic solvent is usually used, and such solvents include diethyl ether, tetrahydrofuran, dimethoxyethane, anisole, 1,4-
Ether solvents such as dioxane, halogen solvents such as chloroform, dichloromethane, 1,2-dichloroethane, monochlorobenzene, o-dichlorobenzene, n-
Examples thereof include hydrocarbon solvents such as hexane, cyclohexane, n-pentane, n-heptane, toluene, and xylene. Preferably, ether solvents are used, and these may be mixed solvents. When using a solvent other than an ether-based solvent, it is preferable to allow an ether compound to coexist.
Such ether compounds include diethyl ether, tetrahydrofuran, dimethoxyethane, anisole,
4-Dioxane and the like are used, and the amount of use is usually about 1 to 10 moles per mole of the diol compound (2).

[0010] The reaction temperature is usually in the range of -20 ° C to the boiling point of the solvent used, preferably in the range of about 20 ° C to 60 ° C. The reaction time varies depending on the type of metal halide used in the reaction and the reaction temperature, but is usually
It ranges from 1 hour to 24 hours. After the reaction, a usual post-treatment operation can be performed to obtain a halogenated sulfone derivative represented by the general formula (1). The raw material diol compound (2) may be a geometric isomer of E or Z, a mixture thereof, a mixture of diastereomers, or a racemic or optically active isomer.

The diol compound (2), which is a raw material compound of the present invention, can be synthesized from linalool or geraniol, which can be obtained relatively inexpensively, by the route shown in the following scheme 1. The synthesis method of cyclogeranyl sulfone (3) is described in Chem. Lett., 479 (1975), and the synthesis method of diol compound (2) is described in EP-900785 A2. Scheme 1

Further, the halogenated sulfone derivative (1) of the present invention can be easily derived into retinol by reacting with a base.

As the base used in the above reaction, an alkali metal compound or an alkaline earth metal compound is used, such as an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alkoxide, an alkaline earth metal alkoxide and the like. And specifically, sodium hydroxide, potassium hydroxide, magnesium hydroxide,
Sodium methoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide,
Examples include calcium methoxide and magnesium methoxide. The amount of the base to be used is usually about 1 to 40 moles per mole of the halogenated sulfone derivative (1).

In the above reaction, an organic solvent is usually used. Examples of such a solvent include hydrocarbon solvents such as n-hexane, cyclohexane, n-pentane, n-heptane, toluene, xylene, diethyl ether, tetrahydrofuran, and the like. Ether solvents such as dimethoxyethane and anisole; alcohol solvents such as methanol, ethanol and isopropanol; N, N-dimethylformamide;
Examples include aprotic polar solvents such as dimethyl sulfoxide, N, N-dimethylacetamide, and hexamethylphosphoric triamide. These can be used as a mixed solvent.

[0015] The reaction temperature is usually in the range of 0 ° C to the boiling point of the solvent used, and preferably in the range of about 15 ° C to 50 ° C. The reaction time varies depending on the type of base and solvent used in the reaction and the reaction temperature, but is usually in the range of about 1 to 24 hours. After the reaction, retinol can be obtained by performing ordinary post-treatment operations. If necessary, it can be purified by crystallization, various types of chromatography and the like.

The obtained retinol can be introduced with a protecting group for a hydroxyl group according to a conventional method. For example, retinyl acetate can be obtained by acetylation.

[0017]

As described above, according to the method of the present invention, the secondary hydroxyl group can be directly selectively halogenated without protecting the primary hydroxyl group of the diol compound (2). The sulfone derivative (1) can be easily converted to retinol by base treatment. In addition, since the diol compound (2) as a raw material compound can be easily derived from relatively inexpensive raw materials such as linalool and geraniol without passing through a β-ionone of C13 or an aldehyde derivative of C10, the present invention relates to industrial production of retinol. Useful as a manufacturing method.

[0018]

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

Example 1 1,5-dihydroxy-3,
7-dimethyl-9- (2,6,6-trimethylcyclo
Xen-1-yl) -9- (4-methylphenylsulfo
Nyl) -nona-2,6-diene (hereinafter, compound (a))
46 g (1.0 mmol) was dissolved in 10 ml of dimethoxyethane (DME).
And 0.095 g (0.50 mmol) of titanium tetrachloride was added dropwise at room temperature
Thereafter, the mixture was stirred at the same temperature for 12 hours and further at 50 ° C. for 4 hours. Anti
After the reaction, quench with 1% aqueous sodium hydroxide
Extracted with ethyl. The obtained organic layer is dried over anhydrous magnesium sulfate.
After drying with urea, the solvent is distilled off to give compound (b).
(1,3-allyl isomer of chlorine bonding site,
Mixture of eight cis / trans isomers and diastereomers
Was obtained as a light brown oil in a yield of 95%. inside that
The main product is 1-hydroxy-5-chloro-3,7-
Dimethyl-9- (2,6,6-trimethylcyclohexe
1-yl) -9- (4-methylphenylsulfoni
) -Nona-2,6-diene (hereinafter, compound (c))
Was. Compound (c)¹ H-NMR δ (CDCl_Three) 0.82-2.64 (27H, m), 3.03-3.17 (1H, m), 3.91 (1H, m), 4.1
3 (2H, m), 4.55-4.78 (1H, m), 5.39 (1H, d, J = 8Hz), 5.53 (1
H, m), 7.10-7.41 (2H, m), 7.65-7.85 (2H, m) .HR-MS found 461.2236 (M-OH)⁺  calcd for C27H38ClO2S 461.2203

Examples 2 to 6 The reaction was carried out in accordance with Example 1 except for the reaction conditions shown in Table 1, and the following results were obtained.

[Table 1] Reaction temperature: 50 ° C THF: tetrahydrofuran DM
E: dimethoxyethane 1) 1 M toluene solution 2) DME 5 mol times the amount of compound (a) was added.

Example 7 676 mg (1.41 mmol) of the crude product (b) obtained according to Example 1 was dissolved in 11 ml of cyclohexane, and 988 mg (14.1 mmol) of potassium methoxide was added.
The mixture was stirred at 40 ° C for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layer was washed again with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product (d) as a red oil. The obtained crude product was confirmed to be retinol by NMR analysis. The obtained crude product (d) was dissolved in 8 ml of toluene, 112 mg (1.41 mmol) of pyridine and 17 mg (0.141 mmol) of dimethylaminopyridine were added, and 158 mg (1.55 mmol) of acetic anhydride was slowly added at 5 ° C. And stirred at room temperature for 18 hours. The reaction mixture was quenched with 5% hydrochloric acid and extracted with toluene. The obtained organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product as a yellow oil. When the obtained crude product was analyzed by liquid chromatography, the total yield (from compound (a)) of retinyl acetate (e) was 74%.
Met.

Example 8 676 mg (1.41 mmol) of the crude product (b) obtained according to Example 1 and 45 mg of methanol
(1.41 mmol) was dissolved in 12 ml of toluene, and potassium hydroxide 7
9 mg (14.1 mmol) and 23 mg (0.071 mmol) of tetra n-butylammonium bromide were added, and the mixture was stirred at 40 ° C for 12 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layer was washed again with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product (d) as a red oil. The obtained crude product was confirmed to be retinol by NMR analysis. The obtained crude product (d) is dissolved in 8 ml of toluene,
After adding 112 mg (1.41 mmol) of pyridine and 17 mg (0.141 mmol) of dimethylaminopyridine, 158 mg of acetic anhydride (1.55 m
mol) was slowly added at 5 ° C., and the mixture was stirred at room temperature for 18 hours.
The reaction mixture was quenched with 5% hydrochloric acid and extracted with toluene. The obtained organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product as a yellow oil. When the obtained crude product was analyzed by liquid chromatography, the total yield (from compound (a)) of retinyl acetate (e) was 56%.

Reference Example 1 40 g of geranyl acetate (0.204 mol
l) was dissolved in 100 ml of n-hexane, and 17.1 g (0.071 mol) of trichloroisocyanuric acid was gradually added at −10 ° C. to 0 ° C.
It was kept warm for 6 hours. After the reaction, excess trichloroisocyanuric acid and by-produced isocyanuric acid were removed from the system by filtration. The filtrate was washed successively with aqueous sodium hydrogen carbonate and water, the obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product. The resulting crude product is
Purified by silica gel column chromatography, 6-chloro-3,7-dimethyl-2,7-octadiene-1-
Acetate (hereinafter, compound (f)) was obtained as a pale yellow oil in a yield of 86%. ¹ H-NMR δ (CDCl ₃ ) 1.71 (3H, s), 1.81 (3H, s), 1.90-2.22 (4H, m), 2.05 (3H, s)
s), 4.34 (1H, t, J = 7Hz), 4.59 (2H, d, J = 7Hz), 4.90 (1H,
s), 5.01 (1H, s), 5.37 (1H, t, J = 7Hz).

Reference Example 2 Fine powder of sodium hydroxide 6.
8g (0.17mol), triphenylphosphine 2.2g (8.5mmo
l), 1.4 g of tetra n-butylammonium chloride
(5.1 mmol), allyl palladium chloride dimer 0.6
2 g (1.7 mmol) were suspended in 100 ml of THF, and stirred therein, while stirring, 150 ml of a solution of 40 g (0.17 mol) of compound (f) in THF.
Was added dropwise at room temperature over 1 hour. After stirring at room temperature for 3 days, the mixture was quenched with water and extracted with ether. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain a crude product. The obtained crude product was purified by silica gel chromatography,
3,7-dimethyl-2,5,7-octatriene-1-
Acetate (hereinafter, compound (g)) was obtained at a yield of 65%. ¹ H-NMR δ (CDCl ₃ ) 1.70 (3H, s), 1.85 (3H, s), 2.08 (3H, s), 2.81 (2H, d, J = 7H
z), 4.58 (2H, d, J = 7Hz), 4.90 (2H, s), 5.37 (1H, t, J = 7H
z), 5.61 (1H, td, J = 16, 7Hz), 6.16 (1H, d, J = 16Hz).

Reference Example 3 20.1 g of compound (g) (0.1 mol
l) was dissolved in 100 ml of acetic acid, and 18.3 g (0.1 mol) of N-bromosuccinimide was slowly added at room temperature. 1 at room temperature
The reaction mass became homogeneous in 0 to 15 minutes, stirred for 2 hours, quenched with water, and extracted with toluene. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 8-bromo-3,7-dimethyl-2,6-octadiene-1,5-diacetate (hereinafter, compound (h) ),
(EZ isomer mixture)) and 8-bromo-3,7-dimethyl-2,5-octadiene-1,7-diacetate (hereinafter, compound (i), (EZ isomer mixture)). A mixture of 1 was obtained in 95% yield. The resulting mixture was separated and purified by silica gel chromatography to obtain Compound (h) and Compound (i) as pale yellow oils, respectively. Compound (h) ¹ H-NMR δ (CDCl ₃ ) 1.77 (3H, s), 1.82 (3H, s), 1.98 (3H, s), 2.02 (3H, s), 2.
19 (2H, m), 3.89 (2H, s), 4.55 (2H, d, J = 7Hz), 5.37 (1H, t, J
= 7Hz), 5.48-5.62 (2H, m). Compound (i) ¹ H-NMR δ (CDCl ₃ ) 1.65 (3H, s), 1.68 (3H, s), 2.05 (3H, s), 2.06 (3H , s), 2.
78 (2H, d, J = 6Hz), 3.67 (1H, d, J = 11Hz), 3.82 (1H, d, J = 11H
z), 4.57 (2H, d, J = 7Hz), 5.35 (1H, t, J = 7Hz), 5.61-5.77
(2H, m).

Reference Example 4 Compound (g) 387 mg (1.99 mmol)
l) was dissolved in 5 ml of acetonitrile, and 400 mg of bromine (2.50 m
(mol) in 5 ml of water and 1 ml of acetonitrile was added dropwise at room temperature and stirred for 8 hours. After the reaction, the reaction was quenched with water and extracted with ether. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 8-bromo-5-hydroxy-3,7-dimethyl-2,6-octadien-1-acete-. To (hereafter,
Compound (j), (EZ isomer mixture)) and 8-bromo-
About 3: 7 mixture of 7-hydroxy-3,7-dimethyl-2,5-octadiene-1-acetate (hereinafter, compound (k) and (EZ isomer mixture)) was obtained at a yield of 98%. Was.
The resulting mixture was separated and purified by silica gel chromatography to obtain Compound (j) and Compound (k) as pale yellow oils, respectively. Compound (j) ¹ H-NMR δ (CDCl ₃ ) 1.76 (3H, s), 1.82 (3H, s), 2.06 (3H, s), 2.20-2.30 (1H,
m), 2.67 (1H, br), 3.95 (2H, s), 4.41-4.53 (1H, m), 4.59
(2H, d, J = 7Hz), 5.42 (1H, t, J = 7Hz), 5.58 (1H, d, J = 9Hz) Compound (k) ¹ H-NMR δ (CDCl ₃ ) 1.43 (3H, s) , 1.70 (3H, s), 2.06 (3H, s), 2.34 (1H, br),
2.78 (2H, d, J = 7Hz), 3.47 (2H, s), 4.59 (2H, J = 7Hz, d), 5.
38 (1H, t, J = 7Hz), 5.57 (1H, d, J = 7Hz), 5.71-5.80 (1H, m)

Reference Example 5 Compound (j) and Compound (k)
A mixture of 41 mg (0.14 mmol) of 3: 7 was dissolved in 0.5 ml of toluene, and while stirring, a mixed solution of 1 mg (0.007 mmol) of concentrated sulfuric acid and 15 mg (0.14 mmol) of acetic anhydride was added at 0 ° C, and the mixture was added at 25 ° C. Stirred for hours. After the reaction, the reaction was quenched with water and extracted with n-hexane. The obtained organic layer was washed successively with 5% aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off to give compound (h), (a mixture of EZ isomers).
As a pale yellow oil in 93% yield.

Reference Example 6 0.30 g (1.0 mmo) of β-cyclogeranyl-p-tolylsulfone (hereinafter referred to as compound (l))
l) and 0.168 g (1.5 mmol) of potassium t-butoxide in N,
Dissolve in 8 ml of N-dimethylformamide (DMF) and add -6
Cooled to 0 ° C. After stirring at the same temperature for 30 minutes, 3 ml of a DMF solution of 0.174 g (0.5 mmol) of compound (h) was added dropwise,
The mixture was stirred at the same temperature for 2 hours. After the reaction, the reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give 1,5-.
Acetoxy-3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -9- (4-methylphenylsulfonyl) -2,6-nonadiene
A three-component mixture of the compound (m), (a mixture of EZ isomers and diastereomers)) and a compound in which one acetoxy group was hydrolyzed (a mixture of EZ isomers and diastereomers) was obtained as a yellow oil. The obtained crude product was analyzed by liquid chromatography, and the combined yield of the three components was 96%. Compound (m) ¹ H-NMR δ (CDCl ₃ ) 0.73-1.04 (6H, m), 1.38-1.70 (6H, m), 1.39 (3H, s), 1.70
(3H, s), 2.00 (3H, s), 2.01-2.31 (2H, m), 2.01 (3H, s),
2.03 (3H, s), 2.44 (3H, s), 2.66-2.95 (2H, m), 3.82-3.86
(1H, m), 4.53 (2H, d, J = 7Hz), 5.08-5.21 (1H, m), 5.34 (1
H, br), 5.56 (1H, br), 7.33 (2H, d, J = 8Hz), 7.76 (2H, d, J =
8Hz). ¹³ C-NMR δ (CDCl ₃ ) 15.1, 16.0, 16.1, 16.6, 18.8, 20.8, 20.9, 21.4, 2
8.2, 29.0, 35.5, 40.5, 40.8, 44.6, 60.8, 65.3, 65.
5, 65.7, 68.3, 68.5, 68.8, 121.9, 127.1, 128.3, 12
9.4, 130.5, 130.6, 136.2, 137.1, 137.6, 137.7, 13
8.4, 144.0, 169.8, 170.0, 170.7.

Reference Example 7 Compound (m) 0.20 g (0.37 mmol)
l) was dissolved in 5 ml of methanol, and while stirring, 0.11 g (0.74 mmol) of a 27% aqueous sodium hydroxide solution was added thereto, followed by stirring at 25 ° C for 4 hours. After the reaction, the reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give 1, as a pale yellow oil.
5-dihydroxy-3,7-dimethyl-9- (2,6,
6-trimethylcyclohexen-1-yl) -9- (4
-Methylphenylsulfonyl) -2,6-nonadiene (compound (a), (a mixture of EZ isomers and diastereomers)) was obtained in a yield of 95%. ¹ H-NMR δ (CDCl ₃ ) 0.83-1.03 (6H, m), 1.33-1.61 (2H, m), 1.38 (3H, s), 1.43
(3H, s), 1.70 (3H, s), 1.90-2.18 (4H, m), 2.44 (3H, s),
2.52-2.62 (1H, m), 2.80-2.95 (1H, br), 2.95-3.13 (1H,
m), 3.77-3.84 (1H, m), 3.90 (1H, t, J = 7Hz), 4.03 (2H, d, J
= 7Hz), 5.33-5.36 (1H, m), 5.48-5.52 (1H, t, J = 7Hz), 7.3
0 (2H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz).

The structural formulas of the compounds of Examples and Reference Examples are described below. Here, the Ts group indicates a p-tolylsulfonyl group.

Claims (11)

[Claims] 1. The general formula (1) (In the formula, Ar represents an aryl group which may have a substituent, and X represents a halogen atom.) 2. The general formula (2) Wherein Ar represents an aryl group which may have a substituent. The diol compound represented by the formula (1) is reacted with a halide of a Group 4 transition metal. A method for producing the halogenated sulfone derivative shown below. 3. A method for producing retinol, comprising reacting a halogenated sulfone derivative represented by the general formula (1) with a base. 4. A diol compound represented by the general formula (2) is reacted with a halide of a transition metal of Group 4 to obtain a halogenated sulfone derivative represented by the general formula (1).
Then, the method for producing retinol comprises reacting the obtained halogenated sulfone derivative with a base. 5. The method according to claim 2, wherein the Group 4 transition metal is titanium. 6. The process according to claim 2, wherein the halide of the Group 4 transition metal is a chloride of titanium. 7. The method according to claim 6, wherein the titanium chloride is titanium tetrachloride, dichlorotitanium diisopropoxide or chlorotitanium triisopropoxide. 8. The method according to claim 2, wherein an ether compound is present in the halogenation reaction of reacting with a halide of a Group 4 transition metal. 9. The method according to claim 8, wherein the ether compound is dimethoxyethane or tetrahydrofuran. 10. The method according to claim 3, wherein the base is an alkali metal compound or an alkaline earth metal compound. 11. The method according to claim 10, wherein the alkali metal compound is an alkali metal hydroxide or an alkali metal alkoxide.