JPH11236357A - Halohydrin derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new halohydrin derivative useful as an intermediate for medicines such as retinol, by reaction of a specific halohydrin derivative with a specific carboxylic acid in the presence of an acid catalyst. SOLUTION: This derivative is a halohydrin derivative of formula I (R is H or a hydroxyl-protective group; X is a halogen) or formula II, e.g. 8-bromo-7- hydroxy-3,7-dimethyl-2,5-octadienyl acetate, 8-bromo-5-hydroxy-3,7-dimethyl-2,6- octadienyl acetate. This halohydrin derivative of formula I or formula II is obtained by halohydrinating reaction of a triene derivative of formula III; for this reaction, a reducing agent such as a perhalogenic acid or halogenic acid, a halogenating agent and water are preferably used, and the reaction temperature is pref. 0-40 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a halohydrin derivative represented by the following general formula (1) or (2), which is 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 Hitherto, halohydrin derivatives represented by the general formula (1) or (2) have not been known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a halohydrin derivative represented by the general formula (1) or (2) and a method for producing the same.

[0004]

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 provides a compound represented by the general formula (1): (Wherein, R 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 general formula (2): (Wherein, R and X have the same meanings as described above) and a process for producing the same.

[0005]

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

The halohydrin derivative (1) or (2) of the present invention has the general formula (3) (Wherein, R represents the same meaning as described above), which is obtained by subjecting the triene derivative to a halohydrination reaction.

In the compounds represented by formulas (1), (2) and (3), R represents a hydrogen atom or a hydroxyl-protecting group. Examples of the hydroxyl-protecting group include, for example, acyl groups such as formyl, acetyl, pivaloyl, benzoyl and p-nitrobenzoyl, silyl groups such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, tetrahydropyranyl, methoxymethyl , Methoxyethoxymethyl, alkoxymethyl groups such as 1-ethoxyethyl, benzyl group, p-methoxybenzyl group, t-butyl group, trityl group, methyl group, 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl group And the like.

In the compound represented by formula (1) or (2), examples of the halogen atom for X include a chlorine atom, a bromine atom and an iodine atom.

The triene derivative represented by the general formula (3), which is a starting compound, can be easily produced from geraniol, and may be any of the geometric isomers of E or Z.
Further, a mixture thereof may be used.

The perhalic acid or halogen acid or a metal salt thereof used in the halohydrination reaction in the present invention includes, specifically, sodium periodate, potassium periodate, periodate, bromate, sodium bromate and the like. ,
Potassium bromate and the like can be mentioned. The amount thereof is usually 0.5 to the triene derivative represented by the general formula (3).
The range is about 5 to about 5 mole times, preferably about 0.8 to 1.2 mole times. As the reducing agent, bisulfite,
Sulfites, thiosulfates or aqueous solutions thereof are preferred, and bisulfites are preferred. Specific examples include sodium bisulfite, sodium sulfite, sodium thiosulfate, and the like. The amount used is generally 1 to 1 with respect to the triene derivative represented by the general formula (3).
The range is about 0 mole times, preferably about 1.6 to 2.4 mole times.

The halogenating agent used in the halohydrination reaction in the present invention includes, for example, chlorine, hypochlorous acid, t-butyl hypochlorite, ethyl hypochlorite, sodium hypochlorite, hypochlorous acid Potassium, calcium hypochlorite,
Chlorinating agents such as N-chlorourea, N-chlorosuccinimide, chloramine T, chloramine B, bromine, hypobromite, t-butyl hypobromite, sodium hypobromite, potassium hypobromite, N- Bromination agents such as bromoacetic acid amide and N-bromosuccinimide; and iodination agents such as iodine and N-iodosuccinimide. The amount of use is not particularly limited, but the purpose can be sufficiently achieved when the amount is about 1 to 2 times the molar amount of the triene derivative represented by the general formula (3).

In the reaction of the present invention, an organic solvent is generally used, and it is preferable to use a mixed solvent with water. As the organic solvent, nitriles such as acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethyl ether, t-butyl alcohol,
alcohols such as t-amyl alcohol and 2-propanol; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; ketones such as acetone, methyl isopropyl ketone and methyl isobutyl ketone; dimethyl sulfoxide; acetonitrile; Aprotic polar solvents such as N-dimethylformamide and N, N-dimethylacetamide. The amount used is not particularly limited.

The reaction temperature of the present invention is generally in the range of -78 ° C to the boiling point of the solvent, preferably in the range of 0 to 40 ° 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, washed with water and the like, and the organic layer is concentrated to obtain a halohydrin derivative represented by the general formula (1) or (2). be able to. Further, if necessary, it can be purified by silica gel chromatography.

[0015]

The general formula (1) obtained by the present invention,
The halohydrin derivative represented by (2) is useful as an intermediate such as a pharmaceutical, for example, an intermediate of retinol.

[0016]

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 (5.16 g, 26.6
mmol) and ion-exchanged water (0.48 g, 26.6)
mmol) of dimethyl sulfoxide (40 mL)
The mixed solution was cooled to 10 ° C.
Imide (4.78 g, 26.6 mmol) was added. Anti
The reaction vessel was taken out of the refrigerant and stirred at room temperature for 40 minutes. Moth
After confirming the disappearance of the raw materials by chromatography,
On-exchange water (40 mL) was added. Ethyl acetate
(40 mL), and the mixture was separated.
Extracted with ethyl (35 mL × 2). Combined organic layers
5% aqueous sodium bicarbonate (20 mL), saturated sodium chloride
Wash sequentially with 20 mL of water, and dry with anhydrous sodium sulfate.
And dried. A yellow oil obtained by concentration under reduced pressure
(9.12 g) on silica gel column chromatography
(Developing solvent hexane: ethyl acetate = 5: 1, then 3:
1), and acetic acid 8-bromo-7-hydroxy-3,
7-dimethyl-2,5-octadienyl (1,2 addition
Isomer) (4.84 g, yield 62.5%) and acetic acid 8-
Bromo-5-hydroxy-3,7-dimethyl-2,6-
Octadienyl (1,4 adduct) (1.28 g, yield 1)
6.5%). [1,2 adduct] Rf: 0.30 (adsorbent silica gel, developing solvent
Sun: ethyl acetate = 3: 1)¹ 1 H NMR (270 MHz, CDCl_Three): Δ 1.4
3 (s, 3H), 1.70 (s, 3H), 2.06
(S, 3H), 2.34 (s, 1H), 2.78 (d,
J = 6.9 Hz, 2H), 3.47 (s, 2H), 4.
59 (d, J = 6.6 Hz, 2H), 5.38 (t, J
= 6.6 Hz, 1H), 5.57 (d, J = 15.5H)
z, 1H), 5.74 (dt, J = 15.5 Hz, 6.
9Hz, 1H) ¹³ C NMR (67.8 MHz, CDCl_Three): Δ 1
6.43, 20.94, 26.15, 41.98, 4
5.00, 61.17, 71.27, 119.43, 1
27.67, 135.38, 140.29, 170.9
8 [1,4 adduct] Rf: 0.14 (adsorbent silica gel, developing solvent
Sun: ethyl acetate = 3: 1)¹ 1 H NMR (270 MHz, CDCl_Three): Δ 1.7
6 (s, 3H), 1.82 (s, 3H), 2.06
(S, 3H), 2.20 (dd, J = 13.5 Hz,
5.6 Hz, 1 H), 2.30 (dd, J = 13.5 H)
z, 7.9 Hz, 1H), 2.67 (br, 1H),
3.95 (s, 2H), 4.49 (ddd, J = 8.6)
Hz, 7.9 Hz, 5.6 Hz, 1H), 4.59
(D, J = 6.9 Hz, 2H), 5.42 (t, J =
6.9 Hz, 1 H), 5.58 (d, J = 8.6 Hz,
1H)¹³ C NMR (67.8 MHz, CDCl_Three): Δ 1
4.94, 16.62, 20.76, 40.07, 4
6.81, 60.90, 66.09, 121.92, 1
32.65, 133.72, 137.48, 170.8
9

Example 2 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-2,6-octadienyl (870 mg, 2.57 mmol) was obtained in 100% yield.

Example 3 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 4 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 5 3,7-Dimethyl acetic acid
2,5,7-octatrienyl (387 mg, 1.99
mmol) in 5 ml of acetonitrile, and a solution of bromine (400 mg, 2.50 mmol) in 5 ml of water and 1 ml of acetonitrile was added dropwise at room temperature. After stirring at room temperature for 8 hours, the disappearance of the raw materials was confirmed by TLC, and water was added, followed by extraction with ether. The organic layer was washed with saline and dried over anhydrous magnesium sulfate,
By distilling off the solvent, about 8-bromo-7-hydroxy-3,7-dimethyl-2,5-octadienyl acetate and about 8-bromo-5-hydroxy-3,7-dimethyl-2,6-octadienyl acetate were obtained. 7: 3 mixture (569
mg, 1.95 mmol) in 98% yield. These could be separated by column chromatography.

Reference Example 1 Geranyl acetate (40 g, 2
0.4 mmol) in hexane (100 mL)
Trichloroisocyanuric acid (17.1 g, 70.0 mm
ol), and the mixture is kept warm at -10 ° C to 0 ° C for 6 hours. After the completion of the reaction, excess trichloroisocyanuric acid and by-produced isocyanuric acid were removed from the system by filtration. The filtrate was washed sequentially with 5% sodium hydrogen carbonate and ion-exchanged water, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain a crude product. This was subjected to silica gel column chromatography to obtain the desired 6-chloro-3,7-dimethyl-2,7-octadienyl acetate as a pale yellow oil in a yield of 85.5%.

REFERENCE EXAMPLE 2 Fine powdered sodium hydroxide (6.8 g, 0.17 m
ol), triphenylphosphine (2.2 g, 8.5 m)
mol), tetra-n-butylammonium chloride (1.4)
g, 5.1 mmol), allyl palladium chloride dimer (0.62 g, 1.7 mmol) and tetrahydrofuran (100 mL). There, with stirring, acetic acid 6-
A solution of chloro-3,7-dimethyl-2,7-octadienyl (40 g, 0.17 mmol) in tetrahydrofuran (150 mL) is added dropwise at room temperature over 1 hour. After stirring at room temperature for 3 days, the disappearance of the starting materials was confirmed by TLC, and the reaction was terminated. The reaction mixture is poured into water and extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a crude product. This was subjected to silica gel column chromatography to obtain 3,7-dimethyl-2,5,7-octatrienyl acetate as a pale yellow oily substance at a yield of 65%.

 ──────────────────────────────────────────────────の Continuing on the front page (72) Inventor Shinzo Seko 2-10-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Industries, Ltd.

Claims (6)

[Claims] 1. The general formula (1) (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group, and X represents a halogen atom), or a halohydrin derivative represented by the following general formula (2): (Wherein, R and X have the same meanings as described above). 2. The general formula (3) Wherein R represents the same meaning as described above, wherein a halohydrin derivative represented by the general formula (1) and a halohydrin derivative represented by the general formula (2) are obtained by subjecting a triene derivative represented by the following formula to a halohydrination reaction. Manufacturing method. 3. The process according to claim 2, wherein a perhalic acid or a halogen acid or a metal salt thereof and a reducing agent are used in the halohydrination reaction. 4. The method according to claim 2, wherein a halogenating agent and water are used in the halohydrination reaction. 5. The method according to claim 3, wherein the reducing agent is a bisulfite, a sulfite, a thiosulfate or an aqueous solution thereof. 6. The method according to claim 2, wherein the reaction temperature is 0 ° C. to 40 ° C.