JPH0211584A - Chroman derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> to R<3> represent H or methyl; R represents H or protecting group of OH). EXAMPLE:2,5,7,8-Tetramethyl-2-(4'-chloro-4'-methylpentyl)-6-chromanol. USE:An intermediate for synthesis of vitamin Es. PREPARATION:Hydroquinones expressed by formula II (example; 2,3,5- trimethylhydroquinone) are condensed with a 1,7-dichloro-3,5-dimethyl-oct-2-ene expressed by formula III preferably in an organic solvent such as ethyl acetate, dichloromethane or dioxane normally using a catalyst (example; Lewis acid or protonic acid) preferably at 25-50 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel intermediate useful in producing tocopherols and a method for producing the same.

[Prior art and problems to be solved by the invention] Vitamin E (tocopherols) has received attention as it has been reported to have various physiological effects, including in-vivo antioxidant effects.
It is an extremely important substance, not only itself but also various derivatives that are widely used in medicines, foods, feeds, etc.

These tocopherols are synthesized by condensation and ring closure of trimethylhydroquinone and phytol or isophytol using a Lewis acid such as zinc chloride or boron trifluoride etherate as a catalyst (Helv, Chim,
Acta, 21.309 (1938); J, Che
w, Soc,, 1938.1382; U, S
, P. 2,723,278 (1955) and Japanese Patent Publication No. 45-23146 (1970)].

The biggest drawback of this method is that the raw materials phytol and isophytol are expensive.

This is the key to the industrial production of tocopherols, and is the reason for the soaring market prices of tocopherols.

Therefore, recently, methods for producing tocopherols that do not require phytol or isophytol have been studied, but as a starting material 2.5,7°8-tetramethyl-
A method using 2-(4'-methyl-3''-pentenyl)-6-chromanol is considered to be a promising method.As a method for producing this starting material, (1) trimethylhydroquinone and geraniol or geranyl halide are mixed with Lewis A method of condensation in the presence of boron trifluoride, a type of acid (Japanese Patent Publication No. 11064/1989), (2) Hydroquinones and geranyl chloride or neryl chloride are condensed in the presence of a Lewis acid such as zinc chloride or aluminum chloride. A method of condensing hydroquinones with myrcene, myrcene halide, geraniol, linalool, etc. in the presence of zinc chloride (Japanese Patent Laid-Open No. 60-75745) has been proposed. ing.

However, as shown below, in all of these methods, a large amount of tricyclic compound (■") is produced due to side reactions, so 2.5.7.8-tetramethyl-2- (4'-methyl-3°-pentenyl)-6
-Chromanol ((■゛).

This is not preferred as a method for obtaining R′=R”=R”=CHz) in a good yield.

That is, hydroquinones represented by formula (IV) and formula (V
) The condensation of C1° terpenes having a double bond at the 6-position shown by formula (Vl) passes through the 2-allyl form represented by formula (Vl) as an intermediate, and the subsequent electron transfer (■ and The routes are considered to proceed simultaneously) by the objective (■
°) and a by-product tricyclic compound (■゛) are thought to be produced.

(■'') (■'') (In the formula, R1, Hl, R:l have the above meanings,
indicates a halogen atom such as chlorine or bromine) In this way, in the conventional method, due to the reaction mechanism, the by-product of the tricyclic compound (■゛) cannot be avoided, and the compound (■゛) and the compound (■'' ) had similar properties, it was extremely difficult to isolate and purify the target compound (■''). Therefore, there has been a long-standing demand for the establishment of an efficient method for synthesizing a compound (■'') to replace it.

[Means to solve the problem]

In view of the above-mentioned circumstances, the present inventors have spent many years intensively studying the industrial production method of the intermediate (■゛), which is an important raw material for producing vitamin E.
The inventors have discovered that the following method can achieve the intended purpose, and have completed the present invention.

That is, hydroquinones represented by the general formula (wherein R1, R1, R2 mean the same or different hydrogen atoms or methyl groups, and R means a hydrogen atom or a hydroxyl group protecting group) can be converted to the following chemical structure: 1,7-dichloro-3,7-dimethyl-octo-2- represented by the formula
The following general formula (in the formula R1, Hl,
1t2 and R have the above-mentioned meanings) The first step for producing a chroman derivative (1)
Then, the chroman derivative (1) is subjected to a dehydrochlorination reaction with an alkali to obtain the following general formula (■),
(■) It is a precursor of compound (■), which is a conductor and an important intermediate in the synthesis of vitamin E.

A mixture of positional isomers of two types of olefin compounds represented by I R' (in the formula R', R'', R3, R have the above-mentioned meanings), followed by an acid-catalyzed prototropic reaction The above general formula (■) is obtained by rearranging the double bond and transferring it to a thermally energetically more stable olefin.
A compound represented by (third step).

According to the above method, the compound represented by the general formula (■) can be obtained in high yield, and it is an extremely advantageous method industrially.

The target compound of the present invention has the following general formula (I) used as a starting material in the 1st and 2nd steps in this series of excellent methods.
A novel or romantic derivative represented by the above general formula In, R means a hydrogen atom or a protecting group for a hydroxyl group, and the protecting group for a hydroxyl group may be any group as long as the protecting group can be removed by hydrolysis or reductive method. Typical commonly used groups include, for example, alkoxyalkyl groups (such as methoxymethyl and ethoxyethyl groups), trialkylsilyl groups, tetrahydropyranyl groups, and benzyl groups.

R1, R2, R2 mean the same or different hydrogen or methyl groups, but α, which has the highest activity as vitamin E,
- When producing tocopherol, R1, R2, R3
Both of these are methyl groups.

Next, a series of the above reactions using the compound of the present invention will be explained in detail.

(First step) In the present invention, hydroquinones represented by general formula (II) and 1,7-dichloro-3,7-dimethyl-oct-2-ene represented by general formula (I[[) The condensation reaction is usually carried out in an organic solvent.

1,7-Dichloro-3,7-dimethyl-oct-2-ene can be easily derived from myrcene, a natural and inexpensive raw material. Either 7 bodies, 8 bodies or a mixture thereof can be used.

Reaction solvents include halogenated hydrocarbons such as dichloromethane, ethylene chloride, and carbon tetrachloride, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate and isopropyl acetate, and diethyl ether. , diisopropyl ether, dioxane and the like. However, particularly preferred are ethyl acetate, dichloromethane, and dioxane, and they can be used alone or in combination.

As a catalyst for the condensation reaction, a Lewis acid or a protonic acid can be used alone or in combination. Examples of Lewis acids include zinc chloride, aluminum chloride, boron trifluoride, titanium tetrachloride, tin tetrachloride, and the use of zinc chloride is particularly preferred. Further, examples of the protonic acid include paratoluenesulfonic acid, trifluoroacetic acid, formic acid, hydrogen chloride, and sulfuric acid, but use of hydrogen chloride is particularly preferred. Furthermore, the combined use of the Lewis acid zinc chloride and the protic acid hydrogen chloride gives particularly favorable results.

The amount of these catalysts used is 20
~90% by weight is preferred.

The reaction temperature in the condensation reaction is usually within the range of room temperature to the boiling point temperature of the solvent used, but in many cases 25
A temperature of ~50°C gives good results such as a low residual rate of raw materials and a low rate of appearance of by-products.

During the condensation reaction, the reaction under a reducing environment by adding a small amount of zinc dust is extremely advantageous in suppressing by-products.

(Second Step) The dehydrochlorination reaction of the chroman derivative represented by the general formula (1) is carried out in an organic solvent or water in the presence of an alkali.

Examples of alkalis include caustic soda, caustic potash, calcium hydroxide, sodium methylate, sodium ethylate, etc., but it is particularly preferable to use caustic soda. It is selected from 2 to 2 times the molar amount, and it is particularly preferable to use 1.5 times the molar amount, but if the dehydrochlorination reaction is carried out without isolating the chroman derivative (1), an excess amount of alkali may be used. It is necessary and gives good results.

Examples of the reaction solvent include organic solvents such as methanol, ethanol, n-propanol, benzene, toluene, and ethyl acetate, and water, but ethanol or aqueous ethanol is particularly preferred.

The reaction temperature is usually within the range of room temperature to the boiling point of the solvent used, and the reaction at the boiling point is particularly preferred.

(Third Step) The acid-catalyzed prototropic reaction of the positional isomer mixture of two types of olefin compounds represented by the general formulas (■) and (■) is carried out in an organic solvent in the presence of an acid catalyst. Examples of the acid catalyst include concentrated sulfuric acid, phosphoric acid, hydrogen chloride, boron trifluoride, zinc chloride, cuprous chloride, magnesium bromide, para-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and the like. Among these acid catalysts, para-toluenesulfonic acid, phosphoric acid, concentrated sulfuric acid and the like give good results, but para-toluenesulfonic acid is particularly preferred.

The reaction solvent is preferably benzene, toluene, etc., and the reaction temperature is preferably the boiling point temperature of the solvent in order to speed up the reaction.

The outline of the method of the present invention has been described above, and the advantages of the method of the present invention are as follows.

(1) According to the conventional method, a tricyclic compound is produced by a side reaction, and since it has similar properties to the target substance (■), it is almost impossible to separate it. However, the method of the present invention does not have these drawbacks.

(2) The third step in the present invention is a reaction in which the double bond of a positional isomer mixture of two types of olefin compounds is rearranged to form an olefin that is more stable in terms of thermal energy. By heating in the presence of the compound, the target substance can be obtained in good yield. Therefore, the method of the present invention is extremely simple and industrially valuable.

Therefore, the present invention relates to an important intermediate used in the extremely excellent method for producing important starting materials for producing vitamin E as described above, and the value of the present invention is high.

〔Example〕

Next, examples of the present invention will be listed, but it goes without saying that the present invention is not limited only to them.

In addition to the Examples of the present invention, a method for producing a compound (■) which is important as an intermediate for vitamin E synthesis using the Compound (I) of the present invention as a starting material is listed as a production example.

Furthermore, the method for producing 1,7-dichloro-3,7-dimethyloct-2-ene used as the starting material in Example 1 was referred to as Reference Example 1, and the known method for producing the above compound (■) ( Special Publication No. 11064 (1977) and No. 11064 (No. 1983)
75475), and the results are shown as Reference Examples 2 and 3, respectively.

, Sei.

2.3.5-) 30.4 g (0.2 mol) of remethylhydroquinone, 27 g of zinc chloride, in a 500 mm four-necked flask equipped with a stirrer, reflux condenser, addition funnel and thermometer.
．． 2 g (0.2 mol), 2 g of concentrated hydrochloric acid 5-1 zinc powder, 180 TL of dichloromethane, and 50 mL of dioxane, and while stirring at room temperature, 1,7-dichloro-3,
62.8 g (0.3 mol) of 7-dimethyl-oct-2-ene (mixture of 8 and 2 bodies) was gradually added dropwise. As the dropwise addition progressed, the reaction temperature rose and reached 35°C. 35
After continuing the reaction at °C for 4 hours, it was confirmed by thin layer chromatography that no raw material trimethylhydroquinone remained, and the mixture was poured into water to separate the oil-water phase. The oil phase was washed successively with water, aqueous sodium bicarbonate, and water to make it neutral, and then dehydrated with anhydrous magnesium sulfate. 80 g of n-hexane was added to 92 g of a pale brown oily residue obtained by distilling off the solvent, and the mixture was dissolved and left in a freezer overnight, and colorless needle crystals were precipitated. The acicular crystals were collected by filtration and recrystallized from a small amount of n-hexane to obtain 2,5
．． 7.8-Tetramethyl-2-(4″-chloro-4°-
methylpentyl)-6-chromanol (1) (R'=
R''=R'=methyl group.

R=H) 58.2 g (yield: 289.6%, calculated as trimethylhydroquinone) was obtained.

The analysis results for the main island are shown below.

(]) Elemental analysis results: C+JzzC10z (MW
324.93) as C (%) ■(%) Analysis value 70.41 8.96 Calculation value ? 0.23 9.01 (2) Mass spectrometry result m/e = 324 (3) NMR spectrum (CDC1,, δ) 1.2
0 (3H, s) 1.51 (6H, s) 1.4
~1.7 (6H, m) 1.82 (28, t)2.
05 (9H, s) 2.50 (2H, t) 4.
12 (IH, s) 1 per operation 2 by combination of various condensation catalysts, reaction solvents, etc.
5,7.8-tetramethyl-2-(4'-chloro-41
-Methylpentyl)-6-chromanol was synthesized according to the method of Example 1.

Table 1 summarizes the reaction conditions and yields.

Production Example 1 50011 with stirring device, reflux condenser, and gas introduction tube
17 Put 300 g of ethanol and 2.9 g (0,072 mol) of caustic soda into a three-necked flask and heat to dissolve 2.5.7.8-tetramethyl-2-(4") in this solution. -chloro-4”-methylpentyl)-
16.2 g (0.05 mol) of 6-chromanol was added and dissolved, and the reaction solution was refluxed for 5 hours with stirring under a nitrogen stream. The reaction solution was poured into water, made weakly acidic with dilute hydrochloric acid, and extracted with ether. The ether extract was washed with water, dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off to form a pale yellow viscous liquid 14.
．． 8g was obtained. This crude extract was purified by column chromatography (silica gel, n-hexane-benzene) to give a colorless viscous liquid showing monospots (Rf: 0.33) on TLC (silica gel-chloroform).14.
2g was obtained.

The main island is HPLC (column: YMCA312. Mobile phase niacetonitrile: methanol = 1: 1. Wavelength: 27
When measured at 0 nm, flow rate: 1 ml/win), the relative area ratio was 49.8% at retention times of 4.73 minutes and 4.92 minutes.
It was found that it was a mixture of almost equal amounts of two substances with very similar properties, showing 744.9%. Also, GC-MS on the main island
The results showed that it was a mixture of two substances that had different retention times and each had a parent peak m/e of 288. Furthermore, as a result of NMR spectrum measurement, 4.95 ppm (t, j=7) and 4.5
7ppm (d+j=1.5) with a relative area ratio of 1:2
A signal indicating .

From the above analysis results, the main island is 2.5.7.8-tetramethyl-2-(4”-methyl-3′-pentenyl)-6-
Chromanol and 2.5.7.8-tetramethyl-2-(
It turned out to be a mixture consisting of approximately equal amounts of 4'-methyl-4''-pentenyl)-6-chromanol.
HPLC comparison with a standard product obtained by separate synthesis of (4'-methyl-3''-pentenyl)-6-chromanol revealed that the component exhibiting a retention time of 4.92 minutes on HPLC coincided with that of Honjima.

2,5.7.8-tetramethyl-2-(4'-chloro-4'-methylpentyl)-6- by various alkalis
The dehydrochlorination reaction of chromanol was carried out according to Production Example 1. That is, 0.01 mole of 4°-chlor compound is boiled and refluxed with 0.1112 to 0.015 mole of alkali in an alcoholic solvent in a nitrogen stream, and then treated by a conventional method.
In Table 2, purified by column chromatography,
The results were displayed all at once.

Table 2 300 m with 111 milk stirrer, reflux condenser, and gas inlet pipe
Z33 flask, 2,5.7°8-tetramethyl-2-(4'-methyl-3'-pentenyl) obtained in Production Example 1
-6-chromanol and 2.5,7.8-tetramethyl-
11.5 g (0.04 mol) of a mixture of 2-(4°-methyl-4°-pentenyl)-6-chromanol, 500 mg of p-toluenesulfonic acid, and 200 mg of benzene were added, and heated with stirring under a nitrogen stream. , and refluxed for 6 hours. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and then benzene was distilled off to obtain 11.8 g of a pale yellow oily residue.

The obtained oily residue was subjected to column chromatography using silica gel and benzene-n-hexane to obtain 11.2 g (97.3%) of a colorless viscous oil.

The main island is 2,5,7.8-tetramethyl-2-(4'-methyl-3''-pentenyl)-, which was synthesized separately in Reference Example 2.
As a result of identification as 6-chromanol, both were completely identical. The analysis results for the main island are shown below.

(1) Elemental analysis results: C198Z80□ (MW 28
8.47) C (%) H (%) Analytical value 78.82 9.87 Calculated value 79.10 9.80 (2) NMR spectrum (CDCI: l, δ) 0.
91 (3H, s) 1.60 (3H, s)
1.65 (3H, s) 1.2~1.6 (4H
, n+) 1.70 (2H, t) 2.05 (9
H, s) 2.55 (2H, t) 3.85 (1
8, s) 4.90 (1) 1. t, j = 7) Next step The acid-catalyzed prototropic reaction carried out in Production Example 5 was
2,5,7,8-tetramethyl-2-(4°-methyl-3′-pentenyl)-6-chromanol and 2,5,7,8-tetramethyl-2-( 4'
-Methyl-4'-pentenyl)=6-chromanol was carried out according to Production Example 5 using another acid catalyst in place of para-toluenesulfonic acid.

Table 3 shows the results.

Table 500 Into a ff17 four-necked flask, add 2.3.5-) 30.4 g (0.2 mol) of remethylhydroquinone, 27.2 g (0.2 mol) of zinc chloride, and 2.3-1 of concentrated hydrochloric acid 5-1 zinc powder.
g, dichloromethane 180 aZ, dioxane 50m7
and while stirring at room temperature, 1,7-dichloro-3
, 7-dimethyloct-2-ene (mixture of the E form and the two forms) 62.8 g (0.3 mol) was gradually added dropwise.

At this time, the dropping rate was adjusted so that the reaction temperature did not rise above 35°C. After continuing the reaction at 30-35°C for 4 hours, the oil phase was separated by pouring into water, and the oil phase was mixed with water,
After sequentially washing with aqueous sodium bicarbonate and water, it was dehydrated with anhydrous magnesium sulfate. 92 g of a pale brown oily residue of crude 2.5,7.8-tetramethy,2-(4'-chloro-4-methylpentyl)-6-chromanol obtained by distilling off the solvent was mixed with 500 g of ethanol and It was added to a solution consisting of 60 g of caustic soda and refluxed for 3 hours. After concentrating the reaction solution to about half its volume, water was added and extracted with benzene. After washing with water and drying, the benzene was distilled off to obtain 76 g of a pale brown viscous oily residue.

The thus obtained 2,5,7.8-tetramethyl-2-
A mixture of (4°-methyl-3'-pentenyl)-6-chromanol and 2.5,7.8-tetramethyl-2-(4'-methyl-4'-pentenyl)-6-chromanol was added with paratoluenesulfone. 10g of acid and 250g of toluene
mZ was added and refluxed for 5 hours. After the reaction was completed, washing with water was repeated, dehydration was performed over anhydrous magnesium sulfate, and toluene was distilled off under reduced pressure to obtain a brown viscous oily residue.

The oily extract obtained in this way was subjected to column chroma + -craphy using silica gel and benzene-n-hexane to obtain the target 2,57.8-tetramethyl-2-(4°-methyl-3゛50.2 g of colorless viscous liquid of -pentenyl)-6-chromanol (yield: 8
7.2%).

In a 500 m7 four-necked flask equipped with a soil stirrer, thermometer, and gas inlet tube, dichloromethane 140-1 acetic acid 90-1,
Add 3 g of triethylamine hydrochloride and 2 g of cuprous chloride and stir under a nitrogen stream to prepare a clear yellow-green solution.

Next, 70 g of myrcene (purity: about 75%) is added thereto, and the mixture is cooled to -20°C. While stirring and maintaining the temperature at -20°C, about 40 g of dry hydrogen chloride gas was bubbled under the liquid surface over a period of about 3 hours. After keeping it at -20°C overnight,
The obtained brown reaction solution is added to a mixture of 200 mZ of 10% ammonium chloride aqueous solution and 200 mZ of n-hexane with stirring, and washing with water is repeated until the mixture becomes neutral.

After dehydration over anhydrous magnesium sulfate, the solvent was distilled off to obtain 98 g of a pale yellow liquid.This product was distilled under reduced pressure using a Widmer rectification tube, resulting in a boiling point of 85-87°C/1. lmm
68 g of a colorless liquid exhibiting Hg are obtained. The main island is one of the known substances.
．． It was a mixture of E and Z isomers of 7-dichloro-3,7-dimethyl-oct-2-ene, and the content as a mixture was 91% by HPLC.

1 thought 1 The method was based on the method of Japanese Patent Publication No. 42-11064.

2.3.5-) 25.0 g of remethylhydroquinone was added to 650 mZ of anhydrous benzene, and further 2.1aZ of boron trifluoride etherate was added. While heating the mixture to reflux with stirring, 5.06 g of geraniol was added to 1.5 g of geraniol.
The mixture was added dropwise over a period of time, and then heated under reflux for an additional 3 hours. After cooling, the reaction solution was diluted with 50 parts of water twice and 25 parts of saturated sodium bicarbonate solution.
Washed twice with 50 d of water.

The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Distill the concentrate under reduced pressure to a boiling point of 180-185
A yellow viscous oil with a temperature of 10°C and 1 ov+Hg was obtained, but as a result of HPLC analysis, the main island was found to be the target substance 2, 5.
It was found that the mixture contained a large amount of by-products in addition to 7.8-tetramethyl-4-(4''-methyl-3''-pentenyl)-6-chromanol.

When the distillate was separated using a flash column (mobile phase: n-hexane-benzene), 2.5.7.
Only 22 g (47%) of 8-tetramethyl-2-(4'-methyl-3'-pentenyl)-6-chromanol was obtained, and 19 g of a tricyclic compound as a by-product.

Emperor's head It was carried out according to the method of JP-A-60-75475.

2. Charge 15.9 g of 3.5-trimethylhydroquinone, 4.0 g of zinc chloride, and 30@1 ethyl acetate with concentrated hydrochloric acid, and while raising the temperature and stirring, add 37.1 g of geraniol.
After the temperature reached 70°C, the reaction was continued for 3 hours.

After cooling the reaction solution, it was neutralized with a 5% aqueous solution of sodium carbonate, and 3% water was added.
Washed twice with 00-. The oil phase was separated, dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off. When the obtained oily residue was distilled under reduced pressure, the boiling point was 181-187°C. In+m
22 g of a viscous oily substance showing Hg was obtained, but as a result of HPLC analysis, as in Reference Example 2, the desired product 2,5°7.8-tetramethyl-2-(4'- Methyl-
It is a mixture of 3゛-pentenyl)-6-chromanol and a by-product tricyclic compound, and the abundance ratio is 45% to 26%.
Met.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1, R^2, R^3 mean the same or different hydrogen atoms or methyl groups, and R is A chroman derivative represented by (meaning a protecting group for a hydrogen atom or a hydroxyl group). 2. The chroman derivative according to claim 1, wherein R^1, R^2, and R^3 are all methyl groups. 3 R^1 and R^3 are both methyl groups, and R^2
The chroman derivative according to claim 1, wherein is a hydrogen atom. 4. The chroman derivative according to claim 1, wherein R^1 is a hydrogen atom, and R^2 and R^3 are both methyl groups. 5 General formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ Reacting hydroquinones expressed by A method for producing a chroman derivative represented by the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^1, R^2, R^3 and R have the above meanings) .