JPS6021989B2 - Method for producing chroman derivatives - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (1) [wherein R is a hydrocarbon group having 1 to 1 carbon atoms, and R1, R2 and R3 are a hydrogen atom or a lower alkyl group; , Z is hydrogen or an acyl group.

More specifically, the present invention relates to a method for producing a chroman derivative (1) using the quinone compound (0) as a raw material and without taking out the intermediate hydroquinone compound (m) as a solid through the following reaction steps. or a compound represented by the general formula (0) [in the above formula, R, R1, R2, R3 and Z are as defined above, and X is a hydroxyl group, an acyloxy group or a halogen atom],
For example, trimethylquinone, 2,3-dimethylquinone, 2
- Hydrogenation of 5-dimethylquinone, 2,6-dimethylquinone, 2-methylquinone, 3-methylquinone, etc. with an aliphatic ketone as a solvent, such as acetone, methyl ethyl ketone, methyl isopropyl, in the presence of a catalyst such as Pd, Ni, Pt, etc. Catalytic hydrogen reduction in ketones etc. gives the general formula (
m), such as trimethylhydroquinone, 2,3-dimethylhydroquinone, 2,5-dimethylhydroquinone, 2,6-dimethylhydroquinone, 2-methylhydroquinone, 3-methylhydroquinone, etc., and then remove hydrogen from the reaction solution. The added catalyst is removed, and then a lower fatty acid ester or a hydrocarbon solvent with a boiling point higher than that of the solvent is added to the surfactant, and the resulting mixed solution is distilled to remove the aliphatic ketone solvent and obtain the solvent. is substituted with a nuclear lower fatty acid ester or a hydrocarbon solvent, and the resulting solution or slurry is treated with a Lewis acid catalyst, such as ZnC12; AIC13:BF3 (C2 is)20:Sn
C12; SnC14: p-toluenesulfonic acid: Add a compound represented by general formula (W) or general formula (V) in the presence of sulfuric acid, etc., and if necessary in the presence of metal zinc, metal tin or metal iron. The target compound, a chroman derivative, is obtained by reaction.

Further, if necessary, the product is further acylated to produce a chroman derivative. The target compound of the present invention represented by the general formula (1) is a useful drug having vitamin E activity, and various manufacturing methods are known. As a subsidiary, as a method for producing Q tocopherol, trimethyl hydroquinone (hereinafter referred to as T
MHQ) and a compound represented by general formula (W) or general formula (V), such as isophytol, phytol or phytyl halide, in a hydrocarbon solvent, such as hexane, ligroin, toluene, etc., in a Lewis acid catalyst. A method of heating under reflux in the presence of a compound is known, and this method has been industrialized.

However, the compound represented by general formula (m), which is a raw material,
For example, TMHQ is a crystalline powder that easily scatters, and when it comes into contact with the skin, many people experience irritation, which significantly worsens the working environment. Furthermore, it is easily charged with static electricity and can easily cause a powder explosion, making it extremely dangerous to handle. In addition, it is easily oxidized in the air, and some of it becomes a quinone form, producing a black quinhydrone form, which causes coloring of the target chroman derivative. In addition, the method using hydroquinone as a starting material has many drawbacks, such as the fact that steps such as crystallization, filtration, and drying of the crystals are required to extract and purify the crystalline powder. In addition, a method using a compound represented by the general formula (0) as a starting material involves direct alkylation, reduction, and elutriation of trimethylquinone as described in British Patent No. 763,784 to produce Q tocopherol. However, the Q-tocopherol produced is extremely colored and cannot be used as a pharmaceutical product that requires high purity.

In addition, this method has disadvantages in that the alkylation and ring-closing reactions are separate steps, resulting in an extra step. The present inventors have arrived at the present invention as a result of studies aimed at improving these points.

That is, as mentioned above, the present invention is characterized in that the compound represented by the general formula (b) is used as a starting material. The advantage of the present invention is that it can be operated with a solvent without handling solids, so it has good workability and can be carried out continuously. The elements of the present invention are the selection of the organic solvent used in the process and the ability to synthesize hydroquinone with high purity. A secondary method for producing hydroquinone is as described in German Patent No. 1940386, in which quinone is reduced in an alcohol solvent, water is added, recrystallization is performed, and hydroquinone is obtained by precipitation. It is. When a quinone form is catalytically reduced to a hydroquinone form in an aliphatic ketone solvent such as acetone, methyl ethyl ketone, or methyl isopropyl ketone as in the present invention, the hydroquinone form is stable in these solutions. However, coloring progresses slowly in systems with oxygen removed. Furthermore, according to the method of the present invention, the conversion rate of the quinone compound can be increased to nearly 100% by the catalytic reduction reaction, and the selectivity to the hydroquinone compound is also good, and after the catalytic reduction, the hydrogenation catalyst is removed by filtration. Then, the residual liquid is added with a lower fatty acid ester or hydrocarbon solvent having a boiling point higher than that of the aliphatic ketone solvent, such as formic acid alkyl ester, acetic acid alkyl ester, propionic acid alkyl ester, toluene, xylene, benzene, and ligroin. By adding , hexane, octane, nonane, etc. and distilling the aliphatic ketone, and replacing it with the added lower fatty acid ester or hydrocarbon solution, the solution or slurry liquid can be directly fed into the next step b. Became. In this solvent exchange, when a solvent in which the hydroquinone compound has a low solubility, such as a hydrocarbon solvent, is used, this substitution may be carried out in the reactor of step b. The lower fatty acid ester or hydrocarbon solvent added has a higher boiling point than the aliphatic ketone. If aliphatic ketones are mixed in step b, the production rate of the chroman derivative obtained in step b will be poor and have an adverse effect, so it is necessary to distill off as much aliphatic ketones as possible. Although crystals of the compound represented by formula (m) may precipitate after the solvent replacement, this does not affect the reactivity in step b. The use of an aliphatic ketone as a solvent for catalytic hydrogenation of the compound represented by the general formula (0) has the following advantages.

The resulting compound represented by formula (m) has high solubility and good solution stability.

The hydrogenation reaction tank can be reduced. During the removal of the hydrogenation catalyst, no crystals are precipitated, there is no clogging, and the operation is extremely easy.

In carrying out the present invention, the catalyst used in the catalytic hydrogenation reaction of the compound represented by the general formula (0) is Pd
, Ni, Pt and the like are preferred.

The compound represented by the general formula (0) is dissolved in the aliphatic ketone solvent, and hydrogenated in the presence of a hydrogenation catalyst in a hydrogen atmosphere under pressure or normal pressure. Reaction temperature is room temperature ~ 200℃
Good range of qo. The concentration of the reaction solution is preferably such that the compound represented by formula (m) does not precipitate as crystals at room temperature or under heating conditions, and a suitable concentration is 5 to 40%. Usually, the reduction reaction is completed in 1 to 5 hours. After the reaction, the catalyst is removed by filtration, then the above-mentioned lower fatty acid ester or hydrocarbon solvent is added to the residual liquid, the aliphatic ketone is removed by distillation, and replaced with the added lower fatty acid ester or hydrocarbon solvent, For example, AIC13, ZnC12, BF3 (C2 ratio) 20, S
After adding one or more Lewis acids such as 14, p-toluenesulfonic acid and sulfuric acid to nC12,S, and adding metallic zinc, metallic tin or metallic iron as necessary, the general formula (
W) or a compound represented by the general formula (V), such as phytol, isophytol, phytyl halide, phytyl acetate, falnesol, nerolidol, falnesyl halide, linalool, geraniol, nerol, geranyl halide, and the mixture is heated and the solvent is refluxed. Make it react. In general formula (W) and general formula (V), X
In the case of a compound where x is a halogen atom, hydrogen halide is generated, and in the case of a compound where x is a hydroxyl group, water is generated,
In addition, in the case of a compound in which X is an acyloxy group, carboxylic acid is generated and the ring is closed to obtain a chroman derivative represented by the general formula (1). The heating time may be 1 to 6 hours. It is preferable to make the conversion rate as close to 100% as possible.
Further, if oxygen or air is present during the reaction, the produced chroman derivative will be oxidized, so the above reaction is preferably carried out in an inert gas atmosphere. After the reaction, the resulting reaction solution is poured into water to transfer the catalyst to the aqueous layer, and the organic layer is dried and then subjected to vacuum distillation and molecular distillation to obtain a pure chroman derivative. If necessary, it is acetylated with acetic anhydride-pyridine or acetic anhydride-sodium acetate to obtain a stable acetylchroman derivative, which is then purified to produce a product.
The present invention will be specifically described below with reference to Examples.

Example 1 Trimethylquinone (hereinafter abbreviated as TMQ) 75.10pm,
Acetone 300 skin and 5% Pd-CO. Add 75 yen to the autoclave with a capacity of 1, hydrogen pressure 7k9/G,
TMQ is reduced at an internal temperature of 55°C.

The reaction is completed in 2 hours. After the reaction, toluene 400'
After adding , acetone is distilled off. Remove the catalyst by filtration. A part of TMHQ precipitates in the toluene solution, but ZnC1268.15 is added to this slurry liquid.
evening, metal zinc powder 6.55 evening and CICH2COO day 5
．． 00 evening plus isophytol 156.
Drop one evening over two hours. After dropping, add 2 more refluxed Takaazusa.
Allow time to complete the reaction. The water produced during the reaction is distilled off as an azeotrope, and the distilled solvent is cooled and separated from the water, and then recycled and used again. After the reaction, the mixture is allowed to cool, poured into water, extracted and washed, and further extracted and washed with 50% methanol water.
After the toluene solution is dehydrated, it is acetylated by refluxing with acetic anhydride-sodium acetate. After the reaction, vacuum concentration and vacuum distillation are performed to obtain bpo. A colorless and transparent fraction of 02205-21yo is collected. As a result, 201.5 ml of dl-Q-tocopheryl acetate was obtained. Example 2 The same method as in Example 1 was carried out except that isopropylester acetate was used in place of toluene in Example 1, and bpo. Collect the fraction between 0.2200 and 215°C.

As a result, dl-Q mountain tocopheryl acetate 215.8
Evening has arrived. Example 3 TMQ1502, acetone 80 [and 5% Pb-
C.O. Add 30 minutes to auto crepe and internal temperature 100qo,
Hydrogenation was carried out at a hydrogen pressure of 5k9/Ga. After the reaction, the hydrogenation catalyst was removed by filtration, and 140% of toluene was added.

The acetone was removed from this, and the resulting toluene solution was mixed with 14.19 g of BF3 etherate and 1.3 g of metal zinc powder.
1 hour and 1.00 hour of trichloroacetic acid were added and reflux was continued for 2 hours to complete the reaction. The water produced during the reaction is removed as a co-nutrient mixture, and the distilled solvent is cooled and separated from the water, after which it is recycled again. After the reaction, the mixture is allowed to cool, poured into water, extracted and washed, and further extracted and washed with 50% methanol water. Perform vacuum concentration and vacuum distillation to obtain bpo. 022
Collect crabs from 00 to 21500. As a result, dl-Q
37.52 tocopherols were obtained. Example 4 TMQ1512, Methyl Ethyl Ketone 60 and 5
%Pd-CO. Add 15 minutes to a 500-degree autoclave and hydrogenate trimethylquinone at an internal temperature of 60 oo and a hydrogen pressure of 7 atm.

After the reaction, the catalyst is filtered through a furnace, 200 g of ligroin is added to the furnace liquid, and methyl ethyl ketone is removed by distillation. To the groin solution thus obtained, add 121.00 g of Z and 2.00 g of tin powder, drop 31.50 g of phytyl chloride under the reflux rope over 2 hours, and further Continue the reflux practice for two hours. To this, 15.4 g of acetic anhydride and 8.0 g of pyridine were added dropwise, and reflux was continued for 2 hours. After the reaction, the organic layer is neutralized by pouring into water, dried, concentrated under reduced pressure, and further distilled under reduced pressure. As a result, bpo. 012
00-21y0 d1-Q-tocopheryl acetate 4
1.8 pm was obtained. Example 5 13.61 g of 2,5-dimethylquinone, 60 g of acetone and 5% Pd-CO. 15 minutes were added to 500 autoclaves, and the same method as in Example 1 was carried out to make W.
O. A colorless and transparent fraction of 02200-21yC is collected.

As a result, 2,5,7-trimethyl-2-(4',8,1
32.5 ml of 16-acetoxychroman (2-trimethyltridecane) was obtained. Example 6 TMQ75.10 ml, 300 ml of acetone and 1.5 ml of Raney Nickel (NDT65 JII Ken Fine Chemical Co., Ltd.) were added to the autoclave to a volume of 1.
TMG is reduced at a hydrogen pressure of 5k9/G and an internal temperature of 11000.

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [R in the formula is a hydrocarbon group having 1 to 18 carbon atoms, and R^1, R^2 and R^3 is a hydrogen atom or a lower alkyl group, and Z is a hydrogen atom or an acyl group]
In producing the chroman derivative represented by the general formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [R_1, R^2 and R^3 in the formula have the same meanings as above] is subjected to catalytic hydrogen reduction in an aliphatic ketone solvent in the presence of a hydrogenation catalyst to obtain the general formula (III
) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ After forming the compound represented by [R^1, R^2 and R^3 in the formula have the same meanings as above], remove the hydrogenation catalyst from the reaction solution. Then, a lower fatty acid ester or a hydrocarbon solvent having a boiling point higher than that of the solvent is added to the residual liquid, and the resulting mixed solution is distilled to remove the aliphatic ketone solvent and convert the solvent into the lower fatty acid. ester or hydrocarbon solvent, and the resulting solution or slurry is treated with a Lewis acid catalyst and general formula (IV) ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ or general formula (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [R in the formula has the same meaning as above, and X is a hydroxyl group, acyloxy group, or halogen atom] A method for producing a chroman derivative, which comprises adding a compound, causing a reaction, and further acylating the product if necessary.