JPS6021988B2 - Method of 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 atom,
R1, R2 and R3 are a hydrogen atom or a lower alkyl group, and Z is a hydrogen atom 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 through the following reaction steps without taking out the intermediate hydroquinone compound (m) as a solid. [However, R is a hydrocarbon group having 1 to 1 carbon atoms, R1, R2 and R3 are a hydrogen atom or a lower alkyl group, X is a hydroxyl group or a halogen atom, and Z is a hydrogen atom or an acyl group ] Compounds represented by general formula (0), such as trimethylquinone, 2,3-dimethylquinone, 2,5
- Hydrogenation of dimethylquinone, 2,6-dimethylquinone, 2-methylquinone, 3-methylquinone, etc. with a catalyst such as P
d, Ni, Pt, etc. in an aromatic hydrocarbon or aliphatic ether as a solvent, such as toluene, xylene, benzene, dioxane, tetrahydrofuran, ethyl isopropyl ether, etc. to obtain the general formula (m ), such as trimethylhydroquinone, 2,3-dimethylhydroquinone, 2,5-dimethylhydroquinoso, 2,6-dimethylhydroquinone, 2-methylhydroquinone, 3-methylhydroquinone, etc., and then the nuclear reaction solution. removing the hydrogenation catalyst from the
Then, the residual liquid is mixed with a lower fatty acid ester having a boiling point higher than that of the solvent, such as an alkyl ester of formic acid, . An alkyl ester of acetic acid, an alkyl ester of propionic acid, etc. are added, and the aromatic hydrocarbon or aliphatic ether is distilled off from the resulting mixed solution to replace the solvent with a lower fatty acid ester. Metallic zinc, metallic tin or metallic iron in the presence of an acid catalyst such as Z12, AIC13, BF3 (C2day5)20, S12, SnC14, p-toluenesulfonic acid, sulfuric acid, etc. A compound represented by general formula (W) or general formula (V) is added and reacted in the presence of the compound to obtain a target compound, a chroman derivative.

Further, if necessary, the product is further acylated to produce a chroman derivative. The target compound of the present invention represented by general formula (1) is a useful pharmaceutical having vitamin E activity, and various manufacturing methods are known.

Subchapter, as a method for producing Q-tocopherol, trimethylhydroquinone (hereinafter abbreviated as TMHQ) and general formula (W)
Alternatively, a method is known in which a compound represented by general formula (V), such as isophytol, phytol, or phytyl halide, is heated under reflux in a hydrocarbon solvent, such as hexane, ligroin, or toluene, in the presence of a Lewis acid catalyst. This method has been industrialized. However, the compound represented by the general formula (m), which is a raw material, such as TM
HQ is a crystalline powder that easily scatters, and when it comes into contact with it, many people get irritated and the working environment becomes significantly worse. Furthermore, it is easily charged with static electricity and can cause powder explosions, 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 need for steps such as crystallization, filtration, and drying of the crystals in order to extract and purify the crystalline powder. In addition, a method using a compound represented by general formula (0) as a starting material,
As described in British Patent No. 763,784, Q-tocopherol is synthesized by directly alkylating trimethylquinone, followed by a closed moat, but the Q-tocopherol produced by this method is colored. It cannot be used as a drug that requires high purity.

Additionally, this method has disadvantages such as the addition of one step since the alkylation and ring-closing reactions are separate steps. The present inventor has 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 solution without handling solids, so it has good workability and can be made continuous very easily. 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. As described in German Patent No. 1940386, the secondary method for producing hydroquinone is to reduce the quinone in a system using alcohol as a solvent, and then add water to the reaction solution for recrystallization and precipitation. The hydroquinone compound is obtained by

When a quinone derivative is catalytically reduced to a hydroquinone form in the aromatic hydrocarbon or aliphatic ether as in the present invention, the hydroquinone form is stable in these solutions, and coloring can be slowed down if oxygen is removed. . In addition, according to the method of the present invention, the conversion rate of quinone can be increased to almost 100% by catalytic reduction reaction, and the selectivity to hydroquinone is also good, and after the catalytic reduction, the hydrogenation catalyst is removed by filtration. Then, the lower fatty acid ester is added to the reaction system, and the aromatic hydrocarbon or aliphatic hydrocarbon is removed by distillation to replace the reaction system with the lower fatty acid ester containing the solvent, and the solution is used in the next step b. It became possible to prepare for.

The lower fatty acid ester added is a solvent with a higher boiling point than the aromatic hydrocarbon or aliphatic ether. Incidentally, after the solvent replacement, crystals of the compound represented by the general formula (m) may be precipitated, but this does not affect the reactivity in step b. In carrying out the present invention, the catalyst used in the catalytic hydrogenation reaction of the compound represented by the general formula (0) is P.
d, Ni, and Pt metals are preferred.

The compound represented by the general formula (0) is dissolved in the aromatic hydrocarbon or aliphatic ether, and hydrogenated in the presence of a hydrogenation catalyst in a hydrogen atmosphere under pressure or normal pressure. The reaction temperature is preferably in the range of room temperature to 200 oo. The concentration of the reaction solution is preferably such that the compound represented by the general formula (m) does not precipitate as crystals at room temperature or under heating, and is usually 5.
A concentration of ~40% is suitable. Usually, the reduction reaction is 1 to 5
Finish in time. After the reaction, the catalyst is removed by filtration, lower fatty acid ester is added to the reaction system, and then aromatic hydrocarbons or aliphatic ethers are distilled off.
Convert to lower fatty acid ester with addition of reaction solvent.
In the solution, as a catalyst, for example, NCl8, 12 for Z, 3
(C2 day 5) 20, after adding one or more Lewis acids such as SnCl2, SnCl4, p-toluenesulfonic acid, and sulfuric acid, and adding metal zinc, metal tin, or metal iron as necessary, the general formula (W) or a compound represented by general formula (V) is added dropwise and reacted with heating and solvent reflux.

In the case of compounds in which X is a halogen atom in the general formula (W) and general formula (V), hydrogen halide is generated, and in the case of compounds in which X is a hydroxyl group, water is generated and remains closed, and the general formula ( A chroman derivative represented by 1) is obtained. The heating time may be 1 to 6 hours. Conversion rate of 1 as much as possible
It is preferable to make it close to 00%. During the reaction, if oxygen or air is present, the produced chroman derivative will be oxidized, so it is preferable to carry out the reaction under 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. In addition, if necessary, acetic anhydride-
It is acetylated with 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 explained below with reference to Examples.

Example 1 Trimethylquinone (hereinafter abbreviated as TMQ) 75.10pm,
300' of tetrahydrofuran and 5% Pb-CO.
Add 75 liters to any autoclave to create a hydrogen pressure of 7 kg.
/'s G is reduced at an internal temperature of 55°C.

The reaction is completed in 2 hours. After the reaction, 400 g of isopropylester acetate was added, and then tetrahydrofuran was removed by distillation. Remove the catalyst by filtration. A portion of TMHQ precipitates in the isopropylester acetate solution, but Znc12 thigh. 15 days later, 6.55 times of metal zinc powder and 5.00 times of CICQCOOH were added, and 156.1 times of isophytol was dripped under the reflux lamp over 2 hours. After the addition, 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 solvent removed along with the water is cooled and separated from the water.
Use in circulation. After the reaction, let it cool, pour it into water, extract and wash.
Further, extract and wash with 50% methanol water. obtained d
The isopropyl acetate solution of l-Q tocopherol is dehydrated and then refluxed with anhydrous sodium acetate monoacetate for acetylation. After the reaction, it is concentrated under reduced pressure and distilled under reduced pressure to obtain bpo.
02, collect a colorless and transparent fraction at 205-215°C. As a result, 202.8% of Yamaichi Q-tocophyllyl acetate was obtained. Example 2 TMQ 15.02 evening, benzene 200 skin and 5% pd
One CO. Add 30 min.
The hydrogenation catalyst was removed by filtration, and acetic acid butyl ester 140
Add and distill off the benzene.

BF3 etherate 14 is added to this acetate butyl ester solution.
．． On the 19th, 1.31 tons of metal zinc powder and 1.00 tons 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 coiso mixture,
The solvent distilled off along with the water is cooled and separated from the water before being 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. Concentrate under reduced pressure and distill under reduced pressure to obtain bpo. Collect the boxes at 02200-215°C.
As a result, 36.83 ml of dl-Q tocopherol was obtained. Example 3 Trimethylquinone 75.10 minutes, tetrahydrofuran 5 hours
Add 1.5 liters of 0.00 liters and Raney Nickel (manufactured by NDT 6F II Ken Fine Chemicals Co., Ltd.) to 12 autoclaves, and reduce at a hydrogen pressure of 5k9/g/G and an internal temperature of 110°C.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [R in the formula is a hydrocarbon group having 1 to 18 carbon atoms, 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 aromatic hydrocarbon or aliphatic ether as a solvent in the presence of a hydrogenation catalyst to form the general formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ R^1, R^2 and R^3 have the same meanings as above], the hydrogenation catalyst is removed from the reaction solution, and the remaining solution is mixed with a lower solvent having a higher boiling point than the solvent. A fatty acid ester is added, the resulting mixed solution is distilled to remove the aromatic hydrocarbon or aliphatic ether, the solvent is replaced with the lower fatty acid ester, and a Lewis acid catalyst is added to the resulting solution or slurry. and general formula (IV) ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼
In the formula, R has the same meaning as above and X is a hydroxyl group or a halogen atom], and the product is further acylated as necessary. How to manufacture.