JPS6148487B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel hydroquinone derivative useful as an intermediate for the production of coenzyme Q and vitamin K.

The introduction of polyprenyl chains into the core, such as 2,3-dimethoxy-5-methyl-1,4-hydroquinone and 2-methyl-1,4-naphthohydroquinone, is one of the main steps in the production of coenzyme Q and vitamin K. Various methods have been proposed in the past. A method of introducing a side chain into a mother nucleus by applying the Grignard reaction is known [for example, J.
Am.Chem.Soc. 96 , 8046 (1974), JP-A-1972-
65236], which results in relatively high reaction yields. Briefly, this method involves preparing a Grignard reagent by reacting metallic magnesium with a brominated mother nucleus, and then coupling it with a side chain component of polyprenyl halide such as decaprenyl bromide, phytyl bromide, geranylgeranyl bromide, etc. Become. In this case, the free hydroxyl group on the mother nucleus interferes with the preparation of the Grignard reagent and the coupling reaction, so it is necessary to protect the hydroxyl group in advance by replacing the hydrogen atom of the hydroxyl group with another group. There is.

As substituents for the hydrogen atom mentioned above, acetyl group, methoxymethyl group, ethoxyethyl group, tetrahydropyranyl group, etc. are known for the mother nucleus of coenzyme Q [for example, Japanese Patent Publication No. 7063/1986,
39655, JP-A No. 52-65236]. Furthermore, regarding the mother nucleus of vitamin K, acetyl group, methyl group, benzyl group, methoxymethyl group, tetrahydropyranyl group, trialkylsilyl group, etc. are known [for example, Japanese Patent Publication No. 14628/1986, Japanese Patent Publication No. 44-28297, same
No. 50-29468, No. 50-39655, J.Am.Chem.Soc.
96 , 8046 (1974)]. It is desirable that the protecting group for the hydroxyl group is one that brings about a high yield in the Grignard reaction, facilitates the preparation of the Grignard reagent, is stable during the reaction, and can be eliminated at a desired stage after the Grignard reaction. It can be done.
In this sense, the above-mentioned substituents are either not suitable at all as a protecting group for a hydroxyl group in the Grignard reaction, or their action as a protecting group is not satisfactory in practice. For example, hydroxyl or methoxy groups substituted with methyl groups are stable to acids and bases;
After the Grignard reaction, it is extremely difficult to remove the methyl group and return it to a hydroxyl group. The acetyl group is completely unsuitable as a protecting group, since the corresponding Grignard reagent cannot be prepared from the nucleus by which the hydrogen atom of the hydroxyl group has been replaced.
Since the Grignard reaction does not occur when the hydroxyl group of trimethylhydroquinone is protected with a benzyl group [J.Am.Chem.Soc., 64 , 440 (1942)],
Regarding 2,3-dimethoxy-5-methyl-1,4-hydroquinone and 2-methyl-1,4-naphthohydroquinone, it is presumed that the Grignard reaction does not occur when the hydroxyl group is protected with a benzyl group. Trialkylsilyl groups cannot continue to protect the hydroxyl group during the Grignard reaction. Since the hydroxyl group protected by the tetrahydropyranyl group is unstable to acids, the mother nucleus must be handled with care, and the reaction conditions are limited. Furthermore, since the hydroxyl group protected by the methoxymethyl group is unstable to acids, the mother nucleus must be carefully purified prior to the Grignard reaction, and the coupling reaction between the Grignard reagent and polyprenyl halide requires careful purification of the mother nucleus prior to the Grignard reaction. The yield is also not satisfactorily high.

The present invention is directed to the hydroquinone core, which is advantageously used in a process for producing coenzyme Q and vitamin K, which includes the step of introducing a polyprenyl chain into the core by Grignard reaction, that is, the following formula which does not have the above-mentioned problems and has a protected hydroxyl group. The present invention provides a hydroquinone derivative represented by ().

[In formula (), R ¹ and R ² represent a CH ₃ O group,
or linked to represent a -CH=CH-CH=CH- group] The hydroquinone derivative of the present invention represented by the formula () can be obtained by adding methoxyethoxymethyl halide to the corresponding hydroquinone derivative () having a free hydroxyl group according to a method known per se. () can be produced by reacting [Tetrahedron
Letters (11) 809 (1976)].

[In the formula, R ¹ and R ² are as defined above, and X is a halogen atom] Since the compound of formula () is stable against acids and bases, impurities derived from the raw material compound () or () can be avoided. The Grignard reagent can be prepared and the coupling reaction with polyprenyl halide can be carried out without applying purification treatment for removal, and the reaction yield is high. In addition, the protecting group according to the present invention can be easily removed by heating in ethanol in the presence of a catalytic amount of hydrobromic acid or hydrochloric acid after the coupling reaction.
It is also extremely useful as an intermediate for the production of vitamin K.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 (1) 2,3-dimethoxy-5-methyl-6-bromohydroquinone 2,3-dimethoxy-5-methyl-6-bromohydroquinone in 500 ml of chloroform
A solution of 39.5 g of bromine in 70 ml of chloroform was added dropwise to a solution of 46.0 g of 5-methylhydroquinone at 5° C. under a nitrogen atmosphere. After stirring at the same temperature for 3 hours, the reaction solution was washed with water until no color was observed in the washing water. It was then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2,3-dimethoxy-5-methyl-6-bromohydroquinone 65.5
I got g.

(2) Methoxyethoxymethyl chloride 152g methyl cellosolve and S-trioxane
66 g of the mixture was cooled on ice, hydrogen chloride gas was blown into the solution until it became a clear solution, and then extracted with pentane. After drying the pentane solution over magnesium sulfate, the solvent was distilled off under reduced pressure, and further distillation was performed under reduced pressure to obtain methoxyethoxymethyl chloride (boiling point: 82°C/75mmHg). Note that this synthesis
This was carried out in accordance with the method described in Tetrahedron Letters (11) 809 (1976).

(3) 2,3-dimethoxy-5-methyl-6-bromohydroquinone-1,4-dimethoxyethoxymethyl ether A solution of 62.5 g of 2,3-dimethoxy-5-methyl-6-bromohydroquinone dissolved in 880 ml of dimethylformamide. was cooled to -30°C, and 22.9 g of 50% sodium hydride was added little by little. After the addition, the mixture was stirred at the same temperature for 1 hour, and then 65 g of methoxyethoxymethyl chloride was added dropwise at -30°C. After the dropwise addition, the mixture was stirred at room temperature for 3 hours, then 50 ml of ethanol was added and stirred for 1 hour. The reaction mixture was poured into ice water and extracted with isopropyl ether. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 91.5 g of 2,3-dimethoxy-5-methyl-6-bromohydroquinone-1,4-dimethoxyethoxymethyl ether. Yield 88%. Confirmation data for the product is as follows.

Infrared absorption spectrum (neat) 2930, 2875, 1458, 1410, 1386, 1340, 1238,
1166, 1115, 1078, 966 cm ^-1 nuclear magnetic resonance spectrum (CDCl ₃ ) δ = 5.12 (d, 4H), 4.05-3.78 (m, 4H),
3.80 (s, 6H), 3.60-3.43 (m, 4H),
3.33 (s, 6H), 2.27 (s, 3H) Example 2 Bromine of 2-methyl-1,4-naphthoquinone according to the method described in J.Am.Chem.Soc., 63 , 528 (1941) 57.8 g of 2-methyl-3-bromonaphthohydroquinone prepared by oxidation and reduction of the bromide with stannous chloride, 50% sodium hydride.
22g and methoxyethoxymethyl chloride
After carrying out a reaction in the same manner as in Example 1 using 62.5 g, the reaction mixture was poured into ice water to precipitate a solid. This was separated and recrystallized from hexane to obtain 92.3 g of 2-methyl-3-bromnaphthohydroquinone-1,4-dimethoxyethoxymethyl ether. Yield 94%. Confirmation data for the product is as follows. Melting point 51-53.8℃.

Infrared absorption spectrum (KBr) 2915, 2885, 1580, 1470, 1450, 1368, 1350,
1236, 1170, 1105, 965, 925 cm ^-1 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ = 8.20-7.90 (m, 2H), 7.55-7.36 (m,
2H), 5.18 (d, 4H), 4.08−3.85 (m,
4H), 3.62-3.45 (m, 4H), 3.33 (s,
6H), 2.48(s, 3H)

Claims (1)

[Claims] 1 General formula () [In formula (), R ¹ and R ² represent a CH ₃ O group,
or linked to represent a -CH=CH-CH=CH- group] A hydroquinone derivative represented by the following.