NO170407B - PROCEDURE FOR PREPARING 6- (10-HYDROXYDECYL) -2,3-DIMETOXY-5-METHYL-1,4-BENZOQUINON AND ANALOGICAL COMPOUNDS - Google Patents

Description

The present invention relates to a method for the production of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone and its analogous compounds useful as intermediates for the production of pharmaceuticals.

6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone-(idebenone) has been known as a compound with specific pharmacological activities such as, among others, immunopotentiating activity, smooth muscle relaxant effect, enzyme activation effect in weaker tissues, especially in cardiac muscle and brain tissue. A known process for producing idebenone with an industrial advantage is the process (Toku-Kai-Sho 59-39855): (Step 1) - alkyl 9-(2-hydroxy-3,4-dimethoxy-6-methylbenzo-yl) nonanoate undergoes reduction to provide 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoate,

(Step 2) - this compound is subjected to further reduction with sodium bis(2-methoxyethoxy)aluminium hydride (Vitride) to provide 10-(hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol,

and

(Step 3) - this compound is subjected to oxidation

for the provision of ideas.

In the reaction in step 3, it is known that the oxidation is carried out using nitrosodisulfonic acid potassium salt as oxidizing agent. In this case, however, yield of the desired compound is not satisfactory. In consideration of this, in the present invention various investigations have been carried out and found that by using nitrosodisulfonic acid dialkali metal salt as an oxidizing agent obtained by subjecting an aqueous solution of hydroxylamine disulfonic acid dialkali metal salt to electrolytic oxidation, 6-(10-hydroxydecyl)-2 ,3-dimethoxy-5-methyl-1,4-benzoquinone and analogous compounds thereof, prepared in high yield with an industrial advantage.

The present invention relates to a method for producing a compound of formula: (where R<1> and R<2> each means a lower alkyl group; n means a number from 0 to 21), characterized by oxidizing a compound of formula:

(wherein R<1>, R<2> and n each have the same meaning as defined above; X means a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or a methoxymethyloxy group; and Y means a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or methoxymethyloxy group) with nitrosodisulfonic acid dialkali metal salt obtained by subjecting an aqueous solution of hydroxylamine disulfonic acid dialkali metal salt to electrolytic oxidation.

Examples of the lower alkyl group shown by R<1> and R<2> in the above formulas (II) and (III) include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, etc. The lower alkoxy group shown by X and Y , is one with 1 to 3 carbon atoms and includes methoxy, ethoxy, etc. The lower acyloxy group shown by X and Y, is one with 2 to 4 carbon atoms and includes acetyloxy, propionyloxy, etc. The silyloxy group shown by X and Y has 3 to 6 carbon atoms and includes trimethylsilyloxy, etc.; n denotes a number from 0 to 21, and preferably 8 to 12.

In the oxidation reaction according to the present invention, nitrosodisulfonic acid dialkali metal salt obtained by subjecting an aqueous solution of hydroxylamine disulfonic acid dialkali metal salt to electrolytic oxidation is used as oxidizing agent.

The dialkali metal salt of hydroxylamine disulfonic acid is exemplified by the disodium salt of hydroxylamine disulfonic acid and the dipotassium salt of hydroxylamine disulfonic acid. The dealkali metal salt of nitrosodisulfonic acid is exemplified by the disodium salt of nitrosodiumsulfonic acid and the dipotassium salt of nitrosodiumsulfonic acid, the disodium salt of nitrosodisulfonic acid being preferred.

Oxidation of compound (II) is carried out by dissolving compound (II) in a water-miscible solvent such as methanol, ethanol, dioxane, tetrahydrofuran, etc., and then adding a dialkali metal salt of nitrosodisulfonic acid. The amount of dialkali metal salt of nitrosodisulfonic acid used in the method of the present invention is stoichiometric, 2.0 times mol relative to compound (II), but if the stability of the dialkali metal salt of nitrosodisulfonic acid is taken into consideration, it is usually 2.6 times mol or more , preferably 3.0 times mol or more. The reaction temperature varies from 20°C to 70°C, preferably about 50°C. When the temperature is too low, the reaction proceeds more slowly, and when the temperature is high, decomposition of the dialkali metal salt to the nitrosodium sulfonic acid is promoted, and undesirable side reactions occur, and which thus not preferred. The reaction time varies with the concentration of starting compound (II), solvent used, the amount of di-alkali metal salt of nitrosodisulfonic acid, the reaction temperature, etc., but when the starting compound is completely used up, the reaction ends. For example, when using a thin-layer chromatograph1, HPLC, ( high performance liquid chromatography), gas chromatography, etc., the reduction of the starting material is followed over time, and when the starting material is no longer detected, the reaction is terminated. When carrying out the reaction at 50°C, the reaction is usually terminated within two hours. The aqueous solution of the dialkali metal salt of nitrosodisulfonic acid used as an oxidizing agent can be provided by subjecting an aqueous solution of a dialkali metal salt of hydroxylamine disulfonic acid to electrolytic oxidation which is carried out in a conventional electrochemical cell. This electrochemical cell is optionally equipped with a separator or diaphragm. In general, the use of a filter press type electrochemical cell equipped with a cation exchange membrane is preferred. The heat generated from the reaction can be suppressed by controlling the increase in cell voltage by keeping the electrode spacing close, and by cooling outside both the analyte and the catholyte circulating through both chambers at high speed. The anode and cathode are made from any common material commonly used for electrodes in electrochemistry, e.g. carbon, platinum, stainless steel, palladium, nickel, nickel alloy, etc. In general, the use of stainless steel mesh electrode is preferable. The electrolytic cell can be equipped with a stirring device, and it is also possible to circulate the reaction mixture using a pump.

The electrolytic oxidation can be carried out by applying a voltage of 0.5 to 50 volts to an aqueous solution containing the dialkali metal salt of hydroxylamine disulfonic acid. Generally, the reaction is conducted using 2 to 20 volts. The current passing through the solution has a strength of up to 50 A/dm<2>. It is generally preferred to use a current density of 2 to 20 A/dm<2> In order to carry out the electrolytic oxidation more efficiently, it is also possible to add a conventional electrolyte to the aqueous solution. Examples of such an electrolyte include sodium hydroxide, sodium acetate, sodium carbonate, sodium hydrogen carbonate, sodium phosphate, sodium chloride, etc. The amount of an electrolyte generally added is preferably in the range of from 0.1 to 30% by weight relative to the aqueous solution. The aqueous solution to be subjected to electrolytic oxidation generally contains the dialkali metal salt of hydroxylamine disulfonic acid at a concentration of at least 0.1 mol, preferably 0.1 mol to 2 mol, relative to one liter of the solution. The electrolytic oxidation can be carried out at a temperature varying from -15°C to 50°C. This reaction is preferably carried out at a temperature varying from 0°C to 35°C. The electrolytic oxidation can be carried out for at least 0.5 h or during a longer period of time. It is generally preferred to carry out the oxidation for 1 to 10 hours.

When starting the electrolytic oxidation, the pH of an aqueous solution of the dialkali metal salt of hydroxylamine disulfonic acid is adjusted to 10 to 13, preferably around 11.5, so as to provide the highest yield of the dialkali metal salt of nitrosodisulfonic acid.

Compound (III) has an immunopotentiating activity, a smooth muscle relaxant effect, an enzyme-activating effect on brain tissue, etc.

Starting compound (I) in the present invention can be obtained by exposing a compound represented by the general formula:

(where R<1>, R<2>, X, Y and n have the same meanings as above, and r<3> means a lower alkyl group) for reduction by a conventional

conventional method, for example Clemensen reduction using zinc amalgam and hydrochloric acid, Wolff-Kishner reduction of hydrazone, desulfuratlv reduction of dithioacetal or catalytic reduction to provide a compound of the general formula:

(where each symbol has the same meaning as above), followed by reduction of compound I.

Examples of the lower alkyl group shown by R<3> in the above formulas (I) and (IV) include those with 1 to 4 carbon atoms such as methyl, ethyl, propyl, etc.

The reduction reaction according to the present invention is preferably carried out in a suitable solvent. Any solvent which has the ability to dissolve starting compound (I) and which does not prevent the reduction reaction can be used as a solvent. Practical examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., and aromatic hydrocarbons such as benzene, toluene, xylene, etc. Reaction temperatures generally range from 0°C to 140°C, preferably 10°C. to 40° C. The amount of sodium borohydride is usually relative to starting compound (I) not 1.5 to 10 times as many moles, preferably about 2 to 6 times as many moles. Aluminum chloride is preferably used in such an amount that the molar ratio between aluminum chloride and sodium borohydride approximately is 1:3.

This reaction will provide more preferred results by allowing a small volume of water to be present in the reaction system. The presence of water suppresses the formation of an undesired side product, i.e., a compound of formula (II) in which one or both R<1> and R<2> are hydrogen, so that the yield of the desired compound (II) is even better. The volume of water used usually varies from 0.1 to 1.7 times as many moles, preferably 0.2 to 1.5 times as many moles relative to aluminum chloride. When an excess of water is used, the desired compound is not provided in a high yield, and the reaction time becomes long.

In the following examples and reference examples, the present invention will be described in detail.

Reference example 1

To a solution of 9-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)nonanoate (2.0 kg) in ethyl acetate (10 1) was added 5£ palladium carbon (water content: 50) (400g) and sulfuric acid (10 ml) added. The mixture was stirred for 5 hours at 30°C to 40°C in hydrogen flow (hydrogen pressure: about 8.5 kg/cm<2>G). The catalyst was filtered out, and the ethyl acetate layer was washed with water (10 L), 5% sodium bicarbonate (10 L) and water (10 L), successively. The ethyl acetate layer was concentrated to provide methyl 10-(2-hydroxy-3,4-dimethoxy-methylphenyl)decanoate (1.8 kg) as an oily product.

film

Infrared absorption spectrum X cm-<1>:3450(OH),1740(C00CH3)

max

CDC13

Nuclear magnetic resonance spectrum S : 1.10 to 1.87

ppm

(14H, multiple, -(CH2)7-), 2.17 to 2.57 (4H, multiple, ring CH2, CH2CO), 2.27(3H, singlet, ring CH3), 3.63

(3H, singlet, COOCH3), 3.80 (3H, singlet, 0CH3), 3.85 (3H, singlet, OCH3), 5.80(1H, singlet, OH), 6.27 (1H, singlet, ring H).

Reference example 2

In tetrahydrofuran (1.8 L) was dissolved methyl 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoate (881 g, 2.5 mol). To the solution was added a suspension of sodium borohydride (340 g, 9 mol) in tetrahydrofuran (10.7 L), and the mixture was stirred. To the resulting suspension was added water (75 mL, 4.16 mol). Aluminum chloride (400 g, 3 mol) was dissolved in tetrahydrofuran (6.0 L). The solution was added dropwise to the above suspension at a given rate lasting 90 minutes, after which the internal temperature of the reaction mixture was maintained at 25 ± 2°C. Then, the reaction mixture was stirred at the same temperature for another 30 minutes, and was then cooled to about 15°C. To the reaction mixture, water (22 L) was added dropwise to provide the solution, and hydrochloric acid (2.7 L) was then added dropwise. The mixture was then subjected to extraction twice with 9 L of toluene. The toluene layers were then combined and washed with an aqueous solution of sodium bicarbonate (4.4 L), followed by washing with water (4.4 L). The toluene layer was concentrated under reduced pressure to provide 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (805 g, 2.48 mol, yield 99.2%) as an oily product .

net

Infrared absorption spectrum 7 cm-<1>: around 3400 (OH)

max

CDC 13

Nuclear magnetic resonance spectrum S : 1.10 to 1.80

ppm

(16H, multiple,-(CH2)g-), 2.22(3H, singlet, CH3), 2.40 to 2.75(2H, multiple,CH2), 3.50 to 3.70 (2H, multiple ) CH2), 3.80 (3H, singlet,0CH3), 3.84 (3H, singlet, 0CH3), 6.25(1H, singlet, ring H)

Reference example 3

Investigations were carried out on the relationship between the volume of added water and the yield of 10-(2-hydroxy-3,4-dimethoxy-6-methyl-phenyl)decan-1-ol. In tetrahydrofuran (35.7 L) was dissolved methyl 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoate (methyl decanoate) (17.3 g, 49.1 mmol). The solution was added to a suspension of sodium borohydride (6.8 g, 180 mmol) in tetrahydrofuran (214.5 mL) and the mixture was stirred. A given volume of water was accurately measured (as described in Table 1), which was added to this suspension. Aluminum chloride (8.0 g, 60 mmol) was dissolved in tetrahydrofuran (1432 mL). The solution was added dropwise to the above-mentioned suspension at an internal temperature of 25 ± 2°C over a period of 90 to 120 minutes. The reaction mixture was then stirred for 30 minutes while the temperature was maintained at 25 ± 2°C. The reaction mixture was then cooled to 15 ± 2°C, and water (446 mL) was added dropwise. To the mixture, hydrochloric acid (53.5 ml) was added dropwise, and the temperature of the reaction mixture was maintained at temperatures not higher than 20°C. The reaction mixture was then subjected to extraction twice with 178.5 ml of toluene each time. The toluene layers were combined and washed twice with water (89.5 mL). The toluene layer was concentrated under reduced pressure to provide 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (decanol compound) as an oily product. Table 1 shows the relationship of the volume of water added with a yield of the decanol compound and with the amount of di-OH compound produced.

Reference example 4

Preparation of an aqueous solution of the disodium salt of hydroxylamine disulfonic acid

In water (7.5 L) sodium nitrite (1875 g) was dissolved, and to this a 35 v/v 56 aqueous solution of sodium hydrogen sulphite (11.5 L) was added dropwise, while the temperature of the solution was maintained at 0° C or below. To the mixture was then added dropwise acetic acid (2.860 ml) at temperatures not higher than 5°C, followed by stirring for 90 minutes at 5°C or below. To the resulting was then added dropwise a 30 v/v56 aqueous solution of caustic soda (3.125 mL) at 10°C or below, followed by dropwise addition of a 25 v/v56 aqueous solution of sodium carbonate (20 L) to provide an aqueous solution of the disodium salt of hydroxylamine disulfonic acid which has the ability to undergo electrolytic oxidation. The yield was approximately 8456.

Reference example 5

Preparation of an aqueous solution of the disodium salt of nitrosodisulfonic acid by electrolytic oxidase. ion Monopolar, two-compartment type and filter press type electrochemical cell (active electrode area: 4.5 dm<2>/cell x 2 cells) was fed an aqueous solution of disodium salt of hydroxylamine disulfonic acid (6 to 8 L) as analyte and with a 10 v/v56 aqueous solution of sodium carbonate (6 to 8 L) as catalyst, then circulation was provided using a pump. Using an amperage for 2 to 3 hours under certain electrolytic conditions (current density: 8 A/dm<2>, circulation line linear velocity: 10.4 cm/sec., temperature: 15°C), an aqueous solution of disodium nitrosodisulfonate provided in a yield of 9056 or higher.

Reference examples 1 to 4

In methanol (5.4 L) 10-(2-hydroxy-3,4-dimethoxy-6-methyl-phenyl)decan-1-ol (271 g) was dissolved, and to this was added an aqueous solution of disodium nitrosodlsulfonate ( 6.7 1, content 0.359 mol/l) produced by electrolytic oxidation. The mixture was stirred for two hours while the temperature was maintained at 50 ± 2°C. After confirming that the starting material was gone by TLC, water (8.6 L) was added to the reaction mixture followed by extraction twice with toluene (5.5 L and 2.7 L). The toluene layers were combined and washed with water. The toluene layer was concentrated under reduced pressure to provide a crude product, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (288 g, content 94.856, yield 96.956). This crude product (20g) was recrystallized from a mixture of toluene (60ml) and n-hexane (180ml). The crystals were dissolved in toluene (60 ml) and the solution was allowed to pass through a pre-coated layer of activated alumina (30 g). The filtrate was concentrated under reduced pressure, and the concentrate was again recrystallized from a mixture of toluene (55 mL) and n-hexane (165 mL). The crystals were further recrystallized from 5056 ethanol (108 mL), followed by drying to provide 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (16.2 g) as orange-yellow crystals , sm.p. 54.0°C.

KB r

Infrared absorption spectrum 7 cm"^: 3550(OH), 1660,

max 1650, 1610 (1,4-benzoquinone)

CDC 13 Nuclear magnetic resonance spectrum S : 1.1 to 1.8(16H,

ppm

multiple, -(CH2)8-), 2.00(3H, singlet, CH3), 2.43 (2H, triplet, J=7Hz,CH2), 3.63(2H, triplet, J=6Hz,CH20H) , 3.97(6H, singlet, 0CH3)

Examples using an aqueous solution of disodium nitrosodisulfonate prepared using electrolytic oxidation are all described in Table 2.

Reference Example 6 to 8

In methanol (110 1) 10-(2-hydroxy-3,4-dimethoxy-6-methyl-phenyl)decan-1-ol (6.84 kg) was dissolved. To this solution were added sodium acetate (27.4 kg) and water (110 L). To this mixture was then added dipotassium nitrosodisulphonate (23.5 kg, content 69.956), which was stirred at 50 ± 3°C for 3 hours. After confirming that the starting material was gone using thin layer chromatography, water (550 L) was added to the mixture, which was stirred at 10°C or below for 30 minutes or longer, then the precipitated crystals were centrifuged. The wet crystals thus collected were dissolved in ethyl acetate (40 L), followed by washing with water (25 L). The ethyl acetate layer was concentrated under reduced pressure to provide a crude product 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (6.70 kg, yield 93.956). The reference examples using dipotassium nitrosodisulfonate (Fremy's salt) are described in Table 3.

Claims (1)

Process for preparing a compound of formula [wherein R<1> and R<2> each represents a lower alkyl group; n means a number from 0 to 21], characterized by oxidizing a compound of formula [where R<*>, R<2> and n each have the same meaning as defined above; X means a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or a methoxymethyloxy group; and Y means a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or methoxymethyloxy group] with nitrosodisulfonic acid dialkali metal salt obtained by subjecting an aqueous solution of hydroxylamine disulfonic acid dialkali metal salt to electrolytic oxidation.