FI90859C - Process for the preparation of 6- (hydroxyalkyl) -2,3-dialkoxy-5-methyl-1,4-benzoquinone derivatives - Google Patents

Description

i 90859

Process for the preparation of 6- (hydroxyalkyl) -2,3-dialkoxy-5-methyl-1,4-benzoquinone derivatives For the preparation of 6- (hydroxyalkyl) -2,3-dialkoxy-5-methyl-1,4-benzene oki nonderi vat

The present invention relates to a process for the preparation of 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone and analogous compounds which can be used as intermediates in the preparation of medicaments.

6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone) is known as a compound having specific pharmacological activities, including an immune response-boosting activity, a smooth muscle-triggering effect, enzyme activating effect in damaged tissues, especially myocardium and brain tissue. As an industrially preferred process for the preparation of idebenone, the following process (Toku-Kai-Sho 59-39855) is known, in which: (Step 1) alkyl-9- (2-hydroxy-3,4-dimethoxy-6-methylbenzoyl) nonano -ate is reduced to give alkyl 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) decanoate, (step 2) this compound is further reduced with sodium bis (2-methoxyethoxy) aluminum hydride (Vitride), to give 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) decan-1-ol and (step 3) this compound is oxidized to give idebenone.

In the reaction of Step 3, it is known to carry out the oxidation using the potassium salt of nitrosodisulfonic acid as an oxidizing agent. In this case, the yield of the desired compound is unsatisfactory. In view of these considerations, the inventors have carried out a number of studies and have found that when a dialkali metal salt of nitrosodisulfonic acid obtained by subjecting an aqueous solution of a dialkali metal salt of hydroxylamine disulfonic-2-acid to an electrolytic (oxygen) 1,3-Dimethoxy-5-methyl-1,4-benzoquinone and compounds analogous thereto can be obtained in good yield industrially advantageously.

The present invention relates to a process for the production of compounds having the formula:

O

ΒΌ A

(j (III)

R20x xCCH2) .- CH2OH O

[wherein both R1 and R2 represent a lower alkyl group; n represents an integer from 0 to 21], wherein the compound of the formula

X

R'O, XA XH3 'θ' '1 (II)

R20 / Y> XCCH:) .- CH20H

Y

[wherein R 1, R 2 and n are as defined above and X represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or a methoxymethyloxy group; and Y represents a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or a methoxymethyloxy group] is oxidized with a dialkali metal salt of a nitrosodulfonic acid obtained by subjecting an aqueous solution of a dialkali metal salt of hydroxylamine disulfonic acid to an electrolyte.

As examples of the lower alkyl group represented by R1 and R2 present in the above formulas (II) and (III), mention may be made of groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, etc. The lower alkoxy groups represented by the symbols X and Y are and include methoxy, ethoxy, etc. The lower acyloxy groups represented by the symbols X and Y contain 2 to 4 carbon atoms and include acetoxy, propionyloxy, etc. The silyl 90859 3 represented by the symbols X and Y contain 3 to 6 carbon atoms. and include trimethylsilyloxy, etc. The number n represents an integer ranging from 0 to 21, preferably from 8 to 12.

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

Examples of the dialkali metal salt of hydroxylamine disulfonic acid include the disodium salt of hydroxylamine disulfonic acid and the dipotassium salt of hydroxylamine disulfonic acid. Examples of the dialkali metal salt of nitrosodisulfonic acid include the disodium salt of nitrosodisulfonic acid and the dipotassium salt of nitrosodisulfonic acid, of which the disodium salt of nitrosodisulfonic acid is preferable.

The oxidation of the compound (II) is carried out by dissolving the compound (II) in a water-miscible solvent such as methanol, ethanol, dioxane, tetrahydrofuran, etc., after which a dialkali metal salt of nitrosodisulfonic acid is added to this solution. The stoichiometric amount of the dialkali metal of nitrosodisulfonic acid used in the process of the present invention is 2.0 times the molar amount of the compound (II), but this amount is usually 2.6 times or more of the molar amount, preferably 3.0 times or more. stability of the dialkali metal salt. The reaction temperature is in the range of 20 to 70 ° C, preferably about 50 ° C. If the temperature is too low, the reaction proceeds slowly, and if the temperature is high, the decomposition of the dialkali metal salt of nitrosodisulfonic acid is intensified and undesirable side reactions begin to occur, which is disadvantageous. The reaction time depends on the concentration of the starting compound (II), the solvent used, the amount of the dialkali metal salt of nitrosodisulfonic acid, the reaction temperature, etc., but usually the reaction is completed when the starting compound is completely consumed. The disappearance of the starting material can be monitored over time using, for example, thin layer chromatography, high performance liquid chromatography (HPLC), gas chromatography, etc., and when the starting material can no longer be detected, the reaction is complete. When the reaction is carried out at a temperature of 50 ° C, it is completely completed in two hours. An aqueous solution of the dialkali metal salt of nitrosodisulfonic acid to be used as an oxidizing agent can be obtained by electrolytically oxidizing an aqueous solution of the dialkali metal salt of hydroxylamine disulfonic acid in a conventional electrochemical cell. This electrochemical cell is optionally equipped with a separator or diaphragm. In general, it is preferable to use an electrochemical cell of the filter press type equipped with a Kati onion exchange membrane. The heat generated in the reaction can be suppressed by controlling the increase in cell voltage by keeping the distance between the electrodes small, as well as by additionally cooling the outside of both the anolyte and the catholyte, which are recycled. The anode and cathode are made of any of the materials commonly used as electrodes in electrochemistry, and examples include carbon, platinum, stainless steel, palladium, nickel, nickel alloys, etc. In general, it is preferable to use stainless steel as the electrode. The electrolyte cell can be equipped with a stirrer and it is also possible to recycle the reaction mixture by using a pump.

Electrolytic oxidation can be accomplished by applying a voltage in the range of 0.5 to 50 volts to an aqueous solution containing a dialkali metal salt of hydroxylamine disulfonic acid.

The reaction is generally preferably carried out using a voltage of 2 to 20 volts. The current flowing through the solution has a maximum current density of 50 amps per square decimetre. In general, it is preferable to use a current density of 2 to 20 amps per square decimeter. In order to carry out this electrolytic oxidation more efficiently, a conventional electrolyte can be added to said aqueous solution. Examples of such an electrolyte include sodium hydroxide, sodium acetate, sodium carbonate, sodium hydrogencarbonate, sodium phosphate, sodium chloride, etc. El. 90859 5 The amount of trolyte added is generally 0.1 to 30% by weight of water. The aqueous solution to be electrolytically oxidized generally contains a dialkali metal salt of hydroxylamine disulfonic acid in a concentration of at least 0.1 mole, preferably 0.1 to 2 moles per liter of solution. The electrolytic oxidation can be carried out at a temperature in the range of -15 to + 50 ° C. This reaction is generally preferably carried out at a temperature in the range of 0 to 35 ° C. The electrolytic oxidation can be continued for a period of at least 0.5 hours or more. In general, it is preferred to continue the oxidation for 1-10 hours.

At the moment when the electrolytic oxidation is started, the pH of the aqueous solution of the dialkali metal salt of hydroxylamine disulfonic acid is adjusted to 10 to 13, preferably to about 11.5, in order to maximize the yield of the dialkali metal salt of nitrosodisulfonic acid.

Compound (III) has an immune response-boosting activity, smooth muscle-triggering activity, an enzyme-activating effect in brain tissue, and so on.

The starting compound (I) of the present invention is obtained by reducing a compound of the general formula:

X

II (IV) R * O-R 2 -COCl 3) n 1 COOR 3 Y o (wherein R 1, R 2, X, Y and n are as defined above and R 3 represents a lower alkyl group) by a conventional method, for example by reduction of dementia zinc amalgam and hydrochloric acid, by Wolff-Kishner reduction of hydrazone, desulfurization reduction of dithioacetal or catalytic reduction to give a compound of general formula

X

6 J. (I)

R20 "y NCCH2) .- COORJ Y

[wherein all symbols are as defined above], followed by reduction of compound (I).

The lower alkyl groups represented by the symbol R3 in the above formulas (I) and (IV) are, for example, alkyl groups having 1 to 4 silicon atoms, such as methyl, ethyl, propyl, and the like.

The reduction reaction according to the present invention is preferably carried out in a suitable solvent. As the solvent, any solvent which is capable of dissolving the starting compound (I) and which does not interfere with the reduction reaction can be used. Examples of such a solvent include diethyl ether, tetrahydrofuran, dioxane, etc., as well as aromatic hydrocarbons such as benzene, toluene, xylene, etc. The reaction temperature is usually in the range of 0 to 140 ° C, preferably 10 to 40 ° C.

Sodium borohydride is usually used in a 1.5 to 10-fold molar excess relative to the starting compound (I), preferably in a 2 to 6-fold molar excess. Aluminum chloride is preferably used in such an amount that the molar ratio of aluminum chloride to sodium borohydride is about 1: 3.

This reaction produces a more favorable result when a small volume of water is present in the reaction system. More specifically, the presence of water suppresses the formation of an undesired by-product, i.e. a compound of formula (II) in which either one or both of R 1 and Ra are hydrogen, further improving the yield of the desired compound (II). The volume of water used is usually 0.1 to 1.7 times the molar amount, preferably 0.2 to 1.5 times the molar amount with respect to aluminum chloride. When too large an amount of water is used, the yield of the desired product cannot be good and the reaction time is extended.

The present invention is illustrated in more detail by the following examples and reference examples.

Reference Example 1

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

film

Infrared absorption spectrum ν cm-1: 3450 (OH), 1740 (COOCH 3) max CDCl 3

Nuclear Magnetic Resonance (NMR) Spectrum δ ppm 1, 10.. . 1, 87 (14H, multiplet, - (CHa)? -), 2, 17.. . 2.57 (4H, multiplet, ring CHa, CHaCO), 2.27 (3H, singlet, ring CH3), 3.63 (3H, singlet, COOCHs), 3.80 (3H, singlet, OCHa), 3, 85 (3H, singlet, OCHa), 5.80 (1H, singlet, OH), 6, 27 (1H, singlet, ring H)

Reference Example 2

Methyl 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) decanoate (881 g, 2.5 mol) was dissolved in tetrahydrofuran (1.8 L). To this solution was added a suspension of sodium borohydride (340 g, 9 moles) in tetrahydrofuran (10.7 L), and the mixture was stirred. Water (75 mL, 4.16 moles) was added to the resulting suspension. Aluminum chloride (400 g, 3 moles) was dissolved in tetrahydrofuran (6.0 L).

This solution was added dropwise to the above suspension at a certain rate over a period of 90 minutes, during which time the internal temperature of the reaction mixture was maintained at 25 ± 2 ° C. The reaction mixture was then stirred at the same temperature for a further 30 minutes, after which it was cooled to about 15 ° C. Water (22 L) was added dropwise to the reaction mixture to effect decomposition, followed by dropwise addition of hydrochloric acid (2.7 L). The mixture was extracted twice with 9 liters of toluene each time. The toluene layers were then combined and washed with 5% aqueous sodium hydrogen carbonate solution (4.4 L), and then water (4.4 L). The toluene layer was concentrated under reduced pressure to give 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) decan-1-ol (805 g, 2.48 mol, yield 99.2%) as an oily product. .

clean

Infrared absorption spectrum ν cm-1: about 3400 (OH) max CDCl 3

Nuclear Magnetic Resonance (NMR) Spectrum δ: ppm 1.10 to 1.80 (16H, multiplet, - (CHa) e-), 2.22 (3H, singlet, (CHs), 2, 40.). .75 (2H, multiplet, CHa), 3.50 ... 3.70 (2H, multiplet, CHa), 3.80 (3H, singlet, OCH3), 3.84 (3H, singlet, OCH3), 6 , 2 5 (1H, singlet, ring H).

Reference Example 3 In this example, the relationship between the volume of water added and the yield of 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) -decan-1-ol was investigated. Methyl 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) decanoate (methyl decanoate; 17.3 g, 49.1 mmol) was dissolved in tetrahydrofuran (35.7 mL). This solution was added to a suspension of sodium borohydride (8.8 g, 80 mmol) in tetrahydrofuran (214.5 mL), and the mixture was stirred. A certain amount of water was accurately measured (as shown in Table 1), and this amount was added to this 90859 9 suspension. Aluminum chloride (8.0 g, 60 mmol) was dissolved in tetrahydrofuran (142 mL). This solution was added dropwise to the above suspension over a period of 90 to 120 minutes at an internal temperature of 25 ± 2 ° C. The reaction mixture was then stirred for 30 minutes maintaining its temperature at 25 ± 2 ° C.

The reaction mixture was then cooled to 15 ± 2 ° C and water (446 ml) was added dropwise. Hydrochloric acid (53.5 ml) was gradually added dropwise to the mixture, during which time the temperature of the reaction mixture was not allowed to exceed 20 ° C. The reaction mixture was then extracted 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 give 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) decan-1-ol (decanol compound) as an oily product. From the table. 1 shows the relationship between the volume of water added and the yield of the decanol compound as well as the amount of di-OH compound formed.

10

table 1

Dependence between the amount of water and the amount of di-OH compound formed as a result of decanol yield

Added Decanol compound di-OH compound water yield tea yield3

Well. ml molar (%) (%) _s ratio 1_ 1 0 0, 0 94, 2 9.2 2 0 0, 0 95, 4 6.9 3 0, 8 0, 74 96, 9 3, 3 4 0, 8 0, 74 98, 2 2, 8 5 1, 0 0, 93 98, 3 1,8 6 1, 0 0, 93 98, 3 2, 7 7 1, 5 1, 39 99, 2 0,6 8 1 .5 1, 39 99, 2 1,4 9 1, 8 1,67 99, 0 1,2 10 1, 8 1,67 98, 7 1,7 11 2, 0 1, 85 97, 6 0,5 12 2, 0 1, 85 90, 4 0,0 13 2,5 2, 31 85, 3 0,0 14 2,5 2, 31 90, 6 0,0

Note 1)

Molar ratio

Added in moles of water in moles of aluminum chloride

Note 2) Yield of di-OH compound * Peak area produced by di-OH compound x 100 Peak area produced by decanol compound di-OH compound: 10- (2,3-dihydroxy-4-methoxy-6-methylphenyl ) decan-1-ol 90859 11

Reference Example 4

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

Sodium nitrite (1875 g) was dissolved in water (7.5 L), and a 35% by weight aqueous solution of sodium hydrogen sulfite (11.5 L) was added dropwise to this solution, keeping the temperature of the solution at 0 ° C or below. Acetic acid (2860 ml) was then added dropwise to this mixture at a temperature of not more than 5 ° C, after which the mixture was stirred for 90 minutes at a temperature of 5 ° C or below. To the resulting mixture was then added dropwise a 30% by weight aqueous solution of sodium hydroxide (3125 ml) at a temperature of 10 ° C or below, followed by dropwise addition of a 25% by weight aqueous solution of sodium carbonate to a diphenyl to give hydroxyl to give hydroxyl. oxidizes electrolytically. The yield was about 84%.

Reference Example 5

Synthesis of an aqueous solution of the disodium salt of nitrosodisulfonic acid by electrolytic oxidation

A single-pole, two-chamber electrochemical cell comprising a filter press (active electrode area: 4.5 dm2 / cell x 2 cells) was charged with an aqueous solution of hydroxylamine disulfonic acid disodium and a 10% aqueous solution of disodium salt recycling was started by a pump. When an electric current was applied to the solutions for 2-3 hours under certain electrolytic conditions (current density 8 A / dm2; linear rotation speed 10.4 cm / s; temperature 15 ° C), an aqueous solution of disodium nitrosodisulfonate was obtained in a yield of 90%. bigger.

Examples 1-4

10- (2-Hydroxy-3,4-dimethoxy-6-12 methylphenyl) decan-1-ol (271 g) was dissolved in methanol (5.4 L), and to this solution was added aqueous disodium nitrosodisulfonate solution (6.7 L). content 0. 359 mol / l) synthesized by electrolytic oxidation. The mixture was stirred for two hours at a temperature in the range of 50 ± 2 ° C. After the disappearance of the starting material was confirmed by thin layer chromatography, water (8.6 L) was added to the reaction mixture, after which it was extracted 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 give 6- (10-hydroxyldecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone (288 g, 94.8%, 96.9% yield) as a crude product. ). This crude product (20 g) was recrystallized from a mixture of toluene (60 ml) and n-hexane (180 ml). The crystals were dissolved in toluene (60 ml) and the solution was passed through a plate coated with previously activated alumina (30 g). The filtrate was concentrated under reduced pressure, and the resulting concentrate was recrystallized again from a mixture of toluene (55 ml) and n-hexane (165 ml). The crystals were recrystallized from 50% ethanol (108 ml) and dried to give 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone (16.2 g). in straight crystals, m.p. 54.0 'C.

KBr

Infrared Absorption Spectrum: cm-1: 3550 (OH), 1660, max 1650, 1610 (1,4-benzoquinone) CDCl3

Nuclear Magnetic Resonance (NMR) Spectrum 6: ppm 1, 1.. . 1.8 (16H, multiplet, - (CHa) a-), 2.00 (3H, singlet, CH3), 2.43 (2H, triplet, J = 7Hz, CHa), 3.63 (2H, triplet, J = 6Hz, CH 2 OH), 3.97 (6H, singlet, OCH 2).

Table 2 summarizes the examples in which an aqueous solution of disodium nitrosodisulfonate synthesized by electrolytic oxidation was used.

Il 90859 13 p

Τ »JJ

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g. / -V

ro ο ο X <0 υ υ * · * • hcoX 3S μ <o -p ο ο ο ο μ ο α; χ. . . .

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Μ μ X

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30 O _ 30 U

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S m μ - * ^ μ ON 00 ON

"νμωΚ = ^ O 'r- vo O

> 5 t "~ - on cn m is 3 η * h μ · η ε 3 ο μ (0 χ ιθ Η χ> c • Η, * U · QJ Ο * μ ον ι ^ ν <} ε c • Η 0 )

U

14

Reference Examples 6-8

10- (2-Hydroxy-3,4-dimethoxy-6-methylphenyl) decan-1-ol (6.84 kg) was dissolved in methanol (110 L). To this solution was added sodium acetate (27.4 kg) and water (110 L). Dipotassium nitrosodisulfonate (23.5 kg, 69.9%) was then added to this mixture, and the mixture was stirred at 50 ± 3 ° C for 3 hours. After the disappearance of the starting material was confirmed by thin layer chromatography, water (550 L) was added to the mixture, and the mixture was stirred at 10 ° C or lower for 30 minutes or longer, after which the precipitated crystals were separated by centrifugation. The wet crystals thus obtained were dissolved in ethyl acetate (40 L), after which the solution was washed with water (25 L). The ethyl acetate layer was concentrated under reduced pressure to give 6- (10-hydroxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone (6.70 kg, yield 93.9%) as a crude product.

Reference examples using dipotassium nitrosodisulfonate (Fremy's salt) are summarized in Table 3.

I! 90859 15 o -μ £ _ σ 'm 03 ao' '' oo _ f- »· ~> ο> ο \ ο> rV. £ _ ^ ~ ο γη οο δ ι ^ ™ ^

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• Η 03 S

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Ο "V

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tOS / \ 03 _ + J

c \ 7 = 522 «> (13 V- / Ο ^ 01 μι

C> -V Ο + J

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C C .X

Ο 03 · Η U

X <ΰ X 03 χ -μ ι & ε-ι 3 03 03 03 νο C0 r — i · η + η ε ^ 3 Ό · Η · Η r-t 03 Æ V 03 Ο

E-Η> *> 03 C

Claims (3)

16 A process for the preparation of a compound of formula (III) R 1 O 2 X x H, (III) R 10 / X 2 CH 2 CH 2 OH 2 CH 2 OH O [wherein R 1 and R 1 represent a lower alkyl group; and n represents an integer from 0 to 21] by oxidation of a compound of formula (II) R 10 (CH) (II) R 10 / (ifxCCH 2) .- CH 2 OH Y [wherein R 1, R 1 and n each have the same meaning as as defined above, X represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or a methoxymethyloxy group; and Y represents a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or a methoxymethyloxy group] with a dialkali metal salt of nitrosodisulfonic acid, t-a Process for the preparation of a compound of formula (III) according to claim 1, characterized in that the compound of formula (II) to be oxidized with a dialkali metal salt of nitrosodisulphonic acid [wherein R 1, R 1, X, Y and n have the same meaning as above] is prepared by reducing general formula (i) X 90859 17 A compound according to Y1 (R3, Ra and n have the same meaning as previously defined; X represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group) , a silyloxy group or a methoxymethyloxy group, and Y represents a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a silyloxy group or a methoxymethyloxy group, and R 3 represents a lower alkyl group]. Process according to Claim 2, characterized in that the reduction is carried out using sodium borohydride and aluminum chloride in the presence of water as reducing agent.