KR20060117430A - Process for the preparation of coenzyme qn and intermediates thereof - Google Patents

Abstract

A process for preparing a coenzyme Qn is provided to simplify the processing steps, to allow use of mild reaction conditions, and to improve the yield and purity of a coenzyme Qn useful as an active ingredient of health-aid foods or pharmaceuticals. The process for preparing a coenzyme Qn comprises the steps of: reacting a compound represented by the following formula 5 with a compound represented by the following formula 6 in the presence of a base to provide a compound represented by the formula 7; subjecting the compound represented by the formula 7 to desulfonation and deprotection under an acidic condition to provide a compound represented by the following formula 8; and carrying out oxidation of the compound represented by the formula 8 by using at least one oxidant selected from the group consisting of FeCl3, FeCl3À6H2O, CuCl2, CuCl2À2H2O, MnO2 and NaOCl to obtain a compound represented by the following formula 1. In the above formulae, n is an integer of 2-12; each of R2 and R3 is a C1-C4 alkyl or alkoxy, or R2 and R3 may form a benzene ring together with the carbon atom to which they are attached; R4 is a halogen-substituted or non-substituted C1-C4 alkyl or nitro-substituted or non-substituted C6-C10 aromatic hydrocarbon: R5 is tetrahydropyranyl, 1-ethoxyethyl or tetrahydrofuranyl; and Y is a halogen atom.

Description

Process for the preparation of coenzyme Qn and intermediates

The present invention relates to a novel method for producing coenzyme Q _n (n = 1-12), in particular coenzyme Q ₁₀ (hereinafter referred to as 'CoQ ₁₀ ') widely used as an active ingredient in dietary supplements or pharmaceuticals.

The present invention also relates to novel intermediates produced during the preparation of coenzyme Q _n and methods for their preparation.

Ubiquinone, commonly called coenzyme Q _n, is an essential cellular construct in various species. In humans, coenzyme Q ₁₀ is a representative of these polyprenoid natural substances and is known to play a major role as redox transporter in the respiratory chain (Renaz, Coenzyme Q. Biochemistry, Bioenergetics, and Clinical Applications of Ubiquinone , Wiley-). Interscience: New York (1985); Trumpower, Function of Ubiquinones in Energy Conserving Systems , Academic Press, New York (1982); Bliznakov et al., The Miracle Nutrient Coenzyme Q ₁₀ , Bantom Books, New York (1987)).

Coenzyme Q ₁₀ plays an essential role in the e-transmission process required for breathing. Almost all vertebrates rely on one or more types of compounds of these series found in the mitochondria of all cells upon respiration (ie, because they are ubiquitous in vivo, another name is ubiquinone). Coenzyme Q ₁₀ , along with its antioxidant role, has a membrane stabilizing effect that contributes to the inhibition of cellular damage in normal metabolic processes by inhibiting the oxidative attack of lipid peroxidation products, polyunsaturated fats. In addition, it plays an important role as an antioxidant to neutralize free radicals, which are partially generated during the energy generation process and can potentially cause damage. As an energy transporter, coenzyme Q ₁₀ enters the redox cycle continuously. When a coenzyme Q ₁₀ molecule receives an electron, it is reduced, and when it releases an electron, it is oxidized again. In the reduced (ubiquinol) state of coenzyme Q ₁₀ , the electrons are loosely held to provide one or two electrons very quickly to neutralize free radicals. Thus, the reduced form rich in electrons has a stronger antioxidant effect than vitamin E.

Coenzyme Q ₁₀ is widely used as an active ingredient in dietary supplements and medicines, and is particularly effective in treating cardiovascular diseases. Specifically, it has been successfully used to treat toxins, hypertension and hyperlipidemia caused by ischemic heart disease, chronic heart failure, cardiomyopathy. Endogenous coenzyme Q ₁₀ acts as an essential coenzyme in various metabolic processes. In addition to the treatment of cardiovascular diseases, it provides an increased energy source and acts as a free radical scavenger or membrane stabilizer to improve the functioning of pathologically altered or ischemic tissues. In addition, coenzyme Q ₁₀ is present in high levels in a healthy heart but low in patients with congestive heart failure, so it may be helpful for the treatment of heart disease when used as an adjuvant. There are two theoretical ways that coenzyme Q ₁₀ can work on the heart: That is, it acts as an antioxidant that blocks damage from free radicals that cause arterial blockage, or enhances energy efficiency by enhancing energy efficiency.

Coenzyme Q ₁₀ is used to treat diseases involving muscular dystrophy or slow muscle degeneration and cardiac complications typically found in these patients.

Coenzyme Q ₁₀ is also known to exert antiviral effects (including HIV) or antimicrobial effects by significantly increasing the production of immune-active cells, or by increasing the production of antibodies, in addition to providing energy and acting as antioxidants. have. Pharmacological use by coenzyme Q ₁₀ is increasing, including anti-cancer effects (particularly breast cancer), oral disease, diabetes, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

Toxicity of coenzyme Q ₁₀ and no drug interactions have been reported. Coenzyme Q ₁₀ is generally applied as an adjuvant, not a replacement for normal medical treatment, and the daily oral dosage ranges from 5-10 mg / dose to 50-100 mg / dose.

This medically important coenzyme Q ₁₀ has been produced by several methods, including:

First, a method in which 2,3-dimethoxy-5-methyl-hydroquinone is reacted with prenyl alcohol or a derivative thereof and then oxidized can be cited. [Reference: GB 928,161; Chemical abstracts , 74, 125168 v, (1971); See Scheme 1 below.

In Scheme 1, n represents an integer from 1 to 12.

The coupling reaction in Scheme 1 is carried out using zinc chloride, aluminum chloride, trifluoroboron or other Lewis acids. However, since the reaction involves side reactions such as cyclization between polyprenyl side chains, chromanol cyclization of the bound target, or a high proportion of stereoisomers (cis isomers), the yield is very low. In addition, the 50 carbon decaprenol used as a starting material is produced in several steps from 45 carbon solarenesols extracted from tobacco leaves, which are expensive for solaresol and low yield of decaprenol from solarenesol. It is therefore not industrially useful [References: JP56092238, JP55118437, JP54046733, JP52042838, US2002 / 0156302A1].

Secondly, the method of Scheme 2 below using solanesol instead of decaprenol, which is applied to 2,3-dimethoxy-5-methyl-6-bromo-1,4-protected hydroquinone (benzene ring) After attaching five carbon chains in advance, the solaresol halogen derivatives are combined. [Reference: J. Org. Chem. (1979), 44 (5), 868 Takeda.

In the method of Scheme 2, the reaction was facilitated by substituting a hydroquinone protecting group with a benzyl group, but later removing the protecting group and sulfone group, the lithium metal, which is dangerous to use industrially at a low temperature below -70 ° C, is not only odorous but also removed. An expensive amine compound (Aldrich 2003-2004 catalog: 562,000 won / 170 g-methylamine, 271,000 won / kg-dimethylamine) was used as a solvent. The use of highly explosive metals and high boiling amine compounds as solvents is not easy to handle industrially, and the yield decreases due to an increase in the amount of isomers in which the double bond is moved at the △ ² position during desulfonation. [Reference: J. Chem. Soc Chem. Commun., (1982) p. 153-154.

Third, as in Scheme 3, there is a method in which 2-methoxyethoxymethyl (MEM) is used as a protecting group, and sodium metal is used for desulfonation [Reference: Bull. Chem. Soc. Jpn., 55 (4), 1325-1326, (1982), Kuraray.

However, when 2-methoxyethoxymethyl chloride (MEM-Cl) is used as a protecting group introduction reagent, the protecting group is well removed later by the strong acid (hydrobromic acid), but the reagent used as the protecting group introduction agent is very expensive. (Aldrich 2003-2004 catalog 186,000 won / 25g). In addition, the sodium metal used for desulfonation is also a highly explosive metal, which is difficult to apply industrially, and has a disadvantage in that isomer formation (7%) is increased. Pharm. Bull., 32 (10), 3959-3967 (1984)].

Fourth, when the alkyl group is used as a protecting group, as shown in Scheme 4, it is easy to introduce the protecting group, but it is difficult to remove the protecting group later. Therefore, a strong oxidizing agent such as cerium ammonium nitrate (CAN) or silver nitrate should be used. 1130-1136]. In addition, this oxidation method has a problem that the yield is lowered by the generation of by-products such as unstable 1,2-quinone or polymer [Ref. J. Prakt. Chem., 808-822 (1985).

Thus, the synthesis of coenzyme Q _n determines the ease of the last stage oxidation reaction depending on which hydroxy protecting group is attached to the hydroquinone, and the economic efficiency or efficiency of the entire process is determined.

Fifthly, the recently disclosed method of Scheme 5 uses a nickel catalyst to couple a benzene ring and an allyl metal and oxidize using a cobalt complex catalyst and oxygen [Tetrahedron 52 (21) 7265-7276, (1996) Lipshutz, BH (US 6545184 B1, 2003).

In the method of Scheme 5, compound A is synthesized in two steps using 3,4-dimethoxy-6-methyl-2-toluenesulfonyloxybenzaldehyde as a starting material, and expensive bis (cyclopenta) is obtained from solanesol. Aluminum compound (Compound B), which is an activating material, is prepared through a four-step reaction using dienyl) zirconium chloride as a catalyst. Compounds A and B thus obtained are combined in the presence of a nickel catalyst to prepare Q-2, and butyllithium (n-BuLi), which is not industrially easy, is used to remove the protecting group (Ts) of the Q-2 compound. . Finally, the target compound is obtained by oxidation with oxygen in the presence of an expensive cobalt complex (Aldrich 2003-2004 catalog, 252,000 won / 5g) catalyst.

As such, the reagents used in the method of Scheme 5, namely trimethylsilyl propine (TMS-Propyne), butyllithium (n-BuLi), trimethyl aluminum (AlMe ₃ ), biscyclopenta dienyl zirconium dichloride (Cp ₂₎ ZrCl ₂ ), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) and N, N' -bis (salicylidene) ethylenediamino cobalt (Co (salen)) are mostly expensive reagents. However, it is difficult to use industrially because of its high flammability. In particular, the last oxidation step using Co (salen) as a catalyst has a high reagent, but the reaction yield (68%) is also a disadvantage compared to the prior art. In addition, since the reaction uses more than 1.2 equivalents of solanesol, which accounts for the largest part of the cost, and the reaction stages based on solanesol are also produced in 7 steps up to coenzyme Q ₁₀ , coenzyme in three steps using only 1 equivalent of solanesol. Compared to the present invention for producing Q ₁₀ , the economy is significantly inferior.

The present invention can also be useful as an intermediate of coenzyme Q _n (n = 1-12), vitamin K, or polyprenyl-trimethylquinone synthesis widely used as an active ingredient in dietary supplements or medicaments. It relates to a new process for the preparation of hydroquinone derivatives.

Wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined below.

Vitamin K, coenzyme Q _n and polyprenyl-trimethyl quinone are quinone derivatives having polyprenyl chains as represented by the following formulae, which are very important medical compounds.

These compounds exhibit various effects depending on the number of isoprene units. In particular, since all double bonds of the polyprenyl chain of these compounds have a trans configuration, a selective stereochemical synthesis process is urgently needed. Most recently reported synthesis methods bind the benzene nucleus with five carbon isoprene chains first to the benzene nucleus to fundamentally block the generation of cis isomers at the △ ² position, which is the most stereochemically problematic. Therefore, the synthesis of an intermediate having one isoprene chain of trans configuration attached to the benzene ring is essential for the synthesis of the above medically important compounds.

Such medically important hydroquinone derivatives have been prepared by various methods as follows.

First, the method of Scheme 6, developed by Takeda, is mentioned. [Reference: J. Org. Chem., 44, 868, (1979)]. In this method, the isoprenyl chain of the trans configuration is introduced into the hydroquinone nucleus by introducing an oxirane ring into the protected hydroquinone, then ring-opening and introducing an aryl sulfone group, but the reaction step is long and therefore unsuitable for industrial use. The disadvantage is that.

Second, the method of Scheme 7 using Grignard reagent using magnesium or copper metal can be cited (Synthesis, 469, (1981)). The method of Scheme 2 can be seen as an improvement over the method of Scheme 1 in that the stereoisomers generated as by-products can be easily removed by the crystallization method, but this method also has a long overall reaction step and is similar to Grignard reagent. It is not an industrially easy reaction, such as using a highly flammable metal.

Third, the method of Scheme 8 below can be used to obtain a stereoselective hydroquinone derivative in a shorter reaction step and higher yield using Lewis acid, an acid catalyst of Friedel-Crafts reaction. Literature: J. Org. Chem., 68 (20), 7925-7927, (2003). In this method, the five-carbon allylsulfone compound has a much better yield when X is a hydroxyl group than when halo (eg chloro). In particular, the reaction mixture was used in an amount of 1.2 equivalents of hydroxy sulfone compound (7b), 1,2-dichloroethane as a reaction solvent, and 1.2 equivalents of zinc bromide as Lewis acid for 8 hours at 80 ° C. The best results of stereoselectivity of Z = 10: 1. However, if the reaction solvent was reacted for 24 hours at 40 ℃ using dichloromethane, the reaction yield was low (30 ~ 56%), and reacted in 1,2-dichloroethane solvent at 80 ℃ for more than 8 hours 12 hours The reaction did not proceed (magnesium bromide, triethylaluminum) or the starting materials were destroyed (titanium tetrachloride, iron (III) chloride), although the yield was low (aluminum chloride, boron trifluoride). , Zinc bromide 20-58%), poor stereoselectivity (tin chloride E / Z = 3: 1). Therefore, this method requires a high reaction temperature of about 80 ℃, and the reaction is properly proceeded only by using zinc chloride or zinc bromide as Lewis acid. In addition, the allylsulfone compound in which X is halo may be prepared in one step from isoprene, which is a starting material, but the compound in which X is hydroxy has a disadvantage in that the yield is reduced.

In this regard, the present inventors conducted intensive research to supplement the disadvantages of existing methods for coenzyme Q _n synthesis, and as a result, a method for preparing coenzyme Q _n compound of formula 1 including coenzyme Q ₁₀ , which is new, economical and industrially useful. Developed.

[Formula 1]

Where

R ₂ and R ₃ each independently represent C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, or may form a benzene ring with the carbon atom to which they are attached,

n is an integer of 2-12.

It is therefore an object of the present invention to provide a novel method for preparing coenzyme Q _n which is widely used as an active substance in dietary supplements or medicines.

It is also an object of the present invention to provide a novel intermediate of formulas (3) and (4) produced in the process of converting a compound of formula (2) to a compound of formula (5) and a process for the preparation thereof.

Where

R ₂ and R ₃ As defined above.

R ₄ represents C ₁ -C ₄ -alkyl unsubstituted or substituted by halogen, or an aromatic hydrocarbon having 6 to 10 carbon atoms unsubstituted or substituted by nitro.

In addition, the present inventors conducted intensive studies to supplement the disadvantages of the existing methods described above for a new method for preparing hydroquinone derivatives, and as a result, using iron chloride as an acid catalyst, the compound of formula (2) in high yield and high stereoselectivity under mild conditions It was found that the compound of can be prepared. In particular, in the prior art of Scheme 8, the reaction is achieved by using a hydroxy compound as compared with the reaction using a halo compound, but in view of the fact that the synthesis of the hydroxy compound itself has a complex problem, the present inventors Efforts have been made to find conditions under which excellent results can be obtained even using halo compounds that are easier to synthesize. As a result, it was found that the use of iron chloride as an acid catalyst can obtain good results under mild conditions even when a halo compound is used as a reactant, thereby completing the present invention. Accordingly, the present invention relates to a method for preparing a hydroquinone derivative of Formula 2 by reacting a compound of Formula 9 with a compound of Formula 10 in the presence of iron chloride.

[Formula 2]

Where

R ₁ represents methyl, methoxymethyl, ethoxymethyl, or benzyl,

R ₂ and R ₃ each independently represent C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, or may form a benzene ring with the carbon atom to which they are attached,

R ₄ represents C ₁ -C ₄ -alkyl unsubstituted or substituted by halogen, or represents an aromatic hydrocarbon having 6 to 10 carbon atoms unsubstituted or substituted by nitro,

X represents a halogen.

First, the present invention is prepared by reacting a compound of Formula 5 with a compound of Formula 6 in the presence of a base to prepare a compound of Formula 7, and performing desulfonation and deprotection under acid conditions for the compound of Formula 7. To prepare a compound of formula (8), and then oxidize the compound of formula (8) relates to a method for producing a compound of formula (1).

[Formula 1]

Where

n is an integer from 2 to 12,

R ₂ and R ₃ each independently represent C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, or may form a benzene ring with the carbon atom to which they are attached,

R ₄ represents C ₁ -C ₄ -alkyl unsubstituted or substituted by halogen, or represents an aromatic hydrocarbon having 6 to 10 carbon atoms unsubstituted or substituted by nitro,

R ₅ represents tetrahydropyranyl (THP), 1-ethoxyethyl (EE) or tetrahydrofuranyl (THF),

Y represents halogen.

Examples of the base used in the step of reacting the compound with a compound of formula 6 of the formula (5) is potassium carbonate, potassium tert-ethoxide and n on-butoxide, sodium-may be mentioned butyl lithium and the like, preferably potassium tert- Butoxide is used.

The reaction may be preferably carried out in an organic solvent, and any solvent which does not adversely affect the reaction may be used. Preferably, ethers such as diethyl ether and tetrahydrofuran; Halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; Or ketones, such as acetone and methyl ethyl ketone, can be used, and these are used individually or in mixture of 2 or more types. The reaction is preferably carried out for 30 minutes to 2 hours in the temperature range of -30 to 30 ℃.

Desulfonation and deprotection of the compound of Chemical Formula 7 obtained in the above reaction give a compound of Chemical Formula 8. Desulfonation can be carried out under conventional conditions, for example, catalysts such as Pd (OAc) ₂ , PdCl ₂ , Ni (OAc) ₂ 4H ₂ O, PdCl ₂ ([1,2-bis) in a solvent such as THF (Diphenylphosphino) ethane] dichloropalladium; dppe) or PdCl ₂ ([1,2-bis (diphenylphosphino) propane] dichloropalladium; dppp) and NaBH ₄ , LiBH ₄ or Super as reducing agent -H (lithium triethylborohydride) and the like can be used, but PdCl ₂ ([1,2-bis (diphenylphosphino) ethane] dichloropalladium; dppe) or PdCl ₂ ([1,2 - bis (diphenylphosphino) propane] dichloropalladium; may utilize conditions using a reducing agent of a catalyst and Super-H ^® (lithium triethyl hydride beam) with the dppp). Deprotection can be carried out under mild conditions using an aqueous acid solution, which is the result of using a specific protecting group (R ₅ ) according to the invention. For example, the protecting group may be removed by carrying out the reaction for 30 minutes to 2 hours in a temperature range of 20 ° C. to 50 ° C. using 1N aqueous hydrochloric acid solution.

In the process of obtaining the compound of Formula 8, the compound of Formula 7 was deprotected and concentrated under desulfonation and acid conditions, and then the residue was dissolved in an organic solvent, acetone or alkane solvent, without purification of silica gel column chromatography. Add methanol or ethanol. After cooling the mixed solution at about 40 ℃ for 30 minutes and then cooled to obtain the title compound as a crystal at 5 ~ 15 ℃. Filtration gives a high purity (95% yield) of the title compound in high yield (95% yield). The preferred amount of methanol or ethanol is 2 to 4 times the volume ratio of acetone or alkane solvent, more preferably 2.5 times. This is because when the solvent ratio is 2.5 times, it is the easiest result to work industrially. That is, if the alcohol solvent is too large compared to the acetone or alkane solvent, the yield of the product is much lowered. If the alcohol solvent is too small, the crystal size is so small that filtration is impossible. Preferred alkanes solvents are heptane, hexane, iso-octane, octane or pentane.

Finally, the compound of formula 8 is oxidized to produce the desired compound of formula 1. At this time, the oxidizing agent is iron chloride (FeCl ₃ ), iron chloride, hexahydrate (FeCl ₃ · 6H ₂ O), copper chloride (CuCl ₂ ), copper chloride, dihydrate (CuCl ₂ 2H ₂ O), manganese dioxide (MnO ₂ ) And one or more mild oxidants selected from the group consisting of sodium hypochlorite (NaOCl). Since the protecting group is removed, the reaction proceeds sufficiently even with a mild oxidizing agent as recited above, so that the desired compound of formula 1 can be produced in high yield, which is very useful industrially. The reaction is preferably carried out in any solvent which does not adversely affect the reaction, but preferably lower alcohols such as methanol, ethanol and isopropanol; Acetone; Alkanes such as pentane, hexane and heptane; Hydrocarbon chlorides such as dichloromethane, dichloroethane and chloroform; Cycloalkanes such as cyclopentane and cyclohexane; Or water can be used and these are used individually or in mixture of 2 or more types. The reaction is preferably carried out for 30 minutes to 2 hours in the temperature range of -20 to 50 ℃.

The compound of Chemical Formula 1 produced through the reaction may be purified in a pure state by a conventional purification method, for example, column chromatography or recrystallization.

Compounds of formula (6) used as starting materials in the above process for preparing compounds of formula (1) can be prepared from compounds having the desired number of prenyl groups [Indian J. Chem., 7 , 574 -576, (1969) and Chem. Lett. 1105-1108, (1984)], for example, if a compound having nine prenyl groups is required, it can be obtained through a halogenation process from solanesol. Halogenation reactions for compounds having the desired number of prenyl groups can be carried out according to conventional methods, for example bromination reactions in PBr ₃ in hexane / tetrahydrofuran solvent systems or tetrahydrofuran / dimethylformamide solvent systems. [Reference: Helv. Chim. Acta. 42, 2616, (1959).

Since the compound of Formula 5 used as a starting material in the method according to the present invention is a known compound, it may be prepared with reference to US Pat. No. 4,270,003 or may be synthesized using a method newly developed by the present inventors. That is, the compound of Formula 5 is prepared by oxidizing the compound of Formula 2, and then reducing the compound of Formula 4 to produce the compound of Formula 4, and protecting the hydroxyl group of the obtained Compound of Formula 4 with a protecting group. It can manufacture. Compounds of formulas (3) and (4) used as intermediates in this process are themselves novel compounds, thus providing novel intermediates and methods for their preparation. That is, the present invention provides a method for preparing the compound of Formula 3 by oxidizing the compound of Formula 2, and a method for preparing the compound of Formula 4 by reducing the compound of Formula 3. Also provided is a method of preparing the compound of formula 5 by protecting the hydroxy group of the compound of formula 4.

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

Where

R ₂ , R ₃ , R ₄ and R ₅ are as defined above,

R ₁ represents methyl, methoxymethyl, ethoxymethyl or benzyl.

The process of oxidizing the compound of formula 2 to prepare the compound of formula 3 is carried out using a strong oxidizing agent such as cerium ammonium nitrate (CAN), for example in acetone / water solvent system or acetonitrile, and reduction to compound of formula 4 Is carried out, for example, using Na ₂ S ₂ O ₄ in a dichloromethane solvent, and the introduction of a protecting group of the hydroxy group to the compound of formula 4 is carried out in a catalytic amount of pyridinium para-toluene in a solvent such as dichloromethane or tetrahydrofuran In the presence of sulfonate (PPTS). In introducing the protecting group, an inexpensive ethyl vinyl ether, 2,3-dihydrofuran or 3,4-dihydro-2H-pyran reagent is used.

The total yield of the three-step reaction is as high as 90%, such that the tetrahydropyranyl (THP) group, 1-ethoxyethyl (EE) group or tetrahydrofuranyl (THF) group introduced through the high yield reaction It is inexpensive and can be easily removed in a short time using an aqueous acid solution such as hydrochloric acid, thus providing a great economic advantage.

On the other hand, the compound of formula (2) used as a starting material in the method for preparing a compound of formula (5) can be prepared by referring to the literature ( Synthesis 469-471, 1981) as a known compound.

In order to help the understanding of the present invention, the entire process of preparing the desired compound of Formula 1 from the compound of Formula 2 is shown in Scheme 9 below.

In particular, the synthesis of coenzyme Q _n determines the ease of the last stage oxidation reaction from the compound of formula (7) to the compound of formula (8), or the economics or efficiency of the whole process, depending on which hydroxy protecting group is attached to the hydroquinone. That is, in Formula 5, i) when R ₅ is hydrogen, the compound is reacted with the compound of Formula 6, the yield is very low due to side reactions, and ii) when R ₅ is a benzyl group, the coupling reaction of Formula 6 is easy, Since there is a disadvantage that the protecting group removal and sulfonyl removal is difficult. In addition, iii) when the compound of formula (5), in which the starting material is R ₅ is a methyl group, is combined with the compound of formula (6), the bonding reaction is good, but a strong oxidizing agent is used to remove the methyl group, which is a protecting group. There is a disadvantage in that the yield is inhibited by producing a byproduct such as quinone or polymer. Therefore, the present invention forms a compound of formula (2) at low cost by using a compound of formula (9) substituted with methyl, methoxy methyl, ethoxymethyl or benzyl in hydroxy which is a low-cost starting material, and then after the coupling reaction with formula (6) Making the compound of formula 5 wherein the protecting group of the compound of formula 2 is converted to tetrahydropyranyl, 1-ethoxyethyl or tetrahydrofuranyl to easily remove the protecting group of the hydroxy group at high yield and low cost. There is a feature of the present invention.

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

In the above formula

R ₂ , R ₃ and n are as defined above,

R ₄ represents C ₁ -C ₄ -alkyl unsubstituted or substituted by halogen, or represents an aromatic hydrocarbon having 6 to 10 carbon atoms unsubstituted or substituted by nitro,

R ₅ represents tetrahydropyranyl (THP), 1-ethoxyethyl (EE) or tetrahydrofuranyl (THF),

Y represents halogen.

The invention also relates to a novel process for the preparation of the compound hydroquinone derivatives of formula (2). That is, the method of preparing a hydroquinone derivative of Formula 2 is characterized by reacting a compound of Formula 9 with a compound of Formula 10 in the presence of iron chloride in dichloromethane (MC).

[Formula 9]

[Formula 10]

[Formula 2]

In the above formula

R ₁ represents methyl, methoxymethyl, ethoxymethyl, or benzyl,

R ₂ and R ₃ each independently represent C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, or may form a benzene ring with the carbon atom to which they are attached,

R ₄ represents C ₁ -C ₄ -alkyl unsubstituted or substituted by halogen, or represents an aromatic hydrocarbon having 6 to 10 carbon atoms unsubstituted or substituted by nitro,

X represents a halogen. More preferably X represents chloride.

This is represented by the reaction scheme shown in Scheme 10 below.

In the present invention, it is preferable to use iron chloride (FeCl ₃ ) in an amount of 0.1 to 1.0 equivalent based on the compound of Formula 9. If the amount of iron chloride is too small, the reaction is slow and the yield is low, if too large a large amount of side reactions are difficult to purify and consequently the yield is lowered.

 When acetic acid is further added to the reaction solution, this assists the action of the acid catalyst, thereby exhibiting the effect of improving the reaction rate and reaction yield together with the pH adjustment of the reaction, thereby contributing to the progress of the reaction more preferably. The reaction is also preferably carried out in organic solvents, wherein the usable organic solvents include hexane, cyclohexane, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, nitromethane, dioxane or mixtures thereof. . The reaction is carried out for 4 to 24 hours in the temperature range of 30 to 60 ℃. Most preferably, dichloromethane is an organic solvent, and the reaction is performed for 4 hours by heating to reflux at 38 ° C to 45 ° C.

The compound of formula 9 used as starting material for preparing the compound of formula 2 is subjected to a three step process according to the method described in J. Organic Chem. 52, 3872, 1987, for example as shown in Scheme 11 below. Compounds of formula 10 may be prepared in a one step process according to the methods described in Bull. Soc. Chim. Fr. 3-4, 519, 1976, for example, as shown in Scheme 12 below. Can be.

The prenyl moiety in the compound of formula (II) prepared according to the process of the present invention is the side chain to be extended by a polyprenyl reaction with a reactant omitting one isoprene unit, for example decaprenol or solanesol. In the conventional method, a method of mainly reacting a prenyl alcohol derivative such as solaresyl halide or decaprenyl halide with hydroquinone directly is used. And attractive in terms of stereoselectivity, economics and industrial ease of use. That is, the compound of formula (2) can be used as a useful intermediate for preparing a compound such as coenzyme Q, vitamin K, or polyprenyl-trimethyl quinone by reacting with a polyprenyl halide having a desired chain length.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Example 1: Preparation of 2- (4-benzenesulfonyl-3-methyl-2-butenyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinone (compound of formula 3)

17.2 g of 1- (4-benzenesulfonyl-3-methyl-2-butenyl) -2,3,4,5-tetramethoxy-6-methylbenzene ( Synthesis 469-471, 1981) After dissolving in, 325.5 g of ammonium cerium nitrate was dissolved in 55 ml of water, and the mixture was stirred for 30 minutes. 130.1 ml of water was added thereto, stirred for 2 hours, filtered, washed with 163.5 ml of water, and dried under reduced pressure to obtain 9.6 g of the title compound as a pearl yellow solid (yield 95%).

mp = 104 ~ 105 ℃

¹ H NMR (300MHz, CDCl ₃ ) δ 7.77 (m, 2H), 7.59-7.44 (m, 3H), 4.83 (t, J = 7.0 Hz, 1H), 3.99 (s, 6H), 3.71 (s, 2H ), 3.11 (d, J = 7.2 Hz, 2H), 1.90 (s, 3H), 1.88 (s, 3H)

Example 2: Preparation of 2- (4-benzenesulfonyl-3-methyl-2-butenyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinol (compound of formula 4)

72.8 ml of dichloromethane with 9.4 g of 2- (4-benzenesulfonyl-3-methyl-2-butenyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinone prepared in Example 1 After dissolving in, 9.2 g of sodium hydrosulfite dissolved in 75 ml of water was added thereto, stirred for 3 hours, and the organic layer was separated. Water was removed with 3.6 g of anhydrous magnesium sulfate, filtered, and the residue was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 9.2 g of the title compound as a white solid ( Yield 97%).

mp = 128 ~ 129 ℃

¹ H NMR (300MHz, CDCl ₃ ) δ 7.74 (m, 2H), 7.52 to 7.35 (m, 3H), 5.33 (s, 1H), 5.22 (s, 1H), 4.92 (t, J = 6.6 Hz, 1H ), 3.89 (s, 3H), 3.87 (s, 3H), 3.70 (s, 2H), 3.24 (d, J = 7.0 Hz, 2H), 1.96 (s, 3H), 1.93 (s, 3H)

Example 3: 1- (4-benzenesulfonyl-3-methyl-2-butenyl) -2,5-bis- (2-tetrahydropyranoxy) -3,4-dimethoxy-6-methylbenzene Preparation of (Compound of Formula 5)

164.0 ml of 8.2 g of 2- (4-benzenesulfonyl-3-methyl-2-butenyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinol prepared in Example 2 After dissolving, 38.1 mL of 3,4-dihydro-2H-pyran was added under a stream of nitrogen, 0.5 g of pyridinium paratoluenesulfonate was added thereto, followed by stirring for 2 hours. To this was added 24.6 ml of ethyl acetate, 41.0 ml of 0.5N sodium hydroxide aqueous solution, and the aqueous layer was removed. The aqueous layer was washed with 41.0 ml of aqueous sodium chloride solution, and the organic layer was separated, dried over 2.1 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 11.1 g of the title compound as a white liquid (yield 95%).

Example 4: 1- (4-benzenesulfonyl-3-methyl-2-butenyl) -2,5-bis- (1-ethoxyethoxy) -3,4-dimethoxy-6-methylbenzene ( Preparation of compound of formula 5

164.0 ml of 8.2 g of 2- (4-benzenesulfonyl-3-methyl-2-butenyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinol prepared in Example 2 After dissolving, 20.1 ml of ethyl vinyl ether was added under a stream of nitrogen, 0.5 g of pyridinium paratoluenesulfonate was added, followed by stirring for 5 hours. 24.6 ml of ethyl acetate was added thereto, 41.0 ml of 0.5N aqueous sodium hydroxide solution was added thereto, and the aqueous layer was removed. An aqueous sodium chloride solution was washed with 41.0 mL, the organic layer was separated, water was removed with anhydrous magnesium sulfate 2.1 g, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 10.8 g of the title compound as a white liquid (yield 97%).

Example 5: 1- (4-benzenesulfonyl-3-methyl-2-butenyl) -2,5-bis- (2-tetrahydrofuranoxy) -3,4-dimethoxy-6-methylbenzene Preparation of (Compound of Formula 5)

8.2 g of 2- (4-benzenesulfonyl-3-methyl-2-butenyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinol prepared in Example 2 was added to dichloromethane 164.0. After dissolving in ml, 31.6 ml of 2,3-dihydrofuran was added under a stream of nitrogen, 0.5 g of pyridinium paratoluenesulfonate was added, followed by stirring for 8 hours. 24.6 ml of ethyl acetate was added thereto, 41.0 ml of 0.5N sodium hydroxide aqueous solution was added thereto, and the aqueous layer was removed. The aqueous layer was washed with 41.0 ml of aqueous sodium chloride solution, and the organic layer was separated, dried over 2.1 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 10.6 g of the title compound as a white liquid (yield 95%).

Example 6: 1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -4-benzenesulfonyl-3,7,11,15,19,23,27,31 , 35,39-decamethyl 2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -2,5-bis- (2-tetrahydropyranoxy)- Preparation of 3,4-dimethoxy-6-methylbenzene (compound of formula 7)

1- (4-benzenesulfonyl-3-methyl-2-butenyl) -2,5-bis- (2-tetrahydropyranoxy) -3,4-dimethoxy-6- prepared in Example 3. 11.1 g of methylbenzene and 14.5 g of solanesyl bromide (purity 95%: prepared in one step according to Helv. Chim. Acta. 42, 2616, (1959)) were prepared with a mixed solution of 85.5 ml of tetrahydrofuran and 10.7 ml of dimethylformamide. And cooled to -10 to -20 ° C. 5.6 g of potassium-t-butoxide was added under a nitrogen stream, followed by stirring for 2 hours. 85.5 ml of purified water was added dropwise, 91.0 ml of ethyl acetate was added thereto, and 20.0 ml of 1N aqueous hydrochloric acid solution was added dropwise and extracted. The extract was washed with 91.0 ml of an aqueous sodium chloride solution, followed by removing water with 8.0 g of anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 21.8 g of the title compound as a white liquid (yield 94%).

Example 7: 1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -4-benzenesulfonyl-3,7,11,15,19,23,27,31 , 35,39-decamethyl 2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -2,5-bis- (1-ethoxyethoxy) -3 Preparation of, 4-dimethoxy-6-methylbenzene (compound of formula 7)

1- (4-benzenesulfonyl-3-methyl-2-butenyl) -2,5-bis- (1-ethoxyethoxy) -3,4-dimethoxy-6-methyl prepared in Example 4 10.4 g of benzene and 14.2 g (95% purity) of solenesil bromide were dissolved in a mixed solution of 85.5 ml of tetrahydrofuran and 10.7 ml of dimethylformamide and cooled to -10 to -20 ° C. 5.6 g of potassium-t-butoxide was added under a nitrogen stream, followed by stirring for 2 hours. 85.5 ml of purified water was added dropwise, 91.0 ml of ethyl acetate was added thereto, and 20.0 ml of 1N aqueous hydrochloric acid solution was added dropwise and extracted. The extract was washed with 91.0 ml of an aqueous sodium chloride solution, dried over 8.0 g of anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 20.9 g of the title compound as a white liquid (yield 94%).

Example 8: 1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -4-benzenesulfonyl-3,7,11,15,19,23,27,31 , 35,39-decamethyl 2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -2,5-bis- (2-tetrahydrofuranoxy)- Preparation of 3,4-dimethoxy-6-methylbenzene (Compound of Formula 7)

1- (4-benzenesulfonyl-3-methyl-2-butenyl) -2,5-bis- (2-tetrahydrofuranoxy) -3,4-dimethoxy-6- prepared in Example 5. 9.5 g of methylbenzene and 13.0 g of pureesane bromide (purity 95%) were dissolved in a mixed solution of 85.5 ml of tetrahydrofuran and 10.7 ml of dimethylformamide and cooled to -10 to -20 ° C. 5.6 g of potassium-t-butoxide was added under a nitrogen stream and stirred for 2 hours. 85.5 ml of purified water was added dropwise, 91.0 ml of ethyl acetate was added thereto, and 20.0 ml of 1N aqueous hydrochloric acid solution was added dropwise and extracted. The extract was washed with 91.0 ml of an aqueous sodium chloride solution, dried over 8.0 g of anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 19.6 g of the title compound as a white liquid (yield 96%).

Example 9:

2-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39-decamethyl-2, Preparation of 6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -5,6-dimethoxy-3-methylbenzene-1,4-diol (compound of formula 8)

(1) Use of the compound prepared in Example 6

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -4-benzenesulfonyl-3,7,11,15,19,23,27,31,35,39 -Decamethyl 2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -2,5-bis- (2-tetrahydropyranoxy) -3,4- 20.4 g of dimethoxy-6-methylbenzene was dissolved in 185.0 ml of tetrahydrofuran, and 0.10 g of [1,2-bis (diphenylphosphino) ethane] dichloropalladium was added under a nitrogen stream. 43.5 mL of super hydride was slowly added thereto and stirred for 3 hours. Diluted with 55.5 ml of ethyl acetate, 148.0 ml of distilled water was slowly added dropwise to the reactor, followed by stirring for 1 hour. After layer separation, water was removed with anhydrous magnesium sulfate 5.0 g, filtered, and concentrated. The concentrated solution was dissolved in 70.0 ml of isopropanol, 20.0 ml of 1N hydrochloric acid aqueous solution was added dropwise, and then heated at 40 ° C. for 1 hour. 100.0 ml of water and 80.0 ml of ethyl acetate were added thereto, and the layers were separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 14.3 g of the title compound as a white liquid (yield 95%).

(2) using the compound prepared in Example 7

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -4-benzenesulfonyl-3,7,11,15,19,23,27,31,35,39 -Decamethyl 2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -2,5-bis- (1-ethoxyethoxy) -3,4-dime 19.2 g of oxy-6-methylbenzene was dissolved in 185.0 mL of tetrahydrofuran, and 0.10 g of [1,2-bis (diphenylphosphino) propane] dichloropalladium was added under a nitrogen stream. 42.5 ml of super hydride was slowly added thereto and stirred for 3 hours. Diluted with 55.5 ml of ethyl acetate, 148.0 ml of distilled water was slowly added dropwise to the reactor, followed by stirring for 1 hour. After layer separation, water was removed with anhydrous magnesium sulfate 5.0 g, filtered, and concentrated. The concentrated solution was dissolved in 70.0 ml of isopropanol, 20.0 ml of 1N hydrochloric acid aqueous solution was added dropwise, and then heated at 40 ° C. for 1 hour. 100.0 ml of water and 80.0 ml of ethyl acetate were added thereto, and the layers were separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 13.6 g of the title compound as a white liquid (yield 94%).

(3) Use of the compound prepared in Example 8

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -4-benzenesulfonyl-3,7,11,15,19,23,27,31,35,39 -Decamethyl 2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -2,5-bis- (2-tetrahydrofuranoxy) -3,4- 16.8 g of dimethoxy-6-methylbenzene was dissolved in 165.0 mL of tetrahydrofuran, and 0.09 g of [1,2-bis (diphenylphosphino) propane] dichloropalladium was added under a nitrogen stream. 36.5 ml of super hydride was slowly added thereto and stirred for 3 hours. Diluted with 50.5 mL of ethyl acetate, 138.0 mL of distilled water was slowly added dropwise to the reactor, followed by stirring for 1 hour. After layer separation, water was removed with anhydrous magnesium sulfate 35.0 g, filtered, and concentrated. The concentrated solution was dissolved in 70.0 ml of isopropanol, 20.0 ml of 1N hydrochloric acid aqueous solution was added dropwise, and then heated at 40 ° C. for 1 hour. 100.0 ml of water and 80.0 ml of ethyl acetate were added thereto, and the layers were separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 12.2 g of the title compound as a white liquid (yield 96%).

(4) Crystallization of the title compound

end. When heptane is used as the crystalline solvent

In Examples (1), (2) and (3) at the bottom of Example 9, the residue was purified by heptane (40.8 mL for Example (1), Example (2) without silica gel purification after the second concentration). Dissolved in 38.4 mL and 33.6 mL of heptane for Example (3), and here EtOH (102 mL for Example (1), 96 mL for Example (2) and Example (3) 84 mL) was added. Then, the mixture was stirred at about 40 ° C. for 30 minutes and cooled to obtain the title compound crystals at 5 to 15 ° C., which was then filtered to obtain high purity (in the case of Example (1), 95.4% of the content of Example (2)). 97.2% in case and 94.8% in Example (3), yielding a high yield of the title compound (98.1% in Example (1), 95.2% in Example (2) and 97.8% in Example (3) )

I. When acetone is used as the crystalline solvent

In Examples (1), (2) and (3) at the bottom of Example 9, the residue was purified by heptane (40.8 mL for Example (1), Example (2) without silica gel purification after the second concentration). Dissolved in 38.4 mL and 33.6 mL of heptane for Example (3), and here EtOH (102 mL for Example (1), 96 mL for Example (2) and Example (3) 84 mL) was then added. After stirring at about 40 ° C. for 30 minutes, the mixture was cooled to obtain the title compound as crystals at 5 to 15 ° C., and then filtered to obtain high purity (in the case of Example (1), content of 96.4%, Example ( 95.2% for 2) and 94.1% for Example (3) to give a high yield (96.1% for Example (1), 96.2% for Example (2) and Example (3) Case 95.8%).

Example 10 CoQ ₁₀ Preparation of (Compound of Formula 1)

(1) Use of iron chloride (FeCl ₃ )

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39 prepared in Example 9 -Decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -5,6-dimethoxy-3-methylbenzene-1,4-diol 12.5 g Was dissolved in 112.8 ml of ethanol, and 3.3 g of iron chloride was added thereto, followed by stirring for 1 hour. 62.6 mL of water was added dropwise, stirred for 30 minutes, the aqueous layer was removed, and extracted again with 187.9 mL of water. Water was removed with 3.1 g of anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 11.8 g of the title compound as a dark yellow solid (yield 95%).

(2) Use of iron chloride and hexahydrate (FeCl ₃ and 6H ₂ O)

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39 prepared in Example 9 -Decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -5,6-dimethoxy-3-methylbenzene-1,4-diol 12.5 g Was dissolved in 112.8 ml of ethanol, 5.4 g of iron chloride and hexahydrate were added, followed by stirring for 1 hour. 62.6 mL of water was added dropwise, stirred for 30 minutes, the aqueous layer was removed, and extracted again with 187.9 mL of water. Water was removed with 3.1 g of anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 11.8 g of the title compound as a dark yellow solid (yield 95%).

(3) the use of copper (II) chloride (CuCl ₂ )

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39 prepared in Example 9 -Decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -5,6-dimethoxy-3-methylbenzene-1,4-diol 12.5 g Was dissolved in 112.8 ml of ethanol, 2.7 g of copper (II) chloride was added, followed by stirring for 1 hour. 62.6 mL of water was added dropwise, stirred for 30 minutes, the aqueous layer was removed, and extracted again with 187.9 mL of water. Water was removed with 3.1 g of anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 11.6 g of the title compound as a dark yellow solid (yield 93%).

(4) Use of copper chloride (II) chloride dihydrate (CuCl ₂ 2H ₂ O)

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39 prepared in Example 9 -Decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -5,6-dimethoxy-3-methylbenzene-1,4-diol 12.5 g Was dissolved in 112.8 ml of ethanol, and 3.8 g of copper (II) chloride dihydrate was added thereto, followed by stirring for 1 hour. 62.6 mL of water was added dropwise, stirred for 30 minutes, the aqueous layer was removed, and extracted again with 187.9 mL of water. Water was removed with 3.1 g of anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 11.7 g of the title compound as a dark yellow solid (yield 94%).

Comparative Example 1: CoQ with Benzyl Protecting Group ₁₀ Preparation of (Compound of Formula 1) [See Scheme 2]

A solution of Q2-Bn (17.8 g, 15 mmol) in Scheme 2 dissolved in anhydrous tetrahydrofuran in a blue solution containing 2.0 g of lithium in a mixed solution of 50 ml of methylamine and 150 ml of dimethylamine was treated at -70 to -75 ° C. Added dropwise. After further stirring for 20 minutes, the excess metal was exhausted by successively adding 5 ml of isoprene, 22 ml of anhydrous methanol and 17 g of ammonium chloride, and then poured into a mixture of ice (500 g) and 200 ml of isopropyl ether and stirring in air for 10 minutes. To oxidize. The orange product was extracted twice with isopropyl ether, washed with dilute hydrochloric acid, dried over sodium sulfate, filtered and dried under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (hexane-isopropylether = 3: 1) to give the resulting orange solid compound which was recrystallized from ether-ethanol to give 10.12 g of pure CoQ ₁₀ (yield 77.3%).

Comparative Example 2: CoQ with MEM Protecting Group ₁₀ Preparation of (Compound of Formula 1) [See Scheme 3]

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39-decamethyl-2, 6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -1,4-bis (2-methoxyethoxymethoxy) -5,6-dimethoxy-3- 118 g (0.1 mol) of methylbenzene (Q2 MEM in Scheme 3) was dissolved in 70 ml of ethanol and 350 ml of dried tetrahydrofuran and administered with crushed sodium metal (18.4 g) at 10 to 15 ° C. under a nitrogen stream. After stirring for 12 hours, 100 ml of ethanol was added to consume excess sodium. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with diisopropyl ether, washed with water and dried over magnesium sulfate. The solution was dried under reduced pressure and purified by silica gel column chromatography to obtain 83.6 g of Q1 MEM of Scheme 3. The compound was dissolved in 1500 ml of isopropyl alcohol, 5 ml of 48% hydrobromic acid was added, and the protective group was removed by stirring at 50 DEG C for 3 hours under a stream of nitrogen. After neutralizing with 10% potassium hydroxide-methanol solution, air was injected at 25 ° C for 3 hours. After drying the solvent under reduced pressure, water was poured, extracted with hexane, and dried over magnesium sulfate. The reaction product was purified by silica gel column chromatography (diisopropylether: hexane = 2: 8) to give CoQ ₁₀ (67.9 g). This was recrystallized from 2500 ml of ethanol at 5 DEG C to obtain 58.4 g of pure CoQ ₁₀ (yield 77%).

Comparative Example 3: CoQ Incorporating Methyl Protecting Group ₁₀ Preparation of (Compound of Formula 1) [See Scheme 4]

1-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39-decamethyl-2, 6,10,14,18,22,26,30,34,38-tetracontadecaenyl] -1,4,5,6-tetramethoxy-3-methylbenzene 154 mg (0.17 mmol) in acetonitrile 0.7 290 mg (0.53 mmol) of ammonium cerium nitrate dissolved in 0.7 ml of dichloromethane and 1.4 ml of 50% acetonitrile solution was added dropwise at 0 ° C for 5 minutes. After stirring at the same temperature for 5 minutes, 10 ml of water was added and extracted with 10 ml of diethyl ether. The organic layer was washed with 10 ml of 5% sodium bicarbonate and 10 ml of water, and water was removed with anhydrous magnesium sulfate. The solution was distilled under reduced pressure to give an oily crude compound which was purified by silica gel column chromatography to give 106 mg of CoQ ₁₀ as a dark yellow solid (yield 72%).

Example 11: Preparation of (2'E) -1- (2,3,4,5-tetramethoxy-6-methylbenzyl) -4'-benzenesulfonyl-3'-methyl-2'-butene

9.2 g of 1,2,3,4-tetramethoxy-5-methylbenzene and 11.6 g of 1-chloro-4-benzenesulfonyl-3-methyl-2-butene are dissolved in 91.6 mL of dichloromethane and under a nitrogen stream. 1.8 g of iron chloride and 0.3 g of acetic acid were added thereto, followed by heating to reflux for 6 hours. The reaction solution was washed with 35.0 ml of 15% aqueous sodium chloride solution, dried with 0.5 g of anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate = 7/3) to give 17.3 g of the title compound as a white solid (yield 93%: E / Z = 18: 1).

Example 12: (2 ' E Preparation of) -2- (1,4-dimethoxy-3-methylnaphthyl) -4'-benzenesulfonyl-3'-methyl-2'-butene

9.2 g of 1,4-dimethoxy-2-methylnaphthalene (prepared in two steps from 2-methyl-1,4-naphthoquinone according to Tetrahedron, 58, 121, (2002)) and 1-chloro-4-benzene 12.3 g of sulfonyl-3-methyl-2-butene are dissolved in 91.6 ml of dichloromethane and ferric chloride under nitrogen stream. After adding 1.8 g and 0.3 g of acetic acid, the mixture was heated to reflux for 6 hours. The reaction solution was washed with 35.0 ml of 15% aqueous sodium chloride solution, dried with 0.5 g of anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate 7: 3) to give 15.6 g of the title compound as a white solid (yield 83%: E).

The process for preparing coenzyme Q _n according to the invention has the following technical features:

First, a specific protecting group, that is, a tetrahydropyranyl (THP) group, a 1-ethoxyethyl (EE) group or a tetrahydrofuranyl (THF) group is selected and used as a hydroxy protecting group. As a result, it was possible to increase the yield of the coupling reaction between the compound of Formula 5 and the compound of Formula 6 and to significantly reduce the rate of cis isomers in the desulfonation process, and to reduce the value of protecting group introduction reagents and to easily remove them under mild acid conditions. There is this.

Secondly, in the step of reacting the compound of Formula 7 to produce the compound of Formula 8, the present invention provides a method of obtaining high purity and high yield through crystallization without purification using silica gel column chromatography. Through this, it is very useful industrially to reduce the effort of the reaction process and obtain a high yield of high purity easily.

Third, in the final step of preparing the compound of Formula 1 by oxidizing the compound of Formula 8, it is very useful industrially because the target compound is obtained in high yield while using a very mild oxidizing agent.

Due to these features, the production method of CoQ _n according to the present invention has the advantage that the yield is improved, economical, easy to process, and stereoselectivity is improved compared to the existing method.

In addition, the compounds of formula (2) which can be used as useful intermediates for the preparation of pharmaceutically active compounds, such as coenzyme Q _n , vitamin K, have a high yield of at least 90% and 18: according to the method of the present invention having the advantages of mild reaction conditions over the existing methods. It can be prepared with high stereoselectivity of about 1 degree.

Claims (16)

The compound of formula 5 is prepared by reacting a compound of formula 5 with a compound of formula 6 in the presence of a base, and a desulfonation reaction and a deprotection reaction under acidic conditions are performed on the compound of formula 7 Iron chloride (FeCl ₃ ), iron chloride, hexahydrate (FeCl ₃ · 6H ₂ O), copper chloride (CuCl ₂ ), copper chloride, dihydrate (CuCl ₂ 2H ₂ O), manganese dioxide (MnO ₂ ) And oxidizing the compound of formula 8 using at least one oxidant selected from the group consisting of sodium hypochlorite (NaOCl): [Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 1]

Where n is an integer from 2 to 12, R ₂ and R ₃ each independently represent C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, or may form a benzene ring with the carbon atom to which they are attached, R ₄ represents C ₁ -C ₄ -alkyl unsubstituted or substituted by halogen, or represents an aromatic hydrocarbon having 6 to 10 carbon atoms unsubstituted or substituted by nitro, R ₅ represents tetrahydropyranyl (THP), 1-ethoxyethyl (EE), or tetrahydrofuranyl (THF), Y represents halogen. The method of claim 1, wherein in the step of preparing the compound of Formula 7 as the compound of Formula 8, the method is characterized in that the purification using a solvent in which acetone or alkane solvent is mixed with methanol or ethanol. The method of claim 2, wherein the alkane solvent is heptane, iso-octane, octane or pentane. The method of claim 2 wherein the volume of methanol or ethanol is 2 to 4 times the volume of the acetone or alkane solvent. According to claim 1, wherein the compound of formula 5 is oxidized the compound of formula (2) to prepare a compound of formula (3), and then reduced to produce a compound of formula (4), the hydroxy group of the obtained compound of formula (4) Method characterized in that the prepared by protecting: [Formula 2]

[Formula 3]

[Formula 4]

Where R ₂ , R ₃ and R ₄ are as defined in claim 1, R ₁ represents methyl, methoxymethyl, ethoxymethyl or benzyl. The method of claim 1, wherein n is 10. 7. A compound of formula [Formula 3]

In the above formula R ₂ , R ₃ and R ₄ are as defined in claim 1. To prepare a compound of formula 3 by oxidizing the compound of formula [Formula 2]

[Formula 3]

In the above formula R ₂ , R ₃ and R ₄ are as defined in claim 1, R ₁ is as defined in claim 5. A compound of formula [Formula 4]

In the above formula R ₂ , R ₃ and R ₄ are as defined in claim 1. To prepare a compound of formula 4 by reducing the compound of formula [Formula 3]

[Formula 4]

In the above formula R ₂ , R ₃ and R ₄ are as defined in claim 1. To prepare a compound of formula 5 by protecting the hydroxyl group of the compound of formula [Formula 4]

[Formula 5]

In the above formula R ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 1. A process for preparing a hydroquinone derivative of formula (II) characterized by reacting a compound of formula (9) with a compound of formula (10) in dichloromethane (MC) in the presence of iron chloride: [Formula 9]

[Formula 10]

[Formula 2]

In the above formula R ₁ represents methyl, methoxymethyl, ethoxymethyl or benzyl, R ₂ and R ₃ each independently represent C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, or may form a benzene ring with the carbon atom to which they are attached, R ₄ represents C ₁ -C ₄ -alkyl unsubstituted or substituted by halogen, or represents an aromatic hydrocarbon having 6 to 10 carbon atoms unsubstituted or substituted by nitro, X represents a halogen. 13. The method of claim 12, wherein iron chloride is used in an amount of 0.1 to 1.0 equivalents based on the compound of formula (9). The method according to claim 12 or 13, further reacted in the presence of acetic acid. The method of claim 12 or 13, wherein X is chloro. The process according to claim 12 or 13, wherein the reaction temperature is heated to reflux at 38 ° C to 45 ° C.