KR100690240B1 - Intermediate compound for ubiquinone and manufacturing method of the same - Google Patents

Abstract

An intermediate compound for preparing ubiquinone and a method for preparing thereof are provided to be able to obtain ubiquinone with high yield and high quality through simple product purification process at relatively cheap cost. The method for preparing a compound represented by the formula(II) or a compound represented by the formula(III) comprises a step of reacting a compound represented by the formula(IV) or a compound represented by the formula(V) with a silylating compound such as trimethylchlorosilane, hexamethyldisilazane, and N,O-bis(trimethylsilyl)acetamide in the presence of an organic polar solvent such as CH2Cl2, 1,2-dichloroethane, acetonitrile and dimethylformamide so as to protect OH group of hydroquinone in the compound of the formula(IV) or the compound of the formula(V). In the formulae, R is alkyl or alkoxy, Z is H or halogen, Y is H, benzene sulfonyl or toluene sulfonyl, and n is an integer from 0 to 9.

Description

Intermediate compound for ubiquinone and manufacturing method of the same

The invention ubiquinone (Ubiquinone) useful new intermediate compounds for the production of (Coenzyme Q ₁₀ (CoenzymeQ ₁₀₎ or ubiquinone deca-fluorenone (Ubidecarenone) by also named compound) and methods for their preparation are shown in the following structural formula (Ⅰ) It is about. Specifically, in the compound represented by the following general formula (IV) or (V), the -OH group of para-hydroquinone is protected by a silyl compound and then ubiquinone represented by the general formulas (II) and (III). It relates to an intermediate compound for preparation.

Wherein R is an alkyl or alkoxy group, Z is hydrogen or halogen, Y is hydrogen, benzenesulfonyl or toluene sulfonyl group and n is an integer from 0 to 9.

The compound represented by formula (IV) or (V) can be easily converted to ubiquinone by protecting the -OH group with a silyl compound as a protecting group, as represented by formula (II) or (III).

In the general formula (II), a compound in which R is a methyl group and Z is hydrogen may be named 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) toluene.

In addition, compounds in which R is a methyl group and Z is bromine may be named 6-bromine-3,4-dimethoxy-2,5-bis (trimethylsilyloxy) toluene.

In the general formula (III), a compound in which R is a methyl group, Y is hydrogen and n = 0 may be named 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6-isoprenyltoluene and n The compound with = 9 is named ubiquinone.

A compound wherein Y is benzenesulfonyl and n = 0 can be named 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (isoprenyl-4-benzenesulfonyl) toluene and n A compound with = 9 may be named 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (decaprenyl-4-benzenesulfonyl) toluene.

A compound wherein Y is toluene sulfonyl and n = 0 can be named 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (isoprenyl-4-toluenesulfonyl) toluene and n A compound with = 9 may be named 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (decaprenyl-4-toluenesulfonyl) toluene.

Ubiquinone is a compound found in bovine heart and is known as a very important bioactive substance present in animals. Ubiquinone is found in all cells of the body and contains about 0.1-1 μmole / ℓ in plasma. It is a substance present in the heart, liver, kidney and pancreas. It is an important physiologically active substance that participates in the oxidation-reduction reaction of the electron transport system through respiration and provides energy to life in mitochondria in cells. In addition, ubiquinone (coenzyme Q ₁₀ ) has been found to be effective in cardiovascular diseases such as heart disease, high blood pressure, diabetes, anti-aging and cancer prevention, and is widely used in cosmetics due to wrinkle improvement, whitening and sun protection. . These compounds must be consumed by food or synthesized in the body. Ubiquinone (coenzyme Q ₁₀ ) is rapidly increasing in use worldwide because diseased or older people need to be supplied externally due to a sharp decrease in their synthesis. And many studies on the preparation method of this compound is in progress.

The production method of ubiquinone (coenzyme Q ₁₀ ) is largely a fermentation method and a synthesis method, and the fermentation method is mainly adopted by Japanese companies.

The following method is known as a manufacturing method by the synthesis method. First, 6-bromo-2,3-dimethoxy-5-methyl-1,4 to a reactant obtained by reacting decaprenyl bromide with lithium trimethyltin, as shown by the chemical equation below. - benzoquinone (6-bromo-2,3- dimethoxy -5 -methyl-1,4-benzoquinone) was reacted by a method of synthesizing ubiquinone (J. org chem, 45, 4097 (1980)... The drawback of this method is that it is difficult to produce decaprenyl bromide and the cost of producing ubiquinone is very high because lithium trimethyltin is very expensive.

Me represents a methyl group and THF represents tetrahydrofuran.

Second, US Patent 6506915 discloses 2,3,4,5-tetramethoxy-6- from 2,3,4,5-tetramethoxytoluene as shown in the following scheme. Geranyltoluene (2,3,4,5-tetramethoxy-6-geranyltoluene) was prepared and then 6,7-epoxygeranyl-2,3,4,5-tetramethoxytoluene (6,7-epoxygeranyl-2 , 3,4,5-tetramethoxytoluene) was prepared and diisopropyl (4E) -1-isopropenyl-4-methyl-6- (2,3,4,5-tetramethoxytoluene-4-hexenyl) Phosphate (diisoprpyl (4E) -1-isopropenyl-4-methyl-6- (2,3,4,5-tetramethoxytoluene-4-hexenyl phosphate) was prepared and reacted with geranylgeranyl magnesium bromide To prepare a compound having 30 carbon atoms in the side chain, and to prepare an isoprenoid compound having 20 carbon atoms in the compound through several steps. Production cost There is a problem of being high.

Third, U.S. Patent 3896153 discloses 6-bromo-2,3,4,5-tetramethoxytoluene and decaprenyl bromide (6-bromo-2,3,4,5-tetramethoxytoluene) as shown in the following scheme. It describes a method for synthesizing ubiquinone through several steps by reacting decaprenyl bromide with nickel carbonyl (Ni (CO) ₄ ). However, this manufacturing method is also difficult to produce decaprenyl broamide, and the purification process is very complicated, the yield is very low.

Fourth, US Pat. No. 40,628,79 reacts 2-hydroxy-3,4,5-trimethyltoluene with boron hydroxide [B (OH) ₃ ] as shown in the following scheme. To protect the -OH group at position 2 with a boron compound, react with decaprenyl bromide to prepare a compound having a decarprenyl group introduced at position 6, remove the protecting group, and remove FeCl ₃ -6H ₂ O. A method of preparing ubiquinone by reduction with is described.

Recently, 3,4-dimethoxy-2,5-dialkylmethyl-6- (isoprenyl-4-benzenesulfonyl) toluene or 3,4-dimethoxy-2 of the following structural formula (VI) Compound represented by the following general formula by reacting, 5-dialkoxymethyl-6- (isoprenyl-4-benzenesulfonyl) toluene with solanesyl bromide brominated -OH group of solanesol extracted from tobacco leaves And ubiquinone by removing a protecting group therefrom. (References JO Chem ., 2003, 68, 7925, Bull. Chem. Soc., Jpn ., 1982, 55, 1325) , Synthesis, 1981, 469)

R group is an alkyl, alkoxymethyl, benzyl group, etc. here.

Recently, a method for preparing ubiquinone includes preparing a compound of Formula (VI) by protecting the OH group of a compound represented by Formula (IV), wherein Z is isoprenyl-4-benzenesulfonyl group. The manufacturing process by introducing the nesil group is simple and economically competitive, and is widely used.

In this case, it is very important to protect the -OH group at the 2,5-position of the para-hydroquinone compound with a protecting group in the intermediate for preparing ubiquinone. In the process of synthesizing ubiquinone, if the -OH group is not protected, a side reaction proceeds and the yield becomes very low, or it is difficult to obtain the final target ubiquinone. Therefore, the selection of the protector is an important factor in determining the production cost and quality of producing the end object. That is, the production yield should be high in the process of introducing R, a protecting group, and a functional group that can be easily removed after the reaction should be selected.

Reagents mainly used to protect the -OH group of para-hydroquinone in the compound represented by the above structural formula (VI) include methyl halide, benzyl halide, halomethyl alkyl ether, halomethylalkoxyethyl ether, alkoxy vinyl ether, dialkoxy Methane and the like were mainly used. However, these reagents are expensive and the reaction proceeds only when the reagents are used excessively to protect the -OH group. In the case of alkyl halides or benzyl halides, sodium alkoxides are used as bases, and halomethyl alkyl ethers and halomethyl alkoxy ethyl ethers are used. , Alkoxy vinyl ether or dialkoxymethane does not proceed unless the acidic catalyst is used. The acid catalyst to be used, too, for example an organic acid having an acid uses an expensive catalyst such as pyridinium p-toluene sulfonate nium (pyridinium p -toluenesulfonate) and Nafion-H. In addition, in this reaction, both OH groups should be protected. When these reagents are used, compounds that protect only one OH group are made of impurities, resulting in low purity of 80-85% and lowering reaction yields. In addition, since there are many kinds of side reaction products, there are many difficulties in pure purification.

In addition, in the process of preparing ubiquinone (coenzyme Q ₁₀ ) by removing a benzenesulfonyl group after preparing compound (iii) and then removing a protecting group of OH group, ammonium cerium (IV) nitrate when the protecting group is alkyl or benzyl group (ammonium cerium (Ⅳ) nitrate) should be used, and the yield is very low, 50-60%. In addition, in case of using halomethyl alkyl ether, halomethyl alkoxy ether, alkoxy vinyl ether or dialkoxymethane, the reaction time is long in the process of removing the protecting group, and the yield is low in this process due to the use of strong acid. Purification is complicated because they are produced and the silica gel chromatography method must be used for purification. For this reason, it is a factor that increases the production cost of the product.

As described above, in the method for preparing ubiquinone by the conventional synthesis method, the para-hydroquinone compound represented by the general formula (III) may be methyl halide, benzyl halide, halomethyl alkyl ether, alkoxy vinyl ether, dialkoxy metal or boron compound. React with [B (OH) ₃ ] to protect the -OH group of the para-hydroquinone compound with alkyl, alkoxy, benzyl, boron, etc., or use a base such as sodium alkoxide, pyridinium paratoluene sulfonate, or Nafion-H. To prepare a compound represented by the general formula (VI) having a purity of about 80-85% in a syrup state, and reacting the compound (VI) with solanesil broamide to introduce a solanesol group to In order to prepare the compound represented by the formula and to remove the protecting group of the OH group protected by the benzenesulfonyl group, an ammonium cerium nitrate catalyst or The ubiquinone was synthesized through a complicated purification process.

However, the aforementioned methods should use an expensive catalyst when introducing a protecting group to the -OH group of para-hydroquinone, and impurity formation and yield reduction of the compound represented by formula (VI) and compound (VI). ) And solanesyl bromide were prepared to remove benzenesulfonyl group, and strong acid was used in OH group protecting group removal process to produce various various by-products and to remove these impurities. There is a problem that the yield is lowered by applying.

The general formula (Ⅳ) compound and formula (Ⅴ) to protect OH group in the compound represented by N, O represented by the invention-bis (trimethylsilyl) acetamide (N, O -bis (trimethylsilyl) acetamide), Using trimethylchlorosilane, hexamethyldisilazane and the like, compounds represented by the above general formulas (II) and (III) in which two OH groups are easily protected with a silane compound can be obtained.

It is an object of the present invention to provide novel intermediate compounds for the preparation of ubiquinones and methods for their preparation.

Specifically, in the method for synthesizing ubiquinone by using the para-hydroquinone compounds represented by the general formulas (IV) and (V) as an intermediate, the -OH group of the para-hydroquinone compound is protected by a silyl compound. It is to provide an intermediate compound for producing ubiquinone represented by the general formulas (II) and (III) and a method for producing the same.

Intermediates for producing ubiquinone of the present invention can be manufactured in high yield and low cost, and has the characteristic of preparing ubiquinone by removing a protecting group by a simple method.

In addition, there is an advantage that can be easily removed from the aqueous hydrochloric acid solution to remove the silane compound introduced to protect the OH group after the reaction of the compound represented by the general formula (III) protected with silane and solanesil bromide. When using this method, the purification process is very simple because almost no impurities are produced in the preparation of ubiquinone as the final target, and it is very economical because the product can be manufactured in high yield and high purity without using the purification method of chromatography. .

The present invention relates to an intermediate compound for producing ubiquinone represented by the following general formula (III) and a method for producing a new intermediate compound for producing ubiquinone represented by the following general formulas (II) and (III).

Specifically, the present invention relates to an intermediate compound for preparing ubiquinone in which a -OH group is protected by a silyl compound in the para-hydroquinone compound represented by the general formula (IV) or (V).

In the present invention, silane compounds such as trimethylchlorosilane, hexamethyldisilazane, N, O -bis (trimethylsilyl) acetamide, and the like may be used to protect the -OH group of the hydroquinone of the silyl compounds, such as methylene chloride, 1,2-dichloroethane, When reacted at 25-80 ° C. in an organic solvent such as acetonitrile, 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) toluene, 6-bromine-3,4-dimethoxy- 2,5-bis (trimethylsilyloxy) toluene, 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (isoprenyl-4-benzenesulfonyl) toluene and 3,4-dimeth The oxy-2,5-bis (trimethylsilyloxy) -6- (decaprenyl-4-benzenesulfonyl) toluene compounds were prepared.

In addition, since the removal of the protecting group is completely removed in a dilute acidic aqueous solution in a short time, the yield of this process is also a useful manufacturing method to lower the manufacturing cost to produce the ubiquinone in a yield of more than 95%. The present invention will be described in detail with reference to the following Examples.

The reaction scheme of the production method of the present invention is as follows.

R in the above formulas is an alkyl or alkoxy group.

Example 1

<Production of 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) toluene>

10 g of 2,3-dimethoxy-6-methyl-1,4-hydroxyquinone (2,3-Dimethoxy-6-methyl-1,4-hydroquinone) contained in the compound represented by the general formula (IV) Is dissolved in 50 ml of 1,2-dichloroethane and completely dissolved. 32 ml of bis (trimethylsilyl) acetamide (BSA) is added and raised to 50 ° C. Stir at 45-50 ° C. for 6 hours and slowly lower the temperature to 30 ° C., add 100 ml of H ₂ O and stir for 20 minutes. The layers were separated and the aqueous layer was removed. The organic layer was taken, 5 g of MgSO ₄ was added, and dehydrated for 20 minutes. Filter and concentrate at 50 ° C. 50 ml of acetone are added to the concentrate, and the mixture is stirred at room temperature for 1 hour. Slowly lower the temperature to 0-5 ° C. and stir for 1 hour. The precipitate is filtered off and washed with acetone. 17g of white crystals were obtained in the same manner as above. As a result, it was confirmed that the white crystal obtained in this example was 3,4-dimethoxy-2,5-bis (trimethylsilyl) toluene.

Example 2

<Preparation of 6-bromine-3,4-dimethoxy-2,5-bis (trimethylsilyloxy) toluene>

5-Bromo-2,3-dimethoxy-6-methyl-1,4-hydroquinone (5-Bromo-2,3-dimethoxy-6-methyl- contained in the compound represented by the general formula (IV) 10 g of 1,4-hydroquinone) is added to 50 ml of 1,2-dichloroethane and completely dissolved. 30 ml of bis (trimethylsilyl) acetamide (BSA) was added to the reactor and raised to 50 ° C. Stir at 45-50 ° C. for 6 hours and slowly lower the temperature to 30 ° C., add 100 ml of H ₂ O and stir for 20 minutes. The layers were separated and the aqueous layer was removed. The organic layer was taken, 5 g of MgSO ₄ was added, and dehydrated for 20 minutes. Filter and concentrate at 50 ° C. 40 ml of ethanol was added to the concentrate, and stirred at room temperature for 1 hour. Slowly lower the temperature to 0-5 ° C. and stir for 1 hour. The precipitate is filtered off and washed with acetone. In the same manner as above, 15 g of white crystals were obtained. As a result, it was confirmed that the white crystal obtained in this example was 3,4-dimethoxy-2,5-bis (trimethylsilyl) toluene.

Example 3

<Production of 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (isoprenyl-4-benzenesulfonyl) toluene>

2,3-dimethoxy-6-methyl-5- (isoprenyl-4-benzenesulfonyl) -1,4-hydroquinone (2,3-dimethoxy contained in the compound represented by the general formula (V) 10 g of -6-methyl-5- (isoprenyl-4-benzenesulfonyl) -1,4-hydroquinone) is added to 50 ml of 1,2-dichloroethane and completely dissolved. 30 ml of bis (trimethylsilyl) acetamide (BSA) was added to the reactor and raised to 50 ° C. Stir at 45-50 ° C. for 6 hours and slowly lower the temperature to 30 ° C., add 100 ml of H ₂ O and stir for 20 minutes. The layers were separated and the aqueous layer was removed. The organic layer was taken, 5 g of MgSO ₄ was added, and dehydrated for 20 minutes. Filter and concentrate at 50 ° C. 40 ml of ethanol was added to the concentrate, and stirred at room temperature for 1 hour. Slowly lower the temperature to 0-5 ° C. and stir for 1 hour. The precipitate is filtered off and washed with acetone. In the same manner as above, 13 g of white crystals were obtained. As a result, it was confirmed that the white crystal obtained in this Example was 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (isoprenyl-4-benzenesulfonyl) toluene.

Example 4

<Production of 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (isoprenyl-4-benzenesulfonyl) toluene>

6-bromo-3,4-dimethoxy-2,5-bis (trimethylsilyloxy) toluene (6-bromo-3,4-dimethoxy-2,5 contained in the compound represented by the general formula (IV) After dissolving 10 g of -bis (trimethylsilyloxy) toluene) in 100 ml of tetrahydrofuran and adding 0.65 g of Mg turning to react for 2.5 hours at 40 ° C. to prepare a Grignard reagent, copper bromide (Ⅰ) Add 3.3 g and stir for 30 minutes. ( E ) -4-chloro-2-methyl-1-phenylsulfonyl-2-butene (( E ) -4-chloro-2-methyl-1-phenyl- sulfonyl-2-butene) 2.8 g of tetrahydrofuran To the solution dissolved in 100 ml was added dropwise at 0 ℃ or more and stirred for 2 hours. 300 ml of diethyl ether are added, 50 ml of saturated ammonium chloride solution is added, stirred for 10 minutes, and the layers are separated. 150 ml of diethyl ether is added to the aqueous layer and extracted again. The layers were separated, the aqueous layer was removed, the ether layers were combined, combined and dehydrated with 5 g of MgSO ₄ for 10 minutes and filtered. Concentrate the filtrate and dissolve completely by adding 15 ml of ethanol. Slowly lower the temperature to -5 ° C, stir for 1 hour and filter the precipitate. In the same way as above, 13g of yellowish white crystals can be obtained. As a result of the analysis, it was confirmed that the white crystals obtained in this example were 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (isoprenyl-4-benzenesulfonyl) toluene.

Example 5

<Production of 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (decaprenyl-4-benzenesulfonyl) toluene>

10 g of 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (decaprenyl-4-benzenesulfonyl) toluene contained in the compound represented by the above general formula (V) was added to the reactor. Add 200 ml of tetrahydrofuran and dissolve completely. 10 g of solanesyl bromide is added to dissolve. Align the temperature at -50 ℃ potassium - exerts a butoxide (potassium tert -butoxide) 2.6 g below -45 ℃ - t. After stirring at −45-50 ° C. for 1 hour, 100 ml of ethyl acetate was added. When the temperature reaches -15 ~ -20 ℃, add a solution of 8g of ammonium chloride to 200ml of H ₂ O. The temperature is raised and stirred at 20 ° C. for 30 minutes. The layers were separated, the aqueous layer was removed, the organic layer was taken, 10 g of MgSO ₄ was added to the organic layer, and dehydrated for 20 minutes. Filter and concentrate at 50 ° C. 150 ml of hexane and 75 ml of acetonitrile were added to the concentrate, stirred for 30 minutes, and the layers separated. 150 ml of hexane is added to the lower layer of acetonitrile and reextracted. Take the hexane layer, combine and concentrate. In the same way as above, 20g of an oil-based yellow concentrate can be obtained. As a result of the analysis, it was confirmed that the concentrate obtained in the present example was 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (decaprenyl-4-benzenesulfonyl) toluene.

Example 6

<Production of Ubiquinone (Coenzyme Q10)>

10 g of 3,4-dimethoxy-2,5-bis (trimethylsilyloxy) -6- (decaprenyl-4-benzenesulfonyl) toluene concentrate contained in the compound represented by the above general formula (III) The solution dissolved in 20 ml of hydrofuran is slowly added dropwise to 30 ml of superhydride at 0-5 ° C. At 0-5 ° C. [1,2-bis (diphenylphosphino) ethane] palladium (II) dichloride ([1,2-bis (diphenylphosphino) ethane] palladium (II) dichloride) is added and stirred for 10 minutes. The temperature is raised to 40-45 ° C. and reacted for at least 14 hours. 100 ml of hexane, 50 ml of isoprophyl alcohol and 100 ml of H ₂ O were added and stirred for 30 minutes. The layers were separated, the aqueous layer was removed, the organic layer was taken, 5 ml of hydrochloric acid and 25 ml of isopropyl alcohol were added, followed by stirring for 2 hours. 100 ml of H ₂ O was added thereto, stirred for 10 minutes, and the layers were separated. The layers were separated, the aqueous layer was removed, the organic layer was taken, 10 g of MgSO ₄ was added to the organic layer, and dehydrated for 20 minutes. The filtrate is completely concentrated, 30 ml of hexane is added to the concentrate, 30 ml of ethanol is dissolved, and 6 g of copper chloride (II) dihydrate is added thereto. 5 ml of hydrochloric acid is added and stirred for 2 hours. 50 ml of H ₂ O was added thereto, stirred for 10 minutes, the layers were separated, the aqueous layer was removed, an organic layer was taken, 10 g of MgSO ₄ was added to the organic layer, and dehydrated for 20 minutes. Filtrate was concentrated, filtrate was added 50ml of ethanol, and stirred at room temperature for 1 hour, and stirred at 0-5 ° C for 1 hour and filtered. Recrystallization of this crystal in isoprophyll alcohol yields 7.1 g of orange crystal ubiquinone.

The intermediate compounds for preparing ubiquinone of the present invention can be prepared at low cost, and have an effect that can be usefully used to prepare ubiquinone in a simple manner.

Claims (4)

delete An intermediate compound for producing ubiquinone represented by the following general formula (III).

Wherein R is an alkyl or alkoxy group, Y is hydrogen, benzenesulfonyl or toluene sulfonyl and n is an integer from 0 to 9. The following compound represented by the general formula (IV) or (V) is reacted with a silyl compound in an organic polar solvent to compound -OH group of the hydroquinone in the compound represented by the general formula (IV) or (V). Method for preparing a compound represented by the general formula (II) or formula (III) after protecting with.

Wherein R is an alkyl or alkoxy group and Z is hydrogen, halogen.

Wherein R is an alkyl or alkoxy group, Y is hydrogen, benzenesulfonyl or toluene sulfonyl and n is an integer from 0 to 9.

In which Z is hydrogen or halogen.

Wherein Y is hydrogen, benzenesulfonyl or toluenesulfonyl and n is an integer of 0-9. The method of claim 3, The organic polar solvent is selected from methylene chloride 1,2-dichloroethane, acetonitrile or dimethylformamide and the silyl compound is selected from trimethylchloro silane, hexamethyldisilazane, or N, 0 -bis (trimethylsilyl) acetamide Method for producing a compound represented by formula (II) or (III).