JPS5826327B2 - Hokosokyuuruino Goseihou - Google Patents

Description

[Detailed description of the invention] The present invention relates to the following chemical formula (I) [In the formula, R is the following formula represents a group, S is O-1 hydrogen atom or represents something that is accomplished.

] This relates to a novel method for synthesizing 2,3-dimethoxy-5-methyl 6-substituted-1,4-benzoquinone in which the bond is represented by the integer 1, A, B, and A-B.

Compound (I) is known as coenzyme Q, and is particularly a compound in which AB forms a bond and S is 9, 2,3-dimethoxy-5-methyl-6-zocaprenylroot 4-benzoquinone [2,3-dimethoxy 5-methyl-6-(3.7.11
・15, 19, 23, 27, 31, 35, 39-decamethyltetracontasicaene-2-6, 10, 14, 18
・22 ・26・30・34 ・38-Eel)-1・
4-benzoquinone] is called coenzyme Q+O, and it is involved in the electron transport system in the body and plays an important role in energy production, and is expected to have many clinical effects from a medical and pharmaceutical standpoint. be.

The method for synthesizing the seven-chain quinone compound represented by coenzyme Q+o is 2,3-dimethoxy6-methyl-1,4
- benzohydroquinone or its 1-monoacylate and (yne)decaprenol or its reactive derivative in a protic acid such as formic acid, sulfuric acid, hydrochloric acid, phosphoric acid, P-toluenesulfonic acid: zinc chloride, aluminum chloride, boron trifluoride ether complex A method is known in which the desired product is obtained by reacting the condensation product in the presence of an acidic condensation catalyst such as a Lewis acid or a mixture thereof, and then subjecting the condensation product to hydrolysis as necessary and then oxidizing it. There is.

(Special Publications No. 39-17513, No. 39-17514, No. 4
6-3967).

However, these methods do not have good yields in the condensation step, so the yield of the desired quinone compound is very low, at most 30% even in the crude product.

Furthermore, the acid catalysts used are not only highly corrosive and undesirable in terms of equipment, but also the eluted metal contaminates the product, which is an unavoidable disadvantage in industrial implementation.

Furthermore, by using the above-mentioned catalyst, operations such as neutralization and extraction are required to separate the desired product from the resulting reaction product, and a large amount of catalyst is used relative to the raw material, and in addition, often have to be discarded after the reaction (which is not desirable from the viewpoint of cost and pollution, and has many industrial difficulties).

Various studies have been made to improve the yield of this condensation step,
2,3-dimethoxy-5-methyl-6 halogenol 1 ・
4-benzohydroquinone 1,4-dimethoxymethyl ether or 1,4-diacetate and the following chemical formula (m
) [In the formula, X represents a halogen atom, and R represents the above meaning.

-1---1 site represents a semi-bond---1--1 site represents a double bond.

] by bonding a π-allylic nickel complex represented by
A method was developed to obtain the corresponding benzo-hydroquinone in high yield.

(Japanese Unexamined Patent Publications No. 47-25137, No. 48-85546).

However, although these methods have greatly improved the condensation yield, the Ni(CO)4 used to prepare the π-allylic nickel complex (III) is toxic to the respiratory system and gaseous. Because it is a spherical substance, handling is complicated and industrialization is difficult.

The present inventors aim to develop a method for efficiently obtaining the quinone compound represented by the chemical formula (n), and to efficiently and industrially obtain the idoquinonation-A compound, which is a precursor of the quinone compound. We strive to improve the condensation process,
The method of the present invention has been arrived at.

The method of the present invention has the following general formula (n) [where m represents an integer of 1 to 3, and n represents an integer of O to 2].

However, m and n always satisfy the relationship m+n=3.

] 2,3-dimethoxy-6=methyl-1.
4-benzohydroquinone 1-borate has the following general formula (m) [wherein R represents the above-mentioned meaning].

Xl or X2 represents that one is a hydroxyl group and the other is a hydrogen atom.

] (iso)prenol or its reactive derivative or its reactive derivative is reacted to form the following general formula (
IV) [In the formula, R, m and n represent the above meanings.

] 2,3-dimethoxy-5-monosubstituted-6-methyl-1,4-benzohydroquinone 1borate (hereinafter referred to as ① process) and the obtained compound (IV
) is treated with a mild oxidizing agent to form the following general formula (I) [wherein R represents the above-mentioned meaning].

2,3-dimethoxy5-monosubstituted-6-methyl-1,4-benzoquinone (
(hereinafter referred to as process port).

In step A, the molar ratio of (iso)prenol or its reactive derivative (III) to be reacted with (n') is 2,3-dimethoxy-6- in compound (II).
This is a numerical value corresponding to the composition ratio of the methyl-1,4-benzinohydroquinone moiety, that is, m.

The reaction is carried out without a solvent or using an organic solvent inert to the reaction, such as evabenzene, toluene, xylene, n-hexane, cyclohexane, ethyl ether, tetrahydrofuran, etc. alone or in a mixed system.

Generally, the use of an organic solvent is advantageous in that the reaction can be carried out smoothly and that post-reaction treatment is easy.

In addition, as a method for carrying out step I, one of compound (n) or (III) can be absorbed using the above-mentioned organic solvent as an adsorption solvent, such as silicic acid, silica gel, clay, kaolin, magnesium silicate (Florisil), activated carbon, palm chit, natural Alternatively, it can be adsorbed onto an adsorbent used in conventional chemical operations such as synthetic zeolite, alumina, silica alumina, silica magnesia, etc., and the other can be dissolved therein, if necessary, with the above-mentioned organic solvent, and then operated in a batch or column method. adsorption, contact and reaction.

The reaction product (IV) is, for example, an ether solvent such as ethyl ether or isopropyl ether, an aromatic hydrocarbon solvent such as benzene, toluene, or xylene, chloroform,
Aliphatic or rhodanized hydrocarbon solvents such as trichloroethane can be extracted or eluted from the adsorbent using a single or mixed system.

Compound (III), which is a starting material of the present invention, is prepared by combining 2,3 dimethoxy-6-methyl-1,4-benzohydroquinone and boric acid or borax according to J, Am, Chem.

Sec, 75.213 (1953) and infrared absorption 1385CrrL'.
Its formation was confirmed by the expansion and contraction of absorption at the 0 site.

Since compound (n) is very unstable against moisture and the like, it is desirable to prepare it before use and proceed to the condensation reaction with (III) without isolation.

Examples of (iso)prenol or its reactive derivative in the present invention include 3-methylbuten-2-ol-1
・3-methylbuten-1-ol-3, geraniol,
Linalool, nerol, nerolitol, phytol, infitol, geranylgeraniol, geranyl linalool, keranyl farnesol, keranyl nerolidol, geranylgeranyl farnesol, Solai Sol,
Decaprenol, indecafrenol, undecaprenol, dodecaprenol or lower alkyl ethers and esters derived from these alcohols
Examples include halides.

Compound (IV) obtained in Step A can be transferred to the process entrance without being isolated and purified.

As a mild oxidizing agent at the process entrance, for example, % Kosho 3
Silver oxide, lead oxide, ferric chloride, etc. described in No. 9 17514 can be used.

The method of the present invention has significant improvements over the conventional method described above in the following points.

(1) Improvement in Yield In the method of the present invention, the condensation efficiency in step (a) is high, so that the final target product, quinone compound (I), can be obtained in high yield.

For example, for coenzyme Q1o, it is 22% when no adsorbent is used.
or more, and when using an adsorbent, 45% or more pure product was obtained.

(il) Reduction in the number of steps Compound (IV) Since the It-increasing step is directly oxidized and converted to Compound (I), the saponification step is not necessary.

(lii) Effect of preventing corrosion and pollution of equipment, etc. Conventionally, when condensing 2,3-dimethoxy-5-methyl-1,4-benzohydroquinone or its derivative with (iso)prenol or its reactive derivative, zinc chloride was Acidic reagents such as trifluoroboronate complex are used as condensation catalysts, but these acidic reagents are highly corrosive to the reaction equipment, so corrosion-resistant materials must be used for the reaction equipment. Furthermore, when metal rides are used, the eluted metal ions cause pollution, but the method of the present invention eliminates these concerns because these acidic condensation catalysts are not used.

From the above, it can be said that the method of the present invention is industrially superior to the conventional method.

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

Example 1 2,3-dimethoxy-5-methyl-6-decafrenyl-
Preparation method of benzoquinone-1,4 2,3-dimethoxy-5-methyl-benzhydroquinone-1,4 (11f) and boric acid 36Z are mixed with benzene 50Tr
Add to Ll and heat.

After removing the azeotrope, the benzene is distilled off.

10 ml of toluene is added to the residue, heated at 50 to 55°C, and while stirring, isodecaprenol (purity 90%) 141 is added, and stirring is continued for 5 hours under the same conditions.

After the reaction is complete, the reaction mixture is diluted with 200rnl of ethyl ether.
The 1-full extract was washed with water, washed with alkaline water, and then dried with mirabilite.

Add 6 g of silver oxide to this ether extract, and let stand overnight at room temperature while stirring.

The reaction mixture is filtered and the solvent is distilled off from the p liquid.

An oily residue of 15.9 P is obtained.

This is purified by silica gel chromatography using n-hexane containing 5% ethyl ether as an eluent.

Evaporation of the solvent yields an orange-yellow oil 5.42.

This is crystallized from acetone to obtain orange crystals with a melting point of 49°C.

Yield: 3.9P (yield: 22.6%) It was identified as the standard product based on ultraviolet absorption spectrum measurements, infrared absorption spectrum measurements, nuclear magnetic resonance spectrum measurements, and mass spectrum measurements.

Example 2 Preparation of 2,3-dimethoxy-5-methyl-6-decaprenylpenzoquinone 4 2,3-dimethoxy-5-methyl-benzohydroquinone 4 (11 g) and boric acid 3.6' ? After refluxing in toluene and removing the azeotrope, the toluene is distilled off.

20 ml of benzene, 30 ml of hexane, and 172 ml of silica alumina N-633H (JGC Chemicals) are added to the residue.

This was heated and stirred at 30°C and decaprenol (purity 94
%) 142 dissolved in 10 ml of n-hexane.
The mixture was added dropwise over 0 minutes, and stirring was continued for 40 minutes at the same temperature.

After the reaction is completed, the adsorbent is removed from door to door, the resulting p liquid is concentrated,
The resulting residue was extracted with 300 ml of ethyl ether, and the ether extract was washed with water, washed with alkaline water, and dried with sodium sulfate.

Silver oxide 61 was added to this ether extract, and the mixture was allowed to stand overnight at room temperature while stirring.

The reaction mixture was filtered and the solvent was distilled off from the p solution to form an oily residue i1.
6. ．． get ll.

This is purified by silica gel chromatography using n-hexane containing 5% ethyl ether as an eluent.

The solvent is distilled off to obtain orange-yellow oil 1071.

This gave monospots in thin layer and reverse layer chromatography.

The above oily substance is crystallized from acetone to obtain orange-yellow crystals with a melting point of 49°C.

Yield 8.51 (yield 49.2%) Various measurements similar to those in Example 1 were performed and the product was identified as a standard product.

Example 3 2. Preparation of 3-dimethoxy-5-methyl-6-zocaprenylpenzoquinone-1.4 2.3-dimethoxy-5-methyl-benzohydroquinone-1.4. (11P), boric acid 3.61, and decaprenol (94% purity) 142 were reacted according to Example 2.

However, Wakogel C-200 (Wako Tsumugi Products) 21' was used as an adsorbent, and the condensation reaction temperature was 70°C.

Orange-yellow crystals with a melting point of 49°C were obtained.

Yield 7.72 (yield 446%) The same measurements as in Example 1 were carried out and it was identified as a standard product.

Example 4 2,3-dimethoxy-5-methyl-6-nonafrenyl-
Production method of benzoquinone-1, 4 2, 3-dimethoxy-5-methyl-benzohydroquinone-1, 4 (1['), borax 362, solanesol 1
2.61 is reacted according to Example 1.

Orange crystals are obtained with a melting point of 45°C.

Yield 4.1'? (Yield 25.8%) The same measurements as in Example 1 were carried out and it was identified as a standard product.

Example 5 Preparation of 2,3-dimethoxy-5-methyl-6-phytyl-benzoquinone-1,4 2,3-dimethoxy-5-methyl-benzohydroquinone-1,4 (18 g), boric acid 5.9 Infitol (90% purity) 111 is reacted according to Example 2.

The desired product was obtained as a red oily substance.

Yield 133P (yield 846%) Various measurements similar to those in Example 1 were performed and the product was identified as a standard product.

Example 6 Preparation of 2,3-dimethoxy-5-methyl-6-7renylpenzoquinone-1,4 2,3-dimethoxy-5-methyl-benzohydroquinone-1,4 (18 g), boric acid 5.6P13-methyl-
Buten-1-ol-361 is reacted according to Example 2.

The desired product is obtained as a dark red oil.

Yield 121 (yield 58.0%) Various measurements similar to those in Example 1 were performed and the product was identified as a standard product.

Claims (1)

[Scope of Claims] First-order general formula [where m represents an integer of 1 to 3 and n represents an integer of O to 2]. However, m and n always satisfy the relationship m+n=3. ] 2,3-dimethoxy-6-methylto 4
-Benzohydroquinone 1-borate has the following general formula [wherein X1 or X2 represents that one is a hydroxyl group and the other is a hydrogen atom. R represents a group of the following formula, S represents an integer from O to 11, A and B represent hydrogen atoms, and L. represents forming a bond with 1-B in some cases. ] Prenol or isofrenol represented by the following general formula [wherein R, m and n represent the above-mentioned meanings] was obtained. 2,3-dimethoxy-5-monosubstituted-6-methyl-1,4-benzohydroquinone 1-borate represented by the following formula [wherein R is express meaning. ] A method for producing 2,3-dimethoxy-5-methyl 6-substituted-1,4-benzoquinone.