KR840001717B1 - Process for the preparation of quininone compounds - Google Patents

Abstract

HCH:CH; Y1=H, OH, CO2H, CN, acyloxy, optionally substituded CONH2; X=CH:CH, C:C; m=0-3; n=0-10; n'1-5; k=1-3) and their pharamaceutically acceptive salts were prepd. Thus, II was treated with 2, 6-dicarboxypyridine N-oxide and ceric ammonium nitrate to give 82% I(R,R1=MeO, R2=OH, X=C: C, m=o, n=4, q=3, k=1) which inhibited the prodn. of the slow-reacting substance of anaphyaxis(SRS-A) by 88% at 10μM compared with eicosatetryaynoic acid which inhibited SRS-A by 56.9% at 10 μM in guinea prgs.

Description

[Name of invention]

Process for preparing quinone compound

Detailed description of the invention

The present invention relates to a process for the preparation of a compound which is of value as a drug or as an intermediate of such a drug.

In particular, the present invention relates to a process for the preparation of quinone compounds of the general formula (Ia) and of pharmaceutically usable salts.

Wherein R ¹ is a methyl or methoxy group or both R ¹ together represent a —CH═CH—CH═CH—group, X is —CH═CH— or —C≡C—, Y ¹ is hydrogen, hydroxyl , Carboxyl, cyano, acyloxy, or -COZ (where Z is an amino or substituted amino group), m is an integer of 0-3, n is an integer of 0-10, n ¹ is an integer of 1-5 k is an integer of 1 to 3, and when k is 2 or 3, n ¹ is an arbitrary variable of 2 times in the range of 1 to 5 3 times.

」이며, 이에 대하여 본 발명의 목적 화합물은 6-위치의 측쇄중에 「-CH=CH-」또는「-C=C-」기를 함유하고 있으므로 양자는 명확히 구별될 수 있다. 또한 본 발명의 목적 화합물은 상기의 공지 화합물에 비하여 SRS-A의 산생(generation and release of SRS-A) 억제작용이 뛰어나다.Conventionally, U.S. Patent No. 3,728,362 (April 17, 1973), filed and filed by the applicant, describes quinone compounds with frequent anti-inflammatory actions. However, the compounds described in the above US patent specification have a 6-position side chain “

On the other hand, since the objective compound of the present invention contains a "-CH = CH-" or "-C = C-" group in the 6-position side chain, the two can be clearly distinguished. In addition, the target compound of the present invention is superior to the generation and release of SRS-A (SRS-A) inhibitory effect compared to the known compounds.

Examples of substituted amino groups represented by Z in -COZ in the aforementioned general formula (Ia) include mono- or di C _1-4 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, dimethylamino , Diethylamino) and 5- or 6-membered cyclic amino (eg, pyrrolidinyl, piperidino, piperazinyl) groups.

The piperazinyl group described above is a C _1-4 alkyl (e.g. methyl, ethyl) or C _7-10 aralkyl (e.g. benzyl, 3,4,5-trimethoxybenzyl) at a nitrogen atom in its 4-position. It may have a substituent such as a group.

Preferred as Z are amino, nomo- or di-C _1-4 alkylamino, pyrrolidinyl, piperidino, or piperazinyl groups, wherein the piperazinyl group described above is a 4-position nitrogen C _1-4 alkyl group. , Benzyl or 3,4,5-trimethoxybenzyl group.

Examples of the acyloxy group represented by Y ¹ include C _2-4 alkanoyl oxy (eg acetyloxy, propionyloxy), benzoyl oxy and the like.

Compound (Ia) of the present invention can be prepared by reacting the following general formula (II) compound with an oxidizing agent to remove the protecting group.

Wherein R ¹ , X, m, n, n ¹ and k are as defined above and R ² hydrogen, hydroxyl, methoxy, methoxymethyloxy, 2-tetrahydropyranyloxy or 2-tetrahydro Furyloxy, R ³ is hydrogen, methyl, methoxymethyl, 2-tetrahydropyranyl or 2-tetrahydrofuryl, the reaction being an oxidizing agent, for example a divalent silver compound (eg AgO) or cerium compound [Example: Ce (NH ₄ ) ₂ (NO ₃ ) ₆ ]. That is, compound (II) is reacted with AgO in the presence of nitric acid in water or a water-soluble container solvent (e.g. dioxane, acetonitrile) or trimellitic acid-pyridine, or pyridine-2,6-dicarboxylic acid or N React with CE (NH ₄ ) ₂ (NO ₃ ) _{6 in} the presence of -oxide, pyridine-2,4,6-tricarboxylic acid or N-oxide thereof. The reaction temperature is usually in the range of about 0 to 30 ° C. The above-mentioned oxidation reaction is particularly suitable for removing two methoxy groups in the p-position and at the same time the other protecting group is removed, thereby obtaining a quinone compound (Ia).

2-tetrahydropyranyl-oxy and 2-tetrahydrofuryl indoor unit of Y ¹ in the above general formula (Ⅱ) through the protective group-removing reaction is converted to a hydroxyl group, the other groups are groups represented by each of Y ¹ .

In compound (II), the compound of the following general formula (IIa) can be converted into quinone compound (Ia) by another oxidation reaction.

Wherein R ² ′ is hydrogen or a hydroxyl group, and the remaining symbols are as described above.

Such oxidation is usually carried out with a mild oxidizing agent (eg premi salt [ON (SO ₃ )) in a suitable water soluble organic solvent (eg dimethylformamide, acetonitrile, dioxane, tetrahydrobutane, methanol, ether, 1,2-dimethoxyethane). K) ₂ ], ferric chloride, silver oxide, and the like), and the reaction temperature is usually in the range of about 0 to 30 ° C.

Y ¹ a quinone compound (Ia) represented a group -COZ is Y ¹ is a carboxyl group in a quinone compound (Ia) Synthesis of the carboxylic acid compound (Ia) the reaction of the amino-day Sean known consisting of (for example, dicyclohexylcarbodiimide Or a reaction using an active ester method used for peptide synthesis).

이다.In addition, the target compound (Ia) of the present invention wherein the group represented by X is -CH = CH- can be prepared by partial contact reduction of compound (Ia) in which X is -C = C- in the presence of a Lindler catalyst. . Reduction using a Lindler catalyst is carried out after addition of quinoline in the range of 1/10 to 2 times the amount of catalyst in order to control the catalytic action in solvents such as methanol, ethanol and ethyl acetate. The part is a double bond as a result of the reduction mainly cis-olefin bond

to be.

The quinone compound (Ia) thus produced can be separated and collected by known separation and purification processes (eg, chromatography, distillation, crystallization) and other methods.

Compounds (Ia) of the present invention are metabolic pathways of poly-unsaturated fatty acids (PUFAs), in particular lipoxygena, such as linoleic acid, linolenic acid, dihomo-γ-linolenic acid, arachidonic acid and eicosapentaenoic acid. It has a very good effect on the metabolic pathways involving agents and cyclooxygenases. For example, the compound inhibits the production of SRS-A, a substance that causes allergies immediately, causing hypersensitivity, and at the same time 5-hydroperoxyeicosatetraenoic acid (5-HPETE). And the production of 5-hydroxyeicosatetraenophosphate (5-HETE).

(5-HPETE) is one of the hydroperoxy-fatty acids produced by arachidonic acid by lipoxygenase in human multinucleated leukocytes, posterior mast cells and the like and is also an important intermediate of SRS-A [Proc, Natl. Acad. Sci., Vol. 76 pp. 4275 (1979). Compound (Ia) of the present invention inhibits, for example, the production of 12-hydroperoxyeicosa tetraenophosphate (12-HPETE) released from platelets, leukocytes and mast cells and human peritoneal cells in human blood. At the same time, by inhibiting the release of several hydroperoxy-fatty acids produced in PUFA, it is not only involved in defending biological tissues and cells from hydroperoxy-fatty acids, but also useful in improving prostaglandin-thrombotic metabolism. For example, the compounds are useful for blocking the inactivation of prostaglandin-I ₂ (PGI ₂ ) synthase by hydroperoxy-fatty acids. In addition, compound (Ia) of the present invention inhibits autooxidation of arachidonic acid at a concentration of almost 1 μM.

Improvement of metabolism of PUFAs In particular, by inhibiting the production of hydroperoxy-fatty acid, i.e., by antioxidant activity, the compound of the present invention (Ia) is anti-asthmatic, anti-allergic, hypotensive, atherosclerosis-improving, atherosclerosis in mammals. It exhibits several physiological actions such as sclerosis-improvement, platelet-aggregation improvement, peripheral-, brain, and coronary-circulatory system improvement, anti-ulcer, diuresis, immune-modulating and inhibitory action against bacteria. Therefore, these compounds are useful in the treatment of asthma, antiallergic, It is valuable as drugs such as antihypertensives, antiulcers, diuretics, thrombosis agents, brain circulation improvers, coronary artery improvers, immune-modulators, bacterial infection defense enhancers and prostaglandin-thrombotic metabolism improvers. In particular, the compounds of the present invention are useful as asthma, allergy, ulcer and brain circulation improvers.

The compounds of the present invention are less toxic and may be mixed with carriers, excipients, etc. which are pharmaceutically usable by conventional methods, such as pharmaceutical compositions [e.g. tablets, capsules (including softcapsules and microcapsules), solutions, injections and suppositories]. It can be safely administered orally or parenterally. Dosage may vary depending on the type of patient, route of administration, symptoms, and the like. In the case of oral administration to patients with hypertension or bronchial asthma, the present formulation is usually suitable to administer about 0.2 to 25 mg / kg body weight, preferably about 0.5 to 10 mg / kg body weight in the range of 1 to 3 times.

Of (Ia), a compound wherein R ¹ is methyl or methoxy and X is -C = C- is preferred for the purpose of inhibiting the production of SRA-A, and for the purpose of an antiulcer agent, R ¹ The compound which is this methoxy is preferable.

In both cases, Y ¹ is hydroxyl and m is 0 or 1, n, n 'and k are 1-4, 1-3 and 1-2, respectively.

The starting compound (IIa) of the present invention can be prepared by hydrolyzing a compound of the following general formula (IIa ').

Wherein R ² ″ is hydrogen, methoxy, methoxymethyloxy, 2-tetrahydropyranyloxy or 2-tetrahydrofuryloxy, and R ³ ′ is methyl, methoxymethyl, 2-tetrahydropyranyl or 2-tetrahydrofuryl, with the remaining symbols as defined above.

Such hydrolysis is carried out in the presence of acid catalysts (e.g. sulfuric acid, camphor sulfonic acid, p-toluenesulfonic acid) and water-soluble organic solvents (e.g. acetone, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, ethanol, methanol). Generally performed. Although reaction temperature changes with the kind of protecting group to remove, normally, reaction is performed in 0-70 degreeC. Protective groups that can be easily removed by this hydrolysis include methoxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuryl and other groups.

Starting materials (IIa) useful in the present invention can be prepared by the following process.

Wherein Ph is phenyl, Z ¹ is halogen (e.g., Br, I) and others are as described above.

The starting material (VI) of the above scheme can be prepared by the production methods described in Japanese Patent Application Publication Nos. 128932/1976 and 7737/1981 (Application No. 84291/1979) and Japanese Patent Application No. 49433/1980. have.

The alcohol compound (VI) can be halogenated or formylated to give the corresponding halogen compound (VI) or aldehyde compound (V). Halogenated compound (IV) can be prepared by treating alcohol compound (VI) with phosphorus trifluoro or by treating the sulfonyl ester form of alcohol compound (VI) with halides.

The bromination reaction of the alcohol compound (VI) is carried out using 1/3 to 1 equivalent molar of three embrittlement in a temperature range of 0 to 70 ° C. in dichloromethane, chloroform, ether, isopropyl ether or tetrahydrobutane.

The method for producing the halogen compound (IV) through the sulfonyl ester is carried out by the following method.

The alcohol compound (VI) is reacted with ethanesulfonyl chloride or p-toluenesulfonyl chloride in an organic solvent (e.g. methylene chloride, chloroform, ether) in the presence of an organic base (e.g. triethylamine, pyridine). Methanesulfonyl or p-toluenesulfonyl ester is prepared, and the halogenated compound (e.g. sodium chloride, sodium bromide, potassium bromide, sodium iodine, potassium iodide) and an organic solvent (e.g. acetone , Dimethylformamide, dimethylsulfoxide) can be prepared to produce the corresponding halogen compound (IV).

The aldehyde compound (V) can be prepared by oxidizing the alcohol compound (VI) or the halogen compound (IV). For example, in the oxidation of alcohol compound (VI), sulfur trioxide-pyridine complex and triethylamine are reacted in pyridine-chromic anhydride or dimethyl sulfoxide, and in the case of halogen compound (IV), for example, dimethyl An aldehyde compound (V) can be prepared by treatment with silver tetrafluoride boric acid (AgBF ₄ ) -triethylamine in sulfoxide.

The halogen compound (IV) or the aldehyde compound (V) thus obtained is subjected to a coupling reaction or a Wittid reaction to produce compound (II-1a) or (II-2b).

Coupling reactions with acetylene compounds (i) are carried out in the presence of sodium amide or richium amide in liquid ammonia or organic solvents (e.g. tetrahydrofuran, hexamethylenephosphoramide, dimethylformamide, dimethylsulfoxide), or organic Compound (II-1a) is prepared by reacting with a halogen compound in a solvent such as diethyl ether or tetrahydrobutane in the presence of ethylmagnesium bromide and a catalytic amount of copper ions.

The acetylene compounds used in this coupling reaction are, for example, 5-hexyncarboxylic acid, 1-hydroxypent-4-yne, 1-hydroxybut-3-yne, propargyl alcohol and teds thereof Lahydropyranyl ether.

Coupling reactions in liquid ammonia or organic solvents are usually carried out at temperatures of about -30 ° C to -70 ° C in an inert gas atmosphere, while Grignard-type couplings in organic solvents are co-catalysts (eg : Cuprous cyanide, cuprous bromide, cuprous iodide). The reaction mixture is separated and purified by conventional processes (eg solvent extraction, silica gel chromatography) to obtain compound (II-1a).

Compound (II-1a) can be prepared by reacting an aldehyde compound (V) with a wittig reagent. With Bt Hi reagents that can be used in this reaction is, for ^{_{example, [Ph 3 P + (CH}} 2) 4 COOH] Br -, [Ph 3 P + (CH 2) 3 -COOH] Br - and the like, and the solvent As the solvent, benzene, toluene, ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dimethyl sulfoxide and the like can be used alone or as a mixed solvent. The reaction is usually carried out at -10 to 40 DEG C in the presence of a basic compound (e.g., n-butyltium, methyltium, sodium hydride, etc.) in an acyclic gas. After completion of the reaction, compound (II-2b) is obtained by separating and purifying the reaction product in a conventional manner.

Compound (II-2a) or (II-2b) obtained by the above process may be used as a starting material itself or may be further reacted and converted into another starting material (II).

Of the compounds (II-1a) obtained in the above-mentioned coupling reaction, a compound in which Y ¹ is a hydroxyl group is subjected to the above-mentioned halogenation reaction to give a corresponding halide, and this compound is subjected to a coupling reaction similar to the above-described acetylene compound (iii). Long chain acetylene compounds (II-3) can be formed. If necessary, a longer chain acetylene compound (II-3) may be prepared by repeating the coupling reaction. In the case of repeating the coupling reaction, n 'in the acetylene compound (i) may be changed to an integer of 1 to 5. When k is 2 or more and n 'is 1, a compound of the formula (II-3) is prepared, it is preferable that the coupling reaction uses a Grignard reagent in tetrahydrofuran or diethyl ether.

The compound (II-3) thus obtained can be used as a starting material (II) by itself, and the compounds (II-1a) and (II-3) partially reduce the acetylene bonds to give an olefin compound (II-2a) or Or (II-4).

Partial reduction is, for example, by catalytic reduction with a Lindler catalyst or partial reduction with Thiom Ohm hydride. The reduction to the Lindler catalyst is carried out under the conditions described above, and the reduction to the lithium aluminum hydride is carried out by reacting under reflux in ether or tetrahydrofuran in an inert gas atmosphere.

In the olefin compounds (II-2a) and (II-4) obtained in the above reduction, the geometric isomers of the di-substituted double bonds are cis-olefin bonds when reduced with a Lindler catalyst, and reduced with lithium aluminum hydride. In the case of trans-olefin bonds.

Compounds (II-1a), (II-2a), (II-2b), (II-3) and (II-4) obtained in the above-described reaction can all be used as starting materials themselves, and, if necessary, The cyano and amide compounds (II) can also be converted by known reactions such as protecting group removal reaction, conversion of halogen compounds to nitrile groups, and amidation reactions of esterification or carboxylation compounds.

The preparation of the starting compound (VI) by the process described in Japanese Patent Application No. 49333/1980 will be described later in detail.

The application discloses, under anhydrous conditions, tetrahydrofur-2 at the 0-position, which acts on an acid catalyst to tetrahydrofur-2-ylether of a compound having at least one unsubstituted phenolic hydroxy group. It relates to a method for producing a phenol compound having a group.

Examples of the acid catalyst in the above method include organic sulfonic acids such as p-toluenesulfonic acid, campasulfonic acid, and methanesulfonic acid, trifluoroacetic acid, sulfuric acid, and brontrifluoride diethyl etherate. The starting compound is used in the range of about 1/100 to 1/5 equivalents with respect to the ether compound, and preferably about 1/30 to 1/10 equivalent.

The reaction is carried out under anhydrous conditions, and anhydrous solvents such as dichloromethane, chloroform, toluene, benzene and isopropyl ether are usually used as the reaction solvent. The reaction temperature is usually in the range of room temperature to about 70 ° C, and the reaction is preferably carried out in an atmosphere of inert gas. The reaction time varies depending on the kind of the compound to be reacted, but the reaction time is usually performed for 1 to 10 hours. The target compound produced from the reaction solution can be isolated by neutralization of the acid catalyst and then by conventional separation and purification processes (eg silica gel chromatography, distillation under reduced pressure).

The process described above is a tetrahydroput-2- of a compound (in this case hereinafter simply referred to as " compound ") in which at least one of the 0-positions has an unsubstituted phenolic hydroxyl group. Applicable to one ether.

Compounds having such phenolic hydroxyl groups are not limited to simple phenols or derivatives thereof, for example, catechol, pyrogarol, resorcinol, catecholamine derivatives, 5-hydroxytryptamine (serotonin), 5- Phenols in a broad sense, including hydroxyindole and the like. Tetrahydrofur-2-yl ether compounds (VIII) are prepared by etherification of these compounds with 2,3-dihydrofuran in the presence of an acid catalyst or etherification with 2-chlorotetrahydroputane in the presence of a base. As the acid catalyst, the above-described acid catalyst can be used, and a sufficient amount thereof is in the range of about 1/500 to 1/100 equivalents relative to the starting compound. In the case of the reaction with 2,3-dihydroputane, the reaction temperature is usually in the range of 0 to 40 ° C, in which case an acid catalyst is further added after the completion of the etherification reaction, and the reaction temperature is raised to continue the potential reaction. You can also do it. Moreover, etherification and dislocation reaction can be performed in one step by applying the catalytic amount and the reaction temperature of the dislocation reaction when starting the reaction with ether. Examples of the base that can be used for the etherification reaction with 2-chlorotetrahydrofuran include triethylamine, pyridine, sodium hydride and the like, and the reaction solvents include dichloromethane, chloroform, dimethylformamide, dimethylacetamide, and the like. You can also use

As a specific example of the said compound (VII), the ether compound of the following general formula (VIIa) is mentioned.

Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, hydroxyl, methyl or methoxy, and two adjacent groups of R ⁴ , R ⁵ , R ⁶ and R ⁷ together represent -CH = CH- CH = CH- may be represented.

In the above process, the tetrahydrofur-2-yl group of compound (VII) is substituted with a phenolic hydroxyl group to an adjacent position or 0-position to have the desired phenol having a tetrahydrofur-2-yl group at the aforementioned 0-position. (In this case, simply referred to as "compound"). Thus, for example, when compound (VIIa) is used as a starting material, a phenol compound (VIIa) having the following structure is obtained.

In the above formula, all symbols are as described above.

By the process described above, tetrahydrofur-2-yl groups can be introduced at very high yields and optionally at the 0-position of phenol under mild reaction conditions.

Compounds (VIII) prepared by this process are novel compounds and are valuable as intermediates for the preparation of several drugs (eg catecholamines, naphthoquinones, benzoquinones, etc.).

That is, the tetrahydrofur-2-yl group at the 0-position of compound (VIII) is ring-opened by catalytic reduction and is easily converted to a 4-hydroxyburyl group. The resulting 4-hydroxy butyl group, when halogenated, becomes a reactive halogeno butyl group, and various valuable phenol derivatives can be conveniently prepared. The ring-opening reaction by catalytic reduction is carried out by pressurizing and warming in a solvent such as acetic acid and ethyl acetate using an acid catalyst (e.g., sulfur phase, permic acid, etc.) and a reducing catalyst (e.g., palladium, platinum, etc.). Halogenation can be carried out, for example, by reaction with methanesulfonyl chloride or p-toluene sulfonyl chloride to derive the corresponding sulfonyl esters, which can be treated by sodium bromide or sodium iodine in a conventional manner. In this reaction, if necessary, the phenolic hydroxyl group may be previously protected and reacted.

The following pathway converts phenols to useful drugs or compounds (VI).

Wherein R ⁸ is a protecting group of phenolic hydroxyl group, R is a protecting group of alcoholic hydroxyl group, Z ¹ is halogen (eg Br or I), -P ⁺ (C ₆ H ₅ ) ₃ I ^- or _{^{-P + (C 6 H 5)}} 3 Br -, Y 3 is formyl, or CH≡C- P- toluenesulfonyl, N being an integer, M of 0 to 18 is an integer of 0 to 2, N and M Is a whole number from 1 to 18.)

As mentioned above, oxidation of process A is performed using a mild oxidizing agent (for example, premi salt, silver oxide, ferric chloride, etc.). The introduction of the protecting group in step B is carried out by known methods for groups commonly used for the protection of phenolic hydroxyl groups, such as methyl, benzyl, methoxymethyl and tetrahydropyranyl groups. In step B, the halogenation reaction is carried out in the steps described below. In step C, the reactions of (XIIa) and (XIV) are carried out in a Wittig reaction when aldehyde is used as (XIV), and by condensation reaction under acidic conditions when acetylene of sulfone is used as (XIV).

M is 1 when aldehyde (XIV) is used, while M is 2 for acetylene and M is 0 for sulfone. The olefin compound or the acetylene compound obtained by these reactions can be converted into the desired quinone compound by catalytic reduction and the oxidation of the protecting group and / or the oxidation reaction in a usual step. Furthermore, the sulfone compound can be desulfonated under basic conditions, and the resulting olefin compound can be treated by the same method as described above (XIIIa).

The compounds (XIIIa) and (XIIIb) are valuable as immunostimulants, tissue metabolizing agents (cerebrovascular agents, heart failure, hypertension, etc.) and the like. (See US Patent No. 4,139,545 (Japanese Laid-Open Patent Publication No. 128932/1967), European Patent Publication No. 214141 and Japanese Patent Application No. 171125/1979).

Compounds (XIa) and (XIIIa) fall within the range of the above-mentioned compounds (VI) and (IV) and are useful as intermediates for the preparation of the compound (Ia) of the present invention.

The following experimental examples, examples and reference examples illustrate the invention in more detail, but are not intended to limit the scope of the invention. In the following table, each symbol represents the following chemical general formula.

Experimental Example

Inhibitory effect on SRS-A production and release

Objectives of the Invention The action of the compounds on SRS-A production and release by Orange and Moore [J. Immunol. Vol. 116, pp. 392 (1976)].

It was. Antigen was added to the lung tissue of guinea pigs (300-350 g of Hartley species male and female) sensitized with egg white albumin as an antigen, and the amount of SRS-A produced and released was determined by Brockle (Brockle). hurst) (J. Physiol., Vol. 51, pp. 416-435, 1960).

The results shown in Table 1 strongly inhibit the production and release of SRS-A at low concentrations of the compounds of the present invention, and these effects are also 5,8,11,14-Eico Satetranoinophosphate (ETYA) and sodium bikallein It is shown to be very excellent compared with known SRS-A inhibitors, such as phosphate (BSP).

TABLE 1

Inverse Actions on the Generation and Release of SSRS-A

Example 1

Mixture of acetonitrile (40 ml) and water (20 ml) in a solvent Reference Example 2 (II, R ¹ = R ² = OCH ₃ , R ³ = CH ₃ , m = 0, n = 4, X = -C) C dissolve 2,6-dicarboxypyridine N-oxide (4.70 g, 8.57 × 3 mmol) and a compound prepared in n ′ = 3, Y ¹ = OH, k = 1, 3.00 g, 8.57 mmol) The solution was stirred under ice cooling.

An ice-cooled solution of cerium ammonium nitrate (14.1 g, 8.57 × 3 mmol) dissolved in 50% acetonitrile aqueous solution (60 ml) was added dropwise to the solution over 30 minutes, stirred for 30 minutes under the same conditions, at room temperature Stirred for 30 minutes.

After completion of the reaction, the insolubles were removed, and isopropyl ether (100 ml) and water (20 ml) were added to the residue obtained by distillation of acetonitrile under reduced pressure.

The organic layer was washed sequentially with saturated aqueous sodium chloride and brine, then dehydrated (MgSO ₄ ), and the organic solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography [developing agent: isopropyl ether: ethyl acetate (98: 2 to 95: 5)] to give 2,3-dimethoxy-5-methyl-6- (9-hydroxynon-5- Inyl) -1,4-benzoquinone (Ia, R ¹ = OCH ₃ , m = 0, n = 4, X = -C≡-, n '= 3, k = 1, Y ¹ = OH, 2.24 g, 82%).

The physical properties are shown in Table 2 (applied as follows).

EXAMPLES 2-15

The compound of Table 2 was obtained by the process of Example 1.

Example 16

Dioxane (10 ml) was prepared in Reference Example 5 (II, R ¹ = R ³ = CH ₃ , R ² = OCH ₃ , m = 0, n = 4, X = -C≡C-, n ' = 3, Y ¹ = OH, k = 1.636 mg, 2.0 mmol), to which silver oxide (AgO, 1.0 g, 8 mmol) was added, 6N nitric acid (2.0 ml) was added under stirring at room temperature, followed by reaction. It was run for 30 minutes.

Water (50 ml) was added and the product extracted with ethyl acetate. The organic layer was washed with water, dehydrated (MgSO) and concentrated. The residue was purified by silica gel chromatography [developing agent: isopropyl ether: ethyl acetate (98: 2)] to give 2,3,5-trimethyl-6- (9-hydroxynon-5-ynyl) -1,4-benzo Quinones (Ia, R ¹ = CH ₃ , m = 0, n = 4, X = -C≡C-, n '= 3, k = 1, Y ¹ = OH, 520 mg, 90%) were obtained.

[Examples 17-20]

In the process of Example 16, the compound of Table 2 was obtained.

Example 21

, n'=4, k=1, Y¹=COOH, 2.40g, 5.0밀리몰)을 용해시키고, 2N황산(5.0ml)을 가한 후 용액을 70℃에서 1시간 동안 환류하에 교반하여 출발화합물(Ⅱa)를 수득하였다.Acetone (25 ml) was prepared in Reference Example 15 (II, R ¹ = OCH ₃ , R ² = OCH ₂ OCH ₃ , R ³ = CH ₂ OCH ₃ , m = 1, n = 1,

, n '= 4, k = 1, Y ¹ = COOH, 2.40g, 5.0mmol), 2N sulfuric acid (5.0ml) was added and the solution was stirred at reflux at 70 ℃ for 1 hour to start the starting compound (IIa) ) Was obtained.

After the reaction solution was cooled, 1 mol of ferric chloride aqueous solution (10.0 ml) was added, followed by stirring at room temperature for 30 minutes.

After completion of the reaction, acetone was distilled off under reduced pressure, and the product was extracted with ethyl acetate (100 ml) and water (50 ml).

, n'=4, k=1, 2.17g, 88%)을 얻었다.The organic layer was washed with brine solution, dehydrated (MgSO ₄ ) and concentrated to give a residue obtained by silica gel chromatography [developing agent: isopropyl ether: ethyl acetate (98: 2)] to give 2,3-dimethoxy-5- Methyl-6- [11-carboxy-3-methyl- (E, Z) -2,6-undecadienyl] -1,4-benzoquinone (Ia, R ¹ = OCH ₃ , m = 1, n = One,

, n '= 4, k = 1, 2.17 g, 88%).

Example 22

The compound of Table 2 was obtained by the process of Example 21.

Example 23

Compound (Ia, R ¹ = CH ₃ , m = 0 n = 4, X = -C≡C-, n '= 1, k = 2, Y ¹ = OH, prepared in Example 7 in ethyl acetate (10 ml) , 0.30 g, 1.0 mmol) were dissolved, and Lindler catalyst (60 mg) and quinoline (10 µL) were added to the solution, and the solution was contact reduced at room temperature.

When 2.5 mol of hydrogen was absorbed, the reaction was emphasized, and the catalyst was filtered. The ethyl acetate solution was washed sequentially with 5% aqueous phosphoric acid solution (5 ml) and brine solution (5 ml), and the organic layer was concentrated. The residue was dissolved in tetrahydrofuran (6 ml), 1 mol aqueous ferric chloride solution was added, and the mixture was stirred at room temperature for 30 minutes.

Tetrahydrofuran was distilled off under reduced pressure, and extracted with isopropyl ether (30 ml) and water (10 ml). The organic layer was washed with brine, dehydrated (MgSO ₄ ), and the solvent was distilled off under reduced pressure and concentrated.

, n'=1, k=2, Y¹=OH, 0.24g, 80%)을 얻었다.The residue was purified by silica gel chromatography [developing agent: isopropyl ether: ethyl acetate (98: 2)] to give 2,3,5-trimethyl-6- [10-hydroxy (Z, Z) -5,8-decadier. Nil] -1,4-benziquinone (Ia, R ¹ = CH ₃ , m = 0 n = 4,

, n '= 1, k = 2, Y ¹ = OH, 0.24 g, 80%).

[Examples 24-26]

The compound of Table 2 was obtained by the process of Example 23.

Example 27

, n'=4, k=1, Y¹=COOH, 0.78g, 2.0밀리몰)과 N-히드록시석신이미드(0.25g, 2.2밀리몰)을 용해시킨 용액을 빙냉하에 교반하였다.In acetonitrile (10 ml) the compound prepared in Example 15 (Ia, R ¹ = OCH ₃ , m = 1, n = 1,

, n '= 4, k = 1, Y ¹ = COOH, 0.78 g, 2.0 mmol) and a solution of N-hydroxysuccinimide (0.25 g, 2.2 mmol) was stirred under ice-cooling.

Dicyclohexylcarbodiimide (0.45 g, 2.2 mmol) was added to the solution, the mixture was ice cooled for 30 minutes, and stirred at room temperature for 1.5 hours. Next Example A mixture to which N- (3,4,5-trimethoxybenzyl) -piperazine (0.59 g, 2.2 mmol) was added was stirred at room temperature for 1 hour.

After completion of the reaction, dicyclotecsilurea was removed by filtration, and acetonitrile was distilled off under reduced pressure.

Ethyl acetate (50 ml) and water (30 ml) were added to the residue, and the organic layer was washed successively with an aqueous sodium bicarbonate solution and brine, dehydrated (MgSO ₄ ), and the solvent was distilled off.

,The residue was purified by silica gel chromatography [developing agent: isopropyl ether; Ethyl acetate (10: 1)] to 2,3-dimethoxy-5-methyl-6-[[3-methyl-11- [N-((N '-(3,4,5-trimethoxybenzyl) -Piperazinocarbonyl))-(E, Z) -2,6-undecadienyl]]]-1,4-benzoquinone (Ia, R ¹ = OCH ₃ , m = 1, n = 1,

,

K = 1, n '= 4 1.08 g, 80%).

[Examples 28-29]

The compound of Table 2 was obtained by the process of Example 27.

Example 30

, 2.07g, 3.98밀리몰)을 용해시키고, 여기에 캄파설폰산(0.1g)을 가하고, 1시간 환류시켰다. 반응액을 냉각시킨 후 중조(0.1g)을 가하고, 용매를 감압하에 증류시킨 잔류물을 이소프로필 에테르(100ml)에 용해시켰다. 유기층을 물로 세척하고, 탈수(MgSO₄)한 후 감압하에 농축시켜서 얻어진 잔류물을 실리카겔크로마토그라피[전개체 : 이소프로필에테르 : 초산에틸(98:2)]하여 2,3-디메톡시-5-메틸-6-[10-히드록시-3-메틸-7-인-(2E)-데세닐]-1,4-히드로 벤조퀴논(Ⅰb, R¹=OCH₃, m=1, n=2, X=-C≡C-, n'=2, k=1, Y¹=OH, 1.29g, 92%)을 얻었다.In methanol (50 ml), the compound prepared in Reference Example 11 (II, R ¹ = R ² = OCH ₃ , R ³ = CH ₃ , m = 1, n = 2, X = -C≡C-, n '= 2, k = 1,

, 2.07 g, 3.98 mmol) was dissolved, camphorsulfonic acid (0.1 g) was added thereto, and the mixture was refluxed for 1 hour. After cooling the reaction solution, sodium bicarbonate (0.1 g) was added, and the residue distilled off under reduced pressure was dissolved in isopropyl ether (100 ml). The organic layer was washed with water, dehydrated (MgSO ₄ ), and concentrated under reduced pressure. The residue was purified by silica gel chromatography [preparation: isopropyl ether: ethyl acetate (98: 2)] to give 2,3-dimethoxy-5- Methyl-6- [10-hydroxy-3-methyl-7-yne- (2E) -decenyl] -1,4-hydro benzoquinone (lb, R ¹ = OCH ₃ , m = 1, n = 2, X = -C≡C-, n '= 2, k = 1, Y ¹ = OH, 1.29 g, 92%).

Example 31

To a mixed solvent of acetonitrile (6 ml) and water (3 ml) 5-methyl-1,2,3,4-tetramethoxy-6- (12-hydroxy-5,10-dodecadiinyl) benzene (II, 0.50 g, 1.29 mmol) and cerium ammonium dissolved in acetonitrile (4.5 ml) and water (4.5 ml) were stirred under ice cooling with a solution of pyridine-2,6-dicarboxylic acid (0.65 g) dissolved therein. A solution of nitrate (2.12 g) was added dropwise over 15 minutes under ice cooling.

The reaction was carried out for 15 minutes under the same conditions, followed by further reaction at room temperature for 15 minutes.

After the reaction was completed, the insolubles were filtered off, and the acetonitrile was distilled off under reduced pressure. Isopropyl ether (20 ml) and water (20 ml) were added to the residue.

The organic layer was washed successively with an aqueous sodium bicarbonate solution and brine, dehydrated (MgOS ₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing agent: mixed solvent of isopropyl ether and ethyl acetate) to give 2,3-dimethoxy. -5-methyl-6- (12-hydroxy-5,10-dodecadiinyl) -1,4-benzoquinone (I, 0.42 g, 91%, oil) was obtained.

Example 32

1.4-dimethoxy-2-methyl-3-[(12-hydroxy-5,10-dodecadiinyl)] naphthalene (II, 0.57 g, 1.5 mmol) and silver oxide (0.74 g, 6.0 mmol) in dioxane ( 15 ml) was added, the mixture was stirred under ice cooling, 6N nitric acid (1.5 ml) was added to the mixture over 5 minutes, and after 5 minutes, the ice bath was removed and stirred at room temperature for 30 minutes.

Water (20 ml) was added to the reaction solution, and dioxane was distilled off under reduced pressure. Ethyl acetate (50 ml) was added to the residue, and the insolubles were filtered off.

The organic layer was separated, washed with water, dehydrated (MgSO ₄ ) and the solvent was distilled off under reduced pressure. The precipitated crystals were recrystallized with isopropyl ether to afford the desired 2-methyl-3- (12-hydroxy-5,10-dodecadiinyl) -1,4-naphthoquinone (I, 0.47 g, 90%). Got it.

Examples 33 to 35

The compound of Table 2 was obtained by the process of Example 31.

TABLE 2

Note: Numbers marked with an * indicate an example number.

The following reference example is a preparation example of the starting compound used in the above example.

Reference Example 1

A liquid ammonia solution (300 ml) of sodium amide (2.88 g sodium and 50 mg ferric nitrate) that has just been prepared by dissolving tetrahydropyranyl ether of propargyl alcohol (16.8 g, 0.12 mmol) in ether (15 ml) ) Was added dropwise in the argon stream at -60 ° C to -40 ° C over 20 minutes, and the mixture was stirred for 40 minutes under the same conditions.

An ether (40 ml) solution of the compound prepared in Reference Example 29 (IV, R ¹ = R ² = OCH ₃ , R ³ = CH ₃ , m = 0, n = 4, Z = I, 39.4 g, 0.10 mol) Was added dropwise to the reaction solution at -60 ° C to -50 ° C over 40 minutes, and stirred for 1 hour under the same conditions.

Ammonium chloride (50 g) was added to the reaction mixture and ammonia was removed under reduced pressure.

Isopropyl ether (300 ml) and water (300 ml) were then added, and the product was extracted. The organic layer was washed twice with saturated ammonia water (300 ml), dehydrated (MgSO ₄ ), and the residue obtained by evaporation of the solvent was dissolved in methanol (30 ml), p-toluenesulfonic acid (0.95 g) was added, and then at 70 ° C. It stirred for 0.5 hours. After cooling the solution, an aqueous sodium bicarbonate solution (50 ml) was added and the methanol was distilled off under reduced pressure.

Isopropyl ether (300 ml) and water (200 ml) were added to the residue, and the organic layer was washed with brine and dehydrated (MgOS ₄ ).

The residue obtained by distilling the solvent under reduced pressure was subjected to silica gel column chromatography [developing agent: isopropyl ether: ethyl acetate (49: 1)] to give 1,2,3,4-tetramethoxy-5-methyl-6- ( 7-hydroxy-5-heptinyl) benzene (II, R ¹ = R ² = OCH ₃ , R ³ = CH ₃ , m = 0, n = 4, X = -C≡C-, n '= 1, k = 1, Y ¹ = OH, 27.4 g, 85%).

Physical properties are shown in Table 3 below.

[Reference Examples 2 to 10]

The compound of Table 3 was obtained by the process of Reference Example 1.

Reference Example 11

In the same manner as in Reference Example 1, 2,3-dimethoxy-1,4-bismethoxymethyloxy-5-methyl-6- (6-iod-3-methyl-2 prepared in Reference Example 28 -Texenyl) -benzene (IV, R ¹ = OCH ₃ , R ² = OCH ₂ OCH ₃ , R ³ = CH ₂ OCH ₃ , m = 1, n = 2, Z ¹ = I, 2.37 g, 4.8 mmol) Was reacted with 3-butyn-1-ol (0.96 g, 5.3 mmol) 2-tetrahydro pyranyl ether in the presence of sodium amide (0.14 g in sodium) in liquid ammonia (30 ml).

After completion of the reaction, ammonium chloride (5 g) was added, water was added to the residue obtained by removing ammonia under reduced pressure, and extracted with isopropyl ether (100 ml).

, 2.07g, 83%)을 얻었다.The organic layer was washed with water, dehydrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing agent: isopropyl ether) to give 2,3-dimethoxy-1,4-bismethoxy methyloxy-5-methyl. -6- [10- (2-tetrahydropyranyl oxy) -3-methyl-7-in-2-decenyl)] benzene (II, R ¹ = OCH ₃ , R ² = OCH ₂ OCH ₃ , R ³ = -CH ₂ OCH ₃ , m = 1, n = 2, k = 1, X = -C≡C-, n '= 2,

, 2.07 g, 83%) was obtained.

Reference Example 12

Anhydrous dimethyl sulfoxide (12 ml) was added to sodium hydride (1.44 g, 60 mmol) in an argon stream, and the mixture was stirred at 65 to 70 ° C for 1 hour.

5-carboxypentyltriphenylphosphonium bromide (시킨, n '= 5, Y ² = COOH, 13.7 g, 30 mmol) dissolved in anhydrous dimethyl sulfoxide (70 ml) after cooling to 10-15 占 폚. Solution was added dropwise to the mixture over 30 minutes, cooled with water and stirred for 15 minutes.

2,3,5-trimethyl-1,4-dimethoxy-6- (3-formylpropyl) -benzene prepared in Reference Example 44 (V, R ¹ = R ³ = CH ₃ , R ² = OCH ₃ , m = 0, n = 4, 5.0 g, 20 mmol) of the solution dissolved in dimethyl sulfoxide (20 ml) was added dropwise to the mixture over 20 minutes, and stirred at room temperature for 40 minutes.

After the reaction was completed, 10% aqueous phosphoric acid solution (40 ml), isopropyl ether (250 ml), and water (150 ml) were added sequentially, and the product was extracted. The organic layer was washed with brine solution and concentrated to dehydration (MgSO ₄ ).

, n'=5, Y²=COOH, 5.66g, 81%)을 얻었다.The residue was chromatographed on a carousel column (developing agent: isopropyl ether: ethyl acetate (98: 2)) to give 2,3,5-trimethyl-1,4-dimethoxy-6-(-9-carboxy- ( 4Z) -nonenyl) -benzene (II, R ¹ = R ³ = CH ₃ , R ² = OCH ₃ , m = 0, k = 1, n = 4,

, n '= 5, Y ² = COOH, 5.66 g, 81%).

[Reference Examples 13-15]

The compound of Table 3 was obtained by the process of Reference Example 12.

Reference Example 16

In ethyl acetate (10 ml) 1,2,3,4-tetramethoxy-5-methyl-6- (12-hydroxy-5,8-dodecadiinyl) -benzene (II, 500 mg, 1.2 mmol) were dissolved and Lindler catalyst (48 mg) and quinoline (7 μL) were added to the solution, followed by hydrogenation at room temperature. The reaction was stopped when the theoretical amount of hydrogen was absorbed, the catalyst was removed and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (producer: isopropyl ether) to give 1,2,3,4-tetramethoxy-5-methyl-6- (12-hydroxy- (5Z, 8Z) -dodecadienyl) -Benzene (II, 470 mg, 93%) was obtained.

[Reference Examples 17-18]

The compound of Table 3 was prepared by the procedure of Reference Example 16.

Reference Example 19

2,3,5-trimethyl-1,4-dimethoxy-6- (7-iodohept-5-ynyl) -benzene (II-1a, R ¹ = R ³ = CH ₃ , R obtained in Reference Example 33. ² = OCH ₃ , m = 0, n = 4, X = -C≡C-, k = 1, n '= 1, Z = 1, 4.00 g, 10 mmol) in a tetrahydrofuran solution over 20 minutes Grignard reagent solution in tetrahydropyran ether of propargyl alcohol prepared in argon stream in advance [This reagent is reaction of ethyl magnesium bromide in tetrahydrofuran solvent in argon stream from magnesium (0.27 g) and ethyl bromide (1.31 g). A tetrahydropyran ether solution of propargyl alcohol (1.56 g) in tetrahydrofuran was added thereto over 20 minutes, the mixture was stirred at 50 ° C for 1 hour, the reaction solution was cooled to room temperature, and brominated. 1 liter (30 mg) was added, and it stirred for 15 minutes at room temperature, and prepared.] Was added dropwise, and the mixture was stirred at 50 ° C for 2 hours.

After the reaction was completed, the reaction solution was cooled, and an aqueous ammonium chloride solution (30 ml) was added thereto and stirred.

The product which distilled tetrahydrofuran under reduced pressure was extracted with isopropyl ether (50 ml).

The organic layer was washed with aqueous ammonium chloride solution (30 ml), dehydrated (MgSO ₄ ) and the residue was distilled off solvent and dissolved in methanol (50 ml). P-toluenesulfonic acid (0.1 g) was added thereto and heated to 70 ° C.

After cooling, a thick aqueous solution (20 ml) was added, and isopropyl ether (100 ml) and water (50 ml) were added to the residue obtained by distilling methanol under reduced pressure, and the product was extracted. The organic layer was washed with brine solution, dehydrated (MgSO ₄ ), and the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel chromatography (developing agent: isopropyl ether) to give 2,3,5-trimethyl-1,4-dimethoxy-6- (10-hydroxydeca-5,8-diynyl) -benzene (II , R ¹ = R ³ = CH ₃ , R ² = OCH ₃ , m = 0, n = 4, X = -C≡C-, n '= 1, k = 2, Y ¹ = OH, 2.44 g, 74 %) Was obtained.

[Reference Examples 20-27]

By the process of Reference Example 19, the compound of Table 3 was obtained.

Reference Example 28

To methylene chloride (250 ml) 2,3,5-trimethyl-1,4-dimethoxy-6- (4-hydroxybutyl) -benzene (IV, R ¹ = R ³ = CH ₃ , R ² = OCH ₃ , m = 0, n = 4, 26.1 g, 0.104 mol) and triethylamine (21.8 ml, 0.104 x 1.5 mol) were dissolved, and the solution was stirred under ice.

A methylene chloride (30 ml) solution of methanesulfonyl chloride (14.3 g, 0.104 x 1.2 mol) was added dropwise to the solution over 30 minutes and stirred for 30 minutes under ice-cooling.

After the reaction was completed, the organic layer was washed sequentially with ice water (250 ml), 10% cold hydrochloric acid (250 ml), saturated aqueous sodium bicarbonate solution (250 ml) and saturated brine (250 ml), and concentrated with dehydration (MgSO ₄ ).

The residual solution was dissolved in acetone (300 ml), sodium iodide (39.0 g) was added thereto, and the mixture was reacted at 50 ° C for 2 hours.

After completion of the reaction, acetone was distilled off under reduced pressure, and extracted with isopropyl ether (300 ml) and water (200 ml).

The organic layer was washed sequentially with 5% aqueous hydrosulfite solution (200 ml) and saline solution (200 ml), then dehydrated (MgSO ₄ ), and the solvent was distilled off. The residue was purified by silica gel chromatography [developing agent: mixed solvent of hexane: isopropyl ether (3: 1 to 21)] to give 2,3,5-trimethyl-1,4-dimethoxy-6- (4-iodobutyl). Benzene (IV, R ¹ = R ³ = CH ₃ , R ² = OCH ₃ , m = 0, n = 4, Z = I, 35.3 g, 94%) was obtained.

Reference Examples 29 to 41

The product of Table 3 was obtained by the process of Reference Example 28.

Reference Example 42

1,2,3,4-tetramethoxy-5-methyl-6- (4-hydroxybutyl) benzene (VI, R ¹ = R ² = OCH ₃ , R ³ = CH in anhydrous dimethyl sulfoxide (75 ml) ₃ , m = 0, n = 4, 14.2 g, 50 mmol) and triethylamine (56.0 ml) were dissolved and the solution was stirred at room temperature. To this solution was added dropwise a solution in which sulfa trioxide pyridine complex (31.8 g, 200 mmol) was dissolved in anhydrous dimethyl sulfoxide (75 ml) over 25 minutes, and stirred at room temperature for 35 minutes.

The reaction solution was poured into ice water (300 g), and the product was extracted with isopropyl ether (500 ml).

The organic layer was washed successively with 10% aqueous phosphoric acid solution and brine, dehydrated (MgSO ₄ ), and the residue obtained by distilling off the solvent was distilled off under reduced pressure to obtain 1,2,3,4-tetramethoxy-5-methyl-. 6- (3-formylpropyl) -benzene (V, R ¹ = R ² = OCH ₃ , R ³ = CH ₃ , m = 0, n = 4, 11.3 g, 80%, bp 0.7 137-140 ° C.) Got.

[Reference Examples 43-44]

The compound of Table 3 was obtained by the process of Reference Example 42.

Reference Example 45

2,3,5-trimethyl-1,4-dimethoxy-6- (12-urido-5,8-dodecadiinyl) -benzene (0.47 g, prepared in Reference Example 35 in dimethyl sulfoxide (4 ml) 1.0 mmol) was dissolved, and sodium cyanide (98 mg, 2.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour.

Extracted by adding ether (20ml) and water (10ml), the organic layer was washed with brine, dehydrated (MgSO ₄ ) to distill the solvent.

The residue was subjected to silica gel chromatography (developing agent: isopropyl ether) to give 2,3,5-trimethyl-1,4-dimethoxy-6- (12-cyano-5,8-dodecadiinyl) -benzene (II , 0.24 g, 66%) was obtained.

Reference Example 46

A suspension in which sodium amide (1.01 g, 20.0 x 1.3 mmol) was suspended in anhydrous tetrahydrofuran (10 ml) was stirred in a stream of nitrogen and 1- (2-tetrahydropyranyloxy) in anhydrous tetrahydrofuran over 30 minutes. -2,7-octadiyne (4.12 g, 20.0 mmol) was added dropwise.

Next, the reaction temperature was raised to 50 ° C, stirred, and reacted for 1.5 hours. The reaction mixture was cooled with ice, hexamethylphosphoamide (5 ml) was added and then 5-methyl-1,2,3,4-tetramethoxy-6- [1- (4 in anhydrous tetrahydrofuran (20 ml). -Iodine butyl)] A solution of benzene (7.88 g, 20.0 mmol) was added dropwise over 30 minutes, and stirred under the same conditions for 30 minutes and then at room temperature for 1 hour. Ammonium chloride (1.4 g) and water (20 ml) were added to the reaction mixture to decompose the excess reagent, and then the solvent was distilled off under reduced pressure, and isopropyl ether (100 ml) and water (50 ml) were added to the residue. The organic layer was washed with brine, dehydrated (MgSO ₄ ) and the solvent was distilled off under reduced pressure to dissolve the residue in methanol (40 ml). P-toluene sulfonic acid (0.19 g) was added here, and it stirred at 70 degreeC for 30 minutes. After cooling, sodium bicarbonate (1 g) was added, the mixture was concentrated under reduced pressure, extracted with isopropyl ether (100 ml) and water (50 ml), and the organic layer was washed with brine solution and dehydrated (MgSO ₄ ). The residue obtained by concentration under reduced pressure was then subjected to silica gel chromatography (developing agent: mixed solvent of isopropyl ether and hexane) to 5-methyl-1,2,3,4-tetramethoxy-6- (12-hydroxy- 5,10-dodecadiinyl) benzene (5.33 g, 75%, oily phase) was obtained.

Reference Example 47

1,4-Dimethoxy-2-methyl-3- (4-iodobutyl) -naphthalene (3.84 g, 10 mmol) and 1- (2-tetrahydropyranyloxy)-according to the procedure of Reference Example 46 above Condensation of 2,7-octadiyne (2.10 g, 10 mmol) to give 1,4-dimethoxy-2-methyl-3- (12-hydroxy-5,10-dodecadiinyl) naphthalene (2.78 g, 73.5 %, Oily material).

1,4-dimethoxy-2-methyl 3 (4-iodobutyl) naphthalene (δ 1.5-2.2 (4H), 2.40 (3H), 2.82 (2H), 3.23 (2H), 3.84 used in this Reference Example (3H), 3.87 (3H), 7.3-7.5 (2H), 7.8-8.1 (2H)] are the methods described in Japanese Patent Application No. 49433 / '80 with 1,4-dimethoxy-2-methyl-3- (4-hydroxybutyl) naphthalene] oil phase material, NMR (CDCI ₃ ), δ 1.5-1.8 (5H), 2.39 (3H), 2.81 (2H), 3.67 (2H), 3.84 (3H), 3.87 (3H ), 7.3-7.5 (2H), 7.7-8.1 (2H)].

[Reference Examples 48-50]

The compound of Table 3 was prepared by partially reducing the compound with triple bonds prepared in Reference Examples 6, 46 and 47 above with a Lindler catalyst in the process of Reference Example 16.

TABLE 3

Reference Example 51

2,3,5-trimethylphenyl (100 g, 0.735 mol) is suspended in toluene (500 ml), and dihydrofuran (56.6 g, 0.735 x 1.1 mol) and campasulphonic acid (0.85 g) are added to the suspension, followed by room temperature. Stirred for 30 minutes.

As the reaction proceeds, heat is generated and dissolved. The resultant tetrahydrofur-2-yl ether was further added to this reaction solution without addition of camphorsulfonic acid (16.1 g), followed by stirring at 60 ° C for 1.5 hours.

After the reaction, the reaction solution was cooled, neutralized by addition of saturated aqueous sodium bicarbonate solution (300 ml), the organic layer was washed with water, dehydrated (MgSO ₄ ), and distilled to remove the solvent.

By further distillation of the residue under reduced pressure to give 2,3,5-trimethyl-6- (tetrahydrofurfuryl-2-yl) phenyl (147g, 97%, bp _{1 and 0} 124 ~ 130 ℃) was obtained.

Reference Example 52

2,3-dimethoxy-5-methyl-1,4-methyl-1,4-benzohydroquinone (18.2 g, 0.1 mol) is suspended in toluene (150 ml), and dihydrofuran (15 g, 0.204 mol) is added thereto. And camphorsulfonic acid (0.15 g) were added, and the mixture was stirred at room temperature for 1 hour.

Campazulfonic acid (2.2 g) was added to the reaction solution without separating the product, and the mixture was stirred at 60 ° C for 3 hours.

The reaction solution was cooled, washed with water, dehydrated (MgSO ₄ ) and the solvent was distilled off. The residue was purified by silica gel chromatography (developing agent: isopropyl ether) to give 2,3-dimethoxy-5-methyl-6- (tetrahydrofur-2-yl) -1,4-benzyhydroquinone (20.8 g, 82 %, Melting point: 77-78 ° C.).

Reference Examples 53 to 57

The compounds of Table 4 were prepared by the procedures of Reference Examples 51 (Step A) and 52 (Step B).

TABLE 4

Reference Example 58

A solution of 2,3,5-trimethyl-6- (tetrahydrofur-2-yl) -1,4-benzohydroquinone (22.2 g, 0.1 mol) in dimethylformamide (200 ml) was ice-cooled in a nitrogen stream. Sodium hydride (8.8 g of Ojin, 0.10x2.2 mol) was added thereto, followed by stirring for 15 minutes.

Methyl iodide (35.5 g, 0.10x2.5 mol) was then added dropwise to the reaction mixture over 15 minutes, followed by stirring for 30 minutes.

Ice water (250 g) was added to the reaction solution, and the extract extracted with isopropyl ether (500 ml) was washed with water, dehydrated, and the solvent was distilled off. By distillation of the residue under reduced pressure to give 1,4-dimethoxy-2,3,5-trimethyl-6- (tetrahydrofurfuryl-2-yl) benzene (24.5g, 98%, bp _{1 and 0} 130 ~ 140 ℃) Got.

The dimethoxy compound (24.5 g) thus obtained was dissolved in ethyl acetate (250 ml), and 5% palladium-carbon (2.5 g) and 70% perchloric acid (1 ml) were added thereto, followed by catalytic reduction at 40 ° C.

After completion of the reaction, the catalyst was filtered off, the ethyl acetate solution was washed with saturated sodium bicarbonate water and water in that order, and then dehydrated. The organic solvent was distilled off under reduced pressure.

The residue was recrystallized in isopropyl ether-hexane to give 1,4-dimethoxy-2,3,5-trimethyl-6- (4-hydroxybutyl) benzene (22.2 g, 90%, melting point 88-88.5 DEG C). Got it.

Reference Example 59

In the process as described in Example 58, 2,3-dimethoxy-5-methyl-6- (tetrahydrofur-2-yl) -1,4-benzohydroquinone (27 g, 0.106 mol) by methylation it led to the 1,2,3,4-methoxy-5-methyl-6- (tetrahydrofurfuryl-2-yl) benzene (28.5g, 98%, bp _{1 and 0} 135 ~ 138 ℃).

This compound was contact reduced to yield 1,2,3,4-tetramethoxy-5-methyl-6- (4-hydroxybutyl) benzene (28.2 g, 99%, oily substance).

Reference Example 60

1,2,3,4-tetramethoxy-5-methyl-6- (4-hydroxybutyl) benzene (28.2 g, 0.1 mol) and triethylamine obtained in Reference Example 59 in anhydrous methylene chloride (300 ml) The solution in which (16 g, 0.15 mol) was dissolved was cooled to 0 ° C, and a solution in which methanesulfonyl chloride (14.3 g, 0.12 mol) was dissolved in methylene chloride (30 ml) was added thereto, followed by stirring for 30 minutes.

The reaction solution was washed sequentially with water, diluted aqueous phosphoric acid solution and water, and the organic layer was dehydrated (MgSO ₄ ) and the solvent was distilled off. Acetone (300 ml) and sodium iodide (39.0 g, 0.26 mol) were added to the residue, and the mixture was warmed at 50 ° C. for 2 hours.

After the reaction was completed, acetone was distilled off under reduced pressure, and isopropyl ether (300 ml) and water (200 ml) were added to the residue and extracted. The organic layer was washed successively with 5% aqueous sodium sulfite solution and water, dehydrated (MgSO ₄ ), and the solvent was distilled off under reduced pressure.

The residue was chromatographed with silica gel column (producer: isopropyl ether: hexane (1: 1)) to give 1,2,3,4-tetramethoxy-5-methyl-6- (4- (iodine) benzene. (37.0 g, 94%) was obtained.

Reference Example 61

Sodium (2.88 g, 0.12 gram atoms) and ferric nitrate (50 ml) were added to liquid ammonia (300 ml) to prepare sodium amide at -60 to 40 ° C, and dissolved in ether (20 ml) over 20 minutes in this ammonia solution. A solution of 1-tetrahydro pyranyloxy-5-hexine (21.8 g, 0.12 mol) was added and stirred for 40 minutes.

An emole (40 ml) solution of the urethral compound (37.0 g, 0.094 mol) obtained in Reference Example 60 was added dropwise to the mixture over 40 minutes, wherein the reaction temperature was maintained at -60 to -50 ° C.

It stirred at the same temperature for 1 hour, and then it stirred at -50--30 degreeC for 1 hour.

Ammonium chloride (50 g) was then added to the reaction mixture, which was stirred for 10 minutes.

Ammonia was removed, isopropyl ether (300 ml) and water (300 ml) were added and extracted. The organic layer was washed with water, dehydrated (MgSO ₄ ) and distilled to remove the solvent to obtain a crude product.

This was dissolved in methanol (300 ml), p-toluenesulfonic acid (0.95 g) was added to this solution, and the mixture was stirred at 70 ° C for 30 minutes. After cooling the solution, adding sodium bicarbonate (2 g), and extracted by adding isopropyl ether (300 ml) and water (200 ml) to the methanol distilled residue under reduced pressure.

The organic layer was washed with water, dehydrated (MgSO ₄ ) and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (developing agent: isopropyl ether) to give 1,2,3,4-tetramethoxy-5. -Methyl-6- (10-hydroxyteki-5-ynyl) benzene (29.4 g, 86%) was obtained.

Reference Example 62

The compound (18.2 g, 0,05 mol) obtained in Reference Example 61 was dissolved in ethanol (200 ml), and 5% palladium-carbon (1 g) was added, followed by contact reduction.

After the absorption of hydrogen was complete, the reaction was completed and the catalyst was filtered off and ethanol was removed under reduced pressure.

The reduced form (18.2 g, 0.05 mole) and 2,6-dicarboxypyridine-1-oxide- (27.4 g) are dissolved in acetonitrile (240 ml) and water (120 ml), the solution is ice-cooled and then 50% aceto A solution of cerium ammonium nitrate (82.2 g, 0.15 mol) dissolved in an aqueous nitrile solution (360 ml) was added dropwise over 1 hour, followed by stirring for 30 minutes at room temperature and 30 minutes under ice cooling.

After the reaction was completed, insolubles were filtered off and acetonitrile was removed under reduced pressure. The product was extracted with isopropyl ether (500 ml), washed successively with saturated aqueous sodium bicarbonate solution and water, dehydrated (MgSO ₄ ), and then isopropyl ether was distilled off.

The residue was chromatographed with silica gel (developing agent: isopropyl ether (by 2,3-dimethoxy-5-methyl-6- (10-hydroxydec-5-ynyl) -1,4-benzoquinone (14.5 g)). , 86%, melting point 52-53 degreeC) was obtained.

Reference Example 63

1,4-dimethoxy-2,3,5-trimethyl-6- (4-hydroxybutyl) benzene obtained in Reference Example 58 and reacted in the same manner as described in Reference Example 60 for 2,3, 5-trimethyl-6- (10-hydroxydec-5-ynyl) -1,4-benzoquinone (65-66 ° C) was obtained.

Reference Example 64

2,3,5-trimethyl-6- (tetrahydrofur-2-yl) -1,4-benzohydroquinone (2,24 g, 0.01 mol) obtained in Reference Example 53 was dissolved in ethyl acetate (50 ml), Perchloric acid (0.1 ml) and 5% palladium-carbon (500 mg) were added to the solution, followed by contact reduction with hydrogen pressure of 100 atm.

After the reaction was completed, the catalyst was filtered off, 5% ferric chloride aqueous solution (50 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.

The organic layer was separated, the aqueous layer was extracted once with ethyl acetate, and the extract was combined with the organic layer, washed with water, dehydrated (MgOS ₄ ) and concentrated.

The resulting crude product was chromatographed with silica gel [developing agent: isopropyl ether: ethyl acetate (95: 5)] to give the desired 2,3,5-trimethyl-6- (4-hydroxybutyl) -1,4- Benzoquinone (1.9 g, 88%, melting | fusing point 36-38 degreeC) was obtained.

Reference Example 65

2,3-dimethoxy-5-metal-6- (tetrahydrofur-2-yl) -1,4-benzohydroquinone (2.56 g, 0.01 mol) obtained in Reference Example 52 is described in Reference Example 64. Catalytic reduction and oxidation such as 2,3, -dimethoxy-5-methyl-6- (4-hydroxybutyl) -1., 4-benzoquinone (2.17 g, 84%, oily substance) Got.

(cm^-1) : 3400(OH), 1660, 1640, 1610(퀴논)IR absorption spectrum

(cm ^-1 ): 3400 (OH), 1660, 1640, 1610 (quinone)

[Examples of Pharmaceutical Compositions]

A) capsule

1) 50 mg of the compound of Example 17

2) Cellulose fine powder 30mg

3) Lactose 37mg

4) Magnesium stearate 3mg

120 mg

The materials were mixed and filled into gelatin capsules.

B) soft capsule

1) 50 mg of the compound of Example 31

2) corn starch oil 100mg

150 mg

The liquid mixture of (1) and (2) was prepared, and it filled into the soft capsule by the conventional method.

C) tablets

1) 50 mg of the compound of Example 32

2) Lactose 34mg

Corn Starch 10.6mg

4) corn starch (luxury) 5mg

5) Magnesium Stearate 0.4mg

6) calcium carboxymethylcellulose 20mg

120 mg

Tablets were prepared by the conventional method of mixing all the ingredients and tableting with a tablet press.

Claims (1)

A process for producing a compound of formula (Ia), wherein the compound of formula (II) is reacted with an oxidizing agent.

Wherein R ¹ represents methyl or methoxy, or both R ¹ together represent a —CH═CH—CH═CH—group, and R ² represents hydrogen, hydroxyl, methoxy-methyloxy, 2-tetrahydropyranyl Oxy or 2-tetrahydrofuryloxy, R ³ is hydrogen, methyl, methoxymethyl, 2-tetrahydropyranyl or 2-tetrahydrofuryl, X is -CH = CH- or -C = C- and , Y ¹ is hydrogen, hydroxyl, carboxyl, cyano, acyloxy or -COZ (where Z is amino or substituted amino), m is an integer from 0 to 3, n is from 0 to 10 Is an integer, n 'is an integer of 1 to 5, k is an integer of 1 to 3, and when k is 2 or 3, n' is an arbitrary variable of 2 or 3 times within the range of 1 to 5.