JP2007169202A - Method for preparing abietane-type quinone methide compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method suitable for the mass production of an abietane-type quinone methide compound useful as an antibacterial substance. <P>SOLUTION: The abietane-type quinone methide compound can be produced in two steps by oxidizing an abietane-type diterpene compound such as ferruginol or a rearrangement abietane-type diterpene compound in a liquid phase with the use of a halogenated benzoyl peroxide, reacting the product of the first half step with a reducing agent, and thereafter reacting the resulting product with an oxidizing agent. The halogenated benzoyl peroxide can be synthesized by reacting a halogenated perbenzoic acid with a carbodiimide compound, and by adding an abietane-type diterpene compound such as ferruginol or a rearrangement abietane-type diterpene compound to this reaction solution, the abietane-type quinone methide compound can be produced in one step. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing an abietane quinone methide compound such as abietaquinone methide from an abietane diterpene compound such as ferruginol and totarol, and more particularly suitable for mass production of an abietane quinone metide compound useful as an antibacterial substance. Related to the method.

In recent years, nosocomial infections caused by bacteria resistant to various antibiotics, especially MRSA (methicillin-resistant Staphylococcus aureus) and VRE (vancomycin-resistant enterococci), have caused serious damage in the medical field. Creation of a novel compound having anti-VRE activity is desired.
As a result of the total synthesis of 12 types of phenolic abietane-diterpenes so far, and the study of the structure-activity relationship with respect to MRSA and VRE, the present inventors have found that quinone methide has a novel anti-MRSA and anti-VRE activity. It was shown to be a substance (Patent Documents 1 and 2). Among them, 11-hydroxy-12-oxo-7,9 (11), 13-abietatriene showed relatively strong activity against MRSA and VRE, but it was isolated from African Labiatae plants. Since it is an abietane-type quinone methide that has not been used in the past, it is also referred to as abietaquinone methide.
The methods for synthesizing abietaquinone methide reported by the inventors so far have many steps and a low yield (Non-patent Documents 1 and 2).

JP2002-80419 JP2003-267910 J. Chem. Soc. Perkin 2657-2664 (2000) Bioorg. Med. Chem., 9 (2), 347-356 (2001)

In the synthetic route of abietaquinone methide reported by the inventors so far, a synthetic intermediate, ferruginol, was totally synthesized through a cyclization reaction of polyene (Non-patent Documents 1 and 2). The synthesis of abietaquinone methide by oxidation at the ortho-position of ferguinol is based on direct oxidation of ferguinol by Se, synthesis by isomerization, or oxidation, reduction, and air oxidation of ferguinol with benzoyl peroxide (BPO). Met. However, Se oxidation itself is a toxic substance, and BPO may explode depending on how it is handled, and since it has been discontinued in Japan, it was necessary to develop a safer ortho-position oxidation reaction. . Furthermore, this synthesis method had many steps and the overall yield was as low as 0.4%.
An object of the present invention is to provide a method for synthesizing a quinone methide compound with abietane skelton containing abietaquinone methide that is safer, simpler and higher in yield than conventional methods.

The present inventors synthesized ferguinol from dehydroabietic acid, which is produced in large quantities as industrial raw materials such as paper and plastic additives and pharmaceuticals, and can be obtained at low cost, and using benzoyl peroxide as an oxidizing agent. Ferguinol was oxidized.
As a result, it has been found that abietaquinone methide can be synthesized in high yield, and the present invention has been completed.

（式中、Ｒ^１〜Ｒ^４は、それぞれ、水素原子、アルキル基、アリール基、水酸基、水酸基含有アルキル基、シアノ基、カルボキシル基、アルコキシカルボニル基、ハロゲン原子又はニトロ基を表し、Ｒ^５及びＲ^６は、いずれも水素原子である、一方が水素で他方が水酸基である、又は両者が結合する炭素原子と共にカルボニル基（＝Ｃ＝Ｏ）を形成する。以下「アビエタン型ジテルペン化合物Ｉ」という。）又は下記一般式

（式中、Ｒ^１、Ｒ^３〜Ｒ^６、は上記と同様に定義される。以下「アビエタン型ジテルペン化合物ＩＩ」という。）で表されるアビエタン型ジテルペン化合物と下記一般式

（式中、Ｘはハロゲン原子を表し、ｎは１又は２を表す。）で表されるハロゲン化過酸化ベンゾイルを反応させる段階、及び前段階の生成物を還元剤と反応させその後酸化剤と反応させる段階から成るアビエタン型キノンメチド化合物の製法であって、該アビエタン型ジテルペン化合物がアビエタン型ジテルペン化合物Ｉの場合には、該アビエタン型キノンメチド化合物が下記一般式

（式中、Ｒ^１〜Ｒ^６は上記と同様に定義される。）で表され、該アビエタン型ジテルペン化合物がアビエタン型ジテルペン化合物ＩＩの場合には、該アビエタン型キノンメチド化合物が下記一般式

（式中、Ｒ^１、Ｒ^３〜Ｒ^６は上記と同様に定義される。）で表されるアビエタン型キノンメチド化合物の製法である。 That is, the present invention provides the following general formula in the liquid phase:

(Wherein, R ¹ to R ⁴ each represent a hydrogen atom, an alkyl group, an aryl group, a hydroxyl group, a hydroxyl group-containing alkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a halogen atom or a nitro group, R ⁵ and R ⁶ is a hydrogen atom, one is hydrogen and the other is a hydroxyl group, or forms a carbonyl group (═C═O) with a carbon atom to which both are bonded, hereinafter referred to as “abietane type diterpene compound I”. Or the following general formula

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above, hereinafter referred to as “abietane type diterpene compound II”) and the following general formula

(Wherein X represents a halogen atom and n represents 1 or 2), and a step of reacting the benzoyl peroxide represented by the formula, and reacting the product of the previous step with a reducing agent, A method for producing an abietane quinone methide compound comprising a step of reacting, wherein the abietane diterpene compound I is an abietane diterpene compound I, the abietane quinone methide compound is represented by the following general formula:

(Wherein R ^{1 to} R ⁶ are defined in the same manner as above), and when the abietane diterpene compound is an abietane diterpene compound II, the abietane quinone methide compound is represented by the following general formula:

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above), and a method for producing an abietane-type quinone methide compound.

（式中、Ｘはハロゲン原子を表し、ｎは１又は２を表す。）で表されるハロゲン化過安息香酸と下記一般式
Ｒ^７−Ｎ＝Ｃ＝Ｎ−Ｒ^７
（式中、Ｒ^７は、同一であっても異なってもよく、アルキル基、シクロアルキル基、又はアリール基を表す。）で表されるカルボジイミド化合物を反応させる段階、前段階の反応液に上記アビエタン型ジテルペン化合物を混合する段階、及び前段階の生成物を還元剤と反応させその後酸化剤と反応させる段階から成る上記アビエタン型キノンメチド化合物の製法である。 The present invention also provides the following general formula in the liquid phase:

(Wherein X represents a halogen atom and n represents 1 or 2) and the following general formula R ⁷ —N═C═N—R ⁷
(Wherein R ⁷ may be the same or different and each represents an alkyl group, a cycloalkyl group, or an aryl group). The step of reacting the carbodiimide compound represented by This is a process for producing the above-mentioned abietane-type quinonemethide compound, which comprises a step of mixing an abietane-type diterpene compound and a step of reacting the product of the previous step with a reducing agent and then reacting with an oxidizing agent.

（式中、Ｘはハロゲン原子を表し、ｎは１又は２を表す。）で表されるハロゲン化安息香酸を混合する段階、前段階の反応液に上記アビエタン型ジテルペン化合物を混合する段階、及び前段階の生成物を還元剤と反応させその後酸化剤と反応させる段階から成る上記アビエタン型キノンメチド化合物の製法である。 Furthermore, the present invention is a step in which the halogenated perbenzoic acid and the carbodiimide compound are reacted in a liquid phase, and the reaction solution of the previous step is represented by the following general formula:

(Wherein X represents a halogen atom and n represents 1 or 2), a step of mixing the halogenated benzoic acid represented by the step, a step of mixing the abiethane type diterpene compound with the reaction solution of the previous step, and This is a process for producing the above abietane-type quinonemethide compound, which comprises the step of reacting the product of the previous step with a reducing agent and then reacting with the oxidizing agent.

  Furthermore, the present invention includes a step of reacting the halogenated benzoic acid and the carbodiimide compound in a liquid phase, a step of mixing the halogenated perbenzoic acid in a reaction solution of the previous step, and the abiethane type in the reaction solution of the previous step. This is a process for producing the above abietane-type quinone methide compound comprising a step of mixing a diterpene compound and a step of reacting the product of the previous step with a reducing agent and then reacting with an oxidizing agent.

  The abietane quinone methide compound, which is a product of the production method of the present invention, has been shown to have an excellent antibacterial action against MRSA and VRE (Patent Documents 1 and 2), but when extracting from natural products The amount was extremely small, and the synthesis method was also not suitable for mass production. Therefore, although antibacterial substances against MRSA and VRE were desired, they could not be supplied for such use. However, according to the present invention, a method capable of producing a large amount of an abietane-type quinone methide compound has been developed, which makes it easy to study and evaluate as an antibacterial substance, and to produce a large amount as an antibacterial substance against MRSA, VRE or other bacteria. It can be said that the way to supply it is opened.

表されるアビエタン型ジテルペン化合物Ｉ、及び下記一般式

で表されるアビエタン型ジテルペン化合物ＩＩを含む。アビエタン型ジテルペン化合物ＩＩは、上記のアビエタン型ジテルペン化合物Ｉの水酸基と置換基Ｒ^１が同様の位置関係を保ちながら転移したものであり、本発明における反応において同様の反応を行う（後述）。 The abietane type diterpene compound which is the starting material of the production method of the present invention is represented by any of the following formulae. That is, this abietane type diterpene compound has the following general formula:

Abietane type diterpene compound I represented, and the following general formula

An abietane type diterpene compound II represented by the formula: The abietane-type diterpene compound II is obtained by transferring the hydroxyl group of the above-mentioned abietane-type diterpene compound I and the substituent R ¹ while maintaining the same positional relationship, and performs the same reaction in the reaction in the present invention (described later).

R ¹ represents a hydrogen atom, an alkyl group, an aryl group, a hydroxyl group, a hydroxyl group-containing alkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a halogen atom or a nitro group, preferably an alkyl group having 4 or less carbon atoms. And more preferably an isopropyl group.
R ² represents a hydrogen atom, an alkyl group, an aryl group, a hydroxymethyl group, a hydroxyl group, a hydroxyl group-containing alkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a halogen atom or a nitro group, preferably a hydrogen atom, an alkyl group Or a cyano group, more preferably a hydrogen atom.
R ³ represents a hydrogen atom, an alkoxycarbonyl group, or an acyl group, and preferably represents a hydrogen atom.
R ⁴ represents a hydrogen atom, an alkyl group, an aryl group, a hydroxyl group, a hydroxyl group-containing alkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a halogen atom or a nitro group, preferably a methyl group, a hydroxymethyl group, an alkoxycarbonyl Represents a group, more preferably a methyl group.

Here, the alkyl group has 1 to 10 carbon atoms and is linear or branched. Specifically, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, hexyl, heptyl, octyl, nonyl, decanyl, etc. Can be mentioned.
The aryl group is preferably a phenyl group or a naphthyl group which may or may not have a substituent.
The hydroxyl group-containing alkyl group is preferably a hydroxymethyl group or a hydroxyethyl group.
The alkoxycarbonyl group is represented by —COOR ⁸ , and R ⁸ is an alkyl group, preferably an alkyl group having 4 or less carbon atoms, more preferably a methyl group, an ethyl group, a propyl group, or an isopropyl group.
The acyl group is represented by —COR ⁹ , and R ⁹ is an alkyl group, preferably an alkyl group having 4 or less carbon atoms, more preferably a methyl group, an ethyl group, a propyl group, or an isopropyl group.
The halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom.

R ⁵ and R ⁶ are both hydrogen atoms, one is hydrogen and the other is a hydroxyl group, or together with a carbon atom to which both are bonded, forms a carbonyl group (═C═O). R ⁵ and R ⁶ are preferably both hydrogen atoms.

Ｘはハロゲン原子、好ましくは塩素原子を表す。
ｎは１又は２を表し、好ましくは１である。
ハロゲン原子は、ｎ＝１の場合にはイプソ(ispo)位炭素に対して3位にあることが好ましく、ｎ＝２の場合には、3位と5位にあることが好ましい。 The benzoyl peroxide (XBPO) used in the present invention is represented by the following general formula.

X represents a halogen atom, preferably a chlorine atom.
n represents 1 or 2, and is preferably 1.
The halogen atom is preferably in the 3rd position relative to the ispo carbon when n = 1, and preferably in the 3rd and 5th positions when n = 2.

（式中、Ｘ及びｎは上記と同様である。）で表されるハロゲン化過安息香酸と下記一般式
Ｒ^７−Ｎ＝Ｃ＝Ｎ−Ｒ^７
（式中、Ｒ^７は、同一であっても異なってもよく、好ましくは同一であり、アルキル基、シクロアルキル基、又はアリール基を表し、好ましくはシクロヘキシル基を表す。）で表されるカルボジイミド化合物を反応させることにより合成できる。 This halogenated benzoyl peroxide may be commercially available or synthesized. When synthesizing, the following general formula is used in the liquid phase:

(Wherein X and n are as defined above) and the following general formula R ⁷ —N═C═N—R ⁷
(Wherein R ⁷ may be the same or different, preferably the same, and represents an alkyl group, a cycloalkyl group, or an aryl group, preferably a cyclohexyl group). It can be synthesized by reacting a compound.

（式中、Ｘ及びｎは上記と同様である。）で表されるハロゲン化安息香酸を加えることによっても合成できる。
この場合、カルボジイミド化合物を含む反応液に、ハロゲン化過安息香酸及びハロゲン化安息香酸を加える順序はいずれが先でもよいが、これらを同時に加えるとこれらの間の反応によるものと思われるハロゲン化過酸化ベンゾイルの収率の低下が起こるため好ましくない。 In addition, the following general formula is added to the reaction solution during this reaction.

(In the formula, X and n are the same as described above.) Synthesis can also be performed by adding a halogenated benzoic acid.
In this case, the order in which the halogenated perbenzoic acid and the halogenated benzoic acid are added to the reaction liquid containing the carbodiimide compound may be any first, but if they are added simultaneously, the halogenated perbenzoic acid is considered to be due to the reaction between them. Since the yield of benzoyl oxide decreases, it is not preferable.

（式中、Ｒ^１〜Ｒ^６は上記と同様に定義される。以下「アビエタン型キノンメチド化合物Ｉ」ともいう。）で表され、反応の出発物質であるアビエタン型ジテルペン化合物がアビエタン型ジテルペン化合物ＩＩの場合には、下記一般式

（式中、Ｒ^１、Ｒ^３〜Ｒ^６、は上記と同様に定義される。以下「アビエタン型キノンメチド化合物ＩＩ」ともいう。）で表される。 The abietane-type quinone metide compound, which is a product of the present invention, has the following general formula when the abietane-type diterpene compound that is the starting material of the reaction is an abietane-type diterpene compound I:

(Wherein R ^{1 to} R ⁶ are defined in the same manner as described above, hereinafter also referred to as “Abietane-type quinone metide compound I”), and the abietane-type diterpene compound, which is a starting material for the reaction, is an abietane-type diterpene compound II. In the case of

(Wherein R ¹ and R ^{3 to} R ⁶ are defined in the same manner as described above. Hereinafter, they are also referred to as “abietane quinone metide compound II”).

  Hereinafter, an outline of a method for synthesizing an abietane quinone methide compound from an abietane diterpene compound according to the present invention will be described. In the present invention, an abietane quinone methide compound is synthesized by any of the following methods. For simplicity, feruginol and totarol are used as the abiethane diterpene compound, and m-chlorobenzoyl peroxide (mCBPO) is used as the halogenated benzoyl peroxide. In addition, the present invention is not limited by the compounds used for the description.

(1) This reaction is carried out in a two-phase reaction in the liquid phase. The reaction mechanism is shown in the following equation.
Reaction of an abietane diterpene compound (for example, ferguinol) with mCPBO produces a peracid ester, a compound 8 or a compound 8 ′ in which the ortho position of the abietane diterpene compound is oxidized via a [3,3] sigmatropic rearrangement. To do. At this time, compound 9 is also produced from compound 8 by transesterification. The structure of the transesterification product can be confirmed by acetylating the phenols of compounds 8 and 9. Subsequently, the mixture of compounds 8 and 9 or compound 8 ′ is reduced, catechol-generated, and oxidized to synthesize an abietane-type quinone methide compound.

  In the first stage reaction (until the mixture of compounds 8 and 9 or the synthesis of compound 8 '), the solvent is preferably methylene chloride, chloroform or toluene. The concentration of each reactant is about 0.1 to 0.05M. The reaction temperature is 15-80 ° C. The reaction time is about 4 to 24 hours.

In the second stage reaction (after the reduction reaction of the mixture of compounds 8 and 9 or compound 8 '), the first stage product is reacted with a reducing agent and then reacted with an oxidizing agent. Since the first-stage products (compounds 8 and 9 of the following formula) are powdery precipitates, it is preferable to use them after purification.
As the reducing _{agent, R n S n H 4-} n, R n SiH 4-n, NaAlH 4, LiAlH n (OR) m, LiAlH 4 -MX n ( The _{MX AlCl 3, BF 3, FeCl} 3), LiAlH ₄ , i-Bu ₂ AlH, AlH ₃ , LiBHR ₃ , KBHR ₃ , LiBH ₄ , NaBH ₃ CN, NaBH ₄ -MX _n (MX is AlCl ₃ , BF ₃ , FeCl ₃ ), NaBH ₄ , BH ₃ , BR _n H _3−n (wherein R represents a suitable hydrocarbon group) and the like. These can be used alone or in combination.
Examples of the oxidizing agent include the following. Oxygen (can be used in oxygen atmosphere or oxygen blowing. Oxygen-containing air may be used), AgO, Ag ₂ O, MnO ₂ , Cu (OH) ₂ , Fe ₂ O ₃ , MoO ₃ , V ₂ O ₅ , CuCl ₂ —PdCl _{2 and the} like. These can be used alone or in combination.
The timing of administration of the oxidizing agent is preferably after the reduction reaction, but not necessarily after the reduction reaction, and the oxidizing agent may be administered from the beginning of the reaction. For example, oxygen or air may be blown into the reaction solution, and the reducing agent may be administered there.
The amount of the reducing agent and the oxidizing agent used is about 0.1 to 0.03M. As the solvent, terahydrofuran (THF) is used. The reaction temperature is 20-40 ° C.

The reaction mechanism in the case of using Abietane type diterpene compound I (the chemical formula is the above-mentioned reference, for example, Ferguinol) as the starting material Abietane type diterpene compound is shown in the following formula.

The reaction mechanism in the case of using Abietane diterpene compound II (refer to the above-mentioned chemical formula, for example, totarol) as the starting material abietane diterpene compound is shown in the following formula.

(2) This method utilizes the mCBPA-DCC adduct, which is a reaction intermediate produced during the mCBPO production reaction. The reaction mechanism is shown in the following equation.
When an abietane type diterpene compound (for example, ferguinol) is added to the mCPBA-DCC adduct, compound 8, 9 or compound 8 ′ is formed. The obtained compound 8, 9 or compound 8 ′ is reduced, and an abietane-type quinonemethide compound is synthesized in an oxygen atmosphere.
This reaction takes place in the liquid phase. As the solvent, methylene chloride, chloroform or toluene is preferable. The concentration of each reactant is about 0.1 to 0.05M. The reaction temperature is 15-80 ° C. The reaction time is about 4 to 24 hours.
The second stage reaction is the same as above.

(3) In the reaction of (2), instead of using halogenated benzoyl peroxide (mCPBA), as described above, a reaction product of a carbodiimide compound and a halogenated perbenzoic acid, or a reaction product of a carbodiimide compound and a halogenated perbenzoic acid. Reactants with acids and halogenated perbenzoic acids may be used.

この反応において、溶媒としては、塩化メチレン、クロロホルム又はトルエンが好ましい。各反応物の濃度は、０．１〜０．０５Ｍ程度である。反応温度は、１５〜３０℃である。反応時間は、１５時間程度である。 Metachlorobenzoyl peroxide (mCBPO) used in the above reaction can be synthesized by any of the following methods.
(1) By reacting m-chloroperbenzoic acid (mCPBA) with dicyclohexylcarbodiimide (DCC) as a condensing agent in a solvent, m-chlorobenzoyl peroxide (mCBPO) is obtained as crystals. As shown in the following formula, the reaction mechanism for generating mCBPO generates an mCPBA-DCC adduct from mCPBA and DCC, and the adduct and unreacted mCPBA react to generate mCBPO.

In this reaction, the solvent is preferably methylene chloride, chloroform or toluene. The concentration of each reactant is about 0.1 to 0.05M. The reaction temperature is 15-30 ° C. The reaction time is about 15 hours.

この反応において、溶媒としては、塩化メチレン、クロロホルム又はトルエンが好ましい。各反応物の濃度は、０．４〜０．６Ｍ程度である。反応温度は、１５〜３０℃である。反応時間は、２〜３時間程度である。 (2) By reacting m-chloroperbenzoic acid (mCPBA) with dicyclohexylcarbodiimide (DCC) in a solvent, an mCBPA-DCC adduct is produced, and m-chlorobenzoic acid (mCBA) is added to this adduct. In addition, m-chlorobenzoyl peroxide (mCBPO) is synthesized. The reaction mechanism is shown in the following equation.

In this reaction, the solvent is preferably methylene chloride, chloroform or toluene. The concentration of each reactant is about 0.4 to 0.6M. The reaction temperature is 15-30 ° C. The reaction time is about 2 to 3 hours.

この反応において、溶媒としては、塩化メチレン、クロロホルム又はトルエンが好ましい。各反応物の濃度は、０．４〜０．６Ｍ程度である。反応温度は、１５〜３０℃である。反応時間は、２〜３時間程度である。 (3) m-Chlorobenzoic acid (DCC) is reacted with m-chlorobenzoic acid (mCBA) in a solvent, and m-chloroperbenzoic acid (mCPBA) is added to the reaction to react. (mCBPO) is synthesized. The reaction mechanism is shown in the following equation.

In this reaction, the solvent is preferably methylene chloride, chloroform or toluene. The concentration of each reactant is about 0.4 to 0.6M. The reaction temperature is 15-30 ° C. The reaction time is about 2 to 3 hours.

The following examples illustrate the invention but are not intended to limit the invention.
Synthesis Example 1 (Synthesis of Ferguinol)
The route of this synthesis is shown in the following formula.

Dehydroabietic acid (Compound 1) (manufactured by Wako Pure Chemical Industries, Ltd.) (21.1039 g, 70.24 mmol) was dissolved in anhydrous THF (50 ml), LAH (3.032 g, 79.87 mmol) was added, and argon was added at 0 ° C. After stirring for 30 minutes, the mixture was further stirred at room temperature for 12 hours. The reaction was quenched by adding EtOAc, water, and 1N HCl. After liquid-liquid extraction with EtOAc, the organic layer was washed with 1N HCl, saturated NaHCO ₃ , and saturated brine. Thereafter, it was dried over MgSO ₄ , concentrated and then purified by silica gel column chromatography (hexane: EtOAc = 3: 1), 7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10 , 10a-octahydrophenanthren-1-yl) -methanol (Compound 2) (18.8480 g, 65.80 mmol) was obtained in 94% yield.

Compound 2 (30.2312 g, 105.54 mmol) was dissolved in pyridine (100 ml), TsCl (26.157 g, 137.20 mmol) was added, and the mixture was stirred at room temperature for 2 hours under argon. The reaction was stopped by adding 1N HCl in ice-cooling, followed by liquid-liquid extraction with EtOAc, and the organic layer was washed with 1N HCl, saturated NaHCO ₃ , and saturated brine. Thereafter, it was dried over MgSO ₄ , concentrated and then purified by silica gel column chromatography (hexane: EtOAc = 10: 1), 7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10 , 10a-octahydrophenanthren-1-ylmethyl para-toluenesulfonate (Compound 3) (43.4673 g, 98.64 mmol) was obtained in a yield of 93%.

Compound 3 (1.634 g, 3.708 mmol) was dissolved in anhydrous DMF (15 ml), NaI (4.058 g, 27.07 mmol) and zinc powder (1.891 g, 28.92 mmol) were added in 4 portions. Stir at 28 ° C. for 28 hours. After stopping the reaction by adding 1N HCl, zinc was filtered. Liquid-liquid extraction was performed with hexane, and the organic layer was washed with 1N HCl, saturated NaHCO ₃ , and saturated saline. Thereafter, it was dried over MgSO ₄ , concentrated, and then purified by silica gel column chromatography (hexane: EtOAc = 100: 1). 7-Isopropyl-1,1,4a-trimethyl-1,2,3,4,4a, 9 , 10,10a-octahydro-phenanthrene (Compound 4) (832.3 mg, 3.077 mmol) was obtained in a yield of 83%.

Compound 4 (500.0 mg, 1.85 mmol) was dissolved in acetic anhydride (5 ml). While cooling, 270 μl of concentrated nitric acid diluted with 2.73 ml of acetic anhydride was added and stirred at room temperature for 45 minutes under Ar. The reaction solution was dissolved in 100 ml of water, followed by liquid-liquid extraction with EtOAc, and the organic layer was washed with 1N NaOH, saturated NaHCO ₃ , and saturated brine. Then, after drying with MgSO ₄ and concentrating, purification was performed by Rica gel column chromatography (hexane: EtOAc = 5: 1), 2-Isopropyl-3-nitro-4b, 8,8-trimethyl-4b, 5,6, 7,8,8a, 9,10-octahydro-phenanthrene (compound 5) and 2-Isopropyl-1-nitro-4b, 8,8-trimethyl-4b, 5,6,7,8,8a, 9,10- A mixture (410.0 mg, 1.30 mmol) of octahydrophenanthrene (compound 6) was obtained with a yield of 70%.

  A mixture of compounds 5 and 6 (29.8 mg, 0.0945 mmol) was dissolved in EtOH (2 ml), 4 mg of Pd / C (10%) was added, and the mixture was stirred at room temperature under hydrogen for 23.5 hours. Pd / C was filtered, concentrated, and purified by silica gel column chromatography (hexane: EtOAc = 5: 1), 2-Isopropyl-4b, 8,8-trimethyl-4b, 5,6,7,8,8a , 9,10-octahydrophenanthren-3-ylamine (Compound 7) (15.2 mg, 0.0532 mmol) was obtained in a yield of 84%.

Compound 7 (700.2 mg, 2.45 mmol) was dissolved in trifluoroacetic acid (8 ml), isopentyl nitrite (2.43 ml, 14.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours under argon. Further, MeOH (4 ml) and potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour under argon. The reaction was stopped by adding 3N HCl under ice-cooling, followed by liquid-liquid extraction with EtOAc, and then the organic layer was washed with 1N HCl, saturated NaHCO ₃ , and saturated brine. Thereafter, it was dried over MgSO ₄ , concentrated and purified by silica gel column chromatography (hexane: EtOAc = 5: 1) to obtain ferruginol (612.4 mg, 2.14 mmol) in a yield of 87%.
colorless oil; ¹ H-NMR (CDCl ₃ , 600 MHz) δ: 6.83 (1H, s), 6.63 (1H, s), 4.63 (1H, br), 3.11 (1H, sept, J = 7.0 Hz), 2.86 (1H, dd, J = 16.5, 6.6 Hz), 2.80-2.73 (1H, m), 2.19-2.14 (1H, m), 1.88-1.83 (1H, m), 1.75-1.56 (5H, m), 1.49 -1.45 (1H, m), 1.41-1.35 (1H, m), 1.32 (1H, dd, J = 12.5, 2.2 Hz), 1.24 (3H, d, J = 7.0 Hz), 1.22 (3H, dd, J = 7.0 Hz) 1.17 (3H, s), 0.936 (3H, s), 0.914 (3H, s); ¹³ C-NMR (CDCl ₃ , 150 MHz) δ: 150.67, 148.66, 131.34, 127.31, 126.61, 111.94, 50.36, 41.69, 38.87, 37.52, 33.45, 33.31, 29.76, 26.83, 24.77, 22.74, 22.54, 21.60, 19.36, 19.25; IR cm ^-1 (NaCl) 3396, 2960, 2941, 2922, 1713, 1616, 1506, 1548 , 1416, 1373, 1230, 892;

Synthesis Example 2 (Synthesis of m-chlorobenzoyl peroxide (mCBPO) -1)
mCBPA (Kanto Chemical Pr.G) (1.000 g, 5.79 mmol) m-chloroperbenzoic acid is dissolved in methylene chloride (15 ml), DCC (Kanto Chemical Special Grade) (621.1 mg, 3.01 mmol) is added, and under argon flow Stir at room temperature for 1 hour 45 minutes. After concentrating the reaction solution, dicyclohexylurea was filtered through Celite (Kanto Chemical 535). The residue was concentrated and the resulting crystals were filtered with hexane and a small amount of EtOAc to give mCBPO (620.0 mg, 1,99 mmol) in 69% yield.
mp 112-113 ° C; ¹ H-NMR (CDCl ₃ , 600 MHz) δ: 8.06 (2H, t, J = 1.8 Hz), 7.98-7.95 (2H, m), 7.65 (2H, ddd, J = 8.1, 2.2, 1.1 Hz), 7.48 (2H, t, J = 8.1 Hz); ¹³ C-NMR (CDCl ₃ , 150 MHz) δ: 161.80, 135.18, 134.50, 130.25, 129.82, 127.90, 127.11; IR cm ^-1 ( KBr) 3101, 3075, 1791, 1768, 1220, 1006, 811, 723;

Synthesis Example 3 (Synthesis of m-chlorobenzoyl peroxide (mCBPO) -2)
mCBPA (500.0 mg, 2.90 mmol) was dissolved in methylene chloride (8 ml), DCC (310.9 mg, 1.51 mmol) was added, and the mixture was stirred at room temperature for 20 minutes under an argon stream. Further, mCBPA (500.0 mg, 2.90 mmol) was added, and the mixture was stirred at room temperature for 2 hours under an argon stream. After the reaction solution was concentrated, dicyclohexylurea was filtered through celite. The residue was concentrated, and the resulting crystals were filtered with hexane and a small amount of EtOAc to obtain mCBPO (621.3 mg, 2.00 mmol) in 69% yield.

Synthesis Example 4 (Synthesis of m-chlorobenzoyl peroxide (mCBPO) -3)
mCBPA (500.0 mg, 2.90 mmol) m-chloroperbenzoic acid was dissolved in methylene chloride (5 ml), DCC (598.0 mg, 2.90 mmol) was added, and the mixture was stirred at room temperature for 20 minutes under a stream of argon. Further, mCBA (454.1 mg, 2.90 mmmol) was added, and the mixture was stirred at room temperature for 2 hours and 25 minutes under an argon stream. After the reaction solution was concentrated, dicyclohexylurea was filtered through celite. The residue was concentrated and the resulting crystals were filtered with hexane and a small amount of EtOAc to give mCBPO (302.3 mg, 0.972 mmol) in 67% yield.

Synthesis Example 5 (Synthesis of m-chlorobenzoyl peroxide (mCBPO) -4)
DCC (682.5 mg, 3.3 mmol) was dissolved in methylene chloride (8 ml), mCBA (471.5 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 20 minutes under argon. Furthermore, mCPBA (523.7 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 4 hours under argon. After concentrating the reaction solution, dicyclohexylurea was filtered using Celite and EtOAc. The residue was concentrated, and the resulting crystals were washed with hexane and a small amount of EtOAc to obtain mCBPO (500.1 mg, 1.6 mmol) in a yield of 53%.

Example 1
The synthesis route of this example is shown in the above reaction formula (Formula 8).
Ferguinol (31.5 mg, 0.110 mmol) obtained in Synthesis Example 1 was dissolved in methylene chloride (3 ml), mCBPO (58.6 mg, 0.188 mmol) obtained in Synthesis Example 2 was added, and the mixture was stirred at room temperature for 4 hours under an argon stream. . The reaction was stopped by adding Na ₂ S ₂ O ₃ (Wako Pure Chemical Industries, Ltd. Grade 1), followed by liquid-liquid extraction with EtOAc, and then the organic layer was washed with Na ₂ S ₂ O ₃ and saturated brine. Then, it is dried with MgSO ₄ (Kanto Chemical Grade 1), concentrated and purified by silica gel column chromatography (hexane: EtOAc = 5: 1) to give an ortho-oxidized mixture of ferguinol (compound 8 of the above reaction formula (Chemical Formula 8)). 9) (23.3 mg, 0.0548 mmol) was obtained in 50% yield.

The ortho-oxidation mixture (20.9 mg) of Ferguinol obtained above was dissolved in THF (5 ml), lithium aluminum hydride (LAH, Kanto Chemical Co., 24115-25) (6.3 mg, 0.166 mmol) was added, and oxygen was added. The mixture was stirred at room temperature for 3 hours under a stream of air. The reaction was quenched by adding EtOAc, water and 1N HCl, and after liquid-liquid extraction with EtOAc, the organic layer was washed with 1N HCl, saturated NaHCO ₃ and saturated brine. After drying with MgSO ₄ and concentrating, it was purified with a TLC plate (hexane: EtOAc = 30: 1), and abietaquinone methide (11-Hydroxy-12-oxo-7,9 (11), 13-abietatriene) (3.4 mg, 0.0113 mmol) was obtained in 23% yield. The product data is shown below.
colorless oil; ¹ H-NMR (CDCl ₃ , 600 MHz) δ: 7.46 (1H, s), 6.81 (1H, dd, J = 7.0, 3.3 Hz), 6.78 (1H, s), 3.07 (1H, sept, J = 7.0 Hz), 3.02-2.98 (1H, m), 2.58 (1H, ddd, J = 20.9, 7.0, 3.7 Hz), 2.40 (1H, ddd, J = 20.9, 12.1, 2.9 Hz), 1.71-1.56 (4H, m), 1.49-1.44 (2H, m), 1.19 (3H, s), 1.15 (3H, d, J = 7.0 Hz), 1.14 (3H, d, J = 7.0 Hz), 0.977 (3H, s), 0.933 (3H, s); ¹³ C-NMR (CDCl ₃ , 150 MHz) δ: 181.42, 148.94, 143.86, 140.57, 136.10, 131.66, 127.33, 50.57, 41.76, 38.69, 36.82, 33.57, 33.30, 26.64 , 25.85, 22.10, 21.82, 21.49, 18.94, 18.48

Example 2
In this example, an ortho-oxidized mixture of ferguinol synthesized by a method different from that in Example 1 (shown in the above reaction formula (Formula 10)) was used.
mCBPA (19.9 mg, 0.116 mmol) was dissolved in methylene chloride (5 ml), DCC (23.9 mg, 0.116 mmol) was added, and the mixture was stirred at room temperature for 20 minutes under a stream of argon. Ferguinol (26.0 mg, 0.0908 mmmol) obtained in Synthesis Example 1 was added thereto, and the mixture was stirred at room temperature for 15 hours under an argon stream. The reaction solution was concentrated and purified by silica gel column chromatography (hexane: EtOAc = 10: 1) to obtain an ortho-oxidation mixture of ferguinol (22.3 mg, 0.0525 mmol) in a yield of 58%. Thereafter, abietaquinone methide was obtained in the same manner as in Example 1.

Example 3
In this example, abietaquinone methide was synthesized by the same method as in Example 1.
mCBPA (19.9 mg, 0.116 mmol) was dissolved in methylene chloride (5 ml), DCC (23.9 mg, 0.116 mmol) was added, and the mixture was stirred at room temperature for 20 minutes under a stream of argon. Ferguinol (26.0 mg, 0.0908 mmmol) was further added, and the mixture was stirred at room temperature for 15 hours under an argon stream. The reaction solution was concentrated and purified by silica gel column chromatography (hexane: EtOAc = 10: 1) to obtain an ortho-oxidation mixture of ferguinol (22.3 mg, 0.0525 mmol) with a yield of 58%. Thereafter, abietaquinone methide was obtained in the same manner as in Example 1.

Claims (7)

The following general formula in the liquid phase

(Wherein, R ¹ to R ⁴ each represent a hydrogen atom, an alkyl group, an aryl group, a hydroxyl group, a hydroxyl group-containing alkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a halogen atom or a nitro group, R ⁵ and R ⁶ is a hydrogen atom, one is hydrogen and the other is a hydroxyl group, or forms a carbonyl group (═C═O) with a carbon atom to which both are bonded, hereinafter referred to as “abietane type diterpene compound I”. Or the following general formula

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above, hereinafter referred to as “abietane type diterpene compound II”) and the following general formula

(Wherein X represents a halogen atom and n represents 1 or 2), and a step of reacting the benzoyl peroxide represented by the formula, and reacting the product of the previous step with a reducing agent, A method for producing an abietane quinone methide compound comprising a step of reacting, wherein the abietane diterpene compound I is an abietane diterpene compound I, the abietane quinone methide compound is represented by the following general formula:

(Wherein R ^{1 to} R ⁶ are defined in the same manner as above), and when the abietane diterpene compound is an abietane diterpene compound II, the abietane quinone methide compound is represented by the following general formula:

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above), and a method for producing an abietane-type quinone methide compound. The halogenated benzoyl peroxide has the following general formula:

(Wherein X represents a halogen atom, and n represents 1 or 2) and a halogenated perbenzoic acid represented by the general formula R ² —N═C═N—R ²
(Wherein R ² may be the same or different and each represents an alkyl group, a cycloalkyl group, or an aryl group), and produced by reacting a carbodiimide compound represented by The manufacturing method described. In preparing the benzoyl peroxide halide, the following general formula

The process according to claim 2, comprising adding a halogenated benzoic acid represented by the formula (wherein X represents a halogen atom and n represents 1 or 2). The halogenated benzoyl peroxide has the following general formula:

(Wherein X represents a halogen atom and n represents 1 or 2) and a general formula R ² —N═C═N—R ²
(In the formula, R ² may be the same or different and each represents an alkyl group, a cycloalkyl group, or an aryl group.) After reacting with the carbodiimide compound represented by 2. The process according to claim 1, wherein the process is produced by adding. The following general formula in the liquid phase

(Wherein X represents a halogen atom and n represents 1 or 2) and the following general formula R ⁷ —N═C═N—R ⁷
(Wherein R ⁷ may be the same or different and each represents an alkyl group, a cycloalkyl group, or an aryl group). The step of reacting the carbodiimide compound represented by General formula

(Wherein, R ¹ to R ⁴ each represent a hydrogen atom, an alkyl group, an aryl group, a hydroxyl group, a hydroxyl group-containing alkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a halogen atom or a nitro group, R ⁵ and R ⁶ is a hydrogen atom, one is hydrogen and the other is a hydroxyl group, or forms a carbonyl group (═C═O) with a carbon atom to which both are bonded, hereinafter referred to as “abietane type diterpene compound I”. Or the following general formula

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above, hereinafter referred to as “abietane type diterpene compound II”), and the production of the previous step A method for producing an abietane-type quinone methide compound comprising a step of reacting a product with a reducing agent and then reacting with an oxidizing agent, wherein the abietane-type diterpene compound I is an abietane-type diterpene compound I. formula

(Wherein R ^{1 to} R ⁶ are defined in the same manner as above), and when the abietane diterpene compound is an abietane diterpene compound II, the abietane quinone methide compound is represented by the following general formula:

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above), and a method for producing an abietane-type quinone methide compound. After reacting the halogenated perbenzoic acid and the carbodiimide compound, the following general formula

The process according to claim 5, which comprises adding a halogenated benzoic acid represented by the formula (wherein X represents a halogen atom and n represents 1 or 2). The following general formula in the liquid phase

(Wherein X represents a halogen atom, and n represents 1 or 2) and the following general formula R ⁷ —N═C═N—R ⁷
(Wherein R ⁷ may be the same or different and each represents an alkyl group, a cycloalkyl group, or an aryl group). The step of reacting the carbodiimide compound represented by General formula

(Wherein X represents a halogen atom, and n represents 1 or 2) The step of mixing the halogenated perbenzoic acid represented by the following general formula

(Wherein, R ¹ to R ⁴ each represent a hydrogen atom, an alkyl group, an aryl group, a hydroxyl group, a hydroxyl group-containing alkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a halogen atom or a nitro group, R ⁵ and R ⁶ is a hydrogen atom, one is hydrogen and the other is a hydroxyl group, or forms a carbonyl group (═C═O) with a carbon atom to which both are bonded, hereinafter referred to as “abietane type diterpene compound I”. Or the following general formula

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above, hereinafter referred to as “abietane type diterpene compound II”), and the production of the previous step A method for producing an abietane-type quinone methide compound comprising a step of reacting a product with a reducing agent and then reacting with an oxidizing agent, wherein the abietane-type diterpene compound I is an abietane-type diterpene compound I. formula

(Wherein R ^{1 to} R ⁶ are defined in the same manner as above), and when the abietane diterpene compound is an abietane diterpene compound II, the abietane quinone methide compound is represented by the following general formula:

(Wherein R ¹ , R ^{3 to} R ⁶ are defined in the same manner as described above), and a method for producing an abietane-type quinone methide compound.