JPS6118734A - Production of lignan - Google Patents

Abstract

PURPOSE:The dimerization of trimethoxyphenyl-2-propanone is followed by reaction with ethyl orthoformate and benzoic acid, then reduction and cyclization, to enable high yield production of benzocyclo-octadiene type lignan which is used as an improver of hepatic disorders. CONSTITUTION:A compound of formula I (R1-R3 are lower alkyl, lower alkoxy or R1 and R2 incorporate to form methylenedioxy, ethylenedioxy; R4 is lower alkyl) to give a dimer of formula II. Then, the product is allowed to react with ethyl orthoformate and benzoic acid at 100-200 deg.C and the reaction mixture is extracted with a halogen-containing organic solvent, dried and the solvent is removed. The resultant residue is recrystallized from a lower alcohol to give a trans-alkene of formula III, while cis-alkene is obtained from the mother liquor. Then, individual isomers are separately reduced and cyclized using a composition for oxidation containing ferric perchlorate and ferric chloride dissolved in acetic anhydride and acetonitrile to give the objective compounds of formula V or VI.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing physiologically active dibenzofuclooctanoene type lignans.

BACKGROUND OF THE INVENTION The present inventors have discovered physiologically active dibenzocyclooctane-type lignans, such as nzandrin (S
hcizandr, in), Gomi'17A (Gomi
sinA) [Kuyo et al., 3rd Natural Drug Development and Application Lecture Abstracts (Tokyo), p. 22 (+
980)], W ueizisu No, which is known to have hepatocellular damage suppressive effects.
C) [Hikin et al. 1 Collection of lecture abstracts from the 104th Annual Meeting of the Pharmaceutical Society of Japan.

1), +29 (1984)], we have conducted repeated research with the aim of synthesizing lignans useful as pharmaceuticals.

Conventional methods for producing dibenzocyclooctane-type lignans can be roughly divided into two routes.

The first route is to form a biphenyl type by oxidizing phenylpropanes, and then to form a he-membered ring by reacting the propenyl group in the side chain of each allyl group using an Ullmann reaction. The present inventors have established a synthesis method using this first route with high yield and simple operation (Japanese Patent Application No. 56-140269).
).

The second route is a route in which propiophenones are dimerized by reacting the active methylene of the side chain in advance, and then ring-closed to form a hemi-membered ring. is also known [T, B1f
t5u and R, 5tevenson.

J,Chem,Soc,, Parkin I,
2276 (1979), G.E.5chneider
s and R, 5tevenson, J, Org.
Chem.

L foot, 2969 (198+)].

Problems to be Solved by the Invention However, in order to obtain the cis isomer as the final product, the above synthetic method passes through the intermediate step of forming a furan ring.
In addition, the final step of bonding allyl groups and closing the ring uses an expensive catalyst called bananol trifluorite, which is not suitable for practical industrial synthesis.

An object of the present invention is to provide a method for producing nohenzonocrooctadiene-type gnanes by a second route that is high-yield and suitable for practical industrial synthesis.

Means for Solving the Problem The present inventors have conducted intensive research in search of a method for synthesizing nohenzone clooctadiene-type sugnanos by a second route with high yield and suitable for practical industrial synthesis. However, the formula (1
) By dimerizing the compound represented by the formula (
A dimer having two homogeneous asymmetric centers represented by 2) [that is, a mixture of stereoisomers (±) and meso forms] was obtained, and this was mixed with edyl orthoformate and benzoic acid. A mixture of a cis-coordinated alkene represented by formula (3) and a trans-coordinated alkene represented by formula (4) is obtained by reacting with cis-coordinated alkene and trans expressed by formula (4)
After separating the coordinating alkenes and reducing each one, each is dissolved in ferric perchlorate or ferric chloride in one or more solvents selected from acetic anhydride, acetonitrile, propionitrile, and butyronitrile. The cis-coordinated alkene represented by formula (3) can be prepared from the cis-coordinated alkene represented by formula (5) in high yield and at a low production cost by ring-closing it using a composition for oxidation. The benzene clooctanoene type lignan is also represented by the formula (4).
They discovered that a dihenzone clooctanoene type lignan represented by formula (6) can be obtained from ans-coordinated alkenes, and completed the present invention.゛The compound represented by the formula (1) which is a starting material in the present invention can be, for example, according to the target compound, methane, ethyl group, propyl group, methquino group, oxidation group, propokine group, Benzaldehydes substituted with methylene diogino group or ethylenenooxy group are dissolved in acetic acid, condensed with nitroethane in the presence of ammonium acetate, the solvent is distilled off, then dissolved in lower alcohol or lower ether, and further dissolved in water. was added and subjected to reductive hydrolysis by applying V and a catalyst in the presence of concentrated hydrochloric acid. After filtering this reaction mixture, the solvent was distilled off from the Shito solution, extracted with lower ether, and this extract was obtained. It is known that [F, ΔRam1r
cz and A, Burger.

J, Am, Chem, Soc,, 72. -,. 27
81 (] 950), 1, A, Pearl and
D., L., Beyer, J., Org., Chem.
I6.

22+(+95])J. Furthermore, among benzaldehydes substituted in advance with a methyl group, an ethyl group, a propyl group, a metquine group, an etogyne group, a propochine group, a methyleneeneogine group, an endylenedioquine group, for example, 3, 4.
5-1 rimethquin benzaldehyde, 3-methquin-4
, 5-methylenedioquinhenzaldehyde and the like are commercially available, but they can also be synthesized from known compounds.

That is, in the case of 3-methoxy-4,5-methyleneoxybenzaldehyde, commercially available vanillin is used as a raw material, it is iodinated, then heated with sodium hydroxide and copper sulfate, and further heated with dichloromethane-fluoride. A method is known for obtaining 3-methogine-4,5-medylenenogynohenzaldehyde by methylenation using potassium chloride-N,N'-nomedylform 1,amide [G,E
,5chneiders andR,5tevenso
n, J, Org, Chem,, 46.2969 (
]981)].

A specific example of the production of the compound represented by formula (1) which is a starting material in the present invention is as follows.

Specific example 1 Commercially available 3, 4. ．． 5-Trimethquine benzaldehyde'
79.6 g, 91.5 g of nitroethane and 29.6 g of ammonium acetate were dissolved in 240Δ acetic acid and heated for 2 hours.
The mixture was refluxed with stirring for 0 minutes. After refluxing, the reaction mixture was poured into ice water, the precipitated yellow precipitate was collected, and after drying, it was recrystallized from methanol to obtain yellow crystals (3,4,5-trimethoxyphenyl) having the following physical and chemical properties. )-2-
Nitro-1-propene was obtained (yield 75%).

The physicochemical properties of this compound are as follows.

Melting point 90-926C KB-1 Infrared absorption spectrum ν171ax-i+640158
0.1520 Proton nuclear magnetic resonance δ in CDCl
5) 2, 50 (3H, d,, J = I,
51-Iz) 3.95 (31(,s) 6, 65 (21(,S) 8, 05 (I l-1brs) High mass spectrum theoretical value (M”) 253.0951 Actual value (M”) 253. 0953 Next (3,4,,5-1-rimethoxyphenyl)~2-
Nitro 1-propene 50g heated ethanol 400Δ
Dissolve in hot water at 100°C while stirring.
00. Add mQ little by little, then add 63 g of iron powder and 2.5 g of ferrous chloride, leave to cool at room temperature, and add 3 g of concentrated hydrochloric acid at room temperature.
2rLLQ was added little by little. When the reaction became calm, it was heated again (stirred at 7,100°C for 3 hours. After the reaction was completed, it was allowed to cool, filtered through Celite, and washed with hot ethanol. The solvent was distilled off from this f solution, and it was diluted with ether. extract,
The ether layer was washed with water, and after removing the water, it was dried over anhydrous sodium sulfate, and the ether was distilled off. The residue was recrystallized using ether, and the following physical and chemical properties were obtained. rate 80%).

The physicochemical properties of this compound are as follows.

Melting point: 57-59℃ Infrared absorption spectrum system WLL: WL-1.

1700, 15'80 Proton nuclear magnetic resonance spectrum (δ in CDCl3
): 2, I O (3 H., s) 3, 5 2 (21-1, s) 3, 7 7 (9 1 (, S) 6, 2 8 (2 I-1.5) High mass spectral theory Value (M-+-)2 2 4, + 0 4 9
Actual measurement i (M-112 2 4, 1 0 5 5
Specific example 2.

Dissolve 190 g of commercially available vanillin in a small amount of ethanol, and add this to a small amount of water (1 periodic acid/14.5 g) in advance.
249.8 g of 5-iodovanillin (249.8 g of 5-iodovanillin)
A product with a melting point of 18.0 to 181°C and a yield of 72% was obtained.

Next, 150 g of 5-iodovanillin, 858 g of copper sulfate, and 4074 mQ of 4N sodium hydroxide solution.
The mixture was refluxed at 120°C for 4 hours and 30 minutes under a nitrogen stream. After the reaction was completed, the reaction mixture was cooled to 60-70°C and filtered with suction. The residue was washed three times with hot water at 540 rnO. Cool the Shito liquid to 10°C, add concentrated hydrochloric acid dropwise to the Shito liquid while stirring so that the temperature does not exceed 25°C, and adjust the pH.
was set at 3 to 4.

The solution was extracted with ether for 16 hours, dried over anhydrous sodium sulfate, and then the ether was distilled off. The residue was recrystallized from heated benzene to obtain 662 g of 3-methoquinol-4.5-enehydroginohens)2-rudehyde (melting point 133-1
A yield of 73% was obtained at 34°C.

Next, 100 g of 3-nodoquino-4,5-nohytrogynobenzaldehyde was dissolved in 3340 mQ of dry N,N'-methylpolamide, and 156 mQ of dry potassium fluoride was dissolved.
g and 900 g of dry chloromethane d),
The mixture was refluxed for 1 hour and 30 minutes at 120°C under a nitrogen stream. After that, add about twice the amount of ice water, extract 3 times with ether, and add 5%
It was washed three times with an aqueous solution of (s)-lium hydroxide and once with tap water. After washing, drying with anhydrous sulfuric acid solution and chlorine solution to remove ether, the residue was recrystallized from methanol to obtain 60 g of 3-methogino-4,5-methylenequinhenzaldehyde (
Melting point I3I-132°C, yield 56%) was obtained. Next 3
-Methoquine-4,5-methylenequinebenzaldehyde 30g, nitroethane 375g and ammonium acetate 122g were dissolved in acetic acid 1001Q for 2 hours and 30 minutes.
The mixture was refluxed with stirring for several minutes. After refluxing, the reaction mixture was poured into ice water, the precipitated yellow precipitate was filtered out, and after drying,
Recrystallization from methanol gave yellow crystals of 13-methoxy-4,,5-(methylenenookine)phenyl]-2-nide[no 1 propene (yield 75%)), which exhibited the following physical and chemical properties.

The physicochemical properties of this compound are as follows.

Melting point 106-108°C Infrared absorption spectrum νKBI-c, -1・l'yl
Kuchi.

+640.1600. +520.1450 Proton nuclear magnetic resonance spectrum (δ in CDC13)2
,48 (31(,d,,,JcoI, 5 Hz)
3, 95 (3)(,S,) 6, 05 (21(,s,) 6.65(2H,s,) 8, 00 (I H, brs,) High mass spectrum theoretical value (M”) 237. 0637 Actual value (M”) 237.0643 Next, 47 g of 13-methoxyno-4,5-(methylenenoquine)phenyl-2-2-l-rho-1-propene was dissolved in 300i (l) of 13-methoxyno-4,5-(methylenenoquine) and heated at 120°C. 500 H)Q of hot water was added little by little while stirring under temperature conditions, 63 g of iron powder and 2.5 g of ferric chloride were added, the mixture was allowed to cool at room temperature, and 32 rrLQ of concentrated hydrochloric acid was added little by little at room temperature. When the reaction became calm, it was heated again and heated at 120℃ for 3
Stir for hours. After the reaction was completed, the mixture was allowed to cool, filtered through Celite, and washed with dioxane.

The solvent was distilled off from this Shito liquid, extracted with ether, the ether layer was washed with water, the water was removed, and the residue was recrystallized using ether. U3-methokino-4 possessing the following physical and chemical properties
, 5-(methylenethioquine)phenyl]-2-propanone was obtained (yield: 80%).The physicochemical properties of this compound are as follows.

Melting point 49-50°C Infrared absorption vector νnujol, -1・az 1695.1620 Proton nuclear magnetic resonance spectrum ('δ in CDCl
5) 2, l 5(3T-(,s,) 3, 52(2H,s,) 3, 90(3N,s,) 5, 9 8 (2H,s,) 6, 4 0(2+-1 ,s,) High mass spectrum theoretical value (M") 208.0734 Actual value (M") 208.0727 In the present invention, dimerization of the compound represented by formula (1) is represented by formula (+) This is done by reacting a compound with titanium tetrachloride and zinc powder.

The reaction between the compound represented by formula (1) and titanium tetrachloride and zinc powder is carried out at -15°C to 0°C in an oxygen-containing organic solvent under an inert gas stream to avoid moisture. It is carried out for 2 to 5 hours under the temperature condition of . Specific examples of the inert gas include nitrogen gas and argon gas, with nitrogen gas being preferred. Specific examples of the oxygen-containing organic solvent include dioxane, tetrahydrofuran, and ether, with tetrahydrofuran being preferred.

After the reaction is complete, add a weak alkali such as a sodium carbonate aqueous solution or a potassium carbonate aqueous solution to the reaction mixture to precipitate unnecessary inorganic substances from the reaction mixture. , chloroform), and the extract is washed with water, or the filtrated residue is extracted with an oxygen-containing organic solvent (e.g., tetrahydrofuran, ether) or a halogen-containing organic solvent (e.g., chloroform, methylene chloride).
After washing with a single or mixed solvent to transfer the reaction product to liquid I, the Shido liquid is extracted with an organic solvent (e.g. ethyl acetate, ether, tetrahydrofuran, chloroform), and the extract is washed with water. , dried by the usual drying method using anhydrous sodium sulfate, and the solvent was distilled off to obtain the formula (
2) A dimer having two homogeneous asymmetric centers [ie, a mixture of stereoisomers (±) and meso forms] is obtained.

This dimer can be used as it is in the next reaction, but in order to perform the next reaction smoothly, it is desirable to purify it by recrystallizing it from a mixed solvent of a halogen-containing organic solvent and a lower alcohol. Specific examples of halogenated organic solvents include chloroform and methylene chloride.
Specific examples of lower alcohols include methanol and ethanol.

Next, the dimer represented by formula (2) is reacted with ethyl orthoformate and benzoic acid (') at a temperature of 100°C to 200°C for 4 to 10 hours. At this time, ethyl orthoformate itself It is not necessary to add a solvent because the solvent also serves as a solvent, but an appropriate organic solvent (e.g. ethanol, dioxane) that does not affect the reaction may be added as a solvent.After the reaction is complete, remove the reaction mixture. Unreacted benzoic acid is removed by extraction with a halogen-based organic solvent (e.g., dichloromethane, methylene chloride), and further washing with a weak alkaline solution such as an aqueous sodium bicarbonate solution and water.
The residue obtained by drying by a conventional drying method using anhydrous sodium sulfate or the like and distilling off the solvent is recrystallized from a lower alcohol to obtain a transS-coordinated alkene represented by formula (4). Further, the solvent of this recrystallization mother liquor is distilled off, and the resulting residue is distilled to obtain a cis-coordinated alkene represented by formula (3).

Distillation can be carried out by any conventional distillation method for separation purposes, or by using a valve-valve distillation set. A preferred method is distillation under a reduced pressure of I-3 mmHg within a temperature range from 150°C to the boiling point of the cis-coordinated alkene produced.

Next, the cis-coordination alkene represented by formula (3) and the trans-coordination alkene represented by formula (4), which are separated as described above, are each reduced using a conventional reduction method. Examples of the solvent used in this case include lower alcohols such as methanol and ethanol, lower carboxylic acids such as acetic acid and propionic acid, or ethyl acetate, and examples of the catalyst include platinum oxide, platinum, palladium, and Raney nickel. Among them, acetic acid and platinum oxide are used to
A reduction method carried out at normal pressure under temperature conditions of .

After this reduction, the catalyst is separated and the solution is washed with water, or if a lower carbonic acid is used as the solvent, the solvent is distilled off from the filtrate, and then the solution is washed with a weak solution such as aqueous sodium bicarbonate solution. By adding alkali? After removing the acid remaining in the solution, washing with water, drying with anhydrous or normal drying method using sodium sulfate, etc., and distilling off the solvent, the respective reduced products obtained can be used directly or (After purification by separation and purification methods such as recrystallization from lower alcohols, separation thin layer chromatography using adsorbents such as chloride, alumina, and column chromatography, ferric perchlorate or ferric chloride The ring is closed by reacting with an oxidizing composition prepared by dissolving iron in one or more solvents selected from acetic anhydride, acetonitrile, propionitrile, and butyronitrile at room temperature or under heating.

In this case, the reduced product may be added directly to the oxidizing composition described in 1, or the reduced product may be dissolved in advance in one or more solvents selected from acetic anhydride, acetonitrile, propionitrile, and butyronitrile. Then, it may be added to the above-mentioned oxidizing composition, and it is desirable that the solvent used for dissolving the reduced product and the solvent used for preparing the oxidizing composition are the same. The temperature is room temperature or below the boiling point of the solvent, preferably room temperature, and the reaction is completed in 1 to 5 minutes.

After the reaction is complete, if acetic anhydride is used in the reaction, the reaction mixture is poured into ice water and stirred to convert acetic anhydride into acetic acid to precipitate the reaction product, which is collected and reacted. Get generation. If ice-free acetic acid is not used in the reaction, pour the reaction mixture into ice water and extract with an organic solvent.
The extract is washed with water and dried by a conventional drying method using anhydrous sodium sulfate, and the solvent is distilled off to obtain a reaction product.

This reaction product is separated using conventional methods such as separation thin layer chromatography using glue gel, alumina, or other adsorbents, column chromatography, or high-performance liquid chromatography using normal-phase or reverse-phase supports. By purifying according to the purification method and further purifying by recrystallizing from a lower alcohol or a mixed solvent of a lower alcohol and a halogen-containing organic solvent (e.g. chloroform, methylene chloride), the product represented by formula (3) is obtained. rucis
The sobenzonochlorooctadieno type lignan represented by the formula (5) is obtained from the coordinated alkene, and the sobenzonochlorooctadieno type lignan represented by the formula (4) is obtained.
Dibenzone chlorooctadiene type lignans represented by formula (6) are obtained from ans-coordinated alkenes.

In the series of reactions described above, the organic solvent used for extraction in each step may be any solvent as long as it has the property of dissolving the product in each step.

In addition, in the reaction of the present invention, the double bond of the carbonyl group in the side chain of the compound represented by formula (1) participates in the reaction to form two into one, and the dimer is converted into ethyl orthooxyate and By reacting with benzoic acid, the hydroxyl group generated during the duplex formation in (1) and (2) is eliminated to obtain an alkene, the resulting alkene is reduced, and finally the ring is closed to form a he-membered ring. This is a reaction.

Therefore, since this reaction proceeds at the carbonyl group of the side chain of the compound represented by formula (1) and the carbon at the 2-position, the substituents (R1, R2, R3
) and the substituent (R4) on the side chain is either defined in L, the reaction proceeds in the same way.

The nobenzonochlorooctadiene-type scunanes represented by formulas (5) and (6) obtained in the present invention exhibit a liver damage-improving action and are useful as a liver damage-improving action.

Effect of the invention The effects of the present invention include the following points.

■According to the present invention, the reagents and solvents used in each step are inexpensive, and most of the purification methods in each step are simple operations such as recrystallization and distillation, so the production cost is very low and physiological activity can be achieved. Nohenzone clooctadiene type lignans represented by formula (5) and formula (6) can be obtained.

(1) According to the present invention, it is possible to convert a cis-coordinated alkene of formula (3) into a cis-coordinated alkene of formula (3) by simple operations such as recrystallization and distillation.
Since it can be separated into an alkene with Lrar+s coordination represented by 4), it is possible to select the V-form of the final product.

Examples Hereinafter, the present invention will be explained in more detail by giving examples.
The present invention is not limited to this in any way.

In the examples, in the case of alkenes, the cis coordination is indicated by Z, and the trans coordination is indicated by E.

Example 1 (1)” - Represented by the following formula (1) obtained in Specific Example 1 (
2.24 g of 3,4.5-trimethogynephenyl)-2-propanone was dissolved in 40 d of dry tetrahydrofuran,
Methanol - Ice-cooled titanium tetrachloride 2IrLQ (2,8
6 g) was added little by little, and further 1.96 g of zinc powder was added, and the mixture was refluxed with stirring under a nitrogen stream for 3 hours. After the reaction, a 10% aqueous potassium carbonate solution was added, and the precipitate was filtered through Celite and mixed with ether-chloroform (3:I).
) solution, and the I solution was washed with ether-chloroform (31
) solution. Further, this extract was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from a chloroform-ether solution to obtain 1,4-bis(3) represented by the following formula (II). ,4,,5-)rimethoquinophenyl)-2,3-dimethyl-2,3-butanediol, melting point 154-155°C, 2.03g (yield -90%)
I got it.

The physicochemical properties of this compound are as follows.

Infrared absorption spectrum ν=i' dl ・3450.
1600 Proton nuclear magnetic resonance spectrum (δ in CDC13
): 1, 20 (61iS) 2, IO (2H, brs) 2.65 (2
H, cl, J = 13.67H2) 3.10 (21-1,
d, J = 13.67Hz) 3, 85, 3.87 (18
H, each s) 6.48 (4tois) High mass spectrum: Theoretical value (M") 450.2253 Actual value (M") 450.2259 (2) Next, it is expressed by the following formula (fl)1 , 10.5 g of 4-his(3,4,5-trime)quinophenyl)-2,3-dimethyl-2,3-butanol and ol I-
Ethyl oxate IO, 5 g and benzoin iN, Gg were mixed and stirred at 100° C. for 1 hour in a Sheikorchen. Thereafter, 0.8 g of benzoic acid was further added, and the mixture was stirred at 180°C for 3 hours. Next, the reaction mixture was extracted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and then washed with water.
Water was removed, dried over anhydrous sodium sulfate, and then concentrated.

The residue was recrystallized from ethanol to obtain (E)-1,4-bis(3,4,5-1-rimethoquinphenyl:)-2,3-tumethyl-2-fan represented by the following formula (■). , melting point 1
19-12]C, 4.37g (yield 45%) was obtained.

Furthermore, the solvent of the recrystallization mother liquor was concentrated, and the residue was distilled using a Norbuhalb distillation set at 220°C and 3mm14
An oily substance (Z
)-1,4-his(3,4,5-trimethquinphenyl)-2,3-dimethyl-2-butene, 4. ．． 37 g (yield 45%) was obtained.

(E) expressed by the following formula (Hl) obtained as above
The physical and chemical properties of -,-1,4-bis(3,4,5-trimethoquinophenyl)-2,3-dimethyl-2-butene are as follows.

Infrared absorption spectrum I・ru νy*u: HoQ , ,, -
1 bu [1 ton nuclear magnetic resonance spectrum (δ in CDC
15) 1.80 (6H, s) 3, 42 (41 (, S) 3, 82.3, .85 (18H, each s)
6, 42 (41-1, s) High mass spectrum.

Theoretical value (M”) 4. + 62197 Actual value (M”)
416.2181 Also, (Z)-1,4-bis(3,4,5-trimethoquinophenyl)-2,3-tumedel-2-butene represented by the following formula (III) obtained as above The physical and chemical properties of are as follows.

Infrared absorption spectrum νnujoQα-1ntc (z l 600 Proton nuclear magnetic resonance spectrum (δ in CDC13
) 1, 72 (6H, s) 3, 50 (4H, s) 3, 80.3, 82 (184 (, each
s) 6,40 (4Hls) high mass spectrum.

Theoretical value (M”) 416.2199 Actual value (M”) 416. , 2.212(3) (E)-1 represented by the following formula (IV) obtained as described in Jz
,4-bis(3,4,5-trime)quinophenyl)-
4,3 g of 2,3-dimethyl-2-butene was mixed with 400 g of acetic acid.
The mixture was subjected to catalytic reduction at room temperature and normal pressure using 430 mg of platinum oxide as a catalyst, and after absorbing 10.3 mmol of hydrogen, the catalyst was separated by SP, and the solvent was distilled off under reduced pressure. The residue was dissolved in ether, washed with a saturated aqueous solution of sodium bicarbonate, then with water, the water was removed, and after drying over anhydrous sodium sulfate, the solvent was concentrated and the residue was recrystallized from ethanol. (Go)-1,4-His (
Obtained 3.46 g (yield: 80%) of 3,4°5-trimethoquinophenyl)-2,3-tumedelbutane, melting point 125-127°C.

The physicochemical properties of this compound are as follows.

Infrared absorption spectrum chart i! L:il.

Nuclear magnetic resonance spectrum (δ in CDC)
13): 0, 86 (6H2d, J = 6 Hz)
1.60-2.0 (2H9m) 230-2, 65 (4H, m) 3, 79 (12I-1, s) 3.82 (6H, s) 6, 28 (4F-1, s) High mass spectrum Theoretical value (M”) 418.2354 Actual value (M”) 418. 2348 Next, (”e: ) −, represented by the following formula (V),
-502 mg of -1,4,-bis(3,4,5-trimethoquinophenyl)-2,3-dimethylbutane was added to 16 mg of acetic anhydride.
Add the solution dissolved in mQ at once to a solution of 1.8 g of anhydrous ferric chloride dissolved in 18 mQ of acetic anhydride, stir at room temperature for 2 minutes, pour into ice water, and stir for 1 hour to remove the precipitate. I rowed things. The precipitate was subjected to silica gel column chromatography (developing solvent: petroleum ether-ether-2;1), and the eluted crystalline portion was recrystallized from methanol. 7
,8,9-tetrahydro-1°2.3. +2.13.
14--no\Jizame)・Gino 7,8-nomethyldihenzo[a,C]ncrooctene, melting point +29-131℃,
75 mg (yield 35%) of I was obtained.

The physicochemical properties of this compound are as follows.

Infrared absorption vector shift Hatake', 1° proton nuclear magnetic resonance spectrum (δ 1ncDc]3): 1.05(
6H, d, J = 4.671Hz) 1, I 7-1.25
(2H, m) 2 0 4 ~ 2.43C4-11, m) 3, 6
4 (6H, s) 3.89 (] 2) (, S) 6, 57 (21-1, s) High mass spectrum theoretical value CM”) 4 ] 6.2 ] 99 Actual value (M”
)4 ] 6. 2189Although ferric chloride was used in the ring-closing reaction described below, ferric perchlorate can also be used in this reaction.

(4) (Z)-1,4-his(3,4,5-)quinophenyl)-2,3methyl-2 expressed by the following formula (1) obtained as described in 1. -1 g of butene to 10 acetic acid
0uf! The mixture was subjected to catalytic reduction at room temperature and normal pressure using 100 mg of platinum oxide as a catalyst, and then the catalyst was separated and the solvent was distilled off under reduced pressure. The residue was dissolved in ether, washed with a saturated aqueous solution of sodium bicarbonate, then washed with water, and after removing the water, dried over anhydrous sodium sulfate, concentrated the solvent, and recrystallized the residue from methanol. Meso-12,4-bis(3,15-)tumethoquinophenyl)-2,3-tumedelbutane represented by formula (■), melting point 115-117°C
, 804 mg (yield, 80%) was obtained.

The physicochemical properties of this compound are as follows.

Infrared absorption spectrum ν"0Qcm-": WIE 600 pcy) Nuclear magnetic resonance spectrum (δ in CDC
L: 0, 87 (6H, d,, J = 6 Hz
) 1.5-2.0 (2'H, m) 2.2-2.8 (4H, m) 3, 85 (] 81 (, S) 6.38 (4H, s) High mass spectrum theoretical value ( M") 418.2354 Actual value (M") 4. + 8.234.2 Next, meso-1,4-his (3,4', 5
- A solution of 502 mg of trimethocin phenyl)-2,3 to tumedelbutane dissolved in 16 ml of acetic anhydride was added at once to a solution of 1.8 g of anhydrous ferric chloride dissolved in 18 ml of acetic anhydride, and stirred for 2 minutes at room temperature. After that, the mixture was poured into ice water, and after stirring for 1 hour, the precipitate that had formed was collected. The precipitate was subjected to glue gel chromatography (developing solvent: petroleum ether-ether-2:I). The eluted crystalline part was recrystallized from methanol, and the following formula (■) was obtained.
cis-6,7,8,9-tetrahydro-1 represented by
, 2, 3, 1, 2, 13, 14--hexano) quin-
30 mg of I (yield: 26%) was obtained.

The physicochemical properties of this compound are as follows.

Infrared absorption spectrum νrL"jol' c7It-1
・ncLr- Proton nuclear magnetic resonance spectrum (δ in CDC13
): 0, 73 (3H, d,, J = 7 Hz)
1,00 (3H, d, J = 7 Hz) 1.8~
2.0 (2H, m) 2.2-2.7 (4H, m) 3, 60 (6t (, s).

3, 9 0(121(,S) 6, 55(21(,S) Hymassbek! Le theoretical value (M"MI6.2199 Actual value (M") 416.2217 In the above closed door reaction, secondary chloride Although iron is used, perchloric acid (V2) can be used instead.

The reaction of Example 1 is expressed as follows.

Example 2 (1)-1 = 21.8 g of [3-methoquino-4,,5-(methylenezoxy)phenyl]-2-propanone represented by the following formula (IX) obtained in Specific Example 2 was The mixture was dissolved in 400 m, Q of dry tetrahydrofuran, cooled with methanol and water, and 22.8 d (32.4 g) of titanium tetrachloride was added little by little, followed by 225 g of zinc powder, stirred for 3 hours under a nitrogen stream, and then refluxed. After the reaction, an aqueous solution of 10% potassium carbonate was added, and the precipitate separated was filtered through Celite:J, washed with an ether-chloroform (31) solution, and the filtrate was diluted with an ether-chloroform (3:l) solution. Extracted. Furthermore, the organic solvent layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from a chloroform-ether solution to obtain 1,4-bis[3-methquin-4, 5-(methylenodioquino)phenyl]-2,3
-Tumedel-2,3-butanediol, melting point 145-1
+9.35 g (yield, 88%) was obtained at 47°C.

The physical and chemical properties of this compound are as follows.1 Infrared absorption spectrum ν"j"ti-': mCLχ.

35] 0,11320 Proton nuclear magnetic resonance spectrum (δ in CDCl2
)・1, I 5 (6T-f, d, J = I
, 51 (z) 2 , 00 (2) (, brs) 2 , 55 (2'H, d, J = I 2 Hz)
3.05 (2 positive (, d, J = l 2 T-
IZ) 3.88 (6H, s) 5, 94 (4, H, s) 6, 45 (41 (, brs) High mass spectrum theoretical value (M”) 4] 8.1628 Actual value (M”) 418. 1640 (2) Next, 1,4-bis[
3-Methoxy-4,5-(methylenodioquino)phenyl]-,-2,3-dimethyl-2,3-butanediol 4
．． 0 g and 4.0 g of ethyl orthoformate and 0.0 g of benzoic acid.
8 g were mixed and stirred at 100° C. for 2 hours in a Kolben. Furthermore, 0.4 g of benzoic acid was added, and the mixture was stirred at 180°C for 4 hours. The reaction mixture was then extracted with dichloromethane,
The mixture was washed with a saturated aqueous solution of sodium bicarbonate, then washed with water, the water was removed, and the mixture was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to obtain (E)-1,4-bis[3-methoquino-4,5 represented by the following formula (Xl+).
-(Methylenedioquino)phenyl]-2,3-dimethyl-2-butene, melting point III - 113°C, 1.7 g (yield: 46%) was obtained. Furthermore, the solvent of the recrystallization mother liquor was concentrated, and the residue was distilled using a valve-bulb distillation set at 240°C.
, 3 mmHg is recrystallized from methanol-ether to obtain (Z)-+ , 4, which is represented by the following formula (Xl).
-bis[3-methoquino-4,5-(methylenedioquino)
phenyl]~2,3-dimethyl=2-butene, melting point 64
~66°C, 17g (46% yield) was obtained.

(E) represented by the following formula (Xl) obtained as above
The physical and chemical properties of -1,4-bis[3-methoquino-4,5-(methylenedioquino)phenyl]-2,3-dimedy-2-butene are as follows.

Infrared absorption spectrum I・LEνYL”Joffimnl:m
αχ.

I 630 proton nuclear magnetic resonance spectrum (δ in CDC13
)・1, 74 (61-1, s) 3, 38 (4J (, S) 3, 90' (61 (, S) 5, 97 (4H, s) 6, 40 (4' + (, S) High Mass Spectrum Theory 4fiCM”) 384.1-574 Actual Measured Value (M”)
384.1586 Also, (Zl-1,4-bis[3-methquine-4,5-(methylenodioquino)phenyl]-2,3- The physical and chemical properties of trimethyl-2-butene are as follows.

nu, joL -1.

Infrared absorption spectrum 'meL1G.

l 630 Pro) Nuclear Magnetic Resonance Spec) Le(δ in CDC
1, 70 (61-1, s) 3, 43 C4) 1.3) 3.88 (6H, s) 5.95 (4H, s) 6, 38 (4H, brs) High mass spectral theory &i ( M”) 384.157] Actual value (M”) 384.1568 (3) (E)-1,4-bis[3-methoxo obtained as described above and represented by the following formula (Xll) 4. , 5-
12 g of (methylene chloride)-2,3-tumedel-2-butene was subjected to catalytic reduction in 50 OIlIQ of acetic acid using 12 g of platinum oxide as a catalyst at room temperature and normal pressure, and 0.031 mole of hydrogen was absorbed. After that, separate the catalyst by I,
The solvent was distilled off under reduced pressure, and the residue was dissolved in ether, washed with a saturated aqueous solution of sodium bicarbonate, then washed with water, the water removed, dried over anhydrous sulfur sulfate, and the solvent was concentrated. The residue was subjected to column chromatography (developing solvent, chloroporm-hexane-21), and among the eluted fractions, a single fraction was combined using a thin layer chromatography (thin layer chromatography) chromatography to obtain an oily product of the following formula (X[I) Represented by (
±)-1,4-his[3-methoquino-4,,5-(methylenenookino)phenyl]-2,3-dimethylbutane 9
65 g (yield 80%) was obtained.

The physicochemical properties of this compound are as follows.

Dazzling J-1° Infrared absorption spectrum I. , 1 [7 tons nuclear magnetic resonance spectrum (δ in CDC
+3) 0, 82 (6H, (1, J = 6H
z) 1.5-2.0 (21 (, m) 2, 2-2.80 (4I (1 m) 3, 90 (61-1, s) 5, 95 (41-1, s) 6,, '32 (2H, d, J = 1.5Hz) 6.36 (
2H, d, J = 1.5Hz) High mass spectrum theoretical value (M'') 386', ] 727 Actual measurement value (M
”)386.1730 Next, 347 mg of (±)-1,4-bis[3-methoquino-4,5-(methylenenoquine]phenyl]2,3-trimethylbutane represented by the following formula (Xi) was added to dry acetate)
・Add the solution dissolved in nitrile 9,7Q all at once to a solution of 132 g of ferric perchlorate dissolved in 15 mQ of dry acetonitrile, stir at room temperature for 1 minute, then pour into ice water to perform ether extraction. The layer was washed with water to remove water, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to Norica gel chromatography (developing solvent: petroleum ether-ether = 41). The eluted crystalline portion was recrystallized from 10 form-methanol to obtain Lrans-6,7,8,9-tetrahydro-1,14-nomethquine-2,3,12, which is represented by the formula (separately).
13-bis(medididioquino)-7,8-dimethyldibenzo[a,C]nochlorooctene, melting point 193-195
℃, 159 mg (yield 46%) was obtained.

The physicochemical properties of this compound are as follows.

Infrared absorption spectrum, rut3oRc, -11lZ Protononuclear magnetic resonance spectrum (δ in CDCl 0, 99 (611, d, J-=4, 8911z
) 1.09-1.33 (2H, m) 2, 00-2. 36(4H,m)3,13
6 (61,1,S) 5.90 (411,s) 6,48 (2H,s) High mass spectrum theoretical value (M'') 384.+572 Actual value (M'') 384 1562 In addition, the ring closure indicated by - Ferric perchlorate was used in the reaction, or ferric chloride can be used instead.

(4) Expressed by the following formula (Kari) obtained as above (
Z)-1,4-His[3-methoquino-4,5-(medylennookino)phenylj-2,3-tumedel-2-bunan (12 g) was added to acetic acid 500@0 using 12 g of platinum oxide as a catalyst at room temperature and normal pressure. The catalyst was separated and washed with a saturated aqueous solution of hydrogen carbonate, followed by water, and after removing the water, it was dried over anhydrous sodium sulfate. The solvent was concentrated. The residue was recrystallized from methanol to obtain meso-1 represented by the following formula (Xv).
,4-bis[3-methoquino-15-(medylenogin)phenyl]-2,3-tumedelbutane, melting point 86-8
9.65 g (yield 80%) was obtained at 8°C.

The physicochemical properties of this compound are as follows.

Infrared absorption spectrum νmtjog 1171αχ l 630 Pro(・n nuclear magnetism) ru(δ in CD
Cl5) 0.85 (61 (, d, J=6Hz) 1, 5-2.0 (21 (, m) 2, 15-2. 90 (4H, m) 3, 89 (6H, s) 5, 9 3 (41-4, s) 6, 32 (21], d, J=1.5Hz) 6, 3
6(2H, d,, J=], 51(z) High mass vector j・le Theoretical value (M”) 386.1727 Actual value (M”) 386.1726 Next, the meso value expressed by the following formula (XV) A solution of 347 mg of -1,4-his[3-methoquino-4,5-(methy1/nnogino)phenyl]-2,3-dimedylbutane in 9 m, Q of dry acetonitrile was dissolved in ferric perchlorate. Add 1.32 g of dry acetonitrile at once to a solution dissolved in 15 ml of dry acetonitrile, stir for 1 minute at room temperature, pour into ice water and perform ether extraction. The residue was subjected to chromatography (developing solvent: 6-ura ether-ether-4.1). The eluted crystalline portion was recrystallized from chloroporum-methanol, and the following formula (sequentially) was applied. ) cis -6,7,8,9-tetrahydro-1,14-nemethoquino-2,312,13-bis(medylenenookino)-7,8-dimethyldibenzo[a
, C] cyclooctene, melting point 158-160°C, 162
mg (yield, 47%).

The physicochemical properties of this compound are as follows.

Infrared absorption spectrum νKB? c71 (+615 Proton nuclear magnetic resonance spectrum (δ in CDCl5
)・0.73(3H,d,,J =7Hz)0.96(
3N, d, J'=7Hz) 16~2,. 7 (6H, m) 3, 84 (6H, s) 5, 96 (4H, s) 6, 51 (21-[, S) High mass spectrum - theoretical value (M”) 384.1593 Actual value (M”) 384.1583 In addition, in the ring-closing reaction described in item 1, ferric perchlorate is used, or ferric chloride may be used instead.

The reaction of Example 2 is expressed as follows.

Claims (1)

[Claims] Formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R_1, R_2, R_3 are the same or different and represent a lower alkyl group, a lower alkoxy group, or R_1 and R_2 together represent a methylenedioxy group or ethylenedioxy group, and R_4 represents a lower alkyl group) Formula (2) obtained by dimerizing the compound , chemical formulas, tables, etc. ▼(2) (wherein R_1, R_2, R_3, R_4 have the same meanings as defined above) A dimer represented by is reacted with ethyl orthoformate and benzoic acid. By making the formula (3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (3) (In the formula, R_1, R_2, R_3, R_4 have the same meaning as defined above) and the alkene represented by the formula (4) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(4) (In the formula, R_1, R_2, R_3, R_4 have the same meaning as defined above.) To obtain a mixture with an alkene represented by the formula After separating the alkene represented by formula (3) and the alkene represented by formula (4), each is reduced, and then each is treated with ferric perchlorate or ferric chloride using acetic anhydride, acetonitrile, or propionic acid. Formula (5) characterized by ring closure using an oxidizing composition dissolved in one or more solvents selected from nitrile and butyronitrile ▲There are mathematical formulas, chemical formulas, tables, etc.▼(5) (Formula 5) (R_1, R_2, R_3, R_4 have the same meaning as defined above) and the dibenzocyclooctadiene type lignan represented by formula (6) ▲Mathematical formula, chemical formula, table, etc.▼(6) ( (wherein R_1, R_2, R_3, R_4 have the same meanings as defined above) A method for producing a dibenzocyclooctadiene-type lignan represented by: