JPH01104066A - Benzodioxaneprostacyclin analog - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or phenoxyalkyl; R2 is H, lower alkyl or aralkyl; R3 is H or protecting group; A is ethylene or vinylene; broken lines indicate alpha- or beta-configuration or a mixture thereof) or salt thereof. EXAMPLE:Methyl [2-hydroxy-1-(3-hydroxy-5-methyl-1-nonenyl)-2,3,3a,9a-tetrahy dro-1H-cyclopenta[b][1,4]benzodioxin-5-yl]oxyacetate. USE:An antiulcer agent and antithrombotic agent. PREPARATION:For example, an aldehyde expressed by formula II (R2 is lower alkyl; R3 is protecting group) is additively reacted with a Grignard reagent to afford the corresponding compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The compounds of the present invention relate to benzodioxane prostacyclin analogs and intermediates thereof that can be utilized as antiulcer and antithrombotic agents in the pharmaceutical field. For more details, please refer to prostacyclin [prostaglandin (hereinafter referred to as PG)
The present invention relates to a compound represented by the general formula (I), a salt thereof, and an intermediate thereof, which has an anti-111 tumor effect and a platelet aggregation inhibitory effect, such as (abbreviated as (abbreviated)).

(Left space below) General formula [wherein j R1 is alkyl, alkenyl, alkynyl,
Cycloalkyl, cycloalkylalkyl or phenoxyalkyl iRm is hydrogen, lower alkyl or aralkyl; R1 is hydrogen or a protecting group; A is ethylene or vinylene; the wavy line is in the α configuration! ! or β configuration or □ represents a mixture thereof] Peptic ulcers are thought to be caused by local malnutrition of the gastric mucosa, which creates areas of weak resistance, and gastric juices acting on these areas. However, the etiology of peptic ulcer is complex, and includes various local factors or stress such as mechanical stimulation, chemical stimulation, gastric juice digestion, gastritis or gastric mucus secretion disorder, autonomic nervous disease, endocrine abnormality, systemic malnutrition, It is thought that multiple factors are involved, including systemic factors such as allergies or constitutional abnormalities. This kind of thinking is shy (S
Hay et al.'s theory of balance between defensive factors and offensive factors, that is, increased secretion of hydrochloric acid and increased secretion of pepsin.

Vagus nerve tone, increased gastrin production, total number of parietal cells i1D
or Zollinger-Ellison syndrome (Zolling
The theory is that an imbalance between mucosal attacking factors such as er-Ellison syndrome and mucosal protective factors such as mucosal barrier, mucosal resistance, or suppression of duodenal gastric juice secretion leads to the development of ulcers. Therefore, in the treatment of ulcers, measures are taken to promote mucosal attacking factors and protect the mucous membranes from attacking factors, and drug treatments include (1) tranquilizers, (2) parasympathetic nerve blockers, and (3) antacids. (4) antipepsin agents, (5) antigastrin agents, (6) gastric mucosal protective agents such as mucin preparations, and (7) gastric tissue regeneration promoters.

Robert et al. reported that PGE, PGl, etc. have an acid secretion suppressing effect and/or a cytoprotective effect (c
ytoprotection), the administration of these PCs or their derivatives has attracted attention as being useful for treating peptic ulcers.

Nileprost (US 4,219.47) as a PGIaM derivative with anti-ulcer effect
9), Hoe-892 [Nis, G., Kontrek et al. (S, J.

Konturek et a1, ), Prostaglandins, Vol. 28, 4
43 pages, 1984], U-68215 [A.

Robert et al.), Prostaglandins, Volume 30, 619
Page, 1985] or the compounds described in JP-A-58-164585.

The light is about to be decided - Since PGI1 was discovered as a new arachidonic acid metabolite, it has been shown to have protective effects on gastric mucosa (suppressing acid secretion or cell protection), suppressing platelet aggregation, vasodilation, and relaxing bronchial smooth muscle. It is attracting attention because it has a variety of interesting biological activities.

PCl's acid secretion suppressing effect or cytoprotective effect (mucus production, secretion enhancement, cell membrane stabilization, sodium pump maintenance, bicarbonate ion secretion, gastric mucosal blood flow increase, etc.) protects the gastrointestinal mucosa from various attacking factors. considered to be protected.

However, natural PC1 has the following disadvantages: (1) It is inactive when administered orally due to its rapid metabolism, and has a short duration of action when administered parenterally; (2) It has various pharmacological effects. , (3) Although there are some problems such as chemical instability, PGI! is still fully satisfactory as an anti-ulcer agent. Analogs have not been developed.

The present inventors conducted research for the purpose of solving these problems and synthesized a benzodioxane prostacyclin analog represented by the formula (1) or a salt thereof.

In the general formula c, R is alkyl/L, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl or phenoxyalkyl; R2 is hydrogen, lower alkyl or aralkyl; Rs is hydrogen or a protecting group; A is ethylene or vinylene; the wavy line represents α or β configuration or a mixture thereof] This new compound The present invention was completed based on the discovery that the compound has a strong gastric mucosal protective effect, has a long duration of action, and is chemically stable.

In this specification, the definitions of terms used are as follows.

"Lower alkyl" means a C4-C1 linear or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-
Mention may be made of butyl, pentyl or hexyl.

"Alkyl" means C1-C1° straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-
Butyl, pentyl, 1-methylpentyl, 1.1-dimethylpendel, 2-methylpendel, hexyl, 1-methylhexyl, 1.1-dimethylhexyl, 2-methylhexyl, peptyl, octyl, nonyl or decyl, etc. can be mentioned.

"Alkenyl" means C8-C1, linear or branched alkenyl, such as vinyl, 1-propenyl, 2-propenyl, 2-pudel-2-propenyl,
1-butenyl, 2-putenyl, 2-pentenyl, 1-methyl-3-pentenyl, 3-hexynyl, 2-methyl-
5-hexynyl, 2,6-dimethyl-5-hebutenyl,
Examples include 3-octenyl and 3-nonenyl.

"Alkynyl" means a C1-C8 straight or branched alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butenyl, 2-butenyl, 2-pentynyl, 2-methyl -3-pentynyl, 3-
Examples include hexynyl, 2-methyl-5-hebutenyl, 3-octenyl and 3-nonynyl.

"Cycloalkyl" means C3-C, cycloalkyl, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

“Cycloalkylalkyl- means lower alkyl substituted by cycloalkyl, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohebutylmethyl or cyclooctylmethyl. be able to.

"Phenoxyalkyl" means lower alkyl substituted with phenoxy, such as phenoxymethyl, phenoxyethyl, 1-phenoxypropyl,
Examples include 2-phenoxypropyl, 1-phenoxy-2-methylpropyl, 1-phenoxybutyl, 2-phenoxybutyl, 1-phenoxypentyl, 1-phenoxyhexyl, 1-phenoxyheptyl, and 1-phenoxyoctyl.

"Aralkyl" means lower alkyl substituted with aryl, such as benzyl, substituted hensyl (2
, 4.6-)limethylbenzyl, 4-bromobenzyl,
4-methoxybenzyl), diphenylmethyl, triphenylmethyl L.

Bis(2-nitrophenyl)methyl or 9-anthrylmethyl can be mentioned.

In general formula (1), more preferable R is alkyl, such as pendel, 1-methylpentyl, 1.1
- such as dimederpentel or 2-methylhexyl,
Arkenino's tweets, for example, 2.

alkynyl, such as 1-methyl-3-pentynyl or 3-hexynyl, cycloalkyl, such as cyclopentyl or Mention may be made of cyclohexyl, cycloalkylalkyl such as cyclohexylmethyl, or phenoxyalkyl such as phenoxy-2-propyl, phenoxy-2-methylpropyl and the like. More preferred examples of R include hydrogen, lower alkyl such as methyl, and aralkyl such as 9-anthrylmethyl. More preferred R3 is hydrogen or a protecting group such as trimethylsilyl, dimethyl-tert-butylsilyl, tar
Examples include commonly used hydroxyl protecting groups such as t-butyldiphenylsilyl. More preferred A is ethylene or vinylene (trans).

When R in the general formula CI) is hydrogen, the salts include alkali metal salts such as libram salt, sodium salt or potassium salt, alkaline earth metal salts such as calcium salt, ammonium salts, organic bases, etc. For example, salts with triethylamine, N-methylmorpholine, dicyclohexylamine, pyridine or trimethylamine or salts with amino acids such as glycine, valine or alanine may be mentioned.

The compound of the present invention is a racemate or an optically active compound in which one steric configuration is shown in the general formula (1), but the technical scope of the present invention includes all of the compounds represented by the general formula (1). Includes stereoisomers or mixtures thereof.

The compound of the present invention can be produced according to the outline shown below.

(Step A) This step is a step in which an aldehyde is additionally reacted with a Grignard reagent to obtain the compounds of the present invention - and -a.

The reaction can be carried out in several tens of minutes to several hours under cooling in a solvent such as diethyl ether or tetrahydrofuran according to the conventional Grignard reaction method. magnesium halides, such as alkylmagnesium halides (n-pentylmagnesium bromide,
1-methylpentylmagnesium bromide, 1.1-dimethylpentylmagnesium chloride, n-hexylmagnesium bromide, 2-methylhexylmagnesium bromide, etc.), alkenylmagnesium halide (2
, 6-dimethyl-5-pentynylmagnesium bromide, etc.), alkynylmagnesium halides (3-hexynylmagnesium bromide, 1-methyl-3-pentynylmagnesium bromide, etc.), cycloalkylmagnesium halides (cyclobentylmagnesium bromide, etc.), bamide, cyclohexylmagnesium bromide, etc.) or cycloalkylalkylmagnesium halides (cyclohexylmethylmagnesium bromide, etc.).

(Step B) This step is a step of reducing enone to unsaturated alcohols La-a and k.

As a reducing agent, aluminum isopropoxide, diisobornyl aluminum isopropoxide, sodium cyanoborohydride, potassium tri-5ec-butylborohydride, zinc borohydride, sodium borohydride, sodium borohydride and cerium chloride. combination with (1), 2,6-tert-butyl-4-methylphenoxide cybdelaluminum, lithium hexyllimonylborohydride or BINAL-H [adjusted from binaphthol, lithium aluminum hydride, ethanol ( Journal of the American Chemical Society, Vol. 106, p. 6709, 1984).

As a solvent, ether type diethyl ether, tetrahydrofuran, alcohol type methanol, ethanol,
Aromatic hydrocarbons such as benzene and toluene or chlorinated hydrocarbons such as dichloromethane and chloroform may be used alone or in combination depending on the properties of the reagent. It can be done in minutes.

When the allyl alcohol obtained in this manner contains a phenylselenyl group, it is oxidatively eliminated to form genyl alcohol.

Phenylselenyl alcohol can be mixed with ozone, sodium periodate, peroxides (e.g. hydrogen peroxide, peracetic acid, m-
It is oxidized with black benzoin #) to form selenoxide,
Subsequently, a chlorinated hydrocarbon solvent (e.g. carbon tetrachloride,
Genyl alcohol can be obtained by refluxing the mixture in chloroform, dichloromethane, etc., optionally in the presence of diisopropylamine.

The alcohol obtained in this step is a mixture of epimers.

This step yields hydroxy-protected compounds of the present invention, Ic-a and Ic-a.

(Step C) This step is a step in which the hydroxy protecting group of compound H or Ic-a is removed to obtain compound Ib-a or Ic-a, respectively.

The reaction is carried out using reagents such as acetic acid, hydrochloric acid, p-toluenesulfonic acid, Kitamotomoto fluoride and pyridine, and tetrabutylammonium fluoride, as necessary, and alcohols such as methanol, ethanol, and ethers such as ethyl ether and solvents. Carboxylic acid methyl ester is produced in a zero step process using tetrahydrofuran or acetonitrile, water, etc. at room temperature or under heating in a few minutes to several hours.
Since it may be hydrolyzed, it may be esterified using diazomethane or the like, if necessary.

This step yields a compound of the present invention from which the hydroxy protecting group has been removed.

(Step D) This step is a step of catalytically reducing Compound (1) to obtain Compound (Kani).

Mixtures of metals such as palladium, platinum, nickel, etc. with their optional supports (e.g. activated carbon, alumina, barium sulfate, calcium carbonate, strontium carbonate, etc.) or nickel boride or chlorotris (
It is preferable to use rhodium (triphenylphosphine) at normal pressure or after absorbing pressurized hydrogen.

As a solvent, alcoholic methanol, ethanol,
Ether diethyl ether, tetrahydrofuran,
Dioxane or ester-based ethyl acetate may be used alone or in combination. The reaction can be carried out at room temperature for several hours to several tens of hours.

(Step E) This step is a step in which the hydroxy protecting group of compound Ie'-a is removed to obtain an understanding of the compound.

The reaction may be carried out in the same manner as in step C.

Through this step, a compound in which the hydroxy protecting group of the compound of the present invention has been removed can be obtained.

(Step F) This step hydrolyzes the compound Ib-a, Id-a or the carboxylic acid ester to obtain a free carboxylic acid ratio.
This is the process of obtaining ``tan'' or ``■'', respectively.

The reaction may be carried out according to a conventional method for hydrolysis reaction.

Through this step, the free carvone M Ib of the compound of the present invention
-b, 臘 or ■" can be obtained.

(Step G) This step is a step of esterifying a free carboxylic acid to obtain an aralkyl ester of carboxylic acid Ib-a'.

The esterification reaction can be carried out according to conventional methods such as 1) a method using a carboxylic acid and an alcohol, 2) a method using an acid chloride and an alcohol, 3) a method using a carboxylic acid salt and a halide, or 4) a method using a carboxylic acid and a diazotide. good.

Aralkyls of alcohols, halokenides and diazotides which form esters include benzyl, substituted benzyl (2,'4.6-h-lymethylbenzyl, 4-bromobenzyl, 4-methoxybenzyl), diphenylmethyl, triphenylmethyl , bis(2-nitrophenyl)methyl or 9-anthrylmethyl.

In the formula, R1, R8, R3 and A have the same meanings as above unless otherwise specified.

The wavy line represents the α or β configuration or a mixture thereof.

Starting compounds (n) and (III) can be produced, for example, by the method shown in the following reaction scheme.

(Left below) Reaction step (first step) In this step, in order to protect the hydroxyl group of alcohol 1, alkylation is performed using an alkyl halide in the presence of a base to form an ether? This is the process of obtaining

The reaction uses methoxymethyl chloride or methoxymethyl bromide as the alkyl halide, and ether diethyl ether, tetrahydrofuran, chlorinated hydrocarbon dichloromethane, chloroform, dimethyl sulfoxide, dimethyl formamide, etc. as the solvent. This can be carried out for several hours to several tens of hours under cooling or at room temperature. As the base, for example, sodium amide, potassium carbonate, triethylamine, diisopropylethylamine, sodium hydroxide, barium oxide, silver oxide or sodium hydride may be used.

(Second step) This step consists of sulfide? This is the process of oxidizing the sulfoxide.

The reaction is carried out using a peroxide such as hydrogen peroxide, t
ert-butyl hydroperoxide, performic acid, peracetic acid,
Using perbenzoic acid, metachloroperbenzoic acid, halanitroperbenzoic acid, etc., in a solvent such as alcohol-based methanol, ethanol, ether-based nodiethyl ether, tetrahydrofuran, or chlorinated hydrocarbon-based dichloromethane, chloroform, etc., under cooling for several tens of minutes. It can be done in minutes to hours.

(Third Step) This step is a step in which Compound 4 is obtained by rearranging the sulfoxide group to a sulfenic acid ester, and further transesterifying the obtained sulfenic acid ester.

In order to shift the equilibrium between the sulfoxide and the sulfenic acid ester to the sulfenic acid ester side, phosphines such as triphenylphosphine or phosphites such as trimethyl phosphite and triethyl phosphite may be used.

The reaction can be carried out in a mixed solvent of aromatic hydrocarbons such as benzene and toluene and alcohols such as methanol and ethanol under heating for several tens of hours.

(Fourth step) This step is a step to obtain compound 2 by oxidizing the double bond of compound 2.

The reaction is carried out using a peroxide, e.g. hydrogen peroxide, as an oxidizing agent.
Using tart-butyl hydroperoxide, performic acid, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, varanitroperbenzoic acid, etc., alcohol-based methanol, ethanol, ether-based diethyl ether, tetrahydrofuran, etc., or chlorinated hydrocarbon-based This can be carried out in a solvent such as dichloromethane or chloroform under cooling for several tens of minutes to several hours.

(Fifth Step) This step is a step of protecting the hydroxy of the compound.

Examples of the compound forming the protecting group include methanesulfonyl chloride and p-toluenesulfonyl chloride. The reaction is carried out in the presence of a base such as sodium hydride, triethylamine, or pyridine, using ethers such as diethyl ether, tetrahydrofuran, chlorinated hydrocarbons such as dichloromethane, chloroform, dimethyl sulfoxide, dimethylformamide, etc. under cooling for several tens of minutes to several minutes. It can be done in time.

(Sixth Step) This step is a step in which methyl of the compound is removed to obtain the compound Nerino.

The reaction uses boron trichloride or boron tribromide, etc.
This can be carried out in a chlorinated hydrocarbon solvent such as dichloromethane or chloroform under cooling for several tens of minutes to several hours.

Alternatively, methyl ether can be oxidized with chromium trioxide-acetic acid to give the corresponding formate ester, which can then be hydrolyzed to give phenol or heated with hydroiodic or hydrobromic acid. There is.

(Step 7) In this step, in order to protect the hydroxy of the compound, alkylation is performed in the presence of a base using an alkyl halide,
This is the process of obtaining ether L.

As alkyl halide, (2-trimethylsilyl)
The reaction preferably using ethoxymethyl chloride or (2-trimethylsilyl)ethoxymethyl bromide is preferably carried out according to the first step.

(Eighth Step) This step is a step of converting the sulfonic acid ester L into phenolic acid.

The reaction is carried out using alkyllithiums as nucleophiles, such as methyllithium, ethyllithium, isopropyllithium,
Using n-butyllithium or an alkylmagnesium halide (Grinard reagent) such as methylmagnesium bromide, ethylmagnesium bromide, inpropylmagnesium bromide, n-butylmagnesium bromide, etc., ethers such as diethyl ether, tetrahydrofuran, etc. This can be carried out by reacting in a solvent under cooling for several tens of minutes to several hours to obtain a metal adduct, which is then decomposed with water.

(Ninth Step) This step is a step of condensing compound 1 and compound 2.

The reaction is carried out by reacting Compound 2 with Compound Rice, which is an acidic substance, in the presence of, for example, triphenylphosphine and azodicarbonate diethyl, under cooling or at room temperature for several tens of minutes to several days. As a solvent, aromatic hydrocarbon type benzene, chlorinated hydrogen dichloromethane type,
It is preferable to use an anhydrous solvent such as chloroform, ether type diethyl ether, or tetrahydrofuran.

(10th Step) This step is a step in which the hydroxy protecting group of Compound U is removed to obtain Compound (1).

The reaction may be carried out by a method normally used for removing a silyl protecting group, for example, using a reagent such as hydrogen fluoride-pyridine or tetrabutylammonium fluoride.
This can be carried out in an ethereal solvent such as diethyl ether or tetrahydrofuran at room temperature or under heating for several hours to several days. Compound U undergoes automatic ring closure to become Compound 12 when the hydroxy protecting group is removed.

(Step 11) This step is a step in which hydroxy of the compound is allylated to obtain the compound.

This process involves the production of tetrahedron (Tetrahedron).
), Vol. 41, pp. 4079-4094, 1985.

First, compound B may be converted into a precursor for carbon radicals, such as a thioacyl derivative, and then the obtained precursor may be irradiated with allyltin, such as allyl-tri-n-butyltin.

The acylation reaction can be carried out using phenyl chlorothionocarbonate, diimidazole thionocarbonate, or dihydrogen disulfide-methyl iodide in an ether type solvent such as diethyl ether or tetrahydrofuran. If necessary, the reaction may be carried out in the presence of a basic substance such as methyllithium or n-butyllithium.

The light irradiation reaction is carried out by irradiating with light for several hours to several tens of hours using a 450 W high-pressure mercury lamp under an argon stream and using a Virex filter. As the solvent, aromatic hydrocarbons such as benzene and toluene or esters such as ethyl acetate may be used alone or in combination.

(Twelfth Step) This step is a step in which methyl ether is demethylated to obtain a chemical compound.

As a reagent, metal salts of thiols such as lithium or sodium, such as lithium methyl thiolate, sodium nibruthiolate, lithium n-propyl thiolate, lithium n-butyl thiolate, etc. may be used. For example, dimethylformamide, hexamethyltriamide phosphate, dimethyl sulfoxide, or the like can be used, and the reaction can be carried out in several tens of minutes to several hours.

(Left below) (13th step) In this step, the length of the compound is determined by using an alkyl halide.
This is a step of alkylating in the presence of a base to obtain a compound.

Examples of the alkyl halide used in the reaction include methyl bromide acetate and methyl iodoacetate.

This step is preferably performed according to the first step.

(Step 14) This step is a step in which the hydroxy protecting group of the compound hook is removed to obtain the compound hook.

The reagent is preferably a combination of a Lewis acid and a sulfide or thiol. Examples of the Lewis acid include boron trifluoride-diedelether complex, aluminum chloride, and aluminum bromide. Examples of the sulfide include dimethyl sulfide, diethyl sulfide, diphenyl sulfide, etc., and examples of the thiol include methanethiol, ethanethiol, benzenethiol, etc. The reaction was carried out at -10℃
The reaction may be carried out at room temperature, if necessary, in the presence of chlorinated hydrocarbons such as dichloromethane, chloroform, etc.

Alternatively, the reaction can be carried out by a hydrolysis reaction using an acid catalyst (eg, hydrochloric acid, acetic acid, etc.).

(Step 15) This step is a step of introducing a protecting group to protect the hydroxyl group of compound 17' from subsequent reaction conditions.

The reaction consists of tert-butyldimethylsilyl chloride,
Using tart-butyldiphenylsilyl chloride, trimethylsilyl chloride, etc., triethylamine,
This can be achieved in the presence of a base such as pyridine, 4-dimethylaminopyridine, imidazole, etc. at room temperature or under heating in several hours to several days. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, and chlorinated hydrocarbons such as chloroform, dichloromethane, and dimethylformamide. Or the reaction is p
-Toluenesulfone Lp-Toluenesulfonic acid pyridinium salt, Amberlyst 15 [Rohm & 11
/”Rohm & Haas Co.]
This can be achieved by treatment with dihydrobilane at room temperature in the presence of an acidic catalyst such as. Examples of the solvent used include ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as hexane, aromatic hydrocarbons such as benzene and toluene, and chlorinated hydrocarbons such as chloroform and dichloromethane.

(Step 16) This step is a step in which the compound lock is subjected to a halogenation reaction accompanied by rearrangement of double bonds to obtain compound lock.

This process consists of Tetrahedron Letters (1'etrahedron Letters),
It may be carried out according to the method described in Vol. 44, pp. 3909-3912, 1977.

Compound 18' was reacted with phenylselenenyl chloride or bromide in carbon tetrachloride for several tens of minutes under cooling to form an anti-Makovnikov adduct (anti-Ma
rkovnikov adduc1,a) is obtained. The obtained adduct was treated with hydrogen peroxide solution containing pyridine.
A compound lock can be obtained by oxidation for several hours under cooling or at room temperature.

(Step 17) This step is a step to obtain a compound by performing a substitution reaction with a carboxylic acid salt on the compound restraint.

As carboxylic acid salts, mention may be made of the sodium or cesium salts of acetic acid, trifluoroacetic acid, chloroacetic acid, methoxyacetic acid, phenoxyacetic acid or benzoic acid.

The reaction is preferably carried out by heating for several hours to several tens of hours in a nonpolar solvent such as aromatic hydrocarbon benzene or toluene, or a polar solvent such as dimethylformamide, hexamethyltriamide phosphate, or dimethyl sulfoxide. When a solvent is used, a crown ether-like organic layer-aqueous layer transfer catalyst, such as 18-
Crown-6 may also be added.

(18th Step) This step is a step of hydrolyzing ester 20゛ to obtain an alcohol positive.

The reaction is preferably carried out according to the conventional method for hydrolysis of esters. If necessary, an acid (e.g., sulfuric acid, sulfuric acid, etc.) or a base (sodium hydroxide, potassium hydroxide, barium hydroxide, etc.) may be used as a catalyst. may be used as a solvent,
Alcohols such as methanol, ethanol, and chlorinated hydrocarbons such as dichloromethane, chloroform, or water may be mixed and used as necessary.

When methyl ester is partially hydrolyzed to carboxylic acid in the hydrolysis reaction, esterification may be carried out using diazomethane or the like.

(19th Step) This step is a step of oxidizing alcohol to aldehyde L.

The reaction is carried out by using a chromic acid-based oxidizing agent such as Collins' reagent, pyridinium chlorochromate or pyridinium dichromate, or by using dimethyl sulfoxide and oxalinochloride, sulfuryl chloride or pyridine trioxide and triethylamine as an oxidizing agent. , 4-dimedelaminopyridine or the like may be used. Depending on the nature of the reagent, the reaction is carried out in a solvent such as aromatic hydrocarbons such as benzene, chlorinated hydrocarbons such as chloroform, dichloromethane, and ethers such as diethyl ether or acetone, under cooling or heating for several tens of minutes to several minutes. It can be achieved in time.

(Twentieth Step) This step is a step of oxidizing the compound to obtain raw glycol.

As the oxidizing agent, it is preferable to use an alkaline potassium permanganate aqueous solution, osmium tetroxide, or the like. When using an alkaline potassium permanganate aqueous solution as the oxidizing agent, magnesium sulfate or the like may be added. When using osmium tetroxide as the oxidizing agent, it is preferable to add an amine such as pyridine to promote the production of cyclic osmium ester, and then treat this with sodium sulfite, sodium hydrogen sulfite, or the like. Solvents used in these reactions include alcohols such as methanol, ethanol, propatool, and tert-butanol, and ethers such as diethyl ether, tetrahydrofuran, and dioxane.
Aromatic hydrocarbons such as benzene, chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, acetone, and ethyl acetate may be used depending on the properties of the reagent. The reaction can be carried out for several hours to several days at room temperature.

(21st Step) This step is a step of cleaving Glyfur 1 to obtain an aldehyde.

As the oxidizing agent, for example, periodate (sodium periodate or potassium periodate) or lead tetraacetate may be used. When using periodate as the oxidizing agent, alcoholic methanol may be used as the solvent. , ethanol, or a mixed solvent of water and an organic solvent such as ether diethyl ether, tetrahydrofuran, or dioxane. When lead tetraacetate is used as the oxidizing agent, a solvent such as aromatic hydrocarbon benzene may be used, and if necessary, an acid such as trichloroacetic acid may be added as a catalyst. The reaction can be carried out at room temperature for several tens of minutes to several hours.

(22nd Step) This step is a step in which aldehyde 23' is reacted with a phosphonic acid ester to obtain unsaturated ketone 1.

The reaction is carried out using a base such as sodium hydride, sodium amide, etc. as the base, and a Horner-Wadsworth-Emmons reaction in a solvent such as 1,2-dimethoxyethane or tetrahydrofuran.
) It is best to follow the reaction.

The phosphonic acid ester used in this reaction is one having a side chain to be condensed, namely dimethyl 2-oxoheptylphosphonate, dimethyl 2-oxo-3-methylbutylphosphonate, 2-oxo-3,3- Dimethyl hebutylphosphonate, dimedel 2-oxo-4-methyloctylphosphonate, 2-year-old xo-4.8-dimethyl-7-ranenylphosphonate dimethyl, 2-year-old xo 3-
Dimethyl methyl-5-hebutynylphosphonate, 2-year-old xo-5-octynylphosphonate dimethyl ester, 2-year-old xo-2-cyclopentylethylphosphonic acid dimethyl ester, 2-year-old Xo-3-cyclohexylpropylphosphonic acid dimedel ester, 2-oxo-4-phenoxypentylphosphonic acid dimethyl ester, (S)
-(-)-2-year old Examples include methyl)octylphosphonic acid dimethyl ester.

For example, dimethyl 2-oxo-4-phenoxypentylphosphonate can be produced as follows.

First, 1°3-butanediol in which the hydroxyl at the 1st position is protected is reacted with phenol, triphenylphosphine and diethyl azodicarboxylate according to the method of the 9th step to form the corresponding 3-0-phenol ester. Next, the hydroxy protecting group at the 1-position is removed, and the resulting alcohol is preferably oxidized to a carboxylic acid using an acid-based oxidizing agent (for example, Jones reagent) and esterified. The target compound can be obtained by treating the obtained ester with dimethyl methylphosphonate and an anion obtained from a basic substance.

Dimethyl 2-oxo-4-methyl-7-otatenylphosphonate can be produced as follows.

Citronellol is oxidized to a carboxylic acid with a chloric acid-based oxidizing agent (e.g., Jones's reagent), followed by esterification to yield a citronellolate ester. Next, the double bond is epoxidized using a peroxide according to the method described in the fourth step, and further oxidatively cleaved with periodate to obtain an aldehyde.

This aldehyde is subjected to a Witzteig reaction using trimethylphosphonium bromide and a basic substance to obtain an olefin. The compound thus obtained can be condensed with dimethyl methylphosphonate in the presence of a basic substance to obtain the target compound. When an optically active compound such as (S)-(-)-citronellol is used as a starting compound and a similar reaction is carried out, an optically active substance such as dimethyl (S)-2-xo-4-methyl-7-otatenylphosphonate is obtained. You can get a body.

Dimethyl 2-oxy-4-(phenoxymethyl)pentylphosphonate can be obtained by condensing 4-phenoxy-3-methylbutanoic acid and dimethyl methylphosphonate in the presence of a basic substance in the same manner as above.

Dimethyl 2-year-old xo-4-(phenylselenylmethyl)octylphosphonate can be obtained as follows.

2(5H)-furanone is alkylated using di-n-butyl copper lithium (prepared from cuprous bromide-dimethyl sulfide complex and n-butyl lithium) in the presence of trimethylsilyl chloride. The selenide is ring-opened with sodium phenylselenate obtained by reduction with sodium borohydride in dry dimethylformamide to yield the carboxylic acid, which is esterified.

The target compound can be obtained by condensing the obtained ester with dimethyl methylphosphonate in the presence of a base.

In the reaction scheme, R1, R8, R1 and A have the same meanings as above unless otherwise specified.

R4 means substituted sulfonyl such as methanesulfonyl and p-toluenesulfonyl.

R8 means thioacyl such as (methylthio)thiocarbonyl, 1-imidazolylthiocarbonyl, and phenoxythiocarbonyl.

R6 means alkanoyl such as acetyl, trifluoroacetyl, chloroacetyl, methoxyacetyl, phenoxyacetyl, or aroyl such as benzoyl.

Hal means halogen such as chlorine, bromine or iodine.

SEM is (2-trimethylsilyl)ethoxymethyl, T
MS represents 2-trimethylsilyl, and Ph represents phenyl.

Reference examples, examples, and physical constants are shown below to clarify aspects of the invention in more detail, but the scope of the invention is not limited thereto.

In the following Reference Examples and Examples, each compound is represented by one enantiomer at each stage. The relative or absolute configuration of a compound is indicated by the R, S or R9, S8 designation of the compound name, respectively.

The wavy line represents the α or β configuration or a mixture thereof.

(Left below) Reference example-1 , (3dan", 4dan1) -4-methoxymethoxy-3-phenylthio-1-cyclopentene-based alcohol 1
B5.0 [C (0,443 mol) and 109 ml (0,626 mol) of diisopropylethylamine were dissolved in 500 ml of dry dichloromethane, and under water cooling, 3 g of metquin methyl chloride and 0 ml (0,500 mol) of diisopropylethylamine were dissolved.
o Add 100 ml of methane solution dropwise. After completion of the dropwise addition, the mixture was returned to room temperature and further stirred for 23 hours. The reaction solution was cooled with water.
Pour into 150 ml of N-hydrochloric acid and extract twice with dichloromethane. The extract was washed once each with water, saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under pressure of 0 g, distillation was carried out under reduced pressure to obtain 911 L, 6 g ( (yield 94.3%) as an oil.

・Boiling point 98-100℃ (0.03mmHg) ・'H-N
MR: 8 (CDC1,) 2.33 (1H, m)
, 2.67 (1H.

m), 3.23 (31(,s), 4.11-4.
23・(1H, m), 4.23-4.40(1H, m
), 4.50 (LH, d, J=9Hz>, 4.5
2 (LH, d.

J:9Hz), 5.64-5.93 (2H, m),
7.13~7.51 (5H, m) ppm・-IR, νmax (CHCIs) 3064.3004
．． 2952.2g28°1585, 1482.1439
．． 1148.1098.1037°! 05 am-'.

-MS: m/z M" 236, Reference Example-2 (3R", 4R")-4-Methoxymethoxy-3-phenylsulfenyl-1-cyclopentene Mainly produced under nitrogen stream, sulfide or (Reference Example-1) )98.6g(
0,418 mol) of dry dichloromethane 1! In the solution, −
At 60 to -70°C, 108 g (0,502 mol) of 85% m-chloroperbenzoic acid in dry dichloromethane 1
．． 4. Add the solution dropwise over 1.5 hours. After the dripping is finished,
9.2 ml (0,125 mol) of dimethyl sulfide was added to the reaction solution which was stirred for an additional 20 minutes at the same temperature to stop the reaction. The reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure. The residue is ether 1.2! After washing with an IN-sodium hydroxide aqueous solution, water, and a saturated ammonium chloride aqueous solution, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 106 g of the desired crude product of sulfoxide as an oily substance. This product is used in the next reaction without purification.

(Left space below) Reference Example 3 Production of (IR", 4R")-4-methoxymethoxy-2-cyclopenten-1-ol 4 Under a nitrogen stream, 106 g of the crude product of sulfoxide and (Reference Example 2) and tri Dissolve 165 units (0,623 mol) of phenylphosphine in a mixed solvent of 1 ml of toluene and 300 ml of methanol,
Stir at 60°C for 40 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in 300 ml of ether and cooled with water.
- Add 300 ml of pentane dropwise. After filtering the precipitated crystals, the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (silica gel 6 Q Q gx ethyl acetate; benzene-〇; 1 to 1:0), and further distilled under reduced pressure to obtain the desired product. 48.3g (2
Total process yield a o , 29) Obtained as an oily substance.

・Boiling point 80-81℃ (bnmHg) -'H-NMR: δ (CDCIs) 1.70-2.3
5 (3H9m), 3.35 (3H,s), 4.65
(2H, s), 4.77-5.20 (2H, m>
, 5.94-6.13 (2H, m>ppm.

・IR Niji max (CHCIs) 3608.300
4.2944.2892゜1360, 1148.109
7.1033.914 crn-'.

・MS: m/z (M-1 unit 143° Reference example-4 (1 degree ", 2 degrees 0.3 times 1.4 degrees") -2,3-epoxy-4-methoxymethoxy-1-cyclopene Tanol
27.0 g (0,188 mol) of Olefin I (Reference Example 3) was dissolved in 400 ml of dry dichloromethane, and 48.5 g (0.0 mol) of 80% m-chloroperbenzoic acid was dissolved at room temperature.
, 225 mol) and #5I! overnight. Add 4.1 ml (0,056 mol) of dimethyl sulfide to the reaction solution cooled in a dry ice-acetone bath and stir for another 10 minutes at the same temperature.The reaction solution is filtered, and the filtrate is mixed with alumina ( Further filtration is carried out through 150 g of grade If). The alumina is washed with 1.81 g of ether, and the filtrate and washings are combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 450 g 1 ethyl acetate: n
-hexane (1:2 to 1:1) to obtain 25.9 g (yield: 86.3%) of the desired epoxide as an oily substance.

・'H-NMR: S (CDCIs) 1.45 (
LH, ddd, J = 6Hz.

8Hz, 15Hz), 2.07 (1H, dd, J
=8) 1z, 15Hz>, 2.27(1H, d, J
=8Hz, -Oj%), 3.37 (3H,s),
3.49-3.60 (2H, m), 4.25 (1)
1. d, J=6Hz>, 4.37~4.60 (1H
, m).

4.64 (2H, s) pl) m.

・IR: L/maX (CHClm) 35g8.30
04.2952.2896°1397, 1150.11
02.1042.915.869 cm-'.

・MS: m/z (M-1)" 159° Reference Example-5 Production of 2-methanesulfonyloxy-1,3-dimethoxybenzene 23.3 g of 60% sodium hydride (0,
A solution of 75 g (0,486 mol) of 2,6-simethoxyphenol [Aldrich] in 130 ml of DMF was added to a 400 ml suspension of dimethylformamide (hereinafter abbreviated as DMF) of 583 mol) under water cooling. After 0 dropwise addition in 30 minutes, stirring was continued for 25 minutes, and 54.3 ml of methanesulfonyl chloride (0
, 680 mol) of DMF130n+1 was added dropwise, and the mixture was further stirred at the same temperature for 30 minutes. Pour the reaction solution into 1.8 ml of ice water and extract twice with benzene. The extract is washed with IN aqueous sodium hydroxide solution, water, and saturated ammonium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 112 g of crude crystals of the desired sulfonic acid ester. This product is used in the next reaction without purification.

Reference Example 6 Production of 2-methanesulfonyloxy-3-methoxyphenol Under a nitrogen atmosphere, 112 g of crude crystals of methyl ether (Reference Example 5) were added to a dichloromethane solution containing -60 to -70
125 g (0,500 mol) of boron tribromide at ℃
Add dropwise 500ml of dichloromethane solution of
Pour the reaction solution into 1.5 ml of water and extract twice with dichloromethane. The extract is washed with dilute aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 94 g of crude crystals of the desired phenol. Recrystallized from benzene, melting point 105-106℃
80. Og (total yield of 2 steps 75.5%) is obtained.

・Melting point 105-106℃ (benzene) ・'H-NMR: 8 (CDCIs) 3.26 (
3)1. s), 3.64 (3H.

s), 5.95 (1H,br,s), 6.53
(LH, dd, J=2Hz, 8Hz).

6.64 (11, dd, J=2)1z, 8Hz),
7.09 (1H, 1, J = 8Hz) ppm.

・IR: νmax(CIC1,) 3568.347
2.1609.1497°1483, 1371.134
4.1146.1092.973.869 am-'.

・MS: m/z M” 21g.

(Left below) Reference example-7 2-methanesulfonyloxy-1-methoxy-3-[[
Production of (2-trimethylsilyl)ethoxy]methoxy]benzene Under a nitrogen stream, phenol! (Reference Example-6) 25.0g (
0,115 mol) and diisopropylethylamine 29
．． 3 ml (0,173 mol) of dichloromethane 400 ml
1 solution, 25.0 ml (2-trimethylsilyl)ethoxymethyl chloride (SEM-CI) (0,
After completing the dropwise addition of 125 ml of dichloromethane (141 mol), the mixture was returned to room temperature, stirred for 3 hours, added with 45 ml (1.11 mol) of dry methanol, and further stirred overnight. The reaction solution is washed with IN hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under pressure to obtain 44 g of the desired crude ether product as an oil. This product is used in the next reaction without purification.

Reference Example-8 Production of 2-methoxy-6-[[(2-trimethylsilyl)ethoxycomethoxy]phenol-L'-Drying of 44 g of crude product of methanesulfonic acid ester (Reference Example-7) under nitrogen stream -60 to - in 750 ml of ether solution
Add 130 ml (0,207 mol) of n-butyllithium (1,6 N, n-hexane solution) dropwise at 70°C. After the dropwise addition, stir at the same temperature for 20 minutes and leave the reaction solution at a low temperature. , and poured into 1.5 P of saturated ammonium chloride aqueous solution to stop the reaction. Extracted twice with ether, the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (700 g of silica gel, ethyl acetate:n-hexane-1:9) to obtain 29.7 g of the desired phenol-10- (total yield of 2 steps: 95.9 g).
7%) obtained as an oil.

・'H-NMR: 8 (CDCIg) 0.0 (9
H,s), 0.94 (2H.

dd, J=8Hz, 9Hz), 3.78 (2H,
dd, J=8Hz, 9Hz>.

3.74 (3H,s), 5.21 (2H,s),
5.83 (LH, br, s).

6.50-6.80 (3H, m) ppm.

・IR: νmax(CHClm> 3544.296
0.1619.1505°1481, 1075. 1
003.860,837 cm-'.

・MS: m/z M” 270° Reference Example-9 1-[[: (IR”, 2S”, 3D-14”)-2° 3-Epoxy-4-methoxymethoxy-1-cyclopentylcooxy ]-2-Methoxy-6-[(2-trimethylsilylethoxy)methoxy]Benzene 11 Production (white space below) )39.3g
(0,146 mol), alcohol (Reference Example-4) 25
．． 8 g (0,161 mol) and triphenylphosphine 49. To a 750 ml solution of sg (o, ts 9 mol) in dry tetrahydrofuran (hereinafter abbreviated as THF) was added 25.2 ml (0,160 mol) of diethyl azodicarboxylate under water cooling.
mol) is gradually added dropwise. After the dropwise addition was completed, the temperature was returned to room temperature, and after stirring for 3 days, 11.4 g of triphenylphosphine (0,
044 mol) and diethyl azodicarboxylate 6.9 ml
(0,044 mol) was added and stirred for an additional 2 days. The solvent was distilled off under reduced pressure, and 500ml of ether was added to the reaction solution residue.
1 and cooled in a dry ice-acetone bath. The precipitated crystals were separated by filtration, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (silica gel 1.5 kg).
, ethyl acetate:benzene-1;50-1:9)L,
Thus, 51.8 g (yield: 86.2%, from compound-10) of the target epoxy ether 11 was obtained as an oily substance.

・'H-NMR: f; (CDC1,) 0.0 (
9H,s), 0.92 (2H.

dd, J=8Hz, 9Hz>, 1.76-2.33
(2H, m), 3.41 (3H.

s), 3.80 (3H, s), 3.65-3.9
0 (4H, m), 4.26 (18°d, J=6H
z), 4.50 (1H, dJ=6Hz>, 4.7
3<2H,s).

5.20 (2H, s), 6゜57 (LH, d
d, J: 2Hz, 8Hz), 6.76 (1H,
dd, 2Hz, 8Hz), 6.96 (11
, 1, J=8Hz) ppm.

・IR: νmax (CHCla) 3004, 296
0.2896, 2840°1598, 1490. 1
476, 1249. 1108. 1073. 10
12°859, 847. 837 am-'.

a MS: m/z M" 412° Reference example-10 (1", 2S", 3a", 9a S") -5-
Methoxy-2-methoxymethoxy-2,3,3a,9a
-tetrahydro-1-cyclopenta[b][1,4]
Production of benzodioxin-1-ol U (blank below) 51.8 g of epoxide 1 (Reference Example 9) under a nitrogen stream
Tetra-n-butylammonium fluoride (LM, Tf (F
Add 251 ml (0,250 mol) of solution) and stir at 55°C for 3 days. 6. Pour the reaction solution into water and extract twice with ethyl acetate. The extract is washed with water and a saturated aqueous ammonium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (700 g of silica gel, ethyl acetate:n-hexane-1:2 to 1:1), and further crystallized from a mixed solvent of ether-n-hexane. , 31.7 g (yield 89.6%) of the target penzodioxin E 1 was obtained.

・Melting point 69.0-70.0°C (ether-n-hexane) ・'H-NMR: S (CDCIs> 2.13
(1H, ddd, J=2.5Hz.

6Hz, 15Hz), 2.62 (1H, ddd,
J=6Hz, 1OHz, 15Hz).

3.37 (3H,s), 3.83, (3H,s)
, 3.50-3.95 (2H, m).

4.05-4.41 (311), 4.67 (2H
,s), 6.47 (1)1. dd.

J=2Hz, 8Hz), 6.57 (1H, dd,
J=2Hz, 8Hz), 6.80(LH,1,J=
8Hz) ppm,.

・IR: νmax (CHCIs) 3476, 300
4.2952.2896°2844, 1603.149
9.1475.12g0.1110゜1082 am-
'.

・MS: m/z M" 282° (blank below) Reference example-11 (IR", 2S", 3aR", 9aR") -5-methoxy-2-methoxymethoxy-1-[:[(phenoxy)
[thiocarbonyl]oxy]-2,3゜3a,9a-tetrahydro-1H-cyclopenta[b][1,4]benzodioxin 13 Preparation of alcohol 1 (Reference Example-10) 15 under nitrogen stream O
g (53.2 mmol) in 150 ml of dry THF at -60 to -70°C.
, 6N n-hexane solution) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 20 minutes, 8.82 ml (63.9 mmol) of phenyl chlorothionocarbonate was added, and the mixture was kept at the same temperature for another 20 minutes. Stir. The temperature was raised to 0°C over 30 minutes, and after further stirring for 1 hour at the same temperature, a saturated aqueous ammonium chloride solution was added to stop the reaction6.
The reaction solution is extracted twice with ethyl acetate, and the extract is washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (silica gel 400 g, acetic acid nibble: n
-hexane (1:5 to 1:2) to obtain 20.4 g (yield: 91.9%) of the desired thiono ester 13 as crystals.

・Melting point 100-102℃ (benzene-n-hexane)・
'H-NMRs S (CDCIg) 2.17 (1
H, d1, J = 7Hz.

15Hz), 2.66 (1)1. ddd, J=6H
z, 8Hz, 15Hz), 3.33 (3H, s)
, 3.85 (3H, s), 4.14-4.75
(51 (, m), 5.82 (1H, 1, J = 4Hz>
, 6.43~6.88 (3H, m), 7.03~
7.52 (5H, m) ppm--IR: max (CHCl,) 3008. 295
6. 1603. 1500°1492. 1477,
1290. 1189. 1111. 1039c
m-'.

・MS: m/z M" 41g.

Reference example-12 (1dan", 2S", 3adan1,9a mutually)-5-methoxy-2-methoxymethoxy-1-(2-propenyl)
-2+ 3.3 a + 9 a-tetrahydro-1dan-cyclopenta[b][1,41benzodioxin ↓
Production of thiono carbonate ester (Reference example-11) U, zo, 44
g (4 g, 9 mmol) and 48.9 g (148 mmol) of allyl-tri-n-butyltin in 400 g of dry benzene.
ml, completely degassed by passing argon for 1 hour, and irradiated with light for 10 hours using a 450W high-pressure mercury lamp through a virex filter under an argon stream. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography [1] 600 g of silica gel, ethyl acetate: Q-
Hexane-1:5-1:3.2) 700g of silica gel,
Ethyl acetate:dichloromethane-1+3:97] to obtain 11,2 g of 1 on the target olefin (yield 74.8
%) Obtained as crystals.

・Melting point 48.5-49.5℃ (n-pentane)
--'H-NMR: δ(CDCIs) 1.93"2.
57 (51, m), 3.33 (3H, s), 3.
85 (3H, s), 3.72~4.23 (2H,
m), 4.26-4.45 (1H, m), 4.5
9 (2H, m), 4.98-5.30 (2H, m
).

5.60-6.13 (1H, m), 6.40-6.
65 (2H, m), 6.78 (LH, 1, J=8H
z) ppm.

・IR: νmax (CHCIs) 3008.294
8.2844.1642゜1603, 1499.14
77.1282. 1254.11 (17,1037°918 cm-'.

-MS: m/z M" 306° (blank below) Reference Example-13 (IR", 2S", 3aR", 9aS")-2-methoxymethoxy-1-(2-propenyl)-2.

3.3a,9a-tetra-drow 1H-cyclopenta[
b][1,41benzodioxin-5-ol Upper 1
Production of n-butyl mercaptan 5.25 ml (4
9 mmol) of phosphoric acid hexamethyltriamide (hereinafter H
30 ml of n-butyllithium (1,58N n-hexane solution) was added to 30 ml of solution (abbreviated as MPA) under water cooling.
7 mmol) was added dropwise.

After completion of the dropwise addition, the temperature is returned to room temperature and n-hexane is distilled off under reduced pressure.Add methyl ether (Reference Example-x2)6.
A solution of OOg (19.6 mmol) in 20 ml of HMPA is added and stirred with JW at 100° C. for 30 minutes. A saturated aqueous ammonium chloride solution is added and extracted three times with ethyl acetate. The extract is washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure is
Purification by silica gel column chromatography (150 g of silica gel, 1:3 ethyl acetate:n-hexane) yielded 5.64 g of the target phenol 15 (yield 98.
5%) obtained as an oil.

・'H-NMR: S (CDCIs) 1.90=2
．． 56 (5H, m), 3.33 (31, s), 3.
72~4.36 (3H, m>, 4.57 (2H,
m>, 4.96-5.26 (2)1. m),
5.43 (1)1. br, s), 5.62-6
．． 11 (ill.

m>, 6.38-6.57 (2H, m), 6
．． 72 (LH,1,J=8Hz>ppm.

・IR: νmax(CHCl,) 3552.300
8.2948.1642゜1610, 1499.148
7.1272.1090.1040°917 cm-'
.

・MS: m/z M" 292° Reference example-14 C (I R", 2 S", 3a dan 8, 9a dan 8) -2
-methoxymethoxy-1-(2-propenyl)-2゜3
．． 3a,9a-tetrahydro-1H-cyclopenta[b
] [1,4]Benzodioxin-5-yl]Methyloxyacetate Preparation Under a nitrogen stream, 850 m @ (21.2 mmol) of 60% sodium hydride was suspended in 50 ml of dry dimethoxyethane (hereinafter abbreviated as DME). 1 liquid,
Under water cooling, phenol top (reference example-ta) s, s4g (
19.3 mmol) in 40 ml of DME is added dropwise.
After the dropwise addition was completed, the temperature was returned to room temperature, stirred for 20 minutes, and 3.65 ml (38.6 mmol) of methyl acetate bromide was added.
A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was stirred overnight, and extracted three times with ethyl acetate. The extract was washed with water and saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (150 g of silica gel, ethyl acetate 20-hexane-172) to obtain the desired methyl ester. 32 g (yield: 89.9%) are obtained as crystals.

・Melting point 65.0-66, 0°C (ether-Q-hexane) ・'H-NMR: δ (CDCIs) 1.94-
2.56 (5H, m), 3.33 (3H, s), 3
．． 76 (3H,s), 3.75~4.46 (3H
, m), 4.58 (2H, s), 4.67 (2H
,s), 4.9111-5.27 (2H,m),
5.59-6.14 (1)1. m), 6.35
~6.85 (3H, n+) ppm.

・IR: νmax(CHCl,) 3012.296
0.1764.1742°1643, 1600.149
9.1476, 1441.1287.1125°103
7,917 cm-'.

・MS: m/z M” 364, (blank below) Reference example-15 [(1dan”, 2S”, 3adan”, 9aS”) 2-hydroxy-1-(2-propenyl)-2,3, 3a, 9
a-tetrahydro-1-cyclopenta[b][1,4
]Benzodioxin-5-yl]Production of methyl oxyacetate (Reference Example-1)
4) To a solution of 6.32 g (17.4 mmol) and 6.38 ml (86.8 mmol) of dimethyl sulfide in 95 ml of dichloromethane, 10.9 ml (86.8 mmol) of boron trifluoride-diethyl ether complex was added under water cooling. mmol)
was added dropwise and stirred at the same temperature for 2 hours. To the reaction mixture was added 600 ml of a saturated aqueous sodium bicarbonate solution, and the mixture was stirred vigorously for 30 minutes. The reaction solution is extracted three times with dichloromethane, and the extract is washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure was purified by silica gel column chromatography (150 g of silica gel, ethyl acetate; n-hexane 1:2).
~1:1), and the desired alcohol content is 5.20%.
g (yield 93.6%) as crystals.

・Melting point 101-102°C (ether) ・'H-NMR: δ (CDCIs) 1.91-2.
60 (6H, m), 3.76 (3H, s), 3.
84-4.20 (2H, m), 4.22-4.43
(1H, m).

4.67 (2H,s), 4.99~5.28 (2
H, m), 5.65-6.10 (1H, m>, 6.
36=6.86 (3H, m) ppm.

・IR: νmax(CHCl,) 3592.301
2.2960.1763°1744, 1642.160
0.1498.1476, 1287.1271°112
5 cm-'.

・MS: m/z M" 320° (margin below) Reference example-16 [(IR", 2R", 3aS°, 9@R") -2- to -
Butyldiphenylsilyloxy-1-(2-propenyl)-2,3,3a,9a-tetrahydro-1dan-cyclopenta[b][1,4]benzodioxin-5-yl]
Production of methyl oxyacetate-18, N
, N-dimethylaminopyridine 3.978 (32,5 mmol) and t-butyldiphenylsilylchloride)'6
．． Add 34 ml (24.4 mmol) and stir at room temperature for 3 days. Pour the reaction solution into water and extract 3 times with ethyl acetate. Wash with water. After drying over anhydrous magnesium sulfate, the FEa-reduced residue was purified by silica gel column chromatography (Merck Lorber columns, size C (2), ethyl acetate:n-hexane-1:5) to obtain the desired silyl ether. 8.82 g (yield 97.1%) of the above-mentioned oil was obtained.

・'H-NMR: 8 (CDCIn) 1.05 (
9H, s), 1.84-2.53 (5H, m), 3.
77 (3H, s), 3.83~4.03 (2H,
a+), 4.13 to 4.35 (1H, m>, 4.
68 (2H, s), 4.75~5.01 (2H,
m).

5.41-5.88 (1H, m), 6.40-6.
87 (38,m), 7.30~7.50 (6H,
m), 7.58-7.78 (4H, m) I)pm
.

・IR: νmax(CHClm) 3076, 29
60. 2936.2864°1764, 1742.
1642. 1600. 1498. 1476,
1429°1287.1115.920,821,81
2 cm-'.

・MS: m/z M" 558° Reference example-17 [(IR", 2R", 3aS", 9aR") -2-
Butyldiphenylsilyloxy-1-[(E)-3-chloro-1-propenyl]-2,3,3a,, 9 m-
Tetrahydro-1H-cyclopenta[bEEl, 4]benzodioxin-5-ylkoxymethyl acetate Part 1
Production (blank below) 'BuPh, SiO Yellow L Under nitrogen flow, olefin superposition (Reference Example-16) 8.82
g (15.8 mmol) in a solution of 70 ml of carbon tetrachloride,
Under water cooling, 3.32 g (17
, 4 mmol) of carbon tetrachloride was added dropwise over 45 minutes. After the completion of one drop, the solution was stirred for an additional 15 minutes, and at the same temperature, 1.66 ml (20.5 mmol) of pyridine and 30
Add 20 ml of % hydrogen peroxide solution and stir for 20 minutes. After returning to room temperature and stirring for 1 hour and 30 minutes, the reaction solution was poured into water and extracted twice with dichloromethane. The extract is washed with IN-hydrochloric acid, water, dilute aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After vacuum concentration,
The residue was purified by silica gel column chromatography (Merck Rover column, size C (2 columns), ethyl acetate:
n-hexane-1: 4) to obtain 7.20 g (yield 77.0%) of the target allyl chloride supramolecule as crystals.

・Melting point: 127-130℃ (ether) ・'H-NMR
: 8 (CDCIs>1.03 (9H,s),
2.04-2.23 (28, m), 2.91 (LH
, d1, J=7Hz, 9Hz), 3.77 (3H
.

s), 3.87-4.28 (5H, m>, 4.7
0 (2H,s), 5.46 (11°dd, J near Hz, 16Hz), 5.68 (18,dd, J=
6Hz, 16Hz).

6.39-6.86 (3H, m), 7.30-7.
50 (6H, m), 7.56~7.75 (4H,
m) ppm.

・LR: νmax(CHCIm) 3012.296
G, 2936.2g64°1764, 1744.16
01.1498.1476, 1429.1289゜11
14, 968.122.613 am-'.

・MS: m/z M” 592.594°Reference example-
18 [(IR”, 2R”, 3aS°, 9adan”)-1-[(
E)-3-acetoxy-1-propenyl]-2-t-butyldiphenylsilyloxy-2,3゜3a,9a-tetrahydro-1-cyclopenta[b][1,4]benzodioxin-5-yl] Production of methyl oxyacetate Main 1'BuPh2Si♂'BuPh2SiO Under a nitrogen atmosphere, allyl chloride 1 (Reference Example-17)5.
To a solution of 10 g (8.60 mmol) in 150 ml of toluene are added 4.95 g (25.8 mmol) of cesium acetate and 62.27 g (g, ao mmol) of 18-crown, and the mixture is heated under reflux for 24 hours. Add the reaction mixture to room temperature,
Add saturated aqueous ammonium chloride solution and extract twice with ethyl acetate. The extract is washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain crude crystals of the desired acetate ester 20. This product is recrystallized twice from a mixed solvent of ethyl acetate and n-hexane to obtain 4.26 g (yield: 80.4%) of (E)-acetic ester having a melting point of 132 to 134°C.

・Melting point = 132-134℃ (ethyl acetate-n-hexane) H-NMR: 8 (CDC1m) 1.0
3 (9H,s), 2.03 (3H1s),
2.0O~2.25 (2H, m), 2.77~3
．． 06 (LH, +n), 3.76 (3H, s),
3.78=4.28 (3H, m), 4.44 (2
H, d, J = 5Hz>.

4.72 (2H,s), 5.33~5゜82 (2
H, m), 6.40-6.87 (3H, m>, 7
．． 30~7.48 (6H, m), 7.59~7
．． 80 (4H, m) ppm.

・LR: νmax(CHCIg> 3012.2
960. 2936. 2864°1763.1738
．． 1600.1498, 1478.1240.1114
゜968.822,695.612 cm-'.

-MS: m/z M” 616° (margin below) Reference example-19 [(1×0, 2×9, 3a mutually 0.9a×”) −2−t−
Butyldiphenylsilyloxy-1-[(E)-3-hydroxy-1-propenyl]-2,3.

3a,9a-tetrahydro-1H-cyclopenta[b]
[1,4] Production of methyl benzodioxin-5-ylkoxyacetate 21 "BuPh, Si6 'BuPh, Si♂ Acetate ester 20 (Reference example-18) 6.12 g (9,
92 mmol) in 40 ml of dichloromethane and 40 ml of methanol, 1.65 g of potassium carbonate (11,
9 mmol) and stirred at room temperature for 2 hours. To the reaction solution was added 26 ml (26 mmol) of IN-hydrochloric acid, and under reduced pressure,
After distilling off the organic solvent, add saturated brine and dilute with ethyl acetate.
Extract times. The extract is washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure contains a portion of the methyl ester-carboxylated carboxylic acid, so it was treated with diazomethane as follows.
Returning to methyl ester, dissolve the reaction product obtained above in 100 ml of methanol, add an ether solution of diazomethane under ice cooling until the reaction solution turns yellow. The solvent from the reaction solution is distilled off under reduced pressure, and the residue is purified with silica gel. Column chromatography purification (Merck Roper column, size C (2
The target allyl alcohol 11 is obtained by converting the mixture to ethyl acetate:n-hexane (1:1) and ethyl acetate:n-hexane (1:1). This product was crystallized from a mixed solvent of ether-n-hexane, giving 5.35%
g (yield 93.7%) of crystals are obtained.

・Melting point: 102.5-103.5°C (ether-n-hexane) -'H-NMR, δ (CDCIs) 1.03 (9H
, s), 1.51 (LH.

s, -0H), 2.08 to 2.27 (2H, m>,
2.75-3.06 (1)1. m).

3.77 (3H,s), 3.87~4.30 (5
H,m), 4.71 (28,s).

5.38 (1H, dd, J=8Hz, 16Hz),
5.66 (1H, td, J=5Hz.

16Hz), 6.39=6.85 (3H, m),
7.29”7.48 (6H, m).

7.58-7.80 (4H) ppm.

・IR: νmax(CHCl,) 3616.301
2.2960.2936°2g64.1764.174
3.1600.1498.1476, 1429°128
8, 1113.971.822.696.612 cm
-'.

・MS: m/z M” 574° (blank space below) Reference example-20 [(11, 2dan”, 3aS”, 9adan”) -2-t-
Butyldiphenylsilyloxy-1-[(E)-3-xo-1-propenyl]-2,3゜3a,9a-tetrahydro-1H-cyclopenta[bco[1,4]benzodioxin-5-yl]- Production of methyl oxyacetate BuPh2Si♂ Allyl alcohol 21 (Reference example-19) 3.35 g (5
, 83 mmol) in dichloromethane, 2.51 g (1
1.6 mmol) and stirred at room temperature for 3 hours. After adding 160 ml of ether to the reaction solution and stirring for 2 minutes, the reaction solution was filtered using 34 g of Florisil. Florisil was washed with 500 ml of ether, the filtrate and washing liquid were combined, and the solvent was distilled off under reduced pressure. The residue is crystallized from a mixed solvent of ether-n-hexane to obtain 3.19 g (yield: 95.6%) of the desired aldehyde as crystals.

・Melting point: 103.5-104.8°C (ether-n-hexane) ・'H-NMR: 8 (CDCIs) 1.03 (
9H, s), 2.20-2.37 (2H, m), 2
．． 98-3.36 (1H, m), 3.78 (3H
,s), 4. oo~4.30 (3H, m), 4.
71 (2H, s), 6.15 <LH, dd, J=
7Hz.

16H2), 6.33 (1H, dd, J=7Hz,
16Hz), 6.40-6.85 (3H, m>,
7.28~7.47 (6H, m>, 7.53~7.
72 (4H, m).

9.23 (1H, d, J=7Hz) ppm.

・IR: l/max (CHCIm) 3012. 2
960. 2936. 2864°1764.1743
, 1692, 1601.1499, 1476.1429
゜1290, 1113.974,823,697.6
12 am-'.

・MS: m/z M” 572° Example-1 [(1〇1.2゜”, 3aS”, 9a゜”) -2-t-
Butyldiphenylsilyloxy-1-[(3S”, IE
)-3-hydroxy-1-octenyl]-2,3,3a
, 9a-tetrahuman 0-1H-cyclopenta[b][1
, 4] methyl benzodioxin-5-yl]oxyacetate Iaa-a and [(IR", 2 R"T3 a
S", 9 a day")-2-t-butyldiphenylsilyloxy-1-[(3R", IE)-3-hydroxy-
1-octenyl]-2,3,3a,9a-tetrahuman t
ff-1H-cyclopenta[b][1,4]benzodioxin-5-ylkoxymethyl acetate 1ea-a
Production of (blank below) Aldehyde under nitrogen flow ↓ (Reference example-20) 962m
g (1,68 mmol) in a solution of 20 ml of dry THF,
At -78°C, 1.83 ml (2,01 mmol) of n-pentylmagnesium bromide (1, IN, THF solution) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for an additional 15 minutes at the same temperature and then saturated. Add ammonium chloride aqueous solution to stop the reaction. The reaction solution was extracted three times with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Merck Roper column, size B (2 columns), ethyl acetate:toluene-1:10
~1:6), and of the target allyl alcohol,
517 mg of low polar isomer Iaa-a (yield 47.7%)
) as an oily substance, and the highly polar isomer Ica-a as 2
52 mg (yield 20.7%) is obtained as crystals.

Iae-a ・'H-NMR: S (CDCIm) 0.87 (
3H11,, J'6Hz).

1.03 (9H,s), 1.00~1.90 (9
H, m), 2.05-2.25 (2H, m), 2
．． 76-3.03 (LH, m), 3.79 (
3H,s), 3.80-4.30 (4H,m>,
4.72 (2H, s), 5.22-5.70
(21, m).

6.40~6.87 (3H, m), 7.30~
7.50 ('3H, m), 7.60-7.80
(4H, m) ppm.

・IR: max(CHC1+>3608.30
08.2960. 2936°2864, 1763.
1743. 1600. 1498. 1475.
1429°1292, 1114. 970. 821
．． 697. 612 cm-'.

・MS: m/z M'' 644°Icd-a ・Melting point 783-84℃ (ether-n-pentane)-'
H-NMR: ε (CDCIs) 0.87 (3H, 1
, J=6Hz>.

1.03 (9H,s), 1.00~1.90 (9
H, m), 2.05-2.25 (2H, m), 2.
76-3.03 (LH, m), 3.79 (3H,
s), 3.80-4.30 (4)1. m), 4.
72 (2H, s), 5.22~5.70 <2H,
m).

6.40-6.87 (3H, m>, 7.30-7.
50 (6H, m), 7.60~7.80 (4H,
m) ppm.

・IR: νmax(CHCl,) 3608.300
8.2960.2936°2864, 1764.174
2. L80Q, 1498.1476, 1429°1
289, 1113.989.821.696.612
am-'.

・MS: m/z M” 644° Examples-2 to 4 According to the method of Example-1, allyl alcohol Ia-a%
The results are shown in Table 1. Regarding Example 4, the reaction was carried out using a racemic Grignard reagent, and four types of allyl alcohols 1ad-a, Iae-a
and obtain Icd-aS Ice-a (blank below) Reference example-21 [(IR", 2R", 3aS", 9aR") -1-[
(1 and 2 and)-3-acetoxy-1,2=dihydroxypropyl]-2-t-butyldiphenylsilyloxy-2,3,3a,9a-tetrahydro-1H-cyclopenta[b][1,4] Production of methyl benzodioxin-5-yl]oxyacetate 11 Under nitrogen flow, olefin 20 (Reference example-18) 6, OO
Trimethylamine-N-oxyto (IN aqueous solution) 19 g (9.72 mmol) was suspended in 120 ml of acetone.
．． 4 ml (19.4 mmol) and 4.86 ml (0.97 mmol) of osmium tetroxide (0.2N, THFil solution) were added to 1 reaction solution and stirred at room temperature for 3 days.
% sodium thiosulfate aqueous solution was added, and acetone was distilled off under reduced pressure. To the reaction solution, saturated brine was added,
Extract three times with ethyl acetate. The extract is washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under fl pressure to obtain 6.60 g of a crude product of the desired diol main 1 as a foamy substance.

This product should not be purified (it will be used in the next reaction).

(Margins below) Reference example-22 [(1x0.2x”, 3aS”, 9ax”) -2-t-
Butyldiphenylsilyloxy-1-formyl-2,3
,3a,9a-tetrahydro-1H-cyclopenta[b
][1,4]Benzodioxin-5-yl]Production of methyl oxyacetate 23 Under a nitrogen stream, diol 22(
Reference Example 6.60g of the crude product of 21) was added to DME180a.
+1, dissolved in a mixed solvent of 60 ml of water and at room temperature,
Add sodium periodate a, tsg (19.4 mmol) and stir for 2 days. To the reaction mixture, 200 ml of 10% sodium thiosulfate aqueous solution is added and extracted three times with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under 0 g pressure, and the residue was purified by silica gel column chromatography (Merck Rover column, size C (2 pieces), ethyl acetate. :Toluene-1:20) to obtain the target aldebide 11.

This product was crystallized from an ether-n-hexane mixed solvent to obtain 3.38 g (total yield of 2 steps, 63.6%) of crystals.

Melting point: 110.3-111.0°C (ether-n-hexane) -'H-NMR: δ (CDCIs) 1.04 (9H
, s), 2.20 (21°1, J=5Hz), 3.
19-3.44 (1H, m), 3.76 (3H,
s).

4.12=4.38 (1H, m), 4.40-4.
60 (21, m), 4.69 (2H, s), 6
．． 42-6.90 (3H, m>, 7.32-7.
50 (6H, m).

7.56-7.80 (41, m), 9.31
(1H, d, J=1.5Hz) pprn.

・IR: Vmax<CHCLs) 2960. 29
36. 2864. 1763°1729.1601.
1499.1476.1429.1295.1114゜821.694. 612 am-'.

” MS: m/Z M” 546° (blank space below) Reference example-23 [(1dan”, 2dan”, 3a5!, 9adan”) -2-t-
Butyldiphenylsilyloxy-1-4(E)-3-xo-1-octenyl]-2,3゜3a,9a-tetrahydro-1H-cyclopenta[b][1,4]benzodioxin-5-ylcooxymethyl acetate 11! 1ra Under nitrogen flow, 15.2 mg of 60% sodium hydride (0
, 381 mmol) in 2 ml of dry THF was added 95 mg of dimethyl (2-oxoheptyl)phosphonate (0
, 430 mmol) in 1.5 ml of dry THF is added and stirred for 12 minutes at room temperature.

A 3 ml solution of dry THF containing 1181 ωg (0.331 mmol) (Reference Example-22) of the main aldehyde was added to the reaction solution and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to stop the reaction. The reaction solution was diluted with ethyl acetate. Extraction is carried out twice, and the extract is washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Merck Roper column, size B).
199 mg (yield 93.5%) of the desired enone 11 was obtained as an oily substance.

-'H-NMR: δ(CDC1, > 0.1119 (
3H, 1, J = 7Hz>.

1.03 (9H, s), 1.05~1.80 (6
H, m), 2.10-2.50 (4H, m), 2.
86-3.21 (1H, m), 3.77 (3H,
s), 4.02-4.26 (3H, m), 4.7
1 (2H, s), 6.09 (1H, d.

J=16Hz), 6.3! IJ~6.88 (4H
, m), 7.29-7.48 (6H, m).

7.53 = 7.73 (4H, m) ppm.

・IR: L/max (CHCl,) 3008. 2
960. 2936. 2864°1763, 174
3. 1696. 1672. 1630. 1601
．． 1498°1475, 1429. 1114.
977, 822. 695. 612 am-'.

・MS: m/z M" 642° Reference example -24~
29.37-4° Converted to enone tan according to the method of Reference Example 23, and the results are shown in Table 2. For reference examples-24, 26 and 29,
A racemic phosphonate is used.

In Reference Example-39, optically active phosphonate [(S)
- placement] is used.

(Left below) Reference Example 30 0H Normal (1) Production of 1-t-butylcarbonyloxy-3-butanol (±)-1,3-butanediol 2413.2ml (0
, 15 mol) and pyridine 17.8 ml (0.23 mol)
A solution of 22.2 ml (0.18 mol) of pivaloyl chloride in 50 ml of dry dichloromethane was added dropwise over 20 minutes to a solution of 22.2 ml (0.18 mol) of pivaloyl chloride in 200 ml of dry dichloromethane under water cooling.

After completion of the dropwise addition, ice water is added to the reaction mixture, which is stirred for an additional 30 minutes while returning to room temperature. After stirring for 5 minutes, IN hydrochloric acid is added, and the mixture is extracted twice with dichloromethane. The extract is washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (
250 g of silica gel, ethyl acetate: n-hexane 1:
9-1:4) to obtain 20.4 g of the desired monopivaloyl ester as an oily substance (yield 78.2%)
obtain.

'H-NMR: l; (CDC1,) 1.21 (
9H,s) 1.23 (3H,d.

J:6Hz) 1.60~1.95 (2H, m) 2
．． 27 (LH, br, s, -OH) 3.72-4.4
7 (3H, m) ppm.

(2) Production of 1-t-butylcarbonyloxy-3-phenoxybutane (Reference Example 30 (1)), 3.47 g (19
, 9 mmol), phenol 2.81 g (29,9 mmol), phenol 2.81 g (29,9 mmol)
J mol) and H, triphenylphosphine 7.88 g (2
9.9 mmol) in 100 ml of dry THF, add 4.65 ml of diethyl azodicarboxylate to 100 ml of dry THF under water cooling.
Add 40 ml of F solution dropwise. After the dropwise addition was completed, the mixture was stirred at the same temperature for 20 minutes, then returned to room temperature, and stirring was continued for an additional 2 hours. The reaction solution residue after distilling off the solvent under reduced pressure was purified by silica gel column chromatography (200 g of silica gel).

Ethyl acetate:n-hexane-1:49-1:19) to obtain the desired phenyl ether as an oily substance at 4.3
5 g (yield 87.4%) is obtained.

'H-NMR (200MHz): S (CDC1m
) 1.10 (9H, s) 1.34 (3H, d, J
=6Hz) 1.83=2.16 (2H, m) 4.
11~4.31 (2H, m) 4.42~4.60 (
1H, m') 6.85-6.98 (3H, m)7.
21-7.32 (2H, m) pPIII.

(3) Synthetic pivaloyl ester conversion of 3-phenoxy-1-butanol (Reference Example 30 (2)) 4.32 g
(17.3 mmol) in 90 ml of dry methanol, 1 M sodium methoxide-methanol solution 17,
Add 3 ml (17.3 mmol) and stir at 55°C for 9 hours. Ion exchange resin IR was added to the reaction solution returned to room temperature.
Add 35g of C-50 and stir for 20 minutes. The ion exchange resin was filtered off, and the solvent was distilled off under reduced pressure to obtain 3.15 g of a crude product of the target alcohol p as an oily substance. This product is used in the next reaction without purification.

(4) Production of 3-phenoxy butylene ether To a solution of 3.15 g of the crude product of alcohol (Reference Example 30 (3)) in 80 ml of acetone, add 10 ml of 8N Johnnes reagent at 20 to 30°C. After gradually dropping 0 drops, stir for 10 minutes, add 3 ml of isopropyl alcohol,
Stir for an additional 10 minutes. Acetone was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted twice with ethyl acetate. After washing the extracted ethyl acetate solution with water, the carboxylic acid is extracted with IN aqueous sodium hydroxide solution.

The extracted aqueous sodium hydroxide solution is adjusted to pH 2 with hydrochloric acid and extracted again with ethyl acetate. The extracted ethyl acetate solution is washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was diluted with ether 5
At 0 ml, add an ether solution of diazoethane at 0°C until the reaction mixture turns orange. The reaction solution residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (50 g of silica gel, 1 ethyl acetate-n-
Hexane (1:19) was used to obtain 2.35 g of the desired ethyl ester heel as an oily substance (total yield 67.0% from the compound).

'H-NMR (200MHz): l; (CDCIs
) 1.24 (3H, t.

J=7Hz> 1.37 (38,d, J=6Hz>
2.53 (1H, dd, J=15Hz.

6.5Hz> 2.79 (1H, dd, J=15Hz
, 7Hz>4.14 (2H,q.

J=7Hz> 4.75~4.92 (1H, m) 6
．． 88-6.98 (3H, m) 7.22-7.33
<2H, m) ppm.

Reference example 31! ! (Optically active substance) (1) Production of (S)-(-)-citronellol equivalent to methyl citronelate (manufactured by Aldrich, 98% e, e,) 10.0 g (64, 84.4 g (224 mmol) of pyridinium dichromate (PDC) was added to a solution of 1 mmol (1 mmol) in 150 ml of dry DMF,
The reaction mixture, which was stirred overnight, was poured into water for 1.5 hours and extracted twice with toluene. After washing the extracted toluene solution with water, the carboxylic acid is extracted with IN aqueous sodium hydroxide solution. The extracted aqueous sodium hydroxide solution is adjusted to pH 2 with 5N hydrochloric acid and extracted again with ethyl acetate. The extracted ethyl acetate solution is washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The residue after distilling off the solvent under reduced pressure,
Dissolve diazomethane in 100 ml of ether and add an ether solution of diazomethane at 0°C until the reaction solution turns yellow. 0 g The solvent is distilled off under pressure. The reaction solution residue is distilled under reduced pressure to obtain the desired methyl ester 4. 7.5 as an oily substance
3'! (yield 63.9%).

Boiling point near 8-81℃ (3mmHg) [αID-7,4±0.1' (C:5.13.CH
CIs)'H-NMRr S (CDCIm) 0.9
4 (3H, d, J=7Hz) 1.10-1.46
(2H, m) 1.62 (3H, s) 1.68 (
3H, s) 1.7 (1 to 2.50 <5H, m) 3
．． 66 (3H, s) 4.93~5.21 (1H,
m) ppm.

(2) Preparation of methyl (S)-3-methyl-6-oxohexanoate A solution of 7.76 g (36 mmol) of 80% m-chloroperbenzoic acid in 2QOml of dry dichloromethane was added with methyl (S)-3-methyl-6-oxohexanoate. (Reference Example 31 (1)) 6.00g (
A solution of 32.6 mmol) in 50 ml of dry dichloromethane is added and stirred for 1 hour at room temperature. A 5% aqueous sodium thiosulfate solution and a dilute aqueous sodium bicarbonate solution are added to the reaction mixture, and the mixture is extracted twice with dichloromethane. The extract is washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 80 ml of THF, and at 0°C, 8.90 g (39 mmol) of periodic acid dihydrate was dissolved in THF8.
Add 0ml solution. After stirring for 20 minutes while returning to room temperature, water was added to the reaction solution and extracted twice with ether. The extract is washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. Under reduced pressure
The solvent was distilled off to obtain 5.2 g of the target crude product of aldehyde 31 as an oily substance.

This product is used in the following reaction without purification.

(3) Production of methyl (S)-(-)-3-methyl-6-heptenoate Methyltriphenylphosphonium bromide 23 under nitrogen stream
．． To a suspension of 3 g (65.2 mmol) in 120 ml of dry THF was added 1.59 N under water cooling.

n-Butyllithium-n-hexane solution 36.9ml (
After the completion of the dropwise addition, the mixture was stirred at the same temperature for 10 minutes, cooled to -so'c, and 5.2 g of the crude product of aldehyde 31 (Reference Example 31 (2)) was dried. Add 80 ml of THF solution dropwise. After the dropwise addition was completed, the reaction mixture was stirred at the same temperature for 10 minutes and then returned to room temperature over 1 hour.A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the solution was diluted with ether.
Extract times. The extract is washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under normal pressure, and 400 ml of n-pentane was added to the residue, followed by stirring for 30 minutes under water cooling. The precipitated triphenylphosphine oxide is filtered through 100 g of silica gel. The silica gel was washed with 500 ml of a 1:9 mixed solvent of ether 20-pentane, the filtrate and the washing liquid were combined, concentrated under normal pressure, and the residue was distilled under reduced pressure to obtain the desired olefin as an oily substance.
．． 19 g (total yield 43.1% from the compound average) was obtained.

Boiling point: 85-86°C (23mmHg) [α]D-6.
6±0.2° (23℃, C=2.06.CHCl5
)'H-NMR(200MHz>'l; (CDC
Is) 0.95 (3H, d.

J=6Hz> 0.97~1.52 (2H, m) 1
．． 88-2.38 (5H, m) 3.67 (3H, s
) 4.90~5゜09 (2H, m) 5.70~5
．． 91 (1H.

m) ppm.

IR: vmax (CHCIs) 2960.173
4.1642.1439°1172, 1006. 9
16 am-'.

(Left below) Reference Example 32 (1) 4-Butyl [dihydro-2(3H)-furanone]
Production of cuprous bromide and dimethyl sulfide complex under nitrogen stream 6.
To a suspension of 17 g (30 mmol) in 100 ml of dry ether was added 38 ml (60 mmol) of a 1.59N n-butyllithium n-hexane solution at -50°C.
After the completion of the 0 dropwise addition over a minute, the mixture was stirred at the same temperature for 15 minutes, cooled to -78°C, and trimethylsilane chloride 3
．． 8 ml (30 mmol) of dry ethyl ether 10 m
1 solution. Subsequently, 2(5H)-furanone length 1
．． A solution of 68 g (20 mmol) of dry ether in 20 ml was added, and the mixture was stirred at the same temperature for 30 minutes, and then a saturated ammonium chloride aqueous solution was added to the reaction solution, which was heated to -10°C over 30 minutes, to stop the reaction. After blowing air for 30 minutes, filter through Celite. The filtrate was diluted with ether.
Extract twice, wash the extract with water and saturated saline, and dry over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure is dissolved in 150 ml of THF, 20 ml of 2N aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 40 minutes. IN hydrochloric acid is added to the reaction mixture to adjust the pH to 2, and the mixture is extracted twice with ether. The extract is washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure is dissolved in 30 ml of anhydrous benzene, a catalytic amount of p-1-luenesulfonic acid is added, and the mixture is heated under reflux for 15 minutes. A dilute aqueous sodium hydrogen carbonate solution is added to the reaction mixture that has been returned to room temperature, and the mixture is extracted twice with ethyl acetate. The extract is washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was distilled under reduced pressure to obtain 2.19 g of the desired lactone as an oily substance (yield 77.
．． 1%).

Boiling point: 94-95°C (2mmHg) 'H-NMR'
l; (CDC1m>0.91 (3H,1,J=
7Hz) 1.12-1.80 (6H, m> 1.9
7~2.83 (3H, m> 3.93 (1H, dd
.

J=9Hz, 6Hz) 4.43 (LH, dd, J
=9Hz, 7Hz) ppm.

t)'1-(Phenylselenylmethyl)hebutane Production of diphenyl diselenide 2.40 g (7,6
9 mmol) in 30 ml of dry DMF, add 55 mg (17.3 mmol) of sodium borohydride a under water cooling.
Add gradually. After hydrogen generation has finished, the reaction solution is
Stir at 00°C for 20 minutes. At the same temperature, add a solution of lactone (Reference Example 32 (1)) 1, aag (1x, s mmol) in 10 ml of dry DMF and stir at 120°C for 2.5 hours. The reaction solution is cooled with water, and 10% hydrochloric acid is added. Gradually drip p
One reaction solution, referred to as H2, is extracted twice with ether, and the extract is washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was diluted with ether 30
A solution of diazomethane in ether is added at 0° C. until the reaction solution turns yellow. The reaction solution residue after evaporating the solvent under reduced pressure was purified by silica gel column chromatography (Merck Rover column, size C1 ethyl acetate-n-hexane 1:19) to obtain the desired methyl ester length as an oily substance. 2.64g (
Yield: 71.5%).

'H-NMR; S (CDC1m) 0.86 (3
H,1,J=7Hz>1,os-1,63<6H,m
) 2.00~2.70 (3H, m) 2.98 (
2H,d.

J=5Hz) 3.63 (3H, m> 7.17=7
．． 33 (3H, m> 7.32~7.62 (2H,
m) ppm.

Reference Example 33 Production of 2-year-old xo-4-(phenylselenylmethyl)octyl dimethyl phosphate 1.35 ml (12
, 5 mmol) in 25 ml of dry THF at -78°C.
7.0 ml (11.5 mmol) of 1.64N n-butyllithium-n-hexane solution was added dropwise. After the completion of the dropwise addition, the solution was stirred at the same temperature for 1 hour, and then the methyl ester solution (Reference Example 32 (2) )) 1.57 g (10,0 mmol)
Add a 10 ml solution of dry THF. After continuing stirring for an additional 30 minutes, a saturated aqueous ammonium chloride solution was added to stop the reaction. The reaction solution was extracted twice with ethyl acetate, and the extract was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Rover column, size B acetone:benzene-1: 4) and the desired phosphonic acid ester as an oily substance with 1.4
2 g (yield 70.0%) is obtained.

')l-NMR;8 (CDCIn>0.86 (3
H, 1, J = 7Hz> 1.02 = 1.70 (6H,
m), 1.90=3.05 (5H, m) 2.95
(2H, d.

J=22Hz) 3.77 (6H, d, 11H
z) 7.15-7.32 <38. m) 7.40~
7.62 (2H, m) ppllll.

Reference Examples 34 to 36 A reaction was carried out according to Reference Example 33, and ester translation (Reference Example -
30(4)) and Noboru (Reference Example-31(3)) 36, Nisder dimethylphosphonate, Chen and O are obtained.

However, the compound η is a Jeanis Marks (G, S,
Marks et al. (Journal of Chemical Society, J.
), p. 3851, (1955), the racemate is produced.

The average physical properties of Compounds 37 and 38 are shown below.

Compound U'H-NMR (200MHz)' δ(CDCI
s) 1.34 (3H, d.

J-6) 1z) 2.78~3.29 (4H, m>
3.78 <6H, d, J=11) 1z) a, 80~4
．． 96 (LH, m) 6.85-7.00 (3H,
m>7.22"7.33 (2H, m) ppm.

Compound Inami [αKoni” -5,5±0.5° (C=0.98
．． CHCl, )'H-NMR (200MHz):
8 (CDCIm) 0.92 (3H, d.

J=7Hz) 1.16~1.50 (2H, m) 1
．． 97~2.19 (38, m>2.46 (LH, d
d, J=17Hz, 7Hz) 2.59 (1H, d
d, J=17Hz; 6Hz>3.07 (2H, d,
J=22Hz) 3.79 (6H,d, J=11Hz
)4.90-5.08 (21,m) 5.61J
~5.90 <LH, m) ppm.

(Margins below) Compound Normal 1'H-NMR (200MHz) ' 8 (CDC1a
) 1.06 (3H, d.

J=6Hz> 2.47~2.67 (2H, m) 2
．． 80~2.96 <LH, m) 3.12 (2H, d
, J=22Hz) 3.77 (3H, d, J=11H
z> 3.78 (31, d, J=11Hz) 3.75
~3.92 (2H, m) 6.84~6.97 (3H
, m) 7.22-7.33 (2H, m) ppm.

(Left below) Example-5 [(IR", 2R", 3aS", 9aR") -2-
Butyldiphenylsilyloxy-1-[(356,ldan)-3-human axy-1-octenyl]-2,3,3a
, 9a-tetrahuman CI-1H-cyclopenta[b][
1,4] Methyl benzodioxin-5-ylkoxyacetate Iaa-a and [(IR", 2R", 3aS", 9
aR”)-2-t-butyldiphenylsilyloxy-1
-[(3R", 11)-3-hydroxy-1-octenyl]-2゜3.3a, 9g-tetrahydro-1H-cyclopenta[b][1,4]benzodioxin-5-yl]oxymethyl acetate Ica -a Production of aa-a Enone mac Reference Example-23) 120 mg (0,187
mmol) and 70 mg of cerium trichloride heptahydrate (
To a methanol 2a+1 solution of 0.188 mmol), 7.1 mg of sodium borohydride, 187
After dropping 0.7 ml of a methanol solution of (mmol) in methanol, add dropwise and stir for 20 minutes at the same temperature. Add saturated ammonium chloride aqueous solution to stop the reaction. Extract the reaction solution twice with ethyl acetate, and extract the extract. After washing with water and saturated saline, dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (
Merck & Co., Lorber column, size A (2 columns), ethyl acetate:toluene-1:15-1:10) L, lower polar isomer of the target allyl alcohol, Ia
84 mg (yield 70.0%) of a-a and 27 mg (yield 22.5%) of the highly polar isomer Ica-a were obtained. The physical properties of Iaa-a, lea-a obtained here completely match those of Iaa-a, lea-a obtained in Example-1.

(Margin below) Examples-6 to 13 According to the method of Example-5, allyl alcohol Ia-a,
It was converted to Ic-a and the results are shown in Table 3. For Example-11, four types of allyl alcohols Iak-a, Iaj
2-a and Ick-a.

Icl-a is obtained. Moreover, Example-6 and 1.

The reaction is carried out at -78°C.

(Margin below) Example 14 [(IR", 2dan", 3 as", 9 aR") -2-
t-Butyldiphenylsilyloxy-1-[(3dan”,
IE)-5-butyl-3-hydroxy-1,5-hexadien-1-yl]-2,3゜3a,9a-tetrahydro-1H-cyclopenta[b][1,4]benzodioxin-5-yl] Methyl oxyacetate Iat-a and [
(1°0゜2R”, 3aS”, 9aR”)-2-t-butyldiphenylsilyloxy-1-[(3R”, 1°)
-5-bugeru-3-hydroxy-1,5-hexadien-1-yl]-2.3,3a,9a-tetrahydro-1
Dan-cyclopenta[b][1,4]benzodioxin-
Production of methyl 5-ylcooxyacetate Ict-a (blank below) According to the method of Example-5, Enone, Ri' (Reference Example 40)
800 mg (0,969 mmol) are reduced to the corresponding allyl alcohol. This reaction crude product was mixed without purification with DMeloml, methanol 30ml, water 5ml.
Dissolved in a mixed solvent of 81.4 m of sodium hydrogen carbonate.
g (0.97 mmol) is added. Add 5 mg of sodium periodate 4i (1,94 mg) to this reaction solution at room temperature.
3 ml of an aqueous solution of 1 mmol) was strained and stirred overnight. A 5% aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The reaction product residue after distilling off the solvent under 0 g pressure was dissolved in 40 ml of carbon tetrachloride, and 0.41 ml (2.91 mmol) of diimpropylamine was added.
and stirred at 60°C for 1 hour. Ice water is added to the reaction mixture that has been returned to room temperature, and the mixture is extracted twice with dichloromethane. The extract is washed with IN-hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Merck Rover columns, size B, 2; ethyl acetate; toluene-1': 15-1
:1.0) and among the target diene alcohols,
350 mg of low polar isomer Iat-a (yield 53.7%)
), and highly polar isomer Ict-a at t55mg (yield 2
3.8%), each obtained as an oil.

Compound Iat-a'H-NMR (200MHz) :S (CDCIn>
0.91 (3H, t.

J=7Hz) 1.04 (9)1. s) 1.227
1.56 (5H, m) 1.96~2.20 (6H
, m) 2.90 (1H, q, J=7Hz> 3.7
9 (3H, s) 3.9fr4.23 (4H, m)
4.73 (21,s) 4.80 (1H,s)4.
87 (LH, s) 5.45 (LH, dd, J=
16Hz, 7Hz > 5.55 (LH, dd, J
=16Hz, 5Hz>6.47 (LH, dd,
J=8Hz, 2Hz) 6.60 (1H, dd, J
=8Hz, 2Hz) 6.77 (1H, tJ=8
Hz) 7.20~7.48 (6H,m>7.63~
7.73 (4H, m) ppm.

IR: vmax (CHCl,)3604.293
6,2864.1763°1742, 1643. 1
600. 1498. 1476, 1429. 12
88°1114.969,904,822,612 c
m-'.

MS: m/z 870 (M”).

Compound Ict-a 'H-NMR (200MHz)'l; (CDCI
s) 0.92 (3H, t.

J=7Hz) 1.04 (9H,s) 1.23~1
．． 60 (5H, m> 1.97~2.20 (6H,
m) 2.90 <LH, q, J=71(z) 3.8
0 (3H, s) 3.95-4.24 (4H, m)
4.73 (2H,s) 4.81 (1H,s)4.
87 (1H, s> 5.46 (LH, dd, J: 1
6Hz, 7Hz) 5.54 (1H, dd, J=16
Hz, 5Hz> 6.46 (1H, dd, J=8H
z, 2Hz) 6.60 (1H, dd, J=8Hz,
2Hz) 6.76 (LH, 1, J=8Hz)7.
20~7.47 (6H,y+) 7.60~7.73
(4H, m) ppm.

IR: Vmax (CHCIs) 3604.293
6.2864.1764゜1743, 1642.160
0.1498.1476, 1429.1287°111
4,969.906.821.613 cm-'.

MS: m/z 670 (M”) Example-15 [(1, 2, 3a, 9a and)-2-t-butyldiphenylsilyloxy-1-[(3S, 5S, 1)-
3-hydroxy-5-methyl-1゜8-7nadiene-1
-yl]-2,3,3a.

9a-tetrahydro-1-cyclopenta[b][1,
4] Methyl benzodioxin-5-ylkoxyacetate I
ar-a and its stereoisomers 1, 1! Any1
, production of far-a (blank below) Enone LL (Reference Example 39) was reduced according to the method of Example 5, and four stereoisomers were obtained.

21, far-a, 1st section'L1 and obtain Icr-a.

Compound Uni 1 (isomer 1) Yield 32.9% Rf: 0.35 (ethyl acetate:toluene-1:6)
[αlo −a3.2±1.6@(24℃, C=
0.53. CHCl, )'H-NMR (200MHz
) :l; (CDCIs) 0.90 (3H, d.

J=7Hz>1.04 (9H,s>1.00-1
．． 72 (6H, m> 1.94~2.29 (4H,
m) 2.88 (LH, q, J near Hz) 3.80
(3H,s)3.95”4.09 (3H,n+)
4.1! r4.23 (LH, m> 4.73 (2H
.

s) 4.88”5.03 (2H, m) 5.35
(1H, ddJ=16Hz.

8Hz) 5.5L (LH, dd, J=16Hz,
6Hz) 5.70-5.91 (11゜m) 6.4
7 (18, dd, J=8Hz, 2Hz) 6.59
(11(, dd.

J=8Hz, 2Hz>6.76 (LH,1,J4
Hz) 7.30=7.50 (6H.

m) 7.60-7.70 (4H, m) pp#IR
: vmax (CHCIg) 3604. 293
6.2864. 1763°1742, 1641.16
00.1498.1476, 1429.1288°11
13.970,908,821.612 am"'.

MS: m/z 670 (M”) Compound 1a
ra (isomer 2) Yield: a3. i% Rf: 0.32 (ethyl acetate:toluene-1:6
) [α] 2' +41.7±1.4° (C=0.60
．． CHCIA)'H-NMR (200MHz>'
S (CDCIs) 0.87 (3H, d.

J=7Hz) 1.04 (9H,s) 1.00~1
．． 73 (6H, m) 1.93~2.30 (4H,
m) 2.88 <1H, q, J=7Hz) 3.80
(3H, s) 3.94-4.09 (3H, m) 4
．． 1! r4.24 <1H, a+) 4.73 (2H
.

s) 4.88-5.06 (2H, m) 5.34
(LH, dd, 16Hz, 8Hz) 5.46 (L
H, dd, J=16Hz, 6Hz) 5.70~5.
91 (1H, m) 6.47 (LH, dd, J=8H
z, 2Hz) 6.58 (1H, dd, 8Hz.

2Hz) 6.76 (1H, 1, J=8Hz) 7.
30~7.50 (6H, m) 7.60~7.70
(4H, m) ppH1°IR: vmax (CHC
Is) 3604.2936.2864.1764゜1
? 44.1641.1600.1499.1476, 1
429.1290°1113, 970.908.822
．． 612 cm-'.

MS: m/z 67G (M”) Compound Upper! Uni 1 (isomer 3) Yield: 10.4% Rf; 0.27 (Nibble acetate: Toluene-1 = 6
) [α]. +45.0±1.6 @ (24℃, C
=0.52. , CHCl, )'H-NMR (200
MHz): δ(CDCII) 0.90 (3
H,d.

J=7Hz) 1.04 (9H,s) 1.0
0~1.75 (6H, m> 1.94~2.29
(4H, m) 2.88 (1H, q, J=7Hz>
3.79 (3H, s) 3.94”4.09 (31,
m) 4.15 to 4.23 (LH, m> 4.73
(2H.

s) 4.88-5.30 (2H, m) 5.3
6 (1B, dd, J=16Hz, 8Hz>5.5
3 (LH, dd, J=16Hz, 6Hz) 5
．． 70~5.91 (LH, m>6.47 <1H,
dd, J=8Hz, 2Hz) 6°60 (1H
, dd, J=8Hz.

2) 1z) 6.76 (1H, 1, J=8Hz>
7.30-7.50 (6H, m>7.60-7
．． 70 (4H, m) ppm.

IR: l/maX (CHCIm) 3608.
2936. 2864°1764, 1743. 1
641. 1600. 1498. 1476, 14
29°1291.1114.970,908,821,
612 am-'.

MS: m/z 670 (M”) Compound Ic
ra (isomer 4) Yield: 8.9% Rf2O,23 (ethyl acetate:toluene-1:6) [
α]o-42,3±1.8° (24℃, C=0.45
．． CHCl5)'H-NMR (200MHz)'
δ(CDC1, > 0.88 (3H, d.

J=7Hz) 1.04 (9H,s) 1.0
5-1.74 (61, m) 1.95-2.27
(4H, m) 2.88 (LH, q, J=7Hz
) 3.80 (3H, s) 3.95-4.09 (
3H, m) 4.15-4.23 (LH, m)
5.39 (LH.

dd, J=16Hz, 7Hz) 5.50 (
LH, ddJ=16Hz, 6Hz>5.70~5.
86 (1H, m) 6.47 (11(, dd
J: 8Hz, 2Hz 6.60 (1H, dd, J
=8Hz, 2Hz) 6.77 (1H,1,,C3
Hz) 7.30~7.50 (6H,m>7.60~
7.70 (4H, m) ppm.

IR: vmax (CHCIg)3608.293
6,2864,1763°1744, 1641. 1
600. 1499. '1476, 1429.
1293°1114, 970. 909. 821.
612 am-'MS: m/z 670
(M”) (blank below) Example-16 [(1, 2, 3a, 9a)-2-t-butyldiphenylsilyloxy-1-[(3S.

55.1)-3-Hydroxy-5-methyl-1-nonenylco2.3,3a,9a-tetrahydro-1-cyclopenta[b][1,4]be)'zodioxin-5-
Methyl]oxyacetate: Production of Iau-a (optically active form) ar-1 (optically active form) au-a Under hydrogen atmosphere, diene far-a (Example-15) 1
51 mg (0,225 mmol) of dry benzene 10 m
7.5 mg of 5% palladium-carbon was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Merck Rover column, size B5 ethyl acetate:
Toluene-1: 15) and target olefin t
98 mg (yield 64.9%) of au-a as an oily substance
)obtain. 'H-NMR of this optically active substance.

The IR, MS spectra completely match those of racemic Iae-a (Example 4).

[α]D ”40.4±0.8° (24℃, C=1
．． 04. ClC1,) (hereinafter blank) Example-17 [(shellfish V, vomit S'', 3adan'', 9a mutually 1)-2-hydroxy-1-[(3R'', 1st)-3-hydroxy-1-
octenylco-2,3,3a,9a-tetrahydro-1
Dan-cyclopenta[b][1,4]benzodioxin-
5-yl] methyl oxyacetate Iba-a 'BuPh2Sz♂ 6H am-a H♂ 6H! ba-a Silyl ether Iaa-a (Examples-1 and 5) 517
Add 1.60 ml (1,60 mmol) of tetra-n-butylammonium fluoride (LM, THF solution) to 6 ml of THF solution of 0.0 mg (0,802 mmol), and add saturated ammonium chloride to the reaction solution. Add the aqueous solution and 2 ml (2 mmol) of IN hydrochloric acid, and add 2 ml (2 mmol) of IN hydrochloric acid, and
Extract times. The extract is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Since this residue contains a portion of methyl ester/saponified carboxylic acid, it is treated with diazomethane as described below to return it to methyl ester. The reaction mixture was dissolved in 6 ml of methanol, and at 0°C, an ether solution of diazomethane was added until the reaction mixture turned yellow. The solvent was distilled off under pressure, and the residue was purified by silica gel column chromatography (Merck Roper column, size B1 ethyl acetate:toluene (2:1) to obtain 282 mg of the desired methyl ester. It was crystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 260ff1g (yield: 80.0%) of crystalline Iba-a.

・Melting point: 121-123°C (ethyl acetate-n-hexane) ・'H-NMR: ε (CDC1s+CDsOD) 0
．． 88 (3H.t.

J=6Hz), 1.10-1.80 (81,m),
1.90=2.20 (1H.m).

2,35~2.81 (28,m), 3.82 <3
8. s), 3.8-4.4 (48.

m), 4.70 (2H.s), 5.43-5.8
6 (2H, m), 6.39-6.87 (31st)
ppm.

・XR: νmax(CHCl.>3608.30
08. 2960. 2940.

2864, 1762. 1744, 1600. 1
498. 1476, 1125.

970 am-'.

Examples 18 to 34 Desilylation reaction was carried out according to the method of Example 17 to obtain methyl ester Ib-a. The results are shown in Table 4.

(Left space below) Example-35 [(1 x 0.2", 3a x 1.9a x 1)-2-hydroxy-1-[(3R", 1)-3-hydroxy-1
-Octenylco-2,3,3a,9a -Tetrahydro-1-cyclopenta[b][1°4]benzodioxin-5-yl]oxyacetic acid Iha-b Production of ba-a ba-b Methyl ester Iba-a (Example-17) 100mg
(0,246 mmol) in 2 ml of methanol solution, I
Add 0.50 ml (0.50 mmol) of N aqueous sodium hydroxide solution and stir at room temperature for 25 minutes.
Add 0 ml (1.0 mmol) of N salt and saturated saline, and extract with chloroform. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude crystals of carboxylic acid Iba-b.
Get mg. This product was recrystallized from a mixed solvent of ethyl acetate and n-hexane, resulting in crystal 1b with a melting point of 156-158°C.
68 mg (yield 70.4%) of a-b is obtained.

・Melting point = 156-158°C (ethyl acetate-n-hexane) ・'H-NMR: 8 (CD, OD) 0.89 (
3H, 1, J = 6Hz).

1.10(,80(8H,m), 1.82-2.10
(1H, m), 2.33-2.75 (2H, m)
, 3.8fr4.35 (4H, m), 4.63
(2H, s>.

5.41-5.81 (2H, m), 6.42-6.
83 (3H, m) ppm.

・IR: izmax (KBr) 3404.296 (
1,2940,2B64°1745,1709.161
5.1596.1501.1477, 1434°113
1.984. 968. 904. 760. 712
am-'.

Examples 36 to 46 Conversion to carboxylic acid Ib21 was performed according to the method of Example 35, and the results are shown in Table 5.

(Left below) Example-47 [(I R”, 2 S”, 3 a R”, 9 a day*)
-2-Hydroxy-1-[(3-8,1-d)-3-hydroxy-1-octenyl]-2,3,3a,9a-tetra-cyclopenta[b][1,4]benzo Methyl dioxin-5-yl]oxyacetate Ida-a
Production of Ida-a A reaction was carried out according to the method of Example 17, and 110 mg of the target methyl ester (yield 69.2%) was obtained from 252 mg of silyl ether 1ea-a (Examples 1 and 5).
) obtained as crystals.

・Melting point: 95-97°C (ethyl acetate-n-hexane)
・'H-NMR: 8 (CDC1*+CDsOD)
0.87 (3)1. t.

J=6Hz>, 1. lO~1.80 (8H, m),
1.92-2.20 (1H, m).

2,30~2.80 (21,+n), 3.80 (
3H. s), 3.8-4.3 (4H.

m), 4.68 (2H.s), 5.50-5.9
0 (2H.m), 6.37-6.87 (3H.m>
ppm.

-IR Nijimax<CHCls) 3608. 300
8. 2960. 2939.

2864, 1763. 1?44. 1600, 1
498. 1479, 1127.

970 cm-'.

Examples 48 to 63 Desilylation reaction was carried out according to the method of Example 17 to obtain methyl ester Id-a. The results are shown in Table 6.

(Left below) Example-64 [(IR”, 2dan-, 3aS”, 9aR”)-2-1
-butyldiphenylsilyloxy-1-[(mutual 0)-3
-hydroxyoctyl]-2,3,3a,9a-tetrahydro-1-cyclopenta[b][x,a]benzodioxin-5-yl]methyloxyacetate 1ea-a
Production of Iaa-*ea-a Allyl alcohol Iaa-a (Example-
1 and 5) 5% palladium-carbon-19 in a solution of 188 mg (0,291 mmol) in 7.5 ml of dry ethanol.
The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Merck Lorber column, size A1 ethyl acetate-toluene 1:20-1: 10) L, 156 mg of the target saturated alfur Iea-a (yield 82.7
%) obtained as an oily substance.

・'H-NMR: S (CDCIs) 0.88 (
3H, 1, J = 7Hz).

1.03 (9H,s), 0.80~1.70 (1
3H, m>, 1.99-2.40 (3H, m), 3
．． 3 (1~3.61 (1H, m), 3.77 (3
H, s), 3.74r4.06 (2H, m), 4
．． 12-4.37 (1H, m), 4.70 (2H
, m).

6.40=6.89 (3)1. m), 7.33-7
．． 50 (6H, m), 7.60~7.80 (4H
, m) ppffil.

-IR: νmax(CHCIm) 3616.300
8.2936.2864゜1763, 1741.160
0.1498.1426.129G, 1110°82
2,611 am-'.

・115: m/z M” 646° Example-65~
70 According to the method of Example-64, a reduction reaction is performed to obtain saturated alcohol Ie-a. The results are shown in Table 7.

(Left below) Example-71 [(l R”, 2 S”, 3 a R”, 9 a S”
) -2-hydroxy-1-[(R”)-3-hydroxyocdelco-2,3,3a,9a-tetrahydro-1
Dan-cyclopenta[b][1,4]benzodioxin-
Preparation of methyl [5-yl]oxyacetate If'a-aea-a a-a A reaction was carried out according to the method of Example-17, and silyl ether 1ea-a (Example-64) 186 mg (0,28
7 mmol), the desired methyl ester If'a
80 mg (yield 68.2%) of -a is obtained as crystals.

・Melting point: 269-70℃ (ethyl acetate-n-hexane)・
'H-NMR: ε (CDC1, +CD, OD) 0.8
7 (3H, t.

J-7Hz), 1.10-2.18 (14H, m)
, 2.22-2.57 (LH, m).

3.42-3.69 (1H, m), 3.79 (3
H, s), 3.73-4.17 (2H, m), 4.
19-4.35 (1H, m), 4.67 (2H,
s), 6.34-6.87 (3H, al) T;)
pllll.

・IR: νmax(CHCl,) 3616.300
8.2936.2g64°1762, 1?43.160
0.1498.1476, 1286°1124 am-
'.

Examples 72 to 77 According to the method of Example 17, a desilylation reaction is performed to obtain methyl ester If'-a. The results are shown in Table 8.

(Margin below) Example-78 [(I R-2S”, 3 a R”, 9 a S”)
-2-hydroxy-1-[(R”)-3-hydroxyofdel]-2,3,3a,9a-tetrahydro-1dan-
Cyclopenta[b][1,4]benzodioxin-5-
Production of If'a-a [yl]oxyacetic acid If'a-a A reaction was carried out according to the method of Example 35 to produce the target carboxylic acid If'a-a from 45 mg (0,110 mmol) of the methyl ester If'a-a. -b34mg (yield 78
．． 2%) as crystals.

・Melting point = 111-113°C (ethyl acetate-n-hexane) ・'H-NMR: S (CDsOD) 0.89 (
3H, 1, J: 6Hz>.

1.08=2.16 (L4H, m), 2.23”2
．． 62 (lH, m), 3.38-3.67 (1H
, m), 3.73-4.0O (LH, m>, 4.0
0-4.32 (21, m), 4.63 (2H, s)
, 6.40-6.85 (3H, m) ppm.

-IR Niji max (NiBr) 3504.336g,
2928.2856°1716, 1615.1598.
1500.1476, 1279.1134°759, 7
13 am-'.

Examples-79 to 82 The reaction was carried out according to the method of Example-35, and carboxylic acid I
Obtain f'-b. The results are shown in Table 9.

(The following is a blank space) Example-83 [(1dan", 2dan", 3aR", 9aS")-2-hydroxy-1-[(3dan9,1 亙)-3-hydroxy-1
-octenyl]-2,3,3a,9a-tetrahydro-
1-Cyclopenta[b][1,4]benzodioxin-5-yl]oxyacetic acid[(9-anthryl)methyl]
Production of Iba-a' H66H Iba-b H6♂H Iba-a'carboxylic acid Iba-b (Example-35) 25n@(0
(9-anthryl)diazomethane (2%
, ethyl acetate solution) 1.5 ml (0,138 mmol)
After dropping one drop, the mixture was stirred for 45 minutes, and the precipitated crystals were collected by filtration to obtain crude (9-anthryl)methyl ester Iba-a.

(27 mg) is obtained. The crude crystals were dissolved in pyridine, insoluble matter was removed, and then recrystallized from ethyl acetate to obtain crystals of Iba-a' with a melting point of 185-188@C.
mg (yield 51.2%).

・Melting point = 185-188℃ (ethyl acetate) ・'H-NM
R: 8 (heavy pyridine) 0.83 (3H, t.

J=6Hz), 1.02-1.93 (8H, m),
2.12-2.70 (2H, m).

2.97-3.31 (1H, m), 4.10-4.
50 (4H, m), 4.95 (2H, s), 5.
86-6.30 (2)1. m), 6.41 (2H
,s), 6.55-6.83 (3H,m), 7.
38~7.70 (4H, m), 8.00~B, L7
(2H, m>, 8.35=8.66 (3H, m)
ppm.

・IR,: L+max(KBr) 3592.342
8.2928.2856°1741, 1596.149
9.1475.1207.1124.973°723
am-'.

Example-84 [(I R”, 2 S”, 3 a R”, 9 a S”
) -2-Hydroxy-1-[(3 mutually 1.1 degrees)-3-
Hydroxy-1-octenyl]-2,3,3a,9a-
Tetra-drow 1H-cyclopenta[b][1,4cobenzodioxin-5-yl]oxyacetic acid Ida-b
Production of da-a da-b A reaction was carried out according to the method of Example 35, and the target carboxylic acid Ida-b was produced from 110 nIg of methyl ester Ida-a (Example 47) to 8 On @ (yield 75 .5
%) obtained as crystals.

・Melting point: 109.5-111.5℃ (ethyl acetate-Q
-hexane) ・'H-NMR: S (CDsOD) 0.89 (
3H, 1, J: 6Hz>.

1.10-1.70 (8H, m), 1.82-2.
12 (LH, m), 2.30-2.77 (21,
m), 3.85=4.43 (4H, m), 4.6
5 (2H, s).

5.47-5.93 (2H, m), 6.43-6.
85 (31, m) ppm.

・IR: νmax (KBr) 3496.3241.
2932.2852°1708, 1617.1596.
1502.1476, 1129.97g.

758, 702 am-'.

Examples 85 and 86 The reaction was carried out according to the method of Example 35, and carboxylic acid I
Get d-b. The results are shown in Table 10.

(Left below) The compound of the present invention is a benzodioxane PC1 analogue which has a long duration of action and is chemically stable.

The compound of the present invention is PGI! Similarly, it has a cytoprotective effect and/or a platelet aggregation inhibitory effect. especially,
The compound of the present invention has a strong cytoprotective effect and can be a useful therapeutic agent for peptic ulcers. Below, test examples of anti-ulcer effects on hydrochloric acid-ethanol ulcers will be shown for representative compounds.

[Effect on hydrochloric acid-ethanol ulcers] 1 ml of 150 mM hydrochloric acid-60% ethanol was orally administered to JCL-8D or CRJ-3D male rats (body weight 220-260 g) that had been fasted for 24 hours, and the stomachs were removed 1 hour later. The length of gastric mucosal damage was measured under a stereomicroscope, and the sum total was taken as the ulcer index. Vehicle (1-10% ethanol) and the test compound were orally administered 30 minutes before the administration of hydrochloric acid-ethanol, and the inhibition rate of the test compound relative to the vehicle-administered group was calculated. The results are shown in Table 11.

Table 11-1 (JCL-5D rat) Comparative control compound Hoe-892 Dose 300 It g/Kg inhibition rate 28 XTable 11-
2 (CRJ-5D rat) Compound numbers correspond to compound numbers in Examples.

The compounds of the present invention strongly suppress hydrochloric acid-ethanol ulcers.

(Margins below) The compound of the present invention, like PCl, has a cytoprotective effect and is useful for ulcerative lesions in the esophagus, stomach, duodenum, or anastomosis after gastric surgery, that is, peptic ulcer. It is a compound whose pharmacological effects are expected to be applied, such as being used as a therapeutic drug.

The compounds of the invention can be administered orally or parenterally. Orally, it is administered in the form of tablets, capsules, emulsions, granules, fine granules, solutions, emulsions, etc. Parenterally, it is administered as suppositories or injections, such as intravenous injections and intramuscular injections. It can be made into a targeted injection or subcutaneous injection. When formulating, a commonly used appropriate carrier or excipient is used.

When administered orally, the compound of the present invention is administered at a dose of approximately 0°1 to 10° per day for adults.
0 mg is administered.

Patent applicant: Shionogi & Co., Ltd.

Claims (1)

[Claims] 1. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 is alkyl, alkenyl, alkynyl,
Cycloalkyl, cycloalkylalkyl or phenoxyalkyl; R_2 is hydrogen, lower alkyl or aralkyl; R_3 is hydrogen or a protecting group; A is ethylene or vinylene; the wavy line represents α or β configuration or a mixture thereof] Or its salt. 2. The compound or its salt according to claim 1, wherein R_2 is hydrogen or lower alkyl; R_3 is hydrogen. 3. The compound or its salt according to claim 1, wherein R_1 is alkyl, alkenyl or cycloalkyl; R_2 is hydrogen or lower alkyl; R_3 is hydrogen. 4, [2-hydroxy-1-(3-hydroxy-5-methyl-1-nonenyl)-2,3,3a,9a-tetrahydro-1H-cyclopenta[b][1,4]benzodioxin-5-yl ] The compound according to claim 1, which is methyl oxyacetate. 5, [2-hydroxy-1-(3-hydroxy-5-methyl-1,8-nonadienyl)-2,3,3a,9a-
2. The compound according to claim 1, which is methyl tetrahydro-1H-cyclopenta[b][1,4]benzodioxin-5-yl]oxyacetate. 6, [2-hydroxy-1-(3-hydroxy-5,9
-dimethyl-1,8-decadienyl)-2,3,3a,
9a-tetrahydro-1H-cyclopenta[b][1,
4] The compound according to claim 1, which is methyl benzodioxin-5-yl]oxyacetate. 7, [2-hydroxy-1-(3-cyclohexyl-3
-hydroxypropyl)-2,3,3a,9a-tetrahydro-1H-cyclopenta[b][1,4]benzodioxin-5-yl]oxyacetate methyl
Compounds described. 8, [2-hydroxy-1-(3-hydroxy-5-methylnonyl)-2,3,3a,9a-tetrahydro-1
H-cyclopenta[b][1,4]benzodioxin-
The compound according to claim 1, which is methyl 5-yl]oxyacetate. 9, [2-hydroxy-1-(3-hydroxy-5-methyl-1-nonenyl)-2,3,3a,9a-tetrahydro-1H-cyclopenta[b][1,4]benzodioxin-5-yl ] The compound according to claim 1, which is oxyacetic acid. 10, [2-hydroxy-1-(3-hydroxy-5,
9-dimethyl-1,8-decadienyl)-2,3,3a
,9a-tetrahydro-1H-cyclopenta[b][1
, 4]benzodioxin-5-yl]oxyacetic acid.