JPH05213811A - Saishin n derivative - Google Patents

Abstract

PURPOSE:To provide a saishin N derivative useful as a medicine for the treatment of peptic ulcer. CONSTITUTION:The compound of formula I [X is carbonyl, CH-ORx or =C(ORx)-O bonded to C atom of Y or Z; Y and Z are carbonyl, =CH-ORy or CH bonded to O atom of X; dotted line represents arbitrary presence of a bond; excluding saishin N], e.g. 4-(4-aminobenzoyloxy)-5-hydroxy-2,6,6- trimethyl-2-cycloheptan-1-one. The compound can be produced e.g. by subjecting an eucarvone-4,5-oxide to alcoholysis with an alcohol of the formula R1-OH (R1 is alkyl, alkenyl or aralkyl) in the presence of an acid catalyst to form the compound of formula II or by acylating saishin N with a carboxylic acid of the formula R<2>COOH (R<2> is alkyl, alkenyl, aromatic hydrocarbon group or heterocyclic group) in the presence of a carbodiimide to form the compound of formula III.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a terpenoid compound,
The present invention relates to a method for producing the same and an antiulcer agent containing the same as an active ingredient. More specifically, it relates to a Saicin N derivative useful as a drug for treating peptic ulcer disease, a method for producing the same, and an antiulcer agent containing the same as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION The present inventors have isolated and identified Saishin N as an anti-ulcer substance from a crude drug, developed a chemical production method thereof, and filed a patent application (JP-A-3-275640).
issue).

[0003]

[Chemical 11]

[0004]

Cycin N has two hydroxyl groups in the molecule, and no marked difference is observed in the reactivity between the two. For this reason, it is difficult to selectively react only one hydroxyl group.
It became an obstacle in the study of derivatives.

The inventors of the present invention have conducted extensive studies on a method for synthesizing a cycin N derivative. As a result, (1) eucarvone-4,5-oxide (chemical name;
4,5-epoxy-2,6,6-trimethyl-2-cyclohepten-1-one) is subjected to an alcoholysis reaction in the presence of an acid catalyst to give a Cycin N having an alkoxy group at the 4-position and a hydroxyl group at the 5-position. Only the derivative is selectively obtained, and (2) by subjecting Cycin N and a carboxylic acid to a dehydration condensation reaction using carbodiimide, only a Cycin N derivative having an acyloxy group at the 4-position and a hydroxyl group at the 5-position is selected. I found that you can get it.

Furthermore, the present inventors utilize the above reaction to modify the hydroxyl groups at the 4- and 5-positions of Cycin N, reduce the oxo group and double bond, reduce the oxo group to a hydroxyl group, and reduce the hydroxyl group. When the modification and the like were studied, a compound having an antiulcer effect superior to that of Cycin N was obtained, and the present invention was completed.

[0007]

According to the present invention, there is provided an anti-ulcer agent containing a Cycin N derivative represented by the following general formula (hereinafter referred to as "compound A") as an active ingredient.

[0008]

[Chemical 12]

R _X and R _Y are the same or different and each is a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or an acyl group.

Examples of the alkyl group include a lower alkyl group having 1 to 4 carbon atoms which may have a substituent on the chain. Examples of the substituent on the chain include a lower acyl group having 1 to 4 carbon atoms, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a 4-methoxytetrahydropyranyl group, a tetrahydrofuranyl group, a 1-ethoxyethyl group, and a 1-methyl group. −
1-methoxyethyl group, 1-isopropyloxyethyl group or other acetal or trimethylsilyl ether, tert
-A hydroxyl group which may be protected by silyl ether or the like such as butyldimethylsilyl ether (hereinafter the same applies to the protective group for the hydroxyl group.

), A carboxyl group and a lower alkoxycarbonyl group having 1 to 4 carbon atoms.

The alkenyl group (including an arylalkenyl group; the same applies hereinafter) includes allyl group and 3-methyl-2.
Examples thereof include a butenyl group and a cinnamyl group which may have one or more substituents on the ring.

Examples of the aralkyl group include a benzyl group, a phenethyl group, a furfuryl group, a tenyl group and a picolyl group which may have one or more substituents on the ring.

The substituents on the ring of the cinnamyl group or aralkyl group include a lower alkyl group having 1 to 4 carbon atoms; a lower alkoxycarbonyl group having 1 to 4 carbon atoms; an acyl group such as acetyl group, benzoyl group, cinnamoyl group, etc. A hydroxyl group which may be protected; a lower alkoxy group having 1 to 4 carbon atoms;
Fluorine, chlorine, bromine, iodine; and a nitro group can be mentioned.

As the acyl group, an acetyl group which may have a substituent on the chain, a propionyl group, a butyryl group,
An aliphatic acyl group such as an isobutyryl group, a valeryl group, an acryloyl group, a methacryloyl group, a 2-butenoyl group or a cinnamoyl group which may have one or more substituents on the ring, and one or more substituents on the ring. Aromatic acyl groups such as benzoyl group and naphthoyl group which may have, or furoyl group which may have one or more substituents on the ring, pyrrolylcarbonyl group, thenoyl group, imidazolylcarbonyl group, benzimidazolyl Heterocyclic acyl groups such as carbonyl group can be mentioned. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and a thiazolyl group, and the substituent on the ring includes a lower group having 1 to 4 carbon atoms. Alkyl group; carboxyl group; lower alkoxycarbonyl group having 1 to 4 carbon atoms; acyl group such as acetyl group, benzoyl group, cinnamoyl group which may have one or more substituents on the chain or ring; protected Optionally substituted hydroxyl group; lower alkoxy group having 1 to 4 carbon atoms; lower acyloxy group such as acetoxy group, propionyloxy group, butyryloxy group; fluorine, chlorine, bromine, iodine; nitro group; 1 on chain or ring
Examples thereof include an acetyl group which may have a substituent, an benzoyl group, an cinnamoyl group and other acyl groups, or an amino group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms.

The compound A has stereoisomers derived from a plurality of asymmetric carbon atoms, and each of them or a mixture thereof is included in the present invention.

The method for producing the compound A will be described below. Note that eucarvone-4,5-oxide (hereinafter referred to as "compound B") was produced by the method described in JP-A-3-275640.

"Step a" is a step of subjecting compound B to an alcoholysis reaction in the presence of an acid catalyst to obtain compound C and compound K.

[0019]

[Chemical 13]

(In the formula, R ¹ represents an alkyl group, an alkenyl group or an aralkyl group.) Examples of the alkyl group include a lower alkyl group having 1 to 4 carbon atoms which may have a substituent on the chain. .. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, and a lower alkoxycarbonyl group having 1 to 4 carbon atoms.

Examples of the alkenyl group include an allyl group, a 3-methyl-2-butenyl group, and a cinnamyl group which may have one or more substituents on the ring.

Examples of the aralkyl group include a benzyl group, a phenethyl group, a furfuryl group, a tenyl group or a picolyl group which may have one or more substituents on the ring.

The substituents on the ring of the cinnamyl group or aralkyl group include a lower alkyl group having 1 to 4 carbon atoms; a lower alkoxycarbonyl group having 1 to 4 carbon atoms; an acyl group such as an acetyl group, a benzoyl group, a cinnamoyl group. A hydroxyl group which may be protected; a lower alkoxy group having 1 to 4 carbon atoms;
Fluorine, chlorine, bromine, iodine; and a nitro group can be mentioned.

The solvent used in the reaction is not particularly limited as long as it dissolves the mixture of the compound B and the alcohol used in the reaction, but aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane and chloroform. , An inert solvent such as halogenated hydrocarbons such as carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like. Further, the alcohol itself used in the alcoholysis reaction can also be used as a solvent.

Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid, trifluorinated boron etherate, Lewis acid such as titanium tetrachloride, zinc chloride and tin tetrachloride, or methanesulfonic acid, Examples thereof include sulfonic acids such as camphor sulfonic acid, benzene sulfonic acid, and toluene sulfonic acid.

Examples of the alcohol include saturated aliphatic alcohol, unsaturated aliphatic alcohol and aralkyl alcohol.

Examples of the saturated aliphatic alcohol include saturated aliphatic alcohols having 1 to 4 carbon atoms which may have a substituent on the chain. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, and an alkoxycarbonyl group having 1 to 4 carbon atoms.

Examples of unsaturated aliphatic alcohols include allyl alcohol, 3-methyl-2-buten-1-ol, and cinnamyl alcohol which may have one or more substituents on the ring.

As the aralkyl alcohol, 1 on the ring
Examples thereof include benzyl alcohol, phenethyl alcohol, furfuryl alcohol, tenyl alcohol, and picolyl alcohol which may have the above substituents.

The substituents on the ring of cinnamyl alcohol or aralkyl alcohol include a lower alkyl group having 1 to 4 carbon atoms; a lower alkoxycarbonyl group having 1 to 4 carbon atoms; an acyl group such as an acetyl group, a benzoyl group, a cinnamoyl group. Group; an optionally protected hydroxyl group; a lower alkoxy group having 1 to 4 carbon atoms; fluorine, chlorine, bromine, iodine; and a nitro group.

The reaction temperature is -70 to 200 ° C., preferably 0.
The reaction is carried out at -100 ° C by stirring or standing for the time until the reaction is completed.

After completion of the reaction, the compound C and the bicyclic compound K are separated by subjecting to column chromatography.

The compound K can be converted into the compound C in a good yield by an acid hydrolysis reaction.

The reaction is preferably carried out in water, but in order to dissolve the compound K, a polar solvent such as alcohol, tetrahydrofuran, dioxane, acetone or dimethylformamide may be added.

As the acid, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid, organic acids such as formic acid, acetic acid, propionic acid and butyric acid, methanesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, Examples thereof include sulfonic acids such as toluene sulfonic acid.

The reaction temperature is -70 to 200 ° C., preferably 0.
The reaction is carried out at -100 ° C by stirring or standing for the time until the reaction is completed.

"Step b" is a step of subjecting compound C to an acylation reaction to obtain compound D and compound L.

[0038]

[Chemical 14]

(In the formula, R ¹ has the same meaning as described above, R ² represents an alkyl group, an alkenyl group, an aromatic hydrocarbon group or a heterocyclic group.) The alkyl group of R ² has a substituent on the chain. It represents a lower alkyl group having 1 to 4 carbon atoms which may be possessed. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms and a thiazolyl group.

The alkenyl group for R ² has 2 to 2 carbon atoms.
And the lower alkenyl group of 4 and a styryl group which may have one or more substituents on the ring.

Examples of the aromatic hydrocarbon group for R ² include a phenyl group and a naphthyl group which may have one or more substituents on the ring.

Examples of the heterocyclic group for R ² include a furyl group, a pyrrolyl group, a thienyl group, an imidazolyl group and a benzimidazolyl group which may have one or more substituents on the ring.

As a substituent on the ring of the styryl group, aromatic hydrocarbon group and heterocyclic group, a lower alkyl group having 1 to 4 carbon atoms; a carboxyl group; a lower alkoxycarbonyl group having 1 to 4 carbon atoms; Acyl group such as acetyl group, benzoyl group, cinnamoyl group which may have one or more substituents on the ring; optionally protected hydroxyl group;
4 lower alkoxy group; lower acyloxy group such as acetoxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group; fluorine, chlorine, bromine, iodine; nitro group; one or more on the chain or ring An acetyl group which may have a substituent, a benzoyl group,
Examples thereof include an acyl group such as a cinnamoyl group and an amino group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms.

The acylation reaction is carried out by reacting the hydroxyl group of compound C with a carboxylic acid in the presence of a condensing agent, or by reacting the hydroxyl group of compound C with a carboxylic acid anhydride or a carboxylic acid halide in the presence of a base. A method of reacting can be mentioned.

As the carboxylic acid, acetic acid which may have a substituent on the chain, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, acrylic acid, methacrylic acid, crotonic acid or 1 on the ring. Aliphatic carboxylic acids such as cinnamic acid that may have the above substituents, benzoic acid that may have one or more substituents on the ring, aromatic carboxylic acids such as naphthoic acid, and the rings And heterocyclic carboxylic acids such as furan carboxylic acid, thiophene carboxylic acid, pyrrole carboxylic acid, imidazole carboxylic acid and benzimidazole carboxylic acid which may have one or more substituents. Examples of the substituent on the chain include an optionally protected hydroxyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms and a thiazolyl group, and a substituent on the ring includes a lower alkyl group having 1 to 4 carbon atoms. A lower alkoxycarbonyl group having 1 to 4 carbon atoms; an acyl group such as an acetyl group, a benzoyl group or a cinnamoyl group which may have one or more substituents on the chain or on the ring; an optionally protected hydroxyl group A lower alkoxy group having 1 to 4 carbon atoms; a lower acyloxy group such as an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group; a fluorine, chlorine, bromine, iodine; nitro group; a chain or a ring Acyl group such as acetyl group, benzoyl group, cinnamoyl group, etc. which may have one or more substituents above, lower alkyl group having 1 to 4 carbon atoms or benzyl , Trityl group, and amino group which may be substituted with a protecting group such as benzyloxycarbonyl group. Active hydrogen on the heterocycle is preferably protected by a protecting group such as a benzyl group, a trityl group and a benzyloxycarbonyl group (hereinafter the same applies to the heterocycle).

As the condensing agent, any reagent can be used as long as it is a reagent usually used in a dehydration condensation reaction between a hydroxyl group and a free carboxylic acid. For example, N, N'-dicyclohexylcarbodiimide (hereinafter referred to as DCC). , 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide, etc., iodide 2
-Chloro-1-methylpyridinium, 2-bromo-1-
Examples thereof include 2-halopyridinium salts such as ethylpyridinium tetrafluoroborate and 2-chloro-1,3-dimethylimidazolinium chloride.

The carboxylic acid anhydride is a carboxylic acid anhydride corresponding to the carboxylic acid or an intramolecular acid anhydride such as phthalic anhydride. The carboxylic acid halide is a carboxylic acid halide corresponding to the carboxylic acid, and the halogen is chlorine or bromine.

Examples of the base include aromatic amines such as pyridine, picoline, lutidine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, quinoline, isoquinoline and N, N-dimethylaniline, trimethylamine, triethylamine, diisopropylethylamine, N-. Uses aliphatic amines such as methylpyrrolidine, N-methylpiperidine and N-methylmorpholine, and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and sodium hydride. be able to.

The solvent used in the reaction is not particularly limited, but aromatic hydrocarbons such as benzene, toluene and xylene, halogenated alkyls such as dichloromethane, chloroform and carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane and the like. Ethers, acetonitrile,
Examples thereof include inert solvents such as ethyl acetate, and heterocyclic amines such as pyridine, picoline, lutidine, quinoline, isoquinoline.

The reaction temperature is -70 to 200 ° C., preferably 0.
The reaction is carried out at -100 ° C by stirring or standing for the time until the reaction is completed.

After completion of the reaction, the compound D and the bicyclic compound L are separated by subjecting to column chromatography.

"Step c" is a step of obtaining the compound E by oxidatively removing the alkoxybenzyl group of the compound D in which R ¹ is an alkoxybenzyl group.

[0053]

[Chemical 15]

(In the formula, R ¹ represents an alkoxybenzyl group and R ² has the same meaning as above.) The alkoxybenzyl group is a p-methoxybenzyl (hereinafter referred to as “MPM”) group, 2,4-. A dimethoxybenzyl group is mentioned.

Examples of the solvent used in the reaction include methanol, water-containing dichloromethane, water-containing tetrahydrofuran and the like.

As the oxidant, 2,3-dichloro-5,
Examples thereof include benzoquinones such as 6-dicyano-p-benzoquinone (hereinafter referred to as "DDQ").

The alkoxybenzyl group can also be removed by an acid hydrolysis reaction using hydrochloric acid, sulfuric acid, nitric acid, trityl fluoroborate, a triarylamine cation, or an electrochemical oxidation reaction.

The reaction is carried out at -70 to 200 ° C., preferably 0.
The reaction is carried out by stirring or standing at ℃ to room temperature until the reaction is completed.

"Step d" is a step of subjecting Cycin N to an acylation reaction (hereinafter simply referred to as "acylation reaction") according to step b to obtain a mixture of compound E, compound F and compound G. Each of these mixtures can be isolated by a usual separation method, for example, silica gel column chromatography.

[0060]

[Chemical 16]

(In the formula, R ² has the same meaning as above.) The reaction is -70 to 200 ° C, preferably -10 to 10 ° C.
The reaction is completed by stirring or leaving it for a period of time.

When this reaction is carried out using a carboxylic acid and a carbodiimide, a compound F in which the 4-hydroxyl group is selectively acylated can be obtained.

[Step e] The 1-oxo group of the compound C in which R ¹ is an alkoxybenzyl group is protected, the hydroxyl group at the 5-position is alkylated, alkenylated or aralkylated, and then deprotected and the alkoxybenzyl group is removed. In this step, compound H is obtained.

[0064]

[Chemical 17]

(In the formula, R ¹ represents an alkoxybenzyl group, W represents a protecting group, and R ³ represents an alkyl group, an alkenyl group or an aralkyl group.) As a protecting group for a 1-oxo group, a usual carbonyl group is used. Although a protecting group for a group can be used, a hydrazone group is preferable, and a method such as Newcome (Organic Syntheses Col.
Vol., 6, p.12) and dimethylhydrazone are preferred.

Alkylation is carried out by reacting with an alkyl halide in the presence of a suitable base. Alkenylation and aralkylation can be performed by the same method as that for alkylation.

Examples of the base include metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, organic amines such as triethylamine and diisopropylethylamine, sodium hydride, potassium hydride, sodium amide, butyllithium and lithium diisopropylamide. Can be mentioned.

Examples of the alkyl halide include a lower alkyl halide having 1 to 4 carbon atoms which may have a substituent on the chain. Examples of the substituent on the chain include a protected hydroxyl group and a lower alkoxycarbonyl group having 1 to 4 carbon atoms.

Examples of the alkenyl halide include a lower alkenyl halide such as an allyl group and a cinnamyl halide which may have one or more substituents on the ring.

Examples of the aralkyl halide include benzyl halide, phenethyl halide, furfuryl halide, tenyl halide and picolyl halide which may have one or more substituents on the ring.

The substituents on the ring of the cinnamyl group or aralkyl group include a lower alkyl group having 1 to 4 carbon atoms; a lower alkoxycarbonyl group having 1 to 4 carbon atoms; an acyl group such as an acetyl group, a benzoyl group, a cinnamoyl group. A hydroxyl group which may be protected; a lower alkoxy group having 1 to 4 carbon atoms;
Fluorine, chlorine, bromine, iodine; and a nitro group can be mentioned.

Halogen is chlorine, bromine or iodine.

Examples of the solvent used in the reaction include ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide.

The reaction is carried out at -70 to 200 ° C., preferably 0.
The reaction is carried out at -100 ° C by stirring or standing for the time until the reaction is completed.

The deprotection and the removal of the alkoxybenzyl group can be carried out simultaneously under the conditions of acid hydrolysis of the hydrazone compound.

"Step f" is a step of obtaining the 1-hydroxycycin N derivative (Compound J) by reducing the 1-oxo group of Compound I in which the 4,5-diol of Cycin N is substituted with an appropriate substituent. ..

[0077]

[Chemical 18]

(In the formula, R ⁴ and R ⁵ are the same, different or together, and represent an alkyl group, an alkenyl group, an aralkyl group, an acyl group or a protecting group.) A lower alkyl group having 1 to 4 carbon atoms which may have a substituent is exemplified. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, and a lower alkoxycarbonyl group having 1 to 4 carbon atoms.

Examples of the alkenyl group include an allyl group, a 3-methyl-2-butenyl group, and a cinnamyl group which may have one or more substituents on the ring.

Examples of the aralkyl group include a benzyl group, a phenethyl group, a furfuryl group, a tenyl group and a picolyl group which may have one or more substituents on the ring.

The substituents on the ring of the cinnamyl group or the aralkyl group include a lower alkyl group having 1 to 4 carbon atoms; a lower alkoxycarbonyl group having 1 to 4 carbon atoms; an acyl group such as an acetyl group, a benzoyl group, a cinnamoyl group. A hydroxyl group which may be protected; a lower alkoxy group having 1 to 4 carbon atoms;
Fluorine, chlorine, bromine, iodine; and a nitro group can be mentioned.

As the acyl group, an acetyl group which may have a substituent on the chain, a propionyl group, a butyryl group,
An aliphatic acyl group such as an isobutyryl group, a valeryl group, an acryloyl group, a methacryloyl group, a 2-butenoyl group or a cinnamoyl group which may have one or more substituents on the ring, and one or more substituents on the ring. Aromatic acyl groups such as benzoyl group and naphthoyl group which may have, or furoyl group which may have one or more substituents on the ring, pyrrolylcarbonyl group, thenoyl group, imidazolylcarbonyl group, benzimidazolyl Heterocyclic acyl groups such as carbonyl group can be mentioned. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and a thiazolyl group, and the substituent on the ring includes a lower group having 1 to 4 carbon atoms. Alkyl group; carboxyl group; lower alkoxycarbonyl group having 1 to 4 carbon atoms; acyl group such as acetyl group, benzoyl group, cinnamoyl group which may have one or more substituents on the chain or ring; protected Optionally substituted hydroxyl group; lower alkoxy group having 1 to 4 carbon atoms; lower acyloxy group such as acetoxy group, propionyloxy group, butyryloxy group; fluorine, chlorine, bromine, iodine; nitro group; 1 on chain or ring
Acetyl group which may have the above substituents, benzoyl group, acyl group such as cinnamoyl group, lower alkyl group having 1 to 4 carbon atoms or benzyl group, trityl group, benzyloxycarbonyl group and the like And amino group.

As the protecting group, in the case of directly reacting with Cycin N, a cyclic acetal is preferable, and an isopropylidene, benzylidene or anisylidene group can be mentioned.

Further, when reacting the compound C, the compound E, the compound F or the compound H, the protecting group for the hydroxyl group is a tetrahydropyranyl group, a tetrahydrothiopyranyl group,
Examples thereof include chain acetals such as 4-methoxytetrahydropyranyl group, tetrahydrofuranyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group and 1-isopropyloxyethyl group.

Since the cyclic acetalization reaction involves the formation of water, it is usually a solvent immiscible with water, such as benzene,
It can be carried out using toluene, carbon tetrachloride, chloroform, dichloromethane or the like while dehydrating by azeotropic distillation under reflux in the presence of an acid catalyst.

The chain acetalization is carried out by reacting a corresponding vinyl ether compound such as dihydropyran in the presence of an acid catalyst. The reaction can be carried out without a solvent, but can also be carried out by adding an inert solvent such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, benzene or toluene.

Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid, organic acids such as formic acid, acetic acid, propionic acid and butyric acid, trifluorinated boron etherate, titanium tetrachloride and zinc chloride. Lewis acids such as tin tetrachloride and sulfonic acids such as methanesulfonic acid, camphorsulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

As a reducing agent, sodium borohydride,
Examples thereof include metal hydrides such as lithium borohydride and lithium aluminum hydride.

The solvent may be any suitable solvent depending on the reducing agent, for example, alcohols in the case of sodium borohydride, ethers such as diethyl ether or tetrahydrofuran in the case of lithium borohydride or lithium aluminum hydride. Kinds are used.

[Step g] The Cycin N derivative having a hydroxyl group at the 4-position is treated with alcohol in the presence of an acid catalyst,
Alternatively, it is a step of subjecting the hydroxyl group at the 4-position to alkylation, alkenylation, aralkylation or acylation reaction in the presence of a base to obtain a bicyclic compound M.

[0091]

[Chemical 19]

(In the formula, R ⁶ and R ⁷ are the same or different and each represents an alkyl group, an alkenyl group, an aralkyl group or an acyl group.) “H step” g of a Cycin N derivative having a hydroxyl group at the 5-position
This is a step for obtaining a bicyclic compound N by the same treatment as the step.

[0093]

[Chemical 20]

(In the formula, R ⁸ and R ⁹ are the same or different and each represents an alkyl group, an alkenyl group, an aralkyl group or an acyl group.) In step g and step h, an alkyl group, an alkenyl group,
The aralkyl group and the acyl group are as follows.

Examples of the alkyl group include a lower alkyl group having 1 to 4 carbon atoms which may have a substituent on the chain. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, and a lower alkoxycarbonyl group having 1 to 4 carbon atoms.

Examples of the alkenyl group include an allyl group, a 3-methyl-2-butenyl group, and a cinnamyl group which may have one or more substituents on the ring.

Examples of the aralkyl group include a benzyl group, a phenethyl group, a furfuryl group, a tenyl group and a picolyl group which may have one or more substituents on the ring.

The substituents on the ring of the cinnamyl group or the aralkyl group include a lower alkyl group having 1 to 4 carbon atoms; a lower alkoxycarbonyl group having 1 to 4 carbon atoms; an acyl group such as an acetyl group, a benzoyl group, a cinnamoyl group. A hydroxyl group which may be protected; a lower alkoxy group having 1 to 4 carbon atoms;
Fluorine, chlorine, bromine, iodine; and a nitro group can be mentioned.

As the acyl group, an acetyl group which may have a substituent on the chain, a propionyl group, a butyryl group,
An aliphatic acyl group such as an isobutyryl group, a valeryl group, an acryloyl group, a methacryloyl group, a 2-butenoyl group or a cinnamoyl group which may have one or more substituents on the ring, and one or more substituents on the ring. Benzoyl group which may have, aromatic acyl group such as naphthoyl group or furoyl group which may have one or more substituents on the ring, pyrrolecarbonyl group, thenoyl group, imidazolylcarbonyl group, benzimidazolylcarbonyl And a heterocyclic acyl group such as a group. Examples of the substituent on the chain include an optionally protected hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and a thiazolyl group, and the substituent on the ring includes a lower group having 1 to 4 carbon atoms. Alkyl group; carboxyl group; lower alkoxycarbonyl group having 1 to 4 carbon atoms; acyl group such as acetyl group, benzoyl group, cinnamoyl group which may have one or more substituents on the chain or ring; protected Optionally substituted hydroxyl group; lower alkoxy group having 1 to 4 carbon atoms; lower acyloxy group such as acetoxy group, propionyloxy group, butyryloxy group; fluorine, chlorine, bromine, iodine; nitro group; 1 on chain or ring
Acyl group such as acetyl group, benzoyl group, cinnamoyl group or the like which may have the above substituents or 1 to 1 carbon atoms
And an amino group which may be substituted with a lower alkyl group of 4 or a protecting group such as a benzyl group, a trityl group, a benzyloxycarbonyl group and the like.

The alcohol treatment can be carried out by the method according to the step a, the acylation reaction can be carried out by the step b, and the alkylation, alkenylation or aralkylation can be carried out by the method according to the step e.

When Cycin N was treated with alcohol, the compounds corresponding to Compound M and Compound N (R ⁶
Alternatively, R ⁸ represents a hydrogen atom. A) mixture is obtained.

"Step i" Saicin N or Saicin N derivative (compound O) obtained in steps a to g is subjected to catalytic reduction reaction to give 2,3-dihydrocycin N derivative (compound P). ..

[0103]

[Chemical 21]

R _X and R _Y have the same meaning as in the case of compound A.

The compound Q having a hydroxyl group at the 5-position exists as an equilibrium mixture with the bicyclic compound R as shown in the following formula.

[0106]

[Chemical formula 22]

(In the formula, R ¹⁰ represents hydrogen, an alkyl group, an alkenyl group, an aralkyl group or an acyl group.) The alkyl group, the alkenyl group, the aralkyl group and the acyl group have the same meanings as described above.

The solvent used in the reaction is not particularly limited, but aromatic hydrocarbons such as benzene, toluene and xylene, alkyl halides such as dichloromethane, chloroform and carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane and the like. Inert solvents such as ethers, alcohols such as methanol and ethanol, and esters such as ethyl acetate can be used.

As the catalyst used in the catalytic reduction reaction, any ordinary metal catalyst can be used, but preferably platinum, palladium, Raney nickel,
Examples include rhodium.

The reaction is carried out by stirring at room temperature for a period of time until absorbing a predetermined amount of hydrogen.

[Step j] According to the step h, the compound Q is treated with an alcohol in the presence of an acid catalyst, or subjected to an alkylation, alkenylation, aralkylation or acylation reaction in the presence of a base to give a bicyclic compound. This is the step of forming compound S.

[0112]

[Chemical formula 23]

(In the formula, R ¹¹ represents an alkyl group, an alkenyl group, an aralkyl group or an acyl group.) The alkyl group, the alkenyl group, the aralkyl group and the acyl group have the same meanings as in step h.

For the Cycin N derivative obtained in steps a to j, alkylation, alkenylation, aralkylation, acylation of the hydroxyl group or oxidation to the oxo group, hydrolysis of the ester group, removal of the alkoxybenzyl group, oxo group Saicin N derivative in which 1-position, 4-position or 5-position is a desired substituent by reducing the hydroxyl group to a hydroxyl group or subjecting the substituent on the chain or ring to hydrolysis, reduction or oxidation reaction to convert the substituent. Can be obtained.

Oxidation of a hydroxyl group to an oxo group can be carried out by an ordinary method for oxidizing a hydroxyl group. Examples of the oxidizing agent include active manganese dioxide, chromic anhydride, pyridinium chlorochromate, dimethylsulfoxide-trifluoroacetic anhydride, dimethylsulfoxide-oxalyl chloride and the like.

With respect to the compound A, the hydroxyl group at the 1-position, 4-position or 5-position can be obtained by a usual inversion method such as Mitsunobu reaction.
The configuration can be reversed.

[0117]

The action of the Cycin N derivative on the experimental ulcer will be described in detail below.

The test was conducted with a body weight of 2 for a hydrochloric acid-ethanol ulcer model, an aspirin ulcer model, a water immersion restraint stress ulcer model, a Shey ulcer model and a serotonin ulcer model.
About 500 g of Wistar male rats (1 group 6), and for ischemia-reperfusion injury model, about 250 g of SD male rats (1 group 6) were used. Except for the ischemia-reperfusion injury model, polyethylene glycol and 0.5% sodium carboxymethyl cellulose solution were appropriately mixed and sufficiently emulsified, and then subjected to the test.
The effect on various ulcer models was evaluated by the inhibition rate obtained by dividing the difference in ulcer index between the non-administration group and the test compound group by the non-administration group.

"Hydrochloric acid-ethanol ulcer" To each rat fasted for 24 hours, 0.5 ml of a 150 mM hydrochloric acid-60% ethanol mixed solution was orally administered per 100 g of body weight. One hour later, each rat was sacrificed, the length of the ulcer formed in the glandular stomach was measured, and the ulcer index was calculated based on this. The test compound was administered intraduodenally 1 hour or 3 hours before the administration of the hydrochloric acid-ethanol mixed solution.

The results 3 hours before are shown in [Table 1] and the results 1 hour before are shown in [Table 2].

[0121]

[Table 1]

[0122]

[Table 2]

As is clear from [Table 1] and [Table 2], the Cycin N derivative is recognized to have an extremely good antiulcer action.

“Aspirin ulcer” The pyloric region of each rat that had been fasted for 24 hours was ligated, and at the same time, the test substance was orally administered to the duodenum 5 minutes later, with aspirin 150 mg / kg.
Each rat was sacrificed 9 hours after ligation, the length of the ulcer formed in the glandular stomach was measured, and the ulcer index was calculated based on this.

[Water immersion restraint stress ulcer] Each rat fasted for 15 hours was fixed in a stress gauge and immersed in a water bath at 21 ° C up to the chest. Each rat was sacrificed after 10 hours,
The length of the ulcer formed in the glandular stomach was measured, and the ulcer index was calculated based on the measured length. The test article was orally administered 10 minutes before stress application.

"Shay's ulcer" The pyloric region of each rat that had been fasted for 48 hours was ligated and left under fasted and starved water for 14 hours.
Then, each rat was sacrificed, the area of the ulcer formed in the forestomach was measured, and the ulcer index was calculated based on this. The test article was administered into the duodenum immediately after ligation.

[Serotonin ulcer model] To each rat that had been fasted for 24 hours, a solution of serotonin creatinine sulfate in physiological saline was subcutaneously administered at 30 mg / kg.
After 30 minutes, each rat was slaughtered, and the area of gastric mucosal damage that occurred facing the central line of the gastric body on the major curvature side was measured, and the ulcer index was calculated based on this. The test article was administered into the duodenum 30 minutes before the administration of serotonin creatinine sulfate.

[Ischemia-Reperfusion Injury Model] Rats fasted for 24 hours were anesthetized by intraperitoneal administration of Nembutal and fixed in a dorsal position on a thermostatic pad. An airway was secured, and blood pressure was measured via a blood pressure transducer from a cannula inserted in the right carotid artery. After incising the abdominal wall and ligating the cardia of the stomach, injecting physiological saline from the pylorus to wash it, and after injecting 0.1 ml of 0.1N hydrochloric acid into the stomach, 1 ml per 100 g of body weight,
The pylorus was ligated. When the blood pressure became stable, blood with a body weight of 2% (w / w) was exsanguinated from the cannula inserted into the left carotid artery into a syringe containing heparinized physiological saline, and 20 minutes later, the exsanguinated blood was retransfused. After standing for 20 minutes, each rat was slaughtered, the area of the porcine tissue generated in the stomach was measured, and the disorder index was calculated based on the area. The test substance was dissolved in dimethylsulfoxide at 40 mg / kg to obtain 30
It was administered from the tail artery 5 minutes before.

The results of the aspirin ulcer model, water immersion restraint stress ulcer model, Shay ulcer model, serotonin ulcer model and ischemia-reperfusion injury model are shown in [Table 3].

[0130]

[Table 3]

Considering the above-mentioned test results, it can be said that the Cycin N derivative has an extremely excellent antiulcer action, and the drug containing the Cycin N derivative as an active ingredient is an excellent antiulcer agent.

The dose of the Cycin N derivative to a patient varies depending on the age, symptoms, etc., but generally it is 1 to 1000 mg orally, preferably 10 to 600 m / day for an adult.
g, which is used 1 to 6 times, preferably 1 to 3 times.

In the present invention, the Saicin N derivative is mixed with a usual pharmaceutical carrier to give a solid preparation such as tablets, hard or soft capsules, granules, powders, fine granules or suppositories, or an injection or a syrup. It is possible to prepare a liquid preparation such as a water solution, a suspension or an emulsion. Solid preparations may be prepared as enteric-coated preparations or sustained-release preparations. The formulation carrier to be blended includes, for example, an excipient, a binder, a disintegrating agent, a lubricant, a coating agent, depending on the desired dosage form.
Dissolution aid, emulsifier, suspension agent, surfactant, absorption aid,
A stabilizer or a solvent may be appropriately selected and used.

[0134]

EXAMPLES The present invention will be further described with reference to examples of Cycin N derivatives.

Unless otherwise specified, the stereochemistry of the 2-position methyl group in the reduced product of the oxygen functional group at the 1-, 4-, or 5-position and the double bond at the 2- or 3-position is 1 based on the 4-position. -Sis, 2-cis, 5-trans is represented, and when specifying stereochemistry, it is represented as 2,4-trans as a prefix for convenience. In addition, those in parentheses after the chemical name represent those tentative names in the present specification.

[0136]

Example 1 Eucarvone-4,5-oxide (50
g, 0.3 mol) of tetrahydrofuran (150 ml)
4-Methoxybenzyl alcohol (55 g, 0.
4 mol) and p-toluenesulfonic acid (2 g) were added to give 8
After heating for 3 hours under reflux, the mixture was concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent to give 5-hydroxy-
4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AUM0
96.7 was obtained (46.7 g, 50%).

IR (KBr, cm ^-1 ): 3528, 16
72, 1612, 1514, 1249, 1099, 10
34,823.

1 H-NMR (CDCl ₃ , ppm):
0.97 (3H, s), 1.12 (3H, s), 1.8
4 (3H, t, J = 2Hz), 2.33 (1H, d, J
= 13 Hz), 2.44 (1H, d, J = 13 Hz),
3.12 (1H, brs), 3.30 (1H, d, J =
9Hz), 3.82 (3H, s), 4.04 (1H, d
m, J = 9 Hz), 4.58 (1H, d, J = 11H
z), 4.76 (1H, d, J = 11 Hz), 6.50
(1H, m), 6.91 (2H, d, J = 8Hz),
7.31 (2H, d, J = 8Hz).

[0139]

Example 2 Eucarvone-4,5-oxide (3.3
2 g, 20 mmol) of tetrahydrofuran (10 m
l) Benzyl alcohol (4.12 ml, 40 mmol) and concentrated sulfuric acid (0.2 ml) were added to the solution, and the mixture was stirred at 0 ° C. for 1 hour and treated in the same manner as in Example 1 to give 4-benzyloxy as a colorless oil. 1.09 g (20%) of -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU156) was obtained.

IR (KBr, cm ^-1 ): 3534, 16
72, 1100, 1072, 738, 698.

1H-NMR (CDCl ₃ , ppm):
0.97 (3H, s), 1.12 (3H, s), 1.8
5 (3H, t, J = 2Hz), 2.34 (1H, d, J
= 12 Hz), 2.45 (1H, d, J = 12 Hz),
3.09 (1H, brs), 3.34 (1H, d, J =
9 Hz), 4.06 (1H, dm, J = 9 Hz), 4.
65 (1H, d, J = 12Hz), 4.83 (2H,
d, J = 12 Hz), 6.51 (1H, m), 7.36
(5H, m).

[0142]

Example 3 Eucarvone-4,5-oxide (1.6
To a solution of 6 g (10 mmol) in methanol (10 ml) was added concentrated sulfuric acid (0.2 ml) under stirring with ice cooling, the mixture was stirred for 30 minutes, and then stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous potassium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (20: 1) as an eluent. Chromatographically purified to give colorless oil 1,4-dimethoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (AU1).
55) was obtained (0.99 g, 46.6%).

1 H-NMR (CDCl ₃ , ppm):
1.22 (3H, s), 1.25 (3H, s), 1.6
7 (3H, t, J = 2Hz), 1.80 (2H, s),
3.36 (6H, s), 3.05 (1H, dd, J =
5,2 Hz), 4.35 (1 H, m), 5.48 (1
H, m).

[0144]

Example 4 Eucarvone-4,5-oxide (4.9
P-Toluenesulfonic acid (0.1 g) was added to a solution of 8 g (30 mmol) in methanol (30 ml) under ice-cooling, the mixture was stirred for 3 hours and concentrated, and acetone (20 ml) and 1N hydrochloric acid (3 ml) were added. And stirred for 1 day. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent. Purified with a yellow oily 5-
Hydroxy-4-methoxy-2,6,6-trimethyl-
2-Cyclohepten-1-one (AU154) was added to 4.9.
4 g (83%) was obtained.

IR (KBr, cm ^-1 ): 3446, 16
70, 1458, 1104.

1 H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.13 (3Hs), 1.85
(3H, t, J = 2Hz), 2.35 (1H, d, J =
12Hz), 2.47 (1H, d, J = 12Hz),
3.11 (1H, brs), 3.28 (1H, d, J =
9Hz), 3.55 (3H, s), 3.79 (1H, d
m, J = 9 Hz), 6.43 (1H, m).

[0147]

Example 5 5-hydroxy-4-obtained in Example 1
(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (11.47 g,
Acetic anhydride (10 ml) was added to a solution of 37 mmol) in pyridine (30 ml), the mixture was stirred overnight at room temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried. The extract was dried over magnesium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (30: 1) as an eluent to give 5-acetoxy-4- (4-methoxybenzyloxy) as a colorless oil. ) -2,6,6-Trimethyl-2-cyclohepten-1-one (AU181) 10.06 g (7
8%) was obtained.

IR (KBr, cm ^-1 ): 1743,16
73, 1514, 1247, 1098, 1035, 82
4.

1 H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.03 (3H, s), 1.8
5 (3H, t, J = 2Hz), 2.07 (3H, s),
2.45 (1H, d, J = 13Hz), 2.53 (1
H, d, J = 13 Hz), 3.82 (3H, s), 4.
19 (1H, dm, J = 9Hz), 4.58 (1H,
d, J = 12 Hz), 4.65 (1H, d, J = 12H)
z), 4.90 (1H, d, J = 9 Hz), 6.50
(1H, m), 6.90 (2H, d, J = 9Hz),
7.25 (2H, d, J = 9 Hz).

[0150]

Example 6 5-hydroxy-4-obtained in Example 1
(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (2.44 g, 8
Benzoic acid anhydride (3.04 g, 10 mmol) and 4-dimethylaminopyridine (0.1 g) were added to a pyridine (10 ml) solution of (mmol) and stirred at room temperature overnight, and post-treated according to Example 5. Hexane-ethyl acetate (10:
Purified by silica gel column chromatography using 1) as an eluent to give 5-benzoyloxy-4- as colorless oil.
3.10 g (95%) of (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU182) was obtained.

IR (KBr, cm ^-1 ): 1723, 16
73, 1514, 1273, 1114, 712.

1 H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.13 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.53 (1H, d, J
= 13 Hz), 2.60 (1H, d, J = 13 Hz),
3.75 (3H, s), 4.31 (1H, dm, J = 9)
Hz), 4.49 (1H, d, J = 12Hz), 4.5
8 (1H, d, J = 12Hz), 5.15 (1H, d,
J = 9 Hz), 6.54 (1 H, m), 6.72 (2
H, d, J = 9Hz), 7.05 (2H, d, J = 9H)
z), 7.46 (2H, t, J = 7Hz), 7.59
(1H, m), 8.05 (2H, d, J = 7Hz).

[0153]

Example 7 A solution of the product of Example 6 (3.69 g, 9.0 mmol) in methylene chloride (40 ml) was treated with water (0.8 ml).
ml) and DDQ (2.72 g, 12 mmol) were added, the mixture was stirred at room temperature for 2 hours, filtered, concentrated, and purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent. 1.82 g of colorless needle crystals of 5-benzoyloxy-4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU183) were crystallized from a mixed solvent of ethyl and hexane.
(70%) was obtained. Melting point 99-100 [deg.] C.

IR (KBr, cm ^-1 ): 3446, 17
20, 1677, 1279, 1118, 716.

1 H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.23 (3H, s), 1.9
0 (3H, t, J = 2Hz), 2.49 (1H, d, J
= 13 Hz), 2.66 (1H, d, J = 13 Hz),
4.66 (1H, m), 4.95 (1H, d, J = 9H
z), 6.55 (1H, m), 7.47 (2H, m),
7.62 (1H, m), 8.08 (2H, m).

[0156]

Example 8 The product of Example 7 (1.01 g, 3.5 mmol) was acetylated according to a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give 4-acetoxy-5-colorless needle crystals. 0.83 g (72%) of benzoyloxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU189) was obtained. Melting point 86-87 [deg.] C.

IR (KBr, cm ^-1 ): 1750, 17
23, 1668, 1269, 1224, 1113, 10
27,715.

1 H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.24 (3H, s), 1.7
7 (3H, s), 1.90 (3H, t, J = 2Hz),
2.54 (1H, d, J = 13Hz), 2.74 (1
H, d, J = 13 Hz), 5.10 (1H, d, J = 9)
Hz), 5.97 (1H, dm, J = 9 Hz), 6.3
6 (1H, m), 7.47 (2H, m), 7.58 (1
H, m), 8.03 (2H, m).

[0159]

Example 9 5-hydroxy-4-obtained in Example 1
(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (4.7 g, 1
5.4 mmol) was treated with 2-chlorobenzoic anhydride (16 g, 54.2 mmol) according to Example 6 to give colorless oil 5- (2-chlorobenzoyloxy) -4- (4.
-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU124).
33 g (63%) was obtained.

IR (KBr, cm ^-1 ): 1736, 16
73, 1514, 1249, 1049, 749.

1 H-NMR (CDCl ₃ , ppm):
1.13 (3H, s), 1.15 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.52 (1H, d, J
= 13 Hz), 2.60 (1H, d, J = 13 Hz),
3.78 (3H, s), 4.31 (1H, dm, J = 8)
Hz), 4.51 (1H, d, J = 12 Hz), 4.6
1 (1H, d, J = 12Hz), 5.16 (1H, d,
J = 9 Hz), 6.54 (1 H, m), 6.76 (2
H, d, J = 9 Hz), 7.12 (2H, d, J = 9H)
z), 7.29 (1H, m), 7.43 (2H, m),
7.75 (1H, m).

[0162]

Example 10 The product of Example 9 (1.5 g, 3.4 mmol) was treated with DDQ according to Example 7 and crystallized from a mixed solvent of ethyl acetate and hexane to give 5 colorless prism-like crystals. 0.78 g (81%) of-(2-chlorobenzoyloxy) -4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU127) was obtained. Melting point 92.5-94 [deg.] C.

IR (KBr, cm ^-1 ): 3507, 17
34, 1656, 1252, 1115, 1050, 74
8.

1 H-NMR (CDCl ₃ , ppm):
1.13 (3H, s), 1.15 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.48 (1H, d, J
= 13 Hz), 2.64 (1H, d, J = 13 Hz),
4.65 (1H, dm, J = 9Hz), 5.00 (1
H, d, J = 9 Hz), 6.54 (1 H, m), 7.3
6 (1H, m), 7.47 (2H, m), 7.87 (1
H, m).

[0165]

Example 11 5-Hydroxy-4 obtained in Example 1
-(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (4.3 g, 1
4 mmol) was treated with 3-chlorobenzoic anhydride (14.4 g, 48.8 mmol) according to Example 6 to give 5- (3-chlorobenzoyloxy) -4- (4 as a colorless oil.
-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU125).
Obtained 56 g (57%).

IR (KBr, cm ^-1 ): 1725, 16
74, 1271, 1117, 1104, 757.

1 H-NMR (CDCl ₃ , ppm):
1.08 (3H, s), 1.11 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.51 (1H, d, J
= 13 Hz), 2.59 (1H, d, J = 13 Hz),
3.77 (3H, s), 4.30 (1H, dm, J = 9)
Hz), 4.45 (1H, d, J = 12 Hz), 4.6
0 (1H, d, J = 12Hz), 5.11 (1H, d,
J = 9 Hz), 6.54 (1 H, m), 6.74 (2
H, d, J = 8 Hz), 7.05 (2H, d, J = 8H
z), 7.41 (1H, t, J = 8Hz), 7.56
(1H, m), 7.92 (1H, m), 7.97 (1
H, m).

[0168]

Example 12 5-hydroxy-4 obtained in Example 1
-(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (5.0 g, 1
6.4 mmol) was treated with 4-chlorobenzoic anhydride (17 g, 57.6 mmol) according to Example 6 to give 5- (4-chlorobenzoyloxy) -4- (4 as a colorless oil.
-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU126).
Obtained 45 g (48%).

IR (KBr, cm ^-1 ): 1725, 16
74, 1271, 1117, 757.

1 H-NMR (CDCl ₃ , ppm):
1.08 (3H, s), 1.11 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.52 (1H, d, J
= 13 Hz), 2.59 (1H, d, J = 13 Hz),
3.77 (3H, s), 4.30 (1H, dm, J = 9)
Hz), 4.46 (1H, d, J = 12Hz), 4.5
8 (1H, d, J = 12 Hz), 5.11 (1H, d,
J = 9 Hz), 6.53 (1 H, m), 6.73 (2
H, d, J = 8Hz), 7.04 (2H, d, J = 8H)
z), 7.43 (2H, d, J = 8Hz), 7.95
(2H, d, J = 8Hz).

[0171]

Example 13 The product of Example 12 (3.00 g, 6.
78 mmol) was treated with DDQ according to Example 7 and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless plate crystals of 5- (4-chlorobenzoyloxy) -4-hydroxy-2,6,6. 1.09 g (48%) of -trimethyl-2-cyclohepten-1-one (AU128) was obtained. Melting point 114.5-151 [deg.] C.

IR (KBr, cm ^-1 ): 3480, 17
14,1676,1274,1123,1094,84
8,758.

1 H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.21 (3H, s), 1.9
0 (3H, t, J = 2Hz), 2.23 (1H, d, J
= 8 Hz; disappeared by adding heavy water), 2.48 (1H,
d, J = 13 Hz), 2.65 (1H, d, J = 13H)
z), 4.63 (1H, m; dm, J = by addition of heavy water)
9Hz), 4.92 (1H, d, J = 9Hz), 6.5
4 (1H, m), 7.46 (2H, d, J = 9Hz),
8.01 (2H, d, J = 9Hz).

[0174]

Example 14 The product of Example 13 (0.79 g, 2.
5 mmol) was acetylated according to a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give 4-acetoxy-5- (4-chlorobenzoyloxy) -2,6,6-trimethyl-2- as colorless prism crystals. Cycloheptene-
0.54 g (61%) of 1-one (AU130) was obtained.

Melting point 86-87 ° C.

IR (KBr, cm ^-1 ): 1747, 17
25, 1675, 1592, 1265, 760.

1H-NMR (CDCl ₃ , ppm):
1.08 (3H, s), 1.22 (3H, s), 1.7
9 (3H, s), 1.90 (3H, t, J = 2Hz),
2.53 (1H, d, J = 13Hz), 2.73 (1
H, d, J = 13 Hz), 5.09 (1 H, d, J = 9)
Hz), 5.95 (1H, dm, J = 9Hz), 6.3
4 (1H, m), 7.44 (2H, d, J = 9Hz),
7.95 (2H, d, J = 9 Hz).

[0178]

Example 15 5-Hydroxy-4 obtained in Example 4
-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (5.18 g, 26 mmol) was acetylated according to a conventional method and benzene-ethyl acetate (20:
Purified by silica gel column chromatography using 1) as an eluent to give 5-acetoxy-4-methoxy-2,6,6-trimethyl-2-cycloheptene-1- as colorless oil.
Obtained 4.16 g (65%) of on (AU161).

IR (KBr, cm ^-1 ): 1744, 16
74, 1238.

1 H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.05 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.12 (3H, s),
2.46 (1H, d, J = 13Hz), 2.56 (1
H, d, J = 13 Hz), 3.45 (3H, s), 3.
96 (1H, dm, J = 9Hz), 4.85 (1H,
d, J = 9 Hz), 6.45 (1 H, m).

13 C-NMR (CDCl ₃ , ppm):
19.0 (q), 20.9 (q), 23.6 (q), 2
7.3 (q), 33.7 (s), 53.9 (t), 5
8.6 (q), 78.6 (d), 79.3 (d), 13
8.4 (s), 141.8 (d), 170.2 (s),
200.3 (s).

[0182]

Example 16 5-hydroxy-4 obtained in Example 4
5-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (1.0 g, 5.0 mmol) was benzoylated according to Example 6 and crystallized from hexane to give colorless needle crystals of 5-. Benzoyloxy-4-methoxy-
0.95 g (63%) of 2,6,6-trimethyl-2-cyclohepten-1-one (AU121) was obtained. Melting point
91.5-93.5 ° C.

IR (KBr, cm ^-1 ): 1716,16
70, 1276, 1114, 714.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.19 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.56 (1H, d, J
= 13 Hz), 2.64 (1H, d, J = 13 Hz),
3.41 (3H, s), 4.11 (1H, dm, J = 9
Hz), 5.12 (1H, d, J = 9 Hz), 6.50
(1H, m), 7.47 (2H, m), 7.58 (1
H, m), 8.07 (2H, m).

[0185]

Example 17 5-hydroxy-4 obtained in Example 4
0 to a solution of -methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (1.0 g, 5.0 mmol) and triethylamine (1.06 ml, 7.6 mmol) in methylene chloride (5 ml). 4-Methoxybenzoyl chloride (1.3 g, 7.62 mmol) was added at 0 ° C. and the mixture was stirred for 30 minutes, then stirred at room temperature overnight, post-treated according to Example 6, and hexane-ethyl acetate (20: 1). Purified by silica gel column chromatography using as the eluent, and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 4-methoxy-5- (4-methoxybenzoyloxy) -2,6,6-trimethyl. 0.53 g (32%) of 2-cyclohepten-1-one (AU129) was obtained. Melting point 100-101 [deg.] C.

IR (KBr, cm ^-1 ): 1711,16
69, 1605, 1281, 1258, 1112, 85
2,770.

1H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.17 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.56 (1H, d, J
= 13 Hz), 2.62 (1H, d, J = 13 Hz),
3.40 (3H, s), 3.87 (3H, s), 4.0
8 (1H, dm, J = 9Hz), 5.09 (1H, d,
J = 9 Hz), 6.49 (1 H, m), 6.94 (2
H, d, J = 9 Hz), 8.02 (2H, d, J = 9H)
z).

[0188]

Example 18 5-Hydroxy-4 obtained in Example 4
-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (9.9 g, 50 mmol) was used in Example 1.
According to 7, treat with 4-nitrobenzoic acid chloride and fractionate by silica gel column chromatography using hexane-ethyl acetate (20: 1-10: 1) as an eluent. The first eluate is ethyl acetate and hexane. Is crystallized from the mixed solvent of 4-methoxy-1- (4-nitrobenzoyloxy) -2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2- EN (AU2
31) was obtained in an amount of 5.75 g (33%). Melting point 95.0-9
5.5 ° C.

IR (KBr, cm ^-1 ): 1745, 15
27, 1261, 1141, 715.

1 H-NMR (CDCl ₃ , ppm):
1.30 (3H, s), 1.34 (3H, s), 1.6
7 (3H, t, J = 2Hz), 2.19 (2H, s),
3.40 (3H, s), 4.24 (1H, dd, J =
5,2Hz), 4.54 (1H, m), 5.52 (1
H, m), 8.22 (2H, d, J = 9 Hz), 8.3
0 (2H, d, J = 9 Hz).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 4-methoxy-5- (4-nitrobenzoyloxy) -2,6,6 as slightly yellow needle crystals.
-Trimethyl-2-cyclohepten-1-one (AU2
30) was obtained in an amount of 3.90 g (22%). Melting point 122-12
3 ° C.

IR (KBr, cm ^-1 ): 1728, 16
70, 1522, 1269, 1114, 714.

1 H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.20 (3H, s), 1.9
0 (3H, t, J = 2Hz), 2.57 (1H, d, J
= 13 Hz), 2.64 (1H, d, J = 13 Hz),
3.40 (3H, s), 4.12 (1H, dm, J = 9
Hz), 5.12 (1H, d, J = 9 Hz), 6.50
(1H, m), 8.23 (2H, d, J = 9Hz),
8.33 (2H, d, J = 9Hz).

[0194]

Example 19 4-Methoxy-5 obtained in Example 18
-(4-Nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (2.78 g,
8 mmol), ammonium chloride (0.17 g), iron (1.2 g), dimethylformamide (9 ml) and water (4 ml) were stirred at 80 ° C. for 20 minutes and then filtered,
After washing with ethyl acetate, the filtrate and washings were combined, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated, and then crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals.
(4-aminobenzoyloxy) -4-methoxy-2,
2.29 g (90%) of 6,6-trimethyl-2-cyclohepten-1-one (AU235) was obtained.

Melting point 138.5-161 ° C.

IR (KBr, cm ^-1 ): 3432, 33
49, 3238, 1684, 1664, 1602, 12
75, 1168, 1115.

1 H-NMR (CDCl ₃ , ppm):
1.08 (3H, s), 1.16 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.56 (1H, d, J
= 13 Hz), 2.61 (1H, d, J = 13 Hz),
3.41 (3H, s), 4.11 (3H, m), 5.0
8 (1H, d, J = 9Hz), 6.50 (1H, m),
6.66 (2H, d, J = 9Hz), 7.88 (2H,
d, J = 9 Hz).

[0198]

Example 20 5-Hydroxy-4 obtained in Example 4
2-Methyl-2,6,6-trimethyl-2-cyclohepten-1-one (0.99 g, 5 mmol) in a mixed solution of acetonitrile (15 ml) and pyridine (4 ml) under stirring with ice cooling 2-tritylaminothiazole- 4-Acetic acid (2.6 g, 6.5 mmol), DCC (1.34 g,
6.5 mmol) and 4-dimethylaminopyridine (0.1 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution is filtered, the filtrate is concentrated, the residue is diluted with ethyl acetate,
After washing sequentially with water, aqueous sodium hydrogen carbonate and saturated brine, drying over anhydrous magnesium sulfate, filtration and concentration, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (5: 1) as an eluent, and colorless. Oily 4-methoxy-
1.31 g of 2,6,6-trimethyl-5- (2-tritylaminothiazol-4-yl) acetoxy-2-cyclohepten-1-one was obtained.

1 H-NMR (CDCl ₃ , ppm):
0.97 (6H, s), 1.84 (3H, t, J = 2H
z), 2.45 (1H, d, J = 13Hz), 2.52
(1H, d, J = 13Hz), 3.35 (3H, s),
3.60 (2H, s), 3.93 (1H, dm, J = 9)
Hz), 4.85 (1H, d, J = 9 Hz), 6.20
(1H, s), 6.43 (1H, m), 6.68 (1
H, brs), 7.29 (15H, m).

80% acetic acid (5 ml) was added to the above product, heated at 70 ° C. for 3 hours and then concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1: 1) as an eluent. , 5- (2-aminothiazol-4-yl) acetoxy-4-methoxy-2, as yellow plate crystals by crystallization from a mixed solvent of ethyl acetate and hexane.
0.40 g (23%) of 6,6-trimethyl-2-cyclohepten-1-one (AU243) was obtained. Melting point 11
6-117 ° C.

IR (KBr, cm ^-1 ): 3376, 32
96, 3127, 1733, 1660, 1532, 12
62.

1H-NMR (CDCl ₃ , ppm):
0.99 (6H, s), 1.85 (3H, t, J = 2H
z), 2.45 (1H, d, J = 13Hz), 2.53
(1H, d, J = 13Hz), 3.40 (3H, s),
3.61 (2H, s), 3.95 (1H, dm, J = 9)
Hz), 4.86 (1H, d, J = 9 Hz), 5.49
(2H, brs), 6.35 (1H, s), 6.44
(1H, m).

[0203]

Example 21 5-hydroxy-4 obtained in Example 4
A solution of -methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (1.98 g, 10 mmol) in pyridine (10 ml) was mixed with phthalic anhydride (1.78 g, 12
Mmol) and 4-dimethylaminopyridine (0.05
g) was added and the mixture was heated at 90 ° C for 3 hours, allowed to cool, poured into ice water, made alkaline with potassium carbonate and extracted with ethyl acetate, and the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The crystals were washed, dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless plate crystals of 5- (2-carboxybenzoyloxy) -4-methoxy-2,6,6. -Trimethyl-2
-Cyclohepten-1-one (AU218) was 1.80.
g (53%) was obtained. Melting point 158.0-158.5 [deg.] C.

IR (KBr, cm ^-1 ): 3600-23
00, 1726, 1694, 1672, 1294, 74
8.

1H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.15 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.53 (1H, d, J
= 13 Hz), 2.61 (1H, d, J = 13 Hz),
3.45 (3H, s), 4.09 (1H, dm, J = 9
Hz), 5.12 (1H, d, J = 9 Hz), 6.51
(1H, m), 7.61 (2H, m), 7.75 (1
H, m), 7.90 (1H, m).

[0206]

Example 22 5-Hydroxy-4 obtained in Example 4
-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (5.95 g, 30 mmol) was treated with 2,4-dinitrobenzoic acid according to Example 20, mixing ethyl acetate and hexane. Recrystallized twice from the solvent to give reddish needle-like crystals of 5- (2,4-dinitrobenzoyloxy) -4-methoxy-2,6,6-trimethyl-2.
-Cyclohepten-1-one (AU407) 7.24
g (61.5%) was obtained. Melting point 147.5-149 [deg.] C.

IR (KBr, cm ^-1 ): 1741,16
69, 1541, 1348, 1284, 1101, 73
5.

1H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.17 (3H, s), 1.9
0 (3H, t, J = 2Hz), 2.51 (1H, d, J
= 13 Hz), 2.59 (1H, d, J = 13 Hz),
3.45 (3H, s), 4.06 (1H, dm, J = 9)
Hz), 5.10 (1H, d, J = 9 Hz), 6.49
(1H, m), 7.99 (1H, d, J = 8Hz),
8.55 (1H, dd, J = 8, 2Hz), 8.78
(1H, d, J = 8Hz).

[0209]

Example 23 The product of Example 22 (5.0 g, 12.
7 mmol) to reduce the nitro group according to Example 19,
Recrystallized twice from methanol to give yellow plate crystals of 5-
(2,4-Diaminobenzoyloxy) -4-methoxy-2,6,6-trimethyl-2-cycloheptene-1-
2.27 g (55.4%) of on (AU408) was obtained.
Melting point 178-179 [deg.] C.

IR (KBr, cm ^-1 ): 3498, 34
51, 3366, 1665, 1624, 1585, 15
42, 1258, 1148, 770.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.16 (3H, s), 1.8
7 (3H, t, J = 2Hz), 2.52 (1H, d, J
= 13 Hz), 2.61 (1H, d, J = 13 Hz),
3.43 (3H, s), 3.92 (2H, brs; disappeared by addition of heavy water), 4.06 (1H, dm, J = 9H)
z), 5.02 (1H, d, J = 9Hz), 5.74
(2H, brs; disappeared by addition of heavy water), 5.87 (1
H, d, J = 2 Hz, 5.99 (1H, dd, J =
9,2Hz), 6.52 (1H, m), 7.69 (1
H, d, J = 9 Hz).

The above product (1.3 g, 4.0 mmol)
Was dissolved in ethyl acetate, a 4N hydrogen chloride / ethyl acetate solution was added, and the resulting precipitate was collected by filtration to obtain 1.5 g (95%) of a hydrochloride as colorless powder. Melting point 115 ° C (decomposition).

IR (KBr, cm ^-1 ): 3450, 33
26, 3200-2400, 1673, 1634, 12
47,1109,769.

1H-NMR (DMSO-d ₆ , pp
m): 0.92 (3H, s), 1.09 (3H, s),
1.79 (3H, brt), 2.39 (1H, d, J =
13Hz), 2.73 (1H, d, J = 13Hz),
3.33 (3H, s), 4.29 (1H, brm),
4.79 (1H, d, J = 9Hz), 6.29 (1H,
m), 6.40 (1H, m), 6.58 (1H, m),
7.71 (1H, m).

[0215]

Example 24 5-hydroxy-4 obtained in Example 4
-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (25.0 g, 126 mmol) was treated with 3,4-dinitrobenzoic acid according to Example 20 and crystallized from methanol, 5- (3, pale yellow needle crystals
4-dinitrobenzoyloxy) -4-methoxy-2,
42.1 g (85%) of 6,6-trimethyl-2-cyclohepten-1-one (AU409) was obtained. Melting point 10
3-104 ° C.

IR (KBr, cm ^-1 ): 1734,16
68, 1545, 1369, 1354, 1251, 84
7.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.19 (3H, s), 1.9
1 (3H, t, J = 2Hz), 2.56 (1H, d, J
= 13 Hz), 2.65 (1H, d, J = 13 Hz),
3.40 (3H, s), 4.13 (1H, dm, J = 9)
Hz), 5.11 (1H, d, J = 9 Hz), 6.49
(1H, m), 8.01 (1H, d, J = 9Hz),
8.43 (1H, dd, J = 9, 2Hz), 8.57
(1H, d, J = 2Hz).

[0218]

Example 25 The product of Example 24 (22 g, 56 mmol) was reduced in the nitro group according to Example 19, and crystallized from methanol to give 5- (3,4-diaminobenzoyl) as pale red needle crystals. Oxy) -4-methoxy-2,6,6
-Trimethyl-2-cyclohepten-1-one (AU4
2.95 g (16%) of 10) was obtained. Melting point 136 ° C (decomposition).

IR (KBr, cm ^-1 ): 3472, 33
62, 1684, 1662, 1310, 1288, 12
24, 764.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.16 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.55 (1H, d, J
= 13 Hz), 2.63 (1H, d, J = 13 Hz),
3.41 (3H, s), 4.09 (1H, dm, J = 9)
Hz), 5.08 (1H, d, J = 9 Hz), 5.50
(1H, m), 6.69 (1H, d, J = 8Hz),
7.43 (1H, d, J = 2Hz), 7.50 (1H,
dd, J = 8, 2 Hz).

[0221]

Example 26 The product of Example 25 (1.44 g, 4.
77 mmol) in tetrahydrofuran (10 ml) was added with cyanogen bromide (0.47 g, 4.78 mmol) at room temperature with stirring, and after 5 hours, cyanogen bromide (0.26 g,
(2.60 mmol) was added and the mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was back-extracted with diluted hydrochloric acid. To this water extract was added sodium bicarbonate to make it alkaline, which was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a glassy substance, 5- (2-aminobenzimidazolyl-5-carbonyloxy) -4-methoxy. -2,6,6-trimethyl-2-cycloheptene-
1.21 g (76%) of 1-one (AU415) was obtained.
Melting point 131-132.5 [deg.] C.

IR (KBr, cm ^-1 ): 3400-31
00, 1709, 1646, 1559, 1289, 11
98.

1H-NMR (CDCl ₃ , ppm):
1.08 (3H, s), 1.19 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.54 (1H, d, J
= 13 Hz), 2.62 (1H, d, J = 13 Hz),
3.41 (3H, s), 4.12 (1H, dm, J = 9
Hz), 5.09 (1H, d, J = 9Hz), 5.51
(2H, br; disappeared by adding heavy water), 6.47 (1
H, m), 7.29 (1H, d, J = 8 Hz), 7.8
2 (1H, d, J = 8Hz), 7.98 (1H, br
s).

[0224]

[0225]

Example 27 The product of Example 25 (1 g, 3 mmol) was added to dimethylformamide dimethyl acetal (1.
(5 ml) and stirred at 50 ° C. for 1 hour, the reaction mixture was concentrated, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1: 3) as an eluent, and a mixed solvent of ethyl acetate and hexane was added. 0.1 g (1) of 5- (5-benzimidazolylcarbonyloxy) -4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU507) in the form of brown glass which was crystallized from
0%) was obtained. Melting point 155-157 [deg.] C.

IR (KBr, cm ^-1 ): 3600-31
00, 1705, 1654, 1302, 1124, 75
0.

1H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.22 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.56 (1H, d, J
= 13 Hz), 2.66 (1H, d, J = 13 Hz),
3.41 (3H, s), 4.13 (1H, dm, J = 9)
Hz), 5.14 (1H, d, J = 9 Hz), 6.52
(1H, m), 7.69 (1H, d, J = 8Hz),
8.05 (1H, d, J = 8Hz), 8.23 (1H,
s), 8.47 (1H, s).

[0228]

Example 28 4-Benzyloxy-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 2 (50 mg, 0.18 mmol)
Was acetylated by a conventional method to give 5-acetoxy-4-benzyloxy-2,6,6-trimethyl-2 as colorless oil.
-Cyclohepten-1-one (AU156 acetate)
Was obtained in an amount of 49 mg (91%).

1H-NMR (CDCl ₃ , ppm):
1.01 (3H, s), 1.02 (3H, s), 1.8
4 (3H, t, J = 2Hz), 2.04 (3H, s),
2.43 (1H, d, J = 13Hz), 2.53 (2
H, d, J = 13 Hz), 4.20 (1H, dm, J =
9 Hz), 4.63 (1H, d, J = 12 Hz), 4.
71 (2H, d, J = 12Hz), 4.91 (1H,
d, J = 9 Hz), 6.52 (1H, m), 7.31
(5H, m).

[0230]

Example 29 Cycin N (5.53 g, 30 mmol) was acetylated according to a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 4,5-diacetoxy-2,6,6-. Trimethyl-2-cyclohepten-1-one (AU102) 6.58 g (81%)
Obtained. Melting point 68-69 [deg.] C.

IR (KBr, cm ^-1 ): 1741,16
81, 1252, 1041.

1H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.09 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.09 (3H, s),
2.10 (3H, s), 2.48 (1H, d, J = 13
Hz), 2.66 (1H, d, J = 13 Hz), 4.8
9 (1H, d, J = 9Hz), 5.75 (1H, dm,
J = 9 Hz), 6.26 (1H, m).

[0233]

Example 30 Cycin N (1.84 g, 10 mmol) was benzoylated according to Example 6 and fractionated by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent. The eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 4-benzoyloxy-5-hydroxy-2,6,6-
Trimethyl-2-cyclohepten-1-one (AU19
0) was obtained (0.98 g, 34%). Melting point 127-128
° C.

IR (KBr, cm ^-1 ): 3551, 17
18,1674,1333,1272,1111,70
5.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.12 (3H, s), 1.16 (3H, s),
1.87 (3H, t, J = 2Hz), 2.45 (1H,
d, J = 13 Hz), 2.67 (1H, d, J = 13H)
z), 3.55 (1H, d, J = 9 Hz), 5.85
(1H, dm, J = 9Hz), 6.42 (1H, m),
7.48 (2H, m), 7.61 (1H, m), 8.0
9 (2H, m).

From the subsequent elution portion, 0.76 g (26%) of 5-benzoyloxy-4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU183) similar to that of Example 7 was obtained. ..

[0237]

Example 31 4-benzoyloxy-5-hydroxy-2,6,6-trimethyl-2-obtained in Example 30
Cyclohepten-1-one (0.60 g, 2.08 mmol) was acetylated by a conventional method and crystallized from water to give 5-acetoxy-4-benzoyloxy-2, colorless crystals.
0.47 g (67%) of 6,6-trimethyl-2-cyclohepten-1-one (AU193) was obtained. Melting point 94
-95 ° C.

IR (KBr, cm ^-1 ): 1735, 17
22, 1672, 1273, 1232, 714.

1H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.15 (3H, s), 1.8
2 (3H, s), 1.90 (3H, t, J = 2Hz),
2.52 (1H, d, J = 13Hz), 2.73 (1
H, d, J = 13 Hz), 5.03 (1H, d, J = 9)
Hz), 6.04 (1H, dm, J = 9 Hz), 6.4
1 (1H, m), 7.47 (2H, brt, J = 7H
z), 7.59 (1H, brt, J = 7 Hz), 8.0
4 (2H, brd, J = 7Hz).

[0240]

Example 32 Cycin N (1.84 g, 10 mmol) was treated with 3,4-dimethoxybenzoyl chloride (2.41 g, 12 mmol) according to Example 17, benzene-ethyl acetate (5: 1). Was fractionated by silica gel column chromatography using as the eluent, and the first eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless plate crystals of 4- (3,4-dimethoxybenzoyloxy).
1.01 g (3 of -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU133)
2%) was obtained. Melting point 161-163.5 [deg.] C.

IR (KBr, cm ^-1 ): 3517, 17
19, 1680, 1517, 1271, 1215, 75
8.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.13 (3H, s), 1.17 (3H, s),
1.89 (3H, t, J = 2Hz), 2.46 (1H,
d, J = 13 Hz), 2.67 (1H, d, J = 13H)
z), 3.54 (1H, d, J = 9 Hz), 3.95.
(3H, s), 3.96 (3H, s), 5.84 (1
H, dm, J = 9 Hz), 6.44 (1H, m), 6.
92 (1H, d, J = 8Hz), 7.58 (1H, d,
J = 2 Hz), 7.74 (1H, dd, J = 8, 2H
z).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and ethanol to give colorless plate crystals of 5- (3,4-dimethoxybenzoyloxy) -4-hydroxy-2,
0.87 g (28%) of 6,6-trimethyl-2-cyclohepten-1-one (AU134) was obtained. Melting point 15
0-151.5 ° C.

IR (KBr, cm ^-1 ): 3485, 17
07, 1669, 1598, 1518, 1279, 12
24,762.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.09 (3H, s), 1.21 (3H, s),
1.90 (3H, t, J = 2Hz), 2.48 (1H,
d, J = 13 Hz), 2.65 (1H, d, J = 13H)
z), 3.94 (3H, s), 3.95 (3H, s),
4.63 (1H, dm, J = 9Hz), 4.91 (1
H, d, J = 9 Hz), 6.55 (1 H, m), 6.9
2 (1H, d, J = 8Hz), 7.57 (1H, d, J
= 2 Hz), 7.72 (1H, dd, J = 8, 2H
z).

[0246]

Example 33 Cycin N (3.68 g, 20 mmol) was treated with 4-methoxybenzoyl chloride (4.27 g, 25 mmol) according to Example 17, eluting with hexane-ethyl acetate (10: 1). Fractionation was performed by silica gel column chromatography as a liquid, and the first eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 5-hydroxy-4- (4-methoxybenzoyloxy) -2,6 as colorless plate crystals. 2.44-g (38%) of 6-trimethyl-2-cyclohepten-1-one (AU195) was obtained. Melting point 108.5-110 [deg.] C.

IR (KBr, cm ^-1 ): 3517, 16
82, 1608, 1342, 1290, 1182, 11
06,774.

1H-NMR (CDCl ₃ , ppm):
1.12 (3H, s), 1.17 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.45 (1H, d, J
= 13 Hz), 2.67 (1H, d, J = 13 Hz),
3.55 (1H, dd, J = 9, 6Hz), 3.89
(3H, s), 5.83 (1H, dm, J = 9Hz),
6.43 (1H, m), 6.96 (2H, d, J = 9H
z), 8.06 (2H, d, J = 9 Hz).

From the subsequent eluate, 4-hydroxy-5- (4-methoxybenzoyloxy) -2,6, which is a pale yellow oil, is obtained.
6-trimethyl-2-cyclohepten-1-one (AU
202) was obtained in an amount of 1.63 g (25%).

IR (KBr, cm ^-1 ): 3474, 17
16, 1671, 1605, 1258, 1169, 11
02,768.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.07 (3H, s), 1.19 (3H, s),
1.88 (3H, t, J = 2Hz), 2.46 (1H,
d, J = 13 Hz), 2.63 (1H, d, J = 13H)
z), 3.87 (3H, s), 4.61 (1H, dm,
J = 9 Hz), 4.89 (1H, d, J = 9 Hz),
6.54 (1H, m), 6.94 (2H, d, J = 9H
z), 8.02 (2H, d, J = 9Hz).

[0252]

Example 34 5-hydroxy-obtained in Example 33
4- (4-methoxybenzoyloxy) -2,6,6-
Trimethyl-2-cyclohepten-1-one (796m
g, 2.5 mmol) was acetylated according to a conventional method, and crystallized from water to give colorless plate crystals of 5-acetoxy-4-.
(4-Methoxybenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU198)
867 mg (96%) was obtained. Melting point 93-94 [deg.] C.

IR (KBr, cm ^-1 ): 1749, 17
19, 1673, 1605, 1256, 770.

1H-NMR (CDCl ₃ , ppm):
1.04 (3H, s), 1.14 (3H, s), 1.8
1 (3H, s), 1.88 (3H, t, J = 2Hz),
2.51 (1H, d, J = 13Hz), 2.72 (1
H, d, J = 13 Hz), 3.87 (3H, s), 4.
99 (1H, d, J = 9 Hz), 6.01 (1H, d
m, J = 9 Hz), 6.41 (1H, m), 6.94
(2H, d, J = 9 Hz), 7.98 (2H, d, J =
9 Hz).

[0255]

Example 35 4-hydroxy-obtained in Example 33
5- (4-methoxybenzoyloxy) -2,6,6-
Trimethyl-2-cyclohepten-1-one (1.46
g, 4.5 mmol) was acetylated by a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give 4-acetoxy-5- (4-methoxybenzoyloxy) -2,6,6- Trimethyl-2-cyclohepten-1-one (AU203) 0.91 g (56
%)Obtained. Melting point 78-80 [deg.] C.

IR (KBr, cm ^-1 ): 1762,17
15,1672,1604,1259,1214,11
76, 1101, 1031, 850, 768.

1H-NMR (CDCl ₃ , ppm):
1.08 (3H, s), 1.23 (3H, s), 1.7
8 (3H, s), 1.89 (3H, t, J = 2Hz),
2.52 (1H, d, J = 13Hz), 2.73 (1
H, d, J = 13 Hz), 3.87 (3H, s), 5.
07 (1H, d, J = 9 Hz), 5.97 (1H, d
m, J = 9 Hz), 6.36 (1H, m), 6.94
(2H, d, J = 9 Hz), 7.98 (2H, d, J =
9 Hz).

[0258]

Example 36 Cycin N (3.68 g, 20 mmol) was treated with 3-nitrobenzoyl chloride (4.45 g, 24 mmol) as in Example 17 and hexane-
Purified by silica gel column chromatography using ethyl acetate (5: 1) as an eluent, and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless prism crystals of 5-hydroxy-4- (3-nitrobenzoyloxy). -2
1.79 g (24%) of 6,6-trimethyl-2-cyclohepten-1-one (AU200) was obtained. Melting point 13
1-133 ° C.

IR (KBr, cm ^-1 ): 3517, 17
18,1668,1534,1355,1288,12
68, 1144, 719.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.14 (3H, s), 1.17 (3H, s),
1.90 (3H, t, J = 2Hz), 2.48 (1H,
d, J = 13 Hz), 2.68 (1H, d, J = 13H)
z), 3.57 (1H, d, J = 9 Hz), 5.93
(1H, dm, J = 9Hz), 6.45 (1H, m),
7.71 (1H, t, J = 8Hz), 8.46 (2H,
m), 8.91 (1H, t, J = 2Hz).

[0261]

Example 37 Product of Example 36 (750 mg, 2.
3 mmol) was acetylated according to a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give 5-acetoxy-4- (3-nitrobenzoyloxy) as colorless needle crystals.
-2,6,6-Trimethyl-2-cycloheptene-1-
733 mg (83%) of on (AU204) was obtained. Melting point 108.5-110 [deg.] C.

IR (KBr, cm ^-1 ): 1742,16
66, 1538, 1350, 1263, 1133, 71
4.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.16 (3H, s), 1.8
7 (3H, s), 1.91 (3H, t, J = 2Hz),
2.56 (1H, d, J = 13Hz), 2.73 (1
H, d, J = 13 Hz), 5.07 (1H, d, J = 9)
Hz), 6.03 (1H, dm, J = 9 Hz), 6.3
8 (1H, m), 7.70 (1H, t, J = 8Hz),
8.35 (1H, m), 8.47 (1H, m), 8.8
8 (1H, m).

[0264]

Example 38 5-hydroxy-obtained in Example 36
4- (3-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (3.03
g, 8 mmol) in benzene (200 ml) was added with active iron (13 g), and heated under reflux with ethanol (2.2 g).
ml), water (0.5 ml) was added little by little, and the mixture was heated under reflux for 4 hours. After filtration, the filtrate was concentrated, and the residue was fractionated by silica gel column chromatography using hexane-ethyl acetate (2: 1) as an eluent, and 4- (3-aminobenzoyloxy) was obtained as a yellow oil from the first eluate. -5
-Hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU210) 1.27 g (52
%)Obtained.

IR (KBr, cm ^-1 ): 3450, 33
75, 1718, 1670, 1291, 1234, 75
2.

1H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.15 (3H, s), 1.8
7 (3H, s), 2.35 (1H, br), 2.44
(1H, d, J = 13Hz), 2.66 (1H, d, J
= 13 Hz), 3.53 (1H, d, J = 9 Hz),
3.85 (2H, br), 5.82 (1H, dm, J =
9 Hz), 6.40 (1 H, m), 6.90 (1 H,
m), 7.24 (1H, m), 7.38 (1H, m),
7.46 (1H, m).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 5- (3-
Aminobenzoyloxy) -4-hydroxy-2,6
6-trimethyl-2-cyclohepten-1-one (AU
209) was obtained in an amount of 0.89 g (37%). Melting point 121-1
23 ° C.

IR (KBr, cm ^-1 ): 3386, 33
26, 1717, 1654, 1285, 1233, 75
2.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.18 (3H, s), 1.8
7 (3H, t, J = 2Hz), 2.46 (1H, d, J
= 13 Hz), 2.52 (1H, br), 2.63 (1
H, d, J = 13 Hz), 3.84 (2H, br),
4.61 (1H, dm, J = 9Hz), 4.91 (1
H, d, J = 9 Hz), 6.51 (1H, m), 6.8
9 (1H, m), 7.23 (1H, t, J = 8Hz),
7.36 (1H, m), 7.45 (1H, m).

[0270]

Example 39 4- (3-Aminobenzoyloxy) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (970 m) obtained in Example 38
(3.2 g, 3.2 mmol) was dissolved in ethyl acetate, 4N hydrogen chloride / ethyl acetate solution was added, and the mixture was left standing overnight, and the precipitate was collected by filtration to obtain 990 mg (91%) of hydrochloride of the same compound.

Melting point 204-204.5 (decomposition).

IR (KBr, cm ^-1 ): 3282, 30
00-2500, 1712, 1664, 1290, 12
76,755.

[0273]

Example 40 5- (3-Aminobenzoyloxy) -4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (152 m) obtained in Example 38
g, 0.5 mmol) was acetylated by a conventional method to give 5- (3-acetaminobenzoyloxy)-as a colorless oil.
125 mg (65 of 4-acetoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU224)
%)Obtained.

IR (KBr, cm ^-1 ): 3362, 17
34, 1675, 1558, 1285, 1229, 75
4.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.23 (3H, s), 1.7
9 (3H, s), 1.89 (3H, t, J = 2Hz),
2.20 (3H, s), 2.53 (1H, d, J = 13
Hz), 2.73 (1H, d, J = 13Hz), 5.0
8 (1H, d, J = 9Hz), 5.96 (1H, dm,
J = 9 Hz), 6.37 (1 H, m), 7.42 (1
H, brt, J = 8 Hz), 7.74 (1H, brd,
J = 8 Hz), 7.95 (1H, brs), 8.06
(1H, brd, J = 8Hz).

[0276]

Example 41 Cycin N (1.84 g, 10 mmol) was treated according to Example 17 with cinnamoyl chloride (2.
00 g, 12 mmol) and fractionated by silica gel column chromatography using hexane-ethyl acetate (5: 1) as an eluent.
-Cinnamoyloxy-5-hydroxy-2,6,6-
Trimethyl-2-cyclohepten-1-one (AU20
6) was obtained 1.28 g (41%).

IR (KBr, cm ^-1 ): 3492, 17
11, 1674, 1636, 1165, 768.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.10 (3H, s), 1.15 (3H, s),
1.87 (3H, t, J = 2Hz), 2.43 (1H,
d, J = 13Hz), 2.64 (1H, d, J = 13H)
z), 3.48 (1H, d, J = 9 Hz), 5.72
(1H, dm, J = 9Hz), 6.38 (1H, m),
6.53 (1H, d, J = 16Hz), 7.41 (3
H, m), 7.56 (2H, m), 7.80 (1H,
d, J = 16 Hz).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 5-cinnamoyloxy-4-hydroxy-2,6,6-trimethyl-2-.
0.72 g of cyclohepten-1-one (AU205)
(22%) obtained. Melting point 85.5-87 [deg.] C.

IR (KBr, cm ^-1 ): 3482, 17
11, 1674, 1279, 769.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.08 (3H, s), 1.15 (3H, s),
1.89 (3H, t, J = 2Hz), 2.46 (1H,
d, J = 13 Hz), 2.62 (1H, d, J = 13H
z), 4.58 (1H, dm, J = 9Hz), 4.82
(1H, d, J = 9 Hz), 6.51 (1H, d, J =
16Hz), 6.53 (1H, m), 7.42 (3H,
m), 7.55 (2H, m), 7.77 (1H, d, J
= 16 Hz).

[0282]

Example 42 4-Cinnamoyloxy-5-hydroxy-2,6,6-trimethyl-2 obtained in Example 41
-Cyclohepten-1-one (0.98 g, 3.1 mmol) was acetylated by a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless plate crystals of 5-acetoxy-4-cinnamoyloxy-. 2,6,6-Trimethyl-2-cyclohepten-1-one (AU208)
Was obtained (0.98 g, 86%). Melting point 138-139 [deg.] C.

IR (KBr, cm ^-1 ): 1743, 17
18, 1675, 1633, 1310, 1232, 11
59,773.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.05 (3H, s), 1.14 (3H, s),
1.89 (3H, t, J = 2Hz), 2.00 (3H,
s), 2.51 (1H, d, J = 13Hz), 2.71
(1H, d, J = 13Hz), 4.95 (1H, d, J
= 9 Hz), 5.93 (1 H, dm, J = 9 Hz),
6.37 (1H, m), 6.44 (1H, d, J = 16
Hz), 7.42 (3H, m), 7.55 (2H,
m), 7.74 (1H, d, J = 16Hz).

[0285]

Example 43 5-Cinnamoyloxy-4-hydroxy-2,6,6-trimethyl-2 obtained in Example 41
-Cyclohepten-1-one (0.39 g, 1.2 mmol) was acetylated according to a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give 4-acetoxy-5-cinnamoyloxy- as colorless prism crystals. 2, 6, 6
-Trimethyl-2-cyclohepten-1-one (AU2
07) was obtained in an amount of 0.19 g (44%). Melting point 64-65
° C.

IR (KBr, cm ^-1 ): 1756,17
16, 1672, 1633, 1312, 1225, 11
58,769.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.18 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.01 (3H, s),
2.52 (1H, d, J = 13Hz), 2.70 (1
H, d, J = 13 Hz), 5.01 (1H, d, J = 9)
Hz), 5.88 (1H, dm, J = 9 Hz), 6.3
2 (1H, m), 6.45 (1H, d, J = 16H
z), 7.42 (3H, m), 7.56 (2H, m),
7.72 (1H, d, J = 16Hz).

[0288]

Example 44 Cycin N (1.84 g, 10 mmol) was treated with 4-nitrobenzoyl chloride (2.23 g, 12 mmol) according to Example 17 and crystallized twice from ethyl acetate to give a fine mixture. 5 of yellow prismatic crystals
-Hydroxy-4- (4-nitrobenzoyloxy)-
0.97 g (26%) of 2,6,6-trimethyl-2-cyclohepten-1-one (AU212) was obtained. Melting point 1
51-152.5 ° C.

IR (KBr, cm ^-1 ): 3556, 17
31, 1660, 1524, 1354, 1273, 11
05,722.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.14 (3H, s), 1.17 (3H, s),
1.90 (3H, t, J = 2Hz), 2.48 (1H,
d, J = 13 Hz), 2.68 (1H, d, J = 13H)
z), 3.55 (1H, d, J = 9 Hz), 5.91
(1H, dm, J = 9Hz), 6.43 (1H, m),
8.27 (2H, d, J = 9Hz), 8.34 (2H,
d, J = 9 Hz).

The above crystal mother liquor was concentrated and washed with ethyl acetate to obtain 2
Repeated crystallization twice to give slightly yellow needle crystals of 4-hydroxy-5- (4-nitrobenzoyloxy) -2,6,6-
Trimethyl-2-cyclohepten-1-one (AU21
0.99 g (26%) of 1) was obtained. Melting point 148-150
° C.

IR (KBr, cm ^-1 ): 3552, 17
16, 1674, 1522, 1349, 1275, 71
9.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.10 (3H, s), 1.23 (3H, s),
1.91 (3H, t, J = 2Hz), 2.50 (1H,
d, J = 13 Hz), 2.66 (1H, d, J = 13H)
z), 4.65 (1H, dm, J = 9Hz), 4.97.
(1H, d, J = 9Hz), 6.53 (1H, m),
8.25 (2H, d, J = 9Hz), 8.32 (2H,
d, J = 9 Hz).

[0294]

Example 45 5-hydroxy-obtained in Example 44
4- (4-Nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (751m
(2 g, 2 mmol) according to Example 38 to reduce the nitro group, and fractionated by silica gel column chromatography using hexane-ethyl acetate (2: 1) as an eluent. Crystallization from a mixed solvent of hexane to give 4- (4-aminobenzoyloxy) -5-hydroxy-2,6,6-trimethyl-2 as colorless prism crystals.
-Cyclohepten-1-one (AU215) 320m
g (53%) was obtained.

Melting point 152-153 ° C.

IR (KBr, cm ^-1 ): 3648, 35
24, 3437, 3360, 1685, 1672, 16
05,1273,770.

1H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.16 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.30 (1H, d, J
= 5 Hz), 2.43 (1H, d, J = 12 Hz),
2.66 (1H, d, J = 12Hz), 3.52 (1
H, dd, J = 9.5 Hz, 4.14 (2H, br
s), 5.79 (1H, dm, J = 9Hz), 6.42
(1H, m), 6.66 (2H, d, J = 9Hz),
7.90 (2H, d, J = 9Hz).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 5- (4-aminobenzoyloxy) -4-hydroxy-2,6,6-trimethyl-2-cycloheptene-1. -On (AU216)
225 mg (37%) was obtained. Melting point 169.5-171
° C.

IR (KBr, cm ^-1 ): 3460, 33
66, 3234, 1676, 1633, 1600, 12
79, 1170.

1 H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.19 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.45 (1H, d, J
= 13 Hz), 2.51 (1H, brd, J = 7H
z), 2.63 (1H, d, J = 13 Hz), 4.14
(2H, brs), 4.61 (1H, brs), 4.8
7 (1H, d, J = 9Hz), 6.55 (1H, m),
6.66 (2H, d, J = 9Hz), 7.88 (2H,
d, J = 9 Hz).

[0301]

Example 46 4-hydroxy-obtained in Example 44
5- (4-Nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one was prepared in Example 45.
Similarly to Example 45, 4- (4-aminobenzoyloxy) -5-hydroxy-2,6,6-
Trimethyl-2-cyclohepten-1-one (AU21
5) and 5- (4-aminobenzoyloxy) -4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU216).

[0302]

Example 47 5-hydroxy-obtained in Example 44
4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (3.33
g, 10 mmol) in ethyl acetate (30 ml) was added with platinum oxide (0.1 g) for catalytic reduction, the catalyst was filtered off and treated in the same manner as in Example 45 to give 4-.
(4-Aminobenzoyloxy) -5-hydroxy-
2.53 g (76%) of 2,6,6-trimethyl-2-cyclohepten-1-one (AU215) was obtained.

[0303]

Example 48 5-hydroxy-obtained in Example 44
4- (4-Nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (638m
g, 2 mmol) was acetylated according to a conventional method and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless acetic crystals of 5-acetoxy-4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-. 2-cycloheptene-
683 mg (91%) of 1-one (AU196) was obtained.
Melting point 147-147.5 [deg.] C.

IR (KBr, cm ^-1 ): 1735, 17
22, 1685, 1523, 1282, 1234, 71
8.

1 H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.15 (3H, s), 1.8
4 (3H, s), 1.91 (3H, t, J = 2Hz),
2.55 (1H, d, J = 13Hz), 2.72 (1
H, d, J = 13 Hz), 5.05 (1 H, d, J = 9)
Hz), 6.03 (1H, dm, J = 9 Hz), 6.3
6 (1H, m), 8.21 (2H, d, J = 9Hz),
8.33 (2H, d, J = 9Hz).

[0306]

Example 49 The product of Example 48 (210 mg, 0.
The nitro group was reduced in the same manner as in Example 38 and crystallized from a mixed solvent of benzene and hexane to give 5-acetoxy-4- (4-aminobenzoyloxy) -2,6,6 as colorless needle crystals. 175 mg (94%) of trimethyl-2-cyclohepten-1-one (AU197)
Obtained. Melting point 158.5-160 [deg.] C.

IR (KBr, cm ^-1 ): 3463, 33
80, 3246, 1747, 1701, 1673, 16
28, 1601, 1267.

1H-NMR (CDCl ₃ , ppm):
1.05 (3H, s), 1.14 (3H, s), 1.8
3 (3H, s), 1.89 (3H, t, J = 2Hz),
2.50 (1H, d, J = 13Hz), 2.73 (1
H, d, J = 13 Hz), 4.13 (2H, brs; disappeared by adding heavy water), 4.98 (1H, d, J = 9H)
z), 6.00 (1H, dm, J = 9Hz), 6.42
(1H, m), 6.66 (2H, d, J = 9Hz),
7.84 (2H, d, J = 9Hz).

[0309]

Example 50 5-hydroxy-obtained in Example 44
4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (1.67
Dihydropyran (4.5 ml) and p-toluenesulfonic acid (0.1 g) were added to a tetrahydrofuran (5 ml) solution of g, 5 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with diluted aqueous potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate,
After filtration, concentration, and crystallization from hexane, colorless needle-like crystals of 5-tetrahydropyranyloxy-4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one were obtained. Obtained 97 g (94%). Melting point 133.5-135 [deg.] C.

IR (KBr, cm ^-1 ): 1721,16
78, 1524, 1280, 720.

The above product (1.79 g, 4.7 mmol) was reduced in the nitro group according to Example 19 and purified by silica gel column chromatography using hexane-ethyl acetate (5: 1) as an eluent. And colorless oily 4- (4
1.28 g (62%) of -aminobenzoyloxy) -5-tetrahydropyranyloxy-2,6,6-trimethyl-2-cyclohepten-1-one was obtained.

The above product (2.88 g, 66 mmol)
Was dissolved in acetic anhydride (15 ml), and concentrated sulfuric acid (2
(Droplet) was added, and the mixture was returned to room temperature and stirred for 2 hours. Ice water was added to the reaction solution and the mixture was stirred, then extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane,
4- (4-acetaminobenzoyloxy) -5-hydroxy-2,6,6-trimethyl-2 as pale yellow needle crystals
-Cyclohepten-1-one (AU237) was 1.47.
g (62%) was obtained. Melting point 133.5-135.0 [deg.] C.

IR (KBr, cm ^-1 ): 3355, 17
11, 1678, 1600, 1538, 1273, 11
10.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.15 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.21 (3H, s),
2.32 (1H, d, J = 6Hz), 2.44 (1H,
d, J = 13 Hz), 2.66 (1H, d, J = 13H)
z), 3.53 (1H, dd, J = 9, 6 Hz), 5.
81 (1H, dm, J = 9Hz), 6.41 (1H,
m), 7.46 (1H, brs), 7.62 (2H,
d, J = 9 Hz), 8.04 (2H, d, J = 9H)
z).

[0315]

Example 51 Cycin N (1.84 g, 10 mmol) was treated with 2-methoxybenzoyl chloride (2.05 g, 25 mmol) according to Example 17, eluting with hexane-ethyl acetate (5: 1). Fractionation was performed by silica gel column chromatography as a liquid, and 5-hydroxy-4- (2-methoxybenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one was obtained as a colorless oil from the first eluate. 1.57 g (49%) of (AU214)
Obtained.

IR (KBr, cm ^-1 ): 3510, 17
19, 1675, 1602, 1299, 1250, 10
99,757.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.10 (3H, s), 1.19 (3H, s),
1.85 (3H, t, J = 2Hz), 2.42 (1H,
d, J = 12 Hz), 2.64 (1H, d, J = 12H)
z), 3.54 (1H, d, J = 9 Hz), 3.94
(3H, s), 5.75 (1H, dm, J = 9Hz),
6.38 (1H, m), 7.02 (1H, brd, J =
8Hz), 7.08 (1H, brd, J = 7Hz),
7.53 (1H, m), 7.86 (1H, dd, J =
7.2 Hz).

From the subsequent eluate, colorless oily 4-hydroxy-5- (2-methoxybenzoyloxy) -2,6,6 was obtained.
-Trimethyl-2-cyclohepten-1-one (AU2
13) was obtained in an amount of 1.53 g (47%).

IR (KBr, cm ^-1 ): 3501,17
18,1670,1602,1302,1253,75
8.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.06 (3H, s), 1.13 (3H, s),
1.88 (3H, t, J = 2Hz), 2.44 (1H,
d, J = 13 Hz), 2.65 (1H, d, J = 13H)
z), 3.93 (3H, s), 4.66 (1H, dm,
J = 9 Hz), 4.93 (1H, d, J = 9 Hz),
6.55 (1H, m), 7.01 (1H, brd, J =
8Hz), 7.05 (1H, brd, J = 7Hz),
7.51 (1H, m), 7.75 (1H, dd, J =
7.2 Hz).

[0321]

Example 52 Cycin N (2.40 g, 13 mmol) was treated with 2-chloro-4-nitrobenzoyl chloride (3.74 g, 17 mmol) according to Example 17, hexane-ethyl acetate (5: Fractionation was performed by silica gel column chromatography using 1) as an eluent, and the first eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 4- (2-chloro-4-nitrobenzoyloxy) -5 as a colorless powder. -Hydroxy-2,6,6-trimethyl-2
-Cyclohepten-1-one (AU219) was 1.45.
g (30%) was obtained. Melting point 108-109.5 [deg.] C.

IR (KBr, cm ^-1 ): 3502, 17
38, 1676, 1528, 1351, 1242, 73
4.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.13 (3H, s), 1.17 (3H, s),
1.89 (3H, t, J = 2Hz), 2.47 (1H,
d, J = 13 Hz), 2.65 (1H, d, J = 13H)
z), 3.55 (1H, d, J = 9 Hz), 5.90
(1H, dm, J = 9Hz), 6.40 (1H, m),
8.07 (1H, d, J = 8Hz), 8.20 (1H,
dd, J = 8, 2 Hz), 8.36 (1H, d, J = 2)
Hz).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless powder of 5- (2-chloro-4-).
Nitrobenzoyloxy) -4-hydroxy-2,6
6-trimethyl-2-cyclohepten-1-one (AU
220) was obtained (1.06 g, 22%). Melting point 221-2
22 ° C.

IR (KBr, cm ^-1 ): 3568, 17
18, 1675, 1523, 1354, 1273, 73
5.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.14 (3H, s), 1.15 (3H, s),
1.90 (3H, t, J = 2Hz), 2.50 (1H,
d, J = 13Hz), 2.64 (1H, d, J = 13H)
z), 4.64 (1H, dm, J = 9Hz), 5.02
(1H, d, J = 9Hz), 6.51 (1H, m),
8.00 (1H, d, J = 8Hz), 8.19 (1H,
dd, J = 8, 2 Hz), 8.36 (1H, d, J = 2)
Hz).

[0327]

Example 53 Cycin N (3.68 g, 20 mmol) was treated with 4-dimethylaminobenzoyl chloride hydrochloride according to Example 17, silica gel column eluting with hexane-ethyl acetate (5: 1). It was purified by chromatography and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 4- (4-dimethylaminobenzoyloxy) -5-hydroxy-2,6,6-.
Trimethyl-2-cyclohepten-1-one (AU23
6) was obtained (0.67 g, 10%). Melting point 162-163
° C.

IR (KBr, cm ^-1 ): 3517, 16
73, 1616, 1286, 1190, 1116, 82
8,770.

1H-NMR (CDCl ₃ , ppm):
1.12 (3H, s), 1.16 (3H, s), 1.8
7 (3H, t, J = 2Hz), 2.39 (1H, br
d), 2.44 (1H, d, J = 13 Hz), 2.67
(1H d, J = 13 Hz), 3.07 (6H, s),
3.51 (1H, dd, J = 9.5Hz), 5.79
(1H, dm, J = 9Hz), 6.44 (1H, m),
6.67 (2H, d, J = 9Hz), 7.95 (2H,
d, J = 9 Hz).

[0330]

Example 54 Cycin N (5 g, 27 mmol) was treated with 4-nitrocinnamoyl chloride according to Example 17, and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 5-hydroxy-. 7.50 g (7) of 4- (4-nitrocinnamoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU150)
7%) was obtained. Melting point 172-173 ° C IR (KBr, cm
^-1 ): 3529,1709,1669,1516,13
45, 1178, 848.

1H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.16 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.16 (1H, br
d, J = 5 Hz; disappeared by addition of heavy water), 2.45 (1
H, d, J = 13 Hz), 2.65 (1H, d, J = 1)
3 Hz), 3.48 (1 H, dd, J = 9.5 Hz; d by heavy water addition, J = 9 Hz), 5.75 (1 H, d
m, J = 9 Hz), 6.36 (1H, m), 6.64
(1H, d, J = 16Hz), 7.71 (2H, d, J
= 9 Hz), 7.82 (1H, d, J = 16 Hz),
8.28 (2H, d, J = 9Hz).

[0332]

Example 55 The product of Example 54 (6.5 g, 18.
1 mmol) to reduce the nitro group in the same manner as in Example 19,
Fractionation was performed by silica gel column chromatography using hexane-ethyl acetate (2: 1) as an eluent, and 4- (4-aminocinnamoyloxy) -5-hydroxy-2,6 was obtained as a yellow glass from the first eluate. , 6-trimethyl-2-
2.55 g of cyclohepten-1-one (AU401)
(43%) obtained. Melting point 72-74 [deg.] C.

IR (KBr, cm ^-1 ): 3452, 33
65, 3234, 1699, 1675, 1596, 15
18, 1156.

1H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.15 (3H, s), 1.8
5 (3H, t, J = 2Hz), 2.34 (1H, br
d, J = 4 Hz; disappeared by adding heavy water), 2.42 (1
H, d, J = 12 Hz), 2.64 (1H, d, J = 1)
2 Hz), 3.46 (1 H, dd, J = 9, 4 Hz; d, J = 9 Hz by addition of heavy water), 5.69 (1 H, d
m, J = 9 Hz), 6.29 (1H, d, J = 16H)
z), 6.37 (1H, m), 6.66 (1H, d, J
= 9 Hz), 7.37 (1H, d, J = 9 Hz), 7.
69 (1H, d, J = 16Hz). From the subsequent elution part, yellow glassy 5- (4-aminocinnamoyloxy) -4
2.55 g (43%) of -hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU402).
%)Obtained. Melting point 49-50 [deg.] C.

IR (KBr, cm ^-1 ): 3459, 33
65, 3233, 1699, 1669, 1623, 15
97, 1518, 1159.

1H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.13 (3H, s), 1.8
7 (3H, t, J = 2Hz), 2.43 (1H, d, J
= 13 Hz), 2.61 (1H, d, J = 13 Hz),
4.04 (1H, brd, J = 4Hz; disappeared by addition of heavy water), 4.56 (1H, dm, J = 9Hz), 4.7
9 (1H, d, J = 9Hz), 6.29 (1H, d, J
= 16 Hz), 6.54 (1 H, m), 6.66 (1
H, d, J = 8Hz), 7.37 (1H, d, J = 8H)
z), 7.66 (1H, d, J = 16Hz).

[0337]

Example 56 Cycin N (5.0 g, 27 mmol)
Was treated with 2-furoic acid chloride according to Example 17, and fractionated by silica gel column chromatography using benzene-ethyl acetate (25: 1) as an eluent. (2-Furoyloxy)-
1.36 g (18) of 5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU403)
%)Obtained.

IR (KBr, cm ^-1 ): 3500, 17
32, 1715, 1682, 1668, 1471.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.16 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.29 (1H, d, J
= 5 Hz; disappeared by adding heavy water), 2.44 (1H,
d, J = 13 Hz), 2.65 (1H, d, J = 13H)
z), 3.53 (1H, dd, J = 9.5 Hz; d, J = 9 Hz by addition of heavy water), 5.80 (1H, dm, J
= 9 Hz), 6.41 (1H, m), 6.57 (1H,
dd, J = 3, 2 Hz), 7.30 (1H, dd, J =
3,1Hz), 7.62 (1H, dd, J = 2,1H
z).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 5- (2-furoyloxy) -4-hydroxy-2,6,6-trimethyl-.
2-Cyclohepten-1-one (AU404) 1.3
Obtained 6 g (18%). Melting point 102.5-103.5 [deg.] C.

IR (KBr, cm ^-1 ): 3508, 31
18, 1712, 1674, 1474, 1306, 11
86, 1129.

1H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.16 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.31 (1H, d, J
= 7 Hz; disappeared by adding heavy water), 2.46 (1H,
d, J = 13Hz), 2.64 (1H, d, J = 13H)
z), 4.63 (1H, m; dm by addition of heavy water),
4.88 (1H, d, J = 9Hz), 6.52 (1H,
m), 6.55 (1H, m), 7.25 (1H, m),
7.63 (1H, m).

[0343]

Example 57 Cycin N (5.53 g, 30 mmol) in methylene chloride (50 ml) in DCC (6.8).
1 g, 33 mmol) and 4-dimethylaminopyridine (50 mg) were added, 4-nitrobenzoic acid (5.51 g, 33 mmol) was added with stirring at 0 ° C., and the mixture was stirred for 4 hours and filtered to obtain a filtrate. .. The residue was extracted with warm ethyl acetate (200 ml) at 40 ° C., combined with the above filtrate, concentrated and crystallized from ethyl acetate to give 5
-Hydroxy-4- (4-nitrobenzoyloxy)-
There was obtained 6.67 g (66%) of 2,6,6-trimethyl-2-cyclohepten-1-one (AU212).

[0344]

Example 58 4-Aminobenzoic acid (5.35 g, 39 mmol) and DCC (8.05) were added to a solution of Cycin N (5.53 g, 30 mmol) in methylene chloride (30 ml).
g, 39 mmol) and 4-dimethylaminopyridine (0.15 g) were added, and the mixture was stirred at 0 ° C. for 10 hours and then filtered.
After washing with ethyl acetate, the filtrate and washings were combined and concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (2: 1) as an eluent, then crystallized from ethyl acetate to give Example 45. The resulting 4- (4-aminobenzoyloxy) -5-hydroxy-2,2,6-
Trimethyl-2-cyclohepten-1-one (AU21
5.52 g (61%) of 5) was obtained.

[0345]

Example 59 Cycin N (9.21 g, 50 mmol) was treated with 3,4-diaminobenzoic acid (12.93 g, 85 mmol) according to Example 20, hexane-
Purified by silica gel column chromatography using ethyl acetate (1: 1) as an eluent, and crystallized from a mixed solvent of ethyl acetate and hexane to give slightly orange crystals of 4- (3,4-diaminobenzoyloxy) -5-hydroxy. -2,6
6-trimethyl-2-cyclohepten-1-one (AU
240) was obtained (6.21 g, 41%). Melting point 136-1
37 ° C.

IR (KBr, cm ^-1 ): 3475, 33
54, 3272, 1690, 1668, 1314, 12
80, 1218.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.14 (3H, s), 1.8
5 (3H, t, J = 2Hz), 2.42 (1H, d, J
= 13 Hz), 2.65 (1H, d, J = 13 Hz),
3.50 (1H, d, J = 9Hz), 5.78 (1H,
dm, J = 9 Hz), 6.40 (1H, m), 6.69
(1H, d, J = 8Hz), 7.43 (1H, d, J =
2Hz), 7.51 (1H, dd, J = 8, 2Hz).

[0348]

Example 60 Cycin N (3.68 g, 20 mmol) was treated according to Example 20 with 2,4-dinitrobenzoic acid (6.79 g, 32 mmol), followed by nitro according to Example 19. The group was reduced and fractionated by silica gel column chromatography using hexane-ethyl acetate (3: 2) as an eluent. The first eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 4- (brown powder). 2,4-
Diaminobenzoyloxy) -5-hydroxy-2,
1.65 g (26%) of 6,6-trimethyl-2-cyclohepten-1-one (AU242) was obtained. Melting point 15
4-156 ° C IR (KBr, cm ^-1 ): 3467,3378,166
8, 1619, 1257.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.15 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.40 (1H, br
s; disappeared by addition of heavy water), 2.43 (1H, d, J =
12Hz), 2.65 (1H, d, J = 12Hz),
3.52 (1H, dd, J = 9, 2Hz; d, J = 9Hz by addition of heavy water), 3.99 (2H, br; disappear by addition of heavy water), 5.72 (2H, br; disappear by addition of heavy water) ), 5.75 (1H, dm, J = 9 Hz), 5.8
7 (1H, d, J = 2Hz), 6.00 (1H, dd,
J = 9, 2 Hz), 6.40 (1 H, m), 7.71
(1H, d, J = 9 Hz).

The subsequent eluate was crystallized from ethyl acetate to give yellow needle crystals of 5- (2,4-diaminobenzoyloxy) -4-hydroxy-2,6,6-trimethyl-2-.
1.63 g of cyclohepten-1-one (AU241)
(26%) obtained. Melting point 185-186.5 [deg.] C. IR (KBr, cm ^-1 ): 3481, 3363, 330
0,1672,1661,1625,1251.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.18 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.44 (1H, d, J
= 13 Hz), 2.55 (1H, d, J = 6 Hz),
2.63 (1H, d, J = 13Hz), 3.97 (2
H, br), 4.62 (1H, m), 4.84 (1H,
d, J = 9 Hz), 5.71 (2H, br), 5.87
(1H, d, J = 2Hz), 6.00 (1H, dd, J
= 9, 2 Hz), 6.57 (1 H, m), 7.71 (1
H, d, J = 9 Hz).

[0352]

Example 61 Cycin N (5.0 g, 27.1 mmol) was treated with 3-methoxy-4-tetrahydropyranyloxycinnamic acid (9.82 g, 35.3 mmol) according to Example 20; Fractionation was carried out by reverse phase column chromatography (Chromatorex ODS; Fuji Davison) using 50% to 70% methanol as an eluent, and hexane-
Fractionation was performed by silica gel column chromatography using ethyl acetate (4: 1) as an eluent, and colorless glassy 5-hydroxy-4- (3-methoxy-4-tetrahydropyranyloxycinnamoyloxy) was collected from the first eluate. ) -2,
4.10 g (34%) of 6,6-trimethyl-2-cyclohepten-1-one was obtained. Further, from the subsequent elution portion, colorless glassy 4-hydroxy-5- (3-methoxy-4-) was obtained.
Tetrahydropyranyloxy cinnamoyloxy)-
4.10 g (34%) of 2,6,6-trimethyl-2-cyclohepten-1-one was obtained.

The first eluted component (2.0 g, 4.5 mmol) was dissolved in tetrahydrofuran (20 ml), 1N hydrochloric acid (10 ml) was added under ice-cooling stirring, and the mixture was stirred for 3 hours and diluted with ethyl acetate. , After washing with water, drying, filtration and concentration,
Purified by silica gel column chromatography using hexane-ethyl acetate (4: 1) as an eluent, and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals of 5-
1.21 g (7) of hydroxy-4- (4-hydroxy-3-methoxycinnamoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU416)
4%) was obtained. Melting point 141.5-142.5 [deg.] C. IR (KBr, cm < ^-1 >): 3482, 3283, 173.
0,1719,1650,1631,1595,152
1,1155.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.15 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.26 (1H, d, J
= 5 Hz; disappears by adding heavy water), 2.43 (1H,
d, J = 12 Hz), 2.65 (1H, d, J = 12H)
z), 3.47 (1H, dd, J = 9, 5 Hz; d, J = 9 Hz by addition of heavy water), 3.94 (3H, s),
5.71 (1H, dm, J = 9Hz), 5.91 (1
H, s; disappeared by addition of heavy water), 6.36 (1H, d,
J = 16 Hz), 6.37 (1 H, m), 6.94 (1
H, d, J = 8Hz, 7.05 (1H, d, J = 2H)
z), 7.10 (1H, dd, J = 8, 2Hz), 7.
47 (1H, t, J = 16Hz).

The second eluted component (3.4 g, 7.6 mmol) was treated as above to give colorless needle crystals of 4-hydroxy-5- (4-hydroxy-3-methoxycinnamoyloxy). 2.19 g (79) of 2,2,6,6-trimethyl-2-cyclohepten-1-one (AU414).
%)Obtained. Melting point 125-127 [deg.] C.

IR (KBr, cm ^-1 ): 3500-32
00, 1737, 1710, 1668, 1631, 16
02,1514,1281,1159. 1H-NMR (CDCl ₃ , ppm): 1.07 (3
H, s), 1.14 (3H, s), 1.88 (3H,
t, J = 2 Hz), 2.35 (1H, d, J = 7 Hz;
Disappeared by addition of heavy water), 2.44 (1H, d, J = 13)
Hz), 2.62 (1H, d, J = 13 Hz), 3.9
5 (3H, s), 4.57 (1H, m), 4.81 (1
H, d, J = 9 Hz), 5.90 (1 H, s; disappeared by adding heavy water), 6.35 (1 H, d, J = 16 Hz),
6.54 (1H, m, J = 2Hz), 6.93 (1H,
d, J = 8 Hz), 7.05 (1H, d, J = 2H
z), 7.11 (1H, dd, J = 8, 2Hz), 7.
68 (1H, d, J = 16Hz).

[0357]

Example 62 Cycin N (1.84 g, 10 mmol) with methylene chloride (10 ml) and pyridine (1.1).
2 ml) was mixed with 1-methyl-2-pyrrolecarboxylic acid (1.25 g, 12 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (2.03 g, 12 mmol) under ice-cooling stirring. After adding, the mixture was stirred overnight at room temperature, the reaction solution was filtered and concentrated, and the residue obtained was purified by silica gel column chromatography using a mixed solution of benzene-ethyl acetate as an eluent, and a mixed solvent of ethyl acetate and hexane. Is crystallized from 4- (1-methyl-2-pyrrolylcarbonyloxy) -5-hydroxy-2,6,6-trimethyl-2-cycloheptene-1
1.97 g (67.7%) of -one (AU501) was obtained. Melting point 141.0-141.5 [deg.] C.

IR (KBr, cm ^-1 ): 3406, 16
84, 1656, 1115, 740.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.15 (3H, s), 1.8
6 (3H, t, J = 2Hz), 2.34 (1H, d, J
= 4 Hz), 2.43 (1H, d, J = 12 Hz),
2.64 (1H, d, J = 12Hz), 3.51 (1
H, dd, J = 9.5Hz), 3.96 (3H, s),
5.74 (1H, dm, J = 9Hz), 6.15 (1
H, dd, J = 4,2 Hz), 6.38 (1H, m),
6.86 (1H, t, J = 2Hz), 7.02 (1H,
dd, J = 4, 2 Hz).

[0360]

Example 63 Cycin N (1.84 g, 10 mmol) was treated according to Example 20 with 5-methyl-4-imidazolecarboxylic acid (1.51 g, 12 mmol),
Fractionation was performed by silica gel column chromatography using hexane-ethyl acetate (3: 1) as an eluent, and the first eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless powder of 5-hydroxy-4- (. 5-Methyl-4-imidazolylcarbonyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU503) was added to 0.
81 g (28%) were obtained. Melting point 99-101 [deg.] C.

IR (KBr, cm ^-1 ): 3600-25
00, 1709, 1673, 1100.

1 H-NMR (CDCl ₃ , ppm):
1.13 (3H, s), 1.16 (3H, s), 1.8
3 (3H, t, J = 2Hz), 2.43 (1H, d, J
= 12 Hz), 2.46 (3 H, s), 2.64 (1
H, d, J = 12 Hz), 3.52 (1H, d, J = 9)
Hz), 5.72 (1H, brd), 6.34 (1H,
m), 7.50 (1H, s).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 4-hydroxy-5-colorless powder.
(5-Methyl-4-imidazolylcarbonyloxy)-
0.32 g (11%) of 2,6,6-trimethyl-2-cyclohepten-1-one (AU504) was obtained. Melting point 2
01-202 ° C.

IR (KBr, cm ^-1 ): 3448, 31
00-2400, 1708, 1668.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.15 (3H, s), 1.8
8 (3H, t, J = 2Hz), 2.54 (1H, d, J
= 13 Hz), 2.56 (3 H, s), 2.62 (1
H, d, J = 13 Hz), 4.10 (1H, dm, J
= 9 Hz), 5.12 (1H, d, J = 9 Hz), 6.
47 (1H, m), 7.65 (1H, s).

[0366]

Example 64 Cycin N (3.68 g, 20 mmol) and 4-tetrahydropyranyloxybenzoic acid (7.
0 g, 30 mmol) was condensed according to Example 20 to give 5
There was obtained 4.93 g (63.5%) of -hydroxy-4- (4-tetrahydropyranyloxybenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one. This compound (2.0 g, 5 mmol) was hydrolyzed according to Example 61 and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless powder of 5-hydroxy-4- (4-hydroxybenzoyloxy) -2. , 6,6-Trimethyl-2-cyclohepten-1-one (AU505) was added to 0.
Obtained 3 g (20%). Melting point 123-125 [deg.] C.

IR (KBr, cm ^-1 ): 3405, 17
12, 1656, 1611, 1267, 1099.

1H-NMR (DMSO-d ₆ , pp
m): 0.96 (3H, s), 1.00 (3H, s),
1.77 (3H, brs), 2.32 (1H, d, J =
13Hz), 2.68 (1H, d, J = 13Hz),
3.31 (1H, dd, J = 9, 6Hz), 5.46
(1H, d, J = 6Hz), 5.72 (1H, dm, J
= 9 Hz), 6.48 (1H, m), 6.86 (2H,
d, J = 9 Hz), 7.92 (2H, d, J = 9H)
z), 10.3 (1H, brs).

[0369]

Example 65 Cycin N (1.84 g, 10 mmol) and 4-tetrahydropyranyloxycinnamic acid (2.9
(8 g, 12 mmol) was treated according to Example 61 to give 5 colorless colorless crystals from a mixed solvent of ethyl acetate and hexane.
-Hydroxy-4- (4-hydroxycinnamoyloxy) -2,6,6-trimethyl-2-cycloheptene-
0.29 g (18%) of 1-one (AU506) was obtained.
Melting point 176-177 [deg.] C.

IR (KBr, cm ^-1 ): 3386, 31
00-2400, 1713, 1654, 1608, 15
16, 1279, 1158.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.15 (3H, s), 1.8
7 (3H, t, J = 2Hz), 2.43 (1H, d, J
= 12 Hz), 2.65 (1H, d, J = 12 Hz),
3.48 (1H, d, J = 9Hz), 5.72 (1H,
dm, J = 9 Hz), 6.33 (1H, d, J = 16H)
z), 6.39 (1H, m), 6.86 (2H, d, J
= 9 Hz), 7.42 (2H, d, J = 9 Hz), 7.
71 (1H, d, J = 16Hz).

[0372]

Example 66 4-Acetoxybenzoic acid (2.16 g, 12 mmol) and iodide 2 were added to a solution of Cycin N (1.84 g, 10 mmol) in methylene chloride (20 ml).
Chloro-1-methylpyridinium (3.07 g, 12 mmol) and triethylamine (3.37 ml, 24
(Mmol) and stirred at room temperature for 7 days, then added water and extracted with ethyl acetate, washed successively with diluted hydrochloric acid, saturated saline, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (5: 1) as an eluent, and crystallized from a mixed solvent of hexane and ethyl acetate to give colorless needle crystals of 4- (4-acetoxybenzoyloxy). 0.85 g (25%) of -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU217) was obtained. Melting point 132-133 [deg.] C.

IR (KBr, cm ^-1 ): 3514, 17
44, 1731, 1675, 1262, 1228, 11
02.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.13 (3H, s), 1.17 (3H, s),
1.89 (3H, t, J = 2Hz), 2.34 (3H,
s), 2.46 (1H, d, J = 13 Hz), 2.67
(1H, d, J = 13Hz), 3.54 (1H, d, J
= 9 Hz), 5.86 (1H, dm, J = 9 Hz),
6.42 (1H, m), 7.23 (2H, d, J = 9H
z), 8.13 (2H, d, J = 9Hz).

[0375]

Example 67 5-Benzoyloxy-4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 7 (0.9 g, 2.4 mmol)
Manganese dioxide (5.5 g) was added to a methylene chloride (20 ml) solution of the above, and the mixture was stirred at room temperature for 2 days, filtered, and concentrated. Purified by the method described above to give colorless plate crystals of 5-benzoyloxy-2,6,6.
0.47 g (69%) of -trimethyl-2-cycloheptene-1,4-dione (AU225) was obtained. Melting point 6
8-68.5 ° C.

IR (KBr, cm ^-1 ): 1720, 16
87, 1274, 1110, 716.

1H-NMR (CDCl ₃ , ppm):
1.27 (6H, s), 2.01 (3H, t, J = 2H
z), 2.69 (1H, d, J = 13Hz), 2.71
(1H, d, J = 13 Hz), 5.10 (1H, s),
6.46 (1H, m), 7.47 (2H, m), 7.6
0 (1H, m), 8.01 (2H, m).

[0378]

Example 68 Pyridinium chlorochromate (1.7
2 g, 8 mmol) and Celite (1.5 g) were added to methylene chloride (40 ml) and the 4-benzoyloxy-5-hydroxy-2,6,6-trimethyl-obtained in Example 30 was stirred at room temperature. 2-cycloheptene-1-
On (0.577 g, 2 mmol) methylene chloride (5
(ml) solution was added dropwise and stirred for 8 hours. Ether (50 ml) and anhydrous magnesium sulfate were added to the reaction solution, and the mixture was left for 30 minutes, filtered and concentrated, the residue was extracted with ether, and thin-layer chromatography (Merck) using hexane-ethyl acetate (3: 1) as a developing solution. 5744), and crystallized from a mixed solution of ethyl acetate and hexane to give 4-
Add benzoyloxy-2,6,6-trimethyl-2-cycloheptene-1,5-dione (AU226) to 0.30
g (69%) was obtained. Melting point 91-92 [deg.] C.

IR (KBr, cm ^-1 ): 1736, 17
21, 1670, 1274, 1122.

1H-NMR (CDCl ₃ , ppm):
1.17 (3H, s), 1.36 (3H, s), 1.9
4 (3H, d, J = 2Hz), 2.74 (1H, d, J
= 14 Hz), 3.27 (1H, d, J = 14 Hz),
6.63 (2H, m), 7.47 (2H, m), 7.6
2 (1H, m), 8.13 (2H, m).

[0380]

Example 69 5-hydroxy-4 obtained in Example 1
-(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (21.3 g,
70 mmol) in ethanol (60 ml) in N, N
-Dimethylhydrazine (15.9 ml, 210 mmol) and acetic acid (3 ml) were added, heated under reflux for 5 hours, concentrated, and purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent. 13.35 g (55%) of orange oily dimethylhydrazone was obtained.

The above dimethylhydrazone (5.20 g, 1
5 mmol) in tetrahydrofuran (30 ml) in 55% sodium hydride (0.79 g, 18 mmol).
And methyl iodide (1.43 ml, 23 mmol) were added, the mixture was stirred at room temperature for 6 hours, poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Then, the residue was fractionated by silica gel column chromatography using hexane-ethyl acetate (20: 1-5: 1) as an eluent to give two stereoisomers of 5-methoxy-4- (4-methoxybenzyl). Oxy)-
3.14 g (58%) of 2,6,6-trimethyl-2-cyclohepten-1-one dimethylhydrazone, respectively.
%) And 0.78 g (14.4%).

1H-NMR (CDCl ₃ , ppm):
0.99 (3H, s), 1.02 (3H, s), 1.9
2 (3H, t, J = 2Hz), 2.05 (1H, d, J
= 14 Hz), 2.41 (6 H, s), 2.92 (1
H, d, J = 8 Hz), 3.00 (1H, d, J = 14)
Hz), 3.55 (3H, s), 3.80 (3H,
s), 4.08 (1H, m), 4.59 (1H, d, J
= 11 Hz), 4.68 (1H, d, J = 11 Hz),
6.01 (1H, m), 6.87 (2H, d, J = 9H
z), 7.31 (2H, d, J = 9Hz).

1H-NMR (CDCl ₃ , ppm):
0.98 (3H, s), 1.10 (3H, s), 1.9
4 (3H, t, J = 2Hz), 2.11 (1H, d, J
= 13 Hz), 2.21 (1H, d, J = 13 Hz),
2.47 (6H, s), 2.90 (1H, d, J = 8H
z), 3.56 (3H, s), 3.80 (3H, s),
3.96 (1H, m), 4.56 (1H, d, J = 11
Hz), 4.67 (1H, d, J = 11 Hz), 5.5
6 (1H, m), 6.87 (2H, d, J = 9Hz),
7.29 (2H, d, J = 9 Hz).

The above isomer mixture (3.14 g, 8.7 mmol) was dissolved in a mixture of ethanol (19 ml) and water (1 ml), methyl iodide (0.8 ml, 13 mmol) was added and the mixture was stirred for 8 hours. After heating under reflux, the mixture was concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (20: 1) as an eluent to give 5-methoxy-4- (4-methoxybenzyloxy) -2, a yellow oil.
1.14 g (41%) of 6,6-trimethyl-2-cyclohepten-1-one (AU221) was obtained.

IR (KBr, cm ^-1 ): 1673,15
14, 1249, 1113.

1H-NMR (CDCl ₃ , ppm):
0.99 (3H, s), 1.06 (3H, s), 1.8
2 (3H, t, J = 2Hz), 2.29 (1H, d, J
= 13 Hz), 2.41 (1H, d, J = 13 Hz),
2.88 (1H, d, J = 8Hz), 3.57 (3H,
s), 3.82 (3H, s), 4.17 (1H, dm,
J = 8 Hz), 4.64 (1H, d, J = 11 Hz),
4.80 (1H, d, J = 11Hz), 6.56 (1
H, m), 6.90 (2H, d, J = 9 Hz), 7.3
3 (2H, d, J = 9 Hz).

[0388]

Example 70 5- Obtained as an intermediate of Example 69
Hydroxy-4- (4-methoxybenzyloxy)-
2,6,6-Trimethyl-2-cyclohepten-1-one Dimethylhydrazone (13.35 g, 38 mmol) was methylated according to Example 69 and then 6N hydrochloric acid (4
0 ml) and tetrahydrofuran (20 ml), dissolved in a mixed solution, heated at 50 ° C. for 6 hours, extracted with ethyl acetate,
The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent to remove ethyl acetate and hexane. 4-Hydroxy-5-methoxy-2-cyclohepten-1-one (AU222) as colorless plate crystals crystallized from the mixed solvent
Was obtained 4.26 g (56%). Melting point 71-72 [deg.] C.

IR (KBr, cm ^-1 ): 3461, 16
69, 1103, 1082.

1H-NMR (CDCl ₃ , ppm):
0.99 (3H, s), 1.12 (3H, s), 1.8
3 (3H, t, J = 2Hz), 2.27 (1H, d, J
= 12Hz), 2.50 (1H, d, J = 12Hz),
2.78 (1H, d, J = 9Hz), 2.96 (1H,
brs), 3.57 (3H, s), 4.41 (1H, d
m, J = 9 Hz), 6.57 (1H, m).

[0391]

Example 71 5-methoxy-4 obtained in Example 69
-(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (2.5 g,
7.8 mmol) was treated with DDQ according to Example 7 to give 4-hydroxy-5-methoxy-2-cyclohepten-1-one (AU222) as in Example 70
21 g (78%) was obtained.

[0390]

Example 72 The product of Example 71 (1.39 g, 7.
0 mmol) was treated with 4-nitrobenzoyl chloride as in Example 17, then benzene-ethyl acetate (2
It was purified by silica gel column chromatography using 0: 1) as an eluent, and crystallized from a mixed solvent of benzene and hexane to give 5-methoxy-4- (4-nitrobenzoyloxy) -2,6,6 as pale yellow crystals. 2.11 g of trimethyl-2-cyclohepten-1-one (AU238)
(87%) obtained. Melting point 136.5-138.0 [deg.] C.

IR (KBr, cm ^-1 ): 1725, 16
82, 1527, 1285, 1124, 1104, 71
7. 1H-NMR (CDCl ₃ , ppm): 1.11 (3
H, s), 1.13 (3H, s), 1.90 (3H,
t, J = 2 Hz), 2.41 (1H, d, J = 13H)
z), 2.65 (1H, d, J = 13Hz), 3.02
(1H, d, J = 9Hz), 3.42 (3H, s),
6.06 (1H, dm, J = 9Hz), 6.49 (1
H, m), 8.30 (2H, d, J = 9 Hz), 8.3
4 (2H, d, J = 9 Hz).

[0394]

Example 73 The product of Example 72 (1.68 g, 4.
8 mmol) to reduce the nitro group according to Example 19,
Crystallization from a mixed solvent of ethyl acetate and hexane gave 4- (4-aminobenzoyloxy) -5- as colorless plate crystals.
0.79 g (51.1) of methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU239).
%)Obtained. Melting point 159-161 [deg.] C.

IR (KBr, cm ^-1 ): 3476, 33
77, 1687, 1602, 1276, 1170, 11
14.

1H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.11 (3H, s), 1.8
7 (3H, t, J = 2Hz), 2.38 (1H, d, J
= 13 Hz), 2.66 (1H, d, J = 13 Hz),
2.98 (1H, d, J = 9Hz), 3.45 (3H,
s), 4.11 (2H, br), 5.99 (1H, d
m, J = 9 Hz), 6.47 (1H, m), 6.67
(2H, d, J = 9 Hz), 7.93 (2H, d, J =
9 Hz).

[0397]

Example 74 4-hydroxy-obtained in Example 71
5-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (397 mg, 2 mmol) was benzoylated according to Example 6 and crystallized from hexane to give colorless plate crystals of 4-benzoyloxy-. 5-methoxy-
510 mg (84%) of 2,6,6-trimethyl-2-cyclohepten-1-one (AU223) was obtained. Melting point 9
7-98 ° C.

IR (KBr, cm ^-1 ): 1724, 16
76, 1272, 1117, 712.

1H-NMR (CDCl ₃ , ppm):
1.10 (3H, s), 1.12 (3H, s), 1.8
9 (3H, t, J = 2Hz), 2.40 (1H, d, J
= 13 Hz), 2.67 (1H, d, J = 13 Hz),
3.01 (1H, d, J = 9Hz), 3.45 (3H,
s), 6.04 (1H, dm, J = 9Hz), 6.49
(1H, m), 7.48 (2H, m), 7.60 (1
H, m), 8.13 (2H, m).

[0400]

[Example 75] To a solution of Cycin N (2.00 g, 11 mmol) in acetone (10 ml) was added p-toluenesulfonic acid (0.3 g), the mixture was stirred overnight at room temperature, concentrated, diluted with ethyl acetate and saturated. 2.30 g (95.7%) of colorless needle crystals of 4,5-O-isopropylidene cycin N, which were washed with sodium bicarbonate water and saturated saline, dried over anhydrous magnesium sulfate, filtered, concentrated, and crystallized from hexane. Obtained. Melting point 65-65.5 [deg.] C.

IR (KBr, cm ^-1 ): 1664,13
74, 1242, 1091, 877.

1H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.15 (3H, s), 1.4
1 (3H, s), 1.43 (3H, s), 1.85 (3
H, t, J = 2 Hz), 2.37 (1H, d, J = 12)
Hz), 2.47 (1H, d, J = 12 Hz), 3.4
2 (1H, d, J = 9Hz), 4.53 (1H, dm,
J = 9 Hz), 6.57 (1H, t, J = 1 Hz).

The above product (2.24 g, 10 mmol)
Lithium aluminum hydride (0.3 g, 8 mmol) was added to a tetrahydrofuran (5 ml) solution of the above under ice-cooling stirring, and the mixture was stirred for 2 hours, and ethyl acetate (50 ml) and water (4
ml) was added, the mixture was stirred for 2 hours, filtered and concentrated to give colorless crystalline 4,5-O-isopropylidene-2,6,6-trimethyl-2-cycloheptene-1,4,5-triol (1). Obtained 0.85 g (82%).

IR (KBr, cm ^-1 ): 3365, 14
50, 1372, 1240, 1069, 1006.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.07 (3H, s), 1.12 (3H, s),
1.37 (3H, s), 1.40 (3H, s), 1.4
8 (1H, dd, J = 13, 2Hz), 1.71 (1
H, dd, J = 13, 11 Hz), 1.79 (3H, b
rs), 3.23 (1H, d, J = 9 Hz), 4.39
(1H, dm, J = 9Hz), 4.49 (1H, br
d, J = 11 Hz), 5.56 (1 H, m).

Methanol (5 ml) of the above product (2.33 g, 10.3 mmol) and tetrahydrofuran (5
2N hydrochloric acid (5 ml) was added to the mixed solution of
After heating for 6 hours at ℃, dilute with ethyl acetate, saturated aqueous sodium hydrogen carbonate,
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, purified by silica gel column chromatography using benzene-ethyl acetate (3: 1) as an eluent, and crystallized from ethyl acetate to give colorless needles. Crystal 2,
6,6-Trimethyl-2-cycloheptene-1,4,5
-0.99 g (54%) of triol (AU103) was obtained. Melting point 138-139 [deg.] C.

IR (KBr, cm ^-1 ): 3600-31
00, 1447, 1435, 1280, 994.

1H-NMR (DMSO-d ₆ , pp
m): 0.95 (3H, s), 0.97 (3H, s),
1.36 (1H, dd, J = 13, 2Hz), 1.47
(1H, dd, J = 13, 10Hz), 1.66 (3
H, brs), 2.78 (1H, dd, J = 10, 3H
z; d by heavy water addition, J = 10 Hz), 3.99 (1
H, m; brd, J = 10 Hz by addition of heavy water), 4.
26 (1H, m; brd by addition of heavy water, J = 10H
z), 4.36 (1H, d, J = 3Hz; disappeared by adding heavy water), 4.62 (1H, d, J = 3Hz; disappeared by adding heavy water), 4.68 (1H, d, J = 4Hz) ; Disappeared by addition of heavy water), 5.17 (1H, m).

[0409]

Example 76 Cycin N (5.0 g, 27 mmol)
4-methoxybenzaldehyde (3.5 ml, 28 mmol) and p-toluenesulfonic acid (0.25 g) were added to a solution of benzene in (60 ml), heated under reflux for 1 hour, diluted with benzene and washed with saturated aqueous sodium hydrogen carbonate, Dry over anhydrous magnesium sulfate, filter, concentrate, and partially crystallize 4,5-O- (4-methoxybenzylidene) cycin N in quantitative yield.
Got

IR (KBr, cm ^-1 ): 1676,12
43,1093,1029.

The above product was reduced with lithium aluminum hydride (1 g, 26 mmol) according to Example 75,
Purification by silica gel column chromatography using toluene-ethyl acetate (20: 1) as an eluent to give partially crystalline 4,5-O- (4-methoxybenzylidene) -2,
6,6-Trimethyl-2-cycloheptene-1,4,5
-I got a triol.

IR (KBr, cm ^-1 ): 3482, 16
13, 1516, 1248, 1089.

The above product was methylated according to Example 69, 80% acetic acid (80 ml) was added, and the mixture was stirred overnight. The reaction mixture was concentrated, neutralized with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was hexane-ethyl acetate (20: 1).
Purified by silica gel column chromatography using as an eluent, colorless oily 1-methoxy-2,6,6-trimethyl-2-cycloheptene-4,5-diol (AU
110) was obtained in an amount of 2.98 g (55%).

IR (KBr, cm ^-1 ): 3418, 11
03,1002.

1 H-NMR (CDCl ₃ + CD ₃ OD,
ppm): 1.07 (3H, s), 1.09 (3H,
s), 1.51 (1H, dd, J = 14, 3Hz),
1.58 (1H, dd, J = 14,9Hz), 1.75
(3H, m), 3.07 (1H, d, J = 10Hz),
3.32 (3H, s), 3.84 (1H, brd, J =
9Hz), 4.20 (1H, br.d, J = 10H
z), 5.33 (1H, m).

[0416]

Example 77 1-Methoxy-obtained in Example 76
2,6,6-trimethyl-2-cycloheptene-4,5
-Diol (0.3 g, 1.5 mmol) was acetylated by a conventional method to give 4,5-diacetoxy- as a colorless oil.
0.41 g (94%) of 1-methoxy-2,6,6-trimethyl-2-cycloheptene (AU112) was obtained.

IR (KBr, cm ^-1 ): 1746, 13
72, 1244, 1102, 1028.

1H-NMR (CDCl ₃ , ppm):
0.95 (3H, s), 1.19 (3H, s), 1.5
6-1.70 (2H, m), 1.76 (3H, brt,
J = 1 Hz), 2.03 (3 H, s), 2.04 (3
H, s), 3.33 (3H, s), 3.94 (1H, b
rd, J = 8 Hz), 4.75 (1H, d, J = 10H)
z), 5.22 (1H, m), 5.58 (1H, dm,
J = 10 Hz).

[0419]

Example 78 1-Methoxy-obtained in Example 76
2,6,6-trimethyl-2-cycloheptene-4,5
-Diol (0.35 g, 1.7 mmol) in Example 6
Methylation according to 9 gave 0.325 g (81.4%) of colorless oily 1,4,5-trimethoxy-2,6,6-trimethyl-2-cycloheptene (AU113).

IR (KBr, cm ^-1 ): 1446, 13
85, 1104.

1H-NMR (CDCl ₃ , ppm):
1.05 (3H, s), 1.07 (3H, s), 1.5
0 (2H, m), 1.75 (3H, brs), 2.69
(1H, d, J = 10Hz), 3.31 (3H, s),
3.43 (3H, s), 3.49 (3H, s), 3.8
4 (1H, brd, J = 10Hz), 3.87 (1H,
dm, J = 10 Hz), 5.30 (1H, m).

[0422]

Example 79 1-Methoxy-obtained in Example 76
2,6,6-trimethyl-2-cycloheptene-4,5
-55% sodium hydride (0.2 g, 4.6 mmol) was added to a tetrahydrofuran (3 ml) solution of diol (0.3 g, 1.5 mmol) under ice-cooling, and the mixture was stirred for 1 hour, and then benzoyl chloride ( 0.53 ml, 4.55
(Mmol) and stirred at room temperature overnight. The reaction mixture was poured into ice water, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent. Fractionation by chromatography and colorless crystals of 4,5-dibenzoyloxy-1-methoxy-2,6,6-trimethyl-2-cycloheptene (A
U114) was obtained in an amount of 0.11 g (17.2%). Melting point 7
8-80 ° C IR (KBr, cm ^-1 ): 1724, 1602, 145
1,1279,1095,711.

1 H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.39 (3H, s), 1.7
0 (1H, dd, J = 14, 2Hz), 1.80 (1
H, dd, J = 14, 10 Hz), 1.83 (3H, b
rs), 3.39 (3H, s), 4.10 (1H, d,
J = 7 Hz), 5.16 (1H, d, J = 10 Hz),
5.43 (1H, m). 6.00 (1H, m), 7.2
3 (4H, m), 7.38 (2H, m), 7.84 (4
H, m).

From the subsequent eluate, colorless crystals of 5-benzoyloxy-1-methoxy-2,6,6-trimethyl-2-
86 mg of cyclohepten-4-ol (AU115)
(19%) was obtained.

1H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.30 (3H, s), 1.6
1 (1H, dd, J = 13, 2Hz), 1.72 (1
H, dd, J = 13,10 Hz), 1.80 (3H, b
rs), 3.35 (3H, s), 3.91 (1H, d,
J = 10 Hz), 4.49 (1H, brd, J = 10H
z), 4.84 (1H, d, J = 10 Hz), 5.41
(1H, m), 7.46 (2H, m), 7.58 (1
H, m), 8.06 (2H, brd, J = 9 Hz).

[0426]

Example 80 1-Methoxy-obtained in Example 76
2,6,6-trimethyl-2-cycloheptene-4,5
-Diol (2.73 g, 13.6 mmol) was benzoylated as in Example 6 and crystallized from a mixed solvent of hexane and ethyl acetate to give colorless needle crystals of 4-benzoyloxy-1-methoxy-2, 6,6-trimethyl-2-
Cyclohepten-5-ol (AU145) 1.01
g (33%) was obtained. Melting point 98-99 [deg.] C.

IR (KBr, cm ^-1 ): 3517, 16
94, 1280, 1095, 720.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.16 (3H, s), 1.18 (3H, s),
1.61 (1H, dd, J = 14.2Hz), 1.65
(1H, dd, J = 14.8Hz), 1.78 (3H,
brs), 3.36 (3H, s), 3.46 (1H,
d, J = 10 Hz), 3.98 (1H, brd, J = 8)
Hz), 5.32 (1H, m), 5.67 (1H, d
m, J = 10 Hz), 7.46 (2H, t, J = 7H
z), 7.59 (1H, t, J = 7Hz), 8.06
(1H, d, J = 7Hz).

[0429]

Example 81 4,5-O- (4-Methoxybenzylidene) -2,6 obtained as a synthetic intermediate of Example 76
6-Trimethyl-2-cycloheptene-1,4,5-triol (918 mg, 3.0 mmol) was acetylated by a conventional method to give 1-acetoxy-4,5-O- (4
-Methoxybenzylidene) -2,6,6-trimethyl-
1.05 g of 2-cycloheptene-4,5-diol
(94.7%) was obtained. This product (961 mg, 2.77)
(Mmol) was hydrolyzed with 80% acetic acid (5 ml) and purified by silica gel column chromatography to obtain colorless oily 1-acetoxy-2,6,6-trimethyl-2-cycloheptene-4,5-diol (AU111). 0.61
5 g (97.2%) were obtained.

IR (KBr, cm ^-1 ): 3444, 17
38, 1374, 1240.

1 H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.11 (3H, s), 1.4
9 (1H, dd, J = 14, 2Hz), 1.69 (3
H, brs), 1.74 (1H, dd, J = 14, 10)
Hz), 2.07 (3H, s), 2.48 (1H, d,
J = 3 Hz; disappeared by addition of heavy water), 2.29 (1H,
d, J = 4 Hz; disappeared by addition of heavy water), 3.14 (1
H, dd, J = 10, 4 Hz; d, J = by adding heavy water
10Hz), 4.30 (1H, brd, J = 10H
z), 5.40 (1H, q, J = 1 Hz), 5.50
(1H, brd, J = 10Hz).

[0432]

Example 82 4,5-O- (4-Methoxybenzylidene) -2,6 obtained as a synthetic intermediate of Example 76
55% Sodium hydride (0.2 g) was added to a solution of 6-trimethyl-2-cycloheptene-1,4,5-triol (1.0 g, 3.29 mmol) in tetrahydrofuran (10 ml) under ice cooling with stirring, and 90 After stirring for minutes, benzyl chloride (0.53 ml, 4.6 mmol) was added, the mixture was heated under reflux for 19 hours, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, Concentrated. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (40: 1) as an eluent to give 1-benzyloxy-4,5-O- as a colorless oil.
816m of (4-methoxybenzylidene) -2,6,6-trimethyl-2-cycloheptene-4,5-diol
g (63.0%) was obtained. This product was hydrolyzed with 80% acetic acid to give colorless oily 1-benzyloxy-2,6,6-
266 mg (43.2%) of trimethyl-2-cycloheptene-4,5-diol (AU116) was obtained.

IR (KBr, cm ^-1 ): 3600-32
00, 1456, 1094, 745, 697.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.01 (3H, s), 1.09 (3H, s),
1.59 (1H, dd, J = 14.2Hz), 1.68
(1H, dd, J = 14, 10Hz), 1.82 (3
H, t, J = 2 Hz), 3.10 (1H, d, J = 10)
Hz), 4.08 (1H, dm, J = 9 Hz), 4.2
1 (1H, brd, J = 10Hz), 4.50 (2H,
s), 5.34 (1H, m), 7.33 (5H, m).

[0435]

Example 83 The 4,5-O- (4 obtained in Example 76
-Methoxybenzylidene) -2,6,6-trimethyl-
2-Cycloheptene-1,4,5-triol (4.9
8 g, 16.4 mmol) according to Example 69
Sodium hydride (0.93 g, 21.3 mmol) and 1-bromo-3-methyl-2-butene (2.5 ml, 2
1.3 mmol) and fractionated by silica gel column chromatography eluting with hexane-ethyl acetate (2: 1) to give colorless oily 1- (3-methyl-2).
-Buten-1-yloxy) -2,6,6-trimethyl-2-cycloheptene-4,5-diol (AU14
1.56 g (38%) of 3) was obtained.

IR (KBr, cm ^-1 ): 3434, 17
14, 1450, 1379, 1069.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.07 (3H, s), 1.09 (3H, s),
1.52 (1H, dd, J = 13, 2Hz), 1.63
(1H, dd, J = 13, 10Hz), 1.67 (3
H, brs), 1.75 (3H, brs), 1.77.
(3H, brs), 3.10 (1H, d, J = 10H
z), 3.94 (2H, m), 3.99 (1H, br
d, J = 10 Hz), 4.25 (1H, dm, J = 9H)
z), 5.32 (2H, m).

[0438]

Example 84 The product of Example 83 (1.25 g, 4.
9 mmol) was benzoylated according to Example 6 and purified by silica gel column chromatography eluting with benzene-ethyl acetate (10: 1) to give 4-
Benzoyloxy-1- (3-methyl-2-butene-1
-Yloxy) -2,6,6-trimethyl-2-cyclohepten-5-ol (AU144) 0.52 g (3
0%) was obtained.

IR (KBr, cm ^-1 ): 3479, 17
32, 1715, 1698, 1451, 1272, 71
2.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.15 (3H, s), 1.17 (3H, s),
1.61 (1H, dd, J = 13, 2Hz), 1.70
(3H, s), 1.76 (3H, s), 1.79 (3
H, t, J = 2 Hz), 3.46 (1H, d, J = 10)
Hz), 3.98 (2H, m), 4.13 (1H, br)
d, J = 11 Hz), 5.33 (2H, m), 5.67
(1H, dm, J = 9Hz), 7.43 (2H, m),
7.56 (1H, m), 8.06 (2H, m).

[0441]

Example 85 4,5-O- (4-Methoxybenzylidene) -2,6 obtained as a synthetic intermediate of Example 76
6-Trimethyl-2-cycloheptene-1,4,5-triol (10.0 g, 32.9 mmol) was used in Example 8.
Treated with ethyl bromoacetate (5.6 ml, 42.6 mmol) according to 3 and hydrolyzed with 80% acetic acid to give 1-ethoxycarbonylmethyloxy-2,6,6 as a colorless oil.
1.84 g (21%) of -trimethyl-2-cycloheptene-4,5-diol (AU146) was obtained.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.10 (3H, s), 1.12 (3H, s),
1.29 (3H, t, J = 7Hz), 1.63 (2H,
m), 1.80 (3H, t, J = 2Hz), 3.10
(1H, d, J = 10Hz), 4.04 (1H, d, J
= 16 Hz), 4.08 (1H, dm, J = 10H
z), 4.22 (2H, q, J = 7Hz), 5.36
(1H, m).

[0443]

Example 86 The product of Example 85 (1.34 g, 3.
(55 mmol) was benzoylated according to Example 6 and purified by silica gel column chromatography using benzene-ethyl acetate (10: 1) as an eluent to give 5 as a colorless oil.
-Benzoyloxy-1-ethoxycarbonylmethyloxy-2,6,6-trimethyl-2-cycloheptene-
0.66 g (36%) of 4-ol (AU147) was obtained.

IR (KBr, cm ^-1 ): 3524, 17
51, 1718, 1275, 1118, 712.

1H-NMR (CDCl ₃ , ppm):
1.03 (3H, s), 1.30 (3H, s), 1.3
0 (3H, t, J = 7Hz), 1.73 (1H, dd,
J = 14.2Hz, 1.79 (1H, d, J = 14H)
z), 1.82 (1H, dd, J = 14, 10Hz),
1.85 (3H, t, J = 2Hz), 4.00-4.2
0 (3H, m), 4.23 (2H, q, J = 7Hz),
4.46 (1H, brd, J = 10Hz), 4.86
(1H, d, J = 10Hz), 5.45 (1H, m),
7.46 (2H, t, J = 7Hz), 7.58 (1H,
t, J = 7 Hz), 8.07 (2H, d, J = 7H
z).

[0446]

Example 87 4,5-O- (4-Methoxybenzylidene) -2,6 obtained as a synthetic intermediate of Example 76
6-Trimethyl-2-cycloheptene-1,4,5-triol (5.0 g, 16.4 mmol) was used in Example 17.
After treatment with 4-nitrocinnamoyl chloride in accordance with the procedure described above, it was hydrolyzed with 80% acetic acid and crystallized from ethyl acetate to give yellow needle crystals of 1- (4-nitrocinnamoyloxy) -2,6,6-. Trimethyl-2-cycloheptene-
2.54 g of 4,5-diol (AU149) (83
%)Obtained. Melting point 152.5-154 [deg.] C.

IR (KBr, cm ^-1 ): 3379, 17
11, 1518, 1342, 844.

1H-NMR (CDCl ₃ , ppm):
1.12 (3H, s), 1.16 (3H, s), 1.5
9 (1H, dd, J = 14, 2Hz), 1.75 (3
H, brs), 1.84 (1H, dd, J = 14, 10)
Hz), 3.18 (1H, d, J = 10 Hz), 4.3
5 (1H, brd, J = 10Hz), 5.46 (1H,
m), 5.66 (1H, brd, J = 10Hz), 6.
57 (1H, d, J = 16Hz), 7.69 (2H,
d, J = 9 Hz), 7.73 (1H, d, J = 16H
z), 8.26 (2H, d, J = 9Hz).

[0449]

Example 88 The product of Example 87 (2.44 g, 6.
(75 mmol) was benzoylated according to Example 6, fractionated by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent, and the first eluate was crystallized from a mixed solvent of ethyl acetate and hexane. Pale yellow needle crystals of 4-benzoyloxy-1- (4-nitrocinnamoyloxy) -2,6,6-trimethyl-2-
Cyclohepten-5-ol (AU405) was 1.36.
g (43%) was obtained. Melting point 156.5-157.5 ° C IR (KBr, cm ^-1 ): 3500, 1732, 171
5,1682, 1668, 1580, 1471, 129
6,763.

1H-NMR (CDCl ₃ , ppm):
1.17 (3H, s), 1.26 (3H, s), 1.6
9 (1H, dd, J = 14, 2Hz), 1.79 (3
H, brs), 1.92 (1H, dd, J = 14, 10)
Hz), 2.19 (1H, d, J = 5Hz; disappeared by adding heavy water), 3.55 (1H, dd, J = 10, 5H)
z; d by heavy water addition, J = 10 Hz), 5.46 (1
H, m), 5.78 (2H, m), 6.59 (1H,
d, J = 16 Hz), 7.58 (5 H, m), 7.75
(1H, d, J = 16Hz), 8.09 (2H, m),
8.28 (2H, m).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give 5-benzoyloxy-1- (4-nitrocinnamoyloxy) -2, a pale yellow needle crystal.
0.35 g (11%) of 6,6-trimethyl-2-cyclohepten-4-ol (AU406) was obtained. Melting point 17
9-181 ° C.

IR (KBr, cm ^-1 ): 3517, 17
07, 1639, 1518, 1340, 1280, 71
6.

1H-NMR (CDCl ₃ , ppm):
1.04 (3H, s), 1.36 (3H, s), 1.6
9 (1H, dd, J = 13, 2Hz), 1.81 (3
H, brs), 1.99 (1H, d, J = 13, 10H
z), 2.02 (1H, d, J = 6 Hz; disappeared by adding heavy water), 4.61 (1H, m; br by adding heavy water)
d, J = 9 Hz), 4.99 (1H, d, J = 10H
z,), 5.56 (1H, m), 5.72 (1H, br
d, J = 10 Hz), 6.60 (1H, d, J = 16H)
z), 7.61 (5H, m), 7.77 (1H, d, J
= 16 Hz), 8.10 (2H, d, J = 8 Hz),
8.27 (2H, d, J = 8Hz).

[0454]

Example 89 4,5-O- (4-Methoxybenzylidene) -2,6 obtained as a synthetic intermediate of Example 76
6-Trimethyl-2-cycloheptene-1,4,5-triol (2.42 g, 8.0 mmol) was benzoylated according to Example 6 and then hydrolyzed with 80% acetic acid (13 ml) to give hexane-acetic acid. Purified by silica gel column chromatography using ethyl (2: 1) as an eluent, and crystallized from a mixed solution of ethyl acetate and hexane to give 1-benzoyloxy-2,6,6-trimethyl-2 as colorless plate crystals.
1.46 g (63%) of -cycloheptene-4,5-diol (AU229) was obtained. Melting point 94-96 [deg.] C.

IR (KBr, cm ^-1 ): 3600-32
00, 1716, 1281, 1115, 1071, 71
3.

1H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.18 (3H, s), 1.6
4 (1H, dd, J = 14, 2Hz), 1.80 (3
H, t, J = 2 Hz), 1.87 (1H, dd, J = 1)
4,10Hz), 2.61 (1H, br; disappears by adding heavy water), 2.83 (1H, br; disappears by adding heavy water), 3.21 (1H, dd, J = 9, 4Hz; by adding heavy water) d, J = 9 Hz), 3.87 (1H, brd,
J = 9 Hz), 5.46 (1 H, m), 5.76 (1
H, brd, J = 10 Hz), 7.46 (2H, m),
7.58 (1H, m), 8.05 (2H, m).

[0457]

Example 90 5-Hydroxy-4 obtained in Example 1
-(4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (30.4 g,
Dihydropyran (43 ml, 0.5 mol) and p-toluenesulfonic acid (0.5 g) were added to a solution of 0.1 mol) in tetrahydrofuran (200 ml), and the mixture was stirred at 0 ° C. for 4 hours, concentrated, and washed with ethyl acetate. Dilute and wash with saturated sodium bicarbonate water,
Dry over anhydrous magnesium sulfate, filter and concentrate to give crude 4
54.7 g of-(4-methoxybenzyloxy) -5-tetrahydropyranyloxy-2,6,6-trimethyl-2-cyclohepten-1-one was obtained.

IR (KBr, cm ^-1 ): 1671, 15
14, 1249, 1034, 819.

Sodium borohydride (7 g, 0.19 mol) was added to a solution of the above product in methanol (200 ml) at 0 ° C., the mixture was stirred for 4 hours, concentrated, diluted with ethyl acetate and washed with saturated brine. Dry over anhydrous magnesium sulfate, filter and concentrate, and concentrate the residue in hexane-ethyl acetate (10: 1).
Is purified by silica gel column chromatography using as an eluent to give 4- (4-methoxybenzyloxy) -5-tetrahydropyranyloxy-2,6,6-
Trimethyl-2-cyclohepten-1-ol 28.
3 g was obtained.

IR (KBr, cm ^-1 ): 3444, 16
13, 1514, 1248, 1032, 820.

The above product (4.69 g, 12 mmol)
Was benzoylated according to Example 6 and purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent to obtain 5.0 g of a colorless oil. This was dissolved in methanol (30 ml), p-toluenesulfonic acid (0.1 g) was added, the mixture was stirred for 30 minutes, concentrated, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. , Concentrated, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless prism crystals of 1-benzoyloxy-4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cycloheptene-5. -2.30 g (46.7%) of ol was obtained.
Melting point 106.5-107 [deg.] C.

1H-NMR (CDCl ₃ , ppm):
1.11 (3H, s), 1.17 (3H, s), 1.6
0 (1H, dd, J = 13, 1Hz), 1.84 (4
H, m), 3.21 (1H, brs; disappeared by addition of heavy water), 3.23 (1H, d, J = 10 Hz), 3.82
(3H, s), 4.14 (1H, dm, J = 10H
z), 4.43 (1H, d, J = 11 Hz), 4.70.
(1H, d, J = 11 Hz), 5.50 (1H, m),
5.77 (1H, brd, J = 11Hz), 6.90
(2H, d, J = 9 Hz), 7.29 (2H, d, J =
9Hz), 7.46 (2H, m), 7.59 (1H,
m), 8.06 (2H, m).

The above product (820 mg, 2 mmol) was benzoylated again and purified by silica gel column chromatography using hexane-benzene (1: 1) and benzene as an eluent to give 740 mg (72 mg) of a colorless oil.
%)Obtained. This was treated with DDQ according to Example 7, purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent, and crystallized from a mixed solution of hexane and ethyl acetate to give colorless prism crystals. 2.30 g (46.7%) of 1,5-dibenzoyloxy-2,6,6-trimethyl-2-cyclohepten-4-ol (AU228) was obtained. Melting point 142-143.
5 ° C.

IR (KBr, cm ^-1 ): 3503, 17
19, 1707, 1285, 709.

1H-NMR (CDCl ₃ , ppm):
1.03 (3H, s), 1.40 (3H, s), 1.7
5 (1H, dd, J = 14, 2Hz), 1.86 (3
H, t, J = 2 Hz), 1.90 (1H, brs; disappeared by addition of heavy water), 2.01 (1H, dd, J = 14,
10Hz), 4.63 (1H, brd, J = 9Hz),
4.97 (1H, d, J = 9Hz), 5.55 (1H,
m), 5.84 (1H, brd, J = 10Hz), 7.
47 (4H, m), 7.58 (2H, m), 8.09
(4H, m).

[0466]

Example 91 4-obtained as intermediate of Example 90
(4-Methoxybenzyloxy) -5-tetrahydropyranyloxy-2,6,6-trimethyl-2-cyclohepten-1-ol (28.3 g) was acetylated by a conventional method and then made into a methanol (80 ml) solution, p-Toluenesulfonic acid (0.2 g) was added, the mixture was stirred at room temperature for 1 hr, concentrated, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate,
The extract was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography using hexane-ethyl acetate (20: 1) as an eluent to give 1-acetoxy-4- (4-methoxybenzyloxy)-as a colorless oil. Two
17.4 g of 6,6-trimethyl-2-cyclohepten-5-ol was obtained.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.08 (3H, s), 1.10 (3H, s),
1.43 (1H, dd, J = 14.2Hz), 1.62
(1H, m), 1.70 (3H, brs), 2.08
(3H, s), 3.16 (1H, dd, J = 10, 2H
z), 3.81 (3H, s), 4.18 (1H, dm,
J = 10 Hz), 4.39 (1H, d, J = 11H)
z), 4.47 (1H, d, J = 11 Hz), 5.43
(1H, m), 5.50 (1H, brd, J = 11H
z), 6.89 (2H, d, J = 8Hz), 7.26
(2H, d, J = 8Hz).

Tetrahydrofuran of the above product (80 m
l) Methylate the solution according to Example 69 and use hexane-
It was purified by silica gel column chromatography using ethyl acetate (30: 1) as an eluent to give 1-acetoxy-5-methoxy-4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2 as a colorless oil. -The cycloheptene was obtained.

1H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.09 (3H, s), 1.4
5 (1H, dd, J = 14, 2Hz), 1.68 (3
H, brs), 1.73 (1H, dd, J = 14, 10)
Hz), 2.07 (3H, s), 2.82 (1H, d,
J = 10 Hz), 3.54 (3H, s), 3.81 (3
H, s), 4.13 (1H, dm, J = 10Hz),
4.57 (1H, d, J = 11Hz), 4.65 (1
H, d, J = 11 Hz), 5.45 (2H, m), 6.
88 (2H, d, J = 8Hz), 7.30 (2H, d,
J = 8 Hz).

The above product was dissolved in methanol (30 ml) and a 28% sodium methoxide methanol solution (1
(ml) and allowed to stand at room temperature overnight, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to 5-methoxy-4- (4-.
Methoxybenzyloxy) -2,6,6-trimethyl-
2-Cyclohepten-1-ol was obtained. This was dissolved in methylene chloride (50 ml) and activated manganese dioxide (3
0 g) was added and the mixture was stirred at room temperature overnight, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent to give Example 69. 7.64 g of -methoxy-4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (AU221)
(24%) was obtained.

[0471]

Example 92 5-Benzoyloxy-4- (4-methoxybenzyloxy) -2,6,6 obtained in Example 6
-Trimethyl-2-cyclohepten-1-one (2.3
1 g, 5.6 mmol) in ethanol (10 ml) was stirred at room temperature under sodium borohydride (0.11 g,
2.8 mmol) and stirred for 1 hour, ice water is added and stirred for 10 minutes, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and benzene-ethyl acetate ( It was purified by silica gel column chromatography using 20: 1) as an eluent to give 5
-Benzoyloxy-4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cycloheptene-
1.52 g (66%) of 1-ol (AU184) was obtained.

IR (KBr, cm ^-1 ): 3474, 17
19, 1514, 1274, 1250, 1118.

1H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.38 (3H, s), 1.7
4 (1H, dd, J = 14, 1Hz), 1.86 (3
H, brs), 2.01 (1H, dd, J = 14, 11
Hz), 2.09 (1H, d, J = 7Hz), 3.88
(3H, s), 4.63 (1H, br), 4.93 (1
H, d, J = 10 Hz), 5.55 (1 H, m), 5.
83 (1H, brd, J = 11Hz), 6.95 (2
H, d, J = 9 Hz), 7.47 (2H, m), 7.5
9 (1H, m), 8.06 (3H, m).

[0474]

Example 93 The product of Example 92 (2.0 g, 4.8)
7 mmol) was acetylated by a conventional method to give 1 as a colorless oil.
-Acetoxy-5-benzoyloxy-4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-
1.63 g (74%) of cycloheptene (AU135)
Obtained.

1H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.27 (3H, s), 1.5
5 (1H, dd, J = 14, 2Hz), 1.74 (3
H, t, J = 2 Hz), 1.88 (1H, dd, J = 1)
4,11Hz), 2.09 (3H, s), 3.74 (3
H, s), 4.24 (1H, dm, J = 10 Hz),
4.34 (1H, d, J = 12Hz), 4.52 (1
H, d, J = 12Hz), 5.01 (1H, d, J = 1
0Hz), 5.56 (2H, m), 6.65 (2H,
d, J = 9 Hz), 6.96 (2H, d, J = 9H)
z), 7.46 (2H, m), 7.58 (1H, m),
8.05 (2H, m).

The above product (1.62 g, 3.58 mmol) was treated with DDQ according to Example 7 and purified by silica gel column chromatography eluting with benzene-hexane (5: 1) to give hexane. 1-acetoxy-5-benzoyloxy-in the form of colorless needles crystallized from
0.69 g (58%) of 2,6,6-trimethyl-2-cyclohepten-4-ol (AU137) was obtained. Melting point 113-114.5 [deg.] C.

IR (KBr, cm ^-1 ): 3541, 34
58, 1734, 1717, 1273, 1249, 11
16,712.

1H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.32 (3H, s), 1.5
8 (1H, dd, J = 14, 2Hz), 1.75 (3
H, brs), 1.88 (1H, dd, J = 14, 11)
Hz), 2.10 (3H, s), 4.55 (1H, br
d, J = 10 Hz), 4.90 (1H, d, J = 10H)
z), 5.49 (1H, m), 5.57 (1H, br
d, J = 11 Hz), 7.47 (2H, m), 7.59
(1H, m), 8.08 (2H, m).

[0479]

Example 94 5-benzoyloxy-4- (4-methoxybenzyloxy) -2,6 obtained in Example 92
6-Trimethyl-2-cyclohepten-1-ol (3.0 g, 7.3 mmol) was methylated according to Example 69 and subjected to silica gel column chromatography using hexane-ethyl acetate (20: 1) as the eluent. Purified and colorless oil of 5-benzoyloxy-1-methoxy-
4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cycloheptene (AU136) was added to 1.0
1 g (33%) was obtained.

IR (KBr, cm ^-1 ): 1723, 16
13, 1514, 1271, 711.

1H-NMR (CDCl ₃ , ppm):
1.01 (3H, s), 1.24 (3H, s), 1.5
9 (1H, dd, J = 13, 2Hz), 1.70 (1
H, dd, J = 13,10 Hz), 1.80 (3H, b
rs), 3.33 (3H, s), 3.74 (3H,
s), 3.90 (1H, brd, J = 10Hz), 4.
19 (1H, dm, J = 10Hz), 4.33 (1H,
d, J = 12 Hz), 4.52 (1H, d, J = 12H)
z), 4.96 (1H, d, J = 10 Hz), 5.48
(1H, m), 6.66 (2H, d, J = 9Hz),
6.97 (2H, d, J = 9Hz), 7.45 (2H,
m), 7.56 (1H, m), 8.08 (2H, m).

[0482]

Example 95 5- Obtained as an intermediate of Example 91
Methoxy-4- (4-methoxybenzyloxy) -2,
6,6-Trimethyl-2-cyclohepten-1-ol (980 mg, 3 mmol) was treated with benzoyl chloride (0.38 ml, 3.3 mmol) according to Example 17 to give hexane-ethyl acetate (50: 1). ) Was used as an eluent for purification by silica gel column chromatography to give colorless oily 1-benzoyloxy-5-methoxy-4- (4
715 mg of -methoxybenzyloxy) -2,6,6-trimethyl-2-cycloheptene was obtained. 1H-NMR (CDCl ₃ , ppm): 1.08 (3
H, s), 1.15 (3H, s), 1.58 (1H, d
d, J = 14.2 Hz), 1.79 (3H, brs),
1.86 (1H, dd, J = 14, 11Hz), 2.8
7 (1H, d, J = 10Hz), 3.57 (3H,
s), 3.81 (3H, s), 4.21 (1H, br
d, J = 10 Hz), 4.61 (1H, d, J = 11H
z), 4.68 (1H, d, J = 11 Hz), 5.53
(1H, m), 5.72 (1H, brd, J = 11H
z), 6.88 (2H, d, J = 9Hz), 7.32
(2H, d, J = 9Hz), 7.47 (2H, m),
7.55 (1H, m), 8.05 (2H, m).

The above product (687 mg, 1.6 mmol) was treated with DDQ according to Example 7 and purified by silica gel column chromatography eluting with benzene-ethyl acetate (20: 1) to give ethyl acetate. 1-benzoyloxy-5-methoxy-2,6,6-trimethyl-2-, which is a colorless plate crystallized from a mixed solvent of hexane and hexane
Cyclomepten-4-ol (AU227) at 197 m
g (40%) was obtained. Melting point 82.5-83.5 ° C IR (KBr, cm ^-1 ): 3488, 1716, 128
2,1099,713.

1H-NMR (CDCl ₃ , ppm):
1.09 (3H, s), 1.14 (3H, s), 1.6
0 (1H, dd, J = 14, 2Hz), 1.80 (3
H, t, J = 2 Hz), 1.88 (1H, dd, J = 1)
4,10Hz), 2.73 (1H, brs; disappeared by adding heavy water), 2.75 (1H, d, J = 10Hz),
3.57 (3H, s), 4.40 (1H, dm, J = 1
0Hz), 5.52 (1H, m), 5.75 (1H, b
rd, J = 10 Hz), 7.45 (2H, m), 7.5
8 (1H, m), 8.05 (2H, m).

[0485]

Example 96 Cycin N (9.2 g, 50 mmol)
P-toluenesulfonic acid (0.4 g) was added to a methanol (700 ml) solution of the above, heated under reflux for 5 hours, concentrated, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, After filtration and concentration, the residue was fractionated by silica gel column chromatography using benzene-acetone (30: 1-10: 1) as an eluent, and the first eluate was crystallized from hexane to give colorless needle-shaped crystals (1). −
Methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-en-4-ol (AU
152) was obtained in an amount of 3.27 g (33%). Melting point 52-54
° C.

IR (KBr, cm ^-1 ): 3455, 14
52, 1277, 1178.

1H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.26 (3H, s), 1.29 (3H, s),
1.67 (3H, t, J = 2Hz), 1.81 (2H,
s), 3.36 (3H, s), 3.92 (1H, dd,
J = 5, 2 Hz), 4.82 (1H, m), 5.44
(1H, m).

13 C-NMR (CDCl ₃ , ppm):
16.35 (q), 26.37 (q), 33.69
(Q), 40.69 (s), 50.45 (t), 51.
43 (q), 70.00 (d), 85.29 (d), 1
08.19 (s), 126.27 (d), 139.35
(S).

The subsequent eluate was crystallized from hexane to give colorless needle crystals of 1-methoxy-3,3,7-trimethyl-.
8-Oxabicyclo [3.2.1] oct-6-ene-
1.41 g (14%) of 4-ol (AU153) was obtained. Melting point 82.5-83.5 [deg.] C.

IR (KBr, cm ^-1 ): 3471, 13
35, 1158, 1005.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 0.95 (3H, s), 1.06 (3H, s),
1.62 (2H, s), 1.76 (3H, brs),
3.30 (3H, s), 3.71 (1H, d, J = 4H
z), 4.56 (1H, m), 6.00 (1H, m).

13 C-NMR (CDCl ₃ , ppm):
12.52 (q), 24.53 (q), 33.58
(Q), 34.32 (s), 41.67 (t), 50.
10 (q), 73.80 (d), 78.90 (d), 1
10.69 (s), 127.86 (d), 142.51
(S).

[0493]

Example 97 1-Methoxy-obtained in Example 96
3,3,7-Trimethyl-8-oxabicyclo [3.
2.1] Oct-6-en-4-ol (396 mg,
2 mmol) was acetylated according to a conventional method and crystallized from a mixed solution of methanol and water to give colorless needle crystals of 4-acetoxy-1-methoxy-3,3,7-trimethyl-8-.
Oxabicyclo [3.2.1] oct-6-ene (AU
159) was obtained (299 mg, 62%). Melting point 54-55
° C IR (KBr, cm-1): 1735, 1244, 116
3,1020.

1H-NMR (CDCl ₃ , ppm):
0.97 (3H, s), 1.02 (3H, s), 1.6
3 (1H, d, J = 14Hz), 1.72 (1H, d,
J = 14 Hz), 1.77 (3H, brs), 2.07
(3H, s), 3.30 (3H, s), 4.61 (1
H, m), 4.90 (1H, d, J = 4 Hz), 5.8
9 (1H, m).

[0495]

Example 98 4-Benzyloxy-5 obtained in Example 2
-Hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (412 mg, 1.5 mmol) in methanol (20 ml) was added concentrated sulfuric acid (0.1 ml) and heated under reflux for 3 hours to react. Dilute the solution with ethyl acetate,
The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (20: 1) as an eluent to give colorless oily 1- Methoxy-4-benzyloxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (AU157)
Was obtained in an amount of 144 mg (33%).

IR (KBr, cm ^-1 ): 1720, 14
53, 1272, 1214, 1060.

1H-NMR (CDCl ₃ , ppm):
1.24 (3H, s), 1.30 (3H, s), 1.6
6 (3H, brs), 1.81 (2H, s), 3.35
(3H, s), 4.02 (1H, dd, J = 5,2H
z), 4.55 (3H, m), 5.52 (1H, m),
7.33 (5H, m).

[0498]

Example 99 5-hydroxy-obtained in Example 44
4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (2.00
g, 6.0 mmol) in methanol (30 ml) was added p-toluenesulfonic acid (0.1 g), heated under reflux for 3 hours, concentrated to half volume, and the precipitated crystals were collected by filtration and recrystallized from methanol. And colorless needle crystals of 1-methoxy-4
-(4-Nitrobenzoyloxy) -2,6,6-trimethyl-8-oxabicyclo [3.2.1] octa-2
1.16 g (74%) of ene (AU244) was obtained. Melting point 140-141 [deg.] C.

IR (KBr, cm ^-1 ): 1713, 15
28, 1348, 1288, 1277, 714.

1H-NMR (CDCl ₃ , ppm):
1.28 (3H, s), 1.33 (3H, s), 1.7
4 (3H, t, J = 2Hz), 1.89 (2H, s),
3.41 (3H, s), 4.25 (1H, dd, J =
5,2 Hz), 5.49 (1 H, m), 6.05 (1
H, m), 8.19 (2H, d, J = 9 Hz), 8.3
1 (2H, d, J = 9 Hz).

[0501]

Example 100 The product of Example 99 (690 mg, 2
Nitro group was reduced according to Example 19 and crystallized from a mixed solvent of ethyl acetate and hexane to give 4- (4-aminobenzoyloxy)-as pale yellow prismatic crystals.
1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (AU245)
Was obtained in an amount of 390 mg (61%). Melting point 117.5-119
° C.

IR (KBr, cm ^-1 ): 3452, 34
18,3362,3247,1702,1641,15
99, 1270, 1170.

1H-NMR (CDCl ₃ , ppm):
1.25 (3H, s), 1.33 (3H, s), 1.7
1 (3H, t, J = 2Hz), 1.87 (2H, s),
3.40 (3H, s), 4.08 (2H, brs),
4.21 (1H, dd, J = 5, 2Hz), 5.48
(1H, m), 5.96 (1H, m), 6.64 (2
H, d, J = 9 Hz), 7.83 (2H, d, J = 9H)
z).

[0504]

Example 101 According to Example 99, 5-hydroxy-
4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (1.00
g, 3.0 mmol) in ethanol (20 ml), p
-Treated with toluenesulfonic acid and crystallized from a mixed solvent of ethyl acetate and hexane to give 1-ethoxy-4- (4-nitrobenzoyloxy) -2,6 as pale yellow scaly crystals.
0.7 g (64%) of 6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (AU246) was obtained. Melting point 144-146 [deg.] C.

IR (KBr, cm ^-1 ): 1713, 15
27, 1346, 1287, 1277, 714.

1H-NMR (CDCl ₃ , ppm):
1.25 (3H, t, J = 7Hz), 1.27 (3H,
s), 1.33 (3H, s), 1.74 (3H, t, J
= 2 Hz), 1.89 (1H, d, J = 12 Hz),
1.92 (1H, d, J = 12Hz), 3.54 (1
H, m), 3.74 (1H, m), 4.23 (1H, d
d, J = 5, 2 Hz), 5.49 (1H, m), 6.0
4 (1H, m), 8.19 (2H, d, J = 9Hz),
8.31 (2H, d, J = 9Hz).

[0507]

Example 102 The product of Example 101 (578 mg,
The nitro group was reduced according to Example 19 and crystallized from a mixed solvent of ethyl acetate and hexane to give 4- (4-aminobenzoyloxy) -1 as orange plate crystals.
293 mg (55%) of -ethoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (AU247) was obtained. Melting point 130.5-131.
5 ° C.

IR (KBr, cm ^-1 ): 3444, 33
59, 3244, 1698, 1606, 1310, 12
67,1171,1100.

1H-NMR (CDCl ₃ , ppm):
1.24 (3H, t, J = 7Hz), 1.24 (3H,
s), 1.32 (3H, s), 1.70 (3H, t, J
= 2 Hz), 1.86 (1H, d, J = 12 Hz),
1.91 (1H, d, J = 12Hz), 3.54 (1
H, m), 3.74 (1H, m), 4.08 (2H, b
rs), 4.19 (1H, dd, J = 5, 2Hz),
5.47 (1H, m), 5.96 (1H, m), 6.6
4 (2H, d, J = 9Hz), 7.82 (2H, d, J
= 9 Hz).

[0510]

Example 103 5-Hydroxy-
4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (1.00
g, 3.0 mmol) to ethylene glycol (5 ml)
And tetrahydrofuran (5 ml) were treated with p-toluenesulfonic acid and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless fine crystals of 1- (2-hydroxyethoxy) -4- (4-. Nitrobenzoyloxy)
-2,6,6-Trimethyl-8-oxabicyclo [3.
2.1] Octa-2-ene (AU248) 0.355
g (31%) was obtained. Melting point 166-17.5 [deg.] C.

IR (KBr, cm ^-1 ): 3446, 17
13, 1527, 1346, 1277, 715.

1 H-NMR (CDCl ₃ , ppm):
1.28 (3H, s), 1.33 (3H, s), 1.7
7 (3H, t, J = 2Hz), 1.91 (1H, d, J
= 12 Hz), 1.96 (1H, d, J = 12 Hz),
2.58 (1H, brs), 3.76 (4H, m),
4.27 (1H, dd, J = 5, 2Hz), 5.51
(1H, m), 6.04 (1H, m), 8.19 (2
H, d, J = 9 Hz), 8.31 (2H, d, J = 9H)
z).

[0513]

Example 104 The product of Example 103 (367 mg,
0.97 mmol) was reduced according to Example 19 for the nitro group and purified by silica gel column chromatography using hexane-ethyl acetate (3: 1) as an eluent to give 4- (4-aminobenzoyl) as a colorless oil. Oxy) -1- (2-
Hydroxyethoxy) -2,6,6-trimethyl-8-
Oxabicyclo [3.2.1] oct-2-ene (AU
249) was obtained.

1H-NMR (CDCl ₃ , ppm):
1.26 (3H, s), 1.33 (3H, s), 1.7
3 (3H, t, J = 2Hz), 1.86 (1H, d, J
= 12 Hz), 1.95 (1H, d, J = 12 Hz),
2.73 (1H, brs), 3.76 (4H, m),
4.11 (2H, brs), 4.23 (1H, dd, J
= 5,2 Hz), 5.50 (1 H, m), 5.96 (1
H, m), 6.64 (2H, d, J = 9 Hz), 7.8
2 (2H, d, J = 9 Hz).

This was dissolved in ethyl acetate (10 ml),
Add 4N hydrochloric acid / ethyl acetate and a small amount of methanol and put in the refrigerator to solidify. 160 mg of hydrochloride as colorless powder.
(44%) was obtained. Melting point 157-159 [deg.] C.

IR (KBr, cm ^-1 ): 3600-33
00, 3000-2500, 1716, 1311, 12
76, 1177, 1120.

[0517]

Example 105 5-hydroxy-4- (4-tetrahydropyranyloxycinnamoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (1. To a solution of 0 g (2.4 mmol) in methanol (60 ml) was added p-toluenesulfonic acid (25 mg), the mixture was stirred at room temperature for 1 day, concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. , Dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless crystals (4).
-(4-Hydroxycinnamoyloxy) -1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (AU508) was added to 0.
Obtained 35 g (42%). Melting point 143-145 ° C IR (KBr, cm ^-1 ): 3378, 1677, 162
9, 1599, 1278, 1205, 1170.

1H-NMR (CDCl ₃ , ppm):
1.24 (3H, s), 1.31 (3H, s), 1.7
2 (3H, t, J = 2Hz), 1.88 (2H, s),
3.40 (3H, s), 4.20 (1H, dd, J =
6,2 Hz), 5.46 (1 H, m), 5.89 (1
H, m), 6.26 (1H, d, J = 16 Hz), 6.
87 (2H, d, J = 9Hz), 7.18 (1H, br
s), 7.42 (2H, d, J = 9Hz), 7.63
(1H, d, J = 16Hz).

[0519]

Example 106 5 obtained as an intermediate of Example 61
-Hydroxy-4- (3-methoxy-4-tetrahydropyranyloxycinnamoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (1.94)
g, 4.36 mmol) were treated according to Example 105 to give colorless crystalline 4- (4-hydroxy-3-methoxycinnamoyloxy) -1-methoxy-2 from a mixed solvent of hexane and ethyl acetate. 6,6-Trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (AU4
0.74 g (45%) of 17) was obtained.

IR (KBr, cm ^-1 ): 3531, 34
34, 1702, 1629, 1603, 1513, 12
64, 1172.

1 H-NMR (CDCl ₃ , ppm):
1.26 (3H, s), 1.29 (3H, s), 1.7
1 (3H, t, J = 2Hz), 1.86 (2H, s),
3.39 (3H, s), 3.94 (3H, s), 4.1
9 (1H, dd, J = 5, 2Hz), 5.45 (1H,
q, J = 2 Hz), 5.86 (1H, s; disappeared by adding heavy water), 5.86 (1H, m), 6.25 (2H,
d, J = 16 Hz), 6.92 (1H, d, J = 8H
z), 7.02 (1H, d, J = 2Hz), 7.08
(1H, dd, J = 8, 2Hz), 7.60 (2H,
d, J = 16 Hz).

[0522]

Example 107 5-hydroxy-obtained in Example 1
4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (3.04
g, 10 mmol) was methylated according to Example 69,
It was purified by silica gel column chromatography using hexane-ethyl acetate (20: 1) as an eluent to give 1-methoxy-4- (4-methoxybenzyloxy)-as colorless oil.
2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Oct-2-ene (1.85 g, 58%) was obtained.

1 H-NMR (CDCl ₃ , ppm):
1.23 (3H, s), 1.28 (3H, s), 1.6
6 (3H, dd, J = 2, 1Hz), 1.81 (2H,
s), 3.35 (3H, s), 3.81 (3H, s),
4.00 (1H, dd, J = 5, 2Hz), 4.40-
4.60 (3H, m), 5.50 (1H, m), 6.8
8 (2H, d, J = 7Hz), 7.26 (2H, d, J
= 7 Hz).

The above product (3.18 g, 10 mmol)
Was treated with 2.6 molar equivalents of DDQ according to Example 7,
Purification by silica gel column chromatography using benzene-ethyl acetate (30: 1) as an eluent gave colorless oily 1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octa-. 2-en-4-one (A
U253) was obtained in an amount of 1.63 g (83%).

IR (KBr, cm ^-1 ): 1686, 16
25, 1438, 1265, 1055.

1H-NMR (CDCl ₃ , ppm):
0.99 (3H, s), 1.36 (3H, s), 1.6
5 (1H, d, J = 13Hz), 1.94 (1H, d,
J = 13 Hz), 2.00 (3H, s), 3.43 (3
H, s), 4.03 (1H, s), 5.84 (1H, b
rs).

A solution of the above product in methanol (10 ml) was added at 0 ° C. to sodium borohydride (0.20 g, 5.3).
(Mmol) and stirred for 1 hour, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue is eluted with hexane-ethyl acetate (5: 1). Example 9: Purification by silica gel column chromatography using a liquid, crystallization from hexane, and Example 9.
1-methoxy-2,6,6-trimethyl-obtained in 6
8-Oxabicyclo [3.2.1] oct-2-ene-
1.30 g (79%) of 4-ol (AU152) was obtained.

[0528]

Example 108 The product of Example 107, 1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Oct-2-en-4-ol (297 mg,
1.5 mmol) was acetylated according to a conventional method and purified by silica gel column chromatography using hexane-ethyl acetate (20: 1) as an eluent to give 4-
Acetoxy-1-methoxy-2,6,6-trimethyl-
312 mg (86%) of 8-oxabicyclo [3.2.1] oct-2-ene (AU158) was obtained.

IR (KBr, cm ^-1 ): 1742,12
37, 1042.

1H-NMR (CDCl ₃ , ppm):
1.22 (3H, s), 1.24 (3H, s), 1.6
9 (3H, t, J = 2Hz), 1.83 (2H, s),
2.06 (3H, s), 3.37 (3H, s), 4.0
9 (1H, dd, J = 5, 2Hz), 5.38 (1H,
m), 5.72 (1H, m).

[0531]

Example 109 5-hydroxy-obtained in Example 1
4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (3.04
g, 10 mmol) of tetrahydrofuran (30 ml)
55% sodium hydride (0.52
g, 12 mmol) was added, and after 10 minutes, the mixture was heated at 60 ° C. for 10 minutes and then cooled with ice, and benzoyl chloride (1.39 m
1, 12 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless prism crystals 1- Benzoyloxy-4-
(4-Methoxybenzyloxy) -2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-
2.75 g (67%) of ene was obtained. Melting point 106.5-1
07 ° C.

IR (KBr, cm ^-1 ): 1736, 16
13, 1514, 1267, 1148, 710.

1 H-NMR (CDCl ₃ , ppm):
1.31 (3H, s), 1.37 (3H, s), 1.6
8 (3H, t, J = 2Hz), 2.19 (2H, s),
3.82 (3H, s), 4.15 (1H, dd, J =
5,2Hz), 4.52 (1H, d, J = 12Hz),
4.57 (1H, d, J = 12Hz), 4.75 (1
H, m), 5.51 (1H, m), 6.89 (2H,
d, J = 9 Hz), 7.28 (2H, d, J = 9H)
z), 7.45 (2H, m), 7.59 (1H, m),
8.06 (2H, m).

The above product (0.4 g, 1 mmol) was treated with DDQ according to Example 7 and separated by silica gel column chromatography eluting with benzene-ethyl acetate (50: 1-5: 1). The colorless oily 1-benzoyloxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-en-4-one (AU168) was eluted from the 50: 1 eluate. Obtained 130 mg (45%).

IR (KBr, cm ^-1 ): 1737, 16
84, 1674, 1454, 1276, 1144, 71
0.

1H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.44 (3H, s), 2.0
1 (3H, d, J = 2Hz), 2.09 (1H, d, J
= 12 Hz), 2.33 (1H, d, J = 12 Hz),
4.21 (1H, d, J = 2Hz), 5.91 (1H,
m), 7.48 (2H, m), 7.62 (1H, m),
8.08 (2H, m).

From the elution portion of 10: 1 to 5: 1, colorless oily 1-benzoyloxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene-4- was obtained. 109 mg (38%) of all (AU169) was obtained.

IR (KBr, cm ^-1 ): 3445, 17
32, 1689, 1452, 1262, 1144, 71
1.

1 H-NMR (CDCl ₃ , ppm):
1.34 (3H, s), 1.37 (3H, s), 1.6
8 (3H, t, J = 2Hz), 2.20 (2H, s),
4.90 (1H, dd, J = 5, 2Hz), 5.03
(1H, m), 5.44 (1H, m), 7.44 (2
H, m), 7.57 (1H, m), 8.05 (2H,
m).

[0540]

Example 110 5-Benzoyloxy-4-methoxy-2,6,6-trimethyl-2-obtained in Example 16
To a solution of cyclohepten-1-one (1.51 g, 5.0 mmol) in methanol (20 ml) was added 10% palladium carbon (0.02 g) for catalytic reduction, the catalyst was filtered off, and the filtrate was concentrated to give a residue. Benzene-ethyl acetate (2
Fractionation was performed by silica gel column chromatography using 5: 1) as an eluent.
4-trans-5-benzoyloxy-4-methoxy-
2,6,6-Trimethylcycloheptan-1-one (A
U123A) was obtained in an amount of 0.26 g (17%). Melting point 101
-102 ° C.

IR (KBr, cm ^-1 ): 1718, 16
98, 1272, 1112, 713.

1H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.15 (3H, s), 1.1
8 (3H, d, J = 7Hz), 2.06 (2H, m),
2.33 (1H, d, J = 13Hz), 2.65 (1
H, m), 2.95 (1H, d, J = 13 Hz), 3.
38 (3H, s), 3.56 (3H, m), 5.22
(1H, d, J = 5Hz), 7.48 (2H, m),
7.58 (1H, m), 8.07 (2H, m).

The subsequent eluate was crystallized from hexane to give colorless needle crystals of 2,4-cis-5-benzoyloxy-4-.
Methoxy-2,6,6-trimethylcycloheptane-1
0.47 g (31%) of -one (AU123B) was obtained.
Melting point 133-134.5 [deg.] C.

IR (KBr, cm ^-1 ): 1725, 16
94, 1270, 1094, 714.

1H-NMR (CDCl ₃ , ppm):
1.06 (3H, s), 1.08 (3H, s), 1.1
9 (3H, d, J = 7Hz), 1.84 (1H, m),
2.09 (1H, m), 2.24 (1H, d, J = 13
Hz), 2.38 (1H, m), 2.87 (1H, d,
J = 13 Hz), 3.29 (3H, s), 3.29 (1
H, m), 5.13 (1H, d, J = 9 Hz), 7.4
7 (2H, m), 7.58 (1H, m), 8.08 (2
H, m).

[0546]

Example 111 5- (3-chlorobenzoyloxy) -4- (4-methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (3.00 g) obtained in Example 11 , 6.78 mmol) was catalytically reduced according to Example 110 to give hexane-ethyl acetate (1
Purified by silica gel column chromatography using 0: 1) as an eluent, and crystallized from a mixed solvent of ethyl acetate and hexane to give 2,4-cis-5- (3-chlorobenzoyloxy) -4 as colorless needle crystals. -(4-Methoxybenzyloxy) -2,6,6-trimethylcycloheptane-1
0.81 g (27%) of -one (AU131) was obtained. Melting point 104-105 [deg.] C.

IR (KBr, cm ^-1 ): 1713,16
15, 1514, 1257, 1069, 820, 74
5.

1H-NMR (CDCl ₃ , ppm):
1.01 (3H, s), 1.06 (3H, s), 1.1
8 (3H, d, J = 7Hz), 1.89 (1H, m),
2.10 (1H, m), 2.22 (1H, d, J = 13
Hz), 2.32 (1H, m), 2.87 (1H, d,
J = 13Hz), 3.50 (1H, brd, J = 9H
z), 3.75 (3H, s), 4.30 (1H, d, J
= 11 Hz), 4.50 (1H, d, J = 11 Hz),
5.17 (1H, d, J = 9Hz), 6.66 (2H,
d, J = 9 Hz), 6.97 (2H, d, J = 9H)
z), 7.40 (1H, t, J = 8Hz), 7.55
(1H, dm, J = 8Hz), 7.89 (1H, dt,
J = 8, 2Hz), 7.94 (1H, t, J = 2H
z).

[0549]

Example 112 The product of Example 111 (795 mg,
1,76 mmol) was treated with DDQ according to Example 7 and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless plate crystals of 2,4-cis-5- (3-chlorobenzoyloxy) -4. 405 mg of -hydroxy-2,6,6-trimethylcycloheptan-1-one (AU132)
(70%) was obtained. Melting point 136-137 [deg.] C.

IR (KBr, cm ^-1 ): 3457, 17
22, 1675, 1261, 982, 746.

1 H-NMR (CDCl ₃ , ppm):
1.05 (3H, s), 1.07 (3H, s), 1.1
8 (3H, d, J = 7Hz), 1.94 (1H, d, J
= 6 Hz; disappeared by adding heavy water), 1.94 (1H,
m), 2.10 (1H, m), 2.21 (1H, d, J
= 13 Hz), 2.44 (1 H, m), 2.89 (1
H, d, J = 13 Hz), 3.82 (1 H, m; brt, J = 9.2 Hz by heavy water addition), 5.03 (1 H,
d, J = 9 Hz), 7.42 (1H, t, J = 8H
z), 7.57 (1H, dm, J = 8Hz), 7.96
(1H, dt, J = 8, 2Hz), 8.04 (1H,
t, J = 2 Hz).

[0552]

Example 113 To a solution of Cycin N (11.05 g, 60 mmol) in methanol (50 ml) was added 10% palladium-carbon (0.2 g), and catalytic reduction was carried out at room temperature, followed by filtration.
28% sodium methoxide methanol solution (2
ml) was added and the mixture was stirred at room temperature for 1 day. After concentrating the reaction solution,
Dilute with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography eluting with hexane-ethyl acetate (10: 1) to give a colorless oil. 2,4-cis-
2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Octane-1,4-diol (AUM11) was obtained in an amount of 8.40 g (76%).

IR (KBr, cm ^-1 ): 3404, 16
94, 1458, 1052, 1034.

[0554]

Example 114 5-hydroxy-obtained in Example 4
4-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (24 g, 0.12 mol) was added to Example 1.
13, catalytically reduced and treated with a base, and crystallized from hexane to give colorless crystalline 2,4-cis-4-methoxy-2,
6,6-Trimethyl-8-oxabicyclo [3.2.
1] 15.2 g of octan-1-ol (AUM13)
(63%) obtained.

IR (KBr, cm ^-1 ): 3356, 12
70, 1114, 1064, 1008, 985, 97
4.

[0556]

Example 115 5-hydroxy-obtained in Example 1
4- (4-Methoxybenzyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (16.6
g, 54.5 mmol) were subjected to catalytic reduction and base treatment according to Example 113 to give 2,4-cis-4- (4 as colorless oil.
-Methoxybenzyloxy) -2,6,6-trimethyl-8-oxabicyclo [3.2.1] octan-1-ol (AUM15) was obtained in an amount of 12.2 g (73%).

IR (KBr, cm ^-1 ): 3384, 15
14, 1247, 1062, 1036, 752.

[0558]

Example 116 A solution of Saishin N (25.8 g, 0.1 mol) in methanol (150 ml) was subjected to catalytic reduction and base treatment according to Example 113, p-toluenesulfonic acid was added, and the mixture was allowed to stand for 2 days. did. Potassium carbonate was added to the reaction solution, the mixture was stirred, concentrated, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered,
After concentrating, the residue was crystallized from hexane to give 2,4-cis-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (as colorless fluffy crystals. 18.1 g (64%) of AU105B) was obtained. Melting point 74-75 [deg.] C.

IR (KBr, cm ^-1 ): 3242, 14
64, 1349, 1056, 1011.

1H-NMR (CDCl ₃ , ppm):
0.85 (3H, d, J = 6Hz), 1.25 (3H,
s), 1.26 (3H, s), 1.43 (1H, t, J
= 14 Hz), 1.57 (1H, d, J = 14 Hz),
1.68 (1H, d, J = 14Hz), 2.02 (2
H, m), 3.36 (3H, s), 3.60 (1H, b
rd, J = 4 Hz), 4.00 (1H, m).

The above crystal mother liquor was purified by silica gel column chromatography using hexane-ethyl acetate (10: 1) as an eluent, and crystallized from hexane to give 2,4-trans-1-methoxy-colorless cotton crystals. 2, 6, 6-
Trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (AU105A) 4.65 g (16
%)Obtained. Melting point 93-93.5 [deg.] C.

IR (KBr, cm ^-1 ): 3217, 14
64, 1354, 1280, 1048.

1H-NMR (CDCl ₃ , ppm):
1.09 (3H, d, J = 7Hz), 1.24 (3H,
s), 1.29 (3H, s), 1.41 (1H, d, J
= 5 Hz; disappeared by adding heavy water), 1.62 (1H,
d, J = 14 Hz), 1.77 (1H, m), 1.88
-2.06 (3H, m), 3.35 (3H, s), 3.
60 (1H, brd, J = 4Hz), 4.15 (1H,
m).

[0564]

Example 117 2,4-cis-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (0.3
g, 1.5 mmol) was acetylated by a conventional method to give colorless crystalline 2,4-cis-4-acetoxy-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Octane (AU108B) 0.35 g (9
6.1%) was obtained. Melting point 52-53 ° C IR (KBr, cm ^-1 ): 1734, 1472, 124
8.

1 H-NMR (CDCl ₃ , ppm):
0.84 (1H, d, J = 6Hz), 1.20 (3H,
s), 1.23 (3H, s), 1.42 (1H, q, J
= 12 Hz), 1.58 (1H, d, J = 13 Hz),
1.70 (1H, d, J = 13Hz), 2.03 (3
H, s), 2.08 (2H, m), 3.37 (3H,
s), 3.71 (1H, d, J = 4Hz), 4.95
(1H, m).

[0566]

Example 118 2,4-trans-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (0.3 g, obtained in Example 116) 1.5 mmol) was acetylated by a conventional method to give 2,4-trans-4-acetoxy-1 as colorless oil.
-Methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane (AU108A) was added to 0.3
2 g (87.3%) was obtained.

IR (KBr, cm ^-1 ): 1738, 12
41, 1041.

1H-NMR (CDCl ₃ , ppm):
1.13 (3H, d, J = 7Hz), 1.22 (3H,
s), 1.23 (3H, s), 1.63 (1H, d, J
= 13 Hz), 1.79 (1 H, m), 2.03 (3
H, s), 1.90-2.10 (3H, m), 3.35.
(3H, s), 3.70 (1H, d, J = 4Hz),
5.11 (1H, m).

[0569]

Example 119 2,4-cis-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (0.3
0 g, 1.5 mmol) was methylated according to Example 69 to give 2,4-cis-1,4-dimethoxy- as colorless oil.
2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Octane (AU109B) 0.235g (7
3.2%).

1H-NMR (CDCl ₃ , ppm):
0.84 (3H, d, J = 6Hz), 1.20 (3H,
s), 1.23 (3H, s), 1.31 (1H, d, J
= 12 Hz), 1.55 (1H, d, J = 13 Hz),
1.66 (1H, d, J = 13 Hz), 1.94-2.
11 (2H, m), 3.34 (3H, s), 3.37
(3H, s), 3.47-3.55 (1H, m), 3.
75 (1H, d, J = 4Hz).

[0571]

Example 120 2,4-trans-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (0.30 g, obtained in Example 116) 1.5 mmol) was treated as in the previous example to give colorless oily 2,4-trans-1,4-dimethoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1]. Octane (AU109A) 0.256
g (80.7%) was obtained.

IR (KBr, cm ^-1 ): 1468, 12
19, 1109.

1H-NMR (CDCl ₃ , ppm):
1.09 (3H, d, J = 7Hz), 1.22 (3H,
s), 1.23 (3H, s), 1.60 (1H, d, J
= 14 Hz), 1.50-2.00 (4H, m), 3.
34 (3H, s), 3.35 (3H, s), 3.64
(1H, m), 3.74 (1H, m).

[0574]

Example 121 2,4-cis-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (1.0 obtained in Example 116)
g, 5.0 mmol) of tetrahydrofuran (50 m
l) A hexane solution of n-butyllithium (1.59 mol / l; 4.7 m) at −60 ° C. in an argon atmosphere.
1) was added, and the mixture was stirred at -60 ° C for 30 minutes, benzoyl chloride (0.84 g, 7.2 mmol) was added, and the mixture was stirred for 30 minutes and then returned to room temperature. The reaction solution was poured into ice water, saturated with sodium chloride, extracted with ethyl acetate, dried and purified by silica gel column chromatography using hexane-ethyl acetate (50: 1) as an eluent. Crystallized from hexane to give colorless needles. 2,4-cis-4-benzoyloxy-
1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane (AU119) was added to 0.7
5 g (49.5%) were obtained. Melting point 89-90 [deg.] C.

IR (KBr, cm ^-1 ): 1709, 15
99, 1469, 1278, 1110, 1013, 71
1.

1H-NMR (CDCl ₃ , ppm):
0.88 (3H, d, J = 7Hz), 1.27 (3H,
s), 1.35 (3H, s), 1.50-1.70 (2
H, m), 1.78 (1H, d, J = 14 Hz), 2.
20 (2H, m), 3.40 (3H, s), 3.83
(1H, d, J = 4Hz), 5.24 (1H, m),
7.44 (2H, m), 7.57 (1H, m), 8.0
0 (2H, m).

[0577]

Example 122 2,4-cis-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (4.5 obtained in Example 116)
55% sodium hydride (1.05 g, 24 mmol) and benzyl bromide (2.85 ml, 24 mmol) were added to a tetrahydrofuran solution of 2 g, 22 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours and then for 30 minutes. Heated to reflux. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was used as hexane-ethyl acetate (100: 1 to 30: 1) as an eluent. It was fractionated by silica gel column chromatography, and a colorless oily 2,4-trans-
4-benzyloxy-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane (AU162A) was obtained in an amount of 1.00 g (15.7%).

IR (KBr, cm ^-1 ): 1466, 12
17,1110.

1 H-NMR (CDCl ₃ , ppm):
1.07 (3H, d, J = 7Hz), 1.22 (3H,
s), 1.30 (3H, s), 1.63 (1H, d, J
= 14 Hz), 1.91 (1H, d, J = 14 Hz),
1.82-2.10 (3H, m), 3.34 (3H,
s), 3.73 (1H, brd, J = 4Hz), 3.8
4 (1H, m), 4.53 (2H, s), 7.31 (5
H, m).

From the subsequent elution, colorless oily 2,4-cis-
2.36 g (37.0%) of 4-benzyloxy-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane (AU162B) was obtained.

IR (KBr, cm ^-1 ): 1466, 12
20, 1114, 1071.

1 H-NMR (CDCl ₃ , ppm):
0.84 (3H, d, J = 7Hz), 1.24 (3H,
s), 1.28 (3H, s), 1.42 (1H, m),
1.57 (1H, d, J = 14Hz), 1.68 (1
H, d, J = 14 Hz), 1.98-2.09 (2H,
m), 3.36 (3H, s), 3.70 (1H, m),
3.75 (1H, m), 4.53 (2H, s), 7.3
0 (5H, m).

[0583]

Example 123 2,4-cis-2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Octane-1,4-diol (0.93 g, 5
Benzoylate according to Example 6 and crystallized from hexane to give colorless needle crystals of 2,4-cis-4-benzoyloxy-2,6,6-trimethyl-8-oxabicyclo [3.2. 1] Octane-1-ol (AU5
02) was obtained (1.04 g, 71%). Melting point 157-15
8 ° C.

IR (KBr, cm ^-1 ): 3467, 16
95, 1317, 1307, 1291, 1128, 72
0.

[0585]

Example 124 The product of Example 123 (0.5 g,
1.72 mmol) was acetylated by a conventional method and crystallized from water to give colorless amorphous crystals of 2,4-cis-5-acetoxy-4-benzoyloxy-2,6,6-trimethylcycloheptan-1-one. (AU194) 0.43
g (75%) was obtained. Melting point 166-200 [deg.] C.

IR (KBr, cm ^-1 ): 1737, 17
10, 1451, 1374, 1273, 1241, 11
12,715.

1H-NMR (CDCl ₃ , ppm):
1.01 (3H, s), 1.05 (3H, s), 1.1
6 (3H, d, J = 7Hz), 1.90 (3H, s),
2.06 (2H, m), 2.26 (1H, d, J = 13
Hz), 2.54 (1H, m), 2.88 (1H, d,
J = 13 Hz), 5.17 (2H, m), 7.45 (2
H, m), 7.58 (1H, m), 7.98 (2H,
m).

[0588]

Example 125 2,4-cis-2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Octane-1,4-diol (0.93 g, 5
(3 mmol) was treated with 3-chlorobenzoyl chloride (0.96 g, 5.5 mmol) according to Example 17, acetylated according to a conventional method, and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals. 0.54 g (32%) of 2,4-cis-5-acetoxy-4- (3-chlorobenzoyloxy) -2,6,6-trimethylcycloheptan-1-one (AU199) was obtained. Melting point 1
91-192 ° C.

IR (KBr, cm ^-1 ): 1743, 17
18,1703,1263,1237,1124,75
4,740.

1H-NMR (CDCl ₃ , ppm):
1.01 (3H, s), 1.05 (3H, s), 1.1
7 (3H, d, J = 7Hz), 1.92 (3H, s),
2.04 (2H, m), 2.27 (1H, d, J = 13
Hz), 2.54 (1H, m), 2.88 (1H, d,
J = 13 Hz), 5.15 (2H, m), 7.40 (1
H, t, J = 8 Hz), 7.55 (1H, brd, J =
8Hz), 7.86 (1H, brd, J = 8Hz),
7.98 (1H, m).

[0591]

Example 126 2,4-cis-2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Octane-1,4-diol (5.59 g, 3
0 mmol) was acetylated according to a conventional method and crystallized from ethyl acetate and hexane to give colorless needle crystals of 2,4-cis-4,5-diacetoxy-2,6,6-trimethylcycloheptan-1-one (AU117). ) 6.73 g (8
3%) was obtained. Melting point 77-78 [deg.] C.

IR (KBr, cm ^-1 ): 1744, 17
00, 1246, 1229.

1 H-NMR (CDCl ₃ , ppm):
0.96 (3H, s), 1.00 (3H, s), 1.1
3 (3H, d, J = 7Hz), 1.91 (2H, m),
2.02 (3H, s), 2.07 (3H, s), 2.2
2 (1H, d, J = 13Hz), 2.47 (1H,
m), 2.81 (1H, d, J = 13Hz), 4.95
(2H, m).

[0594]

Example 127 2,4-cis-4-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-1-ol (1.0 obtained in Example 114)
g., 5 mmol) was acetylated by a conventional method and crystallized from hexane to give colorless crystals of 2,4-cis-5-acetoxy-4-methoxy-2,6,6-trimethylcycloheptan-1-one (AU120). 0.9 g (75%)
Obtained. Melting point 80-82 [deg.] C.

IR (KBr, cm ^-1 ): 1742,16
99, 1239, 1092, 1026.

1H-NMR (CDCl ₃ , ppm):
0.92 (3H, s), 1.00 (3H, s), 1.1
6 (3H, d, J = 7Hz), 1.74 (1H, m),
2.03 (1H, m), 2.11 (3H, s), 2.1
8 (1H, d, J = 13Hz), 2.33 (1H,
m), 2.78 (1H, d, J = 13Hz), 3.13
(1H, m), 3.34 (3H, s), 4.85 (1
H, d, J = 9 Hz).

[0597]

Example 128 2,4-cis-4-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-1-ol (1 g, obtained in Example 114)
5 mmol) was benzoylated according to Example 6 and purified by silica gel column chromatography eluting with benzene-ethyl acetate (50: 1) to give 2,4-cis-1-benzoyloxy- as a colorless oil. 4-methoxy-
2,6,6-trimethyl-8-oxabicyclo [3.
2.1] Octane (AU122) 0.27 g (17.
9%) was obtained.

1H-NMR (CDCl ₃ , ppm):
0.94 (3H, d, J = 7Hz), 1.25 (3H,
s), 1.38 (3H, s), 1.41 (1H, q, J
= 12 Hz), 2.10 (3H, m), 2.72 (1
H, m), 3.37 (3H, s), 3.65 (1H,
m), 3.95 (1H, d, J = 4Hz), 7.43
(2H, m), 7.55 (1H, m), 8.03 (2
H, m).

[0599]

Example 129 2,4-cis-4- (4-methoxybenzyloxy) -2,6,6-obtained in Example 115
Trimethyl-8-oxabicyclo [3.2.1] octane-1-ol (1.83 g, 6 mmol) was acetylated according to a conventional method, and hexane-ethyl acetate (10: 1-
Fractionation was carried out by silica gel column chromatography using 5: 1) as an eluent, and a colorless oily matter of 2,4 was obtained from the first eluate.
0.28 g of -cis-1-acetoxy-4- (4-methoxybenzyloxy) -2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane (AU186)
(13%) obtained.

IR (KBr, cm ^-1 ): 1753,16
12, 1514, 1249.

1H-NMR (CDCl ₃ , ppm):
0.83 (3H, d, J = 6Hz), 1.25 (3H,
s), 1.29 (3H, s), 1.41 (1H, q, J
= 12 Hz), 1.91 (1H, d, J = 13 Hz),
1.94 (1H, d, J = 13Hz), 2.02 (1
H, m), 2.05 (3H, s), 2.55 (1H,
m), 3.75 (1H, m), 3.80 (3H, s),
3.84 (1H, m), 4.46 (2H, s), 6.8
6 (2H, d, J = 9Hz), 7.22 (2H, d, J
= 9 Hz).

From the subsequent elution, colorless oily 2,4-cis-
5-acetoxy-4- (4-methoxybenzyloxy)
1.41 g (67%) of -2,6,6-trimethylcycloheptan-1-one (AU185) was obtained.

IR (KBr, cm ^-1 ): 1740, 17
00, 1613, 1514, 1244, 1031.

1 H-NMR (CDCl ₃ , ppm):
0.91 (3H, s), 1.01 (3H, s), 1.1
3 (3H, d, J = 7Hz), 1.82 (1H, m),
2.04 (3H, s), 2.05 (1H, m), 2.1
7 (1H, d, J = 13Hz), 2.28 (1H,
m), 2.77 (1H, d, J = 13Hz), 3.38.
(1H, m), 3.80 (3H, s), 4.42 (1
H, d, J = 13Hz), 4.53 (1H, d, J = 1)
3 Hz), 4.93 (1H, d, J = 9 Hz), 6.8
6 (2H, d, J = 9Hz), 7.19 (2H, d, J
= 9 Hz).

[0605]

Example 130 2,4-cis-4- (4-methoxybenzyloxy) -2,6,6-obtained in Example 115
Trimethyl-8-oxabicyclo [3.2.1] octane-1-ol (2.13 g, 6.9 mmol) was benzoylated according to Example 6 to give benzene and benzene-ethyl acetate (20: 1). Fractionation was performed by silica gel column chromatography as an eluent, and the first eluate was crystallized from a mixed solvent of ethyl acetate and hexane to give colorless plate crystals of 2,4-cis-1-benzoyloxy-4- (4-
Methoxybenzyloxy) -2,6,6-trimethyl-
8-Oxabicyclo [3.2.1] octane (AU18
8) was obtained (0.40 g, 14%). Melting point 89.5-9
0.5 ° C.

IR (KBr, cm ^-1 ): 1742, 16
14, 1512, 1248.

1 H-NMR (CDCl ₃ , ppm):
0.92 (3H, d, J = 7Hz), 1.30 (3H,
s), 1.37 (3H, s), 1.48 (1H, q, J
= 12 Hz), 2.09 (3 H, m), 2.71 (1
H, m), 3.80 (3H, s), 3.84 (1H,
m), 3.91 (1H, m), 4.47 (1H, d, J
= 12Hz), 4.51 (1H, d, J = 12Hz),
6.87 (2H, d, J = 9Hz), 7.24 (2H,
d, J = 9 Hz), 7.42 (2H, m), 7.52
(1H, m), 8.01 (2H, m).

The subsequent eluate was crystallized from a mixed solvent of ethyl acetate and benzene to give colorless needle crystals of 2,4-cis-5.
0.65 g (23%) of -benzoyloxy-4- (4-methoxybenzyloxy) -2,6,6-trimethylcycloheptan-1-one (AU187) was obtained. Melting point 7
0.5-71.5 ° C.

IR (KBr, cm ^-1 ): 1717, 17
01, 1612, 1515, 1272, 713.

1 H-NMR (CDCl ₃ , ppm):
1.02 (3H, s), 1.07 (3H, s), 1.1
6 (3H, d, J = 7Hz), 1.89 (1H, m),
2.08 (1H, m), 2.23 (1H, d, J = 13
Hz), 2.34 (1H, m), 2.86 (1H, d,
J = 13 Hz), 3.51 (1 H, m), 3.73 (3
H, s), 4.34 (1H, d, J = 13 Hz), 4.
48 (1H, d, J = 13 Hz), 5.18 (1H,
d, J = 9 Hz), 6.64 (2H, d, J = 9H)
z), 6.98 (2H, d, J = 9Hz), 7.46
(2H, m), 7.58 (1H, m), 8.02 (2
H, m).

[0611]

Example 131 2,4-cis-5-benzoyloxy-4- (4-methoxybenzyloxy) -2,6,6-trimethylcycloheptane-1 obtained in Example 130.
-One (574 mg, 1.4 mmol) was treated with DDQ according to Example 7 and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless plate crystals of 2,4-cis-5-benzoyloxy-4. -Hydroxy-2,6,6-trimethylcycloheptan-1-one (AU191) 330m
g (81%) was obtained. Melting point 166-17.5 [deg.] C.

IR (KBr, cm ^-1 ): 3436, 17
17, 1682, 1270, 706.

1 H-NMR (CDCl ₃ + D ₂ O, pp
m): 1.06 (3H, s), 1.07 (3H, s),
1.18 (3H, d, J = 7Hz), 1.96 (1H,
m), 2.10 (1H, m), 2.20 (1H, d, J
= 13 Hz), 2.44 (1 H, m), 2.89 (1
H, d, J = 13 Hz), 3.82 (1 H, m), 5.
03 (1H, d, J = 9Hz), 7.48 (2H,
m), 7.60 (1H, m), 8.09 (2H, m).

[0614]

Example 132 The product of Example 131 (206 mg,
0.7 mmol) was acetylated according to a conventional method and crystallized from water to give colorless crystals of 2,4-cis-4-acetoxy-
190 mg (81) of 5-benzoyloxy-2,6,6-trimethylcycloheptan-1-one (AU192)
%)Obtained. Melting point 119.5-121 [deg.] C.

IR (KBr, cm ^-1 ): 1732, 16
94, 1270, 1106, 712.

1H-NMR (CDCl ₃ , ppm):
1.07 (3H, s), 1.08 (3H, s), 1.1
7 (3H, d, J = 7Hz), 1.98 (2H, m),
2.27 (1H, d, J = 13Hz), 2.51 (1
H, m), 2.90 (1H, d, J = 13 Hz), 5.
13 (1H, m), 5.23 (1H, d, J = 9H
z), 7.45 (2H, m), 7.58 (1H, m),
7.99 (2H, m).

[0617]

Example 133 2,4-cis-4- (4-methoxybenzyloxy) -2,6,6-obtained in Example 115
Trimethyl-8-oxabicyclo [3.2.1] octane-1-ol (1.2 g, 3.9 mmol) was treated with benzoyl chloride according to Example 17 to give Example 13.
2,4-cis-1-benzoyloxy-4 obtained in 1.
0.97 g (60%) of-(4-methoxybenzyloxy) -2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane (AU188) was obtained.

The above product (821 mg, 2.0 mmol) was treated with DDQ according to Example 7 and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals.
4-cis-1-benzoyloxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4
-410 mg (71%) of all (AU252) was obtained.

Melting point 87-88 ° C.

IR (KBr, cm ^-1 ): 3516,17
26, 1276, 997.

1H-NMR (CDCl ₃ , ppm):
0.95 (3H, d, J = 7Hz), 1.31 (3H,
s), 1.40 (3H, s), 1.51 (1H, q, J
= 12 Hz), 1.58 (1H, brs; disappeared by addition of heavy water), 2.07 (1H, d, J = 13 Hz), 2.
08 (1H, m), 2.16 (1H, d, J = 13H
z), 2.74 (1H, m), 3.80 (1H, d, J
= 4 Hz), 4.13 (1H, m), 7.43 (2H,
m), 7.56 (1H, m), 8.02 (2H, m).

[0622]

Example 134 2,4-cis-4- (4-methoxybenzyloxy) -2,6,6-obtained in Example 115
To a solution of trimethyl-8-oxabicyclo [3.2.1] octane-1-ol (1.2 g, 3.9 mmol) in tetrahydrofuran (10 ml) at 0 ° C. was added 55% sodium hydride (0.18 g, 4.1 mmol) was added and after 10 minutes 4-nitrobenzoyl chloride (0.76 g, 4.
(1 mmol) was added and the mixture was stirred for 1 hour, and further stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with dilute aqueous potassium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane to give slightly yellow prismatic crystals. 2,4-cis-4- (4-methoxybenzyloxy) -1- (4-
Nitrobenzoyloxy) -2,6,6-trimethyl-
1.1 g of 8-oxabicyclo [3.2.1] octane
(62%) was obtained. Melting point 116.5-117.5 ° C IR
(KBr, cm ^-1 ): 1740, 1530, 1350,
1276.

1H-NMR (CDCl ₃ , ppm):
0.93 (3H, d, J = 7Hz), 1.32 (3H,
s), 1.38 (3H, s), 1.50 (1H, q, J
= 12 Hz), 2.11 (3H, m), 2.69 (1
H, m), 3.81 (3H, s), 3.85 (1H,
m), 3.92 (1H, m), 4.48 (1H, d, J
= 12Hz), 4.51 (1H, d, J = 12Hz),
6.87 (2H, d, J = 8Hz), 7.24 (2H,
d, J = 8 Hz), 8.18 (2H, d, J = 9H
z), 8.28 (2H, d, J = 9Hz).

The above product (1.00 g, 2.2 mmol) was treated with DDQ according to Example 7 and crystallized from a mixed solvent of ethyl acetate and hexane to give colorless needle crystals.
4-cis-1- (4-nitrobenzoyloxy) -2,
6,6-Trimethyl-8-oxabicyclo [3.2.
1] 0.58 g of octan-4-ol (AU250)
(78%) was obtained. Melting point 103-104 [deg.] C.

IR (KBr, cm ^-1 ): 3600-31
00, 1740, 1530, 1350, 1276.

1H-NMR (CDCl ₃ , ppm):
0.98 (3H, d, J = 7Hz), 1.33 (3H,
s), 1.41 (3H, s), 1.53 (1H, q, J
= 12 Hz), 2.12 (3H, m), 2.72 (1
H, m), 3.82 (1H, d, J = 4Hz), 4.1
6 (1H, m), 8.18 (2H, d, J = 9Hz),
8.28 (2H, d, J = 9Hz).

[0627]

Example 135 The product of Example 134 (436 mg,
1.3 mmol) was reduced at the nitro group according to Example 19 to give orange caramelized 2,4-cis-1- (4-aminobenzoyloxy) -2,6,6-trimethyl-8-oxabicyclo. [3.2.1] Octane-4-ol (A
U251) was obtained in an amount of 360 mg (90%).

IR (KBr, cm ^-1 ): 3462, 33
67, 1706, 1628, 1603, 1279, 11
70.

1H-NMR (CDCl ₃ , ppm):
0.93 (3H, d, J = 7Hz), 1.30 (3H,
s), 1.39 (3H, s), 1.49 (1H, q, J
= 12 Hz), 1.58 (1H, brs), 2.08
(3H, m), 2.72 (1H, m), 3.78 (1
H, d, J = 4 Hz), 4.11 (3 H, m; 1 H, m by addition of heavy water), 6.63 (2 H, d, J = 9 H)
z), 7.83 (2H, d, J = 9Hz).

[0630]

Example 136 Dimethyl sulfoxide (2.84 m
1, 40 mmol) in methylene chloride (20 ml) was kept at −65 ° C. or lower, and trifluoroacetic anhydride (4.
16 ml, 30 mmol) methylene chloride (10 ml)
The solution is added in 20 minutes and after 10 minutes 2,4-cis-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-obtained in Example 116.
A solution of all (4.00 g, 20 mmol) in methylene chloride (20 ml) was added dropwise at the same temperature. After 30 minutes, triethylamine was added at the same temperature, the temperature was returned to room temperature, water was added, and the layers were separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (100: 1-10: 1) as an eluent, and crystallized from hexane to give colorless. 3.25 g (82%) of plate crystals of 1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-one (AU163) were obtained. Melting point 38-39 [deg.] C.

IR (KBr, cm ^-1 ): 1729, 14
58, 1246, 1018.

1H-NMR (CDCl ₃ , ppm):
0.93 (3H, d, J = 7Hz), 1.01 (3H,
s), 1.30 (3H, s), 1.75 (1H, d, J
= 14 Hz), 1.82 (1H, d, J = 14 Hz),
1.88 (1H, m), 2.48 (1H, m), 2.6
0 (1H, m), 3.42 (3H, s), 3.73 (1
H, brs).

13 C-NMR (CDCl ₃ , ppm):
15.40 (q), 22.29 (q), 29.95
(Q), 38.27 (d), 38.35 (t), 39.
74 (s), 42.33 (t), 49.59 (q), 9
0.76 (d), 110.14 (s), 206.27
(S).

[0634]

Front page continuation (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/24 8413-4C 31/245 8413-4C C07C 49/503 6917-4H 49/517 6917-4H 49 / 607 6917-4H 49/717 6917-4H 49/753 B 6917-4H 67/08 69/013 E 8018-4H 69/76 Z 9279-4H 205/45 6917-4H 229/54 8930-4H C07D 493/08 B 9164-4C (72) Inventor Hiroyuki Iizuka 6-29-1, Shimouma, Setagaya-ku, Tokyo Inside Tanabe Pharma Setagaya Dormitory (72) Inventor Eiji Otsubo 1-7-11, Honmachi Higashi, Yono-shi, Saitama Yono City Tea No. 203

Claims (10)

[Claims] 1. A Cycin N derivative represented by the following general formula. [Chemical 1] 2. 5-Hydroxy-4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one, 4- (4-aminobenzoyloxy) -5-hydroxy-2. , 6,6-Trimethyl-2
-Cyclohepten-1-one, 5-hydroxy-4-
(1-methyl-2-pyrrolylcarbonyloxy) -2,
6,6-trimethyl-2-cyclohepten-1-one,
5- (2,4-diaminobenzoyloxy) -4-methoxy-2,6,6-trimethyl-2-cycloheptene-
1-one, 2,4-cis-1-methoxy-2,6,6-
Trimethyl-8-oxabicyclo [3.2.1] heptan-4-ol or 4- (4-aminobenzoyloxy) -1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2. 1] octa-2-ene, The Cycin N derivative according to claim 1. 3. 4- (4-aminobenzoyloxy)
-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one. 4. 2,4-cis-1-methoxy-2,
6,6-Trimethyl-8-oxabicyclo [3.2.
1] Heptan-4-ol. 5. An alcohol represented by the general formula [R ¹ -OH] (in the formula, R ¹ represents an alkyl group, an alkenyl group or an aralkyl group) in the presence of an acid catalyst, eucarboxylic-4,5-oxide. A method for producing a Cycin N derivative represented by the following general formula, which is characterized by subjecting to an alcoholysis reaction according to [Chemical 2] (In the formula, R ¹ has the same meaning as above.) 6. Saicin N and a carboxylic acid represented by the general formula [R ² COOH] (R ² represents an alkyl group, an alkenyl group, an aromatic hydrocarbon group or a heterocyclic group) in the presence of a carbodiimide. A method for producing a Cycin N derivative represented by the following general formula, which comprises subjecting to an acylation reaction. [Chemical 3] (In the formula, R ² has the same meaning as above.) 7. The following general formula: (In the formula, R ⁸ represents an alkyl group, an alkenyl group, an aralkyl group or an acyl group.) A 5-hydroxycycin N derivative represented by the general formula [R ⁹ —OH] (wherein R ⁹ represents an alkyl group, an alkenyl group or an aralkyl group.) A process for producing a Saishin N derivative represented by the following general formula, characterized by treating with an alcohol. [Chemical 5] (In the formula, R ⁸ and R ⁹ are as defined above.) 8. The following general formula: (In the formula, R ⁸ represents an alkyl group, an alkenyl group, an aralkyl group or an acyl group.) The 5-hydroxycycin N derivative is subjected to an alkylation, an alkenylation, an aralkylation or an acylation reaction. A method for producing a Cycin N derivative represented by the following general formula: [Chemical 7] (In the formula, R ⁸ is as defined above, R ⁹ is an alkyl group,
It represents an alkenyl group, an aralkyl group or an acyl group. ) 9. The following general formula: (In the formula, R ¹⁰ represents an alkyl group, an alkenyl group, an aralkyl group or an acyl group.) The 2,3-dihydrocycin N derivative represented by the general formula [R ¹¹ —OH] (formula Wherein R ¹¹ represents an alkyl group, an alkenyl group or an aralkyl group.), The method for producing a Saishin N derivative represented by the following general formula, characterized in that: [Chemical 9] (In the formula, R ¹⁰ and R ¹¹ are as defined above.) 10. The following general formula: An anti-ulcer agent containing a Cycin N derivative represented by