JP4622310B2 - Low-density lipoprotein oxidative degeneration inhibitor and anti-atherosclerotic agent - Google Patents

Description

  The present invention relates to the use of a compound having a chemical structure similar to that of gingerol and gingerol, and the compound has the ability to prevent oxidation of low-density lipoprotein (LDL), and has anti-atherogenic arteries. It can be used as a curing agent.

The onset and progression of arteriosclerosis is known to be closely related to oxidative degeneration of LDL. Pathological features of macrophages macrophages that have accumulated cholesterol and foamed in the initial stage of atherosclerosis are found under the endothelial cells. Macrophage foaming is an important step in the formation of atherosclerotic lesions. It is thought that there is. The source of cholesterol accumulated in foam cells is circulating LDL. As this molecular mechanism, it is said that denatured LDL such as oxidized LDL is taken up into cells through a receptor (scavenger receptor) different from the LDL receptor on the macrophage cell membrane without being saturated. Yes. Such foam cell lesions further progress to complex lesions accompanied by migration and proliferation of vascular smooth muscle cells to the intima, narrowing the intima of the blood vessels.
On the other hand, arteriosclerotic lesions are also considered to be formed on the basis of a chronic inflammatory reaction induced by vascular endothelial cell dysfunction (for example, see Non-patent Document 1 and Non-Patent Document 2). This is because when an endothelial dysfunction factor that causes damage to vascular endothelial cells acts, the function of the endothelial cells changes, and it progresses to arteriosclerosis by the involvement of monocytes and macrophages. Endothelial injury factors include hypertension, smoking, hyperlipidemia, infection, oxidative stress and the like. Oxidized LDL is known to act not only on macrophages but also on vascular endothelial cells (see, for example, Non-Patent Document 3). Expression of leukocyte adhesion molecules and smooth muscle growth factors, and endothelium-dependent blood vessels via nitric oxide. It is involved in suppression of diastolic response or induction of apoptosis. Thus, since oxidized LDL acts not only on macrophages but also on the vascular endothelium to trigger the onset of arteriosclerosis, it is important to prevent oxidative degeneration of LDL.
In hypertensive patients, it has been reported that the oxidizability of blood LDL is enhanced (for example, see Non-patent Document 4). For example, in comparison with normal blood pressure, hypertensive patients produce a large amount of active oxygen in vascular endothelial cells (see, for example, Non-Patent Document 5), and leukocytes produce a large amount of active oxygen (for example, It has been reported that the activity of superoxide dismutase (SOD), which is an active oxygen scavenging enzyme, is reduced (see, for example, Non-Patent Document 7). From these results, it is considered that in hypertension, oxidative degeneration such as LDL is involved in the progression of vascular endothelium damage and in the worsening of symptoms.
Furthermore, it is known that glycated LDL depending on hyperglycemia that occurs in diabetes is susceptible to oxidation, and it has been suggested to be associated with various symptoms caused by diabetes such as diabetic macrovascular disorder.

  On the other hand, gingerol and gingerol are the main components of ginger extract. For example, blood circulation promoting action (see Patent Document 1, "JP-A-6-183959"), body odor suppressing effect (see Patent Document 2, "US Pat. No. 6,264,928"). No.]), an antioxidant effect (see Non-Patent Document 8), a moisturizing effect (see Non-Patent Document 9), and the like. In addition, the in vivo metabolic pathways of gingerol and gingerol have been studied, and the structure of metabolites has been reported (Non-patent Documents 10 and 11).

  In a compound having a chemical structure similar to gingerol, tyrosinase activity inhibitory action (see, for example, Patent Document 3 “Japanese Patent Laid-Open No. 2003-342224”) and lipid peroxide production inhibitory action (for example, Patent Document 4, “International Publication No. WO03 / No. 099752 = PCT / JP03 / 06470 ”).

JP-A-6-183959 US Pat. No. 6,264,928 JP 2003-342224 A International Publication No. WO03 / 099752 Ross, R., England J. Med., 304, 115-126, 1999 Glass, C.K. et al., Cell, 104, 503-516, 2001 Eki Adachi et al., History of Medicine, 193, p. 299, 2000 Maggi, E. et al., J. Hypertens. 11, 1103, 1993 Jameson, M. et al., Hypertens. 21, 280, 1993 Kumar KW. Et al., Free Radic. Res. Commun. 19, 59, 1993 Hunter, GC. Et al., Proc. Soc. Exp. Biol. Med. 196, 273, 1991 Kikuzaki, H. et al., J. Food Sci., 58, 1407-1410 (1993) Supervised by Masato Suzuki, “New Functional Cosmetic Materials 300, Volume 1”, 311-312, CM Publishing, 2002 Takahashi, H. et al., Phytochemistry, 34,1497-1500 (1993) Lee, S. S., Arch. Pharm. Res., 18, 136-137 (1995)

  An object of the present invention is to provide an anti-atherosclerotic agent having an excellent LDL oxidation-suppressing effect in view of the above situation.

  As a result of further research on compounds having chemical structures similar to those of gingerol and gingerol, the present inventors have found that certain compounds also have an excellent activity to prevent oxidative degeneration of LDL, thereby preventing arteriosclerosis. The present invention has been found to be useful for prevention, and the present invention has been completed.

  The present invention is an LDL oxidation inhibitor and an anti-atherosclerotic agent characterized by containing a compound represented by the following general formula (1).

In formula (1), R ¹ is a methyl group, A is an ethylene group, B is an alkylene group having 3 to 5 carbon atoms, R ² is —COOR ³ (where R ³ is a methyl group), a carboxyl group or a -CH ₂ OH, Z is -CO-CH = CH -, - CO-CH 2 CH 2 -, - CHOH-CH 2 CH 2 -, - CHOH-CH 2 CHOH -, - CO-CH 2 CHOR _{^{4 -, - CHOH-CH 2}} CH O R 4 - a and, R ⁴ is a methyl group.

In the general formula (1), R ¹ is a methyl group for the compound represented by the general formula (1). In General formula (1), A is an ethylene group, B is a C3-C5 alkylene group.
In the general formula (1), R ² is —COOR ³ (where R ³ is a methyl group), a carboxyl group or —CH ₂ OH, and Z is —CO—CH═CH—, —CO—CH ₂ CH _{2. -, - CHOH-CH 2 CH} 2 -, - CHOH-CH 2 CHOH -, - CO-CH 2 CHOR 4 -, - CHOH-CH 2 CH O R 4 - a and, R ⁴ is a methyl group.

The compound represented by the general formula (1) is synthesized from a compound represented by the following general formula ( 2 ) (hereinafter also referred to as a compound of the formula ( 2 ), which is also abbreviated in the same manner for the compounds described later in other formulas). be able to.

In the formula ( 2 ), R ¹ represents a methyl group, R ³ represents a methyl group, R ⁵ represents a hydrogen atom, A represents an ethylene group, and B represents an alkylene group having 3 to 5 carbon atoms.

First, a method for synthesizing the compound of formula ( 2 ) will be described.
The compound of the formula ( 2 ) can be synthesized from the compound of the formula ( 5 ) obtained by the reaction between the compound of the formula ( 3 ) and the compound of the formula ( 4 ). The compound of formula ( 3 ) can be synthesized from the compound of formula ( 8 ) obtained by the reaction of the compound of formula ( 6 ) and the compound of formula ( 7 ) described later.

The compound of the formula ( 2 ) is prepared by preparing a compound of the following formula ( 5 ) using the following formula ( 3 ) compound and the following formula ( 4 ) compound as raw materials, and further detaching HX from the compound of the following formula ( 5 ). Can be manufactured.

X—CH ₂ —CH═CH—B—COOR ³ ( 3 )
In the formula ( 3 ), R ³ represents a methyl group, B represents an alkylene group having 3 to 5 carbon atoms, and X represents a benzenesulfonyl group or a toluenesulfonyl group.

式（４）中のＲ¹はメチル基であり、Ｒ⁵は水素原子であり、Ａは炭素数エチレン基を示す。

In the formula ( 4 ), R ¹ is a methyl group, R ⁵ is a hydrogen atom, and A represents a carbon number ethylene group.

R ¹ in the formula ^{(5), R 3, R} 5, A, and B are as defined in formula (1), X is as defined in formula (3).

The compound of formula ( 3 ) is prepared by reacting an alkyl metal compound with the following formula ( 6 ) compound, then reacting the following formula ( 7 ) compound to prepare the following formula ( 8 ) compound, It can be manufactured by doing.

_{CH 2 = CH-CH 2 -X} (6)
X in the formula ( 6 ) is as defined in the formula ( 3 ).

IB-COOR ³ ( 7 )
R ³ and B in the formula ( 7 ) are as defined in the formula (1).

R ³ and B in the formula ( 8 ) are as defined in the formula (1), and X is as defined in the formula ( 3 ).

In the reaction of formula (6) compound with an alkyl metal compound, for Formula (6) compounds, the ratio of the alkyl metal compound is preferably 0.7 to 1.3 chemical equivalents, more preferably, 0 .9 to 1.1 chemical equivalents.
The temperature of the reaction is preferably −100 ° C. to 0 ° C., more preferably −80 ° C. to −20 ° C. If this reaction temperature is too low, it is costly to maintain the temperature, and if the reaction temperature is too high, side reactions may proceed.
The reaction between the compound of formula ( 6 ) and the alkyl metal compound is preferably carried out in an aprotic solvent, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, hexamethylphosphoric triamide. , N, N-dimethylpropylene urea, a mixed solvent thereof and the like can be preferably used.
This reaction time varies depending on conditions, but is usually several minutes to several minutes.

  Examples of the alkyl metal compound include alkyl lithium compounds such as n-butyllithium, s-butyllithium, t-butyllithium, and phenyllithium, n-butylmagnesium chloride, s-butylmagnesium chloride, t-butylmagnesium chloride, and n-butyl. Examples include Grignard compounds such as magnesium bromide, s-butylmagnesium bromide, and t-butylmagnesium bromide, and n-butyllithium, n-butylmagnesium chloride, and n-butylmagnesium bromide can be preferably used. Further, alkali metals such as metallic lithium and metallic sodium may be used in place of the alkyl metal compound.

As described above, the compound of the formula ( 6 ) and the alkyl metal compound are reacted with the compound of the formula ( 7 ) to obtain the compound of the formula ( 8 ).
The temperature of the reaction system when adding the compound of the formula ( 7 ) to the reactant is preferably −100 ° C. to 0 ° C., and preferably −80 ° C. to −20 ° C. If this reaction temperature is too low, it is costly to maintain the temperature, and if the reaction temperature is too high, side reactions may proceed.
Although this reaction time varies depending on conditions, it is usually several minutes to several tens of minutes.
After completion of this reaction, the compound of the formula ( 8 ) can be isolated and purified by a known method such as solvent extraction or column chromatography.

A compound of formula ( 3 ) can be obtained by rearranging the X group in the compound of formula ( 8 ).
Preferable catalysts for this rearrangement reaction include palladium catalysts such as tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium (II) chloride / triphenyl. A phosphine mixture, a palladium (II) acetate / triphenylphosphine mixture, a palladium (II) acetate / tributylphosphine mixture and the like are preferably used. The amount of the metal catalyst used is preferably 0.0001 to 1 mol, more preferably 0.001 to 0.1 mol, relative to 1 mol of the compound of the formula ( 8 ). When the amount of the metal catalyst used is too small, the reaction proceeds slowly, and when the amount used is too large, labor is required for removing the catalyst.

  This rearrangement reaction is preferably carried out in the presence of a solvent. Tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, toluene, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, hexamethylphosphine Formic triamide, N, N-dimethylpropylene urea, methanol, ethanol, isopropyl alcohol, ethylene glycol, glycerin and a mixed solvent thereof can be used, and among them, a mixed solvent of tetrahydrofuran and methanol is preferable.

The reaction temperature of this rearrangement reaction is preferably from 0 ° C to 120 ° C, more preferably from 20 ° C to 100 ° C. This reaction time varies depending on conditions, but is usually several hours to several tens of hours.
After completion of this reaction, the compound of the formula ( 3 ) can be obtained by a known method such as solvent extraction or column chromatography.

Compounds of formula ( 4 ) are described in G. Solladie, et al. , J .; Org. Chem. , 58 , 2181 (1993) and the like.
In the compound of formula ( 4 ), R ¹ represents a hydrogen atom, a lower alkyl group or a protecting group for a phenolic hydroxyl group, and R ⁵ represents a hydrogen atom or a protecting group for a phenolic hydroxyl group. As a lower alkyl group of R < ¹ > of Formula ( 4 ), C1-C3 is preferable, More preferably, it is a methyl group.
As the protecting group for the phenolic hydroxyl group of R ¹ and R ^{2 in} the formula ( 4 ), it is preferable to easily introduce and remove the protecting group, and includes a silyl protecting group, an acyl protecting group, a benzyl protecting group, and Examples include ether type protecting groups. Specifically, a t-butyldimethylsilyl group, propionyl group, butyroyl group, isobutyroyl group, pivaloyl group, benzoyl group, toluoyl group, benzyl group, tetrahydropyranyl group, or methoxymethyl group is preferable.
A in the formula ( 4 ) is an alkylene group having 1 to 4 carbon atoms, preferably an ethylene group or a butylene group, and more preferably an ethylene group.

The compound of the formula ( 5 ), which is a compound for obtaining the compound of the formula ( 2 ), reacts the compound of the formula ( 3 ) that can be produced by the above-described method and the like with an alkyl metal compound, and subsequently reacts the compound of the formula ( 4 ). Can be manufactured.
As this alkyl metal compound, those which do not adversely affect the protecting group of the carboxyl group in the compound of the formula ( 3 ) are preferable, and t-butyllithium, lithium diisopropylamide, or lithium bis (trimethylsilyl) amide can be preferably used. .
Basically, the amount of the alkyl metal compound used is preferably 0.7 to 1.3 chemical equivalents, and more preferably 0.9 to 1.1 chemical equivalents, relative to the compound of the formula ( 3 ).

The above reaction is preferably carried out in an aprotic solvent, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, hexamethylphosphoric triamide, N, N-dimethylpropylene urea, and these. A mixed solvent or the like can be preferably used.
The reaction temperature between the compound of formula ( 3 ) and the alkyl metal compound is preferably -80 ° C to 25 ° C, more preferably -50 ° C to 0 ° C. The reaction time is usually several minutes to several hours.

A compound of formula ( 5 ) can be produced by reacting a compound of formula ( 3 ) and an alkyl metal compound as described above and subsequently reacting the compound of formula ( 4 ).
The temperature of the reaction system when adding the compound of formula ( 4 ) to the reactant is preferably −100 ° C. to 25 ° C., and preferably −80 ° C. to 0 ° C. The reaction time is usually several minutes to several hours.
After completion of this reaction, the compound of the formula ( 5 ) can be isolated and purified by a known method such as solvent extraction or column chromatography.

The compound of the formula ( 2 ) can be synthesized by reacting the compound of the formula ( 5 ) produced by the above method and the basic compound in the presence of a metal catalyst that forms a π-allyl complex.

As the metal catalyst for forming the π-allyl complex, a palladium complex can be preferably used. Specifically, tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform addition Products, palladium chloride (II) / triphenylphosphine mixture, palladium acetate (II) / triphenylphosphine mixture, palladium acetate (II) / tributylphosphine mixture, and the like. The amount of the metal catalyst used is preferably 0.0001 to 1 mol, more preferably 0.001 to 0.1 mol, relative to 1 mol of the compound of formula ( 5 ).

As the basic compound, triethylamine, diisopropylethylamine, and tertiary amines such as N-methylimidazole and pyridine are suitable, and the amount used is 0.9 mol or more with respect to 1 mol of the compound of the formula ( 5 ). The range of 1.0 mol to 10 mol is preferred. Such a basic compound may be used as a solvent.

  The above reaction is preferably carried out in the presence of a solvent. Tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, hexamethylphosphoric triamide , N, N-dimethylpropylene urea, methanol, ethanol, isopropyl alcohol, ethylene glycol, glycerin, and mixed solvents thereof can be used, and among them, a mixed solvent of 1,2-dichloroethane and alcohols is preferable. is there.

The reaction temperature is preferably from room temperature to 150 ° C, more preferably from 50 ° C to 120 ° C.
The reaction time is suitably several hours to several tens of hours.
After completion of this reaction, the compound of the formula ( 2 ) can be obtained by a known method such as solvent extraction or column chromatography.

Of the compounds represented by formula (1), R ² is —COOR ³ and Z is —CO—CH═CH— by removing the protecting group of the phenolic hydroxyl group from the compound of formula ( 2 ) as necessary. Certain compounds can be obtained.

  The reaction for removing the protecting group of the phenolic hydroxyl group is generally performed by a method well known in the field of synthetic organic chemistry, such as T.W. W. Greene. , “Protective Groups in Organic Synthesis”, John Wiley & Sons.

Among the compounds represented by the formula (1), a compound in which R ² is —COOR ³ and Z is —CO—CH ₂ CH ₂ — is a compound having a phenolic hydroxyl group as required from the compound of the formula ( 9 ) described later. It can be synthesized by removing the protecting group.

Among the compounds represented by the formula (1), a compound in which R ² is —COOR ³ and Z is —CHOH—CH ₂ CH ₂ — is a compound having a phenolic hydroxyl group as required from the formula ( 10 ) compound described later. It can be synthesized by removing the protecting group.

The compound of formula ( 9 ) can be produced by performing catalytic hydrogenation on the compound of formula ( 2 ). The compound of the formula ( 10 ) can be produced by reducing the compound of the formula ( 9 ) with a metal hydride complex compound. The conversion from formula ( 2 ) to formula ( 9 ) and formula ( 10 ) is shown below.

R ¹ , R ³ , A and B in formula ( 2 ), formula ( 9 ) and formula ( 10 ) are as defined in formula (1). R ⁵ is as defined in formula ( 2 ).

When producing the compound of formula ( 9 ), a metal catalyst such as palladium-carbon, platinum (IV) oxide, Raney nickel, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate is used. The inside of the reaction vessel is preferably placed in a hydrogen atmosphere. In this reaction, the proportion of the metal catalyst is preferably 0.01 to 100 weight percent, more preferably 0.1 to 10 weight percent, relative to the compound of formula ( 2 ).

The production of the compound of the formula ( 9 ) is preferably carried out in the presence of a solvent. Methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, n-pentane, n -Hexane, toluene, ethyl acetate, acetic acid, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, acetonitrile, N, N-dimethylformamide, N, N-dimethylpropionurea, dimethyl sulfoxide, water and These mixed solvents can be used.

The reaction temperature for producing the compound of formula ( 9 ) is preferably from 0 ° C to 100 ° C, more preferably from room temperature to 50 ° C. As this reaction time, several tens of minutes to several tens of hours are appropriate. After completion of the reaction, the compound of the formula ( 9 ) can be obtained by a known method such as solvent extraction or column chromatography.

As the metal hydride complex compound used when producing the compound of formula ( 10 ), those which do not adversely affect the protecting group of the carboxyl group are preferable, and lithium borohydride, sodium borohydride and the like can be preferably used. More preferred is sodium borohydride. In this reaction, the ratio of the metal hydride complex to the compound of formula ( 9 ) is preferably 0.5 to 10 chemical equivalents, more preferably 1 to 2 chemical equivalents.

The production of the compound of the formula ( 10 ) is preferably carried out in the presence of a solvent, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, acetonitrile, methanol, ethanol, isopropyl alcohol and These mixed solvents can be used.

The reaction temperature for producing the compound of the formula ( 10 ) is -20 ° C to 100 ° C, preferably 0 ° C to room temperature. The reaction time is suitably several minutes to several hours. After completion of the reaction, the compound of the formula ( 10 ) can be obtained by a known method such as solvent extraction or column chromatography.

Among the compounds represented by the formula (1), a compound in which R ² is —COOR ³ and Z is —CHOH—CH ₂ CHOH— is a compound that protects a phenolic hydroxyl group from the formula ( 11 ) described later, if necessary. It can be synthesized by removing the group.

The compound of formula ( 12 ) can be produced by adding a water molecule to the compound of formula ( 3 ). The compound of the formula ( 11 ) can be produced by reducing the compound of the formula ( 12 ) with a metal hydride complex compound. The conversion from formula ( 3 ) to formula ( 12 ) and formula ( 11 ) is shown below.

R ¹ , R ³ , A and B in formula ( 2 ), formula ( 12 ) and formula ( 11 ) are as defined in formula (1). R ⁵ is as defined in formula ( 2 ).

When water molecules are added to the compound of the formula ( 2 ) in order to obtain the formula ( 12 ), it is preferable to use a metal hydroxide such as sodium hydroxide or potassium hydroxide as an aqueous solution. The amount of metal hydroxide used is preferably 1 to 10 chemical equivalents, more preferably 2 to 5 chemical equivalents, relative to the compound of formula ( 2 ). At this time, a phase transfer catalyst may be used in combination. As this phase transfer catalyst, a quaternary ammonium salt such as tetrabutylammonium bromide, benzyltributylammonium bromide, trioctylmethylammonium bromide or the like can be preferably used. The amount of use of the phase transfer catalyst is expressed by the formula ( 2
) It is preferable that it is 0.001-1 chemical equivalent with respect to a compound, More preferably, it is 0.01-0.2 chemical equivalent.

  The above reaction is preferably carried out in the presence of a solvent, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, acetonitrile, toluene, chloroform, dichloromethane, 1,2-dichloroethane, t-butyl alcohol. , N, N-dimethylformamide, N, N-dimethylpropylene urea, dimethyl sulfoxide, and a mixed solvent thereof can be used.

The reaction temperature for producing the compound of the formula ( 12 ) is preferably from 0 ° C to 150 ° C, more preferably from room temperature to 100 ° C. The reaction time is suitably several hours to several tens of hours. After completion of the reaction, the compound of the formula ( 12 ) can be obtained by a known method such as solvent extraction or column chromatography.

In addition, in the above addition reaction of water molecules, ester hydrolysis may occur, and R ³ may be removed. In such a case, esterification is performed after isolation and purification, and the compound of formula ( 12 ) Can be synthesized. The conditions for the esterification are generally known methods in the field of synthetic organic chemistry, such as T.I. W. Greene. , “Protective Groups in Organic Synthesis”, John Wiley & Sons.

The reducing agent used when producing the compound of the formula ( 11 ) is the same as the reducing agent used when producing the compound of the formula ( 10 ) from the compound of the formula ( 9 ), and preferably sodium borohydride.

The solvent used when producing the compound of formula ( 11 ) is the same as the solvent used when producing the compound of formula ( 10 ) from the compound of formula ( 9 ).

The reaction temperature for producing the compound of the formula ( 11 ) is preferably -20 ° C to 100 ° C, more preferably 0 ° C to room temperature. The reaction time is suitably several minutes to several hours. After completion of the reaction, the compound of the formula ( 11 ) can be obtained by a known method such as solvent extraction or column chromatography.

Among the compounds represented by the formula (1), a compound in which R ² is —COOR ³ and Z is —CO—CH ₂ CHOR ⁴ — is a compound having a phenolic hydroxyl group, if necessary, from the formula ( 13 ) compound described later. It can be synthesized by removing the protecting group.

Among the compounds represented by the formula (1), a compound in which R ² is —COOR ³ and Z is —CHOH—CH ₂ CHOR ⁴ — is obtained from a compound of the formula ( 14 ) described later from a phenolic hydroxyl group if necessary. It can be synthesized by removing the protecting group.

The compound of the formula ( 13 ) can be produced by adding a lower alcohol to the compound of the formula ( 2 ) in the presence of a basic compound. The compound of the formula ( 14 ) can be produced by reducing the compound of the formula ( 13 ) with a metal hydride complex compound. The conversion from formula ( 3 ) to formula ( 13 ) and formula ( 14 ) is shown below.

The formula (2), R ¹ of formula (13) and wherein (14), R ^3, A and B are as defined in formula (1), R ⁵ is as defined in formula (2) , R ⁴ represents a methyl group.

As a basic substance used when producing the compound of the formula ( 13 ) from the formula ( 2 ), it is preferable to use alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The amount of alkali metal hydroxide used is preferably 1 to 10 chemical equivalents, more preferably 2 to 5 chemical equivalents, relative to formula ( 2 ). Examples of the lower alcohol used in producing the compound of the formula ( 13 ) from the formula ( 2 ) include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and the like. Further, a lower alcohol may be used as a solvent.

The reaction temperature when producing the compound of the formula ( 13 ) from the formula ( 2 ) is preferably from 0 ° C to 150 ° C, more preferably from room temperature to 100 ° C. The reaction time is suitably several hours to several tens of hours. After completion of the reaction, the compound of the formula ( 13 ) can be obtained by a known method such as solvent extraction or column chromatography.

In the addition reaction of the lower alcohol, ester hydrolysis may occur and R ³ may be removed. In such a case, esterification is performed after isolation and purification, and the compound of the formula ( 13 ) Can be synthesized. The conditions for the esterification are generally known methods in the field of synthetic organic chemistry, such as T.I. W. Greene. , “Protective Groups in Organic Synthesis”, John Wiley & Sons.

The reducing agent used when producing the compound of formula ( 14 ) from the compound of formula ( 13 ) is the same as the reducing agent used when producing the compound of formula ( 10 ) from the compound of formula ( 9 ), preferably hydrogen. Sodium borohydride.

The solvent used when producing the compound of formula ( 14 ) from the compound of formula ( 13 ) is the same as the solvent used when producing the compound of formula ( 10 ) from the compound of formula ( 9 ).

The reaction temperature for producing the compound of formula ( 14 ) from the compound of formula ( 13 ) is preferably from -20 ° C to 100 ° C, more preferably from 0 ° C to room temperature. The reaction time is suitably several minutes to several hours. After completion of the reaction, the compound of the formula ( 14 ) can be obtained by a known method such as solvent extraction or column chromatography.

Among the compounds represented by the formula (1), a compound in which R ² is a carboxyl group and Z is —CO—CH═CH— is R ³ in the above-described compound of the formula ( 2 ), and optionally a phenolic hydroxyl group. It is obtained by removing the protecting group.

The conditions of the reaction to remove the R ³ from formula (2) compounds described above varies depending on the type of R ^3, for example, when R ³ is an ethyl group, sodium hydroxide, alkali catalysts the presence of potassium hydroxide or the like Can be removed.
The amount of the alkali catalyst used varies depending on the structure of R ¹ , R ³ and R ⁵ and the type of the alkali catalyst, but is preferably 1 to 10 chemical equivalents, more preferably 2 to 5 with respect to the compound of the formula ( 2 ). Chemical equivalent. When the amount of the catalyst used is too small, the progress of the reaction may be slow, and when the amount used is too large, a large amount of neutralizing agent may be required for the treatment after the reaction.

  A solvent may be used for the above reaction, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylpropylene urea, water, methanol, ethanol, Isopropyl alcohol, t-butyl alcohol, a mixed solvent thereof and the like can be preferably used.

The reaction temperature of the above reaction is preferably -20 ° C to 80 ° C, more preferably 0 ° C to 50 ° C. When the reaction temperature is too low, the progress of the reaction may be slow, and when the reaction temperature is too high, the side reaction may proceed. This reaction time varies depending on conditions, but is usually from several tens of minutes to several hours.
After completion of the reaction, the target compound can be obtained by a known method such as solvent extraction or column chromatography.

Similarly, among the compounds represented by the formula (1), a compound in which R ² is a carboxyl group and Z is —CO—CH ₂ CH ₂ — is the same as R ³ in the above-mentioned formula ( 9 ) compound and the necessity. Can be obtained by removing the protecting group of the phenolic hydroxyl group.

Similarly, among the compounds represented by the formula (1), a compound in which R ² is a carboxyl group and Z is —CHOH—CH ₂ CH ₂ — is the same as R ³ in the above-mentioned formula ( 10 ) compound and the necessity. Can be obtained by removing the protecting group of the phenolic hydroxyl group.

Similarly, among the compounds represented by the formula (1), a compound in which R ² is a carboxyl group and Z is —CHOH—CH ₂ CHOH— is selected from R ³ in the above-mentioned formula ( 11 ) compound and, if necessary, It is obtained by removing the protecting group of the phenolic hydroxyl group.

Similarly, among the compounds represented by the formula (1), a compound in which R ² is a carboxyl group and Z is —CO—CH ₂ CHOR ⁴ — represents R ³ in the compound of the above formula ( 13 ) and the necessity. Can be obtained by removing the protecting group of the phenolic hydroxyl group.

Similarly, among the compounds represented by the formula (1), a compound in which R ² is a carboxyl group and Z is —CHOH—CH ₂ CHOR ⁴ — is the same as R ³ in the compound of the formula ( 14 ) and necessary Can be obtained by removing the protecting group of the phenolic hydroxyl group.

Among the compounds represented by the formula (1), a compound in which R ² is —CH ₂ OH and Z is —CHOH—CH ₂ —CH ₂ — is a phenolic compound from the formula ( 15 ) described later, if necessary. It can be synthesized by removing the protective group for the hydroxyl group.

The compound of formula ( 15 ) can be synthesized by reducing the ester and ketone of the compound of formula ( 9 ) described above to an alcohol. The conversion from equation ( 9 ) to equation ( 15 ) is shown below.

R ¹ , R ³ , A and B in the formula ( 9 ) and the formula ( 15 ) are as defined in the formula (1), and R ⁵ is as defined in the formula ( 2 ).

The reducing agent used when producing the compound of formula ( 15 ) from the compound of formula ( 9 ) varies depending on the structures of R ¹ , R ³ and R ^5. For example, when the protecting group of the carboxyl group is an ethyl group The compound of formula (15) is obtained by using a metal hydride complex compound or a metal hydride. Examples of the metal hydride complex compound include lithium aluminum hydride, tributoxy lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. Examples of the metal hydride include diisobutylaluminum hydride. Preferred reducing agents are lithium aluminum hydride and diisobutylaluminum hydride.

As the solvent used in producing the compound of the formula ( 15 ), tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, diglyme, toluene, dichloromethane, a mixed solvent thereof and the like can be used. .

The reaction temperature for producing the compound of the formula ( 15 ) is preferably from -100 ° C to 80 ° C, more preferably from -78 ° C to room temperature. The reaction time is suitably from several minutes to several hours. After completion of the reaction, the compound of the formula ( 15 ) can be obtained by a known method such as solvent extraction or column chromatography.

Among the compounds represented by the formula (1), a compound in which R ² is —CH ₂ OH and Z is —CHOH—CH ₂ CHOH— is derived from a compound of the formula ( 16 ) described later, if necessary. It can be synthesized by removing the protecting group.

The compound of the formula ( 16 ) can be synthesized by reducing the compound ( 17 ). The conversion from formula ( 17 ) to formula ( 16 ) is shown below.

R ¹ , R ³ , A and B in the formula ( 17 ) and the formula ( 16 ) are as defined in the formula (1), and R ⁵ is as defined in the formula ( 2 ).

The reducing agent used when producing the compound of formula ( 16 ) from the compound of formula ( 17 ) is the same as the reducing agent used when producing the compound of formula ( 15 ) from the compound of formula ( 9 ), preferably hydrogen. Lithium aluminum hydride and diisobutylaluminum hydride.

The solvent used when producing the compound of formula ( 16 ) is the same as the solvent used when producing the compound of formula ( 15 ) from the compound of formula ( 9 ).

The reaction temperature is preferably from −100 ° C. to 80 ° C., more preferably from −78 ° C. to room temperature. The reaction time is suitably from several minutes to several hours. After completion of the reaction, the compound of the formula ( 16 ) can be obtained by a known method such as solvent extraction or column chromatography.

Among the compounds represented by the formula (1), a compound in which R ² is —CH ₂ OH and Z is —CO—CH ₂ CHOR ⁴ — is a phenolic hydroxyl group as required from the formula ( 17 ) compound described later. It can be synthesized by removing the protecting group.

The compound of the formula ( 17 ) can be synthesized by adding a lower alcohol to the compound of the formula ( 18 ) described later in the presence of a basic compound. The conversion from formula ( 18 ) to formula ( 17 ) is shown below.

R ¹ , R ⁴ , A, and B in the formula ( 18 ) and the formula ( 17 ) are as defined in the formula (1), and R ⁵ is as defined in the formula ( 2 ).

The basic compound used when producing the compound of formula ( 17 ) from the compound of formula ( 18 ) is the same as the basic compound used when producing the compound of formula ( 13 ) from the compound of formula ( 2 ). Moreover, the lower alcohol used when producing the compound of formula ( 17 ) is the same as the lower alcohol used when producing the compound of formula ( 13 ) from the compound of formula ( 2 ).

The reaction temperature for producing the compound of the formula ( 17 ) is preferably from 0 ° C to 150 ° C, more preferably from room temperature to 100 ° C. The reaction time is suitably several hours to several tens of hours. After completion of the reaction, the compound of the formula ( 17 ) can be obtained by a known method such as solvent extraction or column chromatography.

Among the compounds represented by the formula (1), a compound in which R ² is —CH ₂ OH and Z is —CHOH—CH ₂ CHOR ⁴ — is a phenolic hydroxyl group as required from the formula ( 19 ) compound described later. It can be synthesized by removing the protecting group.

The compound of formula ( 19 ) can be synthesized by reducing the ester and ketone of the compound of formula ( 13 ) described above to an alcohol. The conversion from equation ( 13 ) to equation ( 19 ) is shown below.

R ¹ , R ³ , R ⁴ , A, and B in formula ( 13 ) and formula ( 19 ) are as defined in formula (1), and R ⁵ is as defined in formula ( 2 ).

The reducing agent used when producing the compound of formula ( 19 ) from the compound of formula ( 13 ) is the same as the reducing agent used when producing the compound of formula ( 15 ) from the compound of formula ( 9 ), preferably hydrogen. Lithium aluminum hydride and diisobutylaluminum hydride.

The solvent used when producing the compound of formula ( 19 ) is the same as the solvent used when producing the compound of formula ( 15 ) from the compound of formula ( 9 ).

The reaction temperature for producing the compound of the formula ( 19 ) is preferably from -100 ° C to 80 ° C, more preferably from -78 ° C to room temperature. The reaction time is suitably from several minutes to several hours. After completion of the reaction, the compound of the formula ( 19 ) can be obtained by a known method such as solvent extraction or column chromatography.

Among the compounds represented by the formula (1), a compound in which R ² is —CH ₂ OH and Z is —CO—CH ₂ CH ₂ — is a phenolic hydroxyl group, if necessary, from the formula ( 20 ) compound described later. It can be synthesized by removing the protecting group.

The compound of formula ( 21 ) can be synthesized by reducing an ester of the compound of formula ( 22 ) to an alcohol. Furthermore, the compound of the formula ( 20 ) can be synthesized by removing the ketal of the compound of the formula ( 21 ). The conversion from Formula ( 22 ) to Formula ( 21 ) and Formula ( 20 ) is shown below.

R ¹ , R ³ , A, and B in formula ( 22 ), formula ( 21 ), and formula ( 20 ) are as defined in formula (1), and R ⁵ is as defined in formula ( 2 ). Yes, and Y is as defined in formula ( 22 ).

The reducing agent used when producing the compound of formula ( 21 ) from the compound of formula ( 22 ) is the same as the reducing agent used when producing the compound of formula ( 15 ) from the compound of formula ( 9 ), preferably hydrogen. Lithium aluminum hydride and diisobutylaluminum hydride.

The solvent used when producing the compound of formula ( 21 ) is the same as the solvent used when producing the compound of formula ( 15 ) from the compound of formula ( 9 ).

The reaction temperature for producing the compound of the formula ( 21 ) is preferably −100 ° C. to 80 ° C., more preferably −78 ° C. to room temperature. The reaction time is suitably from several minutes to several hours. After completion of the reaction, the compound of the formula ( 21 ) can be obtained by a known method such as solvent extraction or column chromatography.

The reaction for removing the ketal from the compound of formula ( 21 ) is generally carried out by methods well known in the field of synthetic organic chemistry, for example, W. Greene. , "Protective Groups in Organic Synthesis", John Wiley & Sons, and the compound of formula ( 20 ) can be obtained.

  Among the compounds represented by the general formula (1), there are compounds having one or two asymmetric carbons. These are usually obtained as a racemic mixture. If necessary, one optical activity can be obtained by a method of synthesizing only one optically active compound by asymmetric synthesis or a method such as high performance liquid chromatography using an optically active column. It is also possible to use only the body separately.

  Since the compound represented by the general formula (1) suppresses the oxidation of LDL, it can be used as a therapeutic agent, a symptom ameliorating agent, an inhibitor, or the like for a disease involving oxidative modification of LDL. For example, Formula (1) can be used for the treatment of arteriosclerosis, symptom improvement, or onset suppression.

  When used as a pharmaceutical, the compound of the present invention is used alone or in combination with pharmaceutically acceptable excipients or carriers and other additives in various preparation forms. Their proportions and properties are determined by the solubility and chemical nature of the chosen compound, the chosen route of administration and standard pharmaceutical practice. A vaginal or carrier can be a solid, semi-solid, or liquid material, which can serve as a vehicle or carrier for the active ingredient. Suitable excipients or carriers are common in the pharmaceutical field. The pharmaceutical composition can be adapted for oral or parenteral use and can be administered to a patient in the form of tablets, capsules, suppositories, solutions, suspensions, and the like.

  The pharmaceutical composition can be administered orally, for example with an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral administration, the compounds of the invention can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Tablets, troches, capsules and the like can contain one or more auxiliaries. Auxiliaries include binders (eg microcrystalline cellulose, tragacanth gum, gelatin), glazes (eg starch, lactose), disintegrants (eg alginic acid, primogel, corn starch), lubricants (eg magnesium stearate). , Sterotex), lubricants (eg, colloidal silicon dioxide), sweeteners (eg, sucrose, saccharin), and flavoring agents (eg, peppermint, methyl salicylate, orange flavor), and the like. When the dosage unit form is a capsule, it can contain a liquid carrier (eg, polyethylene glycol, aliphatic oil) in addition to the above types of substances. Other dosage unit systems can contain other substances (eg, coatings) that alter the physical form of the dosage unit. Thus, tablets or suppositories can be coated with sugar, shellac or other enteric coatings. In addition to the active ingredient, syrups can contain sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

  For parenteral administration, the compounds of the invention can be incorporated into a solution or suspension. Solutions or suspensions can contain one or more auxiliaries. Auxiliary agents are sterile diluents (eg, water for injection, aqueous salt solution, non-volatile oil, polyethylene glycols, glycerin, propylene glycol, other synthetic solvents), antibacterial agents (eg, benzyl alcohol, methyl parapenes), antioxidants (E.g., ascorbic acid, sodium bisulfite), chelating agents (e.g., ethylenediaminetetraacetic acid), buffers (e.g., acetate, citrate, phosphate), and agents for preparing toxicity (e.g., Sodium chloride, dextrose) and the like. The parenteral preparation can be enclosed in ampoules, disposable injections or multiple dose vials made of glass or plastic.

<Example>
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples. Ts represents a p-toluenesulfonyl group.

<Synthesis Example 1>
As a raw material for synthesizing the compound of formula ( 2 ), Compound 5 was prepared via Compound 2 and Compound 3 using Compound 1 as a starting material.
Compound 1 is a compound of formula ( 6 ), compound 2 is a compound of formula ( 8 ), compound 3 is a compound of formula ( 3 ), compound 4 is a compound of formula ( 4 ), compound 5 is Corresponds to the compound of formula ( 5 ).

・ Compound 1

・ Compound 2

・ Compound 3

Compound 4

Compound 5

First, a conversion reaction of ethyl 6-bromohexanoate to ethyl 6-iodohexanoate was performed.
That is, 39.1 g (175 mmol) of ethyl 6-bromohexanoate was dissolved in 250 ml of acetone, 29.1 g (175 mmol) of potassium iodide was added, and the mixture was heated to reflux for 20 hours. Next, the reaction solution was allowed to cool to room temperature, the solvent was distilled off, and the residue was extracted with 150 ml of ethyl acetate. The obtained organic layer was washed with 50 ml of distilled water and then dried over anhydrous magnesium sulfate. The solvent was distilled off and dried under reduced pressure to obtain 47.4 g of a crude product. As a result of ¹ H-NMR analysis, it was found that the crude product contained 90% ethyl 6-iodohexanoate in molar fraction. This crude product was directly used in the next step.
Next, a solution obtained by dissolving 30.5 g (155 mmol) of Compound 1 in 450 ml of tetrahydrofuran was cooled to −78 ° C. with dry ice / acetone. To this solution, 100 ml (156 mmol) of a 1.56 M n-butyllithium / n-hexane solution was added dropwise. And after stirring for 45 minutes at the same temperature, the solution which melt | dissolved the crude product of the ethyl 6-iodohexanoate prepared as mentioned above in 50 ml of tetrahydrofuran was dripped. After dropping, the mixture was stirred for 10 minutes at the same temperature and then gradually heated. When the temperature of the reaction solution reached −10 ° C., 50 ml of 5% aqueous citric acid solution was added to stop the reaction. The reaction mixture was partitioned by adding 100 ml of 10% aqueous sodium thiosulfate, 150 ml saturated brine and 50 ml ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and purification by silica gel column chromatography was performed to obtain 49.5 g (yield 94%) of a pale yellow low-viscosity liquid compound.

The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 1.20-1.70 (9H, m), 2.03-2.15 (2H, m), 2.23- 2.35 (2H, m), 2.44 (3H, s), 3.43-3.55 (1H, m), 4.11 (2H, q), 5.04 (1H, d), 5 .25-5.35 (1H, m), 5.53-5.68 (1H, m), 7.32 (2H, d), 7.70 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2930, 2860, 1730, 1600, 1300, 1290, 1180, 1140, 940, and 670.
The results of elemental analysis were as follows: carbon 64.09% and hydrogen 7.87%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 2.

Next, the conversion from compound 2 to compound 3 was performed.
49.5 g (146 mmol) of Compound 2 was dissolved in 360 ml of tetrahydrofuran and 120 ml of methanol, and 3.38 g (2.92 mmol) of tetrakistriphenylphosphine palladium was added. The reaction solution was heated to reflux for 16 hours. Next, the reaction solution was allowed to cool to room temperature, and then the solvent was distilled off, followed by purification by silica gel column chromatography to obtain 47.1 g (95%) of a light brown low-viscosity liquid compound. As a result of ¹ H-NMR analysis, infrared absorption spectrum analysis, and elemental analysis shown below, this product contains 73% of Compound 3 by mole fraction, and the remaining 27% is carbon- It was confirmed that the carbon double bond was a geometric isomer arranged in a cis form.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 3 is 1.20-1.33 (7H, m), 1.50-1.60 (2H, m), 1.99 ( 2H, t), 2.20-2.30 (2H, m), 2.45 (3H, s), 3.73 (2H, d), 4.08-4.15 (2H, q), 5 .35-5.55 (2H, m), 7.34 (2H, d), 7.72 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2930, 2860, 1730, 1600, 1320, 1150, 1090, 1030, 820, and 740.
The results of elemental analysis were as follows: carbon 64.03% and hydrogen 7.57%.

Next, the conversion from compound 3 to compound 5 was performed.
A solution of 8.75 g (25.8 mmol) of Compound 3 dissolved in 75 ml of tetrahydrofuran was cooled to −78 ° C. with dry ice / acetone. To this solution, 13.0 ml (26.0 mmol) of a 2.0 M lithium diisopropylamide / heptane-tetrahydrofuran-ethylbenzene solution was added dropwise. After stirring at the same temperature for 60 minutes, a solution of 7.34 g (25.8 mmol) of compound 4 dissolved in 30 ml of tetrahydrofuran was added. After dropping, the mixture was stirred at the same temperature for 30 minutes and then gradually heated. When the temperature of the reaction solution reached −30 ° C., a solution in which 3.0 g of citric acid was dissolved in 10 ml of methanol was added to stop the reaction. The reaction mixture was partitioned by adding 30 ml distilled water, 50 ml saturated brine and 50 ml acetic acid ethyl ester. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.15 g (yield 38%) of a pale yellow medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.25 (3H, t), 1.44 to 2.04 (10 H, m), 2.15 to 2.29 ( 2H, m), 2.45 (3H, s), 2.57-3.00 (2H, m), 3.12-4.62 (8H, m), 4.95-5.83 (2H, m), 6.71-6.88 (2H, m), 6.97-7.06 (1H, m), 7.34 (2H, d), 7.45-7.54 (2H, m) 7.58-7.77 (3H, m), 8.20 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3510, 2940, 2860, 1740, 1600, 1510, 1290, 1270, 1200, 1140, 1061, 1030, 710. It was.
The results of elemental analysis were as follows: carbon 67.27% and hydrogen 6.95%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 5.

<Synthesis Example 2>
Compound 6 was prepared using Compound 5 obtained in Synthesis Example 1 as a raw material.

Compound 6

  To a solution of 5.00 g (8.03 mmol) of Compound 5 in 120 g of 1,2-dichloroethane, 40 g of isopropyl alcohol, and 40 g of glycerin, 3.40 ml (24.4 mmol) of triethylamine, 105 mg (0 400 mmol) of triphenylphosphine and 462 mg (0.400 mmol) of tetrakistriphenylphosphine palladium were added, and the mixture was stirred at a bath temperature of 100 ° C. for 16 hours. After cooling and concentrating, 100 ml of distilled water, 50 ml of saturated brine, and 50 ml of ethyl acetate were added to partition. The organic layer was separated and washed with 30 ml of saturated brine. The combined aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and purification by silica gel column chromatography was performed to obtain 1.45 g (yield 39%) of a pale yellow, medium-viscous liquid compound.

The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.25 (3H, t), 1.30-1.53 (6H, m), 1.57-1.67 ( 2H, m), 2.16-2.32 (4H, m), 2.84-3.00 (4H, m), 3.80 (3H, s), 4.12 (2H, q), 6 .11 (1H, d), 6.77-6.88 (3H, m), 7.05 (1H, d), 7.46-7.53 (2H, m), 7.59-7.67 (1H, m), 8.21 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) are 2930, 2860, 1730, 1700, 1670, 1630, 1600, 1510, 1270, 1200, 1150, 1060, 1030, 710. Met.
The results of elemental analysis were as follows: carbon 71.81% and hydrogen 7.25%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 6.

<Synthesis Example 3>
Compound 7 was prepared using Compound 6 obtained in Synthesis Example 2 as a raw material.

Compound 7

To a solution of 467 mg (1.00 mmol) of compound 6 dissolved in 7 ml of 1,4-dioxane, 3 ml of 1N aqueous sodium hydroxide solution was added and stirred. After stirring for 4 hours, the mixture was neutralized by adding 3 ml of 1N hydrochloric acid. 30 ml of saturated saline was added to the reaction solution, and extraction with 10 ml of chloroform was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 174 mg (52%) of a colorless crystalline compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 1.23-1.50 (6H, m), 1.57-1.69 (2H, m), 2.19 ( 2H, q), 2.34 (2H, t), 2.79-2.90 (4H, m), 3.87 (3H, s), 6.08 (1H, d), 6.64-6 .85 (4H, m).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3530, 2930, 2850, 1700, 1660, 1640, 1520, 1280, 1230, and 1030.
The results of elemental analysis were as follows: carbon 68.48% and hydrogen 8.11%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 7.

<Synthesis Example 4>
A mixture of Compound 7 and Compound 8 was obtained using Compound 6 obtained in Synthesis Example 2 as a raw material.

Compound 8

To a solution of 467 mg (1.00 mmol) of compound 6 in 7 ml of ethanol, 3 ml of 1N aqueous sodium hydroxide solution was added. After stirring for 3 hours, the reaction was stopped by adding 3 ml of 1N hydrochloric acid. 30 ml of saturated saline was added to the reaction solution, and extraction with 10 ml of chloroform was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 237 mg of a pale yellow medium viscosity liquid compound.
As a result of analyzing the ¹ H-NMR spectrum measured in deuterochloroform of this product, compound 7 and a mixture of compound 8 in which ethanol used as a solvent was added to the double bond of compound 7 (compound 7 and compound 8 It was confirmed that the molar ratio was 35:65). In addition, the chemical shift value of the ethoxy group in the compound 8 is 1.12 (3H, t) and 3.35-3.50 (2H, m), and the chemical shift value of CH to which the ethoxy group is bonded is 3. 68-3.78 (1H, m).

<Synthesis Example 5>
As a raw material for obtaining the compound of formula ( 2 ), compound 11 was prepared via compound 9 and compound 10 using compound 1 as a starting material in the same manner as in Synthesis Example 1.

Compound 9

Compound 10

Compound 11

First, a conversion reaction of ethyl 4-bromobutyrate to ethyl 4-iodobutyrate was performed.
34.2 g (175 mmol) of ethyl 4-bromobutyrate was dissolved in 250 ml of acetone, 29.1 g (175 mmol) of potassium iodide was added, and the mixture was heated to reflux for 20 hours. Next, the reaction solution was allowed to cool to room temperature, the solvent was distilled off, and the residue was extracted with 150 ml of ethyl acetate. The obtained organic layer was washed with 50 ml of distilled water and then dried over anhydrous magnesium sulfate. The solvent was distilled off and dried under reduced pressure to obtain 43.2 g of a crude product. As a result of 1H-NMR analysis, it was found that the crude product contained 92% ethyl 4-iodobutyrate in a molar fraction. This crude product was directly used in the next step.
Next, a solution obtained by dissolving 30.5 g (155 mmol) of Compound 1 in 450 ml of tetrahydrofuran was cooled to −78 ° C. with dry ice / acetone. To this solution, 100 ml (156 mmol) of a 1.56 M n-butyllithium / n-hexane solution was added dropwise. And after stirring for 45 minutes at the same temperature, the solution which melt | dissolved the crude product of 4-iodobutyric acid ethyl prepared as mentioned above in 50 ml of tetrahydrofuran was dripped. After dropping, the mixture was stirred for 10 minutes at the same temperature and then gradually heated. When the temperature of the reaction solution reached −10 ° C., 50 ml of 5% aqueous citric acid solution was added to stop the reaction. The reaction mixture was partitioned by adding 100 ml of 10% aqueous sodium thiosulfate, 150 ml saturated brine and 50 ml ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and purification by silica gel column chromatography was performed to obtain 46.0 g (yield 96%) of a pale yellow low-viscosity liquid compound.

The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.23 (3H, t), 1.52-1.63 (1H, m), 1.65-1.80 ( 2H, m), 2.07-2.15 (1H, m), 2.25-2.37 (2H, m), 2.44 (3H, s), 3.45-3.55 (1H, m) m), 4.10 (2H, q), 5.08 (1H, d), 5.31 (1H, d), 5.57-5.66 (1H, m), 7.32 (2H, d) ), 7.70 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2980, 2930, 1730, 1600, 1300, 1290, 1140, 1090, 820, and 670.
The results of elemental analysis were as follows: carbon 61.73% and hydrogen 6.92%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 9.

Next, the conversion from Compound 9 to Compound 10 was performed.
That is, 46.0 g (148 mmol) of Compound 9 was dissolved in 360 ml of tetrahydrofuran and 120 ml of methanol, and 3.42 g (2.96 mmol) of tetrakistriphenylphosphine palladium was added. The reaction solution was heated to reflux for 16 hours. Next, the reaction solution was allowed to cool to room temperature, and then the solvent was distilled off, followed by purification by silica gel column chromatography to obtain 41.0 g (89%) of a light brown low-viscosity liquid compound. As a result of ¹ H-NMR analysis, infrared absorption spectrum analysis, and elemental analysis shown below, this product contains 81% of compound 10 in terms of molar fraction, and the remaining 19% contains carbon − in compound 10 It was confirmed that the carbon double bond was a geometric isomer arranged in a cis form.
Chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of Compound 10 are 1.25 (3H, t), 1.57-1.65 (2H, m), 2.03-2.10 ( 2H, m), 2.20 (2H, t), 2.44 (3H, s), 3.73 (2H, d), 4.12 (2H, q), 5.37-5.55 (2H) M), 7.33 (2H, d), and 7.73 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2980, 2930, 1730, 1600, 1320, 1300, 1150, 1090, 820, and 740.
The results of elemental analysis were as follows: carbon 61.81% and hydrogen 7.01%.

Compound 11 was prepared from compound 10.
That is, a solution obtained by dissolving 6.63 g (21.4 mmol) of Compound 10 in 65 ml of tetrahydrofuran was cooled to −78 ° C. with dry ice / acetone. To this solution, 11.0 ml (22.0 mmol) of a 2.0 M lithium diisopropylamide / heptane-tetrahydrofuran-ethylbenzene solution was added dropwise. After stirring at the same temperature for 60 minutes, a solution prepared by dissolving 6.09 g (21.4 mmol) of Compound 4 in 25 ml of tetrahydrofuran was added. After dropping, the mixture was stirred at the same temperature for 30 minutes and then gradually heated. When the temperature of the reaction solution reached −20 ° C., a solution in which 3.0 g of citric acid was dissolved in 10 ml of methanol was added to stop the reaction. The reaction mixture was partitioned by adding 30 ml distilled water, 50 ml saturated brine and 50 ml acetic acid ethyl ester. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 4.33 g (yield 34%) of a pale yellow medium viscosity liquid compound.

The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of this product is 1.24 (3H, t), 1.38-2.50 (11 H, m), 2.59-3.00 ( 2H, m), 3.15-4.58 (8H, m), 5.08-5.86 (2H, m), 6.69-6.91 (2H, m), 7.00-7. 12 (1H, m), 7.28-7.38 (2H, m), 7.45-7.55 (2H, m), 7.58-7.79 (3H, m), 8.21 ( 2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3510, 2940, 1730, 1600, 1510, 1290, 1270, 1150, 1060, and 710.
The results of elemental analysis were as follows: carbon 66.53% and hydrogen 6.58%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 11.

<Synthesis Example 6>
Compound 12 was prepared using Compound 11 obtained in Synthesis Example 5 as a raw material.

Compound 12

  To a solution of 3.57 g (6.00 mmol) of compound 11 in 90 g of 1,2-dichloroethane, 30 g of isopropyl alcohol, and 30 g of glycerin, 2.50 ml (17.9 mmol) of triethylamine, 78.7 mg. (0.300 mmol) of triphenylphosphine and 347 mg (0.300 mmol) of tetrakistriphenylphosphine palladium were added and stirred at a bath temperature of 100 ° C. for 16 hours. After allowing to cool and concentrate, 80 ml of distilled water, 40 ml of saturated saline, and 40 ml of ethyl acetate were added to partition. The organic layer was separated and washed with 25 ml of saturated brine. The combined aqueous layer was extracted with 25 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 613 mg (yield 23%) of a pale yellow medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.25 (3H, t), 1.46-1.56 (2H, m), 1.61-1.72 ( 2H, m), 2.21-2.35 (4H, m), 2.86-3.00 (4H, m), 3.80 (3H, s), 4.13 (2H, q), 6 .12 (1H, d), 6.77-6.87 (3H, m), 7.03-7.08 (1H, d), 7.47-7.54 (2H, m), 7.59 -7.66 (1H, m), 8.21 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2940, 1740, 1670, 1630, 1600, 1510, 1270, 1200, 1150, 1060, 710.
The results of elemental analysis were as follows: carbon 70.91% and hydrogen 7.17%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 12.

<Synthesis Example 7>
Compound 13 was prepared using Compound 12 obtained in Synthesis Example 6 as a raw material.

Compound 13

To a solution of 439 mg (1.00 mmol) of Compound 12 in 7 ml of 1,4-dioxane, 3 ml of 1N aqueous sodium hydroxide solution was added and stirred. After stirring for 4 hours, the mixture was neutralized by adding 3 ml of 1N hydrochloric acid. 30 ml of saturated saline was added to the reaction solution, and extraction with 10 ml of chloroform was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 90.0 mg (29%) of a pale yellow medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 1.46 to 1.56 (2H, m), 1.60 to 1.72 (2H, m), 2.23 ( 2H, q), 2.38 (2H, t), 2.79-2.91 (4H, m), 3.86 (3H, s), 6.10 (1H, d), 6.64-6 .85 (4H, m).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3400, 2940, 1710, 1660, 1630, 1520, 1270, 1240, 1150, 1030, 820, and 720.
The results of elemental analysis were as follows: carbon 66.90% and hydrogen 7.11%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 13.

<Synthesis Example 8>
As a raw material for obtaining the compound of formula ( 2 ), compound 16 was prepared via compound 14 and compound 15 using compound 1 as a starting material in the same manner as in Synthesis Example 1.

Compound 14

Compound 15

Compound 16

First, conversion from Compound 1 to Compound 14 was performed.
A solution prepared by dissolving 4.91 g (25.0 mmol) of Compound 1 and 656 mg (2.50 mmol) of triphenylphosphine in 80 ml of toluene was cooled to −78 ° C. with dry ice / acetone. To this solution, 13.0 ml (26.0 mmol) of a 2.0 M lithium diisopropylamide / heptane-tetrahydrofuran-ethylbenzene solution was added dropwise. After stirring at the same temperature for 30 minutes, a solution of 3.00 ml (27.7 mmol) of acrylic acid ethyl ester dissolved in 15 ml of toluene was added dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then a reaction in which 3.0 g of citric acid was dissolved in 10 ml of methanol was added to stop the reaction. The reaction mixture was partitioned by adding 60 ml of saturated brine and 50 ml of acetic acid ethyl ester. The organic layer was separated and the aqueous layer was extracted with 20 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and purification by silica gel column chromatography was performed to obtain 2.99 g (yield 40%) of a pale yellow low-viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.23 (3H, t), 1.80-2.00 (1 H, m), 2.30-2.49 ( 6H, m), 3.64 (1H, dt), 4.10 (2H, d), 5.10 (1H, d), 5.33 (1H, d), 5.56-5.68 (1H) M), 7.33 (2H, d), 7.71 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2980, 1730, 1600, 1380, 1290, 1150, 1090, 940, 820, and 670.
The results of elemental analysis were as follows: carbon 60.97% and hydrogen 6.75%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 14.

Next, conversion from Compound 14 to Compound 15 was performed.
4.75 g (16.0 mmol) of Compound 14 was dissolved in 36 ml of tetrahydrofuran and 12 ml of methanol, and 277 mg (0.240 mmol) of tetrakistriphenylphosphine palladium was added. The reaction solution was heated to reflux for 6 hours. Next, the reaction solution was allowed to cool to room temperature, and then the solvent was distilled off, followed by purification by silica gel column chromatography to obtain 3.64 g (77%) of a light brown low-viscosity liquid compound. As a result of 1H-NMR analysis, infrared absorption spectrum analysis, and elemental analysis shown below, this product contains 83% of Compound 15 by mole fraction, and the remaining 17% is carbon-carbon in Compound 15. It was confirmed that the double bond was a geometric isomer arranged in a cis form.
The chemical shift values of ¹ H-NMR spectrum of Compound 15 measured in deuterated chloroform are 1.25 (3H, t), 2.22-2.38 (4H, m), 2.45 (3H, s). 3.73 (2H, d), 4.12 (2H, q), 5.40-5.59 (2H, m), 7.34 (2H, d), 7.72 (2H, d) there were.
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2980, 2930, 1730, 1600, 1320, 1300, 1180, 1150, 1090, 820, and 740.
The results of elemental analysis were as follows: carbon 60.54% and hydrogen 7.67%.

Next, conversion from Compound 15 to Compound 16 was performed.
That is, a solution of 3.64 g (12.3 mmol) of Compound 15 dissolved in 50 ml of tetrahydrofuran was cooled to −78 ° C. with dry ice / acetone. To this solution, 6.80 ml (13.6 mmol) of a 2.0 M lithium diisopropylamide / heptane-tetrahydrofuran-ethylbenzene solution was added dropwise. And after stirring for 60 minutes at the same temperature, the solution which melt | dissolved 3.85 g (13.5 mmol) of compound 4 in 20 ml of tetrahydrofuran was added. After dropping, the mixture was stirred at the same temperature for 30 minutes and then gradually heated. When the temperature of the reaction solution reached −15 ° C., a solution in which 1.0 g of citric acid was dissolved in 5 ml of distilled water was added to stop the reaction. The reaction mixture was partitioned by adding 30 ml of saturated brine and 20 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 20 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and purification by silica gel column chromatography was performed to obtain 2.39 g (yield 33%) of a pale yellow medium viscosity liquid compound.

The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 1.18-1.32 (3H, m), 1.53-2.38 (6H, m), 2.46 ( 3H, s), 2.56-3.03 (2H, m), 3.18-4.59 (8H, m), 4.90-5.80 (2H, m), 6.72-6. 80 (2H, m), 6.97-7.09 (1H, m), 7.30-7.39 (2H, m), 7.40-7.56 (2H, m), 7.61- 7.73 (3H, m), 8.21 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3450, 2940, 1740, 1600, 1510, 1270, 1200, 1150, 1060, 1030, and 710.
The results of elemental analysis were as follows: carbon 65.93% and hydrogen 6.13%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 16.

<Synthesis Example 9>
Compound 17 was prepared using Compound 16 obtained in Synthesis Example 8 as a raw material.

Compound 17

To a solution of 2.33 g (4.01 mmol) of compound 16 in 60 g of 1,2-dichloroethane, 20 g of isopropyl alcohol, and 20 g of glycerin, 0.56 ml (4.02 mmol) of triethylamine, 105 mg (0 .400 mmol) of triphenylphosphine and 232 mg (0.201 mmol) of tetrakistriphenylphosphine palladium were added and stirred at a bath temperature of 100 ° C. for 14 hours. After cooling and concentrating, 30 ml of distilled water, 20 ml of saturated saline, and 50 ml of ethyl acetate were added and partitioned. The organic layer was separated and washed with 10 ml of saturated brine. The combined aqueous layer was extracted with 20 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 744 mg (yield 44%) of a pale yellow medium viscosity liquid compound.
The chemical shift values of the ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.25 (3H, t), 1.74-1.86 (2H, m), 2.21-2.40 ( 4H, m), 2.86-2.99 (4H, m), 3.80 (3H, s), 4.12 (2H, q), 6.13 (1H, d), 6.76-6 .88 (3H, m), 7.03-7.08 (1H, d), 7.45-7.54 (2H, m), 7.58-7.65 (1H, m), 8.21 (2H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2940, 1740, 1670, 1650, 1510, 1270, 1200, 1150, 1060, 1030, and 710.
The results of elemental analysis were as follows: carbon 71.00% and hydrogen 6.43%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 17.

<Synthesis Example 10>
A mixture of Compound 18 and Compound 19 was prepared using Compound 17 obtained in Synthesis Example 9 as a raw material.

Compound 18

Compound 19

To a solution of 506 mg (0.922 mmol) of Compound 17 in 5 ml of ethanol, 5 ml of 1N aqueous sodium hydroxide solution was added. After stirring for 1 hour, the reaction was stopped by adding 5 ml of 1N hydrochloric acid. 50 ml of saturated saline was added to the reaction solution, and extraction with 10 ml of chloroform was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 303 mg of a light yellow, medium viscosity liquid compound.
As a result of analyzing the ¹ H-NMR spectrum measured in deuterochloroform of this product, compound 18 and a mixture of compound 19 in which ethanol used as a solvent was added to the double bond of compound 18 (compound 18 and compound 19 The molar ratio was found to be 45:55). In addition, the chemical shift value of the ethoxy group in the compound 19 is 1.13 (3H, t) and 3.37-3.50 (2H, m), and the chemical shift value of CH to which the ethoxy group is bonded is 3. 68-3.83 (1H, m).

<Synthesis Example 11>
Compound 21 was prepared using Compound 3 and Compound 20 as raw materials for obtaining the compound of formula ( 2 ).

Compound 20

Compound 21

A solution of 11.9 g (35.2 mmol) of Compound 3 in 100 ml of tetrahydrofuran was cooled to -78 ° C. with dry ice / acetone. To this solution, 26.0 ml (36.4 mmol) of a 1.40 M t-butyllithium / heptane solution was added dropwise. After stirring for 10 minutes at the same temperature, a solution of 9.00 g (34.0 mmol) of Compound 20 in 50 ml of tetrahydrofuran was added. After dropping, the mixture was stirred at the same temperature for 5 minutes and then gradually heated. When the temperature of the reaction solution reached −5 ° C., 30 ml of 10% aqueous citric acid solution was added to stop the reaction. The reaction mixture was partitioned by adding 60 ml of saturated brine. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.03 g (yield 29%) of a pale yellow medium viscosity liquid compound.
The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.17-2.30 (24H, m), 2.45 (3H, s), 2.56-2.92 ( 2H, m), 3.15-4.58 (8H, m), 4.95-5.83 (2H, m), 6.65-6.94 (3H, m), 7.29-7. 38 (2H, m), 7.63-7.77 (2H, m).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3510, 2970, 2940, 2860, 1750, 1730, 1600, 1510, 1280, 1200, 1120, 1030, 670. It was.
The results of elemental analysis were as follows: carbon 65.51% and hydrogen 7.45%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 21.

<Synthesis Example 12>
Compound 22 was prepared using Compound 21 obtained in Synthesis Example 11 as a raw material.

Compound 22

To a solution of 6.00 g (9.95 mmol) of compound 21 in 60 g of 1,2-dichloroethane and 15 g of methanol was added 2.10 ml (15.1 mmol) of triethylamine, 130 mg (0.496 mmol) of triethylamine. Phenylphosphine and 575 mg (0.498 mmol) of tetrakistriphenylphosphine palladium were added, and the mixture was stirred at a bath temperature of 100 ° C. for 16 hours. After allowing to cool and concentrate, 50 ml of saturated brine and 50 ml of ethyl acetate were added and partitioned. The organic layer was separated and washed with 10 ml of saturated brine. The combined aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 936 mg (yield 21%) of a pale yellow medium viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of this product is 1.25 (3H, t), 1.29-1.52 (15 H, m), 1.57-1.68 ( 2H, m), 2.16-2.33 (4H, m), 2.82-2.96 (4H, m), 3.80 (3H, s), 4.13 (2H, q), 6 .10 (1H, d), 6.70-6.94 (4H, m).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2970, 2930, 2860, 1750, 1740, 1670, 1630, 1610, 1510, 1270, 1200, 1120, 1040. It was.
The results of elemental analysis were as follows: carbon 70.17% and hydrogen 8.80%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 22.

<Synthesis Example 13>
Compound 23 was prepared using Compound 22 obtained in Synthesis Example 12 as a raw material.

Compound 23

To a solution of 197 mg (0.441 mmol) of Compound 22 in 3.0 ml of methanol, 1.5 ml of 1N aqueous sodium hydroxide solution was added and stirred. After stirring for 1 hour, the reaction mixture was neutralized by adding 1.5 ml of 1N hydrochloric acid. Next, 30 ml of saturated saline was added, and extraction with 10 ml of chloroform was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 59.7 mg (44%) of a pale yellow low-viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 1.22-1.53 (8H, m), 1.57-1.70 (2H, m), 2.32- 2.44 (3H, m), 2.58-2.88 (5H, m), 3.28 (3H, s), 3.60-3.69 (1H, m), 3.87 (3H, s), 5.56 (1H, br), 6.63-6.72 (2H, m), 6.78-6.85 (1H, m).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3410, 2930, 2860, 1710, 1610, 1520, 1270, 1240, 1150, 1120, 1030, 820, 800. It was.
The results of elemental analysis were as follows: carbon 78.56% and hydrogen 10.05%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 23.

<Synthesis Example 14>
Compound 25 was prepared using Compound 3 and Compound 24 as raw materials for obtaining the compound of formula ( 2 ).

Compound 24

Compound 25

From 1.19 g (3.52 mmol) of compound 3 and 851 mg (3.40 mmol) of compound 20 according to the method of Synthesis Example 1, 663 mg (yield 32%) of compound 25 was obtained as a pale yellow medium-viscosity compound. It was.
The chemical shift values of the ¹ H-NMR spectrum of Compound 25 measured in deuterated chloroform are 1.22-1.60 (18H, m), 1.99-2.2.45 (4H, m), 2. 78 (3H, s), 2.77-2.84 (2H, m), 2.94 (1H, t), 3.71-3.80 (4H, m), 4.12 (2H, q) , 5.37-5.543 (1H, m), 5.47-5.53 (1H, m), 6.74-6.94 (3H, m), 7.30-7.35 ( 2H, m), 7.72-7.77 (2H, m).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3510, 2970, 2940, 2860, 1750, 1730, 1600, 1510, 1280, 1200, 1120, 1030, 670. It was.
The results of elemental analysis were as follows: carbon 65.28% and hydrogen 7.53%.

<Synthesis Example 15>
Compound 26 was prepared using Compound 25 obtained in Synthesis Example 14 as a starting material.

Compound 26

According to the method of Example 1, from 6 g (9.95 mmol) of Compound 25, 936 mg (yield 21%) of Compound 26 was obtained as a pale yellow liquid compound having a medium viscosity.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 26 is 1.23-1.73 (17H, m), 2.18-2.31 (4H, m), 2.79-. 2.93 (5H, m), 3.79 (3H, s), 4.12 (2H, q), 6.09 (1H, d), 6.75-6.83 (3H, m), 6 .91 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2979, 1760, 1732, 1668, 1603, 1512, 1468, 1369, 1267, 1150, 1127, 1038.
The results of elemental analysis were as follows: carbon 69.42% and hydrogen 8.39%.

<Synthesis Example 16>
Compound 26 obtained in Synthesis Example 15 was reduced to obtain Compound 27.

Compound 27

A solution of 588 mg (1.36 mmol) of Compound 26 and 1.52 g (4.08 mmol) of cerium chloride heptahydrate dissolved in 24 ml of methanol was cooled to -78 ° C with dry ice / acetone. To this solution, 77.1 mg (2.04 mmol) of sodium borohydride was added and stirred at the same temperature for 15 minutes. The reaction mixture was partitioned by adding 40 ml brine and 80 ml ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 40 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain 575 mg (97.3%) of a pale yellow medium viscosity liquid compound.
Chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.23-1.64 (17H, m), 1.82-1.84 (2H, m), 2.04 ( 2H, dd), 2.29 (2H, t), 2.64-2.70 (2H, m), 2.70-2.84 (1H, m), 3.80 (3H, s), 4 .07-4.15 (3H, m), 5.46-5.52 (1H, m), 5.61-5.68 (1H, m), 6.75-6.79 (2H, m) 6.90 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3504, 2974, 1761, 1736, 1606, 1511, 1467, 1418, 1280, 1182, 1127, 1098, 1036. It was.
The results of elemental analysis were as follows: carbon 69.10% and hydrogen 8.81%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 27.

<Synthesis Example 17>
Compound 27 obtained in Synthesis Example 16 was epoxidized to obtain Compound 28.

Compound 28

To a solution of 257 mg (0.591 mmol) of Compound 27 dissolved in 9 ml of dichloromethane, a solution of 204 mg (1.18 mmol) of m-chloroperbenzoic acid dissolved in 3 ml of dichloromethane was added dropwise under ice cooling. After stirring at the same temperature for 4 hours, 10 ml of 10% aqueous sodium thiosulfate was added to the reaction mixture, and extraction with 10 ml of chloroform was repeated twice. The combined organic layers were dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 257 mg (yield 97%) of a pale yellow, medium viscosity liquid compound.
The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.23-1.95 (21H, m), 2.29 (2H, t), 2.72-2.91 ( 5H, m), 3.51-3.53 (1H, m), 3.80 (3H, s), 4.12 (2H, q), 6.76-6.80 (2H, m), 6 .92 (1H, d).
The results of elemental analysis were as follows: carbon 66.64% and hydrogen 8.50%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 28.

<Synthesis Example 18>
Compound 22 obtained in Synthesis Example 12 was catalytically hydrogenated to obtain Compound 29.

Compound 29

100 mg of palladium-carbon was added to a solution of 1.00 g (2.24 mmol) of compound 22 in 25 ml of ethanol. After the reaction system was stirred for 3.5 hours under a hydrogen atmosphere, the reaction solution was filtered through Celite to separate the palladium catalyst. The filtrate was concentrated under reduced pressure to obtain 0.97 g (yield 97%) of a pale yellow medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.23-1.61 (24H, m), 2.28 (2H, t), 2.37 (2H, t). , 2.71 (2H, t), 2.87 (2H, t), 3.78 (3H, s), 4.12 (2H, q), 6.72-6.77 (2H, m), 6.89 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2930, 1760, 1730, 1639, 1511, 1452, 1419, 1369, 1267, 1183, 1126.
The results of elemental analysis were as follows: carbon 69.61% and hydrogen 8.99%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 29.

<Synthesis Example 19>
Compound 26 obtained in Synthesis Example 15 was catalytically hydrogenated to obtain Compound 30 of the present invention.

Compound 30

According to the method of Synthesis Example 18, 148 mg (yield 91%) of Compound 30 was obtained from 161 mg (0.379 mmol) of Compound 26 as a pale yellow medium viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of compound 30 is 1.23-1.71 (21H, m), 2.28 (2H, t), 2.38 (2H, t). , 2.4-2.45 (1H, m), 2.72 (2H, t), 2.87 (2H, t), 3.79 (3H, s), 4.12 (2H, q), 6.72-6.78 (2H, m), 6.90 (1H, d) The wave number (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) was 2930, 1760. 1730, 1639, 1511, 1452, 1419, 1369, 1267, 1183, 1126, 1098, 1029, 1015.
The results of elemental analysis were as follows: carbon 69.10% and hydrogen 8.81%.

<Synthesis Example 20>
Compound 30 obtained in Synthesis Example 19 was reduced with sodium borohydride to obtain Compound 31.

Compound 31

To a solution of 188 mg (0.433 mmol) of Compound 30 dissolved in 5 ml of methanol, 16.4 mg (0.433 mmol) of sodium borohydride was added under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was partitioned by adding 10 ml of saturated brine and 10 ml of ethyl acetate. After separating the organic layer, the aqueous layer was extracted with 10 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under reduced pressure to obtain 187 mg (99%) of a pale yellow, medium-viscous compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of this product is 1.20-1.72 (28H, m), 2.26 (2H, t), 2.55-2.65 ( 1H, m), 2.70-2.80 (1H, m), 3.54-3.63 (1H, m), 3.76 (3H, s), 4.09 (2H, q), 6 .72-6.75 (2H, m), 6.86 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3466, 2933, 1739, 1600, 1513, 1465, 1371, 1267, 1422, and 1040.
The results of elemental analysis were as follows: carbon 68.78% and hydrogen 9.23%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 31.

<Synthesis Example 21>
Compound 26 obtained in Synthesis Example 15 was ketalized to obtain Compound 32.

Compound 32

This reaction was performed in a nitrogen atmosphere. To a solution of 11 μl (0.0614 mmol) trimethylsilyl trifluoromethanesulfonate and 0.9 ml (3.69 mmol) 1,2-bistrimethylsiloxyethane in 6 ml dichloromethane was added 133 mg (0.307 mmol) under ice cooling. A solution of compound 26 in 1 ml of dichloromethane was added dropwise. After stirring for 50 minutes, triethylamine was added to the reaction mixture to stop the reaction. Next, 5 ml of saturated aqueous sodium hydrogen carbonate and 5 ml of chloroform were added and partitioned. The organic layer was separated and dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel thin layer chromatography to obtain 114 mg (78%) of a pale yellow, medium-viscous liquid compound.
The chemical shift values of the ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.23-1.64 (17H, m), 1.98-2.06 (4H, m), 2.28 ( 2H, t), 2.67-2.71 (2H, m), 2.80-2.84 (1H, m), 3.79 (3H, s), 3.91-3.98 (4H, m), 4.12 (2H, q), 5.38 (1H, d), 5.81 (1H, dt), 6.74-6.78 (2H, m), 6.89 (1H, d) )Met.
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2924, 1758, 1737, 1608, 1510, 1466, 1420, 1127, and 1042.
The results of elemental analysis were as follows: carbon 68.04% and hydrogen 8.46%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 32.

<Synthesis Example 22>
Compound 29 obtained in Synthesis Example 18 was ketalized to obtain Compound 33.

Compound 33

According to the method of Synthesis Example 21, 200 mg (78%) of Compound 33 was obtained from 234 mg (0.522 mmol) of Compound 29 as a pale yellow, medium-viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 33 is 1.23-1.35 (22H, m), 1.59-1.64 (4H, m), 1.90-. 1.94 (2H, m), 2.28 (2H, t), 2.64-2.68 (2H, m), 3.78 (3H, s), 3.98 (4H, s), 4 .12 (2H, q), 6.74-6.78 (2H, m), 6.88 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2936, 1755, 1735, 1606, 1511, 1464, 1418, 1266, 1203, 1117, 1036.
The results of elemental analysis were as follows: carbon 68.54% and hydrogen 8.63%.

<Synthesis Example 23>
The compound 26 obtained in Synthesis Example 15 was added with a water molecule, and the phenolic hydroxyl protecting group and the carboxyl protecting group were removed to obtain the compound 34 of the present invention.

Compound 34

To a solution of 43 mg (99.4 μmol) of Compound 26 dissolved in 3 ml of toluene, 0.2 ml of 1N aqueous sodium hydroxide solution and 3.5 mg (9.9 μmol) of benzyltributylammonium bromide were added, and the mixture was stirred at room temperature for 18 hours. Stir. The organic layer was separated from the reaction mixture, and the aqueous layer was neutralized with 1N hydrochloric acid. This aqueous layer was extracted three times with 5 ml of chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 23.2 mg (66%) of a yellow medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 1.00-1.77 (10H, m), 2.18-2.33 (2H, m), 2.65 ( 2H, t), 2.88 (2H, t), 3.20-3.24 (2H, m), 3.72-3.86 (4H, m), 4.75 (1H, s), 5 .30 (1H, br), 6.68-6.72 (2H, m), 6.83 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3336, 2943, 1723, 1710, 1603, 1514, 1426, 1275, and 1212.
The results of elemental analysis were as follows: carbon 64.75% and hydrogen 8.01%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 34.

<Synthesis Example 24>
Compound 34 obtained in Synthesis Example 23 was reduced to obtain Compound 35.

Compound 35

To a solution of 35.2 mg (0.103 mmol) of Compound 34 in 2 ml of methanol, 5.8 mg (0.154 mmol) of sodium borohydride was added under ice cooling. After stirring at a bath temperature of 60 ° C. for 6 hours, the reaction mixture was partitioned by adding 5 ml of saturated brine and 5 ml of ethyl acetate. After separating the organic layer, the aqueous layer was extracted three times with 5 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 7.4 mg (21%) of a colorless crystalline compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterated methanol of this product are 1.10-1.90 (12H, m), 2.18-2.33 (2H, m), 2.39-. 2.43 (2H, m), 2.79-2.83 (2H, m), 3.64-3.87 (4H, m), 6.65-6.68 (2H, m), 6. 74 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3448, 2924, 1701, 1621, 1560, 1524, 1410, 1212, 1127, 1098, 1028.
The results of elemental analysis were as follows: carbon 64.38% and hydrogen 8.53%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 35.

<Synthesis Example 25>
Methanol was added to the compound 26 obtained in Synthesis Example 15 and the protecting group for the phenolic hydroxyl group was removed to obtain a compound 36. In Compound 26, the ethyl group that was a protecting group for the carboxyl group was substituted with a methyl group.

Compound 36

To a solution of 432 mg (0.999 mmol) of compound 26 dissolved in 6 ml of methanol, a solution of 80 mg (2 mmol) of sodium hydroxide previously dissolved in 4 ml of methanol was added. After stirring at room temperature for 4 hours, 1N hydrochloric acid was added to neutralize. After the solvent was distilled off, 10 ml of saturated brine was added to the resulting residue, and extraction with 10 ml of ethyl acetate was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel thin layer chromatography to obtain 154 mg (41%) of a pale yellow, medium-viscous liquid compound.
The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.29-1.63 (10H, m), 2.30 (2H, t), 2.39 (1H, dd). , 2.64 (1H, dd), 2.73-2.76 (2H, m), 2.81-2.83 (2H, m), 3.25 (3H, s), 3.64-3 .67 (4H, m), 3.88 (3H, s), 5.51 (1H, s), 6.66-6.70 (2H, m), 6.82 (1H, d). .
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) are 3413, 2931, 1733, 1604, 1515, 1436, 1364, 1267, 1238, 1196, 1155, 1127, 1084, 1072. 1028.
The results of elemental analysis were as follows: carbon 66.29% and hydrogen 8.48%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 36.

<Synthesis Example 26>
Compound 27 obtained in Synthesis Example 16 was hydrolyzed to obtain Compound 37.

Compound 37

To a solution of 209 mg (0.480 mmol) of compound 27 in 4 ml of ethanol was added 2 ml of 1N aqueous sodium hydroxide solution and stirred. The mixture was stirred at a bath temperature of 80 ° C. for 6 hours and neutralized by adding 1N hydrochloric acid. The reaction solution was concentrated under reduced pressure, ethanol was distilled off, 10 ml of saturated brine was added, and extraction with 10 ml of ethyl acetate was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel thin layer chromatography to obtain 100 mg (62%) of a yellow medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.12-2.35 (14H, m), 2.60-2.90 (2H, m), 3.86 ( 3H, s), 4.07-4.13 (1H, m), 5.36-5.53 (1H, m), 5.59-5.67 (1H, m), 6.64-6. 70 (2H, m), 6.81 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3403, 2926, 2858, 2368, 1700, 1515, 1417, 1274, 1034.
The results of elemental analysis were as follows: carbon 67.83% and hydrogen 8.39%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 37.

<Synthesis Example 27>
Compound 30 obtained in Synthesis Example 19 was hydrolyzed to obtain Compound 38.

Compound 38

According to the method of Synthesis Example 26, 136 mg (89%) of Compound 38 was obtained as a colorless crystalline compound from 199 mg (0.457 mmol) of Compound 30.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 38 is 1.11-1.64 (12H, m), 2.32-2.38 (4H, m), 2.69 ( 2H, t), 2.82 (2H, t), 3.87 (3H, s), 5.55 (1H, br), 6.65-6.69 (2H, m), 6.81 (1H) , D).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3414, 2935, 1703, 1611, 1520, 1466, 1409, 1279, 1228, 1122, and 1028.
The results of elemental analysis were as follows: carbon 67.83% and hydrogen 8.39%.

<Synthesis Example 28>
Compound 31 obtained in Synthesis Example 20 was hydrolyzed to obtain Compound 39.

Compound 39

According to the method of Synthesis Example 26, 134 mg (91%) of Compound 39 was obtained from 187 mg (0.433 mmol) of Compound 31 as a colorless crystalline compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 39 is 1.23-1.77 (16H, m), 2.33 (2H, t), 2.56-2.63 ( 1H, m), 2.68-2.74 (1H, m), 3.59-3.66 (1H, m), 3.87 (3H, s), 5.50 (1H, br), 6 .67-6.70 (2H, m), 6.82 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3413, 2931, 1705, 1612, 1515, 1435, 1367, 1264, 1154, 1038.
The results of elemental analysis were as follows: carbon 67.43% and hydrogen 8.93%.

<Synthesis Example 29>
Compound 22 obtained in Synthesis Example 12 was reduced with lithium aluminum hydride to obtain Compound 40.

Compound 40

To a solution of 594 mg (1.33 mmol) of compound 22 in 40 ml of tetrahydrofuran, 202 mg (5.32 mmol) of lithium aluminum hydride was added under ice cooling. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture to stop the reaction. Next, 15 ml of distilled water was added, and extraction with 20 ml of ethyl acetate was repeated twice. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 315 mg (73%) of a colorless medium viscosity liquid compound.
The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.23-1.83 (12H, m), 2.02 (2H, m), 2.56-2.69 ( 2H, m), 3.61 (2H, t), 3.84 (3H, s), 4.04 (1H, dd) 5.45-5.49 (1H, m), 5.58-5. 66 (1H, m), 6.65-6.67 (2H, m), 6.79 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3349, 2930, 1666, 1602, 1516, 1464, 1453, 1431, 1368, 1273, 1236, 1154 and 1036. It was.
The results of elemental analysis were as follows: carbon 70.77% and hydrogen 9.38%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 40.

<Synthesis Example 30>
The compound 40 obtained in Synthesis Example 29 was epoxidized to obtain a compound 41.

Compound 41

To a solution of 87.3 mg (0.271 mmol) of compound 40 dissolved in 5 ml of dichloromethane, a solution of 93.6 mg (0.542 mmol) of m-chloroperbenzoic acid dissolved in 3 ml of dichloromethane under ice-cooling. It was dripped. After stirring at the same temperature for 6.5 hours, 5 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and extraction with 5 ml of chloroform was repeated twice. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 44.6 mg (yield 49%) of a pale yellow, medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.33-2.30 (15H, m), 2.64-3.10 (4H, m), 3.62 ( 2H, t), 3.80-3.87 (4H, m), 6.68-6.71 (2H, m), 6.82 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3394, 2931, 1723, 1603, 1517, 1453, 1430, 1368, 1270 and 1035.
The results of elemental analysis were as follows: carbon 67.83% and hydrogen 8.39%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 41.

<Synthesis Example 31>
Compound 30 obtained in Synthesis Example 19 was reduced with lithium aluminum hydride to obtain Compound 42.

Compound 42

According to the method of Synthesis Example 29, 97.4 mg (91%) of Compound 42 was obtained from 148 mg (0.330 mmol) of Compound 30 as a colorless crystalline compound.
Chemical shift values of ¹ H-NMR spectrum of Compound 42 measured in deuterated chloroform are 1.26-1.72 (18H, m), 2.54-2.61 (1H, m), 2.66-. 2.70 (1H, m), 3.54-3.73 (3H, m), 3.85 (3H, s), 6.66-6.68 (2H, m), 6.80 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3426, 2930, 1607, 1515, 1481, 1468, 1437, 1365, 1268, 1239, 1155, 1124, 1039. It was.
The results of elemental analysis were as follows: carbon 70.3% and hydrogen 9.94%.

<Synthesis Example 32>
Compound 32 obtained in Synthesis Example 21 was reduced with lithium aluminum hydride to obtain Compound 43 of the present invention.

Compound 43

To a solution of 159 mg (0.334 mmol) of compound 32 in 6 ml of tetrahydrofuran was added 50.0 mg (1.33 mmol) of lithium aluminum hydride under ice cooling. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture to stop the reaction. Next, 5 ml of saturated saline was added, and extraction with 5 ml of ethyl acetate was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 121 mg (99%) of a yellow medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 1.26 to 1.55 (10H, m), 1.96 to 2.06 (4H, m), 2.62 2.66 (2H, m), 3.62 (2H, t), 3.86 (3H, s), 3.91-3.99 (4H, m), 5.38 (1H, d), 5 .61 (1H, s), 5.81 (1H, dt), 6.66-6.69 (2H, m), 6.82 (1H, d).
The results of elemental analysis were as follows: carbon 69.20% and hydrogen 8.85%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 43.

<Synthesis Example 33>
Compound 33 obtained in Synthesis Example 22 was reduced with lithium aluminum hydride to obtain Compound 44.

Compound 44

According to the method of Synthesis Example 32, 137 mg (99%) of Compound 44 was obtained by using 186 mg (0.378 mmol) of Compound 33 as a yellow medium viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 44 is 1.24-1.70 (16H, m), 1.88-1.93 (2H, m), 2.59-. 2.63 (2H, m), 3.64 (2H, t), 3.87 (3H, s), 3.98 (4H, s), 5.50 (1H, br), 6.67-6 .70 (2H, m), 6.82 (1H, d).
The results of elemental analysis were as follows: carbon 69.20% and hydrogen 8.85%.

<Synthesis Example 34>
The ketal of compound 43 obtained in Synthesis Example 32 was removed to obtain compound 45.

Compound 45

8.4 mg (0.0335 mmol) of pyridinium p-toluenesulfonate was added to a solution of 122 mg (0.335 mmol) of compound 43 dissolved in 2 ml of acetone and 2 ml of distilled water. The reaction solution was heated to reflux for 3 hours. Next, the reaction solution was allowed to cool to room temperature, the solvent was distilled off, 5 ml of saturated brine was added to the resulting residue, and extraction with 5 ml of ethyl acetate was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel thin layer chromatography to obtain 85.2 mg (80%) of a pale yellow, medium-viscous compound.
The chemical shift value of ¹ H-NMR spectrum measured in deuterated chloroform of this product is 1.30-1.58 (10H, m), 2.17 (2H, dd), 2.81-2.86 ( 4H, m), 3.63 (2H, t), 3.86 (3H, s), 5.73 (1H, s), 6.08 (1H, dt), 6.67-6.71 (2H) M), 6.78-6.83 (2H, m).
The results of elemental analysis were as follows: carbon 71.22% and hydrogen 8.81%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 45.

<Synthesis Example 35>
The ketal of compound 44 obtained in Synthesis Example 33 was removed to obtain compound 46.

Compound 46

According to the method of Synthesis Example 34, 120 mg (99%) of Compound 46 was obtained as a colorless crystalline compound from 137 mg (0.377 mmol) of Compound 44.
The chemical shift value of the ¹ H-NMR spectrum of Compound 46 measured in deuterated chloroform is 1.20-1.51 (14H, m), 2.29 (2H, t), 2.62 (2H, t). 2.75 (2H, t), 3.59 (2H, t), 3.81 (3H, s), 5.47 (1H, s), 6.64-6.67 (2H, m), 6.80 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) are 3415, 2920, 1705, 1611, 1520, 1463, 1455, 1365, 1278, 1236, 1151, 1122, 1064, 1028. Met.
The results of elemental analysis were as follows: carbon 70.77% and hydrogen 9.38%.

<Synthesis Example 36>
Compound 28 obtained in Synthesis Example 17 was reduced to obtain Compound 47.

Compound 47

To a solution of 117 mg (0.260 mmol) of compound 28 dissolved in 10 ml of tetrahydrofuran, 59.1 mg (1.56 mmol) of lithium aluminum hydride was added under ice cooling. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture to stop the reaction. Next, 5 ml of saturated saline was added, and extraction with 10 ml of ethyl acetate was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 81.4 mg (92%) of a colorless crystalline compound.
The chemical shift values of the ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.24-1.78 (16H, m), 3.63-3.70 (3H, m), 3.88-. 3.96 (4H, m), 5.49 (1H, s), 6.69-6.73 (2H, m), 6.84 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3416, 2930, 1653, 1609, 1516, 1453, 1429, 1368, 1274, 1239, 1154 and 1030.
The results of elemental analysis were as follows: carbon 67.03% and hydrogen 9.47%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 47.

<Synthesis Example 37>
Compound 36 obtained in Synthesis Example 25 was reduced with lithium aluminum hydride to obtain Compound 48.

Compound 48

According to the method of Synthesis Example 36, 97.1 mg (68%) of Compound 48 was obtained from 154 mg (0.405 mmol) of Compound 36 as a colorless medium viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum of Compound 48 measured in deuterated chloroform is 1.26-1.80 (14H, m), 2.58-2.2.64 (1H, m), 2. 68-2.74 (1H, m), 3.35-3.63 (4H, m), 3.61 (2H, t), 3.79-3.89 (4H, m), 5.78 ( 1H, s), 6, 67-6.73 (2H, m), 6.81 (1H, d).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3389, 2932, 2857, 1602, 1516, 1453, 1428, 1371, 1272, 1238, 1084 and 1036.
The results of elemental analysis were as follows: carbon 68.15% and hydrogen 9.15%.

<Synthesis Example 38>
Methanol was added to the compound 12 obtained in Synthesis Example 6 and the protecting group for the phenolic hydroxyl group was removed to obtain a compound 49. The ethyl group that was a protecting group for the carboxyl group in Compound 12 was substituted with a methyl group.

合成例２５の方法に従い、２．９５ｇ（６．７２ｍｍｏｌ）の化合物１２から、無色中粘度液状の化合物として１．２７ｇ（５４％）の化合物４９を得た。
化合物４９の重クロロホルム中で測定した¹Ｈ−ＮＭＲスペクトルのケミカルシフト値は、１．２９−１．６７（６Ｈ，ｍ），２．３４（２Ｈ，ｔ），２．４１（１Ｈ，ｄｄ），２．６９（１Ｈ，ｄｄ），２．７６−２．７９（２Ｈ，ｍ），２．８６−２．８８（２Ｈ，ｍ），３．３１（３Ｈ，ｓ），３．６８−３．７１（４Ｈ，ｍ），３．９１（３Ｈ，ｓ），５．５２（１Ｈ，ｓ），６．６９−６．７３（２Ｈ，ｍ），６．８５（１Ｈ，ｄ）であった。
また、赤外線吸収スペクトル（ＫＢｒペレット法）で吸収があった波数（ｃｍ^-1）は、３４１３、２９３１、１７３３、１６０４、１５１５、１４３６、１３６４、１２６７、１２３８、１１９６、１１５５、１１２７、１０８４、１０７２、１０２８であった。
さらに、元素分析の結果は、炭素６４．７５％、水素８．０１％であった。 Compound 49

According to the method of Synthesis Example 25, 1.27 g (54%) of Compound 49 was obtained from 2.95 g (6.72 mmol) of Compound 12 as a colorless medium viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of compound 49 is 1.29-1.67 (6H, m), 2.34 (2H, t), 2.41 (1H, dd). , 2.69 (1H, dd), 2.76-2.79 (2H, m), 2.86-2.88 (2H, m), 3.31 (3H, s), 3.68-3 .71 (4H, m), 3.91 (3H, s), 5.52 (1H, s), 6.69-6.73 (2H, m), 6.85 (1H, d). .
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) are 3413, 2931, 1733, 1604, 1515, 1436, 1364, 1267, 1238, 1196, 1155, 1127, 1084, 1072. 1028.
The results of elemental analysis were as follows: carbon 64.75% and hydrogen 8.01%.

<Synthesis Example 39>
Compound 49 obtained in Synthesis Example 38 was reduced with lithium aluminum hydride to obtain Compound 50.

Compound 50

According to the method of Synthesis Example 36, 518 mg (80%) of Compound 50 was obtained from 700 mg (1.99 mmol) of Compound 49 as a colorless medium viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 48 is 1.24-1.70 (12H, m), 2.58-2.2.80 (2H, m), 3. 37-3.53 (4H, m), 3.65 (2H, t), 3.79-3.87 (4H, m), 5.46 (1H, s), 6, 71-6.84 ( 3H, m).
The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3389, 2932, 2857, 1602, 1516, 1453, 1428, 1371, 1272, 1238, 1084 and 1036.
The results of elemental analysis were as follows: carbon 66.23% and hydrogen 9.26%.

○ Measurement of oxidation inhibition effect of LDL

<Acquisition of LDL>
LDL used for the test was obtained by the following procedure.
(1) 10 mM PBS (pH 7.4) containing 1 mg / ml ethylenediaminetetraacetic acid (EDTA) was prepared.
(2) (1) and human plasma (specific gravity 1.24) are layered in a tube, and then centrifuged at 100,000 rpm for 70 minutes at 10 ° C. (centrifuge: TL-100 manufactured by Beckman). The LDL fraction was collected.
(3) The LDL fraction was filled in a dialysis membrane and dialyzed overnight at 4 ° C. using 10 mM PBS containing 100 μM EDTA. In this dialysis, PBS not containing EDTA was used when copper ions were used as an oxidizing agent for LDL.
(4) After dialysis, LDL was collected, and the amount of protein was measured with a BCA reagent (manufactured by PIERCE).

<Inhibition test 1 of LDL oxidation induced by a fat-soluble radical initiator>
Using compound 7 obtained in Synthesis Example 3, the effect of inhibiting oxidation of LDL was measured.
The LDL solution prepared above was prepared to 0.25 mg protein / ml with 10 mM PBS (pH 7.4, including EDTA).
Sample solutions were prepared at various concentrations after dissolving the test sample in acetonitrile.
The oxidant solution was prepared to 10 mM by dissolving 2,2'-Azobis (4-methoxy-2,4-dimethylvaleronitrile) (manufactured by Wako Pure Chemical Industries) in acetonitrile.
10 μl of sample solution and 10 μl of oxidizing agent solution were added to 1.0 ml of LDL solution. These were mixed and then kept at 37 ° C. In order to quantify the reaction product, 100 μl of the reaction solution was sampled over time from the start of the reaction (0 hour).

<Extraction and analysis method>
After adding 200 μl of a chloroform / methanol (2: 1) mixed solution to 100 μl of the reaction solution sampled above and stirring for 1 minute, the mixture was centrifuged at 14,000 rpm for 3 minutes (centifuge 5410 manufactured by Eppendorf). 125 μl was sampled from the chloroform layer, replaced with 125 μl of methanol under a nitrogen atmosphere, and subjected to HPLC analysis described later.
The HPLC system used was a pump; JASCO PU980, detector; JASCO UV-970 and MD-910.

  Cholesterol ester oxide was measured using a column; LC-18 (25 cm × 4.6 φmm × 5 μm), mobile phase; mixed solution of acetonitrile / isopropyl alcohol / water = 44/54/2, flow rate; 1 ml / min, detection; It implemented on the conditions of UV234nm. Under these conditions, the cholesterol ester oxide had a retention time of about 15 minutes.

  The measurement of phosphatidylcholine oxide was carried out using a column; LC-SI (25 cm × 4.6 φmm × 5 μm), mobile phase; methanol / t-butyl alcohol / 40 mM aqueous sodium dihydrogen phosphate solution = 60/30/10, flow rate 1 ml / min, detection; UV 234 nm. Under these conditions, phosphatidylcholine oxide had a retention time of about 13 minutes.

The effect of the compound of the present invention on the oxidation of LDL induced by 2,2′-Azobis (4-methoxy-2,4-dimethylvaleronitrile) is shown in FIGS.
FIG. 1 shows the time course of oxidation of phosphatidylcholine at a final concentration of 10 μM of the compound of the present invention, and FIG. 2 shows the time course of oxidation of cholesterol ester at the same final concentration of 10 μM.
FIG. 3 shows the effect on phosphatidylcholine oxidation after 4 hours with varying concentrations of the compounds of the invention. FIG. 4 shows the effect on the oxidation of cholesterol esters after 4 hours when the concentration of the compound of the invention is varied.

  1 and 2 show that Compound 7 strongly suppresses the oxidation of LDL. As can be seen from the results of FIGS. 3 and 4, the effect was concentration-dependent.

<Suppression test 2 of LDL oxidation induced by fat-soluble radical initiator>
Compound 38 obtained in Synthesis Example 27, Compound 39 obtained in Synthesis Example 28, Compound 42 obtained in Synthesis Example 31, Compound 47 obtained in Synthesis Example 36, Compound 36 obtained in Synthesis Example 25, Using the compound 48 obtained in Synthesis Example 37, the compound 49 obtained in Synthesis Example 38, and the compound 50 obtained in Synthesis Example 39, the oxidation inhibition effect of LDL was measured.

The LDL solution prepared above was prepared to 0.1 mg protein / ml with 10 mM PBS (pH 7.4, including EDTA).
The sample solution was prepared to 500 μM by dissolving the test sample in methanol.
The oxidizing agent solution was prepared to 40 mM by dissolving 2,2′-Azobis (4-methoxy-2,4-dimethylvaleronitrile) (manufactured by Wako Pure Chemical Industries) in methanol.
LDL solution (2.0 ml) was weighed in a quartz cell with a lid, and 20 μl of a sample solution and 20 μl of an oxidizing agent solution were added thereto. The reaction solution was kept at 37 ° C. for 180 minutes, and the resulting lipid peroxide was measured by absorbance at 234 nm. As a control, 20 μl of methanol was added instead of the sample solution, and the same measurement was performed. The results are shown in FIG.

  As a result, it can be seen that Compound 38, Compound 39, Compound 42, Compound 47, Compound 36, Compound 48, Compound 49, and Compound 50 inhibit the oxidation of LDL compared to the control.

  Since the compound represented by the general formula (1) of the present invention suppresses the oxidation of LDL, it can be used as a therapeutic agent, a symptom ameliorating agent, an inhibitor, etc. for a disease involving oxidative modification of LDL. For example, Formula (1) can be used for the treatment of arteriosclerosis, symptom improvement, or onset suppression.

The effect that the compound 7 of the present invention suppresses the oxidation of phosphatidylcholine induced by a fat-soluble radical initiator. The inhibitory effect is displayed over time (sample concentration 10 μM). The effect which the compound 7 of this invention suppresses the oxidation of the cholesterol ester induced | guided | derived by a fat-soluble radical initiator. The inhibitory effect is displayed over time (sample final concentration 10 μM). The effect that the compound 7 of the present invention suppresses the oxidation of phosphatidylcholine induced by a fat-soluble radical initiator. The suppression effect by each concentration is displayed. However, a column with a sample concentration of 0 μM represents a control. The effect which the compound 7 of this invention suppresses the oxidation of the cholesterol ester induced | guided | derived by a fat-soluble radical initiator. The suppression effect by each concentration is displayed. However, a column with a sample concentration of 0 μM represents a control. The effect that the compound of the present invention suppresses oxidation of LDL induced by a fat-soluble radical initiator.

Explanation of symbols

The horizontal axis in FIG. 1 and FIG.
Horizontal axis of FIG. 3 and FIG. 4: concentration (μM) at the time of assay of the compound of the present invention.
The vertical axis in FIGS. 1 and 3 is the concentration of phosphatidylcholine oxide (μM).
The vertical axis | shaft of FIG. 2 and FIG.
In FIG. 1 and FIG. 2, “●” indicates a value by the control.
In FIG. 1 and FIG.
The black columns in FIG. 3 and FIG. However, the column with the sample concentration of 0 μM in FIGS. 3 and 4 represents a control.

Claims (2)

A low-density lipoprotein oxidation inhibitor comprising a compound represented by the following general formula (1):

(In formula (1), R ¹ is a methyl group, A is an ethylene group, B is an alkylene group having 3 to 5 carbon atoms, R ² is —COOR ³ (where R ³ is a methyl group), carboxyl Or —CH ₂ OH, Z is —CO—CH═CH—, —CO—CH ₂ CH ₂ —, —CHOH—CH ₂ CH ₂ —, —CHOH—CH ₂ CHOH—, —CO—CH _2. CHOR ⁴ —, —CHOH—CH ₂ CH O R ⁴ —, and R ⁴ is a methyl group.)
An anti-arteriosclerotic agent comprising the compound represented by the general formula (1) according to claim 1 .

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