JPH0641431B2 - 4-Arylmethylene-5-alkenylidene-2-cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to 4-arylmethylene-5-alkenylidene-
The present invention relates to 2-cyclopentenones and a method for producing the same. More specifically, a novel 4-arylmethylene-5-alkenylidene-2- having excellent anticancer and antiviral effects
The present invention relates to cyclopentenones and a method for producing the same.

<Prior Art> Among brostaglandins, brostaglandins having a double bond in a cyclopentane ring in their skeletal structure are known, and it is reported that these exhibit strong antitumor activity. Has been done. For example, PGD ₂ and its dehydrated product PGJ ₂ are known to strongly suppress the growth of leukemia cells (L1210) at a concentration of about 10 ⁻⁵ to 10 ⁻⁶ mol.

(See Fukushima et al., JP-A-58-124718; Wakazuka et al., JP-A-59-5155; 59-1463).

The PGA _1, Δ ⁷ -PGA ₁ class, PGA ₂ type (Fukushima, pathophysiology 2
(8), 811 (1983); Cancer and chemotherapy 10 (9), 193
0 (see 1983)), and similar activities are known, and these are known to exhibit strong antitumor activity in vivo. Recently, these analogues, 4-substituted-
Among the 5-alkylidene-2-dicloventenones, marine brostaglandins such as clavron and claviridone [Kikuchi et al., Tetrahedron Letters (Tetrahedron
Lett.), 23,5171 (1982), 24,1549 (1983); 24,4433 (198
3); Kobayashi et al., Tetrahedron L
ett.), 23,5331 (1982), Chemical &. Pharmacy Bulletin (Chem, Pharm Bull.), 31,1440
(See (1983)], the same activity is also shown (see Fukushima et al., 42nd Annual Meeting of Japan Medical Society 856 (1983)). Further, similar activity has also become known for PGJ ₂ similar compounds (see Wakatsuka et al., JP-A-58-216155, 59-5154).

<Object of the Invention> The present inventors have paid attention to such a fact, and in these analogs of 2-cyclopentenones, 4-arylmethylene- having a completely novel structure in which a double bond is further conjugated to an enone functional group.
The present invention has been earnestly studied to obtain 5-alkenylidene-2-cyclopentenones.

<Structure and Effect of the Invention> 4-Arylmethylene-5-alkenylidene of the present invention
2-Cyclopentenones are represented by the following formula [I] [In the formula, R ¹ is a hydroxy group, a tri (alkyl having 1 to 4 carbon) silyloxy group, a tetrahydropyranyloxy group, an acetoxy group or a carbon which may be substituted with an alkyloxycarbonyl group having 1 to 6 carbon. Ar having a number of 1 to 10 and Ar having a total of 6 to 10 carbon atoms which may be substituted with at least one group selected from the group consisting of an alkyl group, a hydroxy group, an alkoxy group, an alkyloxycarbonyl group and a halogen atom. The phenyl group of 12 represents a single bond in the E form or Z form with respect to the double bond. ] Is represented.

In the above formula [I], R ¹ may be substituted with a hydroxy group, a tri (alkyl having 1 to 4 carbons) silyloxy group, a tetrahydropyranyloxy group, an acetoxy group or an alkyloxycarbonyl group having 1 to 6 carbons. It represents a good alkyl group having 1 to 10 carbon atoms. Examples of the alkyl group include linear or branched ones such as methyl, ethyl, n-propyl, n-pentyl, n-hexyl and n-decyl.

These alkyl groups may be substituted as described above, and the substituent includes a hydroxy group, a protected hydroxy group and an ester group. Examples of the protected hydroxy group include t-butyldimethylsilyloxy, trimethylsilyloxy, tetrahydropyranyloxy, acetoxy and the like. Examples of the ester group include methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, n-hexyloxycarbonyl, phenoxycarbonyl, acetoxymethyl, propionyloxymethyl, benzoyloxymethyl and the like. A plurality of these substituents may be substituted.
It should be noted that those other than the above definition of R ¹ are reference examples.

Ar is a substituted or unsubstituted phenyl group having a total of 6 to 12 carbon atoms, and examples of the substituent include an alkyl group such as methyl, ethyl and propyl, an alkoxy group such as a hydroxy group and a methoxy group, methoxycarbonyl and ethoxycarbonyl. Alkyloxycarbonyl groups, fluorine, halogen groups such as chlorine, etc. can be mentioned. A plurality of these substituents may be substituted on the phenyl group. Here, the "total carbon number" means the carbon number including the carbon number constituting the substituent.

Such 4-arylmethylene-5-alkenylidene-2
-Specific examples of cyclopentenones include the following compounds.

(1) 4-benzylidene-5- (4-hydroxy-2-octenylidene) -2-cyclopentenone (Compound A) (2) 4-p-fluorophenylmethylene-5- (4-hydroxy-2-octenylidene ) -2-Cyclopentenone (3) 4-p-methylphenylmethylene-5- (4-hydroxy-2-octenylidene) -2-cyclopentenone (4) 4- (3,4-dimethoxyphenyl) Methylene-5
(4-Hydroxy-2-octenylidene) -2-cyclopentenone (5) 4-Pentylidene-5- (4,7-dihydroxy-2-
Hebutenylidene) -2-cyclopentenone (6) 4-p-fluorophenylmethylene-5- (4,7-dihydroxy-2-heptenylidene) -2-cyclopentenone (Compound B) (7) 4-p- Methylphenylmethylene-5- (4,7-hydroxy-2-heptenylidene) -2-cyclopentenone (8) 4- (3,4-dimethoxyphenyl) methylene-5
(4,7-Dihydroxy-2-heptenylidene) -2-cyclopentenone (9) 4-benzylidene-5- (4-hydroxy-6-methoxycarbonyl-2-hexenylidene) -2-cyclopentenone (10) 4 -P-Fluorophenylmethylene-5- (4-hydroxy-6-methoxycarbonyl-2-hexenylidene) -2-cyclopentenone (11) 4-p-methylphenylmethylene-5- (4-hydroxy-6) -Methoxycarbonyl-2-hexenylidene) -2-cyclopentenone (12) 4- (3,4-dimethoxyphenyl) methylene-5-
(4-Hydroxy-6-methoxycarbonyl-2-hexenylidene) -2-cyclopentenone (13) t-butyldimethylsilyl ether of alcohol of compound (1) to (12) (14) compound (1) to ( 12) Acetate of alcohol (15) Carboxylic acid of compounds (9) to (12) (16) Ethyl ester of compound (15) 4-arylmethylene-5-alkenylidene of the present invention
2-Cyclopentenones are represented by the following formula [IV] PhSCH ₂ Ar ... [IV] [wherein, Ar is as defined above. ] The phenyl sulfides represented by the formula [In the formula, R ² represents a protective group for alcohol. ] A protected 4-hydroxy-2-cyclopentenone represented by the following formula is reacted and the reaction product is represented by the following formula [VI] [In the formula, R ¹ and the symbols are the same as defined above. ] Promoted with aldehydes represented by the following formula [VII] ... [VII] [wherein R ¹ , R ² , Ar and symbols are the same as defined above. ] To obtain a ternary condensate represented by, which were detached with R ² OH without isolation and purification, the following formula [III] ... [III] [In the formula, R ¹ , Ar, and symbols are the same as defined above. ] A 2-cyclopentenone compound represented by the formula ... [II] [In the formula, R ¹ , Ar, and symbols are the same as defined above. ] It manufactures by making it into the phenyl sulfides represented by these, oxidizing this, making PhSOH desorb, and subjecting to deprotection reaction as needed.

In the above formula [V], R ² represents an alcohol protecting group, and examples thereof include a tri (C ₁ -C ₇ ) hydrocarbon-silyl group or a group forming an acetal bond with the oxygen atom of the hydroxyl group.

Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include tri (C ₁ -C ₄ ) alkylsilyl such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl group, and diphenyl such as t-butyldiphenylsilyl group. Preferable ones are (C ₁ -C ₄ ) alkylsilyl or tribenzylsilyl groups.

Examples of the group that forms an acetal bond with the oxygen atom of the hydroxyl group include methoxymethyl, 1-ethoxyethyl,
2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl can be mentioned.

The first step of the present invention is the carbanion of the phenyl sulfides of the above formula [IV], the protected 4-hydroxy-2-cyclopentenones of the above formula [V] and the aldehydes of the above formula [VI]. Is a three-component ligation reaction with. The carbanion of phenyl sulfides [IV] can be easily prepared by reacting a base such as n-butyllithium or sec-butyllithium. This carbanion was protected in the presence of hexamethylmelamide phosphate 4
-Conjugate addition to hydroxy-2-cyclopentenones [V] and, if necessary, tri-n-butyltin chloride and then aldehydes [VI] are added to condense these three components at once. Body [VII] is obtained. A similar reaction of this process is already known [Nogami et al., Bulletin of the Chemical Society of Japan (Bull.Chem.Soe.Japan) , 55, 3043 (1982), Tetrahedron Letters. (See Tet-rahedron Lett.), 26, 1985 (1985)], the present inventors obtained the raw material of the formula [VII] all at once using this methodology.

The above-mentioned three-component condensate [VII] is not isolated but can be converted to a 2-cyclopentenone derivative [III] from which R ¹ OH is eliminated from the formula [VII] by a usual post-treatment.

... [III] [wherein R ¹ , Ar and symbols are the same as defined above. ] The 2-cyclopentenone compound obtained in the second step [II
I] is subjected to dehydration reaction. N, N'-dicyclohexylcarbodiimide (DCC) is preferably used as a dehydrating agent, and (DCC)
Is used at 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to the raw materials and reacted at 10 ° C to 40 ° C in an inert medium. Aromatic hydrocarbons such as benzene and toluene are preferably used as the inert medium. At this time, a reaction aid is used. The reaction proceeds smoothly when 1 to 6 equivalents, preferably 1 to 3 equivalents of cuprous chloride and cupric bromide are used as a reaction aid with respect to the raw materials. The reaction product is subjected to a usual post-treatment to give a dehydration product [II].

... [II] [wherein R ¹ , Ar and symbols are the same as defined above. The third step is a reaction in which the above formula [III] is oxidized to eliminate PhSOH. Oxidizing agents such as m-chlorobenzoic acid, peracetic acid, and other organic peracids, or sodium metaperiodate are used to oxidize the sulfur atom of sulphide. Particularly preferably, m-chloroperbenzoic acid is used. The amount of the oxidizing agent used is 0.5 to 2.0 equivalents, preferably 0.8 to 1.2 equivalents, relative to the raw material sulfide. Halogenated hydrocarbons such as methylene chloride and dichloroethane are used as a medium, and the reaction temperature is -78 ° C to 0 ° C, preferably -50.
It is carried out at -20 ° C. The reaction is monitored by following it by thin layer chromatography (TLC) or the like, and the reaction time is usually 30 minutes to 2 hours. After the reaction, an aqueous solution of sodium bicarbonate is added to the reaction product, the temperature of the reaction liquid is returned to around room temperature, and the usual post-treatment is applied.

Thus, the following formula [VIII] ... [VIII] [wherein R ¹ , Ar and symbols are the same as defined above. ] The sulfoxides represented by this are obtained. This product is directly subjected to the elimination reaction of PhSOH as a crude product. The elimination reaction is achieved by heating in an aromatic hydrocarbon such as benzene, toluene or xylene. Of these, toluene is particularly preferably used, and the heating temperature is around the reflux temperature. The reaction is monitored by TLC or the like, and the reaction product is subjected to usual post-treatment and purified by means such as silica gel column chromatography. If R ¹ of the product has a protected hydrogen group or ester group, it may be subjected to a deprotection reaction if necessary. This can be done more easily in a manner known per se.

That is, when the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid or a cation exchange resin is used as a catalyst to remove the protecting group. , Tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile and the like are preferably used as a reaction solvent. The reaction is usually carried out in the temperature range of −78 ° C. to + 100 ° C.
It is performed for 0 minutes to 3 days. The protecting group is tri (C ₁ ~
C ₇₎ hydrocarbon - in the case of silyl group, for example in the presence of acetic acid, is carried out similar time at the same temperature at such a reaction solvent described above. Alternatively, it is carried out in a solution of hydrofluoric acid in acetonitrile.

When the target compound has an ester group, it can be hydrolyzed, and for example, using an enzyme such as lipase, in water or a solvent containing water in a temperature range of -10 ° C to + 60 ° C for 10 minutes to 24 minutes. It takes about an hour.

Thus [I] [In the formula, R ¹ , Ar and symbols are the same as defined above. ] 4-Aryl methylene-5- alkenylidene-2-cyclopentenone represented by the following formula is obtained. The compound of the present invention exhibits a strong anti-cancer effect on L1210 mouse leukemia cells at an extremely low concentration (IC ₅₀ 1 μg / m or less), and is extremely useful as an anticancer agent. It is also a useful compound expected as a compound having antiviral activity. It also showed strong anti-cancer activity in animal experiments. For example, Table 1 shows the L1210 cancer cell growth inhibitory activity in vivo.

Table 2 shows the anticancer activity against P388 mouse leukemia cell transplantation cancer in vivo.

Example 1 Sulfide 1-1 415 mg (2.07 mmol) in THF solution 7 m
N-butyllithium solution 1.45m (2.26mm
ol) and stirred for 15 minutes, and then hexamethyltriamide triphosphate (HMPA) 0.98 m (5.63 mmol) was added immediately to the protected 4-hydroxy-2-cyclopentenone 2 400.
A THF solution of 1 mg (1.89 mmol) was quickly added.
After stirring for 10 minutes, aldehyde 3-1 530 mg (2.07 mmo
1 m of the THF solution of l) was lowered. After stirring for 20 minutes, 4 m of saturated ammonium chloride aqueous solution was added, the temperature of the reaction solution was returned to room temperature, 20 m of ethyl acetate was added for extraction, and the extract was washed twice with water. The extract was treated by a conventional method and then purified by silica gel chromatography (ethyl acetate: hexane = 1: 8) to obtain the target product, 2-cyclopentenone derivative 4 759 mg (yield 75%).

TLC (ethyl acetate: hexane = 1: 3); spectrum data of Rf0.65 4 IR (liquid film) (cm ^-1 ): 3470,3070,3040,2970,2940,2870,1
700,1580,1470,1250,1080,970,835,775,700 Example 2 Allyl sulfide 1-1 110 mg (0.55 mmol) in THF solution 3 m at -76 ° C. n-butyllithium solution 0.38 m
(0.59 mmol) was added, and the mixture was stirred for 15 minutes, then 0.26 m (1.49 mmol) of phosphoric acid hexamethyltriamide (HMPA) was added and immediately, a THF solution of Compound 2 106 mg (0.50 mmol) 0.5
m was added quickly. After stirring for 10 minutes, tri-chloride
0.16 m (0.60 mmol) of n-butyltin was added dropwise. After stirring for 15 minutes, 1 m of a THF solution of 141 mg (0.55 mmol) of compound 3-1 was added dropwise.

After stirring for 30 minutes, 1 m of water was added to bring the temperature of the reaction solution back to room temperature, 4 m of ethyl acetate was added for extraction, and the extract was washed twice with water. The extract was treated by a conventional method to obtain a crude product. After standing for 6 hours, the crude product 4 was obtained and then purified by silica gel chromatography (ethyl acetate: hexane = 1: 8) to obtain 224 g of the target 4 (yield 83%).

TCC (ethyl acetate: hexane = 1: 3); Rf0.65 Example 3 Allyl sulfide 1-2 100 mg (0.46 mmol) in THF solution 3 m (0.50 mmol) was added, and after stirring for 15 minutes, phosphoric acid hexamethyltriamide (HMPA) 0.22 m (1.27 mmol) was added and immediately compound 2 89 mg (0.42 mmol) THF solution 0.5m
Was added quickly. After stirring for 10 minutes, 0.14 m (0.52 mmol) of tri-n-butyltin chloride was added dropwise. After stirring for 15 minutes, 1 m of a THF solution of 118 mg (0.46 mmol) of compound 3-1 was added dropwise. After stirring for 30 minutes, 1 m of water was added, the temperature of the reaction solution was returned to room temperature, and 4 m of ethyl acetate was added for extraction.
The extract was washed twice with water. The extract was treated by a conventional method to obtain a mixture of crude products 5 and 6 . After standing for 6 hours, a crude product was obtained and then purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain 193 mg (yield: 83%) of 2-cyclopentenone derivative 6 as a target product.

Spectral data IR (liquid film, cm ^-1 ): 3480,3070,2970,2950,2870,1700,16
05,1505,1470,1250,1225,1155,1070,835,775,740,690 Example 4 3m of THF solution of sulfid 1-2100 mg (0.46 mmol)
N-butyllithium solution 0.32m (0.50mm at -76 ℃)
ol) and stirred for 15 minutes, 0.22 m (1.27 mmol) of phosphoric acid hexamethyltriamide (HMPA) was added, and immediately 0.5 m of a THF solution containing 89 mg (0.42 mmol) of compound 2 was quickly added. After stirring for 10 minutes, compound 3 -117 mg (0.
1 mmol of a THF solution (46 mmol) was added dropwise. After stirring for 20 minutes, saturated ammonium chloride aqueous solution 2m was added, the temperature of the reaction solution was returned to room temperature, ethyl acetate 10m was added for extraction, and the extract was washed twice with water. The extract was treated by a conventional method and then purified by silica gel chromatography (ethyl acetate: hexane = 1: 8) to obtain 167 mg (yield 72%) of the target product 6 .

TLC (ethyl acetate: hexane = 1: 3); Rf0.61 Example 5 Allylsulfide 1-2502 mg (2.30 mmol) in THF solution 8 m at -76 ° C n-butyllithium solution 1.60 m
(2.50 mmol) was added, and the mixture was stirred for 15 minutes, then 1.09 m (6.27 mmol) of phosphoric acid hexamethyltriamide (HMPA) was added and immediately, a THF solution of Compound 2 444 mg (2.09 mmol) 0.8
m was added quickly. After stirring for 10 minutes, tri-n-butyltin chloride (0.68 m, 2.51 mmol) was added dropwise. 15
After stirring for min, TH compound 3 -2857mg (2.30mmol)
2 m of F solution was dripped. After stirring for 30 minutes, water 2m
Was added, the temperature of the reaction solution was returned to room temperature, and ethyl acetate 5
m was added for extraction, and the extract was washed twice with water. The extract was processed by a conventional method to obtain a crude product. After standing for 6 hours, the product, 2-cyclopentenone derivative 6 , was purified by silica gel chromatography (ethyl acetate: hexane = 1: 8) to obtain 1090 mg of the target product 6 (yield 78%). TL
C (ethyl acetate: hexane = 1: 3); Rf0.42,0.51 Example 6 Allyl sulfide 1-2229 mg (1.05 mmol) in THF solution 5 m at -76 ° C n-butyllithium solution 0.73 m
(1.14 mmol) was added and stirred for 15 minutes, then 0.50 m (2.87 mmol) of phosphoric acid hexamethyltriamide (HMPA) was added and immediately, a THF solution of Compound 2 204 mg (0.96 mmol) 0.5
m was added quickly. After stirring for 10 minutes, trichloride
0.31 m (1.14 mmol) of n-butyltin was added dropwise. After stirring for 15 minutes, 1 m of a THF solution of 240 mg (1.05 mmol) of compound 3-3 was added dropwise. After stirring for 30 minutes, add 1 m of water,
The temperature of the reaction solution was returned to room temperature, ethyl acetate was added for extraction, and the extract was washed twice with water. The extract was treated by a conventional method to obtain a crude product 8 . After standing for 6 hours, the crude product 9 was designated as silica gel chromatography (ethyl acetate: hexane =
The mixture was purified by 1: 3) to obtain the desired product, a 2-cyclopentanone derivative 9 405 mg (yield 80%).

TLC (ethyl acetate: hexane = 1: 1); Rf0.40 spectral data IR (liquid film, cm ^-1 ): 3500,3070,2970,2940,1730,1720,17
00,1600,1585,1505,1475,1440,1370,1240,1170,1095,10
65,1025,960,880,845,790,750,690 Example 7 92 mg (0.93 mmol) of cuprous chloride was added to 0.5 m of a benzene solution of 225 mg (0.42 mmol) of compound 4 at 20 ° C., followed by N,
N'-dicyclohexylcarbodiimide (DCC) 43
1 mg of a benzene solution of 5 mg (2.11 mmol) was added. After stirring for 4 hours, ethyl acetate was used as a solvent, and the filtrate was washed twice with water.

The oily crude product obtained by a conventional method was purified by silica gel chromatography (ethyl acetate: hexane = 1: 10) to obtain the desired product 10 192 mg (yield 88%).

TLC (ethyl acetate: hexane = 1: 3); Rf 0.82,0.7
2 Spectral data of highly polar components (10-1) IR (liquid film, cm ^-1 ): 3080,3040,2970,2950,2870,1695,16
35,1580,1470,1250,1085,975,835,775,740,695 Example 8 Compound 10-1 188 mg (0.36 mmol) of methylene chloride solution 8
m-chloroperbenzoic acid 63 mg (0.36 mmo at -40 ° C)
l) was added and the mixture was stirred for 30 minutes, neutralized with an aqueous sodium bicarbonate solution, returned to room temperature, extracted with methylene chloride, and the extract was washed twice with water.

The oily crude product 11 obtained by a conventional method was directly subjected to the following reaction.

TLC (ethyl acetate: hexane = 1: 2); Rf 0.56 IR (liquid film, cm ⁻¹ ): 3080,2970,2950,2870,1700,1635,15
80,1460,1255,1195,1150,1085,1050,980,940,780,745,7
00 Example 9 20 m of a toluene solution of the oily crude product 11 was stirred under reflux for 1 hour, toluene was removed, and impurities were removed by silica gel chromatography (ethyl acetate: hexane = 1: 15). ) Crude product 12-1
Got

The crude product 12-1 was added to 2 m of an acetonitrile solution with 5% HF0.
After adding 4 m and stirring at 23 ° C. for 6 hours, the solution was neutralized with an aqueous sodium bicarbonate solution, 10 m of ethyl acetate was added for extraction, and the extract was washed twice with water. The extract was treated by a conventional method and then subjected to silica gel chromatography (ethyl acetate: hexane =
The product was purified by 1: 6) to obtain 65 mg of the desired product 12-2 (yield 61% from 10-1 ).

TLC (ethyl acetate: hexane = 1: 2); Rf0.47,0.40 (40%) (20%) Spectral data Compound 12-1 TLC; Rf0.73, EtoAc / hex = 1/5 IR (liquid film, cm ^-1 ): 3070,2960,2860,1690,1620,1530,14
60,1440,1320,1250,1170,1140,1070,970,830,770,745,6
90 Compound 12-2 TLC; Rf0.47,0.40, EtoAc = 1/2 Low polarity component (E, Z type) IR (liquid film, cm ^-1 ): 3450,3070,2970,2940,2870,1680,16
15,1525,1440,1320,1220,1175,1120,1070,1050,970,82
0,750,695 H NMR; 0.89 (3H, br), 1.1-1.7 (6H, br), 4.35 (1H, m, 5-
H), 6.35 (1H, dd J = 6,2Hz, 11-H), 6.4 (1H, m, 7-H), 6.8-7.2
(3H, m, 6-H, 8-H, 14-H), 7.34 (5H, S, Ph), 8.01 (1H, d, J = 6H
z, 12-H) Highly polar component (E, E type) IR (liquid film, cm ^-1 ): 3450,2960,2945,2860,1680,1615,15
35,1440,1220,1185,1160,1125,975,860,820,750,690 H NMR; 0.88 (3H, br), 1.25 (6H, br), 3.80 (1H, m, 5-H), 5.
57 (1H, ddd, J = 15,12,1Hz 7-H), 6.10 (1H, dd, J = 15,5Hz,
6-H), 6.32 (1H, dd, J = 6,1Hz, 11-H), 6.86 (1H, S, 14-H), 6.9
1 (1H, d, J = 6,8-H), 7.34 (5H, S, Ph), 7.73 (1H, d, J = 6Hz, 12
-H) Example 10 122 mg (0.22 mmol) of compound 6 was dissolved in 0.4 m of dry benzene. To this was added 48 mg (0.48 mmol) of cuprous chloride. While stirring the mixture, DCC 225 mg (1.09 mmo
l) was dissolved in 0.5 m of dry benzene and added.

The reaction mixture was stirred at 20 ° C. for 6 hours, filtered using ethyl acetate as a solvent, and the filtrate was washed twice with water.

The oily crude product obtained by a conventional method was purified by silica gel chromatography using ethyl acetate: hexane = 1: 10 to obtain 94 mg of the desired product (E type) 13-1 (yield 80%) and by-products. (Z type) 13-2 10 mg (yield 9%) was obtained.

TLC (ethyl acetate: hexane = 1: 4); Rf 13-2 0.74, 13-1 0.62 Example 11 Compound 13-1 75 mg (0.14 mmol) of methylene chloride solution 4 m
After adding 24 mg (0.14 mmol) of m-chloroperbenzoic acid at −40 ° C. to the mixture and stirring for 30 minutes, 1 m of an aqueous sodium bicarbonate solution was added, the temperature of the reaction solution was returned to room temperature, extraction was performed, and the extract was extracted with 2
It was washed with water twice.

The crude oily product 14 obtained by a conventional method was directly subjected to the following reaction.

Example 12 After stirring 2 m of a toluene solution of the oily crude product 14 under reflux for 45 minutes, the toluene was removed, and impurities were removed by silica gel chromatography (ethyl acetate: hexane = 1: 20) (purification not possible here). The product 15-1 was obtained.

A solution of the crude product 15-1 in 2 m of acetonitrile was added with 5% HF0.
After adding 3 m and stirring at 20 ° C. for 6 hours, the mixture was neutralized with an aqueous sodium bicarbonate solution, 5 m of ethyl acetate was added for extraction, and the extract was washed twice with water. The extract was treated by a conventional method and then subjected to silica gel chromatography (ethyl acetate: hexane =
1: 5) and the desired product 15-2 21 mg (yield from 6 4
8%).

TLC (ethyl acetate: hexane = 1: 2); Rf 0.43 spectral data Compound 15-2 IR (liquid film, cm ^-1 ): 3450,2970,2950,2870,1685,1625,16
00,1535,1505,1230,1160,1130,985,830,730 Compound 15-1 IR (liquid film, cm ^-1 ): 3070,3020,2960,2940,2870,1700,16
40,1585,1505,1470,1440,1360,1255,1225,1160,1135,10
90,980,935,840,800,780,760,690 Example 13 638 mg (0.95 mmol) of compound 7 was dissolved in 0.7 m of dry benzene. To this was added 210 mg (2.12 mmol) of cuprous chloride. While stirring this mixture, 994 mg (4.82 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) dissolved in 0.7 m of dry benzene was added. 2 reaction mixtures
After stirring at 0 ° C for 4 hours, the mixture was filtered using ethyl acetate as a solvent, and the filtrate was washed twice with water.

The crude oily product obtained by a conventional method was purified by silica gel chromatography (ethyl acetate: hexane = 1: 12) to obtain 531 mg of the desired product 16-1 (yield 86%) and a by-product 16- 2 13 mg (yield 2%) was obtained.

TLC (ethyl acetate: hexane = 1: 3); Rf 16-2 0.68 16-1 0.61 Example 14 Compound 16-1 503 mg (0.77 mmol) of methylene chloride solution 5 m
133 mg (0.77 mmol) of m-chlorobenzoic acid at -40 ° C
Was added and stirred for 30 minutes, 3 m of an aqueous sodium bicarbonate solution was added, the temperature of the reaction solution was returned to room temperature, extraction was performed, and the extract was washed twice with water.

The oily crude product 17 obtained by a conventional method was directly subjected to the following reaction.

Example 15 After stirring 5 ml of a toluene solution of the oily crude product 17 under reflux for 1 hour, toluene was removed, and impurities were removed by silica gel chromatography (ethyl acetate: hexane = 1: 20) (here, it could be completely purified. The crude product 18-1 was obtained.

TLC (ethyl acetate: hexane = 1: 4); Rf 0.77 (E, E ₁ type) 0.65 (E, Z type) 0.58 (Z, Z type) Example 16 A solution of the crude product 18-1 in 3 m of acetonitrile was added with 5% HF0.
After adding 4 m and stirring at 20 ° C. for 6 hours, the mixture was neutralized with an aqueous sodium bicarbonate solution, 5 m of ethyl acetate was added for extraction, and the extract was washed twice with water. The extract was treated by a conventional method and then subjected to silica gel chromatography (ethyl acetate: hexane =
8: 1) to obtain the three components as the double bond stereoisomer of the target product 18-2.

TLC (ethyl acetate: hexane = 20: 1); The spectrum data of each component are as follows.

IR (liquid film, cm ^-1 ): 3400 (OH), 2940,2880,1680,1620,153
5,1505,1325,1220,1180,1050,975,870,830 nmr (δ); 1.3-1.7 (4H, m, 2-H ₂ , 3-H ₂ ), 3.56 (2H, t, J = 6H
z, 1-H ₂ ), 3.82 (1H, q, J = 6Hz, 4-H), 5.56 (1H, ddd, J = 1,11,
15Hz, 6-H), 6.06 (1H, dd, J = 6,15Hz, 5-H), 6.24 (1H, dd, J =
1,6Hz, 10-H), 6.72 (1H, d, J = 11Hz, 7-H), 6.73 (1H, S, 13-
H), 6.85-7.40 (4H, m, C ₆ H ₄ ), 7.64 (1H, d, J = 6Hz, 11-H) nmr (δ); 1.64 (4H, br, 2-H ₂ , 3-H ₂ ), 3.59 (2H, br, 1-H ₂ ),
4.30 (1H, m, 4-H), 6.30 (1H, d, J = 6Hz, 10-H) Ca.6.3 (1H, m, 6
-H), 6.7-7.4 (7H, m, 5-H.7-H, 13-H, C ₆ H ₄ ), 7.91 (1H, d, J = 6
Hz, 11-H) nmr (δ); 1.65,1.67 (4H, br, 2-H ₂ , 3-H ₂ ), 3.61 (2H, br, 1-
H ₂ ), 4.3 (1H, m, 4-H), 6.19 (1H, dd, J = 6,15Hz, 5-H) 6.30 (1
H, dd, J = 6,1Hz, 10-H), 6.82 (1H, d, J = 11Hz, 7-H), 6.87 (1
H, S, 13-H), 6.9-7.4 (4H, m, C ₆ H ₄ ), 7.81 (1H, dd, J = 11,15H
z, 6-H) 7.91 (1H, d, J = 6Hz, 11-H) Example 17 332 mg (0.63 mmol) of compound 19 was dissolved in 0.5 m of dry benzene. To this was added 138 mg (1.39 mmol) of cuprous chloride. While stirring this mixture, 654 mg (3.17 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) dissolved in 0.5 m of dry benzene was added. 2 reaction mixtures
After stirring at 0 ° C for 3 hours and 30 minutes, the mixture was filtered using ethyl acetate as a solvent, and the filtrate was washed twice with water.

The crude oily product obtained by a conventional method was purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain 271 mg of the desired product 20-1 (yield 85%) and a by-product.
20-29 mg (yield 3%) was obtained.

TLC (ethyl acetate: hexane = 1: 1); Rf 20-2 0.61, 20-1 0.57 Spectral data IR (liquid film, cm ^-1 ): 3070,3010,2960,2870,1730,1690,16
40,1600,1580,1505,1480,1440,1370,1230,1170,1095,10
25,840,745,690 Example 18 Compound 20-1 244 mg (0.48 mmol) of methylene chloride solution 5
m-chloroperbenzoic acid 83 mg (0.48 mmo at -40 ° C)
l) was added and stirred for 30 minutes, and then 2m aqueous solution of sodium bicarbonate
Was added, the temperature of the reaction solution was returned to room temperature, extraction was performed, and the extract was washed twice with water.

The crude oil product 21 obtained by a conventional method was directly subjected to the following reaction.

Example 19 The oily crude product 21 Toluene solution (10 m) was stirred under reflux for 1 hour, toluene was removed, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 6) to obtain the desired product 22 (161 mg, yield 84 %)was gotten.

TLC (ethyl acetate: hexane = 1: 1); Rf 0.60, 0.51 (127mg) (34mg) (Z, E form) (EE form) Spectral data Low polarity component nmr (δ): 2.01and2.05 Ca, 2.00 (2H, m, 3-H ₂ ), 2.34 (2H, t, J = 7Hz, 2-H ₂ ), 3.61 (3H,
S, -COOCH ₃ ), 5.41 (1H, q, J = 6Hz, 4-H), 5.9-6.3 (1H, m, 5-
H), 6.36 (2H, d, J = 6Hz, 10-H), 6.5-8.0 (8H, m, 6,7,11,13-
H, C ₆ H ₄ ) High polarity component nmr (δ): 2.00 Ca, 2.00 (2H, m, 3-H ₂ ), 2.37 (2H, t, J = 7Hz, 2-H ₂ ), 3.63 (3H,
S, -COOCH ₃ ), 5.85 (2H, m, 4-H, 5-H), 6.36 (1H, dd, J = 2.6Hz,
11-H), 6,7-7,5 (7H, m, 6,7,13-H, C ₆ H ₄ ), 7.98 (1H, d, J = 6H
z, 11-H) IR (liquid film, cm ^-1 ); 1730,1690,1630,1600,1500,1370,12
35,1180,1160,1025,980,870,830

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location // A61K 31/12 ADU 31/557 ADY

Claims (4)

[Claims] 1. The following formula [I]: [In the formula, R ¹ is a hydroxy group, a tri (alkyl having 1 to 4 carbon) silyloxy group, a tetrahydropyranyloxy group, an acetoxy group or a carbon which may be substituted with an alkyloxycarbonyl group having 1 to 6 carbon. Ar having a number of 1 to 10 and Ar having a total of 6 to 10 carbon atoms which may be substituted with at least one group selected from the group consisting of an alkyl group, a hydroxy group, an alkoxy group, an alkyloxycarbonyl group and a halogen atom. The phenyl group of 12 represents a single bond in the E form or Z form with respect to the double bond. ] 4-Arylmethylene-5-alkenylidene-2-cyclopentenones represented by the formula: 2. The 4-arylmethylene-5-alkenylidene-2-cyclopentenones according to claim 1, wherein Ar is phenyl or p-fluorophenyl. 3. 4-Arylmethylene-5-alkenylidene-2 according to claim 1 or 2, wherein R ¹ is monohydroxypentyl or hydroxybutyl.
-Cyclopentenones. 4. The 4-arylmethylene-5-alkenylidene-2-cyclopentenones according to claim 1 or 2, wherein R ¹ is a 1-acetoxy-3-ethoxycarbonylpropyl group.