JPS6243A - 7-(2-alkylidene-3-cyclopentenyl)-5-heptenoic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R and R<1> are H or lower alkyl; R<2> is alkyl, alkenyl, cycloalkyl or aryl; X is CO, group shown by the formula II, or R<1> and R<2> are bonded to form polymethylene with the proviso that when X is CO and R<1> is H, R<2> is not 1-heptenyl). EXAMPLE:7-(2-Octylidene-5-hydroxy-3-cyclopentenyl)-5-heptenoic acid. USE:Useful as a drug having antitumor activity. Being synthesized from easily obtainable raw materials in a short process, showing approximately the same activity as that of prostaglandin A2. PREPARATION:For example, a 6-alkylidene-3-hydroxy-2-oxabicyclo[3,3,0]oct-7-ene derivative shown by the formula III is reacted with a phosphorane compound of Wittig reagent, to give a compound (shown by the formula V) where X is group shown by the formula II.

Description

Detailed Description of the Invention [Object of the Invention] The present invention is based on the general formula (wherein 几 and 几 1 are water JA hoji or a lower alkyl group, 1ζ is an alkyl group, an alkenyl group, A cycloalkyl group or an aryl group. x H, c=.

Alternatively, it is a group represented by C()1)O)i. Furthermore, 0 and 1 can form a polymethylene group together.
However, when X is:;C==O, when roux is the main ship atom, 1
ζ is not an l-hebutenyl group 0) 7
-(2-lyso in alkali/-3-7 clopentenyh)-5-
Regarding Hepden play A4.

[Purpose of industrial use]

The compound in which X in the general formula (1) of the present invention is represented by 〉CI0 is a compound analogous to Q12-dehydroglostagunjin, and anti-I! It can be used as a third agent.

[Conventional technology]

Prostaglanson #i is a lipid-based substance that exists in trace amounts in each tissue of the animal body and has a unique physiological activity.It is a useful substance that has recently begun to be used in the medical field. Recently among these are prostaglandin 2, prostaglandin I) 2. X has been found to have ft tumor activity in gross tag 2 engine J2 and the like (see JP-A-58-124718). Also, 7-dihydroglostagundin A, which is known as dencyclopentenone grosstagundin in alcohol (see JP-A-59-148734), 12
- Dehydroglosstagkun 2 J (Unexamined Japanese Patent Publication No. 59-515
4) It is known that it has excellent anti-accumulative properties 〇〇〇〇〇〇〇〇　〇〇　〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇゛゛However, to manufacture the conventional gross tag landin mentioned above, the number of machines required is long. There are 6 disadvantages such as 6, and 9 mass sales.

The present inventor, Hiromu, has completed the present invention by discovering that this compound, which can be derived from readily available raw materials in a short process, has an anti-abscess activity comparable to that of grosstagun2A2Jt.

[Summary of the invention]

The 7-(2-alkylidene-3-fuclopentenyl)-5-heptene conductor specified by the general formula (1) of the present invention can be produced according to the following reaction formula. Step] This step is performed to convert 6-alcolidene-3-L dorochishi 2-o-sabicyclo (3,3,
L)]] Octo7-2L44 and Rh represented by the formula U),
P=CH-(CI2)3-ω-(2) I9, represented by the above general formula (1-a), is obtained by dispersing a phospho2-phosphatide compound called the Wittig reagent. 7-(2-Al-N-5-Hydro4&V
-3-7 clopentenyl)-5-heptene m1! If desired, this can be esterified with diazomethane etc. (one step can be made into an ester).

6-alcoholic acid-3- represented by the general formula (1)
The human a-2-o-sabicyclo(3,3,0)oct-7-dyne conductor has the general formula (wherein, R' is a hydrogen atom or a lower alkyl group, hp1E
? B7AI is a henyl group, an I-kenyl group, a fuchloryl group, or an aryl group. In addition, R1 and 1- come together to form a polymethinone group.
It is a compound that can be easily produced by subjecting 165 % (165) to an oxidative intrusion reaction and reducing the 2 chtons (see reference side below).

Examples of the substituent W of the compound represented by general formula (IV) include water, lower alkyl groups such as methyl group, ethyl group, propyl group, and butyl group, and branched It may have a group of The alkyl group represented by ♂ can be methyl group, ethyl group, propyl group, butyl group, pentyl group, hechufur group, hegetyl group,
t[
An example of a branched or unsubstituted alkyl group is an alkenyl group having 2 to N3 carbon atoms such as a tenyl group, an octenyl group, a nonenyl group, a decenyl group, or a 2-7 aervinyl group. Examples include stereoisomers and positional isomers. ◎ The fucroal group represented by l is a fucloprobyl group, a cyclobutyl group, and a cyclopeno group. A4% 7-chloroheptyl group, cycloheptel group, etc. can be exemplified. The aryl group represented by i is a phenyl group, a halo group, a tolyl group, an ethylphenyl group, a fluorobylphenyl group, an anicyl group, a nitocuphenyl group, a naphthyl group, a pyridyl group, a pyrrolyl group, or a chenyl group. , furyl group, etc. at
The polymethylene group in which and t are combined has 2 carbon atoms.
An example is a polymethylene group having 6 to 6 polymethylene groups.

In this step, the phosphonic compound represented by the general formula (2) is generated by treating phosphonicumpromide, which is represented by the general formula (%), with a base.

Bases include sodium hydride, aqueous potassium, aqueous lithium, n-butyllithium, various butyllithium, t-butyllithium, dimclunatrichum (cHs8
u2°Na”) etc. can be used.

The reaction is preferably carried out in frjM, for example, dimethyl sulfonate, tetrahydrochloride, dimethoxyethane, ether, benzene, toluene/#
You can melt.

The reaction is carried out once in the range of 0°C to 50°C, but it is convenient to carry out it at room temperature.◎ Similarly, the base used in this step is dimethyl sulfohydride, which can be treated with sodium hydride. By using an excess amount of dimethyl sulfonate produced by Dimsyl Natrichum, it is possible to maintain its role as a solvent and allow a suitable reaction.[Second Step] This step The general formula (1-11
7-(
2-Alkylidene-5-oxo-3-fuclopentenyl)-5-heptene@J conductor.

Oxidizing agents that can be used for the oxidation in this step include monoclinic manganese dioxide, Jones reagent, Collins reagent, pyridiecum chlorochromate (CPc<:), dimethyl Sulho Senshito is defeated. It is preferable to use RI-activated carbon dioxide. The jeans test can be suitably carried out using water, acetone, or a mixture thereof as a solvent. Eccentric placement is carried out at d- of -50°C to 20°C, but preferably at -30Q to 0°C. As a solvent for activated manganese dioxide, carbon tetrachloride, /a myloform methyl chloride 7/, benzene, hemusan, ether, acetono, acetonitrile, etc. are used, but carbon tetrachloride, chloroform, etc. can be preferably used. . The reaction temperature is -10
The uninvented compound represented by the general formula (1-b) was used in an in vitro expansion inhibition experiment using mouse leukemia cells P388. Showed good suppressive effect (see reference example below)
.

Hereinafter, the present invention will be explained in detail with reference to Examples, Reference Examples, and Trial Examples.

Reference example 1 6-hebutylfulvene 5.76 g (32,Tm −
100 μmol of phenothiazine was added to the mixture, and the mixture was cooled on ice under an argon atmosphere. 2-chloroacryloyl chloride 3
．． 77 g (30,2 mmol) of TI (F(15
ml). The mixture was stirred for 30 minutes under water cooling and then for 4 hours at room temperature. The crude 2-chloro-7-octylizombocyclo(2,2゜1)hept-5-uni-2-rubonic acid chloride obtained by distilling off the solvent under reduced pressure was dissolved in DME (40 ml), and sodium azide 4. 3g (66,2mmo
1) was added and stirred at room temperature for 4 hours. Filter out insoluble matter,
Washed with DME (20ml). Then, the 2-chloro-7-ofthyridine bicyclo (2
, 2゜1] A DME solution of hepto-5-uni-2-carboxylic acid azide was heated under reflux for 1 hour to obtain 2-chloro-7-ophthyridinebicyclo(2,2,1)hept-5-uni-2-isocya. Converted to Nato.

Add water (20 ml) and sodium acetate to this solution.
5 g (0,165 mol) was added and stirred at room temperature for 20 hours. After adding water (100ml), ether (
Extracted with 100ml x 3). The extract was diluted with saturated saline (5
After washing with 0ml), it was dried with anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel, hexane:ether-4:
1), and 3.88 g (5
4.4%). Since 895* of the starting raw material Fullpene was recovered, the conversion yield was 64.4%. Furthermore, the bicyclo(2,2,1)hebutenone obtained here is a mixture of two isomers.

IR(neat):2950. 2880°175
0, 1470. 1115°1060, 870. 760. 715c11-'.

NMR (CDCIs); δ 0.89 <3
H.

t, J=6Hz), 1.1-1.66 (1
0H.

m), 1.66-2.26 (4H, ru).

3.26-3.82 (2H, m), 4.96 and 5
．． 11 (Total LH, each t, J-7Hz).

6.29 (IH, m), 6.70 (IH,
m).

MS m/z; 218 (M', 1%),
176 (63%), 105 (77%), 92 (
100%), 91 (95%), 78 (88%)
.

Reference example 2 6-(1-hebutenyl)fulvene 1O, 75g (61,
7 mmol 1) and 200 μl of phenothiazine were dissolved in ether (15 ml), cooled on a water bath under an argon atmosphere, and then 10.
62 g (85 mmo 1) in ether (30 rn
+) and added. After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure to give 1.1/f1 2-chloro7-(2-
octenylidene)bicycloC2,2,1)hept-5-
Uniru-2-rubonic acid chloride was obtained. DME this
(50ml) and 8.0g of sodium azide (
0,123 mol) was added thereto, and the mixture was stirred at room temperature for 3 hours. Inorganics were filtered off and washed with DME (25n11). The DME solution of 2-chloro-7-(2-octenylidene)bicyclo(2,2,1)hept-5-eco-2-carboxylic acid azide thus obtained was heated under reflux for 1 hour, and 2-chloro- -7-(2-octenylidene)bicyclo(
2,2,1) Het-5-enyl-2-isocyanate.

Add water (30 ml) and 25 ml of sodium acetate to this solution.
g (0,305 mol) was added thereto, and the mixture was stirred at room temperature for 9 hours. After adding water (150 ml), ether (15 ml) was added.
0 ml x 3). The extract was diluted with saturated saline (50 m
After washing with l), it was dried with anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel).

Separate and purify with hexane:ether (4:1), 7-(2
-octenylidene)-2-oxobicyclo(2,2,1
] 3.70 g (27.8%) of hept-5-ene was obtained.

Since 1.45 g of fulvene as a starting material was recovered, the conversion yield was 32.1%. Furthermore, the bicyclo(2,2,1)heptenone obtained here is a mixture of two isomers.

IR (neat); 2950, 1750cm-1゜NM
R(CDCIs); δ 0.88 (3H.

t, J=6Hz), 1.05-1.66 (6H.

m), 1.83-2.27 (4H, m).

3.37 (LH, m), 5.43-6.37 (4H,
m), 6.67 (I H, m).

MS m/z; 216 (M”, 11%).

118 (92%), 117 (100%).

104 (56%).

Reference Example 3 6-(2,2-ethylenedioxyheptyl)fulvene as a starting material3. All procedures were carried out in the same manner as in Reference Example 2, except that Og (24 mmol 1) was used, and 7-(3,3-ethylenedioxyoctylidene)-2-oxobicyclo(
2,2,1) 1.80 g (60%) of hept-5-nin was obtained.

IR (nsat); 3050,1745 cm-'.

NMR (CDCis); δ 0.88 (3H.

t, J-6Hz), 1.03-1.87 (8H.

m), 1.97-2.43 (4H, m).

3.27-3.77 (2H, m), 3.90 (4H,
s), 4.97 and 5.12 (together IH, each t,
J-7Hz), 6.22 (IH, m,), 6.86
(IH, m).

Reference Example 4 The same procedure as Reference Example 2 was carried out except that 76 g (9,77 mmol) of 6-(2-phenylethynyl)fulvene L was used as the starting material, and 7-(3-phenyl-2
-probenylidene)-2-oxobicyclo[2,2,1
) Hebdoene 453 .mu. (20.9%) was obtained.

fR(neat); 1750.1680°970.7
50.6951-1°NMR (CDCI; δ 1.77-2.50 (2H,
m), 3.42 (IH, m).

3.88 (LH, m), 5.74 and 5.88 (total 11 (, each t,, r-10Hz).

6.31 (IH, m), 6.50-6.80 (2H
, m), 6.78 and 6.95 (total 11 (, each, J-10Hz), 7.30 (51 (, m,).

MS m/z; 222 (M''', 17%), 18G
(100%), 179 (85%), 178 (50%)
, 165 (52%), 115 (52%).

Reference Example 5 Except for using 2.5 g (12,87 mmo I) of 6-(4-propylphenyl)fulvene as the surrounding substance,
The reaction was carried out in the same manner as in Reference Example 2, and 7-(4-propylbenzylidene)-2-oxobicyclo(2,2,1
) 1.276 g (41.9%) of hebdoene was obtained.

IR(neat);2970.2940°1750.1
690.1510°1110.1050,870,750°710c*-'
.

NMR (CD Cl s) iδ 0.94 (3H
.

t, J=7Hz), 1.63 (2H.

quintet, J=7Hz), 2.22(2H, rt
+), 2.56 (2H, t, J-7H2), 3.48
(IH, m), 4.02 (I H, m), 5J7 and 6
．． 35 (total IH, each s), 6.34 (I
H, m).

6.73 (LH, m), 7.12 and 7.1T (4H in total, 3 each).

MS m/z; 238 (M”, 6%), 196
(100%), 167 (92%), 153 (68%)
.

Reference Example 6 The reaction was carried out in the same manner as in Reference Example 2, except that 1.00 g (6,84 mmo I) of 5-cyclohexylidenecyclopentadiene was used as the starting material, and 7-cyclohexylidene-2-oxo Bicyclo(2,2,11hept-5-ene) 408 μm (31.7%) was obtained.

IR(neat);2945.2870°1?45.1
450,1120.715 Low 1°NMR (CDCI; δ 1.68 (6
H.

m), 2.22 (6H, m), 3.82
(2H.

m, ), 6.43 (IH, m), 6.88
(IH, m).

MS m/z; 188 (M”, 1%
), 146 (100%), 117 (48%
).

Reference Example 7 6-hexyl-6-methylfluridene as starting material)
-2-oxobicyclo(2,2,1)hept-5-ene 812 ml (37.2%) was obtained.

IR(neat);2950. 2870°175
0, 1?20. 1460. 760°7103-'
.

NMR (CDCI; δ 0.86 (3H
.

t, J-6Hz'), 1.26 (8H, m
).

1.50-1.73 (3H, m), 1.80-
2.16 (4H, m), 3.46-2.76 (
2H, m), 6.16-6.36 (IH.

m), 6.56-6.76 (IH, m).

MS m/z; 218 (M”), 190°1
76, 161. 147. 133°119, 10
6. (100%), 91° Reference Example 8 As a starting material, 6-(3-heptyl)fulvene 1.7
Using 6 g (10.0 mmol), 1.23 g (56.3%) of behebuto-5-ene was obtained.

IR(neat); 2960.2920°2860
．． 1750.1?10,1460゜1110.1050
, 865,750° 710 low 1° NMR (CDCIs); 60.60-1.00 (6H,
m), 1.00-1.66 (8H.

4.76 (including IH, each d, J = 10Hz),
6.13-6.36 (IH, m).

6.56-6.83 (IH, m).

MS m/z; 21B (M”), 190°176, 161.147.133.120°(
100%), 105. 91. 78° Reference Example 9 As a starting material, 6-cyclohexylfulvene 1.60
The procedure was repeated in the same manner as in Reference Example 2 except that 7-cyclohexylmethylene-2-oxobicyclo(2,2,1)hept-5-ene 1.04 g (51 , 7%).

IR (nsat); 2950.2860°1750,
1440. 89Q, 760°750. 7 1
0am-'.

NMR (CDC1v); δ 0.80-1.
90 (10H, m), 1.90-2.30 (3
H.

m), 3.20-3.76 (2H, m).

\vinegar 4.78-4.95 (together with IIL each d.

J-9Hz), 6.10-6.76 (2H.

m).

MS m/z; 202 (M”), 174° 160 (100%), 104.78° Reference Example 10 2.40 g (20
,0mmo 1) was carried out in the same manner as in Reference Example 2, and 7-butylidene-2-oxobicyclo(2
,2,13hept-5-ene 1.34 g (41,3
%) was obtained.

rR(neat); 2970.2940°2880.1
750.1?10,1460°1110.750,71
0cs-'.

NMR (CDCIs); δ Q, 73-1.10 (3H
, m), 1.10-1.70 (2H.

m), 1.76-2.36 (4H, m).

\hi1 3.26 3.76 (2H, m), 4.93a=i-
5,10 (Awazete IH, each t, J-6H2).

6.16-6.40 (LH, m), 6.60-
6. 80 (I H, m).

MS m/z; 162 (M”), 147°13
3.120 (100%), 105°92.91,78
゜Reference Example 11 Except for using 4.67 g (25,6 mmo I) of 6-(2-phenyl)ethylfulvene as the starting material,
All procedures were carried out in the same manner as in Reference Example 2, and 7-(3-phenyl)
1 to propylidene-2-oxobicyclo(2,2,1)
1.51y (26%) of 1-5-ene was obtained.

IR(neat);2940,1?50°870.75
0,700cm+-'.

NMR (CDC1,) iδ 1.47-2.87 (6H
, m), 3.17-3.57 (2H.

m), 4.95 and 5.07 (together IH, t.

J=7Hz, ca, 2:1), 6.20 (IH.

m), 6.63 (IH, m), 7.21
(5H.

m).

Reference Example 12 As a starting material, 6,6-titramethylenefulpene8.
34 g (64.7 mmol) was used, everything was carried out in the same manner as in Reference Example 2, and 7-cyclopentylidene +
-2-oxobicyclo(2,2,1)hept-5-ene 1.20B (11%) was obtained.

IR(neat)i 2950,1745°1110
．． 1050.760,710 cm-'.

NMR (CDCl5) iδ 1.43-2.43 (I
OH, m), 3.33-3.53 (2H.

m), 6.23 (LH, m), 6.67 (1M
.

Denki dd, J-2Hz, 4Hz).

MS m/z; 174 (M″″, 3%)
, 132 (90%), 117 (63%), 10
5 (21%), 104 (100%), 91 (7
9%), 78 (30%), 77 (31%),
51 (29%), 39 (44%).

Reference example 13 7-ophthyridine-2-oxobicyclo [2°2.1]
Hept-5-ene 436g (2,0rn-mol)
was dissolved in THF (20 ml), 1.23 g (10.8 mmol) of 30% hydrogen peroxide and 1.05 ml (2.1 mmol) of 2N aqueous sodium hydroxide were added under water cooling, and extracted with ether (20 ml x 4). The liquid was washed with saturated brine (20 ml) and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel 9 ether:hexane-1:I).
6-ophthyridin-2-oxa-3-oxobicyclo(3,3,O)oct-7-ene 212 μ(4
5.3%). This is a mixture of two isomers for exomethylene (syn147).

ant165■), and each was isolated.

Physical property value of syn body IR (neat); 2940, 2870°1780
．． 1170.102102O'.

NMR (CDC13) iδ 0.89 (3H.

tt J-6Hz), 1.30 (IOH, m).

2.08 (2H, m), 2.40 (LH, dd
.

J = 6Hz and 17Hz), 3.0 (I H
,.

dd, J-11Hz and 17Hz).

3.59 (IH, m), 5.4-5.52 (2
H.

m), 6.05 (4H, dd, J-2Hz and 6Hz), 6.39 (LH, d, J-6Hz).

MS m/z; 235 (M”+1.10%).

234 (M”, 33%), 105 (61%).

93 (75%), 92 (90%) 991 (100%
), 77 (56%), 41 (61%).

Elemental analysis (as CCl5H*zOt) Calculated value: C, 76,88;) (,9,46%.

Actual measurements: C, 76,83, H, 9,37%.

Physical property value of anti body IR (neat); 2930, 2B60°1780,
1160. I 020cx-'.

NMR (CDC13); δ 0.89 (3
H.

t, J-6Hz), 2.29 (10H, m
).

2.17 (2H, m), 2.26 (IH,
dd.

J-4Hz and 19Hz), 2.97 (IH, dd,
J-9Hz and 19Hz).

3.54 (LH, m), 5.38 (LH,
t.

J-7Hz), 5.56 (LH, dd, J
-2Hz and 7Hz), 6.14 (LH, m)
.

6.72 (IH, d, J-6Hz).

Reference example 14 7-ophthyridine-2-oxobicyclo [2°2.1]
89 g (0.40 m-mol) of hept-5-ene was dissolved in MeOHHxO (1:1) (10 ml), and 295 μm of 30% hydrogen peroxide solution (2.6 mmol) was dissolved in MeOHHxO (1:1) (10 ml).
1) and 2N sodium hydroxide 0.6rn+ (1,
2 mmol 1) was added. The mixture was stirred for 30 minutes under water cooling and for 5 hours at room temperature. Add water (30ml) and adjust the pH to 2 with oxalic acid.
After that, the mixture was extracted with dichloromethane (10 ml x 4). The extract was washed with saturated brine (10 ml) and then dried over anhydrous magnesium sulfate. The inorganic matter was filtered off and the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by column chromatography (silica gel, hexane:ether-181) to obtain 6-
Ofthyridine-2-oxa-3-oxobicyclo(3,
3,Q) Oct-7-ene 59b (62.8%) was obtained.

This is a mixture of two isomers (s
yn39g, ant120sg), and each was isolated.

Reference Example 15 As a starting material, 7-(2-octenylidene)-2-oxobicyclo(2,2,l)hept-5-x7440w
(2,02mmo 1) was used, all other examples were Reference Example 1.
6-(2-octenylidene)-2-
Oxa-3-oxobicyclo(3,3,0)octo-7
-ene 217■ (45.9%) was obtained.

This is a mixture of two isomers (s
yn172g, an't145w), and each was isolated.

Physical properties of syn body IR (neat); 2950.1780 cm-'.

NMR (CDC1,); δ 0.90 (3
H.

to J-7Hz), 1.06-1.80 (
61(.

m), 2.16 (2H, m), 2.46
(IH.

dd, J-6Hz and 18Hz).

3.05 (IH, dd, J=11Hz and 18Hz
), 3.70 (1)1. m), 5.65(
LH, dd, J-2Hz and 7Hz).

5.48-6.34 (4H, m), 6j2 (I
H, d, J-6Hz).

MS m/z; 232 (M”, 13%
), 91 (51%), 55 (58%), 43 (
88%), 41 (100%), 39 (51%).

29 (56%), 27 (57%).

Elemental analysis (C+sH dew.0.) Calculated value: C,? ? , 55; H, 8,68%.

Actual value: C,? 7.33 i H, 8,70%.

Physical property value of 8014 body IR (neat); 2940.1775.1 1 65
01-'.

NMR (Cocks); δ Q, 88 (3
)1°t, J-6Hz), 1.02-1.78
(6H.

m), 2.12 (2H, m), 2.45
(LH.

dd, J-6H2 and 18Hz).

2.93 (IH, dd, J=7Hz and 18Hz)
, 3.52 (IH, m).

5.52 (IH, dd, J-3Hz and 7Hz),
5.37-6.55 <4H, m).

6.80 (IH, d, J=7Hz).

MS m/z; 235 (M”+1. 14%)
.

234 (M”, 42%), 108 (5
2%).

105 (66%), 93 (78%), 92 (8
0%), 91 (100%), 77 (56%),
41 (55%).

Reference Example 16 As a starting material, ? -(3,3-ethylenedioxyoctylidene)-2-oxobicyclo[2゜2,l]hept-5-ene 190 mm (0,668 mmol) was used in the same manner as in Reference Example 13. conduct, 6-(3,3
-ethylenedioxyoctylidene)-2-oxa-3-
Oxobicyclo(3,3,0)oct-7-ene 103
■(51.2%) was obtained.

This is a mixture of two isomers (s
yn76@, ant 12'7g), and each was isolated.

Physical properties of syn body IR(nsat); 2960.1775es-'.

NMR (CDCIs); δ 0.88 (3H.

t, J=6Hz), 1.03-1.75 (8H.

m) 2.35 (2H, d, J=8Hz).

2.42 (IH, dd, J-6Hz and 18Hz)
, 2.95 (IH, dd, 12Hz and 18Hz)
, 3.57 (IH, m).

3.92 (4H, m), 5.55 (2H, m).

6.03 (IH, m), 6.38 (IH, d.

J”5Hz).

MS m/z; 221 (M"-CsH++7%
).

143 (100%).

Physical property values of ant i-body IR(nsat); 2960.1780c11-'.

NMR (CDC1s) iδ 0.87 (3H.

t, J=6Hz), 1.03-1.77 (8H.

m), 2.42 (IH, dd, J-5Hz and 1B!-1z), 2.45 (2H, d, J-8Hz
), 2.93 (IH, dd, J=12Hz and 1
8H2), 3.48 (IH, m).

3.92 (4H, s), 5.18-5.60 (2H
, m), 6.13 (IH, m).

Reference example 17? -(3,3-ethylenedioquine octylidene)-2-
Oxobicyclo(2,2,1)hept-5-ene 500
w (1,81 mmo 1) was dissolved in 25 ml of methylene chloride, and 40% peracetic acid-acetic acid solution 0.38 ml (2
,0 mmol) and 445 g of sodium acetate (5,4
2 mmol 1) was added under water cooling, and stirring was continued at room temperature for 6 hours. Remove the solvent under reduced pressure, extract with ethyl acetate, add water,
Wash with saturated saline (anhydrous hexane:ethyl acetate-2:l)
The mixture was separated to obtain 6-(3,3-ethylenedioxyoctylidene). One syn body is 157N (0,5
38 mmol, yield 29.7%) The other anLi form is 128* (0,438 mmol, yield 24.2%)
) obtained.

Reference Example 18 As a starting material, 7-(3-phenyl-2-propenylidene)-2-oxobicyclo(2,2°1]hept-5
6- (3-
phenyl-2-propenylidene)-2-oxa-3-oxobicyclo[3°3.0]oct-7-ene62■(
29.6%).

This is a mixture of two isomers (s
yn49■, antt13w), and each was isolated.

Physical properties of syn body IR & product η11775.1340° 970, 765.　690cm-'.

NMR (CDClz) ;6 2.48 (It-
1°dd, J-5Hz and 19Hz).

3.10 (IH, dd, J=8Hz and 19Hz)
, 3.78 (IH, m), 5.65 (LH, dd,
J = 2Hz and 8Hz).

5.92-7.02 (5H, m), 7.35 (
5H, m).

MS m/z; 239 (M” +1. 19%
).

238 (M”, 100%), 193 (
54%).

Physical properties of anti body IR=4; 2945.17so.

117 Qlm-'.

NMR (CDCIs); δ 2.50 (IH.

dd, J-6Hz and 19Hz).

3.00 (IH, dd, J=11) (z and 19
H'z), 3.63 (I H,m), 5.57 (I
H, dd, J-3Hz and 7Hz).

6.00-7.12 (5H, m), 7.35 (5H
, m).

Reference example 19? -(3,3-ethylenedioxyoctylidene)-2-
Oxobicyclo(2,2,1)hept-5-ene 104
g (0,377 mmol) in methylene chloride (1 m+
), dissolve 208 cm of sodium carbonate (1,51 mmo
l) and 178 mg of 80% metachloroperbenzoic acid (0,
830 mmol I) was added under water cooling, and the mixture was stirred for 7 hours while returning to room temperature. Ether was added to this, and the ether layer was washed with water and saturated saline.
2: Separated by applying 1), 6-(3,3-ethylenedioxyoctylidene)-2-oxa-3-oxobicyclo(3,3°0)oct-7-ene is a mixture of two isomers. 25N (0,085mmo 1. Yield 23%)
Obtained.

Reference Example 20 ++ As a starting material, 7-(4-propylbenzylidene)-
2-oxobicyclo(2,2,1)hept-5-ene 9
2 (Ig (3,87 mmol) was used in the same manner as in Reference Example 14, and 6-(4-propylbenzylidene)-2-oxa-3-oxobicyclo(3,3
,0) Oct-7-ene 708 ml (72.0%) was obtained.

This is a mixture of two isomers (s
yn544g, ant i164w), and each was isolated.

Physical properties of syn body mp; 59-60°C.

IR (KBr); 1770, 1170 cm-'.

NMR (CDCl2); δ 0.94 (3H.

t, 7Hz), 1.63 (2H, 5extet.

J-7Hz), 2.40 (IH, dd, J''6Hz and 18Hz), 2.57 (2H.

t, J-IHz), 3.07 (IH, dd.

J = 12Hz and 18Hz), 3.95 (IH, m)
, 5.66 (IH, dd, J-2Hz and 7Hz), 6.13 (IH.

dd, J-2H2 and 5Hz), 6.47 (IH,s
), 6.56 (IH, d, J-6Hz),
7.20 (4H, s).

MS m/z; 255 (M”+1.
17%).

254 (M”, 85%), 1B! (6
8%), 167 (100%).

Elemental analysis (as C+ t Hr * O□) Calculated value:
C, 80,29i H, 7,13%.

Actual value: C, 8G, 01; H, 7, 30%.

Physical property values of ant i-body mp; 54-55°C.

IR (KBr); 1778, 1185 cm-'.

NMR (CDCIs); δ'0.91 (3H.

t, 7H2), 1.60 (2H, 5extet.

J-7Hz), 2.37-2.73 <3H, m).

3.01 (IH, dd, J=12) Iz and 18H
z), 3.66 (IH, m), 5.55 (
LH, dd, J=2Hz and 7H2).

6.30 (2H, m), 6.98 (IH,
d.

J=5Hz), 7.15 (4H, s).

MS m/z; 255 (M′″+1.17
%).

254 (M”, 82%), 181 (6
6%), 167 (100%).

Reference Example 21 As a starting material, 7-cyclohexylidene-2-oxobicyclo(2,2,1)hept-5-ene 408[(2
, 17 mmol) was used to obtain 300 μm (67.8%) of suberitene-2-oxa-3-oxobicyclo[3°3.0]oct-7-ene.

IR(neat); 2940, 2860°1770.1
1?0.1010c11-'.

NMR (CDCl5) iδ 1.57 (6H.

m), 1.90-2.50 (5H, m).

2.97 (IH, dd, J=11Hz and 18H2
), 3.58 (IH, m), 5.60 (IH, dd,
J-3Hz, 9Hz).

5.98 (IH, dd, J-3Hz, 6Hz).

6.67 (IH, d, J-6Hz).

104 (69%), 91 (100%).

Reference Example 22 U As a starting material, 7-(2-ethylhexylidene)-2
-Oxobicyclo(2,2,13hept\powder-5-ene 1.21JC (5,55mmo I) was used, except that everything was carried out in the same manner as in Reference Example 17, and 6-(2-ethylhexylidene)-2 -oxa-3-oxobicyclo(3,3,0)octo-7-enky586■(45,0
%) was obtained.

This is a mixture of two isomers for exomethylene (
The syn form (408w) and the anti form (178g) were isolated.

Physical property value of syn body IR (neat); 297G, 2950°2860, I
T80.1460, 1340°11?0.1020.7
60cm-'.

NMR (CDCl5)jδ 0.66-1.00 (6H
, m), 1.00-1.66 (8H.

m), 1.70-2.16 (LH, m).

2.36 (IH, dd, J=6.18Hz).

2.96 (IH, dd, J-2, 18Hz).

3.33-3.70 (LH, m), 5.50 (IH
, d, J-10Hz), 5.61 (IH, dd, J-2
,9Hz),6.01(11(,dd,J-2,6Hz
), 6.36 (LH, d, J=6Hz).

MS m/z; 234 (M”), 205°1
7? (100%), 149° Antt body physical property value IR (neat); 2970.2950° 2860.1
780.1460,1340°1170.1G20,7
60.130a11-'.

NMR (cDcl, ); δ 0.66-1.00 (6H
, m), 1.00-1.70 (8H.

m), 1.76-2.33 (IH, m).

2.43 (LH, dd, J-6, 18Hz).

2.96 (IH, dd, J-12, 18H2), 3
．． 36-3.70 (IH, m).

5.07 (11 (, d, J-10Hz).

5.55 (IH, dd, J-2, 6Hz).

6.03-6.20 (IH, m), 6.66 (IH
, d, J=6Hz).

MS m/z; 234 (M'), 205°17
7 (100%), 149° Reference Example 23 As a starting material, 7-cyclohexylmethylene=2-oxobicyclo(2,,2,1)hept-5-ene 1. G
The procedure was carried out in the same manner as in Reference Example 17, except that 6-cyclohexylmethylene-2-oxa-3-oxobinclo (3,3,0
) 327 ml (30.3%) of oct-7-ene were obtained.

This is a mixture of two isomers for exomethylene (s
The yn isomer is 222m, and the antt isomer is 105m), and each was isolated.

Physical property value of syn body IR (neat); 2950, 2860°1780.1
? 50,1450. 11TOe1m −'.

NMR (CDCI, ), 60.83-1.90 (10H
, m), 2.20 (IH, d, J -10
Hz), 2.36 (IH, dd, J-6,181(z
), 2.99 (IH, da.

J=18. 12Hz), 3.43-3.76(I
H, m), 5.36 (IH, d, J-10
Hz), 5.61 (IH, dd, J-3°7.5Hz), 6.01 (IH, dd, J
=3゜6Hz), 6.33 (IH, d, J
-6Hz).

MS m/z; 218 (M”, 100%
).

190, 173. 159. 137. 136°1
35, 95. Physical property value IR (neat) of 81° ant i-body; 2950, 1860° 1780.1
450.1170m-'.

NMR (CDCIs); 60.93-1.90 (IOH
, m), 1.90-2.26 (IH.

m), 2.44 (LH, dd, J=6.
18Hz), 2.94 (IH, dd, J-
12゜18Hz), 3.33-3.60 (LH, m>
.

5.21 (IH, m, J=9Hz), 5.54 (IH
, dd, J-2,7,5Hz).

6.03-6.20 (IH, m), 6.70 (
LH, d, J = 6Hz).

MS m/z; 218 (M”, 100%)
.

159, 137. 95. 81° Reference Example 24 As a starting material, 1.32 g of 7-butylidene-2-oxobicyclo(2,2,1)hept-5-ene (8,1
The procedure was carried out in the same manner as in Reference Example 17 except that 6-butylidene-2-oxa-3-oxobicyclo(3,3,0)oct-7-ene 155
10.7%).

This is a mixture of two isomers for exomethylene (s
The yn form was 105cm and the anti form was 50w), and each was isolated.

Physical property value TR (nsat) of syn body; 296G, 1780°1340.1
1?0.1020,750°710cm-'.

NMR (CDCIs); δ 0.93 (3H.

t+ J-7Hz), 1.44 (2H.

5extet, J=7Hz), 2.06(2H,q,J
-7Hz), 2.36 (LH.

dd, J-6, 18Hz), 3.00 (IH.

dd, J-12, 18Hz), 3.40-3.76 (
IH, m), 5.51 (IH, t.

J-7Hz), 5.59 (IH, dd, J-3, 7H
2), 6.00 (IH, dd, J-3,
6Hz), 6.36 (IH, d, J-6Hz).

Physical property value of anti body IR (neat); 2960,1?80°1340.1
170.1020.750am-'.

NMR (CDCIs); δ 0.90 (3H.

t+ J=7Hz), 1.41 (2H.

5exLat, J=7Hz), 2.13(2H,Q,J
-7Hz), 2.43 (IH.

dd, J=6.18Hz), 2.94 (IH.

dd, J=18.10Hz), 3.33-3.66
(IH, m), 5.36 (IH, t.

J-7Hz), 5.52 (IH, dd, J=3.6
Hz), 6.03-6.20 (IH.

m), 6.68 (LH, d, J-6Hz).

Reference Example 25)-2-oxobicyclo(2,2,1)hept-5-
The same procedure as in Reference Example 17 was carried out except that 2.07 g (8,92 mmol I) of ene was used, and 6-(3-oxooctylidene)-2-oxa-3-oxanti compound 22 was prepared.
%.

Physical properties of syn body TR (neat); 1780.1720C! ! −’.

NMR<CDC1,); δ 0.90 (t, 3H.

J-7Hz), 1.03-1.80 (m, 6H).

2.10-2.60 (m, 3H), 2.9
7 (dd, LH, J=12.18Hz).

3.17 (d, 2H, J=7Hz), 3.
3.73.73 (m, IH), 5.50
5.83 (m, 2H), 6.10 (dd
, IH, J-6, 3Hz), 6.41 (d
, IH, J-6H2).

MS m/z; 248 (M”), 150.
99 (100%).

Physical properties of anti body IR (neat); 1780.1720cs-'.

NMR (CDCI; δ 0.90 (e, 3H.

J=7Hz), 1.03-1.77 (m, 6H).

2.30-2.63 (m, 3H), 2.9
7 (dd, IH, J=12.18Hz).

3.27 (d, 2H, J-7Hz), 3.37-3.
73 (m, IH), 5.40-5.83 (m, 2H)
, 6.03-6.30 (m, IH).

6.62 (d, IH, J=6Hz), MS
m/z; 24B (M”), 150.9
9 (100%).

Reference Example 26 As a starting material, 7-(1-methyl)hebutylidene-2
-oxobicyclo(2,2,1)hept-5-ene 21
3I? The same procedure as in Reference Example 13 was carried out except that Ig (1,OOmmo I) was used, and 6-(1-methyl)hebutylidene-2-oxa-3=oxobicyclo(3,3,
0) Two isomers of oct-7-ene were obtained. Isomer A
76■ (32%).

Isomer 870■ (30%).

Physical property values for isomers IR(neat); 1780cm-'.

NMR (CDC13) iδ 0.90 (t, 3H
.

J-6Hz), 1.06-1.66 (m, 8H
).

1.76 (s, 3H), 1.86-2.13 (m,
2H), 2.31 (dd, LH, J -6,1
8Hz), 2.94 (dd, IH.

J-12, 18Hz), 3.40-3.76 (m, IH
), 5.58 (dd, IH, J-2, 6Hz), 5.
98 (dd, IH, J-3, 6Hz), 6.60 (
d, IH, J=6Hz).

MS m/z; 234 (M”, 100%).

105° Physical properties of isomer B IR(nsat); 1780(!11-'.

NMR (CDCl5) iδ 0.90 (t, 3H
.

J=6Hz), 1.10-1.56 (m,
8H) 1.73 (s, 3H), 1.93-
2.30 (m, 2H), 2.43 (dd,
IH, J=G, ] 8Hz), 2.96
(dd, IH.

J=12. 18Hz), 3.33-3.73(m
, LH), 5.60 (dd, IH, J
-2,6Hz), 5.98 (dd, IH
, J -3, 6Hz), 6.63 (d, I
H, J -6Hz).

MS m/z; 234 (M", 100%).

105° Reference Example 27 7-(3-phenyl)propylidene-2-oxobicyclo(2,2,1)hept-5-ene 205■(0,91
5mmo
3 curves (83.1%) were obtained.

This is a mixture of two isomers for exomethylene, each of which was isolated. The ratio is syn:54
．． 5%, anti: 28.6%.

Physical properties of syn body mp; 78-79°C.

IR(neat);2945.1765°11?0,
1020,750,700am-'.

NMR (CDC13) iδ 2.0-3.07 (-6H
, m), 3.42 (LH, m).

5.52 (2H, m), 6.00 (IH, dd.

J-2Hz, 6Hz), 6.35 (IH.

d, J-6Hz), 7.25 (5H, m).

MS m/z; 240 (M”, 22%
).

181 (17), 91 (100).

Elemental analysis (as C+ #, H+ h O*) Calculated: C, 79,97; H, 6,71%.

mp; 60-61°C.

TR(neat)i2950.1765°11?0,1
120,750,700c1m-'.

NMR (CD C1s) iδ 2.24-2.9
7 (6H, m), 3.45 (IH, m).

5.35 (IH, t, J-7Hz), 5.50 (IT
(, dd, J=2Hz, 6Hz).

6.08 (IH,m), 6.57 (If(,d
.

J-6Hz), 7.20 (5H, m).

MS m/z; 240 (M”, 18%).

91 (100).

Elemental analysis (as CI & H+ a Ot) Calculated values:
C, 79,97; H, 6,719g.

Actual value: C, 79,63; Ii, 6.339'
6゜Reference Example 28 As a starting material, 7-cyclobentridene-2-oyasobicyclo(2,,2,1)hept-5-ene 290s
(1,67 mmol) was carried out in the same manner as in Reference Example 13.
7-g (52.7%) was obtained.

rn　p　;　60　　u　2°(:.

[R(neat); 2980.1780°1340
, Li2S, 1020cm.

NMR (CDCIs); δ 1.45-1.9
3 (4H, m), 1.93 2.55 (4H
, m).

2.38 (IH, dd, J=6Hz, 12Hz
).

2.92 (LH, dd, J=8Hz, 12Hz
).

3.42 (LH, m), 5.57 (IH,
dd.

J=IHz, 4Hz), 5.97 (IH.

dd, J=IHz, 4Hz), 6.48(
LH, d, J-4Hz).

Reference Example 29 6-opylidene-2-oxer-3-oxobicyclo(
3,3,0) Octo-7-ene 350■ (1,50mm
of) was dissolved in toluene (8 ml) and cooled to -60°C. In this, diisobutylaluminum hydride (DIB
AL-H, IM solution in hexane) 3.0 ml (3,
0 mmol) was added and stirred for 1 hour. Then methanol (0.1 ml) was added to decompose excess DIBAL-H. (room temperature, 10 minutes), ether (50 ml) was added, and washed with saturated saline (10 ml) (a centrifuge was used at this time).
2). The ether layer was diluted with saturated saline solution (10ffl
1) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 3-hydroxy-6-oftyridine-2
-Oxabicyclo(3,3゜0)oct-7-ene33
2■ (93.8%) was obtained.

IR(neat); 3400, 2940°2860.1
470.103 discharge "1°NMR (CDCl5) iδ 0.88 (3H.

t, J=6Hz), 1.30 (IOH, m
).

1.73-2.60 (4H, m), 3.16 (
IH, broad s), 3.50 (IH
.

m), 5.15-5.60 (3H, m).

5.80-6.47 (2H, m).

Reference Example 30 All reference examples except that sy n + 6-ophthyridine-2-oxa-3-oxobicyclo(3,3,0)oct-7-ene 353m (1,51mmo 1) was used as the starting material. 29, 3-hydroxy-5yn, 5-octylidene-2-oxabicyclo(
3,3,0) oct-7-ene 335■ (94,1%)
I got it.

IR(neat); 3450, 2950°2875.1
470.101030a'.

NMR (CDCIs); δ 0.88 (3H.

t, J-6Hz), 1.30 (10H, m
).

1.45-2.70 (4H, m), 2.82(1)1
．． broad s), 3.52 (LH.

qulntst, J=10Hz), 5.13-5.67
(3H, m), 5.92 (IH.

dd, J-2Hz and 5Hz), 6.12 (IH, d
, J=6Hz).

Reference Example 31 As a starting material, anti, 6-octylidene-2-oxa-3-oxobicyclo(3,3,0)otate-7-
3-hydroxy-anti
, 5-octylidene-2-oxabicyclo(3,3,0
) Oct-7-ene 29 Lw (94.0%) was obtained.

rR(neaL); 343G, 2950°2875.1
470.1Q30cn-'.

NMR (CDCIs): δ 0.87 (3) (.

t, J-6Hz), 1.27 (IOH, m).

1.50-2.48 (4H, m), 3.42 (LH,
m), 5.08-6.72 (3H.

m), 5.97-6.60 (2H, m).

Reference Example 32 \TES/ ++ 6-(2-octylidene)=2-oxa-3-oxobicyclo(3,3,0)oct-7-ene 475+w (2,05 mmol) was used as the starting material. All were carried out in the same manner as in Reference Example 29, and 3-hydroxy-6-
(2-octylidene)-2-oxabicyclo(3,3,
0) 480 μm (100%) of oct-7-ene was obtained.

IR(neat); 3430.2950°28B0,1
030.970am-'.

NMR (CDC1s>; δ 0.90 (3H.

t, J-6Hz), 1.07-3.90 (12H, m)
, 5.07-6.73 (7H.

m).

Reference Example 33 As a starting material, syn, 6-(2-octylidene)-
The same procedure as in Reference Example 29 was carried out except that 2-oxa-3-oxobicyclo[3°3.0]oct-7-ene 318w (1,37m-mo +) was used, and 3-hydroxy-5yn, 6 -(2-octylidene)-2-oxabicyclo(3,3°0)oct-7-ene 314■(97
, 8%).

IR(neat) ;3430. 2950°287
0, 1030. 965c*-'.

NMR (CDCS) i 6 0.90 (3
H.

t, J-6Hz), 1.10-2.66(12
H, m), 3.58 (IH, q, J-7H
z), 5.17-6.40 (7H, m).

Reference Example 34 As a starting material, 6-(3,3-ethylenedioxyoctylidene)-2-oxa-3-oxobicyclo(3,
3,0) Octo-7-ene 104MI (0,356mm
3-hydroxy-6-(3゜3-ethylenedioxyoctylidene)-2-oxabicyclo(3,3,0)oct-7- 99% of en (94%) was obtained.

IR(neat); 3450.2970°1030c
m-'.

NMR (CDCIs); δ 0.64-2.63 (15
H, m), 3.23-3.70 (I H.

m), 3.92 (4H, s), 5.07-5.67
(3H, m), 5.80-6.43 (2H, m).

MS m/z; 223 (M”-71), 205°1
43 (100%).

Reference Example 35 As a starting material, anti,6 (3,3-ethylenedioxyoctylidene)-2-oxa-3-oxobicyclo(3,3,0)oct-7-ene 395w (1
, 35mmo 1) was carried out in the same manner as in Reference Example 29, and 3-hydroxy = anti, 6 (3,
3-ethylenedioxyoctylidene)-2-oxobicyclo(3,3,0)oct-7-ene 258■(65,
0%) was obtained.

IR(neat)=3440.2950°1030c
m-'.

NMR (COCl; δ 0.87 (3H.

t, J-6Hz), 1.03-2.70 (12
11, m), 3.20-3.63 (l H.

rn), 3.91 (4H,s), 5.03-5.7
7 (3H, m), 5.97-6.60 (2H, m).

As starting material, syn, 6-(4-propylbenzylidene)-2-oxa-3-oxobicyclo(3,3,0
) 3-hydroxy-5yn was prepared in the same manner as in Reference Example 29 except that oct-7-ene 423yo (1,67 mmol) was used.

6-(4-propylbenzylidene)-2-aut-+bicyclo(3,3,0)oct-7-ene 398■(93
,0%) was obtained.

mp; 111-112°C.

IR (KBr); 3400.2940°1030.89
5.885c+a-'.

NMR (CDCIs) iδ 0.95 (3H.

t, J-8Hz), 1.70 (2H.

quintet, J=8Hz), 2.58(2H,t,
J18Hz), 1.90-2.85 (2H, m),
3.18 (IH.

broads), 3.95 (IH, Q.

J=9Hz), 5.50 (2H, m).

6.05 (IH, dd, J-3H2 and 6Hz),
6.33 (2H, m), 7.13 (2H, d, J-8
1-[z), 7.35 (2H.

d, J-8Hz).

MS　m/2i257(M′″+1,20%).

256 (M”, 96%), 167 (100%).

Reference Example 37 Syn, 6-(3-oxooctylidene)-2=oxa-3-oxobicyclo(3,3,O)oct-7-ene 830we (3,35mmo I) was dissolved in methanol (9
5ml) and cooled to below 990°C.

There, sodium borohydride (NaBHa) 266
g (7,00 mmol) was added thereto, and stirring was continued for 40 minutes at below 0°C. While cooling, 95 ml of saturated sodium phosphate aqueous solution was added and the temperature was returned to room temperature. The precipitate was removed by filtration, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Remove the solvent under reduced pressure and add sy
840 μm (quantitative) of n,6-(3-hydroxyoctylidene)-2-oxa-3-oxobicyclo(3,3,0)oct-7-ene were obtained.

IR(neat); 3450, 1?70am-'.

NMR (CDC1s); δ 0.90 (t,
3H.

J=7Hz), 1. IQ-1,60 (m.

BH), 2.10-2.33 (m, 2H).

2.43 (dd, IH, J-6, 18Hz).

2.98 (dd, IH, J-12, 18Hz), 3.
40-3.80 (m, IH).

5.47-5.70 (m, 2H), 6.05 (dd,
IH, J-2, 6Hz), 6.38 (d, LH, J-6
Hz).

MS m/zH250 (M”), 150 (100%)
.

Reference Example 38 syn, 6-(3-hydroxyoctylidene)=2-oxa-3-oxobicycloC3,3,0)octo-7-
En84 (Ig (3,35mmol I) and dihydrobilane 0.34ml (310s, 3.69mmo I)
1) was dissolved in 21 ml of methylene chloride, 1 cup of microspertyl pt-toluenesulfonic acid was added, and the mixture was heated to 18 mL at room temperature.
Stirring was continued for an hour. After extraction with ether, the mixture was washed with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting oil was subjected to column chromatography (silica gel).

Hexane:ethyl acetate = 2:1) to obtain the desired syn, 6-(3-tetrahydrobiraΣyyP-cutylidene)-2-oxa-3-oxobicyclo(3,3,0).
836 ml of oct-7-ene (yield 75%) was obtained.

IR (neat); 1780cm-'.

NMR (CDCI; δ 0.'lQ (t, 3H.

J=6T(z), 1.10-1.83 (m.

14H), 2.26 (dd, 2H, J-6, 6Hz
), 2.46 (dd, IH, J-6, 12Hz),
2.96 (dd, IH.

J=12.18Hz), 3.26-4.13(m, 4H
), 4.46-4.70 (m, IH).

5.36-5.70 (m, 2H), 6.01 (dd
, IH,J=2.6Hz), 6.36(d,IH,J-
6Hz).

MS m/z; 334 (M”), 234°150.
85 (100%).

Reference Example 39 syn, 6-(3-tetrahydropyranyloxyoctylidene)-2-oxa-3-oxobicyclo(3,3,
0) The same procedure as in Reference Example 29 was carried out except that oct-7-ene 557■ (1,67 mmol) was used, and syn,
6-(3-tetrahydropyranyloxyoctylidene)
-2-oxa-3-hydroxybicyclo(3,3,0)
Oct-7-ene 504 (yield 90%) was obtained.

rR(neat)i3450cn-'.

NMR (CDCl5) iδ 0.90 (t, 3H.

J-7Hz), 1.06-2.00 (m.

14H), 2.16-2.53 (m, 3H).

2.60-2.80 (m, IH), 3.26-4.
10 (m, 5H), 4.53-4.80 (m, I
H), 5.20-5.66 (m, 3H).

5.95 (dd, LH, J-211z, 6Hz).

6.13 (d, IH, J-6Hz).

MS m/z; 336 (M'), 234°8
5 (10 (1%).

As a starting material, 6-(1-methyl)hebutylidene-2
-oxa-3-oxobicyclo(3,3゜0)octo-
7-ene 376W (1,61 mmo 1) The procedure was carried out in the same manner as in Reference Example 29 except that the isomer mixture was used.
-(2-methyl)hebutylidene-2-oxa-3-hydroxybicyclo(3,3°0)oct-7-ene 341
(2) (yield 90%) was obtained.

IR (neat); 3450 cm-'.

NMR (CDCl2); δ 0.90 (t, 3H.

J=7Hz), 1.10-1.63 (m.

8H), 1.76 (s, 3H), 1.90 =2.
76 (m, 4H), 2.83-3.10 (m.

IH), 3.20-3.73 (m, IH).

5.30 (t, IH, J-6Hz), 5.53 (d
, IH, J-6Hz), 5.90 (d.

LH, J=6Hz), 6.40 (d, IH.

J-6Hz).

Reference Example 41 As a starting material, 2-oxa-3-oxo-5yn, 6
-(3-pheniM propylidene bicyclo(3,3,0)
The procedure was carried out in the same manner as in Reference Example 29 except that 359 mmol of oct-7-ene (1,50 mmol) was used. ,0) oct-7-ene35
8w (98.9%) was obtained.

IR(neat); 3430.2945°1130,
700cx-'.

NMR (CDCIs); δ 2.05-2.90 (6H
, m), 3.12 (IH, broads), 3.45
(IH, m), 5.1-5.67 (3H, m), 5.
93 (LH, dd, J -2Hz, 6Hz), 6.
10 (LH, d.

J-6Hz), 7.21 (5H, m).

Reference Example 42 161 g (0,879 mmol) of 2-oxa-3-oxo-6-cyclopentylidenebicyclo(3,3,0)hept-7-ene was used as the starting material.
The same procedure as in Reference Example 29 was carried out to obtain 155 g (91.7%) of 3-hydroxy-2-oxa-6-cyclopentylidenebicyclo(3,3,0)hept-7-ene.

mpH99-100°C.

IR (KBr); 3400.2950°1020,
940cm-'.

NMR (CDC13) i δ 1.33-1.
87 (4H, m), 1.87-2.53 (4H
, m).

3.23-3.63 (2H, m), 4.60 (
LH, broad s), 5.38 (2H
.

m), 5.57 (IH, m), 5.90 and 6
．． 07 (IH, each d, J-6H2).

6.27 and 6.35 (together IH, each d, J-
6Hz).

Example 1 [Preparation of dimyl anion] 1.40 g (0.029 mmol 1 in 50% oil) of sodium hydride was thoroughly washed with hexane. Dimethyl sulfoxide (DMSo,
15 ml) was added thereto, and the mixture was stirred for 1.5 hours on a 70°C oil bath. Hydrogen evolution stopped, and a dull green solution was formed. This solution has a concentration of 2.0 m m o 1/ml.

[4-(Hydroxycarbonyl)butyl] Triphenylphosphonium bromide 4.4 g (9,93 m-mo
The mouthpiece was dried under reduced pressure on a 100°C oil bath for 4 hours. After cooling, DMSO (8 ml) was added and dissolved, and while cooling, 9.5 ml (19.0 mmo
I) was added. After stirring at room temperature for 5 minutes, 3-hi.
Droxy-6-ophthyridine-2-oxabicyclo(3
,3,0) Octo-7-:L7332mg (1,41
A solution of mmo +) in DMSO (8 ml) was added. After stirring at room temperature for 7 hours, water (80 ml) was added, and a mixed solvent of ethyl acetate and ether (1:1) (40 ml) was added.
mlx4). After adjusting the aqueous layer to a pH of approximately 2, a mixed solvent of pentane and ether (1:1) (
40ml x 5). The extract was diluted with saturated saline (20
ml) and dried over anhydrous magnesium sulfate. Inorganic substances are filtered off, the solvent is distilled off under reduced pressure, and ? -(2-octylidene-5-hydroxy-3-cyclopentenyl)
262 m (58.1%) of -5-heptenoic acid was obtained.

IR (neat); 3700-2200 (OH).

2950, 1710cm-'.

NMR (CDC1s) iδ 0.8B (3H, t.

J-61(z), 1.03-2.48 <20H.

m), 3.06 (LH, q, J=7I(z).

4.86-5.65 (4H, m), 5.77-6.6
7 (2H, m), 8.38 (2H.

broads).

Example 2 As a starting material, 3-hydroxy-5yn,6-ophthyridine-2-oxabicyclo(3,3°0]oct-7
7-(syn,2-octylidene-5-hydroxy-3-si')lobentenyl)-5-heptenoic acid 436* (96%).

TR (neat); 37QO to 22Q'O(OH).

2950.2870,1715,1240°1040
cm-'.

NMR (CDCIg); δ 0.87 (3H, t,.

J-6Hz), 1.27 (12H, m).

1.68-2.07 (2H, m), 2.07-
2.77 (6H, m), 3.25 (LH,
m).

5.02-6.58 (6H, m), 7.85 (
2H, broad s).

Example 3 As starting material, 3-hydroxy-anti.

6-Ofthyridine-2-oxabicyclo(3,3゜0)
Octo-7-en 291tw (1,26mmo +)
Everything was carried out in the same manner as in Example 1 except that 7-(a
nti, 2-octylidene-5-hydroxy-3-cyclopentenyl)-5-heptenoic acid 379w (94,0
%) was obtained.

IR (neat); 3700-2200 (OH).

2950.17150111°NMR (CDCI,) iδ 0.11+8 (3H,
t.

J=6Hz), 1.06-2.87 (21H.

m), 4.77 (IH, dd, J-2Hz and 7Hz), 5.07-5.80 <3H.

m), 6.08 (IH, m), 6.57 (IH.

d, J=7Hz), 7.7 (2H, broadS).

Example 4 As a starting material, 3-hydroxy-6-(2-octenylidene)-2-oxabicyclo(3,3°0]octo-
The same procedure as in Example 1 was carried out except that 7-ene 138w (0,590 m-mol) was used,
-octenylidene)-5-hydroxy-3-cyclopentenyl)-5-heptenoic acid 106* (56.4%) was obtained.

IR (neat); 3700-2200 (OH).

2950.1715cn-'.

NMR (CDCI; δ 0.63-3.33 (20H
, m), 4.87-6.47 (8H.

m), 9.30 (2H, broad s).

Example 5 As starting material, 3-hydroxy-5yn, 6-(2-
octenylidene)-2-oxabicyclo(3,3,0)
Oct-7-ene 549■ (2,35mm o 1)
'fdf4'''To another group, do the same as in 1, 7- (syn, 2- (2-octenylidene)
583 ml (78.1%) of -5-hydroxy-3-cyclopentenyl-5-heptenoic acid were obtained.

TR (neat); 3700-2200 (OH).

2950.2870.1715.1240e1m -'
.

NMR (CDCIs); δ 0.88 (3H.

t, J=6H2), 1.07-3.43 (17H, m)
, 4.93-6.43 (8H-.

m).

Example 6 As a starting material, 3-hydroxy-6-(3°3-ethylenedioxyoctylidene)-2-oxabicyclo(3
,3,0) Octo-7-ene 105w (0,356m
All procedures were carried out in the same manner as in Example 1 except that mo 1) was used. -(2-(3,3-ethylenedioxyoctylidene)-5-hydroxy-3-cyclopentenyl-5-heptenoic acid 115 μm (85.2%) were obtained.

IR (neat); 3700~2200 (OH
).

2960, 1710C11-'.

NMR (CDCl2); δ 0.87 (
3H,・t, J=6Hz), 1.03-2.8
8 (19H, m), 3.92 (4H, s).

4.62-5.10 (IH, m), 5.12-
6.70 (4H, m), 5.75-6.63 (
2H, m).

Example 7 Shi-”? -(2-(3,3-ethylenedioxyoctylidene)
115 w (0,304 m-mol) of -5-hydroxy-3-cyclopentenyl)-5-heptenoic acid was dissolved in ether (5 ml), and an ethereal solution of diazomethane was added until no nitrogen was released. After stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure to give methyl 7-(2-(3,3-ethylenedioxyoctylidene)-5-hydroxy-3-cyclopentenyl-5-heptenoate).
(93.3%) was obtained.

IR (neat); 3450, 1725 cm-'.

NMR (CDC13) iδ 0.87 (3H.

t, J=6Hz), 1.10-3.40 (19H, m)
, 3.85 (3H,s).

3.93 (4H, s), 4.63-6.27 (7H,
m).

Example 8 As starting material, 3-hydroxy-anti.

6-(3,3-ethylenedioxyoctylidene)-2-
Oxabicyclo(3,3,0)oct-7-ene 258
Everything was carried out in the same manner as in Example 1 except that g (0,878 mmo 1) was used. -(2-(3,3-ethylenedioxyoctylidene)-5-hydroxy-3-cyclopentenylgo-5-heptenoic acid 266 µm (80.1%) were obtained.

IR (neat); 370G-2200 (OH).

2950.1710.1240m-'.

NMR (CDC1s); δ 0.67-2.90 (
25H, m), 3.93 (4H, a).

4.57-6.66 (7H, m).

Example 9 As a starting material, ? -[ant t, 2- (3゜3-ethylenedioxyoctylidene)-5-hydroxy-3-cyclopentenyl-5-heptenoic acid 266m
(0,704 mmol) was used in the same manner as in Example 7, and 7-(ant i, 2-(3,3-ethylenedioxyoctylidene)-5-hydroxy-3-cyclopentenyl]-5 -Methyl heptenoate 276■ (1
00%) was obtained.

IR (neat): 3470. 2960°174
0, 1240 countries-1°NMR (CDCIs): δ 0.87 (3
H,t.

J=6Hz), 1.06-2.87 (19H.

m), 3.65 (3H,s), 3.92
(tH.

s), '4.77 (IH, m), 5.13-5
．． 60 (4H, m), 6.13 (IH, m
).

6.53 (IH, d, J-6Hz).

Example 10 As starting material, 3-hydroxy-6-cyclohexylidene-2-oxabicyclo(3,3,0)oct-7-
361 g (1,75 mmol 1) of (2-cyclohexylidene)-5-hydroxy-3-cyclopentenyl)-5-heptene were obtained (89,4%).

TR (neat); 3800-2200 (broad)
OH), 2940°1715.124G, 1050cs-'.

NMR (CDC1s); δ 1.0? -3,50(
19H), 5.00 CLH, d, J-7Hz), 5.
45 (2H, m), 5.83 (IH, dd, J=2H
z, 6H2).

6.50 (IH, dd, J-2Hz, 6Hz).

Example 11 As a starting material, 7-(2-cyclohexylidene-5-
7-(
Methyl heptenoate (2-cyclohexylidene-5-hydroxy-3-cyclopentenyl)-5 was obtained. Yield 10
0%.

NMR (CDCIs) iδ 1.12-2.47 (m,
18H), 2.87-3.25 (m.

IH), 3.65 (s, 3H), 4.78-5.15
(m, IH), 5.15-5.65 (m, 2H), 6
．． 35-6.54 (m, IH).

Example 12 Under an argon atmosphere, 2.050 g of pyridine (25.9 m
Mo 1) was dissolved in 37 ml of methylene chloride, 1.298 g (12,98 m-mol) of chromic anhydride was added, and the mixture was stirred at room temperature for 15 minutes. In this, 392 mg (1,29 m
mol) dissolved in a small amount of methylene chloride was added and stirred for 15 minutes. Add 50ml of ether, remove the chromium through a silica gel column, remove the solvent under reduced pressure and give 7-(2-cyclohexylidene-5-oxo-3).
-cyclopentenyl)-5-methyl heptenoate 316w
(yield 81%).

IR(neat);2940. 2870°174
0, 1698. 1440. 11601-1°NMR (CDCIs) i δ 1.37-3.0
7 (17H, m), 3.67 (3H, s).

5.27 (2H, m), 6.10 (LH,
d.

J = 6Hz), 8.08 (IH, d, J
-6Hz).

MS m/z; 303 (M'+ 1.1
2%).

302 (M”, 45), 162 (100).

81 (78), 67 (68), 41 (
57).

Example 13 U'1゛Hr Syn, 5-(3-tetrahydropyranyloxyoctylidene)-2-oxa-3-hydroxybicyclo[3,3,O]oct-7-ene was used as the starting material. Everything else was carried out in the same manner as in Example 1. −[syn, f~
An ether solution of diazomethane was dissolved in trahydropyranyloxyOoctylidene-5-hydroxy-3-cy.
The mixture was added until the spot of the raw material disappeared on LC, leading to methyl ester. The solvent was removed under fIi pressure, and the resulting oil was subjected to column chromatography (silica gel).

Separate by pouring hexane and ethyl acetate (1:2) into the desired solution. -(syn, 2-7) octylidene-5-hydroxy-3cyclopentenyl]-5-heptenoate 391■ (yield 60%)
I got it.

Example 14 Methyl synoctylidene-5-hydroxy-3-cyclopentenyl]-5-heptenoate 390 μ (0,898 m
mol) in 35 ml of carbon tetrachloride to obtain 1.8 g (2
1 mmol 1) was added and stirring was continued at room temperature for 21 hours. Filter and remove manganese dioxide and manganese using Celite.
The filtrate was concentrated (253W) *This was subjected to column chromatography (silica gel, hexane:ethyl acetate-2:l
) to separate the desired 7-[S)'n,
171 ml of methyl 2-trahydrobyranyl oxyloctylidene-5-oxo-3-cyclopentenyl]-5-heptenoate (yield 44%) was obtained.

IR (neat); 1740.1710 cm-'.

NMR (CDClx) i δ 0.90 (
t, 3H.

J-7Hz), 1.13-1.87 (m.

16H), 1.87-2.76 (m, 10H).

2.76-3.10 (m, IH), 3.3
3-4.16 (m, IH), 3.70
(s, 3H).

4.53-4.76 (m, IH), 5.0
0-5.53 (m, 2f(), 5.66
6.00 (m, LH), 6.13 (d, 1M, J-
6Hz), 7.66 (d, IH, J-6H
z).

MS m/z; 433 (M+1),
248 (100%).

Example 15 As starting material, 3-hydroxy-5yn, 5-(3-
phenyl)propylidene-2-oxabicycloC3,3
, 0) Octo-7-en 344w! (1,42 mmo
The same procedure as in Example 1 was carried out except that 7-
(syn, 2-(3-phenyl)propylidene-5
-Hydroxy-3-cyclopentenyl-5-heptene 9428 (92 was obtained).

IR(neat); 3700 2200(broad)
OH), 2900°1710.1240.700 C11l-'.

NMR (CDCIs); δ 1.07-3.
35 (13H, m), 4.93 (LH, d,
J-7Hz), 5.40 (3H, m),
5.85 (IH, m), 6.17 (LH, d
, J -6Hz), 7.20 (5H, m)
.

Example 16 As starting material, 3-hydroxy-2-oxa-6-cyclopentylidenebicyclo(3,3,0)oct-7-
7-(2-cyclopentylidene-5-hydroxy-3-cyclopentenyl)-
5-heptenoic acid was obtained.

This was treated in the same manner as in Example 7, and 7-(2-cyclopentylidene-5-hydroxy-3-cyclopentenyl)-
It was designated as methyl 5-heptenoate.

This ester 232w (0.80 mmol 1) was dissolved in methylene chloride (10 ml) and added to a previously prepared methylene chloride solution of Collins' reagent (15 ml). After stirring at room temperature for 5 minutes, ether was added and the mixture was purified using a silica gel column. 7-(2-cyclopentylidene-5-oxo-3-cyclopentenyl)-5
-Methyl heptenoate 157* (yield: 67.7%) was obtained.

IR(neat);2970,1740°1700.1
540.1435.1170Qll-'.

NMR (CDCI; 61.37-3.00 (17H,
m), 3.67 (3H, s).

4.97-5.57 (2H, m), 6.07 (LH,
d, J=6Hz), 7.88 (IH.

d, J-6Hz).

Example 17 7-(2-octylidene-5-hydroxy-3-cyclopentenyl)-5-heptene [262μ(0,819m
mo 1) was dissolved in acetone (5 ml) and cooled to -30°C. In this, add Jean's reagent (1.75 mmol
/ml) 0.95ml (1.66mmol) was added and stirred for 30 minutes. Then use isoproper tool (1,0
ml) and stirred at room temperature until the color of the liquid changed from yellowish brown to deep blue. Water (20 ml) was added and extracted with ethyl acetate (20 ml x 5). Saturated salt solution (10ml)
After washing with water, it was dried with anhydrous magnesium sulfate. Inorganic substances were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to TLC (
Separate and purify with silica gel, dichloromethane: methanol = 91), 7-, (2-octylidene-5-oxo-3)
-cyclopentenyl)-5-hebutene M121■ (46
, 5%).

IR (neat); 2940, 1710° 1555 a
m-'.

NMR (CDCIs) iδ 0.83 (3H.

t, J-6Hz), 1.10-3.10 (21H, m)
, 5.2 5.6 (2H, m).

5.76 (IH, t, J=7Hz), 6.12-6.
34 (IH, m), 7.72 and 8.09 (total LH, each d, J = 5H2).

MS m/z; 318 (M''', 7%>, 1
92 (57%), 108 (100%).

Example 18 As a starting material, ? -(syn, 2-octylidene-5-hydroxy-3-cyclopentenyl)-5-heptenoic acid 436w (1,36mmo I) was carried out in the same manner as in Example 17, and 7-(syn, 2-
octylidene-5-oxo-3-cyclopentenyl)-
9195 ml of 5-heptene (45.1%) was obtained.

IR (nsat); 2950, 1730 (shoulder).

1710cm-'.

NMR (CDCIs); δ 0.88 (3H.

t, J-6Hz), 1.03-3.06 (21H, m)
, 5.27 (3H, m).

5.78 (IH, t, J-8Hz), 6.
12(1)(,d, J-6Hz), 7.65
(1) 1°d, J-6Hz).

MS m/z; 3 1 B (M”,
6%), 192 (69%), 10B (
56%), 59 (50%), 43 (100%)
.

Example 19 As a starting material, 7-(anti,2-octylidene-
The same procedure as in Example 17 was carried out except that 379q (1,18 mmo 1) of 5-hydroxy-3-cyclopentenyl)-5-heptenoic acid was used, and 7-(anti, 2-
octylidene-5-oxo-3-cyclopentenyl)-
199 μm (52.8%) of 5-heptenoic acid were obtained.

IR (neat); 2950.1710°1545c*
-'.

NMR (CDCI; 60.88 (3H.

t, J-6Hz), 1.02-2.92 (21H, m)
, 5.27 (3H, m).

5.70 (LH, t, J-8Hz), 6.18 (IH
, d, J-6Hz), 8.01 (IH.

d, J■GHz).

MS m/x; 31 B (M”, 6%)
, 192 (69%), 108 (56%), 59 (5
0%), 43 (100%).

Example 20 7-(anti,2-octylidene-5-oxo-3-
cyclopentenyl)-5-heptenoic acid 49g (0,1
54 mmol 1) was dissolved in ether (5 ml) and an ether solution of diazomethane was added until no nitrogen came out.

After that, stir at room temperature for 30 minutes, and remove the solvent under reduced pressure. −
(anti,2-octylidene-5-oxo-3-cyclopentenyl)-S-heptenoic acid methyl ester 32■
(63%).

IR(neat);2950,1?42°1710.1
545c+m-'.

NMR (CDC1,); δ 0.111111 (3
)T.

t, J-6Hz), 1.07-2.95 (21H, m)
, 3.31 (3H, m).

5.31 (3H, m), 5.71 (IH,
t.

J-6Hz), 6.17 (LH, dd, J
-2Hz and 6Hz), 8.03 (IH, d.

J turbidity 6Hz).

Example 21 As a starting material, ? -(syn, 2-(3-phenyl)propylidene-5-hydroxy-3-cyclopentenyl]-5-heptenoic acid 237μ (0,727mmol
) except that t'< m was carried out in the same manner as Example 17,
? -(syn, 2- (3-phenyl)propylidene-
5-oxo-3-cyclopentenyl)-5-heptenoic acid was obtained. This was dissolved in ether (10 ml) and an ethereal solution of diazomethane (3 ml) was added. 30 at room temperature
After stirring for a minute, the ether was distilled off under reduced pressure. The residue was separated and purified by column chromatography (silica gel, ether:hexane-1:1) to obtain 7-(syn, 2-(3-
Methyl phenyl)propylidene-5-oxo-3-cyclopentenyl]-5-hebutenoate 73■ (profit yield 30%
) was obtained.

IR(nsat);2950,174'0°1705.
1550.750.700cm-'.

NMR (CDCls); δ 1.40-2.9
0 (13H, m), 3.61 (3H, s).

5.23 (2H, m), 5.80 (IH, t.

J=8Hz), 6.10 (LH, d, J-6Hz),
7.22 (5H, m), 7.62 (IH, d, J=6
Hz).

Test Example Mouse lymphocytic leukemia cultured cells (ρ388) were
% tallow baby serum in RPMI-1640 culture medium, 4X1
The compound of the present invention, 0.3 to 12μ
The cells were cultured at 37° C. for 48 hours in the presence of g/ml. The number of floating cells was counted using a Coulter counter, and a dose-response curve was created based on the growth inhibition rate relative to an example without the addition of the compound (control), and rCsa was determined.

The results are shown in the table.

As a solvent for the compound: 0.02-0.5% acetone coexisted, but the growth inhibition rate in the presence of 0.5% acetone was 8.
% or less.

Claims (1)

[Claims] (1) 7-(2-alkylidene-3-cyclobentenyl)-5-heptenoic acid derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R and R^1
is a hydrogen atom or a lower alkyl group, and R^2 is an alkyl group, an alkenyl group, a cycloalkyl group, or an aryl group. X is a group represented by >C=O or >C(H)OH. Further, R^1 and R^2 can be combined to form a polymethylene group. However, if X is >C=O, R
When ^1 is a hydrogen atom, R^2 does not become a 1-heptenyl group. ).