JPS611636A - 4-substituted-5-alkylidene-2-cyclopentenone and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is 1-10C alkyl, ester, carboxyl, or its salt; R<2> is 1-10C alkyl or alkenyl). EXAMPLE:4-(2-Octenyl)-5-(6-carbonyloxyhexylidene)-cyclopentenone methyl ester. USE:Pharmaceuticals. It has excellent carcinostatic and antiviral activities, and is useful as a carcinostatic agent or a synthetic intermediate of known natural clavulone and claviridenone having strong carcinostatic activity. PREPARATION:The compound of formula I wherein R<1> and R<11> can be prepared by (1) reducing and eliminating the PhSO group of the sulfoxide compound of formula II (R<11> is 1-10C alkyl or ester; R<3> is OH-protecting group) to obtain the cyclopenetanone compound of formula III, (2) methanesulfonylating the product to the mesylate compound of formula IV, (3) treating with a base to effect the first elimination reaction, and (4) treating the resultant compound of formula Vwith an acid to effect the second elimination reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to 4-substituted-5-alkylidene-2-cyclopentenones and a method for producing the same. More specifically, it is a novel 4-f derivative with excellent anticancer and antiviral effects.
The present invention relates to 5-alkylidene-2-cyclopentenones and their production method.

<Prior art> Among prostaglandins, prostaglandins are known to have a double bond in the cyclopentane ring in their skeleton structure, and it has been reported that these exhibit strong anticancer activity. ing. For example, PGD and its dehydrated form PGJ.

leukemia cells (
L1210) is known to strongly inhibit proliferation. (See Fukushima et al., JP 58-124718; Wakatsuka et al. JP 59-5155; 59-1463).

Also, PGA, Δ'-PGA, etc. (Fukushima et al., Mtern
rtionMeetiry on Icogamoid
s and Cancer, Ile de Bendor
, France, Saptemher 23 to 25.1
983) and PGA, Class (Fukushima, Pathobiology IJ 2 (8)
1,811 (1983); Cancer and Chemotherapy 10 (91,
1930 (1983)) similar activity has been observed, and these are known to exhibit strong anticancer activity even in vivo. Recently, among these analogs, 4-substituted-5-alkylidene-2-cyclopentenones, marine prostaglandins such as clapron,
Taraviridenones H, Kikuchi et al.

Tetrahedron hett,,23.5]71
(1982), 24, 1549 (1983); 24.4
433 (1983); M. Kobayashi et al.

Tetrakedron h@tt,, 23.5331
(1982)+Chem.

Pharm Bull, 31.1440 (-1983
) is known to exhibit similar activity (see Fukushima et al., 42nd Japanese Society of Medical Therapy Abstracts 856 (1983)).

Furthermore, similar compounds with PGJ have similar activity (Wakatsuka et al.
4? 1972-216155.59-5154) became known.

<Principle of the invention> The present inventors paid attention to this fact and developed the natural product Clublon,
The present invention was achieved through intensive research to obtain novel 4-substituted-5-alkylidene-2-cyclopentenones as analogues of taraviridenone. The object of the present invention is to replace the conventional 4-substituted
The object of the present invention is to provide 4-substituted-5-alkylidene-2-cyclopentenone a having a novel structure different from that of 5-alkylidene-2-cyclopentenones, and a method for producing the same.

<Structure and effects of the invention> The 4-substituted-5-alkylidene-2-cyclopentenones of the present invention have the following formula [1] % formula % In the above formula (1), R1 is an alkyl group having 1 to 10 carbon atoms, Represents an ester group, a carboxyl group, or a salt thereof. Examples of alkyl groups include methyl, ethyl,
n-propyl.

Linear or branched ones such as n-hexyl and n-decyl can be mentioned. Ester groups include methoxycarbonyl, ethoxycarbonyl, and n-propyloxycarbonyl.

Examples include n-hexyloxycarbonyl, phenoxycarbonyl, acetoxymethyl, propionyloxymethyl, and penpyloxymethyl. Further, as the carboxylic acid salt, a salt of 1 equivalent of cation can be mentioned. -Equivalent cations include, for example, NH,'',
Tetramethylammonium, monomethylammonium,
Dimethylammonium, trimethylammonium, benzylammonium, phenethyl ammonium, morpholinium cation, monoethanol ammonium.

Ammonium cations such as piperidinium cations, +N! Alkali metal cations such as 1", K";
1/2Ca”, 1/2Mg”, 1/2Zn”,
Examples include divalent or trivalent metal cations such as 1/3 Aj''. V represents a substituted or unsubstituted furkyl group having 1 to 1 o carbon atoms.

Examples of the unsubstituted furkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, 1so-propyl, n-butyl, 5ee-butyl* tart-
Butyl, n-pentyl, n-hexyl, n-heptyl,
Linear or branched ones such as n-octyl, n-nonyl and n-decyl can be mentioned.

Examples of noble substituents for unsubstituted alkyl groups having 1 to 10 carbon atoms include cycloalkyl groups such as ebacycloprobyl, cyclobutyl, cyclopentyl, and cyclohexyl, and alkenyl groups such as pulvenyl, imbutenyl, and butenyl.

Prenyl, etc. can be mentioned. Also -C(10)
R' (Here, R4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an equivalent cation.) hydroxyl group, phenyl group, flukoxy group having 1 to 6 carbon atoms, acyloquine group having 1 to 7 carbon atoms 2 etc. can be mentioned.

Examples of R4 in -C(10)R' include hydrogen atoms, alkyl groups having 1 to 10 carbon atoms, and -equivalent cations, and examples of the alkyl groups having 1 to 10 carbon atoms include the same alkyl groups as mentioned above. Groups, -equivalent cations can be mentioned.

Examples of the flukoxy group having 1 to 6 carbon atoms include methoxy, ethquin, and n-propoxy.

1so-propoxy, n-butoxy, chloromethoxy,
Preferred examples include dichloromethoxy, trifluoromethoxy, tetrahydropyranyloxy, α-ethyloxyethoxy, and metquinmethoxy.

Examples of the 7-syloxy group having 1 to 7 carbon atoms include acetoxy, propionyloxy, n-butyryloxy,
1so-butyryloxy.

n-valeryloxy, 1so-valeryloxy.

1so-valeryloxo, caproyloxy.

Enantyloxy or benzoyloxy may be mentioned.

Specific examples of such 4-substituted-5-alkylidene-2-cyclopentenones include 1) 4-(2-octenyl)-5-(6-carbonyloxyhexylidene)-2
-cyclopanthenone 2) 4-(2-hexenyl)-5-(6-carbonyloxyhexylitine)-2-kppe/thenone 3) to 4-(2-butenyl)-5-(6-carbonyloxy xylidene)-2-cyclopentenone 4) 4-(8-methyl-2-nonenyl)-5-(6-carbonyloxyhexylidene)-2-cyclopentenone 5) 4-(7-methyl-2-octenyl) )-5-(6-
carbonyloxyhexylidene)-2-cyclopentenone 6) 4-(5-methyl-2-octenyl)-5-(6-
carbonyloxyhexylidene)-2-cyclopentenone 7) 4-(5-cyclohexyl-2-pentenyl)-5
-(6-Carbonyloxyhexylidene)-2-cyclopentenone8) 4-(4-Cyclopentyl-2-butenyl)-5-
(6-Carbonyloxyhexylidene)-2-cyclopentenone9) 4-(4-phenyl-2-butenyl)-5-(6-
carbonyloxyhexylitine)-2-cyclopentenone to)4-(6-methyl-2,5-1-butadienyl)
-5-(6-carbonyloxyhexylidene)-2-cyclopentenone 11) 4-(6,1m--dimethyl-2,9-undecajenyl)-5-(6-carbonyloxyhexylidene)-2-cyclo Pentenone 12) 4-(5-ethoxy-2-pentenyl)-5-(6-carbonyloxyhexylidene)-2-cyclopentenone 13) 4-(7-tetrahydrobilanyloxy-2-heftenyl)-5 -to7'f! I f y -2-cyclopentenone 1.4) 4-(2-octenyl)-5-heptylide/-
2-Cyclopentenone 15) 4-(7-tetrahydrobyranyloxy-2-heptenyl)-5-(6-carbonyloxyhexylidene)-2-cyclopentenone 16) 4-(6-carponyloxy-2-hexenyl) )
-5-heptylidene-2-cyclopentenone 17) 4-(7-7setoxy-2-hebutenyl)-5-
Hebutylidene-2-cyclopentenone 18) 4-(7-hydroxy-2-hebutenyl)-,5
-hair'tylidene-2-cyclopentenone 19) 4-(7-penzoyloxy-2-hebutenyl)
-5-hebuty IIden-2-cyclopentenone 20) 4-(6-carbonyloxy-2-hexenyl)
-5-octylidene-2-cyclopentenone 21) 4-(6-carponyloxy-2-hexenyl)
-5-(7-methyloctylidene)-2-cyclopentenone 24) Compounds 1) to 12) 15) 16) 20)
21) Methyl ester of 25) to compound 1) 12) 15) 16) 20)
21) Ethylnistyl 26) Compound]) ~ 12) 15) 16) 20)
Examples include the sodium salt of 21).

The 4-substituted-5-alkylidene-2-cyclopentenones of the present invention are obtained by reductively eliminating the phsO group from the sulfoxides represented by the following formula (II) as a starting material, and producing the 4-substituted-5-alkylidene-2-cyclopentenones using the following formula (rill). A cyclopentanone represented by OH (in the formula: ゛・R′・纺」&house is the same as the above definition) is subjected to two types of elimination reactions to form the following formula [v] or [■].

R”0 (In the formula, R11, R1, H@ are the same as the above definitions) (In the formula, R
11, 11 are the same as the above definition), respectively 3
, 4-di-substituted-5-fulkyritenecyclopentanones or 4-substituted-5-(1-human-p-gycy4alkyl)22
-Produced via cyclopentenones.

In the above formula [ll], R11 represents a furkyl group or an ester group having 1 to 10 carbon atoms, and the same groups as those listed for the above formula (1) are exemplified, and R1 is also the same.

In the above formula 1'll)[I[)(V), R3 represents a hydroxyl group-protecting group. As a protecting group for hydroxyl group, it is! l(
C,%C? ) A hydrocarbon-silyl group or a group that forms an acecool bond with the oxygen atom of a hydroxyl group.

Examples of the tri(c+-c7) hydrated silyl group include trimethylsilyl and triethylsilyl.

Tri(CI-C,) such as t-butyldimethylsilyl group
Preferable examples include diphenyl(CI C4)furkylsilyl or tribenzylsilyl groups such as furkylsilyl, t-butyldi7-enylsilyl, and the like.

An example of a group that forms an acetal bond with the oxygen atom of a hydroxyl group is methoxymethyl.

l-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-propyl, (2-methoxyethoxy)
Methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxo-bicyclo['3. l, o)
Mention may be made of the hex-4-yl group.

The sulfoxides of starting material rll] are easily produced by the following synthetic route.

hsO, i.e., the carbanion (K) generated from phenyl sulfoxide to protected 4-hydroxycyclobentenone
, in Pivnitsky et al. J.

of General Chemistry (USSR
) 52.2651 (1982)),
Next, when aldehyde (OHC\/ν'!'Rl l > is added, sulfoxides [11) are produced all at once.

The above carbanion is γ with respect to the phenylsulfinyl group
It is already known that conjugate addition occurs at the carbon position (J,
Nakami et al + Bull, Chem, Soc n
, 55.3043p-(1982)) 1 The present inventors captured the elute produced in the reaction with an aldehyde to obtain the desired starting material at once.

Examples of the reducing agent used when subjecting the phenylsulfinyl group to the reductive elimination reaction from the sulfoxides of the above formula [■] include Raney nickel and aluminum amalgam, with Raney nickel being particularly preferred. The amount of reducing agent used is between 2 and 20% for the sulfoxides.
equivalents, particularly preferably 5 to 10 equivalents are used. The reaction solvent was tetrahydrofuran.

Ethers such as dioxane, dimethoxyethane and diethyl ether; alcohols such as methanol and ethanol; methyl sulfoxide, dimenalformamide, hexamethylphosphoric triamide, water and the like are used in any combination thereof.

The reaction temperature is preferably 0 to 80°C, particularly preferably 10
~50°C.

The reaction time depends on the raw material compound and reducing agent used.

Although it varies depending on the reaction solvent, the reaction time is usually 10 minutes to 10 days, preferably 20 minutes to 5 days.

After the reaction, the target compound can be isolated by, for example, silica gel column chromatography, silica gel thin layer p-mography.

It can be separated by means of florisil column chromatography, high performance liquid chromatography, etc., and can be obtained as a cyclopentanone represented by the above formula rI[I].

Next, the cyclopentanone of the above formula [■] is subjected to an elimination reaction. In the elimination reaction, the above formula [■] is methanesulfonylated to generate a mesylate compound represented by the following formula [IV] (wherein R11, R1, and R3 are the same as defined above) in the system, and this is treated with a base. 3,4-di-redemption of the above formula CV)
5-fulkylide/cyclopentanone aK is derived. The amount of methanesulfonyl chloride used is 0.5 to 10 equivalents, particularly preferably 2 to 10 equivalents, based on the above formula [■] which is the raw material.
Use 3 equivalents. As the basic compound used here, amines are preferable, and examples of such amines include 4,4-dimethyl-7minobiridine, pyridine triethylamine, diisoprobylcyclohexylamine,
Examples include inpropylamine, dimethylamine, diisopropylethylamine, and 4,4-dimethylaminopyridine and pyridine are particularly preferred.

This basic compound is used in an amount of 1 to 10 equivalents, preferably 4 to 6 equivalents.

The stock temperature is 0 to 50°C, preferably 10 to 40°C, and the end point of the reaction can be confirmed by tracking the disappearance of the raw material compound using thin-layer p-mography or the like. The reaction time is usually 0.5 to 10 hours. A solvent may be used to make the reaction proceed smoothly. Examples of such solvents include halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; ethers such as ether and tetrahydrofuran; benzene. Hydrocarbons such as , toluz 7 , hairtan, hexane, Schiff-hexane, etc. are used, and dichloromethane is preferably used.The reaction product is obtained by converting the reaction mixture by conventional means,
For example, extraction and washing.

It can be purified by drying, chromatography, etc.

In this way, the above formula [■] is obtained, which is subjected to the second elimination reaction by treatment with an acid.

This reaction is achieved by directly performing the removal of the protecting group for the hydroxyl group at the 3-position and the dehydration reaction in the above formula [■]. When the protecting group is a group that forms a 7-cetal bond with the acid atom of the hydroxyl group, the protecting group can be removed using a catalyst such as acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin, For example, the reaction process is suitably carried out by using, for example, acetic acid, tetrahydrocufuran, ethyl ether, dioxane, acetone, 7-cetonitrile, etc. as the reaction wax. The reaction is usually carried out at a temperature range of -78°C to +100°C for about 10 minutes to 3 days. In addition, when the protecting group is a (C, -C,) hydrocarbon-silyl group,
For example, it is carried out in the presence of acetic acid in a reaction solvent as described above at a similar temperature and for a similar period of time.

In this way, the desired 4-substituted-5-alkylidene-2-cyclobe2fufu compound represented by the following formula (I-8>゛0 (in the formula, R11 and 11 are the same as defined above)) is obtained.

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

When the target compound has a carboxyl group in its molecule, it can then be further subjected to a salt-forming reaction if necessary to obtain the corresponding carboxylate. The salt-forming reaction is known per se, and involves approximately the same amount of sodium hydroxide as the carboxylic acid.

Basic compounds such as hydroxide, sodium carbonate,
Alternatively, it can be carried out by neutralizing with ammonia, trimethylamine, monoethanolamine, morpholine, etc. in a conventional manner.

Thus, the 4-substituted-5-alkylidene- of the above formula [I]
2-cyclopentenones are produced.

The target compound [1,, a) can also be produced by another method. That is, the above formula [■] is first subjected to the above-mentioned second elimination reaction to obtain tolu-4-substituted-5-(1
-hydroxyalkyl)-2-cyclopentenone ζ and subjected it to the first parent reaction described above to obtain the desired product (1
-a) is also possible. In this production method, in addition to the method of eliminating using an acid in the first second elimination reaction, there is also a method of using a base. The bases used include 1,5-di7zabicyclo(4,3
, o ) 1ne-5 (DBN) and other strong bases. The reaction is carried out with a strong base of 0.5 to 2
:0 Drawing quantity Preferably using 0.8 to 1.2 equivalents - 1O
This is achieved by treatment at a temperature of .degree. C. to 40.degree. C., preferably -5.degree. C. to +5.degree. C., and the intermediate [■] can be easily obtained. This is subjected to the first elimination reaction and the target rlm
). Instead of this division-elimination reaction, it is also possible to directly dehydrate the busy intermediate [■] to obtain the target product 0-a)K. That is, N,N'-dicyclohexylcarbodiimide (DCC) is preferably used as a dehydrating agent, and is used in an amount of 1 to 6 equivalents, preferably 1 to 3 equivalents, based on the raw material, and dried in an inert manner at 10° to 40°C. This is done by processing in a solvent. At this time, cuprous chloride or cupric bromide is used as a reaction aid in an amount of 1 to 6 equivalents, preferably 1 equivalent to the raw material.
When ~3 equivalents are used, the reaction proceeds smoothly.

The 4-substituted-5-alkylidene-2-cyclopenteno/s of the present invention exhibits a strong anticancer effect against specific K L1210 leukemia cells at extremely low concentrations (IC, 0.4-1 μI/ml). It is extremely useful as an anticancer agent.

It is also a useful compound that is expected to have antiviral activity.

Also provided by the present invention is 4-substituted-5-alkylidene-
The method for producing 2-cyclopentenone not only provides a new compound useful as a medicine, but is also useful as a synthetic intermediate for the natural products clavulone and claviridenone, which are already known to have strong anticancer activity. be.

Example 1 Compound 2 110 Q (0.18 mmoA!) was dissolved in 2 ml of ethanol, and Raney nickel 40
111 g (W-1 type) was added and heated to reflux. T the reaction
After confirming completion by tracking with LC, the reaction solution was evaporated.

The P solution and the washing solution were combined and treated in a conventional manner to obtain a crude product, which was subjected to silica gel column chromatography (A
Purify with COEt: hexane=1=8) to obtain target product 4
5offIg (purchased amount: 57%) was obtained.

TLC (ACOEt:hexane=1:4);
Rf=0.65IR(neat,ca=);3500
．． 1730'Hnrnr (CDCA! s, δ, p
p); o, 88-0.90 (9H+3H, ρ, t.

J=7H1), 1.0 to 2.80 (24H), 3.
66 (3H, ρ), 3.81 (IH, m)', 4.17
(IH, m), 5.45 (2H, m).

mass (mle); 464 (M" 18), 407 (
M”-57-18).

In addition, this one is 126.66 and 134.
Since absorption was observed in 279III, 126.28, and 132.92 solutions, it was determined that 14Δ was a mixture of 8 bodies and 2 bodies.

Example 2 222 mg (0.46 mmoJ) of compound 4 was dissolved in 10 rr+/: of ether, and 0.090 mA' (0.64 mmoJ) of triethylamine was added thereto, followed by 0.043 mA' (0.55 mmoJ) of methanesulfonyl chloride.
A solution was added dropwise at room temperature. After stirring the reaction solution for 35 minutes, water was added to stop the reaction, and the mixture was extracted three times with ether. The extract was treated in a conventional manner to obtain crude product 258rI@.

This product was dissolved in 120.5 mg of CHtC, and 4-dimethyl 7minobyridiy 169 m@(1,3
1 ml of 8 mmo/)/CH2clt was added and stirred for 6 hours. After the reaction, make the thread slightly acidic with tartaric acid and wash with water 2.
2 times, and CH, C12 extraction was performed twice. The extract was treated in a conventional manner to obtain a crude product, which was subjected to silica gel column chromatography (ACOEt:hexane=1:20).
The target product 7151■ (yield: 71) was obtained.

TLC (ACOEi: hexane-1:4);
Rf=0.70IR(neat, c++t-'); 17
30,1645゜'H-nmr (CDCj!m +δ
If); 0.8 to 0.9 (9H+3B, ρ, t)+1
．． 0(1-3,00(21H), 3.67(3H,ρ)
, 4.25 (IH, m).

5.43 (2H, m), 6.61 (IH, t, J-7
H,) -Mass(mle);407(M”-57)
This one is "Cnmr 126.73 and 133.011
Since absorption was observed at 1P, 126.17, and 132.45 pIIm, it was estimated that 14ΔK was a mixture of 8 and 2 bodies.

Example 3 Compound 7 0.1511 (0,325 mmoj!)
into 2 ml of acetic acid:THF:water=2':1:17
The mixture was stirred at 0°C for 7 hours. Acetic acid and THF were distilled off from the mixture under reduced pressure, and the residue was neutralized by adding an aqueous solution of NaHCO3,
Extracted with ethyl acetate. The extract was treated in a conventional manner to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate:hexane-1:1O) to obtain the desired product 80.0761 (yield: 70%).

TLC (ACOEt:hexane=1:4);
Rfo, 40IR (neat, tx-”); 17
35.17G0, 1655.

'H-nrrtr (CDC)8. δ+IP) ;0
．． 88 (3H+t #J=7HJ1.00~2.
70 (201), 3.45<11. m), 3.67 (3
H, ρ).

5.2-5.5 (2B), 6.31 (IH, dd'),
6.55 (IH, t, J=7Ht), 7, 53
(IH9m)Mass (m/e): 33
2 (M”) This one is 125.11 and 134.03 four 124 for the double bond of △14 from IsC-nmr.
．． 64 and 132.86-, it was estimated that they were a mixture of eight and two bodies, respectively. In addition, there is also a small amount (10'1
．． ) - released, but this one is IR,'Hnmr,"C
According to nmr, it was an isomer with a double bond of △7, and it was estimated that there were 2 isomers compared to the 8 isomers in the main product.

Mixture (9+10) 771+1r (crude) (CaO
, 15 mmoj) of CH, C1* solution to 1 mg of 4-dimethylaminepyridine 55 ■ (0,45 mmoAl) of C
1 ml of H2CJt solution and 1 ml of solution were added and reacted for 6 hours. Tartaric acid was added to the reaction solution to make it a weak acid, water was added, and CB
, Cj, was extracted using □, 11. The extract is processed in a conventional manner to obtain the target product (
11+12) 36■ (yield 57%) was obtained.

TLC (ACOEt:hexane=1:5);R
f=0.65IR(neat, am-1); 1730,
16l64-5n (CDCj, , δ+111m);
0.05and0.06(each S+6H)+0.
84 and 0.85 (each S, 9H), 1.25
(br)andl,'62.7(m)(22H),2.
90 (m) and 3.36 (m) (IB).

4.15 (m, IH), 5.41 (m, 2B), 6.7
2 (dt, J=2in'd8Hz, IH) Double bond isomer mixture (11+12) 22■.

(0,052 mmoj) in acetic acid:THF:water=2:1
:1 was dissolved in 1.5 ml+ and heated and stirred at 70°C for 7 hours. The solvent was distilled off from the reaction solution under reduced pressure, and NaHC was added to the residue.
The mixture was neutralized by adding an Os aqueous solution and extracted with ethyl acetate. The extract was treated in a conventional manner to obtain a crude product, which was subjected to silica gel clostography (ACOEt: hexity=1
:20) to obtain the target product (13+14) 9■ (yield 60%).

-v--- TLC (ACOEt: Hexa7=1:5)
: Rf O, 4! ho, 50IR (neat, cIl
-'); 1700s1650゜nmr (CDC et al., δ
, P1m); 0.88 (br t, 6H), 1.27 (
br)andl, 8-2.5(m)(30H), 3.5
(m), 3.96 (d, J=7Hz), and3.5(
m) (6B), 5.15 (dd, J=7and15)1
g).

5.40 (m) and 5.65 (dt, J = 6 and 1
5Hz) (2H), 6.30(dd, J=2and
6 Hz, IB), 7, 34 (m, IH) Method 1 Compound 4 (195 mg, 0.4 mmol) in acetic acid.

Add 2 mg of a mixture of THF and water (2:1:1) and heat to 65°C. At about 7 o'clock, the bales were opened, acetic acid and THF were removed, extracted with ethyl acetate, and the extract was diluted with deionized water.

Wash with water. The oil obtained by the conventional method was subjected to silica gel column chromatography (ethyl acetate/hexane-1/
Purification in step 4) yielded 77 mg of 15. (54 壬) Method 2 Compound 4 (51Q, 0.1 mmol) was dissolved in 10 mJ of ethyl ether and cooled to 0°C. DBjJ (0,024 ml) was added dropwise to this solution and stirred for 1 hour. This reaction solution is neutralized with an aqueous tartaric acid solution and washed twice with water.

When purified in the same manner as method 1, 15 is 30”1g (81
Section) Obtained.

IR(neat, m, '), 3500.1735,
1700.1690' Hnmr (CDCI, δJ
XD): 0.81 (t, J=16Hz, 3H),
1.0-2.8 (23H), 3.58 (s, 3H), 3
．． 80 (m, IH), 5.37 (m.

2H), 6.07 (d, J=6Hz, IH)
, 7.58(dd, J=2a'nd6Hz,
IH) Example 7 Compound 15 67 IIlg (0.19 mmoJ) was dissolved in 5 ml of dry benzene. This is Hanawa number - @4
2rng (0,38+nmol) was added. While stirring this mixture, add DCC200111K (0,9
6 mmol) was dissolved in 0.5 m/d of dry benzene and added. The reaction mixture was stirred at 30°C for 6 hours and then filtered.
10 ml of ethyl acetate was added to solution F, and the mixture was washed twice with water. The oily crude product obtained by a conventional method was purified using solica gel chromatography using ethyl acetate; hexane = ], : 1O to obtain 857ny, (89φ).

It was judged to be a mixture of "△" E/Z21/] by CNMR.

Example 8 CsaHeoOeSS 1(649,10) C
3o) 1! aOsSi(524,94) compound 16 1
85111 g (0,285 mmoA!) was dissolved in 1 ml of ethanol, about 100 μm of Raney nickel (W-1) was added thereto, and the ethanol was refluxed. After about 1 hour to confirm that the raw material is gone by TLC, silica gel (
About 2I of Wakogel C-200) was filtered through a column packed with a diameter of 1.5 mm using 10 mJ of ethyl acetate. The p solution was concentrated and purified again using silica gel column chromatography using ethyl acetate:hexane=8 to obtain the target product 17 (receivable amount: 40).

TLC ethyl acetate:hexane-1:3, Rto,
46IR (neat, a++'): 3500.17
40') lnmy (CDC et al., δ, P); (1,0
7,0,09 (respectively s, 6) 1).

0.89 (4,9H + 3H), 1.1-2.7 (28H
), 3.2-4.0 (7H).

4, j3 (m, IB), 4.55 (m, IH), 5.4
4(m, 2H) Example 9 +SiOC5oHsa05Sl (524,94)
C24H4゜04 (392,64) Compound 1760■
(0,114 mmol) was dissolved in 20 ml of ethyl ether. This was cooled to 0℃ and DBUo, 026m/(
About 0.17 mmoi) was added and stirred for 1 hour.

It was then neutralized with an aqueous tartaric acid solution and washed twice with water. The aqueous layer was extracted using ethyl acetate]Oml. The organic layers were combined, dried, concentrated, and then subjected to silica gel chromatography.
Purification was performed using ethyl acetate:hexane=1:4. 18
The yield was 39 mg (87 pieces).

TLC ethyl acetate:hexane=2/3, Rf
O,50IR(neat,csa');3500,
1700.1590' Hnm7 (CDCj j+δ
19); 0.81 (brt, J=6H1,3B), 1.
0-2.2 (24H), 2.62 (m, IH),
3.2-4.0 (7H).

4.49 (m, IH), 5.48 (m, 2H), 6.0
8 (dd, J=1 and 6Hz, IH), 7.58 (d
d, J=2and6Hz, IH) Example 10 Ce<H4゜04 (392-64) Cu
Hs*Os (374,62) compound 18 35 q
(0,089 mmoj) was dissolved in 0.3 ml of dry benzene, and 20 μm of cuprous chloride (0,178 mmoA) was dissolved in 0.3 ml of dry benzene.
I) was added and stirred. DCC93■ in this mixture
(0,446 mmo)) in 0,5 mJ
It was dissolved in and dripped. The reaction mixture was kept at 30°C for 1
After stirring for 0 hours, it was filtered, and the solution F was washed twice with water. The oily crude product obtained by a conventional method was purified by Shikukagel Kupuratography using ethyl acetate:hexane = 1:2.
8■ (85 qb) was obtained.

TLC ethyl acetate:hexane=l: 2, Rto
, 5xIR (neat+” '); 1705s165
0嘗Hnmr (CDCjl * J, 1 piece 1!■
-1) ;o -89(br t * J=6Hz,
3B) +1.0-2.7 (23H), 3.2-4.
0. (5H), 4.55 (m, IH).

5.42 (rrr, 2H) -6,32(d, J
=s Hz, 214), 6-57 (tr J
=8Hz, 1B), 7.51(dd, J=2and6H
z, IB) R11WC+4H? 0O5 (236,40)
MwCssHs+0sSSi(607,01)l
a 2 diisopropylamine 0.103 mj (0,735 mmoj) THF
Add n-butyl lithium solution (0,434 mj = 0.68 mmoj) at 30 to -50°C, cool it to -76°C, and add compound 1a 160 (0,68
Add 0.5 mj of THF solution of mmoA dropwise. 1
After stirring for 5 minutes, add 120 m of 4-”t-buty!resilyloxycyclobent-2-en-1-one.
g (0,565 mmoj) of THF solution 0,5 m
1 was quickly added. 89 μm of 6-medoxycarponylhexanal (0,565 mmoj) was stirred for 10 minutes.
) was added to the reaction solution. After stirring for 30 minutes, 2 ml of a saturated aqueous solution of ammonium chloride was added, the temperature of the reaction solution was returned to room temperature, and the system was neutralized with an aqueous tartaric acid solution. The reaction solution was extracted with ether, washed with water (3 times), and the extract was treated in a conventional manner to obtain a crude product. This product was purified using silica gel chromatography (ACOEt:hexane=1:a) to obtain 22 o2 vg of target product 2 (total amount: 59).

TLC (ACOEt:hexane=1:1)
; Rf = 0.35IR (neat, CR-'):
3450, 1735'Hnmr (CDCJa+δ+pp
);0.9(c+H±3H, I+t+J=7H
t-) 1.0-2.9 (241), 3.65 (3B,
ρ), 3.72 (IH, m).

4.14 (IH, m), 6.52 (1B, t, J=7H
z), 7.50 (5B)lsCnmr(CDCjl l
a, pP); 145.49 (C-13), 132.39
(C-14), 70.80 (C-11), 69.63 (
C-7), 57.65 (C-8), 48.14 (C-1
0), 47.85 (C-12>.

Diisopropylamine 0.174 mj (1,24 mmo
Add n-butyllithium solution (0,79m/61,24m+noj) to the THFHF solution of j) at 5°C,
This was cooled to -76°C and compound 1b 366 Q
(1,135 mmoj) of THFHF solution was added.

After stirring for 15 minutes, 219 μ of 4-t-butyldimethylsilyloxysilobent-2-en-1-one (3
,032 mmol) in THF was quickly added, and after stirring for 10 minutes, 0.156 mg (1,135 mmol) of n-heptanal was added dropwise. After stirring for 20 minutes, 3 mj of a saturated aqueous heptammonium chloride solution was added, the temperature of the reaction solution was returned to room temperature, neutralized with an aqueous tartaric acid solution, and extracted with ethyl myacetate.
Washed twice with water. The extract was treated in a conventional manner to obtain m/4 product. This product was subjected to silica gel chromatography (AC
Purify with OEt:hexane-1:3) to obtain the target product at 1650
1■ (receipt of $75) was obtained.

Claims (14)

[Claims] (1) The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...... [I] [In the formula, R_1 represents an alkyl group, ester group, or carboxyl group having 1 to 10 carbon atoms, or a salt thereof, R_2 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, Represents an alkenyl group. ] 4-substituted-5-alkylidene-2-cyclopentenones represented by these. (2) 4-substituted-5-alkylidene-2-cyclopentenones according to claim 1, wherein R_1 is a methyl group or a methoxycarbonyl group. (3) Claim 1, in which R_2 is a pentyl group
4-substituted-5-alkylidene-2-cyclopentenones according to item 1 or 2. (4) 4-substituted-5-alkylidene-2-cyclopentenones according to claim 1 or 2, wherein R_2 is an ω-tetrahydrobyranyloxybutyl group. (5) The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
・・・・・・・・・[II] [In the formula, R^1^1 is the number of carbon atoms 1
~10 alkyl group or ester group, R^
2 is the same as the above definition, and R^3 represents a hydroxyl protecting group. ] The sulfoxides represented by are subjected to a reduction-elimination reaction. The following formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
・・・・・・・・・・・・ [III] (R^1^1 in the formula,
R^2 and R^3 are the same as the above definitions), and this is methanesulfonylated to form the following formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・・・・
・・・・・・・・・・・・[IV] (In the formula, R^1^1, R
＾2, R＾3 are the same as the above definitions), and this is subjected to the first elimination reaction to form the following formula [V] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...・・・・・・
・・・・・・・・・・・・[V] (R^1^1, R in the formula
^2, R^3 is the same as the above definition) 3,4-
The following formula [I]▲ is characterized in that it is a di-substituted-5-alkylidenecyclopentanone, which is subjected to a second elimination reaction and, if necessary, hydrolysis and a salt-forming reaction. There are chemical formulas, tables, etc.▼・・・・・・・・・・・・
A method for producing 4-substituted-5-alkylidene-2-cyclopentenones represented by [I] (in the formula, R^1 and R^2 are the same as defined above). (6) The above formula [III] is subjected to the second elimination reaction to form the following formula [VI] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
・・・・・・・・・・・・[VII] (R^1^1 in the formula,
R^2 is the same as the above definition) 4,5-disubstituted cyclopentenones are methanesulfonylated to form the following formula [VII] ▲ Numerical formulas, chemical formulas, tables, etc. ▼・・・・・・・・・・・・
......[VII] (in the formula, R^1^1 and R^2 are the same as the above definitions), and then the first
4-substituted-5-alkylidene-2-cyclopentenones according to claim 5, which are subjected to an elimination reaction and, if necessary, to a hydrolysis and salt-forming reaction. Manufacturing method. (7) 4-substituted-5-alkylidene-2 according to claim 5, which is dehydrated with the above formula [VI].
-Production method of cyclopentenones. (8) Performing the reduction-elimination reaction using tenen nickel,
A method for producing 4-substituted-5-alkylidene-2-cyclopentenones according to claim 5. (9) A method for producing 4-substituted-5-alkylidene-2-cyclopentenones according to claim 5 or 6, wherein the first elimination reaction is carried out in the presence of a base. (10) The 4-substituted-5-alkylidene-2-cyclopene according to any one of claims 5, 6, and 8, wherein the second elimination reaction is carried out in the presence of an acid. How to make tenons. (11) The 4-substituted-5-alkylidene-2-cyclopene according to any one of claims 5, 6, and 8, wherein the second elimination reaction is carried out in the presence of a base. How to make tenons. (12) A method for producing 4-substituted-5-alkylidene-2-cyclopentenones according to claim 7, wherein the dehydration reaction is carried out in the presence of cuprous chloride and N,N'-dicyclohexylcarbodiimide. (13) Claims 5, 6, 8, 9, 10, and 11, wherein the base in the first elimination reaction is an amine, and the acid in the second elimination reaction is a lower carboxylic acid. any one of the terms
A method for producing 4-substituted-5-alkylidene-2-cyclopentenones as described in 2. (14) The 4-substituted-5-alkylidene-2-cyclo according to claim 11, wherein the base in the second elimination reaction is 1,5-diazabicyclo[5,4,0]undecene-5. Method for producing pentenones.