JPH062709B2 - Method for producing isocarbacycline intermediate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to a method for producing an isocarbacycline intermediate.
More specifically, it relates to a process for producing an intermediate for the production of isocarbacycline, an analog of prostacyclin, which is useful as a drug, by directly introducing an alkenyl chain into a β-ketoester as a raw material.

<Prior Art> Bicyclo [3,3,0] octanes are useful intermediates in the production of prostaglandins useful as pharmaceuticals. [EJ Corey et al., Journal of Olga] Nick Chemistry (J.Org.Che
m.), 40 , 2265 (1975)], and particularly useful as an intermediate in the production of carivacycline and isocarbacycline, which are useful as analogs of prostacyclin in these [Ikegami et al., Chemistry Letters (Chem. .Lett), 1
299 (1979); Ikegami et al., Journal of Chemical Society Chemical Communication (J. Chem.
Soc., Chem. Commun.,), 1602 (0984), JP-A-61-40293, 6
1-122292, Japanese Patent Application No. 61-223907; TW Heart, et al., Tetrhebron Letters
Lett), 26 , 2713 (1985); see JP-A-60-34931].

These intermediates are unique compounds in which the 2-position and the 6- and 7-positions of the bicyclo [3,3,0] octane ring are functionalized separately. In particular, the hydroxymethyl group at the 6-position is a substituent corresponding to the 12-position in the prostaglandin number, and the 15-position in the ω chain of prostaglandins such as prostacyclins that are chemically introduced from the hydroxymethyl group. Alternatively, there is a hydroxyl group at the 16-position (prostaglandin number), which is preferably sterically controlled. For this construction method, a hydroxymethyl group was added to EJ Corey (EJC
orey) et al. [The Journal of American
Chemical Society (J.Amer.Chem.Soc., 91 , 5675
(See (1969))], (i) Collins Oxidation, (ii) Horna-Wadsworth-Emmons Reaction Construction of Conjugated Ehon, (i)
The most general method is ii) reduction of C-15 ketone and (iv) separation of stereoisomers based on 15 alcohol. However, this method has many steps and is not industrially advantageous. Also, several methods for sterically controlling and reducing the C-15 ketone have been proposed [EJ Corey et al., The Journal of American Chemical Society (J. Amer. Che
m.Soc., 94 , 8616 (1972)); Yamamoto and The Journal of Organic Chemistry (J.Org.Chem., 44 ,
1363 (1979)); Noyori et al., The Journal of American Chemical Society (J. Amer. Chem. Soc.,
101 , 5843 (1979)]], but it cannot be said to be a method that satisfies all of three-dimensional control, economical efficiency, and easiness of operation.
A method that avoids the reduction of C-15 ketone has also been proposed [EJ Corey et al., The Journal of American Chemical Society (J. Amer. Chem. Soc., 93 ). , 1490 (1970); F. Johnson et al., Ibid, 104 , 2190 (1982); J. Wicha et al., Tetrahedron Letters (Te)
trahedron Letters) 26 , 5597 (1985)], but has the drawback that the number of steps is rather long. However, these bicyclo
A method for directly introducing an alkenyl compound (ω chain) having a stereo-controlled C-15 hydroxyl group into a β-ketoester of [3,3,0] octane intermediate to obtain an isocarbacycline intermediate As far as the present inventors know, the method of introducing an alkynyl compound by the method of Ikegami et al. [Ikegami et al., Proc.
Not known to anyone else.

<Purpose of the Invention> The inventors of the present invention have taken the above-mentioned technical background into consideration with bicyclo [3,3,0].
Regarding the efficient production of octanes, it is possible to efficiently use a readily available raw material compound, that is, in a short stage, and to convert prostaglandins into hydric chloride [3,3,0] octanes containing an alkenyl ω chain. An intensive study was conducted on a method for producing an isocarbacycline intermediate. As a result, β containing a bicyclo [3,3,0] octane skeleton that can be easily synthesized
-Using a ketone ester as a raw material, a compound having an alkenyl compound corresponding to the ω chain of prostaglandi introduced at the α-position of the ester group of the compound is obtained. The present inventors have found that an isocarbacycline intermediate, which is a bicyclo [3,3,0] octane having a chain introduced therein, can be easily produced, and arrived at the present invention.

DISCLOSURE OF THE INVENTION That is, the present invention provides the following formula [I]. [In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted benzyl group, or a trichloroethyl group. ] A β-ketoester represented by the following formula; [Wherein R ³ is a tri (C ₁ -C ₇ ) hydrocarbon silyl group,
Or represents a group forming an alketal bond with an oxygen atom of a hydroxyl group: R ⁴ represents a hydrogen atom or a methyl group; R ⁵ represents a linear or branched C ₃ -C ₈ alkyl group, and n represents 0 or 1. Represent. ] The alkenyllithium compound represented by the following formula is treated with mercuric chloride or zinc chloride, and then reacted with an active species treated with lead tetraacetate in the presence of a base, if necessary. [In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as above. ] [Alpha] -alkenylated [beta] -ketoesters represented by the following formula are obtained; [In the formula, the definitions of R ¹ , R ³ , R ⁴ and R ⁵ are the same as above. ] The ketones represented by the formula [Vb] are characterized in that the carbonyl group is reduced and subjected to a deprotection reaction. [In the formula, the definitions of R ⁴ and R ⁵ are the same as above. ] It is a process for producing an isocarbacycline intermediate, which is a bicyclo [3,3,0] octane represented by the formula, its optical isomers, or a mixture thereof at any ratio.

The above formula [I] used as a starting material in the present invention
The β-ketraester represented by can be obtained from methyl 2-oxocyclopentane acetate by the method of Ikegami et al. (See Japanese Patent Application No. 61-223907).
That is, 2-oxocyclopentane-1-acetic acid ester [S. Hauptmann et al., Journal.
Chemie, J. Prakt. Chem., 34 , (1966)], followed by acetalization by a known method and then hydrolyzing the ester to give a carboxylic acid, which is reacted with carbonylimidazole to give malonic acid half. The magnesium salt of the ester is reacted and this is carried out in a manner known per se [M. Regitz J. Hocker and A. Lee Doegner,
"Organic Synthesis," Willy New York, 1973, Collective V , P197 (M.Regitz, J. Hocker
and A. Liedhegener, “Organic Syntheses”, Wiley,
New York, 1973, Collective, vol V, p. 197)], and can be easily produced by diazotization and cyclization using a rhodium catalyst (see Ikegami et al., Japanese Patent Application No. 61-223907). reference).

In the above formulas, R ¹ is a hydrogen atom or a methyl group, and R ² is an alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted benzyl group or a trichloroethyl group. Examples of the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, n-propyro, 2-propenyl, i-propyl, t-butyl and n.
-Butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like, and the substituted benzyl group includes nitrobenzyl, methoxybenzyl and the like,
A benzyl group is particularly preferable in view of the steps described below.

In the above formulas, R ³ represents a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a group that forms 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 group, trimethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group; t- Diphenyl (C ₁ -C ₄ ) alkylsilyl group such as butylphenylsilyl group; Di (C ₁ -alkyl group such as dimethylphenyl group
Preferred examples thereof include a C ₄ ) alkylphenyl group; or a tribenzylsilyl group. Among these, a tri (C ₁ -C ₄ ) alkylsilyl group, a diphenyl (C ₁ -C ₄ ) alkylsilyl group, and a phenyldi (C ₁ -C ₄ ) alkylsilyl group are preferable, and a t-butyldimethylsilyl group is particularly preferable. Particularly preferred.

Examples of the group that forms an acetal bond together with the oxygen atom of the hydroxyl group include methoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, and (2-methoxyethoxy group. ) Methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 6,6-dimethyl-3-oxa-2-oxobicyclo [3,1,0] hex-4-yl group Can be mentioned. 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy) methyl group, 6,6-dimethyl-3-oxa-2-oxo The bicyclo [3,1,0] hex-4-yl group is particularly preferred. Of these, a 2-tetrahydropyranyl group is particularly preferable.

It is to be understood that these silyl groups and the groups forming an acetal bond are protecting groups for hydroxyl groups. These and protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to give free hydroxyl groups useful as a drug.

In the above formulas, R ⁴ represents a hydrogen atom or a methyl group. Incidentally, a vinyl group can be cited as a reference example.

In the above formulas, R ⁵ is linear or branched C _{3 to} C ₈
Represents an alkyl group. In addition, as other reference examples, a C ₃ -C ₈ alkyl group containing an oxygen atom; a substituted or unsubstituted phenyl group; a substituted or unsubstituted phenoxy group; a substituted or unsubstituted C _{3 to} C ₁₀ cycloalkyl group; Or a straight chain or branched chain substituted with a C ₁ -C ₆ alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group or an optionally substituted C ₃ -C ₁₀ cycloalkyl group Chain C ₁ -C ₅ alkyl groups are mentioned.

The unsubstituted linear or branched C ₃ -C ₈ alkyl group which may be interrupted by an oxygen atom includes a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, a 2-hexyl group and a 2-methyl group. A 2-hexyl group, a 2-methylbutyl group, a 2-methylpentyl group, a 2-methylhexyl group and a 2,2-dimethylhexyl group are preferable.

Substituted phenyl group, substituted phenoxy group, and C ₃ -C ₁₀
Examples of the substituent of the substituted cycloalkyl group of include a halogen atom, a protected hydroxyl group (eg, a silyloxy group,
Such as C ₁ -C ₆ alkoxy _group), such as C 1 -C ₄ alkyl group. Examples of the cycloalkyl group C ₃ -C _10, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, cyclohexenyl group, cycloheptyl group, cyclooctyl group, etc. cyclodecyl. Among these, cyclopentyl group,
A cyclohexyl group is preferred.

A straight or branched chain substituted with a C ₁ -C ₆ alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C ₃ -C ₁₀ cycloalkyl group. In the chain C ₁ -C ₅ alkyl group, examples of the C ₁ -C ₆ alkoxy group include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butoxy group, t-butoxy group, hexyloxy group and the like. . Examples of the substituent of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted C _{3 to} C ₁₀ cycloalkyl group and the C _{3 to} C ₁₀ cycloalkyl group are the above-mentioned examples. Can be the same as. Examples of the linear or branched C _{1 to} C ₅ alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group and the like. be able to. Examples of R ⁵ include butyl group, pentyl group, hexyl group, heptyl group, 2
-Hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group and the like can be mentioned as preferable ones. In addition, the substituent may be bonded to any position thereof.

In each of the above formulas, n represents 0 or 1.

In the first step of the present invention, β-represented by the above formula [I]
The ketoesters and the active species obtained by treating the alkenyllithium compound represented by the above formula [II] with mercuric chloride or zinc chloride and then treating with lead tetraacetate are reacted in the presence of a base to obtain the desired α- Alkenylated β-ketoesters [III] are produced. The amount of the reactant used is 1.0 to 10.0 for the alkenyllithium compound / mercuric chloride / lead tetraacetate with respect to the equivalent amount of the substrate [I].
/0.5 to 5.0 / 0.5 to 5.0 equivalents, preferably 2.0 to 6.0 / 1.0
~ 3.0 / 1.0 ~ 3.0 equivalents are good.

In addition, it was previously isolated as bis-alkenylmercury [II-a] by the reaction of an alkenyllithium compound and mercuric chloride, [In the formula, the definitions of R ³ , R ⁴ and R ⁵ are the same as above. Next, an active species treated with tetraacetate may be used.
In the case of alkenyllithium compound / zinc chloride / tetraacetic acid, 0.5 to 5.0 / 0.5 to 5.0 / 0.5 to 5.0 equivalents respectively; preferably 1.0 to 2.5 / 1.0 to 2.5 / 1.0 to 2.5 equivalents. The reaction is usually carried out in a medium of a halogenated hydrocarbon such as dichloromethane, dichloroethane or chloroform, or an ether such as ether, tetrahydrofuran or dioxane and a mixture thereof in any ratio, and particularly halogenated hydrocarbons such as chloroform and dicheloloethane. Is preferably used, and usually 5 to 100 volumes, preferably 10 to 50 volumes with respect to the substrate [I] are used. In the reaction, a base is used if necessary, and for example, pyridine, 4-dimethylaminopyridine and the like, particularly pyridine is preferable, and the amount used is 0.5 to 5.0 equivalents, preferably 1.0 equivalent to the substrate [I].
~ 3.0 equivalents.

The reaction temperature is usually 0 ° C to 50 ° C, preferably 10 ° C to 30 ° C, and the reaction time is usually 1 although it depends on the reactivity of the active species.
~ 3 hours to finish. These are usually determined by tracing the reaction by means such as thin layer chromatography.

This is the only α-alkenylation reaction that is expected to reach the present invention.
d JTPinhey, J.Chem.Soc.Chem.Commun., 1984 , 965) using alkane-1-enyllead triacetate is known, but here, monocyclic 2-ethoxycarbonylcyclopentanone is used. There is only a description about a simple alkenyl body having no functional group for,
There is no description of the bicyclic β-ketoester compound disclosed in the present invention, and the alkenylation method via a zinc compound in addition to a mercury compound is the first disclosed in the present invention.

Next, in the deesterification reaction which is the second step of the present invention, the deesterification reaction can be carried out by applying a known method to each ester group. For example, an alkyl ester such as a methyl ester has a decarboxylation reaction and various dealkoxycarbonylation reactions following alkali hydrolysis, and a t-butyl ester body has a decarboxylation reaction following an acid hydrolysis. Further, in the case of trichloroethyl ester, a method by which zinc is not reduced is applied. Among the most preferable benzyl ester compounds, (i) lithium / liquid ammonia-t-butanol, (ii) palladium-barium sulfate / quinoline, (iii) Raney nickel (W-2) / cupric acetate, (iv) Raney nickel (W) -2) / Triethylamine method is applied. Among them, the method according to (iv) is the most preferable method because the configuration at the 6-position is only exo.

Thus, the α-alkenylated β-of the above formula [III]
The desired α-alkenylated ketones [IV] are prepared from ketoesters.

Next, the carbonyl group of the obtained ketones [IV] is reduced to give the desired protected isocarbacycline intermediate [Va].

This reduction of the carbonyl group is a method known per se [HOHouse et al., Modern Synthetic Reactions 2nd Edition].
eacteons 2nd Edition), WBA Benjamin, Inc. (WABenjamin, Inc.) 19
72], for example, using sodium borohydride, sodium cyanoborohydride, lithium tri-t-butoxyaluminum hydride or the like. Particularly, sodium borohydride is preferably used. The reaction proceeds stereoselectively peculiar to the system of bicyclo [3,3,0] octane to produce the above formula [Va].

The above formula [Va] thus obtained is subjected to a deprotection reaction,
It leads to the isocarbacycline intermediate [Vb], which is the desired bicyclo [3,3,0] octane. The deprotection reaction used has a method known per se, and when the acetal protecting group or the hydroxyl protecting group is a group forming an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid or Using a cation exchange resin as a catalyst, for example, water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, etc. as a reaction solvent, and usually treating at a temperature range of −78 ° C. to + 30 ° C. for about 10 minutes to 3 days. It is done by doing. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, for example, in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrogen fluoride water or pyridine-hydrogen fluoride, The protecting group is removed by treating at the same temperature and for the same time in the reaction solvent as described above.

Isocarbacycline intermediate [Vb] thus produced
In each of the compounds, including, the carbon to which the bicyclo [3,3,0] octane ring itself and the substituents attached to its bicyclo [3,3,0] octane ring are bonded (on the ω chain (Carbon substituted with a hydroxyl group) has stereoisomers due to an asymmetric environment, but in the present invention, any stereoisomers are included, and a stereoisomer mixture in any proportion thereof may be used. Absent. Among these, the compound having the three-dimensional structure represented by the formula is most preferred. For example, as shown in the figure below, an intermediate obtained by the present invention is introduced into an isocarbacycline useful as a drug through several steps after introducing an α chain by an aldol condensation reaction [Ikegami et al., JP-A-61-122292. No. gazette].

The feature of the present invention is that (i) the alkenyl ω chain essential for the production of isocarbacycline can be directly introduced, and (ii) the ω chain configuration after the deesterification reaction is a mixture of exo / endo, but triethylamine is added. Therefore, it is possible to control the desired exo form in three dimensions, and (iii) the number of steps is relatively short, which is industrially advantageous as compared with the conventional method.

The present invention will be described below with reference to examples.

Example 1 (a) 3-t-butyldimethylsiloxy-1-in a 3 ml reaction tube
190 mg of (n-tributyltin) -1-octene (0.36 mmo
le) was taken and dissolved in 0.5 ml of anhydrous THF under an argon atmosphere. While stirring at -78 ° C, 0.25 ml (0.40 mmole) of 1.59 Mn-butyllithium in hexane was added dropwise and the mixture was stirred for 30 minutes.
A lithium reagent of -t-butyldimethylsiloxy-1-octene was prepared.

Anhydrous zinc chloride 49.0mg (0.36mmol
The e) was taken and suspended in 0.3 ml of anhydrous THF under an argon atmosphere. Under stirring at −78 ° C., a THF solution of the lithium reagent of 3-t-butyldimethylsiloxy-1-octene prepared above was added using a cannula, and then the temperature was raised to 0 ° C. over 15 minutes, and at the same temperature. Stir for 15 minutes. 90% lead tetraacetate 168mg
Add (0.34mmole) 3.5ml anhydrous chloroflum solution at 20 ℃
Stir for 5 minutes, then ketoester 0.5 ml solution was added and stirred for 3 hours. After confirming the completion of the reaction by TLC, the reaction solution was cooled to 0 ° C., and ethylene glycol 10
5 mg (1.70 mmole) was added and stirred for 10 minutes. This solution was poured into a two-layer solution of 5 ml of a buffer (pH = 7.0) and 5 ml of ether which were vigorously stirred under ice cooling, and the mixture was extracted with 30 ml of ether. The organic layer was washed successively with 2% hydrochloric acid 3 ml, saturated sodium hydrogen carbonate solution-saturated saline (1: 1) 3 ml, saturated saline 3 ml, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product.
271 mg was obtained.

Transfer this crude product to a 20 ml eggplant flask and add 3 ml of THF.
Dissolve in, add 3 ml of saturated ammonium chloride solution to form a two-layer solution, and under stirring at 25 ° C zinc powder 11.1 mg (0.17 mg atom)
Was added and stirred for 5 minutes. After completion of the reaction was confirmed by TLC, the mixture was extracted with 30 ml of ether-hexane (10: 1), the organic layer was washed with 3 ml of saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 265 mg of a crude product. Silica gel column chromatography (MERCK Art 9376, 16g, 10: 56.6 mg (57% yield) was obtained as a pale yellow oily substance, _{^{IR (neat) 1760,1730,1655,1250,1215,1095cm -1 1 H}} -NMR δ 0.05 (6H, S), 0.89 (12H, brs), 1.14~3.18 (22H, m), 3.42~3.76 (2H , m), 4.02 to 4.24 (1H, m), 5.20 (2H, s), 5.52 to 5.96 (2H, m), 7.38 (5H, s), MSm / z: 584 (H ⁺ ), 527 (M ⁺ ) _{-t-C 4 H 9),} 513,419,411,409. (b) 90% lead tetraacetate 197mg (0.40mmole) in a 10ml eggplant flask
It was taken and dissolved in 0.5 ml of anhydrous chloroform under an argon atmosphere. Pyridine 34.8mg (0.44mmole) under stirring at 20 ℃,
Di- (3-t-butyldimethylsiloxy-1-octenyl) mercury 300 mg (0.44 mmole) anhydrous chloroform 1.0 ml
Add the solution sequentially and stir for 30 minutes, then remove the ketoester A 1.0 ml solution was added and the mixture was stirred for 1 hour and 30 minutes. TL at the end of the reaction
After confirming with C, the reaction solution was cooled to 0 ° C., 136 mg (2.20 mmole) of ethylene glycol was added, and the mixture was stirred for 10 minutes.

5 ml of this solution was vigorously stirred under ice cooling (pH = 7)
It was poured into a two-layer solution of ether and 15 ml of ether and extracted with 30 ml of ether. The organic layer was washed successively with 2% hydrochloric acid 3 ml, saturated sodium hydrogen carbonate solution-saturated saline (1: 1) 3 ml, saturated saline 3 ml, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain a crude product. Silica gel column chromatography (MERCK Art 9376, 20g, 10: 1 hexane- Recovered.

The various spectra were consistent with those above.

Example 2 Take 100mg (0.17mmole), dissolve in 1.0ml absolute ethanol under argon atmosphere, and add 1.7mg (0.01mg) of triethylamine.
7mmole) was added. Raney Nickel (W-2) 3 under stirring at 20 ℃
00 mg was added 5 times at 5 minute intervals (1.5 g total). After confirming the disappearance of the starting materials by TLC, the reaction solution was cooled to 0 ° C., 86 mg (0.85 mmole) of triethylamine was added, and the mixture was stirred for 10 minutes. After confirming the completion of the reaction by TLC, dilute the reaction solution with 20 ml of ether,
Passed with paper. The container was washed with 20 ml of ether, transferred to a separating funnel together with the liquid, washed successively with 5 ml of 1% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 96 mg of the obtained crude product was subjected to silica gel column chromatography (B
W-820, 10g, 9: 1 43 mg (yield 56%) was obtained as a pale yellow oily substance.

^{IR (neat) 1740,1250,1095cm -1 1 H} -NMR δ 0.03 (6H, S), 0.87 (12H, brs), 1.05~2.84 (23H, m), 3.30~3.84 (2H, m), 3.92~ 4.19 (1H, m), 5.24-5.64 (2H, m). _{^{MSm / z: 393 (M +}} C 4 H 9), 321,221. Example 3 Take NaBH ₄ 16.6mg (0.44mmole) in a 20ml reaction tube,
Suspend in 0.2 ml of methanol under an argon atmosphere. A solution of (0.088 mmole) in 0.5 ml of methanol was added and stirred for 30 minutes. After completion of the reaction was confirmed by TLC, ether (2 ml) and saturated saline (2 ml) were sequentially added with ice-cooling stirring, and the mixture was extracted with ether (50 ml). The organic layer was washed with 3 ml of saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product.
46 mg of silica gel column chromatography (BW-820,
5g, 4: 32 mg (81% yield) was obtained as a yellow oil.

^{IR (neat) 3430,1250,1090cm -1 1 -NMR} δ 0.03 (6H, S), 0.83 (12H, brs), 1.02~2.27 (24H, m), 3.38~3.79 (3H, m), 3.83~4.11 (1H, m), 5.17-5.71 (2H, m). ^{MSm / z: 434 (M +} -H 2 O), 395 (M + -t-C 4 H 9), 363,323,303. Example 4 mmole) was taken and dissolved in 0.5 ml of THF. 50 μL of concentrated hydrochloric acid was added with stirring at 20 ° C., and the mixture was stirred for 2 hours. After confirming the completion of the reaction by TLC, it was poured into a two-layer solution of 4 ml of ether and 1 ml of a saturated sodium hydrogencarbonate solution vigorously stirred under ice-cooling, and ethyl acetate was added.
10 ml was added and extracted. The organic layer was washed successively with 1.0 ml of saturated sodium hydrogen carbonate solution and 1.0 ml of saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product.
28 mg of silica gel column chromatography (Wako gel C-200, 5 g, 2: 1 ethyl acetate: hexa Obtained as a yellow oil.

^{IR (neat) 3400,1725,1260,1120,1075cm -1 1 H} -NMR δ 0.64~1.03 (3H, m), 1.10~2.63 (19H, m), 3.72~4.20 (2H, m), 5.24~5.86 (2H, m). ^{MSm / z: 248 (M +} -H 2 O), 177,152. Reference example 1 (a) 3-t-butyldimethylsiloxy-1-in a 5 ml reaction tube
(N-Tributyltin) -1-octene 370mg (0.70mmo
le) was taken and dissolved in 0.6 ml of anhydrous THF under an argon atmosphere. Under stirring at -78 ° C, 0.44 ml (0.70 mmoleb) of 1.59M n-butyllithium in hexane was added dropwise and stirred for 30 minutes,
A lithium reagent of 3-t-butyldimethylsiloxy-1-octene was prepared.

Anhydrous zinc chloride 95.0mg (0.70mmol
e) was taken and suspended in 0.5 ml of anhydrous THF under an argon atmosphere. Under stirring at −78 ° C., a THF solution of the lithium reagent of 3-t-butyldimethylsiloxy-1-octene prepared above was added using a cannula, and then the temperature was raised to 0 ° C. over 15 minutes, and at the same temperature. Stir for 15 minutes. 90% lead tetraacetate 326mg
Add (0.66mmole) anhydrous chloroform 5ml solution and add 20
Stir for 5 minutes at ℃, then ketoester A 1.0 ml solution was added and stirred for 3 hours. After confirming the completion of the reaction by TLC, the reaction solution was cooled to 0 ° C., and ethylene glycol 20
4 mg (3.30 mmole) was added and stirred for 10 minutes. This solution was vigorously stirred under ice-cooling 10 ml of buffer (pH = 7.0) and ether 15
It was poured into a two-layer solution of ml and extracted with 60 ml of ether. The organic layer was washed successively with 2% hydrochloric acid 5 ml, saturated sodium hydrogen carbonate solution-saturated saline (1: 1) 5 ml, saturated saline 5 ml, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain a crude product 486 m.
got g.

Transfer this crude product to a 50 ml eggplant flask and add 6 ml of THF.
6 ml of saturated ammonium chloride solution was added thereto to form a two-layer solution, and 21.5 mg (0.33 mg atom) of zinc powder was added with stirring at 23 ° C. and the mixture was stirred for 5 minutes. After completion of the reaction was confirmed by TLC, the mixture was extracted with 50 ml of ether-hexane (10: 1), the organic layer was washed with 5 ml of saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 469 mg of a crude product. Silica gel column chromatography (BW-820, 20g, 15: 1 hexane (60%) as a pale yellow oily substance ^{IR (neat) 1735,1245,1080cm -1 1 H} -NMR δ 0.03 (6H, S), 0.89 (12H, brs), 1.03~2.83 (14H, m), 3.99~4.22 (1H, m), 5.18 ( 2H, s), 5.59 (1H, dd, J = 16.5Hz), 5.84 (1H, d, J = 16Hz), 7.35 (5H, s). ^{MSm / z: 401 (M +} -t-C 4 H 9), 387,357,283. (b) 90% lead tetraacetate 309mg (0.63mmole) in a 10ml eggplant flask
It was taken and dissolved in 1.0 ml of anhydrous chloroform under an argon atmosphere. Pyridine 57.0mg (0.72mmole) under stirring at 20 ℃,
A solution of 495 mg (0.72 mmole) of di- (3-t-butyldimethylsiloxy-1-octenyl) mercury in 1.0 ml of anhydrous chloroform was sequentially added, and the mixture was stirred for 30 minutes. A 1.0 ml solution was added and stirred for 1 hour and 30 minutes. When the reaction ends
After confirmation by LC, the reaction solution was cooled to 0 ° C., 194 mg (3.15 mmole) of ethylene glycol was added, and the mixture was stirred for 10 minutes. This solution was poured into a two-layer solution of 5 ml of a buffer (pH = 7) and 15 ml of ether which were vigorously stirred under ice cooling, and the mixture was extracted with 40 ml of ether. The organic layer was washed successively with 3% of 2% hydrochloric acid, 3 ml of saturated sodium hydrogen carbonate solution-saturated saline (1: 1) and 3 ml of saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 698 mg of the crude product obtained was subjected to silica gel column chromatography (BW-820, 20 g, 15: 1 hexane). Was recovered.

The various spectra were consistent with those above.

(c) Various ester groups were used in place of the benzyl ester, and the results shown in the table below were obtained.

Reference example 2 Take mg (0.10mmole) and dissolve it in 0.5ml of absolute ethanol under argon atmosphere. Triethylamine 1.0mg (0.01mmol
e) was added. Raney Nickel (W-2) 200 mg was added 3 times at 5 minute intervals (total 600 mg) under stirring at 20 ° C.
After confirmation by LC, 10 ml of ether was added to the reaction solution to dilute it, and the mixture was filtered with paper. The container was washed with 10 ml of ether, combined with the solution and transferred to a separating funnel, 3 ml of 1% hydrochloric acid, 3 parts of saturated saline solution.
Washed sequentially with 3 ml, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 35 mg of the crude product obtained was subjected to silica gel column chromatography (BW-820, 5 g, 15: 1). mg (yield 76%) was obtained as a pale yellow oily substance.

^{IR (neat) 1745,1250,1075cm -1 1 H} -NMR δ 0.03 (6H, S), 0.87 (12H, brs), 1.02~2.39 (14H, m), 2.50~2.91 (1H, m), 3.82~ 4.14 (1H, m), 5.22~5.86 (2H, m), MSm / z: 267 (M + -t-C 4 H 9) 253,167.

Claims (10)

[Claims] 1. The following formula [I]: [In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted benzyl group, or a trichloroethyl group. ] A β-ketoester represented by the following formula; [In the formula, R ³ is a tri (C ₁ -C ₇ ) hydrocarbon silyl group,
Or a group forming an acetal bond with an oxygen atom of a hydroxyl group; R ⁴ represents a hydrogen atom or a methyl group; R ⁵ represents a linear or branched C ₃ -C ₈ alkyl group; n represents 0 or 1 Represent. ] The alkenyllithium compound represented by the following formula is treated with mercuric chloride or zinc chloride, and then reacted with an active species treated with lead tetraacetate in the presence of a base, if necessary. [In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as above. ] [Alpha] -alkenylated [beta] -ketoesters represented by the following formula are obtained; [In the formula, the definitions of R ¹ , R ³ , R ⁴ , and R ⁵ are the same as above. ] The ketone represented by the formula: is obtained; the carbonyl group is reduced and a deprotection reaction is carried out, and the following formula [Vb] [In the formula, the definitions of R ⁴ and R ⁵ are the same as above. ] The production method of the bicarbo [3,3,0] octane represented by these, its optical isomers, or the isocarbacycline intermediate which is a mixture of them in arbitrary ratios. 2. A method according to claim 1, wherein R ¹ is a methyl group.
A method for producing the isocarbacycline intermediate described in the above item. 3. The method for producing an isocarbacycline intermediate according to claim 1 or 2, wherein R ² is a benzyl group. 4. The method for producing an isocarbacycline intermediate according to any one of claims 1 to 3, wherein R ³ is a t-butyldimethylsilyl group. 5. A method according to claim 1, wherein R ⁴ is a hydrogen atom.
Item 5. A method for producing the isocarbacycline intermediate according to any one of Items 4 to 4. 6. A scope of claims wherein R ⁵ is a butyl group, a pentyl group, a hexyl group, a heptyl group, a 2-hexyl group, a 2-methyl-2-hexyl group, a 2-methylbutyl group or a 2-methylpentyl group. Any one of the first to fifth items
A method for producing the isocarbacycline intermediate described in the above item. 7. Claims 1 to 6 in which n is 0.
Item 10. A method for producing the isocarbacycline intermediate according to any one of items. 8. The method according to claim 1, wherein the base is pyridine.
Item 8. A method for producing the isocarbacycline intermediate according to any one of Items 7 to 7. 9. The method for producing an isocarbacycline intermediate according to claim 1, wherein the deesterification reaction is carried out with Raney nickel and cupric acetate or triethylamine. 10. The method for producing an isocarbacycline intermediate according to any one of claims 1 to 9, wherein the reduction reaction of the carbonyl group is carried out with NaBH ₄ .