JP2943306B2 - Cyclopentanaldehydes and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

<Industrial application field> The present invention relates to a medicament, a pesticide, a cyclopentane aldehyde useful as an intermediate thereof, particularly a process tagglandin intermediate, and a production method thereof. <Conventional technology> The following general formula [1] useful as a raw material of prostaglandin F ₂ α (In the formula, A represents a hydrogen atom or a protecting group for a hydroxyl group.) Cyclopentanaldehydes represented by the following formula are synthesized using Corey lactone as a raw material. <Problems to be solved by the invention> However, the method using Corey lactone as a raw material
Since many steps are required, it is not always industrially satisfactory. Furthermore, since the lactone itself must be synthesized through many steps and is expensive, a simpler synthesis method has been desired. <Means for Solving the Problems> As a result of intensive studies on an industrially advantageous production method of such cyclopentanaldehydes, the present inventors have found a new production method via a novel intermediate and completed the present invention. That is, the present invention relates to the general formula [2] (Wherein, A represents a hydrogen atom or a hydroxyl-protecting group.) A cyclopentenone derivative represented by the general formula [3] LiC (OR ⁴ ) (SR ⁵ ) Si R ⁶ R ⁷ R ⁸ [3 (Wherein, R ⁴ represents a lower alkyl group, R ⁵ represents a lower alkyl group, a lower alkoxy group or a phenyl group which may have a chlorine atom as a substituent, and R ⁶ , R ⁷ , R ⁸ Each independently represents a methyl group or an ethyl group.) An organic lithium derivative represented by the following formula: (Wherein X represents a halogen atom and R ⁹ represents a lower alkyl group). The ω-haloheptenoic acids represented by the general formula [5] (Wherein A, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ represent the same meaning as described above), and then using a desilylating agent After desilylation and, if necessary, deprotection of a protecting group, the compound represented by the general formula [6] (Wherein, A, R ⁴ , R ⁵ and R ⁹ have the same meanings as described above). Next, the cyclopentane derivative [6] obtained here is reduced with a reducing agent to reduce the ketone moiety to obtain a compound of the general formula [7] (Wherein, A, R ⁴ , R ⁵ and R ⁹ have the same meanings as described above). After obtaining a cyclopentane alcohol represented by the formula (8), R ¹⁰ COOH [8] Wherein R ¹⁰ represents a lower alkyl group.) Esterified with a carboxylic acid represented by

[9] (Wherein, A, R ⁴ , R ⁵ , R ⁹ and R ¹⁰ have the same meanings as described above), and then oxidatively hydrolyze in the presence of an oxidizing agent. By decomposition, the general formula [10] (Wherein, A, R ⁹ and R ¹⁰ have the same meanings as described above). In addition, the present invention provides a compound represented by the general formula [11] by oxidatively hydrolyzing the cyclopentane derivative represented by the general formula [6] in the presence of an oxidizing agent. (Wherein, A and R ⁹ have the same meanings as described above.) Further, the present invention provides a compound represented by the general formula [12] by oxidatively hydrolyzing the cyclopentane alcohol represented by the general formula [7] in the presence of an oxidizing agent. (Wherein, A and R ⁹ have the same meanings as described above.) The present invention is a novel method for producing the compounds represented by the general formulas (10), (11) and (12) useful as such a prostaglandin intermediate, and provides a novel compound not described in the literature. It is. The outline of the present invention is illustrated below. Hereinafter, the present invention will be described in detail. The cyclopentanone derivative represented by the general formula [5] is
Usually, the cyclopentenone derivative represented by the general formula [2] is subjected to a 1,4-addition reaction with the organolithium derivative represented by the general formula [3], and the ω- represented by the general formula [4] is subsequently introduced into the reaction system. It is synthesized by adding haloheptenoic acids. First, the step of reacting the organic lithium [3] with the cyclopentenone derivative [2] will be described. This reaction is usually performed in a solvent. As such a solvent, a single or mixture of solvents inert to the reaction usually used for 1,4-addition reaction such as ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, hexamethylphosphoric triamide, hexane, heptane and the like is used. . The optically active cyclopentenone derivative represented by the general formula [2], which is a raw material, can be easily synthesized by protecting the hydroxyl group of 4R-hydroxy-2-cyclopentenone. Such a protecting group (as A) is, for example, an ether such as a 2-tetrahydropyranyl group or an ethoxyethyl group or a silyl group. Wherein R ¹ and R ² each independently represent a lower alkyl group, or a phenyl group which may have a halogen atom or a lower alkyl group as a substituent, and R ₃ is a t-butyl group , An isopentyl group or a t-pentyl group, or a phenyl group which may have a halogen atom or a lower alkyl group as a substituent. Alternatively, OCOR ¹⁰ (R ¹⁰ represents a lower alkyl group) is exemplified. A 2-tetrahydropyranyl group wherein A is an ether,
The ethoxyethyl groups are synthesized by reacting 4R-hydroxy-2-cyclopentenone with 2-dihydropyran or ethyl vinyl ether in the presence of an acidic catalyst. Silyl ethers are synthesized using silyl chloride with a base catalyst. Further, an acyloxy group is easily synthesized from an acid halide or an acid anhydride of a corresponding carboxylic acid. Examples of such cyclopentenone derivatives include, for example, the following compounds. 4R-dimethyl-t-butyl-silyloxy-2-cyclopentenone, 4R-dimethyl-phenylsilyloxy-
2-cyclopentenone, 4R- (2-pyranyloxy)-
2-cyclopentenone, 4R- (ethoxyethyl) -2-
Cyclopentenone, 4R-acetoxy-2-cyclopentenone. The organolithium derivative represented by the general formula [3] is represented by the general formula [13] HC (OR ⁴ ) (SR ⁵ ) (Si R ⁶ R ⁷ R ⁸ ) [13] (where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^8, lithiating agent conventional active hydrogen silyl derivative represented by represents.) as defined above, for example n- butyl lithium, it is synthesized by reacting lithium diisopropylamide. These are usually synthesized prior to the reaction and used without isolation in the subsequent 1,4-addition reaction. The molar ratio of the organolithium derivative [3] used here is usually from 1 mol to 5 mol, preferably 2 mol 3 mol, per 1 mol of the cyclopentenone derivative [2] as the other raw material. Range. The reaction temperature is in the range of −100 to 10 ° C., preferably −80 to
The range is -10 ° C. The reaction time is not particularly limited, but is usually in the range of 0.2 to 8 hours. As a specific example of the organolithium derivative, in the general formula [3], R ⁴ is, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, and R ⁵ is , A phenyl group, a methylphenyl group, a methoxyphenyl group, a chlorophenyl group and the like, and R ⁶ , R ⁷ and R ⁸ are each independently a methyl group or an ethyl group. Next, the step of reacting the reaction solution obtained above with an ω-haloheptenoic acid represented by the general formula [4] to obtain a cyclopentanone derivative represented by the general formula [5] will be described. The reaction was completed with the reaction solution, ω-
It is carried out by adding haloheptenoic acids. Such ω-haloheptenoic acids include, for example, ω-
Iodo-5-cis-heptenoic acid or ω-bromo-5
-Methyl-, ethyl-, n-, iso-propyl, n-, iso-, tert-butyl esters of cis-heptenoic acid. The molar ratio of the ω-haloheptenoic acids used is usually in the range of 1 to 5 mol per 1 mol of the starting material cyclopentenone derivative [2]. The reaction temperature is usually -100 to 40C, preferably -80 to 30.
It is in the range of ° C. The reaction time is not particularly limited. J. Org. Chem. Vol 54,5003 (1989) describes the following similar reaction. However, it was found that when the ω-haloheptenoic acids of the present invention were used as RX, the desired product could not be obtained at all. As a result of intensive studies, the present inventors have found that the purpose can be achieved by adding a metal ligand such as tetramethylethylenediamine as an additive in this reaction. The amount of such an additive is in the range of 0.3 to 4 mol, preferably 1 to 3 mol, per 1 mol of the cyclopentenone derivative represented by the general formula [2]. This additive may be added in advance at the time of the above 1,4 addition reaction. By this reaction, the desired cyclopentanone derivative represented by the general formula [5] is obtained. Usually, the reaction solution is placed on ice, extracted and concentrated, and the organic layer can be isolated by concentration. Further, if necessary, it can be purified by column chromatography. Of course, the reaction mixture can be used as it is for the next step. Next, the reaction of reacting the cyclopentanone derivative [5] with a desilylating agent to desilylate and obtain the cyclopentane derivative represented by the general formula [6] will be described. Solvents used in this reaction include water, acetic acid, dimethylformamide, dioxane, tetrahydrofuran,
Solvents such as dimethoxyethane and dimethylsulfoxide, alone or in mixture, are exemplified. As the desilylating agent, for example, fluorine compounds such as tetrabutylammonium fluoride and cesium fluoride are preferably used. The amount of the desilylating agent used is in the range of 1 mol to 3 mol per 1 mol of the cyclopentanone derivative [5]. The reaction temperature is usually −10 to 50 ° C., preferably 0 to 40 ° C.
In the range. The reaction time is not particularly limited, and the reaction can be terminated at the disappearance of the starting compound [5]. In this reaction, even when A is a silyloxy group, the silyl group substituted by the 3-position methyl group is preferentially eliminated.
However, it is preferable to avoid unnecessary extension of the reaction time and unnecessary high temperature, and it is desirable to stop the reaction at the time when the silyl group substituted with the methyl group at the 3-position is eliminated, and to carry out post-treatment. After completion of the reaction, the reaction solution is poured into water, extracted with a solvent such as toluene, ethyl acetate, diethyl ether, and dichloromethane, and the organic layer is separated and concentrated to isolate the cyclopentane derivative [6]. Can,
If necessary, it can be purified by column chromatography. Alternatively, the reaction mixture can be used as it is for the next step. Next, the cyclopentane derivative [6] is converted to a cyclopentane alcohol [7] by reduction using a reducing agent capable of reducing ketone to alcohol. As such a reducing agent, those which are as bulky as possible are preferable because the obtained hydroxyl group needs to be α-coordinated. Examples of such a reducing agent include diisobutylaluminum hydride (DIBAL) -2,6-di-t-butyl-4-methylphenol (BHT), L-Selectride (lithium tri-S
ec-butylborohydride) and the like. The amount of the reducing agent to be used is generally 1 mol or more and 20 mol or less with respect to 1 mol of the starting material cyclopentane derivative [6]. As the solvent, in addition to the solvent used in the previous reaction, chloroform, dichloromethane, toluene, hexane, diethyl ether and the like can be used, and, of course, used alone or as a mixed solvent. The reaction temperature is usually −30 to 60 ° C., preferably −20 to 40 ° C.
Range. The reaction time is not particularly limited, and the end point can be determined when the raw materials disappear. After completion of the reaction, cyclopentane alcohols [7] can be isolated by the same post-treatment operation as shown in the previous reaction, and can be purified by column chromatography if necessary. Of course, the reaction mixture can be used as it is for the next step. Cyclopentane derivatives from cyclopentane alcohols [7]

[9] is carried out by esterification using a carboxylic acid represented by the general formula [8] or a derivative thereof. Examples of such carboxylic acids [8] include acetic acid, propionic acid, butanoic acid, and pentanoic acid, and derivatives thereof include acid chloride, acid bromide, and acid anhydride. Specific examples include acetyl chloride, acetyl bromide, and anhydride. Acetic acid, propionic chloride, and propionic anhydride are exemplified. The amount of cyclopentane alcohols [7] 1
It is 1 mol or more and 3 mol or less based on the mol. When the above acid chloride or bromide or acid anhydride is used, an organic or inorganic base such as triethylamine, pyridine, picoline, potassium carbonate or the like is used, and the amount of the base used is 1 mol per cyclopentane alcohol [7]. It is 1 mol or more and 4 mol or less, and can be increased as necessary. The organic base can also be used as a solvent. The reaction is usually carried out under anhydrous conditions, and as a solvent, normal halogenated hydrocarbons such as chloroform, dichloromethane, chlorobenzene, ethyl ether, tetrahydrofuran, acetone, ethyl acetate, hexane, toluene, ether, ketone, ester, aromatic and A single or mixed solvent of aliphatic hydrocarbons is exemplified. The reaction temperature is in the range of -20 to 60C, preferably -20 to 50C. The reaction time is not particularly limited. After completion of the reaction, the desired cyclopentane derivative is obtained by post-treatment and purification by the same operation as described above.

[9] can be isolated. Of course, the reaction mixture may be used as it is for the next reaction. Cyclopentane derivative

The reaction for obtaining the cyclopentane aldides represented by the general formula [10] from [9] is performed by using an oxidizing agent to prepare a cyclopentane derivative

[9] is oxidatively hydrolyzed. Examples of the solvent used in this reaction include solvents alone such as acetone, tetrahydrofuran, water, dioxane, and dimethoxyethane, and mixtures thereof. As the oxidizing agent used for oxidative hydrolysis, for example, divalent mercury salts such as mercuric oxide and mercuric chloride are preferably used. The amount used is a cyclopentane derivative

[9] It is in the range of 1 mol to 4 mol per 1 mol. The reaction temperature is usually -20 to 60 ° C, preferably -10 to 50 ° C.
Range. The reaction time is not particularly limited. After completion of the reaction, the reaction solution is poured into water, and the cyclopentane derivative is added.

The solvent mentioned above for synthesizing [9] is added, insoluble matters are removed by filtration, the filtrate is separated, and the organic layer is concentrated to isolate the desired cyclopentanaldehyde [10]. It can be purified by column chromatography. Alternatively, if the above conditions are separately applied to the cyclopentane derivative represented by the general formula [6], the cyclopentane aldehydes represented by the general formula [11] can be obtained. Further, when the present invention is applied to cyclopentane alcohols represented by the general formula [7], cyclopentane aldehydes represented by the general formula [12] can be obtained in the same manner. In the present invention, the protecting group represented by A in the general formula can be deprotected or introduced as needed during the reaction. Hereinafter, the deprotection will be described. When A is a silyl group, the starting compound is water, dimethylformamide acetate, dioxane, tetrahydrofuran,
It is dissolved in a solvent such as dimethoxyethane or dimethyl sulfoxide, alone or in a mixture, and desorbed at -10 to 50 ° C. using 1 to 5 moles of a fluorine compound such as tetrabutylammonium fluoride or cesium fluoride. Can be protected. When A is an ether, the raw material compound is dissolved in the same solvent as described above in the coexistence of water, and an acid such as trifluoroacetic acid, chloroacetic acid, acetic acid, and toluenesulfonic acid is 0.1 mol to 30 mol times. Can be easily deprotected. When A is an ester, a hydroxyl group can be obtained by adding the above-mentioned acids in an alcohol such as methanol or ethanol and subjecting the ester to interesterification. Next, introduction of a protecting group will be described. In the case where A is a silyl group, in the solvent used for synthesizing cyclopentane alcohols [7], 1
Mole to 4 mole times silyl chloride With amines such as pyridine, triethylamine, dimethylaminopyridine and diazole to the starting compound
It is synthesized by silylation using up to 4 mole times. The reaction temperature is usually −20 to 40 ° C., and the reaction time is 0.5
About 5 hours. Post-treatment is performed by a conventional method. When A is an ether such as a 2-tetrahydropyranyl group or an ethoxyethyl group, the solvent is usually used, if necessary, in an amount of 1 to 20 to the starting compound.
It is synthesized by performing an addition reaction of a molar amount of 2-dihydropyran or ethyl vinyl ether in the presence of an acid catalyst such as trifluoroacetic acid, trienesulfonic acid, sulfuric acid, and dichloroacetic acid in a molar amount of 0.01 to 1 times. Of course, the above etherifying agent can be used instead of the solvent. When A is an acyl group, a cyclopentane derivative

The synthesis condition of [9] is applied as it is. As described above, in the present invention, conversion such as deprotection and introduction of a protecting group can be carried out at each step of the synthesis route as necessary. <Effects of the Invention> According to the present invention, a prostaglandin intermediate which conventionally requires a number of steps can be obtained in a high yield and in a short step, and its industrial value is extremely high. Further, the present invention uses a novel compound which has never been known before as an intermediate, and is extremely valuable. <Example> Hereinafter, the present invention will be described with reference to Production Examples. Production Example 1 Methoxy (phenylthio) (trimethylsilyl) methane [12] 678 mg (3 mmol) and tetrahydrofuran 10 ml
And cooled to −78 ° C. under a stream of N ₂ . Next, 0.88 ml of a 2.5 M solution of n-butyllithium in hexane
(2.2 mmol) at the same temperature for 30 minutes, and further at -40 ° C for 30 minutes.
Stir for minutes. Next, the internal temperature is again cooled to −78 ° C., and 1.79 g (10 mmol) of hexamethylphosphorylamide is added, followed by stirring for 30 minutes. Next, the internal temperature was raised to -55 ° C, and 4 (R) -t-butyldimethylsilyloxy-2-cyclopentenone [2] 202 mg (2 mm
ol) and stirred at −55 to −50 ° C. for 30 minutes. Next, after adjusting the internal temperature to −60 ° C., when 232 mg (2 mmol) of tetramethylethylenediamine was added, 1.34 g of ω-iodo-5-cis-heptenoic acid methyl ester [6] was added.
mmol) and stir for 30 minutes. Next, the reaction solution is added to a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer is washed twice with water and concentrated under reduced pressure. The residue was purified by column chromatography with hexane-acetic acid ethyl ester (20: 1) to give 2R, 3R, 4R-2- (6-methoxycarbonyl) -2-cis-hexenyl-3- [methoxy (phenylthio) (tomethylsilyl) Methyl] -4-t
-Butyl-dimethylsilyloxycyclopentanone [5
-1] 439 mg (76% yield). _{^{1 H NMR (CDCl 3))}} 0.01 (S, 3H), 0.07 (S, 3H), 0.17 (S, 9H), 0.85
(S, 9H), 1.60-1.699 (m, 3H), 1.95-2.72 (m, 9
H), 3.49 (S, 3H), 3.65 (S, 3H), 4.89−4.90 (m, 1
H), 5.34-5.44 (m, 2H ), 7.24-7.50 (m, 5H) TLC: (Merck: Kieselgel 60F 254) Rf 0.4 ( hexane / ethyl acetate = 5/1) Next, obtained above [5 -1] 439 mg (0.76 mmol) and D
8 ml of MF, 1 ml of water and 46 mg of acetic acid are added, and 298 mg (1.14 mmol) of etrabutylammonium fluoride is added at room temperature, followed by stirring for 1 hour. After completion of the reaction, the reaction solution is added to a saturated aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The organic layer is washed three times with water. The organic layer was concentrated under reduced pressure, and the residue was purified by column with hexane-ethyl acetate (10: 5) to give 2R, 3R, 4R-2- (6-
Methoxycarbonyl-2-cis-hexenyl) -3-
[Methoxy (phenylthio) methyl] -4-t-butyl-dimethylsilyloxycyclopentanone [6-1] 28
1 mg (37% yield) is obtained. [Α] _D ²⁰ −3.84 ゜ (C = 1.43, CHCl ₃ ) ¹ H NMR (CDCl ₃ ) 0.01 (S, 2.0H), 0.15 (S, 1.0H), 0.83 (S, 6.0H),
0.84 (S, 1.0H), 1.59-1.66 (m, 2H), 1.96-2.63 (m,
10H), 3.38 (S, 2.0H), 3.39 (S, 1.0H), 3.63 (S, 3
H), 4.27.4.31 (m, 1H), 4.82-4.85 (m, 1H), 5.33-
5.43 (m, 2H), 7.21-7.46 (m, 5H) TLC: (Merck: Kieselgel 60F 254) Rf 0.4 ( hexane / ethyl acetate = 3/1) Next, 2,6-di-t- butyl-4 Methyl-phenol
1.444 g (6.55 mmol) and 20 ml of toluene are charged, and 5 ml (5 mmol) of a 1.0 M diisobutylaluminum hydride (DIBAL) ether solution is added at 0 ° C. under a stream of N ₂ , and the mixture is stirred for 1 hour. Next, the internal temperature was cooled again to -40 ° C, and the above obtained [6-1] was obtained.
Add 255 mg (0.5 mmol) and stir at -20 ° C for 30 minutes. After completion of the reaction, the reaction mixture is added to a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer is washed once with water. The organic layer was concentrated under reduced pressure, and the residue was purified by column with hexane-ethyl acetate (5: 1) to give 1S, 2R, 3R, 4R-1-hydroxy-2- (6-methoxycarbonyl-2-cishexenyl)-. 3- [methoxy (phenylthio) methyl] -4-
t-butyl-dimethylsilyloxycyclopentane [7
-1] 215 mg (84% yield). ¹ H NMR (CDCl ₃ )) 0.07 (S, 1.53H), 0.08 (S, 1.47H), 0.12 (S, 1.53H)
H), 0.14 (S, 1.47H), 0.87 (S, 4.59H), 0.89 (S, 4.4
1H), 1.64−2.43 (m, 12H), 2.90−2.92 (brs, 0.51
H), 3.05-3.09 (brs, 0.49H), 3.37 (S, 4.41H), 3.4
0 (S, 4.59H), 3.65 (S, 3H), 3.63-3.67 (m, 1H), 4.
10-4.18 (m, 1H), 4.30 (brs, 0.49H), 4.45 (d, 0.51
H, J = 4.03Hz), 4.57 (d, 0.49H, J = 5.00Hz), 4.66 (d,
0.51H, J = 5.00Hz), 5.32-5.39 (m, 1H), 5.45-5.53
(M, 1H), 7.22-7.50 (m, 5H) TLC: (Merck: Kieselgel 60F ₂₅₄ ) Rf 0.4 (hexane / ethyl acetate = 3/1) Next, [7-1] 152 mg (0.3 was dissolved in 2 ml of pyridine, and 2 ml of acetic anhydride was added at room temperature, followed by stirring for 2 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is further washed four times with water. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography with hexane-ethyl acetate (5: 1) to give 1S, 2R, 3R, 4R-1-acetoxy-2- (6-methoxycarbonyl-2-cis-hexenyl-). 3- [methoxy (phenylthio) methyl] -4
160 mg (97% yield) of -t-butyl-dimethylsilyloxycyclopentane [9-1] are obtained. _{^{1 H NMR (CDCl 3))}} 0.03 (S, 3H), 0.04 (S, 3H), 0.88 (S, 9H), 1.64-
2.47 (m, 12H), 2.60 (S, 3H), 3.42 (S, 3H), 3.68
(S, 3H), 4.12.4.22 (m, 1H), 4.85 (d, 1H, J = 3.30H
z), 5.80-5.12 (m, 1H) 1, 5.37-5.70 (m, 2H), 7.2
6−7.50 (m, 5H) TLC: (Merck: Kieselgel 60F ₂₅₄ ) Rf 0.4 (hexane / ethyl acetate = 3/1) Next, [9-1] 66 mg (0.12 mmol) obtained here, acetone 5 ml, Charge 1 ml of water, and add 49 mg of mercuric chloride at room temperature
(0.18 mmol) and 39 mg (0.18 mmol) of mercury oxide are added and stirred for 1 hour. The reaction solution is poured into water and extracted with ethyl acetate, and the organic layer is washed with 1% aqueous sodium bicarbonate and water three times. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by column with hexane-ethyl acetate (5: 1) to give 1S, 2R, 3R, 4R-1-acetoxy-2-acetate.
(6-methoxycarbonyl-2-cis-hexenyl)-
37 mg (37% yield) of 3-formyl-4-t-butyl-dimethylsilyloxyclopentane are obtained. Production Example 2 1S, 2R, 3R, 4R-1-acetoxy-2- (6-methoxycarbonyl-2-cis-hexenyl) -3- [methoxy (phenylthio) methyl] -4-t-butyldimethylsilyloxycyclopentane 309 mg (0.56 mmol), 10 ml of tetrahydrofuran and 0.1 ml of water were charged, and 2.19 g (8.4 mmol) of tetrabutylammonium fluoride was added at room temperature.
Stir for hours. After completion of the reaction, the reaction solution is added to a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is washed three times with water and concentrated under reduced pressure. The residue was chromatographed with hexane-ethyl acetate (1: 1) to give 1S, 2R, 3R, 4R-1-acetoxy-2- (6-methoxycarbonyl-2-cis-hexenyl-3- [methoxy (phenylthio) Methyl] -4
-210 mg of hydroxycyclopentane are obtained (80% yield). _{^{1 H NMR (CDCl 3))}} 1.61-2.44 (m, 13H), 2.05 (S, 3H), 3.45 (S, 1.25
H), 3.49 (S, 1.75H), 3.66 (S, 3H), 4.25 (brs, 1
H), 4.68 (d, 0.51H, J = 5.50Hz), 4.78 (d, 0.49H, J =
5.13Hz), 5.17-5.28 (m, 2H), 5.43-5.45 (m, 1H),
7.29-7.34 (m, 3H), 7.48-7.51 (m, 2H) TLC: (Merck: Kieselgel 60F 254) Rf 0.4 ( hexane / ethyl acetate = 1/1) Preparation 3 following 1S obtained above, 2R , 3R, 4R-1-acetoxy 2-
(6-methoxycarbonyl-2-cis-hexenyl-3
176 mg (0.38 mmol) of-[methoxy (phenylthio) methyl] -4-hydroxycyclopentane, cyclomethane 8
ml and 64 mg (0.76 mmol) of dihydropyran are charged and cooled to 0 ° C. Next, 48 mg (0.19 mmol) of p-toluenesulfonic acid is added, and the mixture is stirred for 1 hour and further at room temperature for 3 hours. The reaction solution is poured into ice water, the organic layer is separated, and washed three times with water. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography with hexane-ethyl acetate (5: 1) to give 1S, 2
R, 3R, 4R-1-acetoxy-2- (ω-methoxycarbonyl-2-cis-hexenyl) -3- [methoxy (phenylthio) methyl] -4- (2-tetrahydropyranyloxy) -cyclopentane [9 -2] 178 mg (86 yield
%). _{^{1 H NMR (CDCl 3))}} 1.43-2.52 (m, 18H), 1.96 (S, 2.0H), 1.97 (S, 1.0
H), 3.34 (S, 2.0H), 3.50 (S, 1.0H), 3.59 (S, 3
H), 3.74-3.81 (m, 2H), 4.03-4.12 (m, 1H), 4.52
−5.03 (m, 3H), 5.23-5.30 (m, 2H), 7.15-7.45 (m,
5H) TLC: (Merck: Kieselgel 60F ₂₅₄ ) Rf 0.7 (hexane / ethyl acetate = 2/1) Next, 66 mg (0.12 mmol) of [9-2] obtained here, 4 ml of acetone, and 1 ml of water were charged, and chloride was added. Mercuric 49mg (0.18mmo
l) and oxidized eye 39 mg (0.18 mmol) were added at room temperature,
Stir for 1 hour. The reaction solution is poured into water and extracted with dichloromethane. The organic layer is sequentially washed with 1% aqueous sodium bicarbonate and water three times. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography with hexane-ethyl acetate (5: 1) to give 1S, 2R, 3R, 4R-1-acetoxy-2- (6-methoxycarbonyl-2-cis-hexenyl-). 4.5 mg (68% yield) of 3-formyl-4- (2-tetrahydropyranyloxy) -cyclopentane Production Example 4 1S, 2R, 3R, 4R-1-hydroxy-2- (6-methoxycarbonyl) 143 mg (0.28 mmol) of -2-cis-hexenyl) -3- [methoxy (phenylthio) methyl] -4-t-butyl-dimethylsilyloxycyclopentane [7-1]
l), 7 ml of tetrahydrofuran and 0.1 ml of water, and 1.1 g (4.2 mmol) of tetrabutylammonium fluoride at room temperature
And stirred for 3 hours. After completion of the reaction, the reaction solution is added to a saturated aqueous ammonium solution, and extracted with ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure. The residue was purified by chromatography with toluene-ethyl acetate (5: 2) to give 1S, 2R, 3R, 4R-1-hydroxy-2- (6-methoxycarbonyl-2-cis-hexenyl) -3- [methoxy (phenylthio) ) Methyl] -4-hydroxy-cyclopentane (82 mg, 74% yield). Next, 47 mg (0.12 mmol) of the compound obtained here, acetone
4 ml, water 1 ml was charged, mercuric chloride 49 mg (0.18 mmol),
39 mg (0.18 mmol) of mercury oxide is added, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into saturated saline, extracted with ethyl acetate, and the organic layer is washed with 1% aqueous sodium bicarbonate and water three times, and then concentrated under reduced pressure. The residue was chromatographed on a column and 1S, 2R, 3R, 4R-1
There are obtained 21 mg (65% yield) of -hydroxy-2- (6-methoxycarbonyl-2-hexenyl) -3-formyl-4-hydroxycyclopentane. Production Example 5 2R, 3R, 4R-2- (6-methoxycarbonyl-2-cis-hexenyl) -3- [methoxy (phenylthio) methyl] -4-t-butyl-dimethylsilyloxycyclopentane [6-1] 128 mg (0.25 mmol), acetone 10 ml,
Charge 2 ml of water and 1 ml of tetrahydrofuran, and add mercuric chloride
100 mg (0.36 mmol) and 78 mg (0.36 mmol) of mercury oxide are added, and the mixture is stirred at room temperature for 1.5 hours. The reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with 1% aqueous sodium bicarbonate and water three times and then concentrated under reduced pressure. The residue was purified by chromatography with hexane-ethyl acetate (10: 1) to give 2R, 3R, 4R-2- (6-methoxycarbonyl-2-
(Cis-hexenyl) -3-formyl-4-t-butyldimethylsilyloxycyclopentanone [11-1] 68 mg
(70% yield). _{^{1 H NMR (CDCl 3))}} 0.07 (S, 6H), 0.88 (S, 9H), 1.67-1.72 (m, 2H),
2.02-2.07 (m, 2H), 2.24-24.69 (m, 7H), 2.93-2.9
8 (m, 1H), 3.66 (S, 3H), 4.52-4.57 (m, 1H), 5.31
−5.32 (m, 1H), 5.44−5.48 (m, 1H), 9.85 (d, 2H, J =
1.84Hz) TLC: (Merck: Kieselgel 60F 254) Rf 0.6 ( hexane / ethyl acetate = 3/1) Preparation 6 1S, 2R, 3R, 4R- one - hydroxy-2- (6-methoxycarbonyl-2-cis -Hexenyl) -3- [methoxy (phenylthio) methyl] -4-t-butyl-dimethylsilyloxycyclopentane (50 mg, 0.1 mmol), dissolved in acetone (4 ml) and water (1 ml), and mercuric chloride (41 mg, 0.15 mm
ol) and 32 mg (0.5 mmol) of mercury oxide and add 3
Stir for 0 minutes. The insolubles are removed by filtration, and the filtrate is washed with dichloromethane. The organic layer is washed sequentially with heavy sodium bicarbonate water and water. Further, the organic layer was concentrated under reduced pressure, and the residue was diluted with hexane-ethyl acetate (5:
Purified by column chromatography in 1), 26 mg of 1S, 2R, 3R, 4R-hydroxy-2- (6-methoxycarbonyl-2-cis-hexenyl) -3-formyl-4-t-butyldimethylsilyloxycyclopentanone (65% yield). _{^{1 H NMR (CDCl 3))}} 0.08 (S, 6H), 0.88 (S, 9H), 1.60 (brs, 1H), 1.65
-1.81 (m, 3H), 1.91-2.35 (m, 8H), 2.45-2.55 (m,
1H), 2.70-2.76 (m, 2H), 3.66 (S, 3H), 4.16-4.22
(M, 1H), 4.56-4.59 (m, 1H), 5.40-5.53 (m, 2H),
9.75 (d, 1H, J = 1.83Hz) TLC: (Merck: Kieselgel 60F 254) Rf 0.6 ( hexane / ethyl acetate = 3/1)

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07F 7/08 C07F 7/08 Q 7/18 7/18 A // C07M 7:00 (58) Field surveyed (Int.Cl. . ^6, DB name) C07C 69 / 732,69 / 738 C07C 323/52 C07F 7 / 18,7 / 08 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] (1) General formula (In the formula, A represents a hydrogen atom or a protective group for a hydroxyl group, R ⁴
Represents a lower alkyl group, R ⁵ represents a lower alkyl group, a lower alkoxy group or a phenyl group which may have a chlorine atom as a substituent, and R ⁶ , R ⁷ and R ⁸ are each independently methyl And R ⁹ represents a lower alkyl group. ) A cyclopentanone derivative represented by the formula: 2. The general formula (In the formula, A, R ⁴ , R ⁵ and R ⁹ have the same meanings as described above.) 3. The general formula (Wherein, A, R ⁴ , R ⁵ and R ⁹ have the same meanings as described above). 4. General formula (In the formula, A, R ⁴ , R ⁵ and R ⁹ have the same meaning as described above, and R ¹⁰ represents a lower alkyl group.) 5. The general formula (Wherein, R ⁹ has the same meaning as described above.) 6. The general formula (Wherein, A, R ^4, R ⁵ and R ⁹ are as defined above, X and Y, when X is hydrogen atom, Y represents a hydroxyl group or R ¹⁰ COO. Where R ¹⁰ is Wherein X and Y may form a keto group.) A general formula, wherein an oxidizing agent is allowed to act on a cyclopentane derivative represented by the following formula: (In the formula, A, X, Y and R ⁹ have the same meanings as described above.) 7. The general formula (Wherein, A, R ⁴ , R ⁵ and R ⁹ have the same meanings as described above) and a general formula R ¹⁰ COOH [8] (where R ¹⁰ is a lower alkyl group Is reacted with a carboxylic acid or a derivative thereof represented by the following formula: (Wherein, A, R ⁴ , R ⁵ , R ⁹ and R ¹⁰ have the same meanings as described above), wherein an oxidizing agent is allowed to act on the derivative. (Wherein, A, R ⁹ and R ¹⁰ have the same meanings as described above.) 8. The general formula (Wherein, A, R ⁴ , R ⁵ and R ⁹ have the same meanings as described above). A cyclopentane derivative represented by the following formula is reacted with a reducing agent to obtain the cyclopentane alcohols according to claim 8. The method for producing the cyclopentanaldehyde described in the above. 9. The general formula (Wherein, A, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ have the same meanings as described above). The method for producing cyclopentane aldehydes according to claim 9, wherein the cyclopentane derivative according to claim 9 is obtained. 10. The general formula (Wherein, A, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ have the same meanings as described above). And the general formula (Wherein, A, R ⁴ , R ⁵ and R ⁹ have the same meanings as described above), wherein an oxidizing agent is allowed to act on the derivative. (Wherein, A and R ⁹ have the same meanings as described above.) 11. The general formula (Wherein, A represents. As defined above) formula LiC (OR ⁴⁾ the cyclopentenone derivative represented by ^{(SR 5) Si R 6 R} 7 R 8 (3) (wherein, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ have the same meanings as described above), and then reacting with an organic lithium derivative represented by the general formula (Wherein, X represents a halogen atom and R ⁹ has the same meaning as described above). The cyclopentanone derivative according to claim 9 or 10, which is obtained by reacting an ω-haloheptenoic acid represented by the following formula: Method for producing pentane aldehydes. 12. A is a hydrogen atom, 2-tetrahydropranyl group or ethoxyethyl group. Wherein R ₁ and R ₂ each independently represent a lower alkyl group, or a phenyl group which may have a halogen atom or a lower alkyl group as a substituent,
R ₃ represents a t-butyl group, an isopentyl group or a t-pentyl group, or a phenyl group which may have a halogen atom or a lower alkyl group as a substituent.
Alternatively, OCOR ¹⁰ (R ¹⁰ represents a lower alkyl group.) The compound described in any one of claims 1 to 5 is.