WO2004087724A1

WO2004087724A1 - PROCESS FOR PRODUCING α,ß,Ϝ-SUBSTITUTED CYCLOPENTANONE DERIVATIVE

Info

Publication number: WO2004087724A1
Application number: PCT/JP2004/004484
Authority: WO
Inventors: Akira Onodera; Yohei Kobashi; Yoshihiro Kimura; Koumei Ohta; Chihiro Yokoo
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 2003-03-31
Filing date: 2004-03-30
Publication date: 2004-10-14
Also published as: JP4591778B2; JPWO2004087724A1

Abstract

A practical process by which an α,ß,Ϝ-substituted cyclopentanone derivative which is useful as a medicine or an intermediate for medicine production is more efficiently and safely produced than known techniques. The compound having a desired stereostructure can be highly stereoselectively produced in a satisfactory yield.

Description

Statement

Method for producing a, i3, α-substituted cyclopenenones

Technical field

The present invention relates to a, ^, α-substitution useful as a pharmaceutical or a synthetic intermediate thereof.

'Regarding the method for producing derivatives.

Background art

, β, α-Substituted cyclopentenonone derivatives are useful as pharmaceuticals or their intermediates.

In particular, 13,14-didehydroprostaglandin derivatives (compounds represented by the following formula), which are α ,, α-substituted cyclopentenonone derivatives having a triple bond at the 13-position, have recently attracted attention as compounds having a strong platelet aggregation inhibitory action (Japanese Patent Application Laid-Open No. Hei 6-192922).

X: 0 or S

R: H or He However, there are very few methods for producing 13,14-didehydroprostaglandin E derivatives so far, and to our knowledge only four examples are known. The first example is a method for producing a 13,14-didehydroprostaglandin E derivative using the key reaction of ring opening of an epoxide with an organoaluminum acetylide reagent as shown in Reaction Formula 1 below (J. Fr. i ed et al., Te trahedron Letters, 1973, 14, 3899-3902.).

In this production method, the production of an optically active epoxide, which is a production intermediate, is complicated, the optical resolution efficiency is poor, and the regioselectivity in the ring-opening reaction of the epoxide, which is a key reaction, is low, so that it lacks practicality.

The second example is a production example using Corey lactone as a starting material, as shown in the following reaction formula 2. At the same time, the dehydrohalogenation reaction is allowed to proceed during the Wittig reaction to form a triple bond at the 13-position, resulting in 13,14-didehydroprostaglandin E. This is a method for producing derivatives ( Gandolfi et al., Π Farmaco Edition Sciences, 27, 1255 (1972).)

This production method uses Corey lactone, which is available on an industrial scale, and the dehydrohalogenation reaction of the iS side chain progresses when the α side chain is introduced by the Wittig reaction, creating a triple bond. There is practicality such as. However, 0: since the selective reduction of the triple bond of a double bond and jS side chain in the side chain is found, 13, it is hard to say that practical preparation of 14- E _x derivative. A third example is a method for producing a 13,14-didehydroprostaglandin Ε derivative by reacting an α, α-substituted cyclopentenone derivative with an organometallic reagent represented by the following formula [Β] (Patent No. 2) No. 5,366,226), and the claims contain an organometallic reagent containing a triple bond [Β], but there is no description of the examples.

CuCNLh [B]

0Y

In the fourth example, as shown in the following reaction formula 3, an organoaluminum acetylide reagent is allowed to act on a cyclopentenone derivative having a getylaminomethyl group at the α-position to form an exomethylene compound, and then the α side chain is formed. This is a method for producing a 13,14-didehydroprostaglandin derivative by adding Michael (F. Sato et al., J. Org. Chem., 1991, 56, 3205-3207.).

IZn (CN) Cu C0 ₂ Me

Chain)

TMSC I

R1

=

OTBS (T S) R1 = alkyl group, cyclohexyl group

In this production method, after introducing the three side chains, the a side chain is introduced stepwise, which is advantageous for producing a wide variety of derivatives. However, in this production method, it can be obtained by the introduction reaction of i3 side chain. The ratio of the trans-form to the cis-form of the exo-methylene form fluctuates greatly, from 1.5 to 23: 1, making it difficult to obtain the desired trans-form stably (see Table 1).

table 1

Trance

82: 14

0TBS

83: 8

0TBS

90: 4

0 ¾J, 3 J

50:19 In addition, toxic copper cyanide is used when preparing the α 'side chain organocopper reagent, which is disadvantageous in terms of manufacturing costs, such as the necessity of safety measures and environmental measures in practical use. is there. On the other hand, there is a report of a Michael addition reaction of an organometallic reagent to an α-substituted cycloalkenone derivative in the presence of a trialkylsilyl triflate (Kim et al., Tetrahedron Letters, 1990, 31, 7627-7630). , Kim et al., Synlett, 1995, 163-164.). However, there has been no application of this reaction to a derivative having a hydroxyl group or a protected hydroxyl group at the a-position of the i3-unsaturated cyclopentenone ring. hand

However, a method of introducing the i3 side chain into the trans configuration with high stereoselectivity is not known.

Further, by subjecting the obtained α, β, α-substituted cyclopentene non-trialkylsilyl enol ether to a non-aqueous condition with a mineral acid, an organic acid or a Lewis acid to remove the trialkylsilyl, There is no known example of directing the side chain to the trans configuration in a highly stereoselective manner with respect to the i3 side chain. 'Disclosure of the invention'

The present inventors have made intensive studies to achieve the above object, and as a result, in the presence of a trialkylsilyl triflate, an a, r-substituted cyclopentenone derivative represented by the formula [I] was converted to a compound represented by the formula [III]. By reacting the substituted ethynyl organometallic reagent shown, a substituted ethynyl group can be introduced at the / 3 position in a highly stereoselective manner. Thus, the present inventors have found a process for obtaining a 1,3-i-substituted cyclopentene nonone derivative with higher yield and higher stereoselectivity than ever before, and completed the present invention.

That is, the present invention is shown as follows.

1) The following formula [I]

Two

[Where A is the formula [II]

(In the formula, X ¹ and X ² are the same or different and represent an oxygen atom, a sulfur atom, a methylene group, a vinylene group, an ethynylene group or an arelenylene group, and n and q are the same or different and represent an integer of 0 to 6, ni and p are the same or different and each represent an integer of 0 to 2, r represents an integer of 0 to 3.), R ¹ represents a hydrogen atom, a nitrile group, -OR ⁶ (formula Wherein R ⁶ represents a hydroxyl-protecting group.) Or -C00R ⁷ (wherein, R ⁷ is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted carbon atom number) 2 to 10 alkenyl groups, substituted or unsubstituted alkynyl groups, 2 to 10 alkynyl groups, substituted or unsubstituted cycloalkyl groups, having 3 to 10 carbon atoms, substituted or unsubstituted phenyl a group or a protecting group of carboxyl group.) indicates, R ² is protected hydroxyl groups Represents a group. And an α-substituted cyclo derivative represented by the following formula [III]:

[In the formula, M (wherein, R ⁸ is. Represents an alkyl group of one to six carbon atoms) BrZn or LiR ⁸ ₃ Al indicates, R ³ is a substituted or unsubstituted carbon atoms 1 to 1 0 alkyl groups, substituted or unsubstituted alkenyl groups having 2 to 10 carbon atoms, substituted or unsubstituted alkynyl groups having 2 to 10 carbon atoms, substituted or unsubstituted carbon atoms A cycloalkyl group having 3 to 10 cycloalkyl groups, a substituted or unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenoxy group; Z represents a hydrogen atom or Z′R ⁴ (wherein Z ′ represents an oxygen atom or a sulfur atom, and R ⁴ represents a hydroxyl-protecting group or a thiol-protecting group). Characterized by reacting with an organometallic reagent represented by the following formula in the presence of a trialkylsilyl triflate:

Wherein, R5 represents a trialkylsilyl group, A, RR ^2, R ³ and Z are Ru as defined der above. The method for producing an α, β, τ-substituted cyclopentene non-trialkylsilyl enol ester represented by the formula:

2) In the formula [IV] described in 1), A, R ¹ , R ² , R ³ , R ⁵ and Z are as defined above. A non-aqueous condition of an α, β, τ-substituted cyclopentene non-trialkylsilyl enol ether represented by the formula [V]

[Wherein, RR ² , R ³ and Z are as defined above. A method for producing a, i3, α-substituted cyclopentene non-derivatives represented by the formula:

3) The formula [I] described in 1) [wherein, A, R ¹ and R ² are as defined above. Α, τ-substituted cyclopentenone derivative represented by the formula [III] wherein R ³ , M and Z are as defined above. Wherein at least one equivalent of trialkylsilyl triflate is used in the reaction with the organometallic reagent represented by the formula [V]

Wherein A, R ¹ , R ² , R ³ and Z are as defined above. A method for producing an α, 3, α-substituted cyclopentenonone derivative represented by the formula:

The present invention will be described in detail, but is not particularly limited to those exemplified.

In the present invention, the substituted or unsubstituted alkyl group having 1 to 10 carbon atoms means a linear or branched alkyl group, such as a methyl group, an ethyl group, an η-propyl group, and an isopropyl group. , Η-butyl group, isobutyl group, t_butyl group, n-pentyl group, n-hexyl group, 2-methylpentyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycle Hexoxyloxymethyl, benzyl, phenoxymethyl, 2-methoxyethyl, 2-chloroisopropyl, 2-methylhexyl, 2,5-dimethylhexyl, 2,6-dimethylheptyl Group, 2- (2, -methylcyclohexyl) pentyl group, n-octyl group, 3- (3'-methoxyphenyl) octyl group, 5-chloromethoxyheptyl group, n-decanyl group .

The substituent in the alkyl group is not particularly limited as long as it does not participate in the reaction.Examples include a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyloxy group having 3 to 10 carbon atoms, and phenyl. Group, phenoxy group, linear or branched alkoxy group having 1 to 4 carbon atoms, and one or more groups selected from the group consisting of octylogen atoms. Alkyl, cycloalkyloxy, phenyl and phenoxy groups are unsubstituted, one or more halogen atoms, linear or branched alkyl groups having 1 to 4 carbon atoms or carbon atoms It may have several to four substituents such as a linear or branched alkoxy group.

Examples of the halogen atom include fluorine, chlorine, bromine, and iodine.

Examples of the linear or branched alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an isopropyl group and a t-butyl group.

Examples of the linear or branched alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an isopropyloxy group, an 11-butoxy group and a t-butoxy group.

The substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms means a linear or branched alkenyl group, such as a bier group, an aryl group, a 2,6-dimethyl-5-heptenyl group, 1,3-butadienyl group, Γ-propenyl-butenyl group, 4-pentenyl group, 3-chloro-1,5-hexagenenyl group, 2-methyl-4-pentenyl group,-(1'-ethoxyl) 2-methyl-4-pentenyl group, 3-ethyl-4- (4'-methoxycyclohexyl) -1,5-hexenyl group and 3-isopropyl-4-pentenyl group.

The substituent in the alkenyl group is not particularly limited as long as it does not participate in the reaction.Examples include a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyloxy group having 3 to 10 carbon atoms, and phenyl. Group, a phenoxy group, a linear or branched alkoxy group having 1 to 4 carbon atoms, and one or more groups selected from the group consisting of halogen atoms. Among them, cycloalkyl group, cycloalkyloxy group, phenyl group and phenoxy group are unsubstituted, one or more halogen atoms, linear or branched having 1 to 4 carbon atoms. It may have a substituent such as a chain alkyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms.

The substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms means a linear or branched alkynyl group, for example, 2-propynyl group, n-butynyl group, n-decynyl group, 2- Bromo-3-pentynyl, 2-methyl-5-heptynyl, 2-methoxy-6-methyl-7-en-3-octynyl, 3-cyclohexyloxy-1-en-4- A xynyl group.

The substituent in the alkynyl group is not particularly limited as long as it does not participate in the reaction, for example, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyloxy group having 3 to 10 carbon atoms, phenyl Group, phenoxy group, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom and linear or branched alkenyl group having 2 to 6 carbon atoms. One or more selected groups may be mentioned. Among them, a cycloalkyl group, a cycloalkyloxy group, a phenyl group and a phenoxy group are unsubstituted. One or more halogen atoms, 1 carbon atom It may have a substituent such as a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkoxy group having 1 to 4 carbon atoms.

A linear or branched alkenyl group having 2 to 6 carbon atoms is, for example, a vinyl group, a propenyl group, a 2-methyl-2-butenyl group, a 1,3-butadienyl group, a 2,4- Dimethyl-1,4-pentenyl phenyl group.

A linear or branched alkyl group having 1 to 6 carbon atoms is, for example, a methyl group, an ethyl group, an isopropyl group, an n-propyl group, an n-butyl group, a t-butyl group, a hexyl group Are listed.

A substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms is, for example, a cycl group, a cyclobutyl group, a cyclopentyl group, a 2,4-dimethylcyclopentyl group, a cyclohexyl group, a 2-methylcyclo group. Hexyl, 4-isobutylcyclohexyl, cycloheptyl, 3-chloro-4-methoxycycloheptyl, and 4-butoxycyclooctyl. The substituent in the cycloalkyl group is not particularly limited as long as it does not participate in the reaction.

For example, one selected from the group consisting of octylogen atoms, linear or branched alkyl groups having 1 to 4 carbon atoms, and linear or branched alkoxy groups having 1 to 4 carbon atoms. Or more than one group.

Examples of the substituted or unsubstituted phenyl group include a phenyl group, a 4-bromophenyl group, and a 2-methyl-4-methoxyphenyl group.

The substituent in the phenyl group is not particularly limited as long as it does not participate in the reaction.Examples include a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a carbon atom having 1 to 4 carbon atoms. One or more groups selected from the group of four linear or branched alkoxy groups.

Examples of the substituted or unsubstituted phenoxy group include a phenoxy group, a 2-methylphenoxy group, a 2-chlorophenoxy group, and a 4-isopropoxyphenoxy group.

The substituent in the phenoxy group is not particularly limited as long as it does not participate in the reaction.Examples include a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a carbon atom having 1 to 4 carbon atoms. And one or more groups selected from the group consisting of a single linear or branched alkoxy group.

Examples of the substituted or unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms include a 2-methylcyclohexyloxy group and a 3-bromooxyheptyloxy group.

The substituent in the cycloalkyloxy group is not particularly limited as long as it does not take part in the reaction. Examples thereof include an octogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a carbon atom. One or a plurality of groups selected from the group of linear or branched alkoxy groups having a number of 1 to 4 are exemplified.

The protecting group for the lipoxyl group may be any group that functions as a protecting group in each reaction, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, a benzyl group, a substituted benzyl group. And diphenylmethyl group, methoxymethyl group, trichloroethyl group, triethylsilyl group, t-butyldimethylsilyl group, 2- (trimethylylsilyl) ethyl group, and aryl group.

The substituted benzyl group is not particularly limited as long as it does not participate in the reaction. One or more groups selected from the group consisting of a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms and a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms. Any group may be used as long as it is a substituent on the benzene ring, and examples thereof include 4-chlorobenzyl, 2,6-dimethylpentyl, and 2-bromo-4-methylbenzyl.

The hydroxyl-protecting group may be any group that functions as a protecting group in each reaction, and includes a trialkylsilyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, a trityl group or a tetrahydropyranyl (THP) group. For example, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, methoxymethyl group, benzyloxymethyl group, acetyl group, benzoyl group, benzyl group, P-methoxybenzyl group, p-methoxybenzyl group, And a tri (P-methoxyphenyl) methyl group and a benzyloxycarbonyl group. The protecting group for the thiol group may be any group that functions as a protecting group in each reaction, and examples thereof include a benzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a trityl group, a methoxymethyl group, and a benzyloxycarbonyl group. .

The trialkylsilyl triflate includes, for example, t-butyldimethylsilyl triflate. The trialkylsilyl group includes, for example, a trimethylsilyl group, a t-butyldimethylsilyl group, and a triethylsilyl group.

The acid includes a mineral acid, an organic acid, a Lewis acid, and the like. More specifically, the mineral acid includes, for example, an organic solvent solution of hydrogen chloride, concentrated sulfuric acid, and phosphoric acid.

Examples of the organic acid include trifluoroacetic acid, benzenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid, and dodecylbenzene sulfonic acid.

Lewis acids include, for example, titanium (IV) chloride, zinc chloride, zinc bromide, zinc trifluoromethanesulfonate, magnesium perchlorate, magnesium trifluoromethanesulfonate, boron trifluoride-ethyl chloride complex, aluminum chloride ( 111) and getyl aluminum chloride. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail, but is not particularly limited to those exemplified.

The compound of the formula [I] can be produced, for example, according to the method described in Patent No. 2570796, Eur. J. Org. Chem. 1999, 265-2662, and the like.

In addition, the compound of the formula [III] can be prepared according to a usual method for preparing an organometallic reagent. For example, when preparing an organozinc reagent of the formula [III] (M is BrZn), first heat active zinc and 1,2-dibromoethane in tetrahydrofuran to prepare a tetrahydrofuran solution of zinc bromide (ZnBr ₂ ). Then, it can be prepared by adding it to a separately prepared lithium salt represented by the formula [III] '»ii (CHI). In this method, the amount of zinc bromide used is 0.5 to 2 equivalents, preferably 0.8 to 1.2 equivalents are good.

Organoaluminum ate complex can be prepared by adding trialkylaluminum (A1R ⁸ ₃₎ the lithium salt of the formula was prepared in the same manner as described above [III] '. In this method, the amount of the trialkylaluminum used is 0.5 to 2 equivalents, preferably 0.8 to 1.2 equivalents, relative to the lithium salt. The solvent used for the preparation of the compound of the formula [II] is not particularly limited and may be any solvent which does not inhibit the reaction, and examples thereof include tetrahydrofuran, geethylether, cyclopentyl methyl ether, toluene and hexane.

The compound of the formula [IV] can be produced, for example, by the following method.

In the reaction of the compound of the formula [I] with the organozinc reagent of the formula [111] (M is BrZn), the trialkylsilyl triflate is added to the compound of the formula [I] in an amount of 0.5 to 5 equivalents, preferably 0.8 to 5 equivalents. The organic zinc reagent of the formula [III] is used in an amount of 0.5 to 5 equivalents, preferably 0.8 to 3 equivalents to the compound of the formula [I]. The reaction temperature is -100 to 50 ° C, preferably -80 to 30 ° C, and the reaction time is usually 5 minutes to 50 hours. On the other hand, with respect to the compound of formula in the reaction of the organoaluminum § over preparative complex of a compound of [I] and formula [III] (M is LiR ⁸ ₃ Al), the formula [I], 0.5 to the Toriarukirushi Lil triflate 3 equivalents, preferably 0.8 to 2 equivalents, when the organoaluminate complex of the formula [III] is used in an amount of 0.5 to 4 equivalents, preferably 0.8 to 2 equivalents to the compound of the formula [I] Is good. The reaction temperature is -100 to 20 ° C, preferably _80 to 0 ° C, and the reaction time is usually 5 minutes to 5 hours. The solvent used in these reactions is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, getyl ether, cyclopentylmethyl ether, hexane, and toluene.

In the reaction with organic § Ruminiumuato complex (M is LiR ⁸ ₃ Al) compounds and organozinc reagent of formula [III] of the formula [I] (M is BrZn), or Formula [III],] 3-position of The substituted ethynyl group side chain is introduced into the trans configuration in a highly stereoselective manner to the protected hydroxyl group at the α-position. In particular, in the compound represented by the formula [III], when R ³ is a cyclohexyl group, Z is Z′R ⁴ , Z ′ is an oxygen atom, and R is a t_butyldimethylsilyl group, a very high stereoselectivity Sex was obtained.

The compound of the formula [V] can be produced, for example, by the following method, that is, a method of reacting a compound of the formula [IV] with an acid under non-aqueous conditions. Examples of the acid include a mineral acid, an organic acid, and a Lewis acid, and preferably include benzenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid, and magnesium perchlorate. The acid is used in an amount of 0.5 to 3 equivalents, preferably 1 to 2 equivalents, to the compound of the formula [IV]. The reaction temperature is −100 to 50 ° C., preferably −80 to 30 ° C., and the reaction time is usually 0.5 to 20 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction, and examples include tetrahydrofuran, getyl ether, dichloromethane, chloroform, toluene, and acetonitrile.

In the above detrialkylsilylation reaction, the side chain is highly stereoselectively induced in the trans configuration with respect to the β side chain.

In another embodiment of the present invention, a compound of the formula [IV] is reacted with a compound of the formula [I] and an organometallic reagent of the formula [111] in the presence of one or more equivalents of a trialkylsilyl triflate. This is a process for obtaining a compound of the formula [V] at a stroke without isolating the compound of formula (I).

The term “1 equivalent or more” as used herein means that the trialkylsilyl triflate is 1 to 3 equivalents, preferably 1.5 to 2.5 equivalents, based on the organometallic reagent of the formula [III].

For example, when t-butyldimethylsilyl triflate is used as the trialkylsilyl triflate, the amount of the organozinc reagent of the formula [III] (M is BrZn) to the compound of the formula [I] is 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, and the amount of topyldimethylsilyl triflate used is 1 to 3 equivalents, preferably 1., based on the organozinc reagent of the formula [III] (M is BrZn). 5-2.5 It is better to use the equivalent. The reaction temperature is −100 to 50 ° C., preferably −80 to 30 ° C., and the reaction time is usually 150 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, getyl ether, cyclopentyl methyl ether, hexane, and toluene.

Further, the present invention will be described with reference to Examples and Comparative Examples with the conventional method.

1) By utilizing the present invention, a 1314-didehydroprostaglandin E derivative having a strong physiological activity can be produced safely without using toxic substances, in high yield, high stereoselectivity, and industrially advantageous. I was able to.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples. In the following examples, THF represents tetrahydrofuran, Me represents a methyl group, TBS represents a t-butyldimethylsilyl group, TES represents a triethylsilyl group, and HPLC represents high-performance liquid chromatography. Example

Compound 4 (0.23 g, 0.81 mmol) was dissolved in geethyl ether (3.2 mL) and n-butyllithium (1.57 M, n-hexane solution, 0.51 mL, 0.80 ol) was used at -10 ° C under an argon atmosphere. Was added dropwise and stirred for 20 minutes. After further cooling to −78 ° C., trimethylaluminum (Ι.ΟΟΜ, η-hexane solution, 0.81 mL 0.81 liter) was added dropwise and stirred for 30 minutes. To this was added a solution of compound 1 (0.20 g, 0.54 dragonol) in ethyl ether (1.6 mL), followed by a solution of t-butyldimethylsilyl triflate (0.18 g, 0.69I O1) in dimethyl ether (1.6 mL). . After stirring at the same temperature for 1 hour, a saturated aqueous solution of carbon dioxide was added, extracted with getyl ether, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue (compound 2: compound 3 = 144: 1 by HPLC) was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 20: 1) to give the compound · (

HI ') 82-' (Ηΐ 'ιπ) 80''(HC' fL "g '(HZ'II" 8 '(HZ Ά = ί Ί) S9' I '(HI ¾) 89' Z-99 '' (IK ^£ ui) L 18 ΐ · 1 '(Η8ΐ' 90 — 8S · Γ (H9 ') 82 Ί-δ6 · 0' (Η6 'δ) 26 · 0' (Η6 'δ) 06 · 0' (Η6 's) 680'(Η9's) Ζ ΓΟ '(Η9's) ΟΓΟ' (HS '80 · 0 '(HC' δ) 10 · 0: π Μ ρ (Zffi¾OOZ '3 (D) 丽- Η,

° ¾ ¾ (% ο · Ζ8 «'su' m

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° Pot Fiber Xiao 30 Okina ¾

, ¥ ¾ao 缀氺 ma η 翻 τ ^ mm ° ^ wm (™ · 8) ^ — ェ ^ ェ ω (丽 · ε

'§98 · 0) 4—

缪缪 C 0 · 8) 4 ί 10 (10 maraud 89 'I' §00 Ί) I ^ コ ° 1 ¾ ^ 0 S 丄 Fiber (10 strokes' S0

i, tsuto (1. 丽 so · ^£ TO 'I' ¾¾ -fr ÷ -u '· ΐ) ma fi-u ^ CH-丄 Μ ^ (^^ m ^ (Ί ^ιι ' 0 · 9Ι) One (louuneo 't' §Ζ0 Ί) Ζ f ^^ J-

• (HI -9-30 · 3 '(Ηΐ' 9 'ΐ' 0 Ά = ί 'WZf 1 (Ηΐ' ZHS '' Z · Ζ = ί 'WLZ'f (HS' s) L '8' (HZ 's) IS' (HI 122_6ΐ '8' (HS 09 'Z-09' I '(HZ' ω) II -ίΙ 'I' (H8 90 · Ζ- 06 T (HS 's) 89' ΐ '(Η8' s) 09 T (Η8Ϊ ¾) 62, 1-80 T (H6 's) 26 · 0' (H6 '§) 6800' (HS 'ω) 16 · 0-8 (Η8Ι ¾) 2ΐ · 0-Α0 · 0: (1 ρ (¾) 0S ' ^S I »leakage Η,

° ¾ ¾ (¾8 · 69 umbrella '§62 · 0' 呦 ^ Ζ

9ΐ

Compound 11 (0.20 g, 2.04 dishes ol) was dissolved in THF (4.8 mL), and n-, butyllithium (1.57 M, n-hexane solution, 1.8 mL, 2.01 tol) was dissolved in an argon atmosphere at −10 ° C. ) Was added dropwise and stirred for 20 minutes. After further cooling to -78 ° C, trimethylaluminum (1.00 M, n-hexane solution, 2. OlmL, 2.01 benzene) was added dropwise and stirred for 30 minutes. To this was added a solution of compound 8 (0.30 g, 0.81 mmol) in dimethyl ether (2 mL), followed by a solution of t-butyldimethylsilyl triflate (0.43 g, 1.63 liter) in dimethyl ether (2.4 mL). Was added. After stirring at the same temperature for 1 hour, a saturated aqueous solution of potassium carbonate was added, extracted with getyl ether, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue (compound 9: compound 10 = 75: 1 by HPLC) was subjected to silica gel column chromatography (elution solvent: n-hexane: getyl ether = 20: 1) to give compound 9 (oil, 0.37 g, Yield 78.0%).

^{_{1 H-NMR (CDC1 3,}} 300MHz) δ ppm; 0.09 (s, 3H), 0.10 (s, 3H), 0.11 (s, 3H), 0.12 (s, 3H), 0.84- 0.98 (m, 3H), 0.89 (s, 9H), 0.93 (s, 9H), 1.18-1.70 (m, 12H), 2.10-2.28 (m, 3H), 2.46-2.66 (m, 3H), 3.14-3.22 (m, 1H), 3.22 (s, 2H), 3.73 (s, 3H), 4.22-4.30 (m, 1H).

12 ★: Compound 7 (1.70 g, 6.7 lMiol) showing relative configuration was dissolved in geethylether (6.8 mL), and n-butyllithium (1.37 M, n-hexane solution, -40 ° C) was dissolved in an argon atmosphere at _40 ° C. 90 mL, 6.71 t), add 15 minutes of stirring, add zinc chloride (1.0 M, THF solution, 6.70 mL, 6.70 t) at the same temperature, and stir at room temperature for 10 minutes. Was. After cooling to -40 ° C again, compound 8 (1.0 (^, 2.69 thigh 01) in getyl ether (4.0) solution, t-butyldimethylsilyl triflate (1.54 mL, 6.70 liters) was added, and the mixture was added at the same temperature for 30 minutes. The mixture was stirred for 1 hour at 0 ° C. and for 4 hours at room temperature A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, extracted with diethyl ether, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 1 → 5: 1) to obtain Compound 12 (oil, 1.73 g, yield 87.2%).

_{1 H-NMR (CDC1 3,} 200MHz) δ ppm; 0.07 (s, 3H), 0.08 (s, 3H), 0.10 (s, 6H), 0.12 (s, 6H), 0.89 (s, 9H), 0.90 ( s, 9H), 0.93 (s, 9H), 0.93-1.28 (m, 8H), 1.38-2.05 (m, 9H), 2.18- 2.27 (m, 2H), 2.56-2.58 (m, 1H), 2.63 ( t, J = 7.0Hz, 2H), 3.22 (s, 2H), 3.74 (s, 3H), 4.08 (m, 1H), 4.28 (m, 1H)

Example 5

Compound 7 (0.85 g, 3.35 mraol) was rapidly dissolved in geethylether (3.4 mL), and n-butyllithium (1.37 M, n-hexane solution, 2.45 mL, 3.36 t ol) and stirred for 15 minutes, then zinc bromide (1.0 M, THF solution, 3.35 mL, 3.35 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled again to -40 ° C, and a solution of Compound 1 (0.50 g, 1.34 ol) in getyl ether (2.OmL) and triethylsilyl triflate (0.76 mL, 3.36 inol) were added. 30 minutes at temperature 0. The mixture was stirred at room temperature for 1 hour and at room temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 1 → 5: 1) to obtain Compound 13 (oil, 0.79 g, yield 79.1%).

1 H -丽_{R (CDC1 3, 200MHz) δ} ppm; 0.07 (s, 3H), 0.08 (s, 3H), 0.09 (s, 6H), 0.64 (q, 1 = 1.8Hz, 6H),

剁 ^, ι¾¾ (ιο ο ο 'ο · ο) 邈伞 ^ L0 _o L-, 缀 :: KWT9) く ^ ロ (I0 drawing'0'§0 0) 2 T?

• (HI 'ui) l--S0-S' (Hl 'in) A' G 6S-\ '(HI' 9 = ί 'Β) 8Z' (HS 's) l "g' (H 's ) ΪΖ 'S (Ht ZL 16S' I '(HZ U' I -Zl T (HZ (ui) 90-98 ・ Γ (HS 's) 89 Ί' (Η8 '65 Ί 'O 8 -80Ί' (Η6 's) 06 Ό' (H6 's) 68 Ό' (HC 's) ci · 0'(HS's) n · 0 '(H' s) 60 · 0 '(HS' s) 80 O ^ dd ρ ( zflWOOS ' ^ε 13 (D) leak-H,

(% z08 male 'ι.o) τ (i

: 2 = 腳:-(+. Φν-ιι:

'Γι ¾ (I

: 0 Z = S I: ^ T ^ q Q 31dH) ¾¾ ° ¾ ^ 鹦 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

氺氺

, ¥ 1¾¾ (10 丽 ^ 0 '0'0)

• (Ηΐ'ιπ) OS--'(Ηΐ ¾) 601 -SO 1' (HS 's) l · £'(ΗΖ'δ) 22 · 2 ^£ (HZ 'ZHO = 1 S9' I '(HI 09 0-Ί '(HZ LI -0 Ζ' I '(H6' ui) ΟΟ'Ζ-92 'ΐ' (H6 'z 脱 0 = ί) 86 860' (Η8 ¾) ΖΖ '(Η6' s) 68

6ΐ i ^ o / toozdf / e :) d numa too OAV An aqueous thorium solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue (compound 16: compound 17 = 71: 1 by HPLC) was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 15: 1) to give compound 16 (0.23 g, yield 86.3%). Got.

^{_{1 H-NMR (CDC1 3,}} 200MHz) δ ppm; 0.08 (s, 3H), 0.09 (s, 3H), 0.10 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H), 0.90 ( s, 9H), 0.93-1.28 (ra, 5H), 1.41-1.90 (m, 12H), 2.13-2.2 (m, 2H), 2.63 (t, J-7. OHz, 2H), 2.65-2.72 (m , 2H), 3.2 (s, 2H), 3.74 (s, 3H), 4.09 (dd, J = 1.2, 2.6Hz, 1H), 4.29 (dd, J = 6.7, 13.4Hz, 1H). 8

★ Dissolve compound 9 (0.20 g, 0.34 tmol) showing relative configuration in dichloromethane (4. OiiiL), add benzenesulfonic acid (0.06 g, 0.38 mmol) at -78 ° C, and at the same temperature for 3 hours Stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue (compound 18: compound 19 = 40: 1 by HPLC) was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 20: 1) to give compound 18 (0.130 g, yield 81.3). %).

^{_{1 H-NMR (CDC1 3,}} 300MHz) <5 pm; 0.10 (s, 3H), 0.13 (s, 3H), 0.84-0.92 (m, 3H), 0.90 (s, 9H), 1.21-1.41 (m, 4H), 1.42-1.82 (m, 8Η), 2.10-2.22 (m, 4Η), 2.60-2.71 (m, 4Η), 3.22 (s, 2H),

Example 9

16

★ Show the relative configuration Compound 7 (0.43 1.6811111101) was dissolved in Getyl ether (3.½) and n-butyllithium (1.37 M, n-hexane solution, 1.22 mL, 1.67 t ol), stirred for 15 minutes, and then added the same temperature at the same temperature, followed by stirring at room temperature for 10 minutes at room temperature. Then, the reaction solution was cooled to 0 ° C, and a solution of compound 8 (0.50 g, 1.34 bandol) in acetyl ether (4.0 ml) and topyldimethylsilyl triflate (0.77 mL, 3.35 nmol) were added. The mixture was stirred at the temperature for 7 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, extracted with a jet filter, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 100: 1 → 5: 1) to obtain Compound 16 (oil, 0.36 g, yield 42.9%).

The ¹ H-NMR spectrum of this product was identical to the spectrum of compound 16 obtained in Example 7.

Example 10

30 31 Compound 5 (0.30 g, 0.41 mmol) was dissolved in dichloromethane (6.0 mL), benzenesulfonic acid (0.07 g, 0.40 mmol) was added at -781, and the mixture was stirred at the same temperature for 2 hours. Further, benzenesulfonic acid (0.14 0.80 bandage 01) was added thereto, and the mixture was stirred at the same temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Residue (Compound 30: Compound 31 = 24: 1 by HPLC)

ο τ ~! : Towing, ¾

= ί 'ΡΡ) 62' (Ηΐ9 '9' 1 = 1 'ΡΡ) 80' \ '(Η8' L '8' (HZ 's) U' S '(¾) (HZ 'ZHO · ί = ί' 1) 89 'I' (HZ 'πι) lW (Z \ 06' 1-62 T (HS '«OS' 0 '(H6 '06 · 0' (H6 's) 68 '0' (HS 's) Z ΐ · 0' (HS 's) Οΐ · 0' (HS '60 · 0 '(H' s) 80 · 0: uidd ρ (mOOZ ';) (D) 丽-H,

(% L * 88 '§SZ, 0) 0 £, Π

And

U [Table 2]

3H),,, 4.38-4.43 (m, IH),

,

(i ^) [z 辇]

u

iLLmi mz OAV [Table 2] (continued 2)

2) According to the present invention, the substituted echel side chain at the i3 position is introduced into the trans configuration in a highly stereoselective manner with respect to the protected hydroxyl group at the a position to efficiently obtain a trans form having a desired high physiological activity. (See Table 3). The right column of Table 3 shows the results of the present invention, and the left column shows the results of the conventional method (Table 1).

Dimension ID

CO

Dimension

00

3) The detrialkylsilylation reaction with an acid under non-aqueous conditions of the present invention can control the α side chain to the trans configuration in a highly stereoselective manner with respect to the 3 side chains. As an example, Table 4 shows the results of the detrialkylsilyl terrifying reaction of the t-butyldimethylsilyl enol ether. For comparison, the results for the hydrous system are shown in Reaction Formula 4. The ratio of the trans-form to the cis-form in the detrialkylsilylation reaction by an acid under non-aqueous conditions of the present invention is from 24 to 220: 1, and the desired trans-form is higher than that in a water-containing system. Highly stereoselective. Table 4

4) Compound 1 and compound 8 used in the present invention can be obtained by the following methods (Reference Examples 1 to 13), but are not limited to these Reference Examples.

20 21

Compound 20 (100 g, 0.55 mol) was dissolved in methanol (300 mL), and methyl thioglycolate (64.5 g, 0.61 mol) was added, followed by stirring at room temperature. To this was added sodium methoxide (62.7 g, 1.16 mol) at 5 ° C over 2 hours, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized by adding concentrated hydrochloric acid (5. OmL) at 0 ° C., about half of methanol was distilled off, water and diluted hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude compound 21 (oil, 120 g, crude yield 105.8%).

^{_{1 H-NMR (CDC1 3,}} 200MHz) δ ppm; 159-l.82 (m, 4H), 2.39 (. T, J-7 OHz, 2H), 2.66 (. T, J-7 OHz, 2H), 3.23 (s, 2H), 3.75 (s, 3H). Reference example 2

21 Crude compound 21 (115 g, 0.56 mol) was dissolved in carbon tetrachloride (580 mL), and triethylamine (59.7 g, 0.59 mol) was added, followed by stirring at room temperature. To this, chloroacetyl chloride (66.6 g, 0.59 mol) was added over 40 minutes at 0 and stirred for 3 hours. The precipitated crystals were separated by filtration, and to the filtrate were added furan (59.6 g, 0.88 mol) and boron trifluoride geethylether complex (7.OOmL, 56 mmol), and the mixture was stirred at room temperature for 16 hours. A 5% aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude compound 22 (oil, 19 g, crude yield 90.1%). ).

_{'H-NMR (CDC1 3,} 200MHz) δ ppm; 160-1.90 (m, 4H), 2.68 (t, J = 7.0Hz, 2H), 2.86 (t, J = 7.0Hz, 2H), 3.23 (s, 2H), 3.7 (s, 3H), 6.54 (dd, J = l.6, 3.6Hz, 1H), 7.19 (dd, J = 0.8, 3.6Hz, 1H), 7.59 (dd, J = 0.8, 1.6Hz) , lH). Reference example 3

22 23 Crude compound 22 (129 g, 0.50 mol) was dissolved in methanol (640 mL), sodium borohydride (7.23 g, 0.19 mol) was added little by little at 2 ° C., and the mixture was stirred for 40 minutes. To this was added 2% aqueous sodium hydrogen sulfite and diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude compound 23 (oil, 97.5 g, crude yield 75.2%).

^{_{1 H-NMR (CDC1 3,}} 200MHz) δ ppm; 1.38-1.75 (m, 4H), 1.87 (. Q, J = 7 OHz, 2H), 2.64 (. T, J = 7 OHz, 2H), 3.24 ( s, 2H), 3.74 (s, 3H), 4.69 (t, J = 7.OHz, IH), 6.24 (dd, J-0.8, 3.6Hz, IH), 6.34 (dd, J = 1.8,3.6Hz, IH), 7.38 (dd, J = 0.8, 1.8Hz, IH) .Reference Example 4

Crude compound 23 (92.5 g, 0.36 mol) was dissolved in 1,4-dioxane (512 mL), and an aqueous zinc chloride solution (ZnCl ₂ : 185 1.3611101+ 0: 30510) was heated and stirred. After 1 hour, 1,4-dioxane was distilled off, a saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Compound 24 (oil, 69.3 g, crude yield 74.9%) was obtained.

¹ H -丽_{R (CDC1 3, 200MHz) δ} ppm; l.35-1.78 (m, 6H), 1.78-2.00 (m, 1H), 2.20-2.30 (m, IH), 2.67 (t, 2H), 3.24 (s, 2H), 3.75 (s, 3H), 4.71 (brs, IH), 6.21 (dd, J = l.4, 5.8Hz, IH), 7.51 (dd, J = 2.2, 5.8Hz, IH) .

Crude compound 24 (69.1 g, 0.27 mol) was dissolved in toluene (485 mL), and triethylamine (29. Og, 0.29 mol) and kualaral (2.08 mL, 0.02 mol) were added, followed by stirring at room temperature for 2 hours. The reaction solution was directly subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 1 → 1: 2) to give Compound 25 (oil, 39.8 g, 30.9% yield from Compound 20). ).

_{1 H-NMR (CDC1 3,} 200MHz) (5 ppm; 1.58-1.69 (m, 4H), 2.18-2.26 (m, 2H), 2.32 (dd, J = 2.0, 18.7Hz, 1H), 2.64 (t, J = 7.0Hz, 2H), 2.83 (dd, J = 6.2, 18.7Hz, 1H), 3.22 (s, 2H), 3.74 (s, 3H), 4.94-4,98 (m, 1H), 7.16-7.22 (m, 1H). Reference Example 6

Compound 25 (20. Og, 77.4 mmol) was dissolved in dichloromethane (200 iuL), and triethylamine (4.9.0 g, 0.4.8 mol), t-butyldimethylsilyl chloride (23.3 g, 0.16 mol) was dissolved at -10 ° C. , 4-Dimethylaminopyridine (5.90 g, 48.3 tmol) was added, and after stirring for 2.5 hours, water was added and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 10: 1 → 5: 1) to give compound 8 (26.5 g). , Yield 88.5%).

_{'H-NMR (CDC1 3,} 200MHz) (5 pm; 0.12 (s, 3H), 0.13 (s, 3H), 0.91 (s, 9H), 1.53-1.70 (ra, 4H), 2.15-2.23 (m, 2H), 2.27 (dd, J = 2.2, 18.7Hz, 1H), 2.65 (t, J = 6.8Hz, 2H), 2.7 (dd, J = 6.0, 18.7 Hz, 1H), 3.22 (s, 2H), 3.7 (s, 3H), 4.85-4.93 (m, 1H), 7.04-7.08 On, 1H). Reference Example 7

Lipase (10.2 g) was suspended in vinyl acetate (5 (kL) under an argon atmosphere, and compound 25 (9.57 g, 37.0 tL) dissolved in vinyl acetate (30 mL) was added. Then, the reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure to obtain a mixture of compounds 26a and 27 (oil, 11.5 g).

A mixture of the crude compounds 26a and 27 (11.5 g) was dissolved in dichloromethane (106 mL), and -1 (at T ..) triethylamine (3.76 g, 37.2 mmol), and methyl sulfonyl chloride (4, The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated to give crude compounds 26a and 2g. A mixture of 8 (oil, 12.4 g) was obtained.

To a mixture (12.4 g) of the crude compounds 26a and 28 was added a solution of cesium acetate (10.8 g, 56.3 mol) in t-butyl alcohol (90 mL), and the mixture was stirred at room temperature for 14 hours. Next, water is added to the reaction solution, and acetic acid is added. The organic layer was dried over sulfuric anhydride and concentrated under reduced pressure to give the crude compound.

26 b (oil, 11.2 g) was obtained. Reference example 10

Dissolve 26b (11.2 g) in methanol (1 OOniL), and at 0 ° C, 0.5 M

To the mixture was added a toluene solution (82 mL, 41 bandol), and the mixture was stirred for 1 hour. Then, acetic acid (2.50 g, 41.6 ol) was added, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude compound 29a (oil, 9.70 g). Reference Example 11

Lipase (20.3 g) was added and suspended in vinyl acetate (100 mL) under an argon atmosphere, and crude compound 29a (9.70 g) dissolved in vinyl acetate (60 mL) was added thereto, followed by stirring for 2 days. Then, the reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure.

The crude compound 26c (oil, 8.69 g) was obtained.

Reference Example 12

The crude compound 26c (8.67 g) was dissolved in methanol (90 mL) and, at 0 ° C, 0.5 M guar:

Solution (63 mL, 31.5 tmol) was added and stirred for 1 hour. Then, acetic acid (1.92 g, 31.9 marl) was added, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 → 1: ) To give compound 29b (oil, 5.57 g, 58.2% yield from compound 25, optical purity 99.8% ee).

^{_{1 H-NMR (CDC1 3,}} 200MHz) <5 ppm; 1.58-1.69 (m, 4H), 2.18-2.26 (m, 2H), 2.32 (dd, J = 2.0,18.7 Hz, 1H), 2.64 (t, J = 7. OHz, 2H): 2.83 (dd, J = 6.2, 18.7Hz, IH), 3.22 (s, 211), 3.7 (s, 3H), 4.94-4.98 (m, lH), 7.16-7.22 ( m, IH). Reference Example 1 3

Compound 29b (2.9 g, 9.63 mmol) was dissolved in dichloromethane (25 ml), and triethylamine (6.7 niL, 48.1 marl) and t-butyldimethylsilyl chloride (2.92 g, 19.3 mol) were dissolved at -15 ° C. ), And 4-dimethylaminoviridine (0.59 g, 4.81 marl) were added and the mixture was stirred at 0 ° C for 3 hours. Then, water is added, extracted with dichloromethane, the organic layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 10: 1 → 5: By subjecting to 1), compound 1 (3.33 g, 92.7%) was obtained.

¹ H- negation _{R (CDC1 3, 200MHz) <} 5 ppm; 0.1 (s, 3H), 0.13 (s, 3H), 0.91 (s, 9H), 1.56-1.68 (m, 4H), 2.15-2.22 (m , 2H), 2.27 (dd, J = 2.2, 18.7Hz, IH), 2.65 (t, J = 6.8Hz, 2H), 2.74 (dd, J = 6.0, 18.7 Hz, 1H), 3.22 (s, 2H), 3.74 (s, 3H), 4.85-4.92 (m, 1H), 7.02-7.10 (m, 1H). Availability on

The production method of the present invention provides a safer and more stereoselective method for various substituted ethyl groups at the β-position of an α, α-substituted cyclobennone derivative having a desired side chain than the conventional method. It is possible to provide a synthesis of Q !, a 3, α-substituted cyclopentenonone derivative, which is very useful as an industrially suitable drug or an intermediate thereof.

Claims

The scope of the claims

The following formula [I]

Where A is the formula [II]

-t (CH ₂ ) X'5 _r E (CH ₂ X ² J- ^CH 2 7- [II]

(In the formula, X ¹ and X ² are the same or different and represent an oxygen atom, a sulfur atom, a methylene group, a vinylene group, an ethynylene group or an arelenylene group, and n and q are the same or different and represent an integer of 0 to 6, m and p are the same or different and each represents an integer of 0 to 2, r represents an integer of 0 to 3.), R ¹ represents a hydrogen atom, a nitrile group, -OR ⁶ (formula Wherein, R ⁵ represents a hydroxyl-protecting group.) Or -C00R ⁷ (wherein, R ⁷ is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted carbon atom number) 2 to 10 alkenyl groups, substituted or unsubstituted alkynyl groups of 2 to 10 substituted or unsubstituted cycloalkyl groups of 3 to 10 carbon atoms, substituted or unsubstituted phenyl a group or a protecting group of carboxyl group.) indicates, R ² is a protecting group for a hydroxyl group It is. ], Substituted α-substituted cyclo

'The derivative and the following formula [III]

[In the formula, M (wherein, R ⁸ is. Represents an alkyl group of one to six carbon atoms) BrZn or LiR ⁸ ₃ Al indicates, R ³ is a substituted or unsubstituted carbon atoms 1 to 1 0 alkyl groups, substituted or unsubstituted carbon atoms 2 to 1 Off solid alkenyl groups, substituted or unsubstituted carbon atoms 2 1 to 10 alkynyl groups, substituted or unsubstituted cycloalkyl groups having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkyloxy groups having 3 to 10 carbon atoms, substituted or unsubstituted Represents an unsubstituted phenyl group or a substituted or unsubstituted phenoxy group; Z represents a hydrogen atom or Z'R ⁴ (wherein Z 'represents an oxygen atom or a sulfur atom; represents a hydroxyl-protecting group or a thiol group. Represents a protecting group. Characterized by reacting with an organometallic reagent represented by the following formula [IV]:

Wherein R represents a trialkylsilyl group, and A, R ¹ , R ² , R and Z are as defined above. A method for producing a silyl enol ether compound.

2. The formula [IV] according to claim 1, wherein R ⁵ represents a trialkylsilyl group, and A, RR ² , R ³ and Z are as defined above. [V] wherein the α, β, β-substituted cyclopentene non-trialkylsilyl enol ester represented by the formula [V]

Wherein A, RR ² , R ³ and Z are as defined above. Α, β, α-substituted 'Methods for producing derivatives.

3. The formula [I] according to claim 1, wherein A, R ¹ and R ² are as defined above. And the formula [II I] wherein R ³ , M and Z are as defined above. Wherein at least one equivalent of a trialkylsilyl triflate is used in the reaction with the organometallic reagent represented by the formula [V]

Wherein A, RR ² , R ³ and Z are as defined above. C¾, / 3, α-substituted cyclo

'Methods for producing derivatives.