JPH1017561A - Allylalcohol compounds and their production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially advantageously obtain the subject new alcohol compound important as an intermediate for prostaglandins from easily available raw materials in advantageous productivity by stereospecifically reducing an α,β-unsaturated ketone. SOLUTION: The alcohol compound of formula I [R<1> is methyl, ethyl, trifluoromethyl; R<2> is methyl, ethyl, n-propyl; R<3> is H, an OH-protecting group; (n) is 0, 1, 2]. The alcohol compound is preferably obtained by stereospecifically reducing (A) an α-unsaturated ketone of formula II with (B) a selective reducing agent, especially a reagent of formula III [R<4> is a (substituted) 6-20C aryl; R<5> is a (substituted) 2-6C alkyl]. The component A is preferably obtained by reacting (i) an aldehyde of formula IV with a phosphonate of formula V (R<6> is a lower alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an allyl alcohol which is important as an intermediate for prostaglandins, a method for producing the same, a novel intermediate useful for producing the allyl alcohol, and a method for producing the intermediate About.

[0002]

2. Description of the Related Art Prostaglandins are extremely important substances as medicines, and applications and development of natural and various non-natural prostaglandins, and research on development of production methods thereof are being promoted. Natural prostacyclins, which are a type of prostaglandins, have potent physiological activities in vivo, such as platelet aggregation inhibitory activity, vasodilatory activity, and cytoprotective activity. The range is limited. Therefore, the development of a chemically stable prostacyclin derivative having the same physiological activity as that of the natural type has been studied diligently at home and abroad.

The present inventors have found chemically stable difluoroprostacyclins having high physiological activity (JP-A-7-330752). In particular, the prostaglandins contain a triple bond and a branched alkyl chain in a side chain thereof, and the asymmetric carbon having a branched alkyl group has an S-type absolute configuration.
It has been found that difluoroprostacyclins represented by the following general formula (6) have extremely excellent pharmacological activities and physical properties as pharmaceuticals (provided that R ⁷ and R ⁸ are lower alkyl groups, R ⁹ is a hydrogen atom, A lower alkyl group or a cation, n is 0, 1 or 2).

[0004]

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[0005]

The present inventors thought that allyl alcohols represented by the following general formula (1) could be important intermediates of the above-mentioned difluoroprostaglandins. Is a novel compound having a structural feature that contains a triple bond and a branched alkyl group in the portion corresponding to the side chain of prostaglandins, and the asymmetric carbon having a branched alkyl group has an S-type absolute configuration. A method for stereoselectively producing an allyl alcohol represented by the general formula (1) has not been known at all. The compound most similar to the compound represented by the general formula (1) in the present invention includes [W. Skuballa et al., Tetrahedron Lett., 29, 4285.
(1988)] (represented by the following general formula (7))
It has been known.

[0006]

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However, this known compound is a mixture of a diastereomer having an S-type absolute configuration and a diastereomer having an R-type absolute configuration in which the asymmetric carbon having a branched methyl group in the side chain has a branched alkyl group. Unlike the compounds of the present invention in which the asymmetric carbon having a chain is in the S-configuration absolute configuration.

In general, the Corey method is known as a method for producing prostaglandins. A lactone represented by the following general formula (9) (R ¹¹ is an alkyl group or the like) obtained by introducing a side chain (ω chain) of a prostaglandin into a so-called corey lactone represented by the following general formula (8): Known as an important intermediate of prostaglandins [EJCo
rey et al., J. Am. Chem. Soc. 93, 1491 (1971), J. Am. Chem. Soc.,
94,8616 (1972)].

[0009]

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Usually, the lactone represented by the general formula (9) is represented by the following general formula (11) and the aldehyde represented by the following general formula (10) obtained by oxidizing a hydroxyl group of corey lactone. Wittig-Horner with phosphonates
After the reaction, α, β-unsaturated ketones represented by the following general formula (12) are synthesized, and the target product produced by reducing the same and its stereoisomer are separated and purified to produce.

[0011]

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The separation of the stereoisomers usually requires precise separation and purification operations such as chromatography, which is a major problem in production from the viewpoint of economy, practicality, and the like. Α, represented by (12)
Various methods for stereoselective reduction of β-unsaturated ketones have been studied. These are usually performed using a selective reducing agent. Examples of the selective reducing agent include, for example, [EJCorey et al.
J.Am.Chem.Soc., 93,1491 (1971), J.Am.Chem.Soc., 94,861
6 (1972)] [Noyori et al., J. Am. Soc. Chem., 101, 5843 (19
79)] A lithium aluminum hydride reagent modified with binaphtol according to the above, particularly "(S) -BINAL-
H "((S) -hydrogenated 1,1'-binaphthyl-2,2 '
-Lithium dideoxyethoxyaluminum), [EJ
Corey et al., J. Am. Chem. Soc., 109, 7925 (1987)], a combination of oxaborolidine derived from proline and borane-tetrahydrofuran is known.

Each of these stereoselective reduction methods using a selective reducing agent is an excellent method, and is an intermediate of a natural prostaglandin represented by the general formula (12) (R ¹¹ is n-pentyl). When reducing certain compounds, allyl alcohol (R ¹¹ is n-pentyl) represented by the general formula (9) with stereoselectivity of 82:18, 100: 0 and 90:10 respectively under optimal conditions ) Can be synthesized.

However, there are problems that the raw material of the selective reducing agent is expensive, that strict reaction conditions such as at -100 ° C., and that a reactant that is difficult to handle are required. In addition, the stereoselectivity of the product depends on the substrate of the reaction, and depends on the substituents of the α, β-unsaturated ketones, especially the stereochemistry of the substituent at the α-position of the ketone and the protecting group of the hydroxyl group. Because it is greatly affected, it cannot be said that it can be widely applied to the synthesis of derivatives having unnatural prostaglandin side chains,
Production of a compound containing a triple bond and a branched alkyl group in a side chain and having an asymmetric carbon having a branched alkyl group in an S-type absolute configuration, such as an allyl alcohol represented by the general formula (1) of the present invention. It was not known at all whether it could be used.

The method of Yamamoto et al., [Bull.
C.Jpn., The method according to 54,3033 (1981)] is an excellent method in terms of economy, the reducing intermediates of naturally occurring prostaglandins of the (R ¹¹ represents n- pentyl) In this case, it is known that allyl alcohol represented by the general formula (9) (R ¹¹ represents n-pentyl) can be synthesized with a stereoselectivity of 92: 8. However, the stereoselectivity of the product also depends on the substrate for the reaction, and the stereochemistry of the substituents on the α, β-unsaturated ketones, particularly the hydroxyl-protecting group and the α-position substituent of the ketone, is a substrate. Therefore, it was not known at all whether the compound of the present invention can be used for producing compounds such as allyl alcohols represented by the general formula (1).

Therefore, a practical method for solving these problems and efficiently producing the allyl alcohol represented by the general formula (1) has been desired.

[0017]

Means for Solving the Problems The present inventors have found a practical method for efficiently producing allyl alcohols represented by the following general formula (1). The present invention provides an allyl alcohol represented by the following general formula (1) and a method for producing the same.
And a novel intermediate useful for producing the allyl alcohols and a method for producing the same.

Allyl alcohols represented by the following general formula (1): A method for producing allyl alcohols represented by the following general formula (1) by stereoselectively reducing α, β-unsaturated ketones represented by the following general formula (2) using a selective reducing agent . Α, β-unsaturated ketones represented by the following general formula (2). An aldehyde represented by the following general formula (4) is reacted with a phosphonate represented by the following general formula (5), wherein α, β- represented by the following general formula (2) is used.
A method for producing unsaturated ketones.

[0019]

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[0020]

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However, the above equations (1), (2), (4),
In (5), R ¹ is a methyl group, an ethyl group, or a trifluoromethyl group, R ² is a methyl group, an ethyl group, or an n-propyl group, R ³ is a protecting group for a hydrogen atom or a hydroxyl group, and R ⁶ is a lower group. The alkyl group, n represents 0, 1 or 2.

[0022]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following description of the present specification,
When the organic group is “lower”, it means 1 to 6 carbon atoms. More preferred lower organic groups are organic groups having 1 to 4 carbon atoms. The “alkyl group” may be linear or branched, and a lower alkyl group is preferable unless otherwise specified.
Suitable examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, neopentyl, hexyl and the like.

The "aryl group" refers to a monovalent aromatic hydrocarbon group, and a substituent (for example, a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylamino group, etc.)
And preferably a phenyl group or a derivative thereof, for example, a phenyl group, a tolyl group, a 2,4,6
-Trimethylphenyl group, 2,6-di (t-butyl)-
4-methylphenyl group, 2,6-di (t-butyl) phenyl group, 2,4,6-tri (t-butyl) phenyl group,
p-halophenyl group (for example, p-chlorophenyl group, p
-Bromophenyl group, etc.), alkoxyphenyl group (for example, methoxyphenyl group, ethoxyphenyl group, etc.)
And the like.

As the "alkoxy group", a lower alkoxy group is preferable, and more preferably, it has 1 to 4 carbon atoms.
And suitable examples thereof include a methoxy group, an ethoxy group, a propoxy group and a butoxy group.

The "alkoxyalkyl group" is preferably a lower alkyl group in which the alkoxy group part is a lower alkoxy group. Suitable examples thereof include a 2-methoxyethyl group, a 3-methoxypropyl group and a 2-ethoxyethyl group. And the like.

The "aralkyl group" refers to an aryl group-substituted alkyl group, and examples of the aryl group as the substituent include those described above. The alkyl group has 1 to 4 carbon atoms.
Is preferred. Suitable examples thereof include a benzyl group, a benzhydryl group, a trityl group, a phenethyl group and the like. Further, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The "protecting group" is a group for temporarily protecting a reactive functional group such as a hydroxyl group. Examples of the protecting group for a hydroxyl group include a triorganosilyl group, an acyl group and a cyclic ether group. , An alkyl group, an alkoxyalkyl group and an aralkyl group.

In view of the physiological activity of the prostaglandins finally obtained using the allyl alcohols represented by the general formula (1) (hereinafter referred to as allyl alcohols (1)), In the compounds represented by 1), (2), and (4), R ¹ is a methyl group, an ethyl group, or a trifluoromethyl group, and R ² is a methyl group, an ethyl group, or an n-propyl group. . Since the physiological activity of the finally obtained prostaglandins is particularly excellent, a methyl group is particularly preferred as R ¹ , and an ethyl group is particularly preferred as R ² . The allyl alcohols (1) of the present invention are substantially pure compounds having the steric structure represented by the general formula (1), and do not mean components in a mixture such as a diastereomer mixture.

The general formulas (1), (2) and (4)
R ³ in the compound represented by is a hydrogen atom or a protecting group for a hydroxyl group. R ³ may be different for each compound represented by the general formulas (1), (2) and (4), and when it is a protecting group, it may be a different protecting group for each compound. Usually, R ³ does not change before and after the reaction in the above-mentioned production method, but R ³ may change before and after the reaction, such as deprotection occurring with the reaction. Usually, it is preferable to carry out the reaction using the above-mentioned hydroxyl-protecting group as R ³ , but when the reduction reaction is carried out using a selective reducing agent represented by the following general formula (3), stereoselectivity is required. In terms of R ³
Is particularly preferably a hydrogen atom.

As the protecting group for the hydroxyl group, a known or well-known protecting group can be employed. For example, a triorganosilyl group, an acyl group, a cyclic ether group, an alkyl group or an aralkyl group which may have a substituent are used. The triorganosilyl group is a group in which three organic groups such as an alkyl group, an aryl group, an aralkyl group, and an alkoxy group are bonded to a silicon atom. In particular, at least one group selected from a lower alkyl group and an aryl group is used. A triorganosilyl group having three is preferred. Specifically, for example, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triethylsilyl group, a triphenylsilyl group, a triisopropylsilyl group and the like are preferable.

The acyl group is preferably an acetyl group, a benzoyl group or a p-phenylbenzoyl group. As the cyclic ether group, a tetrahydropyranyl group or a tetrahydrofuranyl group is preferable. Examples of the alkyl group or aralkyl group which may have a substituent include a methoxymethyl group, an alkoxyalkyl group such as a 1-ethoxyethyl group and a 2-methoxyethoxymethyl group, and a benzyl group and a methoxybenzyl group. A trityl group or the like is used.

The hydroxyl-protecting group as described above can be deprotected by a conventional method and converted into a hydrogen atom. For example, “New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I), (I)
I), (V) ”(Maruzen),“ Protective Groups in Organic Synthesis ”(TWGreene
By J. Wiley & Sons).

Α, β-unsaturated ketones represented by the general formula (2) (hereinafter referred to as α, β-unsaturated ketones (2))
Various known selective reducing agents can be used as the selective reducing agent used in the method for producing allyl alcohols (1) by stereoselectively reducing the compound by using a selective reducing agent. These are described in the above-mentioned documents, “New Experimental Chemistry Lecture 15 Oxidation and Reduction (II)” (Maruzen), “Fourth Edition Experimental Chemistry Lecture 26 Organic Synthesis VIII” (Maruzen), and “Ho
uben-Weyl, Method of Organic Chemistry E21d, Stereoselective Synthesis "(G.
Selective reducing agents described in books such as Helmchen et al., Thieme Stuttgart) can be used, and include hydrogenation using a hydrogenation catalyst, hydrosilylation reagents, hydride reducing agents and the like.

Specific examples include hydrogenation catalysts such as rhodium, ruthenium and platinum, hydrosilylation catalysts, hydrides of metals such as aluminum, boron, tin and silicon, aluminum hydride complex compounds and borohydride complex compounds. There are metal hydride complex compounds, metal alkoxides and metal alkylates having metals such as aluminum, magnesium, zinc, potassium, and boron, and combinations thereof with Lewis acids and the like. Further, as the ligand of the metal hydrogen complex compound, an optically active ligand such as an optically active amine, alcohol, and phosphine may be used.

Specifically, for example, diisobutylaluminum hydride, diborane, disiamylborane, texylborane, 9-borabicyclo [3.3.1] nonane, tributyltin hydride, triethylsilane, trichlorosilane, lithium aluminum hydride, trialkoxy hydride Lithium aluminum, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride, sodium trimethoxyborohydride, zinc borohydride, lithium tri-s-butylborohydride ("L-selectride"), hydrogen Potassium tri-s-butyl ("K-selectride"), lithium trithiamylborohydride ("KS-selectride"), lithium triethylborohydride ("superhydride"), (R) or S) - Lithium B- iso Pinot cans phenyl-9-borabicyclo [3.3.1] nonyl hydride ((R) or (S) - "Arupinhidorido"), dialkylaluminum alkoxide, (R)
Or (S) -B-isopinocanphenyl-9-borabicyclo [3.3.1] nonane ((R) or (S)-"
Alpinborane "), diisopinocanephenylchloroborane and the like.

A particularly preferred compound as the selective reducing agent is a dialkylaluminum reactant which is a compound represented by the following general formula (3). However, in the general formula (3), R ⁴ represents a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and R ⁵ represents a substituted or unsubstituted 2 to 2 carbon atoms.
6 represents an alkyl group.

[0037]

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R ⁴ is preferably a phenyl group or a derivative thereof. For example, phenyl group, tolyl group, 2,2
4,6-trimethylphenyl group, 2,6-di (t-butyl) -4-methylphenyl group, 2,6-di (t-butyl) phenyl group, 2,4,6-tri (t-butyl) Phenyl group, 2- (t-butyl) -6- (1,1-diethylpropyl) -4-methylphenyl group, 2,6-diphenylphenyl group, 4-chloro-2,6-di (t-butyl)
A phenyl group, a 4-bromo-2,6-di (t-butyl) phenyl group, a p-chlorophenyl group, a p-bromophenyl group and the like are used. Particularly preferably, 2,6-di (t
-Butyl) -4-methylphenyl group, 2,6-di (t-
Butyl) phenyl group, 2,4,6-tri (t-butyl)
A phenyl group is used.

R ⁵ may be an alkyl group having a halogen atom, an alkoxy group or the like as a substituent. However, an unsubstituted alkyl group having 2 to 6 carbon atoms is preferably used, and in particular, an isobutyl group, an isopropyl group,
An s-butyl group is preferred. Most preferably, an isobutyl group is used.

The dialkylaluminum reactant is described in the aforementioned Yamamoto et al. Reference [Bull. Chem. Soc. Jpn., 54, 3033 (198)
1)]. The most preferred compound as a dialkylaluminum reactant is a compound in which R ⁴ is a 2,6-di (t-butyl) -4-methylphenyl group and R ⁵ is an isobutyl group in the general formula (3), that is, diisobutyl. Aluminum 2,6-di (t-
Butyl) -4-methylphenoxide.

The amount of the selective reducing agent (particularly, the selective reducing agent represented by the general formula (3)) is usually based on the amount of the α, β-unsaturated ketone represented by the general formula (2). 0.01-50
It is a double equivalent, and preferably 5 to 20 equivalents. The reaction temperature is preferably about -150 to + 100 ° C, particularly -80 to 0 ° C.
° C is good. The above selective reduction reaction can be usually performed in the presence of a solvent. As the reaction solvent, a hydrocarbon solvent, an ether solvent, or a mixed solvent thereof is usually used. Examples of the hydrocarbon solvent include toluene, hexane, benzene, pentane, xylene, and petroleum ether. Examples of the ether solvent include diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diglyme, and t-butyl methyl ether. And toluene is particularly preferred.

When the reduction reaction is carried out using the selective reducing agent represented by the general formula (3), R ³ is particularly preferably a hydrogen atom in consideration of the stereoselectivity of the reduction reaction. In this case, the generated allyl alcohols include:
Those having the desired S configuration are obtained with very high stereoselectivity and the formation of the R isomer is minimal. Α, β-unsaturated ketones represented by the general formula (2) wherein R ³ is a hydroxyl-protecting group, and α, β-unsaturated ketones represented by the general formula (2) wherein R ³ is a hydrogen atom. Conversion into ketones may be carried out by a known method.

For example, “New Experimental Chemistry Course 14: Synthesis and Reaction of Organic Compounds (I), (II), (V)” (Maruzen),
"Protective Groups in Organic
Synthesis can be easily deprotected by a method described in a written book such as "Synthesis" (TWGreene, J. Wiley & Sons). For example,
When R ³ is a tetrahydropyranyl group, usually p-
Deprotection can be performed using acidic conditions such as toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrochloric acid, acetic acid, boric acid, and ion exchange resin.

In order to synthesize the α, β-unsaturated ketones (2), generally known methods for producing prostaglandins known as the Cory method can be applied. That is, an aldehyde represented by the general formula (4), which is a known compound, is combined with a phosphonate represented by the general formula (5) by W
α, β-unsaturated ketones (2) can be synthesized by the ittig-Horner reaction. R ⁶ in this phosphonate
A lower alkyl group is used, and an alkyl group having 4 or less carbon atoms such as a methyl group and an ethyl group is preferably used.

An aldehyde represented by the general formula (4) is reacted with a phosphonate represented by the general formula (5) to obtain α, β
-As a method of converting to unsaturated ketones (2), Wittig
When the reaction is carried out using the -Horner reaction, R ³ of the aldehyde represented by the general formula (4) may be a hydrogen atom. Desirably. Phosphonates represented by the general formula (5) are described in [W. Skuballa et al., J. Med. Chem., 29, 315 (1986), M. Ha].
rre et al., Liebigs Ann. Chem., 1081 (1989)].

The Wittig-Horner reaction is usually performed in a solvent in the presence of a base. The reaction temperature varies depending on the type of the base and the solvent used, but is usually preferably about -50 to + 50 ° C, particularly preferably 0 to 30 ° C.

As the base, widely used bases are widely used. Examples thereof include alkali metal hydrides, alkali metal amides, alkali metal alkoxides, carbonates and hydroxides of alkali metals and alkaline earth metals, alkali metals and the like. Alkaline earth metal halides, organic alkali metal compounds, amines such as tertiary amines and aromatic amines, and combinations thereof are used. Preferably, sodium hydride, potassium carbonate, lithium chloride or lithium bromide and diisopropylamine, triethylamine or 1,8-diazabicyclo [5.4.0] undec-7
A combination with -ene, sodium methoxide, sodium ethoxide and the like are used.

As the solvent, a hydrocarbon solvent, an ether solvent, a halogen solvent, an alcohol solvent, a polar solvent or a mixed solvent thereof is used. Examples of the hydrocarbon solvent include toluene, hexane, benzene, pentane, xylene, and petroleum ether. Examples of the ether solvent include diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diglyme, and t-butyl methyl ether. Can be As the halogen-based solvent, methylene chloride, chloroform, carbon tetrachloride, 1,2
-Dichloroethane, chlorobenzene and the like, and as the alcohol solvent, methanol, ethanol, isopropanol, n-butanol, t-butanol and the like are used. As polar solvents, dimethyl sulfoxide, hexamethylphosphoramide (HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU), 1,3-dimethyl-2- Imidazolidinone (DMI), N, N, N ', N'-tetramethylethylenediamine (TMEDA) and the like are used.
Particularly, benzene, toluene, diethyl ether, methylene chloride and the like are preferable.

The compounds represented by formulas (1) and (2) of the present invention have an optically active compound having a triple bond in a side chain (ω chain) and having an optically active branched alkyl group or trifluoromethyl group. And a novel compound. These are important intermediates derivable to various prostaglandins, especially difluoroprostacyclins. For example, JP-A-8-143560 and JP-A-7-32408
1, can be converted into difluoroprostacyclins into which various α-chains are introduced by the method described in JP-A-7-330752 and the like.

The compound which is a starting material of the compound of the present invention is a readily available compound. The production method of the present invention does not require any severe reaction conditions or long-term reaction,
Moreover, it is an excellent method that does not require a special reaction reagent or a reaction device. Therefore, the production method of the present invention is highly advantageous in terms of economy and productivity, and is an extremely excellent method applicable to mass synthesis in actual production.

[0051]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 (1S, 5R, 6R, 7R) -6-[(1E, 4S)-
4-methyl-3-oxo-1-nonen-6-ynyl]-
2-oxa-7-[(tetrahydro-2H-pyran-2
-Yl) oxy] bicyclo [3.3.0] octane-3
-Synthesis of on.

Sodium hydride (60% by weight dispersion in mineral oil, 54.8 mg) was suspended in 7 ml of anhydrous dimethoxyethane, and [(3S) -3-methyl-2-oxo-
A solution of 337 mg of dimethyl 5-octynyl] phosphonate in anhydrous dimethoxyethane (2 ml) was added dropwise at 0 ° C.
Stirred for minutes. To this solution was added (1S, 5R, 6R, 7
R) -6-Formyl-2-oxa-7-[(tetrahydro-2H-pyran-2-yl) oxy] bicyclo [3.
3.0] Octan-3-one A solution of 290 mg of anhydrous dimethoxyethane (4 ml) was added at room temperature. After stirring for 30 minutes, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, dried, concentrated, and silica gel column chromatography (hexane: ethyl acetate = 10:
1-5: 1-3: 1) to give 291 mg of the title compound
I got

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.98 (t, J = 7.4 Hz,
3H), 1.07 (d, J = 6.8Hz, 3H), 1.4-1.7 (m, 6H), 2.0-2.9 (m, 11
H), 3.38 (m, 1H), 3.70 (m, 1H), 3.96 (m, 1H), 4.10 (m, 1H), 4.5
5 (m, 1H), 4.92 (m, 1H), 6.16 (d, J = 15.6Hz, 1H), 6.64 (dd, J =
(7.6, 15.6Hz, 1H).

Example 2 (1S, 5R, 6R, 7R) -6-[(1E, 4S)-
4-methyl-3-oxo-1-nonen-6-ynyl]-
2-oxa-7-benzoyloxy] bicyclo [3.
3.0] Synthesis of octan-3-one.

Sodium hydride (60% by weight dispersion in mineral oil, 1.6 g), 10 g of dimethyl [(3S) -3-methyl-2-oxo-5-octynyl] phosphonate, (1
S, 5R, 6R, 7R) -6-formyl-2-oxa-
Using 9.96 g of 7-benzoyloxybicyclo [3.3.0] octan-3-one, the reaction was carried out in the same manner as in Example 1 to obtain 14.5 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.07 (t, J = 7.4 Hz,
3H), 1.17 (d, J = 6.8Hz, 3H), 2.0-2.9 (m, 11H), 5.12 (m, 1H),
5.34 (m, 1H), 6.34 (d, J = 15.6Hz, 1H), 6.73 (dd, J = 7.8,15.6H
(z, 1H), 7.45 (m, 2H), 7.56 (m, 1H), 7.98 (m, 2H).

Example 3 (1S, 5R, 6R, 7R) -7-hydroxy-6-
[(1E, 4S) -4-Methyl-3-oxo-1-nonen-6-ynyl] -2-oxa-bicyclo [3.3.
0] Synthesis of octane-3-one.

(1S, 5R, 6R, 7R) obtained in Example 1
6-[(1E, 4S) -4-methyl-3-oxo-1-
291 mg of nonene-6-ynyl] -2-oxa-7-[(tetrahydro-2H-pyran-2-yl) oxy] bicyclo [3.3.0] octan-3-one was dissolved in 3 ml of methanol, and p- Toluenesulfonic acid hydrate 1
4.8 mg was added at room temperature, and the mixture was stirred for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, dried and concentrated, and then subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 2: 1 to 1: 2).
Then, 0.14 g of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.03 (t, J = 7.5 Hz,
3H), 1.12 (d, J = 6.8Hz, 3H), 2.0-2.9 (m, 11H), 3.25 (brs, 1
H), 4.08 (m, 1H), 4.99 (m, 1H), 6.26 (d, J = 15.6Hz, 1H), 6.64
(dd, J = 8.3,15.6Hz, 1H).

Example 4 (1S, 5R, 6R, 7R) -7-hydroxy-6-
Synthesis of [(1E, 3S, 4S) -3-hydroxy-4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one.

A solution of 1.29 g of 2,6-di (t-butyl) -p-cresol in anhydrous toluene (6 ml) was added under ice-cooling.
Diisobutylaluminum hydride (1M hexane solution, 2.93 ml) was added and stirred for 1 hour. This is -7
Cool to 8 ° C. and add (1S, 5R, 6R, 7R) -7-hydroxy-6-[(1E, 4S) -4-methyl-3-oxo-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] A solution of 85 mg of octan-3-one in anhydrous toluene (1 ml) was added. 2 hours at -78 ° C, -4
After stirring at 0 ° C for 1 hour and at -20 ° C for 30 minutes, 1N
Hydrochloric acid, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate.

The extract was dried and concentrated, and then subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1).
1: 1 to 1: 5), 54 mg of the title compound, a less polar isomer ((1S, 5R, 6R, 7R) -7-hydroxy-6-[(1E, 3R, 4S) -3-hydroxy) −
4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one) 1.5 mg
I got The production ratio of the desired product and the isomer was about 97: 3.

The title compound: ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (d, J = 6.8 Hz, 3H), 1.09 (t, J
= 7.4Hz, 3H), 1.7-2.7 (m, 11H), 3.20 (br s, 1H), 3.8-3.9 (m,
2H), 4.86 (ddd, J = 3.1, 6.8, 7.1 Hz, 1H), 5.43 (dd, J = 8.4, 15.
1Hz, 1H), 5.56 (dd, J = 7.6,15.1Hz, 1H).

Isomer: ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.96 (d, J = 6.8 Hz, 3H), 1.12 (t, J
= 7.3Hz, 3H), 1.7-2.7 (m, 11H), 4.01 (m, 1H), 4.22 (m, 1H), 4.
92 (ddd, J = 2.9,6.8,7.1Hz, 1H), 5.5 (dd, J = 7.9,15.4Hz, 1
H), 5.65 (dd, J = 5.4,15.4Hz, 1H).

Example 5 (1S, 5R, 6R, 7R) -7-benzoyloxy-
Synthesis of 6-[(1E, 3S, 4S) -3-hydroxy-4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -7-benzoyloxy-6-[(1E, 4S) -4-methyl-3-
2.36 g of oxo-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one was dissolved in 100 ml of methanol and cooled to -78 ° C. 2.67 g of cerium trichloride heptahydrate in methanol (20 m
l) A solution and a solution of 113 mg of sodium borohydride in methanol (20 ml) were added dropwise, and the mixture was stirred while the temperature was gradually raised to -50 ° C. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, water was added, and the mixture was extracted with ethyl acetate, dried and concentrated. The production ratio of the desired product and the isomer was about 1: 1.

Purification by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1 to ethyl acetate) gave 0.39 g of the title compound and an isomer ((1S, 5R,
6R, 7R) -7-benzyloxy-6-[(1E, 3
R, 4S) -3-Hydroxy-4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one) 0.30 g, and 1.33 g of a mixture of both. I got

The title compound: ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.92 (d, J = 6.8 Hz, 3H), 1.11 (t, J
= 7.3Hz, 3H), 1.7-2.9 (m, 11H), 4.04 (m, 1H), 5.07 (t, J = 5.6H
z, 1H), 5.26 (m, 1H), 5.65 (m, 2H), 7.44 (m, 2H), 7.57 (m, 1H),
7.99 (m, 2H).

Isomer: ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.92 (d, J = 6.3 Hz, 3H), 1.10 (t, J
= 7.6Hz, 3H), 1.7-2.9 (m, 11H), 4.18 (m, 1H), 5.06 (m, 1H), 5.
24 (m, 1H), 5.64 (m, 2H), 7.44 (m, 2H), 7.56 (m, 1H), 7.99 (m, 2
H).

Example 6 (1S, 5R, 6R, 7R) -7-benzoyloxy-
Synthesis of 6-[(1E, 3S, 4S) -3-hydroxy-4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one.

1.12 g of 2,6-di (t-butyl) -p-cresol, diisobutylaluminum hydride (1
M hexane solution, 2.54 ml), (1S, 5R, 6
R, 7R) -7-benzoyloxy-6-[(1E, 4
S) -4-Methyl-3-oxo-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octane-3
The title compound and the isomer ((1
S, 5R, 6R, 7R) -7-benzyloxy-6-
47 mg of a mixture of [(1E, 3R, 4S) -3-hydroxy-4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one)
I got The production ratio of the desired product and the isomer was about 4: 6.
This mixture was purified by silica gel column chromatography in the same manner as in Examples 4 and 5 to obtain the title compound.

Example 7 (1S, 5R, 6R, 7R) -7-benzoyloxy-
Synthesis of 6-[(1E, 3S, 4S) -3-hydroxy-4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one.

Using “L-select ride”, (1S,
5R, 6R, 7R) -7-benzoyloxy-6-
[(1E, 4S) -4-Methyl-3-oxo-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0]
Octan-3-one was reduced at -78 ° C to -40 ° C. Title compound and isomer ((1S, 5R, 6R, 7R)
-7-benzyloxy-6-[(1E, 3R, 4S) -3
-Hydroxy-4-methyl-1-nonene-6-ynyl]
-2-oxabicyclo [3.3.0] octan-3-one). The formation ratio of the target compound and the isomer is about 3:
It was 7. This mixture was purified by silica gel column chromatography in the same manner as in Examples 4 and 5, to obtain the title compound.

Example 8 (1S, 5R, 6R, 7R) -7-benzoyloxy-
Synthesis of 6-[(1E, 3S, 4S) -3-hydroxy-4-methyl-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0] octan-3-one.

Using "S-BINAL-H", (1S,
5R, 6R, 7R) -7-benzoyloxy-6-
[(1E, 4S) -4-Methyl-3-oxo-1-nonen-6-ynyl] -2-oxabicyclo [3.3.0]
Octan-3-one was reduced at -100 ° C to -78 ° C.

The title compound and an isomer ((1S, 5R, 6
R, 7R) -7-benzyloxy-6-[(1E, 3R,
4S) -3-Hydroxy-4-methyl-1-nonene-6
-Inyl] -2-oxabicyclo [3.3.0] octan-3-one). The production ratio of the desired product and the isomer was about 4: 6. This mixture was purified by silica gel column chromatography in the same manner as in Examples 4 and 5 to obtain the title compound.

[0078]

According to the present invention, allyl alcohols (1) having a triple bond in the side chain (ω chain) and capable of efficiently synthesizing prostaglandins having an optically active branched alkyl group or the like are provided. Disclosed is an excellent method for producing an allyl alcohol (1) which does not require a reaction condition or a long-time reaction and does not require a special reaction reagent or a reaction apparatus. Furthermore, since the compound used as a raw material is an easily available compound, the production method of the present invention has high utility in terms of economy and productivity, and can be applied to mass production in actual production.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication C07M 7:00

Claims (9)

[Claims] 1. Allyl alcohols represented by the following general formula (1). Embedded image (However, R ¹ is a methyl group, an ethyl group, or a trifluoromethyl group, and R ² is a methyl group, an ethyl group, or n-
A propyl group, R ³ is a protecting group for a hydrogen atom or a hydroxyl group, n
Represents 0, 1 or 2. ) (2) R ¹ is a methyl group, R ² is an ethyl group, R ³ is a hydrogen atom or a hydroxyl-protecting group, and n is 1.
An allyl alcohol according to claim 1. 3. An allyl alcohol represented by the following general formula (1), wherein α, β-unsaturated ketones represented by the following general formula (2) are stereoselectively reduced using a selective reducing agent. Method of manufacturing a kind. Embedded image (However, R ¹ is a methyl group, an ethyl group, or a trifluoromethyl group, and R ² is a methyl group, an ethyl group, or n-
A propyl group, R ³ is a protecting group for a hydrogen atom or a hydroxyl group, n
Represents 0, 1 or 2. ) 4. The method according to claim 3, wherein the selective reducing agent is a reactant represented by the following general formula (3). Embedded image (However, R ⁴ is a substituted or unsubstituted carbon number of 6 to 20)
R ⁵ is a substituted or unsubstituted carbon group having 2 to 2 carbon atoms.
6 represents an alkyl group. ) 5. The method according to claim ³ , wherein R ³ is a hydrogen atom. 6. The compound represented by the general formulas (1) and (2), wherein R ¹ represents a methyl group, R ² represents an ethyl group, R ³ represents a hydrogen atom, and n is 1. , 4 or 5
Manufacturing method. 7. An α, β-unsaturated ketone represented by the following general formula (2). Embedded image (However, R ¹ is a methyl group, an ethyl group, or a trifluoromethyl group, and R ² is a methyl group, an ethyl group, or n-
A propyl group, R ³ is a protecting group for a hydrogen atom or a hydroxyl group, n
Represents 0, 1 or 2. ) 8. R ¹ is a methyl group, R ² is an ethyl group, R ³ is a hydrogen atom or a hydroxyl-protecting group, and n is 1.
An α, β-unsaturated ketone according to claim 7. 9. An aldehyde represented by the following general formula (2) characterized by reacting an aldehyde represented by the following general formula (4) with a phosphonate represented by the following general formula (5):
A method for producing β-unsaturated ketones. Embedded image (However, R ¹ is a methyl group, an ethyl group, or a trifluoromethyl group, and R ² is a methyl group, an ethyl group, or n-
A propyl group, R ³ is a protecting group for a hydrogen atom or a hydroxyl group,
⁶ represents a lower alkyl group, and n represents 0, 1 or 2. )