WO2005007666A1

WO2005007666A1 - Novel method for producing dialdehyde and related compounds

Info

Publication number: WO2005007666A1
Application number: PCT/JP2004/010551
Authority: WO
Inventors: Hiroaki Sasai; Takayoshi Arai; Tomoaki Miura; Kunio Atsumi; Keiichi Ajito
Original assignee: Meiji Seika Kaisha, Ltd.
Priority date: 2003-07-17
Filing date: 2004-07-16
Publication date: 2005-01-27
Also published as: JPWO2005007666A1

Abstract

Disclosed is a method for producing a compound represented by the following formula (I): (I) (wherein R1 is a hydrogen atom or a lower acyl group, R2 represents a hydrogen atom, a lower acyl group or the like, R3 represents a lower alkyl group, R4 represents a hydrogen atom, a lower acyl group or the like, and R5 represents a hydrogen atom, a lower acyl group or the like) or a salt thereof. The method comprises a step for ozone-oxidizing a compound represented by the following formula (II): (II) (wherein R1, R2, R3, R4 and R5 are as defined in the formula (I)) or a salt thereof.

Description

Description New production method of dialdehyde and its related compounds

The present invention relates to a novel production method for providing a macrocyclic compound represented by a macrolide antibiotic. More specifically, the present invention relates to a novel and useful method for producing a dialdehyde compound by once opening a ring of a macrocyclic compound or a derivative thereof, and re-closing the ring using the dialdehyde and another reactive species. Background art

Gram-positive bacteria such as Staphylococcus aureus, pneumococcus and streptococci, Gram-negative bacteria such as Blanchamella and Influenza, Mycoplasma, and macrolide antibiotics that are effective against chlamydia have high safety and are orally administered. Possible and classified as a clinically important anti-infective drug. Since macrolide antibiotics as natural products have room for pharmacokinetic improvement, pharmacokinetics such as rokitamicin, myomycin, clarithromycin, azithromycin, and roxythromycin have been improved. Semisynthetic McRide antibiotics have been added.

However, in recent years, resistant bacteria that cause mutations in a part of the gene of the pathogenic bacterium and resistant bacteria capable of excreting drugs outside the pathogenic bacterium have emerged in clinical practice, and have reduced the effectiveness of antibiotics. In contrast, semi-synthetic 14-membered macrolide antibiotics are described in Bioorg. Med. Chem. Lett., 44, 3075-3080, 1999, J. Med. Chem., 43, 1045-1049, 2000. As described in J. Med. Chem., 44, 4137-4156, 2001, new substances that are effective against constitutive resistant pneumococci have been created.

An overview of the studies on derivatives of macrolide antibiotics up to now shows that, except for azithromycin, few compounds have drastically changed the skeleton of natural products, and additional chemical modifications to the existing carbon skeleton Has created new useful substances. However, recently, as described in Org. Lett., 5, (4), 443-445, 2003, a method of constructing a 14-membered ring macrolide by subjecting a 16-membered ring macrolide to a skeletal transformation reaction has been reported. Was.

As described in W003 / 72589, the present inventors have recently found a method of constructing a 15-membered ring azalide by subjecting a 16-membered ring macrolide to a skeletal transformation reaction, and have newly found a useful semi-synthetic 15-membered azalide system. Patent filed with antibiotics.

(vni) (IX) (X) The skeletal transformation reaction reported by the present inventors will be described in more detail.As described in W003 / 72589, a 16-membered lactone chemically derived from a natural product is opened and re-opened. In the production of a new 15-membered azalide via ring closure, the conjugated double bond represented by the formula (VIII) is converted into a tetraol, and the tetraol represented by the formula (Π) is oxidatively cleaved to obtain a compound represented by the formula (X). The dialdehyde compound represented was produced and used as a key intermediate. However, when oxidizing to tetraol, osmium tetroxide is used as a reaction reagent, which is not necessarily an environmental and health care issue. Lead tetraacetate, which is not necessarily without problems in terms of health and health care, was used as a reaction reagent. In addition, in the oxidative cleavage reaction of tetraol, the site having an adjacent polar functional group may be the reaction site. Therefore, in some cases, the 2 position (2 ′ position) and the Z or 3 position (3 , Place) needed to be protected. As described in W003 / 72589, the present inventors protected the 2-position (2'-position) of the amino sugar moiety with an acyl-substituent represented by an acetyl group. Also, TO03 / 14136 discloses an 11a-azalide compound and a method for producing the same. In this method, the carbon-carbon bond at the 11- and 12-positions of the erythromycin derivative is oxidatively cleaved to lead to 11a-azalide. There are still environmental and health issues to be addressed. Further, after the cleavage, the partial structure is changed, and an intramolecular cyclization reaction is performed, thereby leading to the target 11a-azalide compound.

Therefore, there is a demand for a synthetic intermediate and a production method for obtaining azalide compounds and other related compounds in a short process by using safe trials or using reagents having environmental and health problems. ing. Disclosure of the invention

The present invention is a key intermediate for producing a useful 15-membered azalide compound or any other novel and useful macrolide compound without using a reaction reagent that remains problematic in terms of environment and health. It is intended to provide a new method for producing dialdehyde compounds and related substances.

The present inventors have conducted intensive research to meet the above-mentioned expectations, and as a result, subjected the protected 16-membered ring macrolide derivative to ozone oxidation without using a reaction reagent that remains an environmental and health problem. The present inventors have found a method for producing an important aldehyde compound for producing a novel useful azalide compound, and have completed the present invention. So far, many examples of synthesizing an aldehyde compound by subjecting a compound having a double bond or a conjugated double bond to an ozone oxidation reaction have been known, but by applying the oxidation reaction to a 16-membered ring macrolide derivative, Furthermore, the fact that re-ring closure has been achieved using the dialdehyde compound obtained by this method is not known.

That is, the present invention

(1) The following equation (I)

(I)

[In the formula, is a hydrogen atom or a lower acyl group, R ₂ is a hydrogen atom, a lower acyl group, a lower alkyl group, or a protecting group for a hydroxyl group, and R ₃ is a lower alkyl group, provided that -CH ( 0R ₃ ) ₂ may form a cyclic structure such as dioxolan or dioxane, R ₄ is a hydrogen atom, a lower acryl group, a lower alkyl group, or a protecting group for a hydroxyl group, and R ₅ is a hydrogen atom, a lower acryl group A lower alkyl group, a protecting group for a hydroxyl group, or a myloin which may be protected] or a salt thereof, which is represented by the formula (II)

(Π)

[Wherein, R ₂ , R ₃ , R ₄ , and R ₅ have the same meanings as in formula (I)] or a salt thereof, which comprises a step of oxidizing ozone.

(2) The following equation (III)

Wherein R ₄ is a hydrogen atom or an acetyl group, and R ₆ is a hydrogen atom or an acetyl group;

OAc

(IV)

Wherein R ₄ and R ₆ have the same meanings as in formula (III), or a salt thereof in a single step.

(3) The following equation (V)

(V)

[Wherein, is a hydrogen atom or a lower acryl group, is a hydrogen atom, a lower acryl group, a lower alkyl group, or a protecting group for a hydroxyl group, R ₃ is a lower alkyl group, and _CH (0R ₃ ) ₂ may form a cyclic structure such as dioxolane or dioxane; R ₄ is a hydrogen atom, a lower acetyl group, a lower alkyl group, or a hydroxyl-protecting group; and R ₅ is a hydrogen atom, a lower acryl group, or a lower group. An alkyl group, a hydroxyl-protecting group, or an optionally protected myloose; and R ₇ is a method for producing a compound represented by a lower alkyl group or. (Π)

(ID

[Wherein, R ₂ , R ₃ , R ₄ , and R ₅ have the same meanings as described above], or a salt thereof, which comprises a step of performing an ozone oxidation reaction and a subsequent reclosing reaction.

(4) The following equation (VI)

(VI)

[Wherein, R ₂ is a hydrogen atom or an acetyl group, R ₄ is a hydrogen atom or an acetyl group, R ₆ is a hydrogen atom or an acetyl group, and R ₇ is a lower alkyl group or an aralkyl group]. A method for producing a compound represented by the formula:

(VII)

Wherein R ₂ , R ₄ and R ₆ have the same meaning as in the formula (VI), or a salt thereof, which comprises a step of performing an ozone oxidation reaction and a subsequent reclosing reaction,

I will provide a. BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, the “lower alkyl group” represents, for example, a linear or branched saturated group of Cl to 6, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutynole, sec-butynole, tert-butynole, n-pentynole, n-hexynole, etc., preferably, methyl and ethyl, more preferably, methyl. In this specification, a methyl group may be described as “Me”, and an ethyl group may be described as “Et”.

In the present specification, the “lower acetyl group” includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, norrelyl, isovaleryl, and vivaloyl, and preferably acetyl and propionyl. In this specification, an acetyl group may be described as “Ac”.

In the present specification, the “aralkyl group” means, for example, a group in which a part of alkyl groups is a linear or branched saturated group of Cl to 6, and a part of aralkyl groups is phenyl or quinolinyl. And a group representing an isoquinolyl group. For example, a phenylmethyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl group, a phenylenopentynole group, a phenylhexyl group, a quinolinylmethyl group, a quinolinylethyl group, a quinolinylpropyl group, a quinolinylbutyl group, a quinolinylpentyl group, a quinolinylhexyl group, Examples include an isoquinolinylmethyl group, an isoquinolinylethyl group, an isoquinolinylpropyl group, an isoquinolinylbutyl group, an isoquinolinylpentyl group, and an isoquinolinylhexyl group. Preferably, a phenylpropyl group, a phenylbutyl group, a phenylpentyl group, a quinolinylpropyl group, a quinolinylbutyl group, a quinolylpentyl group, and an isoquinolyl group are: propyl group, isoquinolinylbutyl group, and isoquinolinylpentyl group. And more preferably a phenylbutyl group, a quinolinylbutyl group, and an isoquinolinylbutyl group.

As used herein, the term "hydroxyl protecting group" refers to, for example, a silyl protecting group such as t-butyldimethylsilyl group, a p-nitrobenzoyloxycarbonyl group, or a trichloroethyloxycarbonyl group. Carbonate-type protecting group, acetyl group A group generally used as a protecting group for a hydroxyl group, such as an acyl-type protecting group such as a zyl group, and an acetal-based protecting group such as 1-ethoxyxyl, a tetrahydrofuranyl group, and a tetrahydroviranyl group, and preferably an acetal-based protecting group. And more preferably 1-ethoxyxyl.

In the present specification, —CH (0R ₃ ) ₂ may form a cyclic structure, and examples of the cyclic structure include, for example, dioxolan, dioxane and the like. In the present specification, the term "myloin which may be protected" refers to a force at which one or both of the 3, 'and 4' positions or both hydroxyl groups are acylated, and a protecting group for the above hydroxyl group. It may be protected and represents a compound bonded to R ₅ of the formulas (1), (11) and (V) at the 1, and the position of myloin. Preferred hydroxyl protecting groups are, for example, lower And an acetyl group, more preferably an acetyl group, a propionyl group or an isovaleryl group.

As used herein, the term “salt” refers to, for example, a pharmaceutically acceptable salt. Examples of the salt form include halo such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, and hydroiodic acid. Inorganic acid salts such as hydrogenate, sulfate, nitrate, phosphate, perchlorate, carbonate, etc., acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, sulfuric acid, citric acid, tartaric acid, oxalic acid Acids, benzoic acid, mandelic acid, butyric acid, maleic acid, carboxylic acid salts such as propionic acid, formic acid, malic acid, amino acid salts such as arginic acid, aspartic acid, and glutamate; methanesulfonic acid, paratoluenesulfonic acid, etc. Organic acid salts and the like.

The form of the solvate which can be taken is not particularly limited, and examples thereof include water; alcohols such as methanol, ethanol, and isopropanol; and ethers such as tetrahydrofuran.

In the chemical formulas in this specification, the chemical bond represented by a dotted line or a bond bonded to an asymmetric carbon is a notation according to the absolute configuration of the compound, and is the same as a normal stereo notation. Next, the production method of the present invention will be described.

First, the ring-opening reaction of 16-membered ratataton with a conjugated double bond using ozone was described. I will describe. The ozone oxidation reaction can be performed in a usual organic solvent such as alcohol and ethyl acetate, and is preferably performed in a lower alcohol such as methanol. The reaction can be performed at room temperature to a lower temperature, preferably at a low temperature of not more than 30 ° C.

At the end of the reaction, the reaction can be stopped by, for example, dimethyl sulfide, as in a general ozone oxidation reaction, but instead of this drug, a triarylphosphine such as tributenylphosphine or trinormal Trialkyl phosphine such as butyl phosphine may be used, and dimethyl sulfide is preferably used at a low temperature.

Next, the ring closure reaction using a dialdehyde compound as a key intermediate will be described. For this reaction, it is necessary to add an amine component containing a nitrogen atom which is one of the constituent atoms of the newly formed azalactone ring. In addition to normal alkylamines, for example, aralkylamines such as phenethylamine can be used.

The “aralkyl” of the “aralkynoleamine” refers to a linear or branched saturated group in which some of the alkyl groups of the group are Cl to 6, and some of the aryl groups of the group are phenyl, A group representing a norinyl group or an isoquinolinyl group is shown. For example, phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexynole, quinolinylmethyl, quinolinylethyl, quinolininolepyl pill, quinolinylbutyl, quinolinylpentyl, quinolinylhexyl An isoquinolinylmethyl group, an isoquinolinylethyl group, an isoquinolinylpropyl group, an isoquinolinylbutyl group, an isoquinolinylpentyl group, and an isoquinolinylhexyl group. Preferable examples include a phenylpropyl group, a phenylbutyl group, a phenylpentyl group, a quinolinylpropyl group, a quinolinylbutyl group, and a quinolinylpentyl group. More preferable examples include a phenylbutyl group, a quinolinylbutyl group, and an isoquinolinylbutyl group.

Examples of the “aralkylamine” include phenylalkylamine, quinolinylalkylamine, and isoquinolinylalkylamine. Examples include phenylalkylamine. Mouth pyramine, phenylbutyramine, phenylpentylamine, quinolinylup Mouth pyramine, quinolinylbutyramine, quinolinylpentylamine, isoquinolinylpropylamine, isoquinolinylbutyramine, isoquinolinylpentylamine No. Preferable examples include phenylbutylamine, quinolinylbutylamine and isoquinolinylbutylamine.

Further, it is also possible to use various amine components such as substituted hydrazine.

Examples of the “substituted hydrazine” include, for example, N, N, -dimethylhydrazine, Ν, Ν′—jeti hydrazine, Ν, Ν′—dibenzi ^^ hydrazine, Ν, Ν, 1-bis (phenylenolbutyl) hydrazine And the like, and preferably Ν, ジン ′ -dimethylhydrazine and Ν, Ν′-jetylhydrazine.

In the reductive aminoalkylation reaction, a common organic solvent such as methanol, ethyl acetate, dimethylformamide, and 1,2-dichloroethane can be used alone or as a mixture. Preferably, methanol is used alone. It is good to use one. Improvement of the reaction yield may be observed by adding an organic acid such as acetic acid to the reaction system. Further, for the reductive aminoalkylation reaction, a hydride reagent which can be used in a usual reductive aminoalkylation reaction can be used, and preferably, sodium cyanoborohydride or sodium acetoborohydride is used. Good to use. .

In the process of carrying out these processes, the hydroxyl-protecting group may be partially removed. In the first production step, ozone oxidation, and in the second production step, reductive aminoalkylation, when methanol is used as the reaction solvent, the acetyl group at the 2-position (2-position) of the amino sugar moiety Is completely or partially removed during the reaction. In the second production step, reductive aminoalkylation, the acetyl group at the 9-position is completely or partially removed, depending on the amine component used for the ring closure. When 4-phenylbutylamine is actually used as the amine component, the acetyl group at the 9-position is almost completely removed in this step. These manufacturing processes Throughout the process, the 3-, 3 ", and 4" -positions of the acyl groups are usually less likely to change.

Further, the range encompassed by the present production method will be mentioned. The new process for the preparation of dialdehydes and their related compounds by ozone oxidation is not only applicable to the preparation of compounds of formula (I) or (ΙΠ). The present invention also applies to the production of other synthetic intermediates which are prepared by isolating the compound represented by or without isolation. In this specification, a novel 15-membered azalide compound is exemplified as an example of a useful compound that can be produced via a dialdehyde compound.However, in this specification, a dialdehyde compound is used as a key intermediate. It is not limited to novel useful substances that can be produced, but is also applicable to the production of novel useful compounds other than 15-membered ring azalides that can be used as intermediates for related compounds of dialdehydes. First, it can be used for the production of various new and useful skeleton conversion products. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. Reference example 1

In the formula (VII), a method for producing a compound in which R ₂ = acetyl group, R ₄ = acetyl group, and R ₆ = acetyl group

In the formula (VII), a compound in which R ₂ = acetyl group, R ₄ = hydrogen atom, and R ₆ = acetyl group (described in W002 / 64607) 610 ml of acetonitrile was added to 64.2 g of the compound, and dissolved. 7.8 ml was added, and the mixture was stirred at 40 ° C for 24 hours. After the reaction solution was concentrated under reduced pressure, 660 ml of ethyl acetate was added, and the organic layer was sequentially washed twice with 300 ml of saturated aqueous sodium hydrogen carbonate and 300 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (67.0 g). Example 1

In the formula (VI), a method for producing a compound wherein R ₂ = hydrogen atom, R ₄ == hydrogen atom, R ₆ = acetyl group, and R ₇ = 4_phenylbutyl

In the formula (VII), a compound in which R ₂ = acetyl group, R ₄ = hydrogen atom, and R ₆ = acetyl group (Xiao. 944.11) (150 mg, 0.159 mmol) (W002 / 64607) was converted to anhydrous methanol (5 mL). ) And cooled to -78 ° C, and then the reaction was carried out by introducing ozone gas into the solution. The reaction was continued until the methanol solution turned pale blue (about 15 minutes), and then the excess ozone was driven off with oxygen gas (about 5 minutes). Thereafter, dimethyl sulfide (1 mL) was added as a reducing agent, and stirring was continued at −78 ° C. for 30 minutes to generate a dialdehyde intermediate in the system. Subsequently, 4-phenylbutyramine (28 μM, 0.175 mmol) and sodium triacetoxyborohydride (100 mg, 0.472 mmol) were added, and the temperature was gradually raised to room temperature. Methanol was distilled off under reduced pressure to reduce the liquid volume to approximately half, and the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, concentrated, and purified by silica gel flash column chromatography (ethyl acetate / hexane = 1/5 to 1/1) to give the title compound in a yield of 8% (13. Omg, 0.0127 mmol).

(1) Molecular formula: C ₅₃ H ₈₈ N ₂ 0 ₁₇

(2) Mass spectrum (FAB): m / z 1025 (M + H) ⁺

(3) ¾ NMR spectrum _{(300 MHz, CDC1 3) δ} (ppm): 0.95 (d, 18-H), 1.07 (d, 6 "-H), 1.11 (t, 3- 0C0CH 2 CH 3 ), 1.18 (t, 4 ,, - 0C0C¾CH 3), 1.19 (d, 6, - H), 1.24 (d, 15-H), 1.40 (s, 3 ,, - CH 3), 1.68 (dd, 2 '' -Hax), 1.87 (br dd, 16- H), 2.00 (s, 3 '' -OCOCH3), 2.53 (s, 3, 1 N (CH ₃ ) ₂ ), 2.79 (dd, 2— H) , 3.11 (s, 17-0CH ₃ ), 3.21 (d, 2 '' -Heq), 3.24 (s, 17-0CH ₃ ), 3.38 (dd, 2, -H), 3.54 (br d, 4-1 H ), 3.58 (s, 4 one _{0CH 3), 3.87 (br d} , 5-H), 4.47 (d, 1, - H), 4.51 (dq, 5 ,, - H), 4.57 (d, 4 "- H), 4.78 (m, 14-H), 4.84 (d, 1, '-H), 5.20 (br dd, 3-H), 7.16 (m, C ₆ H ₅ ), 7.26 (m, C ₆ H ₅ ). Example 2

Method for producing a compound of the formula (VI) wherein R ₂ = hydrogen atom, R ₄ = hydrogen atom, R ₆ = acetyl group, R ₇ = 4-phenylbutyl

In the formula (VII) obtained in Reference Example 1, a compound (160 mg, 0.163 mmol) in which R ₂ = acetyl group, R ₄ = acetyl group, and R ₆ = acetyl group was added to anhydrous methanol (5 mL). After dissolving and cooling to -78 ° C, ozone gas was introduced into the solution to carry out the reaction. The reaction was continued until the methanol solution became pale blue (about 20 minutes), and then excess ozone was expelled with oxygen gas (about 10 minutes). Thereafter, dimethyl sulfide (1 mL) was added as a reducing agent, and stirring was continued at −78 ° C. for 30 minutes to generate a dialdehyde intermediate in the system. Subsequently, 4-phenylbutyramine (28 μl, 0.175 butylol), sodium trifluoromethane (26 mg, 0.413 mmol), acetic acid (136 ml, 2.38 ramol) Was gradually added to room temperature. After the temperature was raised to room temperature, sodium cyanoborohydride (26 mg, 0.413 ramol) was added, and after 1 hour, sodium cyanopolohydride (13 mg, 0.207 ramol) was added and the mixture was reacted for 2 hours. Was. Methanol was distilled off under reduced pressure to reduce the liquid volume to almost half. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off under reduced pressure and concentrated.The residue was purified by flash column chromatography on silica gel (ethyl acetate Z hexane = 1/5 to 1/1) to give the title compound in a yield of 7% (11. 5 mg, 0.0117 mmol).

It was confirmed by ¹ H NMR that the compound was the same as that in Example 1. Industrial applicability

Previously manufactured using reagents such as osmium, lead tetraacetate, and periodate, which remain environmentally and healthily challenging to oxidatively cleave the conjugated double bond of macrolide derivatives And the number of steps was multiple.

According to the method of this effort, the ozone oxidation reaction is used in the production of the dialdehyde, thereby eliminating the use of reagents that remain problematic in terms of environment and health care, and eliminating the use of dialdehyde compounds that are important key intermediates. Manufacturing becomes possible. In addition, the amino sugar portion Protection of the 2-position (2'-position) hydroxyl group is completely unnecessary, and the number of steps can be reduced from the conjugated double bond to the target compound (reclosed form) in two steps, and the yield is improved.

Claims

Range of request

1. The following equation (I)

(I)

[In the formula, is a hydrogen atom or a lower acyl group, R ₂ is a hydrogen atom, a lower acyl group, a lower alkyl group, or a protecting group for a hydroxyl group, R ₃ is a lower alkyl group, and 伹 -CH ( 0R ₃ ) ₂ may form a cyclic structure such as dioxolan or dioxane, R ₄ is a hydrogen atom, a lower acryl group, a lower alkyl group, or a protecting group for a hydroxyl group, and R ₅ is a hydrogen atom, a lower acryl group A lower alkyl group, a protecting group for a hydroxyl group, or a myloin which may be protected] or a salt thereof, which is represented by the formula (II)

(Π)

[Wherein, R ₂ , R ₃ , R ₄ , and R ₅ have the same meanings as in the formula (I)] or a salt thereof.

2. The following formula (III) OAc

(HI)

(IV)

[Wherein R ₄ and R ₆ have the same meaning as in formula (III)] or a salt thereof in one step.

3. The following equation (V)

[In the formula, is a hydrogen atom or a lower acyl group, R ₂ is a hydrogen atom, a lower acyl group, a lower alkyl group, or a protecting group for a hydroxyl group, R ₃ is a lower alkyl group, provided that _CH (0R ₃ ) ₂ may form a cyclic structure such as dioxolane or dioxane, and R ₄ is a hydrogen atom, a lower acyl group, a lower alkyl group, or a protecting group for a hydroxyl group. R ₅ is a hydrogen atom, a lower acryl group, a lower alkyl group, a protecting group for a hydroxyl group, or a myloin which may be protected, and R ₇ is a lower alkyl group or an aralkyl group] Or a method for producing a salt thereof, wherein

(Π)

[Wherein, R ₂ , R ₃ , R ₄ , and R ₅ have the same meanings as described above], or a salt thereof, which is subjected to an ozone oxidation reaction and a subsequent ring closure reaction.

4. The following equation (VI)

(VI)

(VII)

Wherein R ₂ , R ₄ and R ₆ are as defined in the formula (VI), or a salt thereof! A method comprising a step of performing an ozone oxidation reaction and a subsequent ring closure reaction.