JP5963278B2 - Novel atopenin analogs with a complex-selective electron transport system complex II inhibitory activity - Google Patents

Description

  The present invention relates to a novel atopenin analog having a species-selective electron transport system complex II inhibitory activity.

In recent years, it is said that there are 1 million deaths worldwide due to diseases or symptoms caused by parasites (hereinafter also referred to as “parasitic diseases”). As parasitic diseases, for example, malaria, dysentery amebiasis, roundworm and the like are known. Various antiparasitic drugs have been developed as pharmaceuticals for preventing or treating such parasitic diseases. However, since the emergence of parasites that are resistant to currently used antiparasitic drugs has been reported, the number of deaths due to parasitic diseases may increase further.

Parasites are taxonomic organisms. Therefore, in order to develop an antiparasitic agent having species selectivity with a host animal, it is necessary to develop a drug that targets a biosynthesis or metabolic pathway specific to the parasite. An electron transport complex II is known as such a parasite-specific pathway. Complex II is one of the proteins constituting the respiratory chain electron transport system, and is involved in the production of adenosine triphosphate (ATP) together with complexes I, III and IV. Complex II converts succinic acid to fumaric acid and transfers electrons to quinone under anaerobic conditions, while it converts electrons from rhodoquinol to fumaric acid to convert to succinic acid under anaerobic conditions. Since parasites such as roundworms have an anaerobic respiratory chain electron transport system, a compound having selective inhibitory activity against the complex II of the parasite may be used as an active ingredient of an antiparasitic agent.

Atpenins isolated from Penicillium FO-125 strain exhibit antiparasitic activity by inhibiting the complex II of the parasite (Non-patent Documents 1 and 2). Among the atopenins, atopenin A5 is a compound that exhibits the highest complex II inhibitory activity. Patent Document 1 is represented by the general formula [II] which is a 2-pyridinol derivative represented by the general formula [I] including atopenin A4, atopenin A5, atopenin B and Hadianopyridone, or a tautomer thereof. An electron transport complex II inhibitor comprising a compound containing a 2-pyridone derivative or a salt thereof as an active ingredient is described. Patent Document 2 describes 2-pyridones represented by general formula (Ik) including atopenins and 2-pyridinols represented by general formula (II-b). Non-Patent Documents 3 and 4 describe the enantioselective total synthesis of atopenin A5.

  In addition to atopenin A5, several compounds having complex II inhibitory activity are known (Non-patent Documents 5 and 6).

International Publication No. 2003/103667 International Publication No. 2010/069495

S. Ohmura et al., J. Antibiot. 1988, 41, p. 1769 H. Kumagai et al., J. Antibiot. 1990, 43, p. 1553 M. Ohtawa et al., J. Antibiot. 2009, 62, p. 289 M. Ohtawa et al., Chem. Pharm. Bull. 2012, 60, p. 898 H. Miyadera et al., Proc. Natl. Acad. Sci. U.S.A. 2003, 100, p. 473 K. Kita et al., Acta. Cryst. 2009, Volume F65, p. 941

Several compounds with high complex II inhibitory activity are known, such as atopenin A5. However, there have been some problems in applying these compounds to the active ingredients of antiparasitic drugs. For example, the complex II inhibitory activity of atopenin A5 has low species selectivity against parasites (Non-patent Document 5). For this reason, when atopenin A5 was applied as an active ingredient of an antiparasitic agent, it also showed inhibitory activity against the host animal complex II, and as a result, there was a possibility of causing a side reaction in the host animal.

  Therefore, an object of the present invention is to provide a novel compound having an electron transport system complex II inhibitory activity with high species selectivity to parasites.

  The present inventors have studied various means for solving the above problems. The inventors of the present invention designed a non-natural type atopenin A5 analog having a modified chemical structure using the natural organic compound atopenin A5 as a lead compound. As a result, the present inventors have found that a specific atopenin A5 analog has low inhibitory activity against the host animal-derived complex II, while showing high inhibitory activity against the parasite-derived complex II. It was. Further, the inventors have found that the novel atopenin A5 analog can be produced by synthetic means without using natural atopenin A5 as a raw material. Based on the above findings, the present inventors have completed the present invention.

  That is, the gist of the present invention is as follows.

［式中、
R¹は、置換若しくは非置換のC₄〜C₉アルキル、置換若しくは非置換のC₄〜C₉アルケニル、置換若しくは非置換のC₄〜C₉アルキニル、置換若しくは非置換のC₃〜C₆シクロアルキル、置換若しくは非置換のC₄〜C₆シクロアルケニル、置換若しくは非置換のC₄〜C₆シクロアルキニル、置換若しくは非置換の3〜6員のヘテロシクロアルキル、置換若しくは非置換のC₇〜C₁₁シクロアルキルアルキル、置換若しくは非置換の3〜6員のヘテロシクロアルキル-C₁〜C₉アルキル、置換若しくは非置換のC₆〜C₁₅アリール、置換若しくは非置換のC₇〜C₂₀アリールアルキル、置換若しくは非置換の5〜15員のヘテロアリール、又は置換若しくは
非置換の5〜15員のヘテロアリール-C₁〜C₉アルキルであり、
R²は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、置換若しくは非置換のヘテロシクロアルキルアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のヘテロアリール、又は置換若しくは非置換のヘ
テロアリールアルキルであり、
R³及びR⁴は、互いに独立して、水素、ハロゲン、ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のヘテロアリールオキシ、又は置換若しくは非置換のヘテロアリールアルキルオキシであり、
X^1’、X^2’、X^3’及びX^4’は、互いに独立して、酸素又は硫黄であり、
R^1’及びR^2’は、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、置換若しくは非置換のヘテロシクロアルキルアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のヘテロアリール、又は置換若しくは非置換のヘテロアリールアルキルであり、
R^3’及びR^4’は、互いに独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、置換若しくは非置換のヘテロシクロアルキルアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のヘテロアリール、又は置換若しくは非置換のヘテロアリールアルキルである。］
で表される化合物若しくはその塩、又はそれらの溶媒和物。 (1) Formula (I):

[Where:
R ¹ is substituted or unsubstituted C _{4 to} C ₉ alkyl, substituted or unsubstituted C _{4 to} C ₉ alkenyl, substituted or unsubstituted C _{4 to} C ₉ alkynyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₉ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₉ alkyl,
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, Or substituted or unsubstituted heteroarylalkyl,
R ³ and R ⁴ are independently of each other hydrogen, halogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, Substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryloxy, or substituted or unsubstituted heteroarylalkyloxy,
X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are independently of each other oxygen or sulfur;
R ^{1 ′} and R ^{2 ′} are, independently of one another, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl,
R ^{3 ′} and R ^{4 ′} , independently of one another, are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. ]
Or a salt thereof, or a solvate thereof.

(2) R ¹ is substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄
-C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₉ alkyl substituted, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, or substituted or heteroaryl -C unsubstituted 5-15 membered ₁ -C ₉ In the above definition (1), which is alkyl (wherein one or more carbon atoms of heterocycloalkyl or heteroaryl are substituted by one or more heteroatoms selected from N, S and O) The described compound.

(3) The compound according to (1) or (2) above, wherein R ¹ is substituted or unsubstituted C ₇ -C ₂₀ arylalkyl.

(4) The above (1), wherein R ² is substituted or unsubstituted alkyl, and R ³ and R ⁴ are each independently a halogen selected from the group consisting of chlorine, bromine, fluorine and iodine
The compound in any one of-(3).

(5) X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are oxygen, R ^{1 ′} and R ^{2 ′} are hydrogen, and R ^3
In any one of the above (1) to (4), ^' and R ^4' are independently of each other substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Compound.

［式中、
X^1’、X^2’、X^3’、X^4’、R^1’、R^2’、R^3’及びR^4’は、前記（1）〜（5）のいずれかに記載の定義と同義であり、
Y^1’は、水素、又は塩素、臭素、フッ素及びヨウ素からなる群より選択されるハロゲンである。］
で表される化合物と、式（IV）：

［式中、R¹、R²、R³及びR⁴は、前記（1）〜（5）のいずれかに記載の定義と同義である。］
で表される化合物とを縮合させて、式（II）：

［式中、X^1’、X^2’、X^3’、X^4’、R^1’、R^2’、R^3’、R^4’、R¹、R²、R³及びR⁴は、前記（1）〜（5）のいずれかに記載の定義と同義である。］
で表される化合物を得る、縮合工程；及び
式（II）で表される化合物を酸化して、式（I）で表される化合物を得る、酸化工程；
を含む、前記方法。 (6) A method for producing the compound according to any one of (1) to (5), wherein:
Formula (III):

[Where:
X ^{1 ′} , X ^{2 ′} , X ^{3 ′} , X ^{4 ′} , R ^{1 ′} , R ^{2 ′} , R ^{3 ′} and R ^{4 ′} have the same definitions as in any one of (1) to (5) above. And
Y ^{1 ′} is hydrogen or a halogen selected from the group consisting of chlorine, bromine, fluorine and iodine. ]
A compound represented by formula (IV):

[Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined in any one of (1) to (5) above. ]
Is condensed with a compound represented by formula (II):

[Wherein, X ^{1 ′} , X ^{2 ′} , X ^{3 ′} , X ^{4 ′} , R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , R ^{4 ′} , R ¹ , R ² , R ³ and R ⁴ are It is synonymous with the definition in any one of (1)-(5). ]
A condensation step for obtaining a compound represented by formula (II); and an oxidation step for obtaining a compound represented by formula (I) by oxidizing a compound represented by formula (II);
Said method.

(7) An antiparasitic agent comprising the compound or salt thereof according to any one of (1) to (5) or a solvate thereof as an active ingredient.

(8) A medicament comprising as an active ingredient the compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

(9) The compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable carriers. A pharmaceutical composition comprising:

(10) Malaria, dysentery amebiasis, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, roundworm, helminthiasis, trichinosis, lymphoid filariasis (elephroderma), onchocerciasis And the medicament according to (8) above, for use in the prevention or treatment of one or more diseases or symptoms selected from the group consisting of schistosomiasis.

(11) Malaria, dysentery amebiasis, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, roundworm, helminthiasis, trichinosis, lymphatic filariasis (elephroderma), onchocerciasis And the pharmaceutical composition according to (9) above, for use in the prevention or treatment of one or more diseases or symptoms selected from the group consisting of schistosomiasis.

  (12) An electron transport complex II inhibitor comprising the compound or salt thereof according to any one of (1) to (5) or a solvate thereof as an active ingredient.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a novel compound having an electron transport complex II inhibitory activity with high species selectivity to parasites.

  Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

  Hereinafter, preferred embodiments of the present invention will be described in detail.

<1. New compound>
As used herein, “alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, “C ₁ -C ₉ alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing at least 1 and at most 9 carbon atoms. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, hexyl, heptyl, octyl, and nonyl. Mention may be made of straight-chain or branched C ₁ -C ₉ alkyl.

In the present specification, “alkenyl” means a group in which one or more CC single bonds of the alkyl are substituted with double bonds. Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 - methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-pentenyl, hexenyl, heptenyl, a C ₂ -C ₉ alkenyl straight or branched chain, such as octenyl and nonenyl Can be mentioned.

In the present specification, “alkynyl” means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls include but are not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, hexynyl, heptynyl And linear or branched C ₂ -C ₉ alkynyl such as octynyl and noninyl.

As used herein, “cycloalkyl” means an alicyclic alkyl containing the specified number of carbon atoms. For example, “C ₃ -C ₆ cycloalkyl” means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, C ₃ -C ₆ cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present specification, “cycloalkenyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with double bonds. Suitable cycloalkenyl includes, but is not limited to, C ₄ -C ₆ cycloalkenyl such as cyclobutenyl, cyclopentenyl, and cyclohexenyl.

In the present specification, “cycloalkynyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with triple bonds. Suitable cycloalkynyl includes, but is not limited to, C ₄ -C ₆ cycloalkynyl such as cyclobutynyl, cyclopentynyl and cyclohexynyl.

In the present specification, “heterocycloalkyl” means that one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O). Means a group substituted with one or more heteroatoms. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heterocycloalkyl include, but are not limited to, for example, 3 Mention may be made of ˜6-membered heterocycloalkyl.

In the present specification, “cycloalkylalkyl” means a group in which one of the hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkylalkyl includes, but is not limited to, C ₇ -C ₁₁ cycloalkylalkyl such as cyclohexylmethyl and cyclohexenylmethyl.

As used herein, “heterocycloalkylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms has been replaced with the heterocycloalkyl. Suitable heterocycloalkylalkyl include, but are not limited to, can be exemplified heterocycloalkyl -C ₁ -C ₉ alkyl, e.g. 3-6 membered.

In the present specification, “alkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the alkyl, alkenyl or alkynyl. Suitable alkoxy includes, but is not limited to, C ₁ -C ₉ alkoxy such as methoxy, ethoxy, propoxy, butoxy and pentoxy.

In the present specification, “cycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the above cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkoxy includes, but is not limited to, C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy and cyclopentoxy.

  In the present specification, “heterocycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heterocycloalkyl. Suitable cycloalkoxy includes, but is not limited to, for example, 3-6 membered heterocycloalkoxy.

In the present specification, “aryl” means an aromatic ring group. Suitable aryls include, but are not limited to, C ₆ -C ₁₈ aryls such as phenyl, biphenyl, terphenyl, naphthyl and anthracenyl.

In the present specification, “arylalkyl” means a group in which one of hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the aryl. Preferred arylalkyl include, but are not limited to, for example, benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, can be exemplified terphenyl methyl and C ₇ -C ₂₀ arylalkyl styryl like.

In the present specification, “heteroaryl” means a group in which one or more carbon atoms of the aryl are each independently substituted with one or more heteroatoms selected from N, S and O. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heteroaryl include, but are not limited to, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Mention may be made of 5- to 15-membered heteroaryl such as pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.

In the present specification, “heteroarylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the heteroaryl. Suitable heteroarylalkyl includes, but is not limited to, 5- to 15-membered heteroaryl-C ₁ -C ₉ alkyl such as pyridylmethyl.

In the present specification, “aryloxy” means a group in which a hydroxyl hydrogen atom is substituted with the aryl. Suitable aryloxy includes, but is not limited to, C ₆ -C ₁₅ aryloxy such as phenoxy, biphenyloxy, naphthyloxy and anthryloxy (anthracenyloxy).

In the present specification, “arylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the arylalkyl. Suitable arylalkyloxy includes, but is not limited to, C ₇ -C ₂₀ arylalkyloxy such as benzyloxy, 1-phenethyloxy, 2-phenethyloxy and styryloxy.

In the present specification, “heteroaryloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroaryl. Suitable heteroaryloxy include, but are not limited to, furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso 5-15 such as oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy and indolyloxy Mention may be made of member heteroaryloxy.

In the present specification, “heteroarylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroarylalkyl. Preferred heteroarylalkyloxy include, without limitation, mention may be made of heteroaryl -C ₁ -C ₉ alkyl oxy example 5-15 membered.

In the present specification, “acyl” means a group in which a monovalent group selected from the groups described above and carbonyl are linked. Suitable acyls include, but are not limited to, C ₁ -C ₅ aliphatic acyls such as formyl, acetyl and propionyl, and C ₇ -C ₁₆ such as benzoyl.
Aromatic acyl can be mentioned.

The groups described above are each independently unsubstituted or can be further substituted with one or more of the above-described monovalent groups.

  In the present specification, “halogen” or “halo” means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

で表される化合物若しくはその塩、又はそれらの溶媒和物に関する。 The present invention is directed to formula (I):

Or a salt thereof, or a solvate thereof.

The present inventors have found a compound represented by the formula (I) as a compound having an electron transport system complex II inhibitory activity with high species selectivity against parasites. The compound represented by the formula (I) was designed by modifying its chemical structure using atopenin A5, which is a natural organic compound, as a lead compound. The compound represented by the formula (I) has a skeleton structure in which the pyridine ring portion and the C ₆ -side chain portion of atopenin A5 are retained. Atopenin A5 can be synthesized by reacting an intermediate having a 3-iodopyridine skeleton with an intermediate having an n-hexanal skeleton (M. Ohtawa et al., J. Antibiot. 2009, Vol. 62, p. 289; and M. Ohtawa et al., Chem.
Pharm. Bull. 2012, 60, p. 898). Therefore, the compound represented by the formula (I) of the present invention can be produced with high purity and low cost by synthetic means similar to the total synthesis of atopenin A5.

The natural organic compound, atopenin A5, has high complex II inhibitory activity, but its inhibitory activity is low in species selectivity to parasites. The inventors of the present invention have developed a three-dimensional structure of a co-crystal (PDB code: 3AEE) of a complex II derived from a pig and a mammal, and a complex II derived from atopenin A5 and a parasite (Ascaris suum). As a result of comparison with the three-dimensional structure of the co-crystal (PDB code: 3VRA), there is a difference in the size of the lipid-soluble pocket of complex II containing the 2'-position group of the C ₆ -side chain part of atopenin A5 I found out. That is, it was found that the fat-soluble pocket of the porcine-derived complex II had a smaller space inside the pocket than the fat-soluble pocket of the complex II derived from A. suum. Due to such steric differences between the complex II from mammals and the complex II from parasites, a bulky lipophilic group at the 2′-position of the C ₆ -side chain moiety The atopenin A5 analog with a stable binding to parasite-derived complex II with a large fat-soluble pocket, while stable with a mammal-derived complex II with a smaller fat-soluble pocket It becomes difficult to combine.

Therefore, in the formula (I), R ¹ needs to be a bulky fat-soluble group, and is preferably a substituted or unsubstituted hydrocarbon group excluding methyl. The hydrocarbon group may optionally contain one or more heteroatoms selected from N, S and O. By having the structural characteristics described above, the compound represented by the formula (I) of the present invention can express complex II inhibitory activity with high species selectivity against parasites.

There are several analogs of atopenin A5 (for example, Patent Documents 1 and 2). However, a compound characterized by having a bulky fat-soluble group at the 2′-position of the C ₆ -side chain moiety has not been known so far. Therefore, the compound represented by the formula (I) of the present invention in which R ¹ is a bulky fat-soluble group is a novel compound found by the present inventors.

In one embodiment of the present invention, R ¹ is a substituted or unsubstituted C ₄ -C ₉ alkyl, substituted or unsubstituted C ₄ -C ₉ alkenyl, substituted or unsubstituted C ₄ -C ₉ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or C ₄ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl Substituted or unsubstituted C _{7 to} C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C _{1 to} C ₉ alkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or heteroaryl -C ₁ -C ₉ alkyl unsubstituted 5-15 membered. R ¹ is substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkynyl, substituted or unsubstituted 3
6-membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₉ alkyl, substituted or unsubstituted C ₇ preferably -C ₂₀ arylalkyl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₉ alkyl, more preferably a substituted or unsubstituted C ₇ -C ₂₀ arylalkyl , Benzyl, 4-phenylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,6-dimethylbenzyl, 2-tert-butylbenzyl, 2-trifluoromethylbenzyl, [1,1'- Biphenyl] -2-ylmethyl, [1,1′-biphenyl] -3-ylmethyl, [1,1′-biphenyl] -4-ylmethyl, 4,1 ′: 4 ′, 1 ″ -terphenylmethyl, naphthalene Must be -1-ylmethyl or naphthalen-2-ylmethyl Are more preferable, and benzyl, 4-phenylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, naphthalen-1-ylmethyl or naphthalen-2-ylmethyl is particularly preferable. In the above definition, one or more carbon atoms of heterocycloalkyl or heteroaryl are substituted by one or more heteroatoms selected from N, S and O. In the case of having R ¹ , the compound represented by the formula (I) has a bulky lipophilic group at a position corresponding to the 2′-position of the C ₆ -side chain part of atopenin A5. Complex II inhibitory activity with particularly high species selectivity can be expressed.

In formula (I), R ² represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Substituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or It must be unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl. R ² is a substituted or unsubstituted C ₁ -C ₉ alkyl, substituted or unsubstituted C ₂ -C ₉ alkenyl, substituted or unsubstituted C ₂ -C ₉ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₉ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or preferably a heteroaryl -C ₁ -C ₉ alkyl unsubstituted 5-15 membered, substituted or unsubstituted C ₁ ~ C ₉ alkyl, location Or unsubstituted C ₂ -C ₉ alkenyl, substituted or unsubstituted C ₂ -C ₉ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₅
More preferred is aryl, or substituted or unsubstituted C ₇ -C ₂₀ arylalkyl. In one embodiment, R ² is particularly preferably substituted or unsubstituted C ₁ -C ₉ alkyl, particularly preferably methyl. In another embodiment, R ² is substituted or unsubstituted C ₄ -C ₉ alkyl, substituted or unsubstituted C ₄ -C ₉ alkenyl, substituted or unsubstituted C ₄ -C ₉ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, or a substituted or particularly preferably a C ₇ -C ₂₀ arylalkyl unsubstituted benzyl, 4-phenylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,6-dimethylbenzyl, 2-tert Butylbenzyl, 2-trifluoromethylbenzyl, [1,1'-biphenyl] -2-ylmethyl, [1,1'-biphenyl] -3-ylmethyl, [1,1'-biphenyl] -4-ylmethyl, 4 , 1 ': 4', 1 ''-Terphenylmethyl, naphthalen-1-yl Particularly preferred is methyl or naphthalen-2-ylmethyl. In the above definition, one or more carbon atoms of heterocycloalkyl or heteroaryl are substituted by one or more heteroatoms selected from N, S and O.

In formula (I), R ³ and R ⁴ are independently of each other hydrogen, halogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or It must be unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryloxy, or substituted or unsubstituted heteroarylalkyloxy. R ³ and R ⁴ are independently of each other hydrogen, halogen, hydroxy, substituted or unsubstituted C _{1 to} C ₉ alkoxy, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6-membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, or substituted Or preferably an unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₉ alkyloxy, hydrogen, halogen, hydroxy, substituted or unsubstituted C ₁ -C ₉ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, more preferably substituted or unsubstituted C ₆ -C ₁₅ aryloxy, or substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, chlorine, odor More preferred is a halogen selected from the group consisting of elemental, fluorine and iodine. In the above definition, one or more carbon atoms of heterocycloalkyl or heteroaryl are substituted by one or more heteroatoms selected from N, S and O.

In the formula (I), X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} need to be oxygen or sulfur independently of each other. X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are preferably oxygen.

In the formula (I), R ^{1 ′} and R ^{2 ′} each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted It must be aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. R ^{1 ′} and R ^{2 ′} , independently of one another, are hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₉ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁
Is preferably -C ₅ alkyl, hydrogen, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, or substituted or unsubstituted C ₂ -C ₅ alkynyl More preferably, it is more preferably hydrogen. In the above definition, one or more carbon atoms of heterocycloalkyl or heteroaryl are substituted by one or more heteroatoms selected from N, S and O.

In the formula (I), R ^{3 ′} and R ^{4 ′} each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl,
It must be substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. R ^{3 ′} and R ^{4 ′} are independently of one another hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₉ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁
Is preferably -C ₅ alkyl, hydrogen, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, or substituted or unsubstituted C ₂ -C ₅ alkynyl more preferably a substituted or unsubstituted C ₁ -C ₅ alkyl, more preferably a substituted or unsubstituted C ₂ -C ₅ alkenyl, or substituted or unsubstituted C ₂ -C ₅ alkynyl, methyl It is particularly preferred. In the above definition, one or more carbon atoms of heterocycloalkyl or heteroaryl are substituted by one or more heteroatoms selected from N, S and O.

In the formula (I), when the group is substituted, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, substituted or unsubstituted alkyl, substituted or non-substituted. From substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy It is preferably a monovalent group selected from the group consisting of halogen (fluorine, chlorine,
Bromine or iodine), cyano, nitro, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted amino, and substituted or unsubstituted C ₁ ~ More preferably a monovalent group selected from the group consisting of C ₅ alkoxy,
C ₁ -C ₅ alkyl, unsubstituted or halogen (fluorine, chlorine, bromine or substituted with halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, unsubstituted or halogen (fluorine, chlorine, bromine or iodine) C ₂ -C ₅ alkenyl substituted with iodine), C ₃ -C ₆ cycloalkyl unsubstituted or substituted with halogen (fluorine, chlorine, bromine or iodine), and unsubstituted or halogen (fluorine, chlorine, bromine or More preferably, it is a monovalent group selected from the group consisting of C ₁ -C ₅ alkoxy substituted with iodine.

Particularly preferred compounds of formula (I) are those in which R ¹ is substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, R ² is substituted or unsubstituted alkyl, R ³ and R ⁴ Are independently selected from the group consisting of chlorine, bromine, fluorine and iodine, X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are oxygen, R ^{1 ′} and R ^{2 ′} is hydrogen and R ^{3 ′} and R ^{4 ′} are, independently of one another, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Particularly preferred compounds of the formula (I) are those in which R ¹ is substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, R ² is substituted or unsubstituted C ₁ -C ₉ alkyl, R ³ and R ⁴ are independently halogen selected from the group consisting of chlorine, bromine, fluorine and iodine, and X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are oxygen. , R ^{1 ′} and R ^{2 ′} are hydrogen, and R ^{3 ′} and R ^{4 ′} are independently of each other substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, or substituted or unsubstituted C ₂ -C ₅ alkynyl.

Particularly preferred compounds of the formula (I) are:
(2R, 4S, 5R) -2-Benzyl-5,6-dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methylhexane-1-one (A5-001);
(2R, 4S, 5R) -2-([1,1'-biphenyl] -4-ylmethyl) -5,6-dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridine- 3-yl) -4-methylhexan-1-one (A5-002);
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (2-methylbenzyl) Hexan-1-one (A5-003);
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (3-methylbenzyl) Hexan-1-one (A5-004);
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (4-methylbenzyl) Hexan-1-one (A5-005);
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (naphthalen-1-ylmethyl) ) Hexan-1-one (A5-006); and
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (naphthalen-2-ylmethyl) ) Hexane-1-one (A5-007)
Selected from the group consisting of

In the present invention, the compound represented by the formula (I) and the formulas (II), (III), (IV), (V), (V-iii), (V-vi), (V The compound represented by -xii) and (V-xiii) includes not only the compound itself but also a salt thereof. Examples of the salt of the compound represented by each formula of the present invention include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or formic acid and acetic acid. , Maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, With organic acid anions such as itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Salts are preferred. When the compound represented by the formula (I) is in the form of the salt, the compound can be used without substantially reducing the species selectivity against the parasite and the complex II inhibitory activity.

Compounds represented by formula (I) and formulas (II), (III), (IV), (V), (V-iii), (V-vi), (V-xii) and The compound represented by (V-xiii) includes not only the compound itself or the following compound itself, but also a solvate of the compound or a salt thereof. Solvents that can form solvates with the compound or salt thereof include, but are not limited to, for example, lower alcohols (eg, 1-6 carbons such as methanol, ethanol or 2-propanol (isopropyl alcohol)). Alcohols having a number of atoms), higher alcohols (eg alcohols having 7 or more carbon atoms such as 1-heptanol or 1-octanol)
Preferred are organic solvents such as dimethyl sulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate, or water. When the compound represented by the formula (I) or a salt thereof is in the form of a solvate with the above-mentioned solvent, the compound can be used without substantially reducing the species selectivity against the parasite and the complex II inhibitory activity. Can be used.

Compounds represented by formula (I) and formulas (II), (III), (IV), (V), (V-iii), (V-vi), (V-xii) and The compound represented by (V-xiii) includes not only the above-mentioned or the following compounds themselves, but also their protected forms. In the present specification, the “protected form” means a form in which a protective group is introduced into one or more functional groups (for example, a hydroxyl group or a carboxylic acid group). In this specification, the protected form of the compound represented by each formula may be referred to as a protected derivative of the compound represented by each formula. In the present specification, a “protecting group” is a group introduced into a specific functional group in order to prevent an undesirable reaction from progressing, and is quantitatively removed under specific reaction conditions. In other reaction conditions, it means a group that is substantially stable, that is, reaction-inactive. The protecting group capable of forming a protected form of the compound is not limited. For example, in the case of a protecting group for a hydroxyl group, silyl (for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) Or tert-butyldiphenylsilyl (TBDPS)) or alkoxy (eg, methoxymethoxy (MOM) or methoxy (Me)) is a protecting group for a carboxylic acid group, an alkyl ester (eg, methyl, ethyl or isopropyl ester), Preference is given to arylalkyl esters (eg benzyl esters) or amides (eg amides with oxazolidinones), respectively. Protection and deprotection by the protecting group can be appropriately performed by those skilled in the art based on known reaction conditions. When the compound represented by the formula (I) is in a protected form by the above-described protecting group, the compound can be used without substantially reducing the species selectivity against the parasite and the complex II inhibitory activity. .

  Compounds represented by formula (I) and formulas (II), (III), (IV), (V), (V-iii), (V-vi), (V-xii) and When the compound represented by (V-xiii) has one or more tautomers, the compound also includes individual tautomeric forms of the compound.

  In addition, the compound represented by the formula (I) and the formulas (II), (III), (IV), (V), (V-iii), (V-vi), (V-xii) described below ) And (V-xiii) have one or more stereocenters (chiral centers), the compounds are the individual enantiomers and diastereomers of the compounds and their racemates such as racemates. Also includes mixtures.

By having the above characteristics, the compound represented by the formula (I) can express complex II inhibitory activity with high species selectivity against parasites.

<2. New compound production method>
We have synthesized the total of atopenin A5 (M. Ohtawa et al., J. Antibiot. 2009, 62, p. 289; and M. Ohtawa et al., Chem. Pharm. Bull. 2012, 60). , p. 898), the compound represented by the formula (I) of the present invention can be obtained by using a compound having a simple 3-iodopyridine skeleton and n -It was found that a compound having a hexanal skeleton can be synthesized as a reaction intermediate. Therefore, the present invention also relates to a method for producing the compound represented by the formula (I) of the present invention.

The method for producing the compound represented by the formula (I) of the present invention needs to include (a) a condensation step; and (b) an oxidation step. The method of the present invention can also optionally include (c) an aldehyde group introduction step; and (d) a side chain substituent introduction step. Hereinafter, each step will be described in detail.

で表される化合物と、式（IV）：

で表される化合物とを縮合させて、式（II）：

で表される化合物を得る、縮合工程を含む。 [2-1. Condensation process]
The method for producing the compound represented by the formula (I) of the present invention comprises the formula (III):

A compound represented by formula (IV):

Is condensed with a compound represented by formula (II):

A condensation step for obtaining a compound represented by the formula:

In the formulas (II) to (IV), X ^{1 ′} , X ^{2 ′} , X ^{3 ′} , X ^{4 ′} , R ^{1 ′} , R ^{2 ′} , R ^{3 ′} and R ^{4 ′} , and R ¹ , R ² , R ³ and R ⁴ are as defined above.

In the formula (II), Y ^{1 ′} is hydrogen or halogen selected from the group consisting of chlorine, bromine, fluorine and iodine. Y ^{1 ′} is preferably a halogen selected from the group consisting of chlorine, bromine, fluorine and iodine, more preferably iodine.

The compound represented by the formula (III) used in this step can be obtained by referring to a known method described in, for example, M. Ohtawa et al., J. Antibiot. 2009, Vol. 62, p. 289. Can be prepared. Moreover, the compound represented by the formula (IV) used in this step can be prepared by performing an aldehyde group introduction step described below. The compounds represented by the formulas (III) and (IV) used in this step may be prepared by self-preparation using the above-mentioned method, purchase the above-mentioned compound prepared in advance by any method, etc. You may prepare by doing. Either case is included in the embodiment of this step.

In this step, for example, the compound represented by formula (III) or a protected derivative thereof and a strong base are reacted, and then the compound represented by formula (IV) or a protected derivative thereof is added to the reaction mixture to react. Can be implemented. Examples of the strong base include, but are not limited to, n-butyl lithium, sec-butyl lithium, and t-butyl lithium. The reaction is preferably carried out in a solvent such as tetrahydrofuran or diethyl ether. The reaction is preferably performed at a low temperature, for example, at a temperature in the range of -100 to -40 ° C. The reaction is preferably carried out for a time in the range of 0.02 to 2 hours. By carrying out this step under the above conditions, a compound represented by the formula (II) can be obtained.

[2-2. Oxidation process]
The method for producing a compound represented by formula (I) of the present invention comprises oxidizing a compound represented by formula (II) obtained in the condensation step to obtain a compound represented by formula (I). Process.

In this step, the secondary hydroxyl group at the 1′-position of the side chain of the compound represented by formula (II) or a protected derivative thereof is oxidized to a carbonyl group. This step can be performed, for example, by reacting the compound represented by formula (II) or a protected derivative thereof with an oxidizing agent. Examples of the oxidizing agent include, but are not limited to, Dess-Martin periodinane and 2-
Mention may be made of iodoxybenzoic acid (IBX). Since a predetermined secondary hydroxyl group can be selectively oxidized to a carbonyl group under mild conditions, Dess-Martin periodinane is preferably used as the oxidizing agent. The reaction is preferably carried out in a solvent such as dichloromethane, dimethyl sulfoxide or acetonitrile. The reaction is preferably performed at room temperature, for example, at a temperature in the range of 0 to 80 ° C. The reaction is preferably performed for a time in the range of 0.1 to 4 hours. By carrying out this step under the above conditions, the compound represented by formula (I) can be obtained.

[2-3. Aldehyde group introduction process]
The method for producing the compound represented by the formula (I) of the present invention can optionally include an aldehyde group introduction step.

で表される化合物又はその保護誘導体の1-位の一級ヒドロキシル基をアルデヒド基へ酸化して、式（IV）で表される化合物又はその保護誘導体を得る。 In this step, the formula (V):

The primary hydroxyl group at the 1-position of the compound represented by formula (1) or a protected derivative thereof is oxidized to an aldehyde group to obtain the compound represented by formula (IV) or a protected derivative thereof.

In the formula (V), R ¹ , R ² , R ³ and R ⁴ are as defined above.

The compound represented by the formula (V) used in this step can be prepared by performing the side chain substituent introduction step described below. The compound represented by the formula (V) used in this step may be prepared by self-preparation using the above-mentioned method, or prepared by purchasing the above-prepared compound by any method. May be. Either case is included in the embodiment of this step.

This step can be performed, for example, by reacting the compound represented by formula (V) or a protected derivative thereof with an oxidizing agent. Examples of the oxidizing agent include, but are not limited to, a combination of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) and iodobenzene diacetate (PhI (OAc) ₂ ), and Dess-Martin periodinane can be mentioned. The reaction is preferably carried out in a solvent such as dichloromethane or dimethyl sulfoxide. Since a predetermined primary hydroxyl group can be selectively oxidized to an aldehyde group under mild conditions, it is preferable to use a combination of TEMPO and PhI (OAc) ₂ as an oxidizing agent. The reaction is preferably performed at room temperature, for example, at a temperature in the range of 0 to 30 ° C. The reaction is preferably carried out for a time in the range of 0.5 to 5 hours. By carrying out this step under the above conditions, a compound represented by the formula (IV) can be obtained.

[2-4. Side chain substituent introduction process]
The method for producing the compound represented by the formula (I) of the present invention can optionally include a side chain substituent introduction step.

で表される化合物又はその保護誘導体の2-位炭素に置換基R¹を導入して、式（V）で表さ
れる化合物又はその保護誘導体を得る。 In one embodiment of this step, formula (V-iii):

A substituent R ¹ is introduced into the 2-position carbon of the compound represented by the formula or a protected derivative thereof to obtain the compound represented by the formula (V) or the protected derivative thereof.

In the present embodiment, R ¹ and R ² are as defined above.

で表される化合物又はその保護誘導体（式中、R²は、前記と同義である。）に、カルボン酸基を有する炭素鎖を結合させることにより、調製することができる。式（V-vi）で表される化合物は、例えば、M. Oikawaら, J. Org. Chem. 1995年, 第60巻, p. 5048に記載の公知の方法を参照することにより、調製することができる。本工程において使用される式（V-vi）で表される化合物は、前記方法を用いて自ら調製することによって準備してもよく、任意の方法で予め調製された前記化合物を購入等することによって準備してもよい。いずれの場合も、本工程の実施形態に包含される。 The compound represented by the formula (V-iii) used in the present embodiment is, for example, the formula (V-vi)
:

Or a protected derivative thereof (wherein R ² has the same meaning as described above) can be prepared by binding a carbon chain having a carboxylic acid group. The compound represented by the formula (V-vi) is prepared by referring to a known method described in, for example, M. Oikawa et al., J. Org. Chem. 1995, Vol. 60, p. 5048. be able to. The compound represented by the formula (V-vi) used in this step may be prepared by self-preparation using the above-mentioned method, or purchase the above-mentioned compound prepared in advance by any method. You may prepare by. Either case is included in the embodiment of this step.

In the present embodiment, the reaction for introducing R ¹ is, for example, a compound represented by the formula (V-iii) by reacting a compound represented by the formula (V-iii) or a protected derivative thereof with a base, or a compound thereof. This can be done by deprotonating the protected derivative and then reacting the deprotonated intermediate with an R ¹ reactant. Examples of the base include, but are not limited to, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide. Examples of the R ¹ reactant include, but are not limited to, halogenated R ¹ . The reaction is preferably carried out in a solvent such as tetrahydrofuran or diethyl ether. The reaction is preferably performed at a low temperature, for example, at a temperature in the range of -100 to -40 ° C.
The reaction is preferably carried out for a time ranging from 0.2 to 4 hours. By carrying out the reaction of the present embodiment under the above conditions, a compound represented by the formula (V) can be obtained.

This step also includes a reaction of converting two hydroxyl groups of the compound represented by the formula (V-iii) into R ³ and R ⁴ , respectively. The reaction for converting to R ³ and R ⁴ may be performed before or after the reaction for introducing R ¹ . The reaction can be carried out, for example, by reacting the compound represented by the formula (V-iii) or a protected derivative thereof with an R ³ reactive agent and an R ⁴ reactive agent. Examples of the R ³ reactant and R ⁴ reactant include, but are not limited to, a combination of N-halogenated succinimide and triphenylphosphine (when R ³ and R ⁴ are halogen), and tetrahalogen. And a combination of carbonized carbon and triphenylphosphine (when R ³ and R ⁴ are halogen). The reaction is preferably carried out in a solvent such as tetrahydrofuran or dichloromethane. The reaction is preferably carried out at a temperature in the range of 0 to 70 ° C, for example. The reaction is preferably carried out for a time in the range of 0.2 to 2 hours. By carrying out the reaction of the present embodiment under the above conditions, a compound represented by the formula (V) can be obtained.

で表される化合物又はその保護誘導体のエポキシ基炭素に置換基R²を導入して、式（V）
で表される化合物又はその保護誘導体を得る。 In another embodiment of this step, the formula (V-xii):

The substituent R ² is introduced into the epoxy group carbon of the compound represented by
Or a protected derivative thereof is obtained.

In the present embodiment, R ¹ and R ² are as defined above.

で表される化合物又はその保護誘導体（式中、R¹は、前記と同義である。）に、エポキシ基を有する炭素鎖を結合させることにより、調製することができる。式（V-xiii）で表される化合物は、例えば、M. Ohtawaら, J. Antibiot. 2009年, 第62巻, p. 289に記載の公知の方法を参照することにより、調製することができる。本工程において使用される式（V-xiii）で表される化合物は、前記方法を用いて自ら調製することによって準備してもよく、任意の方法で予め調製された前記化合物を購入等することによって準備してもよい。いずれの場合も、本工程の実施形態に包含される。 The compound represented by the formula (V-xii) used in the present embodiment is, for example, the formula (V-xiii)
):

Or a protected derivative thereof (wherein R ¹ has the same meaning as described above) can be prepared by bonding a carbon chain having an epoxy group. The compound represented by the formula (V-xiii) can be prepared by referring to a known method described in, for example, M. Ohtawa et al., J. Antibiot. 2009, Vol. 62, p. 289. it can. The compound represented by the formula (V-xiii) used in this step may be prepared by self-preparation using the above-mentioned method, and the above-mentioned compound prepared in advance by any method is purchased. You may prepare by. Either case is included in the embodiment of this step.

In this embodiment, the reaction for introducing R ² can be carried out, for example, by reacting a compound represented by the formula (V-xii) or a protected derivative thereof with an R ² reactant. Examples of the R ² reactant include, but are not limited to, R ² organomagnesium reagents (hereinafter also referred to as “Grignard reagents”) (for example, R ² MgCl), and Grignard reagents or corresponding organolithium reagents. And an organic copper reagent obtained from copper cyanide or copper iodide. The reaction is preferably carried out in a solvent such as tetrahydrofuran, diethyl ether or dichloromethane. The reaction is preferably carried out at a low temperature, for example, at a low temperature in the range of −78 to 25 ° C. The reaction is preferably carried out for a time in the range of 0.1 to 5 hours. By carrying out the reaction of this embodiment under the above-mentioned conditions, the formula (V)
Can be obtained.

In this step, the two hydroxyl groups of the intermediate formed by the reaction for introducing R ² are also converted to R ^3.
And a reaction to convert to R ⁴ respectively. The reaction can be carried out, for example, by reacting an intermediate formed by the reaction of introducing R ² or a protected derivative thereof with an R ³ reactive agent and an R ⁴ reactive agent. Examples of the R ³ reactant and R ⁴ reactant include, but are not limited to, a combination of N-halogenated succinimide and triphenylphosphine (when R ³ and R ⁴ are halogen), and tetrahalogen. And a combination of carbonized carbon and triphenylphosphine (when R ³ and R ⁴ are halogen). The reaction is preferably carried out in a solvent such as tetrahydrofuran or dichloromethane. The reaction is preferably carried out at a temperature in the range of 0 to 70 ° C, for example. The reaction is preferably carried out for a time in the range of 0.2 to 2 hours. By carrying out the reaction of the present embodiment under the above conditions, a compound represented by the formula (V) can be obtained.

[2-5. Protecting group introduction step and deprotection step]
Each step of the method for producing the compound represented by the formula (I) of the present invention may be carried out according to the formula (I), (II), (III), (IV), (V), (V-iii), You may implement using the protected derivative of the compound represented by (V-vi), (V-xii), and (V-xiii). In that case, each said process is a protective group introduction | transduction process which introduce | transduces a protective group into the specific functional group of the compound represented by said each formula, and obtains the protected derivative of this compound, and the compound represented by said each formula It is preferable to further include a deprotecting step of deprotecting a specific protecting group of the protected derivative. Compounds represented by formulas (I), (II), (III), (IV), (V), (V-iii), (V-vi), (V-xii) and (V-xiii) Applicable protecting groups are
Those skilled in the art can appropriately select the functional group to be protected and other functional groups and the type of the protecting group. Further, protection by the protecting group in the protecting group introduction step and deprotection of the protecting group in the deprotecting step can be appropriately performed by those skilled in the art based on known reaction conditions.

By the method described above, a compound having a simple 3-iodopyridine skeleton and a compound having an n-hexanal skeleton are used as reaction intermediates without using the natural product atopenin A5 as a raw material. ) Can be produced. Therefore, according to the present invention, the compound represented by the formula (I) of the present invention, which can be an active ingredient of a medicine, or various compounds derived from the compound can be produced in a large amount with high purity and low cost by synthetic means. Can be provided.

<3. Pharmaceutical use>
The compound represented by the formula (I) of the present invention not only has a complex II inhibitory activity similar to that of atopenin A5, but also has a species selectivity against a parasite that significantly exceeds atopenin A5. Therefore, the present invention relates to a complex II inhibitor of an electron transport system comprising the compound represented by the formula (I) of the present invention or a salt thereof, or a solvate thereof as an active ingredient. In addition, when the compound represented by the formula (I) of the present invention is administered to a mammalian subject, the complex II inhibitory activity having a high species selectivity against the parasite causes the parasite infection to cause the compound. A specific disease or symptom of a subject can be prevented or treated. Therefore, the present invention also relates to an antiparasitic agent or medicament comprising the compound represented by the formula (I) of the present invention or a salt thereof, or a solvate thereof as an active ingredient.

The complex II inhibitory activity of the compound represented by formula (I) of the present invention is not limited,
For example, organs (eg heart) of human or non-human mammals (eg warm blooded animals such as pigs, dogs, cows, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons or chimpanzees), or The mitochondrial fraction prepared from a parasite (eg, swine worm) can be determined as the enzyme source of complex II protein. The enzyme source of the complex II protein may be a mitochondrial fraction prepared from a cultured cell in which the human or non-human mammal or the parasite complex II is highly expressed. The parasite-derived complex II inhibitory activity can be measured as NADH-fumarate reductase inhibitory activity. In this case, the NADH-fumarate reductase inhibitory activity of the compound represented by the formula (I) of the present invention can be determined, for example, by the following procedure. A predetermined amount of buffer (for example, potassium phosphate buffer (pH 7.4)) is put into a quartz cuvette. The enzyme reaction components (eg, antimycin A, glucose oxidase, catalase and β-D-glucose) and the enzyme source are then added to the quartz cuvette. After mixing the reaction solution, a predetermined concentration of the compound represented by the formula (I) of the present invention is added to the reaction solution. After mixing the reaction solution, a predetermined concentration of nicotinamide adenine dinucleotide (NADH) and sodium fumarate, which are substrates for the enzyme reaction, are added to the reaction solution to start the enzyme reaction. The NADH-fumarate reductase inhibitory activity can be quantitatively determined by measuring the absorbance change of NADH in the reaction solution at 340 nm and comparing it with the measured values in the control group and the blank group. The complex II inhibitory activity derived from the human or non-human mammal can be measured as succinic acid-ubiquinone reductase inhibitory activity. In this case, the succinic acid-ubiquinone reductase inhibitory activity of the compound represented by the formula (I) of the present invention can be determined, for example, by the following procedure. A predetermined amount of a buffer solution (for example, a potassium phosphate buffer solution (pH 7.4) containing sucrose laurate and ubiquinone) is placed in a quartz cuvette. The quartz cuvette is then added with an enzyme reaction component (eg, antimycin A), as well as an enzyme source. After mixing the reaction solution, a predetermined concentration of the compound represented by the formula (I) of the present invention is added to the reaction solution. After mixing the reaction solution, a predetermined concentration of sodium succinate as a substrate for the enzyme reaction is added to the reaction solution to start the enzyme reaction. The change in absorbance of ubiquinone in the reaction solution is measured at 278 nm, and the succinic acid-ubiquinone reductase inhibitory activity can be quantitatively determined by comparing with the measured values in the control group and the blank group. The complex II inhibitory activity of the compound represented by the formula (I) of the present invention is determined based on the inhibition rate of NADH-fumarate reductase inhibitory activity or succinate-ubiquinone reductase inhibitory activity determined by the above procedure. 50% activity
It is preferably expressed as the concentration (IC ₅₀ ) of the compound represented by formula (I) of the present invention that inhibits.

The species selectivity of the complex II inhibitory activity of the compound represented by the formula (I) of the present invention can be determined, for example, by the following procedure. By the method described above, the IC ₅₀ value of the compound represented by the formula (I) of the present invention against the parasite or the complex II derived from a human or non-human mammal is determined. Using the obtained IC ₅₀ value, the species selectivity of the complex II inhibitory activity of the compound represented by the formula (I) of the present invention can be determined based on the following formula.

When the compound represented by the formula (I) of the present invention is applied to a pharmaceutical use, the compound represented by the formula (I) is not only the compound itself, but also a pharmaceutically acceptable salt of the compound, and And pharmaceutically acceptable solvates thereof. Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) of the present invention and the pharmaceutically acceptable solvate thereof include, but are not limited to, the salts and solvents exemplified above. Japanese products are preferred. When the compound represented by the formula (I) is in the form of the above-mentioned salt or solvate, the compound can be used as a desired pharmaceutical without substantially reducing the species selectivity against the parasite and the complex II inhibitory activity. It can be applied for use.

When the compound represented by the formula (I) of the present invention is applied to a pharmaceutical use, the compound represented by the formula (I) includes not only the compound itself but also a prodrug form of the compound. As used herein, “prodrug” means a compound that is converted into the parent drug in vivo. Examples of the prodrug form of the compound include, but are not limited to, for example, when a hydroxyl group is present, an ester of the hydroxyl group and an arbitrary carboxylic acid, an amide of the hydroxyl group and an arbitrary amine, and the like. Can be mentioned. When the compound represented by the formula (I) of the present invention is in the above-mentioned prodrug form, the compound represented by the formula (I), which is the parent drug, substantially exhibits species selectivity against the parasite and complex II inhibitory activity. The pharmacokinetics at the time of administration of the prodrug form to the subject can be improved without reducing it.

When the compound represented by formula (I) of the present invention is applied for pharmaceutical use, the compound may be used alone or in combination with one or more pharmaceutically acceptable ingredients. The medicament of the present invention can be formulated into various dosage forms usually used in the art depending on the desired administration method. Therefore, the medicament of the present invention also includes a pharmaceutical composition comprising the compound represented by the formula (I) of the present invention or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers. It can also be provided in the form of The pharmaceutical composition of the present invention comprises, in addition to the above components, one or more pharmaceutically acceptable media (for example, a solvent such as sterile water or a solution such as physiological saline), an excipient, a binder, Vehicles, solubilizers, preservatives, stabilizers, bulking agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffering agents, soothing agents, antioxidants, sweeteners and A flavoring agent etc. may be included.

The pharmaceutical dosage form containing the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is not particularly limited, and parenterally. The preparation may be a preparation for use in administration or a preparation for use in oral administration. The pharmaceutical dosage form of the present invention may be a unit dosage form or a multiple dosage form. Examples of the preparation for use in parenteral administration include injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable media. Ingredients that can be mixed with injections include, but are not limited to, for example, saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol, D-mannose or sodium chloride). Vehicles such as isotonic solutions, solubilizing agents such as alcohols (eg ethanol or benzyl alcohol), polyalcohols (eg propylene glycol or polyethylene glycol) or esters (eg benzyl benzoate), polysorbate 80 ™ or poly Nonionic surfactants such as oxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, benzalkonium chloride or procaine hydrochloride A soothing agent, human serum albumin or Stabilizers such as polyethylene glycol, may be mentioned preservatives, and antioxidants, and the like. The prepared injection is usually filled in an appropriate vial (for example, an ampoule) and stored in an appropriate environment until use.

  Examples of the preparation for use in oral administration include tablets, pills, powders, capsules, microcapsules, elixirs, solutions, syrups, slurries and suspensions. The tablet may be formulated as a sugar-coated tablet with a sugar coating or a soluble coating, a gelatin-encapsulated tablet, an enteric-coated tablet, or a film-coated tablet, if desired, or as a dosage form of a double tablet or a multilayer tablet It may be formulated.

Ingredients that can be mixed into tablets or capsules are not limited, but for example, water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, Binders such as gelatin, corn starch, gum tragacanth or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or silicic acid; dried starch, sodium alginate , Agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch or lactose; white sugar, stearin cacao Disintegration inhibitors such as water or hydrogenated oils; absorption enhancers such as quaternary ammonium salts or sodium lauryl sulfate; humectants such as glycerin or starch; starch, lactose, kaolin, bentonite or colloidal silicic acid Adsorbents such as; refined talc, stearates (eg magnesium stearate), lubricants such as boric acid powder or polyethylene glycol; sweeteners such as sucrose, lactose or saccharin; and peppermint, red oil or cherry And the like. When the preparation is a capsule, it may further contain a liquid carrier such as fats and oils.

The medicament containing the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient can also be formulated as a depot preparation. In this case, the medicament of the present invention in the form of a depot preparation can be administered, for example, by subcutaneous or intramuscular implantation or by intramuscular injection. By applying the medicament of the present invention to a depot preparation, the complex II inhibitory activity of the compound represented by the formula (I) of the present invention can be continuously expressed over a long period of time.

The pharmaceutical comprising the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is one or more other pharmaceutically useful compounds. It can also be used in combination with drugs. Examples of other drugs used in combination with the compound represented by the formula (I) of the present invention include, but are not limited to, santonin, chloroquine, mebendazole, and pyrantel pamoate. In this case, the medicament of the present invention comprises a compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more of the above other It becomes the form of the combined medicine containing a chemical | medical agent. The combination drug is a combination of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more other drugs. 1 type comprising the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The form of the pharmaceutical composition used together with the said other chemical | medical agent above may be sufficient. When the medicament of the present invention is in the form of a combined medicament as described above, the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof A pharmaceutical combination or kit comprising a plurality of formulations separately formulated with one or more other drugs, which may be provided in the form of a single formulation comprising one or more other drugs May be provided in When in the form of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (eg sequentially).

The medicament comprising the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is various diseases in which parasitic infection is involved. Symptoms and / or disorders can be prevented or treated as well. Examples of the disease, symptom and / or disorder include, but are not limited to, malaria, dysentery amebiasis, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, roundworm, helminth Diseases, trichuriasis, lymphoid filariasis (elephroderma), onchocercosis and schistosomiasis. The disease, symptom and / or disorder is preferably roundworm. It is known that all the diseases or symptoms involve parasitic infection. Parasites that may be involved in the disease or symptom include, but are not limited to, roundworms. By administering the medicament of the present invention to a subject in need of prevention or treatment of the disease or symptom, the disease or symptom can be prevented or treated.

The pharmaceutical comprising the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is the symptom associated with parasitic infection, It can be applied to various subjects in need of prevention or treatment of diseases and / or disorders. The subject is a subject or patient of a human or non-human mammal (eg, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon or chimpanzee). Preferably there is. By administering the medicament of the present invention to the subject, various diseases, symptoms and / or disorders possessed by parasites infected with the subject can be prevented or treated.

  As used herein, “prevention” means substantially preventing the occurrence (onset or onset) of symptoms, diseases and / or disorders. In the present specification, “treatment” means to suppress (e.g., suppress progression), relieve, repair, and / or cure a symptom, disease, and / or disorder that has occurred (onset or onset).

The compound represented by the formula (I) of the present invention is a symptom involving the parasitic infection described above,
Diseases and / or disorders (eg, malaria, dysentery amebiasis, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, roundworm, helminthiasis, trichinosis, lymphoid filariasis ( In subjects with elephant skin disease), onchocercosis and schistosomiasis), it can be used for the prevention or treatment of the symptoms, diseases and / or disorders. Therefore, the medicament of the present invention is preferably a medicament for use in the prevention or treatment of the symptoms, diseases and / or disorders described above, and is a medicament for use in the prevention or treatment of roundworm. It is more preferable. By using the medicament of the present invention for the prevention or treatment of the above-mentioned symptoms, diseases and / or disorders associated with parasitic infection, the species selectivity of the compound represented by the formula (I) of the present invention for the parasite is selected. The symptom, disease and / or disorder can be prevented or treated through complex II inhibitory activity.

The compound represented by the formula (I) of the present invention has the symptoms, diseases and / or disorders described above (for example, malaria, dysentery amebiasis, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), Used in the prevention or treatment of symptoms, diseases and / or disorders in subjects with leishmaniasis, roundworm, helminthiasis, trichuriasis, lymphoid filariasis (eldermatoses), onchocercosis and schistosomiasis be able to. Therefore, an embodiment of the present invention provides an effective amount of a compound represented by the formula (I) of the present invention or a compound thereof, in a subject in need of prevention or treatment of the symptoms, diseases and / or disorders described above. It is a method for the prophylaxis or treatment of the disease or symptom, which comprises administering a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. The symptom, disease and / or disorder is preferably roundworm. By administering a compound represented by the formula (I) of the present invention to a subject in need of prevention or treatment of the above-mentioned symptoms, diseases and / or disorders associated with parasitic infections, The symptom, disease and / or disorder can be prevented or treated through the complex II inhibitory activity of the compound represented by (2) having species selectivity against parasites.

Another embodiment of the present invention provides the symptoms, diseases and / or disorders described above (eg, malaria, dysentery amebiasis, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, Compound represented by formula (I) of the present invention or its use for prevention or treatment of roundworm, helminthiasis, trichinosis, lymphoid filariasis (elephroderma), onchocercosis and schistosomiasis) A pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof. Another embodiment of the present invention provides a symptom, disease and / or disorder as described above (eg, malaria, dysentery amebiasis, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, roundworm , Helminthiasis, trichuriasis, lymphoid filariasis (elephroderma), onchocercosis and schistosomiasis) represented by formula (I) of the present invention for the manufacture of a medicament for use in the prevention or treatment Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The symptom, disease and / or disorder is preferably roundworm. By using the medicament of the present invention for the prevention or treatment of the above-mentioned symptoms, diseases and / or disorders associated with parasitic infection, the species selectivity of the compound represented by the formula (I) of the present invention for the parasite is selected. The symptom, disease and / or disorder can be prevented or treated through complex II inhibitory activity.

When administering a compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient to a subject, particularly a human patient, The exact dosage and usage (eg, dosage, frequency of administration, and / or route of administration) depends on the subject's age, sex, symptoms to be prevented or treated, the exact state of the disease and / or disorder (eg, severity), In view of many factors such as the administration route, the doctor in charge should finally determine the therapeutically effective dose, the number of administrations, the administration route, and the like. Therefore, in the medicament of the present invention, the compound represented by the formula (I) as an active ingredient is administered to a subject in a therapeutically effective amount and frequency. For example, when the pharmaceutical of the present invention is administered to a human patient, the dose of the compound represented by the formula (I) which is an active ingredient is usually in the range of 0.001 to 100 mg / kg body weight per administration. Yes, typically in the range of 0.01 to 10 mg / kg body weight per dose, in particular in the range of 0.1 to 10 mg / kg body weight per dose. The number of administrations of the medicament of the present invention is, for example, 1 per day.
It can be once or several times, or once every few days. The administration route of the medicament of the present invention is not particularly limited, and may be administered orally, for example, parenterally (for example, rectal, radial mucosa, intestine, intramuscular, subcutaneous, intramedullary, intrathecal). May be administered directly or intra-ventricularly, intravenously, intravitreally, intraperitoneally, intranasally, or intraocularly). By using the medicament of the present invention in the above-mentioned doses and usages, the compound represented by the formula (I) of the present invention can be controlled through the complex II inhibitory activity with respect to the parasite. Said symptoms, diseases and / or disorders involving infection can be prevented or treated.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

<I. Preparation of new compound>
[material]
In the following production examples and examples, ¹ H-NMR spectrum is measured by Agilent Technologies NMR System-400 (400 MHz) or MERCURY-400 (400 MHz) instrument, and ¹³ C-NMR spectrum is measured by Agilent Technologies NMR System-400. (100 MHz) or MERCURY-400 (100 MHz) apparatus. In the NMR spectrum, the chemical shift is represented by δ (ppm), and the coupling pattern is indicated by the following abbreviation. s: single line; d: double line; t: triple line; q: quadruple line; m: multiple line; brs: wide single line; dd: double double line; dt: double triple line; dq: Double quadruple; ddd: Double double double.

  In the following production examples and examples, mass spectra were measured by JEOL JMS-700 Mstation (FABMS), JEOL JMS-T100LP (ESIMS) or JEOL JMS-AX505HA (EIMS).

  In the following production examples and examples, thin layer chromatography (TLC) was carried out using Merca Silica gel 60 F254. In TLC, UV irradiation (254 nm), phosphomolybdenum color development or anisaldehyde color development was used for the detection of compounds.

In the following Production Examples and Examples, the target compound was purified and isolated by flash column chromatography using a silica gel column packed with Silica gel 60 N manufactured by Kanto Chemical Co., Ltd. in a column tube.

[Example 1]
(2R, 4S, 5R) -2-Benzyl-5,6-dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methylhexane-1-one Synthesis of (A5-001) Compound A5-001 was synthesized according to the following scheme.

Preparation Example 1-1: (S) -5-((S) -but-3-en-2-yl) -2,2,3,3,9,9-hexamethyl-8,8-diphenyl-4, Synthesis of 7-dioxa-3,8-disiladecane (11)

CH _{2 of} compound 5 (M. Oikawa et al., J. Org. Chem. 1995, 60, p. 5048-5060) (4.15 g, 11.7 mmol,> 99% de and 91% ee) under nitrogen atmosphere To a Cl ₂ (39 mL) solution, imidazole (3.19 g, 46.8 mmol) and dimethylaminopyridine (DMAP) (286 mg, 2.34 mmol) were added. Thereafter, tert-butyldimethylsilyl chloride (TBSCl) (3.53 g, 23.4 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Thereafter, H ₂ O was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate (EtOAc). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 294 g, hexane: EtOAc
= 100: 1) Purification gave colorless oil 11 (4.98 g, 91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.68-7.65 (m, 4H, Ph), 7.44-7.36 (m, 6H, Ph), 5.79
(ddd, 1H, J = 8.5, 9.3, 17.3 Hz, CH ₂ = C [H] CH), 5.07-4.99 (m, 2H, C [H ₂ ] = CHCH), 3.62-3.58 (m, 1H, C [H] OTBS), 3.55-3.43 (m, 2H, C [H ₂ ] OTBDPS), 2.63-2.55 (m, 1H, CH ₃ C [H]), 1.05 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.04 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH), 0.83 (s, 9H, SiC (C [H ₃ ]) ₃ ), -0.01 (s, 3H, SiC [ H ₃ ]), -0.13 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺
Calculated value of the following formula: C ₂₈ H ₄₄ NaO ₂ Si ₂ 491.2778, found value: 491.2773.

  In the present specification, “[H]” in the NMR attribution data means an atom corresponding to the chemical shift value indicated in the attribution data.

Preparation Example 1-2: Ethyl (4S, 5S, E) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methylhex-2-enoate (13 )

O ₃ was bubbled through a solution of compound 11 (3.01 g, 6.42 mmol) in CH ₂ Cl ₂ (64 mL) at −78 ° C. for 30 minutes. Thereafter, O ₂ was bubbled for 5 minutes, and triphenylphosphine (PPh ₃ ) (2.07 g,
7.70 mmol) was added and stirred for 2.5 hours. The residue obtained by concentration was purified by column chromatography (silica gel 151 g, hexane: EtOAc = 100: 1) to give a crude material containing the corresponding aldehyde.

  Subsequently, (carboethoxymethylene) triphenylphosphorane (3.25 g, 9.33 mmol) was added to a solution of crude benzene (31 mL) containing the corresponding aldehyde under a nitrogen atmosphere, stirred at room temperature for 35 hours, and then concentrated. did. The obtained residue was purified by column chromatography (silica gel 168 g, hexane: EtOAc = 30: 1) to give colorless oil 13 (3.41 g, 2 steps, 98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.66-7.63 (m, 4H, Ph), 7.44-7.35 (m, 6H, Ph), 6.99 (dd, 1H, J = 8.4, 8.8 Hz, C [H ] = CHCO), 5.84 (dd, 1H, J = 1.2, 8.8 Hz, CH = C [H] CO),
4.19 (q, 2H, J = 7.2 Hz, OC [H ₂ ] CH ₃ ), 3.62 (m, 1H, C [H] OTBS), 3.48 (m, 2H, C [H ₂ ] OTBDPS), 2.78 (m , 1H, CH ₃ C [H]), 1.29 (t, 3H, J = 7.2 Hz, OCH ₂ C [H ₃ ]), 1.08 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 1.04 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.81 (s, 9H, SiC (C [H ₃ ]) ₃ ), -0.03 (s, 3H, SiC [H ₃ ]), -0.16 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₃₁ H ₄₈ NaO ₄ Si ₂ 563.2989, found value: 563.3011.

Preparation Example 1-3: Synthesis of ethyl (4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methylhexanoate (6)

To a solution of compound 13 (4.86 g, 8.98 mmol) in methanol (MeOH) (180 mL) was added Pd / C (5%
) (972 mg) was added. The mixture was then stirred vigorously for 90 minutes at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through celite and concentrated. The obtained residue was purified by column chromatography (silica gel 243 g, hexane: EtOAc = 20: 1),
A colorless oil 6 (4.70 g, 99%) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.68-7.65 (m, 4H, Ph), 7.43-7.35 (m, 6H, Ph), 4.11 (dq, 2H, J = 1.3, 7.2 Hz, OC [H ₂ ] CH ₃ ), 3.60-3.50 (m, 2H, C [H ₂ ] OTBDPS), 3.55-3.50 (m, 1H, C [H] OTBS) 2.41-2.33 (m, 1H, 1/2 CH ₂ C _{[H 2] CO), 2.27-2.19} (m, 1H, 1/2 CH 2 C [H 2] CO), 1.84-1.76 (m, 2H, C [H 2] CH 2 CO), 1.48-1.38 ( m, 1H, CH ₃ C [H]), 1.24 (t, 3H, J = 7.2 Hz, OCH ₂ C [H ₃ ]), 1.04 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.89 (d, 3H, J = 2.8 Hz, C [H ₃ ] CH), 0.82 (s, 9H, SiC (C [H ₃ ]) ₃ ), -0.02 (s, 3H, SiC [H ₃ ]),- 0.11 (s, 3H, SiC [H ₃ ])
HRMS (ESI) [M + Na] ⁺ calculated value: C ₃₁ H ₅₀ NaO ₄ Si ₂ 565.3145, found: 565.3129.

Preparation Example 1-4: (S) -4-benzyl-3-((4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4 -Methylhexanoyl) oxazolidine-2-one (3)

To a solution of compound 6 (1.00 g, 1.84 mmol) in MeOH: H ₂ O = 1: 4 (7 mL), LiOH · H ₂ O (386
mg, 9.20 mmol) was added. The resulting mixture was stirred at 100 ° C. for 5 hours. Thereafter, 2 M HCl aqueous solution was added to stop the reaction, and extraction with diethyl ether (Et ₂ O) yielded a crude material containing the corresponding carboxylic acid.

Subsequently, triethylamine (Et ₃ N) (331 μL, 2.39 mmol), pivaloyl chloride (PivCl) (249) was added to a solution of the corresponding carboxylic acid in tetrahydrofuran (THF) (37 mL) at −78 ° C. under an argon atmosphere. μL, 2.02 mmol) was added. The resulting mixture was warmed to 0 ° C. and stirred for 30 minutes. Then, (S) -4-benzyl-2-oxazolidinone (587 mg, 3.31 mmol) in THF (20 mL) was added at −78 ° C. with n-butyllithium (n-BuLi) (2.06 mL, 3.31 mmol, 1.60). Mn-hexane) was added and the Li salt of (S) -4-benzyl-2-oxazolidinone prepared by stirring for 1 hour was added via cannula. The resulting mixture was stirred at −78 ° C. for 40 minutes. Then saturated NH ₄ Cl
The reaction was stopped with an aqueous solution. The reaction solution was extracted with EtOAc, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 62.0 g, hexane: EtOAc = 20: 1) to give colorless oil 3 (1.18 g, 2 steps, 96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.69-7.66 (m, 4H, Ph), 7.44-7.27 (m, 9H, Ph), 7.22-7.20 (m, 2H, Ph), 4.68-4.62 (m , 1H, NC [H] CH ₂ O), 4.15 (d, 2H, J = 6.8 Hz, NCHC [H ₂ ] O), 3.66-3.62 (m, 1H, 1/2 C [H ₂ ] OTBDPS), 3.64-3.63 (m, 1H, C [H] OTBS), 3.57-3.52 (m, 1H, 1/2 C [H ₂ ] OTBDPS), 3.31 (dd, 1H, J = 2.8, 14.6 Hz, 1/2 C (H ₂ ] Ph), 3.02 (ddd, 1H, J = 5.4, 9.8, 17.0 Hz, 1/2 NC (= O) C [H ₂ ]), 2.89 (ddd, 1H, J = 6.4, 9.8, 17.0 Hz, 1/2 NC (= O) C [H ₂ ]), 2.75 (dd, 1H, J = 6.8, 14.6 Hz, 1/2 NCHC [H ₂ ] Ph), 1.93-1.85 (m, 2H, NC (= O) CH ₂ C [H ₂ ]), 1.52-1.44 (m, 1H, C [H] CH ₃ ), 1.04 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.95 (d , 3H, J = 6.8 Hz, CHC [H ₃ ]), 0.83 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.01 (s, 3H, SiC [H ₃ ]), −0.11 (s , 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₃₉ H ₅₅ NaO ₅ Si ₂ 696.3516, Found value: 696.3504.

Preparation Example 1-5: (S) -4-benzyl-3-((2R, 4S, 5S) -2-benzyl-5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenyl Synthesis of (silyl) oxy) -4-methylhexanoyl) oxazolidine-2-one (15)

Sodium bis (trimethylsilyl) amide (NaHMDS) (2.8 mL, 2.80 mmol, in 1.0 M THF) was added to THF (5.0 mL) at −78 ° C. under an argon atmosphere, and then compound 3 (1.35 g, 2.00 mmol) was added. A THF (15 mL) solution was added. After stirring for 1 hour, benzyl bromide (BnBr) (718 μL, 6.00 mmol) was added and stirred for 2 hours. Thereafter, the reaction was stopped with a saturated aqueous NH ₄ Cl solution. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 76.4 g, hexane: EtOAc = 20: 1) to give a colorless oil 15 (1.02 g, 67%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.69-7.65 (m, 4H, Ph), 7.46-7.36 (m, 6H, Ph), 7.30-7.20 (m, 7H, Ph), 7.19-7.15 (m , 1H, Ph), 6.98-6.96 (m, 2H, Ph), 4.62-4.56 (m, 1H, NC [H] CH ₂ O), 4.39-4.31 (m, 1H, N (CO) C [H] ), 4.06-3.95 (m, 2H, NCHC [H ₂ ] O), 3.63-3.59 (m, 1H, C [H] OTBS), 3.57-3.47 (m, 2H, C [H ₂ ] OTBDPS), 3.02 -2.95 (m, 1H, 1/2 NCHC [H ₂ ] Ph) 2.94-2.90 (m, 2H, NC (= O) CHC [H ₂ ] Ph), 2.31 (dd, 1H, J = 9.6, 13.8 Hz , 1/2
NCHC [H ₂ ] Ph), 2.06-2.00 (m, 1H, CH ₃ C [H]), 1.73 (dq, 1H, J = 4.4, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.56 (dq, 1H, J = 4.4, 6.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.04 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.00 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 0.80 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.05 (s, 3H, SiC [H ₃ ]), −0.15 (s, 3H, SiC [ H ₃ ]); HRMS (ESI) [M + Na] ⁺ calculated value: C ₄₆ H ₆₁ NaO ₅ Si ₂ 786.3986, found value: 786.4016.

Preparation Example 1-6: (2R, 4S, 5S) -2-Benzyl-5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methylhexane-1 -Synthesis of all (16)

Under a nitrogen atmosphere, a solution of compound 15 (285 mg, 0.372 mmol) in Et ₂ O (7.4 mL) was added at 0 ° C. with ethanol (EtOH) (23.9 μL, 0.409 mmol) and LiBH ₄ (136 μL, 0.409 mmol, 3.0 M). THF
Medium) was added. The resulting mixture was stirred for 2 hours. Acetone was added to stop the reaction. The reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated.
The obtained residue was purified by column chromatography (silica gel 11.0 g, hexane: EtOAc = 25: 1) to give colorless oil 16 (154 mg, 70%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.69-7.64 (m, 4H, Ph), 7.46-7.35 (m, 6H, Ph), 7.28-7.24 (m, 2H, Ph), 7.19-7.15 (m , 3H, Ph), 3.59-3.56 (m, 2H, HOC [H ₂ ]), 3.54-3.50 (m, 1H, TBSOC [H]), 3.49 (dd, 1H, J = 4.6, 10.6 Hz, 1 / 2 TBDPSOC [H ₂ ]), 3.41 (dd, 1H, J = 4.6, 6.6 Hz, 1/2 TBDPSOC [H ₂ ]), 2.76 (dd, 1H, J = 4.8, 13.6 Hz, 1/2 PhC [H ₂ ] CH), 2.45 (dd, 1H, J = 9.0, 13.6 Hz, 1/2 PhC [H ₂ ] CH), 2.08-2.02 (m, 1H, CH ₃ C [H]),
1.87-1.80 (m, 1H, PhCH ₂ C [H]), 1.41 (ddd, 2H, J = 4.8, 9.6, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.18 (ddd, 1H, J = 4.8, 9.5, 14.0 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.05 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.94 (d, 3H, J = 6.8 Hz, C [ H ₃ ] CH), 0.82 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.03 (s,
3H, SiC [H ₃ ]), −0.14 (s, 3H, SiC [H ₃ ]); HRMS (FAB, m-NBA) [M + H] ⁺ Calculated value of the following formula: C ₃₆ H ₅₅ O ₃ Si ₂ 591.3690, Found: 591.3707.

Preparation Example 1-7: (6R, 8S, 9S) -6-Benzyl-9-((tert-butyldimethylsilyl) oxy) -8,13,13-trimethyl-12,12-diphenyl-2,4,11 Of 2-Trioxa-12-silatetradecane (17)

Under a nitrogen atmosphere, a solution of compound 16 (413 mg, 0.699 mmol) in CH ₂ Cl ₂ (7.0 mL) was added at 0 ° C. with N, N-diisopropylethylamine (DIPEA) (365 μL, 2.10 mmol) and chloromethyl methyl ether ( MOMCl) (80 μL, 1.05 mmol) was added. The resulting mixture was warmed to room temperature and 5
Stir for hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction solution was extracted with Et ₂ O. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 22.2 g, hexane: EtOAc = 80: 1), whereby colorless oily substance 17 (425 mg, 96%) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.68-7.65 (m, 4H, Ph), 7.44-7.35 (m, 6H, Ph), 7.23-7.22 (m, 2H, Ph), 7.17-7.14 (m , 3H, Ph), 4.55 (s, 2H, CH ₃ OC [H ₂ ] O), 3.60-3.56 (m,
1H, TBSOC [H]), 3.54-3.48 (m, 2H, TBDPSOC [H ₂ ]), 3.33 (dd, 1H, J = 3.6, 9.2 Hz, 1/2 CH ₃ OCH ₂ OC [H ₂ ]), 3.31 (s, 3H, C [H ₃ ] OCH ₂ O), 3.29 (dd, 1H, J = 5.6, 9.2 Hz, 1/2 CH ₃ OCH ₂ OC [H ₂ ]), 2.72 (dd, 1H, J = 5.0, 13.8 Hz, 1/2 PhC [H ₂ ] CH), 2.51 (dd, 1H, J = 8.4, 13.8 Hz, 1/2 PhC [H ₂ ] CH), 2.04-1.96 (m, 1H, CH ₃ C [H]), 1.96-1.89 (m, 1H, PhCH ₂ C [H]), 1.44 (ddd, 1H, J = 3.6, 9.4, 13.4 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.26-1.18 (m, 1H, 1/2 CH ₃ CHC [H ₂ ]), 1.04 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.92 (d, 3H, J = 7.2 Hz, C [ H ₃ ] CH), 0.82 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.04 (s, 3H, SiC [H ₃ ]), −0.14 (s, 3H, SiC [H ₃ ]) HRMS (FAB, m-NBA) [M + Na] ⁺ Calculated value: C ₃₈ H ₅₈ NaO ₄ Si ₂ 657.3771, Actual value: 657.3774
.

Preparation Example 1-8: Synthesis of (2S, 3S, 5R) -5-benzyl-6- (methoxymethoxy) -3-methylhexane-1,2-diol (18)

Under a nitrogen atmosphere, tetrabutylammonium fluoride (TBAF) (332 μL, 0.332 mmol, 1.0 M in THF) was added to a solution of compound 17 (52.8 mg, 0.0831 mmol) in THF (0.83 mL). The resulting mixture was stirred at room temperature for 7 hours. Saturated aqueous NH ₄ Cl was added to quench the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 9.8 g, CH ₂ Cl ₂ : MeOH = 10: 1), whereby white solid 18 (23.2 mg, 99%) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.30-7.26 (m, 2H, Ph), 7.21-7.16 (m, 3H, Ph), 4.55 (s, 2H, CH ₃ OC [H ₂ ] O), 3.63 (dt, 1H, J = 5.9, 7.5 Hz, HOC [H]), 3.49-3.45 (m, 2H, CH ₃ OCH ₂ OC [H ₂ ]), 3.41 (dd, 1H, J = 9.0, 9.8 Hz , 1/2 HOC [H ₂ ]), 3.39-3.33 (m, 1H, 1/2 HOC [H ₂ ]), 3.31 (s, 3H, C [H ₃ ] OCH ₂ O), 2.66 (dd, 1H , J = 7.2, 13.6 Hz, 1/2 PhC [H ₂ ] CH), 2.58 (dd, 1H, J = 7.2, 9.8 Hz, 1/2 PhC [H ₂ ] CH), 2.13 (brs, 2H, CH ₂ O [H], CHO [H]) 2.07-2.00 (m, 1H, CH ₃ C [H]), 1.72 (m, 1H, PhCH ₂ C [H]), 1.53 (ddd, 1H, J = 5.2 , 8.4, 13.8 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.36 (m, 1H, 1/2 CH ₃ CHC [H ₂ ]), 0.91 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₁₆ H ₂₆ NaO ₄ 305.1729, found: 305.1735.

Preparation Example 1-9: Synthesis of ((2R, 4S, 5R) -5,6-dichloro-2-((methoxymethoxy) methyl) -4-methylhexyl) benzene (19)

Under a nitrogen atmosphere, a solution of compound 18 (8.0 mg, 0.0283 mmol) in THF (1.0 mL) was added to PPh ₃ (22.2
mg, 0.0849 mmol) and N-chlorosuccinimide (NCS) (11.3 mg, 0.0849 mmol) were added. The resulting mixture was stirred at 60 ° C. for 90 minutes. Thereafter, H ₂ O was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 452 mg, hexane: EtOAc = 50: 1) to give colorless oily substance 19 (6.8 mg, 72%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.31-7.27 (m, 2H, Ph), 7.22-7.17 (m, 3H, Ph), 4.60 (d, 2H, J = 1.2 Hz, CH ₃ OC [H ₂ ] O), 4.09 (ddd, 1H, J = 3.0, 5.8, 8.8 Hz, ClC [H]), 3.74 (dd, 1H, J = 5.8, 11.4 Hz, 1/2 ClC [H ₂ ]), 3.65 (dd, 1H, J = 8.8, 11.4 Hz, 1/2
ClC [H ₂ ]), 3.42 (dd, 1H, J = 4.8, 9.6 Hz, 1/2 CH ₃ OCH ₂ OC [H ₂ ]), 3.38-3.34 (m, 1H, 1/2 CH ₂ OCH ₂ OC [H ₂ ]), 3.37 (s, 3H, C [H ₃ ] OCH ₂ O), 2.66 (ddd, 2H, J = 5.2, 10.8, 20.8
Hz, PhC [H ₂ ]), 2.32 (dq, 1H, J = 3.0, 7.4 Hz, CH ₃ C [H]), 2.02-1.95 (m, 1H, PhCH ₂ C
[H]), 1.48 (t, 2H, J = 7.4 Hz, CH ₃ CHC [H ₂ ]), 0.93 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (FAB, m- NBA) [M ⁺ Na] + the following formula _{calculated: C 16 H 24 Cl 2 NaO} 2 341.1051, Found: 341.1037
.

Preparation Example 1-10: Synthesis of (2R, 4S, 5R) -2-benzyl-5,6-dichloro-4-methylhexan-1-ol (20)

To compound 19 (10.1 mg, 0.0313 mmol), MeOH: 2 M HCl = 3: 1 (1.0 mL) was added. The resulting mixture was stirred at 50 ° C. for 17 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 431 mg, hexane: EtOAc = 10: 1) to give colorless oil 20 (8.7 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.37-7.31 (m, 2H, Ph), 7.28-7.22 (m, 3H, Ph), 4.14 (ddd, 1H, J = 2.8, 5.8, 8.8 Hz, ClC [H]), 3.80 (dd, 1H, J = 5.8, 11.2 Hz, 1/2 ClC [H ₂ ]), 3.71 (dd, 1H, J = 8.8, 11.2 Hz, 1/2 ClC [H ₂ ]) , 3.58 (ddd, 2H, J = 5.1, 10.8, 21.0 Hz, HOC [H ₂ ]), 2.71 (d, 2H, J = 3.2 Hz, PhC [H ₂ ] CH), 2.37 (dq, 1H, J = 3.2, 6.7 Hz, PhCH ₂ C [H]), 1.99-1.91 (m, 1H, CH ₃ C [H] CH ₂ ), 1.54-1.50 (m, 2H, HOCH ₂ CHC [H ₂ ]), 1.00 ( d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (FAB, m-NBA) [M + Na] ⁺ Calculated value of the following formula: C ₁₃ H ₂₀ Cl ₂ NaO 297.0789, Actual value: 297.0789 .

Preparation Example 1-11: (2R, 4S, 5R) -2-Benzyl-5,6-dichloro-1- (5,6-dimethoxy-2,4-bis (methoxymethoxy) pyridin-3-yl) -4 Of 2-methylhexan-1-one (23)

Under a nitrogen atmosphere, a 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) (3.53 mg, 0.0226 mmol) was added to a solution of compound 20 (62.3 mg, 0.226 mmol) in CH ₂ Cl ₂ (2.3 mL). ) And iodobenzene diacetate (PhI (OAc) ₂ ) (182 mg, 0.565 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. Thereafter, the reaction was stopped by addition of saturated aqueous Na ₂ S ₂ O _3. The reaction solution was extracted with Et ₂ O. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel 3.1 g, hexane: EtOAc = 30: 1)
The crude material containing compound 21 could be obtained by purifying with

N-BuLi (151 μL, 0.401 mmol, 2.65 M in n-hexane) was added to THF (0.44 mL) at −78 ° C. under an argon atmosphere, and then Compound 2 (49.7 mg, 0.182 mmol) in THF (1.6 mL) was added. ) The solution was added. Subsequently, a crude solution of THF (1.6 mL) was added dropwise to the mixture, followed by stirring at −78 ° C. for 90 minutes. Thereafter, MeOH was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 4.8 g, hexane: EtOAc = 5: 1) to give a crude material containing Compound 22.

Subsequently, Dess-Martin periodinane (DMP) (116 mg, 0.273 mmol) was added to a CH ₂ Cl ₂ (1.8 mL) solution of the crude material under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Thereafter, the reaction was stopped by addition of saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO _3. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 4.8 g, hexane: EtOAc = 15: 1) to give colorless oil 23 (63.2 mg, 3 steps, 53%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.32-7.19 (m, 5H, Ph), 5.54 (dd, 2H, J = 6.0, 22.0 Hz, CH ₃ OC [H ₂ ] O), 5.32 (dd, 2H, J = 6.0, 14.6 Hz, CH ₃ OC [H ₂ ] O), 4.16 (ddd, 1H, J =
2.7, 7.2, 7.9 Hz, ArC (= O) C [H]), 4.01 (s, 3H, ArOC [H ₃ ]), 3.81 (s, 3H, ArOC [H ₃ ]) 3.71 (dd, 1H, J = 6.8, 11.4 Hz, 1/2 C [H ₂ ] Cl), 3.63-3.57 (m, 1H, C [H] Cl), 3.62 (dd, 1H, J = 8.4, 11.4 Hz, 1/2 C [ H ₂ ] Cl), 3.52 (s, 3H, C [H ₃ ] OCH ₂ O), 3.51 (s, 3H, C [H ₃ ] OCH ₂ O) 3.29 (dd, 1H, J = 5.8, 13.8 Hz, 1/2 PhC [H ₂ ] CH), 2.66 (dd, 1H, J = 8.2,
13.8 Hz, 1/2 PhC [H ₂ ] CH), 2.32-2.26 (m, 1H, CH ₃ C [H]), 1.89 (ddd, 1H, J = 6.0, 8.4, 14.2 Hz, 1/2 CHC [ H ₂ ] CH), 1.60 (ddd, 1H, J = 5.1, 8.4, 14.2 Hz, 1/2 CHC [H ₂ ] CH), 0.92 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH) HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₅ H ₃₃ Cl ₂ NNaO ₇ 552.1532, found value: 552.1534.

Preparation Example 1-12: (2R, 4S, 5R) -2-Benzyl-5,6-dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4- Synthesis of methylhexan-1-one (A5-001)

To a solution of compound 23 (5.8 mg, 0.0109 mmol) in CH ₂ Cl ₂ (0.35 mL) was added trifluoroacetic acid (TFA) (0.35 mL) at 0 ° C. The resulting mixture was stirred for 1 hour. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. Subsequently, purification was performed by preparative TLC (hexane: EtOAc = 3: 2) to obtain a white solid A5-001 (3.9 mg, 81%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.30-7.14 (m, 5H, Ph), 4.65-4.55 (m, 1H, PhCH ₂ C [H]), 4.17-4.14 (m, 1H, C [H ] Cl), 4.13 (s, 3H, OC [H ₃ ]), 3.79 (s, 3H, OC [H ₃ ]), 3.67 (dd, 1H, J = 6.0, 11.4 Hz, 1/2 C [H ₂ ] Cl), 3.57 (dd, 1H, J = 8.6, 11.4 Hz, 1/2 C [H ₂ ] Cl), 3.08 (dd, 1H, J = 6.2, 13.4 Hz, 1/2 CO (CHC [H ₂ ] Ph)), 2.66 (dd, 1H, J = 7.4, 13.4 Hz, 1/2 CO (CHC [H ₂ ] Ph)), 2.15-2.09 (m, 1H, CH ₃ C [H]), 1.91 ( ddd, 1H, J = 9.5,
13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.58 (ddd, 1H, J = 8.5, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 0.8
9 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₂₁ H ₂₅ Cl ₂ NNaO ₅ 464.1008, Found: 464.1006.

[Example 2]
(2R, 4S, 5R) -2-([1,1'-biphenyl] -4-ylmethyl) -5,6-dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridine- Synthesis of 3-yl) -4-methylhexan-1-one (A5-002) Compound A5-002 was synthesized according to the following scheme.

Preparation Example 2-1: (S) -3-((2R, 4S, 5S) -2-([1,1′-biphenyl] -4-ylmethyl) -5-((tert-butyldimethylsilyl) oxy) Synthesis of -6-((tert-butyldiphenylsilyl) oxy) -4-methylhexanoyl) -4-benzyloxazolidine-2-one (24)

NaHMDS (1.00 mL, 1.00 mmol, 1.0 M in THF) was added to THF (1.4 mL) at −78 ° C. under an argon atmosphere, and then a solution of compound 3 (500 mg, 0.742 mmol) in THF (3.5 mL) was added. It was. After stirring for 1 hour, 4-bromomethylbiphenyl (551 μL, 2.23 mmol) was added and stirred for 5 minutes. Thereafter, the reaction was stopped with a saturated aqueous NH ₄ Cl solution. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel
Purification was performed with 12.7 g, hexane: EtOAc = 30: 1), and colorless oily substance 24 (452 mg, 73%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.75-7.71 (m, 4H, Ph), 7.58-7.53 (m, 4H, Ph), 7.48-7.40 (m, 11H, Ph), 7.37-7.32 (m , 2H, Ph), 7.25-7.23 (m, 2H, Ph), 7.02-7.00 (m, 1H, Ph), 4.68-4.62 (m, 1H, NC [H] CH ₂ O), 4.48-4.41 (m , 1H, NC (= O) C [H]), 4.09-4.01 (m, 2H, NCHC [H ₂ ] O), 3.70-3.66 (m, 1H, C [H] OTBS), 3.65-3.55 (m , 2H, C [H ₂ ] OTBDPS), 3.09 (dd, 1H, J = 9.2, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 3.04-2.98 (m, 2H, C [H ₂ ] PhPh) , 2.39 (dd, 1H, J = 9.2, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 2.13-2.08 (m, 1H, CH ₃ C [H]), 1.82
(ddd, 1H, J = 5.0, 9.2, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.65 (ddd, 1H, J = 5.0, 9.2, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.11 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.07 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 0.86 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.02 (s, 3H, SiC [H ₃ ]), −0.09 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₅₂ H ₆₅ NNaO ₅ Si ₂ 862.4299, found: 862.4285.

Preparation Example 2-2: (2R, 4S, 5S) -2-([1,1′-biphenyl] -4-ylmethyl) -5-((tert-butyldimethylsilyl) oxy) -6-((tert- Synthesis of (Butyldiphenylsilyl) oxy) -4-methylhexan-1-ol (25)

EtOH (32.7 μL, 0.560 mmol) and LiBH ₄ (187 μL, 0.560 mmol, 3.0 M in THF) at 0 ° C. in a solution of compound 24 (427 mg, 0.509 mmol) in Et ₂ O (10.2 mL) under a nitrogen atmosphere Was added.
The resulting mixture was stirred for 1 hour. Acetone was added to stop the reaction. The reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 13.3 g, hexane: EtOAc = 20: 1) to give colorless oil 25 (213 mg, 63%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.71-7.67 (m, 4H, Ph), 7.59-7.56 (m, 2H, Ph), 7.50-
7.48 (m, 2H, Ph), 7.45-7.31 (m, 9H, Ph), 7.27-7.25 (m, 2H, Ph), 3.63-3.51 (m, 4H, 1/2 HOC [H ₂ ], CHOTBS, C [H ₂ ] OTBDPS), 3.46 (dd, 1H, J = 5.6, 10.8 Hz, 1/2 HOCH ₂ ),
2.81 (dd, 1H, J = 4.8, 13.6 Hz, 1/2 C [H ₂ ] PhPh), 2.45 (dd, 1H, J = 8.8, 13.6 Hz,
1/2 C [H ₂ ] PhPh), 2.10-2.05 (m, 1H, CH ₃ C [H]), 1.93-1.86 (m, 1H, HOCH ₂ C [H]), 1.45 (ddd, 1H, J = 4.0, 9.6, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.23-1.17 (m, 1H, 1/2 CH ₃ CHC [H ₂ ]), 1.06 (s, 9H, SiC (C [ H ₃ ]) ₃ ), 0.97 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 0.83 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.02 (s, 3H, SiC [H ₃ ]), −0.12 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ calculated value: C ₄₂ H ₅₈ NaO ₃ Si ₂ 689.3822, actual value: 689.3820.

Preparation Example 2-3: (6R, 8S, 9S) -6-([1,1′-biphenyl] -4-ylmethyl) -9-((tert-butyldimethylsilyl) oxy) -8,13,13- Synthesis of trimethyl-12,12-diphenyl-2,4,11-trioxa-12-silatetradecane (26)

Under a nitrogen atmosphere, DIPEA (87.3 μL, 0.501 mmol) and MOMCl (19.0 μL, 0.251 mmol) were added to a CH ₂ Cl ₂ (1.7 mL) solution of Compound 25 (112 mg, 0.167 mmol) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 3 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction solution was extracted with Et ₂ O. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel 8.37 g, hexane: EtOAc = 30:
By performing the purification in 1), colorless oily substance 26 (119 mg, quantitative) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.78-7.75 (m, 4H, Ph), 7.65 (s, 1H, Ph), 7.63 (s, 1H, Ph), 7.56 (s, 1H, Ph), 7.54 (s, 1H, Ph), 7.51-7.41 (m, 8H, Ph), 7.38 (dt, 1H,
J = 2.8, 8.0 Hz, Ph), 7.33 (s, 1H, Ph), 7.31 (s, 1H, Ph), 4.67 (s, 2H, CH ₃ OC [H ₂ ] O), 3.70-3.59 (m, 3H, C [H] OTBS, C [H ₂ ] OTBDPS), 3.49-3.42 (m, 2H, MOMOC [H ₂ ]), 3.41 (s, 3H, C [H ₃ ] OCH ₂ O), 2.85 (dd , 1H, J = 4.4, 13.6 Hz, 1/2 C [H ₂ ] PhPh), 2.66 (dd,
1H, J = 8.2, 13.6 Hz, 1/2 C [H ₂ ] PhPh), 2.16-2.09 (m, 1H, CH ₃ C [H]), 2.10-2.02 (m,
1H, C [H] CH ₂ PhPh), 1.57 (ddd, 1H, J = 3.8, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.36-1.32 (m, 1H, 1/2 C [H ₂ ] CHCH ₃ ), 1.14 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.04 (d, 3H, J = 7.2 Hz,
C [H ₃ ] CH), 0.91 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.06 (s, 3H, SiC [H ₃ ]), −0.05 (s, 3H, SiC [H ₃ ] ); HRMS (ESI) [M + Na] ⁺ Calculated value: C ₄₄ H ₆₂ NaO ₄ Si ₂ 733.4084, measured value: 733.4081
.

Preparation Example 2-4: (2S, 3S, 5R) -6-([1,1′-biphenyl] -4-yl) -5-((methoxymethoxy) methyl) -3-methylhexane-1,2- Synthesis of diol (27)

To a solution of compound 26 (151 mg, 0.212 mmol) in THF (2.1 mL) under a nitrogen atmosphere, TBAF (848
μL, 0.848 mmol, 1.0 M in THF) was added. The resulting mixture was stirred at room temperature for 24 hours. Saturated aqueous NH ₄ Cl was added to quench the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 7.02 g, hexane: EtOAc = 1: 1) to give white solid 27 (75.9 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.61-7.58 (m, 2H, Ph), 7.53 (dt, 2H, J = 1.6, 8.0 Hz, Ph), 7.43 (d, 2H, J = 1.6, 6.8 Hz, Ph), 7.35-7.31 (m, 1H, Ph), 7.25 (d, 2H, J
= 8.0 Hz, Ph), 4.61 (s, 2H, CH ₃ OC [H ₂ ] O), 3.65 (dd, 1H, J = 7.6, 15.2 Hz, 1/2 C [H ₂ ] OH), 3.52-3.47 (m, 2H, C [H] OH, 1/2 C [H ₂ ] OH), 3.45 (dd, 1H, J = 4.8, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.39 (dd, 1H , J = 3.6, 4.8 Hz, 1/2 MOMOC [H ₂ ]), 3.36 (s, 3H, C [H ₃ ] OCH ₂ O), 2.73 (dd, 1H, J = 5.6, 13.6 Hz, 1/2 C [H ₂ ] PhPh), 2.61 (dd, 1H, J = 8.0, 13.6 Hz, 1/2 C [H ₂ ] PhPh), 2.10-2.03 (m, 1H, C [H] CH ₂ PhPh), 1.84 -1.74 (m, 1H, CH ₃ C [H]), 1.59 (ddd, 1H, J = 4.8, 8.4, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.38 (ddd, 1H, J = 4.8, 8.4, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.94 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value: C ₂₂ H ₃₀ NaO ₄ 381.2042, Found: 381.2049.

Preparation Example 2-5: Synthesis of (2R, 4S, 5R) -2-([1,1'-biphenyl] -4-ylmethyl) -5,6-dichloro-4-methylhexan-1-ol (29)

Under a nitrogen atmosphere, PPh ₃ (136 mg, 0.519 mmol) and NCS (69.3 mg, 0.519 mmol) were added to a THF (1.7 mL) solution of Compound 27 (62 mg, 0.173 mmol). The resulting mixture was stirred at 60 ° C. for 15 minutes. Thereafter, H ₂ O was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 8.78 g, hexane: EtOAc = 50: 1), whereby a crude material containing compound 28 could be obtained.

To the resulting crude material was added MeOH: 2M HCl = 3: 1 (1.7 mL). The resulting mixture was stirred at 50 ° C. for 24 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The resulting residue is
Purification by column chromatography (silica gel 5.67 g, hexane: EtOAc = 5: 1) gave colorless oil 29 (45.1 mg, 2 steps, 74%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.62-7.58 (m, 2H, Ph), 7.54 (d, 2H, J = 8.0 Hz, Ph), 7.45 (dt, 2H, J = 1.6, 8.0 Hz, Ph), 7.34 (dt, 1H, J = 1.6, 8.0 Hz, Ph), 7.28 (d, 2H, J = 8.0 Hz, Ph), 4.11 (ddd, 1H, J = 2.8, 5.6, 9.2 Hz, C [ H] Cl), 3.76 (dd, 1H, J = 5.6, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.67 (dd, 1H, J = 9.2, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.59 (dd, 1H, J = 4.8, 10.6 Hz, 1/2 HOC [H ₂ ]), 3.54 (dd, 1H, J = 4.8, 10.6 Hz, 1/2 HOC [H ₂ ]), 2.71 (d, 2H, J = 6.8 Hz, C [H ₂ ] PhPh), 2.33 (ddd, 1H, J = 2.8, 6.8, 14.0 Hz, CH ₃ C [H]), 1.98-1.90 (m, 1H, HOCH ₂ C [H]), 1.50 (ddd, 2H, J = 4.0, 6.8, 6.8 Hz, HOCH ₂ CHC [H ₂ ]), 0.97 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (FAB, m-NBA) [M] ⁺
Calculated value of the following formula: C ₂₀ H ₂₄ Cl ₂ O 350.1204, found value: 350.1204.

Preparation Example 2-6: (2R, 4S, 5R) -2-([1,1′-biphenyl] -4-ylmethyl) -5,6-dichloro-1- (5,6-
Synthesis of dimethoxy-2,4-bis (methoxymethoxy) pyridin-3-yl) -4-methylhexan-1-one (32)

Under a nitrogen atmosphere, TEMPO (1.7 mg, 0.0108 mmol) and PhI (OAc) ₂ (87.0 mg, 0.270 mmol) were added to a CH ₂ Cl ₂ (1.1 mL) solution of compound 29 (37.9 mg, 0.108 mmol). The resulting mixture was stirred at room temperature for 3 hours. Thereafter, it stopped saturated Na ₂ S ₂ O ₃ aqueous solution was added the reaction. The reaction solution was extracted with Et ₂ O. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 7.56 mg, hexane: EtOAc = 30: 1), whereby a crude material containing compound 30 could be obtained.

After adding n-BuLi (77.4 μL, 2.05 mmol, 2.65 M in n-hexane) to THF (0.20 mL) at −78 ° C. under argon atmosphere, Compound 2 (39.2 mg, 0.102 mmol) in THF (0.50 mL) ) The solution was added. Subsequently, a THF (0.80 mL) solution of the crude material was added dropwise to the mixture, and the mixture was stirred at -78 ° C for 5 minutes. Thereafter, MeOH was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 8.38 g, hexane: EtOAc = 10: 1) to give a crude material containing Compound 31.

Subsequently, DMP (59.4 mg, 0.140 mmol) was added to a CH ₂ Cl ₂ (0.93 mL) solution of the crude material under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 20 minutes. Thereafter, the reaction was stopped by addition of saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO _3. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 5.32 g, hexane: EtOAc = 15: 1) to give colorless oil 32 (13.6 mg, 3 steps, 24%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.57-7.54 (m, 2H, Ph), 7.48 (dt, 2H, J = 2.8, 8.0 H
z, Ph), 7.42 (t, 2H, J = 8.0 Hz, Ph), 7.34-7.30 (m, 1H, Ph), 7.27 (dt, 2H, J = 2.0, 8.0 Hz, Ph), 5.49 (d, 1H, J = 6.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.43 (d, 1H, J = 6.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.29 (d, 1H, J = 5.4 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.26 (d, 1H, J = 5.4 Hz, 1/2 CH ₃ OC [H ₂ ] O), 4.13 (ddd, 1H, J = 2.8, 6.4, 8.0 Hz, C [H] Cl), 3.95 (s, 3H, ArOC [H ₃ ]), 3.74 (s, 3H, ArOC [H ₃ ]), 3.67 (dd, 1H, J = 6.4, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.60-3.57 (m, 1H, ArC (= O) C [H]), 3.58 (dd, 1H, J = 8.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.47 (s, 3H, C [H ₃ ] OCH ₂ O), 3.46 (s, 3H, C [H ₃ ] OCH ₂ O), 3.20 (dd, 1H, J = 6.4, 14.0 Hz, 1/2 C [H ₂ ] PhPh), 2.67 (dd, 1H, J = 6.4, 14.0 Hz, 1/2 C [H ₂ ] PhPh), 2.26 (ddd, 1H, J = 2.8, 6.4, 6.4 Hz, CH ₃ C [H]), 1.86 (ddd, 1H, J = 6.4, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.57 (ddd, 1H, J = 6.4, 8.0 14.0 Hz , 1/2 C [H ₂ ] CHCH ₃ ), 0.92 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₃₁ H ₃₇ Cl ₂ NNaO ₇ 628.1845, Found: 628.1826.

Preparation Example 2-7: (2R, 4S, 5R) -2-([1,1′-biphenyl] -4-ylmethyl) -5,6-dichloro-1- (5,6-
Dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methylhexan-1-one (A5-002)
Synthesis of

To a solution of compound 32 (11.3 mg, 0.0186 mmol) in CH ₂ Cl ₂ (0.25 mL) was added TFA (0.25 mL) at 0 ° C. The resulting mixture was stirred for 10 minutes. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 6.75 g, hexane: EtOAc = 4: 1) to give a white solid A5-002 (9.0 mg, 94%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.55 (d, 2H, J = 7.6 Hz, Ph), 7.47 (d, 2H, J = 7.6 Hz, Ph), 7.41 (t, 2H, J = 7.6 Hz , Ph), 7.30 (dd, 3H, J = 7.6, 12.8 Hz, Ph), 4.74-4.65 (m, 1H, ArC (= O) C [H]), 4.20-4.17 (m, 1H, C [H ] Cl), 4.12 (s, 3H, ArOC [H ₃ ]), 3.78 (s, 3H, ArOC [H ₃ ]), 3.67 (dd, 1H, J = 6.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.58 (dd, 1H, J = 8.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.11 (dd, 1H, J = 6.8, 11.2 Hz, 1/2 C [H ₂ ] PhPh ), 2.71 (dd, 1H, J = 6.8, 11.2 Hz, 1/2 C [H ₂ ] PhPh), 2.16-2.12 (m, 1H, CH ₃ C [H]), 1.93 (ddd, 1H, J = 4.8, 8.8, 11.2 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.63 (ddd, 1H, J = 4.8, 8.8, 11.2 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.91 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₂₇ H ₂₉ Cl ₂ NNaO ₅ 540.1321, Found value: 540.1334.

[Example 3]
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (2-methylbenzyl) Synthesis of Hexan-1-one (A5-003) Compound A5-003 was synthesized according to the following scheme.

Preparation Example 3-1: (S) -4-benzyl-3-((2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) Synthesis of 4-methyl-2- (2-methylbenzyl) hexanoyl) oxazolidine-2-one (33)

NaHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added to THF (5.1 mL) at −78 ° C. under an argon atmosphere, and then a solution of compound 3 (0.750 g, 1.11 mmol) in THF (6.0 mL) was added. It was. After stirring for 1 hour, α-bromo-o-xylene (443 μL, 3.33 mmol) was added and stirred for 50 minutes. Thereafter, the reaction was stopped with a saturated aqueous NH ₄ Cl solution. The reaction was extracted with EtOAc. The combined organic layer was washed with Na ₂ SO ₄
And dried. The obtained residue was subjected to column chromatography (silica gel 22.8
Purification by g, hexane: EtOAc = 40: 1) gave colorless oil 33 (574 mg, 73%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.77-7.73 (m, 4H, Ph), 7.49-7.43 (m, 6H, Ph), 7.31-7.27 (m, 4H, Ph), 7.20-7.18 (m , 1H, Ph), 7.16-7.12 (m, 2H, Ph), 7.00-6.97 (m, 2H, Ph), 4.66-4.61 (m, 1H, NC [H] CH ₂ O), 4.55-4.48 (m , 1H, NC (= O) C [H]), 4.08-3.99 (m, 2H, NCHC [H ₂ ] O), 3.71-3.64 (m, 2H, C [H] OTBS, 1/2 C [H ₂ ] OTBDPS), 3.59 (dd, 1H, J = 4.0, 8.8 Hz, 1/2 C [H ₂ ] OTBDPS), 3.05 (dd, 2H, J = 6.4, 9.6 Hz, C [H ₂ ] PhCH ₃ ) , 2.98 (dd, 1H, J = 3.2, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 2.46 (s, 3H, PhC [H ₃ ]), 2.35 (dd, 1H, J = 9.6, 13.6 Hz , 1/2 NCHC [H ₂ ] Ph), 2.21-2.12 (m, 1H, CH ₃ C [H]), 1.86 (ddd, 1H,
J = 4.0, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.65 (ddd, 1H, J = 4.0, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.12 ( s, 9H, SiC (C [H ₃ ]) ₃ ), 1.09 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 0.88 (s, 9H, SiC (C [H ₃ ]) ₃ ) , 0.04 (s, 3H, SiC [H ₃ ]), −0.07 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₄₇ H ₆₃ NNaO ₅ Si ₂ 800.4142, found: 800.4156.

Preparation Example 3-2: (2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methyl-2- (2-methyl Synthesis of (benzyl) hexan-1-ol (34)

EtOH (47.5 μL, 0.813 mmol) and LiBH ₄ (407 μL, 0.813 mmol, 2.0 M in THF) at 0 ° C. in a solution of Compound 33 (575 mg, 0.739 mmol) in Et ₂ O (15 mL) under nitrogen atmosphere Was added. The resulting mixture was stirred for 1 hour. Acetone was added to stop the reaction. The reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 28.1 g, hexane: EtOAc = 30: 1) to give a colorless oil 34 (262 mg, 59%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, 4H, J = 6.8 Hz, Ph), 7.49-7.42 (m, 6H, Ph), 7.19-7.14 (m, 4H, Ph), 3.67- 3.56 (m, 4H, 1/2 HOC [H ₂ ], C [H] OTBS, C [H ₂ ] OTBDPS), 3.48 (dd, 1H, J = 5.6, 11.2 Hz, 1/2 HOC [H ₂ ] ), 2.81 (dd, 1H, J = 4.4, 14.0 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.49 (dd, 1H, J = 10.0, 14.0 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.37 (s, 3H, PhC [H ₃ ]), 2.15-2.07 (m, 1H, CH ₃ C [H]), 1.94-1.84 (m, 1H, HOCH ₂ C [H]), 1.53 (ddd , 1H,
J = 4.4, 10.0, 14.0 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.31 (ddd, 1H, J = 4.4, 10.0, 14.0 Hz,
1/2 CH ₃ CHC [H ₂ ]), 1.12 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.03 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH), 0.91 ( s, 9H, SiC (C [H ₃ ]) ₃ ), 0.05 (s, 3H, SiC [H ₃ ]), −0.05 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na ] ⁺ the following formula _{calculated: C 37 H 56 NaO 3 Si} 2 627.3666, Found: 627.3637.

Preparation Example 3-3: (6R, 8S, 9S) -9-((tert-butyldimethylsilyl) oxy) -8,13,13-trimethyl-6- (2-methylbenzyl) -12,12-diphenyl- Synthesis of 2,4,11-trioxa-12-silatetradecane (35)

Under a nitrogen atmosphere, DIPEA (223 μL, 1.28 mmol) and MOMCl (48.5 μL, 0.639 mmol) were added to a solution of compound 34 (258 mg, 0.426 mmol) in CH ₂ Cl ₂ (4.3 mL) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 8 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 27.6 g, hexane: EtOAc = 70: 1) to give colorless oil 35 (237 mg, 86%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.79 (dd, 4H, J = 1.6, 8.0 Hz, Ph), 7.53-7.45 (m, 6H, Ph), 7.24-7.17 (m, 4H, Ph), 4.67 (dd, 2H, J = 6.8, 14.0 Hz, CH ₃ OC [H ₂ ] O), 3.70
(dd, 1H, J = 2.8, 6.0 Hz, 1/2 C [H ₂ ] OTBDPS), 3.66-3.62 (m, 2H, C [H] OTBS, 1/2 C [H ₂ ] OTBDPS), 3.50 ( dd, 1H, J = 4.0, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.44 (dd, 1H, J = 5.6,
9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.41 (s, 3H, C [H ₃ ] OCH ₂ O), 2.83 (dd, 1H, J = 4.0, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.64 (dd, 1H, J = 9.6, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.41 (s, 3H, PhC [H ₃ ]), 2.17-2.10 (m, 1H, C [H] CH ₂ Ph), 2.08-1.99 (m, 1H, CH ₃ C [H]), 1.65 (ddd,
1H, J = 4.0, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.44 (ddd, 1H, J = 4.0, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.16 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.07 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH), 0.95 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.10 (s, 3H, SiC [H ₃ ]), −0.01 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₃₉ H ₆₀ NaO ₄ Si ₂ 671.3928, found: 671.3904.

Preparation Example 3-4: Synthesis of (2S, 3S, 5R) -6- (methoxymethoxy) -3-methyl-5- (2-methylbenzyl) hexane-1,2-diol (36)

Under a nitrogen atmosphere, TBAF (1.36 μL, 1.36 mmol, 1.0 M in THF) was added to a solution of compound 35 (221 mg, 0.340 mmol) in THF (3.4 mL). The resulting mixture was stirred at room temperature for 17 hours.
Saturated aqueous NH ₄ Cl was added to quench the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 12.2 g, hexane: EtOAc = 1: 1) to give white solid 36 (100 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.14-7.09 (m, 4H, Ph), 4.58 (dd, 2H, J = 6.8, 8.0 Hz, CH ₃ OC [H ₂ ] O), 3.60 (dd, 1H, J = 6.8, 14.0 Hz, C [H] OH), 3.45 (dd, 2H, J = 8.0, 14.0 Hz, C [H ₂ ] OH), 3.41 (dd, 1H, J = 4.4, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.35 (dd, 1H,
J = 6.0, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.34 (s, 3H, C [H ₃ ] OCH ₂ O), 2.61 (dd, 2H, J = 6.0, 9.6 Hz, C [H ₂ ] PhCH ₃ ), 2.31 (s, 3H, PhC [H ₃ ]), 2.05-1.96 (m, 1H, C [H] CH ₂ Ph), 1.75-1.66 (m, 1H, CH ₃ C [H]) , 1.57 (ddd, 1H, J = 5.2, 8.0, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.42 (ddd, 1H, J = 5.2, 8.0, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.94 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₁₇ H ₂₈ NaO ₄ 319.1885, measured value : 319.1886
.

Preparation Example 3-5: Synthesis of (2R, 4S, 5R) -5,6-dichloro-4-methyl-2- (2-methylbenzyl) hexan-1-ol (38)

Under a nitrogen atmosphere, PPh ₃ (242 mg, 0.921 mmol) and NCS (123 mg, 0.921 mmol) were added to a solution of compound 36 (90.3 mg, 0.307 mmol) in THF (3.1 mL). The resulting mixture was stirred at 60 ° C. for 5 minutes. Thereafter, H ₂ O was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 9.50 g, hexane: EtOAc = 100: 1), whereby a crude material containing compound 37 could be obtained.

To the resulting crude material was added MeOH: 2 M HCl = 3: 1 (3.1 mL). The resulting mixture was stirred at 50 ° C. for 11 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 10.3 g, hexane: EtOAc = 15: 1) to give colorless oil 38 (65.4 mg, 2 steps, 74%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.16-7.10 (m, 4H, Ph), 4.09 (ddd, 1H, J = 2.8, 6.0,
8.8 Hz, C [H] Cl), 3.74 (dd, 1H, J = 6.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.65 (dd, 1H, J = 8.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.58 (dd, 1H, J = 5.2, 10.8 Hz, 1/2 HOC [H ₂ ]), 3.51
(dd, 1H, J = 5.2, 10.8 Hz, 1/2 HOC [H ₂ ]), 2.64 (d, 1H, J = 7.2 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.63 (d, 1H , J = 7.2 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.36-2.27 (m, 1H, HOCH ₂ C [H]), 2.33
(s, 3H, PhC [H ₃ ]), 1.92-1.85 (m, 1H, CH ₃ C [H]), 1.59-1.45 (m, 2H, J = 7.2, 12.4 Hz, C [H ₂ ] CHCH ₃ ), 0.97 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (FAB, m-NBA) [M] ⁺ calculated value: C ₁₅ H ₂₂ Cl ₂ O 288.1048, measured value : 288.1044.

Preparation Example 3-6: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (methoxymethoxy) pyridin-3-yl) -4-methyl-2 Of 2- (2-methylbenzyl) hexan-1-one (41)

Under a nitrogen atmosphere, TEMPO (2.80 mg, 0.0182 mmol) and PhI (OAc) ₂ (147 mg, 0.455 mmol) were added to a CH ₂ Cl ₂ (1.8 mL) solution of compound 38 (52.6 mg, 0.182 mmol). The resulting mixture was stirred at room temperature for 3 hours. Thereafter, it stopped saturated Na ₂ S ₂ O ₃ aqueous solution was added the reaction. The reaction solution was extracted with Et ₂ O. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 11.6 g, hexane: EtOAc = 30: 1), whereby a crude material containing compound 39 could be obtained.

After adding n-BuLi (199 μL, 0.308 mmol, 1.55 M in n-hexane) to THF (0.40 mL) at −78 ° C. under argon atmosphere, Compound 2 (59.3 mg, 0.154 mmol) in THF (0.50 mL) ) The solution was added. Subsequently, a THF (0.55 mL) solution of the crude material was added dropwise to the mixture, followed by stirring at −78 ° C. for 20 minutes. Thereafter, MeOH was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 9.71 g, hexane: EtOAc = 10: 1) to give a crude material containing compound 40.

Subsequently, DMP (89.0 mg, 0.210 mmol) was added to a CH ₂ Cl ₂ (1.4 mL) solution of the crude material under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 15 minutes. Thereafter, the reaction was quenched adding a saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO _3. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 9.59 g, hexane: EtOAc = 5: 1) to give a colorless oily substance 41
(51.1 mg, 3 steps, 52%) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.15 (dd, 1H, J = 3.6, 5.6 Hz, Ph), 7.13-7.08 (m, 1H, Ph), 7.07 (dd, 2H, J = 3.5, 5.6 Hz, Ph), 5.47 (d, 1H, J = 6.0 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.40 (d, 1H, J = 6.0 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.27 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.21 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O) , 4.09 (ddd, 1H, J = 2.8, 6.8,
8.0 Hz, C [H] Cl), 3.95 (s, 3H, ArOC [H ₃ ]), 3.75 (s, 3H, ArOC [H ₃ ]), 3.64 (dd, 1H, J = 6.8, 11.6 Hz, 1 / 2 C [H ₂ ] Cl), 3.57-3.51 (m, 1H, ArC (= O) C [H]), 3.55 (dd, 1H, J = 8.0, 11.6 Hz, 1/2 C [H ₂ ] Cl), 3.44 (s, 3H, C [H ₃ ] OCH ₂ O), 3.42 (s, 3H, C [H ₃ ] OCH ₂ O), 3.16 (dd, 1H, J = 6.8, 14.0 Hz, 1 / 2 C [H ₂ ] PhCH ₃ ), 2.61 (dd, 1H, J = 8.0, 14.0 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.29 (s, 3H, PhC [H ₃ ]), 2.23- 2.18 (m, 1H, CH ₃ C [H]), 1.87 (ddd, 1H, J = 6.0, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.56 (ddd, 1H, J = 6.8 , 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.86 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value: C ₂₆ H ₃₅ Cl ₂ NNaO ₇ 566.1688, found value: 566.1676.

Preparation Example 3-7: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- Synthesis of (2-methylbenzyl) hexan-1-one (A5-003)

To a solution of compound 41 (21.6 mg, 0.0397 mmol) in CH ₂ Cl ₂ (0.40 mL) was added TFA (0.40 mL) at 0 ° C. The resulting mixture was stirred for 15 minutes. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 9.19 g, hexane: EtOAc = 8: 1) to give a white solid A5-003 (16.5 mg, 91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.16-7.13 (m, 1H, Ph), 7.10-7.02 (m, 3H, Ph), 4.81-4.73 (m, 1H, ArC (= O) C [H ]), 4.29 (ddd, 1H, J = 2.4, 6.4, 8.0 Hz, C [H] Cl), 4.11 (s, 3H, ArOC [H ₃ ]), 3.77 (s, 3H, ArOC [H ₃ ]) , 3.66 (dd, 1H, J = 6.4, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.57 (dd, 1H, J = 8.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.00 (dd, 1H, J = 8.0, 9.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.76 (dd, 1H, J = 6.8, 9.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.34 (s, 3H, PhC [H ₃ ]), 2.13-2.07 (m, 1H, CH ₃ C [H]), 1.92 (ddd, 1H, J = 4.8, 9.2, 11.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.17 (ddd, 1H, J = 4.8, 9.2, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.91 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH) HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₂ H ₂₇ Cl ₂ NNaO ₅ 478.1164, found: 478.1165.

[Example 4]
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (3-methylbenzyl) Synthesis of Hexan-1-one (A5-004) Compound A5-004 was synthesized according to the following scheme.

Preparation Example 4-1: (S) -4-benzyl-3-((2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) Synthesis of 4-methyl-2- (3-methylbenzyl) hexanoyl) oxazolidine-2-one (42)

NaHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added to THF (5.1 mL) at −78 ° C. under an argon atmosphere, and then a solution of compound 3 (0.750 g, 1.11 mmol) in THF (6.0 mL) was added. It was. After stirring for 1 hour, α-bromo-m-xylene (450 μL, 3.33 mmol) was added and stirred for 40 minutes. Thereafter, the reaction was stopped with a saturated aqueous NH ₄ Cl solution. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel 22.8
Purification by g, hexane: EtOAc = 40: 1) gave colorless oil 42 (586 mg, 66%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72-7.69 (m, 4H, Ph), 7.47-7.38 (m, 6H, Ph), 7.29-7.24 (m, 3H, Ph), 7.19-7.16 (m , 1H, Ph), 7.12-7.10 (m, 2H, Ph), 7.02-6.99 (m, 3H, Ph), 4.65-4.59 (m, 1H, NC [H] CH ₂ O), 4.39-4.32 (m , 1H, NC (= O) C [H]), 4.08-3.99 (m, 2H, NCHC [H ₂ ] O), 3.65-3.61 (m, 1H, C [H] OTBS), 3.57 (d, 1H , J = 10.0 Hz, 1/2 C [H ₂ ] OTBDPS), 3.53 (dd, 1H, J = 5.2, 10.0 Hz, 1/2 C [H ₂ ] OTBDPS), 3.00-2.89 (m, 2H, C [H ₂ ] PhCH ₃ ), 2.95 (dd, 1H, J = 10.0, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 2.35 (dd, 1H, J = 10.0, 13.6 Hz, 1/2 NCHC [ H ₂ ] Ph), 2.31 (s, 3H, PhC [H ₃ ]), 2.09-2.01 (m, 1H, CH ₃ C [H]), 1.76 (ddd, 1H, J = 5.2, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.59 (ddd, 1H, J = 5.2, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.07 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.03 (d, 3H, J = 7.2
Hz, C [H ₃ ] CH), 0.83 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.02 (s, 3H, SiC [H ₃ ]), −0.12 (s, 3H, SiC [ H ₃ ]); HRMS (ESI) [M + Na] ⁺ calculated value: C ₄₇ H ₆₃ NNaO ₅ Si ₂ 800.4142, found: 800.4151.

Preparation Example 4-2: (2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methyl-2- (3-methyl Synthesis of (benzyl) hexan-1-ol (43)

EtOH (47.4 μL, 0.812 mmol) and LiBH ₄ (406 μL, 0.812 mmol, 2.0 M in THF) at 0 ° C. in a solution of compound 42 (574 mg, 0.738 mmol) in Et ₂ O (15 mL) under nitrogen atmosphere Was added. The resulting mixture was stirred for 1 hour. Acetone was added to stop the reaction. The reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 22.3 g, hexane: EtOAc = 30: 1) to give colorless oil 43 (352 mg, 79%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74-7.71 (d, 4H, J = 6.8 Hz, Ph), 7.48-7.39 (m, 6H, Ph), 7.19 (dd, 1H, J = 7.2, 8.4 Hz, Ph), 7.03 (dd, 3H, J = 7.2, 8.4 Hz, Ph), 3.65-3.60 (m, 1H, C [H] OTBS), 3.63 (d, 1H, J = 8.0 Hz, 1/2 C [H ₂ ] OTBDPS), 3.60 (dd,
1H, J = 5.2, 8.0 Hz, 1/2 C [H ₂ ] OTBDPS), 3.54 (dd, 1H, J = 5.2, 9.8 Hz, 1/2 HOC [H ₂ ]), 3.52 (dd, 1H, J = 5.2, 9.8 Hz, 1/2 HOC [H ₂ ]), 2.80 (dd, 1H, J = 5.2, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.44 (dd, 1H, J = 8.8 , 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.36 (s, 3H,
PhC [H ₃ ]), 2.12-2.04 (m, 1H, CH ₃ C [H]), 1.93-1.85 (m, 1H, J = 5.2, 8.8, 13.6 Hz, HOCH ₂ C [H]), 1.47 ( ddd, 1H, J = 3.2, 8.8, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.24 (ddd, 1H, J = 3.2, 8.8, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ] ), 1.12 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.03 (d, 3H
, J = 6.8 Hz, C [H ₃ ] CH), 0.91 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.05 (s, 3H, SiC [H ₃ ]), −0.05
(s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₃₇ H ₅₆ NaO ₃ Si ₂ 627.3666, Found value: 627.3653.

Preparation Example 4-3: (6R, 8S, 9S) -9-((tert-butyldimethylsilyl) oxy) -8,13,13-trimethyl-6- (3-methylbenzyl) -12,12-diphenyl- Synthesis of 2,4,11-trioxa-12-silatetradecane (44)

Under a nitrogen atmosphere, DIPEA (301 μL, 1.73 mmol) and MOMCl (65.5 μL, 0.863 mmol) were added to a CH ₂ Cl ₂ (5.8 mL) solution of Compound 43 (348 mg, 0.575 mmol) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 3.5 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel 13.7 g, hexane: EtOAc = 80
: Purification by (1) gave colorless oil 44 (305 mg, 82%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.88-7.86 (m, 4H, Ph), 7.58-7.50 (m, 6H, Ph), 7.28 (dd, 1H, J = 7.2, 13.6 Hz, Ph), 7.16-7.13 (m, 3H, Ph), 4.74 (s, 2H, CH ₃ OC [H ₂ ] O),
3.80-3.70 (m, 3H, CHOTBS, C [H ₂ ] OTBDPS), 3.55 (dd, 1H, J = 4.4, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.50 (dd, 1H, J = 6.4 , 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.48 (s, 3H, C [H ₃ ] OCH ₂ O),
2.89 (dd, 1H, J = 5.2, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.69 (dd, 1H, J = 8.4, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.47 (s, 3H, PhC [H ₃ ]), 2.25-2.19 (m, 1H, C [H] CH ₂ Ph), 2.16-2.10 (m, 1H, CH ₃ C [H]), 1.67 (ddd, 1H, J = 4.4, 9.6, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.44 (ddd, 1H, J = 4.4, 9.6, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.25 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.14 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH), 1.03 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.17 (s, 3H, SiC [H ₃ ]), 0.08 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₃₉ H ₆₀ NaO ₄ Si ₂ 671.3928, found: 671.3932.

Preparation Example 4-4: Synthesis of (2S, 3S, 5R) -6- (methoxymethoxy) -3-methyl-5- (3-methylbenzyl) hexane-1,2-diol (45)

Under a nitrogen atmosphere, TBAF (1.78 μL, 1.78 mmol, 1.0 M in THF) was added to a solution of compound 44 (288 mg, 0.444 mmol) in THF (4.4 mL). The resulting mixture was stirred at room temperature for 4 hours. Saturated aqueous NH ₄ Cl was added to quench the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 9.50 g, hexane: EtOAc = 1: 2), whereby colorless oily substance 45 (97.4 mg, 74%) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.16 (t, 1H, J = 8.0 Hz, Ph), 6.98 (dd, 2H, J = 8.0, 12.4 Hz, Ph), 6.97 (s, 1H, Ph) , 4.59 (s, 2H, CH ₃ OC [H ₂ ] O), 3.67-3.63 (m, 1H, C [H] OH), 3.47 (d, 2H, J = 6.0 Hz, C [H ₂ ] OH) , 3.41 (dd, 1H, J = 4.8, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.35 (s, 3H, C [H ₃ ] OCH ₂ O), 3.34 (dd, 1H, J = 6.4, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 2.62 (dd, 1H, J = 5.6, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.27 (dd, 1H, J = 8.0, 13.6 Hz , 1/2 C [H ₂ ] PhCH ₃ ), 2.32 (s, 3H, CH ₂ PhC [H ₃ ]), 2.05-1.98 (m, 1H, C [H] CH ₂ Ph), 1.77-1.70 (m , 1H, CH ₃ C [H]), 1.53 (ddd, 1H, J = 4.8, 8.0, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.37 (ddd, 1H, J = 4.8, 8.0, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.91 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₁₇ H ₂₈ NaO ₄ 319.1885, found: 319.1886
.

Preparation Example 4-5: Synthesis of (2R, 4S, 5R) -5,6-dichloro-4-methyl-2- (3-methylbenzyl) hexan-1-ol (47)

Under a nitrogen atmosphere, PPh ₃ (220 mg, 0.840 mmol) and NCS (112 mg, 0.840 mmol) were added to a THF (2.8 mL) solution of compound 45 (82.9 mg, 0.280 mmol). The resulting mixture was stirred at 60 ° C. for 5 minutes. Thereafter, H ₂ O was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 10.7 g, hexane: EtOAc = 100: 1), whereby a crude material containing compound 46 could be obtained.

To the resulting crude material was added MeOH: 2M HCl = 3: 1 (2.8 mL). The resulting mixture was stirred at 50 ° C. for 13.5 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The resulting residue is
Purification by column chromatography (silica gel 9.50 g, hexane: EtOAc = 20: 1) gave colorless oil 47 (60.9 mg, 2 steps, 75%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.18 (t, 1H, J = 8.0 Hz, Ph), 7.03-6.98 (m, 2H, Ph), 7.01 (s, 1H, Ph), 4.09 (ddd, 1H, J = 2.8, 5.6, 8.8 Hz, C [H] Cl), 3.75 (dd, 1H, J = 5.6, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.66 (dd, 1H, J = 8.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.55 (dd, 1H, J = 5.2, 11.2 Hz, 1/2 HOC [H ₂ ]), 3.50 (dd, 1H, J = 5.2, 11.2 Hz, 1/2 HOC [H ₂ ]), 2.62 (dd, 2H, J = 6.8, 8.0 Hz, C [H ₂ ] PhCH ₃ ), 2.34 (s, 3H, PhC [H ₃ ]), 2.31 (ddd , 1H, J = 2.8, 6.8, 14.0 Hz, CH ₃ C [H]), 1.95-1.85 (m, 1H, C [H] CH ₂ Ph), 1.46 (dd, 2H, J = 8.0, 14.0 Hz, C [H ₂ ] CHCH ₃ ), 0.95 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (FAB, m-NBA) [M] ⁺ Calculated value of the following formula: C ₁₅ H ₂₂ Cl ₂ O 288.1048, Found: 288.1049.

Preparation Example 4-6: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (methoxymethoxy) pyridin-3-yl) -4-methyl-2 Of 2- (3-methylbenzyl) hexan-1-one (50)

Under a nitrogen atmosphere, TEMPO (1.30 mg, 8.44 μmol) and PhI (OAc) ₂ (68.0 mg, 0.211 mmol) were added to a solution of compound 47 (24.4 mg, 0.0844 mmol) in CH ₂ Cl ₂ (0.84 mL). The resulting mixture was stirred at room temperature for 3 hours. Thereafter, it stopped saturated Na ₂ S ₂ O ₃ aqueous solution was added the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 12.2 g, hexane: EtOAc = 35: 1), whereby a crude material containing compound 48 could be obtained.

N-BuLi (92.9 μL, 0.144 mmol, 1.55 M) in THF (0.30 mL) at −78 ° C. under argon atmosphere
After addition of n-hexane), a solution of compound 2 (27.7 mg, 0.0720 mmol) in THF (0.50 mL) was added. Subsequently, a THF (0.50 mL) solution of the crude material was added dropwise to the mixture, followed by stirring at −78 ° C. for 5 minutes. Thereafter, MeOH was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 13.0 g, hexane: EtOAc = 10: 1) to give a crude material containing Compound 49.

Subsequently, DMP (41.7 mg, 0.0983) was added to a crude solution of CH ₂ Cl ₂ (0.66 mL) under a nitrogen atmosphere.
mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction was quenched adding a saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO _3. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 6.75 g, hexane: EtOAc = 15: 1) to give colorless oil 50 (17.8 mg, 3 steps, 39%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.12 (t, 1H, J = 7.2 Hz, Ph), 6.99 (s, 1H, Ph), 6.97 (d, 2H, J = 7.2 Hz, Ph), 5.50 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.43 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.28 (d , 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.24 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 4.14-4.10 (m , 1H, ArC (= O) C [H]), 3.96 (s, 3H, ArOC [H ₃ ]), 3.74 (s, 3H, ArOC [H ₃ ]), 3.66 (dd, 1H, J = 6.0, 11.6 Hz, 1/2 C [H ₂ ] Cl),
3.58-3.48 (m, 1H, C [H] Cl), 3.57 (dd, 1H, J = 8.0, 11.6 Hz, 1/2 C [H ₂ ] Cl), 3.47 (s, 3H, C [H ₃ ] OCH ₂ O), 3.46 (s, 3H, C [H ₃ ] OCH ₂ O), 3.12 (dd, 1H, J = 6.4, 14.0 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.57 (dd, 1H, J = 8.0, 14.0 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.29 (s, 3H, PhC [H ₃ ]), 2.29-2.20 (m, 1H, CH ₃ C [H]), 1.83 (ddd, 1H, J = 6.4, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.54 (ddd, 1H, J = 6.4, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.87 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₆ H ₃₅ Cl ₂ NNaO ₇ 566.1688, measured Value: 566.1688.

Preparation Example 4-7: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- Synthesis of (3-methylbenzyl) hexan-1-one (A5-004)

To a solution of compound 50 (12.5 mg, 0.0230 mmol) in CH ₂ Cl ₂ (0.50 mL) was added TFA (0.50 mL) at 0 ° C. The resulting mixture was stirred for 5 minutes. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 5.40 g, hexane: EtOAc = 5: 1) to give a white solid A5-004 (10.4 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.12 (t, 1H, J = 7.6 Hz, Ph), 7.02 (s, 1H, Ph), 7.01 (d, 1H, J = 7.6 Hz, Ph), 6.97 (d, 1H, J = 7.6 Hz, Ph), 4.68-4.58 (m, 1H, ArC (= O) C [H]), 4.17 (ddd, 1H, J = 2.4, 6.0, 8.8 Hz, C [H ] Cl), 4.13 (s, 3H, ArOC [H ₃ ]), 3.79 (s, 3H, ArOC [H ₃ ]), 3.67 (dd, 1H, J = 6.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.57 (dd, 1H, J = 8.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.04 (dd, 1H, J = 6.8, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.63 (dd, 1H, J = 8.0, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.29 (s, 3H, PhC [H ₃ ]), 2.14-2.09 (m, 1H, CH ₃ C [H]), 1.89 (ddd, 1H, J = 5.6, 9.6, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.59 (ddd, 1H, J = 5.6, 9.6, 13.6 Hz, 1 / 2 C [H ₂ ] CHCH ₃ ), 0.89 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₂₂ H ₂₇ Cl ₂ NNaO ₅ 478.1164, Found: 478.1169.

[Example 5]
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (4-methylbenzyl) Synthesis of Hexan-1-one (A5-005) Compound A5-005 was synthesized according to the following scheme.

Preparation Example 5-1: (S) -4-benzyl-3-((2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) Synthesis of 4-methyl-2- (4-methylbenzyl) hexanoyl) oxazolidine-2-one (51)

NaHMDS (1.55 mL, 1.55 mmol, 1.0 M in THF) was added to THF (5.1 mL) at −78 ° C. under an argon atmosphere, and then a solution of compound 3 (0.750 g, 1.11 mmol) in THF (6.0 mL) was added. It was. After stirring for 1 hour, α-bromo-p-xylene (450 μL, 3.33 mmol) was added and stirred for 20 minutes. Thereafter, the reaction was stopped with a saturated aqueous NH ₄ Cl solution. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel 16.7
Purification by g, hexane: EtOAc = 40: 1) gave colorless oil 51 (564 mg, 65%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74-7.71 (m, 4H, Ph), 7.48-7.40 (m, 6H, Ph), 7.30-7.27 (m, 3H, Ph), 7.22 (d, 2H , J = 8.0 Hz, Ph), 7.11 (d, 2H, J = 8.0 Hz, Ph), 7.00 (dd, 2H, J = 2.4, 8.0 Hz, Ph), 4.67-4.61 (m, 1H, NC [H ] CH ₂ O), 4.40-4.33 (m, 1H, NC (= O) C [H]), 4.09-4.02 (m, 2H, NCHC [H ₂ ] O), 3.68-3.64 (m, 1H, C [H] OTBS), 3.62-3.58 (m, 1H, 1/2 C [H ₂ ] OTBDPS), 3.54 (dd, 1H, J = 5.6, 10.0 Hz, 1/2 C [H ₂ ] OTBDPS), 2.99 (dd, 2H, J = 3.6, 13.6 Hz, C [H ₂ ] PhCH ₃ ), 2.92 (dd, 1H, J = 5.2, 13.6 Hz, 1/2
NCHC [H ₂ ] Ph), 2.41 (dd, 1H, J = 5.2, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 2.32 (s, 3H, PhC [H ₃ ]), 2.10-2.04 (m , 1H, CH ₃ C [H]), 1.77 (ddd, 1H, J = 4.8, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.61 (ddd, 1H, J = 4.8, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.09 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.04 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH) , 0.85 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.01 (s, 3H, SiC [H ₃ ]), −0.10 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [ M + Na] ⁺ calculated value: C ₄₇ H ₆₃ NNaO ₅ Si ₂ 800.4142, found: 800.4133.

Preparation Example 5-2: (2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methyl-2- (4-methyl Synthesis of (benzyl) hexan-1-ol (52)

EtOH (43.0 μL, 0.736 mmol) and LiBH ₄ (368 μL, 0.736 mmol, 2.0 M in THF) at 0 ° C. in a solution of compound 51 (520 mg, 0.669 mmol) in Et ₂ O (13 mL) under nitrogen atmosphere Was added. The resulting mixture was stirred for 1 hour. Acetone was added to stop the reaction. The reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 10.6 g, hexane: EtOAc = 30: 1) to give colorless oil 52 (301 mg, 75%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72-7.68 (m, 4H, Ph), 7.46-7.37 (m, 6H, Ph), 7.09 (s, 4H, Ph), 3.64-3.53 (m, 3H , C [H] OTBS, C [H ₂ ] OTBDPS), 3.51 (dd, 1H, J = 5.6, 10.4 Hz, 1/2 HOC [H ₂ ]), 3.43 (dd, 1H, J = 5.6, 10.4 Hz , 1/2 HOC [H ₂ ]), 2.73 (dd, 1H,
J = 4.8, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.44 (dd, 1H, J = 4.8, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.33 (s, 3H, PhC [H ₃ ]), 2.09-2.01 (m, 1H, CH ₃ C [H]), 1.89-1.80 (m, 1H, HOCH ₂ C [H]), 1.41 (ddd, 1H, J = 4.0, 9.6 , 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.19 (ddd, 1H, J = 4.0, 9.6, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.07 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.96 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH), 0.85 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.00 (s, 3H, SiC [H ₃ ]), −0.11 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ calculated value: C ₃₇ H ₅₆ NaO ₃ Si ₂ 627.3666, measured Value: 627.3667.

Preparation Example 5-3: (6R, 8S, 9S) -9-((tert-butyldimethylsilyl) oxy) -8,13,13-trimethyl-6- (4-methylbenzyl) -12,12-diphenyl- Synthesis of 2,4,11-trioxa-12-silatetradecane (53)

Under a nitrogen atmosphere, DIPEA (249 μL, 1.43 mmol) and MOMCl (54.2 μL, 0.714 mmol) were added to a solution of Compound 52 (288 mg, 0.476 mmol) in CH ₂ Cl ₂ (4.8 mL) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 7 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction.
The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel 11.0 g, hexane: EtOAc = 70:
By performing the purification in 1), a colorless oily substance 53 (261 mg, 85%) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.70-7.67 (m, 4H, Ph), 7.44-7.36 (m, 6H, Ph), 7.06 (s, 4H, Ph), 4.58 (d, 2H, J = 0.8 Hz, CH ₃ OC [H ₂ ] O), 3.61-3.49 (m, 3H, C [H] OTBS, C [H ₂ ] OTBDPS), 3.36 (dd, 1H, J = 5.6, 9.6 Hz, 1 / 2 MOMOC [H ₂ ]), 3.33 (s, 3H, C [H ₃ ] OCH ₂ O), 3.30 (dd, 1H, J = 5.6, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 2.69 ( dd, 1H, J = 4.8, 13.6
Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.49 (dd, 1H, J = 4.8, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.31 (s, 3H, PhC [H ₃ ] ), 2.05-1.97 (m, 1H, CH ₃ C [H]), 1.94-1.87 (m, 1H, C [H] CH ₂ Ph), 1.43 (ddd, 1H, J = 4.4, 9.6, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.26 (ddd, 1H, J = 4.4, 9.6, 14.0
Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.05 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.93 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 0.83 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.02 (s, 3H, SiC [H ₃ ]), −0.13 (s, 3H, SiC [H ₃ ])
HRMS (ESI) [M + Na] ⁺ calculated value: C ₃₉ H ₆₀ NaO ₄ Si ₂ 671.3928, found: 671.3918.

Preparation Example 5-4: Synthesis of (2S, 3S, 5R) -6- (methoxymethoxy) -3-methyl-5- (4-methylbenzyl) hexane-1,2-diol (54)

TBAF (1.38 μL, 1.38 mmol, 1.0 M in THF) was added to a solution of compound 53 (225 mg, 0.346 mmol) in THF (3.5 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 22 hours.
Saturated aqueous NH ₄ Cl was added to quench the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 11.2 g, hexane: EtOAc = 1: 1) to give colorless oil 54 (103 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) 7.08 (d, 2H, J = 8.0 Hz, Ph), 7.04 (d, 2H, J = 8.0 Hz,
Ph), 4.58 (s, 2H, CH ₃ OC [H ₂ ] O), 3.63 (ddd, 1H, J = 6.8, 6.8, 15.2 Hz, C [H] OH), 3.46 (d, 2H, J = 6.8 Hz, C [H ₂ ] OH), 3.40 (dd, 1H, J = 4.8, 9.6 Hz, 1/2 MOMOC [H ₂ ]),
3.34 (s, 3H, C [H ₃ ] OCH ₂ O), 3.33 (dd, 1H, J = 6.4, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 2.62 (dd, 1H, J = 5.6, 14.0 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.52 (dd, 1H, J = 5.6, 14.0 Hz, 1/2 C
[H ₂ ] PhCH ₃ ), 2.31 (s, 3H, PhC [H ₃ ]), 2.04-1.94 (m, 1H, C [H] CH ₂ Ph), 1.79-1.69 (m, 1H, CH ₃ C [ H]), 1.52 (ddd, 1H, J = 4.8, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.35 (ddd, 1H, J = 4.8, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.90 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₁₇ H ₂₈ NaO ₄ 319.1885 , Found: 319.1884.

Preparation Example 5-5: Synthesis of (2R, 4S, 5R) -5,6-dichloro-4-methyl-2- (4-methylbenzyl) hexan-1-ol (56)

Under a nitrogen atmosphere, PPh ₃ (260 mg, 0.993 mmol) and NCS (134 mg, 0.993 mmol) were added to a solution of compound 54 (98.1 mg, 0.331 mmol) in THF (3.3 mL). The resulting mixture was stirred at 60 ° C. for 5 minutes. Thereafter, H ₂ O was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 8.38 g, hexane: EtOAc = 50: 1) to give a crude material containing compound 55.

To the resulting crude material was added MeOH: 2 M HCl = 3: 1 (3.3 mL). The resulting mixture was stirred at 50 ° C. for 22 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 6.89 g, hexane: EtOAc = 10: 1) to give white solid 56 (74.3 mg, 2 steps, 78%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.10 (d, 2H, J = 12.0 Hz, Ph), 7.08 (d, 2H, J = 12.0 Hz, Ph), 4.08 (ddd, 1H, J = 2.8, 6.0, 8.8 Hz, C [H] Cl), 3.74 (dd, 1H, J = 6.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.66 (dd, 1H, J = 8.8, 11.2 Hz, 1 / 2 C [H ₂ ] Cl), 3.55 (dd, 1H, J = 5.2, 11.2 Hz, 1/2 HOC [H ₂ ]), 3.49 (dd, 1H, J = 5.2, 11.2 Hz, 1/2 HOC [H ₂ ]),
2.61 (dd, 2H, J = 6.0, 9.6 Hz, C [H ₂ ] PhCH ₃ ), 2.32 (s, 3H, PhC [H ₃ ]), 2.30 (ddd, 1H, J = 2.8, 6.8, 14.0 Hz, CH ₃ C [H]), 1.94-1.84 (m, 1H, C [H] CH ₂ Ph), 1.45 (dd, 2H, J = 6.8, 14.0 Hz, C [H ₂ ] CHCH ₃ ), 0.97 (d , 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (FAB, m-NBA) [M] ⁺ Calculated value of the following formula: C ₁₅ H ₂₂ Cl ₂ O 288.1048, Found: 288.1043.

Preparation Example 5-6: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (methoxymethoxy) pyridin-3-yl) -4-methyl-2 Synthesis of-(4-Methylbenzyl) hexan-1-one (59)

Under a nitrogen atmosphere, TEMPO (3.2 mg, 0.0204 mmol) and PhI (OAc) ₂ (164 mg, 0.510 mmol) were added to a CH ₂ Cl ₂ (2.0 mL) solution of compound 56 (59.0 mg, 0.204 mmol). The resulting mixture was stirred at room temperature for 2.5 hours. Thereafter, it stopped saturated Na ₂ S ₂ O ₃ aqueous solution was added the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 12.7 g, hexane: EtOAc = 35: 1) to give a crude material containing compound 57.

After adding n-BuLi (220 μL, 0.341 mmol, 1.55 M in n-hexane) to THF (0.30 mL) at −78 ° C. under argon atmosphere, Compound 9 (65.9 mg, 0.171 mmol) in THF (0.60 mL) ) The solution was added. Subsequently, a THF (0.60 mL) solution of the crude material was added dropwise to the mixture, followed by stirring at −78 ° C. for 5 minutes. Thereafter, MeOH was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 7.29 g, hexane: EtOAc = 10: 1) to give a crude material containing Compound 58.

Subsequently, DMP (98.8 mg, 0.233 mmol) was added to a CH ₂ Cl ₂ (1.6 mL) solution of the crude material under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 20 minutes. Thereafter, the reaction was quenched adding a saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO _3. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 7.43 g, hexane: EtOAc = 15: 1) to give colorless oil 59 (58.5 mg, 3 steps, 53%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.07 (d, 2H, J = 12.0 Hz, Ph), 7.05 (d, 2H, J = 12.0 Hz, Ph), 5.50 (d, 1H, J = 5.6 Hz , 1/2 CH ₃ OC [H ₂ ] O), 5.43 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.28 (d, 1H, J = 5.6 Hz, 1 / 2 CH ₃ OC [H ₂ ] O), 5.25 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 4.11 (ddd, 1H, J = 2.4, 6.4, 8.0 Hz , C [H] Cl), 3.96 (s, 3H, ArOC [H ₃ ]), 3.75 (s, 3H, ArOC [H ₃ ]), 3.65 (dd, 1H, J = 6.4, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.57 (dd, 1H, J = 8.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.55-3.49 (m, 1H, ArC (= O) C [H]) , 3.46 (s, 3H, C [H ₃ ] OCH ₂ O), 3.44 (s, 3H, C [H ₃ ] OCH ₂ O), 3.12 (dd, 1H, J = 6.0, 14.0 Hz,
1/2 C [H ₂ ] PhCH ₃ ), 2.56 (dd, 1H, J = 8.0, 14.0 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.28 (s, 3H, PhC [H ₃ ]), 2.25-2.19 (m, 1H, CH ₃ C [H]), 1.81 (ddd, 1H, J = 6.0, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.53 (ddd, 1H, J = 6.0, 8.0, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.86 (d, 3H,
J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₆ H ₃₅ Cl ₂ NNaO ₇ 566.1688,
Found: 566.1687.

Preparation Example 5-7: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- Synthesis of (4-methylbenzyl) hexan-1-one (A5-005)

To a solution of compound 59 (39.6 mg, 0.0727 mmol) in CH ₂ Cl ₂ (0.73 mL) was added TFA (0.73 mL) at 0 ° C. The resulting mixture was stirred for 5 minutes. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 6.48 g, hexane: EtOAc = 5: 1) to give a white solid A5-005 (32.4 mg, 98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.10 (d, 2H, J = 8.0 Hz, Ph), 7.04 (d, 2H, J = 8.0 Hz, Ph), 4.71-4.61 (m, 1H, ArC ( = O) C [H]), 4.17 (ddd, 1H, J = 2.4, 6.0, 8.4 Hz, C [H] Cl), 4.15 (s, 3H, ArOC [H ₃ ]), 3.80 (s, 3H, ArOC [H ₃ ]), 3.66 (dd, 1H, J = 6.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.57 (dd, 1H, J = 8.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.04 (dd, 1H,
J = 6.0, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.62 (dd, 1H, J = 7.6, 13.6 Hz, 1/2 C [H ₂ ] PhCH ₃ ), 2.29 (s, 3H, PhC [H ₃ ]), 2.13-2.07 (m, 1H, CH ₃ C [H]), 1.88 (ddd, 1H, J = 5.2, 9.2, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.58 (ddd, 1H, J = 5.2, 9.2, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.88 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₂ H ₂₇ Cl ₂ NNaO ₅ 478.1164, found: 478.11151.

[Example 6]
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (naphthalen-1-ylmethyl) ) Synthesis of Hexan-1-one (A5-006) Compound A5-006 was synthesized according to the following scheme.

Preparation Example 6-1: (S) -4-benzyl-3-((2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) Synthesis of 4-methyl-2- (naphthalen-1-ylmethyl) hexanoyl) oxazolidine-2-one (60)

NaHMDS (1.58 mL, 1.58 mmol, 1.0 M THF) in THF (5.0 mL) at −78 ° C. under argon atmosphere
Medium) was added, and then a solution of compound 3 (0.764 g, 1.13 mmol) in THF (6.3 mL) was added. After stirring for 1 hour, 1-bromomethylnaphthalene (736 μL, 3.39 mmol) was added and stirred for 1.5 hours.
Thereafter, the reaction was stopped with a saturated aqueous NH ₄ Cl solution. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 20.7 g, hexane: EtOAc = 30: 1) to give a colorless oil 60 (692 mg, 75%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, 1H, J = 8.0 Hz, Ar), 7.84 (dd, 1H, J = 1.2, 8.0 Hz, Ar), 7.72-7.68 (m, 5H, Ar), 7.54 (ddd, 1H, J = 1.2, 6.8, 8.0 Hz, Ar), 7.48 (dd, 1H, J = 1.2, 8.0 Hz, Ar), 7.44 (dd, 1H, J = 1.2, 8.0 Hz, Ar), 7.43-7.35 (m, 7H, Ar), 7.20-7.11 (m, 3H, Ar), 6.82 (dd, 2H, J = 1.2, 8.0 Hz, Ar), 4.64-4.54 (m, 2H, NC [H] CH ₂ O, NC (= O) C [H]), 4.00 (t, 1H, J = 8.8 Hz, 1/2 NCHC [H ₂ ] O), 3.91 (dd, 1H, J = 2.8, 8.8 Hz, 1/2 NCHC [H ₂ ] O), 3.66-3.60 (m, 2H, C [H] OTBS, 1/2 C [H ₂ ] OTBDPS), 3.58-3.53 (m, 1H, 1/2 C [H ₂ ] OTBDPS), 3.48 (dd, 2H, J = 4.8, 8.8 Hz, C [H ₂ ] naphthyl), 2.78 (dd, 1H, J = 2.8, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 2.23-2.19 (m, 1H, CH ₃ C [H]), 2.17 (dd, 1H, J = 9.2, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 1.87 (ddd, 1H, J = 4.0,
9.2, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.63 (ddd, 1H, J = 4.0, 9.2, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.15 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH), 1.07 (s, 9H, Si (CH ₃ ) ₃ ), 0.82 (s, 9H, Si (CH ₃ ) ₃ ), −0.02 (s, 3H, SiCH ₃ ), −0.13 (s, 3H, SiCH ₃ ); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₅₀ H ₆₃ NNaO ₅ Si ₂ 836.4142, found value: 836.4133.

Preparation Example 6-2: (2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methyl-2- (naphthalene-1 Synthesis of (-Ilmethyl) hexan-1-ol (61)

EtOH (56 μL, 0.950 mmol) and LiBH ₄ (475 μL, 0.950 mmol, 2.0 M in THF) at 0 ° C. in a solution of Compound 60 (702 mg, 0.864 mmol) in Et ₂ O (17.3 mL) under nitrogen atmosphere Was added. The resulting mixture was stirred for 1 hour. Acetone was added to stop the reaction. The reaction mixture was concentrated, H ₂ O was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 28.1 g, hexane: EtOAc = 25: 1) to give colorless oil 61 (307 mg, 55%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (dd, 1H, J = 2.4, 6.4 Hz, Ar), 7.88-7.84 (m, 1H, Ar), 7.72 (d, 2H, J = 7.2 Hz, Ar), 7.69 (d, 3H, J = 7.2 Hz, Ar), 7.52-7.47 (m, 2H, Ar), 7.46-7.33 (m, 8H, Ar), 3.62-3.55 (m, 3H, C [H ] OTBS, C [H ₂ ] OTBDPS), 3.52 (dd, 1H, J = 4.8, 10.8 Hz, 1/2 HOC [H ₂ ]), 3.45 (dd, 1H, J = 4.8, 10.8 Hz, 1/2 HOC [H ₂ ]), 3.23 (dd, 1H, J = 4.8, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 2.91 (dd, 1H, J = 8.8, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 2.19-2.08 (m, 1H, CH ₃ C [H]), 2.06-2.00 (m, 1H, HOCH ₂ C [H]), 1.60 (ddd, 1H, J = 4.0, 9.6, 14.0 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.32 (ddd, 1H, J = 4.0, 9.6, 14.0 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.06 (s, 9H, SiC (C (H ₃ ]) ₃ ), 1.01 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH), 0.85 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.01 (s, 3H , SiC [H ₃ ]), −0.11 (s,
3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₄₀ H ₅₆ NaO ₃ Si ₂ 663.3666, measured value: 663.3679.

Preparation Example 6-3: (6R, 8S, 9S) -9-((tert-butyldimethylsilyl) oxy) -8,13,13-trimethyl-6- (naphthalen-1-ylmethyl) -12,12-diphenyl Of -2,4,11-trioxa-12-silatetradecane (62)

Under a nitrogen atmosphere, DIPEA (233 μL, 1.34 mmol) and MOMCl (51.0 μL, 0.671 mmol) were added to a solution of compound 61 (286 mg, 0.447 mmol) in CH ₂ Cl ₂ (4.5 mL) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 5 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction.
The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 8.2 g, hexane: EtOAc = 30: 1) to give colorless oil 62 (280 mg, 92%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, 1H, J = 8.0 Hz, Ar), 7.95 (dd, 1H, J = 2.0, 8.0 Hz, Ar), 7.82-7.78 (m, 5H, Ar), 7.61-7.44 (m, 10H, Ar), 4.69 (dd, 2H, J = 6.4, 10.8 Hz, CH ₃ OC [H ₂ ] O), 3.73 (dd, 1H, J = 3.2, 5.6 Hz, C (H ₂ ] OTBDPS), 3.69-3.64 (m, 2H, CHOTBS, 1/2 C [H ₂ ] OTBDPS), 3.51-3.47 (m, 2H, MOMOC [H ₂ ]), 3.44 (s, 3H, C [H ₃ ] OCH ₂ O), 3.31 (dd, 1H, J = 5.2, 9.6 Hz, 1/2 C [H ₂ ] naphthyl), 3.16 (ddd, 1H, J = 3.2, 5.2, 9.6 Hz, 1 / 2 C [H ₂ ] naphthyl), 2.31-2.20 (m, 2H, CH ₃ C [H], C [H] CH ₂ naphthyl), 1.80 (ddd, 1H, J = 4.0, 8.4, 14.0 Hz, 1 / 2 CH ₃ CHC [H ₂ ]), 1.50 (ddd, 1H, J = 4.0, 8.4, 14.0 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.18 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.12 (d, 3H, J = 6.8
Hz, C [H ₃ ] CH), 0.98 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.11 (s, 3H, SiC [H ₃ ]), 0.01 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₄₂ H ₆₀ NaO ₄ Si ₂ 707.3928, found value: 707.33921.

Preparation Example 6-4: Synthesis of (2S, 3S, 5R) -6- (methoxymethoxy) -3-methyl-5- (naphthalen-1-ylmethyl) hexane-1,2-diol (63)

Under a nitrogen atmosphere, TBAF (1.50 μL, 1.50 mmol, 1.0 M in THF) was added to a solution of compound 62 (259 mg, 0.379 mmol) in THF (3.8 mL). The resulting mixture was stirred at room temperature for 23 hours.
Saturated aqueous NH ₄ Cl was added to quench the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 6.9 g, hexane: EtOAc = 0: 1) to give a colorless transparent oily substance 63 (115 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, 1H, J = 8.0 Hz, Ar), 7.85 (dd, 1H, J = 1.2, 8.0 Hz, Ar), 7.73 (d, 1H, J = 8.0 Hz, Ar), 7.53-7.45 (m, 2H, Ar), 7.39 (t, 1H, J = 8.0 Hz, Ar), 7.32 (dd, 1H, J = 1.2, 8.0 Hz, Ar), 4.58 (dd , 2H, J = 6.4, 11.2
Hz, CH ₃ OC [H ₂ ] O), 3.53 (dd, 1H, J = 7.2, 9.8 Hz, 1/2 C [H ₂ ] OH), 3.44-3.88 (m, 4H,
1/2 C [H ₂ ] OH, C [H] OH, MOMOC [H ₂ ]), 3.35 (s, 3H, C [H ₃ ] OCH ₂ O), 3.08 (dd, 2H, J = 4.0, 7.2 Hz, C [H ₂ ] naphthyl), 2.26-2.17 (m, 1H, C [H] CH ₂ naphthyl) 1.76-1.64 (m, 1H, CH ₃ C [H]), 1.62 (ddd, 1H, J = 4.4, 8.0, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.45 (ddd, 1H, J = 4.4, 8.0, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 0.88 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₀ H ₂₈ NaO ₄ 355.1885, found: 355.1887.

Preparation Example 6-5: Synthesis of (2R, 4S, 5R) -5,6-dichloro-4-methyl-2- (naphthalen-1-ylmethyl) hexan-1-ol (65)

Under a nitrogen atmosphere, PPh ₃ (273 mg, 1.04 mmol) and NCS (138.9 mg, 1.04 mmol) were added to a THF (3.5 mL) solution of compound 63 (116 mg, 0.347 mmol). The resulting mixture is
Stir for minutes. Thereafter, H ₂ O was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 7.4 g, hexane: EtOAc = 60: 1) to give a crude material containing compound 64.

To the resulting crude material was added MeOH: 2 M HCl = 3: 1 (3.5 mL). The resulting mixture was stirred at 50 ° C. for 65 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The resulting residue is
Purification by column chromatography (silica gel 13.7 g, hexane: EtOAc = 5: 1) gave colorless oil 65 (72.2 mg, 2 steps, 64%).

¹ H-NMR (600 MHz, CDCl ₃ ) δ 8.06 (d, 1H, J = 9.0 Hz, Ar), 7.86 (d, 1H, J = 9.0 Hz, Ar), 7.73 (d, 1H, J = 9.0 Hz , Ar), 7.52 (ddd, 1H, J = 1.8, 7.2, 9.0 Hz, Ar),
7.48 (ddd, 1H, J = 1.8, 7.2, 9.0 Hz, Ar), 7.40 (dd, 1H, J = 7.2, 9.0 Hz, Ar), 7.34 (d, 1H, J = 7.2 Hz, Ar), 4.03 ( ddd, 1H, J = 3.0, 6.0, 9.0 Hz, CHCl), 3.70 (dd, 1H, J = 6.0, 11.4 Hz, 1/2 C [H ₂ ] Cl), 3.61 (dd, 1H, J = 9.0, 11.4 Hz, 1/2 C [H ₂ ] Cl), 3.55 (dd, 2H, J = 10.8, 25.2 Hz, HOC [H ₂ ]), 3.13 (dd, 1H, J = 8.4, 13.8 Hz, 1/2 C [H ₂ ] naphthyl), 3.07 (dd, 1H, J = 8.4, 13.8 Hz, 1/2 C [H ₂ ] naphthyl), 2.29 (dq, 1H, J = 3.0, 6.0 Hz, CH ₃ C [H ]), 2.12-2.05 (m, 1H, HOCH ₂ C [H]), 1.61 (t, 2H, J = 6.0 Hz, C [H ₂ ] CHCH ₃ ), 0.94 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (EI) [M] ⁺ calculated value: C ₁₈ H ₂₂ Cl ₂ O 324.1048, found: 324.1046.

Preparation Example 6-6: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (methoxymethoxy) pyridin-3-yl) -4-methyl-2 Of 2- (Naphthalen-1-ylmethyl) hexan-1-one (68)

Under a nitrogen atmosphere, TEMPO (2.50 mg, 0.0160 mmol) and PhI (OAc) ₂ (129 mg, 0.400 mmol) were added to a CH ₂ Cl ₂ (1.6 mL) solution of compound 65 (52.0 mg, 0.160 mmol). The resulting mixture was stirred at room temperature for 1.5 hours. Thereafter, it stopped saturated Na ₂ S ₂ O ₃ aqueous solution was added the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (silica gel 7.7 g, hexane: EtOAc = 35: 1)
The crude material containing compound 66 could be obtained by purification with

After adding n-BuLi (164 μL, 0.255 mmol, 1.55 M in n-hexane) to THF (0.30 mL) at −78 ° C. under argon atmosphere, Compound 2 (49.3 mg, 0.128 mmol) in THF (0.50 mL) ) The solution was added. Subsequently, a THF (0.50 mL) solution of the crude material was added dropwise to the mixture, followed by stirring at −78 ° C. for 10 minutes. Thereafter, MeOH was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 8.2 g, hexane: EtOAc = 3: 1) to give a crude material containing compound 67.

Subsequently, DMP (73.8 mg, 0.174 mmol) was added to a CH ₂ Cl ₂ (1.2 mL) solution of the crude material under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes. Thereafter, the reaction was stopped by addition of saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO _3. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was subjected to column chromatography (
Purification by silica gel 5.7 g, hexane: EtOAc = 5: 1) gave colorless oil 68 (29.9 mg, 3 steps, 32%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.97-7.95 (m, 1H, Ar), 7.84-7.82 (m, 1H, Ar), 7.68 (dd, 1H, J = 2.0, 6.8 Hz, Ar), 7.47 (ddd, 1H, J = 2.0, 6.8, 9.2 Hz, Ar), 7.46 (ddd, 1H, J = 2.0, 6.8, 9.2 Hz, Ar), 7.34 (s, 1H, Ar), 7.33 (t, 1H , J = 9.2 Hz, Ar), 5.26 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.22 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.19 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.14 (d, 1H, J = 5.6 Hz, 1/2 CH ₃ OC [H ₂ ] O), 4.01 (ddd, 1H, J = 2.4, 6.0, 8.0 Hz, C [H] Cl), 3.94 (s, 3H, ArOC [H ₃ ]), 3.80-3.75 (m, 1H, ArC ( = O) C [H]) 3.73 (s, 3H, ArOC [H ₃ ]), 3.62 (dd, 1H, J = 6.0, 14.0
Hz, 1/2 C [H ₂ ] naphthyl), 3.59 (dd, 1H, J = 6.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.50 (dd,
1H, J = 8.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.42 (s, 3H, C [H ₃ ] OCH ₂ O), 3.24 (s, 3H, C [H ₃ ] OCH ₂ O ), 3.07 (dd, 1H, J = 7.2, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 2.21-2.15 (m, 1H, CH ₃ C [H]), 1.95 (ddd, 1H, J = 6.0, 8.4, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.67 (ddd, 1H, J
= 6.0, 8.4, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.84 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Next Calculated value of formula: C ₂₉ H ₃₅ Cl ₂ NNaO ₇ 602.1688, found value: 602.1617.

Preparation Example 6-7: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- Synthesis of (naphthalen-1-ylmethyl) hexan-1-one (A5-006)

To a solution of compound 68 (15.9 mg, 0.0274 mmol) in CH ₂ Cl ₂ (0.27 mL) was added TFA (0.27 mL) at 0 ° C. The resulting mixture was stirred for 3 minutes. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 8.4 g, hexane: EtOAc = 3: 1) to give a colorless transparent oily substance A5-006 (63.2 mg, 99%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.11 (dd, 1H, J = 2.8, 6.8 Hz, Ar), 7.76 (dd, 1H, J
= 2.8, 6.8 Hz, Ar), 7.64 (dd, 1H, J = 2.8, 6.8 Hz, Ar), 7.44-7.38 (m, 2H, Ar), 7.34 (s, 1H, Ar), 7.32 (dd, 1H , J = 6.8, 12.0 Hz, Ar), 4.93 (m, 1H, ArC (= O) C [H]), 4.20 (ddd, 1H, J = 2.4, 6.0, 8.4 Hz, C [H] Cl), 3.89 (s, 3H, ArOC [H ₃ ]), 3.74 (s, 3H, ArOC [H ₃ ]), 3.61 (dd, 1H, J = 6.0, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.53 (dd, 1H, J = 8.4, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.47 (dd, 1H, J = 7.2, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 3.23 ( dd, 1H, J = 7.2, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 2.13-2.06 (m, 1H, CH ₃ C [H]), 2.01 (ddd, 1H, J = 4.8, 9.2, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.73 (ddd, 1H, J = 4.8, 9.2, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.88 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₅ H ₂₇ Cl ₂ NNaO ₅ 514.1164, found: 514.1174.

[Example 7]
(2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- (naphthalen-2-ylmethyl) ) Synthesis of Hexan-1-one (A5-007) Compound A5-007 was synthesized according to the following scheme.

Preparation Example 7-1: (S) -4-benzyl-3-((2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy)-
Synthesis of 6-((tert-butyldiphenylsilyl) oxy) -4-methyl-2- (naphthalen-2-ylmethyl) hexanoyl) oxazolidin-2-one (69)

NaHMDS (1.60 mL, 1.60 mmol, 1.0 M in THF) was added to THF (5.1 mL) at −78 ° C. under an argon atmosphere, and then a solution of compound 3 (0.750 g, 1.11 mmol) in THF (6.0 mL) was added. It was. After stirring for 1 hour, 2-bromomethylnaphthalene (736 μL, 3.33 mmol) was added and stirred for 2 hours. Thereafter, the reaction was stopped with a saturated aqueous NH ₄ Cl solution. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 33.5 g, hexane: EtOAc = 20: 1) to give a colorless oily substance 69 (385 mg, 42%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.79 (dd, 1H, J = 4.8, 8.0 Hz, Ar), 7.77 (d, 2H, J = 8.0 Hz, Ar), 7.72-7.67 (m, 5H, Ar), 7.48-7.37 (m, 9H, Ar), 7.19-7.09 (m, 3H, Ar), 6.83 (dd, 2H, J = 1.2, 8.0 Hz, Ar), 4.63-4.57 (m, 1H, NC [H] CH ₂ O), 4.51-4.44 (m, 1H, NC (= O) C [H]), 4.02 (t, 1H, J = 8.0 Hz, 1/2 NCHC [H ₂ ] O), 3.93 (dd, 1H, J = 2.8, 8.0 Hz, 1/2 NCHC [H ₂ ] O), 3.66-3.63 (m, 1H, C [H] OTBS) 3.58 (dd, 1H, J = 7.2, 10.0 Hz, 1/2 C [H ₂ ] OTBDPS), 3.52 (dd, 1H, J = 5.2, 10.0 Hz, 1/2 C [H ₂ ] OTBDPS), 3.17 (dd, 1H, J = 9.2, 13.6 Hz, C [ H ₂ ] naphthyl), 3.09 (dd, 1H, J = 5.6, 13.6 Hz, C [H ₂ ] naphthyl), 2.92 (dd, 1H, J = 3.2, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph) , 2.16 (dd, 1H, J = 9.6, 13.6 Hz, 1/2 NCHC [H ₂ ] Ph), 2.12-2.06 (m, 1H, CH ₃ C [H]), 1.80 (ddd, 1H, J = 4.8 , 8.4, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.62 (ddd, 1H, J = 4.8, 8.4, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.06 (s, 9H , Si (C [H ₃ ]) ₃ ), 1.04 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH), 0.80 (s, 9H, Si (CH ₃ ) ₃ ), −0.03 (s, 3H, SiCH ₃ ), −0.14 (s, 3H, SiCH ₃ ); HRMS ( ESI) [M + Na] ⁺
Calculated value of the following formula: C ₅₀ H ₆₃ NNaO ₅ Si ₂ 836.4142, found value: 836.4161.

Preparation Example 7-2: (2R, 4S, 5S) -5-((tert-butyldimethylsilyl) oxy) -6-((tert-butyldiphenylsilyl) oxy) -4-methyl-2- (naphthalene-2 Synthesis of (-Ilmethyl) hexan-1-ol (70)

EtOH (39 μL, 0.664 mmol) and LiBH ₄ (38.7 μL, 0.664 mmol, 2.0 M in THF) at 0 ° C. in a solution of compound 69 (491 mg, 0.604 mmol) in Et ₂ O (12 mL) under nitrogen atmosphere Was added. The resulting mixture was stirred for 2 hours. Acetone was added to stop the reaction. The reaction mixture was concentrated, H ₂ O was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 12.7 g, hexane: EtOAc = 30: 1), whereby colorless oily substance 70 (232 mg, 60%) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (dd, 1H, J = 2.0, 8.0 Hz, Ar), 7.75 (dd, 1H, J
= 2.0, 8.0 Hz, Ar), 7.74 (d, 1H, J = 8.0 Hz, Ar), 7.68 (dd, 2H, J = 2.0, 8.0 Hz, Ar), 7.67 (dd, 2H, J = 2.0, 8.0 Hz, Ar), 7.62 (s, 1H, Ar), 7.47-7.35 (m, 8H, Ar), 7.33 (dd, 1H, J = 2.0, 8.0 Hz, Ar), 3.68-3.61 (m, 3H, C [H] OTBS, C [H ₂ ] OTBDPS), 3.58 (dd, 1H, J = 5.2, 10.8 Hz, 1/2 HOC [H ₂ ]), 3.51 (dd, 1H, J = 5.2, 10.8 Hz, 1 / 2 HOC [H ₂ ]), 2.98 (dd, 1H, J = 4.4, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 2.69 (dd, 1H, J = 8.8, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 2.19-2.11 (m, 1H, CH ₃ C [H]), 2.06-1.98 (m, 1H, HOCH ₂ C [H]), 1.47 (ddd, 1H, J = 4.0, 9.6 , 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.23 (ddd, 1H, J = 4.0, 9.6, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.05 (s, 9H, SiC (C [H ₃ ]) ₃ ), 0.97 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 0.82 (s, 9H, SiC (C [H ₃ ]) ₃ ), −0.03 (s , 3H, SiC [H ₃ ]), −0.12 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ calculated value: C ₄₀ H ₅₆ NaO ₃ Si ₂ 663.3666, Found: 663.3653.

Preparation Example 7-3: (6R, 8S, 9S) -9-((tert-Butyldimethylsilyl) oxy) -8,13,13-trimethyl-6- (naphthalen-2-ylmethyl) -12,12-diphenyl Of -2,4,11-trioxa-12-silatetradecane (71)

Under a nitrogen atmosphere, DIPEA (253 μL, 1.45 mmol) and MOMCl (36.6 μL, 0.482 mmol) were added to a solution of compound 70 (206 mg, 0.321 mmol) in CH ₂ Cl ₂ (3.2 mL) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 3 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 10.3 g, hexane: EtOAc = 50: 1) to give colorless oil 71 (208 mg, 95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.83 (dd, 1H, J = 2.0, 8.0 Hz, Ar), 7.79 (dd, 1H, J
= 2.0, 8.0 Hz, Ar), 7.77 (d, 1H, J = 8.0 Hz, Ar), 7.74-7.71 (m, 4H, Ar), 7.65 (s, 1H, Ar), 7.50-7.39 (m, 8H , Ar), 7.37 (dd, 1H, J = 2.0, 8.0 Hz, Ar), 4.62 (d, 2H, J = 1.6 Hz, CH ₃ OC [H ₂ ] O), 3.66-3.61 (m, 2H, C [H] OTBS, 1/2 C [H ₂ ] OTBDPS), 3.57 (dd, 1H, J = 4.8, 9.2 Hz, 1/2 C [H ₂ ] OTBDPS), 3.41 (ddd, 2H, J = 5.2, 9.2, 18.0 Hz, MOMOC [H ₂ ]), 3.37 (s, 3H, C [H ₃ ] OCH ₂ O), 2.95 (dd, 1H, J = 4.8, 13.2 Hz, 1/2 C [H ₂ ] naphthyl ), 2.74 (dd, 1H, J = 4.8, 13.2 Hz, 1/2 C [H ₂ ] naphthyl), 2.15-2.08 (m, 2H, CH ₃ C [H], C [H] CH ₂ naphthyl), 1.56 (ddd, 1H, J = 4.4, 9.2, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.33 (ddd, 1H, J = 4.4, 9.2, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.10 (s, 9H, SiC (C [H ₃ ]) ₃ ), 1.01 (d, 3H, J = 6.8 Hz, C [H ₃ ] CH), 0.87 (s, 9H, SiC (C [ H ₃ ]) ₃ ), −0.02 (s, 3H, SiC [H ₃ ]), −0.08 (s, 3H, SiC [H ₃ ]); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula : C ₄₂ H ₆₀ NaO ₄ Si ₂ 707.3928, found: 707.3903.

Preparation Example 7-4: Synthesis of (2S, 3S, 5R) -6- (methoxymethoxy) -3-methyl-5- (naphthalen-2-ylmethyl) hexane-1,2-diol (72)

Under a nitrogen atmosphere, TBAF (1.21 μL, 1.21 mmol, 1.0 M in THF) was added to a solution of compound 71 (207 mg, 0.302 mmol) in THF (3.0 mL). The resulting mixture was stirred at room temperature for 17 hours.
Saturated aqueous NH ₄ Cl was added to quench the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 13.2 g, hexane: EtOAc = 1: 1) to give a colorless transparent oily substance 72 (100 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, 1H, J = 7.2 Hz, Ar), 7.78 (d, 2H, J = 8.0 Hz, Ar), 7.62 (s, 1H, Ar), 7.48 -7.41 (m, 2H, Ar), 7.33 (d, 1H, J = 8.8 Hz, Ar), 4.59 (s, 2H, CH ₃ OC [H ₂ ] O), 3.63 (dd, 1H, J = 6.8, 15.2 Hz, 1/2 C [H ₂ ] OH), 3.49-3.47 (m, 2H, 1/2 C [H ₂ ] OH, C [H] OH), 3.43 (dd, 1H, J = 4.0, 9.6 Hz, 1/2 MOMOC [H ₂ ]), 3.38 (dd, 1H, J = 4.0, 6.0 Hz, 1/2 MOMOC [H ₂ ]), 3.35 (s, 3H, C [H ₃ ] OCH ₂ O) , 2.85 (dd, 1H, J = 5.2, 13.6 Hz, 1/2 C [H ₂ ] naphthyl), 2.73 (dd, 1H, J = 5.2, 13.6 Hz, 1/2 C [H ₂ ] naphthyl), 2.17 -2.11 (m, 1H, C [H] CH ₂ naphthyl) 1.83-1.77 (m, 1H, CH ₃ C [H]), 1.61 (ddd, 1H, J = 4.8, 8.4 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 1.40 (ddd, 1H, J = 4.8, 8.4, 13.6 Hz, 1/2 CH ₃ CHC [H ₂ ]), 0.94 (d, 3H, J = 7.2 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculated value of the following formula: C ₂₀ H ₂₈ NaO ₄ 355.1885, found value: 355.1887.

Preparation Example 7-5: Synthesis of (2R, 4S, 5R) -5,6-dichloro-4-methyl-2- (naphthalen-2-ylmethyl) hexan-1-ol (74)

Under a nitrogen atmosphere, PPh ₃ (186 mg, 0.711 mmol) and NCS (94.9 mg, 0.711 mmol) were added to a solution of compound 72 (78.9 mg, 0.237 mmol) in THF (2.4 mL). The resulting mixture was stirred at 60 ° C. for 3 minutes. Thereafter, H ₂ O was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 6.4 g, hexane: EtOAc = 50: 1), whereby a crude material containing compound 73 could be obtained.

To the resulting crude material was added MeOH: 2 M HCl = 3: 1 (2.4 mL). The resulting mixture was stirred at 50 ° C. for 38 hours. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 8.4 g, hexane: EtOAc = 3: 1) to give colorless oil 74 (57.1 mg, 2 steps 74%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, 1H, J = 8.0 Hz, Ar), 7.79 (d, 2H, J = 8.0 Hz, Ar), 7.64 (s, 1H, Ar), 7.50 -7.42 (m, 2H, Ar), 7.35 (dd, 1H, J = 1.6, 8.0 Hz,
Ar), 4.11 (ddd, 1H, J = 3.6, 6.8, 9.2 Hz, C [H] Cl), 3.75 (dd, 1H, J = 6.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.66 (dd, 1H, J = 9.2, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.55 (ddd, 2H, J
= 5.2, 10.8, 20.0 Hz, HOC [H ₂ ]), 2.83 (dd, 2H, J = 2.0, 6.0 Hz, C [H ₂ ] naphthyl), 2.35 (dq, 1H, J = 3.6, 6.8 Hz, CH ₃ C [H]), 2.06-1.97 (m, 1H, HOCH ₂ C [H]), 1.50 (ddd, 2H, J = 3.6, 6.8, 6.8 Hz, C [H ₂ ] CHCH ₃ ), 0.96 (d , 3H, J = 6.8 Hz, C [H ₃ ] CH); HRMS
(FAB, m-NBA) [M] ⁺ calculated value: C ₁₈ H ₂₂ Cl ₂ O 324.1048, found: 324.0104.

Preparation Example 7-6: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (methoxymethoxy) pyridin-3-yl) -4-methyl-2 Of 2- (Naphthalen-2-ylmethyl) hexan-1-one (77)

Under a nitrogen atmosphere, TEMPO (2.0 mg, 0.0128 mmol) and PhI (OAc) ₂ (103 mg, 0.320 mmol) were added to a CH ₂ Cl ₂ (1.3 mL) solution of Compound 74 (41.7 mg, 0.128 mmol). The resulting mixture was stirred at room temperature for 2.5 hours. Thereafter, it stopped saturated Na ₂ S ₂ O ₃ aqueous solution was added the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 11.0 g, hexane: EtOAc = 30: 1), whereby a crude material containing compound 75 could be obtained.

After adding n-BuLi (146 μL, 0.238 mmol, 1.63 M in n-hexane) to THF (0.30 mL) at −78 ° C. under argon atmosphere, Compound 2 (45.8 mg, 0.119 mmol) in THF (0.60 mL) ) The solution was added. Subsequently, a THF (0.60 mL) solution of the crude material was added dropwise to the mixture, followed by stirring at −78 ° C. for 5 minutes. Thereafter, MeOH was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was roughly purified by column chromatography (silica gel 8.8 g, hexane: EtOAc = 5: 1) to obtain a crude material containing Compound 76.

Subsequently, DMP (68.7 mg, 0.162 mmol) was added to a CH ₂ Cl ₂ (1.1 mL) solution of the crude material under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes. Thereafter, the reaction was quenched adding a saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO _3. The reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 8.4 g, hexane: EtOAc = 15: 1) to give colorless oil 77 (19.3 mg, 3 steps, 26%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.76 (dd, 2H, J = 1.6, 8.0 Hz, Ar), 7.72 (d, 1H, J = 8.0 Hz, Ar), 7.63 (s, 1H, Ar) , 7.45-7.38 (m, 2H, Ar), 7.34 (dd, 1H, J = 1.6, 8.0 Hz, Ar), 5.46 (d, 1H, J = 6.0 Hz, 1/2 CH ₃ OC [H ₂ ] O ), 5.39 (d, 1H, J = 6.0 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.27 (d, 1H, J = 6.0 Hz, 1/2 CH ₃ OC [H ₂ ] O), 5.22 (d, 1H, J = 6.0 H
z, 1/2 CH ₃ OC [H ₂ ] O), 4.15 (ddd, 1H, J = 2.8, 6.8, 8.4 Hz, C [H] Cl), 3.91 (s, 3H, ArOC [H ₃ ]), 3.73-3.67 (m, 1H, ArC (= O) C [H]) 3.67 (s, 3H, ArOC [H ₃ ]), 3.66 (dd, 1H, J
= 6.8, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.57 (dd, 1H, J = 8.4, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.44 (s, 3H, C [H ₃ ] OCH ₂ O), 3.41 (s, 3H, C [H ₃ ] OCH ₂ O), 3.30 (dd, 1H, J = 6.8, 14.0 Hz,
1/2 C [H ₂ ] naphthyl), 2.81 (dd, 1H, J = 6.8, 14.0 Hz, 1/2 C [H ₂ ] naphthyl), 2.33-2.27 (m, 1H, CH ₃ C [H]) , 1.90 (ddd, 1H, J = 6.0, 8.4, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.60
(ddd, 1H, J = 6.0, 8.4, 14.0 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.82 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [ M + Na] ⁺ calculated value: C ₂₉ H ₃₅ Cl ₂ NNaO ₇ 602.1688, found: 602.1687.

Preparation Example 7-7: (2R, 4S, 5R) -5,6-Dichloro-1- (5,6-dimethoxy-2,4-bis (hydroxy) pyridin-3-yl) -4-methyl-2- Synthesis of (naphthalen-2-ylmethyl) hexane-1-one (A5-007)

To a solution of compound 77 (10.6 mg, 0.0183 mmol) in CH ₂ Cl ₂ (0.18 mL) was added TFA (0.18 mL) at 0 ° C. The resulting mixture was stirred for 5 minutes. Thereafter, saturated NaHCO ₃ aqueous solution was added to stop the reaction. The reaction was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The obtained residue was purified by column chromatography (silica gel 7.0 g, hexane: EtOAc
= 3: 1) By purification, colorless and transparent oily substance A5-007 (9.0 mg, quantitative) could be obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.76 (dd, 2H, J = 2.0, 6.8 Hz, Ar), 7.72, (d, 1H, J
= 8.8 Hz, Ar), 7.64 (s, 1H, Ar), 7.44-7.37 (m, 3H, Ar), 4.77 (m, 1H, ArC (= O) C [H]), 4.19 (ddd, 1H, J = 2.8, 6.4, 9.2 Hz, C [H] Cl), 4.08 (s, 3H, ArOC [H ₃ ]), 3.75 (s, 3H, ArOC [H ₃ ]), 3.66 (dd, 1H, J = 6.4, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.56 (dd, 1H, J = 9.2, 11.2 Hz, 1/2 C [H ₂ ] Cl), 3.24 (dd, 1H, J = 6.4, 13.6 Hz, 1/2 C [H ₂ ] naphthyl), 2.83 (dd, 1H, J = 6.4, 13.6 Hz, 1/2 C [H ₂ ] naphthyl), 2.17-2.12 (m, 1H, CH ₃ C [ H]), 1.66 (ddd, 1H, J = 4.8, 8.8, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 1.64 (ddd, 1H, J = 4.8,
8.8, 13.6 Hz, 1/2 C [H ₂ ] CHCH ₃ ), 0.89 (d, 3H, J = 6.4 Hz, C [H ₃ ] CH); HRMS (ESI) [M + Na] ⁺ Calculation of the following formula _{value: C 25 H 27 Cl 2 NNaO} 5 514.1164, Found: 514.1152.

<I. Pharmacological studies of new compounds>
[Test Example 1: Electron transport complex II inhibitory activity test]
About the compound manufactured by the said procedure, the complex II inhibitory activity of the electron transport system was investigated by the following procedure.

[Method for preparing complex II enzyme protein]
The mitochondrial fraction containing the complex II derived from Ascaris laevis used for the measurement of NADH-fumarate reductase inhibitory activity is described in Kita et al. (Kita et al., Biochim. Biophys. Acta, 2004, 1680, p. 97-103). The mitochondrial fraction containing the complex II derived from bovine heart used for the measurement of succinic acid-ubiquinone reductase inhibitory activity was obtained from Kuwabara et al. (Kuwabara et al., Eur. J. Biochem. 2000, Vol. 267, p. 2538-2546).

[Method for measuring NADH-fumarate reductase inhibitory activity]
The inhibitory activity against the complex II derived from adult swine worms was measured as NADH-fumarate reductase inhibitory activity. A degassed 50 mM potassium phosphate buffer (pH 7.4) was placed in a quartz cuvette so that the total amount of the reaction solution was 1 mL. The quartz cuvette was then loaded with 200 nM antimycin A, 100 μg / mL glucose oxidase (20,000 units / mg), 2 μg / ml.
The mitochondrial fraction containing catalase (10,000 units / mg), 10 mM β-D-glucose, and the complex II derived from adult swineworm prepared by the above method was added and mixed by inversion. Then, each Example compound or Comparative Example compound having a predetermined concentration was added to the reaction solution, and further mixed by inversion. The reaction was incubated at 25 ° C. for 2 minutes. Thereafter, 50 μM nicotinamide adenine dinucleotide (NADH) was added to the reaction solution and mixed by inversion. The reaction was incubated at 25 ° C. for 3 minutes. Subsequently, 5 mM sodium fumarate was added to the reaction solution to start the enzyme reaction. The change in absorbance of NADH in the reaction solution was measured at 340 nm. For each example compound and comparative example compound, a dose response curve regarding NADH-fumarate reductase inhibitory activity was prepared, and 50% inhibitory activity concentration (IC ₅₀ value) of each example compound and comparative example compound was calculated.

[Method for measuring succinic acid-ubiquinone reductase inhibitory activity]
Inhibitory activity against bovine heart-derived complex II was measured as succinate-ubiquinone reductase inhibitory activity. A 50 mM potassium phosphate buffer (pH 7.4) containing 0.1% sucrose laurate and 60 μM ubiquinone was placed in a quartz cuvette so that the total amount of the reaction solution was 1 mL. Next, to this quartz cuvette, 200 nM antimycin A and a mitochondrial fraction (complex II) containing complex II derived from bovine heart prepared by the above method were added and mixed by inversion. Then, each Example compound or Comparative Example compound having a predetermined concentration was added to the reaction solution, and further mixed by inversion. The reaction was incubated at 25 ° C. for 3 minutes. Then, add 10 mM to the reaction solution.
Enzymatic reaction was started by adding sodium succinate. The change in absorbance of ubiquinone in the reaction solution was measured at 278 nm. For each Example compound and Comparative Example compound, a dose response curve regarding succinic acid-ubiquinone reductase inhibitory activity was prepared, and the 50% inhibitory activity concentration (IC ₅₀ value) of each Example compound and Comparative Example compound was calculated.

According to the above procedure, each compound of each example or comparative example IC for complex II activity (NADH-fumarate reductase activity) derived from Ascaris swine or complex II activity (succinate-ubiquinone reductase activity) derived from bovine heart ₅₀ values were determined. Moreover, the seed selectivity of the complex II inhibitory activity of each example compound or comparative example compound was calculated based on the following formula. The results are shown in Table 1.

As shown in Table 1, the Example compounds not only have an inhibitory activity against the complex II derived from swine ascaris, but also have a greater inhibitory activity against the complex II derived from bovine heart compared to the inhibitory activity of atopenin A5. Declined. As a result, it was revealed that all of the example compounds have high species selectivity as compared to atopenin A5. From the above results, it was clarified that the compound of the present invention having complex II inhibitory activity with high species selectivity against parasites can be produced by synthetic means without using atopenin A5 which is a natural product as a raw material.

  In addition, this invention is not limited to an above-described Example, Various modifications are included. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Moreover, it is possible to add, delete, and / or replace another configuration with respect to a part of the configuration of each embodiment.

Claims (10)

Formula (I):

[Where:
R ¹ is benzyl, 4-phenylbenzyl, 2-methylbenzyl or 3-methylbenzyl ,
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, Or substituted or unsubstituted heteroarylalkyl,
R ³ and R ⁴ are independently of each other hydrogen, halogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, Substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryloxy, or substituted or unsubstituted heteroarylalkyloxy,
X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are independently of each other oxygen or sulfur;
R ^{1 ′} and R ^{2 ′} are, independently of one another, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl,
R ^{3 ′} and R ^{4 ′} , independently of one another, are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. ]
Or a salt thereof, or a solvate thereof. The compound according to claim 1, wherein R ² is substituted or unsubstituted alkyl, and R ³ and R ⁴ are independently of each other a halogen selected from the group consisting of chlorine, bromine, fluorine and iodine. . X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are oxygen, R ^{1 ′} and R ^{2 ′} are hydrogen, and R ^{3 ′} and R ^{4 ′} are independently substituted or non-substituted The compound according to claim 1 or 2 , which is substituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. A method for producing the compound according to any one of claims 1 to 3 , comprising:
Formula (III):

[Where:
X ^{1 ′} , X ^{2 ′} , X ^{3 ′} , X ^{4 ′} , R ^{1 ′} , R ^{2 ′} , R ^{3 ′} and R ^{4 ′} have the same definition as defined in any one of claims 1 to 3. Yes,
Y ^{1 ′} is hydrogen or a halogen selected from the group consisting of chlorine, bromine, fluorine and iodine. ]
A compound represented by formula (IV):

[Wherein, R ¹ , R ² , R ³ and R ⁴ have the same definitions as in any one of claims 1 to 3 . And a compound represented by formula (II):

[Wherein X ^{1 ′} , X ^{2 ′} , X ^{3 ′} , X ^{4 ′} , R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , R ^{4 ′} , R ¹ , R ² , R ³ and R ⁴ are claimed It is synonymous with the definition of any one of claim | item 1-3 . ]
And a condensation step for obtaining a compound represented by formula (II); and an oxidation step for obtaining a compound represented by formula (I) by oxidizing a compound represented by formula (II). The antiparasitic agent which contains the compound or its salt of any one of Claims 1-3 , or those solvates as an active ingredient. A pharmaceutical comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. A medicament comprising the compound according to any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable carriers. Composition. Malaria, dysentery amoebic disease, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, roundworm, helminthiasis, trichinosis, lymphatic filariasis (elephroderma), onchocerciasis and schistosomiasis 7. The medicament according to claim 6 , for use in the prevention or treatment of one or more diseases or symptoms selected from the group consisting of diseases. Malaria, dysentery amoebic disease, African trypanosomiasis (sleeping disease), American trypanosomiasis (Chagas disease), leishmaniasis, roundworm, helminthiasis, trichinosis, lymphatic filariasis (elephroderma), onchocerciasis and schistosomiasis 8. The pharmaceutical composition according to claim 7 , for use in the prevention or treatment of one or more diseases or symptoms selected from the group consisting of diseases. 4. An electron transport complex II inhibitor comprising the compound according to any one of claims 1 to 3 or a salt thereof, or a solvate thereof as an active ingredient.