Production method for glycolipid derivatives, synthetic intermediates for same, and crystals of same

Abstract

The present invention provides a production method for a compound represented by formula (XIII) that includes a step for reacting a compound represented by formula (VIII) with a compound represented by formula (XX) to obtain a compound represented by formula (IX), a step for reacting the compound represented by formula (IX) with a compound represented by formula (X) to obtain a compound represented by formula (XI), a step for removing the acetal protecting group from the compound represented by formula (XI) to obtain a compound represented by formula (XII), and a step for removing the protecting group R6 from the compound represented by formula (XII). (In the formulas, R1 is a substituted or unsubstituted C1–35 chain alkyl group or the like, R3 and R4 are a hydrogen atom or the like, R5 is a substituted or unsubstituted C1–35 alkyl group or the like, and R6 is a benzyl group or the like.)

Description

Method for producing glycolipid derivatives, their synthetic intermediates, and their crystals

[0001] The present disclosure relates to a method for producing glycolipid derivatives, their synthetic intermediates, and crystalline forms thereof.

[0002] Autoimmune diseases are mainly classified into systemic autoimmune diseases and organ-specific autoimmune diseases. Organ-specific autoimmune diseases are diseases that cause chronic inflammation in specific organs or tissues (brain, liver, eyes, joints), and are thought to be caused by an immune response (autoimmune response) to autoantigens specific to that organ. Representative organ-specific autoimmune diseases include multiple sclerosis (brain, spinal cord) and rheumatoid arthritis (joints). Although the organs affected are different, these diseases have many things in common, and their treatment methods are basically the same. Furthermore, in many of these diseases, T cells that produce IFN-γ play an important role.

[0003] The compound represented by formula (A) is a glycolipid also known as (2S,3S,4R)-1-O-(α-D-galactosyl)-2-(N-tetracosanoylamino)-1,3,4-nonanetriol or OCH, and is a type of α-galactosylceramide. The compound represented by formula (A) is known to stimulate NKT cells to selectively induce the production of IL-4 (see Patent Document 1).

[0004] The compound represented by formula (A) has the activity of controlling the suppression of Th1 cell immune responses through IL-4 production, and is effective in preventing and / or treating EAE (experimental autoimmune encephalomyelitis), which is characterized by autoimmune central nervous system inflammation (see Non-Patent Document 1). Furthermore, Patent Documents 3 and 4 have reported that the compound represented by formula (A) induces preferential production of Th2 cytokines in human NKT cells (see Non-Patent Document 2), and reduces the proliferation of activated T cells capable of producing GM-CSF and / or their GM-CSF production ability, thereby shifting the Th1 / Th2 immune balance toward an increase in Th2. Furthermore, it has been reported that the compound represented by formula (A) alleviates the late EAE pathology without increasing the production of IL-17 and IFN-γ when administered to NR4A2-deficient mice in which monophasic EAE has been induced. Here, NR4A2-deficient mice are an animal model in which the symptoms of the relapsing-remitting phase of progressive autoimmune disease (corresponding to early EAE pathology) disappear. Early EAE pathology is thought to correspond to the symptoms of relapsing-remitting multiple sclerosis (RRMS), while late EAE pathology is thought to correspond to the symptoms of progressive multiple sclerosis (e.g., primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS)).

[0005] Japanese Patent No. 4064346 Japanese Patent No. 4742220 Japanese Patent No. 6202339 International Publication No. 2015 / 174278 International Publication No. 2022 / 097287

[0006] Miyamoto K et al. 2001, Nature, 413: 531-534.Araki M. et al., 2008, Current Medicinal Chemistry, 15: 2337-2345.

[0007] The compound represented by formula (A) can be produced by the method described in Patent Document 2, but this method requires the use of a stoichiometric amount of an azidation agent (e.g., sodium azide). Reagents such as sodium azide are toxic and explosive, which raises concerns about the environmental and physical burden on workers. Furthermore, this method involves multiple steps, making it unsuitable for commercial-scale production. Therefore, the present disclosure aims to provide a new method for producing the compound represented by formula (A) that requires fewer steps and requires less use of highly toxic and explosive reagents.

[0008] The present disclosure provides the following [1] to

[29] : [1] Formula (VIII) (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, R ３ and R ４ are the same or different and are a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４ are propylene, butylene or pentylene groups which together form a cyclic structure with the carbon atom to which they are attached.) (In the formula, R ５ is a substituted or unsubstituted alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, to obtain a compound represented by formula (IX): (In the formula, R １ , R ３ , R ４ and R ５ is as defined above), and a step of obtaining a compound represented by formula (IX) from a compound represented by formula (X) (In the formula, R ６is a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a p-nitrobenzyl group, a diphenylmethyl group, or a di(p-nitrophenyl)methyl group, and Y is a halogen atom or a methanesulfonyloxy group, to give a compound represented by formula (XI): (In the formula, R １ , R ３ , R ４ , R ５ and R ６ is as defined above), and removing the acetal protecting group from the compound of formula (XI) to obtain a compound of formula (XII): (In the formula, R １ , R ５ and R ６ is as defined above; and removing a protecting group R from a compound represented by formula (XII). ６ and removing the compound of formula (XIII) (In the formula, R １ and R ５ is as defined above. [2] A method for producing a compound represented by formula (VII): (In the formula, R １ , R ３ and R ４ is as defined above.) is hydrolyzed in an aqueous base solution to obtain a compound represented by formula (VIII): (In the formula, R １ , R ３ and R ４ is as defined above. [3] The method according to [1], further comprising a step of obtaining a compound represented by the formula: ２ａ Deprotection of the compound of formula (VI-R) (In the formula, R １ is as defined above, and R ２ａ is a silyl protecting group or a carbamate protecting group. (In the formula, R １ , R ３ and R ４is as defined above, or a step of converting the two hydroxyl groups into a compound represented by formula (VI-H): (In the formula, R １ is as defined above.) with a compound represented by formula (VII) (In the formula, R １ , R ３ and R ４ is as defined above. [4] The method according to [2], further comprising a step of converting a compound represented by formula (V-R): (In the formula, R １ and R ２ａ is as defined above.) is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, and (3) with a permanganate compound to obtain a compound represented by formula (VI-R) (In the formula, R １ and R ２ａ [5] The method according to [3], comprising a step of obtaining a compound represented by formula (IV): (In the formula, R １ is as defined above), and without isolating the compound, the compound is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (1) with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound to obtain a compound represented by formula (VI-H) (In the formula, R １ [6] The method according to [3], comprising a step of obtaining a compound represented by formula (IV): (In the formula, R １is as defined above), and a nitrogen atom of a compound represented by the formula (VR) (In the formula, R １ and R ２ａ is as defined above. [7] The method according to [4], comprising a step of obtaining a compound represented by formula (III): (In the formula, R １ is as defined above, and Boc is a tert-butoxycarbonyl group), with an alkali metal alkoxide, and without isolating the product, protecting the amino group with a protecting group Boc, to prepare a compound represented by formula (V-Boc) (In the formula, R １ and Boc are as defined above. [8] The method according to [4], comprising a step of obtaining a compound represented by formula (III): (In the formula, R １ and Boc are as defined above), to react a compound represented by formula (IV): (In the formula, R １ is as defined above. [9] The method according to [5] or [6], further comprising a step of obtaining a compound represented by formula (I): (wherein Boc is as defined above) with a compound represented by formula (XXX) (In the formula, R １ is as defined above, and X is a halogen atom, to give a compound represented by formula (II): (Wherein, Boc and R １ is as defined above, and reacting the compound represented by formula (II) with p-toluenesulfonic acid to obtain a compound represented by formula (III): (Wherein, Boc and R １ is as defined above.

[10] A compound represented by formula (VR): (In the formula, R １is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, R ２ａ is a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc), wherein R ２ａ is a tert-butoxycarbonyl group (Boc), R １ is not an unsubstituted chain alkyl group having 1, 4 or 14 carbon atoms, an unsubstituted aryl group having 6 carbon atoms, or an unsubstituted aralkyl group having 7 carbon atoms. １ is an alkyl group having 5 carbon atoms, R ２ａ is a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc).)

[11] A compound represented by formula (VI): (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, R ２ is a hydrogen atom or R ２ａ and R ２ａis a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc), with the proviso that R １ is an unsubstituted chain alkyl group having 3, 4, or 14 carbon atoms, or a substituted chain alkyl group having 1, 2, or 10 carbon atoms, R ２ is not a hydrogen atom. １ is an alkyl group having 5 carbon atoms, R ２ is a hydrogen atom or R ２ａ and R ２ａ is a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc).

[12] A compound represented by formula (VII): (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, R ３ and R ４ are the same or different and are a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４are propylene, butylene, or pentylene groups that together form a cyclic structure with the carbon atoms to which they are attached, provided that R ３ and R ４ are the same or different and are unsubstituted alkyl groups having 1 to 6 carbon atoms, R １ is a substituted or unsubstituted linear alkyl group having 5 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, ３ and R ４ are propylene, butylene, or pentylene groups that together form a cyclic structure with the carbon atoms to which they are attached, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms.)

[13] A compound represented by formula (VIII): (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, R ３ and R ４ are the same or different and are a hydrogen atom, a substituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４ are propylene, butylene, or pentylene groups that together form a cyclic structure with the carbon atoms to which they are attached, provided that R ３ and R ４ are the same or different and are unsubstituted alkyl groups having 1 to 6 carbon atoms, R １ is an unsubstituted linear alkyl group having 5 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, ３ and R４ are propylene, butylene, or pentylene groups that together form a cyclic structure with the carbon atoms to which they are attached, R １ is a hydrogen atom, a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms.)

[14] Formula (VIII) (In the formula, R １ , R ３ and R ４ is as defined above.) with a compound represented by formula (XX) (In the formula, R ５ is as defined above) to produce a compound represented by formula (IX): (In the formula, R １ , R ３ , R ４ and R ５ is as defined above.

[15] A method for producing a compound represented by formula (IX), comprising a step of obtaining a compound represented by formula (VII) in a mixed solvent of water and an alcohol-based organic solvent. (In the formula, R １ , R ３ and R ４ is as defined above) with an alkali metal hydroxide to obtain a compound represented by formula (VIII): (In the formula, R １ , R ３ and R ４ is as defined above.

[16] A method for producing a compound represented by formula (VIII), comprising a step of obtaining a compound represented by formula (VIII): ２ is R ２ａ (R ２ and R ２ａ is as defined above), the compound represented by formula (VI) can be obtained by deprotection. (In the formula, R １ and R ２ is as defined above.) with a compound represented by formula (VII) (In the formula, R １ , R３ and R ４ is as defined above.

[17] A method for producing a compound represented by formula (VII), comprising a step of converting a compound represented by formula (V-R) (In the formula, R １ and R ２ａ is as defined above.) is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound to obtain a compound represented by formula (VI-R) (In the formula, R １ and R ２ａ is as defined above.

[18] A method for producing a compound represented by formula (VI-R), comprising a step of obtaining a compound represented by formula (IV): (In the formula, R １ is as defined above.) ２ａ and protecting the compound represented by formula (VR) (In the formula, R １ and R ２ａ is as defined above.

[19] A method for producing a compound represented by formula (V-R), comprising a step of obtaining a compound represented by formula (IV): (In the formula, R １ is as defined above), and without isolating the compound, the compound is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (1) with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound to obtain a compound represented by formula (VI-H) (In the formula, R １is as defined above.

[20] A method for producing a compound represented by formula (VI-H), comprising a step of obtaining a compound represented by formula (III): (In the formula, R １ and Boc are as defined above) with an alkali metal alkoxide, and without isolating the product, the amino group is protected with a protecting group Boc to obtain a compound represented by the formula (V-Boc): (In the formula, R １ and Boc are as defined above.

[21] A method for producing a compound represented by formula (V-Boc), comprising a step of obtaining a compound represented by formula (VII): (In the formula, R １ , R ３ and R ４ is as defined above) with an alkali metal hydroxide to obtain a compound represented by formula (VIII): (In the formula, R １ , R ３ and R ４ is as defined above), and reacting the compound represented by formula (VIII) with a compound represented by formula (XX) (In the formula, R ５ is as defined above, with a compound represented by formula (IX) (In the formula, R １ , R ３ , R ４ and R ５ is as defined above.

[22] A method for producing a compound represented by the formula: ２a Deprotection of the compound of formula (VI-R) (In the formula, R １ and R ２ａ is as defined above.) with a compound represented by formula (VII) (In the formula, R １ , R ３ and R ４is as defined above, or a step of converting the two hydroxyl groups into a compound represented by formula (VI-H): (In the formula, R １ is as defined above.) with a compound represented by formula (VII) (In the formula, R １ , R ３ and R ４ is as defined above.

[23] The method according to

[21] , comprising a step of converting a compound represented by formula (V-R): (In the formula, R １ and R ２ａ is as defined above.) is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound to obtain a compound represented by formula (VI-R) (In the formula, R １ and R ２ａ

[24] The method according to

[22] , further comprising a step of obtaining a compound represented by formula (IV): (In the formula, R １ is as defined above), and without isolating the compound, the compound is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (1) with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound to obtain a compound represented by formula (VI-H) (In the formula, R １

[25] The method according to

[22] , comprising a step of obtaining a compound represented by formula (IV): (In the formula, R １is as defined above.) ２ａ and protecting the compound represented by formula (VR) (In the formula, R １ and R ２ａ is as defined above.

[26] The method according to

[23] , further comprising a step of obtaining a compound represented by formula (III): (In the formula, R １ and Boc are as defined above) with an alkali metal alkoxide, and without isolating the product, protecting the amino group with a protecting group Boc, to produce a compound represented by formula (V-Boc) (In the formula, R １ and Boc are as defined above.

[27] The method according to

[23] , comprising a step of obtaining a compound represented by formula (III): (In the formula, R １ and Boc are as defined above) with an alkali metal alkoxide to obtain a compound represented by formula (IV): (In the formula, R １ is as defined above.

[28] The method according to

[24] or

[25] , comprising a step of obtaining a compound represented by formula (I): (wherein Boc is as defined above) with a compound represented by formula (XXX) (In the formula, R １ and X are as defined above, to give a compound represented by formula (II): (In the formula, R １ and Boc are as defined above; and reacting the compound of formula (II) with p-toluenesulfonic acid or pyridinium p-toluenesulfonate to obtain a compound of formula (III): (In the formula, R １and Boc are as defined above.

[29] A crystal of a compound represented by the following formula (A): A type A crystal, which shows peaks at diffraction angles (2θ) of 4.8°, 6.4°, 19.0°, and 21.3° in a powder X-ray diffraction pattern:

[0009] According to the present disclosure, it is possible to provide a novel method for producing a compound represented by formula (A) which involves fewer steps and requires less amount of highly toxic and explosive reagents.

[0010] FIG. 1 is a diagram showing the powder X-ray diffraction pattern of the compound represented by formula (A).

[0011] The embodiments of the present disclosure are described in detail below.

[0012] As used herein, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0013] In this specification, formula (V) is described as formula (V-H), formula (VR), or formula (V-Boc) depending on the type of substituent on the nitrogen atom constituting the oxazolidinone ring in the formula. For example, among the compounds represented by formula (V), when a hydrogen atom is bonded to the nitrogen atom constituting the oxazolidinone ring, it is represented by formula (V-H), and when a protecting group R ２ａ is bonded, it is represented by the formula (VR), and particularly when Boc is bonded (i.e., R ２ａ =Boc) may be represented by the formula (V-Boc). The same applies to formula (VI).

[0014] In this specification, the amount of component B used may be specified as a volume based on the amount (weight) of component A used. When the amount of component B used is 10 times the volume of the amount (weight) of component A used, if the amount of component A used is 1 g, the amount of component B used is 10 mL.

[0015] As used herein, "substituted" means "substituted." Unless otherwise specified, the position and number of substituents are optional and are not particularly limited. When substituted with two or more substituents, the substituents may be the same or different. Examples of the substituent include a halogen atom, a nitro group, a cyano group, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms, an alkynyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group, an alkenyl group having 1 to 6 carbon atoms substituted with a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms substituted with a hydroxyl group, an alkoxyalkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, an alkenyl group having 1 to 6 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom, an alkylthio group having 1 to 6 carbon atoms substituted with a halogen atom, an amino group, an alkylamino group having 1 to 6 carbon atoms, an alkylaminocarbonyl group having 1 to 6 carbon atoms, Examples of such alkyl groups include a carboxy group, an alkyloxycarbonyl group having 1 to 6 carbon atoms, a carbamoyl group, an alkanoyl group having 1 to 6 carbon atoms, an aroyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a sulfamoyl group, an ammonium group, an aryl group, a heterocyclic group, an alkyl group having 1 to 6 carbon atoms substituted with an aryl group, an alkyl group having 1 to 6 carbon atoms substituted with a heterocycle, an aryloxy group, a heterocyclic oxy group, an arylsulfonyl group, a heterocyclic sulfonyl group, a dihydroxyboryl group, an alkyl group having 1 to 6 carbon atoms substituted with an alkylamino group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms substituted with an aryl group, an alkenyloxy group having 1 to 6 carbon atoms, an acyloxy group having 1 to 6 carbon atoms, and an acylamino group having 1 to 6 carbon atoms.

[0016] [First Embodiment] The first embodiment of the present disclosure is a method for producing a compound represented by formula (XIII), and also has an aspect of a method for producing each synthetic intermediate. The following scheme shows an outline of the method for synthesizing a compound represented by formula (XIII) from a compound represented by formula (VIII).

[0017] In formulas (VIII) to (XIII), R １ represents a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, preferably a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, more preferably an unsubstituted linear alkyl group having 1 to 35 carbon atoms, and even more preferably an unsubstituted linear alkyl group having 5 carbon atoms.

[0018] In formulas (VIII) to (XI), R ３ and R ４ may be the same or different and are a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４ are propylene, butylene, or pentylene groups which together form a cyclic structure with the carbon atoms to which they are attached, and are preferably a hydrogen atom or a substituted or unsubstituted chain alkyl group having 1 to 10 carbon atoms, more preferably an unsubstituted chain alkyl group having 1 to 10 carbon atoms, and even more preferably an unsubstituted chain alkyl group having 1 or 2 carbon atoms.

[0019] In formula (XX) and formulas (IX) to (XIII), R ５ represents a substituted or unsubstituted alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, preferably a substituted or unsubstituted chain alkyl group having 1 to 35 carbon atoms, more preferably an unsubstituted chain alkyl group having 1 to 35 carbon atoms, and even more preferably an unsubstituted chain alkyl group having 23 carbon atoms.

[0020] In formulas (X) to (XII), R ６is a benzyl group or naphthyl group having multiple substituents on the aromatic ring (specifically, a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a p-nitrobenzyl group, a diphenylmethyl group, or a di(p-nitrophenyl)methyl group), preferably a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, or a p-nitrobenzyl group, more preferably a benzyl group or a p-methoxybenzyl group, and even more preferably a benzyl group.

[0021] Y is a halogen atom or a sulfonyloxy group such as a methanesulfonyloxy group, preferably a halogen atom, more preferably a fluorine atom, a chlorine atom, or a bromine atom, and even more preferably a chlorine atom.

[0022] Specific examples of the aryl group having 6 to 14 carbon atoms include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and a biphenyl group.

[0023] Specific examples of the aralkyl group having 7 to 20 carbon atoms include a benzyl group, a diphenylmethyl group, a trityl group, a phenethyl group, a 3-phenylpropyl group, a 2-phenylpropyl group, a 4-phenylbutyl group, a biphenylmethyl group, and a naphthylmethyl group.

[0024] Step 8 is a step of reacting a compound represented by formula (VIII) with a compound represented by formula (XX) to obtain a compound represented by formula (IX). １ , R ３ , R ４ and R ５ is as defined above.

[0025] In step 8, the compound represented by formula (XX) is reacted with an activating agent or a condensing agent to activate the carboxy group, and then an amide bond is formed between the carboxy group and the amino group of the compound represented by formula (VIII).

[0026] The activating agent used in step 8 may be any reagent capable of converting a carboxylic acid into the corresponding acid chloride. Examples of the activating agent include oxalyl chloride and thionyl chloride. After mixing the carboxylic acid and the activating agent, a small amount of DMF is added to convert the carboxylic acid into the acid chloride. The amount of the activating agent used in step 8 may be 1.0 to 5.0 mol, preferably 1.0 to 1.5 mol, per 1 mol of the compound represented by formula (VIII).

[0027] Examples of the condensing agent include carbodiimide condensing agents such as N,N'-dicyclohexylcarbodiimide (DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI or WSC), Oxyma, HATU, bromotripyrrolidinophosphonium hexafluorophosphate, and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). The amount of the condensing agent used may be 1.0 to 5.0 moles, preferably 1.0 to 1.5 moles, relative to 1 mole of the compound represented by formula (VIII).

[0028] When an activator is used, an additive such as an amine such as triethylamine, pyridine, or 4-dimethylaminopyridine (DMAP), or a hydroxybenzotriazole such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) may be further added to accelerate the reaction. The amount of the additive used may be 0.1 to 3.0 mol, preferably 0.5 to 1.5 mol, relative to 1 mol of the compound represented by formula (VIII).

[0029] Step 8 is preferably carried out in an organic solvent. The organic solvent may be any solvent that does not interfere with the condensation of the carboxylic acid and the amine, and examples thereof include aromatic hydrocarbons such as toluene and xylene. Toluene or xylene is preferred, and toluene is more preferred. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the volume (weight) of the compound represented by formula (VIII) used.

[0030] Step 9 is a step of obtaining a compound represented by formula (XI) from a compound represented by formula (IX). １ , R ３ , R ４ , R ５ , R ６ and Y are as defined above.

[0031] In step 9', an activating agent such as oxalyl chloride, thionyl chloride, methanesulfonyl chloride, etc. is added to a compound represented by formula (X') to produce a compound represented by formula (X). In step 9, a glycosidic bond is formed between a compound represented by formula (IX) and a compound represented by formula (X).

[0032] The reagent used in step 9 may be any reagent capable of converting a hydroxyl group into a substituent with high leaving ability in order to proceed with glycosylation. Examples of activating agents include oxalyl chloride, thionyl chloride, and methanesulfonyl chloride. After mixing the galactose derivative with the activating agent, a small amount of DMF is added, thereby converting the galactose derivative into a compound represented by formula (X). The amount of activating agent used in step 9' may be 1.0 to 5.0 mol, preferably 1.5 to 2.0 mol, per 1 mol of the compound represented by formula (X).

[0033] Step 9 and Step 9' are preferably carried out in an organic solvent. The organic solvent may be any organic solvent that does not interfere with the glycosylation of the hydroxyl group, and examples thereof include aromatic hydrocarbons such as toluene and xylene, and ether-based organic solvents such as cyclopentyl methyl ether. The amount of organic solvent used in Step 9 and Step 9' may be 5 to 50 times, and preferably 5 to 10 times, the amount (by weight) of the compound represented by formula (IX) used.

[0034] Step 10 is a step of obtaining a compound represented by formula (XII) from a compound represented by formula (XI). １ , R ３ , R ４ , R ５ and R ６ is as defined above.

[0035] In step 10, the acetal protecting group of the compound represented by formula (XI) is removed to produce a compound represented by formula (XII). The acetal protecting group can usually be removed under protic acidic conditions.

[0036] Examples of acids that can be used include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and carboxylic acids such as formic acid and acetic acid. Acids that form salts with organic amines such as pyridine may also be used. Examples of such salts include pyridinium p-toluenesulfonate. The amount of acid used may be 0.01 mol to 100 mol, preferably 0.1 mol to 1.0 mol, per 1 mol of the compound represented by formula (XI).

[0037] Step 10 is preferably carried out in a hydrophilic organic solvent or water. Examples of the hydrophilic organic solvent include alcoholic organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol, and nitrile solvents such as acetonitrile and propionitrile. The amount of the hydrophilic organic solvent used may be 20 to 100 times, and preferably 30 to 50 times, the volume (weight) of the compound represented by formula (XI) used.

[0038] To accelerate the reaction, the reaction mixture may be heated.

[0039] Step 11 is a step of obtaining a compound represented by formula (XIII) from a compound represented by formula (XII). １ , R ５ and R ６ is as defined above.

[0040] In step 11, the protecting group R of the compound represented by formula (XII) is ６ to give a compound of formula (XIII). Benzylic protecting groups can usually be removed under protic acidic conditions or hydrogenolysis conditions.

[0041] When the reaction is carried out under acidic conditions, examples of acids that can be used include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and carboxylic acids such as formic acid and acetic acid. Acids that form salts with organic amines such as pyridine may also be used. Examples of such salts include pyridinium p-toluenesulfonate. The amount of acid used may be 0.01 to 100 moles, preferably 0.1 to 1 mole, per mole of the compound represented by formula (XII).

[0042] When step 11 is carried out under acidic conditions, it is preferable to carry out the reaction in a hydrophilic organic solvent or water. Examples of the hydrophilic organic solvent include alcoholic organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol, and nitrile solvents such as acetonitrile and propionitrile. The amount of the solvent used may be 20 to 100 times, and preferably 30 to 50 times, the volume (weight) of the compound represented by formula (XII) used. The reaction solution may be heated to promote the reaction.

[0043] When carried out under hydrogenolysis conditions, step 11 involves reacting with hydrogen gas or a hydrogen donor (e.g., 4-methylcyclohexene, formic acid) in the presence of a transition metal catalyst. Examples of transition metal catalysts include palladium on carbon and palladium hydroxide. Acetic acid may be added to the reaction mixture to promote the reaction.

[0044] When hydrogenolysis is performed under these conditions, Step 11 is preferably performed in an organic solvent. Examples of the organic solvent include alcohol-based organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol, nitrile-based solvents such as acetonitrile and propionitrile, and aromatic hydrocarbons such as toluene and xylene. The amount of the solvent used may be 20 to 100 times, and preferably 30 to 50 times, the volume (weight) of the compound represented by formula (XII) used.

[0045] [Alternative Method] Steps 10 and 11 may be performed using a flow synthesis technique utilizing a microreactor. The use of a microreactor can contribute to improving productivity.

[0046] Step 10 of the alternative method is a step of removing the acetal-based protecting group of a compound represented by formula (XI) using a microreactor to produce a compound represented by formula (XII). The compound represented by formula (XI) is dissolved in an organic solvent to prepare solution A. Solution A and acidic solution B are introduced into the microreactor using pumps, respectively, and are joined midway through the flow path, thereby mixing solution A and acidic solution B. Within the flow path of the microreactor, the compound represented by formula (XI) contained in solution A is deprotected by the acid contained in acidic solution B, producing a compound represented by formula (XII), which is then discharged from an outlet. The discharged reaction solution is collected in a container containing an alkaline aqueous solution, or is joined with an alkaline aqueous solution from another flow path.

[0047] The organic solvent used to prepare Solution A may be any organic solvent compatible with water, such as ether-based organic solvents such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and tert-butyl methyl ether; alcohol-based organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol; and nitrile-based solvents such as acetonitrile and propionitrile. The organic solvents described above may be used alone or in combination of two or more. The mixing ratio may be, for example, 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, or 2:1 to 1:2 by volume. A specific example of a mixed solvent is a mixed solvent of tetrahydrofuran and acetonitrile (volume ratio 1:1).

[0048] The concentration of the compound represented by formula (XI) in solution A may be in a range common in the field of organic chemistry, for example, 0.0001 to 0.5 mol / L, 0.001 to 0.1 mol / L, 0.01 to 0.1 mol / L, or 0.01 to 0.05 mol / L.

[0049] The acid used to prepare the acidic solution B may be an organic acid or an inorganic acid. Examples of organic acids include carboxylic acids such as formic acid, acetic acid, and propionic acid, and sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid. Examples of inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid.

[0050] Acidic solution B contains water and an organic solvent in addition to the acid. The organic solvent may be any organic solvent compatible with water, such as ether-based organic solvents such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and tert-butyl methyl ether; alcohol-based organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol; and nitrile-based solvents such as acetonitrile and propionitrile. The organic solvents may be used alone or in combination of two or more. The mixing ratio may be, for example, 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, or 2:1 to 1:2 by volume. From the viewpoint of ease of mixing with solution A, it is preferable to use the same organic solvent as used in preparing solution A.

[0051] The concentration of the acid in acidic solution B may be in a range common in the field of organic chemistry, for example, 0.010 to 10.0 mol / L, 0.10 to 6.0 mol / L, 0.10 to 3.0 mol / L, or 0.10 to 1.0 mol / L.

[0052] The amount of water in the acidic solution B is not particularly limited as long as it is an amount sufficient to deprotect the acetal-based protecting group. When the acid is commercially available as an aqueous solution, that aqueous solution may be used.

[0053] Solution A and acidic solution B are introduced into the microreactor by a pump. The flow rates of each can be set appropriately, and by adjusting the flow rates of the two solutions, the mixing ratio within the flow channel can be adjusted. For example, the flow rate of the flow channel on the solution A side may be set to 1.0 mL / min, and the flow rate of the flow channel on the acidic solution B side may be set to 3.0 mL / min.

[0054] The channel and the reaction solution may be heated or cooled as necessary. In general, the reaction tends to be accelerated by heating the reaction solution and inhibited by cooling. The reaction temperature may be adjusted depending on the reactivity and stability of the compound represented by formula (XI) and the compound represented by formula (XII), the rate of the deprotection reaction, and the boiling point of the organic solvent used. The reaction temperature can be set in the range of -10°C to 100°C, and preferably 0°C to 60°C, 0°C to 55°C, 0°C to 50°C, 5°C to 60°C, 5°C to 55°C, or 5°C to 50°C.

[0055] After flowing through the flow path a distance sufficient for the reaction to proceed, the reaction liquid is discharged from an outlet and collected in a container containing an alkaline aqueous solution. In the flow path of the microreactor, it is preferable to install a cooling device before the outlet. Since the reaction liquid discharged from the outlet is neutralized as well as collected, by cooling the reaction liquid immediately before collection, side reactions due to heat of neutralization can be suppressed. The alkaline aqueous solution may be any aqueous solution that can neutralize the acid contained in acidic solution B. Examples of alkaline aqueous solutions include aqueous ammonia. The collected reaction liquid can be purified according to conventional methods.

[0056] In an alternative method, step 11 is carried out by using a microreactor to remove the protecting group R of the compound represented by formula (XII). ６ to produce a compound represented by formula (XIII).

[0057] In step 11 of the alternative method, a compound represented by formula (XII) is dissolved in an organic solvent to prepare solution C. Solution C is introduced into a microreactor using a pump, and converted into a compound represented by formula (XIII) by hydrogenolysis using a transition metal catalyst installed in the flow channel. The transition metal catalyst may be installed, for example, as a column packed with the transition metal catalyst and a packing material in the flow channel of the microreactor, or may be fixed inside the channel of the microreactor. The packing material can be appropriately selected from Celite (registered trademark), activated carbon, silica gel, cellulose, etc. In the latter case, hydrogen gas can be further introduced into the channel to carry out a three-phase reaction. The protecting group R of the compound represented by formula (XII) contained in solution C is６ is removed by catalytic hydrogen reduction to produce the compound represented by formula (XIII), which is discharged from an outlet.

[0058] The organic solvent used to prepare solution C may be any organic solvent capable of dissolving the compound represented by formula (XII), and examples thereof include ether-based organic solvents such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and tert-butyl methyl ether; alcohol-based organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol; and nitrile-based solvents such as acetonitrile and propionitrile. The organic solvents described above may be used alone or in combination of two or more. The mixing ratio may be, for example, 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, or 2:1 to 1:2 by volume. A specific example of a mixed solvent is a mixed solvent of tetrahydrofuran and ethyl alcohol (volume ratio: 1:1).

[0059] The concentration of the compound represented by formula (XII) in solution C may be in a range common in the field of organic chemistry, for example, 0.0001 to 0.5 mol / L, 0.001 to 0.1 mol / L, 0.01 to 0.1 mol / L, or 0.01 to 0.05 mol / L.

[0060] Examples of the transition metal catalyst used in step 11 include metallic palladium, palladium hydroxide, palladium / carbon, and palladium hydroxide / carbon. In one specific example, palladium / carbon or palladium hydroxide / carbon in which a transition metal catalyst is supported on activated carbon is mixed with a packing material and packed into a column. A hydrogen source is added to Solution C, which is then introduced into the microreactor and passed through the stationary phase in the column. In this case, for example, 4-methylcyclohexene (MCH) can be used as the hydrogen source. In another specific example, a transition metal catalyst is supported on the inner surface of the microreactor channel by coating or the like. In this case, hydrogen gas or 4-methylcyclohexene (MCH) can be used as the hydrogen source.

[0061] The channel and the reaction solution may be heated or cooled as necessary. In general, the reaction tends to be accelerated by heating the reaction solution and inhibited by cooling. The reaction temperature may be adjusted depending on the reactivity and stability of the compound represented by formula (XII) and the compound represented by formula (XIII), the rate of the deprotection reaction, and the boiling point of the organic solvent used. The reaction temperature can be set in the range of 0°C to 100°C, and preferably 10°C to 80°C, 20°C to 75°C, 20°C to 70°C, 25°C to 80°C, 25°C to 75°C, or 25°C to 70°C.

[0062] After flowing through the flow channel for a distance sufficient for the reaction to proceed, the reaction solution is discharged from an outlet and collected in a container. A cooling device may be installed before the outlet in the flow channel of the microreactor. The collected reaction solution can be purified according to conventional methods.

[0063] The following scheme shows an outline of the method for synthesizing a compound represented by formula (VIII) from a compound represented by formula (I).

[0064] In formula (II) to formula (VIII) and formula (XXX), R １ is as defined above.

[0065] In formula (VR) to formula (VI-R), R ２ａ is a silyl protecting group (e.g., trimethylsilyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), tert-Bu (R ７ ) ２ A group represented by Si— (wherein, R ７ is a hydrogen atom, a substituted or unsubstituted chain alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group, and is, for example, a tert-butyldimethylsilyl group (TBDMS, R ７ = methyl group), tert-butyldiphenylsilyl group (TBDPS, R ７= phenyl group), carbamate-based protecting groups (for example, tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), allyloxycarbonyl group (Alloc), 9-fluorenylmethyloxycarbonyl group (Fmoc), 2,2,2-trichloroethoxycarbonyl group (Troc), 2-(trimethylsilyl)ethoxycarbonyl group (Teoc)), preferably a silyl-based protecting group or a carbamate-based protecting group, more preferably tert-Bu(R ７ ) ２ A group represented by Si— (wherein, R ７ is a hydrogen atom, a substituted or unsubstituted chain alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group, and is, for example, a tert-butyldimethylsilyl group (TBDMS, R ７ = methyl group), tert-butyldiphenylsilyl group (TBDPS, R ７ = phenyl group), or a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), or a 9-fluorenylmethyloxycarbonyl group (Fmoc), and more preferably a tert-butyldimethylsilyl group (TBDMS), a tert-butyldiphenylsilyl group (TBDPS), a tert-butoxycarbonyl group (Boc), or a benzyloxycarbonyl group (Cbz).

[0066] In formulas (VII) to (VIII), R ３ and R ４ is as defined above.

[0067] In formulas (I) to (III), Boc is a tert-butoxycarbonyl group.

[0068] In formula (XXX), X is a halogen atom.

[0069] Step 1 is a step of reacting a compound represented by formula (I) with a compound represented by formula (XXX) in the presence of an alkali metal alkoxide to obtain a compound represented by formula (II). １ , Boc and X are as defined above.

[0070] The compound represented by formula (XXX) is a phosphonium salt, which reacts with an alkali metal alkoxide to produce a phosphonium ylide, which reacts with a formyl group to form a carbon-carbon double bond.

[0071] Examples of the alkali metal alkoxide used in Step 1 include sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. The amount of the alkali metal alkoxide used may be 1.0 to 5.0 mol, preferably 1.0 to 1.5 mol, relative to 1 mol of the compound represented by Formula (I).

[0072] Step 1 is preferably carried out in an organic solvent. Examples of the organic solvent include halogenated hydrocarbons such as dichloromethane, aromatic hydrocarbons such as toluene and xylene, and ether-based organic solvents such as diethyl ether, diisopropyl ether, and tetrahydrofuran. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (I) used.

[0073] Step 2 is a step of reacting a compound represented by formula (II) with p-toluenesulfonic acid to obtain a compound represented by formula (III). １ and Boc are as defined above.

[0074] In step 2, the acetal protecting group of the compound represented by formula (II) is removed to produce a compound represented by formula (III). The acetal protecting group can usually be removed under protic acidic conditions.

[0075] The p-toluenesulfonic acid may be pyridinium p-toluenesulfonate. The amount of p-toluenesulfonic acid used may be 0.05 to 10 moles, preferably 0.1 to 1.0 moles, relative to 1 mole of the compound represented by formula (II).

[0076] Step 2 is preferably carried out in a hydrophilic organic solvent or water. Examples of the hydrophilic organic solvent include alcoholic organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol, and nitrile solvents such as acetonitrile and propionitrile. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (II) used.

[0077] To accelerate the reaction, the reaction mixture may be heated.

[0078] Step 3 is a step of reacting a compound represented by formula (III) with an alkali metal alkoxide in an ether-based organic solvent to obtain a compound represented by formula (IV). １ and Boc are as defined above.

[0079] Examples of the alkali metal alkoxide used in step 3 include sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. The amount of the alkali metal alkoxide used may be 1.0 to 5.0 mol, preferably 1.0 to 1.5 mol, per 1 mol of the compound represented by formula (III).

[0080] Step 3 is preferably carried out in a mixed solvent of an ether-based organic solvent and an alcohol-based organic solvent. Examples of ether-based organic solvents include diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and tetrahydrofuran. Examples of alcohol-based organic solvents include methyl alcohol, ethyl alcohol, isopropyl alcohol, and tert-butyl alcohol. The mixing ratio of the ether-based organic solvent and the alcohol-based organic solvent can be set as desired, taking into consideration the solubility of the raw materials. The amount of solvent used may be 5 to 50 times, and preferably 10 to 20 times, the volume (weight) of the compound represented by formula (III) used.

[0081] Step 4 is a step of protecting the amino group of the compound represented by formula (IV) to obtain a compound represented by formula (VR). １ and R ２ａ is as defined above.

[0082] The amino-protecting group is a group that protects the amino group to prevent unexpected reactions during the production process. Examples of the amino-protecting group include silyl-based protecting groups such as tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl, and carbamate-based protecting groups such as benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), and tert-butoxycarbonyl (Boc).

[0083] When protecting with a silyl protecting group, the corresponding silyl chloride can be used as a protecting reagent. Examples of the protecting reagent include tert-butyldimethylchlorosilane, trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane, and tert-butyldiphenylchlorosilane. The amount of the protecting reagent used is 1.0 to 5.0 mol, preferably 1.0 to 2.0 mol, per 1 mol of the compound represented by formula (IV).

[0084] When protecting with a carbamate-based protecting group, the corresponding carbamoyl chloride or dimer can be used as a protecting reagent. Examples of the protecting reagent include benzyloxycarbonyl chloride, allyloxycarbonyl chloride, 9-fluorenylmethyloxycarbonyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, 2-(trimethylsilyl)ethoxycarbonyl chloride, and tert-butoxycarbonyl anhydride. The amount of the protecting reagent used may be 1.0 to 5.0 mol, preferably 1.0 to 2.0 mol, per 1 mol of the compound represented by formula (IV).

[0085] Step 4 is preferably carried out in an organic solvent. Examples of the organic solvent include halogenated hydrocarbons such as dichloromethane, ether-based organic solvents such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and tetrahydrofuran, and aromatic hydrocarbons such as toluene and xylene. The amount of the solvent used may be 5 to 40 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (IV) used.

[0086] One aspect of this embodiment is a compound represented by formula (VR): In the formula (VR), R １ represents a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, preferably a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, more preferably an unsubstituted linear alkyl group having 1 to 35 carbon atoms, and even more preferably an unsubstituted linear alkyl group having 5 carbon atoms. ２ａ is a silyl protecting group (e.g., trimethylsilyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), tert-Bu (R ７ ) ２ A group represented by Si— (wherein, R ７ is a hydrogen atom, a substituted or unsubstituted chain alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group, and is, for example, a tert-butyldimethylsilyl group (TBDMS, R ７ = methyl group), tert-butyldiphenylsilyl group (TBDPS, R ７ = phenyl group), carbamate-based protecting groups (for example, tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), allyloxycarbonyl group (Alloc), 9-fluorenylmethyloxycarbonyl group (Fmoc), 2,2,2-trichloroethoxycarbonyl group (Troc), 2-(trimethylsilyl)ethoxycarbonyl group (Teoc)), preferably a silyl-based protecting group or a carbamate-based protecting group, more preferably tert-Bu(R７ ) ２ A group represented by Si— (wherein, R ７ is a hydrogen atom, a substituted or unsubstituted chain alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group, and is, for example, a tert-butyldimethylsilyl group (TBDMS, R ７ = methyl group), tert-butyldiphenylsilyl group (TBDPS, R ７ = phenyl group), or a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), or a 9-fluorenylmethyloxycarbonyl group (Fmoc), and more preferably a tert-butyldimethylsilyl group (TBDMS), a tert-butyldiphenylsilyl group (TBDPS), a tert-butoxycarbonyl group (Boc), or a benzyloxycarbonyl group (Cbz). ２ａ is a tert-butoxycarbonyl group (Boc), R １ is not an unsubstituted linear alkyl group having 1, 4 or 14 carbon atoms, an unsubstituted aryl group having 6 carbon atoms, or an unsubstituted aralkyl group having 7 carbon atoms. １ represents an alkyl group having 5 carbon atoms, and R ２ａ represents a tert-butoxycarbonyl group (Boc), a tert-butyldimethylsilyl group (TBDMS), or a tert-butyldiphenylsilyl group (TBDPS).

[0087] Step 5 is a step of obtaining a compound represented by formula (VI-R) by any one reaction selected from the following: (1) reacting a compound represented by formula (V-R) with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) reacting a compound represented by formula (V-R) with a mixture of an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, and (3) reacting a compound represented by formula (V-R) with a permanganate compound. １ and R ２ａ is as defined above.

[0088] In step 5, the double bond of compound (V-R) is dihydroxylated to produce compound (VI-R). The dihydroxylation reaction proceeds with a ruthenium-containing compound, an osmium-containing compound, or a permanganate compound. To reoxidize these compounds and proceed through the catalytic cycle, periodic acid or its alkali metal salts, a combination of potassium hexacyanoferrate(III) and potassium carbonate, or N-methylmorpholine-N-oxide can be used.

[0089] An example of a ruthenium-containing compound is ruthenium(III) chloride. The amount of the ruthenium-containing compound used is 0.01 to 5.0 times by weight, preferably 0.05 to 0.3 times by weight, based on the amount (weight) of the compound represented by formula (V-R). The ruthenium-containing compound is reoxidized by adding periodic acid or a salt thereof. An example of a salt of periodic acid is sodium periodate. The amount of periodic acid or a salt thereof used may be 1.0 to 5.0 mol, preferably 1.0 to 2.0 mol, per 1 mol of the compound represented by formula (V).

[0090] When a ruthenium-containing compound is used, Step 5 is preferably carried out in an organic solvent or water. Step 5 may also be carried out in a two-phase system of a hydrophobic organic solvent and water. Examples of organic solvents include ester-based solvents such as ethyl acetate, methyl acetate, and isopropyl acetate; ether-based organic solvents such as cyclopentyl methyl ether; alcohol-based organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol; nitrile-based solvents such as acetonitrile and propionitrile; and halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride. The amount of solvent used may be 5 to 50 times, and preferably 15 to 30 times, the volume (weight) of the compound represented by Formula (V) used.

[0091] Examples of osmium-containing compounds include osmium tetroxide and potassium osmate(VI). The amount of the osmium-containing compound used may be 0.01 to 2.0 mol, preferably 0.05 to 1.2 mol, per mol of the compound represented by formula (V). The osmium-containing compound is reoxidized by adding a combination of potassium hexacyanoferrate(III) and potassium carbonate, or N-methylmorpholine-N-oxide. The amount of potassium hexacyanoferrate(III) used is 2.0 to 10 mol, preferably 2.0 to 4.0 mol, per mol of the compound represented by formula (V). The amount of potassium carbonate used is 2.0 to 10 mol, preferably 2.0 to 4.0 mol, per mol of the compound represented by formula (V). The amount of N-methylmorpholine-N-oxide used may be 2.0 to 10 mol, preferably 2.0 to 4.0 mol, per mol of the compound represented by formula (V).

[0092] When an osmium-containing compound is used, Step 5 is preferably carried out in an organic solvent or water. Step 5 may also be carried out in a two-phase system of a hydrophobic organic solvent and water. Examples of the organic solvent include alcohol-based organic solvents such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and tert-butyl alcohol; nitrile-based solvents such as acetonitrile and propionitrile; and halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (V) used.

[0093] The permanganate compound may be, for example, potassium permanganate. The amount of the permanganate compound used may be 1.0 to 10 mol, preferably 1.0 to 3.0 mol, per 1 mol of the compound represented by formula (V).

[0094] When a permanganate compound is used, Step 5 is preferably carried out in an organic solvent or water. Step 5 may also be carried out in a two-phase system of a hydrophobic organic solvent and water. Examples of the organic solvent include alcohol-based organic solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol; nitrile-based solvents such as acetonitrile and propionitrile; and halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (V) used.

[0095] One aspect of this embodiment is a compound represented by formula (VI): In formula (VI), R １ represents a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group, preferably a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, more preferably an unsubstituted linear alkyl group having 1 to 35 carbon atoms, and even more preferably an unsubstituted linear alkyl group having 5 carbon atoms; R ２ is a hydrogen atom or R ２ａ and R ２ａ is a silyl protecting group (e.g., trimethylsilyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), tert-Bu (R ７ ) ２ A group represented by Si— (wherein, R ７ is a hydrogen atom, a substituted or unsubstituted chain alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group, and is, for example, a tert-butyldimethylsilyl group (TBDMS, R ７ = methyl group), tert-butyldiphenylsilyl group (TBDPS, R ７= phenyl group), carbamate-based protecting groups (for example, tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), allyloxycarbonyl group (Alloc), 9-fluorenylmethyloxycarbonyl group (Fmoc), 2,2,2-trichloroethoxycarbonyl group (Troc), 2-(trimethylsilyl)ethoxycarbonyl group (Teoc)), preferably a silyl-based protecting group or a carbamate-based protecting group, more preferably tert-Bu(R ７ ) ２ A group represented by Si— (wherein, R ７ is a hydrogen atom, a substituted or unsubstituted chain alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group, and is, for example, a tert-butyldimethylsilyl group (TBDMS, R ７ = methyl group), tert-butyldiphenylsilyl group (TBDPS, R ７ = phenyl group), or a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), or a 9-fluorenylmethyloxycarbonyl group (Fmoc), and more preferably a tert-butyldimethylsilyl group (TBDMS), a tert-butyldiphenylsilyl group (TBDPS), a tert-butoxycarbonyl group (Boc), or a benzyloxycarbonyl group (Cbz). Most preferably, R １ represents an alkyl group having 5 carbon atoms, and R ２ represents a tert-butoxycarbonyl group (Boc), a tert-butyldimethylsilyl group (TBDMS), or a tert-butyldiphenylsilyl group (TBDPS).

[0096] However, R ２ is a hydrogen atom, R １ is not a propyl group, an isopropyl group, a tert-butyl group, a tetradecyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 10-hydroxydecyl group, or a 10-((tetrahydro-2H-pyran-2-yl)oxy)decyl group.

[0097] In step 6, a compound represented by formula (VI-R) is protected with an acetal, and then R ２ａto obtain a compound of formula (VII), or R of a compound of formula (VI-R) ２ａ is deprotected and then subjected to acetal protection to obtain a compound represented by formula (VII). １ , R ２ａ , R ３ and R ４ is as defined above.

[0098] In step 6, the two hydroxyl groups of the compound represented by formula (VI-R) are protected with an acetal-based protecting group, and then R ２ａ to form a compound of formula (VII). Alternatively, R ２ａ After deprotection of R, the two hydroxyl groups are protected with acetal-based protecting groups to produce a compound represented by formula (VII). Acetal-based protecting groups can usually be added under protic acidic conditions. ２ａ The silyl group in R can usually be deprotected by fluoride ion. ２ａ The Boc group in the formula (I) can usually be deprotected under acidic conditions.

[0099] Examples of acids that can be used in the acetal-forming reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and carboxylic acids such as formic acid and acetic acid. Acids that form salts with organic amines such as pyridine may also be used. Examples of such salts include pyridinium p-toluenesulfonate. The amount of the acid used may be 0.01 to 20 moles, preferably 0.05 to 10 moles, per mole of the compound represented by formula (VI-R).

[0100] The protecting reagent is preferably added in a solvent that does not inhibit the acetal-forming reaction, and the protecting reagent may be used as the solvent. Examples of the solvent include ether-based organic solvents such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and tetrahydrofuran; nitrile-based solvents such as acetonitrile and propionitrile; halogenated hydrocarbons such as dichloromethane; and aromatic hydrocarbons such as toluene and xylene. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (VI-R) used.

[0101] The protecting reagent may be any reagent capable of forming an acetal. Examples of the protecting reagent include chain ketones such as acetone, ethyl methyl ketone (also known as 2-butanone), and 3-pentanone; chain alkoxyalkanes such as 2,2-dimethoxypropane and 2,2-diethoxypropane; alkoxyalkenes such as 2-methoxypropene and 2-ethoxypropene; cyclic ketones such as cyclobutanone, cyclopentanone, and cyclohexanone; and aromatic aldehydes or ketones such as benzaldehyde and 4-methoxybenzaldehyde. The amount of the protecting reagent used may be 1.0 to 20 moles, preferably 1.0 to 3.0 moles, relative to 1 mole of the compound represented by formula (VI-R).

[0102] R ２ａ Examples of fluoride ions that can be used in the deprotection reaction include tetrabutylammonium fluoride (TBAF), tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and hydrogen fluoride pyridine. The amount of the deprotection reagent used may be 0.05 to 10 moles, preferably 0.1 to 2 moles, relative to 1 mole of the compound represented by formula (VI-R).

[0103] R ２ａ Examples of acids that can be used in the deprotection reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and carboxylic acids such as formic acid and acetic acid. The amount of the acid used may be 1 to 20 moles, and preferably 1 to 10 moles, relative to 1 mole of the compound represented by formula (VI-R).

[0104] The protecting reagent is preferably added in a solvent that does not inhibit the deprotection reaction, and the protecting reagent may be used as the solvent. Examples of the solvent include ether-based organic solvents such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and tetrahydrofuran; nitrile-based solvents such as acetonitrile and propionitrile; halogenated hydrocarbons such as dichloromethane; and aromatic hydrocarbons such as toluene and xylene. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (VI-R) used.

[0105] In step 10, the reaction solution may be heated to promote the reaction.

[0106] One aspect of this embodiment is a compound represented by formula (VII): In formula (VII), R １ represents a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, preferably a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, more preferably an unsubstituted linear alkyl group having 1 to 35 carbon atoms, and even more preferably an unsubstituted linear alkyl group having 5 carbon atoms. ３ and R ４ are the same or different and represent a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, preferably a hydrogen atom, or a substituted or unsubstituted chain alkyl group having 1 to 10 carbon atoms, more preferably an unsubstituted chain alkyl group having 1 to 10 carbon atoms, and even more preferably an unsubstituted chain alkyl group having 1 or 2 carbon atoms.

[0107] However, R ３ and R ４ are the same or different and are unsubstituted alkyl groups, R １represents a substituted or unsubstituted linear alkyl group having 5 carbon atoms, a substituted or unsubstituted cycloalkyl group, a substituted aryl group, or a substituted or unsubstituted aralkyl group; R ３ and R ４ When R are taken together to form a propylene group, butylene group, or pentylene group together with the carbon atom to which they are attached, R １ represents a substituted or unsubstituted chain alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group.

[0108] R ３ and R ４ When both are methyl groups, R １ is not a propyl group, an isopropyl group, a phenyl group, a 10-hydroxydecyl group, a 10-azidodecyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, or a 4-bromophenyl group.

[0109] Alternative Embodiment 1 The conversion of a compound represented by formula (III) to a compound represented by formula (VII) may be carried out in steps 5b and 6b instead of steps 3 to 6. In the above scheme, the hydroxyl group and amino group of the compound represented by formula (III) are protected using the Boc group (step 3), and a further protecting group is introduced (step 4). The following alternative scheme can further reduce the number of steps.

[0110]

[0111] In the formula, R １ , R ３ and R ４ is as defined above. Step 5b is a step of dihydroxylating the compound represented by formula (IV) to obtain a compound represented by formula (VI-H). The reaction conditions for Step 5b can be referenced to the conditions described in Step 5.

[0112] In step 6b, the compound of formula (VI-H) obtained in step 5b is protected with an acetal-based protecting group to obtain a compound of formula (VII). The reaction conditions for step 6b can be determined by referring to the conditions described in step 6.

[0113] <Another embodiment 2>

[0114] In the formula, R １ , R ３ , R ４ and Boc are as defined above. Step 3c is a step of reacting the compound represented by formula (III) with a carbonylating agent in the presence of a base to obtain a compound represented by formula (V-Boc). In this embodiment, the compound represented by formula (V-Boc) is synthesized while leaving the Boc group, which is a protecting group for the amino group.

[0115] Step 3c is preferably carried out in an organic solvent. Examples of the organic solvent include ester solvents such as ethyl acetate, methyl acetate, and isopropyl acetate; ether solvents such as diethyl ether, diisopropyl ether, and tetrahydrofuran; nitrile solvents such as acetonitrile and propionitrile; halogenated hydrocarbons such as dichloromethane; and aromatic hydrocarbons such as toluene and xylene. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (III) used.

[0116] The carbonylating agent may be any carbonyl compound having two leaving groups. Examples of the carbonylating agent include carbonyldiimidazole, phosgene, and triphosgene. The amount of the carbonylating agent used may be 1.0 to 5.0 moles, preferably 1.0 to 1.5 moles, per mole of the compound represented by formula (III).

[0117] The base may be an organic amine capable of deprotonating a hydroxyl group and / or an amide. Examples of the base include triethylamine, N,N-diisopropyl-N-ethylamine, diazabicycloundecene (DBU), and diazabicyclononene (DBN). The amount of the base used may be 0.1 to 3.0 mol, preferably 0.5 to 2.0 mol, per mol of the compound represented by formula (III).

[0118] Step 3c is preferably carried out in a solvent that does not inhibit the esterification and / or amidation reaction. Examples of the solvent include ether-based organic solvents such as diethyl ether, diisopropyl ether, and tetrahydrofuran; nitrile-based solvents such as acetonitrile and propionitrile; halogenated hydrocarbons such as dichloromethane; and aromatic hydrocarbons such as toluene and xylene. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (III) used.

[0119] In step 5c, a compound of formula (V-Boc) is dihydroxylated to obtain a compound of formula (VI-Boc). The reaction conditions for step 5c can be determined by referring to the conditions described in step 5.

[0120] If necessary, a ruthenium-containing compound may be added. Examples of the ruthenium-containing compound include ruthenium(III) chloride. The amount of the ruthenium-containing compound used is 0.01 to 5.0 times by weight, preferably 0.05 to 0.3 times by weight, based on the amount (weight) of the compound represented by Formula (V-Boc). The addition of periodic acid or a salt thereof reoxidizes the ruthenium-containing compound. Examples of salts of periodic acid include sodium periodate. The amount of periodic acid or a salt thereof used may be 1.0 to 5.0 mol, preferably 1.0 to 2.0 mol, per 1 mol of the compound represented by Formula (V-Boc).

[0121] In step 6c, the compound of formula (VI-Boc) obtained in step 6b is protected with an acetal protecting group to obtain a compound of formula (VII). The reaction conditions for step 6c can be the same as those described in step 6.

[0122] Step 7 is a step of reacting the compound represented by formula (VII) with an alkali metal hydroxide to obtain a compound represented by formula (VIII). １ , R ３ and R ４ is as defined above.

[0123] Examples of alkali metal hydroxides include lithium hydroxide, sodium hydroxide, and potassium hydroxide. The amount of alkali metal hydroxide used may be 5 to 30 moles, preferably 10 to 20 moles, per mole of the compound represented by formula (VII).

[0124] Step 7 is preferably carried out in a mixed solvent of water and an alcoholic organic solvent. Examples of alcoholic organic solvents include methyl alcohol, ethyl alcohol, and isopropyl alcohol. The mixing ratio of water to the alcoholic organic solvent can be set as desired, taking into consideration the solubility of the raw materials. The amount of the solvent used may be 5 to 50 times, and preferably 10 to 20 times, the amount (by weight) of the compound represented by formula (VII) used.

[0125] Step 7 may be heated as needed to accelerate the reaction.

[0126] One aspect of this embodiment is a compound represented by formula (VIII): (In the formula, R ３ and R ４ are the same or different and represent a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４ represent a propylene group, a butylene group, or a pentylene group which together form a cyclic structure with the carbon atom to which they are attached, R １ represents a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, ３ and R ４ are the same or different and are unsubstituted alkyl groups, R １ represents a substituted or unsubstituted linear alkyl group having 5 carbon atoms, a substituted or unsubstituted cycloalkyl group, a substituted aryl group, or a substituted or unsubstituted aralkyl group. ３ and R ４When both are methyl groups, R １ is not a vinyl group, a tetradecyl group, a 12-methyl-tridecyl group, or a 1-tetradecenyl group.

[0127] [Second Embodiment] A second embodiment of the present disclosure is a crystal of a compound represented by formula (A) (hereinafter referred to as "A-type crystal"). In powder X-ray diffraction, the A-type crystal has peaks at diffraction angles (2θ) of 4.8°, 6.4°, 19.0°, and 21.3°. In powder X-ray diffraction, the A-type crystal preferably further has a peak at a diffraction angle (2θ) of 38.1°, more preferably has a peak at a diffraction angle (2θ) of 23.1°, and even more preferably has peaks at diffraction angles (2θ) of 17.0°, 37.4°, 36.4°, and 14.6°. Furthermore, the A-type crystal more preferably exhibits the powder X-ray diffraction pattern shown in Table 1 or FIG. 1.

[0128] According to the studies of the present inventors, at least 20 types of crystalline polymorphs have been discovered for the compound represented by formula (A). Type A crystals are anhydrous crystals of the compound represented by formula (A) and are the most stable to heat. When type A crystals are added to aqueous NMP, they transform into type J crystals (poor crystallinity). When type A crystals are heated to 100°C, they transform into type K crystals, and when heated to 125-140°C, they further transform into type L crystals. When heated to 160°C or higher and then cooled to 25°C, they transform into type B1 crystals. When type B1 crystals are left standing for two days at a temperature of 40°C and a relative humidity of 75%, they further transform into type T crystals. Type K crystals are only observed when heated, and revert to type A crystals upon cooling.

[0129] Type A crystals can be obtained by leaving type B crystals (amorphous), type C crystals (hydrate), or type H crystals at 40°C and 75% relative humidity for two days, or by recrystallizing each crystal form in a nitrile solvent or a mixed solvent thereof. Furthermore, recrystallizing type B crystals in a sulfoxide solvent such as DMSO yields type D crystals (solvates), recrystallizing type F crystals in an amide solvent such as DMF yields type F crystals (hydrates), recrystallizing type G crystals in an ether organic solvent such as 1,4-dioxane yields type H crystals (hydrates), and recrystallizing type I crystals in an amine solvent such as morpholine yields type I crystals. Type D crystals are dried under reduced pressure or left to stand under conditions of 40°C and 75% relative humidity for two days to yield type E crystals (anhydrous). Type F crystals are dried under reduced pressure to yield type A crystals. Type G crystals and type I crystals are transformed into type C crystals by drying under reduced pressure.

[0130] The melting point of C-type crystals is 78 to 86°C, that of D-type crystals is 95 to 99°C, and that of F-type crystals is 75 to 85°C.

[0131] The sulfoxide solvent may be any solvent that has a sulfoxide bond and is generally used as a solvent, such as dimethyl sulfoxide (DMSO).

[0132] The amide solvent may be any solvent that has an amide bond and is generally used as a solvent, and examples thereof include N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and N-methylpyrrolidone (NMP).

[0133] The ether-based organic solvent may be any organic solvent that has an ether bond and is generally used as a solvent, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane.

[0134] The alcohol-based organic solvent may be any solvent that has a hydroxyl group (—OH) and is generally used as a solvent, and examples thereof include methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, and n-butyl alcohol.

[0135] Amine solvents have an amino group (-NH ２ , —NH—) and may be any solvent that is generally used as a solvent, such as morpholine, piperidine, piperazine, and pyrrolidine.

[0136] When recrystallization is carried out, if the original crystalline or amorphous form is difficult to dissolve in the solvent, heating may be carried out as appropriate, and if crystals are difficult to precipitate, a poor solvent may be added.

[0137] The present disclosure will be described in detail below using examples, but the present disclosure is not limited to the following examples.

[0138] New Method for Producing OCH (Examples 1 to 12) Example 1 Preparation of tert-butyl (R,Z)-4-(hept-1-en-yl)-2,2-dimethyloxazolidine-3-carboxylate Tetrahydrofuran (300 mL) and hexyltriphenylphosphonium bromide (72.7 g) were added to a reaction vessel and cooled to 0°C. Potassium tert-butoxide (19.1 g) was added and stirred for 30 minutes. The reaction solution was then cooled to -2.5°C, and a solution of tert-butyl (S)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (also referred to as Compound 1, 30.0 g) in tetrahydrofuran (150 mL) was added dropwise at 0°C or below. After the reaction, calcium bromide (26.2 g) was added, and the reaction solution was warmed to room temperature and stirred for 3 hours. Insoluble matter was removed by filtration through Celite and then washed with tetrahydrofuran (90 mL). The filtrate was concentrated under reduced pressure until the liquid volume was 120 mL. Methyl alcohol (300 mL) was added, followed by another concentration under reduced pressure. Methyl alcohol (270 mL) was added to obtain a methyl alcohol solution of Compound 2.

[0139] Example 2 Preparation of tert-butyl (R,Z)-(1-hydroxynon-3-en-2-yl)carbamate To the methyl alcohol solution of compound 2 obtained in Example 1, water (30 mL) and p-toluenesulfonic acid monohydrate (2.25 g) were added, and the temperature was raised to 50°C. After stirring for 16 hours, the mixture was cooled to 30°C, and triethylamine (3.65 mL) was added to the reaction solution, followed by the addition of water (90 mL) to precipitate crystals. After confirming that the crystals had increased, water (60 mL) was added, and the mixture was cooled to 0°C. After stirring for 2 hours, the precipitated crystals were washed with a mixed solution of methyl alcohol (72 mL) and water (48 mL), and the obtained solid was dried under reduced pressure to obtain crude crystals of compound 3 (25.0 g).

[0140] Crude crystals of compound 3 (25.0 g) and ethyl acetate (250 mL) were added to a reaction vessel, and the temperature was raised to 50 ° C. After confirming that the crystals had dissolved, activated carbon (1.25 g) was added and the mixture was stirred for 1 hour. After removing insoluble matter by filtration through Celite, the filtrate was concentrated under reduced pressure until the liquid volume reached 125 mL. The concentrated solution was heated to 50 ° C, and heptane (150 mL) was added dropwise. After cooling to 30 ° C, seed crystals (2.5 mg) were added and an increase in crystals was confirmed. Heptane (100 mL) was then added and the mixture was cooled to 0 ° C. After stirring for 2 hours, the precipitated crystals were collected by filtration, washed with cooled heptane (50 mL), and dried under reduced pressure to obtain compound 3 (yield: 21.2 g).

[0141] Example 3 Preparation of (R,Z)-4-(hept-1-en-1-yl)oxazolidin-2-one Compound 3 (50.10 g) obtained in Example 2, cyclopentyl methyl ether (300 mL), and tert-butyl alcohol (200 mL) were added to a reaction vessel. After cooling to 10°C, sodium tert-butoxide (19.68 g) was added. The reaction solution was stirred at room temperature for 2 hours and 30 minutes, then cooled to 10°C, and 6.1% aqueous ammonium chloride solution (261 g) was added dropwise. After warming the reaction solution to room temperature, the aqueous layer and organic layer were separated, and the organic layer was washed with a 10% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure until the liquid volume was 250 mL, cyclopentyl methyl ether (250 mL) was added, and the mixture was again concentrated under reduced pressure until the liquid volume was 250 mL, yielding a cyclopentyl methyl ether solution of compound 4.

[0142] The data for compound 4 is shown below.１ H NMR (500MHz, CDCl ３ ) δ 5.64 (dt, J = 11.1, 7.6 Hz, 1H), 5.57 (br, 1H), 5.41 (t, J = 10Hz, 1H), 4.74 (q, J = 8.3Hz, 1H), 4.51 (t, J=8.5Hz, 1H), 4.00 (t, J=7.9Hz, 1H), 2.12-2.00 (m, 2H), 1.41-1.22 (m, 6H), 0.89 (t, J=7.0Hz, 3H). １３ C NMR (126MHz, CDCl ３ ) δ 159.77, 135.70, 127.32, 70.39, 49.58, 31.33, 29.11, 27.53, 22.45, 13.99. LC-MS (ESI) m / z: 184 [M+H] ＋

[0143] Example 4 Preparation of (R,Z)-3-(tert-butyldiphenylsilyl)-4-(hept-1-en-1-yl)oxazolidin-2-one A cyclopentyl methyl ether solution (250 mL) of compound 4 obtained in Example 3, ethyl acetate (200 mL), and diazabicycloundecene (44.51 g) were added to a reaction vessel, and the reaction solution was cooled to 10°C. tert-Butyldiphenylchlorosilane (69.64 g) and ethyl acetate (50 mL) were added to the reaction solution, which was then warmed to room temperature and stirred for 5 hours. After the reaction, the reaction solution was cooled to 10°C, and 0.5 M hydrochloric acid (250 mL) was added. After warming to room temperature, the organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL) and mixed with the previous organic layer. The combined organic layer was washed sequentially with 0.5 M hydrochloric acid and water, and then concentrated under reduced pressure until the volume was 250 mL. Heptane (250 mL) was added and the solution was concentrated under reduced pressure to 250 mL. This procedure of adding heptane and concentrating under reduced pressure to 250 mL was repeated twice, after which the organic layer was cooled to 0°C and stirred. The precipitated crystals were washed with heptane and dried under reduced pressure to obtain Compound 5 (yield: 68.50 g).

[0144] The data for compound 5 is shown below. １ H NMR (500MHz, CDCl ３) δ 7.66 (d, J=7.0Hz, 2H), 7.59 (d, J = 7.0Hz, 2H), 7.46-7.33 (m, 6H), 5.40 (t, J = 10Hz, 1H), 5.08-5.03 (m, 1H), 4.50 (t, J = 8.0Hz, 1H), 4.32 (td, J = 8.8, 2 9Hz, 1H), 3.96 (dd, J=8.2, 2.9Hz, 1H), 1.21 (s, 9H), 1.14 (dq, J=15.5, 7.4Hz, 3H), 1.02-0.91 (m, 5H), 0.82 (t, J=7.5Hz, 3H). １３ C NMR (126MHz, CDCl ３ ) δ 162.07, 135.79, 135.75, 132.63, 132.47, 132.00, 129.97, 129.90, 129.88, 12 7.94, 127.79, 71.47, 55.08, 31.29, 28.88, 28.78, 26.67, 22.34, 19.56, 13.96. LC-MS (ESI) m / z: 422 [M+H] ＋

[0145] Example 5 Preparation of (S)-3-(tert-butyldiphenylsilyl)-4-((1S,2R)-1,2-dihydroxyheptyl)oxazolidin-2-one Compound 5 (50.10 g) obtained in Example 4, ethyl acetate (500 mL), acetonitrile (500 mL), water (50 mL), and ruthenium chloride n-hydrate (2.53 g) were added to a reaction vessel, and the reaction solution was cooled to 0 ° C., followed by dropwise addition of 50% aqueous periodic acid solution (57.43 g). After the reaction, 4.2% aqueous sodium bicarbonate solution (261 g) and 19% aqueous sodium thiosulfate solution (307 g) were added sequentially, and the mixture was heated to room temperature and stirred for 1 hour. After removing insoluble matter by filtration through Celite, the insoluble matter was washed with ethyl acetate (250 mL). The filtrate was separated into an aqueous layer and an organic layer, and the organic layer was washed with a 10% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to a volume of 250 mL, and then cyclopentyl methyl ether (250 mL) was added. This operation of concentrating under reduced pressure to 250 mL was repeated three times to obtain a cyclopentyl methyl ether solution of compound 6.

[0146] Example 6 Preparation of (S)-4-((4S,5R)-2,2-dimethyl-5-pentyl-1,3-dioxolan-4-yl)oxazolidin-2-one A cyclopentyl methyl ether solution (250 mL) of Compound 6 obtained in Example 5, cyclopentyl methyl ether (250 mL), and 2,2-dimethoxypropane (50 mL) were added to a reaction vessel, followed by the addition of p-toluenesulfonic acid monohydrate (1.13 g) at room temperature. After stirring the reaction mixture for 2 hours, triethylamine (1.66 mL), methyl alcohol (50 mL), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (12 mL) were added sequentially. After stirring for 2 hours, 15% aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed twice with 15% aqueous ammonium chloride solution (150 mL) and once with water (250 mL). The organic layer was concentrated under reduced pressure until the volume was 250 mL, after which heptane (1250 mL) was added and the mixture was heated to 60°C. After confirming the dissolution of the crystals, the mixture was cooled to 0°C and stirred. The precipitated crystals were washed with heptane and dried under reduced pressure to obtain Compound 7 (yield: 26.00 g).

[0147] The data for compound 7 are shown below. １ H NMR (500MHz, CDCl ３ ) δ 6.28 (s, 1H), 4.47-4.40 (m, 2H), 4.18 (dt, J = 9.4, 5.1Hz, 1H), 4.01 (t, J = 6.7Hz, 1H), 3.89 (q, J = 7.3Hz, 1H), 1.60-1.56 (m, 1H), 1.48-1.31 (m, 13H), 0.90 (t, J = 6.4Hz, 3H) １３ C NMR (126MHz, CDCl ３ ) δ 160.30, 108.38, 79.12, 76.88, 67.75, 51.74, 31.63, 29.32, 27.79, 26.41, 25.29, 22.53, 13.99. LC-MS (ESI) m / z: 258 [M+H] ＋

[0148] Example 7 Preparation of (S)-2-amino-2-((4S,5R)-2,2-dimethyl-5-pentyl-1,3-dioxolan-4-yl)ethan-1-ol Compound 7 (25.02 g) obtained in Example 6, 8 M aqueous potassium hydroxide solution (75 mL), water (50 mL), and ethyl alcohol (125 mL) were added to a reaction vessel, and the reaction solution was heated to 80°C and stirred for 4 hours. The reaction solution was cooled to room temperature, and 23% aqueous ammonium chloride solution (163 g) was added, followed by concentration under reduced pressure until the liquid volume was 250 mL. The reaction solution was extracted three times with ethyl acetate, and the organic layers were mixed and concentrated under reduced pressure until the liquid volume was 125 mL. Toluene (75 mL) was added to the organic layer, and the organic layer was concentrated under reduced pressure until the liquid volume was 125 mL. This operation was repeated three times to obtain a toluene solution of compound 8.

[0149] The data for compound 8 are shown below. １ H NMR (500MHz, CDCl ３ ) δ 4.20-4.16 (m, 1H), 3.88 (dd, J=8.8, 5.7Hz, 1H), 3.74 (dd, J=10.9, 4.7Hz, 1H), 3.58 (dd, J=10.9, 5.8Hz, 1H), 2.95 (dt, J=8.8, 5.3Hz, 1H), 1.74 (br, 3H), 1.61-1.53 ​​(m, 3H), 1.43 (s, 3H), 1.36-1.30 (m, 8H), 0.90 (t, J=6.3Hz, 3H). １３ C NMR (126MHz, CDCl ３ ) δ 108.12, 80.46, 77.88, 66.12, 51.47, 31.86, 29.82, 28.18, 25.95, 25.86, 22.62, 14.04. LC-MS (ESI) m / z: 232 [M+H] ＋

[0150] Example 8 Preparation of N-((S)-1-((4S,5R)-2,2-dimethyl-5-pentyl-1,3-dioxolan-4-yl)-2-hydroxyethyl)tetracosanoic acid amide A toluene solution (125 mL) of compound 8 obtained in Example 7, toluene (250 mL), triethylamine (40 mL), 1-hydroxybenzotriazole monohydrate (17.85 g), and lignoceric acid (32.26 g) were added to a reaction vessel, and the reaction solution was heated to 40 ° C. Subsequently, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.47 g) was added to the reaction solution, and the mixture was stirred for 2 hours. After the reaction, methyl alcohol (125 mL) and Celite (7.70 g) were added to the reaction solution, and insoluble matter was removed by filtration. The mixture was then washed with toluene (125 mL) and methyl alcohol (375 mL). The filtrate was heated to 40 ° C., water (25 mL) was added, and the mixture was cooled to 0 ° C. and stirred. The precipitated crystals were washed with methyl alcohol and dried under reduced pressure to obtain compound 9 (yield: 46.12 g).

[0151] Example 9 Preparation of (2,3,4,6)-tetra-O-benzyl-D-galactopyranosyl chloride (2,3,4,6)-tetra-O-benzyl-D-galactopyranose (compound 10, 27.9 g), toluene (120 mL), and dimethylformamide (0.40 mL) were added to a reaction vessel and stirred at room temperature for 10 minutes. Then, oxalyl chloride (9.81 g) and toluene (20 mL) were added, and after the dropwise addition, the mixture was stirred at room temperature for 4 hours. After the reaction, a 5% aqueous solution of sodium bicarbonate was added and the mixture was stirred for 20 minutes, after which the organic layer and the aqueous layer were separated. The organic layer was washed with 10% saline and concentrated under reduced pressure until the liquid volume reached 75 mL, yielding a toluene solution of compound 11.

[0152] Example 10 Preparation of 2-tetracosanoylamino-1-O-(2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)-3,4-O-isopropylidene-D-ribo-1,3,4-nonanetriol A toluene solution of compound 11 prepared in Example 9 was placed in a reaction vessel, and compound 9 (15.0 g), triethylamine (10.8 mL), and tetrabutylammonium bromide (16.6 g) were added at room temperature. The mixture was then heated to 100°C and stirred for 6 hours. After the reaction, the reaction solution was cooled to room temperature, and methyl alcohol (15.0 mL) was added and stirred for 1 hour. Subsequently, toluene (30.0 mL), acetonitrile (225 mL), and Celite (7.50 g) were added to the reaction solution, and the mixture was stirred for 2 hours. After that, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure until the liquid volume was 105 mL. Acetonitrile (200 mL) was added, and the mixture was again concentrated under reduced pressure until the liquid volume was 105 mL. This operation was repeated twice. Acetonitrile (495 mL) was added to the concentrated solution, and the mixture was heated to 50°C and stirred for 30 minutes. After that, the mixture was cooled to 35°C and stirred for 2 hours. The mixture was further cooled to 25° C. and stirred for 2 hours, after which the precipitated crystals were collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain crude crystals of Compound 12 (yield: 21.0 g).

[0153] The obtained crude crystals of Compound 12 (whole amount) were added to acetonitrile (600 mL), heated to 50° C. and stirred for 30 minutes, then cooled to 35° C. and stirred for 2 hours. After further cooling to 25° C. and stirring for 2 hours, the precipitated crystals were collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain purified crystals of Compound 12 (yield: 18.8 g).

[0154] Example 11 Preparation of 2-tetracosanoylamino-1-O-(2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)-D-ribo-1,3,4-nonanetriol Pyridinium p-toluenesulfonate (1.70 g) was added to a suspension of compound 12 (15.0 g) synthesized in Example 10 in acetonitrile (285 mL) / water (15.0 mL), heated to 70°C, and stirred for 4 hours. After the reaction, the mixture was cooled to 50°C, methyl alcohol (300 mL) was added, cooled to 40°C, and stirred for 4 hours. Thereafter, triethylamine (1.9 mL) was added, cooled to 25°C, and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain compound 13 (yield: 12.2 g).

[0155] Example 12 Preparation of 2-tetracosanoylamino-1-O-α-D-galactopyranosyl-D-ribo-1,3,4-nonanetriol 5% palladium carbon (0.50 g) was added to a suspension of compound 13 (10.0 g) synthesized in Example 11 in ethyl alcohol (300 mL), and the mixture was purged with hydrogen gas and heated to 60 ° C. and stirred for 4 hours. After the reaction, the mixture was cooled to 50 ° C., and insoluble matter was filtered off. Activated carbon (1.0 g) was added to the filtrate and stirred at 50 ° C. The mixture was then filtered off, and the filtrate was concentrated under reduced pressure to 200 mL. The concentrated solution was heated to 50 ° C., and acetonitrile (200 mL) was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes. The mixture was then cooled to 35 ° C. and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain compound 14 (yield: 5.90 g).

[0156] Example 13 Preparation of Compounds 15+16 Compound 4 (1.51 g), ethyl acetate (15 mL), acetonitrile (15 mL), water (1.5 mL), and ruthenium chloride n-hydrate (152.0 mg) were added to a reaction vessel and cooled to 0°C. 50% aqueous periodic acid solution (2.59 mL) was then added dropwise. After the reaction, aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution were added sequentially, and the mixture was heated to room temperature and stirred for 1 hour. Insoluble matter was removed by filtration through Celite, and the insoluble matter was washed with ethyl acetate. The filtrate was separated into an aqueous layer and an organic layer, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were mixed, washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtering off inorganic salts, the mixture was concentrated under reduced pressure and azeotroped with cyclopentyl methyl ether to obtain compounds 15 and 16 as cyclopentyl methyl ether solutions.

[0157] ・Instrument data for compound 15 １ H NMR (500MHz, DMSO-d ６) δ 7.33 (s, 1H), 5.06 (d, J = 5.5Hz, 1H), 4.57 (d, J = 5.6Hz, 1H), 4.26-4.18 (m, 2H), 3.96-3.93 (m, 1H), 3 .25-3.19 (m, 2H), 1.55-1.51 (m, 1H), 1.46-1.41 (m, 1H), 1.31-1.22 (m, 6H), 0.87 (t, J=7.0Hz, 3H). １３ C NMR (126MHz, DMSO-d ６ ) δ 159.67, 74.43, 71.53, 64.97, 53.44, 33.62, 31.96, 25.20, 22.66, 14.45. LC-MS (ESI) m / z: 218 [M+H] ＋

[0158] Example 14 Preparation of (S)-4-((4S,5R)-2,2-dimethyl-5-pentyl-1,3-dioxolan-4-yl)oxazolidin-2-one A mixture of compounds 15 and 16 obtained in Example 13, cyclopentyl methyl ether (50 mL), tetrahydrofuran (15 mL), and 2,2-dimethoxypropane (5 mL) were added to a reaction vessel, followed by the addition of p-toluenesulfonic acid monohydrate (155.1 mg) at room temperature. After stirring for 1 hour, triethylamine (0.57 mL) and ethyl acetate were added, and the reaction solution was washed sequentially with 10% brine and saturated brine. After drying over anhydrous sodium sulfate, inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 7 as a diastereomeric mixture (yield: 1.78 g, diastereomeric ratio of compound 7:compound 17 = approximately 0.7:1.0).

[0159] Sharpless asymmetric dihydroxylation (osmium catalyst) Example 15: Preparation of a mixture of compounds 15 and 16 To a reaction vessel were added potassium hexacyanoferrate(III) (5.55 g), potassium carbonate (2.35 g), hydroquinidine-1,4-phthalazinediyl diether (48.0 mg), potassium osmate(VI) dihydrate (44.1 mg), methanesulfonamide (535.3 mg), tert-butyl alcohol (5 mL), and water (10 mL). Compound 4 (1.03 g) and tert-butyl alcohol (5 mL) were then added at room temperature. After stirring for 3 hours, aqueous sodium sulfite solution was added. Insoluble matter was removed by filtration through Celite, and the insoluble matter was washed with ethyl acetate. The filtrate was separated into an aqueous layer and an organic layer, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off inorganic salts, the mixture was concentrated under reduced pressure and azeotroped with cyclopentyl methyl ether to obtain a mixture of compounds 15 and 16 as a cyclopentyl methyl ether solution.

[0160] Example 16 Preparation of a mixture of compounds 7 and 17 A mixture of Compounds 15 and 16 obtained in Example 15, cyclopentyl methyl ether (10 mL), and 2,2-dimethoxypropane (5 mL) were added to a reaction vessel, followed by the addition of p-toluenesulfonic acid monohydrate (216.3 mg) at room temperature. After stirring for 40 minutes, triethylamine (0.40 mL) and ethyl acetate were added, and the reaction solution was washed sequentially with 5% brine and saturated brine. After drying over anhydrous sodium sulfate, inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain Compound 7 as a diastereomeric mixture (yield: 1.34 g, diastereomeric ratio of Compound 7:Compound 17 = approximately 6.8:1.0).

[0161] Example 17 Preparation of tert-butyl (R,Z)-4-(hept-1-en-1-yl)-2-oxooxazolidine-3-carboxylate Compound 3 (2.04 g), ethyl acetate (30 mL), and carbodiimidazole (1.56 g) were sequentially added to a reaction vessel and stirred at room temperature for 1 hour. Then, diazabicycloundecene (1.18 mL) was added and stirred at room temperature. After the reaction, 1.0 M hydrochloric acid (30 mL) was added dropwise at 0°C, and the mixture was allowed to warm to room temperature. After separating the organic and aqueous layers, the organic layer was washed sequentially with water and saturated brine. After drying over anhydrous sodium sulfate, inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 18 (yield: 2.01 g).

[0162] The data for compound 18 is shown below. １ H NMR (500MHz, CDCl ３ ) δ 5.65 (dt, J=11.2, 7.6Hz, 1H), 5.45 (t, J=10Hz, 1H), 5.02 (td, J=8.8, 5.1Hz, 1H), 4.43 (t, J=8.6Hz, 1H), 3.92 (dd, J=8.7, 5.0Hz, 1H), 2.13-2.09 (m, 2H), 1.51 (s, 9H), 1.45-1.40 (m, 1H), 1.38-1.24 (m, 5H), 0.89 (t, J=6.8Hz, 3H). １３ C NMR (126MHz, CDCl ３ ) δ 152.36, 149.17, 134.54, 126.98, 83.78, 67.38, 52.42, 31.43, 29.11, 27.99, 27.64, 22.47, 13.99. LC-MS (ESI) m / z: 228 [MC(CH ３ ) ３ +2H] ２＋

[0163] Example 18 Preparation of Compounds 19 and 20 Compound 18 (3.08 g), ethyl acetate (30 mL), acetonitrile (30 mL), water (3 mL), and ruthenium chloride (307.1 mg) were added to a reaction vessel and cooled to 0°C, followed by dropwise addition of 50% aqueous periodic acid solution (3.42 mL). After the reaction, aqueous sodium sulfite solution was added, the mixture was warmed to room temperature, and stirred for 1 hour. Insoluble matter was removed by filtration through Celite, and then washed with ethyl acetate. The filtrate was separated into an aqueous layer and an organic layer. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing inorganic salts by filtration, the mixture was concentrated under reduced pressure and azeotroped with cyclopentyl methyl ether to obtain a mixture of compound 19 and compound 20 as a cyclopentyl methyl ether solution.

[0164] Example 19 Preparation of Compounds 7+17 A mixture of compounds 19 and 20 obtained in Example 18, cyclopentyl methyl ether (30 mL), and methanesulfonic acid (6 mL) were sequentially added to a reaction vessel at room temperature and stirred for 1 hour. After confirming the disappearance of compounds 19 and 20, the mixture was cooled to -20°C, and 2,2-dimethoxypropane (6 mL) was added. After stirring for 30 minutes, triethylamine (15 mL) and ethyl acetate were added, and the reaction solution was washed sequentially with a 5% aqueous NaCl solution and saturated brine. After drying over anhydrous sodium sulfate, inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 7 as a diastereomeric mixture (yield: 2.44 g, diastereomeric ratio of compound 7:compound 17 = approximately 2.8:1.0).

[0165] Example 20 Preparation of (R,Z)-3-(tert-butyldimethylsilyl)-4-(hept-1-en-1-yl)oxazolidin-2-one Compound 4 (2.47 g), tetrahydrofuran (25 mL), and diazabicycloundecene (3.0 mL) were added to a reaction vessel and cooled to 10°C. tert-Butyldimethylchlorosilane (2.65 g) was added, the mixture was warmed to room temperature, and then stirred for 4 hours. After the reaction, the mixture was cooled to 0-5°C, 0.5 M hydrochloric acid and ethyl acetate were added, the mixture was warmed to room temperature, and then the organic and aqueous layers were separated. The combined organic layer was washed sequentially with 0.5 M hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 21 (yield: 3.82 g).

[0166] ・Instrument data for compound 21 １ H NMR (500MHz, CDCl ３ ) δ 5.43-5.37 (m, 2H), 4.50-4.46 (m, 1H), 4.31 (t, J=8.3Hz, 1H), 3.81 (dd, J=8.2, 4.3Hz, 1H), 1.9 4-1.90 (m, 2H), 1.46-1.14 (m, 6H), 0.88 (s, 9H), 0.81 (t, J=7.0Hz, 3H), 0.16 (d, J=2.8Hz, 6H). １３ C NMR (126MHz, CDCl ３ ) δ 161.72, 132.41, 130.95, 70.34, 53.94, 31.45, 28.99, 27.59, 26.93, 22.45, 19.02, 13.98, -4.94. LC-MS (ESI) m / z: 298 [M+H] ＋

[0167] Example 21 Preparation of a mixture of compounds 22 and 23 Compound 21 (3.12 g), ethyl acetate (30 mL), acetonitrile (30 mL), water (3.0 mL), and ruthenium chloride n-hydrate (314.9 mg) were added to a reaction vessel and cooled to 0 ° C., followed by dropwise addition of 50% aqueous periodic acid solution (3.30 mL). After the reaction, aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution were added sequentially, and the mixture was heated to room temperature and stirred for 1 hour. After removing insoluble matter by filtration through Celite, the insoluble matter was washed with ethyl acetate. The filtrate was separated into an aqueous layer and an organic layer, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After removing inorganic salts by filtration, the mixture was concentrated under reduced pressure and solvent-substituted with tetrahydrofuran, yielding a mixture of compound 22 and compound 23 as a tetrahydrofuran solution.

[0168] Example 22 Preparation of Compound 7 and Compound 17 A reaction vessel was charged with the mixture of Compound 22 and Compound 23 obtained in Example 21 and 2,2-dimethoxypropane (10 mL), followed by the addition of p-toluenesulfonic acid monohydrate (209.3 mg) at room temperature. After stirring for 2 hours, triethylamine (0.73 mL), methyl alcohol (3.0 mL), and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.0 mL) were added sequentially. After stirring for 5 hours, 15% aqueous ammonium chloride and ethyl acetate were added, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed twice with 15% aqueous ammonium chloride and once with saturated brine. After drying over anhydrous sodium sulfate, the inorganic salts were removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give a mixture of Compound 7 and Compound 17 (yield: 2.30 g, diastereomeric ratio of Compound 7:Compound 17 = approximately 7.5:1.0).

[0169] A mixture of Compound 7 and Compound 17 (2.30 g) and heptane (30 mL) were added to a reaction vessel and cooled to 0° C. After stirring at 0° C. for 30 minutes, the crystals were washed with heptane and dried under reduced pressure to obtain Compound 7 (yield: 2.14 g).

[0170] Example 23 Preparation of 2-tetracosanoylamino-1-O-(2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)-D-ribo-1,3,4-nonanetriol Compound 12 (2.76 g) synthesized in Example 10 was dissolved in a tetrahydrofuran / acetonitrile (volume ratio 1:1) mixed solvent to prepare 50 mL of solution A. Similarly, 6 M hydrochloric acid (55.0 g) was mixed with a tetrahydrofuran / acetonitrile (1:1) mixed solvent to prepare 150 mL of solution B. Both solutions were pumped and mixed in a reaction tube, and the mixture was heated to 50 °C. The reaction solution was then collected in a reaction vessel containing 28% aqueous ammonia (25.0 g) cooled to 0 °C. The reaction solution was concentrated to a volume of 25 mL, ethyl acetate (50 mL) was added to the concentrate, the aqueous layer and organic layer were separated, and the organic layer was washed with water (25 mL). The organic layer was concentrated to 5 mL, and then methanol (50 mL) and acetonitrile (50 mL) were added to the concentrate, heated to 40 °C, and stirred for 4 hours. The reaction solution was then cooled to 25 °C and further stirred for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried under reduced pressure to obtain Compound 13 (yield: 2.42 g).

[0171] Example 24 Preparation of 2-tetracosanoylamino-1-O-α-D-galactopyranosyl-D-ribo-1,3,4-nonanetriol Compound 13 (2.13 g) synthesized in Example 23 and 4-methylcyclohexene (34.1 g) were dissolved in a tetrahydrofuran / ethanol (volume ratio 1:1) mixed solvent to prepare a 50 mL solution. Subsequently, 20% palladium hydroxide on carbon (0.40 g) and Celite (0.55 g) were mixed and packed into a column. The reaction was carried out by passing the solution of compound 13 through a column heated to 70°C using a pump. The solution after the reaction was collected. After heating the collected solution to 50°C, acetonitrile (40 mL) was added dropwise, and the mixture was further stirred for 30 minutes after the completion of the addition. The reaction solution was then cooled to 35°C and stirred for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystals were washed with acetonitrile and dried under reduced pressure to obtain compound 14 (yield: 1.20 g).

[0172] Ethanol (190 mL) was added to compound 14 (1.00 g), and the mixture was heated to 50° C., followed by dropwise addition of acetonitrile (200 mL). After completion of the dropwise addition, the mixture was stirred for 30 minutes. The mixture was then cooled to 35° C. and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain type A crystals (yield: 0.90 g).

[0173] Powder X-ray Diffraction of A-type Crystals The powder X-ray diffraction pattern of A-type crystals was measured using the following equipment and under the following measurement conditions.

[0174] (Apparatus) Rigaku MiniFlex600-C (Operation method) Measurement method: Reflection method Wavelength used: CuKα ray Tube current: 15 mA Tube voltage: 40 kV X-ray incident angle: 1.25° Step width: 0.02° Scan range: 4 to 40°

[0175] Thermal analysis of A-type crystals was carried out using a thermal analyzer (Thermo plus EVO DSC8230, manufactured by Thermo Corporation) at a heating rate of 10°C / min. As a result, endothermic peaks were observed around 124°C and 141°C.

Claims

1. Formula (VIII) (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms; R ３ and R ４ are the same or different and are a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４ are propylene, butylene or pentylene groups which together form a cyclic structure with the carbon atom to which they are attached. (In the formula, R ５ is a substituted or unsubstituted alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, to obtain a compound represented by the formula (IX): (In the formula, R １ , R ３ , R ４ and R ５ is as defined above; and reacting a compound represented by formula (IX) with a compound represented by formula (X) (In the formula, R ６ is a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a p-nitrobenzyl group, a diphenylmethyl group, or a di(p-nitrophenyl)methyl group, and Y is a halogen atom or a methanesulfonyloxy group, to give a compound represented by formula (XI): (In the formula, R １ , R ３ , R ４ , R ５ and R ６ is as defined above; and removing the acetal protecting group from the compound represented by formula (XI) to obtain a compound represented by formula (XII): (In the formula, R １ , R ５ and R ６ is as defined above; and removing a protecting group R from a compound represented by formula (XII). ６ and removing the compound of formula (XIII), (In the formula, R １ and R ５ is as defined above.

2. Formula (VII) (In the formula, R １ , R ３ and R ４ is as defined above.) is hydrolyzed in an aqueous base solution to obtain a compound represented by the formula (VIII): (In the formula, R １ , R ３ and R ４ The method of claim 1, further comprising the step of obtaining a compound represented by the formula:

3. Protection of two hydroxyl groups with acetal-based protecting groups and R ２ａ By deprotection of the compound of formula (VI-R) (In the formula, R １ is as defined above, R ２ａ is a silyl protecting group or a carbamate protecting group. (In the formula, R １ , R ３ and R ４ is as defined above, or by protecting the two hydroxyl groups with an acetal protecting group, to obtain a compound represented by formula (VI-H): (In the formula, R １ is as defined above.) with a compound represented by formula (VII) (In the formula, R １ , R ３ and R ４ wherein R is as defined above.

4. Formula (VR) (In the formula, R １ and R ２ａ is as defined above.) is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium ferricyanide (III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, and (3) with a permanganate compound to obtain a compound represented by formula (VI-R) (In the formula, R １ and R ２ａ The method according to claim 3, comprising the step of obtaining a compound represented by the formula:

5. Formula (IV) (In the formula, R １ is as defined above, and the amino group of a compound represented by the formula (VI-H) is protected, and without isolation, the compound is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound. (In the formula, R １ The method according to claim 3, comprising the step of obtaining a compound represented by the formula:

6. Formula (IV) (In the formula, R １ is as defined above, and a nitrogen atom of a compound represented by the formula (VR) is protected. (In the formula, R １ and R ２ａ The method according to claim 4, comprising the step of obtaining a compound represented by the formula:

7. In a mixed solvent of an ether-based organic solvent and an alcohol-based organic solvent, (In the formula, R １ is as defined above, and Boc is a tert-butoxycarbonyl group, with an alkali metal alkoxide, and protecting the amino group with a protecting group Boc without isolating the product, (In the formula, R １ and Boc are as defined above.

8. In an ether-based organic solvent, (In the formula, R １ is as defined above, and Boc is a tert-butoxycarbonyl group.) is reacted with an alkali metal alkoxide to obtain a compound represented by the formula (IV): (In the formula, R １ The method according to claim 5 or 6, further comprising the step of obtaining a compound represented by the formula:

9. In the presence of an alkali metal alkoxide, a compound represented by the formula (I) (wherein Boc is as defined above) is reacted with a compound represented by formula (XXX) (In the formula, R １ is as defined above, and X is a halogen atom, to obtain a compound represented by formula (II): (Wherein, Boc and R １ is as defined above; and reacting the compound represented by formula (II) with p-toluenesulfonic acid to obtain a compound represented by formula (III): (Wherein, Boc and R １ is as defined above.

10. A compound represented by the formula (VR). (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms; R ２ａ is a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc), where R ２ａ is a tert-butoxycarbonyl group (Boc), R １ is not an unsubstituted linear alkyl group having 1, 4 or 14 carbon atoms, an unsubstituted aryl group having 6 carbon atoms, or an unsubstituted aralkyl group having 7 carbon atoms. １ is an alkyl group having 5 carbon atoms, R ２ａ is a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc).

11. A compound represented by formula (VI). (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms; R ２ is a hydrogen atom or R ２ａ and R ２ａ is a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc), with the proviso that R １ is an unsubstituted linear alkyl group having 3, 4, or 14 carbon atoms, or a substituted linear alkyl group having 1, 2, or 10 carbon atoms, R ２ is not a hydrogen atom. １ is an alkyl group having 5 carbon atoms, R ２ is a hydrogen atom or R ２ａ and R ２ａ is a tert-butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), an allyloxycarbonyl group (Alloc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), or a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc).

12. A compound represented by formula (VII). (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms; R ３ and R ４ are the same or different and are a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４ are propylene, butylene, or pentylene groups which together form a cyclic structure with the carbon atoms to which they are attached, provided that R ３ and R ４ are the same or different and each is an unsubstituted alkyl group having 1 to 6 carbon atoms, R １ is a substituted or unsubstituted linear alkyl group having 5 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms; R ３ and R ４ are propylene, butylene, or pentylene groups which together form a cyclic structure with the carbon atoms to which they are attached, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms.

13. A compound represented by formula (VIII): (In the formula, R １ is a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms; R ３ and R ４ are the same or different and are a hydrogen atom, a substituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or R ３ and R ４ are propylene, butylene, or pentylene groups which together form a cyclic structure with the carbon atoms to which they are attached, provided that R ３ and R ４ are the same or different and each is an unsubstituted alkyl group having 1 to 6 carbon atoms, R １ is an unsubstituted linear alkyl group having 5 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms; R ３ and R ４ are propylene, butylene, or pentylene groups which together form a cyclic structure with the carbon atoms to which they are attached, R １ is a hydrogen atom, a substituted or unsubstituted linear alkyl group having 1 to 35 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted aryl group having 6 to 14 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms.

14. Formula (VIII) (In the formula, R １ , R ３ and R ４ is as described in claim 1.) A compound represented by formula (XX) (In the formula, R ５ is as described in claim 1.) to react with a compound represented by formula (IX) (In the formula, R １ , R ３ , R ４ and R ５ as defined in claim 1. A method for producing a compound represented by formula (IX), comprising the step of obtaining a compound represented by formula (IX):

15. In a mixed solvent of water and an alcohol-based organic solvent, a compound represented by formula (VII) is (In the formula, R １ , R ３ and R ４ is as described in claim 1. The compound represented by the formula (VIII) is reacted with an alkali metal hydroxide to obtain a compound represented by the formula (VIII): (In the formula, R １ , R ３ and R ４ is as defined above.

16. R ２ When R is a hydrogen atom, the two hydroxyl groups are protected by an acetal protecting group, ２ R ２ａ When R ２ａ By deprotection of the compound of formula (VI) (In the formula, R １ and R ２ is as described in claim 11. The compound represented by formula (VII) (In the formula, R １ is as defined in claim 11, and R ３ and R ４ as defined in claim 1. A method for producing a compound represented by formula (VII), comprising the step of converting 17. Formula (VR) (In the formula, R １ is as defined in claim 1, and R ２ａ is a silyl protecting group or a carbamate protecting group.) is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound to obtain a compound represented by formula (VI-R) (In the formula, R １ and R ２ａ is as defined above.

18. Formula (IV) (In the formula, R １ The amino group of the compound represented by the formula (I) is protected by a protecting group R ２ａ and protecting the compound represented by the formula (VR) (In the formula, R １ is as defined above, R ２ａ is a silyl protecting group or a carbamate protecting group.

19. Formula (IV) (In the formula, R １ is as described in claim 1. The present invention provides a compound represented by the formula (VI-H) by protecting the amino group of the compound represented by the formula (VI-H) without isolating the compound, and reacting the compound with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) reacting the compound with an osmium-containing compound in the presence of potassium hexacyanoferrate (III) and potassium carbonate, or reacting the compound with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) reacting the compound with a permanganate compound. (In the formula, R １ is as defined above.

20. In a mixed solvent of an ether-based organic solvent and an alcohol-based organic solvent, a compound represented by the formula (III) is (In the formula, R １ is as described in claim 1, and Boc is a tert-butoxycarbonyl group.) is reacted with an alkali metal alkoxide, and without isolating the product, the amino group is protected with a protecting group Boc to obtain a compound represented by the formula (V-Boc): (In the formula, R １ and Boc are as defined above.

21. In a mixed solvent of water and an alcohol-based organic solvent, a compound represented by formula (VII) is (In the formula, R １ , R ３ and R ４ is as described in claim 1. The compound represented by the formula (VIII) is reacted with an alkali metal hydroxide to obtain a compound represented by the formula (VIII): (In the formula, R １ , R ３ and R ４ is as defined above; and reacting the compound represented by formula (VIII) with a compound represented by formula (XX) (In the formula, R ５ is as defined in claim 1. (In the formula, R １ , R ３ , R ４ and R ５ is as defined above.

22. Protection of two hydroxyl groups with acetal-based protecting groups and R ２a By deprotection of the compound of formula (VI-R) (In the formula, R １ is as defined above, R ２ａ is a silyl protecting group or a carbamate protecting group. (In the formula, R １ , R ３ and R ４ is as defined above, or by protecting the two hydroxyl groups with an acetal protecting group, to obtain a compound represented by formula (VI-H): (In the formula, R １ is as defined above.) with a compound represented by formula (VII) (In the formula, R １ , R ３ and R ４ wherein R is as defined above.

23. Formula (VR) (In the formula, R １ and R ２ａ is as defined above.) is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound to obtain a compound represented by formula (VI-R) (In the formula, R １ and R ２ａ The method of claim 22, further comprising the step of obtaining a compound represented by the formula:

24. Formula (IV) (In the formula, R １ is as defined above, and the amino group of a compound represented by the formula (VI-H) is protected, and without isolation, the compound is reacted with a ruthenium-containing compound in the presence of periodic acid or a salt thereof, (2) with an osmium-containing compound in the presence of potassium hexacyanoferrate(III) and potassium carbonate, or with an osmium-containing compound in the presence of N-methylmorpholine-N-oxide, or (3) with a permanganate compound. (In the formula, R １ The method of claim 22, comprising obtaining a compound represented by the formula:

25. Formula (IV) (In the formula, R １ is as defined above. ２ａ and protecting the compound represented by the formula (VR) (In the formula, R １ and R ２ａ The method of claim 23, further comprising the step of obtaining a compound represented by the formula:

26. In a mixed solvent of an ether-based organic solvent and an alcohol-based organic solvent, (In the formula, R １ is as defined above, and Boc is a tert-butoxycarbonyl group, with an alkali metal alkoxide, and protecting the amino group with a protecting group Boc without isolating the product, (In the formula, R １ and Boc are as previously defined.

27. In a mixed solvent of an ether-based organic solvent and an alcohol-based organic solvent, (In the formula, R １ is as defined above, and Boc is a tert-butoxycarbonyl group. (In the formula, R １ The method according to claim 24 or 25, comprising obtaining a compound represented by the formula:

28. In the presence of an alkali metal alkoxide, a compound represented by the formula (I) (wherein Boc is as defined above) is reacted with a compound represented by formula (XXX) (In the formula, R １ is as defined above, and X is a halogen atom, to obtain a compound represented by formula (II): (In the formula, R １ and Boc are as defined above; and reacting the compound represented by formula (II) with p-toluenesulfonic acid or pyridinium p-toluenesulfonate to obtain a compound represented by formula (III): (In the formula, R １ and Boc are as previously defined.

29. A crystal of the compound represented by the following formula (A): A-type crystal exhibiting peaks at diffraction angles (2θ) of 4.8°, 6.4°, 19.0° and 21.3° in a powder X-ray diffraction pattern.

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