WO2010101061A1

WO2010101061A1 - Nucleoside-type antibiotic derivative

Info

Publication number: WO2010101061A1
Application number: PCT/JP2010/052903
Authority: WO
Inventors: 彰松田; 聡市川
Original assignee: 塩野義製薬株式会社; 国立大学法人北海道大学
Priority date: 2009-03-03
Filing date: 2010-02-24
Publication date: 2010-09-10
Also published as: JP2012102019A

Abstract

Disclosed are a compound having an antibacterial activity, more preferably an antibacterial nucleoside compound that can inhibit the activity of MraY to exert an antibacterial activity, particularly a novel derivative of Muraymycin that is an MraY inhibitor. Specifically disclosed is a novel derivative of Muraymycin or a pharmaceutically acceptable salt thereof. The compound can be supplied synthetic chemically and readily while maintaining the activity thereof at a level equivalent to or higher compared with those of conventional nucleic acid-type antibiotics.

Description

Nucleoside antibiotic derivatives

The present invention relates to a substance having antibacterial activity.

Nucleosides are one of the most important biological substances. These are not only the components of DNA and RNA that control the storage and expression of genetic information, but also function as coenzymes and intracellular signaling substances, and are involved in intracellular metabolism and energy supply. Have a role to play. Nucleosides have long been recognized as a good lead for conducting drug discovery chemistry research, and various nucleoside compounds have been clinically used.

On the other hand, naturally, there are compounds containing nucleosides in the structure. Some of these have useful activities such as anti-cancer, anti-viral, anti-bacterial and anti-fungal activities. Therefore, nucleoside natural products can be good leads for drug development.

In order to realize the potential value as a drug discovery lead as a product in drug discovery research, improvement of physical and chemical stability and activity, simplification of structure, addition of new functions, etc. Modifications are required, and chemical modifications based on synthetic organic chemistry are used.

However, there are several problems to be overcome in the method for synthesizing nucleoside derivatives. For example, since nucleobase, which is a nitrogen-containing aromatic ring, is contained in the substrate, the reagents that can be used are limited due to its high coordination ability, and aldehydes and ketone bodies that are used as raw materials for the carbon increase reaction to the sugar part However, it is unstable under various reaction conditions. In order to overcome these problems, the inventors have conducted synthetic studies on antibacterial nucleosides having a novel mechanism of action.

Peptidoglycan is a main component of the cell wall, and MraY (intracellular membrane enzyme translocase I) acts as an essential enzyme in the biosynthetic pathway. Therefore, the MraY inhibitor that can be a cell wall synthesis inhibitor has recently attracted attention as a new target for the development of antibacterial agents, and is expected to lead to the creation of drugs that are widely effective against bacteria including drug-resistant bacteria. . Because it is located upstream in the biosynthetic pathway from targets of glycopeptides (vancomycin, teicoplanin) and β-lactam antibiotics that are currently widely used in clinical practice, MraY inhibitors are resistant to drug-resistant bacteria such as MRSA and VRE. It is expected to lead to the creation of drugs that are broadly effective against bacteria containing them (see Non-Patent Document 1 and Non-Patent Document 2).

So far, isolation of nucleoside compounds having a novel mechanism of action and antibacterial activity and synthetic studies on derivatives have been conducted.

FR-900493 is a natural product of nucleoside having a broad antibacterial spectrum isolated from Bacillus subtilis by Fujisawa Pharmaceutical Co., Ltd. in 1989 (see Patent Documents 1 and 2). Murraymycins are natural products isolated by Wyeth in 2002 and showed excellent therapeutic effects in a strong MraY inhibitory activity and in vivo activity test using S. aureus infected mice. Moreover, no side effects such as toxicity have been reported in in vivo experiments, and it is expected as a lead for the development of new antibacterial agents (see Patent Documents 3 to 6, Non-Patent Documents 3 and 4). Examples of other nucleoside compounds having an antibacterial action include those described in Patent Documents 3 to 20 and Non-Patent Documents 5 to 9.

Japanese Unexamined Patent Publication No. 1-296992 Japanese Patent Laid-Open No. 5-78385 International Publication No. 2002/085310 Pamphlet International Publication No. 2002/085867 Pamphlet International Publication No. 2002/086139 Pamphlet International Publication No. 2001/12643 Pamphlet International Publication No. 2004/067544 Pamphlet International Publication No. 2008/020560 Pamphlet Japanese Patent Application Laid-Open No. 2003-12687 International Publication No. 97/41248 Pamphlet Japanese Patent Application Laid-Open No. 5-47560 International Publication No. 2004/046368 Pamphlet Japanese Patent Application Laid-Open No. 2005-247725 Japanese Patent Application Laid-Open No. 2008-74710 Japanese Patent Application Laid-Open No. 2004-196780 Japanese Patent Application Laid-Open No. 2005-247725 JP 2006-111594 A Japanese Patent Application Laid-Open No. 2008-74710 Special table 2007-518723 specification JP-A-2-306992

An object of the present invention is to provide a compound having antibacterial activity. More preferably, the present invention provides an antibacterial nucleoside compound that exhibits antibacterial activity by inhibiting the action of MraY, particularly a novel derivative of Muramycin that is a MraY inhibitor.

The present invention provides the following items.
(Item 1)
Formula (I):

Wherein R ¹ is —OH, —O-lower alkyl, or —NR ⁸ R ⁹ ;
R ² is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, or aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl;
R ⁴ and R ⁵ are each independently hydrogen, lower alkyl, carbocyclic ring, heterocyclic ring, carbocyclic alkyl, heterocyclic alkyl, or either R ⁴ or R ⁵ is taken together with R ^3. May form a heterocyclic ring,
R ⁶ and R ⁷ are each independently hydrogen or lower alkyl,
R ⁸ and R ⁹ are each independently hydrogen, C1-C20 alkyl, carbocyclic ring, heterocyclic ring, carbocyclic alkyl, heterocyclic alkyl, or R ⁸ and R ^{9 taken} together to form a heterocyclic ring. May be formed,
m is an integer of 0-3. )
Or a pharmaceutically acceptable salt or solvate thereof.
(Item 2)
The compound according to item (1), wherein R ¹ is —OH, or —O-lower alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 3)
The compound according to item (1) or (2), wherein R ¹ is —NR ⁸ R ⁹ , or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 4)
R ⁸ and R ⁹ are each independently hydrogen, C1-C20 alkyl, carbocyclic ring, heterocyclic ring, or R ⁸ and R ⁹ may be combined together to form a heterocyclic ring ( The compound according to any one of 1) to (3), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 5)
The compound according to any one of items (1) to (4), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is C1-C20 alkyl.
(Item 6)
R ² is C1-C20 alkyl, C9-C20 alkenyl, C3-C20 alkynyl, C1-C20 alkyl, C2-C20 alkenyl or C2-C20 item is aryl substituted with alkynyl (1) either to (5) Or a pharmaceutically acceptable salt or solvate thereof.
(Item 7)
The compound according to any one of items (1) to (6), wherein R ² is C11-C20 alkyl, C9-C20 alkenyl, C1-C10 alkyl, or aryl substituted with C2-C10 alkenyl, or a compound thereof A pharmaceutically acceptable salt or a solvate thereof.
(Item 8)
The compound according to any one of items (1) to (7), wherein R ² is C11-C20 alkyl, or C9-C20 alkenyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 9)
The compound according to any one of items (1) to (8), wherein R ² is lower alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 10)
The compound according to any one of items (1) to (3), wherein R ² is lower alkyl, and R ⁸ and R ⁹ are both lower alkyl, or a pharmaceutically acceptable salt thereof, or a compound thereof Solvate.
(Item 11)
The compound according to any one of items (1) to (10), wherein R ³ is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 12)
R ⁴ and R ⁵ are each independently hydrogen, lower alkyl, or any one of R ⁴ or R ⁵ together with R ³ may form a heterocyclic ring (1) to (11) Or a pharmaceutically acceptable salt or solvate thereof.
(Item 13)
The compound according to any one of items (1) to (12), wherein R ⁶ and R ⁷ are both hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 14)
A pharmaceutical composition comprising the compound according to any one of items (1) to (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 15)
The pharmaceutical composition according to item (14) having MraY inhibitory action.
(Item 16)
The pharmaceutical composition according to item (14) or (15), which has antibacterial activity.
(Item 17)
The compound according to any one of items (1) to (13), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic and / or prophylactic agent for various diseases caused by pathogenic bacteria Use of things.
(Item 18)
The compound according to any one of items (1) to (13), a pharmaceutically acceptable salt thereof, or a solvate thereof for the treatment and / or prevention of various diseases caused by pathogenic bacteria.
(Item 19)
Treatment of various diseases caused by pathogenic bacteria, and / or administration of a compound according to any one of items (1) to (13), a pharmaceutically acceptable salt thereof, or a solvate thereof, and / or Or prevention methods.
(Item 20) A pharmaceutical composition according to any of items (14) to (16), which treats various diseases caused by pathogenic bacteria described below: a respiratory tract infection, Urinary tract infection, respiratory infection, sepsis, nephritis, cholecystitis, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection, etc.
(Item 21) A nucleic acid antibiotic comprising the compound according to any one of items (1) to (13), a pharmaceutically acceptable salt thereof, or a solvate thereof.

From the foregoing, these and other advantages of the present invention will be apparent upon reading the following detailed description.

The compound according to the present invention can be easily supplied synthetically and chemically while having the same or higher activity as compared with existing nucleic acid antibiotics. The supply of an existing compound group requires the steps of synthesizing a furanose ring synthon and its glycosylation reaction, but the compound according to the present invention can be supplied in a short step without going through these steps.

Throughout this specification, it should be understood that expression in the singular includes the plural concept unless otherwise stated. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in the case of English) also include the plural concept unless otherwise stated. Also, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs unless stated otherwise. In case of conflict, the present specification, including definitions, will control.

The meaning of each term used in this specification is explained below. Each term is used in a unified sense and is used with the same meaning whether used alone or in combination with other terms.

In the present specification, “alkyl” includes a linear or branched monovalent hydrocarbon group. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, Examples thereof include n-nonanyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetra syl, n-pentadecyl, n-hexadecyl and the like.

In the present specification, “lower alkyl” includes linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like.

In the present specification, “alkenyl” includes linear or branched alkenyl having one or more double bonds at an arbitrary position. Specifically vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, tetradecenyl, decenyl, decenyl , Pentadecenyl and the like.

In the present specification, “alkynyl” includes linear or branched alkynyl. Specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are included. These may further have a double bond at an arbitrary position.

In the present specification, “carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, non-aromatic fused carbocyclic group and the like.

In the present specification, specifically, “cycloalkyl” is a carbocyclic group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 4 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, Examples include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.

In the present specification, specifically, “cycloalkenyl” includes those having one or more double bonds at any position in the ring of the cycloalkyl, specifically cyclopropenyl, cyclobutenyl. , Cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, cyclohexadienyl and the like.

In the present specification, specifically, “aryl” includes phenyl, naphthyl, anthryl, phenanthryl and the like, and phenyl is particularly preferable.

In the present specification, specifically, the “non-aromatic fused carbocyclic group” is a group in which two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl” are condensed. Specific examples include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.

In the present specification, “aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl” means aryl substituted with alkyl, alkenyl or alkynyl having the number of carbon atoms within the range. And the aryl moiety is the same as the above “aryl”. Preferred embodiments are phenyl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl. A more preferred embodiment is phenyl substituted with C1-C10 alkyl or C2-C10 alkenyl.

In the present specification, the carbocyclic part of “carbocyclic alkyl” is the same as the above “carbocyclic group”.

In the present specification, the alkyl part of “carbocycle alkyl” is the same as the above “alkyl”.

In the present specification, the “heterocyclic group” is a heteroaryl, non-aromatic heterocyclic group or bicyclic ring having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring. And heterocyclic groups such as tricyclic fused heterocyclic groups.

In the present specification, specifically, “heteroaryl” refers to pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiazolyl And 5- to 6-membered aromatic cyclic groups.

In the present specification, specifically, the `` non-aromatic heterocyclic group '' means dioxanyl, thiylyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, Piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, Tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl and the like can be mentioned.

In the present specification, specifically, “bicyclic fused heterocyclic group” means indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl , Benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Zolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl, imidazopyridyl, pyrazolopyridyl, thiazolopyridy , Pyrazolopyrimidinyl, pyrazolotrianidyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydro Isoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxinyl , Dihydrobenzooxedinyl, dihydrobenzodioxepinyl, dihydrothienodioxinyl and the like.

In the present specification, specific examples of the “tricyclic fused heterocyclic group” include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, tetrahydrocarbazolyl and the like. .

In the present specification, a preferred embodiment of the “heterocyclic group” is a 5- to 6-membered heteroaryl or non-aromatic heterocyclic group.

In the present specification, the substituent of “substituted or unsubstituted carbocyclic group” and “substituted or unsubstituted heterocyclic group” is one or more selected from the group consisting of lower alkyl and substituent group α. The group of is mentioned.

Here, the substituent group α is halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, guanidino, hydroxyimino, A group consisting of lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano and nitro.

In the present specification, “lower alkoxy”, “hydroxy lower alkoxy”, “lower alkoxy lower alkoxy”, “lower alkoxycarbonyl”, “lower alkylamino”, “lower alkoxyimino”, “lower alkylthio”, “lower alkylcarbamoyl” ”,“ Hydroxy lower alkyl carbamoyl ”,“ lower alkyl sulfamoyl ”and“ lower alkyl sulfinyl ”are the same as the above“ lower alkyl ”.

In the present specification, the heterocyclic portion of “heterocyclic alkyl” is the same as the above “heterocyclic group”.

In the present specification, the alkyl part of “heterocyclic alkyl” is the same as the above “alkyl”.

In the present specification, a heterocyclic ring of “R ⁴ or R ⁵ together with R ³ forms a heterocyclic ring” and “R ⁸ and R ⁹ together form a heterocyclic ring” are also included. The same as the above “heterocycle”.

In the present specification, the “solvate” includes, for example, a solvate with an organic solvent (for example, an alcohol (eg, ethanol) solvate), a hydrate and the like. When forming a hydrate, it may be coordinated with any number of water molecules.

As the pharmaceutically acceptable prodrug, any form known in the art can be adopted. Prodrugs take the metabolic mechanism of the body in reverse, and in their original form do not show drug action or only show very weak activity, but they show pharmacological activity only after being metabolized in vivo Or it has been modified to increase its pharmacological activity. In addition to salts and solvates, esters, amides and the like can also be mentioned as examples of prodrugs.

The compounds of the present invention include pharmaceutically acceptable salts. For example, alkali metals (such as lithium, sodium or potassium), alkaline earth metals (such as magnesium or calcium), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphorus Acid or hydroiodic acid) and organic acids (acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, Benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like). In particular, hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable. These salts can be formed by a commonly performed method.

Further, the compounds of the present invention are not limited to specific isomers, and all possible isomers (keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ) And racemates.

The feature of the compound according to the present invention is that the aminofuranose moiety of Murraymycins is represented by the partial structural formula (I ′) in the formula (I)

(Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and m are as defined above.)
Is converted to.

Another feature of the compounds according to the invention is that for R ^{2 of} formula (I), C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or C1-C20 alkyl, C2-C20 alkenyl or C2-C20 Application of aryl substituted with alkynyl.

Preferred embodiments of R ² are aryl substituted with C1-C20 alkyl, C9-C20 alkenyl, C3-C20 alkynyl or C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl.

A more preferred embodiment of R ² is aryl substituted with C11-C20 alkyl, C9-C20 alkenyl, or C1-C10 alkyl, or C2-C10 alkenyl.

A more preferred embodiment of R ² is C11-C20 alkyl or C9-C20 alkenyl.

Yet another feature of the compounds according to the invention is that lower alkyl is applied to R ^{2 of} formula (I) and C1-C20 alkyl is applied to R ⁸ .

A preferred embodiment of R ⁸ in this case is C5-C20 alkyl, a more preferred embodiment is C10-C20 alkyl, and a further preferred embodiment is C15-C20 alkyl.

The compound of the present invention is advantageous in synthesis by having the above structure. In addition, intracellular migration and antibacterial activity are improved.

(Method for producing the compound of the present invention)
A general method for producing the compound of the present invention is illustrated below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.

The synthesis of the compound of the present invention can be carried out in consideration of a technique known in the art.

The raw material compounds are commercially available compounds, those described in Non-Patent Documents 5 and 6, those described in the present specification, and those described in other references cited in the present specification, and In addition, known compounds can be used.

Some of the compounds of the present invention may have tautomers, positional isomers and optical isomers, but the present invention includes all possible isomers and mixtures thereof, including these. To do.

When obtaining a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or base is added to form a salt by a conventional method.

In addition, the compounds of the present invention and pharmaceutically acceptable salts thereof may exist in the form of adducts (hydrates or solvates) with water or various solvents, and these adducts are also included in the present invention. Is included.

Examples of the compound of the present invention are variously listed in the Examples, and those skilled in the art can produce and use compounds not exemplified in the present invention with reference to these.

Representative general synthetic methods for the compounds of the present invention described in the examples are shown in the following general synthetic methods. The compounds described in the examples were synthesized generally according to these, but are not particularly limited to these methods. Reaction solvents, bases, reducing agents and the like that can be used in the production of the compounds are described below. In the following general synthesis methods, preferred ones are shown, but the present invention is not particularly limited thereto.
(1) Reaction solvent: N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (example) , Toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl) Ethers, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, Methanol, ethanol, t-butanol, etc.), water and A mixed solvent thereof.
(2) Base: metal hydride (eg, sodium hydride), metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonate (eg, sodium carbonate) , Potassium carbonate, calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metallic sodium, organic amine (eg, triethylamine, diisopropylethylamine, dia) Zabicycloundecene (DBU), 2,6-lutidine, etc.), pyridine, alkyl lithium (n-butyl lithium (n-BuLi), sec-butyl lithium (sec-BuLi), tert-butyl lithium (tert-BuLi) )etc.
(3) Reducing agent: supported metal such as Pd carbon used in H ₂ atmosphere, sodium borohydride, lithium borohydride, sodium triacetoxyborohydride, borane complex, diisobutylaluminum hydride, sodium borohydride sodium Bis (2-methoxyethoxy) aluminum sodium hydride (Red-Al ^™ ), lithium aluminum hydride and the like.

Compound (I) according to the present invention can be produced by the following method.

General synthesis example A: Synthesis of compound (A3)

Wherein R ¹ , R _a ¹ and R _a ² are each independently substituted or unsubstituted lower alkyl, and Pg ¹ is a tert-butoxycarbonyl (t-Boc) group, benzyloxycarbonyl (Cbz ) Group and other amino protecting groups, and other symbols are as defined above)
Non-patent document 5 also discloses a similar synthesis method. Compound (A3) can be synthesized by the following steps using a synthesis method similar to the disclosed method.

First Step A compound (A1) that is commercially available or can be prepared by a known method is represented by R _a ¹ R _a ² C (═O) in the presence of an acid such as concentrated sulfuric acid in a solvent such as toluene, chloroform, or dichloromethane. An acetal-protected compound can be obtained by reacting with a ketone at 0 ° C. to 150 ° C., preferably 0 ° C. or less, for 0.5 to 24 hours, preferably 1 to 12 hours.

Second Step The acetal-protected compound obtained above is subjected to 0 to 150 ° C. in the presence of an oxidizing agent such as 2-iodoxybenzoic acid (IBX) in a solvent such as acetonitrile, toluene, chloroform, dichloromethane, and tetrahydrofuran. The aldehyde compound can be obtained by reacting at 0.5 ° C., preferably under reflux conditions, for 0.5 to 24 hours, preferably for 1 to 12 hours.

The third step above-obtained aldehyde compound, acetonitrile, toluene, chloroform, dichloromethane, in a solvent such as _{tetrahydrofuran,} at _{^{Ph 3 P = CHCO 2 R 1}} (R x O) 2 P (O) CH 2 CO 2 R ¹ ) an ylide obtained by base treatment of the compound shown or (R _x O) ₂ P (O) CH ₂ CO ₂ R ¹ ) (wherein R _x is a phosphate protecting group such as lower alkyl); Compound (A2) can be obtained by reacting at 80 ° C. to 50 ° C., preferably −80 to −20 ° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.

Fourth Step In a solvent such as alcohol, acetonitrile or tetrahydrofuran, the compound (A2) is present in the presence of t-BuOCl / NaOH, and a chiral ligand such as K ₂ OsO ₂ (OH) ₄ catalyst and [DHQD] ₂ AQN In the presence of Pg′NH ₂ is reacted at −80 ° C. to 50 ° C., preferably 0 to 25 ° C., for 0.1 to 24 hours, preferably 0.5 to 12 hours ( The compound (A3) can be obtained by so-called sharpened asymmetric aminohydroxylation reaction.

General synthesis example B: Synthesis of compound (A9)

(Wherein Pg ² is a hydroxy-protecting group such as trimethylsilyl (TMS) group, t-butyldimethylsilyl (TBDMS) group, and other symbols are as defined above).
First Step Compound (A3) is dissolved in a solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or a mixed solvent such as ethanol-water in the presence of an acid such as trifluoroacetic acid, preferably at 0 ° C. to 150 ° C. By reacting at 20 ° C. to 100 ° C. for 0.5 to 24 hours, preferably 1 to 12 hours, a compound in which only the acetal protecting group is deprotected can be obtained.

Second Step The above deprotected compound is converted into Pg ² -X ¹ (X ¹ is chlorine, fluorine, bromine, iodine, etc.) in a solvent such as dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran and the like in the presence of a base such as imidazole. And a compound represented by the following formula: Thus, compound (A4) can be obtained.

Third Step Reduction of compound (A4) with a metal such as palladium hydroxide / carbon in a solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or a mixed solvent such as ethanol-water, for example, in an H ₂ atmosphere. Under the conditions, by reacting at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 to 24 hours, preferably for 1 to 12 hours, only the Pg ^1- group moiety is reduced, and the compound ( A5) can be obtained.

Fourth Step Compound (A5) is dissolved in a solvent such as dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran, etc.

To produce an intermediate (A6) by reacting at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 to 24 hours, preferably 1 to 12 hours. Can do.

Fifth Step An acyl represented by the above intermediate (A6) is represented by R ² C (═O) X ¹ (X ¹ represents a halide such as chlorine, fluorine, bromine or iodine) in the presence of a base such as triethylamine. Compound (A7) can be obtained by reacting with a halide at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.

Sixth Step The compound (A7) is reduced at 0 ° C. to 150 ° C. under reducing conditions using thiophenol (PhSH) and sodium thioacetate (NaSMe) in a solvent such as dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran and the like. Compound (A8) is preferably obtained by reacting at 20 ° C. to 100 ° C. for 0.5 hour to several days, preferably 1 hour to 3 days to deprotect the R ¹ group and reduce the azido group moiety. Can be obtained.

Step 7 Presence of compound (A8) in a solvent such as acetonitrile, dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran or a mixed solvent thereof such as a hydrogen fluoride salt such as 3HF • Et ₃ N complex, HF • pyridine complex The Pg ² group is deprotected by reacting at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. for 0.5 hour to several days, preferably 1 hour to 3 days. Can be obtained.

In another embodiment of General Synthesis Method B, Compound (A8) can be obtained from Compound (A7) via Compound (A10) by the following general synthesis method B ′.

General synthesis method B ': Synthesis of compound (A8)

(Wherein each symbol is as defined above)
First Step a) Compound (A7) is treated with thiophenol (PhSH) and sodium thioacetate (NaSMe) in a solvent such as dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran and the like at 0 ° C. to 150 ° C., preferably 20 ° C. By reacting at -100 ° C. for 0.5 hour to several days, preferably 1 hour to 3 days, the R ¹ group can be deprotected to obtain compound (A10). Or b) Compound (A7) is treated with lithium iodide (LiI) in a solvent such as ethyl acetate, dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran and the like for 0.5 hour to several days, preferably 1 hour to 3 By heating for a day (40 ° C. to 150 ° C.), only the R ¹ group can be deprotected to obtain the compound (A10).

Second Step Reduction of compound (A10) with a metal such as palladium hydroxide / carbon in a solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or a mixed solvent such as ethanol-water, for example, in an H ₂ atmosphere. Under the conditions, the azide group moiety is reduced by reacting at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. for 0.5 to 24 hours, preferably 1 to 12 hours, to give compound (A8 ) Can be obtained.

In another embodiment of the general synthesis method B, the compound (A9) can be obtained from the compound (A10) by the following general synthesis method B ″.

General synthesis method B ′ ′: Synthesis of compound (A9)

(Wherein each symbol is as defined above)
First Step The compound (A10) is converted into a hydrogen fluoride salt such as 3HF · Et ₃ N complex, HF · pyridine complex, etc. in a solvent such as acetonitrile, dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran or a mixed solvent thereof. Compound (A13) in which only Pg ² group is deprotected by reacting in the presence at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 hour to several days, preferably 1 hour to 3 days. ) Can be obtained.

Second Step The obtained compound (A13) is converted into a metal such as palladium hydroxide / carbon in a solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or a mixed solvent such as ethanol-water, for example, in an H ₂ atmosphere. By reducing the azido group moiety by reacting at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours, under reducing conditions using Compound (A9) can be obtained.

General synthesis method C: Synthesis of compound (A11)

(Wherein each symbol is as defined above)
First Step The compound (A7) is converted to a hydrogen fluoride salt such as 3HF · Et ₃ N complex, HF · pyridine complex, etc. in a solvent such as acetonitrile, dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran or a mixed solvent thereof. Compound (A14) in which only Pg ² group is deprotected by reacting in the presence at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 hour to several days, preferably 1 hour to 3 days. ) Can be obtained.

Second Step The obtained compound (A14) is converted into a metal such as palladium hydroxide / carbon in a solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or a mixed solvent such as ethanol-water, for example, in an H ₂ atmosphere. By reducing the azido group moiety by reacting at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours, under reducing conditions using Compound (A11) can be obtained.

General synthesis method D: Synthesis of compound (A12)

(Wherein each symbol is as defined above)
In the presence of a base such as triethylamine in a solvent such as dimethylformamide, toluene, chloroform, dichloromethane, tetrahydrofuran, etc., compound (A11) is converted to R ³ —X ² (X ² is a halide such as chlorine, fluorine, bromine or iodine). And a suitable leaving group) at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 to 24 hours, preferably for 1 to 12 hours. A compound (A12) can be obtained.

Or Compound (A11), ethyl acetate, toluene, chloroform, dichloromethane, in a solvent such as tetrahydrofuran, acid and Sodium triacetoxyborohydride such as acetic (NaBH _{(OAc) 3),} sodium cyanotrihydroborate (NaBH ₃ CN) and the like, in the presence of a reducing agent, a compound represented by R _y —CHO (where R ³ = R _y —CH ₂ —, wherein R _y represents hydrogen or lower alkyl), Compound (A12) can be obtained by reacting at −150 ° C., preferably 20 ° C. to 60 ° C., for 0.5 to 24 hours, preferably for 1 to 12 hours.

General synthesis method E: Synthesis of compound (A15)

(Wherein each symbol is as defined above)
First Step The compound (A10) is reacted with N, N′-dimethylformamide (DMF), dioxane, ethyl acetate, toluene, chloroform, dichloromethane, tetrahydrofuran and the like, for example, N-hydroxybenzotriazole (HOBt) and 1- An amine represented by R ⁸ R ⁹ NH in the presence of [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI), dicyclocarbodiimide, or bis (2-oxo-3-oxazolidinyl) phosphonic chloride And 0 ° C. to 150 ° C., preferably 20 ° C. to 60 ° C., for 0.5 hours to 24 hours, preferably 1 hour to 12 hours, compound (A15) can be obtained.

Second Step A compound (A16) in which the Pg ² group is deprotected can be obtained from the compound (A15) by the same method as in the first step of the general synthesis method B ″.

Third Step A compound (A17) obtained by reducing the azide group moiety from the compound (A16) can be obtained in the same manner as in the second step of the general synthesis method B ″.

In all of the above steps, if there are substituents that interfere with the reaction (for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) Or the like, and the protecting group may be removed at a desired stage.

In addition, for all the above steps, the order of the steps to be performed can be appropriately changed, and each intermediate may be isolated and used in the next step.

(Preferred embodiment)
Preferred embodiments of the present invention are illustrated below. Each symbol has the same meaning as described above.

Of the compounds according to the present invention, the following compounds are preferred.

The definition of each substituent is synonymous with the above item (1) unless otherwise specified.

General formula (I):

In
(A1)
(A1-1) Examples of R ¹ include —OH, —O-lower alkyl, or —NR ⁸ R ⁹ .
(A1-2) R ¹ is preferably a group represented by —NR ⁸ R ⁹ .
(A1-3) R ¹ is more preferably a group which is —OH or —O-lower alkyl.

(A2)
(A2-1) R ² includes C1-C20 alkyl, C2-C20 alkenyl, or aryl substituted with C2-C20 alkynyl, C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl.
(A2-2) R ² is preferably a group which is an aryl substituted with C1-C20 alkyl, C9-C20 alkenyl, C3-C20 alkynyl, C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl. Can be mentioned.
(A2-3) R ² is more preferably a group which is C11-C20 alkyl, C9-C20 alkenyl, or C1-C10 alkyl, or aryl substituted with C2-C10 alkenyl.
(A2-4) R ² is most preferably a group which is C11-C20 alkyl or C9-C20 alkenyl.

(A3)
(A3-1) R ³ includes a group which is hydrogen or lower alkyl.
(A3-2) R ³ is preferably hydrogen.

(A4)
(A4-1) R ⁴ and R ⁵ are each independently hydrogen, lower alkyl, a carbocyclic group, a heterocyclic group, a carbocyclic alkyl, a heterocyclic alkyl group, or R ⁴ or Any of R ⁵ may be combined with R ³ to form a heterocyclic ring.
(A4-2) R ⁴ and R ⁵ are preferably each independently a group which is hydrogen or lower alkyl, or either R ⁴ or R ⁵ together with R ³ forms a heterocyclic ring You may do it.

(A6)
(A6-1) Examples of R ⁶ and R ⁷ include groups each independently being hydrogen or lower alkyl.
(A6-2) is preferably a ^{R 6} and ^{R 7,} ^{R 6} and ^{R 7} are both hydrogen.

(A8)
(A8-1) R ⁸ and R ⁹ each independently include a group that is hydrogen, C1-C20 alkyl, a carbocyclic group, a heterocyclic ring, a carbocyclic alkyl, or a heterocyclic alkyl, or R ⁸ and R ⁹ may be taken together to form a heterocyclic ring.
(A8-2) R ⁸ and R ⁹ are preferably each independently a group which is hydrogen, C1-C20 alkyl, a carbocyclic group or a heterocyclic ring, or R ⁸ and R ⁹ together And may form a heterocyclic ring.
(A8-3) R ⁸ is more preferably C1-C20 alkyl.
(A8-4) R ⁹ is more preferably hydrogen.

(Am)
m is an integer of 0-3.

In the embodiment of the present invention, compounds in which the substituents of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ and the combination of m are as follows are preferred: :
R ¹ is any ^one of (A1-1) to (A1-3);
R ² is any one of (A2-1) to (A2-5);
R ³ is any one of (A3-1) to (A3-2);
R ⁴ is any one of (A4-1) to (A4-2);
R ⁵ is any one of (A4-1) to (A4-2),
R ⁶ is any one of (A6-1) to (A6-2),
R ⁷ is any one of (A6-1) to (A6-2),
R ⁸ is any one of (A8-1) to (A8-3),
R ⁹ is any one of (A8-1), (A8-2) and (A8-4);
A compound wherein m is (Am).

As the compound of the general formula (I), its pharmaceutically acceptable salt or solvate thereof, a compound represented by all possible combinations of all the above-mentioned options for each substituent, its pharmaceutically acceptable Salts or their solvates are included.

(Medicine)
The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. In addition, these pharmaceutical preparations are used for animals and humans.

The compound according to the present invention is a nucleic acid antibiotic. The compounds of the present invention have a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, gallbladder It can be used for the prevention or treatment of inflammation, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.

The compound according to the present invention is particularly effective against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Staphylococcus pneumoniae (PRSP), vancomycin-resistant enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA) and the like. High antibacterial activity. It also exhibits antibacterial activity against gram-negative bacteria including Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae and the like. A compound having an inhibitory effect on MraY acts at a position upstream in the biosynthetic pathway relative to the target of β-lactam antibiotics, and therefore, bacteria having resistance to β-lactam antibiotics, such as β-lactam resistant Pseudomonas aeruginosa, are used. It is expected to be effective against bacteria.

The compound according to the present invention can be easily supplied synthetically while having the same or higher activity as compared with existing nucleic acid antibiotics. The supply of the existing compound group requires the steps of synthesizing the furanose ring synthon and its glycosylation reaction, but the compound according to the present invention can be supplied in a short step without going through these steps. Specifically, the glycosylation reaction produces two isomers (α and β isomers) upon introduction, and separation of the stereoisomers is often difficult, but the present invention does not require this glycosylation step. Therefore, the compound can be supplied in a short process. Moreover, although the supply process of the existing compound group includes the urea dipeptide intermediate synthesis | combination often difficult, since this process is not required in this invention, a compound can be supplied more easily. Furthermore, the final product, compound (I), does not require separation of stereoisomers by, for example, HPLC fractionation, and has a synthetic chemical advantage. Furthermore, the compound according to the present invention has advantages such as high oral absorption, good bioavailability, a long half-life, and intracellular migration. From the above, the compound according to the present invention can be an excellent pharmaceutical product.

The dose varies depending on the disease state, administration route, patient age, or body weight, but when administered orally to an adult, it is usually 0.1 μg to 1 g / day, preferably 0.01 to 200 mg / day. In the case of parenteral administration, it is usually 1 μg to 10 g / day, preferably 0.1 to 2 g / day. The number of administration is preferably once a day or divided.

The administration route is preferably the most effective for treatment, and can be oral or parenteral, for example, rectal, buccal, subcutaneous, intramuscular, intravenous and the like.

Administration forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections, and the like. Liquid preparations such as emulsions and syrups suitable for oral administration are water, sugars such as sucrose, sorbit, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil And preservatives such as p-hydroxybenzoates, and flavors such as strawberry flavor and peppermint. In addition, capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl It can be produced using a binder such as alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin.

Formulations suitable for parenteral administration preferably comprise sterile aqueous preparations containing the active compound that is isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution or a mixture of salt water and a glucose solution.

Topical formulations are prepared by dissolving or suspending the active compound in one or more media such as mineral oil, petroleum, polyhydric alcohol and the like or other bases used in topical pharmaceutical formulations. A preparation for enteral administration is prepared using a normal carrier such as cacao butter, hydrogenated fat, hydrogenated fatty carboxylic acid and the like, and is provided as a suppository.

The compound of the present invention is a compound having utility as a medicine. Here, as usefulness as a medicine, it has a strong antibacterial activity because of its improved intracellular translocation, and is resistant to enzymes such as esterases in the blood, has a small clearance, or is halved. It includes points that are long enough for the period to have a medicinal effect.

The configuration of the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. The reagents used in the following were commercially available unless otherwise specified.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

In the examples and the present specification, the meaning of each abbreviation is as follows.
Me methyl Et ethyl i-Pr isopropyl t-Bu, ^t Bu t-butyl Ph phenyl Bn benzyl Boc t-butoxycarbonyl TFA trifluoroacetic acid THF tetrahydrofuran DMF N, N-dimethylformamide r.p. t. Room temperature aq. Aqueous solution Cbz Benzyloxycarbonyl TBS tert-butyldimethylsilyl Et ₃ N Triethylamine PhSH Thiophenol NaSMe Sodium methylthiolate MeOH Methanol 3HF · Et ₃ N Triethylamine trifluoride salt Pd (OH) ₂ / C Palladium hydroxide / Carbon AcOEt Ethyl acetate
^t BuOH tert-butanol AcCl acetyl chloride EDCI 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide HOBt N-hydroxybenzotriazole.

The underline in the NMR data in the examples indicates that the peak is a part with an underline.

Example 1 Synthesis of Compound (2)

(Wherein H ₂ SO ₄ represents sulfuric acid, IBX represents o-iodoxybenzoic acid, MeCN represents acetonitrile, CH ₂ Cl ₂ represents dichloromethane, and [DHQD] ₂ AQN represents bis (dihydroquinidino) anthraquinone. T-BuOCl represents t-butyl hypochlorite and NaOH represents sodium hydroxide.)
Compound (2) was synthesized by the method described in Hirono, S., Ichikawa, S., Matsuda, A., J. Org. Chem., 2007, 72, 9936 (Scheme 1).

Example 2 Synthesis of Compound (8a)

Compound (8a) was synthesized according to Scheme 2. Each process is shown in detail below.

Example 2-1 Synthesis of compound (3)

Compound (2) (1.4 g, 3.0 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (24 mL) and water (6 mL) and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution was dissolved in N, N-dimethylformamide (30 mL), and imidazole (1.8 g, 27 mmol) and tertiary butyldimethylsilyl chloride (1.4 g, 9.0 mmol) were dissolved at 0 ° C. Were added in order and stirred at room temperature for 3 days. After completion of the reaction, methanol (3 mL) was added to stop the reaction, and the reaction solution was partitioned between ethyl acetate (300 mL) and water (200 mL × 4). The organic layer was washed with 0.2 mol / L hydrochloric acid (200 mL), saturated aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (mobile layer: hexane / ethyl acetate = 2/1) to obtain compound (3) (1.6 g, 2.3 mmol, 75%) as a white solid.
^{1 H NMR (500 MHz, CDCl} 3) δ 8.57 (br s, 1H, -N H), 7.34-7.26 (m, 6H, - Ph, H-6, J 6, 5 = 8.0 Hz), 5.72 (d , 1H, H-5 J _{5, 6} = 8.0 Hz), 5.64 (br s, 1H, -CON H- ), 5.31 (d, 1H, H-1 ', J _{1', 2 '} = 5.7 Hz), 5.09 (m, 2H, -CO ₂ C H _2- ), 4.64 (br s, 1H, H-2 '), 4.48 (br s, 1H, H-6'), 4.36 (br s, 1H, -O H ), 4.12, (br s, 3H, H-3 ', H-4', H-5 '), 3.75 (s, 3H, -CO ₂ Me ), 0.89 (s, 9H, t-butyl), 0.85 (s, 9H, t-butyl), 0.07 (s, 3H, Si- Me ), 0.04 (s, 3H, Si- Me ), 0.03 (s, 3H, Si- Me ), 0.00 (s, 3H, Si- Me ); ESIMS-LR m / z 716 [(M + Na) ⁺ ]; ESIMS-HR calculated 716.3011, found 716.2993.

Example 2-2 Synthesis of compound (4)

Compound (3) (100 mg, 0.14 mmol) was dissolved in methanol (3 mL), palladium hydroxide / carbon (22 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (mobile layer: chloroform / methanol = 99/1) to give compound (4) (80.9 mg, 0.14 mmol, (Quantitative) was obtained as a white foam.
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.95 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.85 (d, 1H, H-1 ', J _{1', 2 '} = 5.2 Hz ), 5.76 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 4.29 (dd, 1H, H-2 ', J _{2', 1 '} = 5.2, J _{2', 3 '} = 4.6Hz ), 4.18 (dd, 1H, H-3 ', J _{3', 2 '} = 4.6, J _{3', 4 '} = 4.0 Hz), 4.08 (dd, 1H, H-4', J _{4 ', 3'} = 4.0, J _{4 ', 5'} = 1.2 Hz), 3.80 (s, 3H, -CO ₂ Me ), 3.71 (d, 1H, H-5 ', J _{5', 6 '} = 7.5 Hz), 3.67 ( d, 1H, H-6 ', J _{6', 5 '} = 7.5 Hz), 0.93 (s, 9H, t-butyl), 0.90 (s, 9H, t-butyl), 0.10 (s, 3H, Si- Me ), 0.09 (s, 3H, Si- Me ), 0.09 (s, 3H, Si- Me ), -0.08 (s, 3H, Si- Me ); ESIMS-LR m / z 560 [(M + H) ⁺ ]; ESIMS-HR calculated 560.2823, observed 560.2808.

Example 2-3 Synthesis of Compound (6a)

Compound (4) (210 mg, 0.38 mmol) is dissolved in dichloromethane (5 mL), 2-azidoacetaldehyde (260 mg, 3.0 mmol) is added, and the mixture is stirred at room temperature for 30 minutes, and then triethylamine (130 mg, 1.3 mmol). Palmitoyl chloride (310 mg, 1.1 mmol) was added in order, and the mixture was stirred at room temperature for 15 hours. The reaction solution was partitioned between chloroform (10 mL) and water (10 mL). The organic layer was washed with 0.2 mol / L hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (mobile layer: hexane / ethyl acetate = 5/1) to obtain compound (6a) (280 mg, 0.32 mmol, 84%) as a yellow foam.
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.24 (br s, 1H, -N H ), 7.52 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.87 (br s, 1H, H -1 '), 5.83 (br s, 1H, H-1''), 5.75 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.76 (d, 1H, H-5', J _{5 ', 6'} = 5.8 Hz), 4.66 (d, 1H, H-6 ', J _{6', 5 '} = 5.8 Hz), 4.22 (br s, 1H, H-3'), 4.13 (m, 2H, H-2 ', H-4'), 3.88 (s, 3H, -CO ₂ Me ), 3.60 (t, 2H, H-2 ”), 2.24 (m, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.56 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.27 (br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.93 ( s, 9H, t-butyl), 0.91 (s, 9H, t-butyl), 0.88 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz), 0.14 (s, 3H , Si- Me ), 0.13 (s, 3H, Si- Me ), 0.12 (s, 3H, Si- Me ), 0.10 (s, 3H, Si- Me ); ESIMS-LR m / z 887 [(M + Na) ⁺ ]; ESIMS-HR calculated 887.5110, found 887.5133.

Example 2-4 Synthesis of compound (6b)

According to Example 2-3, compound (4) (130 mg, 0.22 mmol), 3-azidopropanal (180 mg, 1.8 mmol), dichloromethane (3.0 mL), triethylamine (160 mg, 1.6 mmol), palmitoyl From chloride (440 mg, 1.6 mmol), compound (6b) (68 mg, 0.078 mmol, 35%) was obtained as a yellow foam.
¹ H NMR (500 MHz, CDCl ₃ ) δ 7.96 (br s, 1H, -N H ), 7.49 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.87 (br s, 1H, H -1 '), 5.87 (br s, 1H, H-1''), 5.74 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.63 (d, 1H, H-5', J _{5 ', 6'} = 5.7 Hz), 4.51 (d, 1H, H-6 ', J _{6', 5 '} = 5.7 Hz), 4.21 (br s, 1H, H-3'), 4.10 (m, 2H, H-2 ', H-4'), 3.85 (s, 3H, -CO ₂ Me ), 3.43 (t, 2H, H-3 ”, J _{3”, 2 ”} = 6.9 Hz), 2.14 (m, 2H , -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 2.10-1.92 (m, 2H, H-2 ”), 1.56 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ) , 1.21 (br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.90 (s, 9H, t-butyl), 0.87 (s, 9H, t-butyl), 0.88 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz), 0.12 (s, 3H, Si- Me ), 0.11 (s, 3H, Si- Me ), 0.09 (s, 3H, Si- Me ), 0.07 (s, 3H, Si- Me ); ESIMS-LR m / z 901 [(M + Na) ⁺ ]; ESIMS-HR calculated 901.5267, observed 901.5249.

Example 2-5 Synthesis of compound (6c)

According to Example 2-3, compound (4) (200 mg, 0.35 mmol), 4-azidobutanal (320 mg, 2.8 mmol,), dichloromethane (5.0 mL), triethylamine (320 mg, 3.2 mmol), palmitoyl From chloride (860 mg, 3.2 mmol), compound (6c) (170 mg, 0.21 mmol, 61%) was obtained as a yellow foam.
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.37 (br s, 1H, -N H ), 7.59 (d, 1H, H-6, J _{6, 5} = 8.2 Hz), 5.89 (d, 1H, H- 1 ', J _{1', 2 '} = 2.6 Hz), 5.84 (d, 1H, H-5, J _5,6 = 8.2 Hz), 5.74 (br s, 1H, H-1''), 4.65 (d, 1H, H-5 ', J _{5', 6 '} = 6.4 Hz), 4.53 (d, 1H, H-6', J _{6 ', 5'} = 6.4 Hz), 4.25 (br s, 1H, H-3 '), 4.10 (m, 2H, H-2', H-4 '), 3.88 (s, 3H, 3.44, -CO ₂ Me ), 3.38 (t, 2H, H-4 ”, J _{4”, 3 ”} = 7.2 Hz), 2.80 (t, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 2.49-2.29 (m, 2H, H-2”), 1.95 (m, 2H, H-3 ''), 1.73 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.26 (br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.92 (s, 9H , t-butyl), 0.90 (s, 9H, t-butyl), 0.89 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz), 0.11 (s, 3H, Si- Me ), 0.09 (s, 3H, Si- Me ), 0.05 (s, 3H, Si- Me ), 0.03 (s, 3H, Si- Me ); ESIMS-LR m / z 915 [(M + Na) ⁺ ]; ESIMS-HR calculated 915.5423, found 915.5417.

Example 2-6 Synthesis of compound (7a)

Dissolve compound (6a) (120 mg, 0.14 mmol) in tetrahydrofuran (3 mL), add sodium methylthiolate (32 mg, 0.35 mmol) and thiophenol (38 mg, 0.35 mmol) in this order, and heat at 65 ° C for 3 days. Refluxed. The reaction solution was partitioned between chloroform (5 mL) and 0.2 mol / L hydrochloric acid (5 mL). The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (mobile layer: chloroform / methanol = 99/1) to obtain compound (7a) (69 mg, 0.084 mmol, 60%) as a yellow foam.
¹ H NMR (500 MHz, CD ₃ OD) δ 7.53 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.75 (d, 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.73 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 5.68 (t, 1H, H-1 '', J _{1 '', 2 ''} = 2.2 Hz), 4.62 (dd, 1H, H-5 ', J _{5', 6 '} = 2.3, J _{5', 4 '} = 2.8 Hz), 4.45 (d, 1H, H-6', J _{6 ', 5'} = 2.3 Hz), 4.44 (dd , 1H, H-3 ', J _{3', 2 '} = 5.2, J _{3', 4 '} = 5.2 Hz), 4.40 (dd, 1H, H-2', J _{2 ', 3'} = 5.2, J _{2 ', 1'} = 4.6 Hz), 4.14 (dd, 1H, H-4 ', J _{4', 3 '} = 5.2, J _{4', 5 '} = 2.8 Hz), 3.52 -3.24 (m, 1H, H- 2 ''), 2.38-2.18 (m, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.59 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.28 ( br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.95 (s, 9H, t-butyl), 0.91 (s, 9H, t-butyl), 0.89 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz), 0.18 (s, 3H, Si- Me ), 0.15 (s, 3H, Si- Me ), 0.10 (s, 3H, Si- Me ), 0.05 (IMS, 3H, Si- Me ); ESIMS-LR m / z 823 [(MH) ^- ]; ESIMS-HR calculated value 823.5073, found value 823.5051.

Example 2-7 Synthesis of compound (8a)

Compound (7a) (12 mg, 0.015 mmol) is dissolved in a mixed solution of acetonitrile (0.5 mL) and dichloromethane (0.5 mL), triethylamine hydrogen trifluoride salt (16 mg, 0.10 mmol) is added, and the mixture is stirred at room temperature for 7.5 hours. did. After concentrating the reaction solution, the resulting residue was purified by HPLC (YMC-Pack R & D ODS, 250 × 4.6 mm, moving bed: methanol / water = 90/10, retention time: 9.7 min) to obtain compound (8a) ( 7.5 mg, 0.013 mmol, 86%) was obtained as a white foam.
¹ H NMR (500 MHz, CD ₃ OD) δ 7.61 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.83 (br s, 1H, H-1 '), 5.70 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 5.58 (br s, 1H, H-1 ''), 4.63 (dd, 1H, H-5 ', J _{5', 4 '} = 4.0, J _{5', 6 '} = 3.5 Hz), 4.47 (br s, 1H, H-6'), 4.31 (dd, 1H, H-3 ', J _{3', 2 '} = 5.8, J _{3', 4 '} = 4.6 Hz) , 4.23 (dd, 1H, H-2 ', J _{2', 1 '} = 4.0, J _{2', 3 '} = 5.8 Hz), 4.11 (dd, 1H, H-4', J _{4 ', 3'} = 4.6, J _{4 ', 5'} = 4.0 Hz), 3.38-3.12 (m, 1H, H-2 ”) 2.36-2.24 (m, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.59 (m, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ l), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz): ESIMS-LR m / z 595 [(MH) ⁻ ]; ESIMS-HR calculated 595.3343, found 559.3331.

Example 3 Synthesis of compounds (8b) and (8c)

Compounds (8b) and (8c) were synthesized according to Scheme 3. Each process is shown in detail below.

Example 3-1 Synthesis of compound (9b)

Dissolve compound (6b) (44 mg, 0.050 mmol) in tetrahydrofuran (2 mL), add sodium methylthiolate (11 mg, 0.13 mmol) and thiophenol (14 mg, 0.13 mmol) in this order, and heat at 65 ° C for 3 days. Refluxed. The reaction solution was partitioned between chloroform (5 mL) and 0.2 mol / L hydrochloric acid (5 mL). The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (mobile layer: chloroform / methanol = 99/1) to obtain compound (9b) (29 mg, 0.033 mmol, 67%) as a colorless foam.
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.43 (br s, 1H, -N H ), 7.58 (d, 1H, H-6, J _{6, 5} = 8.1 Hz), 5.90 (t, 1H, H- 1 '', J _{1 '', 2 ''} = 6.3 Hz), 5.76 (br s, 1H, H-1 '), 5.73 (d, 1H, H-5, J _{5, 6} = 8.1 Hz), 4.64 (d, 1H, H-5 ', J _{5', 6 '} = 5.8 Hz), 4.61 (d, 1H, H-6', J _{6 ', 5'} = 5.8 Hz), 4.28 (br s, 1H, H-3 '), 4.11 (m, 2H, H-2', H-4 '), 3.44 (t, 2H, H-3 ”, J _{3”, 2 ”} = 6.9 Hz), 2.32 (m, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 2.13-1.96 (m, 2H, H-2 ''), 1.59 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.24 ( br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.91 (s, 9H, t-butyl), 0.90 (s, 9H, t-butyl), 0.86 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz), 0.13 (s, 3H, Si- Me ), 0.11 (s, 3H, Si- Me ), 0.10 (s, 3H, Si- Me ), 0.09 (s, 3H, Si- Me) ; ESIMS-LR m / z 863 [(MH) -]; ESIMS-HR calc 863.5134, found 863.5142.

Example 3-2 Synthesis of Compound (9c)

According to Example 3-1, compound (6c) (160 mg, 0.17 mmol), tetrahydrofuran (3 mL), sodium methylthiolate (40 mg, 0.43 mmol), thiophenol (48 mg, 0.43 mmol), compound (9c) (110 mg, 0.13 mmol, 75%) was obtained as a white foam.
¹ H NMR (500 MHz, CD ₃ OD) δ 7.67 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.95 (d, 1H, H-1 ', J _{1', 2 '} = 5.9 Hz), 5.76 (m, 2H, H-5, H-1 ”, J _{5, 6} = 8.0Hz), 4.64 (d, 1H, H-5 ', J _{5', 6 '} = 6.3 Hz), 4.59 (d, 1H, H-6 ', J _{6', 5 '} = 6.3 Hz), 4.32 (m, 3H, H-2', H-3 ', H-4'), 3.37 (t, 2H, H -4 ", J _{4", 3 "} = 6.9 Hz), 2.34 (m, 2H, H-2"), 2.24 (t, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 7.2 ), 1.76 (m, 2H, H-3 ”), 1.61 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.28 (brs, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.95 (s, 9H, t-butyl), 0.94 (s, 9H, t-butyl), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz ), 0.14 (s, 3H, Si- Me ), 0.13 (s, 3H, Si- Me ), 0.11 (s, 3H, Si- Me ), 0.09 (s, 3H, Si- Me ); ESIMS-LR m / z 901 [(M + Na) ⁺ ]; ESIMS-HR calculated 901.5267, found 887.5282.

Example 3-3 Synthesis of compound (8b)

Compound (9b) (12 mg, 0.014 mmol) is dissolved in a mixed solution of acetonitrile (0.5 mL) and dichloromethane (0.5 mL), trihydrogenamine trifluoride salt (16 mg, 0.10 mmol) is added, and the mixture is stirred at room temperature for 3 days. did. The reaction solution was partitioned between chloroform (3 mL) and 0.1 mol / L hydrochloric acid (3 mL). The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methanol (1 mL), palladium hydroxide / carbon (4.4 mg) was added, and the mixture was stirred at room temperature for 1 hr in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting residue was HPLC (YMC-Pack R & D ODS, 250 × 4.6 mm, moving bed: methanol / water = 90/10, retention time: 9.9 minutes) To give compound (8b) (5.5 mg, 0.0090 mmol, 64%) as a white foam.
¹ H NMR (500 MHz, CD ₃ OD) δ 7.59 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.85 (d, 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.69 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 5.65 (t, 1H, H-1 ”, J _{1”, 2 ”} = 5.2 Hz), 4.63 (dd, 1H, H-5 ', J _{5', 4 '} = 3.4, J _{5', 6 '} = 5.6 Hz), 4.48 (d, 1H, H-6', J _{6 ', 5'} = 4.6 Hz), 4.28 (dd , 1H, H-3 ', J _{3', 2 '} = 5.9, J _{3', 4 '} = 5.9 Hz), 4.22 (dd, 1H, H-2', J _{2 ', 1'} = 4.6, J _{2 ', 3'} = 5.9 Hz), 4.13 (dd, 1H, H-4 ', J _{4', 3 '} = 5.9, I _{4', 5 '} = 3.4 Hz), 3.06 (m, 2H, H-3 ” ), 2.31 (m, 2H, H-2 ”), 1.58 (m, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.34 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.29 (br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz ); ESIMS-LR m / z 609 [(MH) ⁻ ]; ESIMS-HR calculated 609.3500, observed 609.3502.

Example 3-4 Synthesis of Compound (8c)

According to Example 3-3, compound (9c) (26 mg, 0.029 mmol), acetonitrile (0.5 mL), dichloromethane (0.5 mL), hydrogen trifluoride triethylamine salt (48 mg, 0.29 mmol), methanol (1 mL), and the residue obtained from palladium hydroxide / carbon (8.8 mg) was purified by HPLC (YMC-PackR & D ODS, 250 × 4.6 mm, moving bed: methanol / water = 85/15, retention time: 17 minutes). Compound (8c) (4.1 mg, 0.0066 mmol, 23%) was obtained as a white foam.
¹ H NMR (500 MHz, CD ₃ OD) δ 7.60 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.94 (d, 1H, H-1 ', J _{1', 2 '} = 4.5 Hz), 5.68 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 5.66 (t, 1H, H-1 ”, J _{1”, 2 ”} = 6.0 Hz), 4.93 (br s, 1H , H-5 '), 4.47 (d, 1H, H-6', J _{6 ', 5'} = 5.7), 4.22 (m, 2H, H-2 ', H-3'), 4.18 (dd, 1H , H-4 ', J _{4', 3 '} = 5.2, J _{4', 5 '} = 2.9Hz), 2.29 (m, 2H, H-4 ”), 2.29 (m, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 2.01 (m, 2H, H-2 ''), 1.80 (m, 2H, H-3 ''), 1.60 (br s, 2H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.29 (br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) _{1 2} CH ₂ , J = 6.9 Hz) ESIMS-LR m / z 623 [(MH) ⁻ ]; ESIMS-HR calculated 623.3656, found 623.3664.

Example 4 Synthesis of Compound (10c)

According to Example 3-3, compound (6c) (20 mg, 0.022 mmol), acetonitrile (0.5 mL), dichloromethane (0.5 mL), hydrogen trifluoride triethylamine salt (36 mg, 0.22 mmol), methanol (1 mL), palladium hydroxide / carbon (6.7 mg) residue obtained from HPLC (YMC-PackR & D ODS, 250 × 4.6 mm, moving bed: methanol / water = 85/15, retention time : 4.5 min) to obtain Compound (10) (7.2 mg, 0.011 mmol, 51%) as a white foam.
¹ H NMR (500 MHz, CD ₃ OD) δ 7.55 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.84 (d, 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.69 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 5.63 (brs, 1H, H-1 ”, J _{1”, 2 ”} = 6.9 Hz), 4.93 (dd, 1H, H-5 ', J _{5', 4 '} = 4.0, J _{5', 6 '} = 3.5 Hz), 4.47 (br s, 1H, H-6'), 4.31 (dd, 1H, H-3 ', J _{3 ', 2'} = 5.8, J _{3 ', 4'} = 4.6Hz), 4.23 (dd, 1H, H-2 ', J _{2', 1 '} = 4.0, J _{2', 3 '} = 5.8 Hz), 4.11 (dd, 1H, H-4 ', J _{4', 3 '} = 4.6, J _{4', 5 '} = 4.0 Hz), 3.38-3.03 (m, 1H, H-2''), 2.36-2.24 (m , 2H, H-3 ”), 1.89 (m, 2H, H-4”), 1.74 (m, 2H, -CO CH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.59 (br s, 2H,- COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ CH ₂ , J = 6.9 Hz); ESIMS-LR m / z 639 [(M + H) ⁺ ]; ESIMS-HR calculated 639.3969, found 639.3961.

Example 5 Synthesis of compound (8a), (8b) and (8c) (alternative method)

The compounds (8a), (8b) and (8c) of the present invention were synthesized according to scheme 5. Each process is shown in detail below.

Example 5-1 (2R, 4S, 5S) -2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- (uracil-1- Yl)] tetrahydrofuryl-3-palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (9a)

Compound (6a) (47 mg, 0.054 mmol) was dissolved in ethyl acetate (1 mL), lithium iodide (87 mg, 0.65 mmol) was added, and the mixture was heated to reflux for 5 hours. The reaction solution was returned to room temperature, washed with 0.1 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (mobile layer: chloroform / methanol = 98/2) to obtain compound (9a) (36 mg, 78%) as a yellow syrup.
¹ H NMR (CD ₃ OD, 500 MHz, 3: 1 rotamer mixture, main rotamer data) δ 7.63 (d, 1H, H-6, J _6,5 = 8.0 Hz), 6.00 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.82 (t, 1H, H-1``, J _1'',2'' = 4.6 Hz), 5.76 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.80 (d, 1H, H-6 ', J _{6', 5 '} = 6.4 Hz), 4.65 (br s, 1H, H-5'), 4.31 ( m, 3H, H-2 ', H-3', H-4 '), 3.43 (t, 2H, H-2``, J _2'',1'' = 4.6 Hz), 2.32 (m, 2H , -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.58 (br s, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.95, 0.90 (s, 9H, t-butyl, respectively), 0.89 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz), 0.17, 0.14, 0.09, 0.07 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.4, 165.6, 152.2, 141.3, 103.5, 90.7, 89.5, 85.1, 81.9, 76.4, 73.7, 61.7, 52.7, 35.1, 33.0, 30.7, 30.7, 30.5, 30.4, 30.4, 30.2, 26.4, 26.4, 26.1, 25.7, 23.6, 18.9, 18.9, 14.3, -4.1, -4.3, -4.4, -4.5; ESIMS-HR (Negative mode) Calculated value 849.4983, Actual value 849.5005.

Example 5-2 (2R, 4S, 5S) -2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- (uracil-1- Yl)] tetrahydrofuryl-3-palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (9b)

According to Example 5-1, compound (9b) (35 mg, 67%) was obtained as a yellow syrup from compound (6b) (53 mg, 0.06 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 3: 1 rotamer mixture, main rotamer data) δ 7.65 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.98 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.84 (d, 1H, H-1``, J _1'',2'' = 4.0 Hz), 5.74 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.66 (d, 1H, H-6 ', J _{6', 5 '} = 5.8 Hz), 4.58 (d, 1H, H-5', J _{5 '6 '} = 5.8 Hz), 4.35 (br s, 1H, H-3'), 4.30 (br s, 2H, H-2 ', H-4'), 3.44 (t, 2H, H-3 '', J 3`` _{, 2 ''} = 6.3 Hz), 2.31 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.07 (m, 2H, H-2``), 1.60 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.95, 0.90 (each s, 9H, t- Butyl), 0.89 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz), 0.16, 0.14, 0.09, 0.07 (each s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.0, 165.8 152.2, 141.2, 103.3, 90.0, 89.4, 85.0, 81.3, 76.6, 73.5, 61.8, 52.4, 35.1, 33.3, 33.1, 30.8, 30.8, 30.6, 30.5, 30.5, 30.2, 26.4, 26.1, 25.8, 23.8, 19.0, 18.9, 14.5, -4.1, -4.3, -4.4, -4.5; ESIMS-HR (negative mode) calculation 863.5134, found 863.5142.

Example 5-3 (2R, 4S, 5S) -2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- (uracil-1) -Yl)] tetrahydrofuryl-3-palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (9c)

According to Example 5-1, compound (9c) (50 mg, 74%) was obtained as a yellow syrup from compound (6c) (69 mg, 0.077 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.67 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.96 (d , 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.77 (t, 1H, H-1``, J _1'',2'' = 4.6 Hz), 5.73 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.64 (br s, 1H, H-6 '), 4.63 (br s, 1H, H-5'), 4.34 (br s, 1H, H-3 ' ), 4.29 (m, 2H, H-2 ', H-4'), 3.36 (t, 2H, H-4``, J _{4 '', 3 ''} = 6.9 Hz), 2.33 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.90 (m, 2H, H-3``), 1.77 (m, 2H, H-2 ''), 1.60 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.95, 0.90 (s, 9H, t-butyl, respectively), 0.90 ( t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz), 0.16, 0.14, 0.09, 0.09 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.0, 165.8, 152.2, 141.2, 103.2, 91.8, 89.6, 84.7, 80.7, 76.6, 73.4, 60.9, 52.1, 35.1, 33.1, 32.3, 31.3, 30.8, 30.8, 30.6, 30.5, 30.5, 30.2, 26.4, 26.1, 25.8, 25.5, 23.8, 18.9, 18.9, 14.5, -4.1, -4.3, -4.4, -4.5; ESIMS-HR calculated 901.5267, measured 901.52 82.

Example 5-4 (2R, 4S, 5S) -2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl-3 -Synthesis of palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (11a)

Compound (9a) (27 mg, 0.032 mmol) is dissolved in a mixed solution of acetonitrile (0.5 mL) and dichloromethane (0.5 mL), and hydrogen trifluoride triethylamine salt (51 mg, 0.32 mmol) is added, and the mixture is stirred at room temperature for 80 hours. Stir. After concentrating the reaction solution, the obtained residue was dissolved in chloroform and washed with 0.1 mol / L hydrochloric acid, saturated aqueous sodium carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (mobile layer: chloroform / methanol = 90/10) to obtain compound (11a) (18 mg, 89%) as a yellow syrup.
¹ H NMR (CD ₃ OD, 500 MHz, 4: 1 rotamer mixture, main rotamer data) δ 7.63 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.99 (d , 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.73 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.69 (d, 1H, H-1``, J 1`` _{, 2 ''} = 5.8 Hz), 4.66 (d, 1H, H-6 ', J _{6', 5 '} = 6.3 Hz), 4.43 (d, 1H, H-5', J _{5 ', 6 '} = 6.3 Hz), 4.27 (m, 1H, H-3'), 4.27 (m, 1H, H-2 '), 4.23 (m, 1H, H-4'), 3.50 (m, 2H, H -2``), 2.28 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.56 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 ( br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90, (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.2, 165.9, 152.4, 141.8, 103.3, 90.5, 90.1, 85.0, 82.8, 75.1, 71.8, 62.7, 52.4, 35.2, 33.1, 30.8, 30.8, 30.6, 30.5, 30.5, 30.3 , 25.7, 23.8, 14.5, 9.2. ESIMS-HR (negative mode) calculated 621.3254, measured 621.3263.

Example 5-5 (2R, 4S, 5S) -2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl-3 -Synthesis of palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (11b)

According to Example 5-4, compound (11b) (18 mg, 92%) was obtained as a yellow syrup from compound (9b) (27 mg, 0.031 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 4: 1 rotamer mixture, main rotamer data) δ 7.64 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.99 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.72 (m, 1H, H-1``), 5.71 (d, 1H, H-5, J _5,6 = 8.0 Hz) , 4.60 (d, 1H, H-6 ', J _{6', 5 '} = 6.3 Hz), 4.42 (d, 1H, H-5', J _{5 ', 6'} = 6.3 Hz), 4.27 (br s, 1H, H-3 '), 4.27 (br s, 1H, H-2'), 4.20 (br s, 1H, H-4 '), 3.45 (t, 2H, H-3``, J _{3'' , 2 ''} = 6.9 Hz), 2.29 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.10 (m, 2H, H-2``), 1.56 (m, 2H,- COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90, (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 173.9, 165.9, 152.4, 141.7, 103.2, 90.0, 89.5, 85.1, 82.4, 75.3, 71.8, 62.5, 52.2 , 35.3, 33.5, 33.1, 30.8, 30.8, 30.6, 30.6, 30.5, 30.3, 25.8, 23.7, 14.5, 9.2; ESIMS-HR (negative mode) calculated 635.3405, observed 635.3396.

Example 5-6 (2R, 4S, 5S)-2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of 3-palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (11c)

According to Example 5-4, compound (11c) (31 mg, 95%) was obtained as a yellow syrup from compound (9c) (44 mg, 0.050 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 4: 1 rotamer mixture, main rotamer data) δ 7.65 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.99 (d , 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.71 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 5.63 (d, 1H, H-1``, J 1`` _{, 2 ''} = 4.0 Hz), 4.59 (d, 1H, H-6 ', J _{6', 5 '} = 4.0 Hz), 4.42 (d, 1H, H-5', J _{5 ', 6 '} = 4.0 Hz), 4.28 (m, 1H, H-3'), 4.27 (m, 1H, H-2 '), 4.22 (m, 1H, H-4'), 3.35 (t, 2H, H -4 '', J 4`` _{, 3 ''} = 6.9 Hz), 2.28 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.88 (m, 2H, H-3 '' ), 1.73 (m, 2H, H-2``), 1.57 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 173.9, 165.9, 152.4, 141.8, 103.2, 91.4, 90.0, 85.0, 82.0, 75.3, 71.9, 62.2, 52.2, 35.3, 33.1, 31.3, 30.8, 30.8, 30.6, 30.6, 30.5, 30.3, 25.8, 25.5, 23.7, 14.5, 9.2; ESIMS-HR (Negative mode) Calculated value 649.3567, Actual value 649.3574.

Example 5-7 (2R, 4S, 5S)-2-aminomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of 3-palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (8a)

The compound (11a) (6.1 mg, 0.098 mmol) was dissolved in methanol (1 mL), palladium hydroxide / carbon (0.5 mg) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by HPLC (YMC-Pack R & D ODS, 250 × 4.6 mm, moving bed: methanol / water = 80/20) to give the compound ( 8a) (3.4 mg, 58%) was obtained as a white foam.
¹ H NMR (CD ₃ OD, 500 MHz) δ 7.61 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.83 (d, 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.70 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.58 (d, 1H, H-1``, J _{1 '', 2 ''} = 5.2 Hz), 4.63 (d , 1H, H-5 ', J _{5', 6 '} = 4.6 Hz), 4.48 (d, 1H, H-6', J _{6 ', 5'} = 4.6 Hz), 4.28 (dd, 1H, H-3 ', J _{3', 2 '} = J _{3', 4 '} = 5.8 Hz), 4.23 (dd, 1H, H-2', J _{2 ', 1'} = 4.0, J _{2 ', 3'} = 5.8 Hz) , 4.13 (dd, 1H, H-4 ', J _{4', 3 '} = 5.8, J _{4', 5 '} = 3.4 Hz), 3.07 (m, 2H, H-3``), 2.31 (m, 2H , -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.30-2.15 (m, 2H, H-2``), 1.58 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.7, 166.0, 152.0, 143.6, 103.2, 93.6, 88.7, 85.4, 83.4, 74.2, 70.5, 63.0, 49.6, 40.7, 36.0, 33.1, 30.8, 30.8, 30.6, 30.5, 30.5, 30.3, 25.4, 23.8, 14.5; ESIMS-HR calculated 595.3343, measured 595.3331.

Example 5-8 (2R, 4S, 5S)-2-aminoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of 3-palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (8b)

According to Example 5-7, compound (8b) (5.3 mg, 68%) was obtained as a white foam from compound (11b) (8.1 mg, 0.013 mmol).
¹ H NMR (CD ₃ OD, 500 MHz) δ 7.60 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.85 (d, 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.70 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.65 (d, 1H, H-1``, J _{1 '', 2 ''} = 5.2 Hz), 4.63 (d , 1H, H-5 ', J _{5', 6 '} = 4.6 Hz), 4.48 (d, 1H, H-6', J _{6 ', 5'} = 4.6 Hz), 4.28 (t, 1H, H-3 ', J _{3', 2 '} = J _{3', 4 '} = 5.8 Hz), 4.23 (dd, 1H, H-2', J _{2 ', 1'} = 4.0, J _{2 ', 3'} = 5.8 Hz) , 4.13 (dd, 1H, H-4 ', J _{4', 3 '} = 5.8, J _{4', 5 '} = 3.4 Hz), 3.07 (m, 2H, H-3``), 2.31 (m, 2H , -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.30-2.15 (m, 2H, H-2``), 1.58 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 175.2, 166.0, 152.2, 142.6, 103.1, 91.7, 89.5, 85.0, 82.6, 74.8, 71.2, 63.1, 49.6, 35.9, 35.6, 33.1, 31.7, 30.8, 30.8, 30.6, 30.5, 30.5, 30.3, 25.7, 23.8, 14.5; ESIMS-HR (negative mode) calculated 609.3500, measured 609.3502.

Example 5-9 (2R, 4S, 5S)-2-aminopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of 3-palmitoyl- (1,3) -oxazolidine-4-carboxylic acid (8c)

According to Example 5-7, compound (8c) (5.5 mg, 68%) was obtained as a white foam from compound (11c) (8.4 mg, 0.013 mmol).
¹ H NMR (CD ₃ OD, 500 MHz) δ 7.61 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.94 (d, 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.69 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.66 (d, 1H, H-1``, J _{1 '', 2 ''} = 5.8 Hz), 4.60 (dd , 1H, H-5 ', J _{5', 4 '} = 2.3, J _{5', 6 '} = 5.7 Hz), 4.46 (d, 1H, H-6', J _{6 ', 5'} = 5.7 Hz), 4.22 (m, 1H, H-3 '), 4.21 (m, 1H, H-2'), 4.19 (m, 1H, H-4 '), 2.99-2.93 (m, 2H, H-4'') , 2.30 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.93-1.80 (m, 2H, H-3``), 1.79 (m, 2H, H-2 ''), 1.59 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H,- COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 176.4, 174.3, 166.1, 152.4, 141.9, 103.2, 90.9, 90.4, 85.1, 82.2 , 75.2, 71.8, 62.6, 49.8, 40.4, 35.4, 33.1, 31.2, 30.8, 30.8, 30.6, 30.6, 30.5, 30.3, 25.8, 24.2, 23.7, 14.5; ESIMS-HR (negative mode) calculated 623.3656, measured 623.3664.

Example 6 Synthesis of Compound (10a), (10b) and (10c) of the Present Invention (Alternative Method)

The compounds (10a), (10b) and (10c) of the present invention were synthesized according to Scheme 6. Each process is shown in detail below.

Example 6-1 (2R, 4S, 5S) -2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl-3 Synthesis of methyl palmitoyl- (1,3) -oxazolidine-4-carboxylate (12a)

According to Example 5-4, compound (12a) (46 mg, 90%) was obtained as a colorless syrup from compound (6a) (70 mg, 0.080 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.54 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.89 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.76 (d, 1H, H-1``, J _1'',2'' = 4.6 Hz), 5.73 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.95 (d, 1H, H-6 ', J _{6', 5 '} = 6.9 Hz), 4.94 (dd, 1H, H-5', J _{5 ', 4 '} = 2.3, J _{5', 6 '} = 6.9 Hz), 4.31 (t, 1H, H-3', J _{3 ', 2'} = J _{3 ', 4'} = 5.8 Hz), 4.24 (dd, 1H , H-2 ', J _{2', 1 '} = 4.6, J _{2', 3 '} = 5.8 Hz), 4.13 (dd, 1H, H-4', J _{4 ', 3'} = 5.8, J _{4 ', 5 '} = 2.3 Hz), 3.84 (s, 3H, -CO ₂ Me ), 3.48 (br s, 2H, H-2``), 2.40-2.27 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.58 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.5, 171.5, 165.9, 152.2, 142.2, 103.4, 91.2 , 90.8, 84.8, 81.0, 74.6, 71.1, 60.1, 53.4, 35.0, 33.1, 30.8, 30.8, 30.6, 30.5, 30.2, 30.1, 25.9, 25.6, 23.8, 14.5; ESIMS-HR measured 659.3375, measured 659.3371.

Example 6-2 (2R, 4S, 5S) -2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl-3 Synthesis of methyl palmitoyl- (1,3) -oxazolidine-4-carboxylate (12b)

According to Example 5-4, compound (12b) (57 mg, 89%) was obtained as a colorless syrup from compound (6b) (87 mg, 0.10 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.55 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.92 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.75 (d, 1H, H-1``, J _1'',2'' = 3.4 Hz), 5.71 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 4.87 (br s, 1H, H-6 '), 4.77 (dd, 1H, H-5', J _{5 ', 4'} = 2.3, J _{5 ', 6 '} = 4.6 Hz), 4.28 (dd, 1H, H-3', J _{3 ', 2'} = 5.2, J _{3 ', 4'} = 4.0 Hz), 4.21 (t, 1H, H-2 ', J _{2 ', 1'} = J _{2 ', 3'} = 5.2 Hz), 4.16 (dd, 1H, H-4 ', J _{4', 3 '} = 4.0, J _{4', 5 '} = 2.3 Hz), 3.84 ( s, 3H, -CO ₂ Me ), 3.42 (t, 2H, H-3``, J _{3 '', 2 ''} = 6.9 Hz), 2.40-2.02 (m, 2H, -COC H ₂ CH ₂ ( CH ₂ ) ₁₂ CH ₃ ), 2.12-1.88 (m, 2H, H-2``), 1.58 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.29 (br s, 24H , -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.1, 171.9, 165.9, 152.3, 142.0, 103.4, 90.9, 90.0, 84.5, 80.8, 74.8, 71.3, 60.2, 53.8, 35.1, 33.8, 33.1, 30.8, 30.8, 30.6, 30.5, 30.2, 30.1, 26.0, 25.7, 23.7, 14.5; ESIMS-HR measurement 673.3532 , Measured value 673.3531.

Example 6-3 (2R, 4S, 5S) -2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of methyl 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate (12c)

According to Example 5-4, compound (12c) (64 mg, 92%) was obtained as a colorless syrup from compound (6c) (93 mg, 0.10 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.56 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.92 (d , 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.72 (m, 1H, H-1``), 5.69 (d, 1H, H-5, J _5,6 = 8.0 Hz) , 4.86 (br s, 1H, H-6 '), 4.75 (dd, 1H, H-5', J _{5 ', 4'} = 1.8, J _{5 ', 6'} = 6.9 Hz), 4.27 (dd, 1H , H-3 ', J _{3', 2 '} = 4.0, J _{3', 4 '} = 4.6 Hz), 4.21 (dd, 1H, H-2', J _{2 ', 1'} = 5.2, J _{2 ', 3 '} = 4.0 Hz), 4.16 (br s, 1H, H-4'), 3.84 (s, 3H, -CO ₂ Me ), 3.34 (t, 2H, H-4``, J _{4 '', 3 ''} = 6.9 Hz), 2.28 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.97-1.85 (m, 2H, H-3 ''), 1.80-1.68 (m, 2H , H-2``), 1.58 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ) , 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.1, 171.9, 165.9, 152.3, 142.1, 103.3 , 91.7, 90.8, 84.5, 80.6, 74.9, 71.4, 60.2, 53.7, 35.1, 33.1, 31.7, 30.8, 30.8, 30.6, 30.5, 30.2, 30.1, 26.0, 25.7, 25.3, 23.8, 14.4; ESIMS-HR measurement 687.3688, measured value 687.369 2

Example 6-4 (2R, 4S, 5S) -2-aminomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate HCl salt (10a)

Compound (12a) (7.8 mg, 0.012 mmol) is dissolved in methanol (1 mL), 1 mol / L hydrochloric acid (0.5 mL) and palladium hydroxide / carbon (4.4 mg) are added, and then at room temperature under a hydrogen atmosphere. Stir for 3 hours. After filtration of the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by HPLC (YMC-Pack R & D ODS, 250 × 4.6 mm, moving bed: 0.5% hydrochloric acid-containing methanol / water = 85/15) Compound (10a) (4.2 mg, 54%) was obtained as a white foam.
¹ H NMR (CD ₃ OD, 500 MHz, 9: 1 rotamer mixture, main rotamer data) δ 7.53 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.77 (d , 1H, H-1 'J _{1', 2 '} = 4.0 Hz), 5.70 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.68 (t, 1H, H-1``, J 1`` _{, 2 ''} = 5.2 Hz), 4.99 (d, 1H, H-6 ', J _{6', 5 '} = 3.5 Hz), 4.79 (dd, 1H, H-5', J _{5 ', 4 '} = 2.9, J _{5', 6 '} = 3.5 Hz), 4.32 (dd, 1H, H-3', J _{3 ', 2'} = 5.8, J _{3 ', 4'} = 6.3 Hz), 4.27 (dd, 1H, H-2 ', J _{2', 1 '} = 4.0, J _{2', 3 '} = 5.8 Hz), 4.08 (dd, 1H, H-4', J _{4 ', 3'} = 6.3, J _{4 ' , 5 '} = 2.9 Hz), 3.85 (s, 3H, -CO ₂ Me ), 3.07 (m, 2H, H-3``), 2.35-2.25 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.17-2.08 (m, 2H, H-2``), 1.56 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.29 (br s, 24H,- COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz ) δ 175.1, 172.7, 165.9, 152.0, 143.6, 103.3, 94.0, 88.6, 84.7, 81.7, 74.0, 70.5, 60.6, 54.0, 35.4, 33.1, 30.8, 30.8, 30.6, 30.5, 30.5, 30.1, 25.3, 23.7, 14.4; ESIMS-HR calculated 611.3651, measured 611.3651.

Example 6-5 (2R, 4S, 5S) -2-aminoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate HCl salt (10b)

According to Example 6-4, compound (10b) (4.9 mg, 57%) was obtained as a white foam from compound (12b) (8.2 mg, 0.013 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 9: 1 rotamer mixture, main rotamer data) δ 7.55 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.77 (d , 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.70 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.68 (t, 1H, H-1``, J 1`` _{, 2 ''} = 5.2 Hz), 4.99 (d, 1H, H-6 ', J _{6', 5 '} = 3.5 Hz), 4.79 (dd, 1H, H-5', J _{5 ', 4 '} = 2.9, J _{5', 6 '} = 3.5 Hz), 4.32 (dd, 1H, H-3', J _{3 ', 2'} = 5.8, J _{3 ', 4'} = 6.3 Hz), 4.27 (dd , 1H, H-2 ', J _{2', 1 '} = 4.0, J _{2', 3 '} = 5.8 Hz), 4.08 (dd, 1H, H-4', J _{4 ', 3'} = 6.3, J _{4 ', 5'} = 2.9 Hz), 3.85 (s, 3H, -CO ₂ Me ), 3.07 (m, 2H, H-3``), 2.35-2.25 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.17-2.08 (m, 2H, H-2``), 1.56 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.29 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.8, 172.0, 165.9, 152.2, 143.0, 103.2, 89.9, 84.5, 81.1, 74.4, 70.9, 60.4, 53.8, 36.9, 35.2, 33.1, 32.6, 30.8, 30.8, 30.6, 30.5, 30.5, 30.1, 25.6 , 23.7, 14.4; ESIMS-HR calculated 625.3807, actual Value 625.3803.

Example 6-6 (2R, 4S, 5S) -2-aminopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of methyl 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate HCl salt (10c)

According to Example 6-4, compound (10c) (4.9 mg, 56%) was obtained as a white foam from compound (12c) (8.7 mg, 0.013 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 9: 1 rotamer mixture, main rotamer data) δ 7.55 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.84 (d , 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.69 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.63 (d, 1H, H-1``, J 1`` _{, 2 ''} = 6.9 Hz), 4.93 (d, 1H, H-6 ', J _{6', 5 '} = 4.0 Hz), 4.76 (dd, 1H, H-5', J _{5 ', 4 '} = 2.9, J _{5', 6 '} = 4.0 Hz), 4.28 (t, 1H, H-3', J _{3 ', 2'} = J _{3 ', 4'} = 5.8 Hz), 4.24 (dd, 1H , H-2 ', J _{2', 1 '} = 4.0, J _{2', 3 '} = 5.8 Hz), 4.12 (dd, 1H, H-4', J _{4 ', 3'} = 5.8, J _{4 ', 5 '} = 2.9 Hz), 3.84 (s, 3H, -CO ₂ Me ), 2.96 (m, 2H, H-4``), 2.35-2.19 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.89-1.76 (m, 2H, H-2``), 1.74 (m, 2H, H-3 ''), 1.58 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.4, 171.9, 165.9, 152.2, 142.5, 103.2, 91.4, 91.3, 84.5, 80.7, 74.7, 71.4, 60.3, 53.7, 35.2, 35.2, 33.1, 31.6, 30.8, 30.8, 30.6, 30.6, 30.5, 30.2, 25.7, 24.0, 23.8, 14.5; ESIMS- Calculated HR value 639.3964, measured value 639.3964.

Example 7 Synthesis of compounds (15a), (15b) and (15c) of the present invention

The compounds (15a), (15b) and (15c) of the present invention were synthesized according to Scheme 7. Each process is shown in detail below.

Example 7-1 (2R, 4S, 5S) -2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- (uracil-1- Yl)] tetrahydrofuryl-3-palmitoyl- (1,3) -oxazolidine-4-carboxylate tert-butyl (13a)

Compound (9a) (212 mg, 0.25 mmol) was dissolved in tert-butanol (2 mL) and methylene chloride (2 mL), and N, N'-diisopropyl-O-tert-butylisourea (251 mg, 1.25 mmol) was dissolved. ) And ammonium chloride (41 mg, 1.25 mmol) were added, and the mixture was stirred at 0 ° C. for 20 hours. The reaction mixture was diluted with CHCl ₃ (200 mL), and washed with saturated aqueous sodium carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (mobile layer: hexane / ethyl acetate = 2/1) to obtain compound (13a) (165 mg, 73%) as a white foam.
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.63 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.91 (d , 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.83 (m, 1H, H-1), 5.75 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.84 (d, 1H, H-6 ', J _{6', 5 '} = 6.4 Hz), 4.78 (d, 1H, H-5', J _{5 ', 6'} = 6.4 Hz), 4.30 (m, 1H, H -3 '), 4.28 (m, 1H, H-2'), 4.24 (m, 1H, H-4 '), 3.53 (m, 2H, H-2``), 2.44-2.24 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.60 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.53 (s, 9H, -CO ₂ ^t Bu ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.94, 0.91 (s, 9H, t-butyl, respectively), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz), 0.15, 0.14, 0.10, 0.09 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.4, 169.7, 165.9, 152.1, 141.5 , 103.3, 93.9, 90.3, 84.8, 81.0, 76.3, 72.8, 60.9, 53.4, 34.9, 33.1, 30.8, 30.7, 30.5, 30.5, 30.4, 30.3, 30.1, 30.1, 28.2, 26.4, 26.4, 26.0, 25.6, 23.7 , 18.9, 18.9, 14.5, -4.1, -4.4, -4.4, -4.5; ESIMS-HR calculated 929.5574, measured 929 .5583.

Example 7-2 (2R, 4S, 5S) -2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- (uracil-1- Yl)] tetrahydrofuryl-3-palmitoyl- (1,3) -oxazolidine-4-carboxylate tert-butyl (13b)

According to Example 7-1, compound (13b) (138 mg, 76%) was obtained as a white foam from compound (9b) (171 mg, 0.20 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.63 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.95 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.89 (d, 1H, H-1``, J _1'',2'' = 4.6 Hz), 5.74 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.72 (d, 1H, H-6 ', J _{6', 5 '} = 6.4 Hz), 4.63 (d, 1H, H-5', J _{5 ', 6 '} = 6.4 Hz), 4.29 (m, 2H, H-2', H-3 '), 4.26 (m, 1H, H-4'), 3.46 (t, 2H, H-3``, J ₃ `` _{, 2 ''} = 6.9 Hz), 2.44-2.14 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.10-1.89 (m, 2H, H-2``), 1.62 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.53 (s, 9H, -CO ₂ ^t Bu ), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.95, 0.91 (each s, 9H, t-butyl), 0.88 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz), 0.17, 0.15, 0.10 , 0.09 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 173.9, 170.4, 165.9, 152.2, 141.2, 103.3, 93.9, 89.8, 84.9, 80.5, 76.3, 73.1, 60.6 , 35.0, 33.4, 33.1, 30.8, 30.8, 30.7, 30.5, 30.5, 30.4, 30.2, 30.1, 28.2, 26.4, 26.4, 26.1, 25.7, 23.7, 19.0, 18.9, 14.5, -4.1, -4.4, -4.4, -4.5; ESIMS-HR calculated 943.5731, measured 943.5734.

Example 7-3 (2R, 4S, 5S) -2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- (uracil-1) -Yl)] tetrahydrofuryl-3-palmitoyl- (1,3) -oxazolidine-4-carboxylate tert-butyl (13c)

According to Example 7-1, compound (13c) (184 mg, 77%) was obtained as a white foam from compound (9c) (223 mg, 0.25 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.67 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.92 (br s, 1H, H-1 '), 5.81 (br s, 1H, H-1''), 5.73 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 4.72 (d, 1H, H -6 ', J _{6', 5 '} = 5.7 Hz), 4.62 (d, 1H, H-5', J _{5 ', 6'} = 5.7 Hz), 4.29 (m, 1H, H-3 '), 4.27 (m, 1H, H-2 '), 4.24 (m, 1H, H-4'), 3.37 (m, 2H, H-4 ''), 2.42-2.15 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.99-1.80 (m, 2H, H-2``), 1.78 (m, 2H, H-3 ''), 1.59 (m, 2H, -COCH ₂ C H ₂ ( CH ₂ ) ₁₂ CH ₃ ), 1.53 (s, 9H, -CO ₂ ^t Bu ), 1.29 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.95, 0.91 (each s, 9H, t-butyl), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz), 0.17, 0.15, 0.11, 0.10 (s, 3H, Si- Me respectively) ; ¹³ C NMR (CD ₃ OD, 125 MHz) δ 173.9, 170.4, 165.9, 152.2, 141.2, 103.2, 93.9, 90.0, 84.8, 80.1, 76.5, 73.0, 60.6, 52.1, 35.0, 33.1, 32.1, 30.8, 30.7 , 30.6, 30.5, 30.5, 30.4, 30.3, 30.1, 28.2, 26.4, 26.1, 25.7, 25.5, 23.8, 19.0, 19.0, 14.5, -4.0, -4.4, -4.4, -4 .5; ESIMS-HR calculated 957.5887, found 957.5895.

Example 7-4 (2R, 4S, 5S) -2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl-3 Synthesis of tert-butyl-palmitoyl- (1,3) -oxazolidine-4-carboxylate (14a)

According to Example 5-4, compound (14a) (6.2 mg, 51%) was obtained as a colorless syrup from compound (13a) (16 mg, 0.018 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.54 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.89 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.70 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.69 (d, 1H, H-1``, J 1`` _{, 2 ''} = 3.5 Hz), 4.87 (dd, 1H, H-5 ', J _{5', 4 '} = 2.3, J _{5', 6 '} = 6.4 Hz), 4.80 (d, 1H, H-6 ', J _{6', 5 '} = 4.6 Hz), 4.31 (t, 1H, H-3', J _{3 ', 2'} = J _{3 ', 4'} = 5.2 Hz), 4.23 (dd, 1H , H-2 ', J _{2', 1 '} = 4.6, J _{2', 3 '} = 5.2 Hz), 4.10 (m, 1H, H-4', J _{4 ', 3'} = 5.2, J _{4 ', 5 '} = 2.3 Hz), 3.49 (t, 2H, H-2``, J _2'',1'' = 3.5 Hz), 2.40-2.25 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.59 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.54 (s, 9H, -CO ₂ ^t Bu ), 1.29 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.4 , 169.9, 165.9, 152.3, 142.2, 103.4, 91.1, 90.8, 84.8, 81.3, 74.6, 71.2, 61.3, 53.4, 35.1, 33.1, 30.8, 30.8, 30.7, 30.6, 30.5, 30.4, 30.2, 30.2, 28.1, 26.0 , 25.6, 23.7, 14.5; ESIMS-HR calculated 701.3 845, found 701.3859.

Example 7-5 (2R, 4S, 5S) -2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl-3 Synthesis of tert-butyl-palmitoyl- (1,3) -oxazolidine-4-carboxylate (14b)

According to Example 5-4, compound (14b) (8.2 mg, 55%) was obtained as a colorless syrup from compound (13b) (20 mg, 0.021 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.57 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.93 (d , 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.74 (d, 1H, H-1``, J _1'',2'' = 3.4 Hz), 5.71 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.73 (d, 1H, H-6 ', J _{6', 5 '} = 5.2 Hz), 4.69 (dd, 1H, H-5', J _{5 ', 4 '} = 2.3, J _{5', 6 '} = 5.2 Hz), 4.28 (dd, 1H, H-3', J _{3 ', 2'} = 4.6, J _{3 ', 4'} = 5.2 Hz), 4.21 (dd , 1H, H-2 ', J _{2', 1 '} = 5.2, J _{2', 3 '} = 4.6 Hz), 4.14 (dd, 1H, H-4', J _{4 ', 3'} = 5.2, J _{4 ', 5'} = 2.3 Hz), 3.43 (t, 2H, H-3``, J _{3 '', 2 ''} = 6.4 Hz), 2.40-2.18 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.12-1.88 (m, 2H, H-2``), 1.61 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.53 (s, 9H,- CO ₂ ^t Bu ), 1.29 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.0, 170.5, 165.9, 152.3, 142.0, 103.3, 90.8, 89.9, 84.6, 81.1, 74.9, 71.4, 60.9, 35.2, 33.9, 33.1, 30.8, 30.7, 30.6, 30.6, 30.5, 30.4, 30.2, 30.2, 28.2, 26.1, 25.7, 23.8, 14.5; ESIMS-HR calculated 715.4001, measured 715.4009.

Example 7-6 (2R, 4S, 5S) -2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of tert-butyl 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate (14c)

According to Example 5-4, compound (14c) (110 mg, 90%) was obtained as a colorless syrup from compound (13c) (162 mg, 0.17 mmol).
¹ H NMR (500 MHz, CD ₃ OD, 3: 2 rotamer mixture at 20 ° C, main rotamer data) δ 7.57 (d, 1H, H-6, J _{6, 5} = 8.0 Hz), 5.92 (d, 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.71 (d, 1H, H-5, J _{5, 6} = 8.0 Hz), 5.69 (m, 1H, H-1 ''), 4.72 (d, 1H, H-6 ', J _{6', 5 '} = 5.2 Hz), 4.68 (dd, 1H, H-5', J _{5 ', 4'} = 2.3 Hz, J _{5 ' , 6 '} = 5.2 Hz), 4.29 (m, 1H, H-3'), 4.21 (m, 1H, H-2 '), 4.14 (m, 1H, H-4'), 3.35 (m, 2H, H-4``), 2.39-2.19 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.88-1.76 (m, 2H, H-2``), 1.70 (m, 2H , H-3``), 1.62 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.53 (s, 9H, -CO ₂ ^t Bu ), 1.29 (br s, 24H,- COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃₎ , 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz ) δ 174.0, 170.5, 165.9, 152.3, 142.0, 103.3, 91.7, 90.7, 84.7, 80.8, 74.9, 71.5, 60.8, 52.1, 35.2, 33.1, 31.8, 30.8, 30.7, 30.6, 30.6, 30.5, 30.4, 30.2, 30.2, 28.2, 26.1, 25.7, 25.4, 23.8, 14.5; ESIMS-HR calculated 729.4158, measured 729.4175.

Example 7-7 (2R, 4S, 5S) -2-aminomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of tert-butyl 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate (15a)

According to Example 5-7, compound (15a) (1.2 mg, 27%) was obtained as a colorless syrup from compound (14a) (4.7 mg, 0.0069 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 77.56 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.79 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.70 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.62 (t, 1H, H-1``, J 1`` _{, 2 ''} = 4.6 Hz), 4.82 (d, 1H, H-6 ', J _{6', 5 '} = 3.5 Hz), 4.71 (t, 1H, H-5', J _{5 ', 4 '} = J _{5', 6 '} = 3.5 Hz), 4.34 (dd, 1H, H-3', J _{3 ', 2'} = 5.7, J _{3 ', 4'} = 6.3 Hz), 4.27 (dd, 1H , H-2 ', J _{2', 1 '} = 4.6, J _{2', 3 '} = 5.7 Hz), 4.09 (dd, 1H, H-4', J _{4 ', 3'} = 6.3, J _{4 ', 5 '} = 3.4 Hz), 3.06 (t, 2H, H-2``, J 2'' _{, 1} ''= 4.6 Hz), 2.27 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ) , 1.59 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.54 (s, 9H, t-butyl), 1.29 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.8, 171.7, 165.9, 152.0, 143.7, 103.2, 94.3, 88.6, 84.7, 82.1, 74.1, 70.6, 60.8, 42.1, 35.5, 33.0, 30.8, 30.8, 30.6, 30.5, 30.4, 30.3, 30.2, 30.2, 28.1, 25.3, 23.8, 14.5; ESIMS- HR calculated 653.4120, actual Value 653.4140.

Example 7-8 (2R, 4S, 5S) -2-aminoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of tert-butyl 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate (15b)

According to Example 5-7, compound (15b) (1.4 mg, 27%) was obtained as a colorless syrup from compound (14b) (5.4 mg, 0.0078 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.56 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.77 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.69 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.67 (m, 1H, H-1``) , 4.82 (d, 1H, H-6 ', J _{6', 5 '} = 5.2 Hz), 4.71 (d, 1H, H-5', J _{5 ', 6'} = 5.2 Hz), 4.32 (dd, 1H , H-3 ', J _{3', 2 '} = 5.2, J _{3', 4 '} = 4.6 Hz), 4.27 (dd, 1H, H-2', J _{2 ', 1'} = 4.6, J _{2 ', 3 '} = 5.2 Hz), 4.07 (d, 1H, H-4', J _{4 ', 3'} = 4.6 Hz), 3.16-3.04 (m, 2H, H-3``), 2.32 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.27-2.14 (m, 2H, H-2``), 1.57 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ) , 1.54 (s, 9H, t-butyl), 1.28 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.6, 170.4, 165.9, 152.2, 142.9, 103.2, 90.8, 89.9, 84.5, 81.3, 74.5, 71.1, 61.0, 39.0, 37.1 , 35.3, 33.1, 30.8, 30.8, 30.8, 30.6, 30.6, 30.5, 30.4, 30.2, 28.2, 25.9, 23.7, 14.4; ESIMS-HR calculated 667.4277, observed 667.4284.

Example 7-9 (2R, 4S, 5S) -2-aminopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl- Synthesis of tert-butyl 3-palmitoyl- (1,3) -oxazolidine-4-carboxylate (15c)

According to Example 5-7, compound (15c) (7.1 mg, 54%) was obtained as a colorless syrup from compound (14c) (14 mg, 0.019 mmol).
¹ H NMR (500 MHz, CD ₃ OD, 3: 2 rotamer mixture, main rotamer data) δ 7.56 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.85 (d , 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.68 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.63 (m, 1H, H-1 ”), 4.76 (d, 1H, H-6 ', J _{6', 5 '} = 4.6 Hz), 4.67 (dd, 1H, H-5', J _{5 ', 4'} = 2.9 Hz J _{5 ', 6'} = 4.6 Hz), 4.29 (t, 1H, H-3 ', J _{3', 2 '} = J _{3', 4 '} = 5.8 Hz), 4.22 (dd, 1H, H-2', J _{2 ', 1'} = 4.6, J _{2 ', 3'} = 5.8 Hz), 4.10 (dd, 1H, H-4 ', J _{4', 3 '} = 5.8 Hz, J _4'5' = 2.9 Hz) 3.02 (m, 2H, H -3 ''), 2.31 (m, 2H, -COC H ₂ CH ₂ (CH ₂ ) ₁₂ CH ₃ ), 2.24-1.95 (m, 2H, H-2``), 1.78 (m, 2H, H- 2 '') 1.58 (m, 2H, -COCH ₂ C H ₂ (CH ₂ ) ₁₂ CH ₃ ), 1.54 (s, 9H, t-butyl), 1.29 (br s, 24H, -COCH ₂ CH ₂ (C H ₂ ) ₁₂ CH ₃ ), 0.90 (t, 3H, -COCH ₂ CH ₂ (CH ₂ ) ₁₂ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 174.3, 170.6, 165.9, 152.2, 142.5, 103.3, 91.3, 90.5, 84.5, 81.0, 74.8, 71.3, 61.0, 40.4, 35.3, 33.1, 31.7, 30.8, 30.8, 30.7, 30.6, 30.6, 30.5, 30.2, 30.2, 28.2, 26.0, 24.3, 23.7, 14.5; ESIMS-HR calculation Value 681.4433, found 681.4439.

Example 8 Synthesis of compounds (20a), (20b) and (20c) of the present invention

The compounds (20a), (20b) and (20c) of the present invention were synthesized according to Scheme 8. Each process is shown in detail below.

Example 8-1 (2R, 4S, 5S) -3-acetyl-2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- ( Synthesis of (uracil-1-yl)] tetrahydrofuryl- (1,3) -oxazolidine-4-carboxylate methyl (16a)

Compound (4) (500 mg, 0.72 mmol) is dissolved in dichloromethane (7 mL), 2-azidoacetaldehyde (123 mg, 1.4 mmol) is added, and the mixture is stirred at room temperature for 30 minutes, and then triethylamine (130 mg, 1.3 mmol). ) And acetyl chloride (110 mg, 1.4 mmol) were sequentially added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was partitioned between chloroform (20 mL) and water (20 mL). The organic layer was washed with 0.2 mol / L hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (mobile layer: hexane / ethyl acetate = 2/1) to obtain compound (16a) (414 mg, 86%) as a yellow foam.
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.60 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.96 (d , 1H, H-1 ', J _{1', 2 '} = 6.4 Hz), 5.82 (m, 1H, H-1``), 5.76 (d, 1H, H-5, J _5,6 = 8.0 Hz) , 4.93 (br s, 1H, H-6 '), 4.71 (br s, 1H, H-5'), 4.32 (m, 1H, H-3 '), 4.29 (m, 1H, H-2') , 4.25 (m, 1H, H-4 '), 3.85 (s, 3H, -CO ₂ Me ), 3.46 (t, 2H, H-2``), 2.07 (s, 3H, acetyl), 0.95, 0.91 (Each s, 9H, t-butyl), 0.18, 0.15, 0.10, 0.07 (each s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 172.1, 171.1, 165.7, 152.2, 141.5 , 103.5, 90.8, 90.4, 84.6, 80.6, 76.1, 73.1, 61.0, 53.8, 53.1, 26.4, 26.3, 22.2, 22.0, 18.9, 18.9, 14.5, -4.1, -4.3, -4.4, -4.5; ESIMS-HR Calculated value 691.2914, measured value 691.2909.

Example 8-2 (2R, 4S, 5S) -3-acetyl-2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- ( Synthesis of (uracil-1-yl)] tetrahydrofuryl- (1,3) -oxazolidine-4-carboxylate methyl (16b)

According to Example 8-1, compound (4b) (417 mg, 85%) was converted into yellow foam from compound (4) (500 mg, 0.72 mmol) and 3-azidopnopanal (143 mg, 1.4 mmol). Obtained as material.
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.59 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.98 (d , 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.85 (d, 1H, H-1``, J _1'',2'' = 4.0 Hz), 5.74 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.86 (br s, 1H, H-6 '), 4.74 (d, 1H, H-5', J _{5 ', 6'} = 4.6 Hz), 4.31 ( m, 2H, H-2 ', H-3'), 4.27 (m, 1H, H-4 '), 3.85 (s, 3H, -CO ₂ Me ), 3.44 (t, 2H, H-3'' , J 3`` _{, 2 ''} = 6.3 Hz), 2.16-2.01 (m, 2H, H-2``), 2.03 (s, 3H, acetyl), 0.95, 0.90 (s, 9H, t-butyl, respectively) ), 0.16, 0.15, 0.09, 0.07 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 172.1, 171.1, 165.7, 152.2, 141.5, 103.5, 90.8, 90.4, 84.6, 80.6, 76.1, 73.1, 61.0, 53.8, 53.1, 26.4, 26.3, 22.2, 22.0, 18.9, 18.9, 14.5, -4.1, -4.3, -4.4, -4.5; ESIMS-HR calculated 705.3070, observed 705.3077.

Example 8-3 (2R, 4S, 5S) -3-acetyl-2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- Synthesis of (uracil-1-yl)] tetrahydrofuryl- (1,3) -oxazolidine-4-carboxylate methyl (16c)

According to Example 8-1, compound (16c) (265 mg, 88%) was converted to yellow foam from compound (4) (300 mg, 0.43 mmol) and 3-azidobutanal (98 mg, 0.87 mmol). Obtained as material.
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.65 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.95 (d , 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.80 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.79 (m, 1H, H-1``) , 4.85 (d, 1H, H-6 ', J _{6', 5 '} = 5.8 Hz), 4.70 (d, 1H, H-5', J _{5 ', 6'} = 5.8 Hz), 4.30 (br s, 2H, H-2 ', H-3'), 4.24 (m, 1H, H-4 '), 3.85 (s, 3H, -CO ₂ Me ), 3.36 (t, 2H, H-4``, J 4`` _{, 3 ''} = 6.9 Hz), 2.04 (s, 3H, acetyl), 1.95-1.70 (m, 4H, H-2 ', H-3''), 0.95, 0.91 (s, 9H, respectively) t-butyl), 0.16, 0.15, 0.11, 0.09 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 171.5, 171.1, 165.5, 152.2, 141.1, 103.2, 91.8, 89.9 , 84.1, 79.8, 76.3, 73.1, 60.4, 53.7, 51.9, 32.0, 31.3, 26.4, 26.3, 25.4, 25.3, 22.3, 22.0, 18.9, 18.9, 14.5, -4.1, -4.3, -4.4, -4.5; ESIMS -HR calculated 719.3227, measured 719.3223.

Example 8-4 (2R, 4S, 5S) -3-acetyl-2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- ( Synthesis of (uracil-1-yl)] tetrahydrofuryl- (1,3) -oxazolidine-4-carboxylic acid (17a)

According to Example 5-1, compound (17a) (72 mg, 73%) was obtained as a yellow syrup from compound (16a) (101 mg, 0.15 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 3: 1 rotamer mixture, main rotamer data) δ 7.69 (d, 1H, H-6, J _6,5 = 8.0 Hz), 6.01 (d , 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.77 (t, 1H, H-1``, J _1''2'' = 4.0 Hz), 5.76, (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.68 (d, 1H, H-5 ', J _{5', 6 '} = 6.9 Hz), 4.44 (d, 1H, H-6', J _{6 ', 5 '} = 6.9 Hz), 4.37 (m, 1H, H-3'), 4.31 (m, 1H, H-2 '), 4.30 (m, 1H, H-4'), 3.67- 3.40 (m, 2H , H-4``), 2.04 (s, 3H, acetyl), 1.90 (m, 2H, H-2 ''), 1.79 (m, 2H, H-3 ''), 0.94 0.90 (respectively s, 9H , t-butyl), 0.16, 0.13, 0.09, 0.09 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 176.2, 171.9, 165.8, 152.2, 141.4, 103.4, 90.5, 89.3, 84.6, 82.0, 76.4, 73.7, 62.8, 52.0, 26.4, 26.4, 22.4, 18.9, 18.9, -4.2, -4.4, -4.4, -4.5; ESIMS-HR (negative mode) calculated value 653.2792, actual value 653.2798 .

Example 8-5 (2R, 4S, 5S) -3-acetyl-2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- ( Synthesis of (uracil-1-yl)] tetrahydrofuryl- (1,3) -oxazolidine-4-carboxylic acid (17b)

According to Example 5-1, compound (17b) (88 mg, 75%) was obtained as a yellow syrup from compound (16b) (120 mg, 0.18 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 3: 1 rotamer mixture, main rotamer data) δ 7.70 (d, 1H, H-6, J _6,5 = 8.2 Hz), 5.97 (br s, 1H, H-1 '), 5.80 (t, 1H, H-1``, J _1'',2'' = 3.6 Hz), 5.74 (d, 1H, H-5, J _5,6 = 8.2 Hz), 4.61 (d, 1H, H-5 ', J _{5', 6 '} = 6.4 Hz), 4.45 (d, 1H, H-6', J _{6 ', 5'} = 6.4 Hz), 4.37 ( m, 1H, H-3 '), 4.31 (m, 2H, H-3', H-4 '), 3.47 (m, 2H, H-3''), 2.20-1.98 (m, 2H, H- 2``), 2.04 (s, 3H, acetyl), 0.94, 0.91 (each s, 9H, t-butyl), 0.15, 0.14, 0.09, 0.08 (each s, 3H, Si Me ₃ ); ¹³ C NMR ( (CD ₃ OD, 125 MHz) δ 176.5, 171.6, 165.9, 152.2, 141.3, 103.2, 89.8, 89.5, 84.7, 81.6, 76.6, 73.5, 62.7, 33.2, 26.4, 22.4, 19.0, 18.9, -4.1, -4.3, -4.4, -4.5; ESIMS-HR (negative mode) calculated 667.2949, measured 667.2956.

Example 8-6 (2R, 4S, 5S) -3-acetyl-2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- Synthesis of (uracil-1-yl)] tetrahydrofuryl- (1,3) -oxazolidine-4-carboxylic acid (17c)

According to Example 5-1, compound (17c) (91 mg, 81%) was obtained as a yellow syrup from compound (16c) (115 mg, 0.18 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.75 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.94 (d , 1H, H-1 ', J _{1', 2 '} = 4.2 Hz), 5.74 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.70, (m, 1H, H-1'' ), 4.60 (d, 1H, H-5 ', J _{5', 6 '} = 6.9 Hz), 4.45 (d, 1H, H-6', J _{6 ', 5'} = 6.9 Hz), 4.33 (m, 1H, H-3 '), 4.29 (m, 1H, H-2'), 4.28 (m, 1H, H-4 '), 3.36 (m, 2H, H-4''), 2.05 (s, 3H , Acetyl), 1.93-1.71 (m, 2H, H-2``), 1.79 (m, 2H, H-3 ''), 0.94 0.90 (s, 9H, t-butyl, respectively), 0.15, 0.14, 0.09 , 0.08 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 176.7, 171.5, 165.9, 152.1, 141.3, 103.0, 91.5, 89.6, 84.3, 81.0, 76.7, 73.3, 62.5 , 52.1, 31.9, 31.1, 26.4, 25.6, 22.5, 22.3, 18.9, 18.9, -4.1, -4.3, -4.4, -4.5; ESIMS-HR (negative mode) calculated 681.3105, found 681.3114.

Example 8-7 (2R, 4S, 5S) -3-acetyl-2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- ( Uracyl-1-yl)] tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide (18a)

Compound (17a) (40 mg, 0.061 mmol), hexadecylamine (44 mg, 0.18 mmol) and N-hydroxybenzotriazole (25 mg, 0.18 mmol) in methylene chloride 1- [3- (Dimethylamino) propyl] -3-ethylcarbodiimide (35 mg, 0.18 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with 0.1 mol / L hydrochloric acid, saturated aqueous sodium carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (mobile layer: hexane / ethyl acetate = 1/1) to give compound (18a) (38 mg, 71%) as a yellow syrup.
¹ H NMR (CD ₃ OD, 500 MHz, 1: 1 rotamer mixture, data for one rotamer) δ 7.75 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.98 ( d, 1H, H-1 ', J _{1', 2 '} = 5.2 Hz), 5.92 (t, 1H, H-1``, J _1'',2'' = 4.6 Hz), 5.82 (d, 1H , H-5, J _5,6 = 8.0 Hz), 4.60 (d, 1H, H-5 ', J _{5', 6 '} = 6.9 Hz), 4.54 (d, 1H, H-6', J _{6 ' , 5 '} = 6.9 Hz), 4.33 (m, 1H, H-3'), 4.30 (m, 1H, H-2 '), 4.21 (m, 1H, H-4'), 3.85-3.71 (m, 2H, H-2``), 3.36-3.25 (m, 2H, -CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.99 (s, 3H, acetyl), 1.52 (m, 2H, -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.94, 0.89 (each s, 9H, t-butyl), 0.89 ( t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz), 0.16, 0.14, 0.09, 0.07 (respectively s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 171.9, 170.9, 165.9, 152.2, 141.6, 103.4, 91.1, 90.3, 83.5, 81.9, 76.1, 73.2, 62.4, 52.8, 40.7, 33.1, 30.8, 30.7, 30.5, 28.0, 26.5, 26.4, 23.8, 22.3, 22.2, 19.0, 19.0, -4.2, -4.4, -4.4, -4.5; ESIMS-HR calculated 900.5421, measured 900.5428.

Example 8-8 (2R, 4S, 5S) -3-acetyl-2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- ( (Uracil-1-yl)] tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide (18b)

According to Example 8-7, compound (18b) (27 mg, 70%) was obtained as a yellow syrup from compound (17b) (29 mg, 0.044 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 1: 1 rotamer mixture, data for one rotamer) δ 7.74 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.95 ( br s, 1H, H-1 '), 5.83 (m, 1H, H-1''), 5.80 (d, 1H, H-5, J _5,6 = 8.0 Hz), 4.52 (d, 1H, H -5 ', J _{5', 6 '} = 5.2 Hz), 4.50 (d, 1H, H-6', J _{6 ', 5'} = 5.2 Hz), 4.30 (m, 2H, H-2 ', H- 3 '), 4.22 (m, 1H, H-4'), 3.54 (t, 2H, H-3``, J _{3 '', 2 ''} = 5.2 Hz), 3.36-3.24 (m, 2H,- CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 2.28-2.05 (m, 2H, H-2``), 1.98 (s, 3H, acetyl), 1.51 (m, 2H, -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.94, 0.91 (s, 9H, t-butyl, respectively), 0.89 (t, 3H , -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz), 0.14, 0.14, 0.10, 0.09 (s, 3H, Si Me ₃ ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 171.1, 170.9, 166.0, 152.3, 141.4, 103.2, 90.6, 90.5, 83.5, 81.5, 76.4, 73.2, 62.3, 52.8, 40.8, 33.6, 33.1, 30.8, 30.7, 30.5, 28.0, 26.4, 22.4, 23.8, 22.3 , 22.1, 19.0, 19.0, 14.5, -4.0, -4.0, -4.4, -4.5; MS-HR calculated 914.5577, measured Value 914.5580.

Example 8-9 (2R, 4S, 5S) -3-acetyl-2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-di-tert-butyldimethylsilyloxy-4- Synthesis of (uracil-1-yl)] tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide (18c)

According to Example 8-7, compound (18c) (45 mg, 84%) was obtained as a yellow syrup from compound (17c) (40 mg, 0.059 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 1: 1 rotamer mixture, data for one rotamer) δ 7.82 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.92 ( d, 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.79 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.78 (m, 1H, H-1'' ), 4.52 (m, 1H, H-5 '), 4.50 (m, 1H, H-6'), 4.31 (m, 1H, H-3 '), 4.27 (m, 1H, H-2'), 4.24 (m, 1H, H-4 '), 3.38 (t, 2H, H-4``, J _4'',3'' = 6.9 Hz), 3.36-3.10 (m, 2H, -CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.98 (s, 3H, acetyl), 1.91 (m, 2H, H-2``), 1.80 (m, 2H, H-3 ''), 1.52 (m, 2H , -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.94, 0.91 (each s, 9H, t-butyl ), 0.90 (t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz), 0.15, 0.14, 0.11, 0.11 (s, 3H, Si Me ₃ ); ¹³ C NMR ( (CD ₃ OD, 125 MHz) δ 171.1, 170.6, 165.9, 152.2, 141.4, 103.0, 92.3, 90.5, 83.4, 80.1, 76.5, 73.0, 60.8, 52.1, 40.7, 33.1, 32.3, 31.6, 30.8, 30.7, 30.5, 28.0, 26.5, 25.7, 25.6, 23.8, 22.4, 22.1, 19.0, 19.0, 14.5, -4.0, -4.0, -4.4, -4.5; ESIMS-HR Calculated value 928.5734, found 928.5735.

Example 8-10 (2R, 4S, 5S) -3-acetyl-2-azidomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] Synthesis of tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide (19a)

According to Example 5-4, compound (19a) (16 mg, 81%) was obtained as a yellow syrup from compound (18a) (26 mg, 0.030 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 3: 2 rotamer mixture, main rotamer data) δ 7.63 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.90 (d , 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.73 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.67 (d, 1H, H-1``, J 1`` _{, 2 ''} = 2.3 Hz), 4.66 (dd, 1H, H-5 ', J _{5', 4 '} = 2.3, J _{5', 6 '} = 5.2 Hz), 4.61 (d, 1H, H-6 ', J _{6', 5 '} = 5.2 Hz), 4.31 (m, 1H, H-3'), 4.25 (br s, 1H, H-2 '), 4.12 (m, 1H, H-4 '), 3.65 (m, 2H, H-2``), 3.36-3.14 (m, 2H, -CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 2.01 (s, 3H, acetyl), 1.53 ( m, 2H, -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.90 (t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 172.3, 170.9, 165.9, 152.3, 142.3, 103.3, 91.3, 91.1, 84.0, 82.2, 74.7 , 71.3, 62.6, 52.7, 40.9, 33.1, 30.8, 30.7, 30.7, 30.5, 30.4, 30.4, 30.3, 28.0, 23.8, 22.2, 14.5; ESIMS-HR calculated 672.3691, measured 672.3697.

Example 8-11 (2R, 4S, 5S) -3-acetyl-2-azidoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] Synthesis of tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide (19b)

According to Example 5-4, compound (19b) (14 mg, 76%) was obtained as a yellow syrup from compound (18b) (25 mg, 0.028 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 1: 1 rotamer mixture, data for one rotamer) δ 7.70 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.93 ( d, 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.76 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.75 (m, 1H, H-1'' ), 4.57 (dd, 1H, H-5 ', J _{5', 4 '} = 1.7, J _{5', 6 '} = 6.9 Hz), 4.56 (d, 1H, H-6', J _{6 ', 5'} = 6.9 Hz), 4.27 (dd, 1H, H-3 ', J _{3', 2 '} = 5.2, J _{3', 4 '} = 5.8 Hz), 4.22 (dd, 1H, H-2', J _{2 ' , 1 '} = 4.6, J _{2', 3 '} = 5.2 Hz), 4.13 (dd, 1H, H-4', J _{4 ', 3'} = 5.8, J _{4 ', 5'} = 1.7 Hz), 3.53 ( t, 2H, H-3``, J _{3 '', 2 ''} = 6.9 Hz), 3.36-3.22 (m, 2H, -CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 2.05 (m, 2H, H-2``), 2.00 (s, 3H, acetyl), 1.54 (m, 2H, -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ , 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.90 (t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ ), J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 171.9 , 171.1, 165.9, 152.3, 142.1, 103.3, 91.0, 90.3, 83.9, 81.7, 74.9, 71.4, 62.5, 40.8, 33.9, 33.1, 30.8, 30.7, 30.7, 30.5, 30.4, 30.4, 30.3, 28.0, 23.8, 22.1 , 14.5; ESIMS-HR calculation Value 686.3848, measured value 686.3851.

Example 8-12 (2R, 4S, 5S) -3-acetyl-2-azidopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl) Synthesis of tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide (19c)

According to Example 5-4, compound (19c) (26 mg, 88%) was obtained as a yellow syrup from compound (18c) (39 mg, 0.043 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 1: 1 rotamer mixture, data for one rotamer) δ 7.71 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.92 ( d, 1H, H-1 ', J _{1', 2 '} = 4.6 Hz), 5.75 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.64 (m, 1H, H-1'' ), 4.57 (m, 1H, H-5 '), 4.56 (m, 1H, H-6'), 4.26 (dd, 1H, H-3 ', J _{3', 2 '} = 5.2, J _{3', 4 '} = 4.6 Hz), 4.22 (dd, 1H, H-2', J _{2 ', 1'} = 4.6, J _{2 ', 3'} = 5.2 Hz), 4.13 (d, 1H, H-4 ', J _{4 ', 3'} = 6.9 Hz), 3.42 (t, 2H, H-4``, J _{4 '', 3 ''} = 6.9 Hz), 3.35-3.24 (m, 2H, -CONHC H ₂ CH ₂ ( CH ₂ ) ₁₃ CH ₃ ), 2.00 (s, 3H, Acetyl), 1.92 (m, 2H, H-2``), 1.76 (m, 2H, H-3 ''), 1.53 (m, 2H,- CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.90 (t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 171.9, 171.1, 165.9, 152.3, 142.2, 103.2, 92.2, 90.8, 83.8, 81.5, 74.9, 71.4, 62.5, 52.2, 40.8, 33.1, 31.9, 30.8, 30.8, 30.7, 30.5, 30.4, 30.4, 30.4, 28.0, 25.5, 23.8, 22.1, 14.5; ESIMS-HR calculated 700.4004, observed 700.4006.

Example 8-13 (2R, 4S, 5S) -3-acetyl-2-aminomethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl) Synthesis of tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide HCl salt (20a)

According to Example 5-7, compound (20a) (6.4 mg, 69%) was obtained as a white foam from compound (19a) (9.7 mg, 0.015 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 9: 1 rotamer mixture, main rotamer data) δ 7.57 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.71 (d , 1H, H-5, J _5,6 = 8.0 Hz), 5.67 (d, 1H, H-1 ', J _{1', 2 '} = 3.5 Hz), 5.62 (t, 1H, H-1``, J 1`` _{, 2 ''} = 3.9 Hz), 4.69 (d, 1H, H-6 ', J _{6', 5 '} = 4.6 Hz), 4.61 (dd, 1H, H-5', J _{5 ', 4 '} = 2.3, J _{5', 6 '} = 4.6 Hz), 4.41 (dd, 1H, H-3', J _{3 ', 2'} = J _{3 ', 4'} = 6.3 Hz), 4.32 (dd, 1H , H-2 ', J _{2', 1 '} = 3.5, J _{2', 3 '} = 6.3 Hz), 4.04 (dd, 1H, H-4', J _{4 ', 3'} = 6.3, J _{4 ', 5 '} = 2.3 Hz), 3.51 (m, 2H, H-2``), 3.26 (m, 2H, -CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 2.03 (s, 3H, acetyl), 1.57 (br s, 2H, -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.90 (t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 172.6, 172.2, 165.9, 152.1, 143.8, 103.4, 93.9, 89.2, 85.1, 82.6, 73.9, 70.3, 61.9, 52.7, 41.0, 33.1, 30.8, 30.7, 30.7, 30.4, 30.4, 30.2, 28.0, 23.7, 23.0, 14.4; ESIMS-HR calculated 624.3967, observed 624.3964.

Example 8-14 (2R, 4S, 5S) -3-acetyl-2-aminoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl) Synthesis of tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide HCl salt (20b)

According to Example 5-7, compound (20b) (6.4 mg, 72%) was obtained as a white foam from compound (19b) (9.2 mg, 0.014 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 5: 1 rotamer mixture, main rotamer data) δ 7.63 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.80 (d , 1H, H-1 ', J _{1', 2 '} = 3.5 Hz), 5.71 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.65 (t, 1H, H-1``, J 1`` _{, 2 ''} = 5.2 Hz), 4.62 (d, 1H, H-6 ', J _{6', 5 '} = 4.6 Hz), 4.57 (dd, 1H, H-5', J _{5 ', 4 '} = 2.3, J _{5', 6 '} = 4.6 Hz), 4.32 (dd, 1H, H-3', J _{3 ', 2'} = 6.4, J _{3 ', 4'} = 6.4 Hz), 4.28 (dd , 1H, H-2 ', J _{2', 1 '} = 4.0, J _{2', 3 '} = 5.2 Hz), 4.08 (dd, 1H, H-4', J _{4 ', 3'} = 6.4, J _{4 ', 5'} = 2.3 Hz), 3.34-3.18 (m, 2H, -CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 3.11 (t, 2H, H-3``, J _{3 '', 2 ''} = 6.3 Hz), 2.26 (br s, 2H, H-2 ''), 2.02 (s, 3H, acetyl), 1.56 (br s, 2H, -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.90 (t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 172.2, 171.3, 165.9, 152.2, 142.9, 103.2, 92.7, 90.4, 83.9, 82.0, 74.5, 70.9, 62.5, 41.0, 36.7, 33.1, 32.2, 30.8, 30.7, 30.7, 30.4, 30.3, 30.3, 28.1, 23.7, 22.1, 14.5; ESIMS-HR calculated 638.4123, measured 638.4123.

Example 8-15 (2R, 4S, 5S) -3-acetyl-2-aminopropyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl) Synthesis of tetrahydrofuryl-N-hexadecyl- (1,3) -oxazolidine-4-carboxylamide HCl salt (20c)

According to Example 5-7, compound (20c) (4.8 mg, 51%) was obtained as a white foam from compound (19c) (9.7 mg, 0.014 mmol).
¹ H NMR (CD ₃ OD, 500 MHz, 2: 1 rotamer mixture, main rotamer data) δ 7.65 (d, 1H, H-6, J _6,5 = 8.0 Hz), 5.87 (d , 1H, H-1 ', J _{1', 2 '} = 4.0 Hz), 5.71 (d, 1H, H-5, J _5,6 = 8.0 Hz), 5.60 (t, 1H, H-1``, J 1`` _{, 2 ''} = 4.6 Hz), 4.58 (d, 1H, H-6 ', J _{6', 5 '} = 5.8 Hz), 4.55 (dd, 1H, H-5', J _{5 ', 4 '} = 1.8, J _{5', 6 '} = 5.8 Hz), 4.27 (t, 1H, H-3', J _{3 ', 2'} = J _{3 ', 4'} = 5.8 Hz), 4.23 (dd, 1H , H-2 ', J _{2', 1 '} = 4.0, J _{2', 3 '} = 5.8 Hz), 4.11 (dd, 1H, H-4', J _{4 ', 3'} = 5.8, J _{4 ', 5 '} = 1.8 Hz), 3.33-3.15 (m, 2H, -CONHC H ₂ CH ₂ (CH ₂ ) ₁₃ CH ₃ ), 2.99 (t, 2H, H-4``, J _4'',3'' = 6.9 Hz), 2.00 (s, 3H, acetyl), 1.84 (m, 4H, H-2``, H-3 ''), 1.54 (m, 2H, -CONHCH ₂ C H ₂ (CH ₂ ) ₁₃ CH ₃ ), 1.29 (br s, 26H, -CONHCH ₂ CH ₂ (C H ₂ ) ₁₃ CH ₃ ), 0.90 (t, 3H, -CONHCH ₂ CH ₂ (CH ₂ ) ₁₃ C H ₃ , J = 6.9 Hz ); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 172.2, 171.3, 165.9, 152.2, 142.9, 103.2, 92.7, 90.4, 83.9, 82.0, 74.5, 70.1, 62.5, 41.0, 36.7, 33.1, 32.2, 30.8, 30.8, 30.7, 30.5, 30.4, 30.3, 28.1, 23.7, 22.6 14.5; ESIMS-HR calculated 652.5280, measured 652.4281.

Example 9 (2R, 4S, 5S) -2-aminoethyl-5-[(1R, 2R, 3R, 4R) -2,3-dihydroxy-4- (uracil-1-yl)] tetrahydrofuryl-3- Synthesis of palmitoyl- (1,3) -oxazolidine-4-carboxylamide HCl salt (21)

Compound (21) can be obtained by using the synthesis method described in this specification.

Test Example 1 In vitro measurement of antibacterial activity (test method)
The minimum growth inhibitory concentration (MIC: μg / ml) was determined by a micro liquid dilution method in accordance with NCCLS. The bacterial species used are as follows.
(1) Staphylococcus aureus
(2) Enterococcus faecalis
(3) Enterococcus faecium
Brain Heart Infusion Agar was used for preculture of the bacteria used for MIC measurement. Further, Muller Hinton Broth was used as the medium for MIC measurement. The amount of inoculum for MIC measurement was 5 × 10 ⁵ CFU / ml, and was determined after culturing at 35 ° C. for 20 hours. The test results are shown in Table 1 below.

Formulation Example 1
A granule containing the following ingredients is produced.

Ingredient Compound represented by formula (I) 10mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
1000mg
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer. Add HPC-L (low-viscosity hydroxypropylcellulose) aqueous solution to the powder mixture, knead, granulate (extruded granulation pore size 0.5-1 mm), and dry. The obtained dried granules are combed with a vibrating sieve (12/60 mesh) to obtain granules.

Formulation Example 2
A capsule filling granule containing the following ingredients is produced.

Ingredient Compound represented by formula (I) 15mg
Lactose 90mg
Cornstarch 42mg
HPC-L 3mg
150mg
The compound of formula (I), lactose, is passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder to knead, granulate and dry. After sizing the obtained dry granules, 150 mg thereof is filled into No. 4 hard gelatin capsules.

Formulation Example 3
A tablet containing the following ingredients is produced.

Ingredient Compound represented by formula (I) 10mg
Lactose 90mg
Microcrystalline cellulose 30mg
CMC-Na 15mg
Magnesium stearate 5mg
150mg
The compound represented by the formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. The mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.

Formulation Example 4
The following components were heated and mixed and then sterilized to give an injection.

Ingredient Compound represented by formula (I) 3mg
Nonionic surfactant 15mg
Purified water for injection 1ml

The compound according to the present invention can be a pharmaceutical product such as an antibacterial agent.

Claims

Formula (I):

Wherein R 1 is —OH, —O-lower alkyl, or —NR 8 R 9 ;
R 2 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, or aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl;
R 4 and R 5 are each independently hydrogen, lower alkyl, carbocyclic ring, heterocyclic ring, carbocyclic alkyl, heterocyclic alkyl, or either R 4 or R 5 is taken together with R 3. May form a heterocyclic ring,
R 6 and R 7 are each independently hydrogen or lower alkyl,
R 8 and R 9 are each independently hydrogen, C1-C20 alkyl, carbocyclic ring, heterocyclic ring, carbocyclic alkyl, heterocyclic alkyl, or R 8 and R 9 taken together to form a heterocyclic ring. May be formed,
m is an integer of 0-3. )
Or a pharmaceutically acceptable salt or solvate thereof.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R 1 is —OH or —O-lower alkyl.
The compound according to claim 1, wherein R 1 is -NR 8 R 9 , or a pharmaceutically acceptable salt thereof, or a solvate thereof.
R 8 and R 9 may each independently represent hydrogen, C1-C20 alkyl, a carbocyclic ring, a heterocyclic ring, or R 8 and R 9 together may form a heterocyclic ring. 4. The compound according to 1 or 3, or a pharmaceutically acceptable salt or solvate thereof.
R 8 is a C1-C20 alkyl, A compound according to claim 1 or 3, or a pharmaceutically acceptable salt or solvate thereof.
The R 2 is aryl substituted with C1-C20 alkyl, C9-C20 alkenyl, C3-C20 alkynyl, C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl. Or a pharmaceutically acceptable salt or solvate thereof.
The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 is C11-C20 alkyl, C9-C20 alkenyl, or C1-C10 alkyl, or aryl substituted with C2-C10 alkenyl. Salts or solvates thereof.
The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 2 is C11-C20 alkyl or C9-C20 alkenyl.
The compound according to any one of claims 1 to 5, wherein R 2 is lower alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 2 is lower alkyl, and R 8 and R 9 are both lower alkyl. .
The compound according to any one of claims 1 to 10, wherein R 3 is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
R 4 and R 5 are each independently hydrogen, lower alkyl, or either R 4 or R 5 may be combined with R 3 to form a heterocyclic ring. Or a pharmaceutically acceptable salt or solvate thereof.
The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 6 and R 7 are both hydrogen.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
The pharmaceutical composition according to claim 14, which has MraY inhibitory action.
The pharmaceutical composition according to claim 14, which has antibacterial activity.
Use of the compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, or a solvate thereof for the manufacture of a therapeutic and / or prophylactic agent for various diseases caused by pathogenic bacteria. .
The compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, or a solvate thereof for the treatment and / or prevention of various diseases caused by pathogenic bacteria.
A method for treating and / or preventing various diseases caused by pathogenic bacteria, which comprises administering the compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a solvate thereof. .