阅读说明：本技术 碘代三氟甲氧基化合物的合成方法 (Method for synthesizing iodo-trifluoromethoxyl compound ) 是由 汤平平 黄庆云 于 2019-10-18 设计创作，主要内容包括：本发明实施例提供了三氟甲氧基化合物的合成方法,其特征在于,包括以下步骤：(1)制备预反应体系,所述预反应体系中包含氟盐、碘化剂、式(Ⅱ)化合物及溶剂；(2)向所述预反应体系中加入式(Ⅲ)化合物,以使式(Ⅲ)化合物和式(Ⅱ)化合物发生反应,从而得到式(Ⅰ)化合物。本发明提供的碘代三氟甲氧基化合物的合成方法,可以构建同时具有碘代和三氟甲氧基的官能团化合物。<Image he="143" wi="700" file="DDA0002239569180000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The embodiment of the invention provides a method for synthesizing a trifluoromethoxy compound, which is characterized by comprising the following steps of: (1) preparing a pre-reaction system, wherein the pre-reaction system comprises villiaumite, an iodizing agent, a compound shown in a formula (II) and a solvent; (2) adding a compound of formula (III) to the pre-reaction system to react the compound of formula (III) with a compound of formula (II) to obtain a compound of formula (I). The synthesis method of the iodo-trifluoromethoxy compound provided by the invention can construct a functional group compound simultaneously having iodo and trifluoromethoxy.)

1. The synthesis method of the iodo-trifluoromethoxyl compound is characterized by comprising the following steps of:

(1) preparing a pre-reaction system, wherein the pre-reaction system comprises villiaumite, an iodizing agent, a compound shown in a formula (II) and a solvent;

(2) adding a compound of formula (III) to the pre-reaction system to react the compound of formula (III) with a compound of formula (II) to obtain a compound of formula (I);

wherein R is₁、R₂、R₃And R₄Each independently represents H, halogen, hydroxyl, nitro, cyano, mercapto, amino, C_1-13Alkyl radical, C_2-13Alkenyl radical, C_2-13Alkynyl, C_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14Heteroaryl or Z radical, said C_1-13Alkyl radical, C_2-13Alkenyl radical, C_2-13Alkynyl, C_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C_1-6Alkyl radical, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,

Said C is_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);

the Z radical is

And R is₁、R₂、R₃And R₄At most one of which is said C_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14Heteroaryl or Z group;

or, at R₁、R₂、R₃And R₄The method comprises the following steps:

R₁、R₂one of (1) and R₃、R₄One of them together with the carbon atom to which each is attached forms C_5-8Monocyclic or bicyclic;

R₁、R₂、R₃、R₄wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C_1-13Alkyl radical, C_2-13Alkenyl radical, C_2-13Alkynyl radical, said C_5-8Monocyclic or bicyclic ring, C_1-13Alkyl radical, C_2-13Alkenyl radical, C_2-13Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C_1-6Alkyl radical, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, benzyloxy;

R₅representative H, C_1-6Alkyl, halogen, nitro, cyano, mercapto, amino, C_1-6An alkyloxy group; said C is_1-6Alkyl and C_1-6The alkyloxy group is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl and nitro.

2. The method of claim 1A method for synthesizing iodo trifluoro methoxy compound, characterized in that R₁、R₂、R₃And R₄Each represents H, C respectively_1-13Alkyl radical, C_5-12Cycloalkenyl radical, C_6-10Aryl radical, C_6-10Heteroaryl or Z radical, said C_1-13Alkyl radical, C_5-12Cycloalkenyl radical, C_6-10Aryl radical, C_6-10Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, nitro, cyano, phenyl, C_1-4Alkyl radical, C_1-4Alkylcarbonyloxy, C_1-4Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,

Said C is_5-12Cycloalkenyl radical, C_6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);

the Z radical is

or, at R₁、R₂、R₃And R₄The method comprises the following steps:

R₁、R₂one of (1) and R₃、R₄One of them together with the carbon atom to which each is attached in formula (I) forms C_5-8A single ring; r₁、R₂、R₃、R₄Wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl radical, said C_5-8Monocyclic ring, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, C_1-4Alkyl radical, C_1-4Alkylcarbonyloxy, C_1-4An alkoxycarbonyl group;

R₅represents H, halogen, C_1-6Alkyl radical, C_1-6An alkyloxy group; said C is_1-6Alkyl radical, C_1-6The alkyloxy group is unsubstituted or optionally substituted with one or more halo.

3. The method of synthesizing iodo-trifluoromethoxy compound of claim 1 or 2, wherein R is₁、R₂、R₃And R₄At least one of them represents H.

4. The method for the synthesis of iodo-trifluoromethoxy compounds according to claim 1 or 2, wherein the compound of formula (ii) is selected from the following compounds:

5. the method of synthesizing iodo-trifluoromethoxy compound of claim 1 or 2, wherein the compound of formula (iii) is selected from the group consisting of:

6. the method for synthesizing iodo-trifluoromethoxy compound according to claim 1 or 2, wherein the compound of formula (iii) is in molar excess with respect to the compound of formula (ii), preferably the molar ratio of compound of formula (iii) to compound of formula (ii) is 3 to 5: 1.

7. the method for synthesizing iodo-trifluoromethoxy compound according to claim 1 or 2, wherein the solvent is selected from one or at least two of dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, chloroform, acetonitrile; preferably, the solvent is a mixture of acetonitrile and dichloromethane, and more preferably, the volume ratio of acetonitrile to dichloromethane is (1:2) to (2: 1).

8. The method of synthesizing iodo-trifluoromethoxy compound of claim 1 or 2, wherein the fluoro salt is selected from LiF, NaF, KF, CsF, ZnF₂、MgF₂、CaF₂、NMe₄One or at least two of F; preferably, the molar ratio of the fluorine salt to the compound of formula (II) is (0.5-1): 1.

9. the method for synthesizing iodo trifluoromethoxy compound according to claim 1 or 2, wherein the iodinating agent is one or at least two selected from the group consisting of N-iodo succinimide, N-iodo phthalimide, diiodohydantoin, and iodine; preferably, the molar ratio of the iodinating agent to the compound of formula (II) is (1-5): 1, preferably (3-5): 1.

10. the method for synthesizing iodo-trifluoromethoxy compound according to claim 1 or 2, wherein in step (1), the pre-reaction system further comprises a chiral catalyst; preferably, the chiral catalyst is selected from one or at least two of hydrogenated quinine 1,4- (2, 3-naphthyridine) diether, hydrogenated quinine (anthraquinone-1, 4-diyl) diether or hydrogenated quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether; more preferably, the molar ratio of the chiral catalyst to the compound of formula (II) is (0.05-0.2): 1, preferably (0.1 to 0.15): 1.

11. the method for synthesizing an iodotrifluoromethoxy compound according to claim 1 or 2, wherein in step (1), the pre-reaction system further comprises a silver salt; preferably, the silver salt is selected from one or at least two of silver fluoride, silver carbonate, silver trifluoromethanesulfonate, silver oxide, silver tetrafluoroborate, silver nitrate, silver sulfate and silver benzoate; more preferably, the molar ratio of silver salt to compound of formula (II) (0.2-1.5): 1, preferably (1.0 to 1.5): 1.

12. the method for synthesizing iodo-trifluoromethoxy compound according to claim 1 or 2, wherein in step (2), the reaction temperature is 30 to-20 ℃, preferably 0 to-20 ℃, more preferably-10 ℃; the reaction time is 8-20 hours; preferably, in step (2), the compound of formula (III) is added to the pre-reaction system when the temperature of the pre-reaction system is from 30 ℃ to-20 ℃, preferably from 0 ℃ to-20 ℃, more preferably-10 ℃.

Technical Field

The invention relates to the field of organic chemistry, in particular to a synthetic method of an iodo-trifluoromethoxy compound.

Background

Fluorine-containing drugs have been rapidly developed in recent 30 years, accounting for 36% of small molecule drugs in the market, and the directional fluorination of drug molecules has become the most important part of drug design, and the specific gravity of fluorine-containing molecules in pesticide molecules has also increased year by year. Furthermore, in the field of materials concerned, due to the fluorine-containing materialsThe unique stability and physical properties make it nearly half as much as military tip materials. Fluorine-containing compounds have been widely used in the fields of medicinal chemistry, agricultural chemicals, organic synthesis, materials, PET, and the like. However, due to the specific nature of fluoride, how to construct such compounds has been the subject of synthetic and pharmaceutical chemistry research. In recent years, a plurality of mild and simple methods for constructing small-molecule fluorine-containing compounds are developed, wherein fluorine elements or fluorine-containing functional groups (OCF)₃Etc.) has become an important strategy to improve materials and develop new drugs. Due to trifluoromethoxy group (OCF)₃) Has the characteristics of stronger electroabsorbability and extremely high lipophilicity, and the synthesis of the compounds is concerned by fluorine chemists.

Iodo compounds play an important role in organic synthesis, and can undergo various types of organic reactions, including S, due to the strong activity of iodine atoms_N2 nucleophilic substitution reactions, free radical type reactions, and metal catalyzed coupling reactions, among others, are important intermediates in organic synthesis. The iodo reaction and the trifluoromethoxy reaction are combined, so that the synthesis method of the fluoro compound is enriched, and other fluoro compounds with more complex structures and higher application values can be further synthesized from the products of the type.

Disclosure of Invention

The embodiment of the invention aims to provide a method for synthesizing iodo-trifluoromethoxy compounds, so as to realize the construction of functional compounds with iodo groups and trifluoromethoxy groups. The specific technical scheme is as follows:

1. a method for synthesizing a trifluoromethoxy compound, comprising the steps of:

(1) preparing a pre-reaction system, wherein the pre-reaction system comprises villiaumite, an iodizing agent, a compound shown in a formula (II) and a solvent;

(2) adding a compound of formula (III) to the pre-reaction system to react the compound of formula (III) with a compound of formula (II) to obtain a compound of formula (I);

wherein R is₁、R₂、R₃And R₄Each independently represents H, halogen, hydroxyl, nitro, cyano, mercapto, amino, C_1-13Alkyl radical, C_2-13Alkenyl radical, C_2-13Alkynyl, C_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14Heteroaryl or Z radical, said C_1-13Alkyl radical, C_2-13Alkenyl radical, C_2-13Alkynyl, C_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C_1-6Alkyl radical, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,

Said C is_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);

the Z radical isAnd R is₁、R₂、R₃And R₄At most one of which is said C_5-12Cycloalkyl radical, C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14Heteroaryl or Z group;

or, at R₁、R₂、R₃And R₄The method comprises the following steps:

R₁、R₂one of (1) and R₃、R₄One of them together with the carbon atom to which each is attached in formula (I) forms C_5-8Monocyclic or bicyclic; r₁、R₂、R₃、R₄Wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C_1-13Alkyl radical、C_2-13Alkenyl radical, C_2-13Alkynyl radical, said C_5-8Monocyclic or bicyclic ring, C_1-13Alkyl radical, C_2-13Alkenyl radical, C_2-13Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C_1-6Alkyl radical, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, benzyloxy;

R₅representative H, C_1-6Alkyl, halogen, nitro, cyano, mercapto, amino, C_1-6An alkyloxy group; said C is_1-6Alkyl and C_1-6The alkyloxy group is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl and nitro.

In some embodiments of the invention, R₁、R₂、R₃And R₄Each represents H, C respectively_1-13Alkyl radical, C_5-12Cycloalkenyl radical, C_6-10Aryl radical, C_6-10Heteroaryl or Z radical, said C_1-13Alkyl radical, C_5-12Cycloalkenyl radical, C_6-10Aryl radical, C_6-10Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, nitro, cyano, phenyl, C_1-4Alkyl radical, C_1-4Alkylcarbonyloxy, C_1-4Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,

Said C is_5-12Cycloalkenyl radical, C_6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);

the Z radical is

And R is₁、R₂、R₃And R₄At most one of which is said C_5-12Cycloalkenyl radical, C_6-14Aryl radical, C_6-14Heteroaryl or Z group;

or, at R₁、R₂、R₃And R₄The method comprises the following steps:

R₁、R₂one of (1) and R₃、R₄One of them together with the carbon atom to which each is attached in formula (I) forms C_5-8A single ring;

R₁、R₂、R₃、R₄wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl radical, said C_5-8Monocyclic ring, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, C_1-4Alkyl radical, C_1-4Alkylcarbonyloxy, C_1-4An alkoxycarbonyl group;

R₅represents H, halogen, C_1-6Alkyl radical, C_1-6An alkyloxy group; said C is_1-6Alkyl radical, C_1-6The alkyloxy group is unsubstituted or optionally substituted with one or more halo.

During the experiment, the inventors of the present invention unexpectedly found that the addition sequence of the compound of formula (III) and the compound of formula (II) affects the yield of the compound of formula (I); specifically, the compound of the formula (I) obtained by the reaction is high in generation yield after the compound of the formula (II) is mixed with other reactants such as a solvent and the like and then the compound of the formula (III) is added; on the contrary, the compound of formula (I) obtained by the reaction is low in yield when the compound of formula (III) is mixed with other reactants such as solvent and the like and stirred for a period of time in the absence of light.

In some embodiments of the invention, R₁、R₂、R₃And R₄At least one of them represents H.

In some embodiments of the invention, the compound of formula (ii) is selected from the following compounds:

in some embodiments of the invention, the compound of formula (iii) is selected from the following compounds:

in some embodiments of the present invention, the compound of formula (iii) is in molar excess of the compound of formula (ii), preferably the molar ratio of the compound of formula (iii) to the compound of formula (ii) is 3 to 5: 1.

in some embodiments of the invention, the solvent is selected from one or at least two of dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, chloroform, acetonitrile; preferably, the solvent is a mixture of acetonitrile and dichloromethane, and more preferably, the volume ratio of acetonitrile to dichloromethane is (1:2) to (2: 1).

In some embodiments of the invention, the fluoride salt is selected from LiF, NaF, KF, CsF, ZnF₂、MgF₂、CaF₂、NMe₄One or at least two of F; preferably, the molar ratio of the fluorine salt to the compound of formula (II) is (0.5-1): 1.

in some embodiments of the invention, the iodinating agent is selected from one or at least two of N-iodosuccinimide, N-iodophthalimide, diiodohydantoin, elemental iodine; preferably, the molar ratio of the iodinating agent to the compound of formula (II) is (1-5): 1, preferably (3-5): 1.

the structural formula of each iodinating agent is as follows:

in some embodiments of the invention, in step (1), the pre-reaction system further comprises a chiral catalyst; preferably, the chiral catalyst is selected from one or at least two of hydrogenated quinine 1,4- (2, 3-naphthyridine) diether, hydrogenated quinine (anthraquinone-1, 4-diyl) diether or hydrogenated quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether; more preferably, the molar ratio of the chiral catalyst to the compound of formula (II) is (0.05-0.2): 1, preferably (0.1 to 0.15): 1. each chiral catalyst is commercially available and the molecular formula of the chiral catalyst is shown in table 1.

TABLE 2 molecular formulae of the chiral catalysts

In some embodiments of the invention, in step (1), the pre-reaction system further comprises a silver salt; preferably, the silver salt is selected from one or at least two of silver fluoride, silver carbonate, silver trifluoromethanesulfonate, silver oxide, silver tetrafluoroborate, silver nitrate, silver sulfate and silver benzoate; more preferably, the molar ratio of silver salt to compound of formula (II) (0.2-1.5): 1, preferably (1.0 to 1.5): 1.

in some embodiments of the invention, in step (2), the reaction temperature is from 30 to-20 ℃, preferably from 0 to-20 ℃, more preferably-10 ℃; the reaction time is 8-20 hours; preferably, the compound of formula (III) is added to the pre-reaction system in step (2) when the temperature of the pre-reaction system is from 30 ℃ to-20 ℃, preferably from 0 ℃ to-20 ℃, more preferably-10 ℃.

Herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

Herein, the term "C_1-13Alkyl "refers to straight or branched chain saturated hydrocarbon groups containing 1 to 13 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and n-undecyl. "C_1-6Alkyl group "," C_1-4Alkyl "refers to the above examples containing 1 to 6 carbon atoms, 1 to 4 carbon atoms, respectively.

Herein, the term "C_2-13Alkenyl "means containing 2 to 13 carbon atoms and having one or moreStraight or branched hydrocarbon groups of carbon-carbon double bonds, including but not limited to vinyl, 2-propenyl, and 3-dodecene. "C_2-6Alkenyl "refers to the above examples containing 2 to 6 carbon atoms.

Herein, the term "C_2-13Alkynyl "refers to a straight or branched chain hydrocarbon group containing 2 to 13 carbon atoms and having one or more carbon-carbon triple bonds, and may optionally also include one or more carbon-carbon double bonds, including but not limited to ethynyl, propynyl, and 3-dodecynyl. "C_2-6Alkynyl "refers to the above examples containing 2 to 6 carbon atoms.

Herein, the term "C_5-12Cycloalkyl "means a saturated cyclic hydrocarbon group containing 5 to 12 carbon atoms, which may have one or more rings, preferably one or two rings, including but not limited to cyclopentyl, cyclohexyl, and cyclooctyl.

Herein, the term "C_5-12Cycloalkenyl "refers to a non-aromatic unsaturated cyclic hydrocarbon group containing from 5 to 12 carbon atoms and having one or more carbon-carbon double bonds, which may have one or more rings, preferably one or two rings, including but not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclooctenyl.

Herein, the term "C_6-14Aryl "refers to a cyclic carbocyclic hydrocarbon group containing from 6 to 14 ring carbon atoms consisting of one or more fused rings, at least one of which is aromatic, including but not limited to phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, and indenyl.

The term "C" as used herein_6-14Heteroaryl "means an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, N, preferably 1 to 3 heteroatoms. Heteroaryl groups include mono-heteroaryl and fused heteroaryl groups, representative examples of which include, but are not limited to: furyl, imidazolyl, isoxazolyl, thiazolyl, benzothienyl, benzopyranyl and the like.

Herein, the term "substituted with … …" means that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents selected from the group given, provided that the normal valence of the given atom is not exceeded.

Herein, the term "substituted with one or more substituents" means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from the given group.

In the present invention, in the radical structural formula

Indicates the point of attachment of the group to the rest of the molecule.

Abbreviations

Abbreviations referred to herein are as follows, and for abbreviations referred to herein but not listed, they have the ordinary meaning in the art.

NIS N-iodosuccinimide

Ac₂O acetic anhydride

DMA N, N-dimethylacetamide

DMAP 4-dimethylaminopyridine

EtOAc ethyl acetate

Et₃N-Triethylamine

Me methyl group

MeCN acetonitrile

Ph phenyl

Phth phthaloyl group

Bn benzyl group

t-Bu tert-butyl

Boc tert-butoxycarbonyl

THF tetrahydrofuran

Tol toluene

The embodiment of the invention provides a method for synthesizing iodo-trifluoromethoxy compounds, which can be used for constructing functional compounds with iodo and trifluoromethoxy simultaneously. The method has the advantages of simple operation, mild reaction conditions and high yield. The substrate of the method has wide application range, and the aromatic ring has electron withdrawing groups and electron donating groups, and the olefin substrate comprising ortho-position or meta-position substituent and aliphatic olefin substrate can obtain corresponding products with high yield. Meanwhile, the method can be well suitable for double-bond double-functionalization reaction of the complex natural product in the later period of molecules to prepare the corresponding trifluoromethoxy product, and provides abundant substrate diversity for bioactivity research.

Detailed Description

The technical solutions of the present invention will be described below with reference to specific embodiments, and the described embodiments are only a part of embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Synthesis example of Compound of formula (II)

Preparation of tiamulin diethyl ester

A100 mL reaction flask was taken, and tiamulin (700mg,1.85mmol,1.00equiv) and DMAP (4-dimethylaminepyrdine) (22.0mg,0.185mmol,0.1equiv) were added thereto with dried CH₂Cl₂(20.0mL) and Et was added₃N (1.50mL,11.1mmol,6.00equiv) and Ac₂O (0.700mL,7.40mmol,4.00equiv), reacted at room temperature for 4 h. After the reaction was complete, saturated NaHCO was used₃(20.0mL) quenching, CH₂Cl₂(25.0 mL. times.3) extraction, combined organic phases, anhydrous MgSO₄Drying, suction filtration removed solids, concentration, and column chromatography with n-hexane/EtOAc 4:1(v/v) afforded 429mg of product, 54% yield.

R_f＝0.2(n-hexane:EtOAc＝4:1).NMR Spectroscopy:¹H NMR(400MHz,CDCl₃)δ6.28(dd,J＝17.6,11.2Hz,1H),5.71(d,J＝8.2Hz,1H),5.27(d,J＝11.2Hz,1H),5.19(d,J＝17.6Hz,1H),4.88(d,J＝6.6Hz,1H),4.56–4.38(m,2H),2.52–2.41(m,1H),2.28–2.35(m,1H),2.24–2.06(m,9H),1.86–1.94(m,1H),1.64–1.74(m,2H),1.50–1.53(m,1H),1.44(s,3H),1.31–1.41(m,3H),1.13(td,J＝13.9,4.2Hz,1H),1.01(s,3H),0.80(d,J＝7.0Hz,3H),0.73(d,J＝6.9Hz,3H).¹³C NMR(101MHz,CDCl₃)δ217.2,170.6,170.3,166.6,139.4,116.7,76.7,70.0,61.5,58.6,45.4,44.7,43.2,42.1,36.7,36.3,34.6,30.4,27.8,26.9,25.1,20.9,20.6,16.4,14.9,11.9.Mass Spectrometry:HRMS-ESI(m/z):Calcd for C₂₆H₃₈NaO₇[M+Na]⁺,485.2510.Found,485.2513.

In addition to the above-mentioned tiamulin diethyl ester, the compounds of formula (ii) and formula (iii) used in the following examples can be prepared by the prior art or obtained commercially.

Synthesis examples of Compounds of formula (I)