Macrolide compound and preparation method and application of intermediate compound of macrolide compound

Abstract

The invention provides a macrolide compound and a preparation method and application of an intermediate compound of the macrolide compound, and belongs to the field of organic synthesis. The macrolide compound provided by the invention has the following chemical structure. The macrolide compound prepared by the invention is a compound with a 19-membered lactone ring structure, has a [5, 6]-tetrahydroindene ring structural unit and a (Z, E, Z) conjugated triene unit, and has a chemical structure completely different from that of MRSA drug-resistant bacterium antibiotics clinically used at present, such as polypeptide drugs (vancomycin and the like) and quinolone drugs (ofloxacin and the like), and the MRSA drug-resistant bacterium antibiotics can be used in clinical application. The macrolide is proved to have new drug-resistant bacterium resisting action targets and mechanisms. The macrolide compound provided by the invention has strong anti-MRSA activity, the minimum inhibitory concentration (MIC) is 1-2mg / mL and is equivalent to the anti-MRSA activity of vancomycin, and based on the strong anti-drug-resistant bacterium activity, the macrolide provided by the invention can be developed into a novel anti-drug-resistant bacterium drug. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a macrolide compound and an intermediate compound thereof, and applications thereof. Background Art

[0002] Since the advent of penicillin in the 1940s of the last century, antibiotics have played a crucial role in the prevention and treatment of human health diseases and saved countless lives. However, with the widespread use and even abuse of antibiotics in clinical practice, it has quickly exacerbated bacterial gene mutations, leading to the emergence of drug-resistant bacteria. In particular, the recent emergence of an increasing number of "super drug-resistant bacteria" has once again seriously threatened human health.

[0003] Methicillin-resistant Staphylococcus aureus (MRSA) is often isolated from community- and hospital-acquired infections. Due to the multi-drug resistance characteristics of MRSA, infections in immunocompromised individuals are often very severe, difficult to treat, and have a high mortality rate, with high morbidity and mortality. Moreover, MRSA infections have potential epidemic foci, and the abuse of antibiotics has not been effectively controlled, resulting in an upward trend in the infection rate of MRSA. In addition to being resistant to methicillin, MRSA is resistant to all other β-lactam and cephalosporin antibiotics with a structure similar to methicillin. And MRSA is only sensitive to vancomycin. However, over time, strains that are insensitive or resistant to vancomycin have also emerged. Therefore, seeking new anti-drug-resistant antibiotics has become an urgent medical need. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing a macrolide compound and an intermediate compound thereof, and applications thereof. The macrolide compound prepared by the present invention has potent anti-MRSA activity.

[0005] To achieve the purpose of the present invention, the present invention provides the following technical solutions:

[0006] A macrolide compound, with the following chemical structure:

[0007]

[0008] The present invention provides an intermediate compound for preparing the macrolide compound described in the above technical solution. The intermediate compound for preparing the macrolide compound has the following chemical structure:

[0009]

[0010] The present invention also provides a method for preparing the macrolide compound described in the above technical solution, comprising the following steps:

[0011] (a) Mix the compound of Formula 1, an iodinating reagent, and a silver metal reagent to carry out a halogenation reaction to obtain the compound of Formula 2;

[0012]

[0013] (b) Mix the compound described in Formula 2, a reducing agent, and an organic base to carry out a reduction reaction to obtain the compound of Formula 3;

[0014] (c) Mix the compound of Formula 3 and an oxidizing agent to carry out an oxidation reaction to obtain the compound of Formula 4;

[0015] (d) Mix the compound of Formula 4, an organic selenium reagent, and an alkylphosphine reagent to carry out a substitution reaction to obtain the compound of Formula 5;

[0016] (e) Mix the compound of Formula 5 with a peroxide to carry out a Grieco elimination reaction to obtain the compound of Formula 6;

[0017] (f) Mix the compound of Formula 6, a borate ester, a palladium catalyst, and an inorganic base to carry out a Suzuki coupling reaction to obtain the compound of Formula 7;

[0018] The borate ester has the following structure:

[0019]

[0020] (g) Mix the compound of Formula 7 and a reducing agent to carry out a reduction reaction to obtain the compound of Formula 8;

[0021] (h) Mix the compound of Formula 8, an oxidizing agent, and an organic base to carry out a Parikh-Doering oxidation reaction to obtain the compound of Formula 9;

[0022] (i) Mix the compound of Formula 9, an oxidizing agent, and 2-methyl-1,3-butadiene to carry out a Pinnick oxidation reaction to obtain the compound of Formula 10;

[0023] (j) Mix the compound of Formula 10, a condensation reagent, and an inorganic base to carry out a Mukaiyama esterification reaction to obtain the compound of Formula 11;

[0024] (k) Mix the compound of Formula 11 with a fluorine reagent to carry out an elimination reaction to obtain the macrolide compound.

[0025] Preferably, in (a), the iodinating reagent is N-iodosuccinimide and the silver metal reagent is silver nitrate;

[0026] In (b), the reducing agent is o-nitrobenzenesulfonylhydrazide and the organic base is triethylamine;

[0027] The oxidant described in (c) is 2,3-dichloro-5,6-dicyanobenzoquinone;

[0028] The organoselenium reagent described in (d) is 2-nitrophenylselenocyanate, and the alkylphosphine reagent is tri-n-butylphosphine;

[0029] The peroxide reagent described in (e) is hydrogen peroxide;

[0030] The palladium metal catalyst described in (f) is tetrakis(triphenylphosphine)palladium, the inorganic base is thallium carbonate, and the boron reagent is borate ester;

[0031] The reducing agent described in (g) is diisobutylaluminum hydride;

[0032] The oxidant described in (h) is pyridine sulfur trioxide, and the organic base is triethylamine;

[0033] The oxidant described in (i) is sodium chlorite;

[0034] The condensation reagent described in (j) is 2-bromo-1-ethylpyridinium tetrafluoroborate, and the inorganic base is sodium bicarbonate;

[0035] The fluorine reagent described in (k) is pyridine hydrofluoride.

[0036] Preferably, the molar ratio of the compound of formula 1, the iodinating reagent, and the silver metal reagent described in (a) is 1: 1.0-1.5: 0.3-1.5;

[0037] The molar ratio of the compound of formula 2, the reducing agent, and the organic base described in (b) is 1: 1.0-3.0: 1.5-4.5;

[0038] The molar ratio of the compound of formula 3 and the oxidant described in (c) is 1: 1.0-3.0;

[0039] The molar ratio of the compound of formula 4, the organoselenium reagent, and the alkylphosphine reagent described in (d) is 1: 1.0-5.0: 1.0-5.0;

[0040] The molar ratio of the compound of formula 5 and the peroxide reagent described in (e) is 1: 1.0-5.0;

[0041] The molar ratio of the compound of formula 6, the borate ester, the inorganic base, and the palladium metal catalyst described in (f) is 1: 1.2-2.0: 1.5-3.0: 0.1-0.5;

[0042] The molar ratio of the compound of formula 7 and the reducing agent described in (g) is 1: 2.0-10.0;

[0043] The molar ratio of the compound of formula 8, the oxidizing agent and the organic base described in (h) is 1: 10.0 to 25.0: 10.0 to 25.0;

[0044] The molar ratio of the compound of formula 9, the oxidizing agent and 2-methylbutadiene described in (i) is 1: 10.0 to 35.0: 100.0 to 350.0;

[0045] The molar ratio of the compound of formula 10, the condensing agent and the inorganic base described in (j) is 1: 15.0 to 50.0: 150.0 to 500.0;

[0046] The molar ratio of the compound of formula 11 and the fluorinating agent described in (k) is 1: 20.0 to 100.0.

[0047] Preferably, the temperature of the halogenation reaction described in (a) is 0 to 40 °C and the time is 1 to 5 h;

[0048] The temperature of the reduction reaction described in (b) is 0 to 40 °C and the time is 10 to 30 h;

[0049] The temperature of the oxidation reaction described in (c) is 0 to 30 °C and the time is 1 to 10 h;

[0050] The temperature of the substitution reaction described in (d) is 10 to 40 °C and the time is 1 to 20 h;

[0051] The temperature of the Grieco elimination reaction described in (e) is 0 to 25 °C and the time is 10 to 20 h;

[0052] The temperature of the Suzuki coupling reaction described in (f) is 20 to 40 °C and the time is 2 to 10 h;

[0053] The temperature of the reduction reaction described in (g) is -80 to -40 °C and the time is 1 h to 5 h;

[0054] The temperature of the Parikh-Doering oxidation reaction described in (h) is 0 to 5 °C and the time is 2 to 10 h;

[0055] The temperature of the Pinnick oxidation reaction described in (i) is 0 to 25 °C and the time is 10 to 20 h;

[0056] The temperature of the Mukaiyama esterification reaction described in (j) is 10 to 30 °C and the time is 15 to 30 h;

[0057] The temperature of the elimination reaction described in (k) is -5 to 10 °C and the reaction time is 2 to 10 h.

[0058] Preferably, the steps (a) to (k) further include a reaction solvent,

[0059] The reaction solvent in (a) includes one or more of acetone, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether;

[0060] The reaction solvent in (b) includes one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropanol, ethanol, and methanol;

[0061] The reaction solvent in (c) includes one or more of dichloromethane, chloroform, and 1,2-dichloroethane;

[0062] The reaction solvent in (d) includes one or more of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether;

[0063] The reaction solvent in (e) includes one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether;

[0064] The reaction solvent in (f) includes one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether;

[0065] The reaction solvent in (g) includes one or more of dichloromethane, toluene, and dichloroethane;

[0066] The reaction solvent in (h) includes one or more of dimethyl sulfoxide, dichloromethane, chloroform, and dichloroethane;

[0067] The reaction solvent in (i) includes one or more of tert-butanol, isopropanol, tetrahydrofuran, and 2-methyltetrahydrofuran;

[0068] The reaction solvent in (j) includes one or more of dichloromethane, chloroform, and 1,2-dichloroethane;

[0069] The reaction solvent in (k) includes one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0070] The present invention also provides the use of the macrolide compound described in the above technical solution and the intermediate compound for preparing the macrolide compound described in the above technical solution in the preparation of antibiotics against methicillin-resistant Staphylococcus aureus.

[0071] The present invention provides a macrolide compound, with the specific chemical structure as follows. The macrolide compound prepared by the present invention is a kind of compound with a 19-membered lactone ring structure, featuring a novel and unique structure, having a [5,6]-tetrahydroindene ring structural unit and a (Z,E,Z) conjugated triene unit. Its chemical structure is completely different from the anti-MRSA resistant bacteria antibiotics currently used clinically, such as polypeptide drugs (vancomycin, etc.) and quinolone drugs (ofloxacin, etc.), which proves that there are new anti-resistant bacteria action targets and mechanisms for macrolides, different from the antibacterial mechanisms of existing antibiotic drugs. From the results of the examples of the present invention, it can be seen that the macrolide compound has potent anti-MRSA activity, with the minimum inhibitory concentration MIC being 1 - 2 mg / mL, comparable to the anti-MRSA activity of vancomycin. Based on its potent anti-resistant bacteria activity, the macrolide provided by the present invention can be developed into a novel anti-resistant bacteria drug.

[0072]

[0073] The present invention also provides intermediate compounds for the preparation of macrolides. Using these intermediate compounds as raw materials, macrolide compounds can be prepared in high yields, and their structures can be easily modified to obtain a series of macrolide derivatives with antibacterial activities, providing candidate molecules for the research and development of novel antibiotic drugs. Moreover, the preparation methods of the macrolide compounds and their intermediate compounds provided by the present invention have the advantages of high yields, good reaction selectivity, high product purity, simplicity and high efficiency, and have good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or in the prior art, the following will briefly introduce the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0075] Figure 1 It is the 1H NMR spectrum of the intermediate compound of Formula 3;

[0076] Figure 2 It is the 13C NMR spectrum of the intermediate compound of Formula 3;

[0077] Figure 3 It is the 1H NMR spectrum of the intermediate compound of Formula 6;

[0078] Figure 4 It is the 13C NMR spectrum of the intermediate compound of Formula 6;

[0079] Figure 5 It is the 1H NMR spectrum of the intermediate compound of Formula 7;

[0080] Figure 6 is the carbon-13 NMR spectrum of the intermediate formula 7 compound;

[0081] Figure 7 is the proton NMR spectrum of the macrolide compound of the present invention;

[0082] Figure 8 is the carbon-13 NMR spectrum of the macrolide compound of the present invention. Detailed implementation mode

[0083] The present invention provides a macrolide compound, with the following chemical structure specifically:

[0084]

[0085] The present invention also provides an intermediate compound for preparing the macrolide compound described in the above technical solution, which has the following chemical structure:

[0086]

[0087] The present invention also provides a preparation method of the macrolide compound described in the above technical solution, including the following steps:

[0088] (a) Mix the compound of formula 1, an iodinating reagent and a silver metal reagent, and carry out a halogenation reaction to obtain the compound of formula 2;

[0089]

[0090] (b) Mix the compound of formula 2, a reducing agent and an organic base, and carry out a reduction reaction to obtain the compound of formula 3;

[0091] (c) Mix the compound of formula 3 and an oxidizing agent, and carry out an oxidation reaction to obtain the compound of formula 4;

[0092] (d) Mix the compound of formula 4, an organic selenium reagent and an alkyl phosphine reagent, and carry out a substitution reaction to obtain the compound of formula 5;

[0093] (e) Mix the compound of formula 5 with a peroxide, and carry out a Grieco elimination reaction to obtain the compound of formula 6;

[0094] (f) Mix the compound of formula 6, a borate ester, a palladium catalyst and an inorganic base, and carry out a Suzuki coupling reaction to obtain the compound of formula 7;

[0095] The borate ester has the following structure:

[0096]

[0097] (g) Mix the compound of formula 7 and a reducing agent, and carry out a reduction reaction to obtain the compound of formula 8;

[0098] (h) Mix the compound of Formula 8, an oxidizing agent and an organic base, and carry out a Parikh-Doering oxidation reaction to obtain the compound of Formula 9;

[0099] (i) Mix the compound of Formula 9, an oxidizing agent and 2-methyl-1,3-butadiene, and carry out a Pinnick oxidation reaction to obtain the compound of Formula 10;

[0100] (j) Mix the compound of Formula 10, a condensing agent and an inorganic base, and carry out a Mukaiyama esterification reaction to obtain the compound of Formula 11;

[0101] (k) Mix the compound of Formula 11 and a fluorine reagent, and carry out an elimination reaction to obtain the macrolide compound.

[0102] In the present invention, unless otherwise specified, all starting materials for preparation are commercially available products well-known to those skilled in the art or are prepared by methods known to those skilled in the art.

[0103] In the present invention, the compound of Formula 1, an iodinating reagent and a silver metal reagent are mixed to carry out a halogenation reaction to obtain the compound of Formula 2. In the present invention, the iodinating reagent is N-iodosuccinimide, and the silver metal reagent is silver nitrate; the molar ratio of the compound of Formula 1, the iodinating reagent and the silver metal reagent is 1:1.0 - 1.5:0.3 - 1.5, and in a specific embodiment, it can be 1:1.1:0.3; the temperature of the halogenation reaction is 0 - 40 °C, and the time is 1 - 5 h; the solvent for the halogenation reaction is acetone.

[0104] After obtaining the compound of Formula 2, in the present invention, the compound of Formula 2, a reducing agent and an organic base are mixed to carry out a reduction reaction to obtain the compound of Formula 3. In the present invention, the reducing agent is o-nitrobenzenesulfonylhydrazide (NBSH), and the organic base is triethylamine; the molar ratio of the compound of Formula 2, the reducing agent and the organic base is 1:1.0 - 3.0:1.5 - 4.5, and in a specific embodiment, it can be 1:1.7:2.8 or 1:2:3.5; the temperature of the reduction reaction is 0 - 40 °C, and the time is 10 - 30 h, and in a specific embodiment, it can be 12 h or 24 h; the solvent for the reduction reaction is tetrahydrofuran and isopropanol; the volume ratio of tetrahydrofuran and isopropanol is 1:1.

[0105] After obtaining the compound of Formula 3, the present invention mixes the compound of Formula 3 with an oxidant and conducts an oxidation reaction to obtain the compound of Formula 4. In the present invention, the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ); the molar ratio of the compound of Formula 3 to the oxidant is 1:1.0 - 3.0, and in a specific embodiment, it can be 1:2.9; the temperature of the oxidation reaction is 0 - 30 °C, and the time is 1 - 10 h. In a specific embodiment, it can be 1.5 h; the solvent for the oxidation reaction is dichloromethane; the oxidation reaction is quenched with a saturated aqueous solution of NaHCO 3 to obtain the compound of Formula 4. After obtaining the compound of Formula 4, the present invention mixes the compound of Formula 4, an organic selenium reagent, and an alkylphosphine reagent and conducts a substitution reaction to obtain the compound of Formula 5. In the present invention, the organic selenium reagent is 2-nitrophenylselenocyanate, and the alkylphosphine reagent is tri-n-butylphosphine; the molar ratio of the compound of Formula 4, the organic selenium reagent, and the alkylphosphine reagent is 1:1.0 - 5.0:1.0 - 5.0, and in a specific embodiment, it can be 1:1.9:1.9 or 1:3:3; the temperature of the substitution reaction is 10 - 40 °C, and the time is 1 - 20 h. In a specific embodiment, it can be 1 h; the solvent for the substitution reaction is tetrahydrofuran.

[0106] After obtaining the compound of Formula 5, the present invention mixes the compound of Formula 5 with a peroxide and conducts a Grieco elimination reaction to obtain the compound of Formula 6. In the present invention, the peroxide reagent is hydrogen peroxide; the molar ratio of the compound of Formula 5 to the peroxide reagent is 1:1.0 - 5.0, and in a specific embodiment, it can be 1:2.0; the temperature of the Grieco elimination reaction is 0 - 25 °C, and the time is 10 - 20 h. In a specific embodiment, it can be 15 h or 19 h; the solvent for the Grieco elimination reaction is tetrahydrofuran.

[0107] After obtaining the compound of Formula 6, the present invention mixes the compound of Formula 6, a borate ester, a palladium catalyst, and an inorganic base and conducts a Suzuki coupling reaction to obtain the compound of Formula 7. In the present invention, the metal palladium catalyst is tetrakis(triphenylphosphine)palladium, and the inorganic base is thallium carbonate; the molar ratio of the compound of Formula 6, the borate ester, the inorganic base, and the metal palladium catalyst is 1:1.2 - 2.0:1.5 - 3.0:0.1 - 0.5, and in a specific embodiment, it can be 1:1.2:1.8:0.3; the temperature of the Suzuki coupling reaction is 20 - 40 °C, and the time is 2 - 10 h. In a specific embodiment, it can be 3 h; the solvent for the Suzuki coupling reaction is tetrahydrofuran and water; the volume ratio of tetrahydrofuran to water is 4:1.

[0108] After obtaining the compound of Formula 7, the present invention mixes the compound of Formula 7, a borate ester, a palladium catalyst, and an inorganic base and conducts a Suzuki coupling reaction to obtain the compound of Formula 8. In the present invention, the metal palladium catalyst is tetrakis(triphenylphosphine)palladium, and the inorganic base is thallium carbonate; the molar ratio of the compound of Formula 7, the borate ester, the inorganic base, and the metal palladium catalyst is 1:1.2 - 2.0:1.5 - 3.0:0.1 - 0.5, and in a specific embodiment, it can be 1:1.2:1.8:0.3; the temperature of the Suzuki coupling reaction is 20 - 40 °C, and the time is 2 - 10 h. In a specific embodiment, it can be 3 h; the solvent for the Suzuki coupling reaction is tetrahydrofuran and water; the volume ratio of tetrahydrofuran to water is 4:1.

[0109] After obtaining the compound of formula 7, the present invention mixes the compound of formula 7 with a reducing agent and conducts a reduction reaction to obtain the compound of formula 8. In the present invention, the reducing agent is diisobutylaluminum hydride; the diisobutylaluminum hydride is a toluene solution of diisobutylaluminum hydride with a concentration of 1.5 M; the molar ratio of the compound of formula 7 to the reducing agent is 1:2.0 - 10.0, and in specific embodiments, it can be 1:3 or 1:5; the temperature of the reduction reaction is -80 to -40 °C, and the time is 1 h to 5 h; the solvent for the reduction reaction is dichloromethane; the reduction reaction is quenched with a saturated sodium potassium tartrate solution.

[0110] After obtaining the compound of formula 8, the present invention mixes the compound of formula 8, an oxidizing agent and an organic base and conducts a Parikh-Doering oxidation reaction to obtain the compound of formula 9. In the present invention, the oxidizing agent is pyridine sulfur trioxide and the organic base is triethylamine; the molar ratio of the compound of formula 8, the oxidizing agent and the organic base is 1:10.0 - 25.0:10.0 - 25.0, and in specific embodiments, it can be 1:20.0:20.0 ； The temperature of the Parikh-Doering oxidation reaction is 0 - 5 °C, and the time is 2 - 10 h; the solvent for the Parikh-Doering oxidation reaction is dimethyl sulfoxide and dichloromethane; the volume ratio of dimethyl sulfoxide to dichloromethane is 1:1; the Parikh-Doering oxidation reaction is quenched with a saturated NaHCO 3 solution.

[0111] After obtaining the compound of formula 9, the present invention mixes the compound of formula 9, an oxidizing agent and 2-methyl-1,3-butadiene and conducts a Pinnick oxidation reaction to obtain the compound of formula 10. In the present invention, the oxidizing agent is sodium chlorite; the molar ratio of the compound of formula 9, the oxidizing agent and 2-methyl-1,3-butadiene is 1:10.0 - 35.0:100.0 - 350.0, and in specific embodiments, it can be 1:29.2:292.2; the temperature of the Pinnick oxidation reaction is 0 - 25 °C, and the time is 10 - 20 h, and in specific embodiments, it can be 12 or 14 h; the solvent for the Pinnick oxidation reaction is tetrahydrofuran and tert-butanol; the volume ratio of tetrahydrofuran to tert-butanol is 1:1. In the present invention, the Pinnick oxidation reaction also includes sodium dihydrogen phosphate hydrate; the sodium dihydrogen phosphate hydrate is used as a buffer salt to adjust the pH value of the reaction solution.

[0112] After obtaining the compound of Formula 10, the present invention mixes the compound of Formula 10, a condensation reagent, and an inorganic base to carry out a Mukaiyama esterification reaction to obtain the compound of Formula 11. In the present invention, the condensation reagent is 2-bromo-1-ethylpyridinium tetrafluoroborate (Mukaiyama), and the inorganic base is sodium bicarbonate; the molar ratio of the compound of Formula 10, the condensation reagent, and the inorganic base is 1:15.0 to 50.0:150.0 to 500.0, and in a specific embodiment, it can be 1:19.2:498.0; the temperature of the Mukaiyama esterification reaction is 10 to 30 °C, and the time is 15 to 30 h. In a specific embodiment, it can be 18 h or 24 h; the solvent for the Mukaiyama esterification reaction is dichloromethane.

[0113] After obtaining the compound of Formula 11, the present invention mixes the compound of Formula 11 and a fluorine reagent to carry out an elimination reaction to obtain the macrolide compound. In the present invention, the fluorine reagent is pyridine hydrofluoride; the molar ratio of the compound of Formula 11 to the fluorine reagent is 1:20.0 to 100.0, and in a specific embodiment, it can be 1:40; the temperature of the elimination reaction is -5 to 10 °C, and the reaction time is 2 to 10 h. ； The solvent for the elimination reaction is tetrahydrofuran.

[0114] In the present invention, each reaction in the steps (a) to (k) is carried out under stirring conditions, and the present invention has no special limitation on the stirring rate; after each reaction of the present invention is completed, it further includes successively drying, concentrating, and purifying the obtained reaction product; the present invention has no special limitation on the drying and concentration, and the methods well-known to those skilled in the art can be used; the purification is carried out by gradient elution purification with a silica gel column, and the eluent used for the purification is petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 2 to 10:1, and in a specific embodiment, it can be 4:1, 5:1, or 7:1. In the present invention, extraction is also included before drying, and the reagent used for extraction is diethyl ether; the number of extraction times is 1 to 3 times.

[0115] The present invention also provides the application of the macrolide compound described in the above technical solution in the preparation of antibiotics against methicillin-resistant Staphylococcus aureus.

[0116] In order to further illustrate the present invention, the preparation methods and applications of the macrolide compound and its intermediate compound provided by the present invention will be described in detail below with reference to the drawings and examples, but they cannot be understood as limiting the protection scope of the present invention.

[0117] Example 1

[0118] The synthesis of the intermediate vinyl iodide compound of Formula 3 is specifically carried out as follows:

[0119]

[0120] In a dry round-bottom flask equipped with a stir bar, 3.0 mL of acetone, 0.103 mmol of N-iodosuccinimide (23.4 mg), and 0.094 mmol of alkyne compound 1 (70.0 mg) were added. Then, 0.031 mmol of silver nitrate (5.2 mg) was added. After mixing evenly, the mixture was stirred at room temperature for 1 h for the halogenation reaction. The obtained halogenation reaction product was dried and concentrated successively, and purified by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain 0.088 mmol of alkynyl iodide compound of formula 2 (77.0 mg, yield 94%);

[0121] The above 0.088 mmol of alkynyl iodide compound of formula 2 was dissolved in a mixture of 1.0 mL of tetrahydrofuran and 1.0 mL of isopropanol. 0.25 mmol of triethylamine (0.034 mL) and 0.15 mmol of NBSH (33.2 mg) were added. The mixture was stirred at room temperature for 24 h for the reduction reaction. The obtained reduction reaction product was dried and concentrated successively, and purified by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 10:1 to 5:1 (v / v)) to obtain 0.068 mmol of vinyl iodide compound 3 (60.5 mg, yield 77%); The 1H NMR data and 13C NMR data of the intermediate vinyl iodide compound of formula 3 are as follows:

[0122] R f = 0.54 (PE / EtOAc = 5:1, visualized using an Annis stain or UV light).

[0123] [α] D 20 = +21.11° (c = 1.28, CH 2 Cl 2 ).

[0124] 1 1H NMR (400 MHz, CDCl 3) δ 7.28 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.40 (t, J = 8.6 Hz, 1H), 6.16 (d, J = 7.5 Hz, 1H), 5.89 (br, 1H), 4.52 - 4.46 (m, 2H), 3.90 (dd, J = 3.0, 9.0 Hz, 1H), 3.80 (s, 3H), 3.47 (t, J = 8.6 Hz, 1H), 3.13 - 3.09 (m, 1H), 2.56 (t, J = 10.5 Hz, 1H), 2.48 - 2.43 (m, 1H), 2.20 - 2.12 (m, 1H), 2.10 (s, 3H), 1.91 - 1.87 (m, 1H), 2.56 (s, 3H), 1.83 - 1.79 (m, 1H), 1.68 - 1.64 (m, 1H), 1.10 (s, 3H), 1.02 (s, 3H), 0.96 (s, 9H), 0.17 (s, 6H).

[0125] 13 C NMR (101 MHz, CDCl 3 ) δ 170.0, 159.1, 154.7, 141.0, 138.9, 131.5, 130.9, 129.3, 126.8, 120.3, 113.8, 103.4, 81.7, 75.7, 73.7, 72.7, 55.4, 53.2, 52.4, 49.4, 46.2, 45.9, 42.6, 39.9, 29.5, 27.8, 25.8, 23.2, 21.3, 18.3, -4.2.

[0126] HRMS (ESI): m / z: calculated for [M + Na] + C 38 H 52 I 2 O 5 SiNa 893.1566, found: 893.1563.

[0127] Synthesis of the intermediate formula 4 alcohol compound, the specific steps are as follows:

[0128]

[0129] At 0 °C, 68.95 μmol of the above vinyl iodide compound of formula 3 (60.5 mg) and 6.0 mL of dichloromethane / 0.6 mL of buffer solution (pH = 7.0) were mixed to obtain a mixed solution; then 206.80 μmol of DDQ reagent (47.0 mg) was added, and the resulting mixed system was stirred at 0 °C for 1.5 h, and then quenched with saturated aqueous NaHCO 3 and extracted with ether (3 × 10 mL); after drying and concentration, the crude product was purified by silica gel column gradient elution (petroleum ether: ethyl acetate = 4:1 to 2:1 (v / v)) to obtain 63.98 μmol of the alcohol compound of formula 4 (48.0 mg, 92%). The hydrogen spectrum data and carbon spectrum data of the intermediate alcohol compound of formula 4 are shown below:

[0130] R f = 0.38 (PE / EtOAc = 3:1, visualized using an Annis stain or UV light).

[0131] [α] D 20 = +15.77° (c = 0.35, CH 2 Cl 2 ).

[0132] 1 H NMR (400 MHz, acetone d 6 ) δ 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 6.57 (t, J = 8.5 Hz, 1H), 6.31 (d, J = 7.4 Hz, 1H), 5.91 (br, 1H), 4.02 - 3.99 (m, 1H), 3.70 - 3.67 (m, 1H), 3.65 - 3.59 (m, 1H), 3.15 - 3.12 (m, 1H), 2.82 (s, 1H), 2.68 - 2.58 (m, 2H), 2.12 (s, 3H), 2.02 - 2.01 (m, 1H), 2.10 (s, 3H), 1.97 - 1.94 (m, 2H), 1.87 (s, 3H), 1.86 - 1.83 (m, 1H), 1.76 - 1.72 (m, 1H), 1.18 (s, J = 2.4 Hz, 3H), 1.05 (s, 3H), 0.98 (s, 6H), 0.20 (s, 6H).

[0133] 13 C NMR (101 MHz, acetone d 6)δ170.2,155.3,142.1,139.2,133.0,127.8,120.8,104.6,82.5,76.0,65.7,53.9,52.4,50.2,46.5,46.2,45.8,40.4,33.5,28.1,26.0,23.5,21.1,18.7,-4.1.

[0134] HRMS(ESI):m / z:calculated for[M+Na] + C 30 H 44 I 2 O 4 SiNa 773.0991,found:773.0993.

[0135] Synthesis of the terminal olefin compound of Formula 6, the specific steps are as follows:

[0136]

[0137] Add 3.0 mL of tetrahydrofuran, 63.98 μmol of the alcohol compound of Formula 4 (48.0 mg), and 127.90 μmol of tri-n-butylphosphine (25.8 mg) to a dry round-bottom flask equipped with a stir bar, and then add 127.90 μmol of 2-nitrophenylselenocyanate (29.05 mg). The resulting mixture is subjected to a substitution reaction at room temperature with stirring for 1 h. The resulting substitution reaction product is dried, concentrated, and purified by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain 55.61 μmol of the vinyl iodide of Formula 5 (52.0 mg, yield 86%).

[0138] Dissolve 55.61 μmol of the above-mentioned alkynyl iodide of Formula 5 (52.0 mg) in 10 mL of tetrahydrofuran at 0 °C, add 111.22 μmol of hydrogen peroxide (30% wt), and carry out a Grieco elimination reaction with stirring for 19 h. After quenching with water, it is subjected to extraction, drying, and concentration, and purified by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain 34.42 μmol of the terminal olefin compound of Formula 6 (25.2 mg, yield 61%). The 1H NMR data and 13C NMR data of the terminal olefin compound of Formula 6 are as follows:

[0139] R f =0.65(PE / EtOAc=10:1,visualized using anAnnis stain orUV light).

[0140] [α] D 20= +181.00° (c = 0.10, CH 2 Cl 2 ).

[0141] 1 H NMR (500 MHz, acetone d 6 ) δ 7.11 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.53 (t, J = 8.6 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.97 (br, 1H), 5.29 (s, 1H), 4.73 (s, 1H), 3.34 - 3.32 (m, 1H), 3.07 (dd, J = 4.2, 9.7 Hz, 1H), 2.56 - 2.53 (m, 1H), 2.44 - 2.41 (m, 1H), 2.28 - 2.25 (m, 1H), 2.13 (s, 3H), 2.06 - 2.05 (m, 1H), 1.89 (s, 3H), 1.29 (s, 3H), 1.11 (s, 3H), 0.98 (s, 9H), 0.20 (s, 6H).

[0142] 13 C NMR (126 MHz, acetone d 6 ) δ 170.2, 155.3, 150.0, 141.7, 132.6, 127.6, 120.9, 105.7, 99.9, 81.3, 75.2, 56.5, 52.9, 51.0, 49.5, 46.0, 37.0, 28.7, 26.0, 23.9, 20.9, 18.7, -4.2.

[0143] HRMS (ESI): m / z: calculated for [M+Na] + C 30 H 42 I 2 O 3 SiNa 755.0885, found: 755.0882.

[0144] Synthesis of the intermediate triene compound of Formula 7, the specific steps are as follows:

[0145]

[0146] Dissolve 13.65 μmol of the above terminal olefin compound of formula 6 (10 mg) and 16.39 μmol of borate ester (10.6 mg) in 2.0 mL of tetrahydrofuran and 0.5 mL of water, stir at room temperature, and then sequentially add 24.58 μmol of thallium carbonate (11.5 mg) and 4.09 μmol of tetrakis(triphenylphosphine)palladium (4.7 mg) to the stirred solution. Conduct the Suzuki coupling reaction for 3 h under stirring at room temperature, add water to quench the reaction, extract the obtained coupling reaction product with ether (3 × 10 mL), and after drying and concentration, purify it by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain 9.32 μmol of the triene compound of formula 7 (10.5 mg, yield 68%). The hydrogen spectrum data and carbon spectrum data of the triene compound of formula 7 are as follows:

[0147] R f = 0.65 (PE / EtOAc = 5:1, visualized using an Annis stain or UV light).

[0148] [α] D 20 = +181.67° (c = 0.24, CH 2 Cl 2 ).

[0149] 1 H NMR (500 MHz, acetone d 6)δ 7.28 d, J = 15.6 Hz, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 6.71 (t, J = 13.0 Hz, 1H), 6.22 - 6.12 (m, 2H), 6.09 - 6.04 (m, 2H), 5.92 (br, 1H), 5.78 (d, J = 15.6 Hz, 1H), 5.78 (t, J = 10.4 Hz, 1H), 5.52 (d, J = 10.1 Hz, 1H), 5.29 (s, 1H), 4.70 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.01 - 3.97 (m, 1H), 3.33 (d, J = 11.8 Hz, 1H), 3.13 (dd, J = 3.9, 10.8 Hz, 1H), 2.46 - 2.40 (m, 4H), 2.27 - 2.23 (m, 1H), 2.10 - 2.06 (m, 4H), 1.86 - 1.81 (m, 4H), 1.68 (d, J = 2.3 Hz, 3H), 1.28 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.12 (s, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.99 (s, 9H), 0.99 - 0.93 (m, 18H), 0.66 - 0.57 (m, 12H), 0.22 (s, 6H).

[0150] 13 C NMR (126 MHz, acetone d 6 )δ 170.0, 167.2, 155.4, 150.2, 149.6, 142.3, 140.1, 134.7, 134.5, 133.3, 133.0, 132.1, 130.0, 128.6, 127.4, 127.1, 120.3, 116.6, 105.2, 98.8, 75.3, 73.8, 71.0, 60.3, 56.7, 51.6, 50.9, 48.3, 46.3, 44.4, 36.6, 33.1, 27.8, 25.9, 24.1, 21.0, 14.5, 12.7, 10.0, 7.3, 5.7, -4.1.

[0151] HRMS (ESI): m / z: calculated for [M+Na] + C 59 H 95 IO 5 Si 3 Na 1149.5323, found: 1149.5324.

[0152] Synthesis of the intermediate formula 8 diol compound, the specific steps are as follows:

[0153]

[0154] At -78 °C, 177.50 μmol of diisobutylaluminum hydride (0.11 mL, 1.5 M toluene solution) was slowly added to a 1 mL dichloromethane solution of 7.10 μmol of the triene compound of formula 7 (8.0 mg) above. The reduction reaction was carried out for 1 h under stirring conditions, quenched with a saturated sodium potassium tartrate solution, and the resulting reduction reaction product was extracted with diethyl ether (3 × 5 mL). After drying and concentration, it was purified by silica gel column gradient elution (petroleum ether:ethyl acetate = 8:1 to 4:1) to obtain 4.79 μmol of the diol compound of formula 8 (5.0 mg, yield 67%). The hydrogen spectrum data and carbon spectrum data of the diol compound of formula 8 are shown below:

[0155] R f = 0.45 (PE / EtOAc = 5:1, visualized using an Annis stain or UV light).

[0156] [α] D 20 = +123.73° (c = 0.15, CH 2 Cl 2 ).

[0157] 1 H NMR (800 MHz, acetone d 6)δ 7.20 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.62 (t, J = 12.8 Hz, 1H), 6.27 (d, J = 15.7 Hz, 1H), 6.10 (t, J = 10.9 Hz, 1H), 6.02 (t, J = 11.6 Hz, 1H), 5.70 - 5.67 (m, 1H), 5.63 (t, J = 10.7 Hz, 1H), 5.57 (t, J = 6.6 Hz, 1H), 5.48 (t, J = 9.9 Hz, 1H), 5.28 (s, 1H), 5.21 (br, 1H), 4.69 (s, 1H), 4.66 (t, J = 8.1 Hz, 1H), 4.09 - 4.08 (m, 1H), 4.04 - 4.01 (m, 1H), 3.91 (br, 1H), 3.75 - 3.72 (m, 1H), 3.68 - 3.67 (m, 1H), 3.31 - 3.29 (m, 1H), 3.08 - 3.07 (m, 1H), 2.43 - 2.41 (m, 1H), 2.38 - 2.22 (m, 2H), 2.30 - 2.26 (m, 2H), 2.16 - 2.12 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 1.01 (s, 9H), 1.00 - 0.93 (m, 18H), 0.66 - 0.58 (m, 12H), 0.24 (s, 6H).

[0158] 13 C NMR (201 MHz, acetone d 6 )δ 154.1, 149.9, 141.6, 137.1, 134.5, 134.1, 134.0, 132.9, 131.0, 129.1, 127.8, 127.0, 126.8, 126.7, 119.3, 103.9, 98.3, 73.1, 71.5, 70.1, 62.3, 56.0, 50.8, 50.4, 47.4, 47.0, 43.4, 36.0, 31.6, 30.6, 26.9, 25.2, 23.5, 17.9, 12.3, 9.3, 6.5, 4.9, -4.1.

[0159] HRMS (ESI): m / z: calculated for [M+Na] + C 55 H 91 IO 5 Si 3 Na 1065.5111, found: 1065.5115.

[0160] Synthesis of the intermediate formula 10 acid, the specific steps are as follows:

[0161]

[0162] Dissolve 4.79 μmol of the diol compound of formula 8 (5.0 mg) in 0.5 mL of dimethyl sulfoxide / 0.5 mL of dichloromethane at 0 °C. Subsequently, add 95.92 μmol of triethylamine (9.7 mg) and 95.92 μmol of pyridine sulfur trioxide (15.2 mg) successively. Conduct the Parikh-Doering oxidation reaction under stirring for 2 h, add saturated NaHCO 3 solution, extract with diethyl ether (3 × 15 mL), and after drying and concentration, obtain 4.79 μmol of the crude aldehyde of formula 9;

[0163] At 0 °C, add 1.40 mmol of 2-methyl-2-butene (0.15 mL), 0.14 mmol of sodium chlorite (13.0 mg), and 0.42 mL of an aqueous solution of 0.23 mmol of sodium dihydrogen phosphate hydrate (35.9 mg) successively to a solution of 4.79 μmol of the aldehyde of formula 9 dissolved in 0.6 mL of tetrahydrofuran / 0.6 mL of tert-butanol. Conduct the Pinnick oxidation reaction under stirring overnight, quench the reaction by adding water, extract with diethyl ether (3 × 15 mL), and after drying and concentration, purify by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 2:1 to 1:5) to obtain 2.55 μmol of the acid of formula 10 (2.7 mg, two-step yield 53%). The proton NMR data and carbon NMR data of the acid of formula 10 are as follows:

[0164] R f = 0.25 (PE / EtOAc = 5:1, visualized using an Annis stain or UV light).

[0165] [α] D 20 = +133.11° (c = 0.27, CH 2 Cl 2 ).

[0166] 1 H NMR (800 MHz, acetone d 6)δ 7.33 (d, J = 15.7 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 8.3 Hz, 2H), 6.66 (t, J = 13.0 Hz, 1H), 6.11 (t, J = 11.0 Hz, 1H), 6.07 - 6.03 (m, 3H), 5.79 (d, J = 15.5 Hz, 1H), 5.65 (t, J = 10.8 Hz, 1H), 5.49 (t, J = 9.9 Hz, 1H), 5.28 (s, 1H), 5.22 (br, 1H), 4.70 - 4.69 (m, 2H), 3.99 - 3.97 (m, 1H), 3.75 - 3.73 (m, 1H), 3.63 - 3.62 (m, 1H), 3.31 - 3.29 (m, 1H), 3.10 - 3.08 (m, 1H), 2.46 - 2.41 (m, 3H), 2.30 - 2.26 (m, 2H), 2.18 - 2.15 (m, 1H), 1.86 (s, 3H), 1.84 - 1.81 (m, 1H), 1.66 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H), 1.01 (s, 9H), 1.00 - 0.94 (m, 18H), 0.66 - 0.59 (m, 12H), 0.23 (s, 6H),.

[0167] 13 C NMR (201 MHz, acetone d 6 )δ 167.7, 154.1, 149.9, 149.6, 141.6, 139.4, 137.2, 133.9, 133.8, 133.3, 131.2, 129.2, 127.6, 126.9, 126.5, 119.3, 115.5, 103.9, 98.3, 72.7, 71.4, 70.2, 56.0, 50.8, 50.4, 47.5, 47.0, 43.4, 36.0, 32.2, 30.7, 26.9, 25.1, 23.5, 17.9, 11.9, 9.1, 6.3, 4.9, -4.2.

[0168] HRMS (ESI): m / z: calculated for [M+Na] + C 55 H 89 IO 6 Si 3 Na 1079.4904, found: 1079.4909.

[0169] The synthesis of the intermediate lactone compound of formula 11 is carried out in the following specific steps:

[0170]

[0171] Dissolve 2.55 μmol of the acid of formula 10 (2.7 mg) in 5.6 mL of dichloromethane, then successively add 1.27 mmol of sodium bicarbonate (107.3 mg) and 0.12 mmol of Mukaiyama reagent (34.9 mg), and carry out the Mukaiyama esterification reaction for 18 h under stirring. Quench the reaction solution by adding water, extract the obtained esterification product with ether (3 × 15 mL), and after drying and concentration, purify it by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 30:1 to 10:1) to obtain 1.71 μmol of the lactone compound of formula 11 (1.8 mg, yield 67%). The 1H NMR data and 13C NMR data of the lactone compound of formula 11 are as follows:

[0172] R f = 0.65 (PE / EtOAc = 10:1, visualized using an Annis stain or UV light).

[0173] [α] D 20 = +20.57° (c = 0.14, acetone).

[0174] 1 1H NMR (800 MHz, acetone-d 6 ) δ 7.57 - 7.56 (m, 1H), 7.41 - 7.37 (m, 1H), 7.07 (br, 2H), 6.80 (d, J = 8.2 Hz, 2H), 6.44 - 6.30 (m, 4H), 6.07 (br, 1H), 5.85 (br, 1H), 5.71 - 5.64 (m, 2H), 5.54 (br, 1H), 5.36 - 5.34 (m, 1H), 5.28 (s, 1H), 4.70 (s, 1H), 4.03 - 4.01 (m, 1H), 3.93 - 3.85 (m, 1H), 3.39 - 3.36 (m, 1H), 3.28 - 3.22 (m, 1H), 2.61 - 2.55 (m, 1H), 2.45 - 2.40 (m, 2H), 2.28 - 2.26 (m, 1H), 2.14 - 2.12 (m, 2H), 1.80 (s, 3H), 1.92 - 1.88 (m, 1H), 1.73 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H), 1.19 (s, 3H), 1.06 (br, 9H), 0.99 (s, 9H), 0.88 - 0.86 (m, 9H), 0.79 (br, 6H), 0.66 - 0.65 (m, 6H), 0.22 (s, 6H).

[0175] 13 C NMR (201 MHz, acetone d 6 ) δ 166.8, 155.3, 149.7, 142.4, 141.2, 138.7, 137.3, 135.2, 134.1, 132.1, 130.1, 129.9, 128.1, 127.0, 124.9, 124.4 120.0, 116.3, 104.5, 74.1, 73.5, 64.1, 57.0, 51.0, 47.4, 43.8, 39.2, 36.1, 34.5, 32.1, 31.2, 27.2, 25.5, 23.6, 22.7, 18.3, 13.8, 11.7, 6.7, 5.5, -4.7.

[0176] HRMS (ESI): m / z: calculated for [M+Na] + C 55 H 87 IO 5 Si 3 Na 1061.4798, found: 1061.4799.

[0177] The synthesis of the macrolide compound, the specific steps are as follows:

[0178]

[0179] Dissolve 1.44 μmol of the lactone compound of formula 11 (1.5 mg) in 0.5 mL of tetrahydrofuran, cool to 0 °C, dilute 2 mL of pyridine hydrofluoride solution (70%) with 5.6 mL of pyridine and 9.8 mL of tetrahydrofuran at 0 °C, slowly add 1.0 mL of the diluted pyridine hydrofluoride solution dropwise at 0 °C, and carry out an elimination reaction for 10 h under stirring. Add NaHCO 3 Quench the reaction with a saturated solution, extract the obtained reaction product with ether (3 × 15 mL), dry and concentrate it, and purify it by gradient elution on a silica gel column (petroleum ether:ethyl acetate = 2:1 to 1:3) to obtain 0.86 μmol of the macrolide compound (0.6 mg, yield 59%). The hydrogen spectrum data and carbon spectrum data of the macrolide compound are as follows:

[0180] R f = 0.36 (PE / EtOAc = 1:1, visualized using an Annis stain or UV light).

[0181] 1 H NMR (400 MHz, acetone d 6)δ8.35(s,1H),7.52(d,J=15.7Hz,1H),7.01(d,J=8.4Hz,2H),7.00 - 6.92(m,1H),6.72(d,J=8.5Hz,2H),6.49(t,J=12.9Hz,1H),6.38 - 6.29(m,3H),6.16(t,J=11.1Hz,1H),5.82 - 5.77(m,1H),5.67 - 5.60(m,2H),5.36 - 5.33(m,1H),5.29(s,1H),4.69(s,1H),3.84 - 3.83(m,1H),3.80 - 3.77(m,1H),3.40 - 3.28(m,2H),2.44 - 2.35(m,2H),2.28 - 2.24(m,1H),2.16 - 2.11(m,2H),1.80(s,3H),1.77(d,J=2.1Hz,3H),1.72 - 1.66(m,1H),1.60 - 1.54(m,1H),1.34(s,3H),1.19(s,3H),1.01(d,J=7.0Hz,3H),.

[0182] HRMS(ESI):m / z:calculated for[M + Na] + C 37 H 45 IO 5 Na 1061.4798,found:1061.4799.

[0183] Test Example

[0184] The activity of the macrolide compound prepared in Test Example 1 against MRSA was as follows: The specific steps were as follows:

[0185] Methicillin - resistant Staphylococcus aureus (MRSA) BAA1026, MRSA S19 (2401SP0681) and MRSA S23 (2401SP0713) were clinical strains. Weighed 800 μg of the above - mentioned macrolide compound sample and dissolved it in 781 μl of DMSO to form a drug concentration of 1024 μg / ml, and then further diluted it to 512 and 256 μg / ml concentrations for standby.

[0186] Take a 96 - well culture plate, dilute the sample to be tested, add bacterial suspension to each well, and the final concentration was 5×10 5 CFU / mL; Incubate at 37 °C for 24 h, and measure the OD value at 600 nm with an enzyme - linked immunosorbent assay reader. At the same time, a medium blank control, a bacterial control, and a vancomycin positive drug control were set up in the experiment.

[0187] The minimum inhibitory concentration (MIC) of the macrolide compound prepared by the present invention against three strains of MRSA is 1-2 mg / mL, which is equivalent to the anti-MRSA activity of vancomycin. Based on its potent anti-drug-resistant bacteria activity, the macrolide prepared by the present invention can be developed into a novel anti-drug-resistant bacteria drug.

[0188] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A macrolide compound, characterized in that The specific chemical structure is as follows:

2. An intermediate compound for preparing the macrolide compound according to claim 1, characterized in that: The intermediate compound for preparing the macrolide compound has the following chemical structure:

3. The method for preparing the macrolide compound according to claim 1, characterized in that: The following steps are involved: (a) mixing a compound of formula 1, an iodination reagent and a metallic silver reagent, and performing a halogenation reaction to obtain a compound of formula 2; (b) mixing the compound of formula 2, a reducing agent and an organic base, and performing a reduction reaction to obtain a compound of formula 3; (c) mixing the compound of formula 3 and an oxidant, and performing an oxidation reaction to obtain a compound of formula 4; (d) mixing the compound of formula 4, an organic selenium reagent and an alkyl phosphine reagent, and performing a substitution reaction to obtain a compound of formula 5; (e) mixing the compound of formula 5 with a peroxide and performing a Grieco elimination reaction to obtain a compound of formula 6; (f) mixing the compound of formula 6, borate, palladium catalyst and inorganic base, and performing Suzuki coupling reaction to obtain the compound of formula 7; The borate ester has the following structure: (g) mixing the compound of formula 7 and a reducing agent, and performing a reduction reaction to obtain a compound of formula 8; (h) mixing the compound of formula 8, an oxidant and an organic base, and performing a Parikh-Doering oxidation reaction to obtain a compound of formula 9; (i) mixing the compound of formula 9, an oxidant and 2-methylbutadiene, and performing a Pinnick oxidation reaction to obtain a compound of formula 10; (j) mixing the compound of formula 10, a condensation agent and an inorganic base, and performing a Mukaiyama esterification reaction to obtain a compound of formula 11; (k) mixing the compound of formula 11 and a fluorine reagent and performing an elimination reaction to obtain the macrolide compound.

4. The preparation method according to claim 3, characterized in that: The iodination reagent in (a) is N-iodosuccinimide, and the metallic silver reagent is silver nitrate; In said (b), the reducing agent is o-nitrobenzenesulfonyl hydrazide, and the organic base is triethylamine; The oxidant in (c) is 2,3-dichloro-5,6-dicyanobenzoquinone; The organic selenium reagent in (d) is 2-nitrophenyl selenocyanate, and the alkyl phosphine reagent is tri-n-butylphosphine; The peroxide reagent in (e) is hydrogen peroxide; In (f), the metal palladium catalyst is tetrakistriphenylphosphine palladium, the inorganic base is thallium carbonate, and the boron reagent is borate; The reducing agent in (g) is diisobutylaluminum hydride; In the step (h), the oxidant is pyridine sulfur trioxide and the organic base is triethylamine; The oxidant in (i) is sodium chlorite; In (j), the condensation reagent is 2-bromo-1-ethylpyridinium tetrafluoroborate, and the inorganic base is sodium bicarbonate; The fluorine reagent in (k) is pyridine hydrofluoric acid.

5. The preparation method according to claim 3 or 4, characterized in that: The molar ratio of the compound of formula 1, the iodination reagent and the metallic silver reagent in (a) is 1:1.0-1.5:0.3-1.5; The molar ratio of the compound of formula 2, the reducing agent and the organic base in (b) is 1:1.0-3.0:1.5-4.5; The molar ratio of the compound of formula 3 to the oxidant in (c) is 1:1.0-3.0; The molar ratio of the compound of formula 4, the organic selenium reagent and the alkyl phosphine reagent in (d) is 1:1.0-5.0:1.0-5.0; The molar ratio of the compound of formula 5 to the peroxide reagent in (e) is 1:1.0-5.0; The molar ratio of the compound of formula 6, borate ester, inorganic base and metal palladium catalyst in (f) is 1:1.2-2.0:1.5-3.0:0.1-0.5; (g) The molar ratio of the compound of formula 7 to the reducing agent is 1:2.0-10.0; The molar ratio of the compound of formula 8, the oxidant and the organic base in (h) is 1:10.0-25.0:10.0-25.0; The molar ratio of the compound of formula 9, the oxidant and 2-methylbutadiene in (i) is 1:10.0-35.0:100.0-350.0; The molar ratio of the compound of formula 10, the condensation reagent and the inorganic base in (j) is 1:15.0-50.0:150.0-500.0; The molar ratio of the compound of formula 11 to the fluorine reagent in (k) is 1:20.0-100.

0.

6. The preparation method according to claim 3, characterized in that: The temperature of the halogenation reaction in (a) is 0 to 40° C. and the time is 1 to 5 hours; The reduction reaction temperature in (b) is 0 to 40°C and the time is 10 to 30 hours; The oxidation reaction temperature in (c) is 0 to 30° C. and the time is 1 to 10 hours; The temperature of the substitution reaction in (d) is 10 to 40° C. and the time is 1 to 20 hours; The temperature of the Grieco elimination reaction in (e) is 0 to 25° C. and the time is 10 to 20 h; The temperature of the Suzuki coupling reaction in (f) is 20 to 40° C. and the time is 2 to 10 h; The temperature of the reduction reaction in (g) is -80 to -40°C and the time is 1 to 5 hours; The temperature of the Parikh-Doering oxidation reaction in (h) is 0 to 5° C. and the time is 2 to 10 hours; The temperature of the Pinnick oxidation reaction in (i) is 0 to 25° C. and the time is 10 to 20 hours; The temperature of the Mukaiyama esterification reaction in (j) is 10 to 30° C. and the time is 15 to 30 hours; The temperature of the elimination reaction in (k) is -5 to 10°C, and the reaction time is 2 to 10 hours.

7. The preparation method according to claim 3, characterized in that: The steps (a) to (k) also include a reaction solvent, (a) wherein the reaction solvent comprises one or more of acetone, tetrahydrofuran, diethyl ether and methyl tert-butyl ether; (b) wherein the reaction solvent comprises one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropanol, ethanol and methanol; (c) wherein the reaction solvent comprises one or more of dichloromethane, chloroform and 1,2-dichloroethane; (d) wherein the reaction solvent comprises one or more of tetrahydrofuran, diethyl ether and methyl tert-butyl ether; (e) wherein the reaction solvent comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether; (f) wherein the reaction solvent comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether; (g) wherein the reaction solvent comprises one or more of dichloromethane, toluene and dichloroethane; (h) wherein the reaction solvent comprises one or more of dimethyl sulfoxide and dichloromethane, chloroform and dichloroethane; (i) wherein the reaction solvent comprises one or more of tert-butyl alcohol, isopropyl alcohol, tetrahydrofuran and 2-methyltetrahydrofuran; (j) wherein the reaction solvent comprises one or more of dichloromethane, chloroform and 1,2-dichloroethane; The reaction solvent in (k) includes one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran and 2-methyltetrahydrofuran.

8. Use of the macrolide compound according to claim 1 and the intermediate compound for preparing the macrolide compound according to claim 2 in the preparation of methicillin-resistant Staphylococcus aureus antibiotics.

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