CN101792473A - Novel ketolide compound and preparation method and application thereof - Google Patents

Abstract

The invention discloses a ketolide compound similar with the telithromycin antibiotic. The compound has a structural formula as the accompanying drawing. The compound of the invention belongs to a third generation erythromycin analogue antibiotic, has novel structure and stronger activity than the macrolide antibiotic used clinically, has good antibacterial activity on the drug-resistance bacteria by the primary research and has great industrialization prospect.

Description

A novel ketolide compound and its preparation method and use

technical field

The invention belongs to the field of medicine, and in particular relates to a novel macrolide antibiotic ketolide compound and its preparation method and application, specifically, a thalyl-like compound with an aromatic ring tetrazolidinyl as a side chain Mycin ketolide compound and its preparation method and application.

Background technique

Bacterial infections threaten the survival of humans. Antibiotics are clinically commonly used drugs for infectious diseases, and their demand is huge. However, due to the non-standard use of antibiotics in clinical practice, the problem of bacterial resistance has been caused. In recent years, more and more bacteria have developed resistance to antibiotics, even multi-drug resistance. Bacterial infection has become more and more difficult to deal with, and has become one of the serious problems facing the cause of human health. Methicillin-resistant Staphylococcus aureus (MRSA) was first discovered in 1961. Since then, MRSA infections have increased day by day, and are resistant to most antibiotics, which has brought great difficulties to clinical treatment. With the widespread use of β-lactam antibiotics, the resistance of Streptococcus pneumoniae to them has also increased. Compound sulfamethoxazole is also resistant to multiple drugs. The antibacterial efficacy of many commonly used antibiotics is decreasing day by day, and antibiotic resistance has become a problem facing global public health. With the continuous and inappropriate use of macrolide antibiotics, a large number of macrolide drug-resistant pathogens emerged rapidly, which greatly restricted the application of macrolide antibiotics represented by erythromycin. At present, the speed of bacterial drug resistance is far faster than the speed of new drug development. In order to meet the continuous needs of human anti-infection, it is particularly important and urgent to develop new macrolide antibiotics, especially antibiotics that can fight against drug-resistant bacteria.

Macrolide antibiotics are a class of antibacterial drugs with a basic macrolide ring structure and similar antibacterial effects, and have been developed to the third generation. Erythromycin is the first macrolide antibiotic introduced clinically in 1952. Because of its strong antibacterial effect on Gram-positive bacteria, it is widely used in the treatment of community-acquired respiratory tract infections, skin and soft tissue infections, etc., and has good curative effect. No serious adverse reactions. However, its clinical use is limited due to its low blood concentration, short half-life, extreme instability to gastric acid, narrow antibacterial spectrum, and induction of bacterial resistance. Since the 1980s, a series of new characteristic erythromycin derivatives and new macrolide derivatives have been successfully developed through structural modification, which belong to the second generation of macrolide drugs, such as 14-membered ring clarithromycin, roxithromycin, fluerythromycin and dirithromycin, 15-membered ring azithromycin, 16-membered ring rotamycin, acetylspiramycin, etc. The second-generation macrolides have the characteristics of excellent antibacterial activity, good pharmacokinetic properties, prolonged half-life, reduced dosage and good tolerance. However, due to the abuse of antibiotics and antibacterial drugs, the drug resistance of bacteria has increased rapidly. In recent years, the drug resistance of erythromycin to pneumococcus has increased from 5% to 40%, and the proportion of cross-resistance to penicillin is also increasing. In the past decade, great progress has been made in overcoming bacterial resistance. Telithromycin and ABT-773 are the successful representative compounds of the ketolide family, which are resistant to macrolides Streptococcus pneumoniae and gold Staphylococcus aureus, Enterococcus faecalis, Haemophilus influenzae, etc. all have excellent antibacterial activity. At the same time, it has good antibacterial activity against non-drug-resistant bacteria. At present, telithromycin has been successfully marketed, and ABT-773 has passed the Phase III clinical trial, which shows that the ketolide antibiotics represented by them have a good application prospect. This has aroused great interest and inspired a new wave of research on macrolides and ketolides.

Erythromycin macrolide antibiotics inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit of the V region of 23S rRNA and preventing the binding of polypeptide chains to ribosomes. There are three main mechanisms of drug resistance between pathogenic bacteria and macrolides: (1) Active efflux. (2) Target change: ① resistance caused by 23S rRNA base mutation on the large ribosomal subunit; ② induction or production of methylase, changing the target position of ribosome, resulting in reduced binding to drugs; ③ ribosome Resistance caused by protein mutations on the large subunit; ④ resistance caused by resistant short peptides. (3) Macrolides are inactivated by enzymes produced by bacteria. In view of the above drug resistance mechanism, in recent years, macrolides have been structurally modified to obtain a new third-generation macrolide antibiotic-ketolide. Structural characteristics of ketolide: the cladinose at the 3-position of erythromycin is hydrolyzed and removed and oxidized to a carbonyl group; the hydroxyl groups at the 11 and 12 positions are modified into cyclic carbamate rings; the cyclic carbamate at 11 and 12 positions The ring nitrogen atom or the 6-position oxygen atom is connected to the alkane chain structure with an aromatic ring at the end. Studies have revealed that ketolide has two targets: A752 in the II region of 23S rRNA and A2058 in the V region. It can not only bind to the A2058 target through the deoxyamino sugar at the 5-position, but also bind to the second target A752 through the 11,12-carbamate ring side chain. That is to say, when the bacteria are sensitive bacteria, the ketolide can not only bind to the A2058 target, but also bind to the second target A752 to exert a strong antibacterial activity; when the A2058 of the bacterial V region is modified to become resistant When it is against bacteria, ketolide can still combine with the second target of drug-resistant bacteria, A752, and exert anti-drug-resistant bacteria activity.

Contents of the invention

In order to solve the deficiencies in the above-mentioned prior art, the primary purpose of the present invention is to provide a ketolide compound of a telithromycin antibiotic; according to the characteristics of the third generation macrolides-ketolide antibiotics The 3-position claridine sugar is hydrolyzed to remove and modify it into a carbonyl group; the 11, 12-position hydroxyl group is focused on forming a cyclic carbamate and introducing an aromatic ring-linked tetrazolidinyl side chain on the ring nitrogen atom to obtain a telithromycin-like antibiotic Ketolide compounds.

Another object of the present invention is to provide a preparation method of the ketolide compound of the above-mentioned telithromycin-like antibiotic.

Another object of the present invention is to provide the application of the ketolide compound of the above-mentioned telithromycin-like antibiotic.

In order to achieve the above object, the present invention adopts the following technical solutions: a ketolide compound of a telithromycin antibiotic, which has the following structural formula:

where n is 1, 2 or 3 and R is

The above-mentioned preparation method of a ketolide compound of a telithromycin-like antibiotic comprises the following steps:

(1) Stir clarithromycin I, water and ethanol evenly at room temperature, drop the temperature to 0°C, add hydrochloric acid dropwise, stir at room temperature, drop the temperature to 5°C, adjust the pH to 10.5-11.0, stir, filter, and wash , dry to obtain compound II;

(2) react the dichloromethane solution of compound II, benzoic anhydride, anhydrous triethylamine and 4-dimethylaminopyridine in an ice bath, then add saturated sodium bicarbonate, separate liquids, wash, and dry, Filtration, concentration, column chromatography, to obtain compound III;

(3) Add dropwise dimethyl sulfide to the methylene chloride solution of N-chlorosuccinimide, then add compound III dropwise, then add dropwise the methylene chloride solution of triethylamine to react, dry, filter, Concentration, column chromatography, to obtain compound IV; under the condition of -5 ~ 0 ° C, add methanesulfonyl chloride dropwise to the pyridine solution of compound IV, wash after the reaction, dry, filter, concentrate, and column chromatography to obtain compound V ;

Or add pyridine to the dichloromethane solution of compound III, add triphosgene and dichloromethane dropwise after cooling, rise to room temperature for reaction; cool to below 0°C, add saturated saline for liquid separation, wash, dry, filter, Concentration, column chromatography, to obtain compound VI; dichloromethane solution of compound VI and pyridinium chlorochromate were reacted at room temperature, washed, dried, filtered, concentrated, and column chromatography to obtain compound VII;

(4) Dissolving compound V or compound VII in acetone, adding diazabicyclo, and reflux reaction; evaporating to remove solvent, washing, drying, filtering, concentrating, and column chromatography to obtain compound VIII;

(5) Cool the dimethylformamide solution of sodium hydride to -10°C, add compound VIII under a protective gas atmosphere, add the dimethylformamide solution of carbonyldiimidazole dropwise, and stir at -10°C to -5°C Reaction, washing, drying, filtering, and concentration to obtain compound IX;

(6) Dissolve compound IX in acetonitrile, add aromatic ring tetrazolidinyl amine, stir the reaction at 55°C, cool, add ice water, extract with ethyl acetate, filter and concentrate the obtained residual solid to dissolve in methanol, reflux reacting, concentrating, washing, filtering, and column chromatography to obtain the ketolide compound of the telithromycin antibiotic;

Wherein the structural formulas of I, II, III, IV, V, VI, VII, VIII and IX:

The aromatic ring tetrazolidinyl amine is preferably prepared according to the following steps:

(1) dissolving the aryl nitrile in N, N-dimethylformamide, adding sodium azide and ammonium chloride successively under stirring; in a nitrogen atmosphere, react under oil bath conditions; cool to room temperature, Separate the liquid, adjust the pH to 4-5, leave it to stand after stirring, and precipitate crystals; filter with suction, cool the mother liquor in ice water, and crystals continue to precipitate, combine the crystals obtained above, and wash to obtain the aromatic ring tetrazole A;

Or dissolve aryl formaldehyde in the mixed solution of ammonia water and tetrahydrofuran, add iodine, stir, add sodium thiosulfate solution, extract, dry, filter, dissolve in water after concentration, add sodium azide and zinc bromide, and reflux reaction , add hydrochloric acid and ethyl acetate, stir to dissolve, separate the organic phase, extract the aqueous phase with ethyl acetate, concentrate, then add sodium hydroxide solution, filter, adjust the pH of the filtrate to 4-5, stand still, and precipitate crystals; Suction filtration, the mother liquor was cooled in ice water, crystals continued to be precipitated, and the crystals obtained above were combined and washed to obtain the aromatic ring tetrazole B;

(2) Dissolve aromatic ring tetrazole A or aromatic ring tetrazole B in N,N-dimethylformamide, add potassium carbonate and N-(3-bromopropyl)phthaloyl in turn The amine is reacted under the protection of nitrogen; after the reaction is completed, the reaction solution is poured into ice water, filtered, washed, and column chromatography is obtained to obtain N-aryl ring tetrazolidinyl phthalimide;

(3) Dissolve N-aromatic tetrazolidinyl phthalimide in a mixed solution of absolute ethanol and acetonitrile, add hydrazine monohydrate, and heat to reflux for reaction; after the reaction, cool to room temperature; filter , washed, evaporated to remove the solvent, the residue was added to sodium hydroxide solution, and then extracted with dichloromethane, the organic phases were combined, washed, dried, and column chromatographed to obtain aromatic ring tetrazolidinylamine.

(2-氰基吡啶)、

(3-氰基吡啶)或(4-氰基吡啶)；所述芳基甲醛为

(5-苯基-甲醛)、

(5-(2-噻吩基)-甲醛)或

(5-(2-呋喃基)-甲醛)。The aryl nitrile is

(2-cyanopyridine),

(3-cyanopyridine) or (4-cyanopyridine); The aryl formaldehyde is

(5-phenyl-formaldehyde),

(5-(2-thienyl)-carbaldehyde) or

(5-(2-furyl)-carbaldehyde).

The above-mentioned ketolide compound of the telithromycin-like antibiotic can be applied to the preparation of antibacterial drugs.

The present invention uses an in vitro antibacterial activity test to evaluate the use of the telithromycin-like antibiotic ketolide compound of the present invention in antibacterial aspects. Quality control standard strains and clinically isolated drug-resistant strains were used as test bacteria, and erythromycin and clarithromycin were used as positive control drugs. The results show that the novel ketolide compound of the present invention has good antibacterial activity to sensitive Staphylococcus aureus; it has good antibacterial activity to the drug-resistant Staphylococcus aureus isolated clinically, which is much better than erythromycin and Clarithromycin; antibacterial activity against Pseudomonas aeruginosa and Escherichia coli is better than or equivalent to erythromycin and clarithromycin. Table 1 is the antibacterial activity results (MIC) of the novel ketolide compounds against different bacterial strains.

Table 1 Antibacterial activity results (MIC) of new ketolide compounds against different strains.

Experiments have proved that the series of novel ketolide compounds (shown in FIG. 3 ) prepared by the method of the present invention have good anti-drug-resistant bacteria activity and can be used to prepare antibacterial drugs (such as antibiotics).

Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects: the compound of the present invention belongs to the third generation erythromycin antibiotics, has a novel structure, and is more active than clinically used macrolide antibiotics. The medicinal bacteria have good antibacterial activity and have very important industrialization prospects.

Description of drawings

Figure 1 is a synthetic route diagram of aromatic ring tetrazolidinyl amine compounds.

Fig. 2 is a synthetic route diagram of ketolide compounds of telithromycin-like antibiotics.

Fig. 3 is a structural diagram of a ketolide compound of a telithromycin-like antibiotic.

Detailed ways

The present invention will be further described in detail below in conjunction with the embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto.

Example 1

Preparation of Aromatic Tetrazoles

method one:

Add cyanopyridine (1,1 mmol) into a three-necked flask and dissolve it in N,N-dimethylformamide (1.25mL), add sodium azide (3equiv) and ammonium chloride (3equiv) in sequence under stirring ; Under nitrogen protection, react at 130°C in an oil bath for 22h; cool to room temperature, add saturated sodium bicarbonate solution (2.5mL) and ethyl acetate (2.5mL) to the reaction solution, shake, transfer to a separatory funnel, and separate The organic layer; the solution layer was slowly acidified with concentrated hydrochloric acid to pH 4-5, stirred and left to stand, and crystals were precipitated; suction filtered, the mother liquor was cooled in ice water, and crystals continued to be precipitated, and the above crystals were combined, and an appropriate amount of The product was washed with distilled water to obtain the product. When the aryl nitrile is 2-cyanopyridine, the product 3a is obtained; when the aryl nitrile is 3-cyanopyridine, the product 3b is obtained; when the aryl nitrile is 4-cyanopyridine, the product 3c is obtained.

3a: 5-(2-pyridyl)-tetrazolium, white needle-like crystals, yield 85%, mp211-212°C, ¹ HNMR (DMSO-d6) δ7.63 (m, 1H), 8.09 (d, J=6,1H), 8.22(d, J=6.9,1H), 8.78(m,1H); MS m/z 148(MH ⁺ ).

3b: 5-(3-pyridyl)-tetrazolium. White crystals, 82% yield, MS m/z 148 (MH ⁺ ).

3c: 5-(4-pyridyl)-tetrazolium. Yellowish crystals, yield 79%, MS m/z 148 (MH ⁺ ).

Method Two:

Dissolve aryl formaldehyde (2, 1mmol) in a mixed solution of 10mL ammonia (28% by mass) and 1mL tetrahydrofuran, add 1.1 equiv of iodine, stir for 1-2 hours, and add 5mL of 5% by mass to the reaction solution Sodium thiosulfate solution, extracted with ether (15mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, the residue was dissolved in 2mL of water, 1.1equiv sodium azide and 1equiv zinc bromide were added, and refluxed for 24h. When a large amount of white solids are generated, stop the reaction, add 1.5mL 3mol/L hydrochloric acid solution and 5mL ethyl acetate to the reaction solution, stir to make the solids dissolve completely, and the pH is 1 now (if there are still solids, then increase the amount of ethyl acetate) ), separate the organic phase, extract the aqueous phase with ethyl acetate (5mL × 2), concentrate, add 5mL 0.5mol/L sodium hydroxide solution to the residual solid, fully stir to generate zinc hydroxide solid, filter, and use a small amount of 1mol/L sodium hydroxide solution Wash with 1 L of sodium hydroxide solution, add 3 mol/L hydrochloric acid solution to the filtrate, stir well, at this time the pH is 4-5, let it stand still, and precipitate crystals. After suction filtration, the mother liquor was cooled in ice water, and crystals continued to precipitate, and the crystals obtained above were combined, and the product was washed with an appropriate amount of distilled water to obtain the product. When the aryl formaldehyde is 5-phenyl-carbaldehyde, the product 3d is obtained; when the aryl formaldehyde is 5-(2-thienyl)-carbaldehyde, the product 3e is obtained; when the aryl formaldehyde is 5-(2-furyl)-carbaldehyde , the product 3f was obtained.

3d: 5-phenyl-tetrazolium, white needle-like crystals, yield 84.9%, MS m/z 147 (MH ⁺ ).

3e: 5-(2-thienyl)-tetrazolium, yellow crystal, yield 76.3%, MS m/z 153(MH ⁺ ).

3f: 5-(2-furyl)-tetrazolium, white crystals, yield 91.7%, MS m/z 137(MH ⁺ ).

Example 2

The product 3 (1 mmol) obtained in Example 1 was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (1 mmol) and N-bromoalkylphthalimide (1 mmol) were added in sequence; Under the protection of nitrogen, react at 80°C for 10h. After the reaction is complete, pour the reaction solution into 10 mL of ice water, filter, wash the filter cake with a small amount of ice water, and use petroleum ether: ethyl acetate = 1:1 to petroleum ether: ethyl acetate: dichloromethane = 1:1: 1 is developing agent silica gel (200-300 order) column chromatography, obtains the product. Depending on the starting material 3, different products 4a-4q can be obtained.

4a: 2-[3-(5-(Pyridin-2-yl)-1H-tetrazol-1-yl)propyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 35%, ¹ H NMR (300MHz, CDCl ₃ ): δ8.83(m, 3H), 8.33(d, J=7.8Hz, 1H), 7.83(m, 1H), 7.72(m, 2H), 7.35 (m, 2H), 5.03 (t, J=7.8Hz, 2H), 3.83 (t, J=6.9Hz, 2H), 2.39 (m, 2H); ¹³ C NMR (CDCl ₃ ): δ168.1, 151.5 , 149.2, 144.7, 137.4, 134.1, 131.9, 125.2, 123.3, 47.3, 35.0, 28.9; MS m/z 335 (MH ⁺ ).

4b: 2-[3-(5-(Pyridin-2-yl)-2H-tetrazol-2-yl)propyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 60%, ¹ H NMR (300MHz, CDCl ₃ ): δ8.67(d, J=4.2Hz, 3H), 8.12(d, J=7.8Hz, 1H), 7.77(m, 3H), 7.64(m , 2H), 7.31(m, 1H), 4.73(t, J=7.5Hz, 2H), 3.80(t, J=6.9Hz, 2H), 2.46(m, 2H); ¹³ C NMR (CDCl ₃ ): δ167.9, 164.6, 150.1, 146.9, 136.9, 133.9, 131.6, 124.6, 123.2, 122.2, 51.0, 34.8, 28.2; MS m/z 335 (MH ⁺ ).

4c: 2-[3-(5-(Pyridin-3-yl)-2H-tetrazol-2-yl)propyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 96%, ¹ H NMR (300MHz, CDCl ₃ ): δ9.91 (m, 1H), 8.60 (m, 1H), 8.25 (d, J=7.8Hz, 1H), 7.73 (m, 2H), 7.62 (m, 2H), 7.33(m, 1H), 4.70(t, J=6.9Hz, 2H), 3.81(t ^, J=6.6Hz, 2H), 2.42(m, _2H ); ): δ162.3, 151.0, 147.8, 134.0, 133.8, 131.6, 123.4, 123.3, 50.9, 35.0, 27.9; MS m/z 335 (MH ⁺ ).

4d: 2-[3-(5-(Pyridin-4-yl)-2H-tetrazol-2-yl)propyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 88.6%, MS m/z 335 (MH ⁺ ).

4e: 2-[4-(5-(Pyridin-2-yl)-1H-tetrazol-1-yl)butyl)]-isoindole-1,3-2H-dione, white solid, yield Efficiency 50%, ¹ H NMR (300Mz, CDCl ₃ ): δ8.73(d, J=4.5Hz, 1H), 8.20(d, J=8.1Hz, 1H), 7.82(m, 1H), 7.79(m , 2H), 7.67(m, 2H), 7.41(m, 1H), 5.02(t, J=7.2Hz, 2H), 3.73(t, J=7.2Hz, 2H), 2.02(m, 2H), 1.77 (m, 2H); ¹³ C NMR (CDCl ₃ ): δ168.2, 151.6, 149.4, 144.8, 137.4, 133.9, 125.2, 124.5, 123.2, 48.9, 37.1, 27.1, 25.4; MS m/z 349 (MH ⁺ ), HRMS (FAB) Calcd for C ₁₈ H ₁₇ N ₆ O ₂ (MH ⁺ ): 349.1408. Found: 349.1412

4f: 2-[4-(5-(Pyridin-2-yl)-2H-tetrazol-2-yl)butyl)]-isoindole-1,3-2H-dione, white solid, yield Efficiency 50%, ¹ H NMR (300Mz, CDCl ₃ ): δ8.73(d, J=4.5Hz, 1H), 8.20(d, J=8.1Hz, 1H), 7.82(m, 1H), 7.79(m , 2H), 7.67(m, 2H), 7.36(m, 1H), 4.74(t, J=7.2Hz, 2H), 3.73(t, J=7.2Hz, 2H), 2.11(m, 2H), 1.75 (m, 2H),; ¹³ CNMR (CDCl ₃ ): δ168.2, 164.7, 150.2, 146.7, 137.0, 133.9, 131.9, 124.7, 123.2, 122.3, 52.6, 36.8, 26.5, 25.4; MS m/z 349 ( MH ⁺ ). HRMS (FAB) Calcd for C18H17N6O2 (MH ⁺ ): 349.1408. Found: 349.1412.

4 g: 2-[4-(5-(pyridin-3-yl)-2H-tetrazol-2-yl)butyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 87%, ¹ H NMR (300Mz, CDCl ₃ ) δ9.34(m, 1H), 8.71(m, 1H), 8.40(d, J=8.1, 1H), 7.85(m, 2H), 7.72(m , 2H), 7.44(m, 1H), 4.75(t, J=6.9, 2H), 3.78(t, J=6.9, 2H), 2.12(m, 2H), 1.79(m, 2H); ¹³ C NMR (CDCl ₃ )δ168.2, 162.7, 151.1, 148.0, 134.0, 133.8, 131.8, 123.2, 123.6, 52.5, 36.8, 26.5, 25.4,; MS m/z 349 (MH ⁺ ), HRMS (FAB) Calcd for C ₁₈ H ₁₇ N ₆ O ₂ (MH ⁺ ): 349.1408. Found: 349.1404.

4h: 2-[4-(5-(Pyridin-4-yl)-2H-tetrazol-2-yl)butyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 94%, ¹ H NMR (300Mz, CDCl ₃ ) δ8.76 (d, J=4.5, 2H), 7.99 (d, J=4.5, 2H), 7.84 (d, J=5.4, 2H), 7.73 ( d, J = 5.4, 2H), 4.76 (t, J = 6.9, 2H), 3.78 (t, J = 6.9, 2H), 2.13 (m, 2H), 1.79 (m, 2H); ¹³ C NMR (CDCl3 )δ168.2, 163.0, 162.4, 150.5, 134.6, 134.0, 131.8, 123.2, 120.7, 52.6, 36.8, 26.5, 25.4; MS m/z 349 (MH ⁺ ), HRMS (FAB) Calcd for C18H17N6O2 (MH + ): 349.1408.Found: 349.1412.

4i: 2-[5-(5-(Pyridin-2-yl)-1H-tetrazol-1-yl)pentyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 37.8%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.74(d, J=4.4Hz, 1H), 8.36(d, J=7.9Hz, 1H), 7.92(m, 1H), 7.84(m , 2H), 7.73(m, 2H), 7.46(m, 1H), 4.99(t, J=7.2Hz, 2H), 3.68(t, J=7.1Hz, 2H), 2.04(m, 2H), 1.75 (m, 2H), 1.43 (m, 2H); ¹³ C NMR (CDCl ₃ ): δ168.2, 151.5, 149.4, 144.8, 137.3, 133.8, 133.7, 131.9, 125.2, 124.4, 123.1, 123.0, 49.2, 37.4 , 29.2, 27.8, 23.5; MS m/z 363 (MH ⁺ ).

4j: 2-[5-(5-(Pyridin-2-yl)-2H-tetrazol-2-yl)pentyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 52.8%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.78(d, J=4.7Hz, 1H), 8.25(d, J=7.9Hz, 1H), 7.88(m, 1H), 7.83(m , 2H), 7.71(m, 2H), 7.40(m, 1H), 4.72(t, J=7.1Hz, 2H), 3.69(t, J=7.2Hz, 2H), 2.18(m, 2H), 1.76 (m, 2H), 1.45 (m, 2H); ¹³ C NMR (CDCl ₃ ): δ168.2, 164.7, 150.2, 146.7, 137.0, 133.8, 131.9, 124.7, 123.1, 122.3, 53.1, 37.3, 28.7, 27.8 , 23.5; MS m/z 363 (MH ⁺ ).

4k: 2-[5-(5-(Pyridin-3-yl)-2H-tetrazol-2-yl)pentyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 87.2%, ¹ H NMR (400MHz, CDCl ₃ ): δ9.36(s, 1H), 8.71(m, 1H), 8.41(m, 1H), 7.83(m, 2H), 7.70(m, 2H) , 7.43(m, 1H), 4.69(t, J=7.0Hz, 2H), 3.70(m, 2H), 2.14(m, 2H), 1.77(m, 2H), 1.44(m, 2H); ¹³ C NMR (CDCl ₃ ): δ168.3, 162.7, 151.1, 148.0, 134.0, 133.9, 131.9, 123.7, 123.6, 123.2, 53.1, 37.3, 28.7, 27.8, 23.5; MS m/z 363 (MH ⁺ ).

4l: 2-[5-(5-(pyridin-4-yl)-2H-tetrazol-2-yl)pentyl)]-isoindole-1,3-2H-dione, white solid, yield Yield 92.1%, MS m/z 363 (MH ⁺ ).

4m: 2-(3-(5-Phenyl-2H-tetrazol-2-yl)propyl)]-isoindole-1,3-2H-dione, white solid, yield 93.4%, MS m/z 334(MH ⁺ ).

4n: 2-(4-(5-phenyl-2H-tetrazol-2-yl)butyl)]-isoindole-1,3-2H-dione, white solid, yield 94.8%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.12(m, 2H), 7.83(m, 2H), 7.70(m, 2H), 7.46(m, 3H), 4.72(t, J=7.0Hz, 2H) , 3.75 (m, 2H), 2.13 (m, 2H), 1.78 (m, 2H); ¹³ C NMR (CDCl ₃ ): δ168.3, 165.1, 134.0, 132.0, 130.2, 128.8, 126.8, 123.2, 52.3, 36.9, 26.6, 25.5. MS m/z 348 (MH ⁺ ).

4o: 2-[3-(5-(thiophen-2-yl)-2H-tetrazol-2-yl)propyl)]-isoindole-1,3-2H-dione, yield 80.6% , ¹ H NMR (400MHz, CDCl ₃ ): δ7.83(m, 2H), 7.70(m, 3H), 7.42(m, 1H), 7.11(m, 1H), 4.70(m, 2H), 3.83( m, 2H), 2.48 (m, 2H); ¹³ C NMR (CDCl ₃ ): δ168.2, 168.1, 161.2, 134.1, 133.9, 131.9, 130.2, 129.0, 127.8, 123.4, 123.2, 51.0, 35.2, 28.3; MS m/z 340(MH ⁺ ).

4p: 2-[4-(5-(thiophen-2-yl)-2H-tetrazol-2-yl)butyl)]-isoindole-1,3-2H-dione, yield 62.7% , ¹ H NMR (400MHz, CDCl ₃ ): δ7.83(m, 2H), 7.77(m, 1H), 7.70(m, 2H), 7.43(m, 1H), 7.13(m, 1H), 4.69( t, J=7.0Hz, 1H), 3.76(m, 2H), 2.12(m, 2H), 1.77(m, 2H); ¹³ C NMR(CDCl ₃ ): δ168.3, 161.2, 134.0, 133.9, 132.0 , 127.8, 127.7, 123.3, 52.4, 36.9, 26.5, 25.4; MS m/z 354 (MH ⁺ ).

4q: 2-[4-(5-(furan-2-yl)-2H-tetrazol-2-yl)butyl)]-isoindole-1,3-2H-dione, yield 85.8% , ¹ H NMR (400MHz, CDCl ₃ ): δ7.83(m, 2H), 7.73(m, 2H), 7.68(s, 1H), 7.29(m, 1H), 6.64(m, 1H), 4.74( t, J=7.1Hz, 1H), 3.75(m, 2H), 2.03(m, 2H), 1.77(m, 2H); ¹³ C NMR(CDCl ₃ ): δ168.2, 145.4, 134.0, 133.8, 131.9 , 123.2, 123.1, 114.8, 112.3, 48.0, 36.8, 26.9, 25.3; MS m/z 338 (MH ⁺ ).

Example 3

Dissolve the product 4 (1 mmol) obtained in Example 2 in a mixture of absolute ethanol (7 mL) and acetonitrile (5 mL), add hydrazine monohydrate (2 equiv), and heat to reflux for 6 h; after the reaction is complete, cool to room temperature; Filter the reaction solution, wash the filter cake with a small amount of 95% ethanol, remove the solvent in the filtrate by rotary evaporation, add sodium hydroxide solution (2mol/L, 10mL) to the residue; add dichloromethane (10mL×3) for extraction, and combine the organic phases , washed with saturated brine, and dried over anhydrous sodium sulfate. Filtrate, concentrate, and use dichloromethane:methanol:triethylamine=9:1:0.1 as the developing solvent for silica gel (200-300 mesh) column chromatography to obtain the aromatic ring tetrazolidinyl amine product. According to the different raw materials 4a-4q, the products 5a-5q can be correspondingly obtained respectively.

5a: 3-[5-(pyridin-2-yl)-1H-tetrazol-1-yl]propylamine, yellow oily liquid, yield 86%, ¹ HNMR (300MHz, CDCl ₃ ): δ8.65(d , J=4.1Hz, 1H), 8.11(d, J=4.8Hz, 1H), 7.75(m, 1H), 7.28(m, 1H), 4.72(t, J=6.9Hz, 2H), 2.67(t , J=6.6Hz, 2H), 2.11 (m, 2H), 1.80 (s, br, 2H, -NH2), ¹³ C-NMR (CDCl ₃ ): δ165.1, 150.7, 147.1, 137.6, 125.3, 122.8 , 51.5, 38.9, 32.9. MS (m/z): 205 (MH ⁺ ).

5b: 3-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]propylamine, yellow oily liquid, yield 89%, ¹ HNMR (300MHz, CDCl ₃ ): δ8.51(d , J=4.8Hz, 1H), 8.10(d, J=7.8Hz, 1H), 7.71(m, 1H), 7.27(m, 1H), 4.85(t, J=7.2Hz, 2H), 2.53(t , J=6.9Hz, 2H), 1.90 (m, 2H), 1.81 (s, br, 2H, -NH ₂ ), ¹³ C-NMR (CDCl ₃ ): δ165.1, 150.7, 147.1, 137.6, 125.3, 122.8, 51.5, 38.9, 32.9. MS (m/z): 205 (MH ⁺ ).

5c: 3-[5-(pyridin-3-yl)-2H-tetrazol-2-yl]propylamine, yellow oily liquid, yield 82%, ¹ HNMR (300MHz, CDCl ₃ ): δ9.20(s , 1H), 8.55(d, J=4.8Hz, 1H), 8.24(d, J=7.8Hz, 1H), 7.28(m, 1H), 4.67(t, J=6.9Hz, 2H), 2.66(t , J=6.6Hz, 2H), 2.05 (m, 2H), 1.39 (s, br, 2H, -NH ₂ ), ¹³ C-NMR (CDCl ₃ ): δ162.3, 150.8, 147.6, 133.7, 123.3, 50.6, 38.3, 32.3; MS m/z 205 (MH ⁺ ), HRMS (FAB) Calcd for C ₉ H ₁₃ N ₆ (MH ⁺ ): 205.1196. Found: 205.1204.

5d: 3-[5-(pyridin-4-yl)-2H-tetrazol-2-yl]propylamine, yellow oily liquid, yield 92.1%, MS m/z 205(MH ⁺ ).

5e: 4-[5-(pyridin-2-yl)-1H-tetrazol-1-yl]butylamine, yellow oily liquid, yield 87%, ¹ HNMR (DMSO-d ₆ ): δ8.80( d, J=4.8Hz, 1H), 8.24(d, J=7.8Hz, 1H), 8.08(m, 1H), 7.63(m, 1H), 4.90(t, J=7.2Hz, 2H), 2.50( m, 2H), 1.89 (m, 2H), 1.33 (s, 2H), ¹³ C-NMR (DMSO-d ₆ ): δ151.8, 150.1, 144.4, 138.4, 126.1, 124.6, 49.1, 41.1, 29.9, 27.0. MS (m/z): 219 (MH ⁺ ). HRMS (FAB) Calcd for C10H15N6 (MH ⁺ ): 219.1353. Found: 219.1359.

5f: 4-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]butylamine, yellow oily liquid, yield 87%, ¹ HNMR (DMSO-d ₆ ): δ8.73( d, J=4.8Hz, 1H), 8.13(d, J=7.8Hz, 1H), 7.99(m, 1H), 7.54(m, 1H), 4.75(t, J=6.9Hz, 2H), 2.53( m, 2H), 1.99 (m, 2H), 1.34 (s, 2H), ¹³ C-NMR (DMSO-d ₆ ): δ164.3, 150.4, 146.5, 137.8, 125.4, 122.6, 53.2, 40.9, 29.8, 26.5.

5g: 4-[5-(pyridin-3-yl)-2H-tetrazol-2-yl]butylamine, yellow oily liquid, yield 74%, ¹ HNMR (300MHz, CDCl ₃ ): δ9.24( s, 1H), 8.59(d, J=4.8Hz, 1H), 8.30(d, J=7.8Hz, 1H), 7.32(m, 1H), 4.61(t, J=7.2Hz, 2H), 2.67( t, J=6.9Hz, 2H), 2.05 (m, 2H), 1.89 (s br, 2H), 1.44 (m, 2H), ¹³ C-NMR (CDCl ₃ ): δ162.5, 150.9, 147.8, 147.8 , 133.8, 123.5, 53.0, 41.0, 29.8, 26.5; MS m/z 219 (MH ⁺ ), HRMS (FAB) Calcd for C ₁₀ H ₁₅ N ₆ (MH ⁺ ): 219.1353. Found: 219.1358.

5h: 4-[5-(pyridin-4-yl)-2H-tetrazol-2-yl]butylamine, yellow oily liquid, yield 92%. ¹ HNMR (300MHz, CDCl ₃ ): δ8.72( d, J=5.4Hz, 2H), 7.97(d, J=5.1Hz, 2H), 4.67(t, J=6.9Hz, 2H), 2.76(s, 2H), 2.09(m, 2H), 1.48( m, 2H); ¹³ C-NMR (CDCl ₃ ): δ162.4, 151.0, 134.3, 120.6, 53.3, 40.9, 29.8, 26.5; MS m/z 219 (MH ⁺ ), HRMS (FAB) Calcdfor C ₁₀ H ₁₅ N ₆ (MH ⁺ ): 219.1353. Found: 219.1355.

5i: 4-[5-(pyridin-2-yl)-1H-tetrazol-1-yl]pentylamine, yellow oily liquid, yield 86.9%, ¹ HNMR (400MHz, CDCl ₃ ): δ8.64( d, J=2.8Hz, 1H), 8.22(m, 1H), 7.82(m, 1H), 7.36(m, 1H), 4.88(m, 2H), 2.61(t, J=7.1Hz, 2H), ^MS _{_} (m/z): 233(MH ⁺ ).

5j: 4-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]pentylamine, yellow oily liquid, yield 92.3%, ¹ HNMR (400MHz, CDCl ₃ ): δ8.78( m, 1H), 8.24(m, 1H), 7.87(m, 1H), 7.54(m, 1H), 4.73(t, J=7.1Hz, 2H), 2.80(m, 2H), 2.13(m, 2H ), 1.63 (m, 2H), 1.43 (m, 2H); ¹³ C-NMR (CDCl ₃ ): δ164.7, 150.2, 146.7, 137.1, 124.8, 122.4, 53.2, 40.6, 30.3, 28.9, 23.5, 26.5 .MS (m/z): 233 (MH ⁺ ).

5k: 4-[5-(pyridin-3-yl)-2H-tetrazol-2-yl]pentylamine, yellow oily liquid, yield 84.5%, ¹ HNMR (400MHz, CDCl ₃ ): δ9.26( s, 1H), 8.60(d, J=4.2Hz, 1H), 8.33(d, J=7.9Hz, 1H), 7.36(m, 1H), 4.61(t, J=7.0Hz, 2H), 2.62( t, J=7.0Hz, 2H), 2.01 (m, 2H), 1.46 (m, 2H), 1.32 (m, 2H), ¹³ C-NMR (CDCl ₃ ): δ162.4, 150.8, 147.6, 133.9, 123.5, 123.4, 53.0, 41.2, 32.1, 28.8, 23.4; MS m/z 233 (MH ⁺ ).

5l: 4-[5-(pyridin-4-yl)-2H-tetrazol-2-yl]pentylamine, yellow oily liquid, yield 83.6%, HNMR (400MHz, CDCl ₃ ): δ8.61(m , 2H), 7.88(m, 2H), 4.57(t, J=6.8Hz, 2H), 2.58(t, J=6.8Hz, 2H), 1.96(m, 2H), 1.42(m, 2H), 1.28 (m, 2H), ¹³ C-NMR (CDCl ₃ ): δ162.6, 150.2, 134.6, 120.5, 53.1, 41.1, 31.9, 28.8, 23.3; MSm/z 233 (MH ⁺ ).

5m: 3-(5-phenyl-2H-tetrazol-2-yl)propylamine, pale yellow oily liquid, yield 93.5%, ¹ HNMR (400MHz, CDCl ₃ ): δ8.02 (m, 2H), 7.32(m, 3H) ^, 4.64(m, 2H), 3.74(s, br, 2H, -NH ₂ ), 2.70(t, J=6.8Hz, 2H), 2.09(m, 2H); (400MHz, CDCl ₃ ): δ164.6, 129.9, 128.5, 126.9, 126.3, 50.5, 38.0, 31.4; MS (m/z): 204 (MH ⁺ ).

5n: 4-[5-phenyl-2H-tetrazol-2-yl]butylamine, light yellow oily liquid, yield 87.4%, ¹ HNMR (400MHz, CDCl ₃ ): δ7.99 (m, 2H) ₁₃ ^_ C-NMR (400MHz, CDCl ₃ ): δ164.6, 129.9, 128.5, 126.9, 126.3, 50.5, 38.0, 31.4; MS (m/z): 218 (MH ⁺ ).

5o: 3-[5-(thiophen-2-yl)-2H-tetrazol-2-yl]propylamine, dark yellow oily liquid, yield 87.3%, ¹ H NMR (400MHz, CDCl ₃ ): δ7.69 (m, 1H), 7.35(m, 1H), 7.04(m, 1H), 4.61(m, 2H), 2.70(m, 2H), 2.07(m, 2H), 1.77(s, 2H, _-NH2 ); ¹³ C-NMR (400MHz, CDCl ₃ ): δ160.9, 128.8, 127.7, 127.6, 127.5, 50.5, 38.3, 32.3; MS (m/z): 210 (MH ⁺ ).

5p: 3-[5-(thiophen-2-yl)-2H-tetrazol-2-yl]butylamine, dark yellow oily liquid, yield 95.7%, ¹ H NMR (400MHz, CDCl ₃ ): δ7. 79(m, 1H), 7.45(m, 1H), 7.14(m, 1H), 4.65(t, J=7.1Hz, 2H), 2.75(t, J=7.1Hz, 2H), 2.10(m, 4H ), 1.51 (m, 2H,); ¹³ C-NMR (400MHz, CDCl ₃ ): δ160.9, 128.8, 127.7, 127.6, 127.5, 52.8, 41.0, 29.8, 26.5; MS (m/z): 224 ( MH ⁺ ).

5q: 3-[5-(furan-2-yl)-2H-tetrazol-2-yl]butylamine, yield 94.9%, ¹ H NMR (400MHz, CDCl ₃ ): δ7.49(m, 1H ), 7.00(m, 1H), 6.45(m, 1H), 4.58(m, 2H), 2.64(m, 2H), 2.00(m, 4H), 1.41(m, 2H,); ¹³ C-NMR( 400 MHz, CDCl ₃ ): δ157.9, 145.3, 142.6, 111.5, 111.0, 52.8, 40.8, 29.5, 26.4; MS (m/z): 208 (MH ⁺ ).

The synthesis route of the aromatic ring tetrazolidinyl amine compounds described in Examples 1-3 is shown in FIG. 1 .

Example 4

Preparation of 3-desclardinose-3-hydroxyl-6-O-methylerythromycin (as shown in formula II)

Stir 9.0g (12mmol) of clarithromycin, 100mL of water and 500mL of ethanol at room temperature to form a suspension, put it in an ice bath to 0°C, and add 21.6ml of 1mol/L hydrochloric acid solution dropwise within 50min. Stir and react for 20 hours; cool the reaction solution to 5°C, add 120mL 2mol/L sodium hydroxide solution dropwise, adjust the pH to 10.5-11.0, continue stirring for 1 hour in an ice bath, filter, wash the filter cake with ice water, vacuum After drying, 6.2 g (86.9%) of white powder was obtained, that is, 3-descradinose-3-hydroxy-6-O-methylerythromycin.

Spectrum analysis of 3-descladinose-3-hydroxy-6-O-methylerythromycin is as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ5.18 (dd, J=11.0, 2.1Hz, 1H), 4.41(d, J=7.4Hz, 1H), 3.92(s, 1H), 3.85(s, 1H), 3.69(s, 1H), 3.51～3.58(m, 2H), 3.37～3.41(m, 1H) , 3.22～3.27(m, 2]H), 3.00～3.02(m, 1H), 2.97(s, 3H), 2.64～2.68(m, 1H), 2.64～2.68(m, 1H), 2.56～2.60( m, 2H), 2.32(s, 6H), 2.17(s, 3H), 2.11～2.14(m, 1H), 1.90～1.93(m, 2H), 1.63(s, br, -OH), 1.36(s , 3H), 1.25`1.30(m, 6H), 1.18(s, 3H), 1.11～1.14(m, 9H), 0.84(t, J=7.4Hz, 3H); MS(m/z): 590( MH ⁺ ).

Example 5

Preparation of 3-descladinose-3-hydroxyl-6-O-methyl-2'-benzoyl erythromycin (as shown in Figure III)

Dissolve 6g (10mmol) of 3-desclardinose-3-hydroxy-6-O-methylerythromycin in 25mL of anhydrous dichloromethane, add 3.8g (16mmol) of benzoic anhydride under ice-cooling, 2.2mL (16 mmol) anhydrous triethylamine, a small amount of 5-dimethylaminopyridine, stirred at room temperature for 58 hours. Add 20 mL of cold saturated sodium bicarbonate solution, continue to stir for half an hour, separate the layers, wash the organic phase with water and saturated brine in sequence, dry over anhydrous sodium sulfate, filter, concentrate, and use petroleum ether: acetone: triethylamine = 5: 1:1% is the developing agent silica gel (200~~300 mesh) column chromatography to obtain a white foamy product, which is 3-descradinose-3-hydroxyl-6-O-methyl-2'-benzyl Acylerythromycin (6.03 g, 85.7%).

Spectrum analysis of 3-descladinose-3-hydroxy-6-O-methyl-2'-benzoylerythromycin is as follows: ¹ HNMR (400MHz, CDCl ₃ ): δ8.06(d, J=7.1Hz , 2H), 7.57(d, J=7.4Hz, 1H), 7.45(d, J=7.8Hz, 2H), 5.12(dd, J=11.1, 2.3Hz, 1H), 5.04(m, 1H), 4.75 (d, J=7.6Hz, 1H), 3.94(s, 1H), 3.73~3.75(m, 2H), 3.53~3.58(m, 1H), 3.43~3.57(m, 1H), 2.93(s, 3H ), 2.86～2.90(m, 1H), 2.48～2.68(m, 2H), 2.28(s, 6H), 1.97～1.99(m, 1H), 1.87～1.92(m, 1H), 1.60～1.65(m , 1H), 1.37～1.47(m, 3H), 1.19～1.33(m, 9H), 1.04～1.08(m, 9H), 0.81(t, J=7.4Hz, 3H); MS(m/z): 694 (MH ⁺ ).

Example 6

Preparation of 3-descladinose-3-oxo-6-O-methyl-2'-benzoyl erythromycin (as shown in Figure IV)

Dissolve 0.57g (5.2mmol) N-chlorosuccinimide in 6mL of anhydrous dichloromethane, cool to -10°C, add 0.36mL (5.9mmol) dimethyl sulfide dropwise within 30min, and continue stirring for 10min. Add dropwise 2.0g (2.9mmol) of 3-decladinose-3-hydroxy-6-O-methyl-2'-benzoylerythromycin (12mL) anhydrous dichloromethane solution within 55min, The reaction was stirred for an additional 2 hours. Slowly add 0.5mL (5.5mmol) triethylamine (2mL) dichloromethane solution dropwise, continue to stir for 1 hour, slowly rise to room temperature, wash with saturated sodium bicarbonate solution, saturated brine, anhydrous sodium sulfate Dry, filter, concentrate, and use petroleum ether: acetone: triethylamine = 5: 1: 1% as the developing agent for silica gel (200 ~ -300 mesh) column chromatography to obtain a white foamy product, which is 3-declarate Desan-3-oxo-6-O-methyl-2'-benzoylerythromycin (1.55 g, 77.1%).

Spectrum analysis of 3-descladinose-3-oxo-6-O-methyl-2'-benzoylerythromycin is as follows: ¹ HNMR (400MHz, CDCl ₃ ): δ8.02 (d, J=7.7 Hz, 2H), 7.56(t, J=7.3Hz, 1H), 7.43(t, J=7.6Hz, 2H), 5.10(dd, J=10.8, 2.3Hz, 1H), 5.01～5.05(m, 1H ), 4.55(d, J=7.7Hz, 1H), 4.32(d, J=5.6Hz, 1H), 3.86(s, 1H), 3.6~3.74(m, 2H), 2.92~3.00(m, 2H) , 2.82～2.88(m, 1H), 2.69(s, 3H), 2.55～2.60(m, 1H), 2.26(s, 6H), 1.89～1.94(m, 1H), 1.78～1.81(m, 1H) , 1.56～1.61(m, 2H), 1.41～1.49(m, 3H), 1.33(s, 3H), 1.26～1.30(m, 6H), 1.03～1.18(m, 9H), 0.82(t, J= 7.4 Hz, 3H); MS (m/z): 692 (MH ⁺ ).

Example 7

Preparation of 3-descladinose-3-oxo-6-O-methyl-11-methylsulfonyl-2'-benzoyl erythromycin (as shown in Figure V)

Dissolve 1g (1.55mmol) of 3-desclardinose-3-oxo-6-O-methyl-2'-benzoylerythromycin in 10mL of anhydrous pyridine, and add 0.56 mL (7.25mmol) of methanesulfonyl chloride, keep stirring at 0°C for 3 hours, remove the ice bath, react at room temperature for 18 hours, concentrate, dissolve the residual solid with ethyl acetate, wash with saturated sodium bicarbonate and saturated brine successively, and anhydrous Dry over sodium sulfate, filter, concentrate, and use petroleum ether: acetone: triethylamine = 3: 1: 1% as the developing agent for silica gel (200-300 mesh) column chromatography to obtain a white foamy product, which is 3-declarate Desan-3-oxo-6-O-methyl-11-methanesulfonyl-2'-benzoylerythromycin (0.97 g, 87.2%).

Spectrum analysis of 3-descladinose-3-oxo-6-O-methyl-11-methylsulfonyl-2'-benzoylerythromycin is as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ8. 03(d, J=7.1Hz, 2H), 7.57(m, 1H), 7.46(t, J=7.9Hz, 2H), 5.10(dd, J=10.8, 2.3Hz, 1H), 4.97～5.05(m , 2H), 4.71(s, 1H), 4.57(d, J=7.6Hz, 1H), 4.08(d, J=10.6Hz, 1H), 3.55～3.60(m, 2H), 3.23～3.27(m, 1H), 2.81～2.85(m, 2H), 2.80(s, 3H), 2.44(s, 3H), 2.25(s, 6H), 1.98(s, 1H), 1.89～1.92(m, 1H), 1.76 ～1.82(m, 2H), 1.62～1.66(m, 2H), 1.48(s, 3H), 1.19～1.29(m, 3H), 1.33(s, 3H), 1.26～1.30(m, 12H), 1.01 ~1.10 (m, 6H), 0.81 (t, J=7.3Hz, 3H); MS (m/z): 770 (MH ⁺ ).

Example 8

Preparation of 3-desclardinose-3-hydroxyl-6-O-methyl-11,12 cyclic carbonate erythromycin (as shown in Figure VI)

Dissolve 2g (2.89mmol) of 3-descladinose-3-hydroxy-6-O-methyl-2'-benzoylerythromycin in 27mL of anhydrous dichloromethane, add 1.87mL (23.12mmoL) Anhydrous pyridine, cooled to below 0°C, slowly dropwise added 1.03g of triphosgene dissolved in 5mL of anhydrous dichloromethane solution. After the addition was completed, it was raised to room temperature, and the reaction was stirred for 7h. Cool the reaction solution to below 0°C, slowly add 30mL of cold saturated brine dropwise, separate the organic phase, extract the water phase with (20mL×3) dichloromethane, combine the organic phases, wash with saturated brine, anhydrous sulfuric acid Sodium dry. Filtrate, concentrate, and use petroleum ether: acetone: triethylamine = 5: 1: 1% as the developing agent for silica gel (200-300 mesh) column chromatography to obtain a white foamy product, which is 3-descradinose-3 -Hydroxy-6-O-methyl-11,12 cyclocarbonate erythromycin (1.72 g, 82.9%).

Spectrum analysis of erythromycin 3-descladinose-3-hydroxy-6-O-methyl-11,12 cyclocarbonate is as follows: ¹ HNMR (400MHz, CDCl ₃ ): δ8.06 (d, J=7.8Hz , 2H), 7.56(t, J=7.4Hz, 1H), 7.45(t, J=7.8Hz, 2H), 5.02～5.09(m, 2H), 4.73(d, J=7.6Hz, 1H), 4.68 (s, 1H), 3.72(d, J=2.5Hz, 1H), 3.54～3.60(m, 1H), 3.43～3.48(m, 2H), 2.91(s, 3H), 2.80～2.87(m, 1H) ), 2.54～2.64(m, 2H), 2.28(s, 6H), 1.76～1.89(m, 3H), 1.43～1.51(m, 3H), 1.39～1.41(m, 1H), 1.38(s, 3H ), 1.20～1.32(m, 9H), 1.10～1.17(m, 3H), 1.05(d, J=7.1Hz, 3H), 0.82(t, J=7.4Hz, 3H), 0.70(d, J= 7.5 Hz, 3H); MS (m/z): 720 (MH ⁺ ).

Example 9

Preparation of 3-descladinose-3-oxo-6-O-methyl-11,12 cyclocarbonate erythromycin (as shown in Figure VII)

Dissolve 0.2g (0.28mmol) of 3-desclardinose-3-hydroxy-6-O-methyl-11,12 cyclocarbonate erythromycin in 3mL of anhydrous dichloromethane, add 0.18g (0.85mmol) Pyridinium chlorochromate (PCC), stirred at room temperature for 25h. Stop the reaction, wash with saturated sodium bicarbonate solution and saturated brine respectively, dry over anhydrous sodium sulfate, filter, concentrate, use petroleum ether: acetone: triethylamine = 3: 1: 1% as developing agent silica gel (200-300 eye) column chromatography to obtain a white foamy product, which is erythromycin 3-desclardinose-3-oxo-6-O-methyl-11,12-ring carbonate (0.15 g, 70.7%).

Spectrum analysis of 3-descladinose-3-oxo-6-O-methyl-11,12 cyclocarbonate erythromycin is as follows: ¹ HNMR (400MHz, CDCl ₃ ): δ8.03 (d, J=7.8 Hz, 2H), 7.57(t, J=7.4Hz, 1H), 7.44(t, J=7.8Hz, 2H), 4.95～5.05(m, 2H), 4.60(s, 1H), 4.54(d, J =7.6Hz, 1H), 4.19(d, J=7.8Hz, 1H), 3.59~3.71(m, 2H), 2.80~2.93(m, 3H), 2.64(s, 3H), 2.26(s, 6H) , 1.78～1.85(m, 2H), 1.65(dd, J=14.5, 2.7Hz, 1H), 1.51～1.56(m, 1H), 1.48(s, 3H), 1.25～1.34(m, 9H), 1.17 (d, J=6.8Hz, 3H), 1.13(d, J=7.0Hz, 3H), 0.96(d, J=7.5Hz, 3H), 0.86(t, J=7.4Hz, 3H); MS(m /z): 718 (MH ⁺ ).

Example 10

Preparation of 3-descladinose-3-oxo-6-O-methyl-10,11-dehydro-2'-benzoyl erythromycin (as shown in formula VIII)

1mmol of 3-declarinose-3-oxo-6-O-methyl-11-methanesulfonyl-2'-benzoylerythromycin or 3-declarinose-3-oxo-6- Dissolve O-methyl-11,12 cyclocarbonate erythromycin in 3 mL of acetone, add 2.5 equiv of DBU, reflux for 3 to 5 hours, stop the reaction, evaporate the solvent, dissolve the residual solid in 5 mL of dichloromethane, and wash with saturated Wash with saline solution, dry over anhydrous sodium sulfate, filter, concentrate, and use petroleum ether: acetone: triethylamine = 6: 1: 1% as the developer for silica gel (200-300 mesh) column chromatography to obtain a white foamy product. That is, 3-descladinose-3-oxo-6-O-methyl-10,11-dehydro-2'-benzoylerythromycin (95.6% or 97.6%).

Spectrum analysis of 3-descladinose-3-oxo-6-O-methyl-10,11-dehydro-2'-benzoylerythromycin is as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ8 .01(d, J=8.1Hz, 2H), 7.55(t, J=7.6Hz, 1H), 7.43(t, J=7.6Hz, 2H), 6.55(s, 1H), 4.99～5.04(m, 1H), 4.54(dd, J=9.6, 2.7Hz, 1H), 4.51(d, J=7.6Hz, 1H), 4.15(d, J=8.3Hz, 1H), 3.59～3.64(m, 2H), 3.13～3.16(m, 1H), 2.92～2.96(m, 1H), 2.85(s, 3H), 2.33～2.36(m, 1H), 2.26(s, 6H), 1.99(s, 3H), 1.86～ 1.95(m, 2H), 1.77～1.82(m, 2H), 1.50～1.56(m, 1H), 1.40～1.48(m, 3H), 1.36(s, 3H), 1.26～1.30(m, 9H), 1.15 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 7.4 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); MS (m/z): 674 (MH ⁺ ).

Example 11

3-descladinose-3-oxo-6-O-methyl-10,11-dehydro-12-O-imidazolecarbonyl-2'-benzoyl erythromycin (as shown in formula IX) preparation of

Add 0.25g (6mmol) sodium hydride (60%) to 15mL of anhydrous DMF, cool to -10°C, and add 2g (3mmol) 3-desclardinose-3-oxo-6- O-methyl-10,11-dehydro-2'-benzoyl erythromycin, stirred for 0.5h, added dropwise with 1.56g (9mmol) carbonyldiimidazole dissolved in 15mL DMF solution, at -10℃～-5℃ The reaction was stirred for 2 h, and the reaction was complete as monitored by TLC. Raise the temperature to 0°C, add 50 mL of ice water dropwise, filter with suction, wash the filter cake twice with ice water, dissolve with ether, wash with saturated brine, and dry over anhydrous sodium sulfate. Filtrate, concentrate, and use petroleum ether: acetone: triethylamine = 6: 1: 1% as the developing agent for silica gel (200-300 mesh) column chromatography to obtain a white foamy product, which is 3-descradinose-3 -Oxo-6-O-methyl-10,11-dehydro-12-O-imidazolecarbonyl-2'-benzoylerythromycin (2.05 g, 89.9%).

The spectral analysis of 3-descladinose-3-oxo-6-O-methyl-10,11-dehydro-12-O-imidazolecarbonyl-2′-benzoylerythromycin is as follows: ¹ H NMR (400MHz, CDCl ₃ ): δ8.08(s, 1H), 8.03(d, J=7.1Hz, 2H), 7.56(t, J=7.4Hz, 1H), 7.44(t, J=7.8Hz, 2H ), 7.35～7.36(m, 1H), 7.06～7.07(m, 1H), 6.76(s, 1H), 5.66(dd, J=9.8, 3.2Hz, 1H), 4.99～5.04(m, 1H), 4.51(d, J=7.6Hz, 1H), 4.15(d, J=8.8Hz, 1H), 3.55~3.66(m, 3H), 3.08~3.23(m, 3H), 2.90(s, 1H), 2.80 ～2.97(m, 2H), 2.78(m, 3H), 2.28～2.34(m, 4H), 2.25(s, 6H), 2.17(d, J=3.1Hz, 1H), 1.81(s, 3H), 1.76(s, 3H), 1.59～1.68(m, 4H), 1.40～1.48(m, 3H), 1.36(s, 3H), 1.22～1.35(m, 15H), 1.15(d, J＝6.7Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H),; MS (m/z): 768 (MH ⁺ ).

Example 12

Dissolve 1 mmol of 3-descladinose-3-oxo-6-O-methyl-10,11-dehydro-12-O-imidazolecarbonyl-2'-benzoylerythromycin in 0.5 mL of acetonitrile Add 2 equiv aromatic ring tetrazolidinylamine, stir the reaction at 55°C for 16-25h, stop the reaction, cool to room temperature, add 2mL of ice water, extract three times with ethyl acetate, combine the organic phases, and wash with water, Dry over anhydrous sodium sulfate; filter, concentrate, add 1 mL of methanol to dissolve the residual solid, reflux and stir for 25 hours, concentrate, dissolve with ethyl acetate, wash with saturated sodium bicarbonate solution and saturated brine, anhydrous sodium sulfate, filter, Concentrate, use petroleum ether: acetone: triethylamine = 5: 1: 1% as developing agent silica gel (200～300 mesh) column chromatography, obtain white foamy product, be the ketolide compound of Telithromycin antibiotic 15 (the schematic diagram of the structure is shown in Figure 3). The aromatic ring tetrazolidinylamine is the compound 5 prepared in Example 3. When the aromatic ring tetrazolidinylamine is 5a~5q, different ketolide compounds 15 can be obtained correspondingly: 15a~ 15q.

15a: 3-descradinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(3-(5-(pyridin-2-yl)-1H-tetrazolium-1 -yl)propylimine]erythromycin, yield 57.7%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.76(m, 1H), 8.35(m, 1H), 7.90(m, 1H), 7.42(m, 1H), 5.02～5.11(m, 2H), 4.91(dd, J=10.6, 2.1Hz, 1H), 4.27(d, J=7.3Hz, 1H), 4.20(d, J=8.7Hz , 1H), 3.65～3.82(m, 3H), 3.52～3.56(m, 2H), 3.15～3.20(m, 1H), 3.02～3.09(m, 2H), 2.51(s, 3H), 2.41～2.47 (m, 1H), 2.27(s, 6H), 1.89～1.93(m, 2H), 1.80(dd, J=14.5, 2.3Hz, 1H), 1.66～1.69(m, 1H), 1.52～1.59(m , 2H), 1.45(s, 3H), 1.25～1.33(m, 15H), 1.13(d, J=6.9Hz, 3H), 0.97(d, J=6.9Hz, 3H), 0.82(t, J= 7.3Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ215.8, 203.6, 169.5, 157.1, 151.7, 149.5, 145.1, 137.2, 125.1, 124.5, 103.9, 82.3, 79.6, 78.1, 77.1, 70.3 ,69.6,65.9,60.9,51.1,49.6,47.6,47.5,44.8,41.5,40.2,39.5,38.9,28.2,27.6,22.2,21.1,19.7,18.2,15.7,14.5,14.3,13.8,10.3.MS(m /z): 801.0 (M+H ⁺ ).

15b: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (3-(5-(pyridin-2-yl)-2H-tetrazolium-2 -yl)propylimine]erythromycin, yield 50.2%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.77 (d, J=4.7Hz, 1H), 8.24 (d, J=7.9Hz, 1H), 7.84(ddd, J=7.8, 4.0Hz, 1H), 7.37(m, 1H), 4.95(dd, J=9.7, 2.1Hz, 1H), 4.73～4.86(m, 2H), 4.27(d , J=6.9Hz, 1H), 4.20(d, J=8.8Hz, 1H), 3.78~3.85(m, 2H), 3.65~3.70(m, 1H), 3.51~3.57(m, 2H), 3.15~ 3.18(m, 1H), 3.00～3.12(m, 2H), 2.58(s, 3H), 2.35～2.54(m, 1H), 2.27(s, 6H), 1.93～1.98(m, 2H), 1.79( dd, J=13.4, 2.2Hz, 1H), 1.66~1.69(m, 1H), 1.56~1.59(m, 2H), 1.46(s, 3H), 1.34(d, J=6.8Hz, 3H), 1.24 ～1.29(m, 12H), 1.13(d, J=6.9Hz, 3H), 1.00(d, J=6.9Hz, 3H), 0.88(t, J=7.3Hz, 3H); ¹³ C-NMR (400MHz , CDCl ₃ ): δ215.9, 203.6, 169.6, 164.7, 157.1, 150.2, 147.0, 136.9, 124.5, 122.5, 103.9, 82.3, 79.6, 78.1, 77.2, 70.3, 69.5, 65.9, 60.8, 51.2, 51.1, , 47.6, 44.8, 40.2, 41.5, 40.2, 39.5, 38.9, 28.2, 27.1, 22.2, 21.1, 19.6, 18.2, 15.7, 14.5, 14.3, ^13.8 , 10.3.

15c: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(3-(5-(pyridin-3-yl)-2H-tetrazolium-2 -yl)propylimine]erythromycin, yield 55.8%, ¹ H NMR (400MHz, CDCl ₃ ): δ9.38(s, 1H), 8.69(d, J=4.1Hz, 1H), 8.43( d, J=7.9Hz, 1H), 7.40~7.43(m, 1H), 4.95(d, J=8.7Hz, 1H), 4.71~4.83(m, 2H), 4.26(d, J=7.3Hz, 1H ), 4.20(d, J=8.8Hz, 1H), 3.82～3.87(m, 2H), 3.67～3.76(m, 1H), 3.51～3.57(m, 2H), 3.15～3.19(m, 1H), 2.99～3.13(m, 1H), 2.56(s, 3H), 2.37～2.51(m, 1H), 2.27(s, 6H), 1.93～1.97(m, 1H), 1.78～1.82(m, 1H), 1.66～1.69(m, 1H), 1.56～1.61(m, 2H), 1.47(s, 3H), 1.35(d, J=6.8Hz, 3H), 1.21～1.29(m, 12H), 1.14(d, J=6.9Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.88(t, J=7.3Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.5, 169.7 , 162.8, 157.1, 151.0, 148.2, 134.2, 123.9, 123.5, 103.9, 82.3, 79.6, 78.1, 77.2, 70.3, 69.5, 65.8, 60.7, 51.2, 51.1, 49.6, 47.6, 44.8, 41.3, 90.3, 8.9 , 28.2, 27.1, 22.2, 21.1, 19.5, 18.2, 15.7, 14.5, 14.3, 13.8, 10.3. MS (m/z): 801.0 (MH ⁺ ).

15d: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (3-(5-(pyridin-4-yl)-2H-tetrazolium-2 -yl)propylimine]erythromycin, yield 49.5%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.75 (d, J=4.4Hz, 2H), 8.03 (d, J=5.8Hz, 2H), 4.95(dd, J=10.6, 2.3Hz, 1H), 4.73～4.83(m, 2H), 4.26(d, J=7.3Hz, 1H), 4.19(d, J=8.9Hz, 1H), 3.80～3.85(m, 2H), 3.64～3.71(m, 1H), 3.51～3.55(m, 2H), 3.01～3.20(m, 3H), 2.55(s, 3H), 2.37～2.51(m, 1H) ), 2.29(s, 6H), 1.94～1.98(m, 1H), 1.78～1.81(m, 1H), 1.67～1.69(m, 1H), 1.55～1.61(m, 2H), 1.47(s, 3H ), 1.35(d, J=6.8Hz, 3H), 1.22～1.29(m, 12H), 1.14(d, J=6.9Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.87(t , J=7.4Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.6, 169.7, 163.1, 157.2, 150.5, 135.0, 120.9, 103.9, 82.4, 79.6, 78.2, 77.3, 70.3, MS(m/ z): 801.0(MH ⁺ ).

15e: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(4-(5-(pyridin-2-yl)-1H-tetrazolium-1 -yl)butylimine]erythromycin, yield 60.1%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.78(d, J=4.8Hz, 1H), 8.35(d, J=7.5Hz, 1H), 7.89(t, J=7.8Hz, 1H), 7.44(m, 1H), 4.96～5.08(m, 2H), 4.91(d, J=10.5Hz, 1H), 4.29(d, J=7.3 Hz, 1H), 4.24(d, J=8.7Hz, 1H), 3.83～3.88(m, 1H), 3.64～3.76(m, 2H), 3.53～3.58(m, 2H), 3.03～3.21(m, 3H), 2.61(s, 3H), 2.43～2.48(m, 1H), 2.27(s, 6H), 1.91～2.04(m, 3H), 1.67～1.84(m, 4H), 1.52～1.62(m, 2H), 1.47(s, 3H), 1.24～1.38(m, 15H), 1.16(d, J=6.8Hz, 3H), 1.01(d, J=6.8Hz, 3H), 0.83(t, J=7.3 Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ215.9, 203.6, 169.5, 157.1, 151.5, 149.6, 144.9, 137.2, 125.1, 124.4, 103.9, 82.1, 79.5, 78.1, 77.1, 70.3, MS( m/z): 815.0(MH ⁺ ).

15f: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (4-(5-(pyridin-2-yl)-2H-tetrazolium-2 -yl)butylimine]erythromycin, yield 51.5%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.78(d, J=4.7Hz, 1H), 8.24(d, J=7.9Hz, 1H), 7.86(ddd, J=7.8, 1.7Hz, 1H), 7.37(m, 1H), 4.94(dd, J=10.6, 2.1Hz, 1H), 4.71～4.81(m, 2H), 4.28(d , J=7.3Hz, 1H), 4.23(d, J=8.3Hz, 1H), 3.83(q, J=6.8Hz, 1H), 3.63~3.77(m, 2H), 3.51~3.58(m, 2H) , 3.04～3.21(m, 3H), 2.62(s, 3H), 2.47(m, 1H), 2.28(s, 6H), 2.11～2.17(m, 2H), 1.83～1.97(m, 1H), 1.55 ～1.82(m, 6H), 1.47(s, 3H), 1.23～1.34(m, 15H), 1.16(d, J=7.0Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.87( t, J=7.3Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.6, 169.6, 164.7, 157.2, 150.2, 147.0, 136.9, 124.6, 122.4, 103.9, 82.2, 79.6, 78.1 , 77.3, 70.3, 69.5, 65.9, 52.9, 51.2, 49.8, 47.5, 44.8, 42.6, 40.2, 39.5, 39.0, 28.2, 26.8, 24.1, 22.2, 21.1, 19.7, 18.3, 15.6, 14.6, 14.3, 13.8, 10.4 .MS (m/z): 815.0 (MH ⁺ ).

15g: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(4-(5-(pyridin-3-yl)-2H-tetrazolium-2 -yl)butylimine]erythromycin, yield 65.7%, ¹ H NMR (400MHz, CDCl ₃ ): δ9.36(s, 1H), 8.69(d, J=4.1Hz, 1H), 8.41( dt, J=7.9, 1.7Hz, 1H), 7.40~7.43(m, 1H), 4.95(dd, J=10.5, 1.8Hz, 1H), 4.69~4.74(m, 2H), 4.27(d, J= 7.3Hz, 1H), 4.20(d, J=8.8Hz, 1H), 3.64～3.85(m, 3H), 3.49～3.56(m, 2H), 3.03～3.19(m, 3H), 2.61(s, 3H) ), 2.41～2.47(m, 1H), 2.26(s, 6H), 2.07～2.15(m, 2H), 1.93～1.98(m, 1H), 1.54～1.83(m, 7H), 1.46(s, 3H ), 1.23～1.33(m, 15H), 1.15(d, J=6.9Hz, 3H), 1.00(d, J=6.9Hz, 3H), 0.86(t, J=7.2Hz, 3H); ¹³ C- NMR (400MHz, CDCl ₃ ): δ216.1, 203.6, 169.6, 162.7, 157.3, 151.0, 148.2, 134.2, 123.9, 123.6, 104.0, 82.2, 79.6, 78.2, 70.4, 69.6, 65.9, 60.4, 52.9, 51.2, 49.8, 47.5, 44.5, 42.6, 40.2, 39.6, 39.0, 28.2, 26.8, 24.2, 22.2, 21.2, 19.7, 18.4, 15.6, 14.6, 14.3, 13.9, 10.4. MS (m/z): 814.9 (MH ⁺ ) .

15h: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (4-(5-(pyridin-4-yl)-2H-tetrazolium-2 -yl)butylimine]erythromycin, yield 74.1%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.75(d, J=5.3Hz, 2H), 8.02(d, J=5.4Hz, 2H), 4.92(d, J=9.7, Hz, 1H), 4.70～4.79(m, 2H), 4.28(d, J=7.3Hz, 1H), 4.23(d, J=8.7Hz, 1H), 3.74 ～3.86(m, 2H), 3.63～3.70(m, 1H), 3.52～3.56(m, 2H), 3.03～3.20(m, 3H), 2.61(s, 3H), 2.44～2.49(m, 1H) , 2.27(s, 6H), 2.06～2.15(m, 2H), 1.93～1.98(m, 1H), 1.80～1.84(m, 1H), 1.66～1.75(m, 2H), 1.53～1.62(m, 2H), 1.47(s, 3H), 1.24～1.37(m, 15H), 1.15(d, J=6.9Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.86(t, J=7.4 Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.1, 203.5, 169.6, 162.9, 157.2, 150.5, 135.0, 120.8, 103.9, 82.2, 79.5, 78.2, 70.3, 69.9, 65.9, 60.4, 52.9, 51.1, 49.7, 47.5, 44.8, 42.6, 40.2, 39.5, 38.9, 28.2, 26.7, 24.1, 22.2, 21.1, 19.7, 18.3, 15.6, 14.6, 14.3, 13.8, 10.4. MS (m/z): 814.9 (MH ⁺ ).

15i: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(5-(5-(pyridin-2-yl)-1H-tetrazolium-1 -yl)pentylimine]erythromycin, yield 53.0%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.77(d, J=4.8Hz, 1H), 8.35(d, J=8.0Hz, 1H), 7.89(dt, J=1.7, 7.8Hz, 1H), 7.44(m, 1H), 4.91～4.99(m, 3H), 4.28(d, J=7.3Hz, 1H), 4.24(d, J =8.6Hz, 1H), 3.84(q, J=6.7Hz, 1H), 3.50~3.64(m, 4H), 3.16~3.20(m, 1H), 3.05~3.14(m, 2H), 2.62(s, 3H), 2.42～2.49(m, 1H), 2.27(s, 6H), 1.93～2.00(m, 3H), 1.82(dd, J=14.5, 2.3Hz, 1H), 1.55～1.69(m, 5H) , 1.46(s, 3H), 1.24～1.38(m, 15H), 1.16(d, J=7.0Hz, 3H), 1.00(d, J=6.9Hz, 3H), 0.85(t, J=7.3Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.7, 169.5, 157.1, 151.6, 149.6, 145.0, 137.3, 125.1, 124.5, 103.9, 82.1, 79.5, 78.1, 77.2, 70.3, 69.6, MS( m/z): 829.1(MH ⁺ ).

15j: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(5-(5-(pyridin-2-yl)-2H-tetrazolium-2 -yl)pentylimine]erythromycin, yield 57.6%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.78 (dJ=4.7Hz, 1H), 8.24 (d, J=7.9Hz, 1H) , 7.86(ddd, J=7.8, 1.7Hz, 1H), 7.38(m, 1H), 4.94(dd, J=10.5, 2.2Hz, 1H), 4.68～4.72(m, 2H), 4.28(d, J =7.3Hz, 1H), 4.25(d, J=8.6Hz, 1H), 3.83(m, 1H), 3.52～3.65(m, 4H), 3.06～3.21(m, 3H), 2.65(s, 3H) , 2.44～2.49(m, 1H), 2.28(s, 6H), 2.11～2.16(m, 2H), 1.93～1.96(m, 1H), 1.81(dd, J=14.5, 2.1Hz, 1H), 1.54 ～1.70(m, 5H), 1.47(s, 3H), 1.21～1.35(m, 15H), 1.08(d, J=7.0Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.86( t, J=7.4Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.7, 169.6, 164.7, 157.2, 150.3, 147.0, 137.0, 124.6, 122.4, 103.9, 82.1, 79.6, 78.1 , 77.2, 70.3, 69.6, 65.9, 60.5, 53.4, 51.2, 49.8, 47.5, 44.9, 43.2, 40.2, 39.5, 39.0, 29.0, 28.2, 26.5, 23.8, 22.3, 21.2, 19.7, 18.4, 15.6, 14.4, 14.3 , 13.9, 10.4. MS (m/z): 829.1 (MH ⁺ ).

15k: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (5-(5-(pyridin-3-yl)-2H-tetrazolium-2 -yl)pentylimine]erythromycin, yield 50.9%, ¹ H NMR (400MHz, CDCl ₃ ): δ9.38(s, 1H), 8.70(d, J=4.8Hz, 1H), 8.43( dt, J=8.0, 1.9Hz, 1H), 7.41~7.45(m, 1H), 4.94(dd, J=10.5, 2.3Hz, 1H), 4.65~4.72(m, 2H), 4.28(d, J= 7.3Hz, 1H), 4.24(d, J=8.7Hz, 1H), 3.85(q, J=6.8Hz, 1H), 3.50~3.70(m, 4H), 2.99~3.21(m, 3H), 2.65( s, 3H), 2.41～2.47(m, 1H), 2.28(s, 6H), 2.08～2.16(m, 2H), 1.93～1.98(m, 1H), 1.54～1.83(m, 6H), 1.46( s, 3H), 1.23～1.33(m, 15H), 1.16(d, J=7.0Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.85(t, J=7.4Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.1, 203.7, 169.6, 162.7, 157.2, 151.0, 148.1, 134.2, 123.8, 123.6, 103.9, 82.2, 79.6, 78.2, 70.3, 69.6, 65.9, 60.5, 53.3 , 51.2, 49.8, 47.5, 44.5, 43.2, 40.2, 39.5, 39.0, 28.9, 28.2, 26.4, , 23.7, 22.2, 21.2, 19.7, 18.4, 15.7, 14.6, 14.3, 13.9, 10.3.MS(m/z) : 829.1(MH ⁺ ).

15l: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (5-(5-(pyridin-4-yl)-2H-tetrazolium-2 -yl)pentylimine]erythromycin, yield 55.6%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.76(d, J=4.8Hz, 2H), 8.02(d, J=4.8Hz, 2H), 4.93(d, J=10.2, Hz, 1H), 4.66～4.73(m, 2H), 4.28(d, J=7.3Hz, 1H), 4.24(d, J=8.7Hz, 1H), 3.82 ～3.87(m, 1H), 3.52～3.69(m, 4H), 3.05～3.21(m, 3H), 2.65(s, 3H), 2.44～2.50(m, 1H), 2.32(s, 6H), 2.10 ～2.18(m, 2H), 1.92～1.98(m, 1H), 1.81～1.84(m, 1H), 1.52～1.72(m, 5H), 1.47(s, 3H), 1.24～1.36(m, 15H) , 1.16(d, J=7.0Hz, 3H), 1.01(d, J=6.8Hz, 3H), 0.85(t, J=7.4Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216. 1, 203.7, 169.6, 162.7, 157.1, 150.5, 134.9, 120.8, 103.9, 82.2, 79.5, 78.1, 77.2, 70.3, 69.5, 65.8, 60.4, 53.3, 51.2, 49.7, 47.5, 44.9, 43.3, 40.2, 39.0, 28.8, 28.2, 26.4, 23.7, 22.2, 21.1, 19.7, 18.3, 15.7, 14.6, 14.3, 13.8, 10.4. MS (m/z): 829.1 (MH ⁺ ).

15m: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(3-(5-phenyl-2H-tetrazol-2-yl)propyl Imine] erythromycin, yield 45.2%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.14-8.16 (m, 21H), 7.41-7.49 (m, 3H), 4.95 (dd, J=10.5, 2.1Hz, 1H), 4.70～4.78(m, 2H), 4.26(d, J=7.3Hz, 1H), 4.18(d, J=8.8Hz, 1H), 3.79～3.85(m, 2H), 3.67～ 3.72(m, 1H), 3.57(s, 1H), 3.51～3.54(m, 1H), 3.01～3.18(m, 3H), 2.55(s, 3H), 2.37～2.46(m, 2H), 2.26( s, 6H), 1.93~1.98(m, 1H), 1.79(dd, J=14.5, 2.2Hz, 1H), 1.51~1.68(m, 3H), 1.47(s, 3H), 1.35(d, J= 6.8Hz, 3H), 1.21～1.31(m, 12H), 1.13(d, J=6.9Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.87(t, J=7.3Hz, 3H) ; ¹³ C-NMR (400MHz, CDCl ₃ ): δ215.9, 203.6, 169.6, 165.1, 157.2, 130.0, 128.7, 127.7, 126.0, 103.9, 82.4, 79.6, 78.1, 77.2, 70.3, 69.6, 65.9, 60.8, 51.2, 50.9, 49.7, 47.6, 44.8, 41.5, 40.2, 39.5, 38.9, 29.7, 28.2, 27.1, 22.2, 21.1, 19.5, 18.2, 15.8, 14.5, 14.3, 13.8, 10.3. MS (m/z): 799.9 (MH ⁺ ).

15n: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (4-(5-phenyl-2H-tetrazol-2-yl)butyl) Imine] erythromycin, yield 61.4%, ¹ H NMR (400MHz, CDCl ₃ ): δ8.13～8.15(d, J=7.9Hz, 2H), 7.42～7.50(m, 3H), 4.95(dd , J=10.2, 2.2Hz, 1H), 4.65～4.74(m, 2H), 4.28(d, J=7.3Hz, 1H), 4.24(d, J=8.7Hz, 1H), 3.79～3.90(m, 1H), 3.73～3.81(m, 1H), 3.63～3.71(m, 1H), 3.58(s, 1H), 3.52～3.54(m, 1H), 3.03～3.18(m, 3H), 2.64(s, 3H), 2.58～2.59(m, 1H), 2.43～2.49(m, 1H), 2.27(s, 6H), 2.08～2.15(m, 2H), 1.93～1.98(m, 1H), 1.81(dd, J=14.5, 2.3Hz, 1H), 1.66～1.76(m, 3H), 1.53～1.62(m, 2H), 1.47(s, 3H), 1.18～1.31(m, 15H), 1.15(d, J= 7.0Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.86(t, J=7.3Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.6, 169.6, 165.0 , 157.2, 130.0, 128.8, 127.7, 126.9, 103.9, 82.2, 79.6, 78.2, 77.2, 70.3, 69.6, 65.9, 60.4, 52.7, 51.2, 49.8, 47.5, 44.9, 42.7, 40.2, 39.6, 39.02, 29.7 , 26.8, 24.2, 22.2, 21.1, 19.7, 18.4, 15.6, 14.6, 14.4, 13.9, 10.4. MS (m/z): 813.8 (MH ⁺ ).

15o: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (3-(5-(thiophen-2-yl)-2H-tetrazolium-2 -yl)propylimine]erythromycin, yield 52.6%, ¹ H NMR (400MHz, CDCl ₃ ): δ7.79 (d, J=3.6Hz, 1H), 7.43 (d, J=5.1Hz, 1H), 7.13(d, J=4.3Hz, 1H), 4.95(dd, J=10.6, 2.1Hz, 1H), 4.69～4.75(m, 2H), 4.27(d, J=7.3Hz, 1H), 4.20(d, J=8.8Hz, 1H), 3.77～3.85(m, 2H), 3.65～3.70(m, 1H), 3.52～3.57(m, 2H), 3.16～3.20(m, 1H), 3.02～ 3.10(m, 2H), 2.57(s, 3H), 2.34～2.41(m, 2H), 2.29(s, 6H), 1.93～1.99(m, 1H), 1.79(dd, J=14.5, 2.2Hz, 1H), 1.67～1.70(m, 1H), 1.52～1.61(m, 2H), 1.47(s, 3H), 1.34(d, J=6.8Hz, 3H), 1.17～1.31(m, 12H), 1.14 (d, J=7.0Hz, 3H), 1.01 (d, J=6.9Hz, 3H), 0.82 (t, J=7.3Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ215.9, 203.6, 169.5, 161.2, 157.2, 129.4, 127.7, 127.6, 127.5, 103.9, 82.4, 79.6, 78.1, 70.3, 69.5, 65.9, 60.8, 51.2, 51.0, 49.7, 47.6, 44.8, 41.5, 90.3, 8.39 28.2, 27.1, 22.2, 21.1, 19.5, 18.2, 15.7, 14.6, 14.4, 13.8, 10.3. MS (m/z): 805.9 (MH ⁺ ).

15p: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl(4-(5-(thiophen-2-yl)-2H-tetrazolium-2 -yl)butylimine]erythromycin, yield 56.4%, ¹ H NMR (400MHz, CDCl ₃ ): δ7.79 (d, J=3.5Hz, 1H), 7.43 (d, J=5.0Hz, 1H), 7.13(d, J=4.3Hz, 1H), 4.95(dd J=10.6, 2.0Hz, 1H), 4.65～4.70(m, 2H), 4.28(d, J=7.3Hz, 1H), 4.20 (d, J=8.7Hz, 1H), 3.54~3.85(m, 4H), 3.06~3.20(m, 4H), 264(s, 3H), 2.45(m, 1H), 2.27(s, 6H), 2.08～2.11(m, 2H), 1.95～1.97(m, 1H), 1.81(dd, J=14.6, 2.3Hz, 1H), 1.66～1.74(m, 3H), 1.55～1.62(m, 2H), 1.47(s, 3H), 1.21～1.34(m, 15H), 1.16(d, J=6.9Hz, 3H), 1.01(d, J=6.9Hz, 3H), 0.85(t, J=7.3Hz, 3H ); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.6, 169.6, 161.1, 157.3, 129.3, 127.8, 127.6, 127.5, 103.9, 82.2, 79.6, 78.1, 77.2, 70.3, 69.6, 65.9, 60.4 , 52.7, 51.2, 49.8, 47.5, 44.9, 42.6, 40.2, 39.5, 38.9, 29.7, 28.2, 26.8, 24.1, 22.2, 21.1, 19.7, 18.3, 15.6, 14.6, 14.3, 13.9, 10.4.MS(m/z ): 820.0(MH ⁺ ).

15q: 3-descladinose-3-oxo-6-O-methyl-11,12-[oxycarbonyl (4-(5-(furan-2-yl)-2H-tetrazolium-2 -yl)butylimine]erythromycin, yield 57.7%, ¹ H NMR (400MHz, CDCl ₃ ): δ7.59 (d, J=3.5Hz, 1H), 7.43 (d, J=5.0Hz, 1H), 7.13(d, J=4.3Hz, 1H), 4.93(dd J=10.6, 2.2Hz, 1H), 4.65～4.75(m, 2H), 4.28(d, J=7.3Hz, 1H), 4.24 (d, J=8.7Hz, 1H), 3.84(q, J=6.8Hz, 1H), 3.63～3.78(m, 3H), 3.57(s, 1H), 3.51～3.56(m, 1H), 3.04～ 3.20(m, 3H), 2.63(s, 3H), 2.44～2.47(m, 1H), 2.27(s, 6H), 2.09～2.12(m, 2H), 1.94～1.97(m, 1H), 1.81( dd, J=14.5, 2.3Hz, 1H), 1.65～1.74(m, 3H), 1.55～1.62(m, 2H), 1.47(s, 3H), 1.21～1.34(m, 15H), 1.16(d, J=6.9Hz, 3H), 1.01(d, J=7.0Hz, 3H), 0.87(t, J=7.3Hz, 3H); ¹³ C-NMR (400MHz, CDCl ₃ ): δ216.0, 203.6, 169.6 , 158.2, 157.2, 144.0, 143.1, 111.6, 111.1, 103.9, 82.2, 79.6, 78.1, 70.3, 69.6, 65.9, 60.4, 52.8, 51.2, 49.8, 47.5, 44.9, 40.2, 39.0, 26.8, 21.1, 217. , 18.3, 15.6, 14.6, 14.3, 13.9, 10.4. MS (m/z): 803.7 (MH ⁺ ).

The synthetic routes of the ketolide compounds of the telithromycin-like antibiotics described in Examples 4 to 12 are shown in FIG. 2 .

Example 13 Identification of the antibacterial activity of the ketolide compound compound 15a～q of the present invention

Inhibitory concentration (MIC) was determined by broth microdilution method:

(1) Dissolve the new compound and dilute it to prepare different concentrations of liquid medicine, filter the membrane to sterilize, and store it at -60°C;

(2) Add 100 μL of drug solutions of different concentrations after doubling dilution into a sterilized 96-well plate, and add samples from low concentration to high concentration;

(3) Select 18-24 hour colonies and place them in M-H broth for 4-6 hours. Prepare a 0.5 McFarland turbidimetric tube, and then dilute it 1:200 to make the final concentration 105CFU/mL; inoculate 100μL of the diluted bacterial solution into 96 wells with a micro-injector (completely add within 15 minutes), and make a positive test at the same time , Negative control, cover with a cover plate, place in an incubator at 37°C and incubate for 20-24 hours;

(4) Manually read the results of the turbidity interpretation test. The lowest concentration of antibacterial drug at which the bottom of the hole is clear and no bacterial precipitation occurs is the minimum inhibitory concentration of the antibacterial drug on bacteria, and the MIC is obtained. Parallel experiments were performed three times. The results are shown in Table 1.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (6)

1. the antibiotic ketolide compound of a kind Ketek is characterized in that having following structural formula:

Wherein n is 1,2 or 3, and R is

2. the preparation method of the antibiotic ketolide compound of a kind Ketek according to claim 1 is characterized in that comprising following operation steps:

(1) clarithromycin I, water and ethanol are at room temperature stirred, temperature is reduced to 0 ℃, stirs under the dripping hydrochloric acid, room temperature, and temperature is reduced to 5 ℃, regulates pH to 10.5～11.0, stirs, filter, and washing, drying obtains Compound I I;

(2) dichloromethane solution, benzoyl oxide, anhydrous triethylamine and the 5-dimethyl aminopyridine with Compound I I reacts in ice bath, adds saturated sodium bicarbonate again, separatory, and washing, drying is filtered, and concentrates, and column chromatography obtains compound III;

(3) drip dimethyl sulphide in the dichloromethane solution of N-chlorosuccinimide, drip compound III again, the dichloromethane solution that drips triethylamine then reacts, and drying is filtered, and concentrates, and column chromatography obtains compound IV; Under-5～0 ℃ of condition, in the pyridine solution of compound IV, drip methylsulfonyl chloride, reaction finishes after scouring, and drying is filtered, and concentrates, and column chromatography obtains compound V;

Or in the dichloromethane solution of compound III, adding pyridine, the cooling back drips triphosgene and methylene dichloride, rises to room temperature and reacts; Be cooled to below 0 ℃, add saturated aqueous common salt and carry out separatory, washing, drying is filtered, and concentrates, and column chromatography obtains compound VI; The dichloromethane solution and the pyridinium chloro-chromate of compound VI are at room temperature reacted, washing, drying is filtered, and concentrates, and column chromatography obtains compound VI I;

(5) compound V or compound VI I are dissolved in acetone, add diazabicylo, back flow reaction; Evaporation removes and desolvates, washing, and drying is filtered, and concentrates, and column chromatography obtains compound VIII;

(5) dimethyl formamide solution with sodium hydride is cooled to-10 ℃, adds compound VIII under the shielding gas atmosphere, drips the dimethyl formamide solution of carbonyl dimidazoles, at-10 ℃～-5 ℃ following stirring reactions, washing, drying, filter, concentrate, obtain Compound I X;

(6) Compound I X is dissolved in acetonitrile, adds aromatic ring and connect the tetrazolium alkylamine, in 55 ℃ of following stirring reactions, cooling, add frozen water, use ethyl acetate extraction, concentrate gained residual solid dissolve with methanol after filtration, back flow reaction, concentrate, washing is filtered, column chromatography obtains the antibiotic ketolide compound of class Ketek;

The structural formula of I, II, III, IV, V, VI, VII, VIII and IX wherein:

3. the antibiotic ketolide compound of a kind Ketek according to claim 1, it is characterized in that: described aromatic ring connects the tetrazolium alkylamine and prepares according to the following steps:

(1) the aryl nitrile is dissolved in N, in the dinethylformamide, adds sodiumazide and ammonium chloride successively under stirring; In nitrogen atmosphere, under the oil bath condition, react; Be cooled to room temperature, separatory is regulated pH to 5～5, leaves standstill after the stirring, separates out crystal; Suction filtration, mother liquor are placed on the frozen water cooling, continue to have crystal to separate out, and merge above-mentioned gained crystal, and washing obtains aromatic ring and connects tetrazolium A;

Or aryl formaldehyde is dissolved in the mixing solutions of ammoniacal liquor and tetrahydrofuran (THF), add iodine, stir, add hypo solution, extraction, drying is filtered, and it is water-soluble to concentrate the back, add sodium azide and zinc bromide, back flow reaction adds hydrochloric acid and ethyl acetate, stirring and dissolving is isolated organic phase, the water ethyl acetate extraction, concentrate, add sodium hydroxide solution again, filter, filtrate is regulated pH to 5～5, leave standstill, separate out crystal; Suction filtration, mother liquor are placed on the frozen water cooling, continue to have crystal to separate out, and merge above-mentioned gained crystal, and washing obtains aromatic ring and connects tetrazolium B;

(2) aromatic ring is connected tetrazolium A or aromatic ring and connect tetrazolium B and be dissolved in N, in the dinethylformamide, add salt of wormwood and N-(3-bromopropyl) phthalic imidine successively, under nitrogen protection, react; After reaction finishes, in reaction solution impouring frozen water, filter, washing, column chromatography obtains the N-aromatic ring and connects the tetrazolium alkyl phthalic imide;

(3) the N-aromatic ring is connected in the mixing solutions that the tetrazolium alkyl phthalic imide is dissolved in dehydrated alcohol and acetonitrile, add a hydrazine hydrate, heating reflux reaction; Reaction is cooled to room temperature after finishing; Filter, washing, the evaporative removal solvent, resistates adds sodium hydroxide solution, uses dichloromethane extraction again, merges organic phase, washing, drying, column chromatography obtains aromatic ring and connects the tetrazolium alkylamine.

4. the antibiotic ketolide compound of a kind Ketek according to claim 3, it is characterized in that: described aryl nitrile is

5. the antibiotic ketolide compound of a kind Ketek according to claim 3, it is characterized in that: described aryl formaldehyde is

6. the antibiotic ketolide compound of a kind Ketek according to claim 1 is applied to prepare antibacterials.

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