CN1676529A - Macrilides ketolide compound, and its preparing method and use - Google Patents
Macrilides ketolide compound, and its preparing method and use Download PDFInfo
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- CN1676529A CN1676529A CN 200510066277 CN200510066277A CN1676529A CN 1676529 A CN1676529 A CN 1676529A CN 200510066277 CN200510066277 CN 200510066277 CN 200510066277 A CN200510066277 A CN 200510066277A CN 1676529 A CN1676529 A CN 1676529A
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Abstract
This invention provides a ketone lactone compound of macrolides antibiotics, and this chemical compound has formula III structure: R is selected from H, C1-6 alkyl, nitryl, C1-6 alkoxyl, halogen and C1-6 alkylogen; and the making method and its antibiotics utilization.
Description
Technical field
The present invention relates to a kind of ketolide compound of novel macrolide antibiotics, specifically, be that a class 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-aryl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-erythromycin and preparation method thereof and this compounds are as the purposes of antibacterials.
Background technology
Macrolide antibiotics is in existing half a century of clinical application.As representative, erythromycin is that Mcguire separated from the streptothrix rubra fermented liquid in nineteen fifty-two, is widely used in the treatment of clinical severe infection.As a clinical line medication, its superiority is quite obvious, cost is low, convenient oral, has a broad antifungal spectrum, in-vivo tissue distribute, the tissue concentration height, advantage such as chlamydia, mycoplasma, legionella, helicobacter pylori, bird type Mycobacterium tuberculosis, some spirochete and the parasitic effect of part microorganism be stronger in addition.As drug-fast staphylococcus aureus and hemolytic streptococcal infection treatment choice drug, nearly 50 years of clinical application has been brought into play important effect to the treatment of infection of respiratory system disease, paediatrics, internal medicine, other system.But side effects such as bioavailability is low, GI irritation that erythromycin has, in hydrochloric acid in gastric juice, erythromycin is influenced by acidic conditions to be degraded into the by product of non-activity, and these materials directly cause producing low, the GI irritation of bioavailability.Therefore, launched a large amount of structure of modification research, caused the birth of s-generation macrolide antibiotics for improving the macrolide acid acceptance.
The representative medicine of s-generation macrolide antibiotics has clarithromycin, Roxithromycin, Azythromycin, dirithromycin etc., aspect acid acceptance, be improved, anti-microbial activity strengthens, improved pharmacokinetic property, prolong half-life, side effects such as GI irritation are obviously reduced, and so far, are widely used in clinical as anti-infective main medicine.But s-generation macrolide antibiotics does not improve the inhibition activity to the macrolide resistant organism, thereby along with resistant organism increases rapidly, s-generation macrolide antibiotics is faced with new challenges.
1. erythromycin 2. clarithromycins
3. Azithromycin 4. Roxithromycin
5. Flurithromycin 6. dirithromycins
In addition, also have erythromycin carbonic ether, amber acetyl erythromycin (erythromycin ethylsuccinate), erythromycin lactobionate, erythromycin estolate, erythromycin octadecanoate etc., these medicines mostly are better than erythromycin at medicine for aspects such as character, activity, side effects, reduce inactivation in the stomach, for important effect has been brought into play in clinical anti-infectious treatment.But the bacterial resistance problem is on the rise, and the drug-resistant intensity of clinical medicine is quite severe, and the side effects such as gastrointestinal irritation of erythromycin simultaneously also fundamentally do not solve.
Begin the nineties in last century, improving its side effect, increasing, reducing on the working foundation of GI irritation acid acceptance, at strengthening a large amount of work has been done in aspects such as macrolide resistant organism inhibition activity, expansion antimicrobial spectrum, synthesized third generation macrolide antibiotics-ketone lactone.Such antibiotic typical structure feature is that the 3-cladinosyl group is by the 3-carbonyl substituted, not only the gram-positive microorganism to the erythromycin series antibiotic sensitive has the active effect of good restraining, and the inducibly resistant microorganism of tRNA methylase of Erm (B) genes encoding is had very strong restraining effect.Represent the exploitation of medicine such as Hoechst marion Roussel company, a novel ketone lactone of the Ketek (Telithromycin) of calendar year 2001 listing and the exploitation of U.S. Abbott company, be in clinical match erythromycin (Cethromycin of III phase, ABT-773), it is oral, and renal toxicity and spasm fall out effect etc. are minimum; Various toxicity test display security height; Clearance rate height to anerobe and gram positive organism; Tolerance is good; Side effect is low, and comparatively significant side effects is diarrhoea and vomiting, and other side effect is more rare.
The ketolide compound of macrolide antibiotics becomes carbonyl with the cladinose of C-3 position, to the streptococcus pneumoniae of erythromycin-sensitive or clinical isolating Mef of having or Erm type, to erythromycin-sensitive or inducibly resistant streptococcus aureus, enterococcus faecalis of erythromycin-sensitive or medium sensitivity etc. is all had strong anti-microbial effect.Improved the inhibition activity of the Resistant strain that mediation is brought out to Erm, simultaneously bringing out property macrolide has been become non-bringing out property macrolide, improved the Resistant strain of Mef efflux pump mediation such as the inhibition activity of streptococcus pneumoniae, streptococcus pyogenes etc.Aryl is introduced in the 6-O position, and 11, when connecting aryl on the nitrogen-atoms in the 12-cyclic carbramates, active increasing; Strengthened the affinity ability of ketone lactone, reduced the possibility of bringing out Erm (B) the rrna residue that methylates.On chemical structure, 11, the 12-cyclic carbramates has been stablized the skeleton of ketone lactone, and cyclic carbramates group and rrna have direct interaction simultaneously, and erythromycin-sensitive and resistant micro-organism are all had stronger anti-microbial activity.
Ketek (Telithromycin) match erythromycin (Cethromycin)
Microbiotic and antiseptic-germicide resistant organism are increasing rapidly, the appearance of the faecalis of methicillin-resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis, anti-mould parapneumonia suis, vancomycin resistance etc., the chemical sproof quick growth of streptococcus pneumoniae, the multidrug resistant problem occurs, the acquired respiratory tract infection of resistance and multidrug resistant streptococcus pneumoniae community such as penicillin, Macrolide, Trimethyl phosphate-sulfamethoxazole, tetracyclines, fluoroquinolone and paraxin are rising year by year, and multidrug resistant mycobacterium tuberculosis infection is on the rise.Many microbiotic significantly subtract effect because of resistance.Therefore be necessary to accelerate new antibiotic research, the compound that design and screening have new chemical structure improves the macrolide resistant organism is suppressed active, solves the multidrug resistant problem, and the clinical more efficient drug that provides is provided.
Summary of the invention
The present invention has synthesized a kind of ketolide compound of novel macrolide antibiotic, and has verified the anti-microbial activity of this compound through a large amount of experiments.
The object of the present invention is to provide a kind of ketolide compound of novel macrolide antibiotic, this compound is gone up by 11 N and is introduced the 11-N-[3-[[(N-aryl) carbamate groups] propyl group]] group, can reach the effect that strengthens antagonism multidrug resistant problem, and improve the macrolide resistant organism is suppressed active.
The present invention also aims to provide a kind of ketolide compound synthetic method of macrolide antibiotics.
The present invention also aims to provide the purposes of a kind of ketolide compound of macrolide antibiotics at antibiosis.
In order to achieve the above object, the invention provides a kind of ketolide compound of novel macrolide antibiotic, it takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-aryl for 3-) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-erythromycin, shown in the following formula III of structure:
Wherein, substituent R is selected from H, C
1-6Alkyl, nitro, C
1-6Alkoxyl group, halogen atom and haloalkyl at least a; Be preferably H, methyl, nitro, methoxyl group, Cl or-CF
3More preferably H, a position or contraposition methyl, contraposition nitro, contraposition methoxyl group, ortho position or a position Cl, contraposition CF
3
The present invention also provides the synthetic method of above-mentioned formula III structural compounds, comprising:
(1) takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 with 3-, 11-dehydrogenation-12-O-(imidazoles carbonyl)-2 '-benzoyl erythromycin and the 1-aminopropanol part by weight with 1: 5～10 in polar solvent reacts, the synthetic intermediate Compound I, be that 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 1-N-(3-hydroxypropyl)-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin;
(2) be to react in the non-protic solvent of (comprising weak protic) basically by midbody compound I and aromatic isocyanate, thereby synthetic compound II, be that 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-aryl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 ' benzoyl erythromycin;
(3) Compound I I is synthesized compound III of the present invention through taking off the benzoyl reaction.
The preparation method of The compounds of this invention III, wherein, above-mentioned steps (1) Semi-polarity solvent is acetonitrile, N, dinethylformamide, dimethyl sulfoxide (DMSO) or N-Methyl pyrrolidone; " being non-protonic solvent basically " comprises methylene dichloride, 1,2-ethylene dichloride, ethyl acetate, chloroform or tetrahydrofuran (THF) in the step (2); Step (3) also comprises the synthetic compound III in lower alcohol solvent by Compound I I, and described lower alcohol is C
1-3Alcohol, also comprise the process of backflow under the protection of inert gas, purifying and wash-out.
Wherein, 3-in the above-mentioned steps (1) takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0, and 11-dehydrogenation-12-O-(imidazoles carbonyl)-2 '-benzoyl erythromycin (raw material) can adopt any known method to obtain; for example; can be with reference to J.Med.Chem, 41,4080-4100; the preparation of 1998 methods; itself and at least 5 times of amounts (weight), the 1-aminopropanol synthetic intermediate Compound I of preferred 5～10 times of amounts, as follows:
(raw material) I (intermediate)
Because 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0; 11-dehydrogenation-12-O-(imidazoles carbonyl)-2 '-benzoyl erythromycin is unstable in strong protic solvent; and be subject to the influence of nucleophilicity reagent and take off imidazoles reaction; cause by product to increase; the solvability of compound own is bad in addition; therefore this starting compound and the selection of the reaction solvent of 1-aminopropanol (or the title 3-hydroxypropyl ammonia) polarity of trying one's best is big; protic relatively a little less than; reaction is preferably carried out under gentleness and neutral environment; as acetonitrile; N; dinethylformamide (DMF); dimethyl sulfoxide (DMSO); N-Methyl pyrrolidone etc., wherein preferred acetonitrile or DMF.
Order of addition(of ingredients) does not have strict restriction, and temperature of reaction to reflux temperature, is reacted (preferred 6-12 hour) from room temperature, after adding entry, non-polar solvent (for example hexyl acetate methylene dichloride, 1,2-ethylene dichloride or chloroform) extraction, water or saturated common salt water washing, dry (available anhydrous sodium sulphate), filter filtrate concentrating, silica gel chromatography purifying, acetone-normal hexane wash-out (acetone-normal hexane of for example 1: 0.5～5, preferred 3: 6), obtain intermediate compound I.
Wherein, in the above-mentioned steps (2) since strong protic solvent easily react with phenyl isocyanate, the therefore relative more weak solvent of preferred non-proton property or protic, as methylene dichloride, 1,2-ethylene dichloride, ethyl acetate, chloroform, tetrahydrofuran (THF) etc.; And the easy polymerization reaction take place of phenyl isocyanate self, therefore preferably in room temperature or be lower than under the room temperature and carry out.Consider in the reaction process that activity hydroxy in the raw molecule may form the conformation steric effect of intramolecular hydrogen bond or macrolide ring, cause hydroxyl not react with phenyl isocyanate, so preferably add a spot of non-proton property alkali, as triethylamine, 4-dimethylaminopyridine etc., make yield better.
In a preferred embodiment of the invention, best route by the compound of the intermediate composite structure formula II of structural formula I is: intermediate compound I is dissolved in methylene dichloride, 0 ℃ drips aromatic isocyanate down, more preferably add a spot of non-proton property alkali (as triethylamine, 4-dimethylaminopyridine etc.), normal-temperature reaction under rare gas element (for example nitrogen) protection; Add the methyl alcohol deactivation, remove excessive aromatic isocyanate, filter and discard insolubles, concentrate, the silica gel chromatography purifying with hexanaphthene-eluent ethyl acetate, obtains the compound of structural formula II.
The aromatic isocyanate preparation of wherein being adopted is dissolved in the chloroform by triphosgene, stirs ice bath, the chloroformic solution of an arylamine, finish, room temperature reaction 1-8 hour, reflux to reaction solution was clarified, normal pressure steams and desolventizes, and remaining liquid underpressure distillation gets final product, and the selection of the substituent R on the phenyl ring as described above.
In another preferred embodiment of the present invention; preferable route by the synthetic formula III compound of the present invention of Compound I I is: the above-mentioned Compound I I that obtains is dissolved in the lower alcohol alcoholic solution (methyl alcohol for example; or ethanol); the preferred nitrogen protection refluxes, and filters and discards insolubles; concentrate; the silica gel chromatography purifying, the hexanaphthene-eluent ethyl acetate of 4: 1～1: 1 (v/v), it is anti-to obtain the novel ketolide of structural formula of the present invention shown in formula III
It is the antimicrobial compound (pharmaceutical preparation) of effective constituent that the present invention also provides with the compound of above-mentioned formula III structure, can for example vehicle, thinner etc. are mixed and made into formulations such as formulation gastrointestinal administrations such as tablet, capsule, granule, powder or syrup or injection with administered in parenteral form with this compound and pharmaceutically useful auxiliary material.
The said medicine preparation can prepare by ordinary method.Described auxiliary material can comprise vehicle (for example carbohydrate derivative such as lactose, sucrose, glucose, mannitol and Sorbitol Powder; Starch derivative such as W-Gum, potato starch, dextrin and carboxymethyl starch; Derivatived cellulose such as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine; Gum arabic; Dextran; Silicate derivative such as metasilicic acid magnalium; Phosphate derivative such as calcium phosphate; Carbonate derivative such as lime carbonate; Sulfate-derivatives such as calcium sulfate etc.), tackiness agent (gelatin for example, polyvinylpyrrolidone and polyoxyethylene glycol), disintegrating agent (for example derivatived cellulose such as Xylo-Mucine, polyvinylpyrrolidone), lubricant (talcum for example, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.), correctives (Chang Yong sweeting agent for example, acidic flavoring agent and spices etc.), thinner and injection liquid are with solvent (water for example, ethanol and glycerine etc.).
Compound of the present invention and the clinical administration dosage that contains described compound compositions are different and different with patient's age, sex, race, the state of an illness etc., general adult's about 0.01-5000mg/ day of dosage, preferred 1-1000mg/ day, more preferably 5-500mg/ day.
The present invention also provides the purposes of above-claimed cpd at antibiosis with following in-vitro antibacterial experiment, and the application of the compound of formula III structure in preparation antibacterials (for example microbiotic).
One, experimental technique: the standard agar plate doubling dilution that adopts NCCL to propose carries out minimum antibacterial (MIC) to compound and measures.Judge the power of the anti-microbial activity and the anti-microbial effect of compound with the MIC value.
Two, test medicine:
1, contrast medicine: match erythromycin (Cethromycin, ABT-773), erythromycin-A, azithromycin
2, investigational agent: according to the difference of substituent group R, be respectively CA-9A (R-H), CA-9B (R-contraposition methyl), CA-9C (R-contraposition methoxyl group), CA-9D (R-contraposition nitro), CA-9E (position methyl between R-), CA-9F (R-ortho position chlorine), CA-9G (position chlorine between R-), CA-9H (R-contraposition CF3), CA-9I (intermediate), measure compound concentrations scope: 256mg/L-0.016mg/L
Three, measure bacterium:
MRSA (methicillin-resistant staphylococcus aureus): 10 strains
MSSA (MSSA): 10 strains
MRSE (methicillin resistance staphylococcus epidermidis): 5 strains
MSSE (methicillin-sensitivity staphylococcus epidermidis) 5 strains
8 strains of enterococcus faecalis 12 strain streptococcus pneumoniae
14 strains of bloodthirsty hemophilus influenza 13 strain second suis
Quality Control bacterium: streptococcus aureus ATC29213 faecalis ATCC29212
Four, experimental result sees Table 1,2:
The MIC of table 1 new compound CA-9A～CA-9H of the present invention
50, MIC
90Value (mg/L)
| The medicine mushroom | MSSA erythromycin S | MSSA erythromycin R | ?????????MRSA | ?????????MRSE | ?????????MSSE | |||||
| ??MIC 50 | ??MIC 90 | ??NIC 50 | ??MIC 90 | ??MIC 50 | ??MIC 90 | ??MIC 80 | ?MIC 90 | ??MIC 50 | ??MIC 90 | |
| CA-9A CA-9B CA-9C CA-9D CA-9E CA-9F CA-9G CA-9H CA-9I ABT-773 erythromycin azithromycin | ??1 ??0.062 ??0.031 ??0.25 ??0.125 ??0.062 ??0.25 ??0.062 ??0.5 ??＜0.016 ??0.125 ??0.031 | ??2 ??0.125 ??0.125 ??0.25 ??0.125 ??0.125 ??0.5 ??0.25 ??0.5 ??＜0.016 ??0.25 ??0.125 | ??2 ??0.125 ??0.125 ??0.5 ??0.25 ??0.125 ??>256 ??0.062 ??0.5 ??＞0.016 ??＞256 ??＞256 | ??2 ??0.125 ??0.25 ??0.5 ??0.25 ??0.25 ??＞256 ??2 ??1 ??＜0.016 ??＞256 ??＞256 | ??256 ??128 ??256 ??＞256 ??128 ??128 ??＞256 ??256 ??＞256 ??256 ??＞256 ??＞256 | ??256 ??256 ??＞256 ??＞256 ??256 ??256 ??＞256 ??＞256 ??＞256 ??＞256 ??＞256 ??＞256 | ??2 ??0.062 ??16 ??1 ??1 ??0.5 ??＞256 ??2 ??2 ??＜0.016 ??＞256 ??＞256 | ?16 ?256 ?32 ?8 ?128 ?32 ?＞256 ?256 ?＞256 ?128 ?＞256 ?＞256 | ??0.5 ??0.062 ??0.031 ??0.25 ??0.031 ??0.25 ??0.25 ??0.125 ??0.25 ??＜0.016 ??0.125 ??＜0.016 | ??2 ??0.062 ??0.062 ??0.25 ??0.031 ??0.25 ??0.25 ??0.5 ??0.25 ??＜0.016 ??0.125 ??0.031 |
Table 2. Macrolide new compounds experiment in vitro MIC
50, MIC
90Value Data (mg/L)
| CA-9E?MIC 50??????MIC 90 | ????＞256 ????＞256 | ????0.062 ????0.125 | ????4 ????8 | ????1 ????2 |
| CA-9F?MIC 50??????MIC 90 | ????＞256 ????＞256 | ????2 ????8 | ????64 ????128 | ????8 ????8 |
| CA-9H?MIC 50??????MIC 90 | ????＞256 ????＞256 | ????4 ????32 | ????32 ????64 | ????2 ????4 |
| CA-9I?MIC 50??????MIC 90 | ????＞256 ????＞256 | ????4 ????8 | ????16 ????16 | ????2 ????8 |
| CB-4??MIC 50??????MIC 90 | ????＞256 ????＞256 | ????32 ????＞256 | ????64 ????128 | ????16 ????32 |
| Erythromycin MIC 50??????MIC 90 | ????＞256 ????＞256 | ????2 ????4 | ????4 ????8 | ????2 ????4 |
| Azythromycin MIC 50????????MIC 90 | ????＞256 ????＞256 | ????1 ????2 | ????2 ????8 | ????16 ????16 |
| ABT-773MIC 50???????MIC 90 | ????32 ????32 | ????0.5 ????1 | ????1 ????2 | ????1 ????2 |
Conclusion: the new compound of surveying except that CA-9G to MSSA, MRSE, streptococcus pneumoniae all has the excellent antibiotic activity to erythromycin, Azythromycin resistant organism, MIC value scope is respectively:＜0.016-2mg/L and 0.031-2mg/L, 0.125-32mg/L, MIC
90Value is starkly lower than erythromycin 2-16 doubly and near the MIC of Azythromycin and ABT-773
90Value; The CA-9D that surveys and CA-9E bloodthirsty hemophilus influenza is had certain anti-microbial effect MIC
90The value scope is 8-32mg/L, and is similar with contrast medicine erythromycin, Azythromycin, is weaker than ABT773.
The compound that experiment showed, the formula III structure of the present invention of method for preparing has anti-microbial effect, can be used for preparing antibacterials (for example microbiotic).
Embodiment
Describe technical scheme of the present invention in conjunction with the embodiments in detail, but do not limit protection scope of the present invention.
Embodiment 1: raw material and reactant synthetic
1) raw material is synthetic, and promptly 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 1-N-(3-hydroxypropyl)-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (I) synthetic
According to J.Med.Chem; 41; 4080-4100; the at first synthetic 3-of 1998 methods takes off (own glucopyranosyl)-3-oxygen-6-0-methyl isophthalic acid 0; 11-dehydrogenation-12-O-(imidazoles carbonyl)-2 '-benzoyl erythromycin gets its 10.7g, 1 3.9mmol and 1-aminopropanol (11ml; 14.3mmol) be dissolved in DMF (80ml), stirring at room 62h.Add entry (150ml), with ethyl acetate (100ml * 3) extraction, water (150ml), saturated aqueous common salt (100ml) washing, anhydrous sodium sulfate drying filters, and filtrate concentrates, the silica gel chromatography purifying, acetone-normal hexane (3: 6) wash-out obtains a white solid (10.7g), yield 85%.
1HNMR(CDCl
3，400MHz)δ：8.05(d，J＝7.6Hz，2H，phenl-H
2、phenl-H
6)，7.63(t，J＝6.9Hz，1H，phenl-H
4)，7.49(t，J＝7.6Hz，2H，1H，phenl-H
3、phenl-H
5)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2′-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3′-H)，2.26(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.80(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：775(M
++H)
2) preparation of reactant:
A. benzene isocyanic ester
With triphosgene (16.3g,, 0.55mol) be dissolved in the chloroform (60ml), stir, ice bath, aniline (9.3g, chloroformic solution 0.1mol) (40ml) drips, and finishes, room temperature reaction 1 hour, reheat are back to the reaction solution clarification.Normal pressure steams and desolventizes, and remaining liquid underpressure distillation gets colourless liquid (10.1g), yield 85%.bp?65-68℃/30mmHg。
B.2-methylbenzene isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 2-aminotoluene (10.8g, 0.1mol), room temperature reaction 2 hours, underpressure distillation gets colourless liquid (12.75g), yield 80%.
bp?69-71℃/30mmHg。
C.3-methylbenzene isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 3-monomethylaniline (10.8g, 0.1mol), room temperature reaction 3 hours, underpressure distillation gets colourless liquid (11.13g), yield 70%.
bp?69-70℃/30mmHg。
D.4-trifluoromethylbenzene isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 4-5-trifluoromethylaniline (16.1g, 0.1mol), room temperature reaction 3 hours, underpressure distillation gets colourless liquid (15.01g), yield 80%.
bp?71-73℃/30mmHg。
E.4-methylbenzene isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 4-monomethylaniline (10.8g, 0.1mol), room temperature reaction 2 hours, underpressure distillation gets colourless liquid (14.04g), yield 90%.
bp?69-70℃/30mmHg
F.4-anisole isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 4-anisidine (12.4g, 0.1mol), room temperature reaction 1 hour, underpressure distillation gets colourless liquid (12.75g), yield 85%.
bp?75-77℃/30mmHg
G.2-phenetole isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 2-phenetidine (13.8g, 0.1mol), room temperature reaction 5 hours, underpressure distillation gets colourless liquid (4.92g), yield 30%.
bp?72-73℃/20mmHg
H.4-nitrophenylisocynic acid ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 4-N-methyl-p-nitroaniline (13.8g, 0.1mol), room temperature reaction 3 hours, underpressure distillation gets yellow solid (13.27g), yield 81%.
bp?85-86℃/20mmHg
I.2-chlorobenzene isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 2-chloroaniline (12.85g, 0.1mol), room temperature reaction 1.5 hours, underpressure distillation gets colourless liquid (11.87g), yield 77%.
bp?64-66℃/20mmHg
J.3-chlorobenzene isocyanic ester
With reference to the preparation method of benzene isocyanic ester, and the chloroformic solution of dropping 2-chloroaniline (12.86g, 0.1mol), room temperature reaction 3.5 hours, underpressure distillation gets colourless liquid (11.29g), yield 73%.
bp?66-68℃/20mmHg
K. the preparation of phenyl chloroformate
(16.3g 0.55mol) joins in the three-necked bottle, and (94g 1mol), stirs room temperature reaction 2 hours to add anhydrous phenol with triphosgene under the ice bath.Normal pressure steams and desolventizes, and remaining liquid underpressure distillation gets colourless liquid (125.1g), yield 80%.
bp?81-83℃/6mmHg。
Embodiment 2:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II) synthetic
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 1-N-(3-hydroxypropyl)-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol) be dissolved in methylene dichloride (20ml); DCC (0.11g, 0.516mmol), DMAP (0.063g; 0.516mmol); cooling drips benzene isocyanic ester (0.31g, methylene dichloride 2.58mmol) (10ml) solution, normal-temperature reaction 20h under the nitrogen protection down.Finish, add methyl alcohol 3m1 deactivation, filter and discard insolubles, concentrate, the silica gel chromatography purifying, hexanaphthene: ethyl acetate=5: 1～2: 1 wash-outs obtains white solid (0.387g), yield 82%.
1HNMR(CDCl
3，400MHz)δ：8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.49(t，J＝6.0Hz，2H，1H，
1phenl-H
3、
1phenl-H
5)，7.38(d，J＝8.0Hz，2H，phenl-H
2、phenl-H
6)，7.28(d，J＝8.0Hz，2H，phenl-H
3、phenl-H
5)，7.05(t，J＝7.6Hz，2H，phenl-H
4)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2′-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3′-H)，2.26(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.78(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：894(M
++H)
Embodiment 3:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-aminomethyl phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II)
Take off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N with 3-; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol), 4-methylbenzene isocyanic ester (0.346g; 2.58mmol; 5eq) be raw material; reaction conditions, operation obtain white solid (0.398g), yield 85% with embodiment 2.
1HNMR(CDCl
3，400MHz)δ：8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.49(t，J＝6.0Hz，2H，1H，
1phenl-H
3、
1phenl-H
5)，7.37(d，J＝8.0Hz，2H，phenl-H
2、phenl-H
6)，7.06(d，J＝8.0Hz，2H，phenl-H
3、phenl-H
5)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3′-H)，2.27(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.78(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：908(M
++H)
Embodiment 4:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-p-methoxy-phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II)
Take off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N with 3-; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol), 4-anisole isocyanic ester (0.387g; 2.58mmol; 5eq) be raw material; reaction conditions, operation get white solid (0.395), yield 83% with embodiment 2.
1HNMR(CDCl
3，400MHz)δ：8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.49(t，J＝6.0Hz，2H，1H，
1phenl-H
3、
1phenl-H
5)，7.47(d，J＝8.0Hz，2H，phenl-H
2、phenl-H
6)，6.89(d，J＝8.0Hz，2H，phenl-H
3、phenl-H
5)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.60(s，3H，phenl-OCH
3)，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3′-H)，2.27(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4＇-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.78(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：924(M
++H)
Embodiment 5:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-nitrophenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II)
Take off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N with 3-; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol), 4-nitrophenylisocynic acid ester (0.426g; 2.58mmol; 5eq) be raw material; reaction conditions, operation get white solid (0.38g), yield 78% with embodiment 2.
1HNMR(CDCl
3，400MHz)δ：8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，8.05(d，J＝8.2Hz，2H，phenl-H
2、phenl-H
6)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.63(d，J＝8.2Hz，2H，phenl-H
3、phenl-H
5)，7.49(t，J＝6.0Hz，2H，1H，
1phenl-H
3、
1phenl-H
5)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2′-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.60(s，3H，phenl-OCH
3)，，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3′-H)，2.27(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.78(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：939(M
++H)
Embodiment 6:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(3-aminomethyl phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II)
Take off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N with 3-; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol), 3-methylbenzene isocyanic ester (0.346g; 2.58mmol; 5eq) be raw material; reaction conditions, operation get white solid (0.398g), yield 85% with embodiment 2.
1HNMR(CDCl
3，400MHz)δ：8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.50(s，1H，phenl-H
2)，7.49(t，J＝6.0Hz，2H，1H，
1phenl-H
3、
1phenl-H
5)，7.45(d，J＝7.7Hz，1H，phenl-H
6)，7.04(d，J＝7.7Hz，1H，，phenl-H
5)，6.82(d，J＝7.7Hz，1H，phenl-H
4)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2′-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3-H)，2.27(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.78(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：908(M
++H)
Embodiment 7:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(3-chloro-phenyl-) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II)
Take off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N with 3-; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol); 3-chlorobenzene isocyanic ester (0.396g; 2.58mmol, 5eq) being raw material, reaction conditions, operation are with embodiment 2; get white solid (0.36g), yield 75%.
1HNMR(CDCl
3，400MHz)δ：8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，7.85(s，1H，phenl-H
2)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.55(d，J＝7.7Hz，1H，phenl-H
6)，7.49(t，J＝6.0Hz，2H，1H，
1phenl-H
3、
1phenl-H
5)，7.21(d，J＝7.7Hz，1H，phenl-H
5)，7.032(d，J＝7.7Hz，1H，phenl-H
4)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2′-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3′-H)，2.27(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.78(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：928(M
++H)
Embodiment 8:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(2-chloro-phenyl-) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II)
Take off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N with 3-; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol); 2-chlorobenzene isocyanic ester (0.396g; 2.58mmol, 5eq) being raw material, reaction conditions, operation are with embodiment 2; get white solid (0.37g), yield 78%.
1HNMR(CDCl
3，400MHz)δ：8.10(t，J＝6.9Hz，1H，phenl-H
6)，8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，7.85(s，1H，phenl-H
2)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.49(t，J＝6.0Hz，2H，1H，
1phenl-H
3、
1phenl-H
5)，7.15(t，J＝7.7Hz，1H，phenl-H
3)，7.00(t，J＝8.0Hz，1H，phenl-H
5)，6.92(t，J＝8.0Hz，1H，phenl-H
4)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2′-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3-H)，2.27(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.78(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：928(M
++H)
Embodiment 9:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-trifluoromethyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin (II)
Take off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N with 3-; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.4g; 0.516mmol); 4-trifluoromethylbenzene isocyanic ester (0.486g; 2.58mmol, 5eq) being raw material, reaction conditions, operation are with embodiment 2; get white solid (0.46g), yield 92%.
1HNMR(CDCl
3，400MHz)δ：8.08(d，J＝7.8Hz，2H，
1phenl-H
2、
1phenl-H
6)，7.85(d，J＝7.2Hz，2H，phenl-H
3、phenl-H
5)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.49(t，J＝6.0Hz，2H，，
1phenl-H
3、
1phenl-H
5)，7.44(d，J＝7.2Hz，2H，phenl-H
2、phenl-H
6)，4.92(dd，J＝2.1，8.7Hz，1H，13-H)，4.57(dd，J＝8.0，10.1Hz，1H，2′-H)，4.12(d，1H，J＝10.8Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.72(m，2H，CH
2CH
2CH
2OH)，3.60(s，3H，phenl-OCH
3)，，3.55(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.41(m，1H，4-H)，3.10(q，J＝7.0Hz，1H，8-H)，3.05(ql，J＝6.9Hz，1H，10-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.78(s，3H，6-0-CH
3)，2.7(m，1H，3′-H)，2.27(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.52(s，3H，6-CH
3，)，1.38(m，1H，7-Ha)，1.32(m，1H，7-Hb)，1.26(s，3H，12-CH
3)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.79(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：962(M
++H)
Embodiment 10:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-phenyl) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.447g; 0.5mmol) be dissolved in methyl alcohol (20ml), back flow reaction 20h under the nitrogen protection.Finish, filter and discard insolubles, concentrate, the silica gel chromatography purifying, hexanaphthene: ethyl acetate=5: 2 wash-outs obtains white solid (0.379g), 95%.
1HNMR(CDCl
3，400MHz)δ：8.01(s，1H，OCONHphenl)，7.39(d，J＝7.8Hz，2H，phenl-H
2，phenl-H
6)，7.29(d，J＝8.1Hz，2H，phenl-H
3、phenl-H
5)，7.03(t，J＝7.8Hz，1H，phenl-H
4)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3′-H)，2.29(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2OH)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.85(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：790(M
++H)
Embodiment 11:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-aminomethyl phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-aminomethyl phenyl) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.454g; 0.5mmol) be dissolved in methyl alcohol (20ml); back flow reaction 20h under the nitrogen protection; reaction conditions, operation are with embodiment 10; obtain white solid (0.386g), yield 96%.
1HNMR(CDCl
3，400MHz)δ：8.9(s，1H，OCONHphenl)，7.37(d，J＝8.0Hz，2H，phenl-H
2、phenl-H
6)，7.06(d，J＝8.0Hz，2H，phenl-H
3、phenl-H
5)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3′-H)，2.29(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.85(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：804(M
++H)
Embodiment 12:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-p-methoxy-phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-p-methoxy-phenyl) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.462g; 0.5mmol) be dissolved in methyl alcohol (20ml); back flow reaction 12h under the nitrogen protection; reaction conditions, operation are with embodiment 10; obtain white solid (0.38g), yield 93%.
1HNMR(CDCl
3，400MHz)δ：8.78(s，1H，OCONHphenl)，7.47(d，J＝8.0Hz，2H，phenl-H
2、phenl-H
6)，6.89(d，J＝8.0Hz，2H，phenl-H
3、phenl-H
5)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz??5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.60(s，3H，phenl-OCH
3)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3′-H)，2.29(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.84(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：820(M
++H)
Embodiment 13:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-nitrophenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-nitrophenyl) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.47g; 0.5mmol) be dissolved in methyl alcohol (30ml); back flow reaction 15h under the nitrogen protection; reaction conditions, operation are with embodiment 10; obtain white solid (0.36g), yield 86%.
1HNMR(CDCl
3，400MHz)δ：9.08(s，1H，OCONHphenl)，8.05(d，J＝8.2Hz，2H，phenl-H
2、phenl-H
6)，7.63(d，J＝8.2Hz，2H，phenl-H
3、phenl-H
5)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2O)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3′-H)，2.29(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.84(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：835(M
++H)
Embodiment 14:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(3-aminomethyl phenyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(3-aminomethyl phenyl) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.454g; 0.5mmol) be dissolved in methyl alcohol (20ml); back flow reaction 10h under the nitrogen protection; reaction conditions, operation are with embodiment 10; obtain white solid (0.387g), yield 96%.
1HNMR(CDCl
3，400MHz)δ：9.61(s，1H，OCONHphenl)，7.50(s，1H，phenl-H
2)，7.45(d，J＝7.7Hz，1H，phenl-H
6)，7.04(d，J＝7.7Hz，1H，，phenl-H
5)，6.82(d，J＝7.7Hz，1H，phenl-H
4)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2OH)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3-H)，2.29(s，6H，N(CH
3)
2)，2.24(s，3H，phenl-CH
3)，1.93(m，1H，14-Ha)，1.73(m，1H，4-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.84(t，J＝7.2Hz，3H，15-H)
ESI-MS(m/z)：804(M
++H)
Embodiment 15:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(3-chloro-phenyl-) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(3-chloro-phenyl-) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.454g; 0.5mmol) be dissolved in methyl alcohol (20ml); back flow reaction 18h under the nitrogen protection; reaction conditions, operation are with embodiment 10; obtain white solid (0.37g), 90%.
1HNMR(CDCl
3，400MHz)δ：10.61(s，1H，OCONHphenl)，7.85(s，1H，phenl-H
2)，7.55(d，J＝7.7Hz，1H，phenl-H
6)，7.21(d，J＝7.7Hz，1H，phenl-H
5)，7.032(d，J＝7.7Hz，1H，phenl-H
4)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2O)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3-H)，2.29(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.85(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：824(M
++H)
Embodiment 16:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(2-chloro-phenyl-) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(3-chloro-phenyl-) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.454g; 0.5mmol) be dissolved in methyl alcohol (20ml); back flow reaction 14h under the nitrogen protection; reaction conditions, operation are with embodiment 10; obtain white solid (0.375g), yield 91%.
1HNMR(CDCl
3，400MHz)δ：8.10(t，J＝6.9Hz，1H，phenl-H
6)，7.85(s，1H，phenl-H
2)，7.78(s，1H，OCONHphenl)，7.15(t，J＝7.7Hz，1H，phenl-H
3)，7.00(t，J＝8.0Hz，1H，
phenl-H
5)，6.92(t，J＝8.0Hz，1H，phenl-H
4)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2O)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3′-H)，2.29(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.84(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：824(M
++H)
Embodiment 17:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-trifluoromethyl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(4-trifluoromethyl) carbamate groups] propyl group]]-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.454g; 0.5mmol) be dissolved in methyl alcohol (20ml); back flow reaction 11h under the nitrogen protection; reaction conditions, operation are with embodiment 10; obtain white solid (0.447g), yield 93%.
1HNMR(CDCl
3，400MHz)δ：7.85(d，J＝7.2Hz，2H，phenl-H
3、phenl-H
5)，7.68(t，J＝6.9Hz，1H，
1phenl-H
4)，7.44(d，J＝7.2Hz，2H，phenl-H
2、phenl-H
6)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2O)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3′-H)，2.29(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.85(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：858(M
++H)
Embodiment 18:3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-(3-hydroxypropyl)-11-N, 12-O-cyclic carbramates erythromycin (III)
3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 1-N-(3-hydroxypropyl)-11-N; 12-O-cyclic carbramates-2 '-benzoyl erythromycin (0.387g; 0.5mmol) be dissolved in methyl alcohol (20ml); back flow reaction 17h under the nitrogen protection; operation is with embodiment 10; obtain white solid (0.329g), yield 98%.
1HNMR(CDCl
3，400MHz)δ：4.93(dd，J＝2.1，8.7Hz，1H，13-H)，4.97(dd，J＝2.1，8.7Hz，1H，13-H)，4.27(d，J＝7.5Hz，1H，1′-H)，4.23(d，1H，J＝8.0Hz?5-H)，3.83(q，J＝7.8Hz，1H，2-H)，3.70(m，2H，CH
2CH
2CH
2OCON)，3.59(d，J＝2.5Hz，1H，11-H)，3.50(m，1H，5′-H)，3.10(m，2H，10-H，4-H)，3.20(dd，J＝7.5，8.8Hz，1H，2′-H)，3.10(q，J＝7.0Hz，1H，8-H)，2.86(m，2H，NCH
2CH
2CH
2O)，2.61(s，3H，6-0-CH
3)，2.48(m，1H，3-H)，2.29(s，6H，N(CH
3)
2)，1.93(m，1H，14-Ha)，1.73(m，1H，4′-Ha)，1.65(m，2H，NCH
2CH
2CH
2O)，1.63(m，1H，14-Hb)，1.47(s，3H，12-CH
3)，1.38(m，1H，7-Ha)，1.34(s，3H，6-CH
3，)，1.32(m，1H，7-Hb)，1.24(m，1H，4′-Hb)，1.17(d，J＝7.0Hz，3H，8-CH
3)，1.13(d，J＝7.8Hz，3H，2-CH
3)，1.12(d，J＝6.9Hz，3H，10-CH
3)，1.10(d，J＝7.4Hz，3H，4-CH
3)，0.85(t，J＝7.2Hz，3H，15-H)。
ESI-MS(m/z)：671(M
++H)
Claims (10)
1, a kind of ketolide compound of macrolide antibiotics, it takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[N-substituted aryl for 3-] carbamate groups] propyl group]-11-N, 12-O-cyclic carbramates-erythromycin, this compound has the structure of formula III:
Wherein, substituent R is selected from H, C
1-6Alkyl, nitro, C
1-6Alkoxyl group, halogen atom and C
1-6Haloalkyl at least a.
2, compound as claimed in claim 1, wherein, R is selected from H, C
1-3Alkyl, nitro, C
1-3Alkoxyl group, fluorine, chlorine and C
1-3Fluorine/chloro alkyl at least a.
3, compound as claimed in claim 2, wherein, R is selected from least a in H, methyl, nitro, methoxyl group, fluorine, chlorine, fluoro methyl and the chloro methyl.
4, compound as claimed in claim 3, wherein, R is H, methyl, nitro, methoxyl group, fluorine, chlorine or trifluoromethyl.
5, the preparation method of the described compound of claim 1, comprising:
(1) takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 with 3-, 11-dehydrogenation-12-O-(imidazoles carbonyl)-2-benzoyl erythromycin and the 1-aminopropanol part by weight with 1: 5～10 in polar solvent reacts, the synthetic intermediate Compound I, be that 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 1-N-(3-hydroxypropyl)-11-N, 12-O-cyclic carbramates-2 '-benzoyl erythromycin;
(2) react in the solvent of non-proton property or weak protic by midbody compound I and aromatic isocyanate, thereby synthetic compound II, be that 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-aryl) carbamate groups] propyl group]]-11-N, 12-O-cyclic carbramates-2 ' benzoyl erythromycin;
(3) Compound I I is reacted synthetic compound III through taking off benzoyl
6, the preparation method of compound as claimed in claim 5, wherein, described step (1) Semi-polarity solvent is acetonitrile, N, dinethylformamide, dimethyl sulfoxide (DMSO) or N-Methyl pyrrolidone.
7, the preparation method of compound as claimed in claim 5, wherein, non-protonic solvent is a methylene dichloride, 1 in the described step (2), 2-ethylene dichloride, ethyl acetate, chloroform or tetrahydrofuran (THF).
8, the preparation method of compound as claimed in claim 5, wherein, step (3) also comprises the synthetic compound III in lower alcohol solvent by Compound I I, be that 3-takes off (own glucopyranosyl)-3-oxygen-6-O-methyl isophthalic acid 0 table-11-N-[3-[[(N-aryl) carbamate groups] propyl group]]-11-N, the process of 12-O-cyclic carbramates-erythromycin compounds; Described lower alcohol is C
1-3Alcohol.
9, a kind of antimicrobial compound wherein contains the ketolide compound of each described macrolide antibiotics of claim 1-4.
10, the purposes of the ketolide compound of each described macrolide antibiotics of claim 1-4 in the preparation antibacterials.
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| CNB2005100662775A CN1318441C (en) | 2005-04-25 | 2005-04-25 | Macrilides ketolide compound, and its preparing method and use |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100577678C (en) * | 2006-06-19 | 2010-01-06 | 中国医学科学院药物研究所 | Macrolide analogue drug double sidechain illotycin A derivative, synthesis method and uses |
| CN104650166A (en) * | 2014-11-17 | 2015-05-27 | 广东东阳光药业有限公司 | New preparation method of macrolide |
| CN106928294A (en) * | 2017-03-22 | 2017-07-07 | 上海启雁实业有限公司 | The method for preparing ketone lactone macrolide antibiotics |
| CN114380874A (en) * | 2021-12-16 | 2022-04-22 | 中国医学科学院医药生物技术研究所 | Macrolide antibiotics and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2273964T3 (en) * | 1998-12-10 | 2007-05-16 | Pfizer Products Inc. | CARBAMATE AND CETOLID CARBAZATE ANTIBIOTICS. |
-
2005
- 2005-04-25 CN CNB2005100662775A patent/CN1318441C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100577678C (en) * | 2006-06-19 | 2010-01-06 | 中国医学科学院药物研究所 | Macrolide analogue drug double sidechain illotycin A derivative, synthesis method and uses |
| CN104650166A (en) * | 2014-11-17 | 2015-05-27 | 广东东阳光药业有限公司 | New preparation method of macrolide |
| CN104650166B (en) * | 2014-11-17 | 2017-12-05 | 广东东阳光药业有限公司 | A kind of preparation method of macrolide |
| CN106928294A (en) * | 2017-03-22 | 2017-07-07 | 上海启雁实业有限公司 | The method for preparing ketone lactone macrolide antibiotics |
| CN114380874A (en) * | 2021-12-16 | 2022-04-22 | 中国医学科学院医药生物技术研究所 | Macrolide antibiotics and preparation method and application thereof |
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