CN105524132A - Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof - Google Patents

Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof Download PDF

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CN105524132A
CN105524132A CN201410520787.4A CN201410520787A CN105524132A CN 105524132 A CN105524132 A CN 105524132A CN 201410520787 A CN201410520787 A CN 201410520787A CN 105524132 A CN105524132 A CN 105524132A
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erythromycin
methyl
descladinosylation
dideoxy
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CN105524132B (en
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靳龙龙
雷平生
赵哲辉
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Institute of Materia Medica of CAMS
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Abstract

The invention discloses a series of erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, represented by a formula I. The invention also provides preparation methods and applications of the derivatives, and side-chain intermediates of the compounds and synthesis methods thereof. The key point of the invention is that the compounds represented by the formula I have the efficacy of broad-spectrum antibiotics, and have outstanding antibacterial activity and anti-resistance activity in inhibiting Gram-positive bacteria and Gram-negative bacteria. The compounds provided by the invention can be used as broad-spectrum antibiotics, and also have antibacterial and antiviral activities in inhibiting Gram-positive bacteria and Gram-negative bacteria.

Description

Containing quinoline substituent Erythromycin A ketolide antibiotics derivative, its preparation method and application
Technical field
The invention belongs to medical art.The present invention relates to a series of containing quinoline substituent Erythromycin A ketolide antibiotics derivative and their synthetic method, relevant intermediate synthetic method, and the biological activity of this compounds and as broad-spectrum antibiotics in the purposes suppressing gram-positive microorganism and negative bacterium, anti-virus aspect.
Background technology
Bacterial drug resistance has become the Tough questions of anti-infective therapy of world field face.Bacterial drug resistance and drug-fast bacteria infection are the 21 century huge challenges that face of anti infection region.Increasing along with microbiotic application, drug resistance problems is on the rise, and makes anti-infective therapy's failure, causes sickness rate and case fatality rate to rise and medical expense increases.And having report to point out in recent years, Ketek has hepatotoxic phenomenon, limits its clinical application range.
Therefore, be necessary the new antibiotic research accelerating to have broad spectrum antibiotic activity, especially strengthen the effect of macrocyclic ketone lactone antibiotic medicine for Gram-negative bacteria, and reduce the toxic side effect such as the liver toxicity of medicine.Design and screen the compound of chemical structure novelty, improving Macrolide resistant organism inhibit activities, reduce and avoid medicine to the inducible resistance of bacterial strain, solving multidrug resistant problem, provide medicine more safely and effectively for clinical.
A lot of for the structure of modification research work of macrocyclic ketone lactone at present, this seminar Chen Xiao Zhuo waits people to design and synthesize a series of 11, the macrocyclic ketone lactone derivatives of 12-position sulfur-bearing arylalkyl side chain, and carried out activity test in vitro, wherein some compound shows good activity to macrolide resistance and sensitive organism.At the micrococcus scarlatinae to erythromycin-sensitive and resistance, the streptococcus pneumoniae of erythromycin-sensitive, the hemophilus influenzae aspect of erythromycin-sensitive, the activity of 9n and 9k is better than Ketek, and 9a, 9e, 9k and 9n (as shown in the formula) antimicrobial spectrum and Ketek similar.
The macrocyclic ketone lactone derivatives of 11,12-position sulfur-bearing arylalkyl side chain
Abbott laboratory is successfully being developed on the basis of cethromycin, continues to have carried out deep structure of modification to the 6-position of macrolide.They have synthesized the macrocyclic ketone lactone derivatives 9 of a series of 6-propargyl virtue heterocyclic side chain.Research finds, when fragrant heterocyclic moiety is biaryl ring, the activity of compound is best.With Ketek product in contrast, compound 9d and 9e (as shown in the formula) the erythromycin-resistant bacterium activity gene induced to erm and mef have significant improvement.To containing the streptococcus pneumoniae 5979 of erm gene, the bacteriostatic activity of compound 9d and 9e comparatively Ketek improves 100 times.This compounds is that the macrolide antibiotic of overriding resistance provides new material standed for.
The macrocyclic ketone lactone derivatives of 6-propargyl virtue heterocyclic side chain
This seminar Chen Xiao Zhuo waits people to synthesize a series of 5-dimethylamine sugar 4 ,-O derivative, and research shows at 4 of 5-dimethylamine sugar, and the anti-microbial activity that hydroxyl is conducive to improving penicillin-susceptible bacterium and resistant organism is introduced in position.Compared with Ketek, it maintains the anti-microbial activity to all penicillin-susceptible bacterium and other resistant organisms, is maintaining the activity identical with Ketek in the ESSP bacterium of erythromycin-sensitive and ESSPy bacterium.
Structure activity relationship shows, dimethylamine sugar to be combined with the 23SrRNA in V district by hydrogen bond and to play drug action.Dimethylamine sugar 4 ,-OH provides another hydrogen bond donor and is combined with the amino-acid residue of land and plays a role, therefore compound 26 (as shown in the formula) anti-microbial activity is better than erythromycin and clarithromycin.And 4, hydrophobic grouping is introduced as alkyl, aryl in position, anti-microbial activity (as 25 and 29) can not be improved due to the effect of macrolide and ribosomal subunit can not be strengthened.
The macrocyclic ketone lactone derivatives that 5-dimethylamine sugar 4 ,-OH is modified
Summary of the invention
The object of the present invention is to provide a kind of such as formula the macrocyclic ketone lactone compound with broad-spectrum antibacterial activity shown in I, i.e. new texture Erythromycin A macrocyclic ketone lactone antibiotic derivatives.
The invention provides the preparation method of the above-mentioned type compound, can synthesize safer, convenient, efficiently and suitability for industrialized production.
The invention provides the purposes of above-mentioned ketolide antibiotics derivative, gram-positive microorganism, Gram-negative bacteria and antiviral can be suppressed as having wide spectrum.
Macrocyclic ketone lactone Antibiotique composition of the present invention has following structural formula:
X is selected from sulphur atom, Sauerstoffatom, carbon atom or nitrogen-atoms;
When wherein X is carbon atom, R represents hydrogen atom;
When X is nitrogen-atoms, R can represent hydrogen atom, substituted or unsubstituted C 1 ~ 4alkyl, substituted or unsubstituted C 1 ~ 4thiazolinyl, substituted or unsubstituted C 1 ~ 4alkynyl,
Wherein substituting group can be selected from hydroxyl, fluorine atom, bromine atoms, chlorine atom, atomic iodine, sulfydryl, amino, phenyl, naphthyl, 5 ~ 12 yuan aromatic heterocyclic replace alkyl;
When X is nitrogen-atoms,
R substituent also can represent:
R substituent also can represent:
R substituent can also represent:
Wherein said R ' substituting group can have preferably from the methyl etc. that hydrogen atom, methyl, ethyl, propyl group, butyl, hydroxyl, fluorine atom, bromine atoms, chlorine atom, atomic iodine, nitro, carboxyl, sulfydryl, amino, amido, cyano group, aldehyde radical, methylol, 1 ~ 3 fluorine atom replace.
Aromatic heterocyclic of the present invention is selected from thienyl, furyl, pyrryl, thiazolyl, oxazolyl, triazol radical, tetrazole base, imidazolyl, thiadiazolyl group, pyrazoles or imidazole base, pyridyl, pyrimidyl, pyridazine or pyrazinyl, indyl, benzofuryl, benzothiazolyl and quinolyl.
R substituent in compound structure of the present invention is preferably from benzyl, benzoyl and to Methyl benzenesulfonyl base.
Wherein, above-described " substituted or unsubstituted C 1 ~ 4alkyl " refer to the substituted or unsubstituted straight or branched alkyl containing 1,2,3,4 carbon atom; " substituted or unsubstituted C 1 ~ 4thiazolinyl " refer to the substituted or unsubstituted straight or branched thiazolinyl containing 1,2,3,4 carbon atom; " substituted or unsubstituted C 1 ~ 4alkynyl " refer to the substituted or unsubstituted straight or branched alkynyl containing 1,2,3,4 carbon atom.
The preferred compound of the present invention is specifically listed as follows:
(S1) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-3-sulfydryl substituted propyl) imino-) erythromycin
(S2) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-3-hydroxyl substituted propyl) imino-) erythromycin
(S3) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (the amino substituted propyl of quinoline-3-) imino-) erythromycin
(S4) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (3-quinolyl-3 (E)-butenyl) imino-) erythromycin
(S5) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-4-replaces butyl) imino-) erythromycin
(S6) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-p-toluenesulfonyl-N-3-quinolyl) amido substituted propyl) imino-s) erythromycin
(S7) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-benzyl-N-3-quinolyl) amido substituted propyl) imino-s) erythromycin
(S8) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-benzoyl-N-3-quinolyl) amido substituted propyl) imino-s) erythromycin
(S9) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-propyl group-N-3-quinolyl amido substituted propyl) imino-) erythromycin
(S10) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-3-quinolyl-2 (E)-propenyl amido substituted propyl) imino-) erythromycin
The starting raw material of new texture macrocyclic ketone lactone antibiotic derivatives of the present invention is clarithromycin, adopts reaction method feasible in bibliographical information or synthetic chemistry, and obtain the raw material of suitable intermediate as invention, its structural formula is as follows:
Wherein, Ac is ethanoyl.
The reaction formula of method of the present invention is as follows:
Wherein, described (CH 3cO) 2for diacetyl oxide, ClCO 2cCl 3for superpalite, (COCl) 2for oxalyl chloride, DBU is 1,8-diazabicylo 11 carbon-7-alkene, and DMSO is dimethyl sulfoxide (DMSO), and CDI is carbonyl dimidazoles, and DMF is DMF, and Ac is ethanoyl.
Present invention also offers a kind of preparation method with said structure compound.The method comprises the addition reaction of the erythromycin A derivative raw material 6 suitably protected and the cyclosubstituted primary amine side chain of quinoline selected, product removed the reaction of ethanoyl by methyl alcohol solution.
Above-mentioned method, comprises the following steps:
1, introduce fragrant cyclosubstituted carbamate-functional in 11,12-positions of above-mentioned raw materials 6;
2, the alcoholysis of ethanoyl removes, and obtains the Erythromycin A of corresponding replacement containing quinoline ring side chain ketolide derivatives.
New texture macrocyclic ketone lactone compound of the present invention is namely from clarithromycin, adopt the feasible reaction method that in known bibliographical information or synthetic chemistry, the public is known, obtain suitable derivative as raw material of the present invention, as starting compound 6, document J.Med.Chem can be adopted, 41,4080-4100, the method preparation of 1998 reports.
Second aspect present invention additionally provides a kind of pharmaceutical composition, and said composition contains at least one compound and the pharmaceutically available carrier of quinoline substituent Erythromycin A ketolide antibiotics derivative.This pharmaceutical composition can be prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration can be enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention first particle or micropill be can be made with thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, glidant kind.
For the compounds of this invention is made injection, can with water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepared lyophilized injectable powder, N.F,USP MANNITOL, glucose etc. also can be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
Third aspect present invention provides the compounds of this invention and is preparing the application in anti-bacteria medicine and antiviral.
Described bacterial isolates comprises gram positive bacterium, gram negative bacterium.Wherein, gram positive bacterium comprises staphylococcus, suis, streptococcus pneumoniae, pyococcus, staphylococcus epidermidis; Gram negative bacterium comprises moraxelle catarrhalis, hemophilus influenzae; And other pathogenic agent are as rickettsia Salmonella, mycoplasma pneumoniae, chlamydozoan, Rome pathogenic agent, bird blood plasma body, toxoplasma, mycobacterium, Listeria monocytogenes, meningococcus.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.In general, the Suitable dosage ranges of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, is more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on the clinical experience of doctor and comprises the dosage regimen using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
Advantageous Effects
In the present invention, the Macrocyclic lactone compounds Erythromycin A antibiotics derivatives anti-microbial activity of the overwhelming majority containing the cyclosubstituted side chain of quinoline reaches the level suitable with Ketek, also Ketek is better than for minority bacterial strain, and the sample compound of design and synthesis of the present invention is avoided and may have been caused hepatotoxic side-chain structure; Compared with synthesizing with Ketek, the synthetic route of the sample compound that the present invention relates to is short, simple to operate, and total recovery is high, and cost is low.Thus provide a class formation novel, active strong, synthesize simple drug candidates, can be used as broad-spectrum antibiotics in the purposes suppressing gram-positive microorganism and negative bacterium, anti-virus aspect.
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.
For following whole embodiment, standard operation well known by persons skilled in the art and purification process can be used.Except as otherwise noted, all temperature represent with DEG C (degree Celsius).The structure of compound passes through nuclear magnetic resonance spectrum
(NMR) and/or mass spectrum (MS) determine.
Preparation example part
The structure of compound be by proton nmr spectra ( 1hNMR), carbon-13 nmr spectra ( 13cNMR) and mass spectrum (MS) determine.Proton nmr spectra and carbon spectral displacement (δ) provide with the unit of 1,000,000/(ppm).Proton nmr spectra Mercury-300, Mercury-300 or Mercury-600 type nmr determination, deuterochloroform (CDCl 3) or heavy water (D 2or deuterated dimethyl sulfoxide (DMSO-d O) 6) make solvent, tetramethylsilane (TMS) is interior mark.
High resolution mass spectrum adopts Agilent1100seriesLC/MSDtrapmassspectrometer LC-MS instrument or TheromoExactiveorbitrapplusLC/MSDmassspectrometer LC-MS instrument to measure.
Column chromatography generally uses 160 ~ 200 order silica gel to be carrier.
Anhydrous solvent is all by standard method process.Other reagent is commercially available analytical pure.
Wherein,
Acacetyl ethanoyl
Bnbenzyl benzyl
Brsbroadsingle is wide unimodal
Bzbenzoyl benzoyl
CDI1,1 '-carbonyldiimidazole1,1 '-carbonyl dimidazoles
Ddouble is dual
DBU1,8-diazabicyclo [5,4,0]-7-ene1,8-dioxazole dicyclo [5,4,0]-7-hendecene
DEADdiethylazodicarboxylate azo oxalic acid diethyl ester
DMFdimethylformamideN, dinethylformamide
DMSOdimethylsulfoxide dimethyl sulfoxide (DMSO)
Eq.equivalent equivalent
Etethyl ethyl
ESIelectrosprayinoization electron spray ionisation
Ggram gram
Hhour hour
Hzhertz hertz
Mmultiple is multiple
M/zmasstochargeratio specific charge
Memethyl methyl
μ lmicroliter microlitre
Mgmilligram milligram
MICminimuminhibitoryconcentration minimal inhibitory concentration
Mlmilliliter milliliter
Mmolmillimole mmole
MSmassspectrometry mass spectrum
NMRnuclearmagneticresonance nucleus magnetic resonance
Ppmpartpermillion 1,000,000/
Pypyridine pyridine
Qquarter quadruple
Refreference document
Rtroomtemperature room temperature
Ttriple is triple
THFtetrahydrofuran tetrahydrofuran (THF)
TLCthinlayerchromatography thin-layer chromatography
Preparation example 1
The synthetic route of Scheme1 intermediate 5a
Scheme1Reagentsandconditions:a.CH 3COSK,DIEA，Pd 2(dba) 3,Xantphos,1,4-dioxane，macrowave；b.1),KOH,EtOH,2),H +,r.t；c.K 2CO 3,DMF,90℃；d.NH 2NH 2·H 2O,EtOH,reflux。
The synthesis of compound (2a)
By 3-bromopyridine (1a) (250mg, 1.2mmol), thioacetic acid potassium (275mg, 2.4mmol), Pd 2(dba) 3(27.5mg, 0.03mmol), Xantphos (35mg, 0.06mmol) be added in 10ml microwave tube, seal with threeway scavenging air valve, drawdown pump vacuumizes, and with argon gas by gas displacement in microwave tube three times, diisopropyl ethyl amine (the 0.42ml of calculated amount is taken with syringe, 2.4mmol), 1, 4-dioxane is injected in microwave tube, threeway is taken off rapidly and with microwave tube block, the bottle mouth of pipe is built fast, insert in microwave reactor, by following parameter (Power:150W, Ramp:10min, HoldTime:25min, Temp:160 DEG C, P:150PSI) arrange microwave reactor to react.After reaction terminates; by in the mixing solutions of reaction solution impouring ethyl acetate/water, separate ethyl acetate layer, aqueous phase is extracted with ethyl acetate; merge organic phase; washing, saturated common salt is washed, anhydrous sodium sulfate drying; filter; concentrating under reduced pressure obtains crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:15) obtains compound 3-thioacetyl yl pyridines 2a (132mg, 54.2%).
1HNMR(300MHz,CDCl 3):8.796(d,J＝2.4Hz1H),8.255(s,1H),8.133(d,J＝9.0Hz,1H),7.778～7.842(m,1H),7.594(t,J＝7.2Hz,1H),2.513(t,3H).
13CNMR(75MHz,CDCl 3):δ192.94,153.83,147.77,142.20,130.75,129.51,128.10,127.94,127.35,122.07,30.43.
HR-MS(ESI)(M+H) +m/z204.0488,calcdforC 11H 9NOS203.0405.
The synthesis of compound (3a)
Compound 3-thioacetyl yl pyridines (0.36g, 1.77mmol) is dissolved in 10ml ethanol, adds potassium hydroxide (o.3g, 5.32mmol), be heated to 80 DEG C, back flow reaction 12h.TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.Stopped reaction, is chilled to room temperature by reaction solution, adjusts about pH4.0 with 1N hydrochloric acid soln, solvent evaporate to dryness is obtained reddish-brown residuum by decompression, add a small amount of water and be extracted with ethyl acetate, merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, silica gel column chromatography (ethyl acetate/petroleum ether 1:10) compound 3-mercaptopyridine 3a, not treated directly carry out next step reaction.
HR-MS(ESI)(M+H) +m/z162.0423,calcdforC 9H 7NS161.0299.
The synthesis of compound (4a)
By 3-mercaptoquinoline (3a) (0.285g, 1.77mmol), N-(3-bromopropyl) phthalic imidine (0.522g, 1.95mmol), salt of wormwood (1.25g, 9.0mmol) be added to 10mlN respectively, in dinethylformamide, be heated to 90 DEG C, reaction 10h.TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.Stopped reaction, reaction solution is chilled to room temperature, solids removed by filtration, filtrate concentrates, methylene dichloride dissolves residuum, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:15) obtains faint yellow compound 4a (418mg, two step yields 68%).
1HNMR(300MHz,CDCl 3):δ8.852(s,J＝1.8Hz,1H),8.043～8.111(m,2H),7.831～7.859(m,2H),7.703～7.760(m,4H),7.542～7.569(m,1H),3.869(t,J＝6.9Hz,2H),3.048(t,J＝7.2Hz,2H),2.053(m,J＝6.9Hz,J＝7.2Hz,2H).
HR-MS(ESI)(M+H) +m/z349.0981,calcdforC 20H 16N 2O 2S348.0932.
The synthesis of compound (5a)
Compound 4a (106mg, 0.35mmol) is scattered in 5ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (36mg, 35 μ l, 0.70mmol), be heated to 80 DEG C, back flow reaction 5h, obtains light yellow solid by reaction solution concentrating under reduced pressure, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, and saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains faint yellow oily compound 72mg, without separation, be directly used in the next step.
HR-MS(ESI)(M+H) +m/z219.1691,calcdforC 12H 14N 2S218.0878.
Preparation example 2
The synthetic route of Scheme2 intermediate 3b
Scheme2Reagentsandconditions:a.N-(3-Bromopropyl)phthalimide，K 2CO 3,DMF,90℃；b.NH 2NH 2·H 2O,EtOH,reflux,80℃。
The synthesis of compound (2b)
By 3-hydroxyquinoline (1b) (2.0g, 13.78mmol), N-(3-bromopropyl) phthalic imidine (3.7g, 13.78mmol), salt of wormwood (2.1g, 15.156mmol) be added to N respectively, in dinethylformamide (40ml), be heated to 90 DEG C, reaction 10h.TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.Stopped reaction, reaction solution is chilled to room temperature, solids removed by filtration, filtrate concentrates, and methylene dichloride dissolves residuum, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filters, silica gel column chromatography (ethyl acetate/petroleum ether 1:15) obtains faint yellow compound 2b (4.186g, yield 91.6%).
1HNMR(400MHz,CDCl 3):δ8.457(s,1H),7.956(d,J＝8Hz,1H),7.824～7.843(m,2H),7.676～7.723(m,3H),7.478～7.552(m,2H),7.318(s,1H),4.160(t,2H),3.967(t,2H),2.265～2.311(m,2H).
HR-MS(ESI)(M+H) +m/z333.1362,calcdforC 20H 16N 2O 3332.1161.
The synthesis of compound (3b)
Compound 2b (1.5g, 4.52mmol) is scattered in 30ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (0.52ml, 9mmol), be heated to 80 DEG C, back flow reaction 5h, TLC (methyl alcohol/chloroform 1:10) display reacts completely.Reaction solution concentrating under reduced pressure is obtained light yellow solid, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrated organic phase obtains faint yellow oily compound 0.728g, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z203.1191,calcdforC 12H 14N 2O202.1106.
Preparation example 3
The synthetic route of Scheme3 intermediate 5c
Scheme3Reagentsandconditions:a.Boc 2O，NHMDS,THF,r.t.1h；b.N-(3-Bromopropyl)phthalimide,K 2CO 3,DMF,90℃；c.TFA,DCM,0℃,8h；d.NH 2NH 2·H 2O,EtOH,reflux,80℃。
The synthesis of compound (2c)
By 3-quinolylamine (1c) (0.5g; 3.47mmol) be added in anhydrous tetrahydro furan (15ml); argon shield; two (three Yue base silyls) ammonification sodium (NHMDS is slowly dripped under ice bath; 3.45ml, 3.8mmol, 2MinTHF); mix and blend 15min, is slowly added dropwise to tert-Butyl dicarbonate (Boc in reaction solution 2o, 0.83g, 3.8mmol), under room temperature, react 1h.TLC (methyl alcohol/chloroform 1:10) display reacts completely.In reaction solution, add a small amount of shrend to go out reaction, layering, aqueous phase is extracted with ethyl acetate, and merges organic phase, saturated sodium bicarbonate solution is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:10) obtains faint yellow compound 2c (0.768g, yield 90%).
1HNMR(400MHz,CDCl 3):δ8.646(d,J＝2Hz,1H),8.517(s,1H),8.016(d,J＝8.4Hz,1H),7.566(d,J＝8.4Hz,1H),7.590(t,J＝7.2Hz,1H),7.507(t,J＝7.2Hz,1H),6.881(s,1H),1.557(s,9H).
HR-MS(ESI)(M+H) +m/z245.1459,calcdforC 14H 16N 2O 2244.1212.
The synthesis of compound (3c)
By 70%NaH (0.81g, 23.6mmol) be suspended in dry DMF (50ml), ice bath is cooled to about 0 DEG C, add substrate 2c (2.88g wherein, 11.8mmol), mix and blend 30min, repeatedly add and N-(3-bromopropyl) phthalic imidine (6.4g on a small quantity in reaction solution in batches, 23.6mmol), insulated and stirred 15min, be heated to 80 DEG C of reaction 15h, TLC (ethyl acetate/petroleum ether 1:3) displays react completely.By in reaction solution impouring frozen water, repeatedly extract by ethyl acetate, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:10) obtains faint yellow compound 3c (4.85g, yield 95%).
1HNMR(400MHz,CDCl 3):δ8.794(d,J＝2.4Hz,1H),8.051(d,J＝8.0Hz,1H),7.974(d,J＝1.6Hz,1H),7.767～7.788(m,3H),7.641～7.685(m,3H),7.535(t,J＝7.2Hz,1H),3.823(t,J＝6.8Hz,2H),3.723(t,J＝7.2Hz,2H),2.067(m,J＝6.8Hz,J＝7.2Hz,2H),1.387(s,9H).
HR-MS(ESI)(M+H) +m/z432.1990,calcdforC 25H 25N 3O 4431.1845.
The synthesis of compound (4c)
By compound 3c (3.26g, 7.56mmol) be dissolved in anhydrous methylene chloride (30ml), be placed in ice bath, be cooled to about 0 DEG C, in reaction solution, add trifluoroacetic acid (17.24g, 11.24ml, 151.2mmol), finish, react 8h under room temperature, TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.Reaction solution is used 50ml dchloromethane, and in reaction solution, add the solution of potassium carbonate (adjusting pH to be greater than 10) of 1M, separatory, aqueous phase dichloromethane extraction, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, and silica gel column chromatography (ethanol/methylene 1:100) obtains faint yellow compound 4c (2.4g, yield 96%).
1HNMR(400MHz,CDCl 3):δ8.455(s,1H),7.867(d,J＝8.0Hz,1H),7.847～7.854(m,2H),7.720～7.740(m,2H),7.584～7.598(m,2H),7.392～7.411(m,2H),7.009(s,1H),4.420(s,1H),3.864(t,J＝6.4Hz,2H),3.300(d,J＝6.4Hz,2H),2.067(t,J＝6.4Hz,2H).
HR-MS(ESI)(M+H) +m/z332.1381,calcdforC 20H 17N 3O 2331.1321.
The synthesis of compound (5c)
Compound 4c (0.42g, 1.27mmol) is scattered in 8ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (145 μ l, 2.54mmol), 80 DEG C are heated to, back flow reaction 5h, reaction solution concentrating under reduced pressure is obtained light yellow solid, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains faint yellow oily compound 240mg, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z202.1334,calcdforC 12H 15N 3201.1266.
Preparation example 4
The synthetic route of Scheme4 intermediate 4d and 6d
Scheme4Reagentsandconditions:a.3-Buten-1-ol，DEAD,PPh 3,THF,0℃-r.t.24h；b.3-Bromoquinoline,Pd(OAc) 2,PPh 3,CH 3CN,TEA,reflux,12h；c.NH 2NH 2·H 2O,80℃；d.H 2,Pd/C,EtOH,r.t.18h；e.NH 2NH 2·H 2O,EtOH,reflux,80℃。
The synthesis of compound (2d)
By phthalic imidine (1d) (4.5g, 30.51mmol) be suspended in anhydrous tetrahydro furan (50ml), be placed in ice bath and be cooled to about 0 DEG C, add 3-butene-1-ol (2.0g wherein, 27.74mmol) with triphenylphosphine (8.0g, 30.51mmol), stir in downhill reaction liquid and slowly drip diethyl azodiformate (DEAD, 5.3g, 30.51mmol), finish, naturally rise to room temperature, stirring reaction 24h, TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.Normal hexane is added in reaction solution, filter, filtrate uses 1N hydrochloric acid, saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:30) obtains albefaction compound 2d (3.75g, yield 67.3%).
1HNMR(400MHz,CDCl 3):δ7.820～7.841(m,2H),7.690～7.711(m,2H),5.736～5.839(m,1H),5.002～5.082(m,2H),3.765(t,J＝7.2Hz,2H),2.445(dd,J＝7.2Hz,J＝14.0Hz,2H).
HR-MS(ESI)(M+H) +m/z202.0782,calcdforC 12H 11NO 2201.0790.
The synthesis of compound (3d)
By 3-bromoquinoline (0.5g, 2.4mmol) with compound (2d) (0.56g, 2.9mmol) be dissolved in anhydrous acetonitrile (10ml), acid chloride (5.4mg is added in reaction solution, m/m:1%eq), triphenylphosphine (24mg, and triethylamine (0.97g m/m:4%eq), 1.34ml, 9.6mmol), reaction solution is heated to back flow reaction 12h, and TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.By impouring in reaction solution, filter, be spin-dried for by filtrate solvent, residual solution methylene dichloride repeatedly extracts, and merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, silica gel column chromatography (ethyl acetate/petroleum ether 1:30) obtains white compound 3d (0.677g, yield 86%).
1HNMR(300MHz,CDCl 3):δ8.902(s,1H),8.057(t,J＝8.4Hz,1H),7.966(s,1H),7.826～7.853(m,2H),7.764(d,J＝8.4Hz,1H),7.673～7.713(m,3H),7.513(t,J＝6.9Hz,1H),1.586(d,J＝15.9Hz,1H),6.395～6.472(m,1H),3.912(t,J＝6.9Hz,2H),2.696(dd,J＝7.2Hz,J＝6.9Hz,2H).
HR-MS(ESI)(M+H) +m/z329.1280,calcdforC 21H 16N 2O 2328.1212.
The synthesis of compound (4d)
Compound 3d (0.30g, 0.61mmol) is scattered in 10ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (70 μ l, 1.22mmol), 80 DEG C are heated to, back flow reaction 5h, reaction solution concentrating under reduced pressure is obtained light yellow solid, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains white oil compound 120mg, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z199.1232,calcdforC 13H 14N 2198.1157.
The synthesis of compound (5d)
By compound 3d (0.30g, 0.91mmol) be scattered in 10ml dehydrated alcohol, Pd/C (30mg is added in reaction solution, m/m:10%), under normal pressure, hydrogen balloon passes into hydrogen, react 18h under room temperature, TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.Filter, filtrate reduced in volume is obtained crude product, silica gel column chromatography (ethyl acetate/petroleum ether 1:30) obtains white compound 5d (0.27g, yield 90%).
1HNMR(400MHz,CDCl 3):δ8.894(s,1H),8.070(t,J＝6.9Hz,1H),7.966(s,1H),7.826～7.853(m,2H),7.764(d,J＝8.4Hz,1H),7.673～7.713(m,3H),7.513(t,J＝6.9Hz,1H),3.756(t,J＝5.6Hz,2H),2.858(t,J＝5.6Hz,2H),1.783～1.792(m,2H),1.620(s,2H).
HR-MS(ESI)(M+H) +m/z331.1443,calcdforC 21H 18N 2O 2330.1368.
The synthesis of compound (6d)
Compound 5d (0.15g, 0.45mmol) is scattered in 10ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (52 μ l, 0.9mmol), 80 DEG C are heated to, back flow reaction 5h, reaction solution concentrating under reduced pressure is obtained light yellow solid, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains white oil compound 82mg, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z201.1387,calcdforC 13H 16N 2200.1313.
Preparation example 5
The synthetic route of Scheme5 intermediate 2e
Scheme5Reagentsandconditions:a.TsCl,Py,DCM,r.t.24h；b.NH 2NH 2·H 2O,EtOH,reflux,80℃。
The synthesis of compound (1e)
By compound 4c (0.5g, 1.51mmol) be dissolved in anhydrous methylene chloride (5ml), add pyridine (2.5ml) wherein, Tosyl chloride (0.345g is slowly dripped in ice bath downhill reaction liquid, 1.81mmol), react 24h under room temperature, TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.By in reaction solution impouring frozen water, repeatedly extract with methylene dichloride, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, silica gel column chromatography (ethyl acetate/petroleum ether 1:5) obtains faint yellow compound 1e (0.72g, yield 98%).
1HNMR(400MHz,CDCl 3):δ8.460(s,1H),8.061～8.094(m,2H),7.791～7.830(m,2H),7.745(t,J＝7.6Hz,2H),7.687(t,J＝2.8Hz,2H),7.583(t,J＝7.6Hz,2H),7.471(d,J＝8.0Hz1H),3.747～3.809(m,3H),2.422(s,3H),1.849～1.885(m,2H).
HR-MS(ESI)(M+H) +m/z486.1750,calcdforC 27H 23N 3O 4S485.1409.
The synthesis of compound (2e)
Compound 1e (0.68g, 1.4mmol) is scattered in 15ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (160 μ l, 2.8mmol), 80 DEG C are heated to, back flow reaction 5h, reaction solution concentrating under reduced pressure is obtained light yellow solid, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains faint yellow oily compound 0.48g, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z356.1422,calcdforC 19H 21N 3O 2S355.1354.
Preparation example 6
The synthetic route of Scheme6 intermediate 5f
Scheme6Reagentsandconditions:a.Benzaldehyde,EtOH,reflux；b.NaBH 4,EtOH,r.t.；c.N-(3-Bromopropyl)phthalimide,K 2CO 3,DMF,90℃；d.NH 2NH 2·H 2O,EtOH,reflux,80℃。
The synthesis of compound (2f)
By 3-quinolylamine (1f) (1.63g, 11.3mmol) with phenyl aldehyde (1.0g, 9.42mmol) be added in dehydrated alcohol, be heated to back flow reaction spend the night, TLC display reacts completely, be cooled to room temperature, evaporated under reduced pressure solvent afforded crude material 2f, not treated directly carry out next step reaction.
The synthesis of compound (3f)
Upper step gained crude product (2f) is dissolved in 30ml anhydrous methylene chloride, ice-water bath is cooled to about 0 DEG C, wherein will repeatedly add sodium borohydride (0.43g in batches, 11.3mmol), finish, continue reaction 12h, TLC (ethyl acetate/petroleum ether 2:1) display reacts completely, stopped reaction, in reaction solution, add 5ml shrend to go out reaction, by ethanol evaporate to dryness, add water 25ml, repeatedly extract by ethyl acetate, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, column chromatography (ethyl acetate/petroleum ether 1:5) purifying, obtain sterling 3f (0.76g, two step yields 34.5%).
1HNMR(400MHz,CDCl 3):δ8.495(d,1H,J＝4.0Hz),7.927～7.959(m,1H),7.567(m,1H),7.377～7.425(m,6H),7.332～7.351(m,2H),7.034(d,1H,J＝4.0Hz),4.445(d,2H,J＝6.8Hz),4.375(s,1H).
HR-MS(ESI)(M+H) +m/z235.1216,calcdforC 16H 14N 2234.1157.
The synthesis of compound (4f)
Be dispersed in the DMF of 10ml drying by the NaH (0.36g, 5.44mmol) of 70%, cryostat, is cooled to 0 DEG C, argon shield.Add compound 3f (0.636g, 2.72mmol) and N-(3-bromopropyl) phthalic imidine (1.8g, 6.8mmol).Under room temperature, reaction is spent the night, and TLC (ethyl acetate/petroleum ether 1:1) display reacts completely.Reaction solution is poured on 50ml on ice, methylene dichloride repeatedly extracts, and merges organic phase, washing, and saturated common salt is washed.After this solid with methylene chloride solubilize, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, the white foam solid 4f (0.79g, yield 69%) of petrol ether/ethyl acetate (10:1) column chromatography.
1HNMR(400MHz,CDCl 3):δ8.654(d,1H,J＝2.8Hz),7.894(m,1H),7.834～7.855(m,2H),7.714～7.736(m,2H),7.520(m,1H)7.379～7.402(m,2H),7.213(m,2H),7.124(s,1H),4.676(s,2H),3.791(t,2H,J＝6.8Hz),3.594(t,2H,J＝8.0Hz),2.122(m,2H,J＝6.8Hz,J＝8.0Hz).
HR-MS(ESI)(M+H) +m/z422.1845,calcdforC 27H 23N 3O 2421.1790.
The synthesis of compound (5f)
By compound 4f (0.12g, 0.285mmol) be scattered in 15ml dehydrated alcohol, 85% hydrazine hydrate (32 μ l are dripped in reaction solution, 0.57mmol), be heated to 80 DEG C, back flow reaction 5h, obtains light yellow solid by reaction solution concentrating under reduced pressure, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains faint yellow oily compound (5f) 48mg, without separation, is directly used in the next step.
1HNMR(400MHz,CDCl 3):δ8.654(d,J＝2Hz,1H),7.902(m,1H),7.842(t,J＝4.8Hz,1H),7.728(t,J＝5.2Hz,2H),7.532(dd,J＝5.2Hz,J＝4.4Hz,1H),7.391(t,J＝4.4Hz,2H),7.213～7.287(m,6H),7.203(s,1H),4.676(s,2H),3.790(t,J＝7.2Hz,2H),3.790(t,J＝7.2Hz,2H),3.790(t,J＝7.2Hz,2H).
HR-MS(ESI)(M+H) +m/z292.1804,calcdforC 19H 21N 3291.1735.
Preparation example 7
The synthetic route of Scheme7 intermediate 2g
Scheme7Reagentsandconditions:a.BzCl,Py,DCM,r.t.24h；b.NH 2NH 2·H 2O,EtOH,80℃。
The synthesis of compound (1g)
Compound 4c (0.5g, 1.51mmol) and Benzoyl chloride (0.27ml, 0.32g, 2.26mmol) are added in 15ml pyridine, react 3.5h under being placed in room temperature, TLC (ethyl acetate/petroleum ether 2:1) display reacts completely.By in reaction solution impouring frozen water, repeatedly extract with methylene dichloride, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:3) obtains faint yellow compound 1g (0.638g, yield 97%).
1HNMR(400MHz,CDCl 3):δ8.690(s,1H),8.111(s,1H),7.994(s,1H),7.699～7.814(m,6H),7.574(m,1H),7.320(s,1H),7.148～7.316(m,4H),4.145(s,2H),3.820(s,2H),2.074(s,2H).
HR-MS(ESI)(M+H) +m/z436.1614,calcdforC 27H 21N 3O 3435.1583.
The synthesis of compound (2g)
Compound 1g (0.63g, 1.45mmol) is scattered in 15ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (165 μ l, 2.90mmol), 80 DEG C are heated to, back flow reaction 5h, reaction solution concentrating under reduced pressure is obtained light yellow solid, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains faint yellow oily compound 2g0.4g, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z306.1599,calcdforC 19H 19N 3O305.1528.
Preparation example 8
The synthetic route of Scheme8 intermediate 5h
Scheme8Reagentsandconditions:a.Propionaldehyde,EtOH,reflux；b.NaBH 4,EtOH,r.t.；c.N-(3-Bromopropyl)phthalimide,K 2CO 3,DMF,90℃；d.NH 2NH 2·H 2O,EtOH,reflux,80℃。
The synthesis of compound (2h)
By 3-quinolylamine (1h) (2.0g, 13.56mmol) with positive propionic aldehyde (0.66g, 11.3mmol) be added in 20ml dehydrated alcohol, be heated to back flow reaction spend the night, TLC display reacts completely, be cooled to room temperature, evaporated under reduced pressure solvent afforded crude material 2h, not treated directly carry out next step reaction.
HR-MS(ESI)(M+H) +m/z184.1023,calcdforC 12H 12N 2184.1000.
The synthesis of compound (3h)
Upper step gained crude product (2h) is dissolved in 50ml anhydrous methylene chloride, ice-water bath is cooled to about 0 DEG C, wherein will repeatedly add sodium borohydride (0.516g in batches, 13.56mmol), finish, continue reaction 12h, TLC (ethyl acetate/petroleum ether 2:1) display reacts completely, stopped reaction, in reaction solution, add 5ml shrend to go out reaction, by ethanol evaporate to dryness, add water 40ml, repeatedly extract by ethyl acetate, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, column chromatography (ethyl acetate/petroleum ether 1:5) purifying, obtain sterling 3h (0.94g, two step yields 45.2%).
1HNMR(400MHz,CDCl 3):δ8.496(d,1H,J＝4.0Hz),7.932～7.964(m,1H),7.562(m,1H),7.342～7.358(m,2H),7.036(d,1H,J＝4.0Hz),3.312～3.368(m,2H),1.68(m,2H),0.98(m,2H).
HR-MS(ESI)(M+H) +m/z186.1136,calcdforC 12H 14N 2186.1157.
The synthesis of compound (4h)
Be dispersed in the DMF of 10ml drying by the NaH (0.35g, 5.36mmol) of 70%, cryostat, is cooled to 0 DEG C, argon shield.Add compound 3h (0.5g, 2.68mmol) and N-(3-bromopropyl) phthalic imidine (2.1g, 8.06mmol).Under room temperature, reaction is spent the night, and TLC (ethyl acetate/petroleum ether 1:1) display reacts completely.Reaction solution is poured on 50ml on ice, methylene dichloride repeatedly extracts, and merges organic phase, washing, and saturated common salt is washed.After this solid with methylene chloride solubilize, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, the white foam solid 4h (0.72g, yield 72%) of petrol ether/ethyl acetate (10:1) column chromatography.
1HNMR(400MHz,CDCl 3):δ8.654(d,1H,J＝2.8Hz),7.894(m,1H),7.714～7.736(m,2H),7.520(m,1H)7.379～7.402(m,2H),7.213(m,2H),7.124(s,1H),3.791(t,2H,J＝6.8Hz),3.594(t,2H,J＝8.0Hz),2.122(m,2H,J＝6.8Hz,J＝8.0Hz),3.312～3.368(m,2H),1.68(m,2H),0.98(m,2H).
HR-MS(ESI)(M+H) +m/z373.1845,calcdforC 27H 23N 3O 2373.1790.
The synthesis of compound (5h)
By compound 4h (0.3g, 0.8mmol) be scattered in 15ml dehydrated alcohol, 85% hydrazine hydrate (96 μ l are dripped in reaction solution, 1.6mmol), be heated to 80 DEG C, back flow reaction 5h, obtains light yellow solid by reaction solution concentrating under reduced pressure, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains faint yellow oily compound (5h) 124mg, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z243.1702,calcdforC 15H 21N 3243.1735.
Preparation example 9
The synthetic route of Scheme9 intermediate 6i
Scheme9Reagentsandconditions:a.Acrolein,EtOH,reflux；b.NaBH 4,EtOH,r.t.；c.N-(3-Bromopropyl)phthalimide,K 2CO 3,DMF,90℃；d.3-Bromoquinoline,Pd(OAc) 2,PPh 3,CH 3CN,TEA,reflux,12h；e.NH 2NH 2·H 2O,EtOH,reflux,80℃。
The synthesis of compound (2i)
By 3-quinolylamine (1i) (3.0g, 21.4mmol) with allyl aldehyde (1.0g, 17.8mmol) be added in 30ml dehydrated alcohol, be heated to back flow reaction spend the night, TLC display reacts completely, be cooled to room temperature, evaporated under reduced pressure solvent afforded crude material 2i, not treated directly carry out next step reaction.
HR-MS(ESI)(M+H) +m/z182.1026,calcdforC 12H 10N 2182.0844.
The synthesis of compound (3i)
Upper step gained crude product (2i) is dissolved in 40ml anhydrous methylene chloride, ice-water bath is cooled to about 0 DEG C, wherein will repeatedly add sodium borohydride (0.814g in batches, 21.4mmol), finish, continue reaction 12h, TLC (ethyl acetate/petroleum ether 2:1) display reacts completely, stopped reaction, in reaction solution, add 8ml shrend to go out reaction, by ethanol evaporate to dryness, add water 30ml, repeatedly extract by ethyl acetate, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, column chromatography (ethyl acetate/petroleum ether 1:5) purifying, obtain sterling 3i (1.26g, two step yields 38.6%).
1HNMR(400MHz,CDCl 3):δ8.392(d,1H,J＝4.0Hz),7.931～7.963(m,1H),7.564(m,1H),7.328～7.348(m,2H),7.034(d,1H,J＝4.0Hz),5.873(dd,1H,J＝16.8Hz,J＝6.2Hz),5.228(dd,1H,J＝16.8Hz,J＝2.1Hz),5.204(dd,1H,J＝2.1Hz,J＝6.2Hz),3.846(m,2H).
HR-MS(ESI)(M+H) +m/z184.1478,calcdforC 12H 12N 2184.1000.
The synthesis of compound (4i)
Be dispersed in the DMF of 50ml drying by the NaH (0.72g, 10.88mmol) of 70%, cryostat, is cooled to 0 DEG C, argon shield.Add compound 3i (1.0g, 5.43mmol) and N-(3-bromopropyl) phthalic imidine (4.3g, 16.3mmol).Under room temperature, reaction is spent the night, and TLC (ethyl acetate/petroleum ether 1:1) display reacts completely.Reaction solution is poured on 100ml on ice, methylene dichloride repeatedly extracts, and merges organic phase, washing, and saturated common salt is washed.After this solid with methylene chloride solubilize, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, the white foam solid 4i (1.57g, yield 78%) of petrol ether/ethyl acetate (10:1) column chromatography.
1HNMR(400MHz,CDCl 3):δ8.656(d,1H,J＝2.8Hz),7.892(m,1H),7.835～7.863(m,2H),7.724～7.745(m,2H),7.521(m,1H)7.389～7.412(m,2H),7.215(m,2H),7.123(s,1H),5.875(dd,1H,J＝16.8Hz,J＝6.2Hz),5.224(dd,1H,J＝16.8Hz,J＝2.1Hz),5.214(dd,1H,J＝2.1Hz,J＝6.2Hz),3.846(m,2H),3.792(t,2H,J＝6.8Hz),3.598(t,2H,J＝8.0Hz),2.125(m,2H,J＝6.8Hz,J＝8.0Hz).
HR-MS(ESI)(M+H) +m/z371.1713,calcdforC 23H 21N 3O 2371.1634.
The synthesis of compound (5i)
By 3-bromoquinoline (0.5g, 2.4mmol) with compound (4i) (1.07g, 2.9mmol) be dissolved in anhydrous acetonitrile (20ml), acid chloride (5.4mg is added in reaction solution, m/m:1%eq), triphenylphosphine (24mg, and triethylamine (0.97g m/m:4%eq), 1.34ml, 9.6mmol), reaction solution is heated to back flow reaction 12h, and TLC (ethyl acetate/petroleum ether 1:3) display reacts completely.By impouring in reaction solution, filter, be spin-dried for by filtrate solvent, residual solution methylene dichloride repeatedly extracts, and merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains crude product, silica gel column chromatography (ethyl acetate/petroleum ether 1:30) obtains white compound 5i (1.1g, yield 92%).
1HNMR(400MHz,CDCl 3):δ8.656(d,1H,J＝2.8Hz),7.892(m,1H),7.882(m,2H),7.844(m,2H),7.835～7.863(m,2H),7.724～7.745(m,2H),7.521(m,1H)7.389～7.412(m,2H),7.218(m,2H),7.127(s,1H),5.878(dd,1H,J＝16.8Hz,J＝6.2Hz),5.226(dd,1H,J＝16.8Hz,J＝2.1Hz),5.215(dd,1H,J＝2.1Hz,J＝6.2Hz),3.848(m,2H),3.794(t,2H,J＝6.8Hz),3.596(t,2H,J＝8.0Hz),2.124(m,2H,J＝6.8Hz,J＝8.0Hz).
HR-MS(ESI)(M+H) +m/z498.1880,calcdforC 32H 26N 4O 2498.2056.
The synthesis of compound (6i)
Compound 5i (0.5g, 1.0mmol) is scattered in 30ml dehydrated alcohol, in reaction solution, drips 85% hydrazine hydrate (112 μ l, 2.0mmol), 80 DEG C are heated to, back flow reaction 5h, reaction solution concentrating under reduced pressure is obtained light yellow solid, chloroform extraction, the sodium hydroxide solution of organic phase 2mol/L is washed, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated organic phase obtains faint yellow oily compound 6i0.32g, without separation, is directly used in the next step.
HR-MS(ESI)(M+H) +m/z368.1804,calcdforC 24H 24N 4368.2001.
The preparation of preparation example 10 starting compound 6
New texture macrocyclic ketone lactone compound of the present invention is namely from clarithromycin, adopt the feasible reaction method that in known bibliographical information or synthetic chemistry, the public is known, obtain suitable derivative as raw material of the present invention, as starting compound 6, document J.Med.Chem can be adopted, 41,4080-4100, the method preparation of 1998 reports.
Be dispersed in by clarithromycin (50g, 66.9mmol) in 350ml water, add the hydrochloric acid (350ml) of 1mol/L wherein, stirring at room temperature, reaction solution becomes sticky thick gradually.Continue reaction 3h, reaction solution gradually becomes clear liquor, and TLC (chloroform/methanol 10:1) detection display reacts completely.Adjust pH to 9-10 with the sodium hydroxide solution of 2mol/L, have a large amount of white solid to produce, product repeatedly extracts through methylene dichloride, merges organic phase, and saturated common salt is washed, anhydrous sodium sulfate drying.Concentrating under reduced pressure, methylene chloride/methanol 50:1) reduced pressure chromatography obtains sterling (1) 37.9g, productive rate 96%.
1HNMR(300MHz,CDCl 3):δ5.172(dd,1H,J＝2.1Hz,J＝10.8Hz),4.386(d,1H,J＝7.2Hz),3.917(s,1H),3.851(s,1H),3.681(s,1H),2.965(s,3H),2.262(s,6H),2.114(q,1H,J＝7.5Hz),1.362(s,3H),1.178(s,3H),0.831(t,3H,J＝7.2Hz).
13CNMR(75MHz,CDCl 3):221.116,175.416,107.026,88.749,79.391,78.450,74.604,71.065,70.685,70.184,66.087,49.978,45.936,44.976,40.666,39.153,37.932,36.281,28.452,21.842,21.676,19.178,18.152,16.606,15.606,13.051,10.839,8.644.
HR-MS (ESI) (M+H) +m/z590.3885, calculated value: C 30h 56nO 10590.3898.
Compound 1 (24.322g; after toluene band water, 41.29mmol) be dissolved in the methylene dichloride of 300ml drying; argon shield; ice-water bath cools; completely to be dissolved; triethylamine (6.9ml, 49.55mmol) and diacetyl oxide (4.67ml, 49.55mmol) is dropwise added successively in 0 DEG C.Stirring at room temperature 10h, TCL (chloroform/methanol 10/1) detection display reacts completely, 100ml frozen water termination reaction is added in reaction solution, leave standstill separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrates to obtain weak yellow foam shape crude product 27.38g, decompression silica gel column chromatography separating purification (methylene chloride/methanol/triethylamine 30:1:2%) obtains white foam solid (2) 21.9g, yield 84%.
1HNMR(300MHz,CDCl 3):δ5.158(dd,1H,J＝2.1Hz,J＝10.8Hz),4.742(dd,1H,J＝7.8Hz,J＝10.5Hz),4.592(d,1H,J＝7.5Hz),3.945(s,1H),3.807(s,1H),3.705(d,1H,J＝2.4Hz),3.459(m,2H),3.250(s,1H),2.930(s,3H),2.245(s,6H),2.031(s,3H),0.927(d,3H,J＝7.8Hz),0.819(t,3H,J＝7.2Hz).
13CNMR(75MHz,CDCl 3):221.376,175.066,170.355,100.024,81.446,78.379,78.187,77.192,74.561,71.914,70.021,69.222,63.544,50.126,45.877,44.418,41.013,38.880,41.013,38.880,37.688,36.086,31.455,21.795,21.532,19.658,18.329,17.767,16.585,15.714,13.002,10.852,8.233.
HR-MS (ESI) (M+H) +m/z632.4018, calculated value: C 32h 58nO 11632.4010.
Compound 2 (1.935g, 3.067mmol) fully with being dissolved in after water in the dichloromethane solution of 20ml drying, adds pyridine (3.968ml, 49.065mmol), argon shield through toluene, fully mixes 0.5h under ice-water bath cooling.Dichloromethane solution (3ml) solution of superpalite (0.962ml, 7.973mmol) is dripped in system.Reaction solution becomes faint yellow at once, continues room temperature reaction, and the muddy gradually and color burn of reaction solution, after 24h, TLC (acetone/sherwood oil/triethylamine 1.5:1:1%) display reacts completely.In system, add a small amount of trash ice termination reaction, add a large amount of methylene dichloride and the solid in system is dissolved completely.Carefully add saturated sodium bicarbonate solution, stirring at normal temperature, separatory after no longer including bubble and producing, organic phase is washed with half saturated sodium-chlor respectively, and saturated sodium-chloride is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, (sherwood oil/acetone/triethylamine 2.5:1:0.5%) reduced pressure chromatography, obtains light yellow product (3) 1.51g, productive rate 75%.
1HNMR(300MHz,CDCl 3):δ5.122(d,1H,J＝9.0Hz),4.714～4.774(m,2H),4.578(d,1H,J＝7.5Hz),3.690(s,1H),3.452～3.507(m,2H),2.914(s,3H),2.640～2.746(m,2H),2.549～2.604(m,1H),2.250(s,6H),2.057(s,3H),1.489(s,3H),1.180(d,3H,J＝6.6Hz),1.139(d,3H,J＝7.5Hz),0.937(d,3H,J＝7.2Hz),0.861(t,3H,J＝7.5Hz).
13CNMR(75MHz,CDCl 3):212.527,175.288,170.271,154.452,100.302,85.252,81.591,81.284,78.523,78.158,75.655,71.920,69.315,63.592,50.009,45.650,44.540,41.079,38.969,37.824,36.304,31.359,22.513,21.862,21.524,19.676,18.702,15.630,14.513,13.436,10.520,8.153.
HR-MS (ESI) (M+H) +m/z658.3815, calculated value: C 33h 56nO 12658.3797.
By oxalyl chloride (0.823g; 6.482mmol) be dissolved in dry methylene dichloride (15ml); argon shield; acetone-dry ice bath is cooled to-78 DEG C; drip methylene dichloride (2ml) solution of DMSO (1.013g, 12.963mmol) after stable wherein, after stable, drip fully dry compound 3 (2.839g again; dichloromethane solution (25ml) 4.321mmol), remains on-78 DEG C of reaction 4h.Drip the dichloromethane solution (2ml) of triethylamine (2.624g, 25.927mmol), and make reaction solution be warming up to room temperature gradually, TLC (chloroform/methanol 10:1) display reaction is substantially complete.Use the hydrochloric acid of 1N after dchloromethane respectively, saturated sodium bicarbonate, saturated common salt is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains weak yellow foam shape solid, and reduced pressure chromatography (acetone/sherwood oil 3:1) obtains white foam sterling (4) 1.98g, productive rate 70%.
1HNMR(300MHz,CDCl 3):δ5.054(dd,1H,J＝2.7Hz,J＝9.9Hz),4.732(dd,1H,J＝10.2Hz,J＝8.1Hz),4.623(s,1H),4.377(d,1H,J＝7.8Hz),4.160(d,1H,J＝7.5Hz),3.781(q,1H,J＝6.9Hz),3.543(m,1H),2.941～3.026(m,2H),2.645(s,3H),2.241(s,6H),2.044(s,3H),1.942(s,1H),1.813～1.866(m,1H),1.705～1.736(m,1H),1.540(s,3H),1.472(s,3H),1.401～1.424(m,3H),1.344～1.361(m,3H),1.315(s,3H),1.229～1.265(m,3H),1.129～1.154(m,6H),0.894(t,3H,J＝7.5Hz).
13CNMR(75MHz,CDCl 3):213.277,204.412,170.193,169.492,154.295,101.870,84.890,81.311,78.767,78.571,77.126,72.009,69.600,63.847,51.529,49.963,47.979,44.222,41.082,39.674,38.523,30.859,22.780,21.834,21.421,20.105,18.312,16.612,14.526,13.971,12.904,10.774.
HR-MS(ESI)(M+H) +m/z656.3627,calcdforC 33H 54NO 12656.3641.
The compound 4 (11.48g, 17.5mmol) of abundant drying is dissolved in the acetone of 150ml drying, argon shield; dropwise add DBU (3.92ml; 26.25mmol), reflux 4h, TLC (chloroform/methanol 10:1) display reacts completely.The potassium dihydrogen phosphate dropwise adding 5% adjusts pH to neutral.Dilute with a large amount of dichloromethane solution after decompression evaporates part acetone, saturated common salt is washed, and anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product, through re-crystallizing in ethyl acetate, obtains white solid sterling (5) 8.0g, productive rate 75%.
1HNMR(300MHz,CDCl 3):δ6.597(s,1H),4.987(d,1H,J＝9.6Hz),4.719(t,J＝8.0Hz1H),4.348(d,1H,J＝8.0Hz),4.130(d,1H,J＝8.0Hz),3.724(q,1H,J＝6.8Hz),3.504～3.544(m,1H),3.165(q,1H,J＝6.0Hz),3.032～3.070(m,1H),2.861(s,3H),2.637(t,1H,J＝8.8Hz),2.237(s,6H),2.015(s,3H),2.034(s,3H),1.942(s,1H),1.813～1.866(m,1H),1.705～1.736(m,1H),1.544～1.595(m,3H),1.472(s,3H),1.344～1.361(m,3H),1.325(s,3H),1.229～1.265(m,3H),1.113～1.159(m,6H),0.929(t,3H,J＝7.2Hz).
13CNMR(100MHz,CDCl 3):207.404,170.143,170.109,142.441,139.167,102.170,81.691,81.326,78.676,73.741,71.914,69.478,63.926,51.583,50.770,47.503,41.027,40.522,38.811,30.759,22.791,22.354,21.759,21.380,19.287,15.166,14.396,13.940,11.313.
HR-MS (ESI) (M+H) +m/z612.3755, calculated value: C 32h 54nO 10612.3742.
Be dispersed in the DMF of 60ml drying by the NaH (0.662g, 19.313mmol) of 70%, cryostat, is cooled to-15 DEG C, argon shield.Add compound 5 (5.9g, 9.656mmol) in batches, fully after mixing, drip the DMF solution (40ml) of CDI (4.693g, 28.969mmol).Continue low-temp reaction 2h, TLC (acetone/sherwood oil 1.5:1) display reacts completely.Reaction solution is poured on 150ml on ice, has a large amount of foamy white solid to separate out after placement, suction filtration, wash to obtain white solid.After this solid with methylene chloride solubilize, washing, saturated common salt is washed, anhydrous sodium sulfate drying, white foam solid (6) 5.4g of sherwood oil/acetone (3:1) reduced pressure chromatography, productive rate 80%.
1HNMR(400MHz,CDCl 3):δ8.076(s,1H),7.358(s,1H),7.056(s,1H),6.783(s,1H),5.675(dd,1H,J＝9.6Hz,J＝2.4Hz),4.702(t,1H,J＝8.0Hz),4.332(d,1H,J＝7.6Hz),4.109(d,1H,J＝8.8Hz),3.730(q,1H,J＝6.8Hz),3.457～3.497(m,1H),3.142(d,1H,J＝6.4Hz),3.018(t,3H,J＝6.0Hz),2.769(s,3H),2.624(t,1H,J＝8.8Hz),2.244(s,6H),2.024(s,3H),1.817～1.849(m,6H),1.605～1.726(m,3H),1.412～1.430(m,3H),1.340～1.357(m,3H),1.390(s,3H),1.198～1.229(m,3H),0.934(t,3H,J＝7.2Hz).
13CNMR(100MHz,CDCl 3):205.259,169.983,169.129,146.225,138.421,137.323,131.193,117.380,102.226,84.815,81.232,78.826,71.815,69.425,63.355,53.707,51.309,50.542,47.683,40.912,40.565,39.220,30.550,22.926,21.656,21.218,20.974,20.444,19.190,15.331,14.294,13.540,10.745.
HR-MS (ESI) (M+H) +m/z706.3895, calculated value: C 33h 58n 2o 14706.3883.
Embodiment
The preparation of embodiment 1S1 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-3-sulfydryl substituted propyl) imino-) erythromycin):
The synthetic route of compound S 1:
The preparation of the first step compound (M1)
Compound 5a (70mg, 0.3046mmol) with macrolide intermediates 6 (108mg, 0.1523mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (93mg is dripped in reaction solution, 0.61mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.20mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M1 (68mg, 52%).
1HNMR(300MHz,CDCl 3):δ8.827(d,1H,J＝2.4Hz),8.032～8.053(m,1H),7.784(d,1H,J＝8.0Hz),7.624～7.697(m,2H),7.543(t,1H,J＝6.0Hz),7.110(s,1H),4.872(d,J＝6.9Hz,1H),4.733(dd,1H,J＝6.0Hz,J＝8.0Hz),4.365(d,2H,J＝6.0Hz),4.015(d,1H,J＝7.8Hz),3.722～3.785(m,2H),3.609(m,1H),3.396～3.501(m,2H),3.015～3.064(m,3H),2.677(m,1H),2.575(m,1H),2.503～2.524(m,2H),2.245(s,6H),2.043～2.067(m,3H),1.973(m,2H),1.715～1.748(m,1H),1.658(s,3H),1.474(s,3H),1.234～1.261(m,6H),1.155～1.177(m,3H),0.997(d,3H,J＝5.1Hz),0.821(m,3H).
HR-MS(ESI)(M+H) +m/z856.4349,calcdforC 45H 65N 3O 11S855.4340.
The preparation of second step compound (S1)
Compound M1 (30mg, 0.035mmol) is added in 2ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S1 (24mg, 84%).
1HNMR(400MHz,CDCl 3):δ8.824(s,1H),8.030～8.111(m,2H),7.788(d,1H,J＝8.0Hz),7.639(t,2H,J＝6.9Hz),7.522～7.547(m,1H),4.872(d,J＝6.6Hz,1H),δ4.672(s,1H),4.320(d,2H,J＝6.9Hz),4.034(d,J＝10.5Hz,1H),3.720～3.764(m,3H),3.513(m,2H),3.443(s,1H),3.172～3.231(m,2H),3.012～3.081(m,3H),2.899(s,1H),2.520(m,3H),2.310(s,6H),1.929～2.010(m,3H),1.761～1.856(m,2H),1.654(s,3H),1.532～1.571(m,2H),1.475(s,3H),1.227～1.305(m,6H),1.152(d,3H,J＝6.6Hz),0.986～1.009(d,3H,J＝6.9Hz),0.801～0.870(m,6H).
13CNMR(150MHz,CDCl 3):δ216.646,205.978,173.621,168.157,157.230,151.811,135.053,130.948,129.391,129.147,127.392,127.269,104.162,98.195,82.169,81.925,80.948,78.689,78.583,70.570,69.624,66.083,61.336,49.416,44.792,43.403,40.808,40.472,39.923,39.404,31.544,29.911,28.919,28.675,26.904,22.371,21.364,20.051,18.128,15.641,15.045,14.007,10.543.
HR-MS(ESI)(M+H) +m/z814.4246,calcdforC 43H 63N 3O 10S813.4234.
The preparation of embodiment 2S2 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-3-hydroxyl substituted propyl) imino-) erythromycin):
The synthetic route of compound S 2:
The preparation of the first step compound (M2)
Compound 3b (84mg, 0.413mmol) with macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (26mg is dripped in reaction solution, 0.17mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.5mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M2 (23mg, 65%).
1HNMR(400MHz,CDCl 3):δ8.622(s,1H),8.009(d,1H,J＝8.0Hz),7.707(d,1H,J＝8.0Hz),7.492～7.538(m,2H),7.455(s,1H),4.983(d,1H,J＝10.4Hz),4.732(t,2H,J＝8.0Hz),4.382(t,J＝6.0Hz,1H),4.127(t,J＝6.0Hz,1H),3.810～3.855(m,3H),3.650(s,1H),3.529(t,1H,J＝6.0Hz),3.004～3.122(m,3H),2.677(s,3H),2.621(t,1H),2.248(s,6H),2,073(s,1H),2,050(s,3H),1.657～1.748(m,3H),1.481(s,3H),1.312～1.358(m,6H),1.229～1.254(m,6H),1.137～1.169(m,6H),1.026(d,3H,J＝6.8Hz),0.802～0.856(m,3H).
HR-MS(ESI)(M+H) +m/z839.4568,calcdforC 45H 65N 3O 12839.4568.
The preparation of second step compound (S2)
Compound M2 (48mg, 0.057mmol) is added in 2ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S2 (42.2mg, 92.4%).
1HNMR(400MHz,CDCl 3):δ8.633(s,1H),8.015(d,1H,J＝8.0Hz),7.714(d,1H,J＝8.0Hz),7.477～7.527(m,2H),7.391(s,1H),4.988(d,J＝10.4Hz,1H),4.229～4.290(m,2H),4.138(t,J＝6.0Hz,1H),3.817～3.889(m,3H),3.648(s,1H),3.529(t,1H,J＝6.0Hz),3.053～3.206(m,3H),2.659(s,3H),2.460(t,1H),2.272(s,6H),2,216(t,1H,J＝6.4Hz),1.969(t,2H),1.569～1.687(m,3H),1.472(s,3H),1.351(s,3H),1.289～1.307(m,3H),1.248(s,3H),1.161(d,3H,J＝6.8Hz),1.041(d,3H,J＝6.8Hz),0.810～0.865(m,6H).
13CNMR(150MHz,CDCl 3):δ216.052,203.700,169.753,157.156,152.424,144.911,143.424,129.075,128.851,126.858,126.726,126.448,112.898,103.875,82.284,79.461,78.161,70.296,69.566,65.992,65.890,60.694,51.194,49.814,47.609,44.918,41.236,40.213,39.483,39.011,29.661,28.204,26.918,22.196,21.151,19.727,18.303,15.821,14.443,14.317,13.878,10.382.
HR-MS(ESI)(M+H) +m/z798.4489,calcdforC 43H 63N 3O 11797.4463.
The preparation of embodiment 3S3 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (the amino substituted propyl of quinoline-3-) imino-) erythromycin):
The synthetic route of compound S 3:
The preparation of the first step compound (M3)
Compound 5c (72mg, 0.356mmol) with macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (26mg is dripped in reaction solution, 0.17mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.5mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M3 (21mg, 59%).
1HNMR(400MHz,CDCl 3):δ8.760(d,1H,J＝8.0Hz),8.018(d,1H,J＝8.8Hz),7.797(d,1H,J＝8.0Hz),7.614(t,1H,J＝7.2Hz),7.535(t,1H,J＝7.2Hz),6.583(s,1H),4.996(t,1H),4.714～4.740(m,1H),4.444(s,1H),4.335～4.386(m,1H),4.218(d,1H,J＝7.6Hz),4.134(d,1H,J＝8.0Hz),3.805～3.822(m,1H),3.602(s,1H),3.517～3.544(m,1H),2.856(s,3H),2.248～2.268(m,6H),2.062～2.076(m,3H),1.464(s,3H),1.143(d,3H,J＝6.9Hz),1.073(d,3H,J＝6.6Hz),0.825～0.862(t,3H,J＝7.2Hz).
HR-MS(ESI)(M+H) +m/z839.4777,calcdforC 45H 66N 4O 11838.4728.
The preparation of second step compound (S3)
Compound M3 (34mg, 0.04mmol) is added in 2ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S3 (26.5mg, 82%).
1HNMR(400MHz,CDCl 3):δ8.763(d,1H,J＝10.0Hz),8.034(d,1H,J＝8.0Hz),7.813(d,1H,J＝8.0Hz),7.611～7.649(m,2H),7.517～7.554(m,1H),6.583(s,1H),4.995(m,1H),4.714～4.740(m,1H),4.382(d,1H,J＝7.2Hz),4.288(t,1H,J＝7.2Hz),4.140(d,1H,J＝8.0Hz),3.715～3.732(m,1H),3.571(d,1H,J＝7.2Hz),3.017～3.126(m,6H),2.863(s,2H),2.346(m,3H),2.017(s,1H),1.473(s,3H),1.427(s,3H),1.263(d,3H,J＝9.2Hz),1.137(dd,3H,J＝12.0Hz,J＝7.2Hz),0.928(t,3H,J＝8.0Hz).
13CNMR(150MHz,CDCl 3):δ216.666，203.638，169.844，157.494，143.524，141.844，141.683,130.135,129.687,128.730,126.772,125.907,124.540,109.493,103.455,82.394,80.851,79.500,78.982,70.269,70.008,68.980,66.304,60.653,58.438,53.401,51.204,50.820,49.837,47.532,44.941,41.320,40.226,39.505,39.100,36.049,34.642,31.564,29.675,29.034,27.643,22.590,21.037,20.417,19.405,18.732,18.384,15.800,14.650,14.360,14.287,10.364.
HR-MS(ESI)(M+H) +m/z797.4746,calcdforC 43H 64N 4O 10796.4622.
The preparation of embodiment 4S4 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (3-quinolyl-3 (E)-butenyl) imino-) erythromycin):
The synthetic route of compound S 4:
The preparation of the first step compound (M4)
Compound 4d (124mg, 0.626mmol) with macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (26mg is dripped in reaction solution, 0.17mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.5mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M4 (22.7mg, 64%).
1HNMR(400MHz,CDCl 3):δ8.922(s,1H),8.014～8.072(m,2H),7.765(d,1H,J＝8.0Hz),7.599(t,2H,J＝8.0Hz),7.504(t,1H,J＝6.8Hz),6.729(d,1H,J＝16.0Hz),6.464(m,1H),4.989(d,1H,J＝10.4Hz),4.728(dd,2H,J＝8.0Hz,J＝8.0Hz),4.472(d,1H,J＝8.0Hz),4.374(d,1HJ＝8.0Hz),4.133(t,1H,J＝6.0Hz),3.809～3.873(m,3H),3.630(s,1H),3.529(m,2H),3.123(d,1H,J＝6.0Hz),3.008～3.040(m,2H),2.866(s,2H),2.591(m,3H),2.253(s,6H),2,054(s,3H),1.935(s,1H),1.741～1.758(m,5H),1.458(s,3H),1.318～1.381(m,6H),1.246(m,6H),1.129～1.186(m,6H),1.026(m,3H),0.856(d,3H,J＝6.0Hz).
HR-MS(ESI)(M+H) +m/z836.4722,calcdforC 46H 65N 3O 11835.4619.
The preparation of second step compound (S4)
Compound M4 (18mg, 0.0215mmol) is added in 2ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S4 (15mg, 87.7%).
1HNMR(400MHz,CDCl 3):δ8.940(s,1H),8.028～8.084(m,2H),7.776(d,1H,J＝8.0Hz),7.629(t,1H,J＝8.0Hz),7.508(t,1H,J＝8.0Hz),6.748(d,1H,J＝16.0Hz),6.475(m,1H),5.003(d,1H,J＝10.0Hz),4.307(d,1H,J＝7.2Hz),4.262(d,1H,J＝8.0Hz),3.862(m,3H),3.715(s,1H),3.630(s,1H),3.536(m,2H),3.216(m,2H),3.630(s,1H),3.138(m,3H),2.753(s,3H),2.608(m,3H),2.473(m,2H),2.316(s,6H),1.872(s,1H),1.725～1.823(m,2H),1.616～1.679(m,2H),1.458(s,3H),1.377(s,3H),1.250～1.262(m,6H),1.213(m,6H),1.183(d,3H,J＝7.2Hz),1.037(d,3H,J＝6.8Hz),0.935(m,3H),0.593(d,3H,J＝7.2Hz).
13CNMR(150MHz,CDCl 3):δ216.302,203.959，169.663，157.211，149.828，147.284，131.730，130.424，130.095，129.123，128.872，128.107，127.830，126.640，103.799，82.190，79.529，78.186，77.699，70.246，69.437，66.004，60.479，51.281，49.902，47.713，44.943，42.604，40.208，39.607，39.152，31.374，29.689，28.402，22.173，21.152，19.743，18.397，15.989，14.731，14.332，14.008，10.094.
HR-MS(ESI)(M+H) +m/z794.4603,calcdforC 44H 63N 3O 10793.4513.
The preparation of embodiment 5S5 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-4-replaces butyl) imino-) erythromycin):
The synthetic route of compound S 5:
The preparation of the first step compound (M5)
Compound 6d (52mg, 0.26mmol) with macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (26mg is dripped in reaction solution, 0.17mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.5mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M5.
HR-MS(ESI)(M+H) +m/z838.4774,calcdforC 46H 67N 3O 11837.4776.
The preparation of second step compound (S5)
Compound M5 (25mg, 0.030mmol) is added in 2ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S5 (18mg, two step yields 40.6%).
1HNMR(400MHz,CDCl 3):δ8.776(s,1H),8.077(d,J＝8Hz,1H),7.936(s,1H),7.788～7.852(m,1H),7.674(t,J＝7.6Hz,1H),7.520(t,J＝7.6Hz,1H),
4.954(d,J＝10.4Hz,1H),4.348(s,1H),4.229(t,J＝7.6Hz,1H),3.846(m,2H),3.677(m,1H),3.577～3.615(m,3H),3.387(s,2H),3.090(m,2H),2.952(m,1H),2.825(m,1H),2.743(s,1H),2.578(s,6H),1.871～1.899(m,2H),1.744～1.778(m,3H),1.566(m,3H),1.511(s,3H),1.349(s,3H),1.283～1.307(m,6H),1.171(s,3H),1.019(s,3H),0.825(m,3H).
13CNMR(150MHz,CDCl 3):δ216.027,203.863,169.544,157.213,151.952,149.716,146.678,134.936,134.277,131.797,128.452,127.412,126.417,103.064,82.084,79.313,78.029,69.853,68.579,66.475,60.390,51.202,49.696,47.325,44.881,43.111,40.046,39.368,39.048,32.746,31.349,29.800,28.463,26.851,22.274,20.954,19.685,18.353,15.655,14.378,14.106,13.903,10.436.
HR-MS(ESI)(M+H) +m/z796.4765,calcdforC 44H 65N 3O 10795.4670.
Embodiment 6S6 (11; 12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-p-toluenesulfonyl-N-3-quinolyl) amido substituted propyl) imino-) erythromycin) preparation:
The synthetic route of compound s 6:
The preparation of the first step compound (M6)
Compound 2e (152mg, 0.428mmol) with macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (26mg is dripped in reaction solution, 0.17mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.5mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M6 (24mg, 58%).
1HNMR(400MHz,CDCl 3):δ8.527(d,1H,J＝2.4Hz),8.108(d,1H,J＝8.0Hz),7.923(d,1H,J＝2.4Hz),7.775～7.815(m,2H),7.616(t,1H,J＝8.0Hz),7.475(d,1H,J＝8.0Hz),7.284(s,1H),6.594(s,1H),5.325(s,1H),4.988(dd,1H,J＝10.0Hz,J＝2.8Hz),4.744(t,1H,J＝5.2Hz),4.358(d,1H,J＝8.0Hz),4.212(t,1HJ＝4.0Hz),4.135(d,1H,J＝8.0Hz),3.809(s,1H),3.737～3.753(m,3H),3.529(s,1H),3.367(dd,2H,J＝12.0Hz,J＝6.4Hz),3.203(m,1H),3.006～3.071(m,1H),2.863(s,1H),2.762(m,2H),2.435(s,6H),2.248(s,3H),2,046(s,3H),1.946(s,1H),1.642～1.762(m,5H),1.458(s,3H),1.313(s,3H),1.346～1.363(m,3H),1.253～1.287(m,3H),1.129～1.186(m,6H),1.113～1.159(m,3H),0.912～0.949(m,3H).
HR-MS(ESI)(M+H) +m/z993.5146,calcdforC 52H 72N 4O 13S992.4817.
The preparation of second step compound (S6)
Compound M6 (20mg, 0.020mmol) is added in 1ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S6 (17mg, 85%).
1HNMR(400MHz,CDCl 3):δ8.527(d,1H,J＝2.4Hz),8.106(d,1H,J＝8.0Hz),7.920(s,1H),7.775～7.795(m,2H),7.606(dd,1H,J＝8.0Hz),7.464～7.485(m,2H),7.264(s,1H),4.988(dd,1H,J＝2.8Hz,J＝10.0Hz),4.731(t,1H,J＝5.2Hz),4.212(t,1H,J＝4.0Hz),3.809(s,1H),3.737～3.757(m,2H),3.512(m,1H),3.345～3.390(m,2H),2.803(s,1H),2.433(s,6H),2.248(m,3H),2.252(s,2H),1.946(s,1H),1.642(m,3H),1.474(s,3H),1.340～1.363(m,3H),1.253(s,6H),1.113～1.159(m,3H),0.930(t,3H,J＝7.2Hz).
13CNMR(150MHz,CDCl 3):δ215.833,203.678,157.091,150.313,147.046,143.751,136.055,134.978,132.528,129.890,129.715,129.165,128.855,128.255,127.887,127.711,127.006,80.080,79.638,62.690,60.508,51.134,49.637,48.614,47.434,44.830,40.273,39.524,38.993,31.937,29.711,29.434,29.375,26.446,25.569,24.828,22.704,22.195,21.572,21.145,19.657,18.381,15.628,14.693,14.370,14.131,13.839,10.129.
HR-MS(ESI)(M+H) +m/z951.4789,calcdforC 50H 70N 4O 12S950.4711.
Embodiment 7S7 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-benzyl-N-3-quinolyl) amido substituted propyl) imino-) erythromycin) preparation:
The synthetic route of compound S 7:
The preparation of the first step compound (M7)
Compound 5f (38mg, 0.13mmol) with macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (26mg is dripped in reaction solution, 0.17mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.5mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M7.
HR-MS(ESI)(M+H) +m/z929.5716,calcdforC 52H 72N 4O 11928.5198.
The preparation of second step compound (S7)
Compound M7 (16mg, 0.017mmol) is added in 2ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S7 (10.2mg, two step yields 35.4%).
1HNMR(400MHz,CDCl 3):δ8.094(d,1H,J＝2.4Hz),8.053(s,1H),7.920(s,1H),7.773～7.812(m,2H),7.658～7.710(m,1H),7.546～7.593(m,2H),7.473(d,1H,J＝8.0Hz),4.838(m,1H),4.723(t,1H,J＝9.6Hz),4.336(d,1H,J＝7.6Hz),4.132(d,1H,J＝7.6Hz),3.689～3.734(m,3H),3.571(d,1H,J＝7.2Hz),3.017～3.126(m,6H),2.423(d,3H,J＝8.0Hz),2.349(m,2H),2.252(s,2H),1.849(s,3H),1.599～1.649(m,3H),1.420(s,3H),1.253～1.281(m,6H),1.179(s,3H),1.113(t,3H,J＝6.4Hz),0.960(t,3H,J＝8.0Hz).
13CNMR(150MHz,CDCl 3):δ217.472,204.056，169.677，156.168，141.776，141.246，141.099，137.760，129.303，128.678，128.620，127.002，126.571，126.545，126.203，124.747，121.618，103.722，87.431，80.813，79.078，78.051，70.263，69.513，65.894，62.863，53.400，50.877，50.827，49.322，47.553，44.687，40.197，39.565，39.461，29.666，28.267，22.019，21.149，19.596，18.018，15.813，14.348，14.089，13.791，12.690，10.341.
HR-MS(ESI)(M+H) +m/z887.5121,calcdforC 50H 70N 4O 10886.5092.
Embodiment 8S8 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-benzoyl-N-3-quinolyl) amido substituted propyl) imino-) erythromycin) preparation:
The synthetic route of compound S 8:
The preparation of the first step compound (M8)
Compound 2g (86mg, 0.282mmol) with macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (26mg is dripped in reaction solution, 0.17mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.5mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M8.
HR-MS(ESI)(M+H) +m/z943.5101,calcdforC 52H 70N 4O 12942.4990.
The preparation of second step compound (S8)
Compound M8 (12mg, 0.013mmol) is added in 1ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S8 (4mg, two step yields 16%).
1HNMR(400MHz,CDCl 3):δ8.094(d,1H,J＝8.4Hz),8.053(s,1H),7.920(s,1H),7.773～7.812(m,2H),7.658～7.710(m,2H),7.546～7.593(m,2H),7.463～7.483(m,2H),4.838(m,1H),4.723(t,1H,J＝9.6Hz),4.336(d,2H,J＝7.6Hz),4.032(d,1H,J＝8.0Hz),3.712～3.764(m,3H),3.589(d,1H,J＝7.2Hz),3.396～3.501(m,2H),3.017～3.126(m,2H),2.564(m,1H),2.338～2.369(m,2H),2.248(s,6H),1.838(s,3H),1.569～1.602(m,3H),1.418(s,3H),1.235～1.274(m,6H),1.185(s,3H),1.096(t,3H,J＝6.4Hz),0.942(t,3H,J＝8.0Hz).
13CNMR(150MHz,CDCl 3):δ212.702,171.261,167.799,149.850,146.199,144.065,132.783,132.330,131.551,130.298,129.956,129.289,128.836,128.763,128.168,127.694,127.605,123.342,123.233,83.291,48.393,37.964,31.918,30.293,30.029,29.691,29.651,29.517,29.356,27.430,27.213,25.552,22.686,14.113.
HR-MS(ESI)(M+H) +m/z901.4957,calcdforC 50H 68N 4O 11900.4885.
The preparation of embodiment 9S9 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-propyl group-N-3-quinolyl amido substituted propyl) imino-) erythromycin):
The synthetic route of compound S 9:
The preparation of the first step compound (M9)
Compound 5h (250mg, 1.03mmol) with macrolide intermediates 6 (100mg, 0.14mmol) be dissolved in 5.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (98mg is dripped in reaction solution, 0.64mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.10mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M7.
HR-MS(ESI)(M+H) +m/z880.5716,calcdforC 48H 72N 4O 11880.5198.
The preparation of second step compound (S9)
Above-mentioned gained compound M9 is added in 5ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S9 (57mg, two step yields 48.5%).
1HNMR(400MHz,CDCl 3):δ8.654(d,1H,J＝2.8Hz),7.894(m,1H),7.714～7.736(m,2H),7.520(m,1H)7.379～7.402(m,2H),7.213(m,2H),7.124(s,1H),4.838(m,1H),4.723(t,1H,J＝9.6Hz),4.336(d,1H,J＝7.6Hz),4.132(d,1H,J＝7.6Hz),3.689～3.734(m,3H),3.571(d,1H,J＝7.2Hz),3.017～3.126(m,6H),2.423(d,3H,J＝8.0Hz),2.349(m,2H),2.252(s,2H),1.849(s,3H),1.599～1.649(m,3H),1.427(s,3H),1.253～1.281(m,6H),1.175(s,3H),1.116(t,3H,J＝6.4Hz),0.965(t,3H,J＝8.0Hz).
13CNMR(150MHz,CDCl 3):δ217.47,204.06，169.68，156.17，141.77，141.24，141.10，137.76，129.30，128.68，128.62，127.00，126.57，126.55，126.20，124.75，121.62，103.72，87.43，80.81，79.08，78.05，70.26，69.51，65.89，62.86，53.40，50.88，50.83，49.32，47.55，44.69，40.20，39.56，39.46，29.67，28.27，22.02，21.15，19.59，18.02，15.81，14.35，14.09，13.79，12.69，10.34。
HR-MS(ESI)(M+H) +m/z838.5121,calcdforC 46H 70N 4O 10838.5092.
Embodiment 10S10 (11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-3-quinolyl-2 (E)-propenyl amido substituted propyl) imino-) erythromycin) preparation:
The synthetic route of compound S 10:
The preparation of the first step compound (M10)
Compound 6i (0.32g, 0.87mmol) with macrolide intermediates 6 (100mg, 0.14mmol) be dissolved in 5.0ml anhydrous tetrahydrofuran solution, 12h is reacted under room temperature, DBU (98mg is dripped in reaction solution, 0.64mmol), react 24h under continuing room temperature, TLC (methyl alcohol/chloroform 1:10) display reacts completely.10mlCH is added in system 2cl 2after dilution, organic phase with 5% KH 2pO 4solution is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, methyl alcohol/chloroform (1:100) column chromatography obtains white foam product M10.
HR-MS(ESI)(M+H) +m/z1005.5492,calcdforC 57H 75N 4O 111005.5463.
The preparation of second step compound (S10)
Above-mentioned gained compound M10 is added in 5ml anhydrous methanol, is heated to 50 DEG C of insulation reaction 24h, TCL (methyl alcohol/chloroform 1:10) display and reacts completely.By solvent evaporate to dryness, methyl alcohol/chloroform (1:100) column chromatography obtains white solid S10 (42.6mg, two step yields 42.6%).
1HNMR(400MHz,CDCl 3):δ8.656(d,1H,J＝2.8Hz),7.892(m,1H),7.882(m,2H),7.844(m,2H),7.835～7.863(m,2H),7.724～7.745(m,2H),7.521(m,1H)7.389～7.412(m,2H),7.218(m,2H),7.127(s,1H),5.878(dd,1H,J＝16.8H),5.215(dd,1H,J＝16.8Hz),4.838(m,1H),4.723(t,1H,J＝9.6Hz),4.336(d,2H,J＝7.6Hz),4.032(d,1H,J＝8.0Hz),3.712～3.764(m,3H),3.589(d,1H,J＝7.2Hz),3.396～3.501(m,2H),3.017～3.126(m,2H),2.564(m,1H),2.338～2.369(m,2H),2.248(s,6H),1.838(s,3H),1.569～1.602(m,3H),1.418(s,3H),1.235～1.274(m,6H),1.187(s,3H),1.093(t,3H,J＝6.4Hz),0.945(t,3H,J＝8.0Hz).
13CNMR(150MHz,CDCl 3):δ212.68,171.26,167.80,149.85,146.20,144.06,132.78,132.33,131.55,130.30,129.96,129.29,128.84,128.76,128.17,127.70,127.61,123.34,123.23,83.29,48.39,37.96,31.92,30.29,30.03,29.69,29.65,29.52,29.36,27.43,27.21,25.55,22.69,14.11.
HR-MS(ESI)(M+H) +m/z963.5403,calcdforC 55H 73N 5O 10963.5357.
Experimental sections
Experimental example 1 pharmacological evaluation: antibacterial activity in vitro is tested
The present invention utilizes following antibacterial activity in vitro to test and provides the purposes of above-claimed cpd at antibiosis.
(1) test method: substratum and incubation conditions
Staphylococcus and moraxelle catarrhalis, at CAMHB substratum, hatch 16-20h for 35 DEG C; Streptococcus is adding the CAMHB substratum of 5% horse serum, hatches 20-24h for 35 DEG C; Hemophilus, at HTM broth culture, hatches 20-24h for 35 DEG C.
Minimum inhibitory concentration (MIC) measures
Employing standard trace meat soup doubling dilution.Antibacterials measure concentration range 64-0.004mg/L.Tested bacterium liquid final concentration is about 1 × 10 5cFU/ml.
(2) medicine is contrasted: clarithromycin (Cla), Ketek (Teli)
(3) experimental strain is as follows:
Standard Quality-control strains 3 strain: streptococcus pneumoniae ATCC49619, streptococcus aureus ATCC29213, hemophilus influenzae ATCC49247.
Clinical isolates 10 strain:
Methicillin-sensitivity, erythromycin-sensitive streptococcus aureus-ATCC29213
Methicillin resistance, erythromycin-resistant streptococcus aureus-11B117
Methicillin-sensitivity, erythromycin-sensitive staphylococcus epidermidis-11X315
Methicillin resistance, erythromycin-resistant staphylococcus epidermidis-11C176
Erythromycin-sensitive streptococcus pneumoniae-ATCC49619
Erythromycin-resistant streptococcus pneumoniae-11J011
Erythromycin-sensitive micrococcus scarlatinae-11L264
Erythromycin-resistant micrococcus scarlatinae-11N369
Responsive hemophilus influenzae-the ATCC49247 of Azythromycin
Insensitive hemophilus influenzae-the 11Q373 of Azythromycin
Responsive moraxelle catarrhalis-the 11B363 of Azythromycin
Insensitive moraxelle catarrhalis-the 11B364 of Azythromycin
Every strain bacterium all passes through dull and stereotyped turning before the test and lives point pure, is used for test with new fresh thalli.Each experiment all uses reference culture as sensitive experiment Quality Control bacterium; With not containing the bacterium liquid of antibacterials as test strain growth control.Clarithromycin is to the MIC scope of reference culture streptococcus aureus ATCC29213, streptococcus pneumoniae ATCC49619 and hemophilus influenzae ATCC49247 respectively: 0.125-0.5mg/L, 0.031-0.125mg/L and 4-16mg/L.The MIC scope of Ketek to three strain standard bacteria is: 0.062-0.25mg/L, 0.004-0.031mg/L and 1-4mg/L.This test clarithromycin is respectively 0.25mg/L, 0.062mg/L and 4mg/L to three strain standard bacteria MIC values; The MIC value of Ketek to three strain reference cultures is respectively 0.062mg/L, 0.016mg/L and 1mg/L, all in scope, shows that measurement result can be used.
Experiment proves, structural formula of the present invention prepared by aforesaid method is the compound sample of S1, S2, S4, S5, has outstanding anti-microbial activity and antimicrobial agent activity that broad spectrum suppresses gram-positive microorganism and Gram-negative bacteria simultaneously.
Above chatting is only preferred embodiment of the present invention, therefore all features of chatting according to the present patent application the scope of the claims and method, be included in the scope of the claims of the present invention.
Table 1. compound S 1 and contrast medicine are to the MIC result (mg/L) of 10 strain bacterium
Table 2.7 sample compound and Ketek contrast medicine are to the MIC result (mg/L) of 10 strain bacterium
Experiment proves, structural formula of the present invention prepared by aforesaid method is the compound sample of S1, S2, S4, S5, has outstanding anti-microbial activity and antimicrobial agent activity that broad spectrum suppresses gram-positive microorganism and Gram-negative bacteria simultaneously.
Above chatting is only preferred embodiment of the present invention, therefore all features of chatting according to the present patent application the scope of the claims and method, be included in the scope of the claims of the present invention.

Claims (10)

1. the Erythromycin A class antibiotic derivatives of a class as shown in formula I, it has following general structure:
X is selected from sulphur atom, Sauerstoffatom, carbon atom or nitrogen-atoms;
When wherein X is carbon atom, R represents hydrogen atom;
When X is nitrogen-atoms, R can represent hydrogen atom, substituted or unsubstituted C 1 ~ 4alkyl, substituted or unsubstituted C 1 ~ 4thiazolinyl, substituted or unsubstituted C 1 ~ 4alkynyl, wherein substituting group can be selected from hydroxyl, fluorine atom, bromine atoms, chlorine atom, atomic iodine, sulfydryl, amino, phenyl, naphthyl, 5 ~ 12 yuan aromatic heterocyclic replace alkyl;
When X is nitrogen-atoms,
R substituent also can represent:
R substituent also can represent:
R substituent can also represent:
Wherein said R ' substituting group can be selected from the methyl of hydrogen atom, methyl, ethyl, propyl group, butyl, hydroxyl, fluorine atom, bromine atoms, chlorine atom, atomic iodine, nitro, carboxyl, sulfydryl, amino, amido, cyano group, aldehyde radical, methylol, 1 ~ 3 fluorine atom replacement.
2. compound according to claim 1, is characterized in that,
Described aromatic heterocyclic is selected from thienyl, furyl, pyrryl, thiazolyl, oxazolyl, triazol radical, tetrazole base, imidazolyl, thiadiazolyl group, pyrazoles or imidazole base, pyridyl, pyrimidyl, pyridazine or pyrazinyl, indyl, benzofuryl, benzothiazolyl and quinolyl.
3. compound according to claim 1, is characterized in that, described R substituent is selected from benzyl, benzoyl and to Methyl benzenesulfonyl base.
4. a class Erythromycin A class antibiotic derivatives compound is selected from as follows:
(S1) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-3-sulfydryl substituted propyl) imino-) erythromycin
(S2) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-3-hydroxyl substituted propyl) imino-) erythromycin
(S3) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (the amino substituted propyl of quinoline-3-) imino-) erythromycin
(S4) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (3-quinolyl-3 (E)-butenyl) imino-) erythromycin
(S5) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (quinoline-4-replaces butyl) imino-) erythromycin
(S6) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-p-toluenesulfonyl-N-3-quinolyl) amido substituted propyl) imino-s) erythromycin
(S7) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-benzyl-N-3-quinolyl) amido substituted propyl) imino-s) erythromycin
(S8) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-benzoyl-N-3-quinolyl) amido substituted propyl) imino-s) erythromycin
(S9) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-propyl group-N-3-quinolyl amido substituted propyl) imino-) erythromycin
(S10) 11,12-dideoxy-3-O-descladinosylation-6-O-methyl-3-oxo-12,11-(oxygen carbonyl (N-3-quinolyl-2 (E)-propenyl amido substituted propyl) imino-) erythromycin
5. the preparation method of the compound any one of Claims 1 to 4, is characterized in that, comprises the steps:
By the addition reaction of the macrolide intermediates compound 6 suitably protected and the cyclosubstituted primary amine side chain of fragrance selected, the Methanol product solution of gained removes the reaction of ethanoyl:
1), fragrant cyclosubstituted carbamate-functional is introduced in 11,12-positions of above-mentioned raw materials 6;
2), the alcoholysis of ethanoyl removes, and obtains the Erythromycin A of corresponding replacement containing quinoline ring side chain ketolide derivatives.
6. a pharmaceutical composition, is characterized in that, described composition contains at least one compound any one of Claims 1 to 4 and pharmaceutically acceptable carrier.
7. the compound any one of Claims 1 to 4 is preparing the application in anti-bacteria medicine.
8. application according to claim 7, is characterized in that, described bacterial isolates is selected from gram positive bacterium, gram negative bacterium and other pathogenic agent.
9. application according to claim 8, is characterized in that,
Described gram positive bacterium is selected from staphylococcus, suis, streptococcus pneumoniae, pyococcus, staphylococcus epidermidis;
Described gram negative bacterium is selected from moraxelle catarrhalis, hemophilus influenzae;
Other described pathogenic agent are selected from rickettsia Salmonella, mycoplasma pneumoniae, chlamydozoan, Rome pathogenic agent, bird blood plasma body, toxoplasma, mycobacterium, Listeria monocytogenes, meningococcus.
10. the application of the compound any one of Claims 1 to 4 in preparation antiviral.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632550A (en) * 2016-09-30 2017-05-10 宜昌东阳光药业股份有限公司 Method for preparing clarithromycin impurity I
CN111072740A (en) * 2018-10-18 2020-04-28 中国医学科学院药物研究所 Erythromycin A ketolide antibiotic derivative, and preparation method and application thereof
CN114437154A (en) * 2022-01-30 2022-05-06 北京理工大学 Quinolone-containing ketolide derivative and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1151746A (en) * 1994-05-03 1997-06-11 鲁索-艾克勒夫公司 Novel erythromycin derivatives, method for their preparation and their use as drugs
WO1999021870A1 (en) * 1997-10-29 1999-05-06 Taisho Pharmaceutical Co., Ltd. Erythromycin a 11, 12-carbamate derivatives
WO2006080954A1 (en) * 2004-07-28 2006-08-03 Ranbaxy Laboratories Limited Ketolide derivatives as antibacterial agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1151746A (en) * 1994-05-03 1997-06-11 鲁索-艾克勒夫公司 Novel erythromycin derivatives, method for their preparation and their use as drugs
WO1999021870A1 (en) * 1997-10-29 1999-05-06 Taisho Pharmaceutical Co., Ltd. Erythromycin a 11, 12-carbamate derivatives
WO2006080954A1 (en) * 2004-07-28 2006-08-03 Ranbaxy Laboratories Limited Ketolide derivatives as antibacterial agents

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632550A (en) * 2016-09-30 2017-05-10 宜昌东阳光药业股份有限公司 Method for preparing clarithromycin impurity I
CN111072740A (en) * 2018-10-18 2020-04-28 中国医学科学院药物研究所 Erythromycin A ketolide antibiotic derivative, and preparation method and application thereof
CN111072740B (en) * 2018-10-18 2022-01-11 中国医学科学院药物研究所 Erythromycin A ketolide antibiotic derivative, and preparation method and application thereof
CN114437154A (en) * 2022-01-30 2022-05-06 北京理工大学 Quinolone-containing ketolide derivative and preparation method and application thereof
CN114437154B (en) * 2022-01-30 2024-03-01 北京理工大学 Ketone lactone derivative containing quinolone and preparation method and application thereof

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