CN105524132B - Erythromycin A ketolide antibiotics derivative, preparation method and application containing quinoline substituent group - Google Patents

Erythromycin A ketolide antibiotics derivative, preparation method and application containing quinoline substituent group Download PDF

Info

Publication number
CN105524132B
CN105524132B CN201410520787.4A CN201410520787A CN105524132B CN 105524132 B CN105524132 B CN 105524132B CN 201410520787 A CN201410520787 A CN 201410520787A CN 105524132 B CN105524132 B CN 105524132B
Authority
CN
China
Prior art keywords
compound
erythromycin
preparation
nmr
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410520787.4A
Other languages
Chinese (zh)
Other versions
CN105524132A (en
Inventor
靳龙龙
雷平生
赵哲辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
Original Assignee
Institute of Materia Medica of CAMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to CN201410520787.4A priority Critical patent/CN105524132B/en
Publication of CN105524132A publication Critical patent/CN105524132A/en
Application granted granted Critical
Publication of CN105524132B publication Critical patent/CN105524132B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a series of Erythromycin A ketolide antibiotics derivatives containing quinoline substituent group shown in formula I, preparation method and use, each compounds in side chain intermediate and synthetic methods.Key point of the invention is: Formulas I compound represented has the drug effect of broad-spectrum antibiotics and while inhibiting gram-positive bacteria and the protrusion antibacterial activity and antimicrobial agent of negative bacterium activity.Compound proposed by the invention can be used as broad-spectrum antibiotics, has while inhibiting the antibacterial of gram-positive bacteria and negative bacterium, antiviral activity.

Description

Erythromycin A ketolide antibiotics derivative containing quinoline substituent group, its preparation side Method and application
Technical field
The invention belongs to pharmaceutical technology fields.The present invention relates to a series of Erythromycin A ketone lactone containing quinoline substituent group The bioactivity of class antibiotic derivatives and their synthetic method, related intermediate synthetic method and such compound with And inhibiting gram-positive bacteria and negative bacterium, the purposes of anti-virus aspect as broad-spectrum antibiotics.
Background technique
Bacterial drug resistance has become the serious problem of anti-infective therapy, world field face.Bacterial drug resistance and drug-fast bacteria sense Dye is the huge challenge that 21 century anti infection region faces.With antibiotic application it is increasing, drug resistance problems are increasingly tight Weight, makes anti-infective therapy fail, and disease incidence and case fatality rate rising and medical expense is caused to increase.And finger is had been reported that in recent years Out, Ketek has hepatotoxic phenomenon, limits its clinical application range.
Therefore, it is necessary to accelerate to have the new antibiotic of broad spectrum antibiotic activity to study, especially enhance macrocyclic ketone lactone Effect of the antibiotic medicine for Gram-negative bacteria, and the toxic side effects such as hepatotoxicity wind agitation for reducing drug.It designs and screens chemistry The compound of structure novel improves to macrolides drug-fast bacteria inhibitory activity, reduces and avoid drug resistance to the induction of bacterial strain Medicine solves the problems, such as multidrug resistant, provides more safely and effectively drug for clinic.
Many for the structure of modification research work of macrocyclic ketone lactone at present, this seminar Chen Xiaozhuo et al. is designed and synthesized The macrocyclic ketone lactone derivatives of 11,12- sulfur-bearing aryl alkyl side chains a series of, and activity test in vitro has been carried out, wherein Some compounds show good activity to macrolide drug resistance and sensitive bacteria.In the change to erythromycin-sensitive and drug resistance The activity of Streptococcus pyogenes, the streptococcus pneumonia of erythromycin-sensitive, the haemophilus influenzae aspect of erythromycin-sensitive, 9n and 9k are excellent In Ketek, and 9a, 9e, 9k and 9n (such as following formula) antimicrobial spectrum are similar with Ketek.
The macrocyclic ketone lactone derivatives of 11,12- sulfur-bearing aryl alkyl side chains
Continue to go deep into the position 6- of macrolide on the basis of successfully developing cethromycin in the laboratory Abbott Structure of modification.They have synthesized a series of macrocyclic ketone lactone derivatives 9 of 6- propargyl heteroaromatic side chains.The study found that working as When heteroaromatic part is biaryl ring, the activity of compound is best.Using Ketek as reference substance, compound 9d and 9e is (as follows Formula) have significant improvement to the erythromycin-resistant bacterium activity of erm and mef gene induction.To the pneumonia streptococcus of the gene containing erm The bacteriostatic activity of bacterium 5979, compound 9d and 9e improves 100 times compared with Ketek.Such compound is the macrolide of overriding resistance Antibiotic provides new candidate.
The macrocyclic ketone lactone derivatives of 6- propargyl heteroaromatic side chain
This seminar Chen Xiaozhuo et al. has synthesized a series of 5- dimethylamine sugar 4 ,-O derivative, research shows that in 5- dimethylamine The 4 of sugar, position introduce hydroxyl and are conducive to improve the antibacterial activity to penicillin-susceptible bacterium and drug-fast bacteria.Compared with Ketek, It maintains the antibacterial activity to all penicillin-susceptible bacterium and other drug-fast bacterias, to erythromycin-sensitive ESSP bacterium and Activity identical with Ketek is maintained in terms of ESSPy bacterium.
Structure-activity relationship shows that dimethylamine sugar plays drug action by hydrogen bond in conjunction with the 23S rRNA in the area V.Dimethylamine sugar 4 ,-OH provide another hydrogen bond donor and play a role in conjunction with the amino acid residue of combined area, therefore compound 26 is (as follows Formula) antibacterial activity be better than erythromycin and clarithromycin.And 4, position introduces hydrophobic grouping such as alkyl, aryl, due to that cannot increase The effect of powerful cyclic lactone and ribosomal subunit and antibacterial activity (such as 25 and 29) cannot be improved.
5- dimethylamine sugar 4, the macrocyclic ketone lactone derivatives of-OH modification
Summary of the invention
The purpose of the present invention is to provide one kind to have the active macrocyclic ketone lactone chemical combination of broad-spectrum antibacterial as shown in formula I Object, i.e. new construction Erythromycin A macrocyclic ketone lactone antibiotic derivatives.
The present invention provides the preparation method of the above-mentioned type compound, can it is safer, conveniently, efficiently synthesis and work Industry metaplasia produces.
The present invention provides the purposes of above-mentioned ketolide antibiotics derivative, it can be used as and inhibit gram with wide spectrum Positive bacteria, Gram-negative bacteria and antiviral drugs.
Macrocyclic ketone lactone antibiotic compound of the invention has structural formula below:
X is selected from sulphur atom, oxygen atom, 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 C1~4Alkyl, substituted or unsubstituted C1~4 Alkenyl, substituted or unsubstituted C1~4Alkynyl,
Wherein substituent group can be selected from hydroxyl, fluorine atom, bromine atom, chlorine atom, iodine atom, sulfydryl, amino, phenyl, naphthalene The alkyl that base, 5~12 yuan of aromatic heterocyclic replace；
When X is nitrogen-atoms,
R substituent can also represent:
R substituent can also represent:
R substituent can also represent:
Wherein R ' the substituent group can preferably be selected from hydrogen atom, methyl, ethyl, propyl, butyl, hydroxyl, fluorine atom, bromine Atom, chlorine atom, iodine atom, nitro, carboxyl, sulfydryl, amino, amido, cyano, aldehyde radical, methylol, 1~3 fluorine atom replace Methyl etc..
Aromatic heterocyclic of the present invention be selected from thienyl, furyl, pyrrole radicals, thiazolyl, oxazolyl, triazol radical, Tetrazole base, imidazole radicals, thiadiazolyl group, pyrazoles or imidazole base, pyridyl group, pyrimidine radicals, pyridazine or pyrazinyl, indyl, benzene And furyl, benzothiazolyl and quinolyl.
R substituent in compound structure of the present invention preferably is selected from benzyl, benzoyl and to Methyl benzenesulfonyl base.
Wherein, above-described " substituted or unsubstituted C1~4Alkyl " refers to substituted or unsubstituted containing 1,2,3,4 The linear or branched alkyl group of carbon atom；" substituted or unsubstituted C1~4Alkenyl " refers to substituted or unsubstituted containing 1,2,3,4 The linear chain or branched chain alkenyl of carbon atom；" substituted or unsubstituted C1~4Alkynyl " refers to substituted or unsubstituted containing 1,2,3,4 The linear chain or branched chain alkynyl of carbon atom.
Currently preferred compound is specifically listed below:
(S1) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -3- Sulfydryl substituted propyl) imino group) erythromycin
(S2) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -3- Hydroxyl substituted propyl) imino group) erythromycin
(S3) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -3- Amino substituted propyl) imino group) erythromycin
(S4) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (3- quinoline Base -3 (E)-cyclobutenyl) imino group) erythromycin
(S5) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -4- Replace butyl) imino group) erythromycin
(S6) ((N- is to first for oxygen carbonyl by 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- Benzenesulfonyl-N-3- quinolyl) amido substituted propyl) imino group) 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 group) erythromycin
(S8) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (N- benzene first Acyl group-N-3- quinolyl) amido substituted propyl) imino group) erythromycin
(S9) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (N- propyl - N-3- quinolyl amido substituted propyl) imino group) erythromycin
(S10) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (N-3- quinoline Quinoline base -2 (E)-acrylic amido substituted propyl) imino group) erythromycin
The starting material of new construction macrocyclic ketone lactone antibiotic derivatives of the invention is clarithromycin, using document report Road or the chemically feasible reaction method of synthesis, obtain raw material of the intermediate appropriate as invention, and structural formula is as follows:
Wherein, Ac is acetyl group.
The reaction equation of method of the invention is as follows:
Wherein, the described (CH3CO)2For acetic anhydride, ClCO2CCl3For trichloromethyl chloroformate, (COCl)2For oxalyl chloride, DBU For 1,8- diazabicylo, 11 carbon -7- alkene, DMSO is dimethyl sulfoxide, and CDI is carbonyl dimidazoles, DMF N, N- dimethyl Formamide, Ac are acetyl group.
The present invention also provides a kind of preparation methods with above structure compound.This method includes by suitable protecting Erythromycin A derivative raw material 6 and selection the cyclosubstituted level-one amine side chain of quinoline addition reaction, institute product pass through methanol solution Remove the reaction of acetyl group.
Above-mentioned method, including the following steps:
1, the cyclosubstituted carbamate-functional of fragrance is introduced in the position 11,12- of above-mentioned raw materials 6；
2, the alcoholysis removing of acetyl group has obtained the corresponding substituted Erythromycin A side chain ketolide derivatives of ring containing quinoline.
New construction macrocyclic ketone lactone compound of the invention i.e. from clarithromycin, using known document report or Feasible reaction method known to the synthesis chemically public, obtains derivative appropriate as raw material of the invention, such as raw material chemical combination Object 6 can use document J.Med.Chem, the method preparation of 41,4080-4100,1998 reports.
Second aspect of the present invention additionally provides a kind of pharmaceutical composition, and the composition contains the Erythromycin A of quinoline substituent group At least one compound of ketolide antibiotics derivative and pharmaceutically available carrier.The pharmaceutical composition can be according to this The preparation of method well known to field.It can be by the way that the compounds of this invention and one or more pharmaceutically acceptable solids or liquid be assigned Shape agent and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its pharmaceutical composition Content be usually 0.1-95 weight %.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such 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 forms or semisolid dosage form.Liquid dosage form can be solution (including True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection And infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, Powder, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made, Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute Release agent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, cream Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Mannitol, glucose etc. can be also added as proppant in injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.
Third aspect present invention provides the compounds of this invention and inhibits answering in bacterial drug and antiviral drugs in preparation With.
The bacterium bacterial strain includes gram-positive bacterium, gramnegative bacterium.Wherein, gram-positive bacterium packet Include staphylococcus, streptococcus, streptococcus pneumonia, pyococcus, staphylococcus epidermis；Gramnegative bacterium include catarrh not Draw bacterium, haemophilus influenzae；And other pathogens such as rickettsia Salmonella, mycoplasma pneumoniae, Chlamydia, Rome pathogen, bird Blood plasma body, toxoplasm, mycobacterium, Listeria monocytogenes, meningococcus.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization The daily Suitable dosage ranges for closing object are 0.001-150mg/Kg weight, preferably 0.1-100mg/Kg weight, more preferably 1-60mg/Kg weight, most preferably 2-30mg/Kg weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage lists Position administration, this depends on the clinical experience of doctor and includes the dosage regimen with other treatment means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs. When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
Advantageous effects
Macrocyclic lactone compounds Erythromycin A antibiotics of the overwhelming majority containing the cyclosubstituted side chain of quinoline spread out in the present invention In vitro antibacterial activity reach with the comparable level of Ketek, Ketek, and this hair are also advantageous over for a small number of bacterial strains The sample compound of bright design synthesis, which has been avoided, may cause hepatotoxic side-chain structure；Compared with Ketek synthesis, this hair The synthetic route of the bright sample compound being related to is short, easy to operate, and total recovery is high, at low cost.It is new to provide a class formation Grain husk, activity be strong, the simple drug candidates of synthesis, can be used as broad-spectrum antibiotics inhibit gram-positive bacteria and negative bacterium, The purposes of anti-virus aspect.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention Various change and modification are carried out to the present invention.The present invention carries out the material and test method arrived used in test general And/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art that But the present invention is still described in this detail as much as possible.
For following whole embodiments, standard operation well known by persons skilled in the art and purification process can be used.It removes Non- to be otherwise noted, all temperature are indicated with DEG C (degree Celsius).The structure of compound is to pass through nuclear magnetic resoance spectrum
(NMR) and/or mass spectrum (MS) is come what is determined.
Preparation example part
The structure of compound be by nuclear magnetic resonance spectroscopy (1H NMR), carbon-13 nmr spectra (13C NMR) and mass spectrum (MS) Come what is determined.Nuclear magnetic resonance spectroscopy and carbon spectral displacement (δ) are provided with the unit of hundred a ten thousandths (ppm).Nuclear magnetic resonance spectroscopy is used Mercury-300, Mercury-300 or Mercury-600 type nmr determination, deuterated chloroform (CDCl3) or heavy water (D2) or deuterated dimethyl sulfoxide (DMSO-d O6) make solvent, tetramethylsilane (TMS) is internal standard.
High resolution mass spectrum is joined using 1100 series LC/MSD trap mass spectrometer liquid matter of Agilent It is measured with instrument or Theromo Exactive orbitrap plus LC/MSD mass spectrometer LC-MS instrument.
Column chromatography is generally carrier using 160~200 mesh silica gel.
Anhydrous solvent is handled by standard method.Other reagents are that commercially available analysis is pure.
Wherein,
Ac acetyl acetyl group
Bn benzyl benzyl
Brs broad single width unimodal
Bz benzoyl benzoyl
1,1 ' 1,1 '-carbonyl dimidazoles of-carbonyldiimidazole of CDI
D double is dual
Bicyclic [the 5,4,0] -7- hendecene of DBU 1,8-diazabicyclo [5,4,0] -7-ene 1,8- dioxazole
DEAD diethyl azodicarboxylate azo diethyl diethyl phthalate
DMF dimethylformamide N,N-dimethylformamide
DMSO dimethyl sulfoxide dimethyl sulfoxide
Eq. equivalent equivalent
Et ethyl ethyl
ESI electrospray inoization electrospray ionisation
G gram gram
H hour hours
Hertz hertz of Hz
M multiple is multiple
M/z mass to charge ratio charge-mass ratio
Me methyl methyl
μ l microliter microlitre
Milligram milligrams of mg
MIC minimum inhibitory concentration minimal inhibitory concentration
Milliliter milliliters of ml
Mmol millimole mM
MS mass spectrometry mass spectrum
NMR nuclear magnetic resonance nuclear magnetic resonance
Hundred a ten thousandth of ppm part per million
Py pyridine pyridine
Q quarter quadruple
Ref reference document
Rt room temperature room temperature
T triple is triple
THF tetrahydrofuran tetrahydrofuran
TLC thin layer chromatography thin-layer chromatography
Preparation example 1
The synthetic route of 1 intermediate 5a of Scheme
Scheme 1Reagents and conditions:a.CH3COSK, DIEA, Pd2(dba)3,Xantphos,1,4- Dioxane, macrowave；b.1),KOH,EtOH,2),H+,r.t；c.K2CO3,DMF,90℃；d.NH2NH2·H2O,EtOH, reflux。
The synthesis of compound (2a)
By 3- bromopyridine (1a) (250mg, 1.2mmol), thioacetic acid potassium (275mg, 2.4mmol), Pd2(dba)3 (27.5mg, 0.03mmol), Xantphos (35mg, 0.06mmol) are added into 10ml microwave tube, are sealed with threeway scavenging air valve, Drawdown pump vacuumizes, and with argon gas by gas displacement in microwave tube three times, the diisopropyl ethyl of calculation amount is weighed with syringe Amine (0.42ml, 2.4mmol), Isosorbide-5-Nitrae-dioxane are injected into microwave tube, threeway are removed rapidly and quickly with microwave tube lid Cap covers bottle nozzle, be placed in microwave reactor in, by following parameter (Power:150W, Ramp:10min, Hold Time: 25min, Temp:160 DEG C, P:150PSI) setting microwave reactor reacted.After reaction, reaction solution is poured into acetic acid In ethyl ester/water mixed solution, ethyl acetate layer is separated, water phase is extracted with ethyl acetate, and merges organic phase, washing, saturation food Salt washing, anhydrous sodium sulfate dry, filter, and crude product are concentrated under reduced pressure to obtain, silica gel column chromatography (ethyl acetate/petroleum ether 1:15) must be changed It closes object 3- thioacetyl yl pyridines 2a (132mg, 54.2%).
1H NMR(300MHz,CDCl3): 8.796 (d, J=2.4Hz 1H), 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)
13C NMR(75MHz,CDCl3):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/z 204.0488,calcd for C11H9NOS 203.0405.
The synthesis of compound (3a)
Compound 3- thioacetyl yl pyridines (0.36g, 1.77mmol) are dissolved in 10ml ethyl alcohol, potassium hydroxide is added (o.3g, 5.32mmol) is heated to 80 DEG C, back flow reaction 12h.TLC (ethyl acetate/petroleum ether 1:3) shows fully reacting.Stop It only reacts, reaction solution is cooled to room temperature, with 1N hydrochloric acid solution tune pH 4.0 or so, solvent is evaporated to obtain rufous residue by decompression Object adds a small amount of water and is extracted with ethyl acetate, and merges organic phase, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, filters, Crude product is concentrated under reduced pressure to obtain, silica gel column chromatography (ethyl acetate/petroleum ether 1:10) obtains compound 3- mercaptopyridine 3a, without processing Directly carry out next step reaction.
HR-MS(ESI)(M+H)+m/z 162.0423,calcd for C9H7NS 161.0299.
The synthesis of compound (4a)
By 3- mercaptoquinoline (3a) (0.285g, 1.77mmol), N- (3- bromopropyl) phthalimide (0.522g, 1.95mmol), potassium carbonate (1.25g, 9.0mmol) is added separately in 10ml n,N-Dimethylformamide, is heated to 90 DEG C, React 10h.TLC (ethyl acetate/petroleum ether 1:3) shows fully reacting.Stop reaction, reaction solution is cooled to room temperature, crosses and filters out Solid, filtrate concentration are removed, methylene chloride dissolves residue, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, filters, and depressurizes It is concentrated to give crude product, silica gel column chromatography (ethyl acetate/petroleum ether 1:15) obtains faint yellow compound 4a (418mg, two step yields 68%).
1H NMR(300MHz,CDCl3): δ 8.852 (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/z 349.0981,calcd for C20H16N2O2S 348.0932.
The synthesis of compound (5a)
It disperses compound 4a (106mg, 0.35mmol) in 5ml dehydrated alcohol, 85% hydration is added dropwise into reaction solution Hydrazine (36mg, 35 μ l, 0.70mmol), is heated to 80 DEG C, back flow reaction 5h, light yellow solid, chlorine is concentrated under reduced pressure to obtain in reaction solution Imitative extraction, organic phase are washed with the sodium hydroxide solution of 2mol/L, are washed, and saturated common salt washing, anhydrous sodium sulfate dries, filters, Concentration organic phase obtains faint yellow oily compound 72mg, without separation, is directly used in the next step.
HR-MS(ESI)(M+H)+m/z 219.1691,calcd for C12H14N2S 218.0878.
Preparation example 2
The synthetic route of 2 intermediate 3b of Scheme
Scheme 2Reagents and conditions:a.N- (3-Bromopropyl) phthalimide, K2CO3, DMF,90℃；b.NH2NH2·H2O,EtOH,reflux,80℃。
The synthesis of compound (2b)
By 3- oxyquinoline (1b) (2.0g, 13.78mmol), N- (3- bromopropyl) phthalimide (3.7g, 13.78mmol), potassium carbonate (2.1g, 15.156mmol) is added separately in n,N-Dimethylformamide (40ml), is heated to 90 DEG C, react 10h.TLC (ethyl acetate/petroleum ether 1:3) shows fully reacting.Stop reaction, reaction solution is cooled to room temperature, filters Solid, filtrate concentration are removed, methylene chloride dissolves residue, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, filters, silicon Plastic column chromatography (ethyl acetate/petroleum ether 1:15) obtains faint yellow compound 2b (4.186g, yield 91.6%).
1H NMR(400MHz,CDCl3): δ 8.457 (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/z 333.1362,calcd for C20H16N2O3332.1161.
The synthesis of compound (3b)
It disperses compound 2b (1.5g, 4.52mmol) in 30ml dehydrated alcohol, 85% hydration is added dropwise into reaction solution Hydrazine (0.52ml, 9mmol) is heated to 80 DEG C, and back flow reaction 5h, TLC (methanol/chloroform 1:10) show fully reacting.It will reaction Light yellow solid, chloroform extraction is concentrated under reduced pressure to obtain in liquid, and organic phase is washed with the sodium hydroxide solution of 2mol/L, washed, saturated common salt Washing, anhydrous sodium sulfate dry, filter, and concentration organic phase obtains faint yellow oily compound 0.728g, without separation, are directly used in The next step.
HR-MS(ESI)(M+H)+m/z 203.1191,calcd for C12H14N2O 202.1106.
Preparation example 3
The synthetic route of 3 intermediate 5c of Scheme
Scheme 3Reagents and conditions:a.Boc2O, NHMDS, THF, r.t.1h；b.N-(3- Bromopropyl)phthalimide,K2CO3,DMF,90℃；c.TFA,DCM,0℃,8h；d.NH2NH2·H2O,EtOH, reflux,80℃。
The synthesis of compound (2c)
3- aminoquinoline (1c) (0.5g, 3.47mmol) is added into anhydrous tetrahydro furan (15ml), argon gas protection, ice Bis- (three Yue base silicyls) sodium amides (NHMDS, 3.45ml, 3.8mmol, 2M in THF) are slowly added dropwise under bath, are mixed 15min is slowly added dropwise into di-tert-butyl dicarbonate (Boc into reaction solution2O, 0.83g, 3.8mmol), 1h is reacted at room temperature. TLC (methanol/chloroform 1:10) shows fully reacting.A small amount of water quenching reaction is added into reaction solution, is layered, water phase acetic acid second Ester extraction, merges organic phase, and saturated sodium bicarbonate solution is washed, and washes, and saturated common salt washing, anhydrous sodium sulfate dries, filters, subtracts Pressure is concentrated to give crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:10) obtains faint yellow compound 2c (0.768g, yield 90%).
1H NMR(400MHz,CDCl3): δ 8.646 (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/z 245.1459,calcd for C14H16N2O2244.1212.
The synthesis of compound (3c)
70%NaH (0.81g, 23.6mmol) is suspended in anhydrous DMF (50ml), ice bath is cooled to 0 DEG C or so, Xiang Qi 30min is mixed in middle addition substrate 2c (2.88g, 11.8mmol), in batches a small amount of into reaction solution to be repeatedly added and N- (3- Bromopropyl) phthalimide (6.4g, 23.6mmol), insulated and stirred 15min is heated to 80 DEG C of reaction 15h, TLC (acetic acid Ethyl ester/petroleum ether 1:3) display fully reacting.Reaction solution is poured into ice water, is repeatedly extracted with ethyl acetate, organic phase is merged, Washing, saturated common salt washing, anhydrous sodium sulfate dry, filter, and crude product, silica gel column chromatography (ethyl acetate/petroleum is concentrated under reduced pressure to obtain Ether 1:10) obtain faint yellow compound 3c (4.85g, yield 95%).
1H NMR(400MHz,CDCl3): δ 8.794 (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/z 432.1990,calcd for C25H25N3O4431.1845.
The synthesis of compound (4c)
Compound 3c (3.26g, 7.56mmol) is dissolved in anhydrous methylene chloride (30ml), is placed in ice bath, it is cooling To 0 DEG C or so, trifluoroacetic acid (17.24g, 11.24ml, 151.2mmol) is added into reaction solution, finishes, reacts 8h at room temperature, TLC (ethyl acetate/petroleum ether 1:3) shows fully reacting.Reaction solution 50ml methylene chloride is diluted, and is added into reaction solution Enter the solution of potassium carbonate (pH is adjusted to be greater than 10) of 1M, liquid separation, water phase is extracted with dichloromethane, and merges organic phase, washing, saturated common salt Washing, anhydrous sodium sulfate dry, filter, and crude product is concentrated under reduced pressure to obtain, and silica gel column chromatography (ethanol/methylene 1:100) obtains yellowish Color compound 4c (2.4g, yield 96%).
1H NMR(400MHz,CDCl3): δ 8.455 (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/z 332.1381,calcd for C20H17N3O2331.1321.
The synthesis of compound (5c)
It disperses compound 4c (0.42g, 1.27mmol) in 8ml dehydrated alcohol, 85% hydration is added dropwise into reaction solution Hydrazine (145 μ l, 2.54mmol), is heated to 80 DEG C, back flow reaction 5h, and light yellow solid, chloroform extraction is concentrated under reduced pressure to obtain in reaction solution It takes, organic phase is washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated Organic phase obtains faint yellow oily compound 240mg, without separation, is directly used in the next step.
HR-MS(ESI)(M+H)+m/z 202.1334,calcd for C12H15N3201.1266.
Preparation example 4
The synthetic route of Scheme 4 intermediate 4d and 6d
Scheme 4Reagents and conditions:a.3-Buten-1-ol, DEAD, PPh3,THF,0℃- r.t.24h；b.3-Bromoquinoline,Pd(OAc)2,PPh3,CH3CN,TEA,reflux,12h；c.NH2NH2·H2O,80 ℃；d.H2,Pd/C,EtOH,r.t.18h；e.NH2NH2·H2O,EtOH,reflux,80℃。
The synthesis of compound (2d)
Phthalimide (1d) (4.5g, 30.51mmol) is suspended in anhydrous tetrahydro furan (50ml), ice is placed in 0 DEG C or so is cooled in bath, be added thereto 3- butene-1-ol (2.0g, 27.74mmol) and triphenylphosphine (8.0g, 30.51mmol), diethyl azodiformate (DEAD, 5.3g, 30.51mmol) is slowly added dropwise under stirring into reaction solution, adds Finish, be warmed to room temperature, be stirred to react for 24 hours naturally, TLC (ethyl acetate/petroleum ether 1:3) shows fully reacting.Add into reaction solution Enter n-hexane, filter, filtrate 1N hydrochloric acid, saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous sodium sulfate is dry, mistake Filter, is concentrated under reduced pressure to obtain crude product, and silica gel column chromatography (ethyl acetate/petroleum ether 1:30) obtains white compound 2d (3.75g, yield 67.3%).
1H NMR(400MHz,CDCl3): δ 7.820~7.841 (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/z 202.0782,calcd for C12H11NO2201.0790.
The synthesis of compound (3d)
3- bromoquinoline (0.5g, 2.4mmol) and compound (2d) (0.56g, 2.9mmol) are dissolved in anhydrous acetonitrile In (10ml), acid chloride (5.4mg, m/m:1%eq) is added into reaction solution, triphenylphosphine (24mg, m/m:4%eq) He Sanyi Reaction solution is heated to back flow reaction 12h by amine (0.97g, 1.34ml, 9.6mmol), and TLC (ethyl acetate/petroleum ether 1:3) is aobvious Show fully reacting.It will be poured into reaction solution, filter, filtrate solvent is spin-dried for, raffinate is repeatedly extracted with methylene chloride, is associated with Machine phase, saturated common salt water washing, anhydrous sodium sulfate dry, filter, and crude product, silica gel column chromatography (ethyl acetate/stone is concentrated under reduced pressure to obtain Oily ether 1:30) obtain white compound 3d (0.677g, yield 86%).
1H NMR(300MHz,CDCl3): δ 8.902 (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/z 329.1280,calcd for C21H16N2O2328.1212.
The synthesis of compound (4d)
It disperses compound 3d (0.30g, 0.61mmol) in 10ml dehydrated alcohol, 85% hydration is added dropwise into reaction solution Hydrazine (70 μ l, 1.22mmol), is heated to 80 DEG C, back flow reaction 5h, and light yellow solid, chloroform extraction is concentrated under reduced pressure to obtain in reaction solution It takes, organic phase is washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated Organic phase obtains white oil compound 120mg, without separation, is directly used in the next step.
HR-MS(ESI)(M+H)+m/z 199.1232,calcd for C13H14N2198.1157.
The synthesis of compound (5d)
It disperses compound 3d (0.30g, 0.91mmol) in 10ml dehydrated alcohol, Pd/C is added into reaction solution (30mg, m/m:10%), hydrogen balloon is passed through hydrogen under normal pressure, reacts 18h at room temperature, and TLC (ethyl acetate/petroleum ether 1:3) is aobvious Show fully reacting.Filtrate decompression is concentrated to give crude product by filtering, and silica gel column chromatography (ethyl acetate/petroleum ether 1:30) obtains whitening It closes object 5d (0.27g, yield 90%).
1H NMR(400MHz,CDCl3): δ 8.894 (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/z 331.1443,calcd for C21H18N2O2330.1368.
The synthesis of compound (6d)
It disperses compound 5d (0.15g, 0.45mmol) in 10ml dehydrated alcohol, 85% hydration is added dropwise into reaction solution Hydrazine (52 μ l, 0.9mmol), is heated to 80 DEG C, back flow reaction 5h, and light yellow solid is concentrated under reduced pressure to obtain in reaction solution, and chloroform extracts, Organic phase is washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated organic White oil compound 82mg is mutually obtained, without separation, is directly used in the next step.
HR-MS(ESI)(M+H)+m/z201.1387,calcd for C13H16N2200.1313.
Preparation example 5
The synthetic route of 5 intermediate 2e of Scheme
Scheme 5Reagents and conditions:a.TsCl,Py,DCM,r.t.24h；b.NH2NH2·H2O, EtOH,reflux,80℃。
The synthesis of compound (1e)
Compound 4c (0.5g, 1.51mmol) is dissolved in anhydrous methylene chloride (5ml), pyridine is added thereto (2.5ml) paratoluensulfonyl chloride (0.345g, 1.81mmol) is slowly added dropwise into reaction solution under ice bath, reacts at room temperature for 24 hours, TLC (ethyl acetate/petroleum ether 1:3) shows fully reacting.Reaction solution is poured into ice water, is repeatedly extracted with methylene chloride, is closed And organic phase, washing, saturated common salt washing, anhydrous sodium sulfate dry, filter, silica gel column chromatography (ethyl acetate/petroleum ether 1:5) Obtain faint yellow compound 1e (0.72g, yield 98%).
1H NMR(400MHz,CDCl3): δ 8.460 (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 =8.0Hz 1H), 3.747~3.809 (m, 3H), 2.422 (s, 3H), 1.849~1.885 (m, 2H)
HR-MS(ESI)(M+H)+m/z 486.1750,calcd for C27H23N3O4S 485.1409.
The synthesis of compound (2e)
It disperses compound 1e (0.68g, 1.4mmol) in 15ml dehydrated alcohol, 85% hydration is added dropwise into reaction solution Hydrazine (160 μ l, 2.8mmol), is heated to 80 DEG C, back flow reaction 5h, and light yellow solid, chloroform extraction is concentrated under reduced pressure to obtain in reaction solution It takes, organic phase is washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is 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/z 356.1422,calcd for C19H21N3O2S 355.1354.
Preparation example 6
The synthetic route of 6 intermediate 5f of Scheme
Scheme 6Reagents and conditions:a.Benzaldehyde,EtOH,reflux；b.NaBH4, EtOH,r.t.；c.N-(3-Bromopropyl)phthalimide,K2CO3,DMF,90℃；d.NH2NH2·H2O,EtOH, reflux,80℃。
The synthesis of compound (2f)
3- aminoquinoline (1f) (1.63g, 11.3mmol) and benzaldehyde (1.0g, 9.42mmol) are added to dehydrated alcohol In, it is heated to back flow reaction and stays overnight, TLC shows fully reacting, is cooled to room temperature, evaporated under reduced pressure solvent afforded crude material 2f, without place Reason directly carries out next step reaction.
The synthesis of compound (3f)
Crude product (2f) obtained by upper step is dissolved in 30ml anhydrous methylene chloride, ice-water bath is cooled to 0 DEG C or so, will wherein Sodium borohydride (0.43g, 11.3mmol) repeatedly is added in batches, finishes, the reaction was continued 12h, TLC (ethyl acetate/petroleum ether 2:1) It shows fully reacting, stops reaction, 5ml water quenching reaction is added into reaction solution, ethyl alcohol is evaporated, water 25ml is added, uses second Acetoacetic ester repeatedly extracts, and merges organic phase, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, column layer (ethyl acetate/petroleum ether 1:5) purifying is analysed, sterling 3f (0.76g, two step yields 34.5%) are obtained.
1H NMR(400MHz,CDCl3): δ 8.495 (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/z 235.1216,calcd for C16H14N2234.1157.
The synthesis of compound (4f)
70% NaH (0.36g, 5.44mmol) is dispersed in the dry DMF of 10ml, cryostat, is cooled to 0 DEG C, argon gas Protection.Compound 3f (0.636g, 2.72mmol) and N- (3- bromopropyl) phthalimide (1.8g, 6.8mmol) is added. Overnight, TLC (ethyl acetate/petroleum ether 1:1) shows fully reacting for reaction at room temperature.Reaction solution is poured on 50ml on ice, dichloro Methane repeatedly extracts, and merges organic phase, washing, saturated common salt washing.It after this solid is dissolved with dichloromethane solution, washes, satisfies It is washed with salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, the white foam of petrol ether/ethyl acetate (10:1) column chromatography Shape solid 4f (0.79g, yield 69%).
1H NMR(400MHz,CDCl3): δ 8.654 (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/z 422.1845,calcd for C27H23N3O2421.1790.
The synthesis of compound (5f)
It disperses compound 4f (0.12g, 0.285mmol) in 15ml dehydrated alcohol, 85% water is added dropwise into reaction solution It closes hydrazine (32 μ l, 0.57mmol), is heated to 80 DEG C, back flow reaction 5h, light yellow solid, chloroform extraction is concentrated under reduced pressure to obtain in reaction solution It takes, organic phase is washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated Organic phase obtains faint yellow oily compound (5f) 48mg, without separation, is directly used in the next step.
1H NMR(400MHz,CDCl3): δ 8.654 (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/z 292.1804,calcd for C19H21N3291.1735.
Preparation example 7
The synthetic route of 7 intermediate 2g of Scheme
Scheme 7Reagents and conditions:a.BzCl,Py,DCM,r.t.24h；b.NH2NH2·H2O, EtOH,80℃。
The synthesis of compound (1g)
Compound 4c (0.5g, 1.51mmol) and chlorobenzoyl chloride (0.27ml, 0.32g, 2.26mmol) are added to 15ml It in pyridine, is placed in and reacts 3.5h at room temperature, TLC (ethyl acetate/petroleum ether 2:1) shows fully reacting.Reaction solution is poured into ice It in water, is repeatedly extracted with methylene chloride, merges organic phase, washing, saturated common salt is washed, and anhydrous sodium sulfate dries, filters, and is depressurized It is concentrated to give crude product, silica gel column chromatography (ethyl acetate/petroleum ether 1:3) obtains faint yellow compound 1g (0.638g, yield 97%).
1H NMR(400MHz,CDCl3): δ 8.690 (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/z 436.1614,calcd for C27H21N3O3435.1583.
The synthesis of compound (2g)
It disperses compound 1g (0.63g, 1.45mmol) in 15ml dehydrated alcohol, 85% hydration is added dropwise into reaction solution Hydrazine (165 μ l, 2.90mmol), is heated to 80 DEG C, back flow reaction 5h, and light yellow solid, chloroform extraction is concentrated under reduced pressure to obtain in reaction solution It takes, organic phase is washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated Organic phase obtains faint yellow oily compound 2g 0.4g, without separation, is directly used in the next step.
HR-MS(ESI)(M+H)+m/z 306.1599,calcd for C19H19N3O 305.1528.
Preparation example 8
The synthetic route of 8 intermediate 5h of Scheme
Scheme 8Reagents and conditions:a.Propionaldehyde,EtOH,reflux； b.NaBH4,EtOH,r.t.；c.N-(3-Bromopropyl)phthalimide,K2CO3,DMF,90℃；d.NH2NH2·H2O, EtOH,reflux,80℃。
The synthesis of compound (2h)
By 3- aminoquinoline (1h) (2.0g, 13.56mmol) and positive propionic aldehyde (0.66g, 11.3mmol) be added to 20ml without In water-ethanol, it is heated to back flow reaction and stays overnight, TLC shows fully reacting, it is cooled to room temperature, evaporated under reduced pressure solvent afforded crude material 2h, Next step reaction is directly carried out without processing.
HR-MS(ESI)(M+H)+m/z 184.1023,calcd for C12H12N2184.1000.
The synthesis of compound (3h)
Crude product (2h) obtained by upper step is dissolved in 50ml anhydrous methylene chloride, ice-water bath is cooled to 0 DEG C or so, will wherein Sodium borohydride (0.516g, 13.56mmol) repeatedly is added in batches, finishes, the reaction was continued 12h, TLC (ethyl acetate/petroleum ether 2: 1) it shows fully reacting, stops reaction, 5ml water quenching reaction is added into reaction solution, ethyl alcohol is evaporated, water 40ml is added, use Ethyl acetate repeatedly extracts, and merges organic phase, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, column (ethyl acetate/petroleum ether 1:5) purifying is chromatographed, sterling 3h (0.94g, two step yields 45.2%) are obtained.
1H NMR(400MHz,CDCl3): δ 8.496 (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/z 186.1136,calcd for C12H14N2186.1157.
The synthesis of compound (4h)
70% NaH (0.35g, 5.36mmol) is dispersed in the dry DMF of 10ml, cryostat, is cooled to 0 DEG C, argon gas Protection.Compound 3h (0.5g, 2.68mmol) and N- (3- bromopropyl) phthalimide (2.1g, 8.06mmol) is added. Overnight, TLC (ethyl acetate/petroleum ether 1:1) shows fully reacting for reaction at room temperature.Reaction solution is poured on 50ml on ice, dichloro Methane repeatedly extracts, and merges organic phase, washing, saturated common salt washing.It after this solid is dissolved with dichloromethane solution, washes, satisfies It is washed with salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, the white foam of petrol ether/ethyl acetate (10:1) column chromatography Shape solid 4h (0.72g, yield 72%).
1H NMR(400MHz,CDCl3): δ 8.654 (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/z 373.1845,calcd for C27H23N3O2373.1790.
The synthesis of compound (5h)
It disperses compound 4h (0.3g, 0.8mmol) in 15ml dehydrated alcohol, 85% hydrazine hydrate is added dropwise into reaction solution (96 μ l, 1.6mmol), is heated to 80 DEG C, back flow reaction 5h, light yellow solid is concentrated under reduced pressure to obtain in reaction solution, chloroform extraction has Machine is mutually washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and organic phase is concentrated Faint yellow oily compound (5h) 124mg is obtained, without separation, is directly used in the next step.
HR-MS(ESI)(M+H)+m/z 243.1702,calcd for C15H21N3243.1735.
Preparation example 9
The synthetic route of 9 intermediate 6i of Scheme
Scheme 9Reagents and conditions:a.Acrolein,EtOH,reflux；b.NaBH4,EtOH, r.t.；c.N-(3-Bromopropyl)phthalimide,K2CO3,DMF,90℃；d.3-Bromoquinoline,Pd (OAc)2,PPh3,CH3CN,TEA,reflux,12h；e.NH2NH2·H2O,EtOH,reflux,80℃。
The synthesis of compound (2i)
3- aminoquinoline (1i) (3.0g, 21.4mmol) and allyl aldehyde (1.0g, 17.8mmol) are added anhydrous to 30ml It in ethyl alcohol, is heated to back flow reaction and stays overnight, TLC shows fully reacting, is cooled to room temperature, evaporated under reduced pressure solvent afforded crude material 2i, no Next step reaction is directly carried out through handling.
HR-MS(ESI)(M+H)+m/z 182.1026,calcd for C12H10N2182.0844.
The synthesis of compound (3i)
Crude product (2i) obtained by upper step is dissolved in 40ml anhydrous methylene chloride, ice-water bath is cooled to 0 DEG C or so, will wherein Sodium borohydride (0.814g, 21.4mmol) repeatedly is added in batches, finishes, the reaction was continued 12h, TLC (ethyl acetate/petroleum ether 2: 1) it shows fully reacting, stops reaction, 8ml water quenching reaction is added into reaction solution, ethyl alcohol is evaporated, water 30ml is added, use Ethyl acetate repeatedly extracts, and merges organic phase, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, column (ethyl acetate/petroleum ether 1:5) purifying is chromatographed, sterling 3i (1.26g, two step yields 38.6%) are obtained.
1H NMR(400MHz,CDCl3): δ 8.392 (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/z 184.1478,calcd for C12H12N2184.1000.
The synthesis of compound (4i)
70% NaH (0.72g, 10.88mmol) is dispersed in the dry DMF of 50ml, cryostat, is cooled to 0 DEG C, argon Gas shielded.Addition compound 3i (1.0g, 5.43mmol) and N- (3- bromopropyl) phthalimide (4.3g, 16.3mmol).Overnight, TLC (ethyl acetate/petroleum ether 1:1) shows fully reacting for reaction at room temperature.Reaction solution is poured on On ice, methylene chloride repeatedly extracts 100ml, merges organic phase, washing, saturated common salt washing.This solid dichloromethane solution After dissolution, washing, saturated common salt is washed, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, petrol ether/ethyl acetate (10:1) column The white foam solid 4i (1.57g, yield 78%) of chromatography.
1H NMR(400MHz,CDCl3): δ 8.656 (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/z 371.1713,calcd for C23H21N3O2371.1634.
The synthesis of compound (5i)
3- bromoquinoline (0.5g, 2.4mmol) and compound (4i) (1.07g, 2.9mmol) are dissolved in anhydrous acetonitrile In (20ml), acid chloride (5.4mg, m/m:1%eq) is added into reaction solution, triphenylphosphine (24mg, m/m:4%eq) He Sanyi Reaction solution is heated to back flow reaction 12h by amine (0.97g, 1.34ml, 9.6mmol), and TLC (ethyl acetate/petroleum ether 1:3) is aobvious Show fully reacting.It will be poured into reaction solution, filter, filtrate solvent is spin-dried for, raffinate is repeatedly extracted with methylene chloride, is associated with Machine phase, saturated common salt water washing, anhydrous sodium sulfate dry, filter, and crude product, silica gel column chromatography (ethyl acetate/stone is concentrated under reduced pressure to obtain Oily ether 1:30) obtain white compound 5i (1.1g, yield 92%).
1H NMR(400MHz,CDCl3): δ 8.656 (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/z 498.1880,calcd for C32H26N4O2498.2056.
The synthesis of compound (6i)
It disperses compound 5i (0.5g, 1.0mmol) in 30ml dehydrated alcohol, 85% hydrazine hydrate is added dropwise into reaction solution (112 μ l, 2.0mmol), is heated to 80 DEG C, back flow reaction 5h, and light yellow solid is concentrated under reduced pressure to obtain in reaction solution, and chloroform extracts, Organic phase is washed with the sodium hydroxide solution of 2mol/L, washing, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated organic Faint yellow oily compound 6i 0.32g is mutually obtained, without separation, is directly used in the next step.
HR-MS(ESI)(M+H)+m/z 368.1804,calcd for C24H24N4368.2001.
The preparation of 10 raw material compound 6 of preparation example
New construction macrocyclic ketone lactone compound of the invention i.e. from clarithromycin, using known document report or Feasible reaction method known to the synthesis chemically public, obtains derivative appropriate as raw material of the invention, such as raw material chemical combination Object 6 can use document J.Med.Chem, the method preparation of 41,4080-4100,1998 reports.
Clarithromycin (50g, 66.9mmol) is dispersed in 350ml water, the hydrochloric acid of 1mol/L is added thereto (350ml), is stirred at room temperature, and reaction solution gradually becomes viscous.The reaction was continued 3h, reaction solution gradually become clarified solution, TLC (chloroform/first Alcohol 10:1) detection display fully reacting.With the sodium hydroxide solution tune pH to 9-10 of 2mol/L, there are a large amount of white solids to generate, Product is repeatedly extracted through methylene chloride, merges organic phase, saturated common salt washing, anhydrous sodium sulfate drying.It is concentrated under reduced pressure, dichloromethane Alkane/methanol 50:1) reduced pressure chromatography obtains sterling (1) 37.9g, yield 96%.
1H NMR(300MHz,CDCl3): δ 5.172 (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)
13C NMR(75MHz,CDCl3):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/z 590.3885, calculated value: C30H56NO10590.3898.
Compound 1 (24.322g, 41.29mmol) is dissolved in the dry methylene chloride of 300ml after toluene is with water, and argon gas is protected Shield, ice-water bath is cooling, to be dissolved complete, and triethylamine (6.9ml, 49.55mmol) and acetic anhydride are successively added dropwise in 0 DEG C (4.67ml,49.55mmol).10h, TCL (chloroform/methanol 10/1) detection display fully reacting, into reaction solution is stirred at room temperature 100ml ice water is added and terminates reaction, stands liquid separation, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated to give light Yellow foam crude product 27.38g, decompression silica gel column chromatography separating purification (methylene chloride/methanol/triethylamine 30:1:2%) obtain White foam solid (2) 21.9g, yield 84%.
1H NMR(300MHz,CDCl3): δ 5.158 (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)
13C NMR(75MHz,CDCl3):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/z 632.4018, calculated value: C32H58NO11632.4010.
Compound 2 (1.935g, 3.067mmol) through toluene sufficiently with water after be dissolved in the dry dichloromethane solution of 20ml In, it is added pyridine (3.968ml, 49.065mmol), argon gas protection is sufficiently mixed 0.5h under ice-water bath is cooling.It is dripped into system Dichloromethane solution (3ml) solution of chlorination diphosgene (0.962ml, 7.973mmol).Reaction solution immediately becomes yellowish Color continues to react at room temperature, and reaction solution is gradually muddy and color burn, for 24 hours after TLC (acetone/petroleum ether/triethylamine 1.5:1: 1%) fully reacting is shown.Into system plus a small amount of trash ice terminates reaction, and a large amount of methylene chloride, which are added, keeps the solid in system complete Fully dissolved.It is carefully added into saturated sodium bicarbonate solution, stirring at normal temperature, the liquid separation after generating there is no bubble, organic phase uses respectively Half saturated sodium chloride is washed, and saturated sodium-chloride is washed, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, (petroleum ether/acetone/triethylamine 2.5: 1:0.5%) reduced pressure chromatography obtains light yellow product (3) 1.51g, yield 75%.
1H NMR(300MHz,CDCl3): δ 5.122 (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)
13C NMR(75MHz,CDCl3):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/z 658.3815, calculated value: C33H56NO12658.3797.
Oxalyl chloride (0.823g, 6.482mmol) is dissolved in dry methylene chloride (15ml), argon gas protection, acetone-is dry Ice bath is cooled to -78 DEG C, methylene chloride (2ml) solution of DMSO (1.013g, 12.963mmol) is added dropwise after stablizing thereto, surely The dichloromethane solution (25ml) of sufficiently dry compound 3 (2.839g, 4.321mmol) is added dropwise after fixed again, is maintained at -78 DEG C React 4h.The dichloromethane solution (2ml) of triethylamine (2.624g, 25.927mmol) is added dropwise, and is gradually warming up to reaction solution Room temperature, TLC (chloroform/methanol 10:1) display reaction is substantially completely.The hydrochloric acid of 1N, unsaturated carbonate are used after methylene chloride dilution respectively Hydrogen sodium, saturated common salt washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure to obtain weak yellow foam shape solid, reduced pressure chromatography (acetone/ Petroleum ether 3:1) obtain white foam sterling (4) 1.98g, yield 70%.
1H NMR(300MHz,CDCl3): δ 5.054 (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)
13C NMR(75MHz,CDCl3):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/z 656.3627,calcd for C33H54NO12656.3641.
Sufficiently dry compound 4 (11.48g, 17.5mmol) is dissolved in the dry acetone of 150ml, argon gas protection, dropwise It is added DBU (3.92ml, 26.25mmol), is heated to reflux 4h, TLC (chloroform/methanol 10:1) shows fully reacting.It is added dropwise 5% potassium dihydrogen phosphate tune pH is to neutrality.Decompression is diluted after evaporating part acetone with a large amount of dichloromethane solutions, saturation food Salt washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and crude product obtains white solid sterling (5) 8.0g through re-crystallizing in ethyl acetate, produces Rate 75%.
1H NMR(300MHz,CDCl3): δ 6.597 (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)
13C NMR(100MHz,CDCl3):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/z 612.3755, calculated value: C32H54NO10612.3742.
70% NaH (0.662g, 19.313mmol) is dispersed in the dry DMF of 60ml, cryostat, is cooled to -15 DEG C, argon gas protection.Compound 5 (5.9g, 9.656mmol) is added portionwise, after being sufficiently mixed be added dropwise CDI (4.693g, DMF solution (40ml) 28.969mmol).Continue low-temp reaction 2h, TLC (acetone/petroleum ether 1.5:1) shows fully reacting. Reaction solution is poured on 150ml on ice, there are a large amount of foamy white solids to be precipitated after placement, filters, washes to obtain white solid.This is solid After body is dissolved with dichloromethane solution, washing, saturated common salt washing, anhydrous sodium sulfate is dry, petroleum ether/acetone (3:1) decompression White foam solid (6) 5.4g of column chromatography, yield 80%.
1H NMR(400MHz,CDCl3):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)
13C NMR(100MHz,CDCl3):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/z 706.3895, calculated value: C33H58N2O14706.3883.
Embodiment
Embodiment 1S1 (11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -3- sulfydryl substituted propyl) imino group) erythromycin) preparation:
The synthetic route of compound S1:
The preparation of first step compound (M1)
Compound 5a (70mg, 0.3046mmol) and macrolide intermediates 6 (108mg, 0.1523mmol) are dissolved in 2.0ml Anhydrous tetrahydrofuran solution reacts 12h at room temperature, and DBU (93mg, 0.61mmol) is added dropwise into reaction solution, continues anti-at room temperature Should for 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.20ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white bubble Foam shape product M1 (68mg, 52%).
1H NMR(300MHz,CDCl3): δ 8.827 (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/z 856.4349,calcd for C45H65N3O11S 855.4340.
The preparation of second step compound (S1)
Compound M1 (30mg, 0.035mmol) is added into 2ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S1 (24mg, 84%).
1H NMR(400MHz,CDCl3): δ 8.824 (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), δ 4.672 (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)
13C NMR(150MHz,CDCl3):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/z 814.4246,calcd for C43H63N3O10S 813.4234.
Embodiment 2S2 (11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -3- hydroxyl substituted propyl) imino group) erythromycin) preparation:
The synthetic route of compound S2:
The preparation of first step compound (M2)
Compound 3b (84mg, 0.413mmol) and macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml without Water tetrahydrofuran solution, reacts 12h at room temperature, and DBU (26mg, 0.17mmol) is added dropwise into reaction solution, and continuation is reacted at room temperature For 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.5ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white foam Shape product M2 (23mg, 65%).
1H NMR(400MHz,CDCl3): δ 8.622 (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/z 839.4568,calcd for C45H65N3O12839.4568.
The preparation of second step compound (S2)
Compound M2 (48mg, 0.057mmol) is added into 2ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S2 (42.2mg, 92.4%).
1H NMR(400MHz,CDCl3): δ 8.633 (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)
13C NMR(150MHz,CDCl3):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/z 798.4489,calcd for C43H63N3O11797.4463.
Embodiment 3S3 (11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -3- amino substituted propyl) imino group) erythromycin) preparation:
The synthetic route of compound S3:
The preparation of first step compound (M3)
Compound 5c (72mg, 0.356mmol) and macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml without Water tetrahydrofuran solution, reacts 12h at room temperature, and DBU (26mg, 0.17mmol) is added dropwise into reaction solution, and continuation is reacted at room temperature For 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.5ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white foam Shape product M3 (21mg, 59%).
1H NMR(400MHz,CDCl3): δ 8.760 (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/z 839.4777,calcd for C45H66N4O11838.4728.
The preparation of second step compound (S3)
Compound M3 (34mg, 0.04mmol) is added into 2ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S3 (26.5mg, 82%).
1H NMR(400MHz,CDCl3): δ 8.763 (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)
13C NMR(150MHz,CDCl3): δ 216.666,203.638,169.844,157.494,143.524, 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/z 797.4746,calcd for C43H64N4O10796.4622.
Embodiment 4S4 (11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (3- quinolyl -3 (E)-cyclobutenyl) imino group) erythromycin) preparation:
The synthetic route of compound S4:
The preparation of first step compound (M4)
Compound 4d (124mg, 0.626mmol) and macrolide intermediates 6 (30mg, 0.0425mmol) are dissolved in 2.0ml Anhydrous tetrahydrofuran solution reacts 12h at room temperature, and DBU (26mg, 0.17mmol) is added dropwise into reaction solution, continues anti-at room temperature Should for 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.5ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs white Foam-like product M4 (22.7mg, 64%).
1H NMR(400MHz,CDCl3): δ 8.922 (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, 1H J=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/z 836.4722,calcd for C46H65N3O11835.4619.
The preparation of second step compound (S4)
Compound M4 (18mg, 0.0215mmol) is added into 2ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S4 (15mg, 87.7%).
1H NMR(400MHz,CDCl3): δ 8.940 (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).
13C NMR(150MHz,CDCl3): δ 216.302,203.959,169.663,157.211,149.828, 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/z 794.4603,calcd for C44H63N3O10793.4513.
Embodiment 5S5 (11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -4- replace butyl) imino group) erythromycin) preparation:
The synthetic route of compound S5:
The preparation of first step compound (M5)
Compound 6d (52mg, 0.26mmol) and macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml without Water tetrahydrofuran solution, reacts 12h at room temperature, and DBU (26mg, 0.17mmol) is added dropwise into reaction solution, and continuation is reacted at room temperature For 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.5ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white foam Shape product M5.
HR-MS(ESI)(M+H)+m/z 838.4774,calcd for C46H67N3O11837.4776.
The preparation of second step compound (S5)
Compound M5 (25mg, 0.030mmol) is added into 2ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S5 (18mg, two step yields 40.6%).
1H NMR(400MHz,CDCl3): δ 8.776 (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).
13C NMR(150MHz,CDCl3):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/z 796.4765,calcd for C44H65N3O10795.4670.
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 group) erythromycin) and preparation:
The synthetic route of compound s 6:
The preparation of first step compound (M6)
Compound 2e (152mg, 0.428mmol) and macrolide intermediates 6 (30mg, 0.0425mmol) are dissolved in 2.0ml Anhydrous tetrahydrofuran solution reacts 12h at room temperature, and DBU (26mg, 0.17mmol) is added dropwise into reaction solution, continues anti-at room temperature Should for 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.5ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white bubble Foam shape product M6 (24mg, 58%).
1H NMR(400MHz,CDCl3): δ 8.527 (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, 1H J=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/z 993.5146,calcd for C52H72N4O13S 992.4817.
The preparation of second step compound (S6)
Compound M6 (20mg, 0.020mmol) is added into 1ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S6 (17mg, 85%).
1H NMR(400MHz,CDCl3): δ 8.527 (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)
13C NMR(150MHz,CDCl3):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/z 951.4789,calcd for C50H70N4O12S 950.4711.
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 group) erythromycin) and preparation:
The synthetic route of compound S7:
The preparation of first step compound (M7)
Compound 5f (38mg, 0.13mmol) and macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml without Water tetrahydrofuran solution, reacts 12h at room temperature, and DBU (26mg, 0.17mmol) is added dropwise into reaction solution, and continuation is reacted at room temperature For 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.5ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white foam Shape product M7.
HR-MS(ESI)(M+H)+m/z 929.5716,calcd for C52H72N4O11928.5198.
The preparation of second step compound (S7)
Compound M7 (16mg, 0.017mmol) is added into 2ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S7 (10.2mg, two step yields 35.4%).
1H NMR(400MHz,CDCl3): δ 8.094 (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)
13C NMR(150MHz,CDCl3): δ 217.472,204.056,169.677,156.168,141.776, 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/z 887.5121,calcd for C50H70N4O10886.5092.
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 group) erythromycin) and preparation:
The synthetic route of compound S8:
The preparation of first step compound (M8)
Compound 2g (86mg, 0.282mmol) and macrolide intermediates 6 (30mg, 0.0425mmol) be dissolved in 2.0ml without Water tetrahydrofuran solution, reacts 12h at room temperature, and DBU (26mg, 0.17mmol) is added dropwise into reaction solution, and continuation is reacted at room temperature For 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.5ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white foam Shape product M8.
HR-MS(ESI)(M+H)+m/z 943.5101,calcd for C52H70N4O12942.4990.
The preparation of second step compound (S8)
Compound M8 (12mg, 0.013mmol) is added into 1ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/chloroform 1:10) shows fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S8 (4mg, two step yields 16%).
1H NMR(400MHz,CDCl3): δ 8.094 (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)
13C NMR(150MHz,CDCl3):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/z 901.4957,calcd for C50H68N4O11900.4885.
Embodiment 9S9 (11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (N- propyl-N-3- quinolyl amido substituted propyl) imino group) erythromycin) preparation:
The synthetic route of compound S9:
The preparation of first step compound (M9)
Compound 5h (250mg, 1.03mmol) and macrolide intermediates 6 (100mg, 0.14mmol) be dissolved in 5.0ml without Water tetrahydrofuran solution, reacts 12h at room temperature, and DBU (98mg, 0.64mmol) is added dropwise into reaction solution, and continuation is reacted at room temperature For 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.10ml CH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white foam Shape product M7.
HR-MS(ESI)(M+H)+m/z 880.5716,calcd for C48H72N4O11880.5198.
The preparation of second step compound (S9)
Above-mentioned gained compound M9 is added into 5ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (methanol/ Chloroform 1:10) display fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S9 (57mg, two steps Yield 48.5%).
1H NMR(400MHz,CDCl3): δ 8.654 (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)
13C NMR(150MHz,CDCl3): δ 217.47,204.06,169.68,156.17,141.77,141.24, 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/z 838.5121,calcd for C46H70N4O10838.5092.
Embodiment 10S10 (11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (N-3- quinolyl -2 (E)-acrylic amido substituted propyl) imino group) erythromycin) preparation:
The synthetic route of compound S10:
The preparation of first step compound (M10)
Compound 6i (0.32g, 0.87mmol) and macrolide intermediates 6 (100mg, 0.14mmol) be dissolved in 5.0ml without Water tetrahydrofuran solution, reacts 12h at room temperature, and DBU (98mg, 0.64mmol) is added dropwise into reaction solution, and continuation is reacted at room temperature For 24 hours, TLC (methanol/chloroform 1:10) shows fully reacting.10mlCH is added into system2Cl2After dilution, organic phase is with 5% KH2PO4Solution is washed, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, and methanol/chloroform (1:100) column chromatographs to obtain white foam Shape product M10.
HR-MS(ESI)(M+H)+m/z 1005.5492,calcd for C57H75N4O111005.5463.
The preparation of second step compound (S10)
Above-mentioned gained compound M10 is added into 5ml anhydrous methanol, is heated to 50 DEG C of insulation reactions for 24 hours, TCL (first Alcohol/chloroform 1:10) display fully reacting.Solvent is evaporated, methanol/chloroform (1:100) column chromatographs to obtain white solid S10 (42.6mg, two step yields 42.6%).
1H NMR(400MHz,CDCl3): δ 8.656 (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)
13C NMR(150MHz,CDCl3):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/z 963.5403,calcd for C55H73N5O10963.5357.
Experimental sections
1 pharmacological evaluation of experimental example: antibacterial activity in vitro experiment
The present invention provides above compound in the purposes of antibiosis using the experiment of following antibacterial activity in vitro.
(1) test method: culture medium and incubation conditions
Staphylococcus and moraxelle catarrhalis are in CAMHB culture medium, 35 DEG C of incubation 16-20h；5% horse is being added in streptococcus The CAMHB culture medium of serum, 35 DEG C of incubation 20-24h；Hemophilus is in HTM broth bouillon, 35 DEG C of incubation 20-24h.
Minimum inhibitory concentration (MIC) measurement
Using the micro meat soup doubling dilution of standard.Antibacterials measure concentration range 64-0.004mg/L.It is tested bacterium solution Final concentration is about 1 × 105CFU/ml。
(2) comparison medicine: clarithromycin (Cla), Ketek (Teli)
(3) experimental strain is as follows:
3 plants of standard Quality-control strains: streptococcus pneumonia ATCC49619, staphylococcus aureus ATCC29213, influenza are bloodthirsty Bacillus ATCC49247.
It is clinically separated 10 plants of bacterium:
Methicillin-sensitivity, erythromycin-sensitive staphylococcus aureus-ATCC29213
Methicillin resistance, erythromycin-resistant staphylococcus aureus -11B117
Methicillin-sensitivity, erythromycin-sensitive staphylococcus epidermis -11X315
Methicillin resistance, erythromycin-resistant staphylococcus epidermis -11C176
Erythromycin-sensitive streptococcus pneumonia-ATCC49619
Erythromycin-resistant streptococcus pneumonia -11J011
Erythromycin-sensitive micrococcus scarlatinae -11L264
Erythromycin-resistant micrococcus scarlatinae -11N369
Azithromycin sensitivity haemophilus influenzae-ATCC49247
Insensitive haemophilus influenzae-the 11Q373 of azithromycin
Azithromycin sensitivity moraxelle catarrhalis -11B363
Insensitive moraxelle catarrhalis-the 11B364 of azithromycin
Every plant of bacterium all turns a work by plate point pure before the test, is used to test with new fresh thalli.Experiment is with mark every time Quasi- bacterial strain is as sensitive experiment Quality Control bacterium；With the bacterium solution without antibacterials as test strain growth control.Clarithromycin pair Reference culture staphylococcus aureus ATCC29213, streptococcus pneumonia ATCC49619 and haemophilus influenzae ATCC49247's MIC range is respectively: 0.125-0.5mg/L, 0.031-0.125mg/L and 4-16mg/L.Ketek is to three plants of standard bacterias MIC range is: 0.062-0.25mg/L, 0.004-0.031mg/L and 1-4mg/L.This test clarithromycin is to three plants of standards Bacterium MIC value is respectively 0.25mg/L, 0.062mg/L and 4mg/L；Ketek is respectively to the MIC value of three plants of reference cultures 0.062mg/L, 0.016mg/L and 1mg/L show that measurement result is available in range.
It is demonstrated experimentally that the structural formula of the present invention of above method preparation is S1, S2, S4, the compound sample of S5, tool There is broad spectrum activity while inhibiting the antibacterial activity and antimicrobial agent outstanding of gram-positive bacteria and Gram-negative bacteria active.
Above chat is only presently preferred embodiments of the present invention, therefore all features chatted according to scope of the present invention patent and side Method is included within the scope of the invention patent.
The MIC result (mg/L) of 1. compound S1 of table and comparison medicine to 10 plants of bacterium
The MIC result (mg/L) of 2.7 sample compounds of table and Ketek comparison medicine to 10 plants of bacterium
It is demonstrated experimentally that the structural formula of the present invention of above method preparation is S1, S2, S4, the compound sample of S5, tool There is broad spectrum activity while inhibiting the antibacterial activity and antimicrobial agent outstanding of gram-positive bacteria and Gram-negative bacteria active.
Above chat is only presently preferred embodiments of the present invention, therefore all features chatted according to scope of the present invention patent and side Method is included within the scope of the invention patent.

Claims (6)

1. a kind of Erythromycin A class antibiotic derivatives as shown in general formula I, with general structure below:
The 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 group) erythromycin
(S2) 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- (oxygen carbonyl (quinoline -3- hydroxyl Substituted propyl) imino group) erythromycin
(S6) ((N- is to toluene sulphur for oxygen carbonyl by 11,12- dideoxy -3-O- descladinosylation -6-O- methyl -3- oxo -12,11- Acyl group-N-3- quinolyl) amido substituted propyl) imino group) 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 group) 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 group) erythromycin
2. a kind of pharmaceutical composition, which is characterized in that the composition contains at least one compound and medicine in claim 1 Acceptable carrier on.
3. the compound in claim 1 inhibits the application in bacterial drug in preparation.
4. application according to claim 3, which is characterized in that the bacterium bacterial strain is selected from gram-positive bacterium, gram Negative bacteria, rickettsia Salmonella, mycoplasma pneumoniae, Chlamydia, Rome pathogen, bird blood plasma body, toxoplasm, mycobacterium, list Monocytogenes Salmonella, meningococcus.
5. application according to claim 4, which is characterized in that
The gram-positive bacterium is selected from staphylococcus, streptococcus, streptococcus pneumonia, pyococcus, epidermis grape ball Bacterium；
The gramnegative bacterium is selected from moraxelle catarrhalis, haemophilus influenzae.
6. application of the compound in preparation antiviral drugs in claim 1.
CN201410520787.4A 2014-09-30 2014-09-30 Erythromycin A ketolide antibiotics derivative, preparation method and application containing quinoline substituent group Active CN105524132B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410520787.4A CN105524132B (en) 2014-09-30 2014-09-30 Erythromycin A ketolide antibiotics derivative, preparation method and application containing quinoline substituent group

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410520787.4A CN105524132B (en) 2014-09-30 2014-09-30 Erythromycin A ketolide antibiotics derivative, preparation method and application containing quinoline substituent group

Publications (2)

Publication Number Publication Date
CN105524132A CN105524132A (en) 2016-04-27
CN105524132B true CN105524132B (en) 2019-07-02

Family

ID=55766693

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410520787.4A Active CN105524132B (en) 2014-09-30 2014-09-30 Erythromycin A ketolide antibiotics derivative, preparation method and application containing quinoline substituent group

Country Status (1)

Country Link
CN (1) CN105524132B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632550B (en) * 2016-09-30 2018-03-06 宜昌东阳光药业股份有限公司 A kind of method for preparing CLA impurity I
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
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

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

Also Published As

Publication number Publication date
CN105524132A (en) 2016-04-27

Similar Documents

Publication Publication Date Title
TW472060B (en) 4""-substituted-9-deoxo-9a-aza-9a-homoerythromycin a derivatives
CN109575018A (en) A kind of anti-infective compounds
JP2000514097A (en) C-4 "substituted macrolide derivative
CN112778284B (en) Pyrimido-cyclic derivative and application thereof in medicine
WO2011147316A1 (en) Levocarrimycin, pharmaceutical compositions, preparation methods and uses thereof
CN104211708B (en) Benzoxazinone derivatives and its application as antiseptic
AU2015272398A1 (en) Polyene macrolide derivative
WO2013186384A1 (en) N-substituted second generation derivatives of antifungal antibiotic amphotericin b and methods of their preparation and application
TW201002728A (en) Heterocyclic urea derivatives and methods of use thereof
CN108778288A (en) It can be used for treating antagonist derived from the mannose of the FimH of disease
CN105524132B (en) Erythromycin A ketolide antibiotics derivative, preparation method and application containing quinoline substituent group
CN110386944A (en) For inhibiting two (miscellaneous) aryl macrocyclic compound of protein kinase activity
CN100486985C (en) 9a-azalides with anti-inflammatory activity
JP2010501541A (en) Novel macrolides and ketolides with antibacterial activity
CN108727406A (en) The cyclosubstituted benzene of nitrogen-containing hetero and Evil piperazine oxazolidinone compounds and its preparation method and application
CN107257789A (en) It is used as the new N acyl groups aryl sulfamide derivatives of aminoacyl TRNA synthetase inhibitors
CN107129514A (en) Erythromycin A ketolide antibiotics derivative, its preparation method and application
CN109384712A (en) Target the application in NK1 receptor antagonist and its treatment of the Nausea and vomiting caused by chemotherapy
CN107987020A (en) 3,5- diaryl pyrazoles or 3,4- diaryl pyrazoles azole derivative and its application
CN108929329A (en) 2- azacyclo- -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds
CN108101948A (en) Macrocyclic compound and its making and use method
CN105399737B (en) Oxazolidinone compounds and application thereof
CN110964078A (en) Hederagenin compound H-X with anti-lung cancer effect and preparation method and application thereof
CN108864089B (en) Indolopyridone drug molecule and preparation method and application thereof
JP2000351794A (en) Erythromycin derivative

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant