CN102146085B - 9-oxime-ether ketolide derivative, and preparation method and medical composite thereof - Google Patents
9-oxime-ether ketolide derivative, and preparation method and medical composite thereof Download PDFInfo
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- CN102146085B CN102146085B CN201010110079.5A CN201010110079A CN102146085B CN 102146085 B CN102146085 B CN 102146085B CN 201010110079 A CN201010110079 A CN 201010110079A CN 102146085 B CN102146085 B CN 102146085B
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- 0 C*(CC(C1O*)[N+])C[U]C1OC(CC(C(*)C(OCC(C)(C(C(C)/C(/C(C)C1)=N/O*)O)O)=O)OC)C1(C)OC Chemical compound C*(CC(C1O*)[N+])C[U]C1OC(CC(C(*)C(OCC(C)(C(C(C)/C(/C(C)C1)=N/O*)O)O)=O)OC)C1(C)OC 0.000 description 7
- GRDCBQZNVZUIMT-UHFFFAOYSA-O CCC(C(C)(C(C(C)C(C(C)CC(C)(C(CC(C1C)O)OC(C2O)OCC(C)CC2[NH3+])OC)=NO)O)O)OC1=O Chemical compound CCC(C(C)(C(C(C)C(C(C)CC(C)(C(CC(C1C)O)OC(C2O)OCC(C)CC2[NH3+])OC)=NO)O)O)OC1=O GRDCBQZNVZUIMT-UHFFFAOYSA-O 0.000 description 1
- SQFUVROJWULABV-WKQYESSYSA-N CC[C@H]([C@](CC)([C@@H]([C@@H](C)/C(/[C@H](C)C[C@](C)([C@@H](CC([C@H]1C)O)OC(C2OCC)OCC(C)CC2N)OC)=N/OCC=C)O)O)OC1=O Chemical compound CC[C@H]([C@](CC)([C@@H]([C@@H](C)/C(/[C@H](C)C[C@](C)([C@@H](CC([C@H]1C)O)OC(C2OCC)OCC(C)CC2N)OC)=N/OCC=C)O)O)OC1=O SQFUVROJWULABV-WKQYESSYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
The invention provides a compound shown in the general formula (I) and an acceptable salt or ester prepared from the compound and an inorganic acid or organic acid. In the general formula (I), Ar represents heteroarylhydroxyl or substituted heteroarylhydroxyl; and X is hydrogen or fluorine. The compound provided by the invention has a novel structure, a heteroarylhydroxyl is connected with the 9-oxime hydroxyl of ketolide through an allyl side chain; and the compound is simple to synthesize and is suitable for industrial production. The compound has prominent antibacterial activity to common clinical sensitive bacteria and antibiotic resistance bacteria such as Staphylococcus aureus, Streptococcus penumoniae, Streptococcus pyogenes and Staphylococcus epidermidis, and can be used alone or used as active ingredient to be mixed with other medicines for curing the infections of bacteria and the like in various dosage forms by various routes of administration. Correspondingly, the invention also provides a preparation method of the compound and the application of the compound used as anti-infective medicine.
Description
Technical field
The present invention relates to the invention belongs to chemosynthesis and pharmacy field, relate to a kind of novel ketone lactone (9-oxime ether ketolide derivatives) and synthetic method thereof, and this compounds is as the purposes of anti-infectives.
Background technology
Widespread use clinically of ten quaternary macrolide antibiotic-erythromycin more than 50 year, is especially applicable to penicillin anaphylaxis person.S-generation erythromycin, as clarithromycin, Azythromycin, Roxithromycin etc. have overcome the acid nonfast problem of erythromycin.At present, the more and more demonstrations of the separated respiratory tract disease bacteria strain obtaining have resistance clinically, as streptococcus aureus (S.aureus) and streptococcus pneumoniae (S.pneumoniae).Compare with erythromycin, clarithromycin and Azythromycin etc., third generation erythromycin derivatives-one lactone has the activity (Agour ida s, C. etc., J.Med.Chem.1998,41:4080-4100) of anti-polymorphic type resistant organism.Its structure activity relationship shows: the inducible resistance of 3-cladinose in original macrolide has been avoided in the introducing of 3-carbonyl, proves 3-cladinose non-essential group simultaneously.But only depend on the introducing of 3-carbonyl cannot improve antimicrobial agent activity, the upper new aromatic side chain of introducing of large ring has produced new combination target spot to resistant organism, thereby it is active to have obtained antimicrobial agent.Therefore, 3-carbonyl and aromatic side chain have formed the important structure feature of ketolide antibiotics.
The power that the binding site of aromatic side chain on ketone lactone and side chain lengths thereof directly have influence on its antimicrobial agent activity.As the aromatic side chain of Ketek (Telithromycin) is connected on 11,12-carbamate, length is 4 atoms (Denis A. etc., Bioorg.Med.Chem.Lett.1999,9:3075-3080.); It is upper that the aromatic side chain of cethromycin (Cethromycin) is connected to 6-OH, and length is 3 atoms (Or Y.S. etc., J.Med.Chem.2000,43:1045-1049).
In the derivative of erythromycin, 9-carbonyl changes into after oxime hydroxyl, and the 9-oxime ether being connected to form with various alkyl or aromatic alkyl is important direction of modification (Gasc J.C. etc., J.Antibiot.1991, a 44:313-330; Kawashima Y. etc., Chem.Pharm.Bull.1994,42:1088-1095; Kato H. etc., WO00/61593; Pandey, D. etc., Bioorg.Med.Chem.2004,12,3807-3813.).Recently, the introducing of oxime ether is also applied in and finds (Agouridas, C. etc., J.Med.Chem.1998,41:4080-4100 on the ketone lactone with antimicrobial agent activity; ChenS.X. etc., J.Antibiot.2001,54:506-509; Ma Z. etc., US2002/0019355; Searle X.B., WO03/090761; Nomura T. etc., Bioorg.Med.Chem.2005,13:6615-6628; Nomura T. etc., Bioorg.Med.Chem.2006,14:3697-3711).
In a word, need the urgent technical problem solving of those skilled in the art to be exactly: how a kind of 9-oxime ether ketolide derivatives can be provided, can adapt to preferably suitability for industrialized production, and there is good anti-sensitive organism and antimicrobial agent is active for respiratory tract germ etc.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of novel ketone lactone (9-oxime ether ketolide derivatives) and synthetic method thereof, with the purposes of this compounds as anti-infectives, can adapt to preferably suitability for industrialized production, and there is good anti-sensitive organism and antimicrobial agent is active for respiratory tract germ etc.
In order to address the above problem, the invention discloses a kind of the have compound of following general formula and acceptable salt or the ester forming with mineral acid or organic acid thereof:
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen or fluorine.
Preferably, described Ar is that nitrogen atom heterocycle or Ar are replacement nitrogen atom heterocycle.
Preferably, described Ar is pyridyl, pyrimidyl, benzopyrazines base, benzo pyridazinyl, quinolyl, isoquinolyl, imidazoles phenyl, indyl; Or Ar is substituted pyridinyl, substituted pyrimidyl, replacement benzo pyrazinyl, replaces benzo pyridazinyl, substd quinolines base, substituted isoquinoline base, substituted imidazole phenyl, substituted indolyl.
Preferably, described Ar is 3-pyridyl, 5-pyrimidyl, 3-quinolyl, 4-isoquinolyl, 6-quinolyl, 4-(1-imidazoles) phenyl.
Preferably, described mineral acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide or phosphoric acid; Described organic acid is selected from acetic acid, propanedioic acid, methylsulfonic acid, succsinic acid, tosic acid, citric acid, toxilic acid, fumaric acid or stearic acid.
According to another embodiment of the present invention, a kind of method of compound as claimed in claim 1 of preparing is also disclosed, comprising:
(1), from erythromycin oxime, through etherificate, silanization, methylating obtains the midbody compound of clarithromycin synthesis technique: 2 ', 4 " two (trimethyl silicane)-6-0-erythromycin A9-0-(oxyethyl group cyclohexyl) oximes of O-;
(2), hydrolysis obtains compound: 3-OH-6-0-erythromycin oxime;
(3), protection reagent effect under, obtain compound:
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly; Described protection reagent is used for realizing R protecting group;
(4), in the mono-solvent of THF or THF/DMSO mixed solvent, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of the acting in conjunction selectivity displacement step 3 gained compounds of allylation reagent and highly basic; And in dichloromethane solvent, use and close cyclization reagent by 11,12-OH pass ring, and with oxidising agent, 3-OH is oxidized to 3-carbonyl, obtain compound:
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly;
(5), in acetonitrile or DMF solvent, under the catalysis of palladium salt and phase-transfer catalyst, allyl group effect on substituted aroma hydrocarbon and 9-oxime hydroxyl forms aromatic side chain, and sloughs 2 '-O-R protecting group, obtains having the compound of following general formula;
Or in acetonitrile or DMF solvent, under the catalysis of palladium salt and phase-transfer catalyst, the allyl group effect on substituted aroma hydrocarbon and 9-oxime hydroxyl forms aromatic side chain; Further in 2-position, introduce fluorine atom, and slough 2 '-O-R protecting group, obtain having the compound of following general formula:
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen or fluorine.
Preferably, the equivalence ratio scope of described allylation reagent and compound 3 is 1.0-2.0; The equivalence ratio scope of described highly basic and compound 3 is 1.0-3.0.
Preferably, described protection reagent is selected from acetic anhydride, benzoyl oxide, trimethyl silicane chlorine or hexamethyldisilazane; Described allylation reagent is selected from allyl bromide 98 or allyl iodide; Described highly basic is selected from potassium tert.-butoxide, potassium hydroxide, sodium hydride or hexamethl disilamine potassium; Described pass cyclization reagent is selected from triphosgene, phosgene or trichloromethyl chloroformyl ester; The oxide compound reagent that described oxidising agent is selected from N-chloro succinimide/dimethyl sulphide or contains methyl-sulphoxide; Described phase-transfer catalyst is selected from three o-methyl-phenyl-phosphines, triphenylphosphine, or quaternary ammonium salt.
According to another embodiment of the present invention, a kind of medicinal compositions for antibacterial therapy is also disclosed, comprise the compound with following general formula or its pharmaceutically acceptable additive salt or the ester of antimicrobial effective amount, and pharmaceutically acceptable carrier;
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen or fluorine.
The also application of claimed foregoing compound in the medicine for the preparation of the treatment of antibacterium infected by microbes of the present invention.
Compared with prior art, the present invention has the following advantages:
Compound of the present invention has novel texture, on the 9-of ketone lactone oxime hydroxyl, by allyl side chain, connects an aromatic heterocycle hydrocarbon, and synthetic easy, is applicable to suitability for industrialized production.
And compound of the present invention all has outstanding anti-microbial activity to clinical common sensitive organism and resistant organism, as streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, staphylococcus epidermidis etc., can separately or mix the treatment that is used for the infection such as bacterium with various formulations or route of administration with other medicines as one of activeconstituents.
Embodiment
For above-mentioned purpose of the present invention, feature and advantage can be become apparent more, below in conjunction with the drawings and specific embodiments, the present invention is further detailed explanation.
The invention provides a kind of acceptable salt or ester that there is following general structure and form with mineral acid or organic acid.
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen atom or fluorine atom.
Wherein, preferred, Ar can be 3-pyridyl, 5-pyrimidyl, 3-quinolyl, 4-quinolyl, 4-isoquinolyl, 5-quinoline, 5-isoquinolyl, 6-quinolyl, 6-isoquinoline 99.9,8-quinolyl, 4-(1-imidazoles) phenyl, 5-indyl etc.
The compound that the present invention has above-mentioned general formula can also form salt or ester with medicinal acceptable various mineral acids or organic acid.Preferably, mineral acid can be selected from hydrochloric acid, sulfuric acid, Hydrogen bromide or phosphoric acid; Organic acid can be selected from acetic acid, propanedioic acid, methylsulfonic acid, succsinic acid, tosic acid, citric acid, toxilic acid, fumaric acid, stearic acid.But the present invention be not limited to above for example.
To thering is the preparation method of the compound of above-mentioned general formula, be briefly described below.
Preparation process of the present invention is as follows:
1, from erythromycin oxime, through etherificate, silanization, methylate obtain the midbody compound 1,2 of clarithromycin synthesis technique ', 4 " two (trimethyl silicane)-6-0-erythromycin A9-0-(oxyethyl group cyclohexyl) oximes of O-;
2, then hydrolysis obtains compound 2:3-OH-6-0-erythromycin oxime;
3 and then, under the effect of acetic anhydride, 2 '-OH and 9-oxime hydroxyl diacetyl obtain compound 3:2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-acetyl oxime.The technological process of above three steps has had mentioned in open source literature, is not described in detail in this.Similar technique is referring to Liang Jianhua etc., organic chemistry, 2005,438-441; Zhou Baige etc., fine chemistry industry, 2005,314-316; Japanese plum guest etc., fine chemistry industry, 2007,678-680.
4, in the single solvent of THF (tetrahydrofuran (THF)) or THF/DMSO (dimethyl sulfoxide (DMSO)) mixed solvent, the allyl bromide 98 of 1.0-2.0 equivalent (molar weight) and the potassium tert.-butoxide acting in conjunction of 1.0-3.0 equivalent can selectivity ethanoyl on the 9-oxime hydroxyl of displacement compound 3 obtain compound 4:2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime.
5, further; in dichloromethane solvent; use triphosgene by 11; 12-OH closes ring; 3-OH is become 3-carbonyl to obtain key compound 5:2 '-O-ethanoyl-3-carbonyl-CAMA A 9-O-allyl group oxime-11,12-cyclic carbonate ester by Corey-Kim oxidation (in section-Jin oxidation) reagent oxidation again.
6, last, in acetonitrile or DMF (dimethyl formamide) solvent, under palladium salt and three o-methyl-phenyl-phosphine catalysts, substituted aroma hydrocarbon (for example, halogenated aromatic) the allyl group effect and on 9-oxime hydroxyl forms aromatic side chain, and in methyl alcohol, slough 2 '-O-Ac and obtain target compound 6:3-carbonyl-CAMA A 9-O-[3-aryl-2-propenyl] oxime-11,12-cyclic carbonate ester;
Or, in acetonitrile or DMF (dimethyl formamide) solvent, under palladium salt and three o-methyl-phenyl-phosphine catalysts, allyl group effect on substituted aroma hydrocarbon and 9-oxime hydroxyl forms aromatic side chain, further in THF (tetrahydrofuran (THF)) or DMF (dimethyl formamide) solvent, under sodium hydride and the effect of N-fluorobenzene sulphonyl imido, fluorine atom is introduced in 2-position, and in methyl alcohol, sloughs 2 '-0-Ac and obtain the target compound 6 of fluoridizing 2-position.
Fluoridizing of 2-position at ketone lactone can be improved anti-microbial activity.The technical matters comparative maturity of fluoridizing due to the 2-position of ketone lactone, therefore, does not repeat them here.For example, refer to Denis, A. etc., Drug.Future.2001,26,975; Phan, L.T. etc., Org.Lett.2000,2,2951; Searle X.B., WO03/090761.
It should be noted that, some of them synthesis step can reverse the right order, as first 11,12-OH carbonic acid esterification, then in selectivity allylation; Or first 3-OH oxidation and then the esterification of 11,12-OH carbonic acid, etc.The variation of these order of operation does not have influence on the synthetic of target compound.
Wherein, some reagent also can be replaced, as the acetic anhydride as protection reagent (for realizing the reagent of protecting group) can change benzoyl oxide into, or silylating reagent is as trimethyl silicane chlorine, hexamethyldisilazane etc., obtain the analogue of compound 3, be that ethanoyl on compound 3 is replaced by benzoyl, trimethyl silicon based, this analogue can be equally for follow-up reaction;
Allyl bromide 98 as allylation reagent can change allyl iodide etc. into;
Potassium tert.-butoxide as highly basic can change potassium hydroxide, sodium hydride, hexamethl disilamine potassium etc. into;
As the triphosgene of closing cyclization reagent, can change phosgene, trichloromethyl chloroformyl ester etc. into;
Corey-Kim oxidising agent (N-chloro succinimide/dimethyl sulphide) as oxidising agent can change the various oxide compound reagent that contains methyl-sulphoxide into as methyl-sulphoxide/oxalyl chloride, methyl-sulphoxide/acetic anhydride etc.;
The three o-methyl-phenyl-phosphines as phase-transfer catalyst can change the quaternary ammonium salts such as triphenylphosphine, or tetra-n-butyl ammonium bromide into;
For changing commercialization reagent Selectifluor into the fluorination reagent N-fluorobenzene sulphonyl imido of fluoridizing of the 2-position of ketone lactone
tM.
The variation of above-mentioned these reagent does not have influence on the synthetic of target compound.
By the mode of structural formula, preparation process is above provided to a concrete example below, is simply described as follows:
Reaction reagent and condition: (a) HCl, EtOH. (b) Ac
2o, CH
2cl
2. (c) KOtBu, AllylBromide, THF. (d) bis (trichloromethyl) carbonate, Pyridine, CH
2cl
2. (e) Me
2s, N-chlorosuccinimide, Et
3n, CH
2cl
2. (f) ArBr, Pd (OAc)
2, P (o-tolyl)
3, Et
3n, CH
3cN. (g) MeOH.
Below in conjunction with embodiment, invention is described further, but and limits the scope of the invention never in any form.
Embodiment 1 (generating compound 2)
3-hydroxyl-CAMA oxime
In 140ml anhydrous acetonitrile, add successively erythromycin oxime 20.0g, 1-oxyethyl group tetrahydrobenzene 12.0ml, pyridine hydrochloride 4.8g, react 1-3 hour at 25 ℃.TLC demonstration is added pyridine hydrochloride 4.8g after having reacted, HMDS 10ml, and the reaction times is 30-60 minute.Reaction finishes rear by 80ml NaOH termination reaction, adds the extraction of 80ml ethyl acetate, then uses saturated common salt water washing, anhydrous MgSO
4dried overnight, obtain 2 ', 4 " two (trimethyl silicane) Erythromycin A 9-O-(oxyethyl group cyclohexyl) oximes of O-.
Upper products therefrom is filtered to rear underpressure distillation and boil off solvent, with THF displacement once, add THF 70ml, DMSO 70ml dissolves, then adds methyl iodide 2.5ml, KOH 2.5g, at 3 ℃, react 30-60 minute, reaction finishes rear by 80ml water termination reaction, be extracted with ethyl acetate 2 ', 4 " two (trimethyl silicane)-CAMA A9-O-(oxyethyl group cyclohexyl) oximes of O-.Methylate evaporated under reduced pressure solvent by upper step, adds 30ml dissolve with ethanol, and 8ml HCl adds 80ml water droplet to be added in reaction solution, at 40 ℃, react one hour, after reaction finishes, add ammoniacal liquor to regulate pH value to 9 left and right, adularescent Precipitation, filters white precipitate.This is deposited in to recrystallization in ethanol, water and obtains 3-OH clarithromycin oxime 10.4g.MS(M+H
+)m/z:605.5
Embodiment 2 (generating compound 3)
2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-acetyl oxime
By being equipped with in the flask of 5.0g 3-hydroxyl clarithromycin oxime, add 50ml methylene dichloride, drip 2.4ml acetic anhydride, react end in a hour, reaction solution is used respectively saturated sodium bicarbonate solution, water, and saturated common salt water washing is also spent the night with anhydrous magnesium sulfate drying.Filter, removal of solvent under reduced pressure obtains white blister compound 5.4g.
Embodiment 3 (generating compound 4)
2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime
2.0g 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-acetyl oxime is dissolved in 20mlTHF solution; add allyl bromide 98 0.47ml and potassium tert.-butoxide 907mg reaction to add 20ml ethyl acetate and 20ml water after one hour; stratification; upper strata is with saturated common salt water washing and spend the night with anhydrous magnesium sulfate drying; filter, evaporated under reduced pressure solvent obtains 1.7g glassy yellow solid.
1H?NMR(CDCl
3,600MHz),δ:0.81(t,J=7.2Hz,3H,15-CH
3),0.88(d,J=7.8Hz,3H,8-CH
3),0.95(d,J=6.6Hz,3H,4-CH
3),1.12(d,J=7.2Hz,3H,10-CH
3),1.14(s,3H,12-CH
3),1.20-1.24(m,7H),1.27(s,3H,6-CH
3),1.31-1.49(m,3H,H-7,H-14ax),1.73(br,1H,H-4′eq),1.92-1.95(m,1H,H-14eq),2.06-2.08(m,4H,H-4,2′-OCOCH
3),2.28(s,6H,N(CH
3)
2),2.53(q,J=4.8Hz,1H,H-10),2.63-2.65(m,1H,H-2),2.75(br,1H,H-3′),2.94(s,3H,6-OCH
3),3.27(s,1H,12-OH),3.41-3.47(m,2H,H-3,H-5′),3.63-3.69(m,2H,H-8,H-5),3.76(s,1H,H-11),4.39-4.51(m,2H,9-O-CH
2CH=CH
2),4.58(d,J=7.2Hz,1H,H-1′),4.60(s,1H,11-OH),4.75(br,1H,H-2′),5.16-5.20(m,2H,9-O-CH
2CH=CH
2),5.25(dd,J=17.4Hz,1H,H-13),5.92-5.97(m,1H,9-O-CH
2CH=CH
2).HRMS(ESI)(M+H
+)m/z:687.4425,calcd?for?C
35H
63N
2O
11687.4426(M+H
+).
Embodiment 4 (generating compound 4)
2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime
2.18g 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-acetyl oxime is dissolved in 20ml THF/DMSO mixing solutions; add allyl bromide 98 0.3ml and potassium tert.-butoxide 461mg reaction to add 20ml ethyl acetate and 20ml water after one hour; stratification; upper strata saturated common salt water washing; concentrated by rotary evaporation, is dried to obtain product 1.88g.
Embodiment 4 has provided the embodiment of another kind of generation 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime.Embodiment 3 has adopted THF solution, and embodiment 4 has provided the example in THF/DMSO mixing solutions.
Embodiment 5 (generating the first step of compound 5)
2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime-11,12-cyclic carbonate ester
1.7g 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime is dissolved in 70ml methylene dichloride; add 2.4ml pyridine; at-5 ℃, stir 10 minutes, start to drip the 1.5g triphosgene that is dissolved in methylene dichloride in 30ml, within 30 minutes, dropwise.-5 ℃ of reactions slowly drip 100ml saturated aqueous common salt and finish reaction after 17 hours.Stratification, lower floor's organic phase saturated sodium bicarbonate, water, saturated common salt water washing is also spent the night with anhydrous magnesium sulfate drying, filters, and evaporated under reduced pressure solvent obtains 1.4g yellow solid.
Or; first 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-acetyl oxime is adopted to the carbonic ether conditioned response of embodiment 5; further use again the allylation condition of embodiment 3 or embodiment 4; can obtain equally 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime-11,12-cyclic carbonate ester.
Owing to generating compound 5, need two steps, the first step is that 11,12-OH is closed to ring, and second step is that 3-OH is oxidized to 3-carbonyl, and embodiment 5 has provided the example that obtains the synthetic result of the first step, and embodiment 6 has provided the concrete example of second step.
Embodiment 6 (generating the second step of compound 5)
2 '-O-ethanoyl-3-carbonyl-CAMA A9-O-allyl group oxime-11,12-cyclic carbonate ester
In 250ml there-necked flask, add 30ml methylene dichloride, add 0.43g N-chloro succinimide under stirring, maintenance system-15 ℃, slowly drip 0.27ml dimethyl sulphide and occur white flocks.To be dissolved with 1.4g 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-allyl group oxime-11; the 15ml methylene dichloride of 12-cyclic carbonate ester is added drop-wise in system; dropwise half an hour; at-15 ℃, react 1.5 hours; TLC demonstration has been reacted; drip triethylamine 0.6ml termination reaction, it is clear that system becomes, and stirs one hour at-5 ℃.Reaction solution is used respectively saturated sodium bicarbonate, water, and saturated common salt water washing is also spent the night with anhydrous magnesium sulfate drying, filters, and evaporated under reduced pressure solvent obtains 1.3g yellow solid.
1H?NMR(CDCl
3,400MHz),δ:0.87(t,J=7.4Hz,3H,15-CH
3),0.96(d,J=6.9Hz,3H,8-CH
3),1.09-1.11(d,J=7.6Hz,3H,4-CH
3),1.20-1.23(m,7H),1.25-1.35(m,7H),1.49-1.58(m,5H),1.70-1.74(m,1H),1.86-1.90(m,1H),2.02(s,3H,2′-OCOCH
3),2.23(s,6H,N(CH
3)
2),2.47-2.49(m,1H,H-10),2.62-2.68(m,4H,6-OCH
3,H-3′),2.95-3.00(m,1H,H-4),3.49-3.53(m,1H,H-5′),3.62(br,1H,H-8),3.78(q,J=6.8Hz,1H,H-2),4.14(d,J=7.8Hz,1H,H-5),4.35(d,J=7.6Hz,1H,H-1′),4.45-4.53(m,2H,9-O-CH
2CH=CH
2),4.72(dd,J=10.5,7.6Hz,1H,H-2′),4.77(s,1H,H-11),5.01-5.26(m,3H,9-O-CH
2CH=CH
2,H-13),5.92-6.01(m,1H,9-O-CH
2CH=CH
2).
13C?NMR(CDCl
3,100MHz)δ:10.4,13.2,14.0,15.4,15.5,18.8,19.6,20.9,21.3,22.4,26.0,30.4,37.9,40.6,47.2,49.6,51.1,63.4,69.0,71.5,74.6,76.5,78.2,78.4,82.9,84.6,101.4,116.9,134.5,154.4,164.2,168.9,169.7,203.9.HRMS(ESI)(M+H
+)m/z:711.40714,calcd?for?C
36H
59N
2O
12711.40625(M+H
+).
Embodiment 7 (generating the compound 6 of 3-quinolyl)
3-carbonyl-CAMA A9-O-[3-(3-quinoline)-2-propenyl] oxime-11,12-cyclic carbonate ester
By 1.3g 2 '-ethanoyl-3-carbonyl-CAMA A9-O-allyl group oxime-11; 12-cyclic carbonate ester, 82mg palladium, 218mg tri-o-tolyl phosphine; 0.5ml 3-bromoquinoline; 0.34ml triethylamine, adds in the pressure bottle that 9ml acetonitrile is housed, and system is under nitrogen protection; at 60 ℃, stir one hour; then be warming up to 80 ℃ of reactions and finish for 24 hours, in system, add 10ml ethyl acetate and 10ml water, stratification.Organic layer water and saturated common salt water washing.(moving phase is sherwood oil: acetone: triethylamine=7: 5: 0.2) obtain faint yellow compound 223mg after evaporated under reduced pressure solvent, with silicagel column, to carry out purifying.This compound dissolution, in 10ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.3: 0.15) obtain pure compounds 35mg.
1H?NMR(CDCl
3,400MHz),δ:0.90(t,J=7.4Hz,3H,15-CH
3),1.01(d,J=6.9Hz,3H),1.20-1.28(m,9H),1.35-1.37(m,4H),1.43(s,3H,6-CH
3),1.55(s,3H,12-CH
3),1.57-1.72(m,3H),1.89-1.92(m,1H),2.26(s,6H,N(CH
3)
2),2.42-2.47(m,1H),2.55(q,J=6.7Hz,1H,H-10),2.69(s,3H,6-OCH
3),3.02-3.06(m,1H,H-4),3.16-3.21(m,1H,H-2′),3.51-3.54(m,1H,H-5′),3.70(br,1H,H-8),3.82(q,J=6.8Hz,1H,H-2),4.19(d,J=8.4Hz,1H,H-5),4.30(d,J=7.3Hz,1H,H-1′),4.70-4.76(m,2H,9-O-CH
2CH=CH-Ar),4.77(s,1H,H-11),5.05(dd,J=10.1,2.7Hz,1H,H-13),6.60(dt,J=16.1,6.0Hz,1H,9-O-CH
2CH=CH-Ar),6.78(d,J=16.1Hz,1H,9-O-CH
2CH=CH-Ar),7.51-7.55(m,1H,quinolyl),7.64-7.69(m,1H,quinolyl),7.80(dd,1H,quinolyl),8.05-8.07(m,2H,quinolyl),8.99(d,1H,quinolyl).
13C?NMR(CDCl
3,100MHz)δ:10.3,13.1,14.2,15.5,15.8,18.8,19.7,21.1,22.4,26.2,28.2,38.3,40.2,47.8,49.6,51.1,65.8,69.4,70.3,73.9,76.3,78.4,79.3,82.8,84.6,103.8,126.8,127.8,127.9,128.4,129.1,129.3,129.8,132.5,147.4,149.3,154.4,164.7,169.0,203.9.HRMS(ESI)(M+H
+)m/z:796.43798,calcd?for?C
43H
62N
3O
11796.43789(M+H
+).
Embodiment 8 (generating the compound 6 of 4-isoquinolyl)
3-carbonyl-CAMA A9-O-[3-(4-isoquinoline 99.9)-2-propenyl] oxime-11,12-cyclic carbonate ester
By 1.3g 2 '-ethanoyl-3-carbonyl-CAMA A9-O-allyl group oxime-11; 12-cyclic carbonate ester, 82mg palladium, 218mg tri-o-tolyl phosphine; 757mg 4-bromo-isoquinoline; 0.34ml triethylamine, adds in the pressure bottle that 9ml acetonitrile is housed, and system is under nitrogen protection; at 60 ℃, stir one hour; then be warming up to 80 ℃ of reactions and finish for 24 hours, in system, add 10ml ethyl acetate and 10ml water, stratification.Organic layer water and saturated common salt water washing.(moving phase is sherwood oil: acetone: triethylamine=7: 5: 0.2) obtain faint yellow compound 376mg after evaporated under reduced pressure solvent, with silicagel column, to carry out purifying.This compound dissolution, in 10ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.3: 0.15) obtain pure compounds 55mg.
1H?NMR(CDCl
3,400MHz),δ:0.88-0.91(t,J=7.4Hz,3H,15-CH
3),1.00-1.02(d,J=6.9Hz,3H,8-CH
3),1.20-1.27(m,10H),1.35-1.37(m,4H),1.44(s,3H,6-CH
3),1.56(s,3H,12-CH
3),1.57-1.72(m,3H),1.89-1.92(m,1H),2.26(s,6H,N(CH
3)
2),2.42-2.56(m,2H),2.67(s,3H,6-OCH
3),3.00-3.08(m,1H,H-4),3.16-3.20(m,1H,H-2′),3.49-3.56(m,1H,H-5′),3.72(br,1H,H-8),3.81(q,J=6.8Hz,1H,H-2),4.17(d,J=8.4Hz,1H,H-5),4.29(d,J=7.3Hz,1H,H-1′),4.75-4.85(m,3H,9-O-CH
2CH=CH-Ar,H-11),5.04(dd,J=10.0,2.7Hz,1H,H-13),6.42(dt,J=15.8,6.1Hz,1H,9-O-CH
2CH=CH-Ar),7.23(d,J=15.8Hz,1H,9-O-CH
2CH=CH-Ar),7.59-7.64(m,1H,isoquinolyl),7.72-7.76(m,1H,isoquinolyl),7.96(d,1H,isoquinolyl),8.11(d,1H,isoquinolyl),8.58(s,1H,isoquinolyl),9.15(s,1H,isoquinolyl).
13C?NMR(CDCl
3,100MHz)δ:10.3,13.1,14.2,15.5,15.8,18.8,19.7,21.1,22.4,26.2,28.2,30.8,38.2,40.2,40.3,47.8,49.6,51.0,65.8,69.4,70.2,70.3,74.0,76.3,78.4,79.3,82.8,84.6,103.7,123.1,126.8,127.1,127.8,127.9,128.3,130.4,130.8,133.6,140.5,151.9,154.4,164.7,168.9,203.9.HRMS(ESI)(M+H
+)m/z:796.43900,calcd?forC
43H
62N
3O
11796.43789(M+H
+).
Embodiment 9 (generating the compound 6 of 3-pyridyl)
3-carbonyl-CAMA A9-O-[3-(3-pyridine)-2-propenyl] oxime-11,12-cyclic carbonate ester
By 1.3g 2 '-ethanoyl-3-carbonyl-CAMA A9-O-allyl group oxime-11; 12-cyclic carbonate ester, 82mg palladium, 218mg tri-o-tolyl phosphine; 0.35ml 4-bromo-isoquinoline; 0.34ml triethylamine, adds in the pressure bottle that 9ml acetonitrile is housed, and system is under nitrogen protection; at 60 ℃, stir one hour; then be warming up to 80 ℃ of reactions and finish for 24 hours, in system, add 10ml ethyl acetate and 10ml water, stratification.Organic layer water and saturated common salt water washing.(moving phase is sherwood oil: acetone: triethylamine=7: 5: 0.2) obtain faint yellow compound 309mg after evaporated under reduced pressure solvent, with silicagel column, to carry out purifying.This compound dissolution, in 10ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.3: 0.15) obtain pure compounds 47mg.
1H?NMR(CDCl
3,400MHz),δ:0.90(t,J=7.4Hz,3H,15-CH
3),1.01(d,J=6.9Hz,3H,8-CH
3),1.21-1.30(m,9H),1.33-1.37(m,4H),1.41(s,3H,6-CH
3),1.55(s,3H,12-CH
3),1.57-1.71(m,3H),1.88-1.91(m,1H),2.27(s,6H,N(CH
3)
2),2.43-2.54(m,2H),2.66(s,3H,6-OCH
3),3.01-3.05(m,1H,H-4),3.16-3.21(m,1H,H-2′),3.51-3.55(m,1H,H-5′),3.68(br,1H,H-8),3.82(q,J=6.7Hz,1H,H-2),4.18(d,J=8.4Hz,1H,H-5),4.29(d,J=7.2Hz,1H,H-1′),4.67-4.71(m,2H,9-O-CH
2CH=CH-Ar),4.79(s,1H,H-11),5.05(dd,J=10.1,2.6Hz,1H,H-13),6.44(dt,1H,J=16.1Hz,J=6.0Hz,9-O-CH
2CH=CH-Ar),6.60(d,J=16.1Hz,1H,9-O-CH
2CH=CH-Ar),7.23-7.26(m,1H,pyridyl),7.69-7.72(m,1H,pyridyl),8.46(dd,1H,pyridyl),8.58(d,1H,pyridyl).
13C?NMR(CDCl
3,100MHz)δ:10.3,13.1,14.2,15.4,15.8,18.8,19.7,21.1,22.4,26.2,28.2,38.2,40.2,47.8,49.6,51.1,65.8,69.4,70.2,73.8,76.3,78.4,79.2,82.8,84.6,103.7,123.4,128.3,128.8,132.4,132.8,148.3,148.6,154.4,164.6,169.0,203.9.HRMS(ESI)(M+H
+)m/z:746.42314,calcd?for?C
39H
60N
3O
11746.42224(M+H
+).
Embodiment 10 (generating the compound 6 of 4-(1-imidazoles) phenyl)
3-carbonyl-CAMA A9-O-{3-[4-(1-imidazoles) benzene]-2-propenyl } oxime-11,12-cyclic carbonate ester
By 0.601g 2 '-ethanoyl-3-carbonyl-CAMA A9-O-allyl group oxime-11; 12-cyclic carbonate ester, 38mg palladium, 104mg tri-o-tolyl phosphine; 240mg 1-(4-imidazoles)-bromobenzene; 0.7ml triethylamine, adds in the pressure bottle that 9ml acetonitrile is housed, and system is under nitrogen protection; at 60 ℃, stir one hour; then be warming up to 80 ℃ of reactions and finish for 24 hours, in system, add 20ml ethyl acetate and 20ml water, stratification.Through column chromatography, (200-300 order silicagel column, moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be compared with pure products (0.348g).This compound dissolution, in 20mL methyl alcohol, after stirring reaction 3h, is revolved to the methyl alcohol boiling off except in reaction solution at 65 ℃, must take off the thick product of acetyl.Through column chromatography, (200-300 order silicagel column, moving phase is sherwood oil: acetone: triethylamine=5: 7: 0.2) obtain deacetylated compound sterling 50mg.
1H?NMR(CDCl
3,400MHz),δ:0.88(t,J=7.4Hz,3H,15-CH
3),1.00(d,J=6.9Hz,3H,8-CH
3),1.18-1.26(m,9H),1.35-1.38(m,4H),1.41(s,3H,6-CH
3),1.56(s,3H,12-CH
3),1.57-1.72(m,3H),1.89-1.94(m,1H),2.33(s,6H,N(CH
3)
2),2.51-2.54(m,2H,H-3′,H-10),2.67(s,3H,6-OCH
3),3.02-3.06(m,1H,H-4),3.20-3.24(m,1H,H-2′),3.52-3.56(m,1H,H-5′),3.68(br,1H,H-8),3.82(q,J=6.8Hz,1H,H-2),4.18(d,J=8.3Hz,1H,H-5),4.29(d,J=7.3Hz,1H,H-1′),4.70(d,J=6.2Hz,2H,9-O-CH
2CH=CH-Ar),4.80(s,1H,H-11),5.05(dd,J=10.2,2.6Hz,1H,H-13),6.42(dt,J=16.0,6.2Hz,1H,9-O-CH
2CH=CH-Ar),6.63(d,J=16.0Hz,1H,9-O-CH
2CH=CH-Ar),7.21(s,1H,imidazolyl),7.27(s,1H,imidazolyl),7.34(d,J=8.4Hz,1H,phenyl),7.48(d,J=8.4Hz,1H,phenyl),7.86(s,1H,imidazolyl).
13C?NMR(CDCl
3,100MHz)δ:10.4,13.2,14.2,15.5,15.8,18.8,19.7,21.1,22.4,26.2,28.5,38.3,40.2,47.8,49.6,51.1,66.0,69.3,70.2,74.0,76.4,78.4,79.4,82.9,84.6,103.8,121.5,127.2,127.8,130.4,131.3,136.3,136.4,154.5,164.4,169.1,204.0.HRMS(ESI)(M+H
+)m/z:811.44967,calcd?for?C
43H
63N
4O
11811.44879(M+H
+).
Embodiment 11 (generating the compound 6 of 6-quinolyl)
3-carbonyl-CAMA A9-O-[3-(6-quinoline)-2-propenyl] oxime-11,12-cyclic carbonate ester
By 1.196g 2 '-ethanoyl-3-carbonyl-CAMA A9-O-allyl group oxime-11; 12-cyclic carbonate ester, 75mg palladium, 205mg tri-o-tolyl phosphine; 0.46ml 6-bromoquinoline; 0.47ml triethylamine, adds in the pressure bottle that 9ml acetonitrile is housed, and system is under nitrogen protection; at 60 ℃, stir one hour; then be warming up to 80 ℃ of reactions and finish for 24 hours, in system, add 20ml ethyl acetate and 20ml water, stratification.Through column chromatography, (200-300 order silicagel column, moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be compared with pure products (0.490g).This compound dissolution, in 20mL methyl alcohol, after stirring reaction 3h, is revolved to the methyl alcohol boiling off except in reaction solution at 65 ℃, must take off the thick product of acetyl.Through column chromatography, (200-300 order silicagel column, moving phase is sherwood oil: acetone: triethylamine=5: 7: 0.2) obtain deacetylated compound sterling 123mg.
1H?NMR(CDCl
3,400MHz),δ:0.90(t,J=7.4Hz,3H,15-CH
3),1.01(d,J=6.9Hz,3H,8-CH
3),1.19-1.30(m,9H),1.35-1.36(m,4H),1.42(s,3H,6-CH
3),1.52(d,J=8.5Hz,1H),1.56(s,3H,12-CH
3),1.57-1.71(m,3H),1.89-1.93(m,1H),2.29(s,6H,N(CH
3)
2),2.46-2.55(m,2H,H-3′,H-10),2.69(s,3H,6-OCH
3),3.00-3.06(m,1H,H-4),3.19-3.23(m,1H,H-2′),3.51-3.57(m,1H,H-5′),3.70(br,1H,H-8),3.81(q,J=6.8Hz,1H,H-2),4.18(d,J=8.4Hz,1H,H-5),4.29(d,J=7.3Hz,1H,H-1′),4.70-4.79(m,2H,9-O-CH
2CH=CH-Ar),4.81(s,1H,H-11),5.06(dd,J=10.1,2.6Hz,1H,H-13),6.53(dt,J=15.9,6.2Hz,1H,9-O-CH
2CH=CH-Ar),6.79(d,J=16.0Hz,1H,9-O-CH
2CH=CH-Ar),7.37-7.40(m,1H,quinolyl),7.71(s,1H,quinolyl),7.83(dd,1H,quinolyl),8.03(d,1H,quinolyl),8.12(d,1H,quinolyl),8.86(dd,1H,quinolyl).
13C?NMR(CDCl
3,100MHz)δ:10.3,13.2,14.2,15.5,15.8,18.8,19.7,21.1,22.4,26.2,28.2,38.3,40.2,47.8,49.6,51.1,65.9,69.4,70.3,74.1,76.4,78.4,79.4,82.9,84.6,103.8,121.4,125.8,127.3,127.4,128.4,129.6,132.0,135.1,136.0,148.0,150.1,154.4,164.5,169.0,203.9.HRMS(ESI)(M+H
+)m/z:796.43587,calcd?forC
43H
62N
3O
11796.43789(M+H
+).
Embodiment 12 (generating the compound 6 of 5-pyrimidyl)
3-carbonyl-CAMA A9-O-[3-(5-pyrimidine)-2-propenyl] oxime-11; 12-cyclic carbonate ester is by 0.912g 2 '-ethanoyl-3-carbonyl-CAMA A9-O-allyl group oxime-11; 12-cyclic carbonate ester; 58mg palladium; 156mg tri-o-tolyl phosphine; 0.611mg 5-bromo pyrimi piperidine; 0.36ml triethylamine; add in the pressure bottle that 5ml acetonitrile is housed; system, under nitrogen protection, stirs one hour at 60 ℃, is then warming up to 80 ℃ of reactions and finishes for 24 hours; in system, add 15ml ethyl acetate and 15ml water, stratification.Organic layer water and saturated common salt water washing.(moving phase is methylene dichloride to silica gel column chromatography after solvent evaporated: ethanol: ammoniacal liquor=15: 0.4: 0.1) obtain compound 352mg.This compound dissolution, in 50ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) obtain deacetylated compound 37mg.
1H?NMR(CDCl
3,400MHz),δ:0.90(t,J=7.4Hz,3H,15-CH
3),1.01(d,J=7.0Hz,3H,8-CH
3),1.22-1.28(m,9H),1.35-1.38(m,4H),1.41(s,3H,6-CH
3),1.55(s,3H,12-CH
3),1.57-1.72(m,3H),1.88-1.92(m,2H),2.27(s,6H,N(CH
3)
2),2.44-2.54(m,2H,H-3′,H-10),2.67(s,3H,6-OCH
3),3.01-3.07(m,1H,H-4),3.17-3.21(m,1H,H-2′),3.52-3.56(m,1H,H-5′),3.70(br,1H,H-8),3.82(q,J=6.8Hz,1H,H-2),4.19(d,J=8.4Hz,1H,H-5),4.29(d,J=7.3Hz,1H,H-1′),4.70-4.77(m,2H,9-O-CH
2CH=CH-Ar),4.79(s,1H,H-11),5.05(dd,J=10.2,2.6Hz,1H,H-13),6.52-6.54(m,2H,9-O-CH
2CH=CH-Ar,9-O-CH
2CH=CH-Ar),8.74(s,2H,pyrimidyl),9.08(s,1H,pyrimidyl).HRMS(ESI)(M+H
+)m/z:747.41743,calcd?for?C
38H
59N
4O
11747.41749(M+H
+).
Embodiment 13
Medicinal compositions
The present invention can also be provided for the medicinal compositions of antibacterial therapy, and said composition can comprise the compound with aforementioned formula of antimicrobial effective amount, or its pharmaceutically acceptable additive salt or ester, and pharmaceutically acceptable carrier.
Antibacterial therapy effect to the medicinal compositions of above-mentioned 9-oxime ether ketolide derivatives is measured.
Adopt broth dilution method determination part target compound to responsive streptococcus pneumoniae ATCC49619, erm+mef type Antimicrobial Streptococcus Pneumoniae PU-11 and PU-13, responsive streptococcus aureus ATCC29213, erm structure-type resistant Staphylococcus aureus PU-19, erm induction type resistant Staphylococcus aureus PU-32.Measurement result is in Table 1.
The anti-microbial activity MIC value (μ g/mL) of table 1 part 9-oxime ether ketolide derivatives
As shown in Table 1, target compound is compared with Azythromycin with current clinical main medication clarithromycin, has all shown outstanding anti-sensitive organism and antimicrobial agent active.
It should be noted that, in the medicine that the present invention can treat for infected by microbes such as multiple antibacteriums, comprise chlamydozoan or mycoplasma infection etc.
Above to a kind of novel ketone lactone provided by the present invention (9-oxime ether ketolide derivatives) and synthesis preparation method thereof, with the purposes of this compounds as anti-infectives, be described in detail, applied specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof; , for one of ordinary skill in the art, according to thought of the present invention, all will change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention meanwhile.
Claims (8)
2. compound as claimed in claim 1 or acceptable salt, is characterized in that,
Described Ar is 3-pyridyl, 5-pyrimidyl, 3-quinolyl, 4-isoquinolyl, 6-quinolyl, 4-(1-imidazoles) phenyl.
3. compound as claimed in claim 1 or acceptable salt, is characterized in that,
Described mineral acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide or phosphoric acid;
Described organic acid is selected from acetic acid, propanedioic acid, methylsulfonic acid, succsinic acid, tosic acid, citric acid, toxilic acid, fumaric acid or stearic acid.
4. prepare a method for compound as claimed in claim 1, it is characterized in that, comprising:
(1), from erythromycin oxime, through etherificate, silanization, methylating obtains the midbody compound of clarithromycin synthesis technique: 2', 4 " two (the trimethyl silicane)-CAMA A9-O-(oxyethyl group cyclohexyl of O-) oxime;
(2), hydrolysis obtains compound: 3-OH-6-O-erythromycin oxime;
(3), protection reagent effect under, obtain compound:
Wherein, R base is ethanoyl, benzoyl or trimethyl silicon based accordingly; Described protection reagent is used for realizing R protecting group;
(4), in the mono-solvent of THF or THF/DMSO mixed solvent, ethanoyl, benzoyl or trimethyl silicon based under the acting in conjunction of allylation reagent and highly basic on the 9-oxime hydroxyl of selectivity displacement step (3) gained compound; And in dichloromethane solvent, use and close cyclization reagent by 11,12-OH pass ring, and with oxidising agent, 3-OH is oxidized to 3-carbonyl, obtain compound:
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly, described allylation reagent is selected from allyl bromide 98 or allyl iodide, described highly basic is selected from potassium tert.-butoxide, potassium hydroxide, sodium hydride or hexamethl disilamine potassium, described pass cyclization reagent is selected from triphosgene, phosgene or trichloromethyl chloroformyl ester, and described oxidising agent is selected from N-chloro succinimide/dimethyl sulphide, methyl-sulphoxide/oxalyl chloride or methyl-sulphoxide/acetic anhydride;
(5), in acetonitrile or DMF solvent, under the catalysis of palladium salt and phase-transfer catalyst, the allyl group effect formation aromatic side chain on the assorted aromatic hydrocarbon of halo and 9-oxime hydroxyl, and slough 2'-O-R protecting group, obtains having the compound of following general formula, wherein, X is hydrogen;
Or in acetonitrile or DMF solvent, under the catalysis of palladium salt and phase-transfer catalyst, the allyl group effect on the assorted aromatic hydrocarbon of halo and 9-oxime hydroxyl forms aromatic side chain; Further in 2-position, introduce fluorine atom, and slough 2'-O-R protecting group, obtain having the compound of following general formula, wherein, X is fluorine;
Wherein, Ar is pyridyl, pyrimidyl, benzopyrazines base, benzo pyridazinyl, quinolyl, isoquinolyl, imidazoles phenyl, indyl; X is hydrogen or fluorine, and described phase-transfer catalyst is selected from three o-methyl-phenyl-phosphines, triphenylphosphine, or quaternary ammonium salt.
5. preparation method as claimed in claim 4, is characterized in that,
The equivalence ratio scope of described allylation reagent and step (3) gained compound is 1.0-2.0;
The equivalence ratio scope of described highly basic and step (3) gained compound is 1.0-3.0.
6. preparation method as claimed in claim 4, is characterized in that,
Described protection reagent is selected from acetic anhydride, benzoyl oxide, trimethyl silicane chlorine or hexamethyldisilazane.
7. for a medicinal compositions for antibacterial therapy, it is characterized in that, comprise the compound with following general formula or its pharmaceutically acceptable additive salt of antimicrobial effective amount, and pharmaceutically acceptable carrier;
Wherein, Ar is pyridyl, pyrimidyl, benzopyrazines base, benzo pyridazinyl, quinolyl, isoquinolyl, imidazoles phenyl, indyl; X is hydrogen or fluorine.
8. the application of medicinal compositions as claimed in claim 7 in the medicine for the preparation of the treatment of antibacterium infected by microbes.
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CN105935355B (en) * | 2016-05-17 | 2019-06-04 | 上海大学 | The purposes of 12- oxime ether dehydroabietic acid derivative |
CN110234323A (en) * | 2016-10-04 | 2019-09-13 | Ti生物制药有限公司 | Ketone lactone with antibacterial activity |
CN106916194B (en) * | 2017-01-13 | 2020-05-08 | 北京理工大学 | Novel ketolide derivative containing amino, preparation method and application |
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US6946446B2 (en) * | 2000-02-24 | 2005-09-20 | Abbott Laboratories | Anti-infective agents useful against multidrug-resistant strains of bacteria |
AU2003211923A1 (en) * | 2002-02-13 | 2003-09-04 | Taisho Pharmaceutical Co., Ltd. | Process for producing erythromycin a derivative |
WO2003090761A1 (en) * | 2002-04-25 | 2003-11-06 | Abbott Laboratories | 9-oxime macrolide antibacterials |
JP4737495B2 (en) * | 2004-01-14 | 2011-08-03 | 塩野義製薬株式会社 | Erythromycin derivative |
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