CN104844671A - 11-O-aromatic aralkyl carbamate clarithromycin derivatives as well as preparation method and application thereof - Google Patents

11-O-aromatic aralkyl carbamate clarithromycin derivatives as well as preparation method and application thereof Download PDF

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CN104844671A
CN104844671A CN201510257126.1A CN201510257126A CN104844671A CN 104844671 A CN104844671 A CN 104844671A CN 201510257126 A CN201510257126 A CN 201510257126A CN 104844671 A CN104844671 A CN 104844671A
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clarithromycin
ethyl
formamyl
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compound
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CN104844671B (en
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马淑涛
郭珍珍
沈艳
郭丽威
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Shandong University
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses 11-O-aromatic aralkyl carbamate clarithromycin derivatives as well as a preparation method and application thereof. The 11-O-aromatic aralkyl carbamate clarithromycin derivatives are characterized in that a carbamate side chain structure is introduced to a C-11 position, and various substituted substitutive aromatic groups are arranged at the tail end of the carbamate side chain structure; the side chain has a certain flexibility, so that the side chain is favorably combined with nucleotide residues on the surface of a peptide channel of a ribosome 23S rRNA (Ribosomal Robonucleic Acid). On the basis that the series of derivatives are modified at the C-11 position, benzoic acid is introduced to hydroxyl at the C4 position to form a benzoate side chain, and further a secondary acting mechanism is obtained; the determination on in vitro antibacterial activity shows that the introduction of the side chain at the C4 position is extremely important for obtaining the activity of drug-resistant bacteria; the 11-O-aromatic aralkyl carbamate clarithromycin derivatives show excellent activity of resisting gram positive bacteria, wherein some compounds have outstanding properties on in vitro antibacterial activity of ermB type anti-drug streptococcus pneumonia. The 11-O-aromatic aralkyl carbamate clarithromycin derivatives particularly have excellent effect on the activity of drug-resistant bacteria of various streptococcus pneumonia, and can be used for preparing medicines for treating bacterial infection.

Description

11-O-''-aralkyl carbamic acid ester clarithomycin derivative and preparation method thereof and application
Technical field
The present invention relates to class 11-O-''-aralkyl carbamic acid ester clarithomycin derivative and preparation method thereof, and the application in antibacterial.
Background technology
Macrolide is the weakly alkaline lipophilic compound that a class contains ten four to ten hexa-atomic macrolide rings.Although its subbranch just in anti-infectives, compares with some other clinical conventional microbiotic with penicillins, its curative effect certainly, without serious adverse reaction, has now been widely used in the treatment of respiratory tract, soft tissue infection and urinary system infection.
Antibiotic use inevitably produces selective action to mutant bacteria, causes bacterial drug resistance, and the speed that bacterial resistance produces is far away faster than the speed of novel antibacterials exploitation.The semi-synthetic modification being skeleton for Macrolide becomes one of current antibacterials research emphasis, is the safe and effective approach that current drug development research field solves bacterial drug resistance.
At present, the main modification position of researchist to clarithromycin is: C-3 position, C-6 position, C-9 position and C-11,12, in addition, the modification of C-2 position, C-5 position and C-15 position also has good effect.C-11 position is the very potential decorating site of macrolide antibiotic, and the modification for clarithromycin C-11 position rarely has report.The effective ways that different carboxylamine ester side chains is exploitation antimicrobial agent macrolide antibiotic are introduced in this site.
Main respiratory tract pathogenic bacterium have streptococcus aureus, streptococcus pneumoniae, micrococcus scarlatinae.The mixing resistance streptococcus pneumoniae of the Antimicrobial Streptococcus Pneumoniae of erm gene mediated, the resistance streptococcus pneumoniae of mef gene mediated and erm and mef gene mediated is three kinds of main macrolide resistant organisms.
Summary of the invention
For solving the problem, the invention provides the 11-O-''-aralkyl carbamic acid ester clarithomycin derivative of series of novel, antibacterial activity in vitro research is done to multiple gram-positive microorganism and negative bacterium, has found that target compound has significant antibacterial activity in vitro to above three kinds of resistant organisms.
The present invention is achieved by the following technical solutions:
11-O-''-aralkyl carbamic acid ester clarithomycin derivative, has the structure of general formula I:
Wherein, R1 is selected from-(CH=CH) n (C 6h 4) X, wherein n=0 or 1; X is selected from-H, halogen, nitro, amino, methoxyl group, saturated or undersaturated alkyl; R2 represents hydrogen, acetyl or benzoyl base; R3 represents hydrogen, acetyl or benzoyl base.
Preferably, described R1 is 3-nitrophenyl, 4-aminomethyl phenyl, 4-nitrophenyl, 4-bromophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 2,4 dichloro benzene base, 4-p-methoxy-phenyl, 4-nitrophenyl propenyl, 4-fluorophenyl propenyl, 4-chloro-phenyl-propenyl, 4-bromophenyl propenyl, 4-aminomethyl phenyl propenyl, 4-methoxyphenylpropene base or cinnamyl; R2 is hydrogen or benzoyl; R3 is hydrogen.
It is further preferred that described Compound I is one of following:
11-O-(2-(4-nitrobenzamide base) ethyl) formamyl-clarithromycin;
11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin;
11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin;
11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin;
11-O-(2-(4-toluyl amido) ethyl) formamyl-clarithromycin;
11-O-(2-(4-methoxy benzamide base) ethyl) formamyl-clarithromycin;
11-O-(2-(3-nitrobenzamide base) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-oil of mirbane) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-chlorobenzene) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-bromobenzene) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-methylbenzene) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-anisole) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-cinnamide ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin.
Present invention also offers described preparation method's (synthetic route is shown in Fig. 1) with the 11-O-''-aralkyl carbamic acid ester clarithomycin derivative of general formula I, step is as follows:
(1) clarithromycin is mixed with acid anhydrides, add solvent, triethylamine, DMAP (DMAP) successively, in 10 ~ 50 DEG C of reactions 1 ~ 14 hour, generate the compound of general formula 1;
(2) compound of general formula 1 obtained above is mixed with pyridine, add appropriate solvent, then add triphosgene, in-5 ~ 5 DEG C of reactions 1 ~ 8 hour, generate the compound of general formula 2;
(3) compound of general formula 2 obtained above is mixed with quadrol, in 5 ~ 25 DEG C of reactions 1 ~ 4 hour, generate the compound of general formula 3;
(4) corresponding substituted benzaldehyde is mixed with propanedioic acid, add solvent, piperazine successively, in 80 ~ 120 DEG C of reactions 6 ~ 24 hours, generate the compound of general formula 4;
(5) compound of corresponding substituted benzoic acid or general formula 4 is dissolved in tetrahydrofuran (THF), add N, N'-dicyclohexylcarbodiimide (DCC) and I-hydroxybenzotriazole (HOBt), in-5 ~ 5 DEG C of reactions 1 ~ 6 hour, again the compound of general formula 3 obtained above is mixed with it, react 1 ~ 4 hour at 0 ~ 25 DEG C, generate the derivative with general formula I;
(6) compound of general formula I obtained above, makes solvent with lower alcohol, in 0 ~ 65 DEG C of reaction 12 ~ 72 hours, generates the compound of general formula 5.
In above-mentioned steps (1): solvent is DMF, tetrahydrofuran (THF), ethyl acetate or methylene dichloride, preferred DMF; The mol ratio of clarithromycin and acid anhydrides is 1:(2 ~ 4); The mol ratio of clarithromycin and catalyzer DMAP is 1:(0.02 ~ 1.2); The mol ratio of clarithromycin and triethylamine is 1:(1 ~ 5); Preferably reaction 4 hours at 45 DEG C;
In above-mentioned steps (2): solvent is tetrahydrofuran (THF), ethyl acetate or methylene dichloride, preferred methylene dichloride; The compound of general formula 1 and the mol ratio of triphosgene are 1:(1 ~ 3), preferred 1:2; The compound of general formula 1 and the mol ratio of pyridine are 1:(3 ~ 15), preferred 1:9.5; Preferably reaction 4 hours at 0 DEG C;
In above-mentioned steps (3): solvent is DMF, tetrahydrofuran (THF) or quadrol, preferred quadrol; Preferably reaction 2 hours at 25 DEG C;
In above-mentioned steps (4): solvent is DMF, tetrahydrofuran (THF) or pyridine, preferred pyridine; The mol ratio of substituted benzaldehyde and propanedioic acid is 1:(1 ~ 4), preferred 1:2.5; Preferably reaction 12 hours at 100 DEG C;
In above-mentioned steps (5): the mol ratio of the compound of general formula 3 and the compound of corresponding substituted benzoic acid or general formula 4 is 1:(0.5 ~ 3), preferred 1:1.2; The compound of general formula 3 and the mol ratio of DCC are 1:(0.5 ~ 3), preferred 1:1.4; The compound of general formula 3 and the mol ratio of HOBt are 1:(0.5 ~ 3), preferred 1:1.4; Preferably react 2 hours at reaction 4 hours and 25 DEG C at 0 DEG C;
In above-mentioned steps (6): lower alcohol particular methanol, preferred inorganic weak bases, preferred Anhydrous potassium carbonate, preferably reaction 12 hours at 15 DEG C under alkaline condition, preferably reaction 12 hours at 55 DEG C under non-alkaline condition.
11-O-''-aralkyl carbamic acid ester clarithomycin derivative of the present invention, there is anti-microbial activity, obvious to gram-positive microorganism resistant organism anti-microbial effect, especially good to the Streptococcus pneumoniae activity performance of the micrococcus scarlatinae of erythromycin-resistant, the streptococcus pneumoniae of ermB type resistance and ermB+mefA type resistance, may be used for the medicine preparing treatment bacteriological infection, during concrete preparation, this pharmaceutical pack contains 11-O-''-aralkyl carbamic acid ester clarithomycin derivative or its pharmacy acceptable salt of therapeutic dose, and the pharmaceutical excipient of other routine or carrier.
11-O-''-aralkyl carbamic acid ester clarithomycin derivative of the present invention, its feature is: the carbamate side-chain structure that C-11 position is introduced, and end has various substituted aryl, side chain has certain flexibility, is conducive to combining with rrna 23S rRNA peptide channel surface nucleotide residue." hydroxyl of position introduces phenylformic acid define benzoic ether side chain on the basis that this series derivates is modified in C-11 position, also at C4, thus obtain secondary mechanism of action; Antibacterial activity in vitro measures and shows, C4, and " introducing of position side chain is very important for acquisition antimicrobial agent activity.It is active that 11-O-''-aralkyl carbamic acid ester clarithomycin derivative shows fabulous resisting gram-positive bacteria, and the antibacterial activity in vitro of some compounds to the streptococcus pneumoniae of ermB type resistance is had outstanding performance.
(1) best to the Streptococcus pneumoniae activity of ermB type resistance compound (compd B 7 and B8) (MIC=1 μ g/mL) is 128 times of control drug clarithromycin anti-microbial activity.
(2) to the active best compound (compd B 3) (MIC=4 μ g/mL) of the micrococcus scarlatinae of erythromycin-resistant be 32 times of control drug clarithromycin anti-microbial activity.
(3) best to the Streptococcus pneumoniae activity of ermB+mefA type resistance compound (compd A 1) (MIC=8 μ g/mL) is 16 times of control drug clarithromycin anti-microbial activity.
96 orifice plate micro-dilution methods are adopted to measure target compound to responsive type streptococcus aureus (S.aureusATCC25923), methicillin-resistant staphylococcus aureus (S.aureus ATCC29213), intestinal bacteria (E.coli ATCC25922), Pseudomonas aeruginosa (P.aeruginosa ATCC27853), micrococcus scarlatinae sensitive organism (S.pyogenes 1), micrococcus scarlatinae resistant organism (S.pyogenes 2), the streptococcus pneumoniae (S.pneumoniae B1) of ermB type resistance, the antibacterial activity in vitro (expression of MIC value) of the streptococcus pneumoniae (S.pneumoniae 22072) of mefA type resistance and the streptococcus pneumoniae (S.pneumoniaeAB11) of ermB+mefA type resistance, result is as table 1, shown in table 2:
Table 1. target compound is to the antibacterial activity in vitro of sensitive organism
Table 2. target compound is to the antibacterial activity in vitro of resistant organism
Wherein compounds represented:
(A1) 11-O-(2-(4-nitrobenzamide base) ethyl) formamyl-clarithromycin;
(A2) 11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin;
(A3) 11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin;
(A4) 11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin;
(A5) 11-O-(2-(4-toluyl amido) ethyl) formamyl-clarithromycin;
(A6) 11-O-(2-(4-methoxy benzamide base) ethyl) formamyl-clarithromycin;
(A7) 11-O-(2-(3-nitrobenzamide base) ethyl) formamyl-clarithromycin;
(B1) 4 "-O-benzoyl-11-O-(2-(3-(4-oil of mirbane) acrylamido) ethyl) formamyl-clarithromycin;
(B2) 4 "-O-benzoyl-11-O-(2-(3-(4-chlorobenzene) acrylamido) ethyl) formamyl-clarithromycin;
(B3) 4 "-O-benzoyl-11-O-(2-(3-(4-bromobenzene) acrylamido) ethyl) formamyl-clarithromycin;
(B4) 4 "-O-benzoyl-11-O-(2-(3-(4-methylbenzene) acrylamido) ethyl) formamyl-clarithromycin;
(B5) 4 "-O-benzoyl-11-O-(2-(3-(4-anisole) acrylamido) ethyl) formamyl-clarithromycin;
(B6) 4 "-O-benzoyl-11-O-(2-cinnamide ethyl) formamyl-clarithromycin;
(B7) 4 "-O-benzoyl-11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin;
(B8) 4 "-O-benzoyl-11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin;
(B9) 4 "-O-benzoyl-11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin.
Accompanying drawing explanation
Fig. 1: the synthetic route of the compound of general formula I.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1.
2 ', 4 " preparation of-O-diacetyl group-clarithromycin
By clarithromycin (30g, 40mmol) be dissolved in anhydrous methylene chloride (180mL), add aceticanhydride (12mL successively, 127mmol), DMAP (0.1g, 0.82mmol) with triethylamine (13.5mL, 97.6mmol), 30 DEG C are stirred 12h.After completion of the reaction, add equal-volume saturated sodium bicarbonate solution, separatory, organic layer saturated sodium bicarbonate solution washing 2-3 time, uses saturated common salt water washing afterwards again.Anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure, obtains white foam solid 35.12g, crude yield 105%.Rf=0.40 (developping agent: methylene dichloride: methyl alcohol=15:1; The vitriol oil-ethanol colour developing).
Embodiment 2.
2 ', 4 " preparation of the two benzoyl-clarithromycin of-O-
By clarithromycin (5g, 6.7mmol) be dissolved in DMF (25mL), add DMAP (0.9g successively, 7.4mmol), triethylamine (4.5mL, 32.5mmol) with benzoyl oxide (5.25g, 23.2mmol), 45 DEG C are stirred 4h.After completion of the reaction, add 50ml distilled water and stir 2h, add 25%NaOH solution afterwards and adjust PH to 9-10.Suction filtration, gets filter cake, vacuum-drying, obtains Tan solid 6.36g, crude yield 99.4%.Rf=0.67 (developping agent: acetone: hexanaphthene=1:2).
Embodiment 3.
2 ', 4 " preparation of-O-diacetyl group-11,12-cyclic carbonate esters-clarithromycin
By 2', 4 "-O-diacetyl group-clarithromycin (35.12g, 42.2mmol) is dissolved in anhydrous methylene chloride (500mL), adds pyridine (32.3mL, 401mmol) in 0 DEG C of stirring, nitrogen protection.Afterwards triphosgene (23.81g, 80.18mmol) is dissolved in anhydrous methylene chloride (200mL), and slowly instills in above-mentioned mixing solutions.0 DEG C is stirred 6h.After completion of the reaction, appropriate distilled water quencher reaction is added.Organic layer saturated sodium bicarbonate solution washs 2-3 time to neutral.Use saturated common salt water washing more afterwards.Anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure, obtains weak yellow foam shape solid 35.6g, crude yield 98%.Rf=0.56 (developping agent: methylene dichloride: methyl alcohol=10:1).
2 ', 4 " two benzoyl-11, the 12-cyclic carbonate esters-clarithromycin of-O-is prepared according to above method.
Embodiment 4.
2 ', 4 " preparation of-O-diacetyl group-11-O-(2-aminoethyl) carbamyl-clarithromycin
By 2 ', 4, "-O-diacetyl group-11,12-cyclic carbonate esters-clarithromycin (35.6g, 41.5mmol) is dissolved in 150ml quadrol, stirring at room temperature 3h.After completion of the reaction, add appropriate ethyl acetate and isopyknic distilled water, separatory, organic layers with water is washed till neutrality.Use saturated common salt water washing more afterwards.Anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure, obtains weak yellow foam shape solid 32g, crude yield 84%.Rf=0.2 (developping agent: methylene dichloride: methyl alcohol=10:1).Silica gel column chromatography, eluent is methylene dichloride: methyl alcohol: triethylamine=30:1:0.1, obtains white foam solid 7.5g, sterling yield 23.4%.
2 ', 4 " two benzoyl-11-O-(2-aminoethyl) carbamyl-clarithromycin of-O-is prepared according to above method.
Embodiment 5.
The synthesis of cinnamic acid derivative
Be dissolved in 40ml pyridine by phenyl aldehyde (4.24g, 40mmol), add propanedioic acid (10.4g, 100mmol), piperazine (0.34g, 4mmol), 100 DEG C are stirred 12h.After completion of the reaction, by pyridine evaporated under reduced pressure, add appropriate acetic acid ethyl dissolution, organic phase saturated sodium bicarbonate solution washing 2-3 time, merge the water layer of washing, and regulate aqueous phase PH to 7-8 with concentrated hydrochloric acid, suction filtration, gets filter cake, vacuum-drying, obtains white solid 1.28g, crude yield 21.6%.Rf=0.25 (developping agent: ethyl acetate: sherwood oil=1:3).
Other cinnamic acid derivative replaced is prepared according to above method.
Embodiment 6.
2 ', 4 " preparation of-O-diacetyl group-11-O-(2-(4-nitrobenzamide base) ethyl) formamyl-clarithromycin
Add in THF (6ml) by p-nitrobenzoic acid (0.08g, 0.5mmol) and HOBt (0.08,0.59mmol), 0 DEG C of stirring, adds DCC (0.12g, 0.58mmol), continues to stir 4-6h.Afterwards, "-O-diacetyl group-11-O-(2-aminoethyl) carbamyl-clarithromycin (0.38g, 0.41mmol) that adds 2 ', 4.Move to stirring at room temperature 2-4h.After completion of the reaction, by THF evaporated under reduced pressure, add appropriate acetic acid ethyl dissolution, cross leaching filtrate.Filtrate, with the washing of appropriate saturated sodium bicarbonate solution, uses saturated common salt water washing afterwards again.Anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure, obtains white foam solid 0.38g, crude yield 86%.Rf=0.68 (developping agent: methylene dichloride: methyl alcohol=10:1).
Embodiment 7.
2 ', 4 " preparation of two benzoyl-11-O-(2-(3-(4-oil of mirbane) acrylamido) ethyl) formamyl-clarithromycin of-O-
Add in THF (10ml) by 4-nitrocinnamic acid (0.1g, 0.5mmol) and HOBt (0.08,0.59mmol), 0 DEG C of stirring, adds DCC (0.12g, 0.58mmol), continues to stir 4-6h.Afterwards, " two benzoyl-11-O-(2-aminoethyl) carbamyl-clarithromycin (0.5g, 0.48mmol) of-O-that adds 2 ', 4.Move to stirring at room temperature 2-4h.After completion of the reaction, by THF evaporated under reduced pressure, add appropriate acetic acid ethyl dissolution, cross leaching filtrate.Filtrate, with the washing of appropriate saturated sodium bicarbonate solution, uses saturated common salt water washing afterwards again.Anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure, obtains weak yellow foam shape solid 0.45g, crude yield 79%.Rf=0.57 (developping agent: methylene dichloride: methyl alcohol=10:1).
Embodiment 8.
The preparation of 11-O-(2-(4-nitrobenzamide base) ethyl) formamyl-clarithromycin (A1)
By 2 ', 4, "-O-diacetyl group-11-O-(2-(4-nitrobenzamide base) ethyl) formamyl-clarithromycin (0.38g, 0.36mmol) is dissolved in 8ml methyl alcohol, adds solid carbonic acid potassium 0.1g, and 15 DEG C are stirred 12h.React complete, remove methyl alcohol under reduced pressure, obtain weak yellow foam shape solid.Silica gel column chromatography, eluent is methylene dichloride: methyl alcohol=30:1, and gradient elution obtains white foam solid 0.15g, yield 43%.Rf=0.35 (developping agent: methylene dichloride: methyl alcohol=10:1).
Compd A 2-A7 is prepared according to above method.
Embodiment 9.
4 " preparation of-O-benzoyl-11-O-(2-(3-(4-oil of mirbane) acrylamido) ethyl) formamyl-clarithromycin (B1)
By 2 ', 4, " two benzoyl-11-O-(2-(3-(4-oil of mirbane) acrylamido) ethyl) formamyl-clarithromycin (0.1g, 0.085mmol) of-O-is dissolved in 1ml methyl alcohol, and 55 DEG C are stirred 12h.React complete, remove methyl alcohol under reduced pressure, obtain weak yellow foam shape solid.Silica gel column chromatography, eluent is methylene dichloride: methyl alcohol=30:1, and gradient elution obtains white foam solid 0.05g, yield 50%.Rf=0.38 (developping agent: methylene dichloride: methyl alcohol=10:1).
Compd B 2-B9 is prepared according to above method.
Structural identification:
11-O-(2-(4-nitrobenzamide base) ethyl) formamyl-clarithromycin (A1)
White solid,yield 42％，mp:168～174℃；TLC Rf＝0.35(methanol/dichlormethane,1:10)； 1H NMR(400MHz,CDCl 3,δppm):8.3-8.22(m,2H),8.15-8.03(m,2H),7.8-7.7(m,1H),5.0-4.9(m,2H),4.88-4.8(m,1H),4.75(m,1H),4.5-4.4(m,1H),4.05-3.92(m,2H),3.82-3.7(m,3H),3.6-3.45(m,3H),3.4-3.3(m,3H),3.28-3.2(m,6H),3.13(m,1H),3.05-3.0(m,1H),2.98-2.89(m,1H),2.78-2.7(m,1H),2.58-2.45(m,7H),2.4-2.32(m,1H),2.1-1.9(m,4H),1.65-1.45(m,5H),1.35-1.1(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 48H 78N 4O 17982.54,found[M+H] +983.9.
11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin (A2)
White solid,yield 40％,mp:156～164℃；TLC Rf＝0.38(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.05-7.9(m,1H),7.85-7.75(m,2H),7.15-7.0(m,2H),5.0-4.8(m,3H),4.75(m,1H),4.5-4.4(m,1H),4.05-3.92(m,2H),3.82-3.65(m,3H),3.6-3.45(m,2H),3.41-3.35(m,2H),3.32-3.28(m,2H),3.26-3.15(m,6H),3.05-2.93(m,2H),2.8-2.7(m,1H),2.6-2.5(m,4H),2.48-2.4(m,3H),2.4-2.35(m,2H),1.95-1.89(m,2H),1.71-1.65(m,1H),1.6-1.53(m,2H),1.48-1.4(m,4H),1.35-1.1(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 48H 78FN 3O 15955.54，found[M+H] +956.9.
11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin (A3)
White solid,yield 44％,mp:154～156℃；TLC Rf＝0.36(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):7.88-7.75(m,2H),7.45-7.3(m,3H),4.97-4.9(m,2H),4.85-4.8(m,1H),4.75(m,1H),4.4-4.32(m,1H),4.05-3.95(m,2H),3.75-3.68(m,3H),3.5-3.4(m,3H),3.35-3.2(m,10H),3.19-3.13(m,1H),3.05-2.97(m,1H),2.78-2.6(m,1H),2.42-2.3(m,8H),2.1-1.96(m,4H),1.95-1.9(m,1H),1.5-1.42(m,4H),1.32-1.1(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 48H 78ClN 3O 15971.51,found[M+H] +972.9.
11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin (A4)
White solid,yield 41％,mp:148～154℃；TLC Rf＝0.36(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):7.75-7.7(m,2H),7.6-7.5(m,3H),4.97-4.9(m,2H),4.85-4.8(m,1H),4.75(m,1H),4.4-4.35(m,1H),4.05-3.92(m,3H),3.75-3.68(m,3H),3.5-3.4(m,3H),3.32-3.21(m,10H),3.05-3.0(m,1H),2.75-2.7(m,1H),2.45-2.35(m,8H),2.1-2.0(m,3H),1.95-1.87(m,2H),1.5-1.43(m,4H),1.32-1.1(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.forC 48H 78BrN 3O 151015.46,found[M+H] +1016.8.
11-O-(2-(4-toluyl amido) ethyl) formamyl-clarithromycin (A5)
White solid,yield 38％,mp:162～166℃；TLC Rf＝0.38(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):7.73-7.65(m,2H),7.25-7.2(m,2H),7.1-7.04(m,1H),4.98-4.92(m,1H),4.9-4.8(m,2H),4.7(m,1H),4.4(m,1H),4.05-3.92(m,3H),3.82-3.61(m,4H),3.55-3.48(m,2H),3.43-3.37(m,1H),3.32-3.21(m,9H),3.05-3.0(m,1H),2.8-2.7(m,1H),2.6(m,3H),2.45-2.32(m,8H),2.1-2.0(m,2H),1.85-1.8(m,1H),1.55-1.5(m,2H),1.48-1.42(m,4H),1.3-1.05(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 49H 81N 3O 15951.57，found[M+H] +952.9.
11-O-(2-(4-methoxy benzamide base) ethyl) formamyl-clarithromycin (A6)
White solid,yield 39％,mp:142～146℃；TLC Rf＝0.39(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):7.82-7.75(m,2H),7.65-7.6(m,1H),6.95-6.88(m,2H),4.98-4.92(m,1H),4.9-4.8(m,2H),4.7(m,1H),4.4(m,1H),4.05-3.92(m,2H),3.85-3.8(m,4H),3.79-3.7(m,2H),3.58-3.45(m,2H),3.3-3.2(m,7H),3.15-3.05(m,5H),3.04-3.0(m,1H),2.8-2.65(m,6H),2.5-2.33(m,3H),2.1-1.95(m,3H),1.8(m,1H),1.65-1.55(m,1H),1.5-1.4(m,4H),1.3-1.05(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 49H 81N 3O 16967.56,found[M+H] +969.
11-O-(2-(3-nitrobenzamide base) ethyl) formamyl-clarithromycin (A7)
White solid,yield 43％,mp:170～176℃；TLC Rf＝0.37(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.8(m,1H),8.4-8.2(m,2H),7.8(m,1H),7.7-7.6(m,1H),4.95-4.85(m,2H),4.82-4.75(m,1H),4.65(m,1H),4.6-4.54(m,1H),4.05-3.85(m,3H),3.8-3.7(m,3H),3.69-3.62(m,2H),3.43-3.28(m,4H),3.22-3.09(m,7H),3.0(m,1H),2.92-2.75(m,7H),2.7(m,1H),2.5-2.4(m,1H),2.38-2.3(m,1H),2.25-2.18(m,1H),2.0-1.92(m,2H),1.8-1.75(m,1H),1.45-1.4(m,4H),1.35-1.1(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 48H 78N 4O 17982.54,found[M+H] +983.9.
4 "-O-benzoyl-11-O-(2-(3-(4-oil of mirbane) acrylamido) ethyl) formamyl-clarithromycin (B1)
White solid,yield 50％,mp:142～146℃；TLC Rf＝0.38(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.25-8.15(m,2H),8.13-7.95(m,2H),7.7-7.58(m,4H),7.45(m,2H),6.9-6.6(m,2H),5.05-4.9(m,3H),4.75(m,1H),4.6-4.4(m,2H),4.1(m,1H),3.8(m,2H),3.65-3.45(m,4H),3.4-3.3(m,3H),3.25-3.18(m,7H),3.0(m,1H),2.65(m,1H),2.45(m,2H),2.4-2.2(m,6H),2.15(m,1H),1.95(m,1H),1.68-1.55(m,3H),1.5(m,2H),1.4(m,2H),1.3-1.1(m,24H),0.9-0.75(m,6H)；MS(ESI)m/z calcd.for C 57H 84N 4O 181112.58,found[M+H] +1114.
4 "-O-benzoyl-11-O-(2-(3-(4-chlorobenzene) acrylamido) ethyl) formamyl-clarithromycin (B2)
White solid,yield 45％,mp:133～138℃；TLC Rf＝0.42(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.15-7.95(m,2H),7.65(m,2H),7.54-7.38(m,4H),7.35-7.28(m,2H),6.68-6.5(m,1H),4.9(m,4H),4.75(m,1H),4.6-4.4(m,2H),4.0(m,1H),3.85-3.75(m,2H),3.65(m,2H),3.5(m,2H),3.4-3.15(m,10H),3.0(m,1H),2.8(m,1H),2.75-2.6(m,2H),2.45-2.35(m,6H),2.17(m,1H),2.13-2.05(m,1H),1.95-1.8(m,1H),1.7-1.6(m,3H),1.53-1.42(m,3H),1.3-1.05(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 57H 84ClN 3O 161101.55,found[M+H] +1103.1.
4 "-O-benzoyl-11-O-(2-(3-(4-bromobenzene) acrylamido) ethyl) formamyl-clarithromycin (B3)
White solid,yield 47％,mp:124～130℃；TLC Rf＝0.41(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.18-8.05(m,2H),7.6-7.55(m,2H),7.45-7.4(m,3H),7.38(m,2H),6.65(m,1H),6.5(m,1H),5.05-4.9(m,4H),4.75(m,1H),4.6-4.45(m,2H),4.1(m,1H),3.93(m,1H),3.8(m,2H),3.5(m,2H),3.4-3.3(m,3H),3.25-3.15(m,8H),2.75(m,1H),2.5-2.4(m,2H),2.38-2.2(m,7H),1.95(m,2H),1.73-1.55(m,4H),1.53-1.42(m,3H),1.3-1.1(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 57H 84BrN 3O 161145.50,found[M+H] +1146.9.
4 "-O-benzoyl-11-O-(2-(3-(4-methylbenzene) acrylamido) ethyl) formamyl-clarithromycin (B4)
White solid,yield 41％,mp:148～151℃；TLC Rf＝0.40(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.18-7.96(m,2H),7.6-7.55(m,2H),7.5-7.42(m,2H),7.4(m,2H),7.2-7.1(m,2H),6.6-6.4(m,1H),5.0-4.85(m,4H),4.75(m,1H),4.6-4.45(m,2H),3.96(m,1H),3.85-3.75(m,3H),3.55-3.45(m,2H),3.4-3.15(m,10H),2.87-2.7(m,2H),2.53-2.4(m,8H),2.35-2.28(m,3H),2.1-2.0(m,2H),1.73-1.62(m,2H),1.55-1.45(m,3H),1.38-1.13(m,27H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 58H 87N 3O 161081.61,found[M+H] +1083.1.
4 "-O-benzoyl-11-O-(2-(3-(4-anisole) acrylamido) ethyl) formamyl-clarithromycin (B5)
White solid,yield 38％,mp:150～154℃；TLC Rf＝0.42(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.15-7.95(m,2H),7.62-7.53(m,2H),7.51-7.4(m,4H),6.9-6.8(m,1H),6.65-6.3(m,2H),5.1-4.85(m,4H),4.75(m,1H),4.6-4.45(m,2H),4.05-3.9(m,1H),3.85-3.7(m,4H),3.68-3.65(m,1H),3.6-3.45(m,2H),3.4-3.15(m,12H),2.97(m,1H),2.7-2.6(m,1H),2.58-2.35(m,8H),2.0(m,3H),1.75-1.6(m,3H),1.5-1.35(m,5H),1.3-1.1(m,22H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 58H 87N 3O 171097.6,found[M+H] +1099.0.
4 "-O-benzoyl-11-O-(2-cinnamide ethyl) formamyl-clarithromycin (B6)
White solid,yield 43％,mp:162～166℃；TLC Rf＝0.40(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.05(m,2H),7.61(m,2H),7.47(m,4H),7.35(m,3H),6.55(m,2H),4.95(m,3H),4.7(m,1H),4.5(m,2H),4.0(d,1H),3.8(m,2H),3.65(m,2H),3.5(m,2H),3.4-3.2(m,10H),3.0(d,1H),2.83(m,1H),2.7(m,2H),2.45-2.3(m,6H),2.15-2.0(m,3H),1.65(m,3H),1.5(m,3H),1.3-1.1(m,24H),0.9-0.75(m,6H)；MS(ESI)m/z calcd.for C 57H 85N 3O 161067.59,found[M+H] +1069.0.
4 "-O-benzoyl-11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin (B7)
White solid,yield 40％,mp:138～142℃；TLC Rf＝0.39(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.15-7.95(m,2H),7.87-7.8(m,2H),7.6(m,1H),7.51-7.4(m,2H),7.15-7.0(m,2H),5.0-4.85(m,4H),4.75(m,1H),4.6-4.45(m,2H),4.0(m,1H),3.82-3.65(m,4H),3.55-3.42(m,2H),3.37-3.15(m,10H),2.7-2.6(m,2H),2.5-2.42(m,2H),2.4-2.3(m,6H),2.1-2.0(m,2H),1.73-1.55(m,4H),1.5-1.43(m,3H),1.3-1.12(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 55H 82FN 3O 161059.57,found[M+H] +1061.0.
4 "-O-benzoyl-11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin (B8)
White solid,yield 41％,mp:116～124℃；TLC Rf＝0.40(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.15-7.95(m,2H),7.9-7.75(m,2H),7.6(m,1H),7.51-7.43(m,2H),7.42-7.31(m,2H),5.0-4.87(m,4H),4.75(m,1H),4.6-4.45(m,2H),4.0(m,1H),3.82-3.73(m,3H),3.55-3.45(m,3H),3.4-3.15(m,10H),3.0(m,1H),2.7-2.6(m,1H),2.5-2.42(m,2H),2.4-2.23(m,6H),2.05-2.0(m,1H),1.9(m,1H),1.7-1.6(m,3H),1.42-1.31(m,4H),1.3-1.15(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 55H 82ClN 3O 161075.54,found[M+H] +1077.0.
4 "-O-benzoyl-11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin (B9)
White solid,yield 43％,mp:153～158℃；TLC Rf＝0.40(methanol/dichlormethane,1:10)；1H NMR(400MHz,CDCl 3,δppm):8.15-7.95(m,2H),7.83-7.65(m,2H),7.62-7.55(m,3H),7.54-7.47(m,2H),5.0-4.87(m,4H),4.75(m,1H),4.6-4.45(m,2H),4.0(m,1H),3.82-3.73(m,3H),3.70-3.41(m,3H),3.4-3.15(m,10H),3.0-2.9(m,1H),2.85-2.75(m,1H),2.65-2.4(m,8H),2.15(m,1H),2.05-1.95(m,2H),1.85-1.78(m,1H),1.74-1.59(m,2H),1.51-1.4(m,3H),1.35-1.02(m,24H),0.9-0.8(m,6H)；MS(ESI)m/z calcd.for C 55H 82BrN 3O 161119.49,found[M+H] +1120.9.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment made, equivalent replacement, improvement etc., all should be included within the scope of protection of the invention.

Claims (9)

1.11-O-''-aralkyl carbamic acid ester clarithomycin derivative, is characterized in that: the structure with general formula I:
Wherein, R1 is selected from-(CH=CH) n(C 6h 4) X, wherein n=0 or 1; X is selected from-H, halogen, nitro, amino, methoxyl group, saturated or undersaturated alkyl; R2 represents hydrogen, acetyl or benzoyl base; R3 represents hydrogen, acetyl or benzoyl base.
2. 11-O-''-aralkyl carbamic acid ester clarithomycin derivative according to claim 1, it is characterized in that: described R1 is 3-nitrophenyl, 4-aminomethyl phenyl, 4-nitrophenyl, 4-bromophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 2,4 dichloro benzene base, 4-p-methoxy-phenyl, 4-nitrophenyl propenyl, 4-fluorophenyl propenyl, 4-chloro-phenyl-propenyl, 4-bromophenyl propenyl, 4-aminomethyl phenyl propenyl, 4-methoxyphenylpropene base or cinnamyl; R2 is hydrogen or benzoyl; R3 is hydrogen.
3. 11-O-''-aralkyl carbamic acid ester clarithomycin derivative according to claim 1, is characterized in that: described Compound I is one of following:
11-O-(2-(4-nitrobenzamide base) ethyl) formamyl-clarithromycin;
11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin;
11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin;
11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin;
11-O-(2-(4-toluyl amido) ethyl) formamyl-clarithromycin;
11-O-(2-(4-methoxy benzamide base) ethyl) formamyl-clarithromycin;
11-O-(2-(3-nitrobenzamide base) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-oil of mirbane) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-chlorobenzene) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-bromobenzene) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-methylbenzene) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(3-(4-anisole) acrylamido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-cinnamide ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(4-fluorobenzoyl amido) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(4-chloro-benzoyl amino) ethyl) formamyl-clarithromycin;
4 "-O-benzoyl-11-O-(2-(4-Bromophenacyl amido) ethyl) formamyl-clarithromycin.
4. the preparation method of claim 1 or the 11-O-''-aralkyl carbamic acid ester clarithomycin derivative described in 2 or 3, is characterized in that: step is as follows:
(1) clarithromycin is mixed with acid anhydrides, add solvent, triethylamine, DMAP (DMAP) successively, in 10 ~ 50 DEG C of reactions 1 ~ 14 hour, generate the compound of general formula 1;
(2) compound of general formula 1 obtained above is mixed with pyridine, add appropriate solvent, then add triphosgene, in-5 ~ 5 DEG C of reactions 1 ~ 8 hour, generate the compound of general formula 2;
(3) compound of general formula 2 obtained above is mixed with quadrol, in 5 ~ 25 DEG C of reactions 1 ~ 4 hour, generate the compound of general formula 3;
(4) corresponding substituted benzaldehyde is mixed with propanedioic acid, add solvent, piperazine successively, in 80 ~ 120 DEG C of reactions 6 ~ 24 hours, generate the compound of general formula 4;
(5) compound of corresponding substituted benzoic acid or general formula 4 is dissolved in tetrahydrofuran (THF), add N, N'-dicyclohexylcarbodiimide (DCC) and I-hydroxybenzotriazole (HOBt), in-5 ~ 5 DEG C of reactions 1 ~ 6 hour, again the compound of general formula 3 obtained above is mixed with it, react 1 ~ 4 hour at 0 ~ 25 DEG C, generate the derivative with general formula I;
(6) compound of general formula I obtained above, makes solvent with lower alcohol, in 0 ~ 65 DEG C of reaction 12 ~ 72 hours, generates the compound of general formula 5.
5. the preparation method of 11-O-''-aralkyl carbamic acid ester clarithomycin derivative according to claim 4, is characterized in that: step 1) in, described solvent is DMF, tetrahydrofuran (THF), ethyl acetate or methylene dichloride; The mol ratio of clarithromycin and acid anhydrides is 1:2 ~ 4; The mol ratio of clarithromycin and catalyzer DMAP is 1:0.02 ~ 1.2; The mol ratio of clarithromycin and triethylamine is 1:1 ~ 5.
6. the preparation method of 11-O-''-aralkyl carbamic acid ester clarithomycin derivative according to claim 4, is characterized in that: in step (2), and described solvent is tetrahydrofuran (THF), ethyl acetate or methylene dichloride; The compound of general formula 1 and the mol ratio of triphosgene are 1:1 ~ 3; The compound of general formula 1 and the mol ratio of pyridine are 1:3 ~ 15.
7. the preparation method of 11-O-''-aralkyl carbamic acid ester clarithomycin derivative according to claim 4, is characterized in that: in step (3), and described solvent is DMF, tetrahydrofuran (THF) or quadrol; In step (4), described solvent is DMF, tetrahydrofuran (THF) or pyridine; The mol ratio of substituted benzaldehyde and propanedioic acid is 1:1 ~ 4; In step (5), the mol ratio of the compound of described general formula 3 and the compound of corresponding substituted benzoic acid or general formula 4 is 1:0.5 ~ 3; The compound of general formula 3 and the mol ratio of DCC are 1:0.5 ~ 3; The compound of general formula 3 and the mol ratio of HOBt are 1:0.5 ~ 3.
8. claim 1 or the 11-O-''-aralkyl carbamic acid ester clarithomycin derivative described in 2 or 3 application in the medicine of preparation treatment bacteriological infection.
9. application according to claim 8, is characterized in that: described bacterium comprises: the streptococcus pneumoniae of the streptococcus pneumoniae of responsive type streptococcus aureus, methicillin-resistant staphylococcus aureus, intestinal bacteria, Pseudomonas aeruginosa, micrococcus scarlatinae sensitive organism, micrococcus scarlatinae resistant organism, ermB type resistance, the streptococcus pneumoniae of mefA type resistance, ermB+mefA type resistance.
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