CN101423539A - 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof - Google Patents
4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof Download PDFInfo
- Publication number
- CN101423539A CN101423539A CNA2008102381676A CN200810238167A CN101423539A CN 101423539 A CN101423539 A CN 101423539A CN A2008102381676 A CNA2008102381676 A CN A2008102381676A CN 200810238167 A CN200810238167 A CN 200810238167A CN 101423539 A CN101423539 A CN 101423539A
- Authority
- CN
- China
- Prior art keywords
- formamyl
- compound
- azythromycin
- aliphatic group
- general formula
- 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.)
- Granted
Links
Abstract
The invention relates to a novel fifteen-member macrolide derivative which has a general formula (I) and comes from azithromycin, wherein R1 represents hydrogen, acetyl or benzoyl, and R2 and R3 represent an aliphatic group, a substituted aroma aliphatic group or a substituted aroma heterocycle aliphatic group respectively. The invention also relates to an intermediate product and a preparation method thereof, acceptable addition salts formed by the fifteen-member macrolide derivative together with inorganic acid or organic acid, and a preparation method for a medicine compound and the application of the medicine compound to the treatment of bacterial infection.
Description
Technical field
The present invention relates to Azithromycin derivative and preparation thereof, relate in particular to 4 ＂, 11-diamino formic ether azithromycin derivates, preparation method and pharmaceutical composition thereof.
Background technology
Macrolide antibiotics is as the important anti-infectives of a class, because of its anti-microbial activity good, no anaphylaxis, side effect is little, safe, development through nearly 50 years has become the second largest class anti-infectives that clinical application is only second to β-Nei Xiananleikangshengsu, has consequence on clinical treatment.Erythromycin is as first-generation macrolide antibiotic, once be widely used in the infection that treatment streptococcus aureus, streptococcus pneumoniae, Streptococcus hemolyticus and mycoplasma pneumoniae etc. cause, be particularly useful for penicillin anaphylaxis person, yet owing to cause its application to be restricted the acid medium unstable.The s-generation macrolide antibiotic that with the Azythromycin is representative has solved this problem, and very big improvement is being arranged aspect drug effect and the pharmacokinetics.Azythromycin (9-deoxidation-9a-methyl-9a-azepine-9a-a-homoerythromycin A) is first 15 membered macrolide microbiotic that Bright (U.S. Pat 4,474,768) and Kobrehel (U.S. Pat 4,517,357) etc. find.It is that erythromycin is introduced a nitrogen-atoms through oximate, Beckmann rearrangement on lactonic ring, then the special macrolide antibiotic of a class that obtains through reducing, methylating.Its outstanding feature is: stable to acidic medium, tissue permeability is good, plasma half-life is long, clinical indication is wide, evident in efficacy and untoward reaction is few.Particularly Azythromycin has antimicrobial spectrum widely, has the activity that suppresses multiple gram-positive cocci, mycoplasma, chlamydozoan and legionella pneumophilia, especially some important gram negative bacillis such as hemophilus influenzae etc. are had good antibacterial activity, remedied the deficiency of macrolide antibiotic aspect anti-gram-negative bacteria.But, along with antibiotic widespread use, particularly lasting, improper use, bacterium has almost all produced resistance to the microbiotic of all clinical uses, has brought very big difficulty to clinical treatment.Therefore, for this severe problem of reply drug-fast bacteria infection, to the macrolide antibiotics further investigation, exploitation anti-microbial activity novel macrocyclic lactone microbiotic strong, has a broad antifungal spectrum has become the research focus of anti infection region.
4 ＂-carbamate macrolides compound is the novel derivative of macrolides of a class of report in 1998.This compounds is introduced the carboxylamine ester side chain and is obtained in the C-4 of macrolide cladinose ＂ position.Anti-microbial activity is similar with acyl lactone to the ketone lactone, and is not subjected to resistant organism to carry the influence of gene kind.At present, 4 ＂ that reported-carbamate macrolide derivatives (U.S. Pat 6025350, world patent WO2004101589, WO2005108413, WO2006050941, WO2006050942, WO2006050943 etc.) all have better performance aspect antimicrobial agent, the research of this compounds is subjected to extensive concern.The modification of macrolide C-11 position hydroxyl also more and more comes into one's own, and has synthesized many active macrolide derivatives of antimicrobial agent that have by the different side chains of introducings such as etherificate, acidylate.11-carbamate macrolides compound, especially the 11-carbamate Azithromycin derivative (U.S. Pat 6043227) reported have antimicrobial agent and antiprotozoal effect.C-4 ＂ position and C-11 position are the very potential decorating sites of macrolide, and introducing identical or different carboxylamine ester side chain simultaneously in these two sites is the effective ways of exploitation antimicrobial agent macrolide antibiotic.
According to known and definite prior art, also do not describe up to now from 4 ＂, and 11-diamino formic ether azithromycin derivates, the intermediate product that relates to its preparation and method, related to acceptable addition salt that itself and inorganic or organic acid form, relate to the purposes that preparation of drug combination method and pharmaceutical composition are used for the treatment of infectation of bacteria.
Summary of the invention
The invention provides a kind of novel 4 ＂, 11-diamino formic ether azithromycin derivates, preparation method and pharmaceutical composition thereof.
The present invention also provides 4 ＂, the purposes of the pharmaceutical composition of 11-diamino formic ether azithromycin derivates.
Technical scheme of the present invention is as follows:
One, 4 ＂, the 11-diamino formic ether azithromycin derivates
4 ＂ of the present invention, the 11-diamino formic ether azithromycin derivates, the acceptable addition salt that has following general formula (I) and form with inorganic and organic acid:
Wherein, R
1Represent hydrogen, acetyl or benzoyl base, R
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group.
Preferably, R
2Be 4-luorobenzyl, 4-methoxy-benzyl, 2-chlorobenzene ethyl, 4-leptodactyline etc., R
3Be benzyl, 4-luorobenzyl, 2-chlorobenzene ethyl, 4-leptodactyline, normal-butyl, n-pentyl etc.
Two, Azithromycin 4 ＂, 11-diamino acid ester derivative prepares used intermediate
First intermediate has following general formula (II): R wherein
1Represent the acetyl or benzoyl base.
Second intermediate has following general formula (III): R wherein
1Represent the acetyl or benzoyl base.
Three, 4 ＂, the preparation method of 11-diamino formic ether azithromycin derivates
4 ＂ of the present invention, the preparation method of 11-diamino formic ether azithromycin derivates, step is as follows:
With 2 of the Azythromycin of general formula (IV) '-protection of OH acidylate, acylating reagent aceticanhydride, acetic acid, Acetyl Chloride 98Min., benzoyl oxide, phenylformic acid or Benzoyl chloride, in the presence of inorganic or organic bases,, react under 0～40 ℃ temperature as solvent with acetone, ethyl acetate, tetrahydrofuran (THF) or methylene dichloride, generate compound with above-mentioned general formula (II);
2. the compound that will have general formula (II) is in inert solvent, and in the presence of inorganic or organic bases, with N, N '-dicarbapentaborane imidazoles (CDI) generates the compound with general formula (III) in 0～110 ℃ of reaction 2～72h;
3. the compound of above-mentioned general formula (III) and aliphatic amide, substituted aroma aliphatic amide or replace fragrant heterocycle aliphatic amide, at N, react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or the mixed solvent, catalyzer 1.8-diazabicylo (5.4.0) hendecene-7 (DBU), in 0～65 ℃ of reaction 2～24h, generate the compound of logical formula V.R wherein
1Represent the acetyl or benzoyl base, simultaneously R
2Represent aliphatic group, substituted aroma aliphatic group or replace fragrant heterocycle aliphatic group;
4. the compound R of working as above-mentioned logical formula V
1During for the acetyl or benzoyl base, with aliphatic amide, substituted aroma aliphatic amide or replace the reaction of fragrant heterocycle aliphatic amide, or be dissolved in the basic solvents such as N-Methylimidazole, triethylamine, quadrol catalyzer pyridine hydrochloride or imidazoles, in 0～40 ℃ of reaction 12～120h, generate the compound of general formula (I); R wherein
1Represent the acetyl or benzoyl base, simultaneously R
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group;
5. the compound R of working as above-mentioned general formula (I)
1During for the acetyl or benzoyl base, further in the lower alcohols solvent alcoholysis slough 2 '-acyl group on the position, produce the compound of general formula (VII); R wherein
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group;
6. when the compound R that leads to formula V
1During for the acetyl or benzoyl base, further in the lower alcohols solvent alcoholysis slough 2 '-acyl group on the position, produce the compound of general formula (VI); R wherein
2Represent aliphatic group, substituted aroma aliphatic group or replace fragrant heterocycle aliphatic group;
7. the compound R of working as above-mentioned general formula (VI)
2For aliphatic group, substituted aroma aliphatic group or when replacing fragrant heterocycle aliphatic group, with aliphatic amide, substituted aroma aliphatic amide or replace the reaction of fragrant heterocycle aliphatic amide, or be dissolved in the basic solvents such as N-Methylimidazole, triethylamine or quadrol, catalyzer pyridine hydrochloride, imidazoles etc., in 0～40 ℃ of reaction 12～120h, generate the compound of general formula (VII); R wherein
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group.
In the above-mentioned steps 1: the mol ratio 1:1 of acylating reagent and Azythromycin～5, preferred 1:3.
In the above-mentioned steps 1: preferred acetylation reagent is an aceticanhydride.
In the above-mentioned steps 1: preferred organic bases is a triethylamine.
In the above-mentioned steps 1: preferred solvent is a methylene dichloride.
In the above-mentioned steps 1: preferably under 25 ℃ of conditions, react 3～24h.
Preferably, post-treating method is as follows in the above-mentioned steps 1: in alkaline media, the preferably time extraction in pH8.0～10.0 comes separated product by separating organic layer and solvent evaporated.In case of necessity, the silica gel column chromatography by recrystallization (acetone-water) or use methylene chloride-methanol (20:1) system carries out purifying again, can produce the chromatogram homogeneous and have R
fValue is the compound of 0.52 general formula (II).
In the above-mentioned steps 2: the compound and the N of control general formula (II), mol ratio 1:1～6 of N '-dicarbapentaborane imidazoles (CDI), preferred molar ratio 1:4.
In the above-mentioned steps 2: preferably under 25 ℃ of conditions, react 36h, can produce the compound of the general formula (III) more than 90%.
In the above-mentioned steps 2: inert solvent is selected from methylene dichloride, tetrahydrofuran (THF) or toluene, preferred toluene.
In the above-mentioned steps 2: described inorganic or organic bases is selected from sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, pyridine or 4-Dimethylamino pyridine, preferred triethylamine.
In the above-mentioned steps 3: the preferred N of reaction solvent, dinethylformamide.
In the above-mentioned steps 4,7: described aliphatic amide, substituted aroma aliphatic amide or replace under the fragrant heterocycle aliphatic amide reaction conditions when liquid, preferred catalyst is a pyridine hydrochloride; Described aliphatic amide, substituted aroma aliphatic amide or replace under the fragrant heterocycle aliphatic amide reaction conditions when solid-state, preferred solvent is the N-Methylimidazole.
In the above-mentioned steps 5,6: the lower alcohol particular methanol.
Above-mentioned general formula (I) compound reacts in inert solvent with the inorganic or organic acid of equimolar amount at least, and the pharmaceutically acceptable additive salt of acquisition also belongs to target compound of the present invention.
Above-mentioned mineral acid is selected from hydrochloric acid, hydroiodic acid HI, sulfuric acid or phosphoric acid.
Above-mentioned organic acid is selected from acetate, propionic acid, trifluoroacetic acid, toxilic acid, fumaric acid, lactobionic acid, citric acid, stearic acid, succsinic acid, ethyl succsinic acid, methylsulfonic acid, benzene methanesulfonic acid, to benzene methanesulfonic acid or lauryl sulfonic acid.
If the additive salt of gained is soluble in inert solvent, generally by separating additive salt with non-polar solvent precipitation, solvent evaporation or lyophilization.
If the additive salt of gained is insoluble, can separate described additive salt by filtering in inert solvent.
The component of unqualified consumption in more than reacting, all the prior art by such reaction gets final product.
Four, pharmaceutical composition
4 ＂ of the present invention, the pharmaceutical composition of 11-diamino formic ether azithromycin derivates, said composition comprises compound or its pharmaceutically acceptable additive salt of the general formula (I) of antimicrobial effective amount, and pharmaceutically acceptable carrier.Its pharmaceutical composition significant quantity is with corresponding 4 ＂, and the 11-diamino formic ether azithromycin derivates is converted.
Five, use
4 ＂, the pharmaceutical composition of 11-diamino formic ether azithromycin derivates is used for the purposes of bacterial-infection resisting.
Adopt the test tube doubling dilution to measure the part target compound to responsive streptococcus pneumoniae ATCC49619, MLS
BType resistance streptococcus pneumoniae B1 (erm), M type resistance streptococcus pneumoniae A22072 (mef) and MLS
BThe antibacterial activity in vitro of+M type resistance streptococcus pneumoniae (erm+mef).Measurement result sees Table 1:
Table 1 part 4 ＂, 11-diamino formic ether azithromycin derivates and the MIC value (μ g/mL) that has main macrolide antibiotic now
Wherein, 1～11 representation compound is as follows successively:
4 ＂-O-(4-leptodactyline-formamyl)-11-O-normal-butyl formamyl-Azythromycin,
4 ＂-O-(4-leptodactyline-formamyl)-11-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin,
4 ＂-O-(4-leptodactyline-formamyl)-11-O-benzylamino formyl radical-Azythromycin,
4 ＂-O-(4-methoxy-benzyl-formamyl)-11-O-amyl group formamyl-Azythromycin,
4 ＂-O-(4-methoxy-benzyl-formamyl)-11-O-normal-butyl formamyl-Azythromycin,
4 ＂-O-(4-luorobenzyl-formamyl)-11-O-(β-styroyl-formamyl)-Azythromycin,
4 ＂-O-(4-luorobenzyl-formamyl)-11-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin,
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-n-pentyl formamyl-Azythromycin,
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-benzylamino formyl radical-Azythromycin,
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-(4-luorobenzyl-formamyl)-Azythromycin,
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-(4-leptodactyline-formamyl)-Azythromycin.
As shown in Table 1: the listed responsive streptococcus pneumoniae of target compound 1～11 antagonism shows stronger anti-microbial activity; Compare with control drug erythromycin, clarithromycin, Azythromycin, the resistance streptococcus pneumoniae of 1～11 pair of different drug resistant gene mediation of listed target compound shows tangible antimicrobial agent trend.
Embodiment:
Illustrate present method by the following example, they limit scope of the present invention never in any form.
Embodiment 1.
A) 2 '-preparation of O-ethanoyl-Azythromycin
With Azythromycin (2.0g 2.67mmol) is dissolved in anhydrous methylene chloride (20mL), add aceticanhydride (0.75mL, 7.96mmol) and triethylamine (3.00mL, 21.6mmol), stirring at room 24h.After reaction finishes, add equal-volume 5% sodium hydrogen carbonate solution, separatory, dichloromethane extraction (10mL * 2) merges organic layer, anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure gets white foam shape solid, and acetone-water (2:1) recrystallization gets white object product (1.84g), yield 92%.167～170 ℃ of fusing points, R
fBe 0.522 (developping agent is a methylene dichloride: methyl alcohol=10:1).Molecular formula is C
40H
74N
2O
13, molecular weight is 791.0, MS 792.0 (M+H
+).
B) 2 '-preparation of O-benzoyl-Azythromycin
With Azythromycin (2.0g 2.67mmol) is dissolved in anhydrous methylene chloride (20mL), add under the room temperature 95% benzoyl oxide (1.25g, 5.34mmol) and triethylamine (0.74ml, 5.33mmol), stirring at room 48h.Add saturated sodium bicarbonate solution (15mL), stir 20min, standing demix, organic layer is water and salt water washing respectively, anhydrous sodium sulfate drying.Filtration removes solvent under reduced pressure, steams to pulpous state, adds the normal hexane-ethyl acetate (20:1) of heat, and the adularescent solid is separated out, filter, and the normal hexane washing, vacuum-drying gets 1.81g, yield 95.5%.181～184 ℃ of fusing points, R
fBe 0.585 (developping agent is a methylene dichloride: methyl alcohol=10:1).Molecular formula is C
45H
76N
2O
13, molecular weight is 853.0, MS is 853.9 (M+H
+).
Embodiment 2.
4 ＂-O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 2 '-(1.5g 1.90mmol) in dry toluene (20mL), adds triethylamine (0.60mL in O-ethanoyl-Azythromycin dissolving; 4.33mmol) and N, N '-dicarbapentaborane imidazoles (CDI) (N, N '-dicarbapentaborane imidazoles) (1.23g; 7.6mmol), 110 ℃ of heated and stirred 2h.After reaction finishes, add saturated sodium bicarbonate solution (40mL), separatory, methylbenzene extraction (6mL * 2) merges organic layer, anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure gets white foam shape solid 1.65g, yield 95.5%.117～120 ℃ of fusing points, R
fBe 0.610 (developping agent is a methylene dichloride: methyl alcohol=10:1).Molecular formula is C
45H
74N
4O
15, molecular weight is 911.1, MS 912.1 (M+H
+).
Embodiment 3.
A): 4 ＂-O-(4-leptodactyline-formamyl)-2 '-O-ethanoyl-Azythromycin 11; the preparation of 12-cyclic carbonate ester is with 4 ＂-O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11; 12-cyclic carbonate ester (1.5g; 1.65mmol) be dissolved in N; N-dimethyl formamide (DMF) (15mL) in, add 1.8-diazabicylo (5.4.0) hendecene-7 (DBU) (0.33mL, 2.25mmol) and 4-hydroxyphenethylamine (0.31g; 2.25mmol), stirring at room 12h.After reaction finishes, add entry (30mL), ethyl acetate (15mL * 3) extraction merges organic layer, saturated aqueous common salt (15mL * 3) washing, and anhydrous sodium sulfate drying, evaporated under reduced pressure gets white solid foam 1.33g, yield 82.0%.Fusing point 155-157 ℃, Rf is that 0.556 (developping agent is a methylene dichloride: methyl alcohol=10:1), molecular formula is C
50H
81N
3O
16, molecular weight is 980.2, MS 981.1 (M+H
+).
B): 4 ＂-O-(4-methoxy-benzyl-formamyl)-2 '-O-ethanoyl Azythromycin 11; the preparation of 12-cyclic carbonate ester is with 4 ＂-O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11; 2-cyclic carbonate ester (1.5g; 1.65mmol) be dissolved in N; N-dimethyl formamide (DMF) (15mL) in, add 1.8-diazabicylo (5.4.0) hendecene-7 (DBU) (0.33mL, 2.25mmol) and 4-methoxybenzylamine (0.31g; 2.25mmol), stirring at room 12h.After reaction finishes, add entry (30mL), ethyl acetate (15mL * 3) extraction merges organic layer, saturated aqueous common salt (15mL * 3) washing, and anhydrous sodium sulfate drying, evaporated under reduced pressure gets white solid foam 1.40g, yield 86.5%.Fusing point 133-135 ℃, Rf is that 0.632 (developping agent is a methylene dichloride: methyl alcohol=10:1), molecular formula is C
50H
81N
3O
16, molecular weight is 980.2, MS 981.1 (M+H
+).
C): 4 ＂-O-(4-luorobenzyl-formamyl)-2 '-O-ethanoyl Azythromycin 11; the preparation of 12-cyclic carbonate ester is with 4 ＂-O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11; 2-cyclic carbonate ester (1.5g; 1.65mmol) be dissolved in N; N-dimethyl formamide (DMF) (15mL) in, add 1.8-diazabicylo (5.4.0) hendecene-7 (DBU) (0.33mL, 2.25mmol) and NSC 158269 (0.28g; 2.25mmol), stirring at room 12h.After reaction finishes, add entry (30mL), ethyl acetate (15mL * 3) extraction merges organic layer, saturated aqueous common salt (15mL * 3) washing, and anhydrous sodium sulfate drying, evaporated under reduced pressure gets white solid foam 1.39g, yield 87.2%.Fusing point 135-137 ℃, Rf is that 0.612 (developping agent is a methylene dichloride: methyl alcohol=10:1), molecular formula is C
49H
78FN
3O
15, molecular weight is 968.1, MS 969.1 (M+H
+).
D): 4 ＂-O-(2-chlorobenzene ethyl-formamyl)-2 '-O-ethanoyl Azythromycin 11; the preparation of 12-cyclic carbonate ester is with 4 ＂-O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11; 2-cyclic carbonate ester (1.5g; 1.65mmol) be dissolved in N; N-dimethyl formamide (DMF) (15mL) in, add 1.8-diazabicylo (5.4.0) hendecene-7 (DBU) (0.33mL, 2.25mmol) and 2-chlorobenzene ethamine (0.35g; 2.25mmol), stirring at room 12h.After reaction finishes, add entry (30mL), ethyl acetate (15mL * 3) extraction merges organic layer, saturated aqueous common salt (15mL * 3) washing, and anhydrous sodium sulfate drying, evaporated under reduced pressure gets white solid foam 1.41g, yield 85.5%.Fusing point 124-126 ℃, Rf is that 0.620 (developping agent is a methylene dichloride: methyl alcohol=10:1), molecular formula is C
50H
80ClN
3O
15, molecular weight is 998.6, MS 999.4 (M+H
+).
Other embodiment adopts the method identical with embodiment 3, but with other aliphatic amide, substituted aroma aliphatic amide, replace the virtue aliphatic amide replacement embodiment 3a that mixes) in 4-hydroxyphenethylamine, b) in 4-methoxybenzylamine, c) in NSC 158269 or d) in 2-chlorobenzene ethamine.
Embodiment 4.
A): 4 ＂-O-(4-leptodactyline-formamyl)-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 ＂-O-(4-leptodactyline-formamyl)-2 '-O-ethanoyl-Azythromycin 11,12-cyclic carbonate ester (1.35g) is dissolved in the methyl alcohol (15mL), and 55 ℃ are stirred 20h, and evaporated under reduced pressure gets white foam shape solid.(eluent is a methylene dichloride to silica gel column chromatography: methyl alcohol=20:1), get white foam shape solid (1.02g), yield 78.5%.Fusing point 152-155 ℃, R
fBe that 0.598 (developping agent is a methylene dichloride: methyl alcohol=5:1), molecular formula is C
48H
79N
3O
15, molecular weight is 938.2, MS 939.1 (M+H
+).
B): 4 ＂-O-(4-methoxy-benzyl-formamyl)-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 ＂-O-(4-methoxy-benzyl-formamyl)-2 '-O-ethanoyl Azythromycin 11,12-cyclic carbonate ester (1.35g) is dissolved in the methyl alcohol (15mL), and 55 ℃ are stirred 20h, and evaporated under reduced pressure gets white foam shape solid.(eluent is a methylene dichloride to silica gel column chromatography: methyl alcohol=20:1), get white foam shape solid (1.10g), yield 84.5%.Fusing point 138-142 ℃, R
fBe that 0.657 (developping agent is a methylene dichloride: methyl alcohol=5:1), molecular formula is C
48H
79N
3O
15, molecular weight is 938.2, MS 939.1 (M+H
+).
C): 4 ＂-O-(4-luorobenzyl-formamyl) Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 ＂-O-(4-luorobenzyl-formamyl)-2 '-O-ethanoyl Azythromycin 11,12-cyclic carbonate ester (1.35g) is dissolved in the methyl alcohol (15mL), and 55 ℃ are stirred 20h, and evaporated under reduced pressure gets white foam shape solid.(eluent is a methylene dichloride to silica gel column chromatography: methyl alcohol=20:1), get white foam shape solid (1.29g), yield 82.0%.Fusing point 140-142 ℃, Rf is that 0.622 (developping agent is a methylene dichloride: methyl alcohol=5:1), molecular formula is C
47H
76N
3O
14, molecular weight is 926.1, MS 927.1 (M+H
+).
D): 4 ＂-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 ＂-O-(2-chlorobenzene ethyl-formamyl)-2 '-O-ethanoyl Azythromycin 11,12-cyclic carbonate ester (1.35g) is dissolved in the methyl alcohol (15mL), and 55 ℃ are stirred 20h, and evaporated under reduced pressure gets white foam shape solid.(eluent is a methylene dichloride to silica gel column chromatography: methyl alcohol=20:1), get white foam shape solid (1.29g), yield 86.0%.Fusing point 130-133 ℃, R
fBe that 0.641 (developping agent is a methylene dichloride: methyl alcohol=5:1), molecular formula is C
48H
78ClN
3O
14, molecular weight is 956.6, MS 957.1 (M+H
+).
Other embodiment adopts the method identical with embodiment 4; but replace embodiment 4a with other target product that embodiment 3 obtains) in 4 ＂-O-(4-leptodactyline-formamyl)-2 '-O-ethanoyl-Azythromycin 11; the 12-cyclic carbonate ester; b) 4 ＂ in-O-(4-methoxy-benzyl-formamyl)-2 '-O-ethanoyl Azythromycin 11; the 12-cyclic carbonate ester; c) 4 ＂ in-O-(4-luorobenzyl-formamyl)-2 '-O-ethanoyl Azythromycin 11; the 12-cyclic carbonate ester; or d) 4 ＂ in-O-(2-chlorobenzene ethyl-formamyl)-2 '-O-ethanoyl Azythromycin 11, the 12-cyclic carbonate ester.
Embodiment 5.
A): the preparation of 4 ＂-O-(4-leptodactyline-formamyl)-11-O-normal-butyl formamyl-Azythromycin (target compound 1)
With 4 ＂-O-(4-leptodactyline-formamyl)-Azythromycin 11; (1.40g 1.50mmol) is dissolved in the n-Butyl Amine 99 (5mL) the 12-cyclic carbonate ester, adds pyridine hydrochloride (0.34g; 3.00mmol) stirring at room 2～5 days; after reaction finishes, add entry (30mL), methylene dichloride (15mL * 3) extraction; merge organic layer; the saturated common salt water washing is extremely neutral, anhydrous sodium sulfate drying, and evaporated under reduced pressure gets white solid foam.(eluent is a methylene dichloride to silica gel column chromatography: methyl alcohol=20:1), get white foam shape solid (1.21g), yield 78.6%.Fusing point 104-107 ℃, R
fBe 0.445 (developping agent is a methylene dichloride: methyl alcohol=5:1); IR (KBr): 3419,2974,2934,2874,1724,1615,1516,1459,1382,1301,1251,1170,1118,1072,1049,1034,1016cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.02-7.01 (m, 4H, HAr), 5.05 (m, 1H, 1 '-CH), 4.98 (d, 1H, 1 ＂-CH), 4.50-4.46 (m, 3H, 4 ＂-CH, 5 ＂-CH and 11-CH), 4.36 (m, 1H, 13-CH), 4.26 (m, 2H,
CH 2CH
2Ar), 3.57-3.50 (m, 3H, 5 '-CH, 3-CH and2 '-CH), 3.48 (m, 2H ,-NH
CH 2CH
2CH
2CH
3), 3.32 (m, 2H, CH
2 CH 2 Ar), 3.29 (s, 3H, 3 ＂-OCH
3), 3.15-3.13 (m, 3H, 10-CH, 3 '-CH and 2-CH), 2.97 (d, 1H, 5-CH), 2.74 (m, 7H, 3 ＂-N (CH
3)
2And 9b-CH), 2.22 (s, 3H, 9a-NCH
3), 2.10 (m, 1H, 4-CH), 2.01 (m, 2H, 9a-CH and 2 ＂ b-CH), 1.90 (m, 1H, 8-CH), 1.74 (d, 1H, 2 ＂ a-CH), 1.73 (dd, 1H, 4 ' b-CH), 1.65 (dd, 1H, 4 ' a-CH), 1.36 (m, 6H ,-NHCH
2 CH 2 CH 2 CH
3, 7b-CHand 7a-CH), 1.26 (s, 3H, 6-CH
3), 1.22 (m, 2H, 13-
CH 2CH
3), 1.20-1.17 (m, 6H, 2-CH
3And 5 ＂-CH
3), 1.14 (d, 3H, 3 ＂-CH
3), 0.99-0.95 (m, 12H, 5 '-CH
3, 10-CH
3, 12-CH
3And 8-CH
3), 0.92-0.89 (m, 9H ,-NHCH
2CH
2CH
2 CH 3, 4-CH
3And 13-CH
2 CH 3); MS:m/zcalcd.for C
52H
90N
4O
151011.3; Found (M+1)
+1012.0
Compound 2-10 adopts and embodiment 5a) identical method; but replace embodiment 5a with target product in other respective embodiments 4) in 4 ＂-O-(4-leptodactyline-formamyl)-Azythromycin 11; the 12-cyclic carbonate ester replaces embodiment 5a with other liquid amine) middle n-Butyl Amine 99.
4 ＂-O-(4-leptodactyline-formamyl)-11-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin (target compound 2) white crystal; Yield: 75.6%; Fusing point: 110-113 ℃; Rf be 0.448 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3426,2974,2937,2877,2830,1708,1614,1516,1457,1382,1344,1253,1170,1111,1093,1073,1046,1037,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.37 (m, 1H, HAr), 7.20-7.02 (m, 3H, HAr), 7.01 (m, 4H, HAr), 5.05 (d, 1H, 1 '-CH), 4.99 (d, 1H, 1 ＂-CH), 4.50-4.44 (m, 3H, 4 ＂-CH, 5 ＂-CH and11-CH), 4.42 (m, 1H, 13-CH), 4.29-4.26 (m, 3H, 5 '-CH, 3-CH and 2 '-CH), 3.59-3.56 (m, 4H
CH 2CH
2Ar and
CH 2CH
2Ar), 3.55 (m, 4H, CH
2 CH 2 Ar and CH
2 CH 2 Ar), 3.30 (s, 3H, 3 ＂-OCH
3), 3.00 (m, 3H, 10-CH, 3 '-CH and 2-CH), 2.74 (m, 6H, 3 ＂-N (CH
3)
2), 2.65 (d, 1H, 5-CH), 2.22 (d, 1H, 9b-CH), 2.21 (s, 3H, 9a-NCH
3), 2.10 (m, 1H, 4-CH), 2.01 (m, 2H, 9a-CH and 2 ＂ b-CH), 1.90 (m, 2H, 8-CH), 1.74 (d, 1H, 2 ＂ a-CH), 1.73 (dd, 1H, 4 ' b-CH), 1.65 (dd, 1H, 4 ' a-CH), 1.47 (m, 2H, 7b-CH, 7a-CH), 1.26 (s, 3H, 6-CH
3), 1.20 (m, 2H, 13-
CH 2CH
3), 1.18-1.17 (m, 6H, 2-CH
3, 5 ＂-CH
3), 1.11 (d, 3H, 3 ＂-CH
3), 1.04-1.01 (m, 9H, 5 '-CH
3, 10-CH
3And12-CH
3), 0.97 (d, 3H, 8-CH
3), 0.89-0.88 (m, 6H, 4-CH
3And 13-CH
2 CH 3); MS:m/zcalcd.for C
56H
89ClN
4O
151093.7; Found (M+H)
+1094.0.
4 ＂-O-(4-leptodactyline-formamyl)-11-O-benzylamino formyl radical-Azythromycin (target compound 3) white crystal; Yield: 77.5%; Fusing point: 118-120 ℃; Rf be 0.415 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3423,2975,2937,2874,1728,1615,1516,1456,1379,1301,1253,1170,1111,1073,1047,1034,1016cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.36 (m, 2H, HAr), 7.30 (m, 3H, HAr), 7.21 (m, 3H, HAr), 7.03 (m, 2H, HAr), 5.00 (d, 1H, 1 '-CH), 4.98 (d, 1H, 1 ＂-CH), 4.46-4.36 (m, 4H, 4 ＂-CH, 5 ＂-CHand 11-CH and 13-CH), 4.26 (m, 2H, NH
CH 2Ar), 3.62 (m, 1H, 2 '-CH), 3.57 (m, 2H,
CH 2CH
2Ar), 3.50 (m, 2H, 5 '-CH and 3-CH), 3.45 (m, 1H, 10-CH), 3.27 (s, 3H, 3 ＂-OCH
3), 3.00 (m, 2H, CH
2 CH 2 Ar), 2.62 (m, 2H, 3 '-CH and 2-CH), 2.50 (m, 6H, 3 ＂-N (CH
3)
2), 2.32 (m, 2H, 5-CH and9b-CH), 2.25 (s, 3H, 9a-NCH
3), 2.10 (m, 1H, 4-CH), 2.02 (m, 2H, 9a-CH and 2 ＂ b-CH), 1.90 (m, 2H, 8-CH), 1.74 (m, 3H, 2 ＂ a-CH, 4 ' b-CH and 4 ' a-CH), 1.45 (m, 2H, 7b-CH, 7a-CH), 1.26-1.24 (m, 9H, 6-CH
3, 13-
CH 2CH
3And 2-CH
3), 1.18-1.17 (d, 3H, 5 ＂-CH
3), 1.13 (m, 9H, 3 ＂-CH
3, 5 '-CH
3And10-CH
3), 1.07 (m, 6H, 12-CH
3, 8-CH
3), 1.01 (d, 3H, 4-CH
3), 0.89-0.88 (m, 3H, 13-CH
2 CH 3); MS:m/z calcd.for C
55H
88N
4O
151045.3; Found (M+H)
+1045.9
4 ＂-O-(4-methoxy-benzyl) formamyl-11-O-amyl group formamyl-Azythromycin (target compound 4) white crystal; Yield: 68.5%; Fusing point: 115-117 ℃; Rf be 0.501 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3427,2974,2934,2873,1728,1613,1514,1489,1379,1301,1248,1173,1109,1093,1072,1049,1034,1015cm
-1,
1H NMR (600 MHz, CDCl
3, δ ppm) 7.21 (m, 2H, HAr), 6.86 (m, 2H, HAr), 5.05 (d, 1H, 1 '-CH), 5.00 (d, 1H, 1 ＂-CH), 4.61 (m, 2H, 4 ＂-CH, 5 ＂-CH), 4.44 (m, 1H, 11-CH), 4.34 (m, 2H,
CH 2Ar), 3.85 (m, 1H, 13-CH), 3.81 (s, 3H, Ar-O
CH 3), 3.63-3.60 (m, 3H, 2 '-CH, 5 '-CH, 3-CH), 3.33 (s, 3H, 3 ＂-OCH
3), 3.17 (m, 2H, 3 '-CH, 10-CH), 2.68 (m, 2H ,-NH
CH 2CH
2CH
2CH
2CH
3), 2.42-2.39 (m, 3H, 2-CH, 5-CH, 9b-CH), 2.30 (s, 6H, 3 ＂-N (CH
3)
2), 2.23 (s, 3H, 9a-NCH
3), 2.10-2.01 (m, 3H, 4-CH, 9a-CH and 2 ＂ b-CH), 1.90 (m, 2H, 8-CH, 2 ＂ a-CH), 1.65 (m, 2H, 4 ' b-CH, 4 ' a-CH), 1.51 (m, 4H ,-NHCH
2 CH 2CH
2CH
2CH
3And 13-
CH 2CH
3), 1.37 (m, 6H ,-NHCH
2CH
2 CH 2 CH 2 CH
3, 7b-CH and 7a-CH), 1.26 (s, 3H, 6-CH
3), 1.25-1.23 (m, 6H, 2-CH
3And5 ＂-CH
3), 1.19 (m, 6H, 3 ＂-CH
3And 5 '-CH
3), 0.99-0.96 (m, 9H, 10-CH
3, 12-CH
3And 8-CH
3), 0.92-0.89 (m, 9H ,-NHCH
2CH
2CH
2CH
2 CH 3, 4-CH
3And 13-CH
2 CH 3); MS:m/zcalcd.forC
53H
92N
4O
151025.3; Found (M+H)
+1026.1
4 ＂-O-(4-methoxy-benzyl-formamyl)-11-O-normal-butyl formamyl-Azythromycin (target compound 5) white crystal; Yield: 63.5%; Fusing point: 106-109 ℃; Rf be 0.500 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3419,2974,2935,2854,1726,1610,1513,1460,1379,1301,1248,1173,1109,1092,1073,1049,1033,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.20 (m, 2H, HAr), 6.87 (m, 2H, HAr), 5.04 (d, 1H, 1 '-CH), 4.97 (d, 1H, 1 ＂-CH), 4.61 (m, 2H, 4 ＂-CH and 5 ＂-CH), 4.44 (m, 1H, 11-CH), 4.34 (m, 2H,
CH 2Ar), 3.85 (m, 1H, 13-CH), 3.81 (s, 3H, Ar-O
CH 3), 3.63-3.60 (m, 3H, 2 '-CH, 5 '-CH and 3-CH), 3.33 (s, 3H, 3 ＂-OCH
3), 3.17 (m, 2H, 3 '-CH and 10-CH), 2.68 (m, 2H ,-NH
CH 2CH
2CH
2CH
3), 2.42-2.39 (m, 3H, 2-CH, 5-CH and 9b-CH), 2.30 (s, 6H, 3 ＂-N (CH
3)
2), 2.23 (s, 3H, 9a-NCH
3), 2.10-2.01 (m, 3H, 4-CH, 9a-CH and 2 ＂ b-CH), 1.90 (m, 2H, 8-CH and 2 ＂ a-CH), 1.65 (m, 2H, 4 ' b-CH and, 4 ' a-CH), 1.37 (m, 6H ,-NHCH
2 CH 2 CH 2 CH
3, 7b-CH and 7a-CH), 1.26 (s, 3H, 6-CH
3), 1.22 (m, 2H, 13-
CH 2CH
3), 1.25-1.23 (m, 6H, 2-CH
3And5 ＂-CH
3), 1.19 (m, 6H, 3 ＂-CH
3And 5 '-CH
3), 0.99-0.96 (m, 9H, 10-CH
3, 12-CH
3And 8-CH
3), 0.95-0.89 (m, 9H ,-NHCH
2CH
2CH
2 CH 3, 4-CH
3And 13-CH
2 CH 3); MS:m/zcalcd.for C
52H
90N
4O
151011.2; Found (M+H)
+1012.0
4 ＂-O-(4-luorobenzyl-formamyl)-11-O-(β-styroyl-formamyl)-Azythromycin (target compound 6) white crystal; Yield: 64.5%; Fusing point: 105-108 ℃; Rf be 0.503 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3435,2974,2935,2854,1727,1604,1511,1456,1379,1339,1254,1169,1112,1093,1073,1049,1036,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.31 (m, 2H, HAr), 7.24 (m, 5H, HAr), 7.02 (m, 2H, HAr), 5.01 (m, 2H, 1 '-CH, 1 ＂-CH), 4.70 (m, 1H, 11-CH), 4.58 (m, 1H, 13-CH), 4.47 (m, 2H, 4 ＂-CH, 5 ＂-CH), 4.40 (m, 2H,
CH 2Ar), 4.25-4.20 (m, 3H, 2 '-CH, 5 '-CH and 3-CH), 3.54 (m, 1H, 10-CH), 3.45 (m, 2H,
CH 2CH
2Ar), 3.32 (s, 3H, 3 ＂-OCH
3), 3.19 (m, 1H, 5-CH), 2.86 (m, 2H, 2-CHand3 '-CH), 2.63 (m, 2H, CH
2 CH 2Ar), 2.37 (d, 1H, 9b-CH), 2.32 (m, 6H, 3 ＂-N (CH
3)
2), 2.23 (s, 3H, 9a-NCH
3), 2.20 (m, 1H, 4-CH), 2.05 (m, 2H, 9a-CH and 2 ＂ b-CH), 1.95 (m, 2H, 8-CH and 2 ＂ a-CH), 1.81 (m, 2H, 4 ' b-CH and 7a-CH), 1.64 (m, 2H, 7b-CH and 4 ' a-CH), 1.50 (m, 2H, 13-
CH 2CH3), 1.26 (s, 3H, 12-CH
3), 1.25-1.21 (m, 12H, 3 ＂-CH
3, 2-CH
3, 6-CH
3And5 '-CH
3), 1.20 (d, 3H, 5 ＂-CH
3), 1.10 (d, 3H, 10-CH
3), 1.03 (d, 3H, 8-CH
3), 0.97 (d, 3H, 4-CH
3), 0.88 (m, 3H, 13-CH
2 CH 3); MS:m/z calcd.for C
55H
87FN
4O
141048.3; Found (M+H)
+1048.0
4 ＂-O-(4-luorobenzyl-formamyl)-11-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin (target compound 7) white crystal; Yield: 66.5%; Fusing point: 104-106 ℃; Rf be 0.498 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3428,2974,2928,2854,1727,1605,1511,1456,1380,1344,1254,1169,1111,1093,1073,1049,1036,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.36 (m, 1H, HAr), 7.25 (m, 2H, HAr), 7.24 (m, 3H, HAr), 7.02 (m, 2H, HAr), 5.01 (m, 2H, 1 '-CH and 1 ＂-CH), 4.70 (m, 1H, 11-CH), 4.59 (m, 1H, 13-CH), 4.41-4.40 (m, 2H, 4 ＂-CH and 5 ＂-CH), 4.38 (m, 2H
CH 2Ar), 4.30-4.27 (m, 2H, 2 '-CH, 5 '-CH), 4.19 (m, 1H, 3-CH), 3.55 (m, 1H, 10-CH), 3.48 (m, 2H,
CH 2CH
2Ar), 3.32 (s, 3H, 3 ＂-OCH
3), 2.99 (m, 3H, 5-CH, 2-CH and 3 '-CH), 2.70 (m, 2H, CH
2 CH 2Ar), 2.38 (d, 1H, 9b-CH), 2.33 (m, 6H, 3 ＂-N (CH
3)
2), 2.23 (s, 3H, 9a-NCH3), 2.20 (m, 1H, 4-CH), 2.05 (m, 2H, 9a-CH and2 ＂ b-CH), 1.95 (m, 2H, 8-CH and 2 ＂ a-CH), 1.81 (m, 2H, 4 ' b-CH and 7a-CH), 1.64 (m, 2H, 7b-CHand4 ' a-CH), 1.50 (m, 2H, 13-
CH 2CH
3), 1.26 (s, 3H, 12-CH
3), 1.26-1.22 (m, 12H, 3 ＂-CH
3, 2-CH
3, 6-CH
3And 5 '-CH
3), 1.20 (d, 3H, 5 ＂-CH
3), 1.10 (d, 3H, 10-CH
3), 1.03 (d, 3H, 8-CH
3), 0.90-0.88 (m, 6H, 4-CH
3, 13-CH
2 CH 3); MS:m/z calcd.for C
55H
84ClFN
4O
141081.7; Found (M+H)
+1082.0
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-amyl group formamyl-Azythromycin (target compound 8) white crystal; Yield: 66.8%; Fusing point: 98-111 ℃; Rf be 0.530 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3435,2974,2935,2872,2830,1727,1515,1457,1379,1344,1254,1169,1110,1092,1073,1046,1036,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.36 (m, 1H, HAr), 7.26-7.18 (m, 3H, HAr), 5.09 (m, 2H, 1 '-CH and 1 ＂-CH), 4.53 (d, 1H, 11-CH), 4.41 (t, 1H, 13-CH), 4.29 (m, 2H, 4 ＂-CH and 5 ＂-CH), 3.63-3.50 (m, 5H, 2 '-CH, 5 '-CH, 3-CH, 10-CH and 5-CH), 3.32 (m, 2H
CH 2CH
2Ar), 3.31 (s, 3H, 3 ＂-OCH
3), 3.15 (m, 2H, NH
CH 2CH
2CH
2CH
2CH
3), 2.98 (m, 2H, CH
2 CH 2Ar), 2.68 (m, 2H, 2-CHand 3 '-CH), 2.44 (d, 1H, 9b-CH), 2.38 (m, 6H, 3 ＂-N (CH
3)
2), 2.24 (s, 3H, 9a-NCH
3), 2.18 (m, 1H, 4-CH), 2.09-1.98 (m, 2H, 9a-CH and 2 ＂ b-CH), 1.89 (m, 2H, 8-CH, 2 ＂ a-CH), 1.61 (m, 1H, 4 ' b-CH), 1.50-1.47 (m, 4H, 4 ' a-CH, NHCH
2 CH 2CH
2CH
2CH
3And 7b-CH), 1.44 (s, 3H, 12-CH
3), 1.33-1.29 (m, 7H, NHCH
2CH
2 CH 2 CH 2 CH
3, 7a-CH and 13-
CH 2CH
3), 1.25-1.19 (m, 12H, 3 ＂-CH
3, 2-CH
3, 6-CH
3And 5 '-CH
3), 1.15 (s, 3H, 6-CH
3), 1.10 (s, 3H, 5 ＂-CH
3), 1.08 (d, 3H, 10-CH
3), 1.06 (d, 3H, 8-CH
3), 0.91 (m, 9H, 4-CH
3, NHCH
2CH
2CH
2CH
2 CH 3And 13-CH
2 CH 3); MS:m/z calcd.forC
55H
91ClN
4O
141043.7; Found (M+H)
+1043.9.
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-benzylamino formyl radical-Azythromycin (target compound 9) white crystal; Yield: 65.8%; Fusing point: 115-117 ℃; Rf be 0.480 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3449,2974,2937,2877,2830,1728,1634,1510,1455,1379,1344,1253,1170,1111,1093,1073,1046,1037,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.38 (m, 1H, HAr), 7.35 (m, 2H, HAr), 7.33 (m, 3H, HAr), 7.20 (m, 3H, HAr), 4.96 (d, 1H, 1 '-CH), 4.95 (d, 1H, 1 ＂-CH), 4.46-4.41 (m, 4H, 4 ＂-CH, 5 ＂-CH, 11-CH and 13-CH), 4.33-4.31 (m, 2H, NH
CH 2Ar), 3.62 (m, 1H, 2 '-CH), 3.56 (m, 2H,
CH 2CH
2Ar), 3.51 (m, 2H, 5 '-CH, 3-CH), 3.49 (m, 1H, 10-CH), 3.28 (s, 3H, 3 ＂-OCH
3), 2.99 (m, 2H, CH
2 CH 2 Ar), 2.62 (m, 2H, 3 '-CH and 2-CH), 2.36 (m, 6H, 3 ＂-N (CH
3)
2), 2.29 (m, 2H, 5-CH and9b-CH), 2.26 (s, 3H, 9a-NCH
3), 2.10 (m, 1H, 4-CH), 2.02 (m, 2H, 9a-CH and 2 ＂ b-CH), 1.90 (m, 2H, 8-CH), 1.74 (m, 3H, 2 ＂ a-CH, 4 ' b-CH and 4 ' a-CH), 1.45 (m, 2H, 7b-CH and 7a-CH), 1.26-1.24 (m, 8H, 6-CH
3, 13-
CH 2CH
3And 2-CH
3), 1.18 (d, 3H, 5 ＂-CH
3), 1.13 (m, 9H, 3 ＂-CH
3, 5 '-CH
3And10-CH
3), 1.07 (m, 6H, 12-CH
3And 8-CH
3), 1.01 (d, 3H, 4-CH
3), 0.90-0.89 (m, 3H, 13-CH
2 CH 3); MS:m/z calcd.for C
55H
87ClN
4O
141063.7; Found (M+H)
+1064.1.
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-(4-luorobenzyl-formamyl)-Azythromycin (target compound 10) white crystal; Yield: 78.6%; Fusing point: 119-121 ℃; Rf be 0.425 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3445,2975,2938,2854,1727,1605,1511,1456,1380,1344,1254,1169,1111,1093,1073,1049,1037,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.36 (m, 1H, HAr), 7.35 (m, 2H, HAr), 7.21 (m, 3H, HAr), 7.02 (m, 2H, HAr), 4.96 (d, 1H, 1 '-CH), 4.95 (d, 1H, 1 ＂-CH), 4.46-4.41 (m, 4H, 4 ＂-CH, 5 ＂-CH, 11-CH and 13-CH), 4.33-4.31 (m, 2H, NH
CH 2Ar), 3.62 (m, 1H, 2 '-CH), 3.56 (m, 2H,
CH 2CH
2Ar), 3.51 (m, 2H, 5 '-CH and 3-CH), 3.49 (m, 1H, 10-CH), 3.27 (s, 3H, 3 ＂-OCH
3), 2.99 (m, 2H, CH
2 CH 2 Ar), 2.62 (m, 2H, 3 '-CH and 2-CH), 2.36 (m, 6H, 3 ＂-N (CH
3)
2), 2.29 (m, 2H, 5-CHand 9b-CH), 2.25 (s, 3H, 9a-NCH
3), 2.10 (m, 1H, 4-CH), 2.02 (m, 2H, 9a-CH and 2 ＂ b-CH), 1.91 (m, 2H, 8-CH), 1.60-1.59 (m, 3H, 2 ＂ a-CH, 4 ' b-CH and 4 ' a-CH), 1.48 (m, 2H, 7b-CH and 7a-CH), 1.26-1.24 (m, 8H, 6-CH
3, 13-
CH 2CH
3And 2-CH
3), 1.18 (d, 3H, 5 ＂-CH
3), 1.13 (m, 9H, 3 ＂-CH
3, 5 '-CH
3And 10-CH
3), 1.07 (m, 6H, 12-CH
3And 8-CH
3), 1.01 (d, 3H, 4-CH
3), 0.91-0.89 (m, 3H, 13-CH
2 CH 3); MS:m/z calcd.for C
55H
84ClFN
4O
141081.7; Found (M+H)
+1082.0
4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-(4-leptodactyline-formamyl)-Azythromycin (target compound 11)
White crystal; Yield: 64.5%; Fusing point: 121-124 ℃; Rf be 0.485 (methyl alcohol: methylene dichloride, 1:5); IR (KBr): 3429,2974,2936,2854,1728,1614,1594,1515,1457,1376,1344,1245,1170,1111,1093,1073,1050,1036,1015cm
-1,
1H NMR (600MHz, CDCl
3, δ ppm) 7.28 (m, 1H, HAr), 7.21 (m, 3H, HAr), 7.09 (m, 2H, HAr), 6.84 (m, 2H, HAr), 5.00-4.95 (m, 2H, 1 '-CH and 1 ＂-CH), 4.56 (m, 2H, 4 ＂-CHand 5 ＂-CH), 4.40 (m, 1H, 11-CH), 4.42 (m, 1H, 13-CH), 4.29-4.26 (m, 3H, 5 '-CH, 3-CH and2 '-CH), 3.59-3.56 (m, 4H
CH 2CH
2Ar and
CH 2CH
2Ar), 3.55 (m, 4H, CH
2 CH 2 Ar and CH
2 CH 2 Ar), 3.30 (s, 3H, 3 ＂-OCH
3), 3.00 (m, 3H, 10-CH, 3 '-CH and 2-CH), 2.74 (m, 6H, 3 ＂-N (CH
3)
2), 2.65 (d, 1H, 5-CH), 2.22 (d, 1H, 9b-CH), 2.23 (s, 3H, 9a-NCH
3), 2.10 (m, 1H, 4-CH), 2.01 (m, 2H, 9a-CHand 2 ＂ b-CH), 1.90 (m, 2H, 8-CH), 1.74 (d, 1H, 2 ＂ a-CH), 1.73 (dd, 1H, 4 ' b-CH), 1.65 (dd, 1H, 4 ' a-CH), 1.47 (m, 2H, 7b-CH and 7a-CH), 1.26 (s, 3H, 6-CH
3), 1.20 (m, 2H, 13-
CH 2CH
3), 1.25-1.13 (m, 18H, 2-CH
3, 5 ＂-CH
3, 3 ＂-CH
3, 5 '-CH
3, 10-CH
3And 12-CH
3), 1.02 (m, 6H, 8-CH
3And4-CH
3), 0.89 (m, 3H, 13-CH
2 CH 3); MS:m/z calcd.for C
56H
89ClN
4O
151093.7; Found (M+H)
+1094.0
B): the preparation of 4 ＂-O-(2-chlorobenzene ethyl-formamyl)-11-O-(4-leptodactyline-formamyl)-Azythromycin (target compound 11)
With 4 ＂-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin 11; 12-cyclic carbonate ester ester (1.43g, 1.50mmol) and tyrasamine (0.41g 3.00mmol) is dissolved in the N-Methylimidazole (15mL); stirring at room 2～5 days; after reaction finishes, add entry (30mL), methylene dichloride (15mL * 3) extraction; merge organic layer; the saturated common salt water washing is extremely neutral, anhydrous sodium sulfate drying, and evaporated under reduced pressure gets white solid foam.(eluent is a methylene dichloride: methyl alcohol=20:1), get white foam shape solid (1.06g) is target compound to silica gel column chromatography.Yield 64.5%.Fusing point 121-124 ℃, R
fBe 0.485 (developping agent is a methylene dichloride: methyl alcohol=5:1).
When the described amine reaction conditions of other embodiment is down liquid, adopt and embodiment 5a) identical method; When described amine reaction conditions is down solid-state, adopt and embodiment 5b) identical method.
Claims (6)
1. general formula (I) compound or this compound and the inorganic and pharmaceutically acceptable additive salt of organic acid,
Wherein, R
1Represent hydrogen, acetyl or benzoyl base, R
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group.
2. according to the compound of claim 1, it is characterized in that R
2Be 4-luorobenzyl, 4-methoxy-benzyl, 2-chlorobenzene ethyl or 4-leptodactyline; R
3Be benzyl, 4-luorobenzyl, 2-chlorobenzene ethyl, 4-leptodactyline, normal-butyl or n-pentyl.
3. according to the compound of claim 1 or 2, it is characterized in that comprising following several:
1) 4 "-O-(4-leptodactyline-formamyl)-11-O-normal-butyl formamyl-Azythromycin,
2) 4 "-O-(4-leptodactyline-formamyl)-11-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin,
3) 4 "-O-(4-leptodactyline-formamyl)-11-O-benzylamino formyl radical-Azythromycin,
4) 4 "-O-(4-methoxy-benzyl-formamyl)-11-O-amyl group formamyl-Azythromycin,
5) 4 "-O-(4-methoxy-benzyl-formamyl)-11-O-normal-butyl formamyl-Azythromycin,
6) 4 "-O-(4-luorobenzyl-formamyl)-11-O-(β-styroyl-formamyl)-Azythromycin,
7) 4 "-O-(4-luorobenzyl-formamyl)-11-O-(2-chlorobenzene ethyl-formamyl)-Azythromycin,
8) 4 "-O-(2-chlorobenzene ethyl-formamyl)-11-O-n-pentyl formamyl-Azythromycin,
9) 4 "-O-(2-chlorobenzene ethyl-formamyl)-11-O-benzylamino formyl radical-Azythromycin,
10) 4 "-O-(2-chlorobenzene ethyl-formamyl)-11-O-(4-luorobenzyl-formamyl)-Azythromycin,
11) 4 "-O-(2-chlorobenzene ethyl-formamyl)-11-O-(4-leptodactyline-formamyl)-Azythromycin.
4. the preparation method of claim 1 or 2 described compounds, step is as follows:
(1) with 2 of the Azythromycin of general formula (IV) '-protection of OH acidylate, acylating reagent aceticanhydride, acetic acid, Acetyl Chloride 98Min., or benzoyl oxide, phenylformic acid or Benzoyl chloride, in the presence of inorganic or organic bases,, react under 0～40 ℃ temperature as solvent with acetone, ethyl acetate, tetrahydrofuran (THF) or methylene dichloride, generate compound with above-mentioned general formula (II);
(2) compound that will have general formula (II) is in inert solvent, and in the presence of inorganic or organic bases, with N, N '-dicarbapentaborane imidazoles (CDI) generates the compound with general formula (III) in 0～110 ℃ of reaction 2～72h;
(3) compound of above-mentioned general formula (III) and aliphatic amide, substituted aroma aliphatic amide or replace fragrant heterocycle aliphatic amide, at N, react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or the mixed solvent, catalyzer 1.8-diazabicylo (5.4.0) hendecene-7 (DBU), in 0～65 ℃ of reaction 2～24h, generate the compound of logical formula V; R wherein
1Represent the acetyl or benzoyl base, simultaneously R
2Represent aliphatic group, substituted aroma aliphatic group or replace fragrant heterocycle aliphatic group;
(4) when the compound R of above-mentioned logical formula V
1During for the acetyl or benzoyl base, with aliphatic amide, substituted aroma aliphatic amide or replace the reaction of fragrant heterocycle aliphatic amide, or be dissolved in N-Methylimidazole, triethylamine, the quadrol medium basic solvent, catalyzer pyridine hydrochloride or imidazoles, in 0～40 ℃ of reaction 12～120h, generate the compound of general formula (I); R wherein
1Represent the acetyl or benzoyl base, simultaneously R
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group;
(5) when the compound R of above-mentioned general formula (I)
1During for the acetyl or benzoyl base, further in the methyl alcohol kind solvent alcoholysis slough 2 '-acyl group on the position, produce the compound of general formula (VII); R wherein
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group;
(6) when the compound R that leads to formula V
1During for the acetyl or benzoyl base, further in the methyl alcohol kind solvent alcoholysis slough 2 '-acyl group on the position, produce the compound of general formula (VI); R wherein
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group;
(7) when the compound of above-mentioned general formula (VI); R wherein
2, R
3Represent aliphatic group, with aliphatic amide, substituted aroma aliphatic amide or replace the reaction of fragrant heterocycle aliphatic amide, or be dissolved in N-Methylimidazole, triethylamine or the quadrol neutral and alkali solvent, catalyzer pyridine hydrochloride or imidazoles in 0～40 ℃ of reaction 12～120h, generate the compound of general formula (VII); R wherein
2, R
3Represent aliphatic group, substituted aroma aliphatic group respectively or replace fragrant heterocycle aliphatic group.
5. as the preparation method of compound as described in the claim 4, it is characterized in that the aliphatic amide described in step (4), (7), substituted aroma aliphatic amide or replace under the fragrant heterocycle aliphatic amide reaction conditions when liquid that preferred catalyst is a pyridine hydrochloride; Described aliphatic amide, substituted aroma aliphatic amide or replace under the fragrant heterocycle aliphatic amide reaction conditions when solid-state, preferred solvent is the N-Methylimidazole.
6. the pharmaceutical composition that is used for the treatment of infectation of bacteria in human body and the animal comprises compound or its pharmaceutically acceptable additive salt of the general formula (I) of the claim 1 of antimicrobial effective amount, with pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008102381676A CN101423539B (en) | 2008-12-09 | 2008-12-09 | 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008102381676A CN101423539B (en) | 2008-12-09 | 2008-12-09 | 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101423539A true CN101423539A (en) | 2009-05-06 |
| CN101423539B CN101423539B (en) | 2011-04-27 |
Family
ID=40614442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008102381676A Expired - Fee Related CN101423539B (en) | 2008-12-09 | 2008-12-09 | 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101423539B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101899076A (en) * | 2010-07-13 | 2010-12-01 | 山东大学 | Azithromycin derivative, preparation method and intermediate thereof |
| CN102260305A (en) * | 2011-06-01 | 2011-11-30 | 山东大学 | 4''-((substituted benzamido)alkyl)carbamate azithromycin11-carbamate derivatives and intermediates thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043227A (en) * | 1998-08-19 | 2000-03-28 | Pfizer Inc. | C11 carbamates of macrolide antibacterials |
| US6100240A (en) * | 1998-10-09 | 2000-08-08 | Pfizer Inc | Macrolide derivatives |
| CA2411293A1 (en) * | 1999-01-28 | 2000-07-28 | Pfizer Products Inc. | Novel azalides and methods of making same |
| RS51479B (en) * | 2005-01-13 | 2011-04-30 | Glaxo Group Limited | Macrolides with anti-inflammatory activity |
| CN101074251B (en) * | 2007-06-22 | 2011-06-15 | 山东大学 | Azithromycin 4-phenproester derivative, its production and medicinal composition |
| CN101074252B (en) * | 2007-06-22 | 2011-06-15 | 山东大学 | 11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition |
-
2008
- 2008-12-09 CN CN2008102381676A patent/CN101423539B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101899076A (en) * | 2010-07-13 | 2010-12-01 | 山东大学 | Azithromycin derivative, preparation method and intermediate thereof |
| CN101899076B (en) * | 2010-07-13 | 2013-06-05 | 山东大学 | Azithromycin derivative, preparation method and intermediate thereof |
| CN102260305A (en) * | 2011-06-01 | 2011-11-30 | 山东大学 | 4''-((substituted benzamido)alkyl)carbamate azithromycin11-carbamate derivatives and intermediates thereof |
| CN102260305B (en) * | 2011-06-01 | 2014-08-27 | 山东大学 | 4''-((substituted benzamido)alkyl)carbamate azithromycin11-carbamate derivatives and intermediates thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101423539B (en) | 2011-04-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2008316830A1 (en) | Process for the preparation of macrolide antibacterial agents | |
| CZ303474B6 (en) | 6-O-substituted erythromycin ketolide derivative, process for its preparation, its use and pharmaceutical composition containing thereof | |
| EP1070077B1 (en) | 15-membered lactams ketolides with antibacterial activity | |
| CA2306963C (en) | Novel 3,6-hemiketals from the class of 9a-azalides | |
| WO2004087728A2 (en) | 6,11-3c-bicyclic 9a-azalide derivatives | |
| EP1161438A1 (en) | 6-o-substituted macrolides having antibacterial activity | |
| CA2301643A1 (en) | 6,9-bridged erythromycin derivatives | |
| CN101074251B (en) | Azithromycin 4-phenproester derivative, its production and medicinal composition | |
| CN102260305B (en) | 4''-((substituted benzamido)alkyl)carbamate azithromycin11-carbamate derivatives and intermediates thereof | |
| CN101423539B (en) | 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof | |
| CN101074252B (en) | 11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition | |
| Kashimura et al. | Synthesis and antibacterial activity of the tricyclic ketolides TE-802 and its analogs | |
| WO2007044927A2 (en) | 6, 11-bridged tricyclic macrolides | |
| EP1181298B1 (en) | Novel 8a- and 9a-15-membered lactams | |
| US6169168B1 (en) | Erythromycin A derivatives | |
| WO2008019240A2 (en) | 3, 6-bridged tylosin derivatives | |
| Narandja et al. | 10, 11, 12, 13-tetrahydro derivatives of tylosin II. Synthesis, antibacterial activity and tissue distribution of 4'-deoxy-10, 11, 12, 13-tetrahydrodesmycosin | |
| HRP960497A2 (en) | 9-n-ethenyl derivatives of 9(s)-erythromycylamine | |
| CA1202619A (en) | Intermediates for the preparation of n-methyl 11-aza- 10-deoxo-10-dihydroerythromycin a | |
| JP2006507315A (en) | Substituted 9a-N- of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A and 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A {N '-[4- (sulfonyl) phenylcarbamoyl]} derivatives | |
| WO2009137737A2 (en) | Anti-bacterial activity of 9-hydroxy derivatives of 6, 11-bicyclolides | |
| CN101845069A (en) | Derivative of 4'-substituted 6,11-2-oxygen-carithromycin A | |
| CZ20003704A3 (en) | 15-membered lactam ketolides exhibiting antibacterial activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110427 Termination date: 20131209 |