CN101074252A - 11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition - Google Patents

11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition Download PDF

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CN101074252A
CN101074252A CNA2007100150507A CN200710015050A CN101074252A CN 101074252 A CN101074252 A CN 101074252A CN A2007100150507 A CNA2007100150507 A CN A2007100150507A CN 200710015050 A CN200710015050 A CN 200710015050A CN 101074252 A CN101074252 A CN 101074252A
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马淑涛
咸瑞卿
娄红祥
焦波
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Shandong University
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Abstract

A compound with general formula (I), accepted additional salts of inorganic and organic acid medicines, its production, medicinal composition and usage are disclosed. It belongs to azithromycin pentadecenic macrolide derivative, R1 represents hydrogen or acetyl or methane; R2 represents fatty hydrocarbon, substituted aromatic fatty hydrocarbon or substituted aromatic heterocyclic fatty hydrocarbon. It can be used to prepare medicines in treatment of bacterial infections.

Description

11,12-cyclic carbonate ester-Azithromycin 4 " mephenesin Carbamate derivative, preparation method and pharmaceutical composition thereof
Technical field
The present invention relates to Azithromycin derivative and preparation thereof, relate in particular to 11,12-cyclic carbonate ester-Azithromycin 4 " mephenesin Carbamate derivative, preparation method and pharmaceutical composition thereof.
Background technology
Macrolide antibiotic be a class can be oral, the respiratory tract infection pathogenic bacterium are had a microbiotic of anti-microbial activity.Erythromycin once was used widely as first-generation macrolide antibiotic, yet owing to caused its application to be restricted to 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, antibiotic being extensive use of, particularly improper use causes bacterial drug resistance to increase year by year.The direct result that bacterial drug resistance produces is to weaken antibiotic validity, and the limit treatment Scheme Selection has a strong impact on clinical efficacy, even causes the treatment failure.Therefore, drug-resistance of bacteria has become the key issue that presses for solution clinically.
Amino formate compounds is the novel derivative of macrolides of another class of report in 1998.This compounds is 4 of the macrolide cladinose, and " position is introduced the carboxylamine ester side chain and is obtained.Anti-microbial activity is similar with acyl lactone to the ketone lactone, and is not subjected to the influence of the gene kind that resistant organism carries.At present, the carboxylamine ester side chain of different lengths is introduced in the Azithromycin 4 of having reported " carbamate derivatives mainly is at Azithromycin 4 " position, 7 link to each other (world patent WO2004101589, WO2005108413, WO2006050941, WO2006050942, WO2006050943 etc.) of the other end of side chain and Carbostyril derivative.
The structural modification of 11,12 hydroxyls of macrolide also is when previous research focus.The modification of 11,12 hydroxyls not only can stop intramolecular ketal increase stability, but also can strengthen anti-microbial activity.For example, 11, the inside and outside anti-microbial activity of 12-cyclic carbonate ester erythromycin (ECC) (commodity are called Davercin) all is better than erythromycin, antibacterial activity in vitro can compare favourably with erythromycin derivatives of new generation such as Roxithromycin, clarithromycin, dirithromycin, Azythromycins, and interior curative effect and Roxithromycin are suitable.At present, Azythromycin 11, the synthetic of 12-cyclic carbonate ester derivative mainly utilizes diethyl carbonate (ethylenecarbonate) to synthesize (S.Djokic et al.J.Chem.Res. (S) 1988,152).11,12-cyclic carbonate ester-Azythromycin 4 " carboxylamine ester side chain (world patent WO2004101585, WO2004101587, WO2004101589, WO2006050941, WO2006050942, WO2006050943), sulphonate side chain (world patent WO2006050940) or the ether side chain (world patent WO2006050942) of different lengths introduced in the position, and 7 of the other end of side chain and Carbostyril derivative link to each other.
According to known and definite prior art, also do not describe from 11 12-cyclic carbonate ester-Azithromycin 4 up to now and " mephenesin Carbamate derivative, the intermediate product derivative that relates to its preparation and method, relate to itself and the inorganic or pharmaceutically acceptable additive salt of organic acid, 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 11,12-cyclic carbonate ester Azithromycin 4 " mephenesin Carbamate derivative, preparation method and pharmaceutical composition thereof.
The present invention also provides 11,12-cyclic carbonate ester-Azithromycin 4, and " the mephenesin Carbamate derivative prepares related intermediate product derivative.
The present invention also provides 11,12-cyclic carbonate ester-Azithromycin 4 " purposes of the pharmaceutical composition of mephenesin Carbamate derivative.
One, 11,12-cyclic carbonate ester-Azithromycin 4 " mephenesin Carbamate derivative
Of the present invention 11,12-cyclic carbonate ester-Azithromycin 4 " the mephenesin Carbamate derivative, have following general formula (I) and with acceptable addition salt inorganic and that organic acid forms:
Figure A20071001505000051
Wherein, R 1Represent hydrogen, acetyl or benzoyl base, R 2Represent aliphatic group, substituted aroma aliphatic group or replace fragrant heterocycle aliphatic group.
Preferably, R 2Be benzyl, 4-luorobenzyl, 4-methoxy-benzyl, β-styroyl, 2-chlorobenzene ethyl, 4-leptodactyline, 2-(3, the 4-methylene dioxy phenyl group) ethyl, propyl group, propenyl, butyl, amyl group, sec.-propyl, cyclohexyl, 3-aminopropyl or 6-aminopropyl etc.
Two, 11, " the mephenesin Carbamate derivative prepares used intermediate to 12-cyclic carbonate ester-Azithromycin 4
First intermediate has following general formula (II): R wherein 1Represent the acetyl or benzoyl base.
Figure A20071001505000052
Second intermediate has following general formula (III): R wherein 1Represent the acetyl or benzoyl base.
Figure A20071001505000061
Three, 11,12-cyclic carbonate ester-Azithromycin 4 " preparation method of mephenesin Carbamate derivative
Of the present invention 11,12-cyclic carbonate ester-Azithromycin 4 " preparation method of mephenesin Carbamate derivative, step is as follows:
With 2 of the Azythromycin of general formula (N) '-protection of OH acidylate; acylating reagent aceticanhydride, acetic acid, Acetyl Chloride 98Min., benzoyl oxide, phenylformic acid, Benzoyl chloride etc.; in the presence of inorganic or organic bases; with acetone, ethyl acetate, tetrahydrofuran (THF) or methylene dichloride is solvent; under 0～40 ℃ temperature, react, generate compound with above-mentioned general formula (II).
With the compound of general formula (II) and CDI (N, N '-dicarbapentaborane imidazoles) in inert solvent, in the presence of inorganic or organic bases,, generate compound with general formula (III) in 30～110 ℃ of reaction 2～24h.
3. the product and the aliphatic amide of above-mentioned general formula (III), the assorted amine of aromatic amine or virtue, at solvent N, react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or their mixed solvent, catalyzer 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU), 0～65 ℃ of reaction 2～24h; Generate the compound of general formula (I); 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 R that works as above-mentioned general formula (I) product 1During for the acetyl or benzoyl base, further in the lower alcohols solvent alcoholysis slough 2 '-acyl group on the position, produce R 1Compound for the general formula (I) of hydrogen.
Preferably, the mol ratio 1: 1～5 of acylating reagent and Azythromycin in the above-mentioned steps 1, 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 reacted 3～24 hours at 25 ℃.
Preferably, the post-treating method of product 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 0.522 general formula (II).
Preferably, in the above-mentioned steps 2: the mole 1: 1～6 of the compound of control general formula (II) and CDI (N, N '-dicarbapentaborane imidazoles), preferred 1: 4 mol ratio.
Preferably, under 110 ℃ of temperature, react 2h in the above-mentioned steps 2, can produce the compound of the general formula (III) more than 90%.
Inert solvent in the above-mentioned steps 2 is selected from methylene dichloride, tetrahydrofuran (THF) or toluene, preferred toluene.
Mineral alkali described in the above-mentioned steps 2 is selected from sodium bicarbonate, yellow soda ash or salt of wormwood, and described organic bases is selected from triethylamine, pyridine or 4-Dimethylamino pyridine, further preferred triethylamine.
The preferred N of reaction solvent in the above-mentioned steps 3, dinethylformamide.
Lower alcohol particular methanol in the above-mentioned steps 4.
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 additive salt is soluble in inert solvent, generally by separating additive salt with non-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
Of the present invention 11, " pharmaceutical composition of mephenesin Carbamate derivative, said composition comprise compound or its pharmaceutically acceptable additive salt of the general formula (I) of antimicrobial effective amount to 12-cyclic carbonate ester-Azithromycin 4, and pharmaceutically acceptable carrier.Its pharmaceutical composition significant quantity is with corresponding 11, " the mephenesin Carbamate derivative conversion of 12-cyclic carbonate ester-Azithromycin 4.
Five, use
11, " pharmaceutical composition of mephenesin Carbamate derivative is used for the purposes of bacterial-infection resisting to 12-cyclic carbonate ester-Azithromycin 4.Adopt the test tube doubling dilution to measure the part target compound to streptococcus pneumoniae, mixed type resistance streptococcus pneumoniae (MLS B+ M) antibacterial activity in vitro.Measurement result sees Table 1.
Table 1: part 11,12-cyclic carbonate ester-Azithromycin 4 " mephenesin Carbamate derivative antibacterial activity in vitro
Compound Streptococcus pneumoniae (MLS B+ M) mixed type resistance streptococcus pneumoniae
MIC (μg/mL) MIC (μg/mL)
a b c d e f g h i j ＜0.03 0.06 ＜0.03 0.06 0.06 ＜0.03 ＜0.03 0.06 0.125 0.125 8 4 16 2 2 4 2 16 128 16
k l m ERY CLA AZI 0.06 0.25 0.06 ＜0.03 ＜0.03 ＜0.03 16 128 32 ＞256 128 256
Wherein ERY is an erythromycin, and CLA is a clarithromycin, and AZI is an Azythromycin.A～m is representation compound 4 successively " O-benzylamino formyl radical-Azythromycin 11; 12-cyclic carbonate ester; 4 "-O-(4-luorobenzyl-formamyl)-Azythromycin 11; the 12-cyclic carbonate ester; 4 " O-(4-methoxy-benzyl-formamyl)-Azythromycin 11; 12-cyclic carbonate ester; 4 "-O-(β-styroyl-formamyl)-Azythromycin 11; the 12-cyclic carbonate ester; 4 " O-(2-chlorobenzene ethyl-formamyl)-Azythromycin 11; 12-cyclic carbonate ester; 4 "-O-((4-hydroxyl-styroyl)-formamyl)-Azythromycin 11; the 12-cyclic carbonate ester; 4 " O-(2-(3; the 4-methylene dioxy phenyl group) ethyl-formamyl)-Azythromycin 11; 12-cyclic carbonate ester; 4 "-O-propyl group formamyl-Azythromycin 11; the 12-cyclic carbonate ester; 4 " O-propenyl formamyl-Azythromycin 11; 12-cyclic carbonate ester; 4 "-O-butyl formamyl-Azythromycin 11; the 12-cyclic carbonate ester; 4 " O-amyl group formamyl-Azythromycin 11; 12-cyclic carbonate ester; 4 "-O-sec.-propyl formamyl-Azythromycin 11; the 12-cyclic carbonate ester; 4 " O-cyclohexyl carboxyamide base-Azythromycin 11, the 12-cyclic carbonate ester.
As shown in Table 1, listed target compound a～m shows stronger anti-microbial activity to responsive streptococcus pneumoniae, and wherein part of compounds is to mixed type resistance streptococcus pneumoniae (MLS B+ M) produce anti-microbial activity.
Embodiment
Illustrate present method by the following example, they limit scope of the present invention never in any form.
The preparation of 1: the first intermediate of embodiment
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 that 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 is 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 (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 that 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 +).
2: the second intermediates 4 of embodiment " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 2 '-O-ethanoyl-Azythromycin dissolving (1.5g, 1.90mmol) in dry toluene (20mL), add triethylamine (0.60mL, 4.33mmol) and 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 that 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 is 912.1 (M+H +).
Embodiment 3: the target product 11, " preparation of mephenesin Carbamate derivative of 12-cyclic carbonate ester-Azithromycin 4
A) 4 " O-propyl group-formamyl-2 '-O-ethanoyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester (target product)
With 4 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11, the 2-cyclic carbonate ester (1.5g 1.65mmol) is dissolved in N; dinethylformamide (DMF) (15mL) in, add DBU (0.33mL, 2.25mmol) and Tri N-Propyl Amine (0.25mL; 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 1.35g, yield 91.0%.Rf is that 0.621 (developping agent is a methylene dichloride: methyl alcohol=10: 1), molecular formula is C 45H 79N 3O 15, molecular weight is 902.0, MS 903.1 (M+H +).
B) 4 " O-benzyl-formamyl-2 '-O-ethanoyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11, the 12-cyclic carbonate ester (1.5g 1.65mmol) is dissolved in N; dinethylformamide (DMF) (15mL) in, add DBU (0.33mL, 2.25mmol) and benzylamine (0.25mL; 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 1.45g, yield 92.5%.R fBe that 0.610 (developping agent is a methylene dichloride: methyl alcohol=10: 1), molecular formula is C 49H 79N 3O 15, molecular weight 950.1, MS 951.1 (M+H +).
C) 4 " O-(2-(3, the 4-methylene dioxy phenyl group) ethyl-formamyl-2 '-O-ethanoyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11; the 12-cyclic carbonate ester (1.5g; 1.65mmol) be dissolved in N; dinethylformamide (DMF) (15mL) in; add DBU (0.33mL; 2.25mmol) and homopiperony lamine (0.22mL, 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 1.53g, yield 92.0%.R fBe that 0.605 (developping agent is a methylene dichloride: methyl alcohol=10: 1), molecular formula is C 51H 81N 3O 17, molecular weight is 1008.2, MS 1009.2 (M+H +).
D) 4 " O-(6-amino hexyl)-formamyl-2 '-O-ethanoyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With hexanediamine (0.35g; 3.00mmol) and DBU (0.33mL; 2.25mmol) be dissolved in N; dinethylformamide (DMF) (15mL); stirring at room, gradation adds 4 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11,12-cyclic carbonate ester (1.33g; 1.50mmol), reaction 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 1.28g, yield 89.9%.R fBe that 0.485 (developping agent is a methylene dichloride: methyl alcohol: triethylamine=20: 100: 1), molecular formula is C 48H 86N 4O 15, molecular weight is 959.2, MS is 960.1 (M+H +).
Other more embodiment can adopt the method identical with embodiment 3, and different is with other aliphatic amide, substituted aroma aliphatic amide, replace the assorted aliphatic amide of virtue replaces embodiment 3a) in propylamine, b) in benzylamine, c) in homopiperony lamine or d) in hexanediamine.
Embodiment 4: slough 2 '-target product 11 of acyl group on the position, " the preparation of mephenesin Carbamate derivative of 12-cyclic carbonate ester-Azithromycin 4
A) 4 " O-propyl group-formamyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester (target product)
With 4 " O-propyl group-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 (1.00g), yield 92.4%.202～205 ℃ of fusing points, R fBe that 0.635 (developping agent is a methylene dichloride: methyl alcohol=5: 1).IR(KBr)：3435，2971，2935，2875，2830，2788，1815，1730，1631，1508，1458，1379，1354，1336，1300，1260，1166，1110，1088，1074，1047，1015cm -1； 1HNMR(600 MHz，CDCl 3，δppm)5.05(d，1H，1′-CH)，4.88(d，1H，1″-CH)，4.83(m，1H，13-CH)，4.56(m，2H，5″-CH，4″-CH)，4.45(m，1H，2′-CH)，4.38(m，2H，5′-CH，11-CH)，3.65(m，1H，3-CH)，3.62(d，1H，10-CH)，3.32(s，3H，3″-OCH 3)，3.16(m，3H，5-CH，3′-CH，2-CH)，2.80(m，2H，4″-OCONHCH 2CH 2CH 3)，2.44(d，1H，9b-CH)，2.38(dd，1H，4-CH)，2.19(s，6H，3″-N(CH 3) 2)，2.05-2.02(m，2H，9a-CH and 2″b-CH)，1.82(s，3H，9a-NCH 3)，1.66(m，2H，8-CH and 4′b-CH)，1.60(m，1H，2″a-CH)，1.57(dd，1H，4′a-CH，)，1.28-1.25(m，7H，4″-OCONHCH 2CH 2CH 3，7b-CH，12-CH 3 and 7a-CH)，1.22-1.20(m，8H，13-CH 2CH 3，5′-CH 3，5″-CH 3)，1.17(s，6H，3″-CH 3，2-CH 3)，1.07-1.06(d，6H，10-CH 3，6-CH 3)，0.93-0.84(m，12H，8-CH 3，4-CH 3，4″-OCONHCH 2CH 2CH 3 and 13-CH 2CH 3)；MS：m/z calcd.for C 43H 77N 3O 14860.1；found(M+1) +961.1.
B) 4 " O-benzyl-formamyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 " O-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 (1.20g), yield 93.0%.202～205 ℃ of fusing points, R fBe that 0.628 (developping agent is a methylene dichloride: methyl alcohol=5: 1); IR (KBr): 3435,2973,2936,2880,2830,2788,1818,1731,1634,1506,1455,1380,1352,1337,1300,1236,1166,1110,1075,1046,1015cm -1 1HNMR (600 MHz, CDCl 3, δ ppm) 7.34 (m, 2H, HAr), 7.28 (m, 3H, HAr), 5.15 (d, 1H, 1 '-CH), 5.09 (d, 1H, 1 " CH), 4.90 (m, 1H, 13-CH), 4.61 (d, 1H, 11-CH), 4.48-4.35 (m, 6H, 4 " CH5 "-CH, 2 '-CH, CH 2Ar, 5 '-CH and 3-CH), 3.61-3.60 (m, 2H, 10-CH, 5-CH), 3.32 (s, 3H, 3 " OCH 3), 2.88 (m, 2H, 2-CH and 3 '-CH), 2.44-2.33 (m, 7H, 3 " N (CH 3) 2, 1H, 9b-CH), 2.20 (s, 3H, 9a-NCH 3), 2.18 (m, 1H, 4-CH), 2.02 (m, 2H, 9a-CH and 2 " b-CH), 1.92 (m, 2H, 8-CH, 2 " a-CH), 1.83 (m, 2H, 4 ' b-CH and 7a-CH), 1.67 (m, 2H, 7b-CH and 4 ' a-CH), 1.62 (m, 2H, 13-CH 2CH 3), 1.45 (s, 3H, 12-CH 3), 1.32 (s, 3H, 3 " CH 3), 1.24 (d, 6H, 2-CH 3And 6-CH 3), 1.18 (m, 6H, 5 '-CH 3And 5 " CH 3), 1.08 (m, 6H, 10-CH 3And 8-CH 3), 0.93 (m, 6H, 4-CH 3And13-CH 2CH 3); MS:m/z calcd.for C 47H 77N 3O 14908.1; Found (M+1) +909.1.
C) 4 " O-(2-(3; the 4-methylene dioxy phenyl group) ethyl-formamyl-Azythromycin 11; preparation of 12-cyclic carbonate ester is with 4, and " (2-(3 for O-; the 4-methylene dioxy phenyl group) ethyl-formamyl-2 '-O-ethanoyl-Azythromycin 11; 12-cyclic carbonate ester (1.35g) is dissolved in the methyl alcohol (15mL); 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 (1.19g), yield 92.0%.202～205 ℃ of fusing points, R fBe that 0.624 (developping agent is a methylene dichloride: methyl alcohol=5: 1).IR(KBr)：3434，2972，2936，2881，2787，1813，1727，1632，1504，1491，1456，1379，1353，1337，1299，1247，1167，1110，1074，1044，1015cm -1； 1HNMR(600MHz，CDCl 3，δppm)6.75(d，1H，HAr)，6.68(s，1H，HAr)，(d，1H，HAr)，6.63(d，1H，O-CH 2-O)，5.07(d，1H，1′-CH)，4.90(dd，1H，1″-CH)，4.57(d，2H，4″-CH，5″-CH)，4.44-4.33(m，4H，13-CH，CH 2CH 2Ar，2′-CH)，3.61(m，1H，5′-CH)，3.51-3.48(m，2H，3-CH，11-CH)，3.39(m，2H，CH 2CH 2Ar)，3.31(s，3H，3″-OCH 3)，2.87(m，1H，10-CH)，2.75(t，2H，3′-CH and 2-CH)，2.44(d，1H，5-CH)，2.38-2.32(m，3H，9b-CH，9a-CH and 2″b-CH)，2.20(s，3H，9a-NCH 3)，2.05-1.83(m，6H，3″-N(CH 3) 2)，1.80(m，1H，8-CH)，1.63(m，7H，2″a-CH，4′b-CH，4′a-CH，7b-CH，7a-CH，13-CH 2CH 3)，1.46(s，3H，6-CH 3，)，1.29(s，3H，2-CH 3)，1.19(m，6H，5″-CH 3，3″-CH 3)，1.17-1.13(m，6H，5′-CH 3，10-CH 3)，1.09-1.05(m，6H，12-CH 3，8-CH 3)，0.94-0.89(m，6H，4-CH 3 and 13-CH 2CH 3)；MS：m/zcalcd.for C 49H 79N 3O 16966.2；found(M+1) +967.1.
D) 4 " O-(the amino hexyl of 6-)-formamyl)-and Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 4 " O-(the amino hexyl of 6-)-formamyl-2 '-O-ethanoyl-Azythromycin 11,12-cyclic carbonate ester (1.28g) 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: triethylamine=100: 10: 1), get white foam shape solid (1.22g), yield 91.5%.Fusing point is 165～168 ℃, R fBe that 0.485 (developping agent is a methylene dichloride: methyl alcohol: triethylamine=20: 100: 1).IR(KBr)：3436，2973，2937，2888，2831，2789，1815，1728，1633，1510，1458，1379，1236，1167，1110，1074，1046，1015cm -1， 1HNMR(600 MHz，CDCl 3，δppm)5.09(d，1H，1′-CH)，4.90(d，1H，1″-CH)，4.89(m，1H，13-CH)，4.57(d，1H，11-CH)，4.45(d，1H，4″-CH)，4.40-4.38(m，3H，5″-CH，2′-CH，5′-CH)，3.65(m，1H，10-CH)，3.62(dd，1H，3-CH)，3.33(s，3H，3″-OCH 3)，3.21(d，3H，5-CH)，3.20(m，2H，-NHCH 2CH 2CH 2 CH 2CH 2 CH 2NH 2)，2.87(m，2H，2-CH and 3′-CH)，2.75(m，2H，-NHCH 2CH 2CH 2 CH 2CH 2CH 2NH 2)，2.44-2.34(m，7H，3″-N(CH 3) 2，9b-CH)，2.20(s，3H，9a-NCH 3)，2.05-1.99(m，4H，4-CH，9a-CH and 2″b-CH，8-CH)，1.92(m，1H，2″a-CH)，1.83(m，2H，4′b-CH and 7a-CH)，1.64(m，2H，7b-CH and 4′a-CH)，1.60(m，2H，13-CH 2CH 3)，1.49(m，4H，-NHCH 2CH 2CH 2CH 2 CH 2CH 2 NH 2)，1.45(s，3H，12-CH 3)，1.34(m，4H，-NHCH 2CH 2CH 2CH 2CH 2CH 2NH 2)，1.30(s，3H，3″-CH 3)，1.22(m，9H，2-CH 3，5′-CH 3 and5″-CH 3)，1.17(s，3H，6-CH 3)，1.07(m，6H，10-CH 3 and 8-CH 3)，0.93(m，6H，4-CH 3 and13-CH 2CH 3)；MS：m/z calcd.for C 44H 86N 4O 13 917.2；found(M+1) +918.1.

Claims (10)

  1. The compound of general formula (I) representative and with the inorganic and pharmaceutically acceptable additive salt of organic acid,
    Figure A2007100150500002C1
    R wherein 1Represent hydrogen, acetyl or benzoyl base, R 2Represent aliphatic group, substituted aroma aliphatic group or replace fragrant heterocycle aliphatic group.
  2. 2. according to the compound of claim 1, it is characterized in that R 2Be benzyl, 4-luorobenzyl, 4-methoxy-benzyl, β-styroyl, 2-chlorobenzene ethyl, 4-leptodactyline, 2-(3, the 4-methylene dioxy phenyl group) ethyl, propyl group, propenyl, butyl, amyl group, sec.-propyl, cyclohexyl, 3-aminopropyl, 6-aminopropyl etc.
  3. 3. the preparation method of the described compound of claim 1, step is as follows:
    (1) with general formula (IV) Azythromycin and acylating reagent: aceticanhydride, acetic acid; Acetyl Chloride 98Min.; benzoyl oxide; phenylformic acid; or Benzoyl chloride, in the presence of inorganic or organic bases, with acetone, ethyl acetate, tetrahydrofuran (THF) or methylene dichloride as solvent; under 0～40 ℃ temperature, react, generate compound with general formula (II).
    Figure A2007100150500002C2
    R wherein 1Represent the acetyl or benzoyl base,
    (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;
    Figure A2007100150500002C3
    R wherein 1Represent the acetyl or benzoyl base,
    (3) compound of above-mentioned general formula (III) and aliphatic amide, substituted aroma aliphatic amide or replace fragrant heterocycle aliphatic amide, at solvent N, react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or their mixed solvent, catalyzer 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU), in 0～65 ℃ of reaction 2～24h, generate the compound of general formula (I);
    (4) as the R of general formula (I) product 1During for the acetyl or benzoyl base, further in the lower alcohols solvent alcoholysis slough 2 '-acyl group protecting group on the position, R 1Compound for the general formula (I) of hydrogen.
  4. 4. as the preparation method of compound as described in the claim 3, it is characterized in that the mol ratio 1: 1～5 of acylating reagent and Azythromycin in the step (1), preferred 1: 3.
  5. 5. as the preparation method of compound as described in the claim 3, it is characterized in that acetylation reagent is an aceticanhydride in the step (1), organic bases is a triethylamine, and solvent is a methylene dichloride.
  6. 6. as the preparation method of compound as described in the claim 3, it is characterized in that step (1) is to react 3～24 hours under 25 ℃ of conditions.
  7. 7. as the preparation method of compound as described in the claim 3, it is characterized in that the product postprocessing method is as follows in the step (1): in alkaline media, pH8.0～10.0 time extraction comes separated product by separating organic layer and solvent evaporated.
  8. 8. as the preparation method of compound as described in the claim 3, it is characterized in that the compound of control general formula (II) in the step (2) and the mol ratio 1: 1～6 of CDI, preferred 1: 4 mol ratio.
  9. 9. as the preparation method of compound as described in the claim 3, it is characterized in that step (2) is to react 2h under 110 ℃ of temperature, inert solvent is selected from methylene dichloride, tetrahydrofuran (THF) or toluene, described mineral alkali is selected from sodium bicarbonate, yellow soda ash or salt of wormwood, and described organic bases is selected from triethylamine, pyridine or 4-Dimethylamino pyridine.
  10. 10. 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.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101423539B (en) * 2008-12-09 2011-04-27 山东大学 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof
CN103130848A (en) * 2013-02-22 2013-06-05 中国人民解放军第二军医大学 Macrolide antibacterial compounds, and preparation method and application thereof
CN103288897A (en) * 2013-06-18 2013-09-11 山东大学 4'-O-(1-aralkyl-1,2,3-triazole-4-methyl-formamyl) azithromycin derivatives
RU2570425C1 (en) * 2014-12-22 2015-12-10 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт по изысканию новых антибиотиков имени Г.Ф. Гаузе" Chimeric antibiotics based on glycopeptides and 11,12-cyclic carbonate azithromycin and method for production thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101423539B (en) * 2008-12-09 2011-04-27 山东大学 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof
CN103130848A (en) * 2013-02-22 2013-06-05 中国人民解放军第二军医大学 Macrolide antibacterial compounds, and preparation method and application thereof
CN103288897A (en) * 2013-06-18 2013-09-11 山东大学 4'-O-(1-aralkyl-1,2,3-triazole-4-methyl-formamyl) azithromycin derivatives
CN103288897B (en) * 2013-06-18 2015-10-21 山东大学 4 "-O-(1-aralkyl-1,2,3-triazole-4-methyl-cabanaoyl) Azithromycin derivative
RU2570425C1 (en) * 2014-12-22 2015-12-10 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт по изысканию новых антибиотиков имени Г.Ф. Гаузе" Chimeric antibiotics based on glycopeptides and 11,12-cyclic carbonate azithromycin and method for production thereof

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