CN101074253A - Macrolide-dimer derivative, its production, and medicinal composition - Google Patents
Macrolide-dimer derivative, its production, and medicinal composition Download PDFInfo
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- CN101074253A CN101074253A CN 200710015051 CN200710015051A CN101074253A CN 101074253 A CN101074253 A CN 101074253A CN 200710015051 CN200710015051 CN 200710015051 CN 200710015051 A CN200710015051 A CN 200710015051A CN 101074253 A CN101074253 A CN 101074253A
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Abstract
A macrolide dimmer derivative with general formula (I), its intermediate and production, medicinal composition and usage are disclosed. A represents fatty hydrocarbon or substituted aromatic fatty hydrocarbon or substituted aromatic heterocyclic fatty hydrocarbon; X1 and X2 represent -C(O)-, -CH2-N(CH3)-, -CH(NH2)- or -CH(NHOH)-; R1 and R2 represent H or C(O)- and -C(O)NH-; R3 and R4 represent H or C(O)- or -C(O)NH-; R5 and R6 represent H or -CH3. It can be used to prepare medicines in treatment of bacterial infections.
Description
Technical field
The present invention relates to macrolide-dimer derivative and preparation thereof, relate in particular to Azythromycin, clarithromycin, erythromycin, erythromycylamine and red mould oxime dimer derivate, 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.With Azythromycin and clarithromycin is that the s-generation macrolide antibiotic of representative has solved this problem, and very big improvement is being arranged aspect drug effect and the pharmacokinetics.Yet, antibiotic being extensive use of, particularly improper use causes drug-resistance of bacteria 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.
The structure principle of hybridization is one of important principles that instructs the medicinal design exploitation.According to this theory, many novel structures, medicine evident in efficacy have been synthesized in design, are put together by acetylsalicylic acid and Paracetamol as Benorilate (antipyretic and analgesic); Sultamicillin (microbiotic) is put together by Ampicillin Trihydrate and Sulbactam.Robert J.Kerns etc. has synthesized a plurality of quinolone dimers, and discovery has certain antimicrobial agent activity (R.J.Kerns, et al.Bioorg.Med.Chem.Lett.13,2003), the structure splicing object of macrolide and quinolone has many pieces of patent reports, this compounds also has better antibacterial activity, referring to WO2004101585, WO2004101587, WO2004101589, WO2006050941, WO2006050942, WO2006050943, WO2006050940 and WO2006050942.
According to known and definite prior art, also there is not disclosure of the Invention mistake up to now from macrolide-dimer derivative, preparation intermediate product and pharmaceutical composition.
Summary of the invention
The invention provides a kind of macrolide-dimer derivative, preparation method and pharmaceutical composition thereof.
The present invention also provides macrolide-dimer derivative to prepare related intermediate product derivative.
The present invention also provides the purposes of the pharmaceutical composition of macrolide-dimer derivative.
One, macrolide-dimer derivative
Macrolide-dimer derivative of the present invention, the pharmaceutically acceptable additive salt that has following general formula (I) and form with inorganic and organic acid:
Wherein, A represents aliphatic group, substituted aroma aliphatic group, replaces fragrant heterocycle aliphatic group;
X
1, X
2Respectively representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-;
R
1, R
2Represent H respectively, or R
1With R
2Together representative-C (O)-,-C (O) NH-;
R
3, R
4Represent H respectively, or R
3With R
4Representative-C (O) NH-together;
R
5, R
6Represent H or-CH
3
The particularly preferred compound of general formula (I) is:
1) 1,3-two (Azythromycin-4 " the O-formyl radical)-propylene diamine;
2) 1,6-two (Azythromycin-4 " the O-formyl radical)-hexanediamine;
3) 1,3-two (11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-propylene diamine;
4) 1,6-two (11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-hexanediamine;
5) 1-(11,12-cyclic carbonate ester Azythromycin-4 " O-formyl radical)-3-(Azythromycin-4 "-O-formyl radical)-propylene diamine;
6) 1-(11,12-cyclic carbonate ester Azythromycin-4 " O-formyl radical)-6-(Azythromycin-4 "-O-formyl radical)-hexanediamine;
7) 1-(11,12-cyclic carbonate ester Azythromycin-4 " O-formyl radical)-3-(Azythromycin-4 "-O-formyl radical)-propylene diamine;
8) 1-(Azythromycin-4 " O-formyl radical)-3-(erythromycin-4 "-O-formyl radical)-propylene diamine.
Two, macrolide-dimer derivative prepares used intermediate
Intermediate 1 has following general formula (II):
Among the formula II, X
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3
Intermediate 2 has following general formula (III):
X in the formula III
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Together representative-C (O)-,-C (O) NH-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3
Intermediate 3 has following general formula (IV):
A represents aliphatic group, substituted aroma aliphatic group, replaces fragrant heterocycle aliphatic group among the formula IV; X
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Together representative-C (O)-,-C (O) NH-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3
Three, the preparation method of macrolide-dimer derivative
The preparation method of macrolide-dimer derivative of the present invention, step is as follows:
With 2 of the compound of following logical formula V representative '-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 as solvent, under 0～40 ℃ temperature, react, generate compound with above-mentioned general formula (II).
X among the formula V
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-or-CH (NHOH)-; R
8Represent H or-CH
3
2. with the compound and the N of general formula (II), N '-dicarbapentaborane imidazoles (CDI) in the presence of inorganic or organic bases, in 30～110 ℃ of reaction 2～24h, generates the compound with general formula (III) in inert solvent.
3. the product and the aliphatic diamine of above-mentioned general formula (III), at N, react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or the blended solvent, or add catalyzer 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU), in 0～65 ℃ of reaction 2～24h; Generate the compound of general formula (IV);
4. the product of the product of above-mentioned general formula (IV) and general formula (III) is at N; react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or the blended solvent; or adding catalyzer 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU); in 0～65 ℃ of reaction 2～24h; products therefrom further in the lower alcohols solvent alcoholysis slough 2 '-acyl group on the position, produce the compound of general formula (I).
Preferably, the mol ratio 1: 1～5 of acetylation reagent and logical formula V compound in the above-mentioned steps 1, preferred 1: 3.
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.
Above-mentioned steps 1 was preferably reacted 3～24 hours at 25 ℃.
Preferably, the product postprocessing method is as follows in the above-mentioned steps 1: in alkaline medium, the preferably time extraction in pH8.0～10.0 comes separated product by separating organic layer and solvent evaporated.In case of necessity, use the silica gel column chromatography of methylene chloride-methanol (20: 1) system to carry out purifying, can produce the compound of chromatogram homogeneous general formula (II).
Preferably, control the compound of general formula (II) and the mole 1: 1～6 of CDI (N, N '-dicarbapentaborane imidazoles) in the above-mentioned steps 2, preferred 1: 4 mol ratio.
In the above-mentioned steps 2: preferred 55 ℃ are reacted 12h, can produce the compound of general formula (III).
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 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.Preferred organic alkali triethylamine.
The preferred N of reaction solvent described in the above-mentioned steps 3, dinethylformamide.
Lower alcohols solvent particular methanol described 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 purpose 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
The pharmaceutical composition of macrolide-dimer derivative of the present invention, said composition comprise 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 the chemical compound conversion of corresponding general formula (I) representative.
Five, use
The pharmaceutical composition of macrolide-dimer derivative is used to prepare the pharmaceutical use of bacterial-infection resisting.
Embodiment
Illustrate present method by the following example, they limit scope of the present invention never in any form.
Embodiment 1: the preparation of intermediate 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 that 0.522 (developping agent is a methylene dichloride: methyl alcohol=10: 1).MF 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 solution (15mL), stir 20min, standing demix, organic layer is water and salt water washing respectively, anhydrous Na
2SO
4Drying, 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, filters, the normal hexane washing, vacuum-drying gets 1.65g, yield 87.1%.
Other more embodiment can adopt the method identical with embodiment 1, but with logical formula V (X wherein
1, X
2Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-; R
8Represent H or-CH
3) other compound of representative, replace the Azythromycin among the embodiment 1.
Embodiment 2: the preparation of intermediate 2
A) 4 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin 11, the preparation of 12-cyclic carbonate ester
With 2 '-O-ethanoyl-Azythromycin (1.5g 1.90mmol) is dissolved in dry toluene (20mL), add triethylamine (0.60mL, 4.33mmol) and CDI (N, N '-dicarbapentaborane imidazoles) (1.23g, 7.6mmol), in 110 ℃ of stirring 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).MF is C
45H
74N
4O
15, molecular weight is 911.1, MS is 912.1 (M+H
+).
B) 4 " preparation of O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin
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) (0.672g, 3.80mmol), stirring at room 48h.After reaction finishes, add saturated sodium bicarbonate solution (20mL), separatory, toluene extraction (6mL * 2) merges organic layer, anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure gets white foam shape solid 1.6g, yield 95.4%.147～150 ℃ of fusing points, R
fBe that 0.592 (developping agent is a methylene dichloride: methyl alcohol=10: 1).Molecular formula is C
44H
76N
4O
14, molecular weight is 884.5, MS is 885.5 (M+H
+).
Other more embodiment can adopt the method identical with embodiment 2, but with general formula (II) (X wherein
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3) other compound of representative replaces 2 among the embodiment 2 '-O-ethanoyl-Azythromycin.
Embodiment 3: the preparation of intermediate 3
4 " O-(3-aminopropyl)-formamyl-2 '-preparation of O-ethanoyl-Azythromycin
With propylene diamine (0.22mL, 3.00mmol) and DBU (0.33mL 2.25mmol) is dissolved in DMF (15mL), and stirring at room, gradation adds 4 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin (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 1.22g, yield 91.0%.153～156 ℃ of fusing points, R
fBe that 0.565 (developping agent is a methylene dichloride: methyl alcohol: triethylamine=20: 100: 1).Molecular formula is C
44H
82N
4O
14, molecular weight is 891.1, MS is 892.0 (M+H
+).
Other more embodiment can adopt the method identical with above embodiment 3, but with other aliphatic diamine, replace the propylene diamine among the embodiment 3; With general formula (III) (X wherein
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Represent together C (O)-,-C (O) NH-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3) other compound of representative replace 4 among the embodiment 3 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin.
Embodiment 4: target product 1, the preparation of 3-two (Azythromycin-4 " O-formyl radical)-propylene diamine
With 4 " O-(3-aminopropyl)-formamyl-2 '-O-ethanoyl-Azythromycin (1.22g; 1.37mmol) be dissolved in N; dinethylformamide (DMF) is (20mL); adding DBU (0.45mL; 3.08mmol) with 4 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin (1.73g; 2.05mmol), stirring at room 24h.After reaction finishes, add entry (45mL), ethyl acetate (20mL * 3) extraction merges organic layer, saturated aqueous common salt (20mL * 3) washing, and anhydrous sodium sulfate drying, evaporated under reduced pressure gets white solid foam.This solid 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 (1.45g) yield 65.2%.Fusing point is 167～169 ℃, R
f=0.611 (developping agent is a methylene dichloride: methyl alcohol: triethylamine=20: 100: 1).Molecular formula is C
81H
150N
6O
26, molecular weight is 1624.1, MS is 1625.2 (M+H
+).IR(KBr)：3435，2972，2937，2877，2831，1726，1632，1509，1458，1379，257，1169，1109，1094，1073，1045，1014cm
-1；
1HNMR(600MHz，CDCl
3，δppm)5.13(d，2H，1′-CH)，4.75(d，2H，1″-CH)，4.56(m，2H，13-CH)，4.53(d，2H，11-CH)，4.46(d，2H，4″-CH)，4.35-4.28(m，6H，5″-CH，2′-CH，5′-CH)，3.75(m，2H，10-CH)，3.65(dd，2H，3-CH)，3.34(s，6H，3″-OCH
3)，3.26(m，6H，5-CH，-NHCH
2CH
2CH
2NH-)，2.80(m，4H，2-CH?and?3′-CH)，2.42-2.39(m，14H，″-N(CH
3)
2，9b-CH)，2.37(s，6H，9a-NCH
3)，2.05-2.00(m，8H，4-CH，9a-CH，2″b-CH?and8-CH)，1.92(m，2H，-NHCH
2CH
2CH
2NH-)，1.85(m，2H，2″a-CH)，1.82(m，4H，4′b-CH?and7a-CH)，1.67-1.64(m，8H，7b-CH?and?4′a-CH，13-CH
2CH
3)，1.45(s，6H，12-CH
3)，1.32(s，6H，3″-CH
3)，1.23-1.20(m，18H，2-CH
3，5′-CH
3?and?5″-CH
3)，1.17(s，6H，6-CH
3)，1.10(m，12H，10-CH
3?and?8-CH
3)，0.93(m，12H，4-CH
3?and?13-CH
2CH
3)；MS：m/z?calcd.for?C
81H
150N
6O
261624.1；found(M+1)
+1625.9。
Adopt the method identical, but (wherein A represents aliphatic group, substituted aroma aliphatic group, the fragrant heterocycle aliphatic group of replacement with general formula (N) with embodiment 4; X
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Represent together C (O)-,-C (O) NH-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3) other compound of representative replace 4 among the embodiment 4 " O-(3-aminopropyl)-formamyl-2 '-O-ethanoyl-Azythromycin; With general formula (III) (X wherein
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Represent together C (O)-,-C (O) NH-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3) other compound of representative replace 4 among the embodiment 3 " O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-Azythromycin.Can prepare following target product respectively:
1,6-two (Azythromycin-4 " the O-formyl radical)-hexanediamine; 1,3-two (11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-propylene diamine; 1,6-two (11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-hexanediamine; 1-(11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-3-(Azythromycin-4 "-the O-formyl radical)-propylene diamine; 1-(11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-6-(Azythromycin-4 "-the O-formyl radical)-hexanediamine; 1-(11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-3-(Azythromycin-4 "-the O-formyl radical)-propylene diamine; 1-(Azythromycin-4 " the O-formyl radical)-3-(erythromycin-4 "-the O-formyl radical)-propylene diamine.
Claims (10)
1. the compound of general formula (I)
And the pharmaceutically acceptable additive salt that forms with inorganic and organic acid, wherein, A represent aliphatic group, substituted aroma aliphatic group, the fragrant heterocycle aliphatic group of replacement; X
1, X
2Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-, or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Represent together C (O)-,-C (O) NH-; R
3, R
4Represent H, or R
3With R
4With represent C (O)-,-C (O) NH-; R
5, R
6Represent H or-CH
3
2. compound according to claim 1 is characterized in that, is following compound:
1) 1,3-two (Azythromycin-4 " the O-formyl radical)-propylene diamine;
2) 1,6-two (Azythromycin-4 " the O-formyl radical)-hexanediamine;
3) 1,3-two (11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-propylene diamine;
4) 1,6-two (11,12-cyclic carbonate ester Azythromycin-4 " the O-formyl radical)-hexanediamine;
5) 1-(11,12-cyclic carbonate ester Azythromycin-4 " O-formyl radical)-3-(Azythromycin-4 "-O-formyl radical)-propylene diamine;
6) 1-(11,12-cyclic carbonate ester Azythromycin-4 " O-formyl radical)-6-(Azythromycin-4 "-O-formyl radical)-hexanediamine;
7) 1-(11,12-cyclic carbonate ester Azythromycin-4 " O-formyl radical)-3-(Azythromycin-4 "-O-formyl radical)-propylene diamine;
8) 1-(Azythromycin-4 " O-formyl radical)-3-(erythromycin-4 "-O-formyl radical)-propylene diamine.
3. the preparation method of the described compound of claim 1, step is as follows:
(1) with 2 of the compound of following logical formula V representative '-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 as solvent, under 0～40 ℃ temperature, react; generation has the compound of general formula (II)
X in the formula V
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-or-CH (NHOH)-; R
8Represent H or-CH
3
X in the formula (II)
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-or-CH (NHOH)-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3
(2) with the compound and the N of above-mentioned general formula (II), N '-dicarbapentaborane imidazoles (CDI) in the presence of inorganic or organic bases, in 30～110 ℃ of reaction 2～24h, generates the compound with general formula (III) in inert solvent:
X in the formula (III)
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Together representative-C (O)-,-C (O) NH-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3
(3) product and the aliphatic diamine of above-mentioned general formula (III), at N, react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or the blended solvent, or add catalyzer 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU), in 0～65 ℃ of reaction 2～24h; Generate the compound of general formula (IV);
A represents aliphatic group, substituted aroma aliphatic group, replaces fragrant heterocycle aliphatic group among the formula IV; X
1Representative-C (O)-,-CH
2-N (CH
3)-,-CH (NH
2)-or-CH (NHOH)-; R
1, R
2Represent H, or R
1With R
2Together representative-C (O)-,-C (O) NH-; R
7Represent the acetyl or benzoyl base; R
8Represent H or-CH
3
(4) product of the product of above-mentioned general formula (IV) and general formula (III) is at N; react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile, acetonitrile-water or the blended solvent; or adding catalyzer 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU); in 0～65 ℃ of reaction 2～24h; products therefrom further in the lower alcohols solvent alcoholysis slough 2 '-acyl group on the position, produce the compound of general formula (I).
4. the preparation method of compound as claimed in claim 1 is characterized in that the mol ratio 1: 1～5 of acetylation reagent and logical formula V compound in the step (1), preferred 1: 3.
5. the preparation method of compound as claimed in claim 1 is characterized in that acetylation reagent is an aceticanhydride in the step (1); Organic bases is a triethylamine; Solvent is a methylene dichloride; Reacted 3～24 hours at 25 ℃.
6. the preparation method of compound as claimed in claim 1, it is characterized in that the product postprocessing method is as follows in the step (1): in alkaline medium, pH8.0～10.0 time extraction, come separated product by separating organic layer and solvent evaporated, in case of necessity, use the silica gel column chromatography of methylene chloride-methanol (20: 1) system to carry out purifying, can produce the compound of chromatogram homogeneous general formula (II).
7. the preparation method of compound as claimed in claim 1 is characterized in that the mol ratio 1: 1～6 of the compound and the CDI of step (2) formula of (II), preferred 1: 4 mol ratio.
8. the preparation method of compound as claimed in claim 1 is characterized in that inert solvent is selected from methylene dichloride, tetrahydrofuran (THF) or toluene in the step (2), preferred toluene.
9. the preparation method of compound as claimed in claim 1, it is characterized in that the mineral alkali described in the step (2) is selected from sodium bicarbonate, yellow soda ash or salt of wormwood, described organic bases is selected from triethylamine, pyridine or 4-Dimethylamino pyridine, preferred organic alkali triethylamine.
10. the pharmaceutical composition that is used for the treatment of infectation of bacteria in human body and the animal comprises on the compound of general formula (I) of the claim 1 of antimicrobial effective amount or its medicine and can accept additive salt and pharmaceutically acceptable carrier.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710015051 CN101074253A (en) | 2007-06-22 | 2007-06-22 | Macrolide-dimer derivative, its production, and medicinal composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200710015051 CN101074253A (en) | 2007-06-22 | 2007-06-22 | Macrolide-dimer derivative, its production, and medicinal composition |
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| CN101074253A true CN101074253A (en) | 2007-11-21 |
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| CN 200710015051 Pending CN101074253A (en) | 2007-06-22 | 2007-06-22 | Macrolide-dimer derivative, its production, and medicinal composition |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101597311A (en) * | 2009-07-02 | 2009-12-09 | 沈阳药科大学 | Erythromycin derivatives and uses thereof |
| 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 |
-
2007
- 2007-06-22 CN CN 200710015051 patent/CN101074253A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101597311A (en) * | 2009-07-02 | 2009-12-09 | 沈阳药科大学 | Erythromycin derivatives and uses thereof |
| CN101597311B (en) * | 2009-07-02 | 2014-05-21 | 沈阳药科大学 | Erythromycin derivative and application thereof |
| 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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