CN103319553A - Method for preparing 3'-N-demethylazithromycin - Google Patents
Method for preparing 3'-N-demethylazithromycin Download PDFInfo
- Publication number
- CN103319553A CN103319553A CN201310236710XA CN201310236710A CN103319553A CN 103319553 A CN103319553 A CN 103319553A CN 201310236710X A CN201310236710X A CN 201310236710XA CN 201310236710 A CN201310236710 A CN 201310236710A CN 103319553 A CN103319553 A CN 103319553A
- Authority
- CN
- China
- Prior art keywords
- azythromycin
- oxide compound
- demethyl
- reaction
- solution
- 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
Images
Abstract
The invention relates to a method for preparing 3'-N-demethylazithromycin, and belongs to the technical field of organic synthesis. The method comprises the following steps: dissolving azithromycin into a methanol solution; adding an oxidant solution, agitating until reaction is ended, and drying to obtain a crude product of 3'-N-azithromycin oxide; re-crystallizing the coarse product to obtain 3'-N-azithromycin oxide after dissolving by an acetone solution; dissolving the coarse product or the 3'-N-azithromycin oxide into an organic solvent, so that the concentration is 0.033 mol/L; then adding a hydrochloric acid water solution of a reducing agent, agitating for reaction, and filtering insoluble substances to obtain solution after the reaction is ended; adjusting the pH value of the solution to 10 by using an alkali liquor, then extracting by an extracting solvent, mixing with an organic phase, and drying to obtain the 3'-N-demethylazithromycin. By adopting the method, a reaction reagent is non-toxic; ultraviolet irradiation is not needed; the product purity is improved; the reducing agent can be filtered and separated; the reaction is simple and convenient; the reducing agent is fast in reaction and high in yield when being used as ferrous sulfate.
Description
Technical field
The present invention relates to a kind of method for preparing 3 '-N-demethyl Azythromycin, specifically, described 3 '-N-demethyl Azythromycin is the 3 '-N-demethylation compound in a kind of Azythromycin impurity correlative, belongs to technical field of organic synthesis.
Background technology
Azythromycin (Azithromycin) is as s-generation macrolide antibiotics, it is first semi-synthetic azepine fifteen-membered ring macrolide antibiotic, compare with erythromycin, Azythromycin has kept the advantage of erythromycin, and antimicrobial spectrum further enlarges, and is outstanding and tissue concentration is high to the anti-microbial effect of chlamydia trachomatis, streptococcus pneumoniae.Azythromycin is very powerful and exceedingly arrogant kind on international antibiotic medicine market owing to having the advantages such as long half time, administration number of times is few, the course for the treatment of is shorter, adverse reaction rate is low always.Now, Azythromycin is proposed as the medicine that infects for the caused respiratory tract of sensitive bacterial, urogenital tract, skin and soft tissue etc., and in sexually transmitted disease (STD) sickness rate more and more higher today, also just meaning has more wide market outlook.Simultaneously, this medicine is put into " the basic medicine register of country " and " basic medical insurance medicine register ".China produces Azythromycin per year near 2000 tons, is one of country of in the world Azythromycin turnout maximum.
In recent years, along with popularizing and increase that China's scientific research drops into of New Instruments etc., the raising work of China's pharmaceutical standards is also more and more deep.The raising of pharmacopeia Chinese traditional medicine standard not only directly standard standard and the safe medication of the medicines such as bulk drug, injection itself, and has indirectly directive function for the production of medicine, for superseded old technique, the promotion technology improves and process modification has immeasurable meaning." standard of Azythromycin also is improved in the Chinese pharmacopoeia 2010 editions, except adopting HPLC method detection of drugs, also stipulated 5 kinds of impurity correlatives: Erythromycin A iminoether, 3 '-N-demethyl Azythromycin, 3-O-remove cladinose Azythromycin, Azythromycin impurity Gx and Azythromycin B.With the regulation of European Pharmacopoeia and USP standard 16 kinds of relevant phases of impurity relatively, China's standards of pharmacopoeia still has much room for improvement, particularly the preparation of impurity correlative should become the basis that standards of pharmacopoeia improves.Wherein, 3 '-N-demethyl Azythromycin is not only a kind of of impurity correlative, or the precursor compound of other several impurity correlatives.
The chemistry of 3 '-N-demethyl Azythromycin is called 3 '-N-demethyl-9A-methyl-9-deoxidation-same Erythromycin A of 9A-azepine-9A-, and structural formula is as shown in the formula shown in the I:
3 '-N-demethyl Azythromycin mainly is to take off a methyl by the dimethyl on the desosamine of Azythromycin to obtain.When the Azythromycin long-term storage, if envrionment temperature is higher, the existence of more 3 '-N-demethyl Azythromycin will appear.In addition, 3 '-N-demethyl Azythromycin also can be by the 3 '-N-demethyl Erythromycin A in the raw material of preparation during Azythromycin through oximate, rearrangement, reduce and the reaction generation and being present in the Azythromycin such as methylate.
At patent US2007043214A1, the method for the preparation 3 ' of having reported among WO2004092736A2 and the WO9426758-N-demethyl Azythromycin all be by Azythromycin under the irradiation (a) of UV-light, at sodium acetate trihydrate (NaOAc3H
2O) under the existence, by iodine (I
2) adding carry out demethylation reaction and obtain 3 '-N-demethyl Azythromycin, shown in the response path of following formula II:
Described method defective is as follows: productive rate is lower, is approximately 45%; The demethylation reagent iodine that uses is toxic reagent; Adopt UV-irradiation in the reaction, the operator has the danger that is exposed to the open air under ultraviolet lighting; Process is comparatively loaded down with trivial details.
Summary of the invention
For the defective for preparing the existence of 3 '-N-demethyl Azythromycin method in the prior art, the object of the present invention is to provide a kind of method for preparing 3 '-N-demethyl Azythromycin, described method mainly utilizes oxidation-reduction reaction to finish, described method is used non-toxic agent, reduce the danger of ultraviolet radiation, be convenient to industrial scale amplification and yield higher.
Purpose of the present invention mainly realizes by following technique means.
A kind of method for preparing 3 '-N-demethyl Azythromycin, described method steps is as follows:
(1) oxidation Azythromycin
Azythromycin is dissolved in the methanol solution, adds oxidizing agent solution, be stirred to reaction and finish, drying obtains 3 '-N-Azythromycin oxide compound crude product.
Wherein, described methanol solution is that percent by volume is 80% methanol solution, and namely the volume ratio of methyl alcohol and water is 80:20.
The mass percent of oxidizing agent solution is 1%～10%, and namely the mass ratio of oxygenant and water is 1～10:90～99, and the mass percent of oxidizing agent solution is preferably 3%; Oxygenant is hydrogen peroxide (H
2O
2), potassium permanganate or potassium bichromate, because it is higher than the yield of potassium permanganate or potassium dichromate oxidation acquisition 3 '-N-Azythromycin oxide compound crude product that hydrogen peroxide oxidation obtains the yield of 3 '-N-Azythromycin oxide compound crude product, so oxygenant is preferably hydrogen peroxide; Oxygenant is 1～2:1 with the ratio of the amount of substance of Azythromycin, is preferably 1.5:1.
Temperature of reaction is 0 ℃～60 ℃, is preferably 20 ℃.
3 '-N-Azythromycin oxide compound crude product is for containing 3 '-N-Azythromycin oxide compound of 3 '-N-azithromycin oxide compound; The concentration that proceeds to 3 '-N-Azythromycin oxide compound when reaction does not increase, and can think that reaction finishes; Can adopt the rp-hplc analysis method to judge that the change in concentration of 3 '-N-Azythromycin oxide compound is to determine reaction end.
Reaction times is preferably 2h～72h, more preferably 24h.
3 '-N-Azythromycin oxide compound crude product can adopt the method for recrystallization to obtain 3 '-N-Azythromycin oxide compound of purity 〉=90%, and described recrystallization can adopt following method to carry out:
With acetone soln dissolving 3 '-N-Azythromycin oxide compound crude product, recrystallization obtains 3 '-N-Azythromycin oxide compound of white; The volume ratio of acetone and water is 2:1 in the acetone soln.
(2) reduction 3 '-N-Azythromycin oxide compound
3 '-N-Azythromycin oxide compound of 3 '-N-Azythromycin oxide compound crude product or recrystallization acquisition is dissolved in the organic solvent, making the concentration of 3 '-N-Azythromycin oxide compound of 3 '-N-Azythromycin oxide compound crude product or recrystallization acquisition is 0.033mol/L, then the aqueous hydrochloric acid that adds reductive agent, stirring reaction, remove by filter insolubles after reaction finishes and obtain solution, pH value with the alkali lye regulator solution is 10, then extract with extraction solvent, merge the organic phase that extraction obtains, dry, get 3 '-N-demethyl Azythromycin, the purity to 30% of described 3 '-N-demethyl Azythromycin～80%.
Wherein, step (1) is preferably used 3 '-N-Azythromycin oxide compound that recrystallization obtains.
Organic solvent is acetone, methyl alcohol, ethanol, Virahol, dimethyl formamide or methyl-sulphoxide; Be preferably acetone.
Reductive agent is ferrous sulfate, ferrous ammonium sulphate, S-WAT or sodium bisulfite, is preferably ferrous sulfate; The molar ratio of reductive agent and Azythromycin oxide compound is 2:1～6, is preferably 1:2; The pH value of reductive agent aqueous hydrochloric acid is 1～6, is preferably 3.
Temperature of reaction is 0 ℃～70 ℃, is preferably 20 ℃.
The concentration that proceeds to 3 '-N-demethyl Azythromycin when reaction does not increase, and can think that reaction finishes, and can adopt the rp-hplc analysis method to judge that the change in concentration situation of 3 '-N-demethyl Azythromycin is to confirm reaction end.
Reaction times is preferably 0.5h～4h, more preferably 2h.
Alkali lye is aqueous sodium hydroxide solution or ammoniacal liquor, is preferably the 2mol/L aqueous sodium hydroxide solution.
Extraction solvent is sherwood oil, ethyl acetate, methylene dichloride or chloroform, is preferably methylene dichloride.
Reaction principle
The invention provides a kind of method for preparing 3 '-N-demethyl Azythromycin, described method is oxidized to Azythromycin first 3 '-N-Azythromycin oxide compound crude product, then 3 '-N-Azythromycin oxide compound crude product is reduced, obtain 3 '-N-demethyl Azythromycin.The present invention obtains the oxide compound of tertiary amine compound by the tertiary amine of 3 '-N of the suitable oxygenant oxidation Azythromycin of employing; Adopt suitable reductive agent that a methyl on the tertiary amine is sloughed in proportion, obtain the product secondary amine of tertiary amine demethyl.According to above-mentioned reaction mechanism, polarize between the nitrogen-oxygen bond on the Azythromycin desosamine on the oxide compound of 3 '-N of dimethylamino, because electronegative difference, because negative charge on the polarized action band, and nitrogen-atoms loses corresponding electronics and the lotus that becomes positively charged on the electrophilic Sauerstoffatom; Under acidic conditions, hydrogen proton in the solution is combined with the oxygen with negative charge, then loses an electronics with the reductive agent reaction, and nitrogen-oxygen bond obtains an electronics and disconnects, hydrogen ion in hydroxide ion and the solution generates a part water, and tertiary amino oxides is reduced to tertiary amine; Simultaneously, the carbon atom of nitrogen-atoms and methyl forms two keys, and owing to the effect of reductive agent, methylene radical and a molecular water effect make the tertiary amine demethylating and generate secondary amine under acidic conditions.
Beneficial effect
1. reaction reagent is nontoxic, and pollutes little;
2. reaction needn't be adopted ultraviolet lighting;
3. the purity of product improves, and is higher than 30%;
4. the separation of reductive agent can be accomplished by filtration;
5. reaction process is comparatively easy;
6. reaction was carried out soon when reductive agent was ferrous sulfate, and 3 '-N-demethyl potency of azithromycin is apparently higher than using other reductive agents in the product.
Description of drawings
Fig. 1 is the HPLC analysis chart of 3 '-N-Azythromycin oxide compound among the embodiment 4.
Fig. 2 is the 3 '-N-demethyl Azythromycin HPLC analysis chart among the embodiment 13.
Embodiment
In order to further specify details of the present invention, the below enumerates preferred embodiment.
3 '-N-demethyl Azythromycin that 3 '-N-Azythromycin oxide compound that embodiment 1～11 makes and embodiment 12～32 make adopts Azythromycin detection method in 2010 editions Chinese Pharmacopoeias, concrete detection method is as follows: use UC-3010 high performance liquid chromatograph (Beijing Qin Fang Science and Technology Ltd.) and Duracell C18 chromatographic column (4.6x250mm, Tianjin Ai Jieer Science and Technology Ltd.), at 20 ℃, employing moving phase is phosphoric acid salt (0.02mol/L dipotassium hydrogen phosphate solution, transferring pH with phosphoric acid is 8.2)/acetonitrile=55/45(volume ratio), use UV-detector to detect at 210nm.Qualitative employing reference material adds and relative retention time is carried out qualitative.
The product purity that makes among the embodiment adopts normalization method to measure; Adopt calibration curve method to carry out quantitatively.
Embodiment 1
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 3% H at 20 ℃ of lower 18ml mass percents that slowly drip then
2O
2Solution, stirring reaction 20h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, and drying obtains 3 ' of 6.97g-N-Azythromycin oxide compound, and yield is 91.1%, and purity is 98%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, only have retention time 4min place that one chromatographic peak is arranged in the color atlas, be shown as 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 98%.
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 1% H at 20 ℃ of lower 54ml mass percents that slowly drip then
2O
2Solution, stirring reaction 20h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, the dry 3 '-N-Azythromycin oxide compound that gets 5.64g, and yield is 73.7%, purity is 98%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, only have retention time 4min place that one chromatographic peak is arranged in the color atlas, be shown as 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 98%.
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 10% H at 20 ℃ of lower 5.4ml mass percents that slowly drip then
2O
2Solution, stirring reaction 20h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, the dry 3 '-N-Azythromycin oxide compound that gets 7.12g, and yield is 93.1%, purity is 90%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, and two chromatographic peaks of with a hook at the end in the color atlas time 2.1min and 4min, the chromatographic peak of retention time 4min are 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 90%.
Embodiment 4
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 3% H at 60 ℃ of lower 18ml mass percents that slowly drip then
2O
2Solution, stirring reaction 20h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, the dry 3 '-N-Azythromycin oxide compound that gets 7.02g, and yield is 91.8%, purity is 82%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, and two chromatographic peaks of with a hook at the end in the color atlas time 2.1min and 4min, the chromatographic peak of retention time 4min are 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 82%.
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 3% H at 20 ℃ of lower 18ml mass percents that slowly drip then
2O
2Solution, stirring reaction 72h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, the dry 3 '-N-Azythromycin oxide compound that gets 5.74g, and yield is 75.0%, purity is 91%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, and two chromatographic peaks of with a hook at the end in the color atlas time 2.1min and 4min, the chromatographic peak of retention time 4min are 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 91%.
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 3% H at 20 ℃ of lower 12ml mass percents that slowly drip then
2O
2Solution, stirring reaction 20h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, and drying obtains 3 ' of 6.03g-N-Azythromycin oxide compound, and yield is 78.8%, and purity is 95%.
The 3 '-N-Azythromycin oxide compound that makes being detected through described reversed-phased high performace liquid chromatographic, only have retention time 4min place that one chromatographic peak is arranged in the color atlas, is 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 95%.
Embodiment 7
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 3% H at 20 ℃ of lower 24ml mass percents that slowly drip then
2O
2Solution, stirring reaction 20h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, and drying obtains 3 ' of 6.41g-N-Azythromycin oxide compound, and yield is 83.8%, and purity is 89%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, and two chromatographic peaks of with a hook at the end in the color atlas time 2.1min and 4min, the chromatographic peak of retention time 4min are 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 89%.
Embodiment 8
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 3% H at 0 ℃ of lower 18ml mass percent that slowly drips then
2O
2Solution, stirring reaction 20h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, and drying obtains 3 ' of 6.25g-N-Azythromycin oxide compound, and yield is 81.7%, and purity is 98%.
The 3 '-N-Azythromycin oxide compound that makes being detected through described reversed-phased high performace liquid chromatographic, only have retention time 4min place that one chromatographic peak is arranged in the color atlas, is 3 '-N-Azythromycin oxide compound; Getting its percentage composition according to normalization method is 98%.
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, is 3% H at 20 ℃ of lower 18ml mass percents that slowly drip then
2O
2Solution, stirring reaction 2h adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, and reaction finishes, and steams solvent with Rotary Evaporators, and obtaining white solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2:1 in the acetone soln, and drying obtains 3 ' of 6.78g-N-Azythromycin oxide compound, and yield is 88.6%, and purity is 42%.
The 3 '-N-Azythromycin oxide compound that makes being detected through described reversed-phased high performace liquid chromatographic, except retention time 4min place one chromatographic peak is arranged in the color atlas, is outside 3 '-N-Azythromycin oxide compound, also has unreacted raw material Azythromycin; Getting its percentage composition according to normalization method is 42%.
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, then be 5% potassium permanganate solution at 20 ℃ of lower 30ml mass percents that slowly drip, stirring reaction 20h, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction finishes, steam solvent with Rotary Evaporators, obtaining solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2: 1 in the acetone soln, and drying obtains 3 ' of 3.25g-N-Azythromycin oxide compound, and yield is 42.5%, and purity is 76%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 4min place in the color atlas, is outside 3 '-N-Azythromycin oxide compound, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 76%.
Embodiment 11
It is in 80% the methanol solution that the 7.49g Azythromycin is dissolved in the 200ml percent by volume, then be 9% potassium dichromate aqueous solution at 20 ℃ of lower 30ml mass percents that slowly drip, stirring reaction 20h, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction finishes, steam solvent with Rotary Evaporators, obtaining solid is Azythromycin oxide compound crude product.With Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, the volume of acetone and water is 2: 1 in the acetone soln, and drying obtains 3 ' of 2.97g-N-Azythromycin oxide compound, and yield is 38.9%, and purity is 83%.
The 3 '-N-Azythromycin oxide compound that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 4min place in the color atlas, is outside 3 '-N-Azythromycin oxide compound, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 83%.
Embodiment 12
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, and then adding with the pH value is the ferrous sulfate (FeSO of 3 23mg
4) aqueous hydrochloric acid 2.0ml, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopts the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, and reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then sodium hydroxide (NaOH) aqueous solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.21g, are 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 75%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 75%.
Embodiment 13
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml methyl alcohol, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 58%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 58%.
Embodiment 14
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml ethanol, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.21g, are 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 52%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 52%.
Embodiment 15
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml Virahol, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.19g, are 3 '-N-demethyl Azythromycin, yield is 86%, and purity is 41%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 41%.
Embodiment 16
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml dimethyl formamide, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.14g, are 3 '-N-demethyl Azythromycin, yield is 63%, and purity is 54%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 54%.
Embodiment 17
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml methyl-sulphoxide, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.17g, are 3 '-N-demethyl Azythromycin, yield is 77%, and purity is 48%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 48%.
Embodiment 18
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 15mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 63%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 63%.
Embodiment 19
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 91mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.21g, are 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 59%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 59%.
Embodiment 20
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous ammonium sulphate aqueous hydrochloric acid 2.0ml of 3 59mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 32%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 32%.
Embodiment 21
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the S-WAT aqueous hydrochloric acid 2.0ml of 3 20mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.21g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 55%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 55%.
Embodiment 22
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the sodium bisulfite aqueous hydrochloric acid 2.0ml of 3 16mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.21g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 64%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 64%.
Embodiment 23
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 1 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.21g, are 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 69%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 69%.
Embodiment 24
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 6 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 67%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 67%.
Embodiment 25
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 0 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 45%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 45%.
Embodiment 26
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 70 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.21g, are 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 31%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 31%.
Embodiment 27
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 0.5h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 34%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 34%.
Embodiment 28
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 4h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 47%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 47%.
Embodiment 29
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then add 5%(quality percentage composition) ammonia soln regulator solution pH value to 10, then divide 2 extractions with methylene dichloride, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 51%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 51%.
Embodiment 30
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with chloroform, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.20g, are 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 74%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 74%.
Embodiment 31
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with ethyl acetate, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.19g, are 3 '-N-demethyl Azythromycin, yield is 86%, and purity is 76%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 76%.
Embodiment 32
The 3 '-N-Azythromycin oxide compound 0.23g that makes among the embodiment 1 is dissolved in the 9ml acetone, then add the pH value and be the ferrous sulfate aqueous hydrochloric acid 2.0ml of 3 23mg, at 20 ℃ of stirring reaction 2h, solution colour becomes sorrel by light green, adopt the rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction finishes; Remove insolubles with filter paper filtering and obtain solution, then the aqueous sodium hydroxide solution regulator solution pH value to 10 that adds 2mol/L, then divide 2 extractions with sherwood oil, merge organic phase, use anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying get white solid 0.16g, are 3 '-N-demethyl Azythromycin, yield is 72%, and purity is 73%.
The 3 '-N-demethyl Azythromycin that makes is detected through described reversed-phased high performace liquid chromatographic, and main chromatographic peak is the chromatographic peak at retention time 7.6min place in the color atlas, is outside 3 '-N-demethyl Azythromycin, also has other chromatographic peaks of failing to identify; Getting its percentage composition according to normalization method is 73%.
The present invention includes but be not limited to above embodiment, every any being equal to of carrying out under the spirit and principles in the present invention, replace or local improvement, all will be considered as within protection scope of the present invention.
Claims (9)
1. method for preparing 3 '-N-demethyl Azythromycin, it is characterized in that: step is as follows:
(1) oxidation Azythromycin
Azythromycin is dissolved in the methanol solution, adds oxidizing agent solution, be stirred to reaction and finish, drying obtains 3 '-N-Azythromycin oxide compound crude product;
Methanol solution is that percent by volume is 80% methanol solution; The mass percent of oxidizing agent solution is 1%～10%, and oxygenant is hydrogen peroxide, potassium permanganate or potassium bichromate, and oxygenant is 1～2:1 with the ratio of the amount of substance of Azythromycin; Temperature of reaction is 0 ℃～60 ℃; The concentration that proceeds to 3 '-N-Azythromycin oxide compound when reaction does not increase, and reaction finishes;
(2) reduction Azythromycin oxide compound
3 '-N-Azythromycin oxide compound crude product is dissolved in the organic solvent, making the concentration of 3 '-N-Azythromycin oxide compound crude product is 0.033mol/L, then the aqueous hydrochloric acid that adds reductive agent, stirring reaction removes by filter insolubles after reaction finishes and obtains solution, and making the pH value of solution with alkali lye is 10, then extract with extraction solvent, merge the organic phase that extraction obtains, drying gets 3 '-N-demethyl Azythromycin;
Organic solvent is acetone, methyl alcohol, ethanol, Virahol, dimethyl formamide or methyl-sulphoxide; Reductive agent is ferrous sulfate, ferrous ammonium sulphate, S-WAT or sodium bisulfite, and the molar ratio of reductive agent and Azythromycin oxide compound is 2:1～6, and the pH value of reductive agent aqueous hydrochloric acid is 1～6; Temperature of reaction is 0 ℃～70 ℃; The concentration that proceeds to 3 '-N-demethyl Azythromycin when reaction does not increase, and reaction finishes; Alkali lye is aqueous sodium hydroxide solution or ammoniacal liquor; Extraction solvent is sherwood oil, ethyl acetate, methylene dichloride or chloroform.
2. a kind of method for preparing 3 '-N-Azythromycin oxide compound according to claim 1, it is characterized in that: the mass percent of oxidizing agent solution is 3%; Oxygenant is hydrogen peroxide; Oxygenant is 1.5:1 with the ratio of the amount of substance of Azythromycin.
3. a kind of method for preparing 3 '-N-demethyl Azythromycin according to claim 2, it is characterized in that: temperature of reaction is 20 ℃; Reaction times is 2h～72h.
4. a kind of method for preparing 3 '-N-demethyl Azythromycin according to claim 3, it is characterized in that: the reaction times is 24h.
5. a kind of method for preparing 3 '-N-demethyl Azythromycin according to claim 1, it is characterized in that: organic solvent is acetone; Reductive agent is ferrous sulfate, and the molar ratio of reductive agent and Azythromycin oxide compound is 1:2, and the pH value of reductive agent aqueous hydrochloric acid is 3.
6. a kind of method for preparing 3 '-N-demethyl Azythromycin according to claim 5, it is characterized in that: temperature of reaction is 20 ℃; Reaction times is preferably 0.5h～4h.
7. a kind of method for preparing 3 '-N-demethyl Azythromycin according to claim 6, it is characterized in that: the reaction times is 2h.
8. a kind of method for preparing 3 '-N-demethyl Azythromycin according to claim 5, it is characterized in that: alkali lye is the 2mol/L aqueous sodium hydroxide solution; Extraction solvent is methylene dichloride.
9. each described a kind of method for preparing 3 '-N-demethyl Azythromycin is characterized in that: dissolve 3 '-N-Azythromycin oxide compound crude product with acetone soln in the step (1), recrystallization acquisition 3 '-N-Azythromycin oxide compound according to claim 1～8; The volume ratio of acetone and water is 2:1 in the acetone soln; In the step (2) 3 '-N-Azythromycin oxide compound is dissolved in the organic solvent, making the concentration of 3 '-N-Azythromycin oxide compound is 0.033mol/L.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310236710.XA CN103319553B (en) | 2013-06-14 | 2013-06-14 | One prepares the method for 3 '-N-demethyl Azythromycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310236710.XA CN103319553B (en) | 2013-06-14 | 2013-06-14 | One prepares the method for 3 '-N-demethyl Azythromycin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103319553A true CN103319553A (en) | 2013-09-25 |
| CN103319553B CN103319553B (en) | 2015-08-05 |
Family
ID=49188639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310236710.XA Expired - Fee Related CN103319553B (en) | 2013-06-14 | 2013-06-14 | One prepares the method for 3 '-N-demethyl Azythromycin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103319553B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262434A (en) * | 2014-10-28 | 2015-01-07 | 武汉大学 | Chemical demethylation method of N<6>-methyladenosine in RNA |
| CN104558069A (en) * | 2014-12-31 | 2015-04-29 | 广东东阳光药业有限公司 | Synthesis method for macrolide impurities |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998022488A1 (en) * | 1996-11-22 | 1998-05-28 | Abbott Laboratories | Process for preparation of n-demethyl-4'-deoxy-erythromycins a and b |
| US5883236A (en) * | 1997-11-19 | 1999-03-16 | Abbott Laboratories | Process for N-desmethylating erythromycins and derivatives thereof |
| US6034069A (en) * | 1997-09-30 | 2000-03-07 | Abbott Laboratories | 3-'N-modified 6-O-substituted erythromycin ketolide derivatives having antibacterial activity |
| WO2000012521A1 (en) * | 1998-08-26 | 2000-03-09 | Abbott Laboratories | 3', 3'-n-bis-desmethyl-3'-n-cycloalkyl erythromycin derivatives as lhrh antagonists |
| US6124269A (en) * | 1997-10-29 | 2000-09-26 | Abbott Laboratories | 2-Halo-6-O-substituted ketolide derivatives |
| CN101522027A (en) * | 2006-06-05 | 2009-09-02 | 奥斯拜客斯制药有限公司 | Preparation and utility of substituted erythromycin analogs |
-
2013
- 2013-06-14 CN CN201310236710.XA patent/CN103319553B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998022488A1 (en) * | 1996-11-22 | 1998-05-28 | Abbott Laboratories | Process for preparation of n-demethyl-4'-deoxy-erythromycins a and b |
| US6034069A (en) * | 1997-09-30 | 2000-03-07 | Abbott Laboratories | 3-'N-modified 6-O-substituted erythromycin ketolide derivatives having antibacterial activity |
| US6124269A (en) * | 1997-10-29 | 2000-09-26 | Abbott Laboratories | 2-Halo-6-O-substituted ketolide derivatives |
| US5883236A (en) * | 1997-11-19 | 1999-03-16 | Abbott Laboratories | Process for N-desmethylating erythromycins and derivatives thereof |
| WO2000012521A1 (en) * | 1998-08-26 | 2000-03-09 | Abbott Laboratories | 3', 3'-n-bis-desmethyl-3'-n-cycloalkyl erythromycin derivatives as lhrh antagonists |
| CN101522027A (en) * | 2006-06-05 | 2009-09-02 | 奥斯拜客斯制药有限公司 | Preparation and utility of substituted erythromycin analogs |
Non-Patent Citations (2)
| Title |
|---|
| JIE-WEI JIANG，等: "Synthesis and antibacterial evaluation of a novel series of 10-hydroxyl ketolide derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 李玲莉，等: "罗红霉素相关物的制备", 《化工学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262434A (en) * | 2014-10-28 | 2015-01-07 | 武汉大学 | Chemical demethylation method of N<6>-methyladenosine in RNA |
| CN104558069A (en) * | 2014-12-31 | 2015-04-29 | 广东东阳光药业有限公司 | Synthesis method for macrolide impurities |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103319553B (en) | 2015-08-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bakheit et al. | Azithromycin | |
| CN103319553B (en) | One prepares the method for 3 '-N-demethyl Azythromycin | |
| CN103965273B (en) | A kind of macrolides compound | |
| CN104231016A (en) | Etimicin sulfate preparation method | |
| CN102070539B (en) | 1-oxo-2-methyl-3-(1-ethoxyl)-quinoxaline and preparation method and application thereof | |
| CN101628903A (en) | Defervescence anti-inflammatory and anti-infection medicine with immunization function, preparation and application thereof | |
| CN110642907B (en) | Synthesis method of prazolamide or salt thereof | |
| DE60026718T2 (en) | UNIVERSAL PROCESS FOR THE PREPARATION OF 7,16-DEOXY-2-AZA-10-O-CLADINOSIL-12-O-DESOSAMINIL-4,5-DIHYDROXI-6-ETHYL-3,5,9,11,13,15-HEXAMETHYLBICYCLE (11.2.11) HEXADECA-1 (2) -EN-8-ONA AND A NEW FORM OF 9-DESOXO-9A-METHYL-9A-AZA-9A-HOMOERYTHROMYCIN A | |
| US20130102550A1 (en) | Amorphous roxithromycin composition | |
| CN102070540B (en) | 1-oxygen-2-(1-ethoxy)-3-methyl-quinoxaline, and preparation method and application thereof | |
| CN102250066B (en) | Fasudil derivative and preparation method thereof | |
| CN105949253B (en) | A kind of purification process of Clindamycin Hydrochloride | |
| JP2019520363A (en) | Crystal form of 9-aminomethyl substituted tetracycline compound and method for producing the same | |
| CN107722084A (en) | A kind of synthetic method of high-purity Gamithromycin | |
| CN104844604B (en) | A kind of preparation method of allopurinol sodium | |
| CN105152975B (en) | Synthetic method for acetohydroxamic acid | |
| CN101973906B (en) | Preparation method of amorphous tigecycline | |
| WO2014019282A1 (en) | Meropenem bulk drug, preparation method thereof and pharmaceutical composition containing same | |
| CN102850265A (en) | Flupirtine conjugate and preparation method and use thereof | |
| CN108727418A (en) | A kind of preparation method of Cefditoren pivoxil Cephalosporins dimer | |
| CN103172686A (en) | Preparation method of clarithromycin-N-oxide | |
| CN108727410A (en) | A kind of preparation method of methylol Cefditoren pivoxil Cephalosporins | |
| CN111039885A (en) | Method for preparing high-purity combretastatin | |
| CN111018777B (en) | Preparation method of dequalinium chloride | |
| CN117736202A (en) | Berberine 9 oxygen canagliflozin derivative and synthetic method and application thereof |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150805 Termination date: 20190614 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |