CN103319553B - One prepares the method for 3 '-N-demethyl Azythromycin - Google Patents
One prepares the method for 3 '-N-demethyl Azythromycin Download PDFInfo
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Abstract
The present invention relates to the method that one prepares 3 '-N-demethyl Azythromycin, belong to technical field of organic synthesis.Method is as follows: by azithromycin dissolution in methanol solution, adds oxidizing agent solution, is stirred to reaction and terminates, dry 3 '-N-Azythromycin oxide compound crude product, and after this crude product can dissolve with acetone soln, recrystallization obtain 3 '-N-Azythromycin oxide compound; Described crude product or 3 '-N-Azythromycin oxide compound are dissolved in organic solvent, its concentration is made to be 0.033mol/L, then the aqueous hydrochloric acid of reductive agent is added, stirring reaction, reaction terminates rear filtering insolubles of crossing and obtains solution, makes the pH value of solution be 10, then extract with extraction solvent with alkali lye, merge organic phase, dry 3 '-N-demethyl Azythromycin.The method reaction reagent is nontoxic, and without ultraviolet lighting, product purity improves, and reductive agent can filtering separation, reacts easy, and when reductive agent is ferrous sulfate, reaction is carried out fast, and productive rate is high.
Description
Technical field
The present invention relates to the method that one prepares 3 '-N-demethyl Azythromycin, specifically, described 3 '-N-demethyl Azythromycin is 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, first semi-synthetic azepine fifteen-membered ring macrolide antibiotic, compared with erythromycin, Azythromycin remains the advantage of erythromycin, and antimicrobial spectrum expands further, to the anti-microbial effect of chlamydia trachomatis, streptococcus pneumoniae is outstanding and tissue concentration is high.Azythromycin, 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, international antibiotic medicine market is always very powerful and exceedingly arrogant kind.Now, Azythromycin is proposed as the medicine infected for the respiratory tract caused by sensitive bacterial, urogenital tract, skin and soft tissue etc., in today that sexually transmitted disease (STD) sickness rate is more and more higher, also just means there are more wide market outlook.Meanwhile, this medicine is put into " the basic medicine register of country " and " basic medical insurance medicine register ".China produces Azythromycin per year close to 2000 tons, is one of country that Azythromycin turnout is maximum in the world.
In recent years, along with the universal of New Instruments etc. and the increase of China's science research input, the raising work of China's pharmaceutical standards is also more and more deep.The raising of pharmacopeia Chinese traditional medicine the standard not only directly standard of the specification medicine such as bulk drug, injection itself and safe medication, and for the production of medicine, there is indirectly directive function, for superseded old technique, facilitated technique improves and process modification has immeasurable meaning.In " Chinese Pharmacopoeia " 2010 editions, the standard of Azythromycin have also been obtained raising, except adopting HPLC method detection of drugs, also specify 5 kinds of impurity correlatives: Erythromycin A iminoether, 3 '-N-demethyl Azythromycin, 3-O-remove cladinose Azythromycin, Azythromycin impurity Gx and Azythromycin B.Compare with the 16 kinds of impurity correlatives that define of USP standard with European Pharmacopoeia, China's standards of pharmacopoeia still has much room for improvement, and particularly the preparation of impurity correlative should become the basis that standards of pharmacopoeia improves.Wherein, 3 '-N-demethyl Azythromycin is not only the one of impurity correlative, or the precursor compound of other several impurity correlatives.
The chemistry same Erythromycin A of 3 '-N-demethyl-9A-methyl-9-deoxidation-9A-azepine-9A-by name of 3 '-N-demethyl Azythromycin, structural formula is as shown in the formula shown in I:
3 '-N-demethyl Azythromycin is mainly taken off a methyl by the dimethyl on the desosamine of Azythromycin and is obtained.When Azythromycin long-term storage, if envrionment temperature is higher, just there will be the existence of 3 ' more-N-demethyl Azythromycin.In addition, 3 '-N-demethyl Azythromycin also can by 3 '-N-demethyl Erythromycin A in raw material when preparing Azythromycin through oximate, rearrangement, to reduce and the reaction such as to methylate generates and is present in Azythromycin.
The method of the preparation 3 '-N-demethyl Azythromycin reported in patent US2007043214A1, WO2004092736A2 and WO9426758 is all by Azythromycin under the irradiation (a) of UV-light, at sodium acetate trihydrate (NaOAc3H
2o) under existence, by iodine (I
2) add carry out demethylation reaction and obtain 3 '-N-demethyl Azythromycin, as shown in the response path of following formula II:
Described method defect is as follows: productive rate is lower, is approximately 45%; The demethylation reagent iodine used is toxic reagent; Adopt UV-irradiation in reaction, operator has by the danger exposed to the open air under ultraviolet lighting; Process is comparatively loaded down with trivial details.
Summary of the invention
For the defect preparing 3 '-N-demethyl Azythromycin method existence in prior art, one is the object of the present invention is to provide to prepare the method for 3 '-N-demethyl Azythromycin, described method mainly utilizes oxidation-reduction reaction to complete, described method uses non-toxic reagent, reduce the danger of ultraviolet radiation, be convenient to industrial scale amplify and yield is higher.
Object of the present invention realizes mainly through following technique means.
One prepares the method for 3 '-N-demethyl Azythromycin, and described method steps is as follows:
(1) Azythromycin is oxidized
By azithromycin dissolution in methanol solution, add oxidizing agent solution, be stirred to reaction and terminate, dry, obtain 3 '-N-Azythromycin oxide compound crude product.
Wherein, described methanol solution to be percent by volume be 80% methanol solution, 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, the yield obtaining 3 '-N-Azythromycin oxide compound crude product due to hydrogen peroxide oxidation is higher than the yield of potassium permanganate or potassium dichromate oxidation acquisition 3 '-N-Azythromycin oxide compound crude product, and therefore 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 DEG C ~ 60 DEG C, is preferably 20 DEG C.
3 '-N-Azythromycin oxide compound crude product is the 3 '-N-Azythromycin oxide compound containing 3 '-N-azithromycin oxide compound; The concentration proceeding to 3 '-N-Azythromycin oxide compound when reaction does not increase, and can think that reaction terminates; Rp-hplc analysis method can be adopted to judge, and the change in concentration of 3 '-N-Azythromycin oxide compound is to determine reaction end.
Reaction times is preferably 2h ~ 72h, is 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 be adopted and carry out with the following method:
Dissolve 3 '-N-Azythromycin oxide compound crude product with acetone soln, recrystallization obtains 3 '-N-Azythromycin oxide compound of white; In acetone soln, the volume ratio of acetone and water is 2:1.
(2) reduction 3 '-N-Azythromycin oxide compound
The 3 '-N-Azythromycin oxide compound that 3 '-N-Azythromycin oxide compound crude product or recrystallization obtain is dissolved in organic solvent, the concentration of the 3 '-N-Azythromycin oxide compound that 3 '-N-Azythromycin oxide compound crude product or recrystallization are obtained is 0.033mol/L, then the aqueous hydrochloric acid of reductive agent is added, stirring reaction, reaction terminates rear mistake and filters insolubles and obtain solution, be 10 by the pH value of alkali lye regulator solution, then extract with extraction solvent, merge the organic phase extracting and obtain, dry, obtain 3 '-N-demethyl Azythromycin, the purity of described 3 '-N-demethyl Azythromycin can reach 30% ~ 80%.
Wherein, step (1) preferably uses the 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; Reductive agent is 2:1 ~ 6 with the amount of substance ratio of Azythromycin oxide compound, is preferably 1:2; The pH value of reductive agent aqueous hydrochloric acid is 1 ~ 6, is preferably 3.
Temperature of reaction is 0 DEG C ~ 70 DEG C, is preferably 20 DEG C.
The concentration proceeding to 3 '-N-demethyl Azythromycin when reaction does not increase, and can think that reaction terminates, rp-hplc analysis method can be adopted to judge, and the change in concentration situation of 3 '-N-demethyl Azythromycin is to confirm reaction end.
Reaction times is preferably 0.5h ~ 4h, is more preferably 2h.
Alkali lye is aqueous sodium hydroxide solution or ammoniacal liquor, is preferably 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 the method that one prepares 3 '-N-demethyl Azythromycin, Azythromycin is first oxidized to 3 '-N-Azythromycin oxide compound crude product by described method, then 3 '-N-Azythromycin oxide compound crude product is reduced, obtain 3 '-N-demethyl Azythromycin.The present invention, by adopting the tertiary amine of 3 '-N of suitable oxidizing Azythromycin, obtains the oxide compound of tertiary amine compound; Adopt suitable reductive agent that on tertiary amine methyl is sloughed in proportion, obtain the product secondary amine of tertiary amine demethyl.According to above-mentioned reaction mechanism, on Azythromycin desosamine 3 '-N of dimethylamino oxide compound on nitrogen-oxygen bond between polarize, due to electronegative difference, because negative charge on polarized action band on electrophilic Sauerstoffatom, and nitrogen-atoms loses corresponding electronics and the lotus that becomes positively charged; In acid condition, Hydrogen Proton in solution is combined with the oxygen with negative charge, then reacts with reductive agent and loses an electronics, and nitrogen-oxygen bond obtains an electronics and disconnects, hydrogen ion in hydroxide ion and solution generates a part water, and tertiary amino oxides is reduced to tertiary amine; Meanwhile, the carbon atom of nitrogen-atoms and methyl forms double bond, and in acid condition due to the effect of reductive agent, methylene radical and a molecular water effect make tertiary amine demethylating and generate secondary amine.
Beneficial effect
1. reaction reagent is nontoxic, and pollutes little;
2. reaction need not adopt ultraviolet lighting;
3. the purity of product improves, higher than 30%;
4. the separation of reductive agent can be accomplished by filtration;
5. reaction process is comparatively easy;
6. when reductive agent is ferrous sulfate, reaction is carried out fast, and in product, 3 '-N-demethyl potency of azithromycin is apparently higher than other reductive agents of use.
Accompanying drawing explanation
Fig. 1 is the HPLC analysis chart of 3 '-N-Azythromycin oxide compound in embodiment 4.
Fig. 2 is 3 '-N-demethyl Azythromycin HPLC analysis chart in embodiment 13.
Embodiment
In order to further illustrate details of the present invention, enumerate preferred embodiment below.
The 3 '-N-Azythromycin oxide compound that embodiment 1 ~ 11 is obtained and the 3 '-N-demethyl Azythromycin that embodiment 12 ~ 32 obtains adopt 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 DEG C, employing moving phase is phosphoric acid salt (0.02mol/L dipotassium hydrogen phosphate solution, pH is adjusted to be 8.2 with phosphoric acid)/acetonitrile=55/45(volume ratio), UV-detector is used to detect at 210nm.Qualitative employing reference material adds and carries out qualitative with relative retention time.
Product purity obtained in embodiment adopts normalization method to measure; Calibration curve method is adopted to carry out quantitatively.
Embodiment 1
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 20 DEG C, slowly dripping 18ml mass percent is the H of 3%
2o
2solution, stirring reaction 20h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and drying obtains the 3 '-N-Azythromycin oxide compound of 6.97g, and yield is 91.1%, and purity is 98%.
3 ' obtained-N-Azythromycin oxide compound is detected through described reversed-phased high performace liquid chromatographic, only has retention time 4min place to have a chromatographic peak in color atlas, be shown as 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 98%.
Embodiment 2
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 20 DEG C, slowly dripping 54ml mass percent is the H of 1%
2o
2solution, stirring reaction 20h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and the dry 3 '-N-Azythromycin oxide compound obtaining 5.64g, yield is 73.7%, and purity is 98%.
3 ' obtained-N-Azythromycin oxide compound is detected through described reversed-phased high performace liquid chromatographic, only has retention time 4min place to have a chromatographic peak in color atlas, be shown as 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 98%.
Embodiment 3
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 20 DEG C, slowly dripping 5.4ml mass percent is the H of 10%
2o
2solution, stirring reaction 20h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and the dry 3 '-N-Azythromycin oxide compound obtaining 7.12g, yield is 93.1%, and purity is 90%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, two chromatographic peaks of time 2.1min and 4min that with a hook at the end in color atlas, the chromatographic peak of retention time 4min is 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 90%.
Embodiment 4
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 60 DEG C, slowly dripping 18ml mass percent is the H of 3%
2o
2solution, stirring reaction 20h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and the dry 3 '-N-Azythromycin oxide compound obtaining 7.02g, yield is 91.8%, and purity is 82%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, two chromatographic peaks of time 2.1min and 4min that with a hook at the end in color atlas, the chromatographic peak of retention time 4min is 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 82%.
Embodiment 5
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 20 DEG C, slowly dripping 18ml mass percent is the H of 3%
2o
2solution, stirring reaction 72h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and the dry 3 '-N-Azythromycin oxide compound obtaining 5.74g, yield is 75.0%, and purity is 91%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, two chromatographic peaks of time 2.1min and 4min that with a hook at the end in color atlas, the chromatographic peak of retention time 4min is 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 91%.
Embodiment 6
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 20 DEG C, slowly dripping 12ml mass percent is the H of 3%
2o
2solution, stirring reaction 20h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and drying obtains the 3 '-N-Azythromycin oxide compound of 6.03g, and yield is 78.8%, and purity is 95%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, only having retention time 4min place to have a chromatographic peak in color atlas, is 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 95%.
Embodiment 7
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 20 DEG C, slowly dripping 24ml mass percent is the H of 3%
2o
2solution, stirring reaction 20h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and drying obtains the 3 '-N-Azythromycin oxide compound of 6.41g, and yield is 83.8%, and purity is 89%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, two chromatographic peaks of time 2.1min and 4min that with a hook at the end in color atlas, the chromatographic peak of retention time 4min is 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 89%.
Embodiment 8
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 0 DEG C, slowly dripping 18ml mass percent is the H of 3%
2o
2solution, stirring reaction 20h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and drying obtains the 3 '-N-Azythromycin oxide compound of 6.25g, and yield is 81.7%, and purity is 98%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, only having retention time 4min place to have a chromatographic peak in color atlas, is 3 '-N-Azythromycin oxide compound; Obtaining its percentage composition according to normalization method is 98%.
Embodiment 9
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, and then at 20 DEG C, slowly dripping 18ml mass percent is the H of 3%
2o
2solution, stirring reaction 2h, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, and steam solvent with Rotary Evaporators, obtaining white solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2:1, and drying obtains the 3 '-N-Azythromycin oxide compound of 6.78g, and yield is 88.6%, and purity is 42%.
Detecting through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, except there is a chromatographic peak at retention time 4min place in color atlas, is outside 3 '-N-Azythromycin oxide compound, also has unreacted raw material Azythromycin; Obtaining its percentage composition according to normalization method is 42%.
Embodiment 10
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, then at 20 DEG C, slowly dripping 30ml mass percent is the potassium permanganate solution of 5%, stirring reaction 20h, rp-hplc analysis method is adopted to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, steam solvent with Rotary Evaporators, obtaining solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2: 1, and drying obtains the 3 '-N-Azythromycin oxide compound of 3.25g, and yield is 42.5%, and purity is 76%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, in color atlas, main chromatographic peak is the chromatographic peak at retention time 4min place, is outside 3 '-N-Azythromycin oxide compound, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 76%.
Embodiment 11
7.49g Azythromycin being dissolved in 200ml percent by volume is in the methanol solution of 80%, then at 20 DEG C, slowly dripping 30ml mass percent is the potassium dichromate aqueous solution of 9%, stirring reaction 20h, rp-hplc analysis method is adopted to judge that the concentration of 3 '-N-Azythromycin oxide compound no longer increases, reaction terminates, steam solvent with Rotary Evaporators, obtaining solid is Azythromycin oxide compound crude product.By Azythromycin oxide compound dissolving crude product recrystallization in acetone soln, in acetone soln, the volume of acetone and water is 2: 1, and drying obtains the 3 '-N-Azythromycin oxide compound of 2.97g, and yield is 38.9%, and purity is 83%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-Azythromycin oxide compound, in color atlas, main chromatographic peak is the chromatographic peak at retention time 4min place, is outside 3 '-N-Azythromycin oxide compound, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 83%.
Embodiment 12
Be dissolved in 9ml acetone by 3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1, then adding by pH value is the ferrous sulfate (FeSO of the 23mg of 3
4) aqueous hydrochloric acid 2.0ml, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, and adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then sodium hydroxide (NaOH) aqueous solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.21g, is 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 75%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 75%.
Embodiment 13
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml methyl alcohol, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 58%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 58%.
Embodiment 14
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml ethanol, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.21g, is 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 52%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 52%.
Embodiment 15
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml Virahol, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.19g, is 3 '-N-demethyl Azythromycin, yield is 86%, and purity is 41%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 41%.
Embodiment 16
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml dimethyl formamide, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.14g, is 3 '-N-demethyl Azythromycin, yield is 63%, and purity is 54%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 54%.
Embodiment 17
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml methyl-sulphoxide, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.17g, is 3 '-N-demethyl Azythromycin, yield is 77%, and purity is 48%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 48%.
Embodiment 18
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 15mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 63%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 63%.
Embodiment 19
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 91mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.21g, is 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 59%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 59%.
Embodiment 20
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous ammonium sulphate aqueous hydrochloric acid 2.0ml that pH value is the 59mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 32%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 32%.
Embodiment 21
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the S-WAT aqueous hydrochloric acid 2.0ml that pH value is the 20mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.21g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 55%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 55%.
Embodiment 22
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the sodium bisulfite aqueous hydrochloric acid 2.0ml that pH value is the 16mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.21g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 64%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 64%.
Embodiment 23
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 1 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.21g, is 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 69%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 69%.
Embodiment 24
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 6 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 67%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 67%.
Embodiment 25
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 0 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 45%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 45%.
Embodiment 26
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 70 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.21g, is 3 '-N-demethyl Azythromycin, yield is 95%, and purity is 31%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 31%.
Embodiment 27
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 0.5h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 34%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 34%.
Embodiment 28
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 4h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 47%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 47%.
Embodiment 29
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then add 5%(mass percentage) ammonia soln regulator solution pH value to 10, then divide 2 extractions with methylene dichloride, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 51%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 51%.
Embodiment 30
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with chloroform, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.20g, is 3 '-N-demethyl Azythromycin, yield is 91%, and purity is 74%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 74%.
Embodiment 31
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions by ethyl acetate, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.19g, is 3 '-N-demethyl Azythromycin, yield is 86%, and purity is 76%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 76%.
Embodiment 32
3 '-N-Azythromycin oxide compound 0.23g obtained in embodiment 1 is dissolved in 9ml acetone, then the ferrous sulfate aqueous hydrochloric acid 2.0ml that pH value is the 23mg of 3 is added, at 20 DEG C of stirring reaction 2h, solution colour becomes sorrel from light green, adopt rp-hplc analysis method to judge that the concentration of 3 '-N-demethyl Azythromycin no longer increases, reaction terminates; Solution is obtained with filter paper filtering removing insolubles, then the aqueous sodium hydroxide solution regulator solution pH value to 10 of 2mol/L is added, then divide 2 extractions with sherwood oil, merge organic phase, with anhydrous magnesium sulfate drying, filter, solvent evaporated, vacuum-drying obtains white solid 0.16g, is 3 '-N-demethyl Azythromycin, yield is 72%, and purity is 73%.
Detect through described reversed-phased high performace liquid chromatographic 3 ' obtained-N-demethyl Azythromycin, in color atlas, main chromatographic peak is the chromatographic peak at retention time 7.6min place, is outside 3 '-N-demethyl Azythromycin, also has the chromatographic peak that other fail to identify; Obtaining its percentage composition according to normalization method is 73%.
The present invention includes but be not limited to above embodiment, every any equivalent replacement of carrying out under the spirit and principles in the present invention or local improvement, all will be considered as within protection scope of the present invention.
Claims (9)
1. prepare a method for 3 '-N-demethyl Azythromycin, it is characterized in that: step is as follows:
(1) Azythromycin is oxidized
By azithromycin dissolution in methanol solution, add oxidizing agent solution, be stirred to reaction and terminate, dry, obtain 3 '-N-Azythromycin oxide compound crude product;
Methanol solution to be percent by volume be 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 DEG C ~ 60 DEG C; The concentration proceeding to 3 '-N-Azythromycin oxide compound when reaction does not increase, and reaction terminates;
(2) reduction Azythromycin oxide compound
3 '-N-Azythromycin oxide compound crude product is dissolved in organic solvent, the concentration making 3 '-N-Azythromycin oxide compound crude product is 0.033mol/L, then the aqueous hydrochloric acid of reductive agent is added, stirring reaction, reaction terminates rear mistake and filters insolubles and obtain solution, makes the pH value of solution be 10 with alkali lye, then extract with extraction solvent, merge the organic phase extracting and obtain, dry, obtain 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 amount of substance of reductive agent and 3 '-N-Azythromycin oxide compound is than being 2:1 ~ 6, and the pH value of reductive agent aqueous hydrochloric acid is 1 ~ 6; Temperature of reaction is 0 DEG C ~ 70 DEG C; The concentration proceeding to 3 '-N-demethyl Azythromycin when reaction does not increase, and reaction terminates; Alkali lye is aqueous sodium hydroxide solution or ammoniacal liquor; Extraction solvent is sherwood oil, ethyl acetate, methylene dichloride or chloroform.
2. one according to claim 1 prepares the method for 3 '-N-Azythromycin oxide compound, 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. one according to claim 2 prepares the method for 3 '-N-demethyl Azythromycin, it is characterized in that: temperature of reaction is 20 DEG C; Reaction times is 2h ~ 72h.
4. one according to claim 3 prepares the method for 3 '-N-demethyl Azythromycin, it is characterized in that: the reaction times is 24h.
5. one according to claim 1 prepares the method for 3 '-N-demethyl Azythromycin, it is characterized in that: organic solvent is acetone; Reductive agent is ferrous sulfate, and the amount of substance of reductive agent and 3 '-N-Azythromycin oxide compound is than being 1:2, and the pH value of reductive agent aqueous hydrochloric acid is 3.
6. one according to claim 5 prepares the method for 3 '-N-demethyl Azythromycin, it is characterized in that: temperature of reaction is 20 DEG C; Reaction times is preferably 0.5h ~ 4h.
7. one according to claim 6 prepares the method for 3 '-N-demethyl Azythromycin, it is characterized in that: the reaction times is 2h.
8. one according to claim 5 prepares the method for 3 '-N-demethyl Azythromycin, it is characterized in that: alkali lye is 2mol/L aqueous sodium hydroxide solution; Extraction solvent is methylene dichloride.
9. the one according to any one of claim 1 ~ 8 prepares the method for 3 '-N-demethyl Azythromycin, it is characterized in that: dissolve 3 '-N-Azythromycin oxide compound crude product with acetone soln in step (1), recrystallization obtains 3 '-N-Azythromycin oxide compound; In acetone soln, the volume ratio of acetone and water is 2:1; Be dissolved in organic solvent by 3 '-N-Azythromycin oxide compound in step (2), the concentration making 3 '-N-Azythromycin oxide compound is 0.033mol/L.
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