Preparation method of nitrosamine impurity

Abstract

The invention provides a preparation method of a nitrosamine impurity, and belongs to the technical field of heterocyclic compounds. The clarithromycin related nitrosamine impurity is 3 '-N-demethyl-3'-N-nitroso-6-O-methyl erythromycin, and is prepared by carrying out demethylation and nitrosation on clarithromycin. The clarithromycin intermediate erythromycin oxime related nitrosamine impurity is 3 '-N-demethyl-3'-N-nitroso erythromycin A (E)-9-oxime, and the clarithromycin intermediate erythromycin oxime related nitrosamine impurity is prepared from erythromycin A (E)-9-oxime through demethylation, etherification, nitrosation and hydrolysis.

Description

Technical Field

[0001] The present application relates to a method for preparing nitrosamine impurities, especially clarithromycin and its intermediate erythromycin oxime-related nitrosamine impurities, and belongs to the technical field of heterocyclic compounds. Background Art

[0002] The chemical name of clarithromycin is 6-O-methylerythromycin, and its structural formula (I) is as follows:

[0003]

[0004] Clarithromycin is a second-generation macrolide antibiotic. It is also known as erythromycin methyl, and is a derivative of erythromycin. Its in vitro and antibacterial spectrum are similar to those of erythromycin, but it is resistant to gastric acid and has good tissue permeability. Its antibacterial activity against Staphylococcus, Streptococcus, Haemophilus influenzae, etc. is stronger than that of erythromycin.

[0005] Nitrosamines are a class of substances with a characteristic structure in which the nitrogen (N) of the nitroso group (-NO) is connected to the nitrogen (N) of the amino group. The structural formula (II) is as follows:

[0006]

[0007] Its derivative structural formula (III) in clarithromycin is shown as follows:

[0008]

[0009] Its derivative structural formula (IV) expressed in clarithromycin intermediate erythromycin oxime is as follows:

[0010]

[0011] Due to the carcinogenicity of nitrosamine structures, many countries have set extremely strict requirements on the nitrosamine content in drugs. The US FDA and the Korean KFDA both require that the content of 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin (structural formula (III)) in clarithromycin finished products should not exceed 1ppm. Therefore, for the sake of human life and health and drug safety, research on nitrosamine impurities in clarithromycin and its intermediates is urgent. Summary of the invention

[0012] In view of this, the present application provides a method for preparing nitrosamine impurities related to clarithromycin and its intermediate erythromycin oxime. The obtained related nitrosamine substances have high purity and can be used as reference substances for qualitative and quantitative analysis of clarithromycin nitrosamine impurities.

[0013] Specifically, the present application is implemented through the following scheme:

[0014] The first is clarithromycin-related nitrosamine impurities, and its specific preparation steps are as follows:

[0015] Step 1, preparation of 3'-N-demethyl-6-O-methylerythromycin:

[0016] Take clarithromycin as the raw material, add ethanol, heat it to 60-70°C, then continue to add sodium acetate, water and iodine, adjust the pH to 10-11, keep warm for 6-12 hours, concentrate the ethanol under reduced pressure, add dichloromethane for extraction, combine the organic layers, wash with saturated brine, recover the organic layers under reduced pressure to obtain a crude product, add acetone to the crude product, heat it to 50-55°C and keep warm for 1-3 hours, cool it to 10-20°C, filter, dry, and bake the filter cake under reduced pressure to obtain 3'-N-demethyl-6-O-methylerythromycin.

[0017] The above process reaction is expressed as follows:

[0018]

[0019] Step 2, preparation of 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin:

[0020] An organic solvent is added to 3'-N-demethyl-6-O-methylerythromycin, the temperature is raised to 50-75°C, a nitrosating agent and water are added, the molar ratio of 3'-N-demethyl-6-O-methylerythromycin to the nitrosating agent is 1:5-15, the pH is adjusted to 5-6, the reaction is carried out for 4-6 hours, the mixture is cooled to 10-20°C, filtered, and the filter cake is dried under reduced pressure to obtain a crude product. Acetone is added to the crude product, the temperature is raised to 50-55°C and kept for 1-3 hours, the temperature is lowered to 30-40°C, filtered, and the filtrate is recovered under reduced pressure to obtain 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin, which is the related nitrosamine impurity.

[0021]

[0022] Among the above schemes, preferably:

[0023] The organic solvent is a C1-C4 alcohol, such as methanol, ethanol, isopropanol, n-propanol, etc.

[0024] 3'-N-demethyl-6-O-methylerythromycin mass (g): organic solvent volume (mL) = 1:5-15.

[0025] In step 2, the pH is adjusted with a C-C4 organic acid or a common inorganic acid. The organic acid can be formic acid, acetic acid, propionic acid, etc., and the inorganic acid can be dilute hydrochloric acid, dilute sulfuric acid, nitrous acid, etc.

[0026] The nitrosating agent is a nitrite compound, such as nitrous acid, sodium nitrite, potassium nitrite, etc.

[0027] The second is nitrosamine impurities related to erythromycin oxime, an intermediate of clarithromycin, and its specific preparation steps are as follows:

[0028] Step 1, preparation of 3'-N-demethylerythromycin A(E)-9-oxime:

[0029] Erythromycin A(E)-9-oxime is used as a raw material, ethanol is added thereto, the temperature is raised to 60-70°C, sodium acetate, water and iodine are continuously added, the pH is adjusted to 10-11, the reaction is kept warm for 6-12 hours, ethanol is concentrated under reduced pressure, dichloromethane is added for extraction, the organic layers are combined, and saturated brine is washed. The organic layers are recovered under reduced pressure to obtain a crude product, acetone is added to the crude product, the temperature is raised to 50-55°C and kept warm for 1-3 hours, the temperature is lowered to 10-20°C, filtered, dried, and the filter cake is baked under reduced pressure to obtain 3'-N-demethylerythromycin A(E)-9-oxime.

[0030] The above process reaction is expressed as follows:

[0031]

[0032] Step 2, preparation of 3'-N-demethylerythromycin A(E)-9-oxime ether:

[0033] Add dichloromethane to 3'-N-demethylerythromycin A(E)-9-oxime, recover part of dichloromethane under normal pressure, cool to 15-20°C, add N-methylpyrrolidone hydrochloride, add 2-ethoxypropylene after the system is clarified, heat to 25-30°C and keep warm for reaction for 30-40 minutes, add water to terminate the reaction, adjust the pH to 9-11, separate layers, extract the water layer with dichloromethane, combine the organic layers, wash the layers with saturated brine, and recover the organic layer under reduced pressure to obtain 3'-N-demethylerythromycin A(E)-9-oxime ether.

[0034] The above process reaction is expressed as follows:

[0035]

[0036] Step 3, preparation of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime ether:

[0037] After adding organic solvent 1 to 3'-N-demethylerythromycin A(E)-9-oxime ether, stirring and dissolving, the temperature is raised to 50-75°C, and a nitrosating agent and water are added, the molar ratio of 3'-N-demethylerythromycin A(E)-9-oxime ether to the nitrosating agent is 1:5-15, the pH is adjusted to 5-6, the reaction is kept warm for 5-6 hours, and the organic solvent is concentrated under reduced pressure. After concentration, organic solvent 2 and water are added, the pH of the water layer is adjusted to 9-12, the layers are separated, the water layer is extracted with organic solvent 2, the organic solvent layers are combined, washed with saturated brine, recovered under reduced pressure, filtered, and the filtrate is recovered under reduced pressure to obtain 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime ether.

[0038] The above process reaction is expressed as follows:

[0039]

[0040] Step 4, preparation of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime:

[0041] After 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime ether, ethanol and water are stirred evenly, acetic acid and sodium bisulfite are added, the temperature is raised to 70-75°C and reacted for 3-4 hours, cooled to 20-30°C, the pH is adjusted to 10-12, stirred, and filtered to obtain a crude product. After the crude product is dried under reduced pressure, acetone is added at 50-55°C and kept warm for 1-3 hours, the temperature is lowered to 10-20°C, filtered, and the filter cake is dried under reduced pressure to obtain 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime.

[0042] The above process reaction is expressed as follows:

[0043]

[0044] In the above scheme:

[0045] In step three,

[0046] The first organic solvent is a C1-C4 alcohol, such as methanol, ethanol, isopropanol, n-propanol, etc.

[0047] 3'-N-demethylerythromycin A(E)-9-oxime ether mass (g): organic solvent volume (mL) = 1:5-15.

[0048] The second organic solvent is dichloromethane, chloroform, DMF or ethyl acetate.

[0049] 3'-N-demethylerythromycin A(E)-9-oxime ether mass (g): organic solvent volume (mL) = 1:2-5.

[0050] To adjust the pH, use C-C4 organic acid or common inorganic acid. Organic acid can be formic acid, acetic acid, propionic acid, etc., and inorganic acid can be dilute hydrochloric acid, dilute sulfuric acid, nitrous acid, etc.

[0051] The nitrosating agent is a nitrite compound, such as nitrous acid, sodium nitrite, potassium nitrite, etc.

[0052] The above preparation process determines the structures of 3"-N-demethyl-3"-N-nitroso-6-O-methylerythromycin and 3"-N-demethyl-3"-N-nitro-erythromycin A(E)-9-oxime, and the purity of the prepared related substances is as high as more than 90%. They can be used as reference substances in the qualitative and quantitative analysis and removal research of clarithromycin nitrosamine impurities, which is beneficial to improving the drug safety of clarithromycin and filling the gap in the research of clarithromycin impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0054] Figure 1 The infrared absorption spectrum (IR) of 3'-N-demethyl-3'-N-nitrosoclarithromycin prepared in Example 2;

[0055] Figure 2 The 3'-N-demethyl-3'-N-nitrosoclarithromycin prepared in Example 2 13 C-NMR carbon spectrum;

[0056] Figure 3 The mass spectrum of 3'-N-demethyl-3'-N-nitrosoclarithromycin prepared in Example 2;

[0057] Figure 4 The infrared absorption spectrum (IR) of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime prepared in Example 6;

[0058] Figure 5 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime prepared in Example 6 13 C-NMR carbon spectrum;

[0059] Figure 6 This is the mass spectrum of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime prepared in Example 6. DETAILED DESCRIPTION

[0060] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below in conjunction with the drawings in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0061] Example 1

[0062] The present application prepares 3'-N-demethyl-6-O-methylerythromycin, and the process is as follows:

[0063] Put 110g clarithromycin in a four-necked bottle, add 1100ml ethanol, heat to 60℃, add 84g sodium acetate, 200ml water and 34g iodine, add 10% liquid alkali to adjust the pH to 10.5, keep warm for 6h, and concentrate the ethanol under reduced pressure. After concentration, add 400ml dichloromethane, stir and separate, use 100ml dichloromethane for the water layer, combine the dichloromethane layers, wash once with 100ml saturated brine, and recover the dichloromethane layer under reduced pressure to obtain a crude product. Add 300g acetone to the crude product, heat to 50℃ and keep warm for 1h, cool to 20℃, filter, and dry the filter cake under reduced pressure to obtain 60.57 solids. The liquid content is 96.63%.

[0064] Example 2

[0065] The present application prepares 3'-N-demethyl-3'-N-nitroso-6-O-erythromycin, and the process is as follows:

[0066] Put 60g of 3'-N-demethylclarithromycin in a four-necked bottle, add 900ml of ethanol, heat to 60°C, add 55g of sodium nitrite and 150ml of water, add acetic acid dropwise to control the pH to 5.5, react for 4h, cool to 20°C and filter to obtain a crude product. Add 1200ml of acetone to the crude product, heat to 50°C and keep warm for 1h, cool to 40°C, filter, and recover the filtrate under reduced pressure to obtain 40.79g of solid with a liquid content of 94.91%.

[0067] Mass spectrometry analysis Figure 3 As shown: The molecular weight is 762.94, which is consistent with the inferred molecular formula C 37 H 66 N 2 O 14 be consistent.

[0068] The infrared absorption spectrum (IR) of the obtained solid is as follows Figure 1 As shown, the carbon spectrum ( 13 C-NMR) Figure 2 As shown, Figure 1 , Figure 2 The structure of the sample was confirmed.

[0069] Example 3

[0070] The present application is to prepare 3'-N-demethylerythromycin A(E)-9-oxime, and the process is as follows:

[0071] Put 100g of erythromycin A(E)-9-oxime in a four-necked bottle, add 800ml of ethanol, heat to 60℃, add 88g of sodium acetate and 200gml of water, add 34g of iodine, add 10% of liquid alkali to adjust the pH to 10, react for 6h, concentrate the ethanol under reduced pressure, add 600ml of dichloromethane, extract and separate the layers, extract the water layer once with 100ml of dichloromethane, combine the organic layers, wash with saturated brine, and recover the organic layers under reduced pressure. Add 100g of acetone to the crude product, heat to 50℃ and keep warm for 1h. Cool to 20℃, filter, and dry to obtain 35.26g of solid with a content of 96.24%.

[0072] Example 4

[0073] The present application is to prepare 3'-N-demethylerythromycin A (E)-9-oxime ether, the process is as follows:

[0074] Put 25g 3'-N-demethylerythromycin A(E)-9-oxime in a four-necked bottle, add 400ml dichloromethane, recover 150ml dichloromethane, cool to 20℃, add 5.5g N-methylpyrrolidone hydrochloride, add 10.6g 2-ethoxypropylene after the system is clarified. Heat to 25℃ and keep warm for 40min. Add 50ml water to terminate the reaction, adjust the pH to 11 with 10% liquid alkali. Stir for 10min and separate. Extract the water layer with 70ml dichloromethane and combine the organic layers. Wash with 50ml saturated brine. Recover the organic layer under reduced pressure to obtain 21.24g solid with a content of 84.38%.

[0075] Example 5

[0076] The present application prepares 3'-N-demethyl-3'-N-nitrosoerythromycin A (E)-9-oxime ether, and the process is as follows:

[0077] Put 20g of 3'-N-demethylerythromycin A(E)-9-oxime ether in a four-necked bottle, add 200ml of methanol, stir and dissolve, and heat to 50°C. Add 28g of sodium nitrite and 50ml of water, and adjust the pH to 3 with formic acid. Keep the reaction warm for 5.5h. Concentrate the methanol under reduced pressure, add 100ml of dichloromethane and 50ml of water, adjust the pH of the water layer to 10, separate the layers, extract the water layer with 50ml of dichloromethane, combine the organic layers, wash with saturated brine, and recover the organic layer under reduced pressure to obtain 15.48g of solid with a content of 78.21%.

[0078] Example 6

[0079] The present application prepares 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime, and the process is as follows:

[0080] In a four-necked bottle, add 15g of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime ether, add 115ml of ethanol and 115ml of water, stir for 5 minutes, add 10g of acetic acid and 21g of sodium bisulfite to control the pH at about 4.5, keep warm at 75℃ for reaction, react for 3.5h, drop 10% liquid alkali to adjust the pH to 11, stir for 30min, filter, and dry under reduced pressure to obtain a crude product. Add 25g of acetone, heat to 50℃ and keep warm for 1h, cool to 20℃, filter, and dry the filter cake under reduced pressure to obtain 7.49g of solid with a content of 90.99%.

[0081] Mass spectrometry in positive ion mode Figure 6 As shown: the ion peaks at m / z 764.4488, 786.4329, and 1549.8740 correspond to (M+H)+, (M+Na)+, and (2M+Na)+ signals), and the molecular weight is 763.92, which is consistent with the inferred molecular formula C 36 H 65 N 3 O 14 be consistent.

[0082] The infrared absorption spectrum (IR) of the obtained solid is as follows: Figure 4 As shown, the carbon spectrum ( 13 C-NMR) Figure 5 As shown, Figure 4 , Figure 5 The structure of the sample was confirmed.

[0083] The synthesis of nitrosamine impurities related to clarithromycin and its intermediate erythromycin oxime is conducive to the development of detection methods for nitrosamine impurities related to clarithromycin and its intermediate erythromycin oxime. Secondly, the synthesized high-purity clarithromycin nitrosamine can be directly used as a reference substance for the detection of nitrosamine impurity content in clarithromycin finished products. In addition, through the study of the synthesis and generation mechanism of related nitrosamines, we discovered the source of related nitrosamine impurities in the production process of clarithromycin. By adding inhibitors to the reaction and optimizing the refining method, we have effectively reduced the content of nitrosamine impurities 3'-N-demethyl-3'-N-nitroso-6-O-erythromycin in clarithromycin, meeting the customer's requirement of less than 1ppm.

[0084] The above shows that the two related nitrosamine substances prepared in this case can be used as reference substances in the qualitative and quantitative analysis and removal research of clarithromycin nitrosamine impurities, which is beneficial to improving the drug safety of clarithromycin and filling the gap in the research of clarithromycin impurities.

[0085] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing nitrosamine impurities, characterized in that: The nitrosamine impurity is 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin or 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime, 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin is a clarithromycin-related nitrosamine impurity. Clarithromycin is used as a raw material. 3'-N-demethyl-6-O-methylerythromycin is first obtained by demethylation reaction, and then reacted with a nitrosating agent in an organic solvent. The structural formula is: 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime is a nitrosamine impurity related to erythromycin oxime, an intermediate of clarithromycin. Erythromycin A(E)-9-oxime is used as a raw material. 3'-N-demethylerythromycin A(E)-9-oxime is first obtained by demethylation reaction. Then, it is reacted with N-methylpyrrolidone hydrochloride and 2-ethoxypropylene to obtain 3'-N-demethylerythromycin A(E)-9-oxime etherate. The oxime etherate is reacted with a nitrosating agent in an organic solvent to obtain 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime etherate. The nitrosated oxime etherate is obtained by hydrolysis reaction. The structural formula is:

2. The method for preparing nitrosamine impurities according to claim 1, characterized in that: The preparation steps of 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin are as follows: Step 1, preparation of 3'-N-demethyl-6-O-methylerythromycin: Using clarithromycin as a raw material, adding ethanol thereto, heating to 60-70°C, then adding sodium acetate, water and iodine, adjusting the pH to 10-11, keeping the temperature for reaction for 6-12 hours, concentrating the ethanol under reduced pressure, adding dichloromethane for extraction, combining the organic layers, washing with saturated brine, recovering the organic layers under reduced pressure to obtain a crude product, adding acetone to the crude product, heating to 50-55°C for 1-3 hours, cooling to 10-20°C, filtering, drying, and baking the filter cake under reduced pressure to obtain 3'-N-demethyl-6-O-methylerythromycin; Step 2, preparation of 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin: An organic solvent is added to 3'-N-demethyl-6-O-methylerythromycin, the temperature is raised to 50-75°C, a nitrosating agent and water are added, the molar ratio of 3'-N-demethyl-6-O-methylerythromycin to the nitrosating agent is 1:5-15, the pH is adjusted to 5-6, the reaction is performed for 4-6 hours, the mixture is cooled to 10-20°C, filtered, the filter cake is dried under reduced pressure to obtain a crude product, acetone is added to the crude product, the temperature is raised to 50-55°C and kept for 1-3 hours, the temperature is lowered to 30-40°C, filtered, and the filtrate is recovered under reduced pressure to obtain 3'-N-demethyl-3'-N-nitroso-6-O-methylerythromycin.

3. The method for preparing nitrosamine impurities according to claim 2, characterized in that: The ratio of the mass of 3'-N-demethyl-6-O-methylerythromycin to the volume of the organic solvent is 1:5-15.

4. The method for preparing nitrosamine impurities according to claim 2, characterized in that: To adjust pH, use C1-C4 organic acid or common inorganic acid.

5. The method for preparing nitrosamine impurities according to claim 2, characterized in that: The organic solvent is a C1-C4 alcohol.

6. The method for preparing nitrosamine impurities according to claim 1, characterized in that: The preparation process of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime is as follows: Step 1, preparation of 3'-N-demethylerythromycin A(E)-9-oxime: Erythromycin A(E)-9-oxime is used as a raw material, ethanol is added thereto, the temperature is raised to 60-70°C, sodium acetate, water and iodine are continuously added, the pH is adjusted to 10-11, the temperature is kept for reaction for 6-12 hours, ethanol is concentrated under reduced pressure, dichloromethane is added for extraction, the organic layers are combined, saturated brine is washed, the organic layers are recovered under reduced pressure to obtain a crude product, acetone is added to the crude product, the temperature is raised to 50-55°C for 1-3 hours, the temperature is lowered to 10-20°C, filtered, dried, and the filter cake is baked under reduced pressure to obtain 3'-N-demethylerythromycin A(E)-9-oxime; Step 2, preparation of 3'-N-demethylerythromycin A(E)-9-oxime ether: Add dichloromethane to 3'-N-demethylerythromycin A(E)-9-oxime, recover part of the dichloromethane under normal pressure, cool to 15-20°C, add N-methylpyrrolidone hydrochloride, add 2-ethoxypropylene after the system is clarified, heat to 25-30°C and keep warm for 30-40 minutes, add water to terminate the reaction, adjust the pH to 9-11, separate the layers, extract the water layer with dichloromethane, combine the organic layers, wash the layers with saturated brine, and recover the organic layer under reduced pressure to obtain 3'-N-demethylerythromycin A(E)-9-oxime etherified product; Step 3, preparation of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime ether: 3'-N-demethylerythromycin A(E)-9-oxime ether is added with organic solvent 1, stirred and dissolved, and then heated to 50-75° C., a nitrosating agent and water are added, the molar ratio of 3'-N-demethylerythromycin A(E)-9-oxime ether is 1:5-15, the pH is adjusted to 5-6, the reaction is kept warm for 5-6 hours, the organic solvent 1 is concentrated under reduced pressure, and after concentration, organic solvent 2 and water are added to adjust the pH of the water layer to 9-12, separate the layers, extract the water layer with organic solvent 2, combine the organic solvent layers, wash with saturated brine, recover under reduced pressure, filter, and recover the filtrate under reduced pressure to obtain 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime ether; Step 4, preparation of 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime: After 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime ether, ethanol and water are stirred evenly, acetic acid and sodium bisulfite are added, the temperature is raised to 70-75°C and reacted for 3-4 hours, cooled to 20-30°C, the pH is adjusted to 10-12, stirred, and filtered to obtain a crude product. After the crude product is dried under reduced pressure, acetone is added at 50-55°C and kept warm for 1-3 hours, the temperature is lowered to 10-20°C, filtered, and the filter cake is dried under reduced pressure to obtain 3'-N-demethyl-3'-N-nitrosoerythromycin A(E)-9-oxime.

7. The method for preparing nitrosamine impurities according to claim 6, characterized in that: The ratio of the mass of 3'-N-demethylerythromycin A(E)-9-oxime ether to the volume of the organic solvent is 1:5-15.

8. The method for preparing nitrosamine impurities according to claim 6, characterized in that: The ratio of the mass of 3'-N-demethylerythromycin A(E)-9-oxime ether to the volume of the organic solvent is 1:2-5.

9. The method for preparing nitrosamine impurities according to claim 6, characterized in that: The first organic solvent is a C1-C4 alcohol, and the second organic solvent is dichloromethane, chloroform, DMF or ethyl acetate.

10. The method for preparing nitrosamine impurities according to any one of claims 1 to 9, characterized in that: The nitrosating agent is any one of nitrous acid, sodium nitrite and potassium nitrite.

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