A method for preparing spiramycin ep impurity g
Spiramycin EP impurity G was prepared from spiramycin I through selective esterification and hydrolysis, which solves the problem of lack of synthetic methods in the prior art, realizes the preparation of high-purity impurity G, and supports drug quality control and safety research.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-04-10
- Publication Date
- 2026-06-26
AI Technical Summary
The lack of a synthetic method for spiramycin EP impurity G in the existing technology affects drug quality control and safety.
Spiramycin I was used as the starting material, and spiramycin EP impurity G was prepared through selective esterification, esterification and two-step selective hydrolysis. The synthetic route was reasonably designed and the overall yield was over 60% after optimization.
This study achieved efficient preparation of impurity G in spiramycin EP, with a product purity of over 94%, which is helpful for studying the absorption, distribution, metabolism, and excretion characteristics of the drug.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a preparation method of a compound, in particular to a preparation method of spiramycin EP impurity G. BACKGROUND
[0002] Spiramycin, consisting of the main component: spiramycin I ((4R, 5S, 6S, 7R, 9R, 10R, 11E, 13E, 16R)-6-[[3, 6-dideoxy-4-O-(2, 6-dideoxy-3-C-methyl-α-L-ribo-hexopyranosyl)-3- (dimethylamino)-β-D-glucopyranosyl]oxy]-4-hydroxy-5-methoxy-9, 16-dimethyl-7-(2-oxoethyl)- 10-[[2, 3, 4, 6-tetradeoxy-4-(dimethylamino)-Derythro-hexopyranosyl]oxy]oxacyclohexadeca-11, 13- dien-2-one) and the secondary components spiramycin II (4-O-acetylspiramycin I), spiramycin III (4-O-propanoylspiramycin I). Isolated from Streptomyces ambofaciens metabolites by French Rhone-Poulenc Laboratory in 1954, containing a 16-membered ring, belongs to macrolide antibiotics. It is generally believed that spiramycin acts on the bacterial ribosome 50S subunit (does not affect human ribosomes, human is 80S ribosome, higher safety), hinders the elongation of the peptide chain, thereby terminating the synthesis of proteins, thereby inhibiting the synthesis of bacterial proteins. The antibacterial spectrum of spiramycin is similar to that of erythromycin, mainly acting on gram-positive bacteria and some gram-negative bacteria, rickettsia and large viruses, etc., such as streptococcus, meningococcus, pertussis bacillus, mycoplasma pneumoniae, diphtheria bacillus, chlamydia trachomatis, leptospira and clostridium, etc. The product has strong effect on penicillin, streptomycin, tetracycline and chloramphenicol resistant bacteria. It is mainly used for various sensitive bacterial infections in clinic, such as upper respiratory tract infection, urinary tract infection, meningitis, mastitis, osteomyelitis, scarlet fever, otitis media, buccal infection and sinusitis, etc.
[0003] Any drug may contain a small amount of impurities due to synthesis, storage and other factors. The study of impurities is an important part of drug development. Whether the impurities can be controlled comprehensively and accurately is directly related to the controllability and safety of drug quality. Therefore, in the supply, production, research and clinical use of drugs, the purity of the drug must be ensured. The study of impurities should be standardized, and the impurities should be controlled within a safe and reasonable limit range, so as to ensure the effectiveness and safety of the drug. Especially the impurities reported by EP (European Pharmacopoeia), which has high legal and scientific practicality in the whole process of drug research and development, production, quality control and reporting, is the core basis for drug compliance and quality control in the European Union and global mainstream markets, and is widely adopted by ICH, FDA, PMDA and others. The use of EP impurity standards for detection in drug reporting can directly serve as a quality control basis, significantly reducing the risk of supplementing and accelerating the review. The spiral mycin EP impurity G reported in this paper is the impurity G in the spiral mycin reported by EP. At present, there is no report on the synthesis method of the impurity. SUMMARY
[0004] The purpose of the present application is to provide a preparation method of spiral mycin EP impurity G with reasonable process design.
[0005] Technical scheme: The preparation method of spiral mycin EP impurity G provided by the present application comprises the following steps:
[0006] (1) Add spiral mycin I to the solvent, add base and esterification reagent, and carry out selective esterification reaction to obtain compound ; the reaction temperature of the selective esterification is 10-30℃, and the molar ratio of spiral mycin I to esterification reagent is 1:1-1:1.2;
[0007] (2) Take compound and add it to the solvent, add base and esterification reagent, and carry out esterification reaction to obtain compound :
[0008] (3) Take compound and add it to the acidic solvent to carry out selective hydrolysis reaction to obtain compound : the reaction temperature of the selective hydrolysis reaction is 0-40℃, and the pH of the acidic solvent is 0.8-2.0;
[0009] (4) Take compound and add it to the solvent, add base, and carry out selective hydrolysis reaction to obtain compound IV, i.e. spiral mycin EP impurity G; the synthesis route is as follows:
[0010] .
[0011] In step (1), selective esterification can be achieved by controlling the appropriate temperature and the amount of esterification reagent. Excessive temperature or excessive amount of esterification reagent will lead to multi-site esterification.
[0012] Preferably, in step (1), the reaction time is 2-16 hours.
[0013] Preferably, in step (1), the esterification reagent is benzoic anhydride or benzoyl chloride.
[0014] Preferably, in step (1), the base is one of triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), or 4-dimethylaminopyridine (DMAP), and the molar ratio of spiramycin I to the base is 1:1.5-1:5.
[0015] Preferably, in step (1), the solvent is one of tetrahydrofuran, acetonitrile, DMF, and dichloromethane, and the mass-volume ratio of spiramycin I to the solvent is 1:5-1:30 g / mL.
[0016] Preferably, in step (2), the esterification reaction is carried out at a temperature of 40-60°C for 2-16 hours.
[0017] Preferably, in step (2), the esterification reagent is acetic anhydride or acetyl chloride.
[0018] Preferably, in step (2), the solvent is one of tetrahydrofuran, acetonitrile, DMF, and dichloromethane, and the base is one or more of triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), and 4-dimethylaminopyridine (DMAP).
[0019] In step (3), disaccharides can be selectively hydrolyzed by controlling the pH. If the pH is not controlled properly or the reaction time is too long, other sugars will also be hydrolyzed.
[0020] Preferably, in step (3), the reaction time is 2-8 hours.
[0021] Preferably, in step (3), the acidic solvent is one of dilute hydrochloric acid, dilute sulfuric acid, trifluoroacetic acid / dichloromethane, dilute hydrochloric acid / tetrahydrofuran, dilute hydrochloric acid / acetonitrile, dilute sulfuric acid / tetrahydrofuran, and dilute sulfuric acid / acetonitrile.
[0022] Preferably, in step (3), the compound The mass-to-volume ratio with the acidic solvent is 1:5-1:30 g / mL.
[0023] In step (4), by using a base and controlling the equivalent amount, the benzoyl group can be selectively hydrolyzed while retaining the acetyl group. Preferably, the base is one of benzyltrimethylammonium hydroxide, tetrabutylammonium fluoride, or lithium hydroxide. More preferably, the molar ratio of compound III to the base is 1:0.5-1:8.
[0024] Preferably, in step (4), the reaction temperature is -30~30℃. More preferably, the reaction time is 0.5~10h.
[0025] Preferably, in step (4), the solvent is one of tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, and methanol.
[0026] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The present invention provides a method for preparing spiramycin EP impurity G, starting with spiramycin I, and obtaining spiramycin EP impurity G through selective esterification, esterification and two-step selective hydrolysis. The preparation route is reasonably designed and the total yield after optimization is more than 60%; (2) The raw materials involved in this method are readily available, the synthetic route is highly operable, and the product purification is convenient; (3) The purity of the target product obtained can reach more than 94%, which helps to study the metabolic pathway and process of spiramycin and clarify the absorption, distribution, metabolism and excretion characteristics of the drug. Attached Figure Description
[0027] Figure 1 This is a schematic diagram of the synthetic route of the present invention;
[0028] Figure 2 The NMR spectrum of Spiramycin EP Impurity GDitrifluoroacetate, obtained in Example 1 of the present invention, i.e. Spiramycin EP impurity G;
[0029] Figure 3 The liquid phase diagram shows the compound Spiramycin EP Impurity GDitrifluoroacetate, obtained in Example 1 of the present invention, i.e., Spiramycin EP impurity G. Detailed Implementation
[0030] The technical solution of the present invention will be further described below with reference to the embodiments.
[0031] Example 1
[0032] The method for preparing spiramycin EP impurity G of the present invention includes the following steps:
[0033] (1) Compound Preparation: 10.00 g (11.9 mmol) of spiramycin I [CAS: 24916-50-5 purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd. (Lot: EQX088)] was dissolved in 100.0 mL of dichloromethane. 3.3 mLTEA (23.7 mmol) and 3.22 g benzoic anhydride (13.0 mmol) were added at 20 °C. The mixture was stirred at 20 °C for 8 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 10:1). The reaction solution was extracted twice with saturated NaHCO3 aqueous solution (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 10.80 g of the compound. White solid, yield 96.1%.
[0034] (2) Compounds Preparation: Take 8.00 g (8.4 mmol) of the compound. Dissolved in 80.0 mL of dry dichloromethane, 4.7 mL of TEA (33.8 mmol), 0.10 g of DMAP (0.8 mmol), and 2.4 mL of acetic anhydride (25.3 mmol) were added at 20 °C. The mixture was stirred at 50 °C for 12 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 20:1). The reaction solution was washed twice with saturated NaHCO3 aqueous solution (100.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 7.95 g of the compound. White solid, yield 91.3%.
[0035] (3) Compounds Preparation: Take 7.00 g of compound Dissolve in 35.0 mL acetonitrile, add 35 mL 1N HCl (pH=1), and react at 20 °C for 4 hours. Monitor the reaction end by TLC (stationary phase silica gel, mobile phase DCM:MeOH=10:1). Add 200.0 mL water, adjust pH to 8 with saturated NaHCO3 aqueous solution, and extract three times with ethyl acetate (200.0 mL x 3). Combine the organic phases, wash three times with saturated brine (200 mL x 3), dry to anhydrous sodium sulfate, filter, and evaporate to dryness. 5.10 g of the compound is then removed by rotary evaporation. White solid, yield 88.9%.
[0036] (4) Preparation of Spiramycin EP Impurity G Ditrifluoroacetate (i.e., Spiramycin EP Impurity G): Take 3.00 g (3.6 mmol) of the compound Dissolve in 60.0 mL dichloromethane, cool to -25℃, and add 3.4 mL benzyltrimethylammonium hydroxide (40% aqueous solution, 21.3 mmol molar amount of base). Maintain the reaction at -25℃ with stirring for half an hour. Monitor the reaction completion by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 10:1). Add 50.0 mL water. Wash the organic phase four times with saturated ammonium chloride (50.0 mL x 2) and saturated saline (50.0 mL x 2). Rotate the organic phase to dryness and purify using a Hanhuang UV3000 / NP7000 high-performance liquid chromatograph. The chromatographic column is DAC-50, the packing material is C18 (ODS-P), the particle size is 8 μm, the UV detection wavelength is 220 / 254 nm, the mobile phase A is acetonitrile, and the mobile phase B is 0.05% trifluoroacetic acid (TFA) aqueous solution, with a gradient of 5%-30% (0-5 min). 30%-40% (5-35 min), flow rate 40 mL / min, lyophilized to obtain 2.77 g Spiramycin EP Impurity G Ditrifluoroacetate (the product is a trifluoroacetate, which has no effect on the use of the standard. If removal is required, the sample can be dissolved in acetonitrile and water at a ratio of 1:1, exchanged with hydroxide anion exchange resin, and then lyophilized to obtain the free product). It is a white solid with a yield of 80.5%.
[0037] The NMR spectrum of impurity G of spiramycin EP is as follows: Figure 2 As shown, the obtained spiramycin EP impurity G was correctly detected by NMR. 1H NMR ( in DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 9.31 (br, 1H), 8.86 (br,1H), 6.39 (dd, 1H), 6.21 (d, 1H), 6.04 (m, 2H), 5.62-5.55 (m, 2H), 4.97-4.88(m, 2H), 4.56 (d, 1H), 4.42 (d, 1H), 3.85 (dd, 1H), 3.71(d, 2H), 3.45-3.18(m, 9H), 3.01 (m, 1H), 2.88-2.76 (m, 9H), 2.64 (d, 3H), 2.54-2.48 (m, 3H),2.30 (d, 1H), 2.13 (s, 3H), 1.97-1.85 (m, 4H), 1.71 (q, 1H), 1.41 (t, 2H),1.19 (m, 6H), 1.13 (d, 3H), 0.94 (m, 1H), 0.88 (d, 3H).
[0038] The liquid chromatography diagram of impurity G in spiramycin EP is shown below. Figure 3 As shown, the HPLC yield was 94.7640%, with all four steps yielding over 80% and a total yield of 62.8%. The intermediates did not require additional purification, making the operation simple.
[0039] Example 2
[0040] The method for preparing spiramycin EP impurity G of the present invention includes the following steps:
[0041] (1) Compound Preparation: 10.00 g (11.9 mmol) of spiramycin I was suspended in 100.0 mL of dichloromethane, and 3.3 mL of TEA (23.7 mmol) and 2.00 g of benzoyl chloride (14.2 mmol) were added. The mixture was reacted at 10 °C for 2 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 10:1). The reaction solution was extracted twice with saturated NaHCO3 aqueous solution (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 9.10 g of the compound. White solid, yield 81.0%.
[0042] (2) Compounds Preparation: Take 8.00 g (8.4 mmol) of the compound. Dissolved in 80.0 mL dichloromethane, 4.7 mL TEA (33.8 mmol) was added, and 1.8 mL (25.3 mmol) acetyl chloride was added dropwise at 20 °C. The reaction was carried out at 40 °C for 3 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 20:1). The reaction solution was quenched in 100.0 mL water, and extracted twice with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by rotary evaporation and column chromatography to obtain 7.43 g of the compound. White solid, yield 85.3%.
[0043] (3) Compounds Preparation: Take 7.00 g (6.8 mmol) of the compound. The compound was dissolved in 70.0 mL of 0.16N HCl (pH=0.8) and reacted at 0℃ for 3 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH=10:1) until completion. The pH was adjusted to 8 with saturated sodium bicarbonate, and then extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography to obtain 4.51 g of the compound. White solid, yield 78.6%.
[0044] (4) Preparation of Spiramycin EP Impurity G Ditrifluoroacetate (i.e., Spiramycin EP Impurity G): Take 3.00 g (3.6 mmol) of the compound Dissolve in 60.0 mL tetrahydrofuran, cool to 0℃ and add 10.7 mL of 1M tetrabutylammonium fluoride (TBAF, 10.7 mmol) tetrahydrofuran solution. React at 15℃ for 8 hours. Monitor the reaction end by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 10:1). Add 100.0 mL water and 100.0 mL dichloromethane. Wash the organic phase twice with saturated brine (100.0 mL x 2). Rotate the organic phase to dryness and purify using a Hanhuang UV3000 / NP7000 high-performance liquid chromatograph. The chromatographic column is DAC-50, the packing material is C18 (ODS-P) with a particle size of 8 μm, the UV detection wavelength is 220 / 254 nm, the mobile phase A is acetonitrile, and the mobile phase B is 0.05% TFA (trifluoroacetic acid) aqueous solution with a gradient of 5%-30% (0-5 min). 30%-40% (5-35 min), flow rate 40 mL / min, lyophilized to obtain 2.69 g Spiramycin EP Impurity G Ditrifluoroacetate, a white solid, with a yield of 78.2%.
[0045] Example 3
[0046] The method for preparing spiramycin EP impurity G of the present invention includes the following steps:
[0047] (1) Compound Preparation: 10.00 g (11.9 mmol) of spiramycin I was dissolved in 100.0 mL of dichloromethane. 1.8 mL of TEA (17.8 mmol) and 2.68 g of benzoic anhydride (11.9 mmol) were added at 20 °C. The mixture was stirred at 30 °C for 4 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 10:1). The reaction solution was extracted twice with saturated NaHCO3 aqueous solution (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 9.86 g of the compound. White solid, yield 87.8%.
[0048] (2) Compounds Preparation: Take 8.00 g (8.4 mmol) of the compound. Dissolved in 80.0 mL of dry dichloromethane, 4.7 mL of TEA (33.8 mmol), 0.10 g of DMAP (0.8 mmol), and 2.4 mL of acetic anhydride (25.3 mmol) were added at 20 °C. The mixture was stirred at 60 °C for 6 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 20:1). The reaction solution was washed twice with saturated NaHCO3 aqueous solution (100.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 7.82 g of the compound. White solid, yield 89.8%.
[0049] (3) Compounds Preparation: Take 7.00 g of compound Dissolve in 35.0 mL THF, add 50 mL 0.005 MH2SO4 (pH=2), and react at 40 °C for 8 hours. Monitor the reaction end by TLC (stationary phase silica gel, mobile phase DCM:MeOH=10:1). Add 200.0 mL water, adjust pH to 8 with saturated NaHCO3 aqueous solution, and extract three times with ethyl acetate (200.0 mL x 3). Combine the organic phases, wash three times with saturated brine (200 mL x 3), dry to anhydrous sodium sulfate, filter, and evaporate to dryness to 4.81 g of compound. White solid, yield 83.9%.
[0050] (4) Preparation of Spiramycin EP Impurity G Ditrifluoroacetate (i.e., Spiramycin EP Impurity G): Take 3.00 g (3.6 mmol) of the compound Dissolved in 60.0 mL of 1,4-dioxane, 42.5 mg LiOH (1.8 mmol) was added, and the mixture was stirred at 20 °C for 10 hours. The reaction was monitored by TLC (stationary phase silica gel, mobile phase DCM:MeOH = 10:1) until the reaction was complete. 50.0 mL of saturated ammonium chloride was added, and the mixture was extracted with DCM (50.0 mL x 2). The organic phase was evaporated to dryness, and purification was performed using a Hanhuang UV3000 / NP7000 high-performance liquid chromatograph. The chromatographic column was DAC-50, the packing material was C18 (ODS-P) with a particle size of 8 μm, the UV detection wavelength was 220 / 254 nm, the mobile phase A was acetonitrile, and the mobile phase B was 0.05% TFA (trifluoroacetic acid) aqueous solution. The gradient was 5%-30% (0-5 min) ~ 30%-40% (5-35 min), the flow rate was 40 mL / min, and the product was lyophilized to obtain 1.93 g Spiramycin EP Impurity. GDitrifluoroacetate, also known as spiramycin EP impurity G, is a white solid with a yield of 56.1%.
[0051] Comparative Example 1
[0052] Based on Example 1, in step (1), the reaction temperature was changed to 45°C, while the other conditions remained unchanged, yielding 3.40 g of the compound. White solid, yield 30.3%.
[0053] As the reaction temperature increases, the esterification selectivity becomes poor, resulting in the residue of multiple esterification products and raw materials, which leads to a decrease in yield.
[0054] Comparative Example 2
[0055] Based on Example 1, in step (1), the amount of esterifying reagent was changed to 6.70 g (29.7 mmol), while the other conditions remained unchanged, yielding 3.73 g of compound. White solid, yield 33.2%.
[0056] Adding too much esterifying reagent can lead to the production of polyesterification byproducts, resulting in a decrease in yield.
[0057] Comparative Example 3
[0058] Based on Example 1, in step (3), the acid solvent was 0.5N HCl, the pH was 0.3, and the other conditions remained unchanged, yielding 1.10 g of the compound. White solid, yield 19.2%.
[0059] Increased acidity leads to increased hydrolysis of other sugars, resulting in a decrease in yield.
[0060] Comparative Example 4
[0061] Based on Example 1, in step (3), the acid solvent was 0.001N HCl, the pH was 3, and the other conditions remained unchanged, yielding 0.81 g of the compound. White solid, yield 14.1%.
[0062] Because the acidity is reduced, the reaction is less frequent, leading to a decrease in yield.
[0063] Comparative Example 5
[0064] Based on Example 1, in step (3), the temperature was changed to 60°C, while the other conditions remained unchanged, yielding 1.68 g of the compound. White solid, yield 29.3%.
[0065] The reaction temperature was changed to 60℃, which was too high, leading to increased hydrolysis of other sugars and a decrease in yield.
Claims
1. A method for preparing spiramycin EP impurity G, characterized in that, Includes the following steps: (1) Spiramycin I was added to a solvent, followed by the addition of a base and an esterification reagent, to induce a selective esterification reaction and obtain the compound. The selective esterification reaction temperature is 10-30℃, and the molar ratio of spiramycin I to the esterification reagent is 1:1 to 1:1.
2. (2) Take the compound When added to a solvent, a base and an esterification reagent are added, and an esterification reaction occurs to give the compound. : (3) Take the compound When added to an acidic solvent, it undergoes a selective hydrolysis reaction to yield the compound. The reaction temperature for the selective hydrolysis is 0-40℃, and the pH of the acidic solvent is 0.8-2.
0. (4) Take the compound The compound was added to a solvent, and then a base was added, resulting in a selective hydrolysis reaction to yield compound IV, which is impurity G of spiramycin EP. The synthetic route is as follows: 。 2. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (1), the esterification reagent is benzoic anhydride or benzoyl chloride.
3. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (1), the base is one of triethylamine, N,N-diisopropylethylamine or 4-dimethylaminopyridine, and the molar ratio of spiramycin I to the base is 1:1.5 to 1:
5.
4. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (1), the solvent is one of tetrahydrofuran, acetonitrile, DMF or dichloromethane, and the mass-volume ratio of spiramycin I to the solvent is 1:5~1:30 g / mL.
5. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (2), the esterification reagent is acetic anhydride or acetyl chloride.
6. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (2), the solvent is one of tetrahydrofuran, acetonitrile, DMF or dichloromethane, and the base is one or more of triethylamine, N,N-diisopropylethylamine or 4-dimethylaminopyridine.
7. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (3), the acidic solvent is one of dilute hydrochloric acid, dilute sulfuric acid, trifluoroacetic acid / dichloromethane, dilute hydrochloric acid / tetrahydrofuran, dilute hydrochloric acid / acetonitrile, dilute sulfuric acid / tetrahydrofuran, or dilute sulfuric acid / acetonitrile.
8. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (3), the compound The mass-to-volume ratio with the acidic solvent is 1:5-1:30 g / mL.
9. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (4), the reaction temperature is -30 to 30°C.
10. The method for preparing spiramycin EP impurity G according to claim 1, characterized in that, In step (4), the base is one of benzyltrimethylammonium hydroxide, tetrabutylammonium fluoride or lithium hydroxide, and the molar ratio of compound III to the base is 1:0.5-1:8.