Preparation method of prazomicin impurity A000160
By converting the key intermediate A00007 of prazomicin into the target impurity A000160 under mild reaction conditions, the problem of lack of this impurity preparation method in the prior art is solved, and efficient preparation of high-purity impurities is achieved, and the reliability of drug quality and stability research is improved.
Patent Information
- Application Number
- CN202311645168.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-04
- Publication Date
- 2025-06-06
AI Technical Summary
The lack of preparation method of the prazomibcin impurity A000160 in the prior art makes it difficult to obtain as a standard reference product, affecting the quality and stability of the drug.
The target impurity A000160 was prepared by reducing and deprotection reaction under acidic conditions using mild reactions and efficient synthesis. Specific steps include hydrogenation reaction at room temperature, deprotection reaction and purification by under-pressure distillation, dissolution, extraction and lyophilization.
The high-purity prazomicin impurity A000160 was successfully prepared, providing a standard reference product for identification of impurities in prazomicin finished products, improving the reliability of drug quality and stability research.
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Figure CN120098055A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of merging, and in particular to a method for preparing prazomicin impurity A000160. Background Art
[0002] Plazomicin is a new type of semi-synthetic aminoglycoside antibiotic that has just been launched in recent years. In June 2018, plazomicin injection (Zemdri) was approved by the US Food and Drug Administration for marketing. It is suitable for the treatment of patients over 18 years old with complicated urinary tract infections, including pyelonephritis. Compared with previous generations of aminoglycosides, its risk of nephrotoxicity is relatively low.
[0003] The mechanism of action of plazomicin is to bind to the bacterial 30S ribosomal subunit, interfere with bacterial protein synthesis and thus have a bactericidal effect. It can avoid being destroyed by the main aminoglycoside antibiotic inactivating enzyme and lose its activity. Plazomicin has good activity against many Gram-negative bacteria and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus isolates.
[0004] The starting material for the synthesis of prazomicin is a fermentation product with many types of impurities. The study of impurities plays an important role in ensuring the production, quality and stability of drugs. Therefore, it is very important to provide impurity reference materials for drug quality research. However, the finished product of prazomicin is not found on the market to contain prazomicin impurity A000160 (as shown below). Therefore, no one has considered synthesizing this impurity and using it as a standard reference material for the identification of impurities contained.
[0005] Summary of the invention
[0006] The present invention aims to overcome the above-mentioned defects and obtains A000160 by adopting mild reaction conditions and an efficient synthesis process.
[0007] 1. The prazomicin impurity A000160 provided by the present invention is characterized in that it is a compound shown in the following structure:
[0008]
[0009] The preparation method of the prazomicin impurity A000160 provided by the present invention is characterized in that: using the key intermediate A000007 of prazomicin as a starting material, reducing to obtain a reduction product, and deprotecting the reduction product under acidic conditions to obtain the target impurity A000160;
[0010] The structure of the key intermediate A000007 of plazomicin is shown below:
[0011]
[0012] The structure of the above target impurity A000160 is as follows:
[0013]
[0014] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000160 as claimed in claim 1, characterized in that:
[0015] The above acidic conditions refer to the addition of a halogen-containing reagent during the deprotection process.
[0016] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000160 as claimed in claim 1, characterized in that:
[0017] The halogen-containing reagent is selected from trifluoroacetic acid, trichloroacetic acid, hydrobromic acid and TMSI.
[0018] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000160 as claimed in claim 1, characterized in that:
[0019] The deprotection reaction is carried out at room temperature under protective gas protection;
[0020] The ratio of the reduced product to the deprotecting agent is 500-1000 mg of the reduced product / 5 ml of the deprotecting agent.
[0021]
[0022] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000160 as claimed in claim 1, characterized in that:
[0023] The deprotection reaction is carried out in a haloalkyl solvent.
[0024] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000160 as claimed in claim 1, characterized in that:
[0025] The crude product after deprotection is purified by vacuum distillation, dissolution, extraction and freeze-drying.
[0026] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000160 as claimed in claim 1, characterized in that:
[0027] The above reduction conditions are palladium carbon and catalytic hydrogenation.
[0028] Application of prazomicin impurity A000160 in identifying impurities contained in prazomicin finished products. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] Figure 1 , the analytical spectrum of the product of Example 1;
[0030] Figure 2 , the analytical spectrum of the product of Example 1; DETAILED DESCRIPTION
[0031] In this example, the key intermediate A000007 of plazomicin is used as the starting material, and a hydrogenation reaction is carried out at normal pressure to obtain compound 1. Next, under acidic conditions, four protecting groups are removed at the same time and reduced to amino groups to obtain the target impurity A000160. The reaction equation of this preparation method is as follows:
[0032]
[0033] The preferred embodiments are as follows:
[0034] Example 1
[0035] Compound A000007 (900 mg, 1 mmol) and methanol (10 mL) were added to the reaction bottle at 25°C and stirred to dissolve, Pd / C (0.45 g, 50% water) was added, hydrogen was replaced three times, and the reaction was stirred overnight for about 16 hours at room temperature and hydrogen. LCMS showed that the reaction was complete, and the filtrate was filtered and concentrated to obtain an off-white solid product 1 (880 mg, yield: 97%). MS (ESI, m / z): 995.2 [M+H] +.
[0036] Compound 1 (880 mg, 0.88 mmol), dichloromethane (5 mL), and trifluoroacetic acid (5 mL) were added to the reaction bottle at 25°C. The mixture was stirred for 2 hours under argon protection at 25°C. LCMS showed that the reaction was complete. The solvent was evaporated under reduced pressure, 10 mL of water was added to dissolve, and the mixture was washed three times with ethyl acetate. 0.05 g of activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and freeze-dried in a freeze dryer to obtain an off-white solid A000160 (363 mg, yield: 82.90%) with a purity of 88.04%.
[0037] MS(ESI,m / z):495.2[M+H]+.1HNMR(400MHz,D2O)δ5.22(d,J=1.6Hz,1H),5.14(d,J=3.6Hz,1H),4.2 5(dd,J=9.2,4.0Hz,1H),4.19-4.16(m,3H),4.02(dd,J=9.2,4.0Hz,1H),3.90-3.82(m,4H),3.80-3 .75(m,2H),3.42-3.38(m,2H),3.34-3.20(m,5H),3.18(t,J=7.2Hz,2H),2.91(s,3H),2.23-2.15(m ,4H),2.06-1.92(m,1H),1.82-1.71(m,2H),1.51-1.43(m,1H),1.33(s,3H),1.24(d,J=6.4Hz,1H).
[0038] Example 2
[0039] Compound A000007 (900 mg, 1 mmol) and methanol (10 mL) were added to the reaction bottle at 25°C and stirred to dissolve, Pd / C (0.45 g, 50% water) was added, hydrogen was replaced three times, and the reaction was stirred overnight at room temperature and hydrogen for about 16 hours. LCMS showed that the reaction was complete, and the filtrate was filtered and concentrated to obtain an off-white solid product 1 (883 mg, yield: 97.33%). MS (ESI, m / z): 995.2 [M+H] +.
[0040] Compound 1 (880 mg, 0.88 mmol), dichloromethane (5 mL), and trichloroacetic acid (5 mL) were added to the reaction flask at 25°C in sequence. The mixture was stirred for 3 hours under argon protection at 25°C. LCMS showed that the reaction was complete. The solvent was evaporated under reduced pressure, 10 mL of water was added to dissolve, and the mixture was washed three times with ethyl acetate. 0.05 g of activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and freeze-dried in a freeze dryer to obtain an off-white solid A000160 (180 mg, yield: 41.10%) with a purity of 81.21%.
[0041] Example 3
[0042] Compound A000007 (900 mg, 1 mmol) and methanol (10 mL) were added to the reaction bottle at 25°C and stirred to dissolve, Pd / C (0.45 g, 50% water) was added, hydrogen was replaced three times, and the reaction was stirred overnight at room temperature and hydrogen for about 16 hours. LCMS showed that the reaction was complete, and the filtrate was filtered and concentrated to obtain an off-white solid product 1 (885 mg, yield: 97.55%). MS (ESI, m / z): 995.2 [M+H] +.
[0043] Compound 1 (880 mg, 0.88 mmol), dichloromethane (5 mL), and 40% hydrobromic acid (5 mL) were added to the reaction bottle at 25°C. The mixture was stirred for 2 hours under argon protection at 25°C. LCMS showed that the reaction was complete. The solvent was evaporated under reduced pressure, 10 mL of water was added to dissolve, and the mixture was washed three times with ethyl acetate. 0.05 g of activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and freeze-dried in a freeze dryer to obtain an off-white solid A000160 (218 mg, yield: 49.78%) with a purity of 83.13%.
[0044] Example 4
[0045] Compound A000007 (900 mg, 1 mmol) and methanol (10 mL) were added to the reaction bottle at 25°C and stirred to dissolve, Pd / C (0.45 g, 50% water) was added, hydrogen was replaced three times, and the reaction was stirred overnight at room temperature and hydrogen for about 16 hours. LCMS showed that the reaction was complete, and the filtrate was filtered and concentrated to obtain an off-white solid product 1 (882 mg, yield: 97.22%). MS (ESI, m / z): 995.2 [M+H] +.
[0046] Compound 1 (880 mg, 0.88 mmol), acetonitrile (5 mL), and TMSI (2 mL) were added to the reaction bottle at 25°C. The mixture was stirred for 2 hours under argon protection at 25°C. LCMS showed that the reaction was complete. The solvent was evaporated under reduced pressure, 10 mL of water was added to dissolve, and the mixture was washed three times with ethyl acetate. 0.05 g of activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and freeze-dried in a freeze dryer to obtain an off-white solid A000160 (265 mg, yield: 60.52%) with a purity of 81.67%.
[0047] Example 5
[0048] Compound A000007 (900 mg, 1 mmol) and methanol (10 mL) were added to the reaction bottle at 25°C and stirred to dissolve, Pd / C (0.45 g, 50% water) was added, hydrogen was replaced three times, and the reaction was stirred overnight at room temperature and hydrogen for about 16 hours. LCMS showed that the reaction was complete, and the filtrate was filtered and concentrated to obtain an off-white solid product 1 (882 mg, yield: 97.22%). MS (ESI, m / z): 995.2 [M+H] +.
[0049] Compound 1 (880 mg, 0.88 mmol), acetonitrile (5 mL), and TMSI (2 mL) were added to the reaction bottle at 25°C. The mixture was stirred for 2 hours at 40°C under argon protection. LCMS showed that the reaction was complete. The solvent was evaporated under reduced pressure, 10 mL of water was added to dissolve, and the mixture was washed with ethyl acetate three times. 0.05 g of activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and freeze-dried in a freeze dryer to obtain an off-white solid A000160 (170 mg, yield: 38.82%) with a purity of 73.36%.
Claims
1. Prazomicin impurity A000160, Features: The compound is shown in the following structure:
2. A method for preparing the impurity A000160 of prazomicin, Features: The key intermediate A000007 of prazomicin is used as the starting material, and a reduction product is obtained by reduction. The reduction product is deprotected under acidic conditions to prepare the target impurity A000160; wherein the structure of the key intermediate A000007 of prazomicin is as follows: The structure of the target impurity A000160 is as follows:
3. The preparation method of the prazomicin impurity A000160 according to claim 2, Features: The acidic conditions refer to the addition of a halogen-containing reagent during the deprotection process.
4. The method for preparing the prazomicin impurity A000160 according to claim 2, Features: The halogen-containing reagent is selected from trifluoroacetic acid, trichloroacetic acid, hydrobromic acid, and TMSI.
5. The method for preparing the prazomicin impurity A000160 according to claim 2, Features: The deprotection reaction is carried out at room temperature under protective gas protection; The ratio of the reduced product to the deprotecting agent is 500-1000 mg of the reduced product / 5 ml of the deprotecting agent.
6. The method for preparing the prazomicin impurity A000160 according to claim 2, Features: The deprotection reaction is carried out in a haloalkyl solvent.
7. The method for preparing the prazomicin impurity A000160 according to claim 2, Features: The crude product after deprotection is purified by vacuum distillation, dissolution, extraction and freeze-drying.
8. The method for preparing the prazomicin impurity A000160 according to claim 2, Features: The reduction conditions are palladium carbon and catalytic hydrogenation.
9. Application of prazomicin impurity A000160 in identifying impurities contained in prazomicin finished products.