Preparation method of prazomicin impurity A000045
The prazomibcin impurity A00045 was prepared by degradation and deprotection reactions catalyzed by ion exchange resin, which solved the problem of lack of this impurity preparation method in the prior art, and provided standard reference materials for impurity identification and drug quality control.
Patent Information
- Application Number
- CN202311645166.4
- 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 preparation method of the prazomibcin impurity A000045 is lacking in the prior art, resulting in the failure of the impurity to be identified as a standard reference.
The target impurity A000045 was prepared by taking compound A00005 as the starting material and carrying out degradation and deprotection reactions under the catalytic action of the ion exchange resin. The method includes reacting under a protective gas environment, using a hydrogen type or cation exchange resin, and controlling the reaction temperature below 40°C.
The prazomicin impurity A000045 was successfully prepared, providing a standard reference for the impurity for identification of impurities and quality control of pharmaceutical production.
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Figure CN120098054A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of chemical synthesis, and in particular relates to the preparation of prazomicin impurity A000045. 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. However, the finished product of prazomicin on the market has not been found to contain prazomicin impurity A0000045 (as shown below). Therefore, no one has considered synthesizing the impurity and using it as a standard reference substance for the identification of impurities.
[0005] Summary of the invention
[0006] The present invention aims to overcome the above-mentioned defects and provides a method for preparing impurity A000045.
[0007] The present invention provides a prazomicin impurity A000045, which is characterized by being a compound shown in the following structure:
[0008]
[0010] The preparation method of the prazomicin impurity A000045 provided by the present invention is characterized in that:
[0011] Using compound A000005 as the starting material, the target impurity A000045 was obtained by first degradation and then deprotection under the catalytic action of ion exchange resin;
[0012] Among them, the structure of compound A000005 is shown below:
[0013]
[0014] The structure of the target impurity A000045 is shown below:
[0015]
[0016] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000045, characterized in that:
[0017] The reaction is carried out under a protective gas environment.
[0018] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000045, characterized in that:
[0019] The ion exchange resin is selected from hydrogen type resin and cation exchange resin.
[0020] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000045, characterized in that:
[0021] The mass ratio of the compound A000005 to the ion exchange resin is 1:5-8.
[0022] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000045, characterized in that:
[0023] The reaction is carried out at a temperature below 40°C.
[0024] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000045, characterized in that:
[0025] The reaction product is filtered, the filtrate is concentrated, and the primary product is obtained by column chromatography, which is then dissolved with halogenated alkane, stirred with halogenated acetic acid for 1-3 hours, concentrated to dryness, diluted with water, and freeze-dried to obtain the product.
[0026] That is, the selective cleavage of the bond is achieved through ion exchange resin, and then the product is obtained through deprotection.
[0027] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000045, characterized in that:
[0028] The eluent for column chromatography was DCM:MeOH=0-10%.
[0029] Furthermore, the present invention provides a method for preparing the prazomicin impurity A000045, characterized in that:
[0030] The relationship between the amount of the above-mentioned halogenated acetic acid and the amount of compound A000005 is that each gram of compound A000005 corresponds to 1-10 ml of halogenated acetic acid.
[0031] Application of prazomicin impurity A000045 in identifying impurities contained in prazomicin finished products. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1 . Example 1 Product spectrum
[0033] Figure 2 . Example 1 Product spectrum DETAILED DESCRIPTION
[0034] In this example, the key intermediate A000005 of prazomicin was used as the starting material to obtain the target impurity A000045 under the catalytic action of an ionic resin. The impurity is a degradation product, and the specific reaction equation is as follows:
[0035]
[0036] When the mass ratio of compound A000005 to ion exchange resin is 1:5-8, the relationship between the amount of halogenated acetic acid used and the amount of compound A000005 used is that the product can be obtained within the range of 1-10 ml of halogenated acetic acid per gram of compound A000005. The most preferred scheme is as follows:
[0037] Example 1
[0038] Compound A000005 (1.3 g, 1.15 mmol) and tetrahydrofuran (100 mL) and activated hydrogen type 50 resin (8 g) were added to the reaction bottle in sequence at 25°C. The mixture was stirred for reaction under argon protection at 25°C for 1 hour. LCMS showed that the reaction was complete. The mixture was filtered, concentrated, and passed through a silica gel column with DCM / MeOH = 0-10% to obtain 300 mg of a preliminary product. The product was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added to stir the reaction for 2 hours. The product was concentrated to dryness, diluted with 10 mL of water, and lyophilized to obtain the product as a light yellow solid A000045 (200 mg, yield: 41.2%) with a purity of 94.73%.
[0039] MS(ESI,m / z):423.2[M+H]+.1HNMR(400MHz,D2O)δ5.16(d,J=4Hz,1H),4.28(dd,J=9.2,3.6 Hz,1H),4.23(d,J=12.8Hz,1H),4.16-4.09(m,1H),4.02(dd,J=10.8,4.0Hz,1H),3.81-3.76 (m,1H),3.54-3.51(m,1H),3.40(d,J=13.2Hz,1H),3.34-3.31(m,2H),3.18(t,J=7.2Hz,2H ),2.92(s,3H),2.21(m,2H),2.01-1.95(m,1H),1.75(dd,J=25.2,12.4Hz,1H),1.34(s,3H).
[0040] Example 2
[0041] Compound A000005 (1.3 g, 1.15 mmol) and tetrahydrofuran (100 mL) and activated hydrogen type 50 resin (8 g) were added to the reaction bottle in sequence at 25°C, and the reaction was stirred for 1 hour under argon protection at 25°C. LCMS showed that the reaction was complete, and the mixture was filtered, concentrated, and passed through a silica gel column with DCM / MeOH = 0-10% to obtain 305 mg of the initial product, which was dissolved in 10 mL of dichloromethane, and 5 mL of trichloroacetic acid was added to stir the reaction for 2 hours. The mixture was concentrated to dryness, diluted with 10 mL of water, and lyophilized to obtain the product as a light yellow solid A000045 (237 mg, yield: 48.70%) with a purity of 89.23%.
[0042] Example 3
[0043] Compound A000005 (1.3 g, 1.15 mmol) and tetrahydrofuran (100 mL) and activated hydrogen type 50 resin (8 g) were added to the reaction bottle at 25 °C in sequence. The mixture was stirred for 0.5 hour under argon protection at 40 °C. LCMS showed that the reaction was complete. The mixture was filtered, concentrated, and passed through a silica gel column with DCM / MeOH = 0-10% to obtain 289 mg of the initial product. The product was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added to stir the reaction for 2 hours. The product was concentrated to dryness, diluted with 10 mL of water, and lyophilized to obtain the product as a light yellow solid A000045 (189 mg, yield: 38.83%) with a purity of 91.36%.
[0044] Example 4
[0045] Compound A000005 (1.3 g, 1.15 mmol) and tetrahydrofuran (100 mL) and cation exchange resin 120 type (8 g) were added to the reaction bottle in sequence at 25°C, and the reaction was stirred for 1 hour under argon protection at 40°C. LCMS showed that the reaction was complete, and the mixture was filtered, concentrated, and passed through a silica gel column with DCM / MeOH = 0-10% to obtain 292 mg of the initial product, which was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added to stir the reaction for 2 hours. The mixture was concentrated to dryness, diluted with 10 mL of water, and lyophilized to obtain the product as a light yellow solid A000045 (197 mg, yield: 40.47%) with a purity of 93.11%.
[0046] Example 5
[0047] Compound A000005 (1.15 mmol), tetrahydrofuran (100 mL) and hydrogen iodide (1 mol) were added to the reaction bottle in sequence at 25°C. The reaction was stirred at 25°C under argon protection for 1 hour. LCMS showed chaos, and it seemed that selective bond cleavage could not be achieved.
Claims
1. Prazomicin impurity A000045, Features: The compound is shown in the following structure:
2. A method for preparing the impurity A000045 of prazomicin, Features: Using compound A000005 as the starting material, the target impurity A000045 was obtained by first degradation and then deprotection under the catalytic action of ion exchange resin; Among them, the structure of compound A000005 is shown below: The structure of the target impurity A000045 is shown below:
3. The preparation method of the prazomicin impurity A000045 according to claim 2, Features: The reaction is carried out under a protective gas environment.
4. The method for preparing the prazomicin impurity A000045 according to claim 2, Features: The ion exchange resin is selected from hydrogen type resin and cation exchange resin.
5. The method for preparing the prazomicin impurity A000045 according to claim 2, Features: The mass ratio of the compound A000005 to the ion exchange resin is 1:5-8.
6. The method for preparing the prazomicin impurity A000045 according to claim 2, Features: The reaction is carried out at a temperature below 40°C.
7. The method for preparing the prazomicin impurity A000045 according to claim 2, Features: The reaction product is filtered, the filtrate is concentrated, and the primary product is obtained by column chromatography, which is then dissolved with halogenated alkane, stirred with halogenated acetic acid for 1-3 hours, concentrated to dryness, diluted with water, and freeze-dried to obtain the product.
8. The method for preparing the prazomicin impurity A000045 according to claim 2, Features: The eluent for column chromatography was DCM:MeOH=0-10%.
9. The method for preparing the prazomicin impurity A000045 according to claim 2, Features: The relationship between the amount of the halogenated acetic acid and the amount of compound A000005 is that each gram of compound A000005 corresponds to 1-10 ml of halogenated acetic acid.
10. Application of prazomicin impurity A000045 in identifying impurities contained in prazomicin finished products.