Preparation method of ring-opening impurity of oxamecycline 4-ketone

Abstract

The method comprises the following steps: introducing ammonia gas and oxygen at a certain flow rate ratio into an N, N-dimethylformamide low-temperature solution of the oxamazole, obtaining the 4-ketone ring-opening impurity at a high conversion rate, and after the reaction is finished, adding acetonitrile to separate out the 4-ketone ring-opening impurity at high purity.

Description

Technical Field

[0001] The invention relates to a method for preparing omadacycline impurities and belongs to the technical field of medicines. Background Art

[0002] Omadacycline (also known as OMC or PTK 0796) is a 9-aminomethyltetracycline derivative. It is a semi-synthetic compound obtained by modifying minocycline through chemical groups. It is an antibiotic in the tetracycline family. The U.S. FDA approved omadacycline for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in 2018. In 2021, the indications of omadacycline tosylate for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections were officially approved by the National Medical Products Administration.

[0003] The chemical synthesis of omadacycline has been reported, for example, in U.S. Patent 9434680, U.S. Patent 9522872 and U.S. Patent 8383610. However, due to the particularity of the structure of omadacycline, its stability is poor, and the raw material drug generally needs to be purified by column. Even so, the total impurity limit of the commercial preparation is ≤8.0%, indicating that the impurity content of the commercial preparation of omadacycline is relatively large. Summary of the invention

[0004] The inventors conducted a long investigation on the impurity spectrum of omadacycline during the development process. After a large number of experiments, it was found that an impurity with a molecular weight of 499 was more likely to appear in omadacycline. Mass spectrometry and nuclear magnetic resonance analysis proved that its structure was an omadacycline 4-keto ring-opening impurity, which would gradually degrade and increase in omadacycline, affecting the safety of medication. Therefore, it is particularly important to develop a method for preparing the impurity reference substance stably and with high purity, so as to detect and control the corresponding impurities in omadacycline raw materials and preparations.

[0005] .

[0006] The ketone ring-opening impurity has a special structure, and it is difficult to prepare it in a targeted manner using a synthetic route. In addition, its structure is complex and unstable, and it is not easy to convert it from omadacycline by conventional means. Through a large number of experimental explorations, the inventor unexpectedly discovered that by passing ammonia and oxygen at a certain flow rate ratio into a low-temperature solution of omadacycline in N,N-dimethylformamide, 4-ketone ring-opening impurities can be obtained with a high conversion rate. After the reaction is completed, acetonitrile is added to precipitate the 4-ketone ring-opening impurity with high purity. The purity is higher than 95.0% after testing, which meets the qualitative and quantitative purity requirements of the impurity reference substance.

[0007] The amount of N,N-dimethylformamide used has a great influence on the progress of the reaction. The preferred volume weight ratio of N,N-dimethylformamide to omadacycline is 15-30V / m, preferably 20-25V / m. The reaction temperature is low, which can effectively increase the selectivity of the reaction and the stability of the 4-ketone ring-opening impurity. The low temperature is -10°C to -40°C, preferably -15°C to -25°C. The flow rate ratio of ammonia to oxygen is particularly important. If the ratio is too high, the 4-ketone ring-opening impurity is easily further degraded, or even no 4-ketone ring-opening impurity is obtained. If the ratio is too low, the 4-ketone impurity in the obtained product is large. The flow rate ratio of ammonia to oxygen is preferably 5-8:1, particularly preferably 6.5:1, and the flow rate of oxygen is 10-20ml / min, preferably 15ml / min. DETAILED DESCRIPTION

[0008] Example 1: Add 220 ml of N,N-dimethylformamide to a reactor, cool to -20°C, add 10 g of omadacycline, introduce ammonia and oxygen at a flow rate ratio of 6.5:1, and the oxygen flow rate is 15 ml / min. Maintain the above conditions for 9 hours, add 1000 ml of acetonitrile, stir for 1 hour, filter, wash the filter cake with 100 ml of methyl isopropyl ether, and dry under reduced pressure at 15°C to obtain 7.6 g of 4-keto ring-opening impurity with a purity of 97.2%.

[0009] Example 2: Add 200 ml of N,N-dimethylformamide to a reactor, cool to -15°C, add 10 g of omadacycline, introduce ammonia and oxygen at a flow rate ratio of 5:1, and the oxygen flow rate is 10 ml / min. Maintain the above conditions for reaction for 12 hours, add 1000 ml of acetonitrile, stir for 1 hour, filter, wash the filter cake with 100 ml of methyl isopropyl ether, and dry under reduced pressure at 15°C to obtain 7.9 g of 4-keto ring-opening impurity with a purity of 95.1%.

[0010] Example 3: Add 250 ml of N,N-dimethylformamide to a reactor, cool to -25°C, add 10 g of omadacycline, introduce ammonia and oxygen at a flow rate ratio of 8:1, and the oxygen flow rate is 20 ml / min. Maintain the above conditions for 7 hours, add 1000 ml of acetonitrile, stir for 1 hour, filter, wash the filter cake with 100 ml of methyl isopropyl ether, and dry under reduced pressure at 15°C to obtain 6.1 g of 4-keto ring-opening impurity with a purity of 95.3%.

Claims

1. A method for preparing a 4-ketone ring-opening impurity, characterized in that: The 4-keto ring-opening impurity is prepared by passing ammonia and oxygen at a certain flow rate ratio into a low-temperature solution of N,N-dimethylformamide. 。 2. The method for preparing the 4-ketone ring-opening impurity according to claim 1, characterized in that: The temperature of the cryogenic solution is -10°C to -40°C.

3. The method for preparing the 4-ketone ring-opening impurity according to claim 2, characterized in that: The temperature of the cryogenic solution is -15°C to -25°C.

4. The method for preparing the 4-ketone ring-opening impurity according to claim 1, characterized in that: The flow rate ratio of ammonia to oxygen is 5-8:

1.

5. The method for preparing the 4-ketone ring-opening impurity according to claim 4, characterized in that: The flow rate ratio of ammonia to oxygen was 6.5:

1.

6. The method for preparing the 4-ketone ring-opening impurity according to claim 1, characterized in that: The flow rate of oxygen is 10-20 ml / min.

7. The method for preparing the 4-ketone ring-opening impurity according to claim 6, characterized in that: The flow rate of oxygen was 15 ml / min.

8. The method for preparing the 4-ketone ring-opening impurity according to claim 1, characterized in that: The volume-to-weight ratio of N,N-dimethylformamide to omadacycline is 20-25 V / m.

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