Refining method of omacycline tosylate

Abstract

The invention belongs to the field of medicine synthesis, and relates to a method for purifying omagazines tosylate. Comprising a process of crystallizing in an acetone or acetonitrile mixed solvent. The refining method provided by the invention is good in purification effect, high in purity, high in yield and capable of obtaining high-purity omagazines tosylate with the crystal form of 3.

Description

Technical Field

[0001] The invention relates to omadacycline, in particular to a method for refining omadacycline tosylate, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] Omadacycline was approved by the FDA in October 2018 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. In January 2020, Zai Lab was approved for marketing in China on December 16, 2021.

[0003] The mechanism of action of omadacycline is to specifically bind to the A site of the bacterial ribosome 30S subunit, inhibit the normal binding of aminoacyl-tRNA to this site, terminate the peptide chain extension, block protein synthesis and thus produce an antibacterial effect. The post-antibiotic effect (PAE) of omadacycline on Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus, and Escherichia coli is better than linezolid and similar to tigecycline.

[0004] The structural formula of omadacycline tosylate is as follows:

[0005] Omadacycline Tosylate Molecular formula: C 36 H 48 N4O 10 S Molecular weight: 728.85.

[0006] Patent CN115667210 of the original Palatek company reports that the crude free base of omadacycline is purified by HPLC, concentrated and then recrystallized, and then salified with toluenesulfonic acid to obtain omadacycline toluenesulfonate. The preparation method reported in the patent requires preparation and purification to prepare a product with qualified purity, which is not conducive to industrial production and has high production costs.

[0007] Omadacycline tosylate is a polymorphic drug. The original patent reported Type 1, Type 2, Type 3, and Type 4 crystals. However, the medicinal crystal form 3 reported in the original Palatek patent CN1021050558 was declared invalid on July 4, 2024.

[0008] GLENMARK's patent WO2023047323 reports the use of methanol and methyltetrahydrofuran to purify omadacycline tosylate. Although the purity of this method can reach 99.3%, the resulting crystal form is not the original medicinal Type 3 crystal, and the refining yield is only 65%. Further crystal transformation is required to obtain the original medicinal Type 3 crystal.

[0009] Omadacycline tosylate is the latest generation of tetracycline antibiotics. It is not easy to develop drug resistance and has a very promising future. Therefore, it is of great significance for generic drug manufacturers to imitate this drug. However, omadacycline has poor stability and is not easy to purify to obtain a high-purity product. The original research is to obtain omadacycline tosylate by preparing, purifying, crystallizing, and then salifying. Therefore, it is necessary to develop an omadacycline tosylate that can obtain type 3 crystals with high yield, which is of great significance. Summary of the invention

[0010] The object of the present invention is to provide a method for purifying omadacycline tosylate, which can obtain type 3 crystals of omadacycline tosylate in high yield.

[0011] In order to achieve the above object, the present invention adopts the following technical scheme: a method for refining omadacycline tosylate, specifically comprising the following steps: 1) adding the omadacycline tosylate into an organic solvent, heating to 25° C.-30° C. and stirring to obtain a suspension; 2) Optionally, slowly add water to the suspension obtained in step 1) to dissolve and precipitate solid; 3) adding an organic solvent to the suspension obtained in step 2), cooling, and stirring to precipitate a solid; 4) Filter and separate, wash the filter cake with methyl tert-butyl ether, drain and dry under reduced pressure to obtain a solid; The organic solvent is acetone or acetonitrile.

[0012] In some embodiments, the volume weight ratio of acetone to omadacycline tosylate in step 1) is 5.0 ml / g-10.0 ml / g, preferably 6.0 ml / g-8.0 ml / g.

[0013] In some embodiments, in step 1), the volume weight ratio of acetonitrile to omadacycline tosylate is 4.0 ml / g-8.0 ml / g, preferably 5.0 ml / g-7.0 ml / g.

[0014] In some embodiments, in step 2), the volume weight ratio of water to omadacycline tosylate is 0.8 ml / g-1.7 ml / g, preferably 0.9 ml / g-1.5 ml / g.

[0015] In some embodiments, in step 3), the volume weight ratio of acetone to omadacycline tosylate is 2.0 ml / g-4 ml / g, preferably 2 ml / g-3 ml / g.

[0016] In some embodiments, in step 3), the volume weight ratio of acetonitrile to omadacycline tosylate is 3.0 ml / g-5 ml / g, preferably 3 ml / g-4 ml / g.

[0017] In step 3), the temperature is preferably lowered to 10°C-15°C to precipitate solid.

[0018] In step 3), the temperature is lowered to between 10°C and 15°C, and the stirring time is continued for 0.5h to 5h, preferably 1-2h.

[0019] In step 4), drying is performed under reduced pressure at 35° C.-45° C. for 5-10 h, preferably at 35° C.-38° C. for 5-8 h.

[0020] By utilizing the method for refining omadacycline tosylate of the present invention, the target compound can be obtained in a high yield, and the 4-isomer impurities and M+2 impurities which are difficult to remove in the compound can be removed very effectively. . DETAILED DESCRIPTION

[0021] The present invention is further described below in conjunction with specific embodiments.

[0022] In the present invention, unless otherwise specified, the scientific and technical terms used in the present invention have the meanings commonly understood by those skilled in the art. In addition, the laboratory operation steps used in the present invention are all conventional steps widely used in the corresponding fields.

[0023] The following synthetic examples are used to illustrate the method of purifying omadacycline tosylate. They are only to be regarded as illustrative methods, and the present invention is not limited to the contents thereof.

[0024] HPLC method .

[0025] Example 1: Preparation method of omadacycline tosylate .

[0026] At room temperature and under nitrogen protection, 120 g of omadacycline free base, 400 ml of methanol and 350 ml of 2-methyltetrahydrofuran were added to a 1000 ml three-necked flask and stirred until completely dissolved. The mixture was cooled to 5-10°C and 2-methyltetrahydrofuran toluenesulfonic acid solution (35 g dissolved in 150 ml of methyltetrahydrofuran) was added dropwise. The addition was completed in about 20 minutes, and solids were slowly precipitated. The mixture was stirred for 1 hour. After the reaction was completed, the mixture was filtered and dried, washed once with 2-methyltetrahydrofuran, washed once with methyl tert-butyl ether, and dried at 38°C overnight for about 8 hours to obtain 133 g of solids with a purity of 92%, 1.1% of M+2 impurities, 3.5% of 4-isomer impurities, a yield of 80%, and an amorphous crystal form.

[0027] Example 2: Refining of Omadacycline Tosylate Dissolve 50 g of crude omadacycline toluenesulfonate in 300 ml of acetone, heat to 25°C-30°C and stir, slowly add 45 ml of water, after the system is dissolved, solid precipitates, stir for 20 min, add 100 ml of acetone and cool to 10°C-15°C, continue stirring for 1 h, filter, wash the filter cake with 100 ml of methyl tert-butyl ether, drain, and dry under reduced pressure at 38°C for 6 h to obtain refined omadacycline toluenesulfonate product 42 with a purity of 99.46%, M+2 impurity of 0.05%, 4-isomer impurity of 0.2%, yield of 84%, and type 3 crystal.

[0028] Embodiment 3-7: The main changes are the type and proportion of solvents, and other conditions remain unchanged: .

Claims

1. A method for refining omadacycline tosylate, characterized in that: The following steps are involved: ； 1) adding the omadacycline tosylate into an organic solvent, heating to 25°C-30°C and stirring to obtain a suspension; 2) slowly adding water to the suspension obtained in step 1), stirring to precipitate solid after dissolving; 3) adding an organic solvent to the suspension obtained in step 2), cooling, and stirring to precipitate a solid; 4) Filter and separate, wash the filter cake with methyl tert-butyl ether, drain and dry the filter cake under reduced pressure to obtain a solid; The organic solvent is acetone or acetonitrile.

2. The method according to claim 1, characterized in that Step 1) The volume weight ratio of acetone to omadacycline tosylate is 5.0 ml / g-10.0 ml / g.

3. The method according to claim 1, characterized in that Step 1) The volume weight ratio of acetonitrile to omadacycline tosylate is 4.0 ml / g-8.0 ml / g.

4. The method according to claim 1, characterized in that: Step 2) The volume weight ratio of water to omadacycline tosylate is 0.8 ml / g-1.7 ml / g.

5. The method according to claim 1, characterized in that Step 3) The volume weight ratio of acetone to omadacycline tosylate is 2.0 ml / g to 4 ml / g.

6. The method according to claim 1, characterized in that Step 3) The volume weight ratio of acetonitrile to omadacycline tosylate is 3.0 ml / g-5 ml / g.

7. The method according to claim 1, characterized in that In step 3), the temperature is lowered to precipitate solids, and the temperature is lowered to between 10°C and 15°C.

8. The method according to claim 1, characterized in that In step 3), the temperature is lowered to between 10°C and 15°C and the stirring time is continued for 0.5h to 5h.

9. The method according to claim 1, characterized in that: In step 4), the mixture is dried at 35°C-45°C under reduced pressure for 5-10 hours.

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