Synthetic method of Ommacycline and application of Ommacycline in preparation

Abstract

The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of omagazines, which comprises the step of preparing omagazines by mannich reaction of minocycline hydrochloride, pivalamine and aldehyde in one step. The method provided by the invention has the advantages of easily available raw materials, low cost, simple reaction operation and recyclable solvent.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a synthesis method of omadacycline and application thereof in preparations. Background Art

[0002] Omadacycline, English name: Omadacycline, chemical name: ((4aS,4S,5aR,12aS)-4,7-bis(dimethylamino)-9-{[(2,2-dimethylpropyl)amino]methyl}-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide; (4aS,4S,5aR,12aS)-4,7-bis(dimethylamino)-9-{[(2,2-dimethylpropyl)amino]methyl}-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide. Trade name: NUZYRA. Its chemical structure is as follows: Omadacycline MW:556.66.

[0003] Omadacycline was developed by Paratek and is a new third-generation semi-synthetic tetracycline broad-spectrum antibiotic. On October 2, 2018, the intravenous injection and oral preparations of omadacycline salts were approved for marketing by the U.S. Food and Drug Administration (FDA). They are mainly used in the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI).

[0004] Omadacycline has no cross-resistance with other types of antibiotics and has good antibacterial activity against common clinical Gram-positive bacteria, Gram-negative bacteria, atypical pathogens, anaerobic bacteria, etc. The mechanism of action of omadacycline is the same as the classical mechanism of tetracycline antibiotics. It specifically binds to the A site of the bacterial ribosome 30S subunit, inhibits the normal binding of aminoacyl-tRNA to this site, causes the termination of peptide chain extension, blocks protein synthesis, and thus produces an antibacterial effect. Under in vitro conditions, the affinity of omadacycline to the ribosome 30S subunit is significantly stronger than that of tetracycline. Studies have found that bacteria can develop resistance to tetracycline drugs using mechanisms such as gene-encoded efflux pumps, ribosomal protection proteins, and modification enzymes. The modified group of C7 of omadacycline helps it overcome the bacterial efflux pump resistance mechanism, and the aminomethyl modification of C9 enables it to overcome the bacterial ribosome protection mechanism, showing effective inhibitory activity against related resistant bacteria.

[0005] The clinical trial results of omadacycline showed the following advantages: 1) a broad antibacterial spectrum; 2) high oral bioavailability, and PK parameters are not affected by age, gender, and liver / kidney function; 3) low gastrointestinal side effects and low risk of interaction with other drugs.

[0006] There are many patent reports on the preparation of omadacycline at home and abroad. The classic synthetic routes reported (US7553828, US2008005452, WO2023047323) are as follows: .

[0007] Omadacycline synthesis uses minocycline hydrochloride as the starting material and is prepared through a three-step reaction. The post-processing purification of omadacycline is currently difficult and requires the use of preparative liquid phases, resulting in a low yield. In addition, the first alkylation reaction involves strong acids such as trifluoromethanesulfonic acid, which are prone to corrode the reactor. Summary of the invention

[0008] The purpose of the present invention is to provide a method for preparing omadacycline with simple process and short steps to address the shortcomings of the existing preparation technology of omadacycline.

[0009] In order to achieve the technical purpose of the present invention, the present invention provides the following technical solutions: The present invention uses commercially available minocycline hydrochloride as a starting material to prepare omadacycline through a one-step reaction, and the route is as follows: .

[0010] The aldehyde used is one or more of 37% to 40% formaldehyde aqueous solution, trioxymethylene, and polyformaldehyde; wherein the amount of the aldehyde used is 4-20 times the molar weight of minocycline hydrochloride; Wherein, the amount of tert-amylamine used is 4-20 times the molar weight of minocycline hydrochloride; Wherein, the solvent used is one or more of methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, acetic acid; Wherein, the amount of solvent used is 15-30 times the amount of minocycline hydrochloride; Wherein, the reaction temperature is 40-80°C; The method comprises dissolving minocycline hydrochloride in a selected solvent, stirring at 5-15° C. to dissolve the minocycline, adding tert-pentylamine and aldehyde at 5-15° C., and reacting at 40-80° C. for 4-6 hours.

[0011] The present invention has short steps, mild reaction conditions, convenient operation, avoids the use of strong acid conditions and hydrogenation conditions, and is conducive to large-scale production. The purity of the prepared crude omadacycline is greater than 95%.

[0012] Beneficial effects of the invention: The invention provides a method for preparing omadacycline, which, compared with the existing process technology, has the characteristics of being green and environmentally friendly, easy to obtain raw materials, simple operation, high yield, less impurities, and high product purity. Instruction Manual

[0013] Figure 1 This is the HPLC chromatogram of the purity of crude omadacycline. DETAILED DESCRIPTION

[0014] In order to further understand the present invention, the preparation method of omadacycline provided by the present invention is described in detail below in conjunction with the examples. It should be understood that these examples are only for further illustrating the features of the present invention in detail, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0015] Example 1 Dissolve minocycline hydrochloride (10 g, 20 mmol) in 200 mL methanol, cool to 5-15 ° C, add t-amylamine (24 mL, 200 mmol) and 37%-40% formaldehyde aqueous solution (15.2 mL, 202.8 mmol) at 5-15 ° C, react at 65 ° C, and concentrate the reaction solution after the reaction is completed. Add 50 mL of dichloromethane and 50 mL of purified water to the residue, extract and stratify, collect the organic phase, add 50 mL of water to the organic phase, adjust the pH to 4-4.5 with 10% dilute hydrochloric acid, extract and stratify, collect the water layer, adjust the pH of the water layer to 8-8.5 with 10% NaOH aqueous solution, add 50 mL of dichloromethane for extraction and stratification, collect the dichloromethane layer, add a desiccant, dry for 20 min, filter, decompress and spin dry the solvent, add 40 mL of methyl tert-butyl ether, beat for 30 min, filter, and dry to obtain 7.1 g of solid with a yield of 63%.

[0016] Example 2 Dissolve minocycline hydrochloride (10 g, 20 mmol) in a mixed solution of 200 mL methanol and 30 mL acetic acid, and cool to 5-15°C. Add t-amylamine (19 mL, 160 mmol) and 37%-40% formaldehyde aqueous solution (12 mL, 160 mmol) at this temperature, and react at 55°C. After the reaction is completed, concentrate the reaction solution. The residue was added with 50 mL of dichloromethane, 65 mL of purified water, and 10% NaOH aqueous solution to adjust the pH to 8-8.5, and the organic phase was extracted and layered. 50 mL of water was added to the organic phase, and the pH was adjusted to 4-4.5 with 10% dilute hydrochloric acid, and the aqueous layer was collected. The pH of the aqueous layer was adjusted to 8-8.5 with 10% NaOH aqueous solution again, and 50 mL of dichloromethane was added for extraction and layering to obtain a dichloromethane layer. A desiccant was added, and the mixture was dried for 20 min. The mixture was filtered and the solvent was dried under reduced pressure. 40 mL of methyl tert-butyl ether was added, and the mixture was pulped for 30 min. The mixture was filtered and dried to obtain 8.8 g of a solid with a yield of 78%.

[0017] Example 3 Minocycline hydrochloride (10 g, 20 mmol) was dissolved in a mixed solution of 200 mL ethanol and 10 mL N, N-dimethylformamide, cooled to 5-15 ° C, added with tert-amylamine (10 mL, 80 mmol) and trioxymethylene (7.2 g, 80 mmol) at this temperature, reacted at 80 ° C, and concentrated the reaction solution after the reaction was completed. The residue was added with 80 mL of dichloromethane and 50 mL of purified water, and the pH was adjusted to 4-4.5 with 10% dilute hydrochloric acid, and extracted and layered, and the water layer was collected. The water layer was adjusted to pH 8-8.5 with 10% NaOH aqueous solution again, and then 50 mL of dichloromethane was added for extraction and layering to obtain a dichloromethane layer, a desiccant was added, and the mixture was dried for 20 min, filtered, and the solvent was dried under reduced pressure, 40 mL of methyl tert-butyl ether was added, and the mixture was pulped for 30 min, filtered, and dried to obtain 5.2 g of solid, with a yield of 46%.

[0018] Example 4 Minocycline hydrochloride (10 g, 20 mmol) was dissolved in a mixed solution of 200 mL ethanol and 10 mL N, N-dimethylformamide, cooled to 5-15 ° C, added with tert-amylamine (36 mL, 300 mmol) and paraformaldehyde (9 g, 300 mmol) at this temperature, reacted at 80 ° C, and concentrated the reaction solution after the reaction was completed. The residue was added with 80 mL of dichloromethane and 50 mL of purified water, and the pH was adjusted to 4-4.5 with 10% dilute hydrochloric acid, and extracted and layered, and the water layer was collected. The water layer was adjusted to pH 8-8.5 with 10% NaOH aqueous solution again, and then 50 mL of dichloromethane was added for extraction and layering to obtain a dichloromethane layer, a desiccant was added, and the mixture was dried for 20 min, filtered, and the solvent was dried under reduced pressure, 40 mL of methyl tert-butyl ether was added, and the mixture was beaten for 30 min, filtered, and dried to obtain 6.1 g of solid with a yield of 54%.

Claims

1. A method for synthesizing omadacycline using minocycline hydrochloride as a starting material, the synthetic route is as follows: 。 2. The preparation method according to claim 1, characterized in that The aldehyde used is one or more of 35% to 40% formaldehyde aqueous solution, trioxymethylene, and polyformaldehyde.

3. The preparation method according to claim 1, characterized in that The amount of the aldehyde used is 4 to 20 times the molar weight of minocycline hydrochloride.

4. The preparation method according to claim 1, characterized in that The amount of tert-amylamine used is 4 to 20 times the molar weight of minocycline hydrochloride.

5. The preparation method according to claim 1, wherein the solvent used is one or more of methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, and acetic acid.

6. The preparation method as claimed in claim 1, wherein the amount of solvent used is 15 to 30 times the mass of minocycline hydrochloride.

7. The preparation method according to claim 1, characterized in that The reaction temperature is preferably controlled at 40-80°C.

8. The preparation method according to claim 1, wherein minocycline hydrochloride is dissolved in a selected solvent, stirred at 5-15°C until dissolved, tert-amylamine and aldehyde are added at 5-15°C, and reacted at 40-80°C for 4-6h.

Images