Refining process of tedizolid and preparation method of tedizolid phosphate

A technology of tedizolid phosphate and tedizolid, which is applied in the field of drug synthesis, can solve the problems of reduced yield of tedizolid phosphate, lower yield of tedizolid phosphate, insufficient purity of tedizolid, etc., so as to avoid decomposition or produce Isomers, reducing the difficulty of purification, reducing the effect of side reactions

Active Publication Date: 2021-08-06
HAINAN GENERAL & KANGLI PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Among them, there have been a lot of reports on the purification and purification of tedizolid phosphate, but there is little mention of the purification and purification of its intermediate tedizolid, but the purity and yield of tedizolid are higher than that of tedizolid phosphate. The synthesis of amines has a very important influence. The purity of tedizolid is not enough and contains too many impurities. In the process of synthesizing tedizolid phosphate, the impurities and phosphorus oxychloride will take the lead in side reactions, resulting in the formation of new impurities and Inhibit the synthesis of tedizolid

Method used

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  • Refining process of tedizolid and preparation method of tedizolid phosphate
  • Refining process of tedizolid and preparation method of tedizolid phosphate
  • Refining process of tedizolid and preparation method of tedizolid phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 A kind of preparation method of tedizolid phosphate M1

[0031] The present embodiment provides a kind of preparation method of tedizolid phosphate, it is 1) take by weighing 7.7kg2-(2-methyl-2H-tetrazol-5-yl)pyridine-5-boronic acid pinacol ester and 7.8 kg respectively kg(5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one was added to 155L 1,4-dioxane under nitrogen protection, and then added Dissolved with 30.8kg of potassium carbonate in water and 0.4kg of Pd(dppf)Cl 2 , replace the air with nitrogen again, raise the temperature to 80°C for Suzuki reaction for 4 hours, monitor the reaction by HPLC, separate the water phase while still hot, concentrate the organic phase to the remaining 20L, add 40L ethyl acetate and saturated saline, and heat Stir at 40°C for 1 hour, let stand to separate the liquids, concentrate the organic phase to the remaining 15L, add 2L of dichloromethane, 20L of toluene and 10L of ethanol in sequence after cooling, he...

Embodiment 2～6

[0036] The preparation method of embodiment 2~6 tedizolid phosphate M2~M6

[0037] Examples 2 to 6 respectively provide a preparation method of tedizolid phosphate, the preparation method is basically the same as that of Example 1, the only difference is that some process parameters are different, and the specific parameters are shown in Table 1.

[0038] Table 1: Preparation process parameters of tedizolid phosphate M2-M6

[0039]

[0040] Other parameters are all the same as in Example 1.

Embodiment 7

[0041] The refining process contrast of embodiment 7 tedizolid

[0042]This embodiment uses the method of the Chinese invention patent whose application number is 201410628814. -(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-ketone obtained through Suzuki reaction (with 2-(2-methyl-2H-tetrazole-5- base) pyridine-5-boronic acid pinacol ester feedstock calculation tedizolid yield), namely tedizolid X (yield is 49%, purity is 99.97%), and use it according to step 2 in embodiment 1 ) preparation method to prepare tedizolid phosphate Y;

[0043] Gained tedizolid X and tedizolid phosphate Y are used as a control group, and tedizolid N1-N6 and tedizolid phosphate M1-M6 obtained in Examples 1 to 6 are used as test groups to compare their purity and yield data, See Table 2.

[0044] Table 2: Refining process refining effect comparison data table of tedizolid

[0045] group Yield (%) purity(%) Tedizolid N1 73 99.98 Tedizolid N2 70 99.99 Tedizol...

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Abstract

The invention belongs to the field of medicine synthesis, and discloses a refining process of tedizolid. According to the invention, a mixed solution of dichloromethane, toluene and ethanol is prepared, tedizolid generated through Suzuki reaction is purified through steps of liquid separation, filtration and the like, and the obtained tedizolid pure product is used for tedizolid phosphate synthesis. While the purity of tedizolid is ensured, the consumption of tedizolid in the refining process is reduced, the yield of tedizolid is improved, the utilization rate of raw materials is improved, the production cost is saved, the tedizolid with higher purity participates in synthesis of tedizolid phosphate, the side reaction in the tedizolid phosphate synthesis process is reduced, the purification difficulty of tedizolid phosphate is reduced, and the purity and the yield of tedizolid phosphate are improved. The method is suitable for refining tedizolid compounds, and is especially suitable for refining an intermediate tedizolid in a tedizolid phosphate synthesis process.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a refining process for synthesizing an intermediate of tedizolid phosphate, in particular to a refining process for tedizolid. Background technique [0002] Tedizolid phosphate was approved by the US FDA in 2014 for complicated skin and soft tissue infections caused by methicillin-resistant aureus. Tedizolid Phosphate is a bacterial protein synthesis inhibitor and an upgraded version of Linezolid. Different from traditional antibiotics, tedizolid phosphate selectively binds to bacterial 50S subunit ribosomes, interferes with the formation of 70S initiation complexes including mRNA, 30S ribosomes and initiation factors, thereby inhibiting bacterial protein synthesis. Because this inhibition process is in the early stage of protein translation, it is not easy to cross-resistance to antibiotics with other mechanisms. [0003] There are many patents disclosing the synthetic method of te...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07F9/6558
CPCC07D413/14C07F9/65583
Inventor 钟海雄彭先芬符永红林方育肖汉文郑元女林小雪唐雄肇
Owner HAINAN GENERAL & KANGLI PHARMA
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