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Preparation method of tedizolid phosphate and intermediate thereof

A technology for tedizolid phosphate and intermediates, which is applied in the field of preparation of tedizolid phosphate and its intermediates, and can solve problems such as operational hazards, environmental pollution, and harsh reaction conditions

Active Publication Date: 2020-02-18
上海新礼泰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the harsh reaction conditions, dangerous operation, need to use highly toxic reagents, serious environmental pollution, and low reaction yield in the preparation method of tedizolid phosphate intermediate in the prior art, which is not suitable for industrial production. A kind of preparation method of tedizolid phosphate and its intermediate is provided

Method used

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  • Preparation method of tedizolid phosphate and intermediate thereof
  • Preparation method of tedizolid phosphate and intermediate thereof
  • Preparation method of tedizolid phosphate and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Embodiment 1: Preparation of tedizolid phosphate intermediate II

[0070]

[0071] Under nitrogen protection, add 4.7Kg (14.5mol) of benzyl 3-fluoro-4-bromophenylcarbamate to 35.3L of tetrahydrofuran, stir at 20°C to 30°C and add 3.8Kg (58.1mol) of zinc powder, Dicyclocene cobalt 27.4g (0.145mol), stirred at 20°C to 30°C for 4 hours to 5 hours, filtered, and washed with 11.7L of tetrahydrofuran to obtain a solution that was stored under nitrogen as a solution of tedizolid phosphate intermediate III. Stir the solution of tedizolid phosphate intermediate III at 20°C to 30°C, add 3.83Kg (15.95mol) of 2-methyl-5-(5-bromopyridin-2-yl)tetrazolium and 3.1Kg of sodium carbonate (29.2 mol), 26.5 g (0.029 mol) of tris(dibenzylideneacetone) dipalladium, heated to 65° C. to 70° C. and stirred for 5 hours to 6 hours. After cooling, filter through diatomaceous earth 2.5Kg, add tetrahydrofuran 10L and mass concentration to mother liquor and be 15% saline (the described mass concen...

Embodiment 2

[0072] Embodiment 2: Preparation of tedizolid phosphate intermediate II

[0073]Under nitrogen protection, add 40 g (0.123 mol) of benzyl 3-fluoro-4-bromophenylcarbamate to 400 mL of acetonitrile, stir at 10°C to 20°C and add 49 g (0.749 mol) of zinc powder, 1,1 '-Diethylnickelocene 0.60g (0.00245mol), stirred at 10℃~20℃ for 7 hours~8 hours, filtered, and washed with 200mL acetonitrile to obtain a solution and stored under nitrogen, it is an intermediate of tedizolid phosphate Solution of III. Stir the solution of tedizolid phosphate intermediate III at 10°C to 20°C, add 2-methyl-5-(5-bromopyridin-2-yl)tetrazolium 31.0g (0.129mol), triethylamine 18.6 g (0.184mol), tetrakistriphenylphosphine palladium 0.15g (0.000129mol), heated to 55°C to 65°C and stirred for 7 to 8 hours. After cooling, filter with 25 g of diatomaceous earth, concentrate the mother liquor in vacuum (temperature 45°C~65°C, pressure -0.08MPa~-0.1MPa) to dryness, then add tetrahydrofuran and ethyl acetate with...

Embodiment 3

[0074] Embodiment 3: Preparation of tedizolid phosphate intermediate II

[0075] Under the protection of nitrogen, add 80 g (0.247 mol) of benzyl 3-fluoro-4-bromophenylcarbamate to 400 mL of dioxane, stir at 35 ° C ~ 45 ° C and add 40.5 g (0.619 mol) of zinc powder , 0.36g (0.00124mol) of benzoylferrocene, stirred at 35°C to 45°C for 5.5 hours to 6.5 hours, filtered after cooling, and washed with 240mL of dioxane to obtain a solution stored under nitrogen, which is tedizol phosphate Solution of Amine Intermediate III. The solution of tedizolid phosphate intermediate III was stirred at 35°C to 45°C, and 2-methyl-5-(5-bromopyridin-2-yl)tetrazolium 71.1g (0.296mol) and potassium phosphate 209g ( 0.984mol), bis(tricyclohexylphosphine)palladium 0.83g (0.00124mol), heated to 75°C-85°C and stirred for 3-4 hours. After cooling, filter with 60 g of diatomaceous earth, add 80 mL of ethyl acetate and mass concentration of 15% saline (the mass concentration refers to the percentage of t...

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Abstract

The invention discloses a preparation method of tedizolid phosphate and an intermediate thereof. The preparation method of a tedizolid phosphate intermediate II comprises the following steps: 1, in anorganic solvent, under a condition of presence of a catalyst and zinc powder, performing a reaction on 3-fluorine-4-bromophenyl amino benzyl formate so as to obtain a solution of a tedizolid phosphate intermediate III; and 2, in an organic solvent, under a condition of presence of a palladium catalyst and a base, performing a coupling reaction on the solution of the tedizolid phosphate intermediate III obtained in the step 1 with 2-methyl-5-(5-bromopyridine-2-yl) tetrazole, so as to obtain the tedizolid phosphate intermediate II. The preparation method disclosed by the invention is free of toxic reagent, mild in reaction condition, safe to operate, environmentally friendly, high in yield, high in prepared product purity and low in production cost. Tedizolid phosphate prepared from the tedizolid phosphate intermediate II disclosed by the invention is high in yield, high in purity, capable of meeting raw material medicine standards and applicable to industrial production.

Description

technical field [0001] The invention relates to a preparation method of tedizolid phosphate and an intermediate thereof. Background technique [0002] Tedizolid phosphate (I), a new type of antibacterial drug, is a second-generation oxazolidinone antibiotic developed by East Asia Pharmaceuticals, authorized by Cubist Pharmaceuticals and Bayer for commercial development, and was released on June 20, 2014 Obtained FDA marketing approval. Tedizolid phosphate is indicated for the treatment of skin infections in adult patients caused by certain susceptible bacteria such as Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible strains), various streptococci, and Enterococcus faecalis Acute bacterial skin and skin tissue infections (ABSSSI), administered intravenously and orally. Phase III clinical trials of tedizolid phosphate showed that its clinical effect was comparable to that of linezolid, and that it had fewer adverse reactions in the gastroint...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D413/14C07F9/6558
CPCC07B2200/07C07D401/04C07D413/14C07F9/65583
Inventor 陈健刘振峰应述欢
Owner 上海新礼泰药业有限公司
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