Method for preparing tedizolid phosphate

A technology of tedizolid phosphate and glycerin butyrate, which is applied in the field of preparation of tedizolid phosphate, can solve the problems of phosphate bond being easily broken and hydrolyzed, unstable yield and impurity spectrum, and harsh water requirements, so as to avoid breakage Hydrolysis, good reaction reproducibility, and the effect of reducing the cost of raw materials

Active Publication Date: 2017-01-11
NANJING YOKO PHARMA +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, unfortunately, there are following problems in this route: (1) the organic base bistrimethylsilylamide lithium (LiHMDS) used in the oxazolinone cyclization reaction is extremely hygroscopic and has harsh requirements on water. The yield and impurity spectrum of the oxazolinone cyclization reaction are unstable, and the reaction solvent tetrahydrofuran needs to be re-distilled, which is cumbersome t

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  • Method for preparing tedizolid phosphate
  • Method for preparing tedizolid phosphate
  • Method for preparing tedizolid phosphate

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0034]Example 1: (5R)-3-(4-(6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl)-3-fluorophenyl)-5-hydroxymethyl Oxazolin-2-one (III) preparation of

[0035] Option 1: Potassium tert-butoxide as base

[0036] Add tetrahydrofuran (20 L) and N-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl]phenyl]carbamate to the kettle Benzyl ester compound (II) (1 Kg, 2.47 mol), after stirring at 20~30°C, add 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU, 0.63 Kg, 4.94 mol, 2 times equivalent) and potassium tert-butoxide (0.33 Kg, 2.96 mol, 1.2 times equivalent), add R-glycidyl butyrate (0.39 Kg, 2.72 mol, 1.1 times equivalent), and react at 0~30°C for 15 hours. After the reaction was completed, the ammonium chloride solution (1 Kg / 10 L) with a mass-volume concentration of 10% was added to quench the reaction, concentrated under reduced pressure, and the residue was added to methanol (10 L), stirred for 0.5 hours to obtain suction filtration, The filter cake was washed with methanol a...

Embodiment 2

[0045] Example 2: (5R)-3-(4-(6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl)-3-fluorophenyl)-2-oxo-5 -oxazolidinyl) methyl phosphate (I) Crude preparation

[0046] Add tetrahydrofuran (30 L) and (5R)-3-(4-(6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl)-3-fluorobenzene to the reaction kettle base)-5-hydroxymethyloxazolin-2-one compound (III) (1.5 Kg, 4.05 mol), after stirring evenly, add triethylamine (1.23 Kg, 12.15 mol, 3 times of equivalents), drop phosphorus oxychloride (1.86 Kg, 12.15 mol , 3 times the equivalent) of tetrahydrofuran (12 L) solution, after the dropwise addition, continue to maintain the temperature at 0 ~ 15 ° C and stir for 2 hours, add purified water (25 L) to quench the reaction, stir at 0 ~ 15 ° C for 15 hours, Suction filtration, the filter cake was washed with purified water and acetone successively, and vacuum-dried at 45~50°C to obtain (5R)-3-(4-(6-(2-methyl-2H-tetrazole-5 -yl)-3-pyridyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl phosphate compound (I)...

Embodiment 3

[0047] Example 3: (5R)-3-(4-(6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl)-3-fluorophenyl)-2-oxo-5 -oxazolidinyl) methyl phosphate (I) preparation of

[0048] Option 1: The base is sodium bicarbonate

[0049] Add (5R)-3-(4-(6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl)-3-fluorophenyl)-2-oxo- 5-oxazolidinyl) methyl phosphate (I) Crude product (0.8 Kg), adjust the pH value of the reaction solution to 7~9 with a mass-volume concentration of 5% sodium bicarbonate solution (0.4 Kg / 8 L), heat to 40~45°C and stir for 0.5 hours, add acetone dropwise (16 L), cooled to 0 ~ 5 ° C after the dropwise addition, stirred for 20 minutes, suction filtered to obtain tedizolid phosphate sodium salt, dissolved in ethanol (16 L), heated to 40 ~ 45 ° C, Use 2 mol / L hydrochloric acid solution (4 L) to adjust the pH value of the reaction solution to 1~2, cool down to 0~5°C, filter with suction, wash the filter cake with purified water and acetone successively, and vacuum dry at 45~50°C (5R)-3-(4-(6-(2-Met...

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Abstract

The invention discloses a method for preparing tedizolid phosphate, wherein the method specifically includes the steps: with N-[3-fluoro-4-[6-(2-methyl-2H-tetrazole-5-yl)-3-pyridyl]phenyl]benzyqcarbamate as a starting raw material, in the presence of R1-O-M, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, carrying out a reaction with R-glycidyl butyrate, and then esterfying with POCl3 phosphoric acid to obtain a tedizolid phosphate crude product; and adjusting the pH value to 7-9 with an alkali solution, converting the tedizolid phosphate crude product into a salt, and adjusting the pH value to 1-2 with hydrochloric acid to obtain the refined tedizolid phosphate. The method has the advantages of mild reaction conditions, relatively low cost, simple and convenient operation, less side reaction, high yield, good reaction reproducibility, economy and environmental protection, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of tedizolid phosphate. Background technique [0002] Tedizolid phosphate is an oxazolidinone antibiotic developed by Cubist, which was approved by the FDA on June 10, 2014. Its trade name is Sivextro, and it is used for the treatment of Acute bacterial skin and skin structure infections caused by Staphylococcus aureus and gram-positive bacteria such as various Streptococcus species and Enterococcus faecalis. Tedizolid phosphate is an oxazolidinone antibiotic. By binding to the 50S subunit of bacterial ribosome, it inhibits bacterial protein synthesis and exerts antibacterial effect. It is not easy to produce cross-resistance with other types of antibiotics. It is the same as the first oxazolidine Compared with the ketone antibiotic linezolid, it has better efficacy and higher safety. [0003] Tedizolid phosphate, chemical name ((5R)-3-(4-(6-(2-methyl-2H-tetra...

Claims

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Application Information

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IPC IPC(8): C07F9/6558
Inventor 李上车晓明赵赞赞朱素华薛峪泉张峰
Owner NANJING YOKO PHARMA
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