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Process for preparing tedizolid

A technology of tedizolid and tetrazole, which is applied in the field of chemical drug synthesis, can solve the problems of high reagent cost, harsh reaction conditions, and high price, and achieve the effects of cheap and easy-to-obtain reagents, mild reaction conditions, and easy operation

Inactive Publication Date: 2016-10-05
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The coupling reaction of this method uses the more expensive Pd 2 (dba) 3 It is a catalyst, and tricyclohexylphosphine, which is particularly sensitive to oxygen, is used as a ligand. Therefore, the reagent cost of the reaction is high and the reaction conditions are harsh, which is not conducive to industrial scale-up

Method used

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  • Process for preparing tedizolid
  • Process for preparing tedizolid
  • Process for preparing tedizolid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1. Preparation of tedizolid

[0033]

[0034] Add 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxaborane- 2-yl)pyridine (1.8g, 0.00627mol), 1,4-dioxane:water=5:1 mixed solvent 32mL, stirred, added (5R)-3-(4-bromo-3-fluorophenyl )-5-Hydroxymethyloxazolidin-2-one (1.82g, 0.00627mol), K 2 CO 3 (2.60g, 0.01881mol), degassed, nitrogen protection, adding Pd(PPh 3 ) 4 (0.72g, 0.000627mol), degas three times, nitrogen protection. Heat to 80°C, react for 20h, stop the reaction, add methanol:water=4:1 mixed solvent 20mL, stir for 1h, filter, filter cake with H 2 O was washed and dried to obtain 2.48 g of blue-gray solid, which was slurried with 30 mL of ethyl acetate for 5 h, filtered and dried to obtain 2.11 g of tedizolid with a yield of 90.95%.

[0035] 1 H NMR (DMSO-d 6 )δ8.93(s,1H), 8.23~8.18(m,2H), 7.76~7.68(m,2H), 7.53~7.51(dd,1H, J=1.2,8.4Hz), 5.26~5.23(t, 1H, J=5.6Hz), 4.78~4.74(m,1H), 4.47(s,3H), 4.18~4.13(m,1H), 3.92~3.88(m,1H), 3.7...

Embodiment 2

[0036] Example 2. Preparation of tedizolid

[0037] Add 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxaborane- 2-yl)pyridine (1g, 0.00348mol), 1,4-dioxane:water=5:1 mixed solvent 18mL, stirred, added (5R)-3-(4-bromo-3-fluorophenyl) -5-Hydroxymethyloxazolidin-2-one (1.01g, 0.00522mol), K 2 CO 3 (1.44g, 0.0104mol), degassed, nitrogen protection, added PdCl 2 (dppf)DCM (0.28g, 0.000348mol), degassed 3 times, nitrogen protection. Heat to 80°C, react for 20h, stop the reaction, add 20mL H 2O, stirred for 1 h, filtered, the filter cake was washed with water, slurried with 20 mL of methanol: water = 4:1 mixed solvent for 3 h, filtered, and dried to obtain 1.15 g of tedizolid, with a yield of 89.15%.

Embodiment 3

[0038] Example 3. Preparation of tedizolid

[0039] Add 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxaborane- 2-yl)pyridine (1g, 0.00348mol), DMF18mL, stirred, added (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (1.01g ,0.00348mol), K 2 CO 3 (1.44g, 0.0104mol), degassed, nitrogen protection, added PdCl 2 (dppf)DCM (0.28g, 0.000348mol), degassed 3 times, nitrogen protection. Heat to 100°C, react overnight, stop the reaction, filter, add 50mL H to the filtrate 2 O, stir for 1h, filter, filter cake with H 2 O was washed, and 20 mL of mixed solvent of methanol:water=4:1 was used for beating for 3 hours, filtered, and dried to obtain 1.15 g of tedizolid, with a yield of 89.15%.

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Abstract

The invention provides a method for preparing tedizolid. The method comprises the step of subjecting 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxoboran-2-yl)pyridine (II) and (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolid-2-one (III) to a coupling reaction in a polar solvent in the presence of a metal palladium catalyst and alkali, so as to produce the tedizolid; and a reaction formula is as follows: formulae shown in the description. According to the method, the yield is greatly increased compared with the prior art and reaches up to 80% to 91%; in addition, the reaction conditions are mild, the operation is simple and convenient, and reagents used are moderately-priced and readily available, so that the method is adaptable to small-scale preparation of laboratories and also large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of chemical drug synthesis, and in particular relates to a preparation method of tedizolid, a new generation of oxazolidinone antibacterial drug. Background technique [0002] Tedizolid Phosphate is a new generation of oxazolidinone antibacterial drug developed by Carbister, which is used for the treatment of acute bacterial skin and skin structure infections in adults. It was approved by the US FDA on June 20, 2014. , trade name Sivextro. Tedizolid phosphate is the second-generation oxazolidinone antibacterial drug, and it is also the first antibacterial drug of this type approved in more than ten years since the fully synthetic oxazolidinone antibacterial drug - Linezolid; its molecular formula It is C17H16FN6O6P, CAS registry number: 856867-55-5. [0003] Tedizolid Phosphate, the structural formula is as follows: [0004] [0005] Tedizolid phosphate is a prodrug, which is rapidly hydrolyzed by phosphatase in...

Claims

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Application Information

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IPC IPC(8): C07D413/14
Inventor 张仕昌郝群周伟澄
Owner SHANGHAI INST OF PHARMA IND
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